Multiresistant bacteria

16.09.2011 - MRE - Düsseldorf 1

Multiresistant bacteria in conflict between theory and practice

16th September 2011, Düsseldorf

Old and new insights into multiresistant bacteria

h m i

hygiene microbiology infectious diseases

Prof. Dr. med. B. WilleDoctor of hygiene and environmental medicineDoctor of microbiology, virology and the epidemiology of

infection


Deaths (per 100 000 citizens) due to infection in the U.S.A., 1900-1996

Influenza Pandemic

First use of penicillin


1962:

“It‘s time to close the book on infectious diseases“

(Quoted by a senior American health official)


Definitionof multiresistant

bacteria?


List of known viruses according to § 23 Abs. 1 S. 1Types of bacteria: resistance to the following substances has been tested in the framework of clinical-

microbiological diagnostics.1 S. aureus:Vancomycin, Oxacillin, Gentamicin, Quinolone Gr. IV (e.g. Moxifloxacin), Teicoplanin,Quinupristin / Dalfopristin2 S. pneumoniae:Vancomycin, Penicillin (Oxacillin 1 µg), Cefotaxim, Erythromycin, Quinolone Gr. IV (e.g. Moxifloxacin)3 E. faecalis / E. faecium:Vancomycin, Gentamicin (“high level”: Gentamicin 500 mg/l; Streptomycin1000 mg/l (Mikrodil.) or 2000 mg/l (Agardil.), TeicoplaninE. faecium: zusätzlich Quinupristin / Dalfopristin4 E. coli / Klebsiella spp.: Imipenem / Meropenem, Quinolone Gr. II (e.g. Ciprofloxacin), Amikacin, Ceftazidim,Piperacillin / Tazobactam, Cefotaxim or analogous test substances5 Enterobacter cloacae / Citrobacter spp. / Serratia marcescens:Imipenem / Meropenem, Chinolon Gr. II (e.g. Ciprofloxacin), Amikacin6 P. aeruginosa / A. baumannii: : Imipenem / Meropenem, Quinolone Gr. II (e.g. Ciprofloxacin), Amikacin, Ceftazidim, Piperacillin / Tazobactam7 S. maltophilia: Quinolone Gr. II (e.g. Ciprofloxacin), Amikacin, Ceftazidim, Piperacillin /Tazobactam, Cotrimoxazol8 Candida spp. * Fluconazol* Only recorded in establishments with haemotological-oncological departments. For the main resistant

species the leading resistances are in bold and underlined.

Multiresitant bacteria 2010


Causes of MRB

1. Misuse of antibiotics in medicine- MRSA: Gyrase inhibitors - ESBL: 3rd generation Cephalosporines- VRE: Vancomycin use

2. Reduced cost of valuable antibiotics

3. Use of antibiotics in veterinary medicine/ intensive farming


Rate of multiresistant bacteria per 1,000 patient days


Increase in resistance through use of antibiotics

Increase in Quinolone use of around 1 % After one month, increase in the

incidences of nosocomial ESBL infections reached

4.43 %


Increase in resistance through antibiotic use

Increase in the use of 3rd Generation Cephalosporins over 12

weeks:

Doubling of ESBL-related nosocomial infections


A common wrong interpretation:

Out of the 600,000 new incidences per year in Germany

“only“ 5-10 % are due to multiresistant bacteria!


Basic principle of MRB

MRB are not different from bacterial infections

apart from by their

RESISTANCE TO ANTIBIOTICSThis means:

- They transfer from person to person easily

- They are capable of surviving (epidemic MRSA strains)?

- Disinfection treatments have limitations

*Discussion: Is MRSA connected to increased virulence?


