Staphylococcusaureusinfectionsinfection management challengesacross acute & community boundaries

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READING LIST

Guidance on the diagnosis and

management of PVL-associated

Staphylococcus aureus infections

(PVL-SA) in England

Guidelines for UK practice for the

diagnosis and management of

methicillin-resistant Staphylococcus

aureus (MRSA) infections presenting in

the community

J. Antimicrob. Chemother., May 2008; 61:

976 - 994.

Guidelines (2008) for the prophylaxis and

treatment of methicillin-resistant

Staphylococcus aureus (MRSA) infections

in the United Kingdom

NHS QI Scotland. Health Technology

Assessment No 9: The clinical and cost

effectiveness of screening for meticillin-

resistant Staphylococcus aureus (MRSA)

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1

Guidance on the diagnosis and management of PVL-associated Staphylococcus aureus

infections (PVL-SA) in England

Report prepared by the PVL sub-group of the Steering Group on Healthcare Associated

Infection

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CONTENTS

1. Background 4

1.1 Clinical features of PVL-SA 5

1.2 Skin and soft tissue infections 5

1.3 Invasive infections 6

1.4 Risk factors for PVL-SA 6

1.5 When to suspect PVL-SA infection 8

2. Microbiological Sampling 8

2.1 Microbiological testing of clinical samples 8

2.2 PVL testing 8

2.3 Microbiological testing of screening samples 10

2.4 Suspected outbreaks 10

2.5 Antimicrobial susceptibility testing . 10

3. Management of cases 10

3.1 Skin and soft tissue infections 10

3.1.1 General care 10

3.1.2 When antimicrobials are indicated for skin and soft tissue infection 12

3.2 Community-acquired necrotising pneumonia 12

3.2.1 Clinical management of necrotising pneumonia (mainly supportive) 13

3.2.2 Antimicrobial therapy of necrotising pneumonia 13

3.2.3 Adjunctive therapy with Intravenous Immunoglobulin (IVIG) in

necrotising pneumonia 14

3.3 Osteomyelitis and other deep-seated infections 15

3.3.1 Investigations 15

3.3.2 Therapy of osteomyelitis and other deep-seated infections 15

3.4 Special consideration of infections in children 16

3.4.1 Skin and soft tissue infections in children 16

3.4.2 Deep-seated infections in children 16

4. Decolonization and screening of patients and their close contacts 18

4.1 Principles of decolonization 18

4.2 Decolonization of infected patients 18

4.3 Screening and decolonization of contacts 19

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4.3.1 Decolonization of family contacts of a case of necrotising pneumonia 19

4.4 Clusters of PVL-SA infection in the community 20

4.4.1 Care homes and residential facilities, including prisons and barracks 20

4.4.2 Nurseries and schools 20

4.4.3 Gyms and sports facilities 20

5. Infection prevention and control in hospital and the community 20

5.1 Infection prevention and control for hospitalised patients 20

5.1.1 Community-acquired infections 21

5.1.2 Hospital-acquired infections 21

5.1.3 Occupational Health 21

5.2 Infection prevention and control for affected people in the community 22

6. Surveillance 22

Appendices

Appendix 1 – PVL-Staphylococcus aureus information for patients 24

Appendix 2 – Decolonization procedure for PVL-Staphylococcus aureus: how to use

the decolonization preparations 27

Appendix 3 – Guidance for reducing the spread of PVL-Staphylococcus aureus in

communal and other recreational settings 29

Appendix 4 – Guidance for reducing the spread of PVL-Staphylococcus aureus

(PVL-SA) in schools and nurseries 33

Appendix 5 – Advice for managers of care homes to help reduce spread of PVL-

Staphylococcus aureus 35

Appendix 6 – Guidance for the screening and treatment of PVL-Staphylococcus

aureus for Primary Care 37

Appendix 7 - Special consideration of infections in children 39

Membership of the sub-group and acknowledgements 41

Glossary 43

References 45

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Guidance on the diagnosis and management

of PVL-associated Staphylococcus aureus infections (PVL-SA) in England

This guidance was prepared by a sub-group of the Steering Group on Healthcare Associated Infections (SG-HCAI) at the request of the Department of Health and replaces that drafted by Health Protection Agency (HPA) working group in 2006. It is based on expert opinion following review of the literature and experiences of colleagues in the UK, Europe, the USA and Canada. There is little hard research evidence to support this guidance, particularly with reference to screening and decolonization. Existing international guidance and expert opinion range from a highly proactive ‘search and destroy’ approach to a more pragmatic, reactive approach. This guidance tries to steer a course between these, based on risk assessment of the situation and will be updated as developments in the field occur. This guidance is intended to provide healthcare professionals with easily accessible advice on the recognition, investigation and management of PVL-Staphylococcus aureus (PVL-SA) cases. Guidance on the diagnosis and management of meticillin-resistant Staphylococcus aureus (MRSA) infections presenting in the community1 has been produced by the British Society for Antimicrobial Chemotherapy (BSAC) to supplement existing MRSA guidelines at the request of the Specialist Advisory Committee on Antimicrobial Resistance (SACAR) and there has been close collaboration and joint membership between the sub-groups to ensure that guidance in areas of overlap is consistent. 1. Background Panton-Valentine Leukocidin (PVL) is a toxin that destroys white blood cells and is a virulence factor in some strains of Staphylococcus aureus. Strains of PVL-SA producing a new pattern of disease have emerged in the UK and worldwide. In the UK the genes encoding for PVL are carried by < 2% of clinical isolates of S. aureus submitted to the national Reference Laboratory, whether meticillin-sensitive (MSSA) or meticillin-resistant (MRSA).2 While PVL is currently accepted as an important virulence factor in S. aureus, some recent publications call this into question. Alternatives such as the Arginine Catabolism Mobile Element (ACME), α-toxin, regulation of gene expression, and/or newly described cytolytic peptides have been put forward to explain the pathogenicity associated with PVL-SA. These bacterial aspects, in conjunction with host factors, are the subject of intense investigation and are key to furthering our understanding of the virulence of PVL-SA. Nevertheless, PVL has been strongly associated epidemiologically with virulent, transmissible strains of S. aureus, including community-associated (CA) MRSA. In summary, PVL remains a valuable marker and target for screening for virulence in some strains of S. aureus. Strains of S. aureus encoding the PVL genes were recognised in the early 1900s in staphylococcal skin abscesses. In the 1950s and ‘60s, the ‘phage type 80/81 strain spread widely. This strain was PVL-positive (PVL-MSSA) and proved highly successful in the

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UK and abroad, causing widespread disease (most commonly boils and abscesses) in previously healthy individuals in the community, as well as in hospitalised patients and healthcare workers. The escalation in morbidity and mortality associated with PVL-MRSA has caused public health concern worldwide. To date most PVL-SA strains in the UK have been MSSA, but a major problem has emerged with CA-MRSA in North America, most of which produce PVL. One strain in particular, the USA300 clone, is now spreading in hospitals in the USA.3 From a UK perspective, occasional fatalities due to PVL-SA and outbreaks in both community and healthcare settings have attracted high-profile media attention and prompted concern regarding the transmissibility and virulence sometimes associated with these organisms. Following national alerts and improved case ascertainment initiatives, the HPA has been monitoring PVL-related disease throughout England and Wales. During 2005 and 2006, a total of 720 cases of PVL-SA were identified from isolates referred to the Reference Laboratory for testing and characterization. Of these, 224 were in 2005 and 496 in 2006, representing a two-fold increase. However, initiatives have been underway in this period to raise awareness of PVL-SA, so it is unclear how much of this increase is due to improved ascertainment. The majority of referred isolates were PVL-MSSA (444, 62%). Most PVL-SA were from sporadic cases presenting with relatively mild skin and soft tissue infections. Occasional clusters of disease centred around close household contacts; two outbreaks in healthcare settings have been documented. On the basis of these data, infections caused by PVL-SA are currently uncommon in England and Wales and it is not clear whether the increasing numbers observed between 2005 and 2006 reflect improved case ascertainment of PVL-related syndromes and/or an increasing prevalence of PVL-SA. Planned systematic surveillance-based studies will provide more robust data for monitoring trends. 1.1 Clinical features of PVL-SA Like other S. aureus strains, PVL-SA predominantly cause skin and soft tissue infections (SSTI), but can also cause invasive infections. The most serious of these is a necrotising haemorrhagic pneumonia with a high mortality, which often follows a “flu-like” illness, and may affect otherwise healthy young people in the community. 1.2 Skin and soft tissue infections These are often recurrent and include:

• Boils (furunculosis), carbuncles, folliculitis, cellulitis, purulent eyelid infection • Cutaneous lesions ≥5cm in diameter, which need different treatment from smaller

lesions • Pain and erythema out of proportion to severity of cutaneous findings • Necrosis

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1.3 Invasive infections • Necrotising pneumonia

• Necrotising fasciitis • Osteomyelitis, septic arthritis, and pyomyositis • Purpura fulminans

Patients who develop necrotising pneumonia commonly have a preceding "flu-like" illness. The percentage of genuine virus infections is unknown, but co-infection with respiratory viruses, including influenza, should be investigated. 1.4 Risk factors for PVL-SA The risk factors for PVL-SA seen in the UK correspond to those described for CA-MRSA in North America. These include compromised skin integrity, skin to skin contact, and sharing of contaminated items such as towels. Worldwide experience suggests that closed communities with people in close contact are higher risk settings for transmission of staphylococcal infections. In North America the following settings have been identified as higher risk for transmission from an individual colonised or infected with CA-MRSA:

• households

• close contact sports e.g.: wrestling, American football, rugby, judo

• military training camps

• gyms • prisons

CDC guidance refers to risk factors for PVL-related infection as "5 C's”: 1) Contaminated items; 2) Close contact; 3) Crowding; 4) Cleanliness; 5) Cuts and other compromised skin integrity.4 CA-MRSA has become endemic in some hospitals in North America and caused several outbreaks. Features which differentiate typical healthcare-associated (HA)-MRSA (e.g. EMRSA-15 and -16 in the UK) from CA-MRSA in these circumstances are well documented and summarised in Table 1.

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Table 1. Hospital-associated MRSA versus Community-associated-MRSA* Hospital-associated MRSA Community-associated MRSA** Typical patients Elderly, debilitated and/or critically Young healthy people, students or chronically ill athletes, military service personnel Infection site Wounds/invasive devices Often spontaneous Often cause bacteraemia Skin, cellulitis, abscess Transmission Within healthcare settings; little spread among Community-acquired; may spread in close household contacts community settings, e.g. families and sports teams, via pets (not so far in UK). Diagnosis is typically made In an in-patient setting In an out-patient setting Medical history History of MRSA colonization/infection, No significant medical history recent surgery, admission to hospital or nursing home, antibiotics, renal dialysis, permanent indwelling catheter, skin ulcers, diabetes Virulence factors Community spread limited. PVL genes absent Community spread readily, PVL genes

present, predisposition to necrotising skin and soft tissue infection

Antibiotic susceptibility Choice of agents limited Currently more susceptible to antibiotics** * From the North American literature; many points resonate with experience thus far in the UK.

** This is an evolving situation and CA-MRSA infections have been acquired in some countries, albeit rarely in the UK, hence the need for vigilance. More resistant CA-MRSA are emerging in some parts of world and distinguishing these from HA-MRSA based on susceptibility profiles can be problematic.

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1.5 When to suspect PVL-SA infection PVL-associated SA infection should be suspected if a patient has a necrotising SSTI, recurrent furunculosis or abscesses, or there is clustering of SSTIs within a household or social group; also in invasive infections in immunocompetent people, particularly community-acquired necrotising/haemorrhagic pneumonia in young, previously fit people. Haemophthisis should be a major alerting sign. PVL infections are associated with enhanced inflammatory response (higher ESR and C-reactive protein [CRP]), local disease (myositis/pyomyositis), acute haematogenous osteomyelitis or osteoarticular infections in children.5 2. Microbiological Sampling Figure 1 shows an algorithm for the appropriate testing of specimens in suspected PVL-SA related disease. PVL genes can be carried by both MSSA and MRSA. PVL-MSSAs display variable antimicrobial susceptibility profiles, which can be geographically distinct. Whilst most PVL-MRSAs in the UK are susceptible to ciprofloxacin, resistance has occasionally been found, for example in PVL-MRSA isolated from patients returning from USA. 2.1 Microbiological testing of clinical samples Appropriate clinical samples (e.g. pus, swab of exudate from an abscess or other lesion, sputum) from suspected cases should be sent to the local microbiology department. In case of queries, the local microbiology department should be asked for advice. Accident and Emergency (A&E) departments and GPs must be alerted to the importance of taking specimens when incising and draining abscesses. Samples should be cultured on non-selective media (e.g. blood agar) for the recovery of potential pathogens, including S. aureus. If necrotising pneumonia is suspected, co-infection with a respiratory virus, including influenza, should be investigated. 2.2 PVL testing MSSA or MRSA isolated from suspected cases should be referred to the Staphylococcus Reference Unit at the HPA’s Centre for Infections at Colindale for toxin gene profiling, which includes PVL testing (Figure 1). This PCR-based assay is performed daily and completed within a working day. If cases are urgent, results will be telephoned to the submitting laboratory. Even if PVL testing is performed locally, isolates must be sent to the Reference Unit for further toxin testing and typing, as this is currently the basis of national surveillance and provides early warning of changes in the national situation. MRSAs with a typical susceptibility pattern for HA-MRSA and likely to have been acquired in a healthcare setting should not be referred unless the history suggests a PVL-SA infection, e.g. necrotising pneumonia, recurrent boils. This information must be included on the referral forms. Ciprofloxacin-resistant MRSA should not be referred to the Staphylococcus Reference Unit for PVL testing unless they are associated with typical PVL-SA-related disease.

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Figure 1. PVL-related disease: Microbiology algorithm 6

*For urgent requests, please contact Staphylococcal Reference Unit (Tel: 020 8327 7227).

Patient with suspected PVL-related disease, e.g.: - Recurrent boils/abscesses/eyelid infection - Necrotising skin and soft tissue infections - Community-acquired necrotising/haemorrhagic pneumonia

(especially if haemophthisis)

Refer sample to local microbiology laboratory for culture (e.g. pus, swab of exudate, sputum)

If either MSSA or MRSA isolated (latter usually

ciprofloxacin susceptible), refer to Staphylococcal Reference Unit for PVL-testing*

PVL-positive finding = confirmed case

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2.3 Microbiological testing of screening samples Where a confirmed case is due to PVL-MSSA, screening swabs should be cultured on non-selective media (e.g. blood agar). Where S. aureus with an antibiogram which matches that of the confirmed case is recovered, isolate(s) should be referred to the Staphylococcus Reference Unit. Where the confirmed case is due to PVL-MRSA, screening swabs should be cultured on selective media, such as Mannitol Salt Agar or chromogenic media. As most PVL-MRSA are currently susceptible to ciprofloxacin, selective media which contain ciprofloxacin must be avoided. Where MRSA is recovered with an antibiogram which matches that of the confirmed case, isolate(s) should be referred to the Staphylococcus Reference Unit. 2.4 Suspected outbreaks To investigate outbreaks in community or healthcare settings, inter-strain comparisons (e.g. DNA fingerprinting) should be performed to determine strain relatedness. This can be performed by the Staphylococcus Reference Unit. Criteria for referring isolates to the unit are on the HPA website at: http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1204619484795 2.5 Antimicrobial susceptibility testing . This should be performed in the routine way for the laboratory and should include testing for dissociated resistance (D-test) to clindamycin.1

3. Management of cases 3.1 Skin and soft tissue infections Minor SSTIs (furunculosis, folliculitis, small abscesses/boils without cellulitis) do not need systemic antibiotic treatment unless the patient is immunocompromised, an infant or deteriorating clinically. Incision and drainage is the optimal management for abscesses. Moderate SSTIs including cellulitis and larger abscesses (especially those > 5cm) should be treated with oral anti-staphylococcal antibiotics in addition to drainage - see 3.1.2. If there is systemic involvement suggestive of toxic shock or pyomyositis (hypotension, tachycardia, diarrhoea, vomiting, high creatine kinase) use empirical parenteral antibiotics effective against MRSA together with immunoglobulin (IVIG) — see Figure 2. 3.1.1 General care Lesions should be covered, personal hygiene emphasised (avoid sharing towels, bath water etc.), and patients advised to return if the lesions do not resolve or there is clinical deterioration. See Appendix 1 for a patient information leaflet.

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Figure 2. Management of patient with suspected PVL-related pneumonia

CAP hospitalised – treat with local hospital severe CAP regimen – cefotaxime/ co-amoxiclav and clarithromycin

Clinical suspicion of PVL–S. aureus pneumonia

Pneumococcal & legionella Ag flu serology ± NPA - exclude other causes of symptoms as appropriate – vasculitis / PE

Obtain cultures: (isolation and masks to be worn if exposed to respiratory secretions)

- Bronchoalveolar lavage Immediate - Protected specimen brush Gram - Tracheal aspirate or sputum stain

Start empiric antibiotics covering MRSA - linezolid 600mg bd + clindamycin 1.2g qds - and if deteriorating or features of severe disease e.g. TSS add IVIG 2g/kg + rifampicin 600mg bd

Continue empiric antibiotic therapy for 48-72 hours or until culture results finalised – if clindamycin sensitive change to clindamycin +

rifampicin; if resistant, to linezolid + rifampicin

No improvement in symptoms Increasing failure to ventilate

Exclude complicating issues (e.g. abscess, empyema) and non-

infectious issues

Re-evaluate for infection with antibiotic-resistant pathogen not covered by

initial antimicrobial regimen

Consider 2nd dose of IVIG

Admit to ICU

Multilobular infiltrates Resp Rate>30 Pulse Rate>140 Haemoptysis Leukopaenia ± SSTI Young

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3.1.2 When antimicrobials are indicated for skin and soft tissue infection Most PVL-SA in the UK are susceptible to flucloxacillin, erythromycin and clindamycin, although tests need to be performed for dissociated resistance to clindamycin in erythromycin-resistant strains (see 2.5). Adult doses are given – for paediatric doses see BNFc. For moderate SSTI with MSSA use either:

• flucloxacillin 500mg qds or

• clindamycin 450 mg qds When PVL-MRSA is suspected and hospital admission is not warranted use:

• rifampicin 300mg bd PLUS doxycycline (100mg bd – not for children <12 y) or

• rifampicin 300mg bd PLUS fusidic acid 500mg tds or

• rifampicin 300 mg bd PLUS trimethoprim 200 mg bd or

• clindamycin 450 mg qds

Treatment should last 5-7 days. Some PVL-MRSA strains are resistant to doxycycline and fusidic acid (A Kearns, Staphylococcal Reference Unit, unpublished data), so treatment must be guided by antimicrobial susceptibility tests. Care should also be taken with rifampicin and fusidic acid in combination as resistance to both agents may be selected. There should also be vigilance for hepatotoxicity. For severe infections where PVL-SA (MSSA or MRSA) is suspected parenteral vancomycin, teicoplanin, daptomycin or linezolid have been used. Tigecycline may also offer broader polymicrobial cover. There is no evidence that any one agent is superior. In severe infections with features of toxic shock, necrotising fasciitis, or purpura fulminans there may be a theoretical case for using two or three agents such as linezolid 600mg bd combined with clindamycin 1.2 - 1.8g qds and rifampicin 600mg bd. This case is based on in-vitro synergy and the ability of linezolid and clindamycin to switch off toxin production.7 It is very important to undertake early surgical debridement. Treatment should be continued for 10-14 days until the patient has improved and is clinically stable. 3.2 Community-acquired necrotising pneumonia Figure 2 shows an algorithm for the management of patients with suspected PVL-SA pneumonia. Early clinical diagnosis is difficult but essential for survival, especially as only 25% of cases may have current, or a history of, skin lesions (however, there may be a family history of spreading or recurrent PVL-SA skin sepsis 8). Respiratory symptoms and sepsis in a previously fit young patient following a "flu-like" illness warrant prompt referral to hospital. Once admitted, the following classical constellation of findings9 strongly suggests the diagnosis, although in early cases only some may be present.

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Clinical signs • airway bleeding/haemoptysis • hypotension • non-specific findings of “flu-like” illness e.g. myalgia, chills, fever of 39°C or

above, tachycardia >140 beats/min, diarrhoea and vomiting (may be due to associated toxic shock)

Radiography • multilobular infiltrates on chest X-ray, usually accompanied by effusions and

later cavitation. Laboratory investigations

• Gram film of sputum reveals numerous gram-positive cocci in grape-like clusters

• marked leukopenia (may be within normal limits early in illness as destruction by toxins is just beginning)

• very high CRP level (>200g/L: unusual in viral infections)

• negative pneumococcal and legionella antigen

• significantly raised serum creatine kinase (suggests myositis)

• the CURB65 score10 may be misleadingly low in young adults as age is a score factor

3.2.1 Clinical management of necrotising pneumonia (mainly supportive) • Admit to Intensive Care — preferably a side room with isolation (wear appropriate

PPE) • Aggressive antimicrobial therapy — see 3.2.2

• Give intravenous immunoglobulin (IVIG) in a dosage of 2g/kg — see below

Activated Protein C should not be used in case there is active pulmonary haemorrhage, and is contra-indicated in children. It may be indicated for adults with severe sepsis due to other causes, who do not have haemorrhagic pneumonia.11

3.2.2 Antimicrobial therapy of necrotising pneumonia The efficacy of many antibiotics in treating necrotising pneumonia is decreased by reduced penetration into necrotic tissue and diminished activity in anaerobic conditions. There are many differing opinions on therapy for PVL-associated pneumonia. Unfortunately few reports include doses, and some involve antibiotics not routinely available in the UK. Work is ongoing to establish optimal therapy. The following points from the published literature are intended as background information. Intravenous flucloxacillin is not recommended, even in combinations with agents such as rifampicin or clindamycin. Although bactericidal, there are concerns that at concentrations just above the MIC (likely with poor penetration into necrotic tissue) flucloxacillin may increase PVL production as it does in vitro.12

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Where an agent that inhibits toxin production was included, the outcome has been generally more favourable, but with so few cases and so many regimens, there is no proof that any one is unequivocally superior. Combinations of clindamycin with rifampicin,13 linezolid with rifampicin,14,15 vancomycin with rifampicin,16 and vancomycin with clindamycin have all been successful, but with widely differing durations of intravenous therapy, sometimes as long as four weeks.16 Rifampicin should never be used alone as resistance is rapidly selected. Co-trimoxazole is not recommended for pneumonia. The only report of successful therapy described highly unusual chronic (3-months) pneumonia and involved three days of intravenous vancomycin followed by six weeks of co-trimoxazole.17 Although three cases of success with vancomycin as sole initial therapy have been reported,18-20 vancomycin should not be used alone because of poor extracellular fluid levels21 and poor penetration of lung tissue. 22

Clinical failures with continuing bacteraemia and persistence in bronchial secretions have necessitated repeated courses of vancomycin,23 or changing to linezolid and rifampicin.14,15 A loading vancomycin dose of 25mg/kg has been suggested, and thereafter dosage adjusted to give trough serum levels of 15-20 mg/dl to achieve a plasma concentration of 3-4 mg/dl.24 Even with a dose of 1.5g bd and trough levels of 18-35 mg/dl, fluid from bronchiolar lavage was not sterilised after seven days.14

There are reports of success following "salvage" therapy using linezolid alone or with rifampicin to replace failing vancomycin therapy.14,15,25,26 Rifampicin has been used in different antibiotic combinations. It has excellent tissue penetration, reaching intracellular staphylococci, and exhibits synergistic activity with other antibiotics, including linezolid.27 Taking all the information above into consideration, the sub-group recommends empirical therapy with a combination of clindamycin 1.2 g iv qds, linezolid 600 mg iv bd (to suppress PVL and alpha toxin production12,28,29) and rifampicin 600 mg bd (for intracellular clearance of staphylococci). Providing the infecting organism is susceptible on testing, this combination should be continued until the patient has improved and is clinically stable, when continuation therapy with linezolid plus rifampicin, or with clindamycin plus rifampicin, may be considered for 10-14 days, guided by the clinical response and infection markers such as CRP. 3.2.3 Adjunctive therapy with Intravenous Immunoglobulin (IVIG) in necrotising pneumonia IVIG should be considered in addition to intensive care support and high dose antimicrobial therapy because of its action in neutralizing exotoxins and superantigens, particularly enterotoxins A, B and C and TSST-1. The expected benefits outweigh the risks in a condition with such a high mortality (>60%). The dosage of 2g/kg of IVIG recommended for streptococcal toxic shock syndrome 30,31 may be applicable for PVL- SA infections, and may be repeated after 48 h if there is still evidence of sepsis, or failure

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to respond. For children a dose of 1g/kg may be preferable to reduce the risk of hyperviscosity, and this may be repeated after 48 hours. 3.3 Osteomyelitis and other deep-seated infections 3.3.1 Investigations

• blood culture

• microscopy/culture of bone/joint specimens and any skin lesions

• serial MRI scan to determine extent of disease and response to therapy

• radio-isotope scan for metastatic infection

• assessment for deep vein thrombosis

• additional imaging for metastatic infection if not responding to treatment 3.3.2 Therapy of osteomyelitis and other deep-seated infections PVL-MSSA infections: if the infection is known to be caused by PVL-MSSA, treatment should be guided by antimicrobial susceptibilities, using agents with good penetration into the relevant body compartment and which inhibit toxin production, such as clindamycin in combination with rifampicin or linezolid (see 3.2.2 for dosage). If PVL-SA infection is suspected and antimicrobial susceptibilities are not yet known, treat as for PVL-MRSA (below). PVL-MRSA infections: the BSAC guidelines 1 suggest that for MRSA osteomyelitis and other deep-seated infections the following protocol is used: First-line:

Either teicoplanin (400–800 mg iv) every 24 h (following loading dose) or vancomycin (1 g iv 12 hourly)

PLUS either

gentamicin (5–7 g/kg iv once daily) or rifampicin (300 mg po twice daily) or sodium fusidate (500 mg po thrice daily).

Second-line:

linezolid (600 mg iv/po 12 hourly) or daptomycin (4 mg/kg iv once daily). or tigecycline (100 mg loading dose followed by 50 mg iv twice daily).

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Notes: (a) Assessment in hospital likely to be required, with orthopaedic advice. (b) Bone and joint infections may require prolonged treatment and repeated surgery. (c) Serum vancomycin/teicoplanin and gentamicin concentrations should be monitored (trough concentrations for teicoplanin of 10–20 mg/L and for vancomycin of 10–15 mg/L). 3.4 Special consideration of infections in children The approach is tabulated in Appendix 7. 3.4.1 Skin and soft tissue infections in children These should be suspected if there are recurrent boils or abscesses or a close contact who has skin lesions. The management is as for adults (see 3.1). The need for isolation should be discussed with the Infection Control Team. 3.4.2 Deep-seated infections in children 3.4.2.1 Clinical pointers Abscesses: localised abscesses (e.g. retropharyneal or in lymph nodes) may be associated with local venous thrombosis, very high CRP and patient or close family contact has current, or a history of, recurrent boils/abscesses or skin infections. Bone and joint infections: suspect if patient or close family contact has current, or a history of, recurrent boils/abscesses or skin infections or there is severe sepsis, multiple sites of infection/abscesses, extensive local lesions, myositis/pyomyositis, local venous thrombosis, very high CRP and a need for repeated surgical intervention. Severe sepsis: suspect if patient or close family contact has current, or a history of, recurrent boils/abscesses or skin infections, and there are bone or joint infection, necrotising pneumonia, deep venous thrombosis, purpura fulminans. Pneumonia: suspect if there is preceding “flu-like” illness, haemoptysis, multi-lobular infiltrates, bone or joint infection, leukopenia/neutropenia or patient or close family contact has current, or a history of, recurrent boils/abscesses or skin infections. 3.4.2.2 Investigation of deep-seated infections in children General: cultures of blood, skin lesions, bone and joint specimens, sputum, bronchial secretions or lavage, as relevant. Assess for deep vein thrombosis adjacent to any site of infection. Bone and Joint: see 3.3.1 Severe sepsis: imaging for occult foci of infection – especially bone/joint Pneumonia: investigate using rapid tests for fast diagnosis of co-infection with influenza and other viruses.

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3.4.2.3 Initial approach to therapy of deep-seated infections in children General:

• rescuscitate and stabilize using APLS guidelines

• consider thromboembolism prophylaxis and manage deep vein thromboses in

consultation with a paediatric haematologist

• discuss need for isolation with Infection Control Team

• administer antibiotics according to local guidelines for empirical management of

infections, but add clindamycin if PVL-MSSA is suspected and linezolid if PVL-

MRSA is suspected or there is a suspicious travel history or failure to respond to

treatment

• close monitoring of clinical condition is essential as some patients will deteriorate

even after several days receiving appropriate antibiotic therapy

Bone and joint infections:

• aggressive approach to drainage of foci of infection

Severe sepsis/pneumonia:

• consider transfer to paediatric ICU

• give 1-2g/kg IVIG and repeat lower dose after 24-48 hours if needed (see below).

3.4.2.4 Further therapy of deep-seated infections in children Once infection with PVL-SA is confirmed, use intravenous clindamycin (if susceptible) plus rifampicin, and consider addition of linezolid. Addition of linezolid may be particularly useful in bone and joint infections. Linezolid should be used for a maximum of 4-weeks due to the risk of development of peripheral neuropathy. For all antibiotics use the maximum dosages listed in the British National Formulary for children (BNFc). As continuation therapy for bone/joint infections use clindamycin plus rifampicin, or an alternative combination advised by a specialist in paediatric infectious disease. Repeated surgical intervention for drainage may be required, and the duration of antibiotic treatment may need to be very prolonged. Maintain vigilance for the occurrence of thromboses. Use of IVIG: an initial dose of 1-2g/kg IVIG may be used in children, with some experts preferring a lower dose to reduce the risk of hyperviscosity occurring. This lower dose may be repeated after 24-48 hours if there is no clinical improvement. Ensure appropriate consultation, for instance with medical microbiologist, paediatric infectious disease physician, orthopaedic surgeon or hematologist, as required.

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4. Decolonization and screening of patients and their close contacts 4.1 Principles of decolonization Topical decolonization is often used to try and interrupt transmission. Little data exist on its effectiveness for eradicating a particular strain of S. aureus and thereby preventing further infections, especially in non-healthcare settings and with prolonged follow-up. It can be achieved temporarily, but re-colonization can occur relatively quickly. So, whilst awaiting definitive trials, an empirical approach to screening and topical decolonization should be adopted. It should only be attempted after reinforcing standard prevention measures. Factors that may reduce long-term success of topical decolonization include:

• non-compliance with the topical decolonization regimen • attempts to decolonise whilst still shedding S. aureus from an infected lesion, e.g.

healing abscess or break in the skin (chronic ulcer) • re-colonization from a close contact • re-colonization from the patient's own flora, e.g. gut, throat, vagina • re-colonization from the environment.

For these reasons, the merits of undertaking a topical decolonization regimen should be critically assessed

i. in a setting where non-compliance with the regimen is likely to be an issue ii. where there are breaks in the skin, e.g. varicose ulcers, from which S.

aureus may continue to be shed. Decolonization of neonates, especially premature neonates, is difficult and unstandardised. Where decolonization is required, nasal mupirocin may be used. Antiseptic solutions, such as chlorhexidine, may damage the fragile skin of premature neonates. In these circumstances, washing with plain water, even if just “topping and tailing”, may be helpful. When it is felt appropriate to use an antiseptic, this must always be an aqueous preparation and never alcohol-based (risk of burn injuries in neonates). 4.2 Decolonization of infected patients Topical decolonization without prior screening should be offered to primary cases. Patients should be given a patient information leaflets describing how to minimise cross-infection and when and how to use the topical agents (Appendix 1; Appendix 2). The topical decolonization regimen should be limited to five days. Topical decolonization should be started after the acute infection has resolved. In patients with dermatological conditions it is important to seek a dermatological opinion. Chlorhexidine is inappropriate for premature infants as it may damage their fragile skin and there may be systemic absorption as the skin’s barrier function is less effective. Patients in whom recurrent infections or persistent colonization occur, despite reasonable efforts to decolonise or because of their underlying conditions, should maintain sensible precautions to prevent transmission in households and community settings, and this advice should be included in the patient information leaflet (example in Appendix 1).

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Repeated screening is not recommended unless the patient is particularly vulnerable to infection, poses a special risk to others (e.g. a healthcare worker) or spread of infection is continuing in close contacts. 4.3 Screening and decolonization of contacts Risk assessment should be undertaken to identify whether screening and/or decolonization are appropriate or feasible. The first step is an appraisal of the close contacts (household, family, partner) seeking information on current or previous possible PVL-SA infections in the previous year, such as septic skin lesions. In addition, it is important to enquire about employment history and contact with healthcare settings. Where close contacts are infected or likely to be colonised because of a history of past infection, they should undergo decolonization at the same time as the patient, without prior screening. If screening is undertaken, it must include a swab of the anterior nares, throat and any suspicious lesions, including damaged skin. Other sites that may be swabbed include perineum and axilla. Until new research becomes available it may be simpler to use local MRSA screening protocols. If any household contacts are found to be positive on screening, it is recommended that decolonization is offered to the whole household at the same time. Patients and their families should have a heightened awareness of any continuing problems of PVL-SA-related disease in the family or close contacts and return to their GP for consultation should this happen. Repeated screening is not recommended unless the contacts are particularly vulnerable to infection, pose a special risk to others (eg a healthcare worker) or spread of infection is continuing. In these circumstances repeat screening should not be undertaken until at least one week post-decolonization, and a second round of topical decolonization prescribed if still positive. The focus should be on emphasizing good hygiene and infection control procedures as described in Appendix 1. The advice of a dermatologist should be sought where there are pre-existing dermatological conditions. 4.3.1 Decolonization of family contacts of a case of necrotising pneumonia Close (e.g. partner) or household contacts of a patient diagnosed with necrotising pneumonia likely to be caused by PVL-SA may be the source of, or acquire and subsequently suffer, infections with PVL-SA.32 Close contacts should be offered a five-day topical decolonization regimen starting immediately (including chlorhexidine gargle if feasible). Consideration should be given to using oseltamivir prophylaxis if the index case is found to have had influenza and advice obtained from a Consultant Virologist or Respiratory Physician.

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4.4 Clusters of PVL-SA infection in the community These can occur in various "social" groups, some of which are considered below. 4.4.1 Care homes and residential facilities, including prisons and barracks Where there has been one case of PVL-SA-related infection enquiries should be made regarding other confirmed cases or recurrent septic lesions in residents and staff. The local Health Protection Unit (HPU) should be informed. A risk assessment should be performed to balance the number of cases of PVL-associated disease against the practicalities of screening all staff and residents. Individual cases may be suitable for topical decolonization. If a significant number (for example ≥4) of residents and staff are affected, an outbreak meeting should be arranged to discuss infection control issues and feasibility and practicalities of topical decolonization. A five-day course of therapy for all residents and staff is a significant undertaking and lack of compliance and acceptance are major issues where this has been tried. Furthermore, antiseptic washes may exacerbate pre-existing skin conditions and dermatological advice may be needed. 4.4.2 Nurseries and schools The local HPU should be notified if there is suspicion of spread of PVL-associated infection in nurseries and schools. Screening of children and staff in a class may be warranted if there are two or more confirmed cases. Questioning may reveal a family/child with recurrent skin infections, e.g. boils, acting as the primary source. It is also important to establish that there are no children or staff with chronic skin conditions, such as eczema, acting as a continuing source. When screening children, parental consent will be required, and nasal swabs should be collected, as well as swabs from the throat (if feasible) and skin lesions. Information about precautions to reduce the spread of PVL-SA is given in Appendix 4. 4.4.3 Gyms and sports facilities The local HPU should be notified if there is suspicion of spread of PVL-SA-associated infection in sports facilities. A risk assessment should be performed to balance the number of cases of PVL-SA-associated disease against the practicalities of screening attendees and staff. Information about precautions to reduce the spread of PVL-SA is given in Appendix 3.

5. Infection prevention and control in hospital and the community 5.1 Infection prevention and control for hospitalised patients Hospitals should have policies and procedures which deal with MRSA and these are generally appropriate for the control of PVL-SA. For advice about the control of MRSA see BSAC/HIS guidelines.33 The following section reflects some of the important control measures.

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5.1.1 Community-acquired infections 5.1.1.1 Skin and soft tissue infections (SSTIs) The majority of patients admitted to hospital with PVL-SA will be admitted for incision and drainage of abscesses; a smaller number will be admitted with other SSTIs, such as cellulitis. The principles for MRSA prevention and control should be applied to those affected by PVL-SA (MSSA or MRSA). These include isolation in a single room, use of personal protective equipment (PPE) (most commonly plastic apron and gloves), meticulous hand hygiene, and environmental cleaning. 5.1.1.2 Necrotising pneumonia Transmission of PVL-SA to staff has occurred following contact with respiratory secretions during intubation of a case of necrotising pneumonia where PPE was not worn.34 Healthcare workers (HCWs) should wear PPE, including face and eye protection (e.g. surgical mask with integral eye protection), during intubation and respiratory care of a patient with possible necrotising pneumonia. HCWs in direct contact with respiratory secretions (particularly during intubation or mouth-to-mouth resuscitation from a PVL-positive patient) and who were not protected by appropriate PPE should be screened three to seven days after the exposure and advised to report to a physician should symptoms of infection present subsequently. Screening should be arranged through the occupational health department in liaison with the infection control team. HCWs not in direct contact with respiratory secretions should not be screened. 5.1.2 Hospital-acquired infections If a case of PVL-SA infection was acquired or possibly acquired in hospital, suitable investigations need to be undertaken. Screening other patients and staff should be performed based on risk assessment and decolonization of positive individuals undertaken. Frequently, questioning patients and staff for previous individual and family history of recurrent skin infections identifies a potential source. The microbiology department should search its database for S. aureus infections with a similar antibiogram that may be related and any isolates, if still available, sent to the Staphylococcal Reference Unit for PVL-testing. This will help to ascertain any unidentified clusters of cases in the hospital. 5.1.3 Occupational Health Occupational health departments in hospitals must be aware of this guidance. In line with good infection control practice, HCWs should not work with infected skin or purulent eye lesions, and all cuts and grazes should be covered. All such lesions should be reported promptly to the Occupational Health Service. A HCW with a proven PVL-SA infection should not work until the acute infection has resolved and 48 hours of a five day decolonization regimen has been completed. Enquiries regarding PVL-SA-related disease in close contacts of the staff member should be made, so that families can be treated simultaneously, if required.

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Follow up screens following topical decolonization are advised as for MRSA guidelines (three screens one week apart). Unlike HA-MRSA, staff who are found to have PVL-SA are likely to have acquired the infection in the community, and hence re-colonization may occur from a close contact. Therefore, even if screens have been negative, staff should understand that they should stop working if a further skin lesion develops. If, despite two courses of decolonization treatment, a staff member remains a carrier, they should be able to continue work providing they are not implicated in hospital transmission of PVL-SA infection and they cease working as soon as a possibly infected skin lesion develops. 5.2 Infection prevention and control for affected people in the community The key principles of preventing and controlling the spread of infection in the community setting centre on:

• early suspicion of infection, with rapid diagnosis and appropriate treatment

• ensuring lesions are covered with clean, dry dressings, which are changed as soon as discharge seeps to the surface

• personal hygiene and good skin care (particularly those with eczema)

• using separate towels and not sharing personal items such as razors, toothbrushes, face cloths etc.

• ensuring laundry of towels, bedlinen, clothing etc using a hot wash (60oC), where possible

• regular household cleaning

• avoiding communal and recreational settings until lesions are healed if they cannot be adequately contained by a dressing; certain facilities such as gyms, saunas, swimming pools, those offering massage, manicure or similar, should be avoided until the lesions have healed.

• those who work in occupations where they might pose a risk of infection to others, such as healthcare workers; carers in nurseries, residential or care homes or similar; or food handlers, should be excluded from work until the lesions have healed.

These principles are addressed in more detail in Appendix 1. 6. Surveillance Surveillance of PVL-SA is based currently on isolates referred to the Staphylococcal Reference Unit and shown to be PVL-positive. All S. aureus from suspected PVL cases and any PVL-positive strains identified locally should be sent to the Staphylococcal Reference Unit. A short questionnaire will then be sent to the requesting laboratory to ascertain basic clinical and epidemiological features. Comprehensive reporting of the clinical infections diagnosed as PVL-SA will enable the monitoring of the clinical impact

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of these strains in the general population and early warning of changing trends. The Department of Health is sponsoring two major projects to determine the prevalence of PVL-SA in different settings. The first is to determine the proportion of SSTIs caused by PVL-SA among patients presenting to A&E departments. The second is a study of prevalence of nasal carriage in a random sample of people with no clinical symptoms related to S. aureus infection in Bristol, Gloucester and Devon. In addition, a small study is being undertaken in Devon to identify risk factors for PVL-SA infection.

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Appendix 1 PVL- Staphylococcus aureus Information for Patients What is PVL Staphylococcus aureus? Staphylococcus aureus ('SA') is a bacterium (germ) that commonly lives on healthy skin. About one third of healthy people carry it quite harmlessly, usually on moist surfaces such as the nostrils, armpits and groin. This is known as colonization. Some types of Staphylococcus aureus produce a toxin called Panton-Valentine Leukocidin (PVL) and they are known as PVL-SAs. (Panton and Valentine were two doctors who first found this chemical which can kill white blood cells called leukocytes – hence ‘leukocidin’). What type of illness does it cause? All SAs, including PVL-SAs, can cause harm if they get an opportunity to enter the body, for example through a cut or a graze. They can cause boils or skin abscesses and are occasionally associated with more serious infections of the lungs, blood, joints and bones. Some SAs such as PVL-SA are more likely to cause infections than others. How do you catch PVL-SA? Anyone can get a PVL-SA infection. Infection can occur in fit, healthy people. PVL-SA can be picked up by having:

• skin-to-skin contact with someone who is already infected, for example close family or during contact sports, or

• contact with an item or surface that has PVL-SA on it from someone else, for example shared gym equipment, shared razors, shared towels.

How is PVL-SA treated? Boils and abscesses should be drained by incision by a doctor or nurse. Some infections may be treated with a course of antibiotics. In addition, the PVL-SAs carried on your skin may be eliminated with a five day skin treatment (washes, creams and shampoos). This is done to reduce the chances of you getting repeated infections and reduce the chances of you spreading PVL-SAs to others. In some patients this skin treatment may not be entirely successful, but the more carefully you follow the instructions, the more likely you are to clear the PVL-SAs from your skin. Your GP may recommend checking members of your household and close contacts, e.g. partners/children, in case they are also carrying PVL-SAs, and offering them skin treatments where necessary. How do I prevent passing PVL-SAs to other people?

• You need to keep infected areas of your body covered with clean, dry dressings or plasters. Change these regularly and as soon as discharge seeps to the surface. It is important that fluid or pus from infected skin is contained, because it has large numbers of PVL-SAs that can spread to others.

• Do not touch, poke or squeeze infected skin. This contaminates your hands and

can push the PVL-SAs deeper into the skin. Contact your GP surgery if you have a boil or abscess that needs draining.

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• Cover your nose and mouth with a tissue when you cough or sneeze, particularly if

you have a cold, because PVL-SAs can live in your nose. Throw the tissue in the bin at once and then wash your hands.

• Wash your hands frequently with liquid soap and water, and especially after

changing your plasters, dressings, and bandages or touching infected skin.

• Encourage others at home to wash their hands regularly with liquid soap.

• Use a separate towel and keep it separately, so others don't use it by mistake. Have it washed frequently in a hot wash.

• Regularly vacuum and dust (wiping with a damp cloth) your bedroom, bathroom,

kitchen and other rooms, as well as personal items and shared items, such as keyboards. Household detergent is adequate for cleaning.

• Clean your sink, taps and bath after use with a disposable cloth and household

detergent, then rinse clean and throw away the cloth. Can I go to work or school when I have a PVL- SA infection?

• You should not work as a carer in a nursery, hospital, residential or care home or similar place until your skin has healed and you have permission to return to work from your local occupational health department, GP or manager.

• You should not work in the food industry, e.g. waitress, chef, food production,

until your skin has healed and you have permission to return to work from your local occupational health department or GP.

• You may carry on with other types of work, provided you keep infected skin areas

covered with clean, dry dressings. If you are not sure about working, contact your local occupational health department or your GP.

• Children can only go to school if they are old enough to understand the importance

of good hand hygiene, and if their infected skin is covered with a clean dry dressing which will stay dry and in place until the end of the school day. Children should not take part in contact sports, or use communal gym equipment until their skin is healed. The GP’s advice is essential, and school management should be informed.

• People who have eczema or a more generalised skin condition should remain off

work or school until treatment has been completed for both the eczema or skin condition and the PVL-SA infection. You need to continue treating your skin to keep it in good condition. In the long term this helps to reduce the risk of spread of PVL-SA to others.

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Can I go to swimming pools, gyms or sports facilities when I have a PVL- SA infection? • You should not use communal facilities for example gym equipment, saunas,

swimming pools, or have a massage, manicure or similar until your skin has healed.

How do I prevent becoming infected again? • You should take good care of your skin. If you suffer from eczema, discuss the

best treatment for this with your GP • Keep all cuts and grazes clean with liquid soap and water, apply disinfectant

cream, and cover with dry dressings until scabbed over or healed

• Shower or bathe daily

• Put on clean clothes daily and wash bedclothes and towels on a regular basis using normal washing detergent but at the highest temperature the materials will allow

• Do not share personal items such as towels, razors, toothbrushes, water bottles,

and facecloths

• In shared facilities, such as gyms, use fresh towels. Only go when skin lesions have healed and put a towel between your skin and the equipment. Importantly, shower afterwards and use a separate (second) clean towel to dry yourself. Wash any towels which you have taken to shared facilities after each visit

• Seek medical help at the first sign of infection in a cut, such as redness, swelling,

pain, or pus

• If you are found to carry PVL-SA persistently on your skin or nose, or if you suffer from repeated infections, you may be prescribed a further course of skin treatment. If this fails to eliminate it and you suffer repeated infections then you may be prescribed antibiotics and skin treatment together. Sometimes the skin treatment will be extended to your household or close contacts. In these circumstances it is important that all affected people in a household or social group are treated at the same time

• If you have a further infection of any type, if you are admitted to hospital

unexpectedly, or if you are going to be admitted to hospital for an operation, always tell the doctor or nurse looking after you that you have had a PVL-SA infection. This will ensure that you receive appropriate treatment.

Further information about PVL-SA is available on the HPA website at http://www.hpa.org.uk/webw/HPAweb&Page&HPAwebAutoListName/Page/1207208304710?p=1207208304710

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Appendix 2 Decolonization procedure for PVL-Staphylococcus aureus: how to use the decolonization preparations The purpose of decolonization is to try to rid the body of the bacteria that have caused boils or other infections. Preparations must be used as detailed below. General notes on skin treatment As with all treatments to be applied to the skin, avoid contact with the eyes. Those who are pregnant, have eczema, or are under a year old should be screened first to see if they are carrying the bacteria (the doctor or nurse who is arranging your treatment will explain how this is done). The doctor will then decide whether treatment is appropriate. This treatment should not be used if there are any boils or skin lesions that are still leaking. Wait until boils or lesions are dry. Whilst the skin treatments are being used the following will help reduce spread of the bacteria within the care home or household:

• Sheets/towels should be changed daily • Regular vacuuming and dusting, particularly the bedrooms

• If possible avoid bar soap and use pump action liquid soap

• Use individual personal towels and facecloths. Wash them frequently in a hot

wash.

• Clean sink and bath with a disposable cloth and detergent after use, and then rinse clean

Chlorhexidine 4% bodywash/shampoo or Triclosan 2% use once a day for 5 days:

• Use daily as liquid soap in the bath, shower or bowl and as a shampoo on days 1, 3 and 5

• Do NOT dilute it beforehand in water as this will reduce its efficacy — apply

directly to wet skin on a disposable wipe or on hand

• Do not use regular soap in addition during baths/showers

• Do NOT apply to dry skin

• Pay particular attention to armpits, groins, under breasts, hands and buttocks

• It should remain in contact with the skin for about a minute

• Rinse off well before drying skin thoroughly. This is particularly important in people with skin conditions (e.g. eczema).

• Towels should be for individual person use and, if possible, changed daily

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Mupirocin (Bactroban Nasal) (use three times a day for 5 days): • Apply a matchstick head-sized amount (less for a small child) on the end of a

cotton bud to the inner surface of each nostril. Press the sides of the nose together and massage gently to spread the ointment inside the nostrils.

Sometimes you might also be asked to gargle with an antiseptic solution. For individual concerns or further advice please contact your GP or your local Health Protection Unit.

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Appendix 3 Guidance for reducing the spread of PVL-Staphylococcus aureus in communal and other recreational settings 1. What is PVL-Staphylococcus aureus? Staphylococcus aureus (SA) is a type of bacterium (germ) commonly found living on healthy skin. It particularly likes moist surfaces of the body, such as the nostrils, armpits and groin. People carry many different strains of SA, some causing more infections than others. Some strains can produce the Panton-Valentine Leukocidin (PVL) toxin. (Panton and Valentine were two doctors who first found this chemical which can kill white blood cells – hence ‘leukocidin'). These strains commonly cause boils or skin abscesses and are occasionally associated with more serious infections of the lungs, blood, joints and bones. Some strains of meticillin-resistant Staphylococcus aureus (MRSA) present in the community can also produce PVL toxin. 2. Standard precautions including handwashing and general hygiene Management are responsible for ensuring basic training for staff in hygiene, and maintenance of equipment. While on the premises staff, clients or visitors should follow

the establishment's procedure on infection control. All premises should be encouraged to have a policy which includes a statement that individuals with boils, open sores or cuts which cannot be contained by a dressing should be excluded until the wound has healed.

• The establishment should ensure that access to basic handwashing facilities is provided. Pump action liquid soap, warm running water and paper handtowels are recommended. Where hand towels are not available, hot air dryers can be used;

• It is the responsibility of each individual using the premises to ensure that they

use the handwashing facilities before entering and when leaving, or any time when hands are visibly soiled;

• Staff must keep skin lesions (e.g. boils, open sores, or cuts) covered with a clean

dry dressing. If fluid seeps through the dressing and it cannot be contained, exclusion of the individual is advised until the wound has healed and treatment or decolonization has begun;

• Personal items (e.g. towels, robes etc) should not be shared; they can be used by

others only after laundering; • Soap, razors, toothbrushes and water bottles should never be shared; • A barrier (e.g. a towel or a layer of clothing) between the skin and shared

equipment should be used; • If there has been substantial skin-to-skin contact with another person or

communal gym equipment has been used, users should take a shower.

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Shared equipment (e.g. exercise machines) While using shared equipment on the premises, users should be encouraged to:

• Use a towel or clothing to act as a barrier between surfaces of shared

equipment and bare skin; • Wipe surfaces of equipment with disinfectant before and after use, especially if

the surface has become wet with sweat. Staff should be encouraged to:

• Provide hard surface detergent wipes for users of the equipment and encourage

use before using equipment; • Check with equipment manufacturers for recommendations on the appropriate

cleaning and disinfection of their products;

• Clean shared equipment surfaces at least daily and when visibly soiled;

• Disinfect shared equipment surfaces with a detergent disinfectant according to manufacturer's instructions; Management should ensure that staff have access to good standard detergent for cleaning;

• Repair or dispose of equipment and furniture with damaged surfaces that

cannot be adequately cleaned. Frayed and damaged surfaces are an infection risk; proper upkeep of equipment is critical to prevent spread of infection;

• Ensure that there is a policy for regular environmental cleaning;

• Managers should ensure staff receive appropriate training in general cleaning

of the equipment and the environment. 3. Steam rooms, saunas and pools While using these facilities, users should be encouraged to

• Use a towel or clothing to act as a barrier between the benches and bare skin; • Shower before and after use of the facilities.

Staff should be encouraged to:

• Clean and disinfect frequently used surfaces at least daily or when visibly soiled;

• Consider painting wood benches with a non-slip water-proof paint or varnish

to seal and smooth the surface, facilitate drying, and reduce areas where bacteria may grow;

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• Use a recommended disinfectant (e.g. chlorine or other halides) for swimming

pools, spa pools and other basins or tanks used for immersion by multiple patrons;

• Ensure spa pools used for single-use immersion are flushed through, cleaned

and rinsed after each user, using the recommended disinfectant;

• For non-porous surfaces (e.g. tile, stainless steel, epoxy, and linoleum), ensure a detergent disinfectant suitable for the type of surface being treated is used. A dilution of household chlorine bleach may be suitable, according to manufacturer’s instructions;

• For wood surfaces, scrub and disinfect with a dilution of household chlorine

bleach according to manufacturer’s instructions. Bleach solutions should be left on surfaces for at least 10 minutes to achieve maximum disinfection;

• If bleach is used, cleaning and disinfection should be done at room

temperature and surfaces should be rinsed well before re-starting the heat to prevent breathing difficulties and irritation of the eyes.

4. Laundry Staff in facility laundries should be encouraged to:

• Wash shared linens (e.g. towels, sheets, blankets, or uniforms) using a hot wash (60°C) where possible;

• Use laundry detergents according to the manufacturer's instructions;

• Distribute towels, uniforms, etc. only when they are completely dry;

• Wash hands after handling dirty laundry.