New concept for multi-resistent bacteria

ESKAPE (bad bugs, no drugs:

no ESKAPE)


E: Enterococcus faeciumS: Staphyloccocus aureusK: Klebsiella pneumoniaeA: Acinetobacter baumanniiP: Pseudomonas aeruginosaE: Enterobacter species

Eskape


MRSA-related deaths in Intensive Care Units

KISS-Data: 274 ICUs / 505487 Patients

6,888 Pneumonia 1,851 S. aureus

2,357 Primary Septicaemia 378 S. aureus

Pneumonia:

105 of 1502 MSSA ( 7 %)

59 of 349 MRSA ( 16.9 %)

Primary Septicaemia:

17 of 283 MSSA ( 6 %)

16 of 95 MRSA ( 16.8 %)

Gastmeier et al.: Mortality Risk Factors with Nosocimial S. aureusInfections in Intensive Care UnitsInfection 2005; 33: 50-55


ESBL – clinical significance

Seoul, Children‘s hospital. Bacteremia withE. coli & K.pneumoniae:

Lethality ESBL +: 26,7%; ESBL -: 5,7 % p=0.001

Kim et al. AAC 2002; 46: 1481-91

Los Angeles; Alter 56y, Bacteremia with E. coli & K. pneumoniae:

Failure of initial treatment: ESBL+: 82 %; ESBL -: 20 %; p=0.009 Wong-Beringer et al. CID 2002; 34: 135-46


Profile: MRSA / MRSE Omnipotent pyogenic organism

MRSA: strong tendency to spread, also among out-patients

Outbreaks are falling

Large general interest


MRSA in Germany (2008)

Resistance (in %) against other selected antibiotics

2006 2007 2008

Ciprofloxacin 93.8 97.8 91.1

Moxifloxacin - 94.4 89.6

Clindamycin 65.4 72.0 73.4

Gentamycin 13.3 9.8 10.5

Oxytetrazyklin 7.4 6.8 7.8

Rifampicin 2,5 1,1 0.4

Cotrimoxazol 3.1 2.0 10.8

Fosfomycin 3.3 0.6 1.1

Linezolid 0.04 0.11 0.1

Muporizin 2.6 3.3 5.3


MRSA and other multiresistant bacteria

Frequency of multiresistant bacteria in German hospitals

MRSA: 1990: 1.7 % 1998: 15.2 % 2001: 20.7 %

(MRSA proportion of all S. aureus isolates)

ICUs: 2003 > 30 %

Retirement and care homes: 1-3% of patients(Source PEG, 2003)


Breakdown of MRSA

ha-MRSA (hospital acquired-MRSA) ca-MRSA: community acquired

(community associated MRSA) la-MRSA: lifestock-associated MRSA

(presumably low infectivity und pathogenicity from la-MRSA ST 398)


Saarland (from 18/10 to 12/12/2010)All registered in-patients during this

time periodResults: More than 80%, 90% in some hospitals around 20,000 patients with a total

of 405 positive results- corresponding prevalence around

0.52 %

New data from MRSA screening


Reduction of nosocomial MRSA infections after the introduction of MRSA screening with the LightCycler MRSA advanced test in the Southwest clinical network, Germany (colours correspond with

areas within the network),

Number of ha-MRSA infections/colonisations

New screening implemented


An increased risk for an MRSA colonisation in line with RKI* recommendations exists for:

1. Patients with known MRSA anamnesis

2. Transfers from regions/establishments with a known

high MRSA prevalence

3. In-patients who have stayed in hospital for more

than 3 days in the last 12 months

4. Patients who have direct (occupational) contact

with animals and agricultural animal feed (pigs)

5. In-patients who during their stay have had contact

with MRSA carriers (e.g. by staying in the same

room)*Robert Koch Institute, Germany


An increased risk for an MRSA colonisation in line with RKI recommendations exists for:

6. Patients with two or more of the following risk factors:

- They are in need of constant care- They have had a course of antibiotics in the

last 6 months - They have a catheter (e.g. bladder catheter,

PEG tube)- They have dialysis- They have skin ulcers/ gangrene/ chronic

wounds/ deep infection of soft tissues- They have burns


The microbiological screening rules include:- A swab of the nose, mouth and- A swab of wounds if necessary