5. Use of disinfectants on surfaces

• Staff should be fully trained in disinfectant use; • Check the product's label to ensure that the disinfectant is suitable for the type of

surface being treated (e.g. vinyl, cloth, plastic or wood);

• Ensure that the disinfectant is diluted to the correct strength and that this working solution remains on the surface of the equipment for the recommended contact time and it is rinsed off thoroughly after cleaning;

• Unused working solutions of disinfectant should not be stored for later use; they

can be poured down the drain. Disposable wipe cloths can be discarded as a routine solid waste;

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• If a bleach-based solution is used, it must only be used on appropriate surfaces to reduce risk of damage to equipment and other surfaces. It must be diluted correctly and must rinsed off thoroughly afterwards.

Further Reading Infection Control Nurses Association (2002). Hand decontamination guidelines. Bathgate ICNA. Management of spa pools: Controlling the risk of infection. London: Health Protection Agency, March 2006.

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Appendix 4 Guidance for reducing the spread of PVL-Staphylococcus aureus (PVL-SA) in schools and nurseries 4.1 General Measures 1. Hand hygiene should be facilitated by providing adequate washing facilities and supplies. Liquid soap dispensers (not soap bars) should be used and paper towel dispensers should replace cloth towels.

2. Children should wash hands after using toilets, before eating and drinking, before and after use of the gymnasium and other communal sports activities, and whenever hands are contaminated or soiled.

3. Open wounds should be covered with a clean, dry occlusive dressing.

4. Children and staff with uncontained wound drainage should be excluded from

school and must not participate in sports until their wound is no longer draining (see below).

5. Contaminated surfaces should be cleaned promptly with detergent and water.

6. Common areas in school/nursery (e.g. toilets, locker rooms, dining room etc),

should be kept clean by following regularly scheduled cleaning protocols. 4.2 For individual cases with PVL-SA infection

1. Individuals can go to school provided they feel well, are of an age where they can understand the importance of good hand hygiene, and the infected skin is covered with a clean dry dressing able to stay dry and in place until the end of the school day.

2. Individuals should not be at school if they have a boil that requires drainage or a

newly discharging boil or abscess, the leakage from which cannot easily be contained.

3. Individuals must be given a patient information sheet outlining precautions they

should take to avoid infecting others (example in Appendix 1).

4. Individuals should not take part in contact sports or use communal gym equipment until their skin lesion has totally healed.

5. Those with eczema or a more generalised skin condition should remain off school

until treatment has been optimised and a course of decolonization has been completed. Treating the skin condition is essential if decolonization is to be successful. Maintaining optimal treatment for the skin condition in the long term will reduce the risk of spread of PVL-SA to others.

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4.3 Increasing numbers of skin infections If it appears that infection is spreading between children, the local Health Protection Unit should be contacted. (Contact details available at: http://www.hpa.org.uk/web/HPAweb&Page&HPAwebAutoListName/Page/1158945066055 ).

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Appendix 5 Advice for managers of care homes to help reduce spread of PVL-Staphylococcus aureus 5.1 Standard Infection Control Precautions All personnel involved in providing care should be trained in Standard Principles for Infection Control.1 These are divided into three broad categories:

• Hand hygiene • Personal Protective Equipment (PPE)

• Safe use and disposal of sharp instruments

In any environment that delivers care, staff must be trained in the Standard Principles for Infection Control. In an environment where one (or more) individual has a confirmed or suspected PVL-SA lesion, these principles must be reinforced to reduce the potential for further spread and outbreak among residents and staff. Staff should be asked to report any skin or eye lesions. If it appears that infection is spreading, the local Health Protection Unit should be contacted. (Contact details available at: http://www.hpa.org.uk/web/HPAweb&Page&HPAwebAutoListName/Page/1158945066055 ). Hand hygiene is the single most important activity for reducing the transmission of micro-organisms from one area of the body to another and subsequently to other residents and staff. The establishment must provide sufficient quantities of liquid soap, hot and cold running water and paper towels. Hands should be washed before and after every individual client activity, taking particular care when in contact with blood, bloodstained body fluids, pus, or other secretions. Hands must be washed when visibly soiled. Personal Protective Equipment includes disposable gloves and aprons, mask, goggles. A risk assessment of the action to be undertaken should be carried out by the staff member involved to identify what is required. In most settings this will be gloves (appropriate to procedure) and an apron. Aprons are a single use item and should be worn for all direct patient care including bed making, cleaning equipment following use, and when there is a risk of contamination of staff clothing. Aprons must be used for one procedure or activity only and then disposed of as clinical waste and hands washed afterwards. Gloves are not a substitute for hand washing and should also be used for one activity only and then be disposed of as clinical waste and hands must then be washed. Staff members should ensure that they have risk assessed the activity and have well-fitting gloves appropriate for the activity.

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5.2 Environment and General Cleaning All care facilities should be cleaned to the highest possible standard. A clear and specific plan should be set to identify the cleaning service, detailing what needs to be cleaned, how it should be cleaned, frequency of cleaning and the roles and responsibilities of those involved. This should incorporate plans for dealing with an outbreak or significant risk of infection. This plan should also clearly identify procedures for terminal cleaning (i.e. a thorough clean when a room has been vacated by an infected person), which may include the employment of outside contractors. Staff employed to provide an environmental cleaning service must have had training and education to provide the best possible outcome. It is the individual's responsibility to take up this training but the home manager and the registered owner MUST make this available. 5.3 Laundry Facilities A designated laundry area should be made available for the laundry process, which should include two doors, an entrance for soiled linen and an exit for the clean linen. An industrial washing machine and dryer should be installed and a maintenance contract agreed to ensure effective decontamination of linen. Personal Protective Equipment should be made available for laundry staff. A hand wash basin, pump action soap and disposable paper towels must be available within the laundry along with a pedal-operated bin. Manual sluicing should not be undertaken. Contaminated or infected linen should be taken from the individual and bagged in water soluble liners which are transferred directly to the laundry. A coding system for categories of laundry should be in place. If possible, staff uniforms should be laundered on site. Where this is not possible, staff should be advised to launder their uniforms at no less then 60°C. Staff should, where possible, be allocated changing rooms and change into their uniform at the beginning of the shift and out of their uniform at the end of the shift. A clean uniform should be worn for each shift. 2 Further Reading 1. Infection Control Guidance for Care Homes. Deptarment of Health, London 2006 2. Wilson JA, Loveday HP, Hoffman PN, Pratt RJ. Uniform: an evidence based review of the microbiology significance of uniforms and uniform policy in the prevention and control of healthcare-associated infections. Report to the Department of Health (England). J Hosp Infect 2007; 66: 301-307

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Appendix 6 Guidance for the screening and treatment of

PVL-Staphylococcus aureus for Primary Care

Panton-Valentine Leukocidin (PVL) is a toxin produced by less than 2% of S. aureus, including MRSA(1). PVL-SA cause recurrent skin and soft tissue infections, but can also cause invasive infections, including necrotising haemorrhagic pneumonia in otherwise healthy young people in the community.

CHARACTERISTICS OF INFECTIONS WITH PVL-SA Recurrent skin infections:

• Boils (furunculosis), carbuncles, folliculitis, cellulitis • Cutaneous lesions can be >5cm • Pain/erythema out of proportion to severity of signs

Invasive infections: • Necrotising pneumonia often after “flu-like” illness • Necrotising fasciitis • Osteomyelitis, septic arthritis and pyomyositis • Purpura fulminans(2)

RISK FACTORS & GROUPS

Risk factors: • Sharing contaminated items • Close contact • Crowding • Cleanliness • Cuts and other compromised skin integrity

Risk groups: • close contact sports e.g.: wrestling, rugby, judo • military training camps • gyms • prisons

WHEN SHOULD I INVESTIGATE FOR PVL S. AUREUS?(3)

• Recurrent boils/abscesses – especially if ≥ 1 case in a household, home or closed community • Necrotising skin and soft tissue infections • Community-acquired necrotising/haemorrhagic pneumonia What swabs should I take? • Swab skin lesion, damaged skin, throat and anterior nares – send in transport medium How should I take an anterior nares swab? • Wipe a swab around inside rim of patient’s nose for 5 seconds

HOW CAN PATIENTS REDUCE SPREAD IN CARE HOMES OR HOUSEHOLDS? • Cover infected skin with dressing, change regularly

• Do not to touch or squeeze skin lesions • Regularly wash hands • Avoid bar soap and use pump action liquid

soap instead • Clean sink and bath after use with a disposable

cloth and detergent, and then rinse clean

• Cover coughs and sneezes with tissue and dispose of immediately.

• Towels should be for individual person use and changed daily

• Regular vacuuming & dusting, especially bedrooms • If colonisation persists consider other hygiene

measures eg. change sheets daily WHEN AND HOW DO I TREAT WITH ANTIBIOTICS?

Infection Antibiotic Dosage Duration

Minor skin and soft tissue infections (SSTIs)

None, unless immunocompromised or deteriorating clinically

Abscesses Incision and drainage

Moderate SSTIs eg cellulitis Flucloxacillin or Clindamycin

500 mg qds 450 mg qds

5-7days

38

If PVL is likely to be MRSA treat empirically on advice of microbiologist, and then base on antibiotic susceptibility results

Rifampicin PLUS Sodium fusidate or Doxycycline (not children) Alternative regimen Rifampicin PLUS Trimethoprim Third line Linezolid

300 mg bd 500mg tds 100 mg bd 300 mg bd 200 mg bd 600 mg bd

5-7days

Severe SSTIs Refer immediately

SUPPRESSION OF PVL IN PATIENTS AND THEIR CLOSE CONTACTS • Topical treatment aims to reduce colonisation and may prevent further infections and interrupt transmission.

• Decolonisation is ineffective if skin lesions are still leaking. Only start after infection has resolved. TOPICAL TREATMENT PROCEDURE FOR PVL-STAPHYLOCOCCUS AUREUS

• Use Chlorhexidine 4% bodywash/shampoo or Triclosan 2% daily as liquid soap in the bath, shower or bowl for 5 days and as a shampoo on day 1, day 3 and day 5

• Do NOT dilute product in water as this reduces its efficacy • Apply product directly to wet skin as soap on a disposable wipe or on hand • Do not use regular soap in addition during baths/showers • Do NOT apply to dry skin • Pay particular attention to armpits, groins, under breasts, hands and buttocks • It should remain in contact with the skin for about a minute • Rinse off before drying thoroughly, especially if skin conditions • Apply matchstick head-sized amount (less for small child) of Mupirocin (Bactroban Nasal) on the end

of cotton bud to inner surface of each nostril and massage gently upwards. 3 times a day for 5 days. • Dermatological opinion may be necessary in patients with skin conditions eg eczema.

FOLLOW-UP

• Give patient information leaflet (see Appendix 1 and 2). • Advise patient to return if infection persists or recurs. • Patients with recurrent infections or persistent colonization should maintain sensible precautions to prevent

transmission in households and community settings (see patient information leaflet, example in Appendix 1). • Repeated screening and decolonization are not recommended unless the patient is particularly vulnerable to

infection, poses a special risk to others (e.g. a healthcare worker, carer in nursery etc, food handler) or spread of infection is continuing in close contacts.

When should the local Health Protection Unit be informed? • Where there has been one case of PVL-related infection in a care home or residential facilities, including

prisons and barracks • Suspicion of spread of PVL-associated infection in families, nurseries, schools and sports facilities (Contact details for Health Protection Units available at: http://www.hpa.org.uk/web/HPAweb&Page&HPAwebAutoListName/Page/1158945066055 ).

References 1. Holmes A, Ganner M, McGuane S, Pitt TL, Cookson BD, Kearns AM. Staphylococcus aureus isolates

carrying Panton-Valentine leucocidin genes in England and Wales: frequency, characterization, and association with clinical disease. J Clin Microbiol 2005 May;43(5):2384-90.

2. Hawkes M, Barton M, Conly J, Nicolle L, Barry C et al. Community-associated MRSA: superbug at our

doorstep. CMAJ 2007;176(1): 54-6. 3. Kearns A. Staphylococcal Reference Laboratory, Health Protection Agency 2007.

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Appendix 7: Special consideration of infections in children Skin and

Soft Tissue Bone and Joint

Severe Sepsis

Pneumonia

Suggestive Clinical Features

Recurrent furunculosis or abscesses Close contacts with skin lesions in child or other family members

Close contacts with skin lesions in child or other family members Associated severe sepsis Multiple sites of infection / metastatic abscesses Locally extensive infection Associated myositis / Pyomyositis Locally associated venous thrombosis Very high CRP Need for repeated surgical intervention

Close contacts with skin lesions in child or other family members Associated with bone or joint infection Associated with necrotising pneumonia Associated with recurrent furunculosis or abscesses Associated with deep venous thrombosis Associated with pupura fulminans

Close contacts with skin lesions in child or other family members Preceding “flu-like” illness Associated with severe sepsis Associated with bone or joint infection Associated with recurrent furunculosis or abscesses Haemoptysis Multilobular infiltrates and pleural effusions Leucopoenia / neutropaenia

First Line – Empiric Antibiotic Therapy*

If possible await results of culture and sensitivities before commencing antibiotics If there is a clinical need to treat empirically follow local guideline for treatment of skin and soft tissue infection Manage severe infections as for severe sepsis

Follow local antibiotic guidelines for the specific type of infection

ADD Clindamycin if there are any features suggestive of PVL-SA

ADD Linezolid if MRSA is suspected based on contact history, travel history or failure to respond to treatment, or once PVL status is confirmed

First Line – Other Empiric Management

Incision and drainage of abscesses Standard and contact precautions Discuss need for isolation with infection control team Decontamination for child and contacts

Resuscitation and stabilisation following APLS guidelines Aggressive early orthopaedic intervention to drain focus of infection Consider thromboembolism prophylaxis Standard and contact precautions Discuss need for isolation with infection control team Decontamination for child and contacts

Resuscitation and stabilisation following APLS guidelines Early discussion and transfer to Paediatric Intensive Care Unit Administer IVIG 1-2g/kg initial dose, repeated after 24-48 hours at lower dose if necessary Consider thromboembolism prophylaxis Standard and contact precautions Discuss need for isolation with infection control team Decontamination for child and contacts

Resuscitation and stabilisation following APLS guidelines Early discussion and transfer to Paediatric Intensive Care Unit Administer IVIG 1-2g/kg initial dose, repeated after 24-48 hours at lower dose if necessary Consider thromboembolism prophylaxis Standard and respiratory precautions Discuss need for isolation with infection control team Decontamination for child and contacts

Investigations Send swabs and pus specimens for culture and sensitivity

Blood culture Microscopy and culture of bone and joint specimens, and swabs from any skin lesions

Blood culture Microscopy and culture of swabs from any skin lesions

Blood culture Microscopy and culture of sputum / tracheal secretions / broncheoalveolar lavage

40

Serial MRI scans to determine extent of local disease and response to treatment Radioisotope scan to determine metastatic sites of infection which may not be clinically apparent Additional imaging for metastatic sites of infection if there is failure to respond to initial management Assessment for occult deep vein thrombosis

Imaging for foci of infection, particularly clinically occult bone and joint infection Assessment for occult deep vein thrombosis

Investigations for influenza A (using nasopharyngeal aspirate / tracheal secretions / broncheoalveolar lavage fluid) Assessment for occult deep vein thrombosis

Rationalisation of Antibiotic Therapy once PVL status is confirmed*and antibiotic sensitivities are known

Guided by antibiotic sensitivity profile, and acceptability of antibiotic regimen

Guided by antibiotic sensitivity profile of organism Initial Phase of treatment: Intravenous Clindamycin plus linezolid plus rifampicin until inflammatory markers return to normal and infection is controlled (absolute maximum of 4-weeks of linezolid treatment, ideally only 2-3 weeks) Continuation phase of treatment: IV / Oral Clindamycin plus rifampicin, duration & route directed by a specialist in Paediatric Infectious Diseases

Guided by antibiotic sensitivity profile of organism If clindamycin sensitive, use clindamycin plus rifampicin +/- linezolid; if resistant, use linezolid plus rifampicin

Guided by antibiotic sensitivity profile of organism If clindamycin sensitive, use clindamycin plus rifampicin +/- linezolid; if resistant, use linezolid plus rifampicin

Other Definitive Management

Repeated surgical intervention to drain / remove foci of infection may be required

Surgical intervention to drain / remove foci of infection may be required

Surgical intervention to drain / remove foci of infection may be required

Consultations Local microbiologist Surgeon / Paediatric Surgeon

Orthopaedic Surgeon with Paediatric expertise Paediatric Infectious Diseases Specialist Paediatric Intensive Care Unit Microbiologist Haematologist with Paediatric Expertise

Paediatric Infectious Diseases Specialist Paediatric Intensive Care Unit Microbiologist Surgeon with Paediatric Expertise Haematologist with Paediatric Expertise

Paediatric Infectious Diseases Specialist Paediatric Intensive Care Unit Microbiologist Surgeon with Paediatric Expertise Haematologist with Paediatric Expertise

Screening and decolonization

Follow recommendations in section 4

* Antibiotic doses should follow the recommendations in the British National Formulary for Children (use the highest recommended IV doses for severe infections).

41

Membership of the sub-group The sub-group was convened by the Steering Group on Healthcare Associated Infection in December 2006 and comprised the following members: Dr Deirdre Lewis (Chair) Regional Epidemiologist, HPA South West Ms Rachel Campbell Health Protection Nurse, Devon Health

Protection Unit (representing Infection Prevention Society)

Professor Barry Cookson Director, HPA Laboratory of Healthcare-Associated Infection

Dr Chris Day Lead Clinician, Intensive Care Medicine, Royal Devon and Exeter Foundation Trust Professor Brian Duerden Inspector of Microbiology and Infection Control,

Department of Health Dr Georgia Duckworth Director, HPA Department of Healthcare-

Associated Infection and Antimicrobial Resistance

Professor Peter Hawkey Professor of Clinical and Public Health Bacteriology and Consultant Medical Microbiologist, HPA Heart of England NHS Foundation Trust

Dr Robin Howe Consultant Microbiologist, Microbiology Cardiff (Velindre NHS Trust), University Hospital of Wales

Professor Don Jeffries Chair of the Steering Group on Healthcare- Associated Infection

Dr Angela Kearns Head of HPA Staphylococcus Reference Unit

Dr Marina Morgan Consultant Medical Microbiologist, Royal Devon and Exeter NHS Foundation Trust

Dr Christine McCartney Director, Regional Microbiology Network, Health Protection Agency

Professor Dilip Nathwani Consultant Physician, Ninewells Hospital & Medical School, Dundee

Dr Andrew Pearson Consultant Epidemiologist, HPA Department of Healthcare-Associated Infection and Antimicrobial Resistance

Dr Jane Steer Consultant Microbiologist, Plymouth Hospitals NHS Trust

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ACKNOWLEDGEMENTS Special thanks to: Dr. Bill Newsom who provided invaluable help in editing, analyzing and incorporating feedback from the consultation Dr. Aubrey Cunnington, Dr Marianne Nolan and Dr Hermione Lyall who prepared the paediatric section at short notice Dr. Cliodna McNulty who prepared the table for Primary Care Mr. Peter Hoffman for advice on antisepsis and cleaning and decontamination matters And all those who responded to the consultation. Equality Impact Assessment This guidance aims to improve practice and consequently patient care and outcomes. As part of standard practice, we considered the need for an equality impact assessment. We are not aware of any evidence that different groups have different priorities in relation to PVL, or that any group is affected disproportionately or any evidence or concern that this guidance may discriminate against a particular population group. Thus, we decided that an equality impact assessment was not required.

43

Glossary A&E Accident & Emergency Department APLS Advanced Paediatric Life Support BNF British National Formulary BNFc British National Formulary for children BSAC British Society for Antimicrobial Chemotherapy CA-MRSA Community-associated meticillin-resistant Staphylococcus aureus CAP Community-acquired pneumonia CRP C- Reactive Protein CURB65 a score for assessing the severity of illness in patients with pneumonia -

each risk factor scores one point, for a maximum score of 5: Confusion; Urea greater than 7 mmol/l; Respiratory rate of 30 breaths per minute or greater; Blood pressure less than 90 systolic or diastolic blood pressure 60 or less; age 65 or older

EMRSA Epidemic meticillin-resistant Staphylococcus aureus ESR Erythrocyte Sedimentation Rate GP General Practitioner HA-MRSA Hospital-associated meticillin-resistant Staphylococcus aureus HCW Healthcare worker HIS Hospital Infection Society HPU Health Protection Unit (contactable via

http://www.hpa.org.uk/web/HPAweb&Page&HPAwebAutoListName/Page/1158945066055 ) ICU Intensive Care Unit IV Intravenous IVIG Intravenous immunoglobulin

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MIC Minimum inhibitory concentration MRI Magnetic Resonance Imaging MRSA Meticillin-resistant Staphylococcus aureus MSSA Meticillin-sensitive Staphylococcus aureus NPA Nasopharyngeal aspirate PE Pulmonary embolus PPE Personal protective equipment PVL Panton-Valentine Leukocidin SA Staphylococcus aureus SSTI Skin and soft tissue infection TSS Toxic shock syndrome

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References 1. Nathwani D, Morgan M, Masterton RG, Dryden M, Cookson BD, French G, Lewis D on behalf of the British Society for Antimicrobial Chemotherapy Working Party on community-onset MRSA Infections. Guidelines for UK practice for the diagnosis and management of methicillin-resistant Staphylococcus aureus (MRSA) infections presenting in the community. J Antimicrob Chemother 2008;61: 976-994. 2. Holmes A, Ganner M, McGuane S, Pitt TL, Cookson BD, Kearns AM. Staphylococcus aureus isolates carrying Panton-Valentine leucocidin genes in England and Wales: frequency, characterization, and association with clinical disease. J Clin Microbiol 2005; 43: 2384-90. 3. Patel M, Waites KB, Hoesley CJ, Stamm AM, Canupp KC, Moser SA. Emergence of USA300 MRSA in a tertiary medical centre: implications for epidemiological studies. J Hosp Infect 2008; 68: 208-213. 4. Hawkes M, Barton M, Conly J, Nicolle L, Barry C et al. Community-associated MRSA: superbug at our doorstep. CMAJ 2007; 176: 54-6. 5. Bocchini CE, Hulten KG, Mason EO, Gonzalez BE, Hammerman WA, Kaplan S. Panton-Valentine Leukocidin genes are associated with enhanced inflammatory response and local disease in acute haematogenous Staphylococcus aureus osteomyelitis in children. Paediatrics 2006; 117: 433-440. 6. Kearns A (personal communication). Staphylococcal Reference Unit, Health Protection Agency 2007. 7. Coyle EA. Targeting bacterial virulence: the role of protein synthesis inhibitors in severe infection. Pharmacotherapy 2003; 5: 638-42. 8. Morgan MS. Diagnosis and treatment of Panton-Valentine leukocidin (PVL)-associated staphylococcal pneumonia. Int J Antimicrob Ag Chemother 2007; 30: 289-296. 9. Gillet Y, Issartel B, Vanhems P et al. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 2002; 359: 753-9 10. Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, Lewis SA, Macfarlane JT. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003; 58: 377-382. 11. Surviving Sepsis guidelines. Critical Care Medicine 2008; 36: 296-327. 12. Stevens DL, Ma Y, Mclndoo E, Wallace RJ, Bryant A. Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and

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methicillin-resistant Staphylococcus aureus. J Infect Dis 2007; 195: 202-11. 13. Torrell E, Molin D, Tabno E, Ehrenborg C, Ryden C. Community-acquired pneumonia and bacteraemia in healthy young woman caused by methicillin-resistant Staphylococcus aureus (MRSA) carrying the genes encoding Panton-Valentine leukocidin (PVL). Scand J infect Dis 2005; 7: 902-4. 14. Micek T, Dunne M, Kollef MH. Pleuropulmonary complications and Panton-Valentine Leucocidin-positive community-acquired methicillin-resistant Staphylococcus aureus: importance of treatment with antimicrobials inhibiting exotoxin production. Chest 2005; 128: 2732-8. 15. Francis JS, Doherty MC, Lopatin U, et al. Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis 2005; 40:100-7. 16. Peleg AY, Munckhof WJ, Kleinschmidt SL, Stephens AJ Huygens F. Life-threatening community-acquired meticillin-resistant Staphylococcus aureus infection in Australia. Eur J Infect Dis 2005; 24: 384-7. 17. Enayet I, Nazeri A, Johnson LB, Riederer K, Pawlak J, Saravolatz LD. Community-associated methicillin-resistant Staphylococcus aureus causing chronic pneumonia. Clin Infect Dis 2006; 42: 357-9. 18. Al-Tawfiq JA, Aldaabil RA. Community acquired MRSA bacteremic necrotising pneumonia in a patient with scrotal ulceration. J Infect 2005; 51: e241-e243 19. Mijklaevics E, Haeggman S, Sanchez B, Martinsons A, Olsson-Liljequist B, Dumpis U. Report on the first PVL-positive community acquired MRSA strain in Latvia. Eurosurveillance 2004; 9: 29-30. 20. Nimmo GR, Playford E G. Community acquired MRSA bacteraemia: four additional cases including one associated with severe pneumonia Med J Aust 2003; 177: 55-6. 21. Lamer C, de Beco V, Soler P. Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients. Antimicrob Ag Chemother 2002; 46: 1475-80. 22. Cruciani M, Gatti G, Lazarini L. Penetration of vancomycin into human lung tissue. Antimicrob Ag Chemother 1996; 38: 865-9. 23. Moise PA, Schentag JJ. Vancomycin treatment failures in Staphylococcus aureus lower respiratory tract infections. Int J Antimicrob Agents 2000; 16: 231-4. 24. Wargo KA, Eiland EH. Appropriate therapy for community acquired methicillin resistant Staphylococcus aureus carrying the Panton Valentine leukocidin gene. Clin Infect Dis 2005; 40:1376-7.

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25. Hampson FG, Hancock SW, Primark RA. Disseminated sepsis due to a Panton Valentine Leukocidin producing strain of community acquired methicillin resistant Staphylococcus aureus and use of intravenous immunoglobulin therapy. Arch Dis Child 2006; 91: 201-3. 26. Tronci M, Parisi G, Pantosti A, Monaco M. Valentini PA. CA MRSA strain with decreased vancomycin susceptibility as a cause of serious invasive infection in an immunocompetent adolescent. ECCMID - ICC 2007 Munich; poster 1599. 27. Jeyaratnam D, Reid C, Kearns A, Klein J. Community-associated MRSA: an alert to pediatricians. Arch Dis Child 2006; 91: 511-2 28. Dumetrescu O, Boisset S, Bes M, et al. Effect of antibiotics on Staphylococcus aureus producing Panton-Valentine leukocidin. Antimicrob Ag Chemother 2007; 51: 1515-9. 29. Ohlsen K, Ziebuhr W, Koller P, Hell W, Wichelhaus TA, Hacker J. Effects of sub -inhibitory concentrations of antibiotics on alpha-toxin [HLA] expression on methicillin-sensitive and methicillin-resistant I isolates. Antimicrob Ag Chemother 1998; 42: 2817-2823 30. Norrby-Teglund A, Ihendyanne N, Darenberg J. Intravenous immunoglobulin adjunctive therapy in sepsis, with special emphasis on severe invasive Group A streptococcal infections. Scand J Infect Dis 2003; 35: 683-689. 31. Darenberg J, Soderquist B, Normark BN, Norrby-Teglund A. Differences in potency of intravenous polyspecific immunoglobulin G against streptococcal and staphylococcal superantigens: implications and therapy of toxic shock syndrome. Clin Infect Dis 2004; 38: 836-42. 32. Osterlund A, Kahlmeter B, Bieber L, Runehagen A, Breider J-M. Intrafamilial spread of highly virulent Staphylococcus aureus strains carrying the Panton-Valentine leukocidin. Scand J Infect Dis 2002; 34: 763-87 33. Coia E, Duckworth GJ, Edwards DI, Farrington M, Fry C et al. Guidelines for the control and prevention of methicillin resistant staphylococcus (MRSA) in healthcare facilities. J Hosp Infect 2006; 63 Suppl 1:S1-44. 34. Chalumeau M, Bidet P, Leina G, et al. Transmission of Panton-Valentine leukocidin-producing Staphylococcus aureus to a physician during resuscitation of a child. Clin Infect Dis 2005; 41: 29-30.