If the MRSA results are positive(ICD-10: U 80.0):

Take hygiene measures (see text)

Recommended measures include isolation

If the MRSA results are negative:

Standard hygiene practices

Source: Epi. Bull. 46/2004


Isolation in a single room: 84.5 % Protective overalls: > 90 % Gloves: > 90 % Covered mouth or nose: > 85 % Covered head: 40-50 % (more nurses than doctors) Surface disinfection: daily, almost without exception

New MRSA results (Results of a survey from the DGKH* and the BVÖGD**,

Autumn 2010)

*Deutsche Gesellschaft für Krankenhaushygiene (German Society for Hospital Hygiene) **Bundesverband der Ärztinnen und Ärzte des Öffentlichen Gesundheitsdienstes (German Federal Association of Doctors in the Public Health Service)


Sanitation of MRSA positive patients: 60% antiseptic washes/showers Mupirocin nose salve: 52 % antiseptic mouthwash: 43 % Entry screening: 38 % refer to the KRINKO* recommendations!

New MRSA results (Results of a survey from the DGKH and the BVÖGD, Autumn 2010)

*Kommision für Krankenhaushygiene und Infektionsprävention (The Commission for Hospital Hygiene and Infection Control)


Summary: In 8-12 % of hospitals the MRSA patient recommendations were not satisfactorily applied. 78 % carry out the risk-based screening with at least 50% of the KRINKO recommendations.Source: Hyg. Med. 2011; 36-6, pp. 254-255

New MRSA results (Results of a survey from the DGKH and the BVÖGD, Autumn 2010)


MRSA

General characteristics of MSSA and MRSA Transfer: Predominately through

physical contact (particularly hands!) Aerogens (dust, droplets)

Virulence depends on the strain!

Contagiousness: depends on the strain and the patient

Mode of infection: both endogenous and exogenous



Bacteria-related measures for MRSA

Strict isolation (including “just“ colonisation

cases)

Adequate therapy

Sanitisation

Prevent re-colonisation

Avoid postponments in hospital

Epidemiological recording/ analysis


Psychological aspects of isolation

- Measures: Keep isolated patients better informed Show understanding for the unusual situation For longer periods of isolation: a room with a toilet A bathroom for shared rooms Adequate number of staff on wards Daily contact with the ward‘s doctor (very important!) Facilitate flexible visiting hours Aim for individual isolation (thereby protecting personal space) When entering the room, staff should always introduce

themselves Always maintain hygiene measuresC. Hartmann: Wie erleben Patienten die Isolation im Krankenhaus aufgrund einer Infektion o. Kolonisation mit MRSA* Hyg. Med. 30. Jg. 2005 - Issue 7/8, S. 234 - 243

*How patients experience isolation in hospital due to MRSA infection or colonisation


c-MRSA

Occurs along with: Deep skin infection

(USA, Australia) Invasive infections such as Septicaemia,

Endocarditis, Osteomyelitis in prisons, homosexual scenes, sailors

It is possibly brought into hospitalsUSA: Puerperal Mastitis


Profile: VRE

VR-E. faecalis VR-E. faecium among others No marked virulence Found in the bowels Survival ability: high environmental

resistance Not particularly adhesive Immunodeficient patients at risk Nevertheless: outbreaks (oncology)



Epidemiology Glycopeptide-Resistant Enterococci

(VRE - GRE)

USA: from 1989 0.4 % general wards / 0.6 % ICUs

2002: 76.3 % with E. faecium / 4.5 %

with E. faecalis

Europe: high rates in England, Italy, Portugal,

Greece

Germany: E. faecium 5 % maximum

E. faecalis < 1 %


VRE

Strains/ mechanisms of Glycopeptid-Resistence 1

5 strains “Acquired resistance“: VanA, VanB, VanD,

VanE “Natural resistance“: VanC with 3

subdivisionsVanC1 (E. gallinarum)VanC2VanC3 (E. casselliflavus / E. flavescens)Cross-resistance between VAN and TPL