Guidelines for UK practice for the diagnosis and management ofmethicillin-resistant Staphylococcus aureus (MRSA) infections

presenting in the community

Dilip Nathwani1*, Marina Morgan2, Robert G. Masterton3, Matthew Dryden4, Barry D. Cookson5,

Gary French6 and Deirdre Lewis7 on behalf of the British Society for Antimicrobial Chemotherapy

Working Party on Community-onset MRSA Infections

1Infection Unit, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK; 2Royal Devon & Exeter NHS

Foundation Trust, Exeter EX2 5DW, UK; 3Lothian University Hospitals NHS Trust, Edinburgh EH3 9YW, UK;4Royal Hampshire County Hospital, Winchester SO22 5DG, UK; 5Laboratory of Healthcare-Associated Infection,

HPA Centre for Infections, London 9W9 5HT, UK; 6St Thomas’ Hospital, Kings’ College, London SE1 7EH, UK;7HPA Southwest, Stonehouse, Gloucester GL10 3RF, UK

These guidelines have been developed by a Working Party convened on behalf of the British Societyfor Antimicrobial Chemotherapy. Their aim is to provide general practitioners and other community-and hospital-based healthcare professionals with pragmatic advice about when to suspect MRSAinfection in the community, when and what cultures should be performed and what should be the man-agement options, including the need for hospitalization.

Keywords: community onset, case scenarios, MRSA infection, diagnosis, management

Contents

1. Introduction2. Background and definitions

2.1 Definitions2.1.1 MRSA (methicillin-resistant S. aureus)2.1.2 CA-MRSA (community-associated MRSA)2.1.3 HA-MRSA (healthcare-associated MRSA)

3. Guideline remit4. Guideline development and methodology5. General principles of diagnosis and management

5.1 Clinical assessment5.2 Laboratory investigation

5.2.1 Clinical samples5.2.2 Testing for PVL5.2.3 Antimicrobial susceptibility testing

6. Clinical case scenarios6.1 Community-associated and community-onset MRSAskin and soft tissue infection

6.1.1 What is the likely clinical diagnosis?

6.1.2 When to suspect PVL+ CA-MRSA6.1.2.1 Clinical presentation6.1.2.2 Treatment factors6.1.2.3 Other risk factors6.1.2.4 Prevalence of CA-MRSA

6.1.3 When should specimens be sent for culture?6.1.4 When should specimens for culture not be taken?6.1.5 Treatment principles6.1.6 Empirical antibiotic therapy

6.2 Community-associated and community-onset pneumo-nia suspected to be due to PVL-producing MRSA6.2.1 What is the likely clinical diagnosis?6.2.2 When to suspect PVL+ CA-MRSA

6.2.2.1 Clinical presentation6.2.2.2 Treatment factors6.2.2.3 Other risk factors6.2.2.4 Prevalence of CA-MRSA

6.2.3 When should specimens be sent for culture?6.2.4 Radiological investigation

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

*Corresponding author. Tel: þ44-1382-660111; Fax: þ44-1382-816178; E-mail: dilip.nathwani@nhs.net

Journal of Antimicrobial Chemotherapy (2008) 61, 976–994

doi:10.1093/jac/dkn096

Advance Access publication 13 March 2008

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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For Permissions, please e-mail: journals.permissions@oxfordjournals.org

6.2.5 Treatment principles6.2.6 Empirical antibiotic therapy6.2.7 Adjunctive therapy options

6.2.7.1 Immunoglobulin therapy (IVIG)6.2.7.2 Other adjunctive therapy

6.3 Healthcare-associated community-onset MRSA skinand soft tissue infection6.3.1 What is the likely clinical diagnosis?6.3.2 When to suspect HA-MRSA

6.3.2.1 Clinical presentation6.3.2.2 Risk factors

6.3.3 When should specimens be sent for culture?6.3.4 Treatment principles6.3.5 Empirical antibiotic therapy

1. Introduction

This guidance aims to complement existing guidance on preven-tion and treatment of infections caused by methicillin-resistantStaphylococcus aureus (MRSA) and focuses on typical commonand less common community-onset infections with an emphasison community-associated MRSA (CA-MRSA). An importantissue covered by these guidelines is the management of seriousinfection caused by MRSA arising in the community. Althoughsuch infections are rare at present, they usually affect young,previously healthy people and may have a rapid and devastatingcourse. Specific guidance is given on the management of staphy-lococcal pneumonia, although other serious manifestations ofthese infections are emerging. Serious S. aureus infections canbe caused by strains that are methicillin-resistant or -susceptibleand which may or may not express the pathogenic Panton–Valentine leucocidin (PVL) toxin. The role of the general prac-titioner (GP) is to recognize that the patient is seriously unwelland needs to be managed in hospital (see Section 6, Appendix 1and the algorithm in Figure 1).

A summary of the commonest MRSA clinical problems [skinand soft tissue infections (SSTIs); serious and deep seated infec-tions] presenting to GPs and guidance on their treatment is pre-sented in Appendix 1. Practical advice on the isolation ofMRSA in the urine is also provided in the Appendix but notcovered in the main body of the guidelines because the evidencebase for the management of this situation is poor. The rec-ommendations could be implemented, for example, by their inte-gration into new or existing care pathways.

Guidelines on various aspects of the management and controlof MRSA are available and are revised regularly.

† This guidance is for the diagnosis and management ofMRSA infections that arise in the community. Much ofthis is relevant to GPs.

† Guidance for the control of MRSA in healthcare facilitiesis given by Coia et al.1

† Laboratory diagnosis of MRSA is discussed by Brownet al.2

† Revision of previous interim guidance on the diagnosisand management of infection due to PVL-producing

staphylococci is currently undergoing consultation.3

Whether to decolonize infected patients or screen anddecolonize contacts if positive is a key issue that is dis-cussed in the PVL guidance4 and will not be repeated here.However, the evidence base supporting many of the rec-ommendations related to screening and decolonization ispoor and worthy of further investigation.

† Antibiotic treatment of MRSA in general is discussed byGemmell et al.4 This guidance is currently being revised.

All of these documents can be accessed via the HealthProtection Agency (HPA) web site.5

2. Background and definitions

S. aureus is the major bacterial cause of skin, soft tissue andbone infections, and one of the commonest causes ofhealthcare-associated bacteraemia. About one-quarter of healthypeople carry one or more strains asymptomatically at any giventime and infections are commonly endogenous being caused bythe patient’s colonizing strain.6 Antibiotics and surgical drainageare the basis of treatment of staphylococcal infections, but theemergence of multiple resistance to penicillin, methicillin andother agents has compromised therapy. Methicillin resistancewas first detected in S. aureus in 1961,7 shortly after the agentwas introduced clinically, and over the last four decades, therehas been a global epidemic of MRSA.8,9

MRSA is usually acquired during exposure to hospitals andother healthcare facilities, and causes a variety of serioushealthcare-associated infections. A number of UK and USAguidelines have been produced on the prevention, control,

Figure 1. PVL-related disease: microbiology algorithm.

Review

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diagnosis and treatment of MRSA infections in hospitals andother healthcare facilities.2,10 – 12 However, there has been anincrease in MRSA infections presenting in the community thathas not been properly addressed by existing guidelines.4

Many (and in the UK at the present time, most) MRSA infec-tions that appear to have a community onset occur in patientswho are found to have had direct or indirect contact with hospi-tals, care homes or other healthcare facilities.13,14 These MRSAstrains are typical of the local healthcare-associated MRSA(HA-MRSA) and may be carried asymptomatically by patientsfor months after discharge. However, new strains of MRSA haverecently emerged that cause infections in community patientswho have no previous history of direct or indirect healthcarecontact. These strains have been designated CA-MRSA.15

CA-MRSA strains are genetically and phenotypically distinctfrom HA-MRSA. They typically resemble some strains ofmethicillin-susceptible S. aureus (MSSA) in being susceptible toa wider range of anti-staphylococcal antibiotics (some are resist-ant only to b-lactams), and often produce PVL, a toxin thatdestroys white blood cells and is a staphylococcal virulencefactor.16,17 Differences between CA- and HA-MRSA are sum-marized in Table 1. PVL-producing strains of CA-MRSA appearto be associated with increased risk of transmission, compli-cations and hospitalization. For example, in one large commu-nity outbreak of CA-MRSA, 23% of patients requiredhospitalization.18 PVL has a clear role in the pathogenesis ofsevere necrotizing pneumonia17,19,20 and is associated withgreater pulmonary and bone-related complications. Its role inskin infections is less certain, although PVL is a potent dermato-necrotic toxin.21

In the UK, the overall prevalence of S. aureus strains thatcarry the gene for PVL production is believed to be ,2%, andthese are mainly MSSA.22 Although the overall prevalence ofCA-MRSA is also presently low worldwide (thought to be,0.5% of all MRSA),23 there is clear evidence that this is

increasing, particularly in the USA, Canada and Australia. Insome areas of the USA, a significant proportion of seriousS. aureus infections presenting in community practice or at acci-dent and emergency departments is now due to CA-MRSAtypes.15,24 – 26 There are also emerging reports of CA-MRSAfrom Europe, including Scandinavian countries that have, untilnow, been almost free of HA-MRSA.27 – 30 There have been rela-tively few reports of CA-MRSA from the UK,31 – 33 but experi-ence elsewhere suggests that these are likely to increase in thefuture.

The Department of Health asked the HPA to lead in the pro-duction of guidance for PVL-related disease.3 In 2007, theSpecialist Advisory Committee on Antimicrobial Resistance alsoidentified the need to produce some specific guidance arounddiagnosis and treatment of infections caused by PVL-positivestaphylococci. The British Society of AntimicrobialChemotherapy (BSAC) on the other hand independently wishedto consider producing guidance with the broader remit of diag-nosis and management of community-onset MRSA includinginfections acquired in the healthcare setting but which wouldinclude PVL-related disease. HPA members with expertise inthis area were included in the BSAC Working Party and this gui-dance recognizes HPA and other related guidance where appro-priate. It is hoped that this will raise general awareness about theepidemiology and pathological significance of CA-MRSA. It ishoped that the early implementation of effective diagnosis, man-agement, prevention and control of these new infections willprevent some of the present difficulties with HA-MRSA34 devel-oping with CA-MRSA.

2.1 Definitions

The internationally agreed definitions of HA-MRSA, CA-MRSAand other S. aureus strains and their limitations are givenbelow.35 The definitions were originally based on

Table 1. HA-MRSA versus CA-MRSA

Parameter HA-MRSA CA-MRSA

Typical patient elderly, debilitated and/or critically or chronically ill young, healthy people; students, professional athletes and

military service personnel

Infection site often bacteraemia with no obvious infection focus.

Also surgical wounds, open ulcers, IV lines and

catheter urines. May cause ventilator associated

pneumonia

predilection for skin and soft tissue, producing cellulitis and

abscesses. May cause necrotising community acquired

pneumonia, septic shock or bone and joint infections

Transmission within healthcare settings; little spread among

household contacts

community-acquired. May spread in families and sports

teams

Clinical setting of

diagnosis

in an inpatient setting, but increasingly HA-MRSA

infections in soft tissue and urine are occurring in

primary care

in an outpatient or community setting

Medical history history of MRSA colonization, infection, recent

surgery; admission to a hospital or nursing home,

antibiotic use; dialysis, permanent indwelling

catheter

no significant medical history or healthcare contact

Virulence of

infecting strain

community spread is limited, PVL genes usually

absent

community spread occurs easily. PVL genes often present,

predisposing to necrotising soft tissue or lung infection

Antibiotic

susceptibility

often multiresistant with result that choice of agents

often very limited

generally susceptible to more antibiotics than HA-MRSA

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epidemiological features but, for the reasons outlined below,microbiological characteristics are now also important.

2.1.1 MRSA (methicillin-resistant S. aureus)

. Strains of S. aureus that are resistant to the isoxazoyl penicillinssuch as methicillin, oxacillin and flucloxacillin. MRSA arecross-resistant to all currently licensed b-lactam antibiotics.

2.1.2 CA-MRSA (community-associated MRSA)

. MRSA strains isolated from patients in an outpatient or commu-nity setting (community onset), or within 48 h of hospital admis-sion (hospital onset). Patients also typically have no previoushistory of MRSA infection or colonization, hospitalization,surgery, dialysis or residence in a long-term care facility withinthe previous year, and absence of indwelling catheters or percu-taneous devices at the time of culture (Table 2).

2.1.3 HA-MRSA (healthcare-associated MRSA)

. MRSA strains that are transmitted to and circulate between indi-viduals who have had contact with healthcare facilities. Theseinfections can present in the hospital or healthcare setting (hos-pital or healthcare onset) or in the community (communityonset), for example after hospital discharge.

However, the boundaries between HA-MRSA andCA-MRSA are becoming blurred due to the movement ofpatients and infections between hospitals and the community,and to nosocomial outbreaks of CA-MRSA following admissionof colonized or infected patients.36 In the USA, whereCA-MRSA is now common, it is becoming increasingly difficultto distinguish between CA- and HA-MRSA on clinical and epi-demiological grounds.37 Since HA-MRSA and CA-MRSAstrains are often genotypically and phenotypically different(Table 1), the microbiological characteristics of the S. aureusisolates may help distinguish between HA- and CA-infections.

3. Guideline remit

This guideline provides recommendations based on evidenceobtained from existing guidance on best practice in the

principles of diagnosis and management of MRSA infections inthe community. Infection prevention guidance is kept to aminimum as other guidance exists in this area. Our guidancecovers:

(1) Patients whose infections were acquired in the hospital butwho present in the community (hospital orhealthcare-associated and community-onset MRSA infec-tions). This is the commonest MRSA-related communityproblem in the UK. GPs may expect to encounter this on adaily basis in patients who are chronically ill, elderly, dia-betic with open skin lesions, have had recent surgery or inpatients who are regular hospital attendees.

(2) Infections acquired in the community in patients with nohospital contact or other related risk factors. These maypresent in the community (community-associated andcommunity-onset, for example the skin infection or pneumo-nia scenarios) or, rarely, in hospital (community-associatedand hospital-onset).

Infections due to hospital or healthcare-associated S. aureusstrains presenting in hospital (hospital-onset andhospital-acquired) are excluded, since they are already coveredin disease-specific guidance (e.g. ventilator-associated pneumo-nia, endocarditis, surgical site infection). The guidance on anti-microbial treatment and prophylaxis of MRSA infectionsproduced by the Joint Working Party of the BSAC, the HospitalInfection Society and the Infection Control Nurses Association4

is due to be updated in 2008.The Working Party recognizes that in the UK, PVL toxin-

producing staphylococci are presently uncommon and when theycause infection they are more frequently MSSA. Interim gui-dance for the diagnosis and management of PVL-associatedS. aureus infections in the UK has been published by a groupconvened by the HPA.3 However, in light of the global emer-gence of severe infections and outbreaks due to PVL-producingCA-MRSA,38 infections with PVL-producing MRSA in the UKare likely to increase.

4. Guideline development and methodology

The Working Party was convened under the auspices of theBSAC and comprised microbiologists, an infectious diseasephysician and public health physicians, all of whom had aninterest in MRSA infections and had previous experience inguideline development. Advice regarding guideline format andcontent from a GP and nurse were sought prior to guidelinedevelopment.

The Working Party adopted a ‘common clinical scenario’approach to the diagnosis and recognition of these infectionswhich they hope will be useful for the community prac-titioner and broader healthcare team. The evidence base forthe guidance in these scenarios has been provided by a systema-tic appraisal of existing guidelines or consensus documentsusing the approach developed by the ADAPTE Group.39 Thisadaptation process involves six steps: (1) searching for existingguidelines; (2) assessment of guideline quality; (3) assessmentof applicability and adaptation of recommendations to targetsetting; (4) literature update; (5) adaptation of guideline format;

Table 2. Populations at increased risk of community-associated

MRSA (adapted from references 20, 32–34 and 38)

Risk groups

Children ,2 years old

Athletes (mainly contact-sport participants)

Injection drug users

Men who have sex with men

Military personnel

Inmates of correctional facilities, residential homes or shelters

Vets, pet owners and pig farmers

Patients with post-flu-like illness and/or severe pneumonia

Patients with concurrent SSTI

History of colonization or recent infection with CA-MRSA

History of antibiotic consumption in the previous year, particularly

quinolones or macrolides

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and (6) implementation. We felt that this was more appropriatethan a new systematic literature review, since recent guidelinesfrom Canada40 included a thorough systematic review of muchof the relevant CA-MRSA literature. Furthermore, other gui-dance on community-onset healthcare-acquired MRSA exists butis not presented in the context of ‘a community onset’ infection.

The levels of evidence and the strength of recommendationswere categorized using the Scottish Intercollegiate GuidelinesNetwork (SIGN) evidence statements and grades of recommen-dations (SIGN Guideline 50—a guideline developers’ handbookat www.sign.ac.uk), the details of which are shown in Tables S1and S2 [Supplementary data available at JAC Online (http://jac.oxfordjournals.org/)]. On occasion, guideline developmentgroups find that there is an important practical point that theywish to emphasize but for which there is not, nor is there likelyto be, any research evidence. This will typically be where someaspect of treatment is regarded as being of such sound clinicalpractice that nobody is likely to question it. These are marked inthe guideline as Good Practice Points, and are indicated by theacronym ‘GPP’. It must be emphasized that these are not analternative to evidence-based recommendations and have onlybeen used where there was no alternative means of highlightingthe issue.

An English language only literature search was undertakenfor existing guidance related to clinical presentation, diagnosisand treatment of CA-MRSA infection with particular referenceto SSTIs and pneumonia. We searched Medline and Google/Google Scholar as well as the various guideline databases withthe following keywords: ‘community-acquired or -onsetS. aureus’, ‘Panton–Valentine Leucocidin’ and ‘methicillin-resistant S. aureus’. The following guideline databases weresearched in detail: Guideline International Network, NationalInstitute for Health and Clinical Excellence, National GuidelineClearing, SIGN, as well as a recent Canadian guideline.40 Thiswas deemed sufficiently important to be worthy of more detailedappraisal using the AGREE instrument.41 The scope andpurpose of the Canadian guideline, stakeholder involvement,clarity and presentation were judged to be of good quality,although the guideline provided few support tools for its appli-cation. However, the rigour of development was judged moder-ate to poor because there was no consistent explicit linking ofthe evidence to the recommendation, no tables of evidence, nosupporting evidence for many recommendations, references wereoften missing and there were no details of how consensus state-ments were developed for many of the statements. The basis forthe Canadian guidelines’ recommendations and strength of evi-dence was less explicit than with the SIGN methodology andmore generous in making high-level or strong recommendationsbased on grade 3 evidence (such as expert opinion, case studiesand so on). Other weaknesses include failure to identify theapplicability of the guideline to an organization or healthcaresystem, no appreciation or mention of potential cost implicationsof the guideline and no criteria for monitoring quality improve-ment. The guideline group appeared to have editorial indepen-dence although there were no conflict of interest statements. Wehave attempted to address some of these weaknesses in thepresent guidance.

The other documents looked at included other publishedreviews of the subject.15,42 Zetola et al.15 were particularlythorough in defining search strategy and selection criteria, andincluded papers in Spanish. There were also statements from

governmental and regional expert groups.43,44 Although none ofthese documents gave evidence of a systematic process of produ-cing evidence-based recommendations, they provided usefulinformation for some areas of our guidance. Most of our rec-ommendations based on existing guidance, primarily theCanadian guidelines, were SIGN grade D and arose from evi-dence in non-controlled studies and expert opinion. Only in afew cases did evidence come from the results of case–control orcohort studies, reflecting the evolving nature of the disease. Inmany areas, our recommendations are simply recommendationsfor good medical practice and reflect the experience andopinions of the Working Party.

The Working Party assessed all the contributions and agreedon the key recommendations before submitting the draft forexternal peer review. Changes suggested by the external reviewwere incorporated before finalizing its adoption, endorsementand implementation. The BSAC agreed that this guideline wouldbe developed in close collaboration and consultation with aWorking Group of the HPA which was revising guidance onPVL-associated staphylococcal infections in England. Otherstakeholders are the Royal College of Nursing, the InfectionPrevention Society (formerly the Infection Control NursesAssociation), the Hospital Infection Society, the BritishInfection Society, the Royal College of General Practitioners,the Royal College of Physicians, the Royal College of Surgeons,the College of Emergency Medicine, the Royal College ofPaediatricians and the UK Pharmacy Association.

5. General principles of diagnosis and management

5.1 Clinical assessment

When presented with a patient in the community who the clini-cian thinks may have a staphylococcal infection, the decision-making process related to diagnosis and treatment includesanswering the following questions:

(1) What is the severity of illness?(2) Is distinction between MSSA or MRSA infection possible?(3) If MRSA is suspected, is it likely to be CA-MRSA or

HA-MRSA?(4) Should further microbiological assessment/investigation be

undertaken and, if so, how?(5) Does empirical antibiotic therapy (or definitive therapy if

microbiology results are available) need to be started?(6) Does adjunct therapy (for example surgical drainage) need

to be considered?(7) Does the patient need to be admitted to hospital?(8) What advice should be given to direct contacts and house-

hold members?

This clinical risk-assessment is detailed for each of the‘typical’ clinical scenarios below. Many factors in theserisk-assessments are similar for all the scenarios, including dis-tinguishing between CA-MRSA and HA-MRSA strains(Table 1) and risk factors for CA-MRSA based on clinical, epi-demiological, laboratory and treatment factors (Tables 1 and 2).The predictive value of these risk factors for distinguishingbetween different strains, healthcare associated as opposed to

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community associated, is poor. Nevertheless, the scenarios pre-sented provide guidance for best practice.

5.2 Laboratory investigation

Because of the changing epidemiology of community-onsetMRSA and the need to optimize antibiotic therapy, clinicalsamples should be sent for microbiological testing.

5.2.1 Clinical samples

. Appropriate clinical samples (e.g. pus, swabs from lesions, sputaetc.) from suspected cases should be submitted to the localmicrobiology department for analysis. Accident and emergencystaff, GPs and other healthcare practitioners should be alerted tothe importance of taking specimens when incising and drainingabscesses. Samples should be cultured on non-selective media(e.g. blood agar) for the recovery of potential pathogens, includ-ing S. aureus.

5.2.2 Testing for PVL

. Genes encoding PVL may be carried by both MSSA andMRSA. PVL-positive MSSA display variable antimicrobial sus-ceptibility profiles, whereas the majority of PVL-positive MRSAcurrently found in the UK are susceptible to ciprofloxacin.45

S. aureus (MSSA or ciprofloxacin-susceptible MRSA) recoveredfrom suspected cases should be referred to the HPAStaphylococcus Reference Laboratory for toxin gene profilingincluding PVL testing. This is a PCR-based assay that can becompleted within a working day. Figure 1 is a suggestedalgorithm.

5.2.3 Antimicrobial susceptibility testing

. This should be performed by the laboratory’s routine methods.However, if the organism is erythromycin-resistant by disctesting, inducible clindamycin resistance should be tested for bythe D-zone test, which involves placement of erythromycin andclindamycin discs in close proximity on an agar plate inoculatedwith a standardized suspension of the isolate. Flattening of theclindamycin zone of inhibition in the area between the two discs(resulting in a D-shaped zone of inhibition) indicates the pre-sence of inducible clindamycin resistance in the presence of ery-thromycin resistance (positive D-zone test).

6. Clinical case scenarios

In the following section, three case scenarios are presented. Thekey questions related to clinical assessment are presented andguidance in the form of recommendations (in bold) are pro-vided. Additional guidance is provided on isolation of MRSA inthe urine.

6.1 Community-associated and community-onset MRSA

skin and soft tissue infection

A 14-year-old school boy with a skin infection is brought by hismother to their GP. He is not systemically unwell but has a red,tender, fluctuant discharging skin lesion over his thigh. There is

a moderate amount of surrounding erythema. It has notresponded to topical antiseptic cream. He gives a history ofthree previous ‘skin infections’ over the last year, treated withseveral courses of oral antibiotics. The current infectionappears to have been precipitated by a ‘minor’ injury to histhigh during football at school.

6.1.1 What is the likely clinical diagnosis?

. The clinical diagnosis of an SSTI presenting as an abscess isstraightforward. Pain, tenderness, erythema and swelling arecommon in SSTIs and offer around a 93% to 97% sensitivity(95% CI 83–100) in the clinical diagnosis of cellulites.46 Themost likely microbial cause of this is S. aureus, althoughpyogenic streptococci (e.g. b-haemolytic streptococci such asStreptococcus pyogenes, and group C or G streptococci) areother possibilities.

6.1.2 When to suspect PVLþ CA-MRSA (currently rare)

6.1.2.1 Clinical presentation. The spectrum of disease caused byCA-MRSA appears to be similar to that caused by CA-MSSA.Furuncles (abscesses in hair follicles, or ‘boils’), carbuncles (coa-lesced masses of furuncles with deeper tissue involvement) andother abscesses appear to be the most frequently reported clinicalmanifestations. They may or may not have accompanying celluli-tis. Erythematous papules and nodules, folliculitis and/or impetigoare less common presentations.

One specific presentation appears to be typical of cutaneousCA-MRSA infections. This is the spontaneous appearance of araised tender red lesion, which may progress to develop anecrotic centre. This may lead to the suspicion of a ‘spider bite’where such occurrences are common, e.g. North America orAustralia. Most reports of such lesions have come from the USAand have not been as frequently reported from other countries.In the UK, where spider bites are rare, these ‘dermatonecrotic’lesions increase the likelihood of a diagnosis of CA-MRSA butare not pathognomic. They can also be found in infections dueto PVL-positive MSSA strains.

Recommendation 1

† If ‘spider bite’ lesions are present, the possibility ofCA-MRSA or PVL-positive MSSA infection should beconsidered and appropriate investigation and manage-ment instituted. [D3].