Profile: ESBL(Extended-Spectrum Beta-Lactamases)

Concerning Enterobacteria (E. coli, Klebsiella spp., among others) but also non-fermenters (P. aeruginosa, Acinetobacter sp., Stenotrophomonas maltophilia, among others)

= not a uniform group Resistance: particularly against 3rd and 4th

generation cephalosporine Survival ability: love humid environments Bowels, humid biotop Not particularly adhesive

(except for P. aeruginosa → biofilms)



ESBL (Extended-Spectrum Beta-Lactamases) showresistance to 2nd and 3rd generation

Gephalosporins: Germany < 1 -5 % Southern European countries up to 30 % India up to 70 % 20 recorded cases of outbreaks in retirement

and care homesNo data for: Pseudomonas aeruginosa / Stenotrophomonas maltophilia, Acinetobacter

sp.


Development of the rate of 3rd Generation Cephalosporin resistant E. coli

Average

ESBL strains make up a

growing proportion of E. coli-isolates in German ICUs

Month/Year

y axis: percent of resistant bacteria


ESBL – clinical significance

Seoul, Children‘s hospital. Bacteremia withE. coli & K.pneumoniae:

Lethality ESBL +: 26,7%; ESBL -: 5,7 % p=0.001

Kim et al. AAC 2002; 46: 1481-91

Los Angeles; Alter 56y, Bacteremia with E. coli & K. pneumoniae:

Failure of initial treatment: ESBL+: 82 %; ESBL -: 20 %; p=0.009 Wong-Beringer et al. CID 2002; 34: 135-46


Costs due to multiresistant gram-negative bacteria vs. MRSA

F. Dachsböck, Medizinische Universität Wien (Medical University Vienna)

Hyg. Med. 31. Jahrgang 2006 – Issue 6, pp. 284-285

n/MRGRN: 99n/MRSA: 74

Length of stay in both groups: + 6 days compared with normal patientsCost per patient with MRGN:

12,429 EURCost per patient with MRSA: 4,545

EUR


ESBL Principles

ESBL is considerably less persistent on surfaces, appliances, hands and protective clothing than MRSA and VRE.

The airborne transmission of ESBL plays a secondary role as it does for nosocomial infection bacteria generally.


3rd generation Cephalosporin-resistant Enterobacteria (CRE)

Quinolone and 3rd generation Cephalosporin-resistant Enterobacteria (Chin-CRE)

Carbapenem-resistant Enterobacteria (Carb-CRE)

Consensus recommendation, Baden-Württemberg: Umgang mit Patienten mit hochresistenten Enterobakterien inkl. ESBL-Bildnern*, Hyg.-Med. 2010; 35 (1/2), pp. 40-45

Management of antibiotic resistant Enterobacteria

*Dealing with patients with high resistant Enterobacteria including ESBL-producers


Infected patients• Stool• Urine• Anogenital region• Respiratory tract (rarer)

Colonisation of the bowels of staff of healthcare establishments

Sources of infection for CRE:


Longer patient stays, particularly in ICUs Stays in long-term care facilities Antibiotic use (3rd generation

Cephalosporins, SXT, Ciprofloxacin) Transurethral catheter, intubation,

tracheotomy, gastrostomy Decubital ulcers Heavy need for care

Risks from CRE:


Dependent on details about antibiotic resistance

Dependent on the type of ward First requirement: a series of Chin-CRE und

Carb-CRE negative swabs Carb-CRE: always placed in single room Chin-CRE: room isolation if necessary

(Consensus recommendations, Baden-Württemberg)