Many other severe cutaneous complications of CA-MRSAhave been reported and include extensive cellulitis, necrotizingfasciitis and purpura fulminans.47 Involvement of adjacent struc-tures, either by direct spread or bacteraemia, such as septicthrombophlebitis, pyomyositis, septic arthritis and osteomyelitis,has all been described.15,40,42 No particular patterns of clinicalpresentation have yet emerged to allow differentiation fromMSSA infections.

Anecdotal reports suggest that recurrent (two or more in 6months) furuncles or abscesses, or clusters of infections within ahousehold may indicate PVL-positive CA-MRSA. [D3]. However,this pattern can also be seen in PVL-positive MSSA infections.

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Recommendation 2

† If there is a history of recurrent abscesses or householdclusters of infection, the possibility of CA-MRSA or PVL-positive MSSA infection should be considered and appro-priate investigation and management instituted. [D3].

6.1.2.2 Treatment factors. In the absence of an undrained abscessor focus of infection, a poor response to existing therapy (whichin most cases will be an isoxazole penicillin such as fluclox-acillin) increases the likelihood of CA-MRSA infection [D3].

Recommendation 3

† If there has been a prior poor response to b-lactamtherapy, the possibility of CA-MRSA or PVL-positiveMSSA infection should be considered and appropriateinvestigation and management instituted. [D3].

Exposure to one or more antibiotics in the past year (as opposedto no use) and use of quinolones or macrolides are potentialtreatment-related risk factors for CA-MRSA infection. [D2].

In a large English case–control study, there was a significantrelationship between exposure to increasing numbers of anti-biotics and diagnosis of CA-MRSA. This paper made no distinc-tion related to the PVL status of these organisms. For exposureto 1, 2–3 or �4 antibiotics in the previous year, the odds ratios(ORs) were, respectively, 1.57 (CI 1.36–1.80), 2.46 (CI 2.15–2.83) and 6.24 (CI 5.43–7.17). Receipt of quinolones [OR 3.37(CI 2.80–4.09)] and macrolides [OR 2.50 (CI 2.14–2.91)] inthe previous year was specific associations.48 However, it is notclear in this study whether these cases were due to PVL-positiveor -negative strains of S. aureus. In another large prospectivestudy of adult patients in the USA with SSTIs presenting to theemergency department, results of a multi-regression analysesshowed that use of an antibiotic in the past month (as opposedto no use) had a 2.4-fold (95% CI 1.4–4.3) greater risk of infec-tion with CA-MRSA.24

Recommendation 4

† If there is a history of exposure to one or more anti-biotics in the past year, especially quinolones or macro-lides, the possibility of CA-MRSA infection should beconsidered and appropriate investigation and manage-ment instituted. [D2].

6.1.2.3 Other risk factors. A recent prospective USA cohortstudy found that clinical and epidemiological risk factors inpersons hospitalized for CA-MRSA infection cannot distinguishreliably between MRSA and MSSA.37 Indeed, in this study, posthoc modelling revealed that in a country where the prevalenceof MRSA in the community is ,10%, as is presently the casein the UK, patients lacking the three strongest risk factors wouldonly have a 7% post-test probability of MRSA. In another pro-spective prevalence study of MRSA infections among patients inthe emergency department, the presence or absence of theseclinical and epidemiological risk factors was not useful inguiding decisions about the use of antibiotic therapy. Mostpatients without MRSA had at least one of these risk factors,

and almost half of those without any of these factors were foundto have MRSA.24

CA-MRSA has been linked to the specific risk factors out-lined in Table 2. However, the value of these risk factors in dif-ferentiating between MRSA and MSSA and predictingsuccessful antimicrobial therapy is uncertain and currentlyshould not be relied upon. [C22]. In UK practice, many of theserisk factors are probably not relevant, except for (1) history oftravel to an endemic area such as North America and (2) recentcolonization or contact with CA-MRSA.

Recommendation 5

† If any of the risk factors outlined in Table 2 arepresent, especially recent travel to an endemic areasuch as North America and recent colonization orcontact with CA-MRSA, the possibility of CA-MRSAinfection should be considered and appropriate investi-gation and management instituted. [C2 –].

6.1.2.4 Prevalence of CA-MRSA. The threshold where the preva-lence of CA-MRSA in the community becomes an importantconsideration in determining the choice of initial empirical anti-biotic therapy is uncertain. In the UK, the prevalence ofCA-MRSA infection is very low or unknown. Although there isevidence of emerging PVL-related infection in certain parts ofthe country, prevalence of infection or colonization on its owncurrently cannot be regarded as a reliable indicator of the likeli-hood of MRSA infection in an individual patient and thereforeis not a guide to antibiotic choice. [GPP].

Recommendation 6

† Because the prevalence of CA-MRSA in the UK is pre-sently very low, suspected community staphylococcalinfections should not be treated as if they wereCA-MRSA in the absence of significant specific riskfactors. This is an evolving situation and the localprevalence of CA-MRSA should be monitored andadvice modified as necessary.

6.1.3 When should specimens be sent for culture?

Recommendation 7

† Cultures should be taken from septic sites if:

(1) CA-MRSA is suspected because of the risk assessmentbased on clinical presentation, treatment factors andother risk factors outlined in Tables 1 and 2. [D3].

(2) There are recurrent furuncles or abscesses (two ormore in 6 months). [D3].

(3) There is a history of spread in the family or to others,e.g. sporting contacts (the information may be avail-able from the public health/infection control team).[D4].

(4) If there is severe infection (extensive or progressivedisease with evidence of systemic sepsis), the patientshould be hospitalized and a skin/abscess culture andblood culture should be taken. [GPP].

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Cultures will determine the prevalence of these infections ina particular setting or community and will allow appropriaterationalization of antibiotic treatment.

6.1.4 When should specimens for culture not be taken?

Recommendation 8

† Do not take cultures routinely from patients presentingwith minor SSTIs and without a history of previousMRSA. [D4].

† Do not routinely aspirate material for culture from cel-lulitis in the absence of discharge or broken skin.[GPP].

6.1.5 Treatment principles

Recommendation 9A

† Do not give systemic antibiotics to patients with minorSSTIs or small abscesses (<5 cm). [D3].

† Incise and drain small abscesses without cellulitis anddo not give antibiotic therapy. [A12].

† After incision and drainage start empirical or culture-guided systemic antibiotic therapy for larger abscessesor if there are infections in other family members. [D3].

Recommendation 9B

† Guidance regarding topical antibiotic treatment, deco-lonization and screening is beyond the remit of thisguideline although the group recommend that existingevidence for need and effectiveness is poor. For furtherinformation, refer to guidance provided by the HPA.3

A recent randomized controlled trial, in a single centre withlarge numbers of injecting drug users, compared treatment withcefalexin, which lacks activity against MRSA, with placebo in166 adult patients who had surgically drained abscesses.Although MRSA was isolated from most patients, more than 85%of patients in both arms were cured without the need foradditional therapy at a 1 week follow-up visit, suggesting thatmost of these infections resolve without antimicrobial therapy.49

Another prospective study of otherwise healthy children with skinand soft tissue abscesses concluded that incision and drainage ofCA-MRSA abscesses with a diameter of less than a 5 cm withoutantibiotics was adequate.50 However, these findings should bebalanced by reports of recurrence or worsening of infections nottreated with systemic antibiotics effective against MRSA.51

Recommendation 9C

† In compromised patients or those with severe disease,give systemic antibiotic therapy based on clinical assess-ment and local susceptibilities of strains while awaitingdefinitive susceptibility results. [GPP].

† Ensure that empirical treatment also provides coveragainst S. pyogenes. [GPP]. Oral flucloxacillin and clin-damycin have activity against S. pyogenes, whereastetracycline and trimethoprim often do not.

6.1.6 Empirical antibiotic therapy

. There is conflicting evidence that inappropriate empirical therapyfor SSTIs at the time of initial clinical presentation leads to aninferior outcome. Four studies18,24,50,51 compared susceptibility ofthe pathogen to the prescribed antimicrobial agent with clinicaloutcome. The patients involved mainly had abscesses. There wasno difference in outcomes, suggesting that these infections, evenwhen caused by MRSA, can be cured with drainage only.However, in one recent retrospective analysis of the impact ofantimicrobial therapy on outcome for uncomplicated community-onset SSTIs, there was a small but significant (OR 2.80; 95% CI1.26–6.22; P ¼ 0.01) increase in treatment failures (defined asworsening of signs of infection, requiring additional incision anddrainage, subsequent hospital admission, microbiological failureor new culture proven lesions during antimicrobial therapy), inthose who received initial therapy with agents ineffective invitro.52 Use of ineffective agents was the only independent predic-tor of treatment failure in multivariate analysis.

The discrepancy between the results in this study and thoseof previous reports could be due to a variety of reasons. Theyinclude: the larger size of the study population,52 which may bemore likely to detect a true difference in outcome comparedwith smaller studies; different patient populations, such as adultsfrom one healthcare system compared with children fromanother; and differences in underlying health status.53

Furthermore, since most of these patients had non-life-threatening cutaneous infections, it is difficult to extrapolatethese data to more severe infections. Additional support forempirical therapy that is active against the isolated pathogencomes from a retrospective chart review of 399 sequential,culture-confirmed community-onset S. aureus SSTIs, of which227 were due to MRSA. Use of an effective agent in empiricaltherapy was associated with an increased odds ratio [OR 5.91(95% CI 3.14–11.13)] of clinical resolution when controlledfor incision, drainage and HIV status.54 This study confirmedthe effectiveness of trimethoprim/sulfamethoxazole as theempirical therapy in this setting. A further prospective random-ized trial of empirical therapy of trimethoprim/sulfamethoxazoleor doxycycline for outpatient SSTIs in an area of high MRSAprevalence showed the equivalent effectiveness of eithertherapy, although the treatment failure rates were 9% in thetrimethoprim/sulfamethoxazole arm compared with none inthe other.55

Epidemiological profiling of CA-MRSA strains inEngland and Wales over a 2 year period 2004–05 suggeststhat all were susceptible to clindamycin, trimethoprim,vancomycin, linezolid and mupirocin.56

CA-MRSA strains that are erythromycin-resistant (by posses-sion of the erm gene) and are initially susceptible to clindamy-cin can potentially develop resistance to clindamycin duringtherapy. The global reported rates of such inducible resistancevary from 2% to 94%. A double disc diffusion test (D-test)can be used to determine whether clindamycin-susceptibleCA-MRSA strains harbour inducible resistance.57 The locallaboratory should perform a D-test.

In severe infections with features of toxic shock or necrotiz-ing fasciitis, there is a theoretical case for using two or threeagents such as linezolid combined with clindamycin and rifam-picin. This is based on in vitro synergy58 and the ability of line-zolid and clindamycin to inhibit toxin production.58,59 [GPP]. AD-test should be performed if clindamycin is used. Existing

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MRSA treatment guidance does not recommend three agents butrather linezolid with rifampicin as initial therapy.4

Recommendation 10

† Because of the absence of evidence of rising prevalenceof CA-MRSA in the UK and the lack of unequivocalevidence that inappropriate antimicrobial therapyalters outcome, there is no need to change existingempirical therapy recommendations (below) for non-severe presumed S. aureus infections. [C3].

† In the UK, the recommended community treatment forsuspected MSSA infections is oral flucloxacillin 500–1000 mg 6 hourly (or oral clindamycin 300–450 mg 6hourly in penicillin allergic patients); 5–7 days of treat-ment is normally sufficient.

† If the patient is known to be MRSA-positive OR lesioncultures yield MRSA alone, then community treatmentshould be either oral doxycycline (contra-indicated inchildren <12 years) 100 mg 12 hourly, or fusidic acid500 mg 8 hourly, or trimethoprim 200 mg 12 hourly,each combined with rifampicin 300 mg 12 hourly (seeAppendix). Fusidic acid and rifampicin should NOTbe used as monotherapy because of the danger of resist-ance emergence. All these agents can be used in penicil-lin allergic patients.

† Trimethoprim (combined with sulfamethoxazole) ordoxycycline without rifampicin is also effective forambulatory therapy of MRSA SSTIs.51 [A11]. Orallinezolid 600 mg twice daily is an alternative option foruse ‘under expert guidance’, but because of its highcost it should be reserved for patients who are not ableto take or tolerate the above regimens. Linezolid maynot be readily available in primary care pharmacies.

† If Group A streptococcal (GAS) infection is suspected,oral therapy should include an agent active against thisorganism (b-lactam or clindamycin).

† For severe infections with known or suspectedCA-MRSA, start treatment in hospital with parenteralvancomycin, teicoplanin, daptomycin (but not for pneu-monia) or linezolid. Tigecycline may also offer broaderpolymicrobial cover if required. There is no evidencethat one agent is superior to another. [GPP].

† In severe infections with features of toxic shock ornecrotizing fasciitis, there is a theoretical case for usingtwo or three agents such as linezolid combined withclindamycin and rifampicin.

More detailed guidance in this area is available.4 A goodexample of a care pathway for SSTIs has recently been pub-lished from Washington, USA (http://www.metrokc.gov/health/providers/epidemiology/MRSA-guidelines.pdf ).

6.2 Community-associated and community-onset

pneumonia suspected to be due to PVL-producing MRSA

(this would apply to PVL-producing MSSA also)

A 37-year-old mother of two young children is admitted to hos-pital very unwell with a 48 h history of pleuritic chest pain,cough with frank haemoptysis and increasing shortness of

breath. Nobody else in the family has been unwell. She was pre-viously healthy, but had a flu-like illness 5 days prior to herrapid deterioration. She had been given amoxicillin the previousday by her GP. She is admitted to hospital with the workingdiagnosis of community-acquired pneumonia (CAP). Her temp-erature is 39.58C, respiratory rate is 40/min, white cell count is3.7�109/L and C-reactive protein (CRP) 360 mg/L. Chest X-rayreveals some increased shadowing in both lungs, with fluffyopacities.

6.2.1 What is the likely clinical diagnosis?

This clinical diagnosis is of a community-acquired lower respir-atory tract infection, with the unusual feature of severe haemop-tysis. Severe CAP with haemoptysis following a flu-like illnesscould also indicate primary influenza pneumonia, although theabsence of family members with flu-like symptoms is againstthis. The most likely microbial cause of the pneumonia is bac-terial and S. aureus should be considered as a potential pathogenbecause of the combination of high CRP and low white cellcount in a young patient with haemoptysis. Streptococcus pneu-moniae and S. pyogenes may also present with a similar picture.The fact that she has worsened on amoxicillin therapy also sup-ports a diagnosis of staphylococcal rather than streptococcalpneumonia. Pulmonary embolus is unlikely because the featuresof sepsis predominate, but this should be excluded if in doubt.

6.2.2 When to suspect CA-MRSA

6.2.2.1 Clinical presentation. There is nothing in this history tosuggest infection with CA-MRSA rather than with CA-MSSA.There are features, however, consistent with PVL-associated sta-phylococcal disease, including haemoptysis, high respiratory rateand a low white cell count (leucopenia) in the presence of ahigh CRP and systemic sepsis in a previously healthy individ-ual.20,60 The presence of blood in sputum should alert the clini-cian to the possibility of PVL production. Assessing the severityof pneumonia in children or young adults should not includeage-dependent scoring systems such as CURB-65 as the scorewill be misleadingly low.

Recommendation 11

† Consider a diagnosis of lower respiratory tract infectioncaused by PVL-producing S. aureus in rapidly progress-ive pneumonia evolving into acute respiratory distresssyndrome. A fever of >3988888C, respiratory rate of >40breaths per minute, a tachycardia of >140 beats perminute with haemoptysis and hypotension make thediagnosis likely. The presence of significant haemoptysisand hypotension usually confirms the diagnosis. [C21].

Additional questions should be asked to elicit whether anyfamily members have a history of skin sepsis, any contact withhealthcare facilities or are known MRSA carriers.

Recommendation 12

† Although relatively few patients developing necrotizingpneumonia due to CA-MRSA have a previous history ofskin sepsis themselves,60 – 64 consider the possibility ofCA-MRSA infection if there is a history of recurrent(two or more in 6 months) furuncles or abscesses in

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family members or clustering of infections within thehousehold. [D3].

6.2.2.2 Treatment factors. Use of any antibiotic in the pastmonth (versus no use) has been identified as a potentialtreatment-related risk factor for CA-MRSA SSTI. [D2].However, there are no such data for CA-MRSA pneumonia.

Recommendation 13

Until further evidence is available, do not discount thepossibility of CA-MRSA infection in severe pneumonia onthe basis of a lack of history of recent antibiotic therapy.

6.2.2.3 Other risk factors.

Recommendation 14

† If any of the risk factors outlined in Table 2 arepresent, especially (in the UK) recent travel to anendemic area such as North America and recent coloni-zation or contact with CA-MRSA, the possibility ofCA-MRSA infection should be considered and appro-priate investigation and management instituted. [C22].

6.2.2.4 Prevalence of CA-MRSA. The threshold where the preva-lence of CA-MRSA in the community becomes an importantconsideration in determining the choice of empirical antibiotictherapy is uncertain. In the UK, the prevalence of this infectionis very low or unknown. Therefore, local variations in preva-lence currently have very little influence on the likelihood of anindividual patient having CA-MRSA infection.

Recommendation 15

† Consider the possibility of CA-MRSA infection insevere community pneumonia regardless of the localprevalence of CA-MRSA. [GPP].

Clinical Practice PointIn this patient, the absence of previous recurrent infections

does not lessen the probability that the infection is due toPVL-producing S. aureus. Previous exposure to antibiotics hasbeen recognized as a potential risk factor for HA-MRSA but isnot yet identified clearly as a risk for CA-MRSA.65

6.2.3 When should specimens be sent for culture?

Recommendation 16

† Gram’s stain and culture should be performed immedi-ately on admission. The Gram stain result may point tothe identity of the likely infecting organism. Relativepaucity of neutrophils in the Gram stain in a patientwith advanced pneumonia, severe haemoptysis and alow white count is supportive of PVL-associated staphy-lococcal pneumonia. [GPP].

† The 2004 update of the British Thoracic Society (BTS)guidelines recommends taking blood cultures frompatients with severe CAP preferably before antibiotictherapy is commenced in patients with a severity

CURB-65 score of three or above. However, if a diagno-sis of CAP has been definitely confirmed, and a patienthas no severity indicators or co-morbid disease, thenblood cultures may be omitted. [A2].66

Taking cultures will help to estimate the prevalence ofCA-MRSA and rationalize antibiotic treatment. Fewer than 25%of patients with CA-MRSA pneumonia have had positive bloodcultures.64,67 – 76

6.2.4 Radiological investigation

Multilobular alveolar infiltrates are still usual in pneumonia dueto PVL-producing staphylococci. Compared with pneumoniadue to HA-MRSA, they are more likely to cavitate and produceeffusions.61 However, more commonly, acute PVL-related infec-tions produce initially few, if any, chest X-ray changes, leadingclinicians to misdiagnose infections as simple exacerbations ofbronchitis or asthma.77,78 Radiological changes develop rapidly,with single or multiple opacities ,3 cm diameter being sugges-tive of staphylococcal infection. Cavitation may appear on serialX-rays and may be detected earlier with ultrasound. However,computed tomography (CT) scanning or magnetic resonanceimaging allows the best evaluation of the ongoing pathology,particularly with cystic changes.74,79 The classical multilobularinfiltrates and diffuse multilobar opacities followed by cavityformation may develop after only a few days and are best con-firmed with CT.80,81 Overall, the incidence of complicated pneu-monia caused by PVL-producing S. aureus is far higher thanwith non-PVL-producing strains.

Recommendation 17

† Consider the possibility of PVL-producing CA-MRSApneumonia if there are suggestive chest radiological fea-tures such as multilobular alveolar infiltrates, cavitationand pleural effusions. [D3].

6.2.5 Treatment principles

Owing to the small numbers of cases reported, there is not yetclear evidence that early appropriate antibiotic therapy willimprove outcomes in PVL-producing staphylococcal pneumonia.However, with an expected mortality approaching 75%,60,82 andin line with data from other types of CAP, hospital-acquiredpneumonia, ventilator-associated pneumonia and severe sepsis,early intensive care support and appropriate antimicrobialtherapy are essential.

Recommendation 18

† Refer patients with suspected CA-MRSA pneumonia tointensive care as soon as possible. Basic principles ofresuscitation should be followed and ventilatory supportimplemented when clinically necessary. [GPP].

† Pending antibiotic susceptibility results implementempirical antibiotic therapy that covers CA-MRSA assoon as possible. [GPP].

6.2.6 Empirical antibiotic therapy

According to the BTS guidance,66 patients with severe CAPshould receive antibiotics (co-amoxiclav or cefuroxime or

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cefotaxime plus a macrolide) within 2 h of hospital admission.[C]. Many current hospital antibiotic policies recommend avoid-ing cephalosporin use because of the association between theseantibiotics and Clostridium difficile colitis. The Working Partyrecommends that the CURB-65 severity scoring tool for CAPshould not be applied to young people or children who initiallymay appear to only have a mild respiratory illness. [GPP].

Unsuspected MRSA caused fatal pneumonia in fourMinnesotan children who were initially treated empirically withcephalosporins.61 Conventional doses of vancomycin mayproduce inadequate lung concentrations for MRSA infectionand, despite high trough serum levels, breakthrough continuousbacteraemia has been reported days into glycopeptidetherapy.79,82

Antimicrobials effective against MRSA that also decreaseexotoxin production, such as clindamycin and linezolid, aretheoretically desirable. Clindamycin decreases production oftoxic shock syndrome toxin 1 by 95% in stationary-phase cul-tures83 and stops the normal peak of a-toxin production duringthe late exponential phase of growth.59 Clindamycin and line-zolid both markedly suppress PVL production as staphylococciapproach stationary phase and there may be no PVL detectable12 h after starting treatment.59 Flucloxacillin is bactericidal, butthe low subinhibitory concentrations achievable in vivo innecrotic tissue may further augment PVL toxin anda-haemolysin production.59 Subinhibitory concentrations ofclindamycin, linezolid and fusidic acid all induce aconcentration-dependent decrease of PVL concentration,whereas with low concentrations of oxacillin, the concentrationof PVL increases up to 3-fold.84

Various combinations of vancomycin, clindamycin, linezolid,rifampicin and co-trimoxazole have been used in differing dosesand combinations in PVL pneumonia cases, with varyingdegrees of success.20,79,82 – 85 Linezolid treatment successes havebeen reported by several authors.79 – 81,86 – 88 Three of fourpatients with necrotizing pneumonia clinically failing vancomy-cin therapy responded to a change to linezolid and rifampicin.79

Decreased vancomycin susceptibility discouraged the use ofvancomycin in two cases.63,81 A PVL-positive USA300 MRSAstrain for which the vancomycin MIC was 2–4 mg/L respondedto a combination of linezolid, teicoplanin and rifampicin,although the infected patient was hospitalized for 6 weeks.81

Predicting the susceptibility of staphylococci is becomingincreasingly difficult and depends largely on the geographicallocation and clonality of the circulating strains. Most isolates ofstrain USA300 are resistant only to b-lactams and macrolides,but recently mupirocin, tetracycline, clindamycin and fluoroqui-nolone resistances have been reported.89 Twelve of 123 isolatesexamined contained tetK and ermC genes, but remained suscep-tible to doxycycline and minocycline. S. aureus isolates resistantto erythromycin but sensitive to clindamycin must be ‘D-tested’to exclude inducible clindamycin resistance. Combining clinda-mycin with linezolid is synergistic in vitro.58 In the UK, pneumo-nia due to clindamycin-resistant CA-MRSA has not been reportedso far and the majority of CA-MRSA are PVL-negative (AngelaKearns, Laboratory of Healthcare-Associated Infection, HPA, per-sonal communication).

Although there is as yet no unequivocal clinical evidence tosupport the combination of linezolid (intravenous, 600 mg 12hourly) plus clindamycin (intravenous, 1.2–1.8 g 6 hourly),because of the life-threatening nature of this disease, the

Working Party recommends that consideration be given to usingthis combination for initial therapy.90 The combination can bestarted empirically in a patient with the clinical features listedabove AND Gram-positive cocci in clusters in respiratorysecretions. Some experts suggest adding rifampicin 600 mgtwice daily, based on synergistic activity and intracellular clear-ance of staphylococci.91 The potential role of tigecycline (a gly-cylcycline) or tetracyclines in severe necrotizing PVL-associatedpneumonia is as yet unclear and daptomycin is not indicated asit is inactivated by lung surfactant.92

Recommendation 19

† The CURB-65 severity scoring tool for CAP should notbe applied to young people or children who initiallymay appear to only have a mild respiratory illness.[GPP].

† If a risk assessment suggests the possibility ofCA-MRSA, then empirical therapy for CAP shouldinclude cover for CA-MRSA. Consider adding linezolid600 mg 12 hourly and high dose clindamycin 1.2–1.8 g6 hourly. If the organism is isolated, check that it issusceptible to clindamycin and the D-test is negative.[GPP]. Some authors have also suggested the routineaddition of rifampicin 600 mg twice daily ifPVL-positive staphylococcal pneumonia is suspected.3,90

[GPP]. The roles of ceftobiprole (a cephalosporin withanti-MRSA properties) and tigecycline in this settinghave yet to be determined.

6.2.7 Adjunctive therapy options

6.2.7.1 Immunoglobulin therapy (IVIG). IVIG neutralizes thecytopathic effect and pore-formation of PVL in vitro, the inhi-bition being concentration dependent.93 No randomized con-trolled trials have been performed to assess the role ofimmunoglobulin therapy in this setting. It has been used inseveral patients with PVL-associated pneumonia.63,77,86,94 Theoptimal dosage of IVIG is uncertain; 2 g/kg is recommended forstreptococcal toxic syndrome,95 repeated at 48 h if there is stillevidence of sepsis or failure to respond. The combination oflinezolid and IVIG was effective in a boy with septic arthritisand pneumonia, who was discharged from intensive care to thegeneral ward on day 5.86

Recommendation 20

† Although most supporting evidence is anecdotal, theuse of immunoglobulin (IVIG) should be considered insevere sepsis and necrotizing pneumonia known or sus-pected to be due to S. aureus. IVIG should be given at adose of 2 g/kg, repeating the dose if improvement is notsatisfactory. [GPP].

6.2.7.2 Other adjunctive therapy. Anecdotal reports of the usageof granulocyte colony-stimulating factor96 and extra-corporealmembrane oxygenation64,94,97 suggest that they are largelyunsuccessful. Although of theoretical benefit in very earlysepsis, once active haemorrhage has occurred, activated proteinC should not be used. It therefore has no role in PVL-associatedpneumonia.

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Recommendation 21

† Based on current available evidence and experience, theWorking Party cannot provide guidance on the value ofthe above adjunct therapies.

Figure 2 provides an algorithm that may help cliniciansimplement the recommendations related to suspected staphylo-coccal pneumonia.

6.3 Healthcare-associated community-onset MRSA skin and

soft tissue infection

Although we have chosen the example below, another verycommon scenario is a recently discharged hospitalized patientwho presents with an ‘infected leg ulcer’ from which MRSA isisolated. The generic guidance and decision-making process pro-vided here should also apply to this scenario.