Proposed measures for CRE


MBL-producers = Metallo-Beta-Lactamase-producers

For infections with ESBL-producers regular therapy with Carbapenems is recommended:

- Imipenem - Meropenem- Doripenem- Ertapenem Start educating about

•Carbapenemases and •Metallo-Beta-Lactamases


MBL

Carbapenemase-producers discovered so far

The phenomenon of Carbapenem resistance is not new; 4 different resistance mechanisms are currently known

Italy Turkey India


MBLCabapenemase/ Metallo-Beta-Lactamase Development

- VIM, 1999 Italy- KPC, 2001 USA- OXA 48, 2004 Turkey- NDM-1, 2008, India

Affected bacteria:Klebsiellen, A. baumannii, E. coli, E. cloacae, P. aeruginosa u.a.

Actual data from Germany: - NRZ* 1/1/11 to 28/2/11- 66 strains nationwide, particularly Berlin, North Rhine-

Westphalia, Baden-Württermberg- At the time, no recommendations made regarding screening or

specific measures

*Nationales Referenzzentrum für Surveillance von nosokomialen Infektionen (National Reference Centre for the Surveillance of Nosocomial Infections)


ESBL / MBL

Applicable antibiotics:

Tigecycline Colistin Fosfomycin Combinations

Pharmacokinetics and side effects!Pan-resistance possible (Tigecycline: higher mortality rate)


Hygiene measures for patients with MBL colonisation/infection

Generally the same as ESBL:- Gloves/overalls- Hygenic disinfection of hands- Basic hygiene measures!- Individual treatment only if high risk of

pathogens spreading (diarrhoea, large open wounds, tracheotomy etc.)


Measures for ESBL

Isolation Customised solution for every house In unproblematic cases no isolation

Screening Use not yet established, possibly to be

considered for selected situations(Eich, 2006)


Measures for ESBL

Decolonisation:

No sustained success documented Problems:

- Quinolone resistance- General development of resistance- Other areas with colonisation

(Nasopharynx: Iodopovidone: J Hosp Infect 2001; 48: 207-213.)


Aspects of hospital hygiene for outbreaks of multiresistant bacteria

Measures to avoid MRB

1. General antibiotic therapy

2. Antibiotic therapy for patients with MRE in

accordance with regulations

3. Quick sanitisation (Example: MRSA)

4. Discharge patients quickly if possible

5. BASIC HYGIENE!!!


Increase in the use of alcoholic hand disinfectants of around 1 %

after 4 monthsReduction in incidences of infection by

around

7 %

Basic hygiene/ Disinfection of hands


MRSA

Measures

Sanitisation

Skin:• Most important principle: Wash when

possible!• Varied handwashes ( no antiseptics!)

Reduces skin irritation• Complete body wash

Alternative: “wash“ without water with wipes impregnated with active agents.


MRSA

Measures

Sanitisation

Mouth:• Various solutions

(Polyhexanide/ PVP-I/ Octenidine/ others)


MRSA

Measures

Preventing recontamination in the area

• Change clothing/ underwear daily

• Change beds daily

• Electric tootbrushes/ razers (wet)

• Disinfect dentures

• Disinfect personal belongings and everyday items


MRSA

Measures

Take action on failures in hygiene

• Most recontamination in same areas!

• Switch to other agents?

• Second attempt is worth it but have a more stringent course of action


Not enough staff: more deaths

ICUs with high staff numbers: 17 % patient deaths

ICUs with low staff numbers: 45 % patient deaths

Increase in staff numbers monitored over 4 years: Number of patient deaths dropped from 34 to

18 %

Tarnoff-Mordi WO, How C, Warden A, Shearer AJ: Hospital mortality in relation to staff work

load: 4-year-study in adult intensive-care unit Lancet 2000; 356: 185-189

Prospects and limitations of hygiene


Louis Pasteur 1895:

“The microbes always

have the last word!“

Health & Medicine

Multiresistant bacteria