The district nurse requests a GP to do a home visit on a73-year-old man. She has been attending the patient regularly

Figure 2. Management of patient with suspected staphylococcal pneumonia in the healthcare setting. IVIG, intravenous immunoglobulin.

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over the last 3 weeks to dress a pressure sore that had developedover the sacrum. The man had recently been in hospital for arevision of his left hip prosthesis. The procedure was compli-cated by an episode of healthcare-acquired pneumonia andrehabilitation had been slow. He had spent 4 weeks in hospitalbefore discharge and during this time he had developed a 6 cmirregular pressure sore over the sacrum. In the 2 days before theattendance of the GP, the lesion had become slightly larger withan increase in foul-smelling exudate. On the day of the visit,there was now a spreading area of redness (erythema) aroundthe site. Although there was now some pain at the lesion, therewere no other systemic signs of infection.

6.3.1 What is the likely clinical diagnosis?

The pressure ulcer in this case would be defined as Grade 3 as itinvolves full-thickness skin loss with damage or necrosis of thesubcutaneous tissues, extending down to, but not penetratingthrough, the underlying fascia.98 All such ulcers are colonizedwith a mixture of organisms. A chronic non-healing ulcer mayreflect underlying osteomyelitis. The diagnosis of active infec-tion involving a pressure ulcer must therefore depend upon clini-cal assessment rather than microbiology culture results. TheEuropean Wound Management Association has defined the cri-teria for recognizing early wound infection and implementing anescalating therapeutic strategy.99 The overt signs of local infec-tion (Stage 3 involvement) include the discharge of pus withswelling, pain, erythema and local warmth. On examination, thesurrounding tissues may appear unhealthy and deteriorating. Theprincipal pathogens associated with active wound infections ofpressure ulcers are S. aureus, Streptococcus species, anaerobesand Pseudomonas aeruginosa.100 The likely diagnosis here istherefore of a locally infected pressure ulcer where S. aureus isone of the most frequently associated pathogens.

6.3.2 When to suspect HA-MRSA

6.3.2.1 Clinical presentation. There are no specific clinicalappearances or relationships that reliably identify a SSTI lesionas being infected with S. aureus or any particular type ofS. aureus.44,53 Three types of S. aureus are recognized as causingdisease in community settings, namely MSSA, CA-MRSA andHA-MRSA. The spectrum of disease caused is similar, with SSTIbeing the commonest related condition. However, CA-MRSA ismore strongly associated with SSTI than HA-MRSA and is morelikely to occur in younger patients.101 Although the appearancesof SSTI with these types of pathogen are very similar, CA-MRSAis more often associated with red, raised lesions with a centralarea of necrosis (see case scenario 1).

Recommendation 22

† There are no clinical characteristics that allow differen-tiation between different strains of MRSA infection.[GPP].

6.3.2.2 Risk factors. The risk factors associated with HA-MRSAare well defined and include:44,102,103 advanced age; underlyingco-morbidities and severity of illness; inter-institutional transferof the patient, especially from a nursing home or residence in along-term care facility; prolonged hospitalization (including a

history of frequent hospital admissions or admission to hospitalwithin the last 6 months); surgery or admission to an intensivecare unit within the last 6 months; exposure to invasive devicesof all types, especially central venous catheters; previous MRSAcolonization/infection or exposure to an MRSA-colonizedpatient; the presence of extensive wounds and/or burns; andexposure to antimicrobial drugs, especially cephalosporins,fluoroquinolones and macrolides.47

The ability of these risk factors to predict the likelihood ofHA-MRSA is uncertain. In recently hospitalized (,24 h)patients with staphylococcal bacteraemia, one case-controlledstudy identified previous MRSA infection or colonization as thestrongest predictor of HA-MRSA. In this model, previousMRSA infection or colonization, presence of a central venouscatheter, documentation of a skin ulcer or cellulitis at hospitaladmission were all independently associated with HA-MRSAbacteraemia. The model identified 75% of the cases correctlywith a sensitivity of 76% and specificity of 73%.14 In anothercohort study of inpatients with S. aureus bacteraemia, infectionwith HA-MRSA was associated with prior antibiotic exposure(within 60 days of the bacteraemic episode) [OR 9.2 (95% CI4.8–17.9)]; presence of decubitus ulcers [OR 2.5 (95% CI 1.2–4.9)], hospital onset [OR 3.0 (95% CI 1.9–4.9)] and history ofhospitalization within 6 months of episode of infection [OR 2.5(95% CI 1.5–3.8)]. In this model, the clinicians first had toidentify the bacteraemia as community or hospital onset, then,depending on the risk factors of either prior antibiotic exposureand/or decubitus ulcer, an estimate of the risk of MRSA couldbe made. Thus, if the infection was community onset, thepatient had recent antibiotic exposure and had a decubitus ulcer,the likelihood of MRSA is 91%. This model is limited to aspecific cohort of patients from one site, needs broader vali-dation and is applicable only to hospitalized patients with sta-phylococcal bacteraemia. However, these principles may provehelpful in assessing patients in the community.

Recommendation 23

† When managing a patient with a community-onsetSSTI, the possible involvement of HA-MRSA should beconsidered and the appropriate risk assessment done.Recent hospitalization, previous MRSA infection orcolonization, previous antibiotic exposure and the pre-sence of a decubitus ulcer or wound should alert clini-cians to the possibility of HA-MRSA. [D3].

6.3.3 When should specimens be sent for culture?

The early diagnosis and treatment of infection in patients with aStage 3 infected pressure ulcer reduces the risk of complicationsand leads to improved patient outcomes. Knowing the identityand antimicrobial susceptibility of organisms infecting pressureulcers is of help when an antimicrobial treatment has failed,when the presence of a resistant pathogen is suspected or whena patient requires screening for a specific organism.99 Becausethe presence of MRSA will alter the choice of antimicrobialtherapy, it is sensible to culture for MRSA when there is a sig-nificant risk and infection is sufficiently severe to warrant sys-temic therapy. If systemic therapy is not indicated, then there islittle benefit from taking a sample except for infection controlpurposes.

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Recommendation 24

† In an episode of SSTI involving an infected pressuresore or another type of wound infection, a cultureshould be taken if the condition warrants systemic anti-microbial treatment or for infection control purposes.[GPP].

6.3.4 Treatment principles

The principles of antibiotic therapy are as outlined in scenario 1and in the Appendix.

† Give appropriate systemic antibiotic treatment guided bylaboratory susceptibility results.

† Use appropriate topical antimicrobial and dressing care.† Implement appropriate surgical adjunctive management.† Consider the possibility of underlying complications such

as osteomyelitis.

6.3.5 Empirical antibiotic therapy

In the majority of such patients, MRSA will have been isolatedfrom a recent microbiological specimen at the time of the con-sultation and appropriate MRSA treatment can be started. Thistherapy should be guided by susceptibility results.

Recommendation 25

† In cases where empirical therapy is required and thereare significant risk factors for HA-MRSA, the WorkingGroup recommends starting one of the regimens ident-ified in the Appendix after taking appropriate microbio-logical specimens. This therapy should be rationalized inlight of microbiological culture results. [GPP].

† For severe or more progressive SSTIs, there is as yet noconclusive evidence that empirical therapy coveringMRSA leads to improved outcome. However, in severeinfections, where a risk assessment suggests the likeli-hood of HA-MRSA, high-dose empirical therapyagainst MRSA should be used. [GPP].

† Patients with severe infections should be admitted tohospital where skin and blood cultures should be taken,collections drained, tissues debrided as necessary andparenteral antibiotic therapy started. Appropriateinfection control measures should be instigated andurgent consultation made with a local infection special-ist. [GPP].

† For severe infections where HA-MRSA might beinvolved, the Working Party recommends starting thetreatment recommended in the Appendix. [GPP].Wound care should be carried out in the communityunder strict aseptic technique. Hand hygiene is necess-ary before and after direct patient contact.

† For further information relating to isolation, screeningand decolonization, refer to the guidelines for thecontrol and prevention of MRSA in healthcarefacilities.2

HA-MRSA carriage constitutes a greater risk for the develop-ment of S. aureus infection than MSSA carriage.103 The risk

over an 18 month period of MRSA infection among adultpatients harbouring MRSA has been shown to be �29%,104

with 28% of them complicated by bacteraemia and 56% bypneumonia, soft tissue infection, osteomyelitis or septic arthritis.On subsequent admission to hospital, MRSA carriage is associ-ated with an increased risk of sepsis. One study showed that19% of the patients who were MRSA culture positive from anadmission nasal sample subsequently developed infection withMRSA during their hospital stay, compared with 1.5% of casescolonized with MSSA and 2.0% of uncolonized patients.105

Hence, MRSA colonization at admission significantly increasedthe risk of subsequent S. aureus infection compared with MSSAcolonization. There are also data to show that morbidity andmortality are increased with MRSA when compared with MSSAinfections, even when controlling for co-morbidities and otherrisk factors.106,107 This may be related to the increased risk ofinitial therapy not covering MRSA. A significant increase inmortality has been found to be associated with MRSA whencompared with MSSA bacteraemia [OR 1.93; 95% CI 1.54–2.42; P , 0.001].106 MRSA infection may also carry an increasein morbidity related to additional days of treatment requiredresulting in increased hospital stay.107,108 No strong relationshipshave been identified with other morbidity outcomes.109

Thus, HA-MRSA carriage is associated with an increasedrisk of infection and morbidity and mortality. However, no suchdata are available for CA-MRSA. To date, there are no data tosupport the use of agents to eliminate S. aureus colonization inrelation to community MSSA or CA-MRSA SSTIs.

Recommendation 26

† Standard infection control advice should be given topatients with SSTIs due to HA-MRSA. This shouldinclude the importance of dressings management, handdecontamination and the avoidance of transfer of infec-tion by, for example, sharing razors, contact sports etc.

Acknowledgements

The review of this guideline was initiated by the SpecialistAdvisory Committee on Antimicrobial Resistance (SACAR), theDepartment of Health and the HPA. It was undertaken indepen-dently by a Working Party of the BSAC in close collaborationwith the HPA.

Transparency declarations

D. N. declares that during the preparation of this document, hewas not in the employment of any pharmaceutical firm withinterest in the content of the guidelines although he did acceptappointments to the advisory boards of Pfizer, Wyeth, Johnson& Johnson and Novartis, and has spoken at symposia supportedby them.

M. D. has received honoraria for consultation and speakingsymposia from Bayer, Novartis, Arpida and Pfizer.

B. D. C. accepted appointments to the advisory boards ofGlaxoSmithKline, Wyeth and Merck Sharp and Dohme, and hasspoken at symposia supported by 3M.

G. F. has accepted appointments to the advisory boards ofPfizer, Wyeth and Novartis, and has spoken at symposia sup-ported by them.

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R. G. M. has received speaker honoraria from AstraZenecaand Wyeth.

M. M. and D. L. have nothing to declare relevant to thispublication.

Comment on editorial process

This Working Party Report was put out for consultation on11 October 2007 (consultation period closed on 8 November2007) and amended in light of the comments prior to its sub-mission to the journal. This consultation exercise replaced thejournal’s peer review process.

Supplementary data

Tables S1 and S2 show the SIGN system used to grade the evi-dence and recommendations and are available as Supplementarydata at JAC Online (http://jac.oxfordjournals.org/).

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Appendix. Summary of treatment recommendationsfor MRSA infections in the community

Before treating, clinicians may wish to seek advice of a localmicrobiologist.

A. Patients with SSTIs

(a) Follow local guidelines for treating SSTIs, for example flu-cloxacillin or clindamycin for minor SSTI without systemicupset. If the patient is febrile, appears unwell or is toxicwith SSTI, consider assessment in hospital.

(b) Swab the lesion if purulent exudate is present.(c) If MRSA is suspected because of previous colonization/iso-

lation, or surgical/healthcare-related, it is very important tocollect a microbiology sample.

(d) If MRSA is isolated or strongly suspected, treat with:

W Rifampicin* (300 mg po twice daily) PLUS sodium fusi-date (500 mg thrice daily) OR doxycycline (100 mg potwice daily) (doxycycline not recommended for paedia-tric use) for 5–7 days.

W Rifampicin (300 mg po twice daily) PLUS trimethoprim(200 mg po twice daily) for 5–7 days.

W Linezolid† (600 mg po twice daily) following discussionwith Consultant Microbiologist or Infectious Diseasephysician.

*When rifampicin is used please consider drug interactions, e.g.warfarin, methadone, hormone contraceptives, theophylline etc.

†Linezolid is an expensive alternative and may not be readilyavailable at community pharmacies.

Note: if GAS infection is suspected, oral therapy shouldinclude an active agent against this organism (b-lactam or clinda-mycin). Tetracyclines and trimethoprim, although active againstMRSA, are not recommended for suspected GAS infections.

B. Serious and deep-seated MRSA infections

The Working Party recommends that suspected serious anddeep-seated MRSA infections are assessed and treated in hospi-tal. This includes suspected bacteraemia and staphylococcalpneumonia as in Scenario 2. Refer to MRSA treatment guide-lines for more detail.4

B1. For MRSA pneumonia (þ/2 PVL), treat with:

† Linezolid (600 mg intravenous 12 hourly) PLUS clindamy-cin (1.2–1.8 g intravenous 8 hourly) þ/2 rifampicin(600 mg intravenous 12 hourly).

B2. For other deep-seated MRSA infections, such as

bacteraemia, osteomyelitis, abscesses, endocarditis, and

including those infections caused by PVL-producing

CA-MRSA, treat with:

† First-line: Either teicoplanin (400–800 mg intravenousevery 24 h (following loading) or vancomycin (1 g intrave-nous 12 hourly) PLUS one of the following: gentamicin(5–7 g/kg intravenous once daily), rifampicin (300 mg potwice daily) or sodium fusidate (500 mg po thrice daily).

† Second-line: Linezolid (600 mg intravenous/po 12 hourly)† Alternative: Daptomycin (4 mg/kg intravenous once daily).

Licensed for SSTIs, and for bacteraemia and right-sidedendocarditis due to S. aureus.

† Alternative: Tigecycline (100 mg loading dose followed by50 mg intravenous twice daily). Licensed for complicatedSSTIs.

Notes:

(a) Assessment in hospital likely to be required.(b) Bone and joint infections may require a prolonged course of

treatment.(c) Monitor serum vancomycin/teicoplanin and gentamicin

concentrations (for example adjust doses to achieve troughconcentrations for teicoplanin of 10–20 mg/L and forvancomycin of 10–15 mg/L).

C. MRSA in urine

The Working Party believes that while this area is not coveredin a clinical scenario in the text, it is often a frequently encoun-tered clinical problem. The Working Party felt that recommen-dations are warranted to provide guidance for practice in thecommunity.

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† Antibiotics are unlikely to clear MRSA in the presence ofa urinary catheter. There is no good evidence that catheterchanges need to be covered with appropriate antibioticprophylaxis to prevent catheter-related urinary tractinfections.110

† A significant MRSA urinary tract infection with systemicsymptoms and the presence of white cells in the urine is

likely to require systemic antibiotic treatment. [GPP]. TheWorking Party recommends that in patients with normalrenal function (children excluded), doxycycline (100 mgtwice daily) or tetracycline (250–500 mg 6 hourly) shouldbe used. Trimethoprim (200 mg 12 hourly) or nitrofuran-toin (50–100 mg four times a day for 5–7 days) could bealternatives.4

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Guidelines (2008) for the prophylaxis and treatment of meticillin-resistant 1 Staphylococcus aureus (MRSA) infections in the United Kingdom 2 3 F. Kate Gould1, Richard Brindle2, Paul R Chadwick3, Adam P Fraise4, Simon 4 Hill5, Dilip Nathwani 6, Geoff L Ridgway7, Michael J Spry1, Rod E Warren 8 5 For the BSAC/MRSA Working Party 6 7

1 Department of Microbiology, Freeman Hospital, Freeman Road, High Heaton, 8 Newcastle upon Tyne NE7 7DN Portsmouth 9 2 Department of Microbiology, Queen Alexandra Hospital, Portsmouth PO6 3LY 10 3 Department of Microbiology, Salford Royal Hospital, Salford M6 8HD 11 4 Department of Medical Microbiology, City Hospital NHS Trust, Dudley Road, 12 Birmingham B18 7QH 13 5 Department of Microbiology, Poole Hospital, Longfleet Road, Poole BH15 2JB 14 6 Infection Unit, Ninewells Hospital and Medical School, Dundee DD1 9SY 15 7 Department of Health, Wellington House, 133-135 Waterloo Road, London SE1 16 8UG 17 8 Department of Microbiology, Royal Shrewsbury Hospital, Mytton Oak Road, 18 Shrewsbury SY3 8XQ 19 20 1. Introduction 21

22 Staphylococcus aureus infections are casting an increasing burden upon the UK 23 healthcare economy (1). Guidelines for the control of meticillin- resistant 24 Staphylococcus aureus (MRSA) infection in the UK have been previous published by 25 a joint Working Party of the British Society of Antimicrobial Chemotherapy (BSAC), 26 and the Hospital Infection Society (HIS) in 1986(2), 1990 (3), and together with the 27 Infection Control Nurses’ Association (ICNA) in 1998 (4). In 2006, a revised 28 guidelines concentrating on prophylaxis and treatment of MRSA infections was 29 prepared by the joint Working Party (5) and it is these guidelines we have updated to 30 take account of new antibiotics and information. This revision does not repeat all the 31 considerations of previous guidelines but includes revised opinion and new 32 information and a summary of continuing and new recommendations. More specific 33 guidance related to diagnosis and treatment of community onset and acquired MRSA 34 has also recently been published (6). Where available, the Working Party has also 35 considered information on unlicensed compounds in Phase 3 clinical trials. In the 36 implementation of any guidelines an assessment of the economic value or impact of 37 the proposed therapy for a healthcare setting is deemed increasingly important (7). In 38 our guidance we have not reviewed the literature related to this and therefore are not 39 able to give any guidance related to this. We suggest that local policy makers decide 40 on the resource implications of some of the therapies recommended in this guidance. 41 42 For this update of the guidelines, literature searches of the following databases were 43 conducted in August 2007: Medline, Embase, Cochrane Library (issue 3, 2007), and 44 Science Citation Index Expanded. For these searches, MeSh and Emtree Subject 45 1 2 3 4 5

headings relevant to MRSA were used together with free text terms, and a total of 46 3398 records were retrieved and assessed for their relevance by members of the 47 Working Party. Additional recommendations for references were also made by 48 members of the Working Party. 49 50 The recommendations made in these guidelines are followed by the same category 51 classification indicating the level or strength of evidence supporting the 52 recommendation as in the previous guidance. The category given is taken from the 53 evidence grades of the Healthcare Infection Control Practices Advisory Committee, 54 Centres for Diseases Control and Prevention’s (CDC).(8) Each recommendation is 55 categorised on the basis of existing scientific data, theoretical rationale, applicability 56 and economic impact. The categories are: 57 58 1A: Strongly recommended for implementation and strongly supported by well-59 designed experimental, clinical or epidemiological studies. 60 1B: Strongly recommended for implementation and supported by certain 61 experimental, clinical or epidemiological studies and a strong theoretical rationale. 62 1C: Required for implementation, as mandated by federal or state regulation or 63 standard or representing an established association standard 64 II: Suggested fo r implementation and supported by suggestive (non-definitive) clinical 65 or epidemiologic studies or a theoretical rationale. 66 Unresolved issue: No recommendation is offered. No consensus reached, or 67 insufficient evidence exists regarding efficacy. 68 The use of alternative agents for patients who are either hypersensitive to, or 69 intolerant of, first line agents has not been comprehensively addressed since there is 70 usually insufficient evidence or indication of which agent should be used. 71 Nevertheless, the wide choice of agents included in these guidelines gives some 72 indications of potential appropriate choice, if antimicrobial susceptibility data are 73 taken into account. 74 75 There has been a major attempt in recent years in the UK to reduce cases of MRSA 76 bacteraemia by setting targets for hospitals. Some measures have been specifically 77 aimed at bacteraemias and their common causes such as line sepsis and some aimed at 78 general cross infection measures but with the exception of ‘screen and treat’ carriage 79 programmes, no advice touching on therapy has been issued. MRSA presenting from 80 the community is sometimes associated with silent acquisition previously in the 81 healthcare environment (9;10), or household contacts (11), and one study suggests that 82 silent acquisition is associated with in-patient care for more than 5 days within the last 83 year (12). There is also a less common emerging UK problem, more widespread in 84 some parts of the USA and Europe, of truly community acquired MRSA with Panton-85 Valentine leucocidin (13-16)and elsewhere but not yet in the UK, spread of these strains 86 in hospital confuses a previously straightforward epidemiological and therapeutic 87 picture. Once established within hospitals or long-term care centres, any MRSA is 88 difficult to control and its survival is probably promoted by the increasing use of 89 antibiotics, (17;18) although the Society for Healthcare Epidemiology of America 90 (SHEA) in a careful analysis of potential interventions did not quote any specific 91 example of successful general control by antibiotic policy. (19) 92 93 Selection of new clones of MRSA may follow changes made in usage in antibiotic 94 prophylaxis and treatment. The time course for evolution and spread of an antibiotic-95

resistant strain is not well-described, but antibiotic use needs to adapt in a timely 96 fashion to both national and sometimes local changes in prevalence of resistance. 97 Overall, antibiotic use in the UK resembles that in low-MRSA-prevalence countries 98 such as Finland. (20) Reversion to the use of first generation cephalosporins in 99 surgery,(21) reduced use of third-generation cephalosporins and clindamycin, (22) and 100 reduced use of ceftazidime and ciprofloxacin (23) have been described as contributing 101 to reduced prevalence of MRSA in different hospitals. Reduced rates with modified 102 antibiotic policies in healthcare settings smaller than whole hospitals are described but 103 difficult to evaluate.(24-26) High usage of cephalosporins (27-30) and fluoroquinolones (29-37) 104 apparently have been important in selecting for MRSA in some settings, as has use of 105 macrolides, penicillins and to some extent aminoglycosides (38) but the evidence was 106 not conclusive. Quinolone use has been associated in one study with prolongation of 107 MRSA carriage. A recent report using the UK GP Research database showed that 108 community acquired MRSA in the UK was associated with quinolone or macrolides 109 use in the previous year. (39) Latest SHEA guidelines lay emphasis on good antibiotic 110 stewardship and specifically that for fluoroquinolone use. (40) Changes in overall 111 antibiotic usage advocated to reduce C.difficile infections would not be expected to 112 have as much effect on MRSA characteristics but changes in the specific classes of 113 agent used and the widespread use of mupirocin in ‘screen-and-treat’ programmes 114 require careful monitoring for their effect on MRSA resistance. 115 116 Reduced use of an antibiotic has also coincided in the past with elimination of certain 117 clones resistant to the drug and these referred to in previous guidance continue to have 118 current relevance e.g. the reduced use of tetracyclines in the 1970s was associated 119 with reductions in tetracycline-resistant MRSA in Denmark and Birmingham. (41;42) 120 However, this was not conclusive as additional interventions such as infection control 121 measures may have confounded the association. Antibiotics that achieve high skin 122 concentrations include fluoroquinolones, macrolides, tetracyclines and clindamycin. 123 Information on the value of restriction of the use of these compounds in particular in 124 diminishing MRSA selection is scanty but their role in selecting for resistant 125 Staphylococcus epidermidis is well recognised especially with quinolones. (43; 44) This 126 may be important for MRSA selection given the extensive use of macrolides, and 127 licensing of fluoroquinolones, for the treatment of respiratory tract infection, and 128 widespread susceptibility to tetracyclines of MRSA currently in the UK. Guidelines 129 for appropriate antibiotic use in COPD and pneumonia in the UK are overdue for 130 change to take account of wider availability of diagnostic tests for pneumococci and 131 Legionella and a greater emphasis on support measures and less on treatment of 132 Haemophilus influenzae in COPD. 133 134 The appearance of strains of MRSA with raised MICs and clinical resistance to 135 vancomycin and teicoplanin is a cause for concern because the use of more expensive 136 and less familiar new agents could be driven by the emergence of such resistance. The 137 presence of the VanA gene in some cases suggests transfer from other Gram-positive 138 organisms (45;46) but most isolates are resistant by non-transferable mechanisms.(47) The 139 number of cases of vancomycin resistant and intermediate resistant S. aureus in the 140 UK and internationally remain low despite alarm at their initial emergence. (48) 141 However, there is no new, comprehensive or adequate national information or 142 surveillance on the prevalence of heteroresistant GISA strains or on the ‘creep’ 143 upwards in vancomycin MICS and the impact of such changes on the comparative 144 outcome of treatment. European information on such strains remains patchy (49;50). No 145

new information is available on methods for detection of such strains and no routine 146 changes have been made to laboratory practice and BSAC susceptibility testing 147 guidance to reflect a reduction in CLSI reductions in the vancomycin breakpoint. 148 There is no new information since their description in 2002 on spread of teicoplanin-149 resistant MRSA including EMRSA -17. (51;52) Vancomycin treatment failures occur 150 with strains apparently susceptible in vitro. (53-55) Infections with susceptible strains 151 with MICs >=1mg are said to be more likely to fail on vancomycin therapy than those 152 susceptible strains with MIC <1mg/L. This is associated with Group2 polymorphism 153 at the accessory gene regulator. (56; 57) It is important to note that in the original report 154 treatment failure was not associated with changed 30 day mortality but this may 155 reflect changed treatment after vancomycin failure. This poor response has been 156 confirmed in a study in renal unit S.aureus bacteraemia where previous vancomycin 157 use was a risk factor for raised vancomycin MICs (58), but this subject has not been 158 prospectively studied. There is data that even high dose vancomycin treatment does 159 not improve the prognosis in renal patients which may suggest poor outcome is 160 related to other biological factors (59). It might suggest that other treatment should be 161 used for MRSA infections with MICs between 1 and 4mg/l and therefore that 162 vancomycin MICs should always be measured for MRSA treated with this drug. 163 However, routine substitution of other agents may not necessarily be the appropriate 164 response. A recently reported study of S.aureus bacteraemia and endocarditis 165 indicated that daptomycin resistance was more likely to emerge at the trial dosage 166 with strains with heteroGISA phenotypes, so trial information is essential in this area 167 with cell wall and membrane active agents. The absence of improved response with 168 high plateau vancomycin levels of 20-25mg/l suggest that increasing the dose of the 169 drug and accepting that higher serum levels are needed for treatment is not necessarily 170 an appropriate response to the heteroVISA resistance phenomenon(60). Examination of 171 data stratified on vancomycin trough levels and AUV did not differ between survivors 172 and non survivors in one study of healthcare-acquired pneumonia due to MRSA (61) 173 and accepting that higher serum levels are needed for therapy. Alternative higher 174 dosing schedules have not been specifically trialled attached for improved efficacy in 175 heteroGISA MRSA infections and there are emerging reports of increased renal 176 impairment associated with vancomycin levels in excess of 15mg/l although it is not 177 clear which is cause and which is effect (62). Mortality associated with MRSA 178 bacteraemia has been found to be significantly higher when vancomycin was 179 empirically used to treat strains with a high vancomycin MIC (>1mg/l) (63). 180 Meanwhile, the rationale for the Clinical and Laboratory Standards Institute’s 181 decision to change vancomycin breakpoints to 2mg/l as indicating susceptibility has 182 been reviewed and includes 14 cases of treatment failure where the vancomycin MIC 183 was 4mg/l. (64). 184 185 Mortality rates with MRSA are higher than MSSA in most studies and this appears to 186 be attributable mortality in a meta-analysis, (65) but the difficulty of interpretation is 187 that MRSA infection is usually acquired in hospital, when other cofactors of illness 188 that require a hospital stay are present and so mortality may not be due to the 189 antibiotic resistance per se. (65-72) A recent study confirms this effect of comorbidity 190 (Charlson score) and previous hospitalisation to outcome(73;74). UK information on 191 outcome in MRSA and MSSA bacteraemia using record linkage has also been 192 published (74). We referred in previous guidance to 2 studies that the relatively short 193 period of up to 48 hours delay in switching from beta- lactam antibiotics to appropriate 194 therapy for meticillin- resistant strains, does not affect outcome. (75; 76) Previous 195

guidance of a step-down approach to S.aureus infection was accepted (77) but there is 196 little audit information that vancomycin use empirically or in meticillin-susceptible 197 S.aureus infection is being reliably implemented in the UK. The use of initial anti- 198 MRSA treatment may become less relevant in institutions which have achieved 199 excellent control of serious MRSA infection and it will become increasingly 200 important to ensure that step-down is actually being followed. 201 202 For meticillin-susceptible S.aureus (MSSA), we reiterate our advice that flucloxacillin 203 or cloxacillin are preferable agents and they are available orally for when this is the 204 preferred route of administration. These drugs are safer and have higher cure rates 205 than glycopeptides for susceptible strains in patients with bacteraemia and infection in 206 respiratory primary sites. (67; 78) Other factors including acute physiological score have 207 been shown to be important in predicting mortality in bacteraemia overall.(76; 79) Good 208 control of diabetes mellitus, drainage of abscesses and particularly removal of sources 209 such as intravenous lines, (80) are important in predicting outcome. The reasons for use 210 of B- lactams are overall patient safety, convenience and cost, rather than survival, but 211 the higher relapse rate in patients with meticillin-susceptible S.aureus infections 212 treated with vancomycin means that B- lactams are preferable agents if the infecting 213 strain is susceptible (81-83). It is notable but unexplained that such studies contain a 214 preponderance of patients with renal impairment. The use of flucloxacillin or 215 cloxacillin, when appropriate, in these patients is particularly emphasised. 216 Nevertheless, overall 30-day mortality rates in patients treated with glycopeptides, or 217 B-lactams for MSSA staphylococcal bacteraemia, were similar in two studies. (68; 79) 218 There are few data comparing cloxacillin or flucloxacillin to nafcillin or other 219 penicillinase-resistant penicillins, and little reason to expect differences in efficacy. 220 221 Flucloxacillin or cloxacillin are still important agents for treatment of staphylococcal 222 infection in patients in the community but not in environments with a high prevalence 223 of MRSA e.g. some areas of hospitals. Flucloxacillin is the drug of choice for 224 definitive treatment of MSSA in the UK and is also preferred for empirical therapy 225 except in situations where MRSA is highly prevalent. 226 227 The prevalence level at which flucloxacillin or other penicillinase-stable 228 penicillins, in a patient group, becomes no longer the drug of choice is debatable, 229 our previous recommendation of a 10% resistance rate was thought to be too low 230 and the precise level is controversial and would depend on relative mortalities in 231 MSSA and MRSA infection, the severity of the infection and their accurate 232 categorisation as hospital or community acquired. 233 234 Recommendation 1 235 Despite there being little available data, extrapolating from urinary tract 236 infections a threshold of 10-20% or greater may be a useful indicator when 237 contemplating treatment of staphylococcal infections with isoxazolylpenicillins or 238 cephalosporins (84;85).(II) 239 240 Recommendation 2 241 Step-down therapy from an agent that encompasses MRSA to flucloxacillin if the 242 strain proves to be flucloxacillin susceptible is a safer process than the 243 alternative of escalation therapy, unless the proportion of hospital acquired and 244

community-acquired MRSA infections is known to be very low as established by 245 local surveillance which is now well established in the UK. (II) 246 247 2. Prevalence of antibiotic resistance in MRSA in the United Kingdom 248 249 The Working Party has reviewed recent data on the prevalence of antibiotic resistance 250 within MRSA infection in the UK. There remains a relative lack of data and good 251 quality systematic surveillance is needed. In the previous guidelines we included data 252 from bacteraemia surveillance from 2001-3. Data from this ongoing surveillance 253 project in 23 UK laboratories are now available for 2004-6 and indicate resistance to 254 ciprofloxacillin in 96% of isolates, erythromycin in 77%, trimethoprim in 21%, 255 gentamicin in 6%, tetracycline in 3%, sodium fusidate in 8% and rifampicin in 1%.(86) 256 257 Mupirocin testing has only recently been added to the above panel: mupA was 258 detected in 5 MRSA isolates in 2006 (87), giving a resistance rate of approximately 5% 259 based on a small sample. We do, however, appreciate that other resistance 260 mechanisms exist. 261 262 3 Use of glycopeptides 263

In the UK vancomycin has been widely used as parenteral treatment. Clear guidelines 264 on the overall use of glycopeptides are required in hospital. The national guidelines 265 for the judicious use of glycopeptides in Belgium provide a useful basis for 266 discussion. (88) 267 268 Recommendation 3 269 We continue to endorse the specific areas of the Belgian recommendations on use 270 of glycopeptides for severe MRSA infection, except in the circumstances below 271 where we commend early use of an agent active against MRSA: 272 273

a. Surgical prophylaxis where the local epidemiology of antibiotic resistance 274 in staphylococci also influence choice of agents. (II) 275

b. Neutropenic sepsis if there is severe line infection and the patient has 276 previously had cultures positive for MRSA. 277

278 279 4. Skin and soft tissue infections (SSTI) 280 281 4.1 Impetigo and boils 282 Impetigo and boils are usually community acquired. The prevalence of community 283 acquired MRSA infections in the UK is not systematically surveyed. (89) Incidence 284 data from the General Practice Research Database for the period 2000 to 2004 285 estimated an average incidence of adult MRSA infection or colonisation of 15.2 per 286 100,000. (39) The definition of community acquired was a patient with no 287 hospitalisation within the past 2 years and no previous diagnosis of MRSA. 288 289 The use of topical agents for the treatment of impetigo has been reviewed (90). All the 290 trials indicate that topical mupirocin is as effective as oral erythromycin and has fewer 291 systemic side effects. The studies did not focus on MRSA. The conclusion was that 292

topical mupirocin is the first treatment of choice in systemically well children with 293 impetigo. (91; 92) 294 295 Recommendation 4 296 Impetigo should be treated with topical mupirocin, where the isolate is 297 susceptible. [Level 2 – Studies considered were either 1 or 3.] 298 299 There is no UK wide surveillance of MRSA antibiotic susceptib ilities other than 300 MRSA bacteraemia. There is evidence that antibiotics are unnecessary and that 301 drainage of small (<5 cm diameter) boils is adequate. (93) 302 303 Recommendation 5 304 Incision and drainage of small abscesses that are without cellulitis and antibiotic 305 therapy is not generally required. 306 307 308 4.2 Ulcers and sores 309 Colonisation is more common than infection. Occasionally colonised ulcers may 310 require systemic therapy as part of eradication therapy. Treatment is also required if 311 there is evidence of cellulitis, contiguous osteomyelitis (see below) or bacteraemia. 312 Special consideration should be made for foot ulcers in diabetics as colonisation may 313 rapidly progress to infection. 314 315 4.3 Cellulitis/surgical site infections 316 An open label prospective comparative study in the United States demonstrated the 317 efficacy of doxycycline or co-trimoxazole in outpatient or community skin and soft 318 tissue infections with MRSA and demonstrated equivalence between the agents. (94) 319 However, the number of evaluable patients was small and there has been no new 320 information on these older antibiotics. An open labelled randomised multicentre 321 international study comparing linezolid with vancomycin has reported marginally 322 improved clinical and microbiological outcomes with linezolid in a subset of patients 323 with proven MRSA skin and soft tissue infections (95). In a follow up study designed 324 to seek superiority (LEAPS presented at ECCMID 2008) did not confirm superiority 325 in the ITT population. Other agents, for example, clindamycin or macrolides could be 326 considered if the isolated organism is sensitive. 327 328 Recommendations for non-hospitalised patients 6 329

a. Doxycycline or clindamycin dependent on susceptibility tests could be 330 considered (including a D test for clindamycin resistance on erythromycin 331 resistant strains) unless the infections are considered severe and/or carry 332 a high risk of bacteraemia or endocarditis. [Category 1B]. 333

b. In strains of MRSA resistant to doxycycline or clindamycin, glycopeptides 334 or linezolid should be used or the use of cotrimoxazole could be 335 considered bearing in mind the hazards of sulphonamide allergy. 336

c. Outpatient parenteral therapy with glycopeptides or daptomycin may 337 offer a cost-effective option in moderately severe infections where 338 continuing IV therapy is deemed necessary. [Category 1C](96) 339

340 The possible superiority of linezolid in patients with proven complicated MRSA skin 341 and soft tissue infections, its availability as an oral agent with a high bioavailability 342

may also facilitate early hospital discharge and provides another cost-effective 343 alternative where appropriate. 344 345 There are a number of new agents licensed for SSTI. Since our last recommendation, 346 two agents (daptomycin and tigecycline) have been licensed for the treatment of SSTI 347 and studies published and analysed (97;98). Clinical trials with other new as yet 348 unlicensed agents such as ceftibiprole, ceftalorine, telavancin and dalbovancin have 349 also been reported. All of these studies have been powered for equivalence with 350 variable end points. 351 352 Recommendation 7 353 We presently cannot make any recommendations on the use of these new licensed 354 agents based on their efficacy alone and relatively early ‘real world’ clinical 355 experience. However we note that all of these agents have the limitations and 356 advantages of parenteral therapy, and should be regarded as alternatives in clinical 357 situations where other agents are deemed inappropriate or failing. Such factors 358 include the type and severity of infection, ease of administration, beta- lactam 359 hypersensitivity, clinical failure or poor response, resistance, poor tolerability, 360 duration of therapy, cost and so on which may or may not be needed depending on 361 severity and likely failure to take unsupervised oral regimens would be needed. Since 362 the last guidelines were published, a separate set of guidelines devoted to community 363 onset MRSA have been published (6). Although we accept that there may be 364 differences in recommendations, these differences can be explained by the difference 365 in emphasis between community treatment of minor infection in the community and 366 serious infection in a hospital setting. 367 368 Recommendations for hospitalised patients 8 369 A. Glycopeptides, linezolid or daptomycin should be considered for use in 370 hospitalised patients with severe skin and soft tissue infection and/or where the 371 risk of bacteraemia is high. [Category 1A] Linezolid may provide marginally 372 greater effectiveness compared with glycopeptides in this patient population 373 [Category 1B]. If the infection is deemed polymicrobial and where MRSA is 374 considered to be an important pathogen, tigecycline may be considered as an 375 alternative. [1B] 376 377 B. In the absence of clinical trials on the use of combination therapy, owing to 378 the risk of additive toxicity, we are unable to make any recommendations. In the 379 light of the availability of newer agents to treat SSTI with low incidences of 380 unwanted effects, and previous reports (Cox et al) of an unwanted effect rate of 381 15-20% with this combination we no longer think the recommendation to use the 382 combination of rifampicin and fusidic acid is justifiable. 383 384 C. For clinical treatment failure with glycopeptide monotherapy, we are unable 385 to make a recommendation between adding a second antistaphylococcal agent 386 such as doxycycline or rifampicin or fusidate or monotherapy with linezolid or 387 daptomycin. A meta-analysis has also suggested that linezolid may be superior to 388 glycopeptides for Gram positive infections in SSTIs and bacteraemia (99). 389 390 We recommend that clindamycin be considered for use in treatment of MRSA 391 susceptible to erythromycin (which will be clindamycin susceptible) because 392

emergence of clindamycin resistance requires two mutations and its 393 bioavailability is superior. In erythromycin resistant strains susceptibility using a 394 D test should always be performed rather than use of a clindamycin disc alone. 395 Patients should be warned of the risk of C.difficile and the necessity to cease 396 treatment and seek medical attention if they develop diarrhoea. Vigilance for 397 clindamycin-associated C.difficile diarrhoea should be maintained if its use is 398 encouraged as it is not clear a change in the likelihood of C.difficile being 399 associated with this antibiotic has occurred. 400 401 4.4 Intravenous infusion sites 402 403 Recommendation 9 404 Having reviewed the evidence since our last published guidelines, we see no 405 reason to change our recommendation that intravenous antibiotics are used in 406 cases of severe intravenous site infection associated with severe induration, 407 cellulitis or bacteraemia and in such cases a glycopeptides or linezolid should be 408 prescribed. Mild infections may respond well to oral agents. [Category 1B] 409 410

5. Urinary Tract Infections 411 412 Oral agents are usually appropriate fo r treatment of MRSA including the lower UTI 413 antiseptic nitrofantoin and if susceptibility in in vitro tests is confirmed, tetracycline 414 or trimethoprim. The higher resistance rate reported for trimethoprim in laboratory 415 surveillance has been maintained (21% vs. 3% for tetracyclines). In complicated 416 situations especially involving surgical sepsis new agents offer an alternative to 417 glycopeptides. Daptomycin is a potential unlicensed agent for the treatment of urinary 418 tract infection (UTI) caused by MRSA. Studies of in vitro activity of daptomycin 419 against Gram positive pathogens causing complicated urinary tract infections have 420 shown all the strains, including MRSA, to be susceptible with MICs up to 2mg/l (100) 421 and daptomycin used to treat complicated UTI due to Gram positive bacteria had 422 bacteriological eradication rates of 83% and clinical success rates of 93%.(101) 423 424 Most excretion of daptomycin is via the kidney with 80% urine recovery of the total 425 dose, two thirds as intact drug. (102). 426 427 Tigecycline may not achieve adequate concentration in urine to treat complicated 428 UTI. Only 8-11% of the drug is excreted in urine as unchanged drug over 48 hours. 429 (103) There are no published studies of its efficacy in treating UTI due to MRSA. 430 431 Approximately 65% of the total clearance of linezolid is non-renal and of the drug 432 excreted in urine only 30% is as the parent drug (summary of Product Characteristics, 433 Pfizer, February 2007). There is no published data regarding the use of linezolid in 434 UTI. 435 436 Quinupristin-dalfopristin similarly is only partially excreted in urine (104) with no 437 published data of its use for UTIs. 438 439 Recommendation 10 440

For simple UTI an oral agent (nitrofuratoin, trimethoprim, cotrimoxazole or 441 tetracycline) should be considered according to in vitro sensitivity (II). For 442 complicated UTI glycopeptides should be considered. (II) 443 444

6. Bone and Joint Infection 445 446 Of the newer agents, daptomycin has demonstrated to be effective in a limited number 447 of cases (105) series and in animal models (106). It is well released from 448 polymethylmethacrylate (PMAA) cement incorporation (107). There is animal model 449 data for tigecycline (108;109) which suggests it is effective alone or in combination with 450 rifampicin. 451 452 The management of bone and joint surgery is complicated and must involve a 453 multidisciplinary approach. Choice of antibiotics in these circumstances will depend 454 on the surgical management plan. 455 456 Two medium sized studies on the prolonged use of linezolid, sometimes only as one 457 antibiotic amongst others, in patients with prosthetic joint infections and chronic 458 osteomyelitis including some patients with MRSA. In one series (110) 21 out of 66 459 patients developed reversible anaemia requiring transfusion in 16 cases after a median 460 time of 7.3 weeks’ treatment (range 4-12 weeks) and 6 developed peripheral 461 neuropathy of whom 4 remained symptomatic after 24 months. In the other series,(111) 462 5 out of 51 developed thrombocytopenia and 5 out of 51 developed anaemia and a 463 further patient developed reversible optic neuropathy and irreversible peripheral 464 neuropathy after 24 months linezolid therapy. The manufacturers recommend that 465 courses of therapy should not exceed 4 weeks. Nevertheless these infections are 466 difficult to treat even with the necessary surgery and initial reports of short term 467 successes including these, (112) are important. However, should it be clinically relevant 468 to provide treatment for longer then it is important to monitor liver function. 469 The Working Party considers that oral linezolid has a place in the follow-on treatment 470 of bone and joint infections with MRSA after appropriate surgery although this is not 471 a licensed indication for the drug but with weekly monitoring of full blood count and 472 platelets for signs of bone marrow suppression, with short duration therapy 473 neuropathy should not be a problem. 474 Further large-scale formal studies in patients fully categorised as prosthetic joint 475 infection or prosthetic joint infection with or without retained metalwork are required 476 before firm recommendations on extended linezolid use can be made. 477 478 Recommendation 11 479 The choice of antibiotic therapy for MRSA bone and joint infection should be 480 based on a multidisciplinary approach. More trials in this area of single new 481 agents are underway and welcomed. Until these areas can be assessed, our 482 previous recommendation to use parenteral glycopeptides with or without 483 adjunctive agents such as rifampicin or sodium fusidate as initial parenteral 484 therapy still stands. Unwanted effects, the patient’s desire to be out of hospital, 485 the extent of debridement and removal of metalwork will affect the duration of 486 treatment and use of oral follow-on agents. There is no evidence that any single 487 agent or combination is superior. (II) 488 489

7. Bacteraemia and endocarditis 490

491 There is a single controlled comparative study evaluating daptomycin for the 492 treatment of staphylococcal bacteraemia and endocarditis which demonstrated 493 equivalence with the comparator. (113) However, in this study the failure rate for both 494 arms was surprisingly high and probably related to the protocol definitions requiring 495 late follow-up blood culture before the patient could be deemed a success as distinct 496 from improved. The emergence of daptomycin resistant strains was documented in 497 5% of treated cases but toxicity was minimal compared with the comparator arms 498 where vancomycin use or use of isoxazoyl penicillin with gentamycin was associated 499 with nephrotoxicity. Outcomes for left sided endocarditis were disappointing with 500 daptomycin. Open studies in endocarditis reported from a data registry have not 501 confirmed the poor outcomes in left sided endocarditis (114;115). Preliminary experience 502 with 23 cases of MRSA endocarditis has been reported with limited successes (116). 503 Many cases have received rifampicin and/or gentamicin in combinations. 504 505 For suspected PVL infections, either linezolid or clindamycin should be considered 506 since both have been show to modify the expression of Panton-Valentine leucocidin 507 (PVL) in vitro. (117) 508 509 Recommendation 12 510 A minimum duration of 14 days’ treatment with glycopeptides or linezolid for 511 uncomplicated bacteraemia. Longer treatment will be required in patients with, 512 or at higher risk of, endocarditis, and transoesophageal echocardiographic 513 assessment is important. The manufacturer’s recommendation of a 4 week limit 514 on linezolid treatment and adverse effects previously referred to may limit use of 515 this agent (see above). Daptomycin could be considered as an alternative (II). 516 517 518

8. Respiratory tract infection 519 520 Of the new agents daptomycin is inactivated by lung surfactant and therefore not 521 recommended in the management of respiratory tract infection. There are as yet no 522 data for tigecycline or anti-MRSA cephalosporins demonstrating superiority or even 523 equivalence. Our analysis of the lack of convincing evidence for the superiority of 524 linezolid over glycopeptides in MRSA HAP and AVAP has not changed since the last 525 guidelines. Although we accept there is evidence of equivalence in trials, cost, the 526 apparently unique appearance of a novel plasmid-mediated linezolid resistance 527 mechanism in MRSA (118) and descriptions of an outbreak of linezolid resistant 528 Staphylococcus epidermidis in an intensive care unit with a heavy usage (119)and of 529 linezolid- and vancomycin-resistant enterococci including in intensive care units (120-530 122) all need to be taken into account and heavy usage of either agent may be unwise. 531 The use of antibiotics for MRSA in patients with bronchiectasis, bronchitis or COPD 532 and the significance of these isolates has not been supported by clinical trial although 533 there are anecdotal reports that they are significant. Making a recommendation for 534 treatment is difficult. Sputum penetration of glycopeptides is likely to be poor. 535 Tigecycline is not currently licensed for respiratory tract infections. 536 537 Recommendation 13 538

Infections in patients with bronchiectasis or chronic suppurative lung disease 539 without pneumonia, where MRSA is deemed significant, should be treated with 540 non-glycopeptide agents (II). 541 542 It is recognised that PVL positive strains of MRSA can cause severe necrotising 543 pneumonia in the community. In these circumstances there is some in vitro evidence 544 that staphylococcal toxin production can be suppressed by both clindamycin and 545 linezolid, As recommended in the recent published guidelines on community onset 546 and acquired MRSA we recommend that either linezolid, or if erythromycin sensitive, 547 clindamycin should be included in therapy (6). 548 549 We recommend that particular care be taken to improve the certainty of diagnosis of 550 lower respiratory tract infection as distinct from colonisation. 551 552 Recommendation 14 553 Glycopeptides or linezolid for pneumonic infections where MRSA is the 554 aetiological agent. [Category 1A] 555 556

9. Eyes and CNS infections 557 558 The limited published data suggest that linezolid may be considered for the treatment 559 of patients with meningeal or cerebral infections. (123) The evidence of good 560 penetration into the eye and the relative toxicity of acidic vancomycin in delicate 561 tissues mean that comparative assessment of linezolid in Gram positive eye infections 562 in animals is overdue to permit formulation of appropriate human trials in deep eye 563 infections. 564 Animal datum suggests that daptomycin may have some advantages over vancomycin 565 owing to its superior bactericidal activity but there are no dosing recommendations or 566 human data to support this. (124) 567 568 Recommendation 15 569 There is insufficient evidence to make a specific recommendation in deep eye and 570 CNS infection. [Category Unresolved issue] gentamicin, sodium fusidate or 571 chloramphenicol may be used for superficial eye infections if the strain is 572 susceptible. [Category 1B]. 573 574 575

10. Elimination of carriage 576 577 We have not encountered new studies which bear on this topic extensively discussed 578 in previous guidelines. 579 There continues to be very limited data available regarding the use of oral 580 vancomycin as prophylaxis or as part of clearance regimens for MRSA. A study 581 showed that a short course of oral vancomycin plus intranasal mupirocin eradicated 582 MRSA in 69% (N=24) of patients and staff after one course. (125) However, 11 required 583 further treatment and 80% (N=28) reported side effects, consequently there is 584 insufficient evidence to recommend this regimen. 585 586 587 Clearance of enteric carriage 588

589 There are studies which examine the use of enteral vancomycin to prevent MRSA 590 infection in intensive care units (ICU). (126; 127) Lower airway infection and 591 oropharyngeal carriage were reduced in the treatment groups compared to controls. In 592 addition, enteral vancomycin has been used to control an MRSA outbreak in ICU. (128) 593 Despite multiple trials on its use we remain concerned regarding the potential 594 selection for resistant Gram positive organisms including enterococci and 595 staphylococci and do not support its regular use. 596 597 If treatment and clearance of mupirocin-susceptible MRSA in patients with carriage 598 or where it is uncertain if there is a soft tissue lesion, we recommend that mupirocin 599 should be used with a systemically active agent to improve clearance rates beyond 600 those achieved with nasal or topical mupirocin alone. For mupirocin-resistant strains 601 there are no trials to assess efficacy. A range of agents has been used topically but 602 emergence of resistance to topical antibiotics is well documented.(129) With mupirocin-603 resistant MRSA in soft tissues and other potentially infected sites and given high rates 604 of unwanted effects necessitating treatment withdrawal with rifampicin and sodium 605 fusidate in combination (Cox et al), of clearance failure and neomycin resistance with 606 naseptin alone, we believe similar treatment principles of using a systemically active 607 agent with a nasal cream containing an antibiotic that is active against the strain 608 should also be applied. 609 610 An association between usage of mupirocin and resistance rate has been 611 demonstrated.(130) Wider use of screening and consequent decontamination has been 612 recommended in the UK. An active local and national programme for monitoring high 613 and low level resistance using a validated method is therefore essential not only in 614 bacteraemia but also other infections as the preva lence of particular types of MRSA 615 may change under selective pressure. 616 617 Recommendation 16 618 We do not recommend the use of oral vancomycin as prophylaxis or part of 619 clearance regimens for MRSA. In soft tissue lesions, clearance of MRSA should 620 include a systemically active oral or parenteral agent as well as an active nasal 621 cream such as mupirocin. With increased use of mupirocin, mupirocin resistance 622 may become a problem and resistance should be carefully monitored at a locality 623 level. 624 625

11. Surgical site infection prophylaxis 626 627 Recommendation 17 628 We see no reason to change our recommendation that patients who require 629 surgery and have a history of MRSA colonisation or infection without 630 documented eradication receive glycopeptides prophylaxis alone or in 631 combination with other antibiotics active against other potential pathogens. The 632 use of glycopeptides may also be considered if there is an appreciable risk that 633 patients’ MRSA carriage may have recurred or they come from facilities with a 634 high prevalence of MRSA. 635 We recommend that the use of aminoglycosides be reassessed in patients not 636 expected to have MRSA colonisation for prophylaxis of staphylococcal infections 637 (II) 638

639 Agent Use as

Monotherapy?

Key indications

Unwanted effects

Comments

Aminoglycosides No Use in prophylaxis

Ototoxicity especially in renal impairment. Nephrotoxicity, especially when used with vancomycin

Chloramphenicol Yes CNS infections

Rare cause of marrow aplasia

Clindamycin Yes Skin and soft tissue infections. Bone and joint infections

Clostridium difficile colitis and antibiotic-associated diarrhoea

Evidence of efficacy as sole agent against strains with macrolide resistance but risk of emergence of resistance

Co-trimoxazole Yes Skin and soft tissue infections; eradication therapy in combination

Stevens Johnson syndrome and marrow hypoplasia associated with sulphonamide usage

Trimethoprim alone may be preferred

Daptomycin Yes Bacteraemia. Skin and soft tissue infections

Skeletal muscle necrosis. Monitor creatine kinase.

Inactivated by surfactant and not to be used in respiratory infections

Fusidic acid Never Skin and soft tissue infections. Elimination of carriage

Jaundice on parenteral therapy. Highly protein bound.

Resistance – an emerging problem with topical and systemic use. Hepatic excretion.

Linezolid Yes Pneumonia. Serious soft tissue infections, Bacteraemia. GISA and

5-10% incidence of marrow suppression. Caution in pre-existing liver

No information on combination therapy with antimicrobials

GRSA infection.

insufficiency. Peripheral neuropathy. Cortical blindness, interactions with anaesthetic agents and MAOIs.

against MRSA. Limited data in severe renal impairment. Recommended maximum duration of therapy of 28 days limits use in bone and joint infection. Availability of oral agent attractive.

Mupirocin Yes (nasal carriage as sole site)

Not recommended for therapeutic use. Use in eradication therapy.

Minor/ Established and increasing high level resistance is a problem.

Quinupristin/Dalfopristin

Yes Reserve drug. GISA and GRSA infections.

Flu- like syndrome with joint pains. Thrombocytopenia. P450 cytochrome oxidase-related drug interactions.

Central line administration required. No oral formulation.

Rifampicin Never Bone and joint infections. Use in skin and soft tissue infections. Eradication therapy.

Possible jaundice with fusidic acid. Hepatic enzyme changes. Drug interactions and hepatic enzyme induction.

Emergence of resistance during therapy a hazard. Active against organisms in biofilms.

Teicoplanin Yes Serious soft tissue infections. Bacteraemia (but loading doses essential and adequate levels

High protein binding

Not orally absorbed. Dose adjustment required in renal impairment. Poorly

unpredictable) predictable blood levels mean monitoring essential in serious infection.

Tetracyclines Yes Skin and soft tissue infections. Urinary tract infections. Eradication of carriage.

Avoid in renal impairment or use doxycycline

Emergence of resistance

Tigecycline Yes Skin and soft tissue

Nausea

Trimethoprim No Urinary tract infection. Other use in combination therapy

Dearth of data in MRSA infection

Vancomycin Yes Bacteraemia. Serious soft tissue infections. Bone infection.

Renal toxicity associated with concurrent aminoglycoside use.

Dose adjustment required in renal impairment. Not orally absorbed. Poorly predictable blood levels mean monitoring essential in serious infection.

640 641 Acknowledgements 642 643 The BSAC Working Party would like to thank Vittoria Lutje for her invaluable 644 assistance in the collection of references for these Guidelines. 645 646

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(93) Rajendran PM, Young D, Maurer T, Chambers H, Harris H. Treatment of 1031 abscesses in the era of meticillin resistant Staphylococcus aureus-are 1032 antibiotics necessary? Journal of the American College of Surgeons 2006; 1033 203(3):S59. 1034

(94) Cenizal MJ, Skiest D, Luber S, Bedimo R, Davis P, Fox P et al. Prospective 1035 randomized trial of empiric therapy with trimethoprim-sulfamethoxazole or 1036 doxycycline for outpatient skin and soft tissue infections in an area of high 1037 prevalence of meticillin- resistant Staphylococcus aureus. Antimicrobial 1038 Agents & Chemotherapy Vol 51(7) (pp 2628-2630), 2007; (7):2628-2630. 1039

(95) Weigelt J, Itani K, Stevens D, Lau W, Dryden M, Knirsch C. Linezolid versus 1040 vancomycin in treatment of complicated skin and soft tissue infections. 1041 Antimicrob Agents Chemother 2005; 49(6):2260-2266. 1042

(96) Tice A, Rehm SJ, Dalovisio J, et al. Practice guidelines for parenteral 1043 antibiotic therapy. Clinical Infectious Diseases 2004; 38:1651-1672. 1044

(97) Arbeit RD, Maki D, Tally FP, et al. The safety and efficacy of daptomycin for 1045 the treatment of complicated skin and skin-structure infections. Clinical 1046 Infectious Diseases 38, 1673-1681. 2004. 1047

Ref Type: Generic 1048

(98) Postier RG, et al. Results of a multicenter, randomized, open- label efficacy 1049 and safety study of two doses of tigecycline for complicated skin and skin-1050 structure infections in hospitalized patients. Clinical Therapeutics 2004; 1051 26(5):704-714. 1052

(99) Falagas ME, Siempos II, Vardakas KZ. Linezolid versus glycopeptide or ß-1053 lactam for treatment of Gram-positive bacterial infections: meta-analysis of 1054 randomised controlled trials. Lancet Infectious Diseases 2008; 8(1):53-66. 1055

(100) Wagenlehner FM, Lehn N, Witte W, Naber KG. In vitro activity of 1056 daptomycin versus linezolid and vancomycin against gram-positive 1057 uropathogens and ampicillin against enterococci, causing complicated urinary 1058 tract infections. Chemotherapy 2005; 51(2-3):64-69. 1059

(101) Naber KGEBITFP. Daptomycin versus Ciprofloxacin in the treatment of 1060 complicated urinary tract infection due to gram positive bacteria. Infectious 1061 Diseases in Clinical Practice 2004; 12(6):322-327. 1062

(102) Tally FP, Zeckel M, Wasilewski MM. Daptomycin: a novel agent for Gram 1063 positive infections. Expert Opin Investig Drugs 1999; 8(8):1223-1238. 1064

(103) Stein GE, Craig WA. Tigecycline: a critical analysis. Clin Infect Dis 2006; 1065 43(4):518-524. 1066

(104) Bergeron MG, Montay G. The parmocokinetus of quinupristin/dalfopristin in 1067 laboratory animals and in humans. Journal of Antimicrobial Agents 1068 Chemotherapy 1997; 39 (Suppl A):129-138. 1069

(105) Falagas ME, Giannopoulou F, Ntziora F, Papagelopoulos PJ. Daptomycin for 1070 treatment of patients with bone and joint infections: a systematic review of the 1071 clinical evidence. International Journal of Antimicrobial Agents 2007; 30:202-1072 209. 1073

(106) Rouse MS, Piper KE, Jacobson M, Jacofsky DJ, Steckelberg JM, Patel R. 1074 Daptomycin treatment of Staphylococcus aureus experimental chronic 1075 osteomyelitis. Journal of Antimicrobial Chemotherapy 2006; 57(2):301-305. 1076

(107) Hall EW, Rouse MS, Jacofsky DJ, Osmon DR, Hanssen AD, Steckelberg JM. 1077 Release of daptomycin from polymethylmethacrylate beads in a continuous 1078 flow chamber. Diagnostic Microbiology and Infectious Disease 2004; 50:261-1079 265. 1080

(108) Kandemir O, Oztuna V, Colak M, Akdag A, Camdeviren H. Comparison of 1081 the efficacy of tigecycline and teicoplanin in an experimental meticillin-1082 resistant Staphylococcus aureus osteomyelitis model. Journal of 1083 Chemotherapy 2008; 20:53-57. 1084

(109) Yin LY, Lazzarini L, Li F, Stevens CM, Calhoun JH. Comparative evaluation 1085 of tigecycline and vancomycin, with and without rifampicin, in the treatment 1086 of meticillin-resistant Staphylococcus aureus experimental osteomyelitis in a 1087 rabbit model. Journal of Antimicrobial Chemotherapy 2005; 55(6):995-1002. 1088

(110) Rao N, Hamilton CW. Efficacy and safety of linezolid for Gram-positive 1089 orthopaedic infections: a prospective case series. Diagn Microbiol Infect Dis 1090 2007; 59:173-179. 1091

(111) Senneville E, Legout L, Valette M, Yazdanpanah Y, Beltrand E, Caillaux M et 1092 al. Effectiveness and tolerability of prolonged linezolid treatment for chronic 1093 osteomyelitis: A retrospective study. Clinical Therapeutics 2006; 28(8):1155-1094 1163. 1095

(112) Bassetti M, Vitale F, Melica G, Righi E, Di Biagio A, Molfetta L et al. 1096 Linezolid in the treatment of Gram-positive prosthetic joint infections. J 1097 Antimicrob Chemother 2005; 55(3):387-390. 1098

(113) Fowler VG, Boucher HW, Corey R, Abrutyn E, et al. Daptomycin versus 1099 Standard Therapy for Bacteraemia and Endocarditis Caused by 1100 Staphylococcus aureus. New England Journal of Medicine 2006; 355(7):653-1101 665. 1102

(114) Levine DP, Lamp KC. Endocarditis treated with daptomycin: Experience from 1103 a registry. 2005. 359. 1104

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(115) Levine DP, Lamp KC. Daptomycin in the treatment of patients with infective 1106 endocarditis: experience from a registry. American Journal of Medicine 2007; 1107 120:S28-S33. 1108

(116) Martone WJ, Katz D. Community phenotype meticillin resistant 1109 Staphylococcus aureus infections: experience in the 2005 Cubicin outcomes 1110 registry and experience (CORE 2005). 2006. 382. 1111

Ref Type: Slide 1112

(117) Stevens DL, Ma YS, Salmi DB, McIndoo E, Wallace RJ, Bryant AE. Impact 1113 of antibiotics on expression of virulence-associated exotoxin genes in 1114 meticillin-sensitive and meticillin- resistant Staphylococcus aureus. Journal of 1115 Infectious Diseases 2007; 195(2):202-211. 1116

(118) Toh S, Xiang L, Arias CA, Villegas M, Lolans K, Quinn J et al. Acquisition of 1117 a natural resistance gene renders a clinical strain of meticillin-resistant 1118 Staphylococcus aureus resistant to the synthetic antibiotic linezolid. Molecular 1119 microbiology 2007; 64:1506-1514. 1120

(119) Kelly S, Collins J, Maguire M, Gowing C, Flanagan M, Donnelly M et al. An 1121 outbreak of colonisation with linezolid-resistant Staphylococcus epidermidis in 1122 an intensive therapy unit. Journal of Antimicrobial Chemotherapy 2008; 1123 61:901-907. 1124

(120) Kainer MA, Devasia RA, Jones TF, Simmons BP, Melton K, Chow S et al. 1125 Response to emerging infection leading to outbreak of linezolid-resistant 1126 enterococci. Emerging Infectious Diseases Vol 13(7) (pp 1024-1030), 2007; 1127 (7):1024-1030. 1128

(121) Dobbs T, Patel M, Waites KB, Moser SA, Stamm AM, Hoesley CJ. 1129 Nosocomial spread of enterococcus faecium resistant to vancomycin and 1130 linezolid in a tertiary medical center. Journal of Clinical Microbiology 2006; 1131 44:3368-3370. 1132

(122) Bonora M, Solbiati M, Stepan E, Zorzi A, Luzzani A, Catania M et al. 1133 Emergence of linezolid resistance in the vancomycin-resistant Enterococcus 1134 faecium multilocus sequence typing C1 epidermic lineage. Journal of Clinical 1135 Microbiology 2006; 44:1153-1155. 1136

(123) Ntziora F, Falagas ME. Linezolid for the treatment of patients with central 1137 nervous sys tem infection. Ann Pharmacother 2007; 41(2):296-308. 1138

(124) Gerber P, Stucki A, Acosta F, Cottagnoud M, Cottagnoud P. Daptomycin is 1139 more efficacious than vancomycin against a meticillin-susceptible 1140 Staphylococcus aureus in experimental meningitis. J Antimicrob Chemother 1141 2006; 57(4):720-723. 1142

(125) Maraha B, van Halteren J, Verzijt JM, et al. Decolonization of meticillin-1143 resistant Staphylococcus aureus using oral vancomycin and topical mupirocin. 1144 Clinical Microbiology and Infection 8, 671-675. 2002. 1145

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(126) Silvestri L, van Saene HK, Milanese M. Prevention of MRSA pneumonia by 1147 oral vancomycin decontamination: a randomised trial. European Respiratory 1148 Journal 2004; 23:921-929. 1149

(127) de la Cal MA, Cerda E, van Saene HK, et al. Effectiveness and safety of 1150 enteral vancomycin to control endemicity of meticillin-resistant 1151 Staphylococcus aureus in a medical/surgical intensive care unit. Journal of 1152 Hospital Infection 56, 175-183. 2004. 1153

Ref Type: Generic 1154

(128) Silvestri L, Milanese M, Oblach L, et al. Enteral vancomycin to control 1155 meticillin-resistant Staphylococcus aureus outbreak in mechanically ventilated 1156 patients. American Journal of Infection Control. 30, 391-399. 2002. 1157

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(129) Perez-Roth E, Lopez-Aguilar C, Alcoba-Florez J, Mendez-Alvarez S. High-1159 level mupirocin resistance within meticillin-resistant Staphylococcus aureus 1160 pandemic lineages. Antimicrob Agents Chemother 2006; 50(9):3207-3211. 1161

(130) Vivoni AM, Santos KR, de Oliveira MP, Giambiagi-Demarval M, Ferreira 1162 AL, Riley LW et al. Mupirocin for controlling meticillin- resistant 1163 Staphylococcus aureus: lessons from a decade of use at a university hospital. 1164 Infect Control Hosp Epidemiol 2005; 26(7):662-667. 1165

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RecommendationsNHS Quality Improvement Scotland recommends that a pilot screeningprogramme for meticillin-resistant Staphylococcus aureus (MRSA) be conductedin patients on admission to hospital.

• Patient screening - A primary study should be set up in acute inpatient care within a whole NHSBoard area (which should include a tertiary referral hospital and one or more large general hospitals)to assess whether screening all patients for MRSA is effective in preventing MRSA infection. Datafrom this study should be collected for at least one year to decide whether MRSA screening results ina reduction in prevalence of MRSA. The Scottish Government should fund and manage this study.

• Staff screening - There is currently insufficient evidence on staff MRSA transmission to determinean appropriate schedule of screening and subsequent management. Therefore, current guidelinesindicating screening on occasion of unexplained outbreaks should be followed.

• Service requirements - Systems should be developed to collect patient-based data on theprevalence of MRSA colonisation and infection to determine the effectiveness of infection controlstrategies.

• Patient information - High-quality patient information on MRSA, the purposes of screeningand methods to achieve infection control should be distributed to all patients and/or relatives onadmission to hospital.

• Patient care - Care of patients isolated as a result of MRSA colonisation or infection should notresult in their being or feeling unnecessarily disadvantaged.

Health Technology Assessment Advice 9 ~ October 2007

The clinical and cost effectiveness ofscreening for meticillin-resistantStaphylococcus aureus (MRSA)

1

Assessment Advice

1 Introduction1.1 This Advice from NHS Quality Improvement Scotland (NHS QIS) is the

outcome of a Health Technology Assessment (HTA) evaluating the clinical andcost effectiveness of a screening programme for meticillin-resistant Staphylococcusaureus (MRSA) of patients admitted to hospital. The Assessment also consideredhow colonised patients should be managed. All HTAs consider the needs andpreferences of patients.

1.2 Staphylococcus aureus is a bacterium that many healthy people carry without itcausing infection. If it enters the body, it can cause a range of illnesses fromminor localised skin infections to systemic life-threatening illnesses. Antibioticsare used to treat more serious staphylococcal infections but some strains ofStaphylococcus aureus have developed resistance to commonly used antibioticsincluding meticillin. MRSA is a major cause of healthcare associated infection.Infections with MRSA are associated with greater risk of treatment failure,increased patient mortality and high costs.

A major aspect of controlling the spread of MRSA is screening to identifycolonised patients, and then managing them to reduce the risk of transmission.Screening involves taking swabs from one or more body sites, followed bylaboratory analysis of these samples. The HTA evaluated a number of screeningstrategies using a combination of clinical risk assessment and microbiologicalscreening. The strategies were modelled for different types of laboratory tests.This work only considered the screening of patients admitted to acute inpatientcare, with patients grouped on the basis of admission to low or high-risk hospitalspecialty units.

1.3 This Advice is based on critical appraisal and analysis of evidence published inscientific literature and submitted by experts, professional groups, patient interestgroups, manufacturers and other interested parties. The assessment process,evidence base, methodology, results and recommendations are described in detailin Health Technology Assessment Report 9: The clinical and cost effectiveness ofscreening for meticillin-resistant Staphylococcus aureus (MRSA). To help users ofthis Advice locate additional information provided in the report, relevant sectionsare referenced in the margins of this document. The words which are in bold aredefined in the Glossary.

1.4 The Advice represents the evidence-based views of NHS QIS. Healthprofessionals in NHSScotland should take account of this NHS QIS Adviceand ensure that the recommended actions are implemented to meet clinicalneed. However, this Advice does not override or replace the individualresponsibility of health professionals to make appropriate decisions in thecircumstances of their individual patient, in consultation with the patient and/orguardian or carer.

HTA Report 9,Chapter 2

HTA Report 9,Chapter 4

HTA Report 9, Chapters 5, 6, 7 and 8

2

2 Summary of clinical and cost effectivenessLaboratory screening method

2.1 There was a paucity of high-quality data on the effectiveness of laboratory tests toidentify MRSA. This was compounded by the lack of an agreed referencestandard for MRSA testing.

Based on data in the literature, it was estimated that screening agar had asensitivity of 68% with a 6% incidence of a false-positive test and a turnaroundtime of 48 hours, chromogenic agar had 98% sensitivity, a 0.2% false-positiverate and a turnaround time of 24 hours, and real-time polymerase chain reactionhad 96% sensitivity with a 5% false-positive rate and a 24-hour turnaround time.

Clinical risk assessment2.2 No standard risk assessment tool for predicting MRSA colonisation has been

established. Furthermore, no studies were identified which assessed the riskfactors recommended in the joint British Society for AntimicrobialChemotherapy, the Hospital Infection Society and the Infection Control NursesAssociation (BSAC/HIS/ICNA) MRSA working party guidelines.

Only one study reporting data on the effectiveness of clinical risk assessment atpredicting MRSA colonisation was considered appropriate for the HTA. Itindicated that limited laboratory testing of patients with at least one risk factorfor MRSA colonisation would target 65% of patients for screening and identify88% of MRSA carriers. Further research into clinical risk assessment is requiredin the Scottish setting.

Decolonisation2.3 The British Society of Antimicrobial Chemotherapy recommends that

decolonisation of all patients who tested positive for MRSA be undertaken. Thisinvolves using antiseptic detergents daily for bathing and applying topicalantibacterial nasal cream three times a day for a five-day period. Systemictreatment for throat decolonisation should be used in conjunction with nasal andskin decolonisation treatments.

Isolation2.4 A systematic review reported that there was sufficient evidence to advocate the

use of isolation facilities in decreasing MRSA spread, despite methodologicalweaknesses of the studies reviewed. There was no evidence that patient cohortingwas effective at reducing MRSA transmission.

HTA Report 9, Section 5.3.3

and Table 6-16

HTA Report 9, Section 5.3.2

HTA Report 9, Section 5.3.4

HTA Report 9,Section 5.3.7

3

Assessment Advice

Prevalence rates2.5 An economic model, constructed to estimate the costs and benefits of different

screening strategies in a tertiary referral hospital, showed that:

• screening of patients admitted to both high and low-risk specialty units provedmost effective at reducing MRSA prevalence rates.

• screening all patients for MRSA colonisation by a laboratory test is a moreeffective strategy in reducing prevalence and preventing infection thanscreening by clinical risk assessment only.

• chromogenic agar has a relatively high sensitivity and specificity at low cost, andis the most cost-effective method of screening in reducing MRSA prevalence.

Staff screening2.6 Currently there is insufficient evidence to support routine screening of healthcare

workers to control MRSA transmission. The joint BSAC/HIS/ICNA guidelinesrecommend screening of staff with skin lesions and all staff in the event ofunexplained persistent outbreaks. These recommendations are consideredappropriate until the effects of exposure to MRSA on staff caring for colonisedpatients and the nature of transient colonisation are better understood.

HTA Report 9,Section 6.5

HTA Report 9,Section 5.4

4

3 Patient issues findings3.1 The literature relating to patient views and the understanding of MRSA infection

control is very limited. Similarly, there is a paucity of evidence on staffperspectives of MRSA screening.

3.2 Both the literature and patient experience highlighted the anxiety and stigmaassociated with MRSA colonisation and infection. Both sources identified amisunderstanding of the nature of infection, how MRSA can be acquired andwhether it could be treated, and the need for nursing in isolation. The focusgroup findings emphasised the need for clear reliable information for the public.

3.3 Studies reported conflicting results of patient experiences of being nursed inisolation. Some research reported considerable patient anxiety and negativeexperiences about being nursed in isolation, where as other studies and focusgroups described more positive aspects of being in a single-bedded room. There isevidence that there may be subtle changes in the way patients are cared for inisolation compared with those cared for on an open ward, for example patients inisolation are often the last in line for certain hospital services.

3.4 Literature reported inconsistencies in compliance with isolation practices amongstaff and visitors, which was considered, by the focus groups, to send out mixedmessages to patients.

3.5 A preadmission screening policy for MRSA was viewed positively by both patientand staff focus groups. Staff had concerns about the logistics of implementingsuch a service.

HTA Report 9, Chapter 7

HTA Report 9, Sections 7.3.1.2, 7.3.1.4

and 7.3.2.1

HTA Report 9, Sections 7.3.1.3, 7.3.2.1

and 7.3.4.3

HTA Report 9, Sections 7.3.2.1

and 7.3.3.1

HTA Report 9, Section 7.3.4.2

5

Assessment Advice

4 Summary of organisational issues4.1 A national survey of current practice in MRSA screening found variation in the

assessment of MRSA colonisation and susceptibility to MRSA infection,laboratory MRSA testing and subsequent patient management. Of the hospitalunits surveyed, almost 60% performed clinical risk assessment on admission and41% assessed patients’ susceptibility to MRSA infection.

4.2 Ethical issues of MRSA screening include the right of the individual to make aninformed choice and the balance of benefit over harm related to screening andsubsequent patient management. Patient concordance with a screeningprogramme could be maximised through open and informed discussion regardingthe reasons for screening and by emphasising that the care provided to thoserequiring isolation is acceptable and appropriate. The legal implications of anMRSA screening programme have not yet been fully explored.

4.3 The organisation of an MRSA screening policy is linked to the wider issues ofhospital infection control. More specific issues relating to the organisation of aquality MRSA screening service include:

• building and site issues - the provision of dedicated single-bed isolation roomsand the expansion of laboratory testing facilities and new equipment

• staff resources and training - appropriately trained laboratory staff to processadditional samples, training of nursing staff in clinical risk assessment andpatient screening

• information technology - the use of information systems to monitor MRSAscreening data

• quality assurance and audit - accreditation of laboratories, audit of practice inoutbreak situations and development of protocols for clinical risk assessmentand swabbing techniques, and laboratory procedures.

4.4 Appropriate coordination and communication between preadmission andadmission units and laboratory services is required to ensure the success of anMRSA screening programme.

4.5 The information needs of both staff and patients should be met at various stagesof the screening process in a variety of ways. Staff require sufficient knowledge onMRSA screening to support patient decision making. Training should be in linewith the healthcare associated infection Code of Practice. Information on MRSAand the reasons for screening should be readily available to patients at bothpreadmission clinics and on admission to hospital in a variety of formats andlanguages.

HTA Report 9, Section 8.2

HTA Report 9, Section 8.4

HTA Report 9, Sections 8.5 to 8.8

HTA Report 9, Section 8.9

HTA Report 9, Section 8.10

6

5 Budget impact5.1 The total costs to NHSScotland of screening all patients for MRSA on admission

to hospital using chromogenic agar are estimated to be £14.3 million in the firstyear, decreasing to £9.7 million in the fifth year. This amounts to a total of £55million over a five-year period.

5.2 The annual estimated costs for a nominal 840-bed tertiary referral hospitaloperating at 85% occupancy are:

• £158,800 in Year 1 rising to £160,600 in Year 5 for screening

• £289,500 in Year 1 increasing to £291,500 in Year 5 for laboratory testanalysis

• £209,800 in Year 1 decreasing to £32,000 in Year 5 for the increased costassociated with isolation in single rooms

• £41,200 in Year 1 decreasing to £9,300 in Year 5 for administeringdecolonisation treatment

• £60,300 in Year 1 reducing to £9,200 in Year 5 for administering contactprecautions.

6 ImplicationsAll NHS boards should consider the findings of this report when planning andreviewing their screening and decolonisation policies.

7 ReviewAs NHS QIS chooses broad topics for HTAs, it is likely that new evidence willemerge which bears on the specific recommendations on an ongoing basis.Rather than having a fixed review period, NHS QIS will determine theimportance of new evidence and produce report addenda in which the evidenceis analysed and any alteration to the recommendations is explained. If a majorchange is required, the Health Technology Assessment Report, Advice andUnderstanding our Advice will be rewritten.

HTA Report 9, Section 6.7

HTA Report 9, Section 6.7

7

Assessment Advice

Further information• Health Technology Assessment 9: The clinical and cost effectiveness of screening for

meticillin-resistant Staphylococcus aureus (MRSA)

• Understanding our Advice: The clinical and cost effectiveness of screening for meticillin-resistant Staphylococcus aureus (MRSA)

• All NHS QIS documents are available in a variety of formats on request and from the NHS QIS website, www.nhshealthquality.org

8

GlossaryBacterium A microorganism that has the potential to cause disease.

Clinical risk assessment An estimation of the patient’s risk of being an MRSAcarrier by reviewing their medical history.

Cohorting A group of patients with a similar status (eg MRSAcarriers) who are separated from other patients, and caredfor by dedicated nursing staff in the same geographicalarea.

Colonisation The presence and multiplication of a microorganism onthe body without it causing harm.

Decolonisation Controlled eradication of a microorganism.

False positive A test result which indicates an abnormality, when onedoes not exist.

Infection The entry into the body of a microorganism (eg bacteria,virus, parasite) and its establishment and growth in thetissues, causing harm.

Isolation facilities A single-bedded room with its own toilet andhandwashing facilities.

Meticillin An antibiotic.

Scottish Executive Formerly the name of the Scottish Government.See Scottish Government.

Scottish Government The devolved government for Scotland, withresponsibilities including health policy and theadministration of NHSScotland. Until September 2007,the devolved government was named the ScottishExecutive.

Screening A public health service offered to groups of the populationto identify risk of a particular disorder, infection or disease.This therefore involves examination of people with no

symptoms, to detect unsuspected disease.

Sensitivity The ability of a test to detect a disease. A test with asensitivity of 90% will give a positive result in 9 out of 10people who have the disease.

Turnaround time Time from taking a blood sample to receipt of a result bythe decision maker.

9

Assessment Advice

NHS Quality Improvement ScotlandNHS QIS was set up to improve the quality of health care in Scotland. Its role is to setstandards and monitor performance and provide NHSScotland with advice, guidanceand support on effective clinical practice and service improvements.

© NHS Quality Improvement Scotland, 2007

ISBN 1-84404-474-2

First published October 2007

NHS Quality Improvement Scotland consents to the photocopying, electronicreproduction by ‘uploading’ or ‘downloading’ from the website,retransmission, or other copying of this document for the purpose ofimplementation in NHSScotland and educational and ‘not for profit’ purposes.No reproduction by or for commercial organisations is permitted without theexpress written permission of NHS Quality Improvement Scotland.

This document can be viewed on the NHS QIS website. It is also available, on request, from NHS QIS in the

following formats:

• electronic

• audio cassette

• large print.

NHS Quality Improvement Scotland

Glasgow Office - Delta House 50 West Nile Street Glasgow G1 2NP Tel 0141 225 6999

Edinburgh Office - Elliott House 8-10 Hillside Crescent Edinburgh EH7 5EA Tel 0131 623 4300

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