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Rational antibiotic use insurgerySarah Thompson

Elisabeth J Ridgway

AbstractRational use of antibiotics is crucial to limit the evolution of resistant

organisms, reduce the occurrence of healthcare-associated infections,

and reduce costs.

Once an infection has been diagnosed, empirical therapy (started

before definitive identification of the pathogen) is common. To aid the

selection of an effective antibiotic, several variables should be consid-

ered, such as the previous microbiology results, recent antibiotics, the

patient’s journey through the hospital, antibiotic allergies and renal/

liver abnormalities.

The duration of antibiotic courses should be as short as possible, and

intravenous antibiotics can usually be switched to an oral regimen after

48 h. The presence of undrained collections, foreign bodies and infected

intravascular lines are common reasons for treatment failure despite an

appropriate antibiotic.

Keywords antibiotic; Clostridium difficile; empirical treatment;

guidelines; infection; MRSA; resistance

Most hospitals have antibiotic policies to guide the clinician in

making rational antibiotic choices. However, complex cases

should be discussed with a microbiologist.

Appropriate antibiotic use in the clinical environment is vital.

Resistant organisms are being increasingly encountered, as are

healthcare-associated infections (HCAIs) related to inappropriate

antibiotic prescribing. A logical approach to the infected patient

(i.e. choosing the correct antibiotic, giving it by the optimal route

and for the correct duration) is essential.

This contribution looks at the rationale behind antimicrobial

prescribing in the surgical patient, and should be read in

conjunction with ‘Prophylactic Antibiotics in Surgery’, on pages

431e434 of this issue.

Resistance

What is driving antibiotic resistance?

Bacterial resistance to antibiotics is not a new phenomenon.

However, decreased antibiotic susceptibility among common,

Sarah Thompson MBChB BSc is a Specialty Registrar in Medical Micro-

biology at Sheffield Teaching Hospitals Trust, Sheffield, UK and

a member in Department of Microbiology, Northern General Hospital,

Herries Road, Sheffield S5 7AU, UK. Conflicts of interest: none declared.

Elisabeth J Ridgway MBBS FRCPath MD is a Consultant Microbiologist at

Sheffield Teaching Hospitals Trust, Sheffield, UK and a member in

Department of Microbiology, Royal Hallamshire Hospital, Glossop

Road, Sheffield S10 2JF, UK. Conflicts of interest: none declared.

SURGERY 27:10 435

previously sensitive bacterial species is, and is concerning

patients, doctors and policy-makers. Widespread antibiotic use is

driving this trend and has two main consequences. First, it

promotes the emergence of organisms that are resistant to the

agents in use and, secondly, it suppresses the protective normal

flora and allows organisms such as Candida species, Steno-

trophomonas maltophilia and Clostridium difficile to become

established.1 The antibiotics in widespread use in surgical prac-

tice (e.g. co-amoxiclav, cephalosporins, quinolones) are partic-

ularly to blame in this respect as they are both broad-spectrum

and have limited activity against the common resistant

organisms.

A growing number of patients have an increased susceptibility

to infection (e.g. elderly, immunocompromised). This has

created a desire to intervene and treat infections early with

broad-spectrum agents. The mounting pressure on hospital beds

has led to a tendency to treat on suspicion, before the necessary

evidence is gathered to make a firm diagnosis of infection.

Antibiotic stewardship is the key to minimizing the trend

towards antimicrobial resistance, and preserving antibiotic effi-

cacy. This is the concept of responsible caretaking; it is based on

the premise that we don’t own resources, but simply manage

them and are responsible to future users for the maintenance of

their usefulness. It takes into account the needs of individuals

and the interests of society, and accepts significant answerability

to both.

Put simply, the challenge is to treat infected individual

patients optimally whilst preventing antibiotic overuse.

How common are resistant organisms?

Escherichia coli is a Gram-negative organism commonly impli-

cated in intra-abdominal and urinary tract infections. Between

2000 and 2007, the UK has seen increasing resistance, through

extended-spectrum b lactamases, of E. coli to cephalosporins

(12-fold increase), quinolones (5-fold increase) and amino-

glycosides (3-fold increase).2 The isolation of Gram-negative

organisms that are inherently resistant to commonly used anti-

biotics (e.g. Citrobacter spp., Serratia spp., Acinetobacter spp.) is

also rising.2

Methicillin-resistant Staphylococcus aureus (MRSA) is another

resistant organism with an increasing prevalence. It is important

because strains are resistant to flucloxacillin, and often to other

useful agents. 53% of post-operative surgical-site infections

(SSIs) are caused by S. aureus, and 64% of these are now MRSA.3

Identifying these patients and treating them appropriately is

important, as those with MRSA-associated SSI have a greater

90-day mortality, longer hospital stay and incur more costs than

those infected with methicillin-sensitive S. aureus (MRSA).4

Enterococci are enteric Gram-positive organisms often

involved in polymicrobial abdominal infections. Although they

are intrinsically resistant to many classes of antibiotics (e.g.

cephalosporins, quinolones) most are sensitive to amoxicillin.

Glycopeptides (e.g. vancomycin) are the mainstay of treatment in

amoxicillin resistance or in patients with a penicillin allergy.

Currently, 10% of enterococci are resistant to glycopeptides,2

and these organisms are also almost always amoxicillin resistant,

presenting significant therapeutic challenges.

C. difficile can cause debilitating diarrhoea (C. difficile-

associated diarrhoea, CDAD), and severe disease may lead to

� 2009 Elsevier Ltd. All rights reserved.

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colonic perforation and sepsis; 90% of infections follow antibi-

otic use.5 Exposure to antibiotics alters the normal flora of the

gut, providing an environment in which C. difficile can flourish.

Whilst certain antibiotics (e.g. cephalosporins, ciprofloxacin,

clindamycin) are particularly associated with the development of

disease, diarrhoea can follow the use of any antibiotic,5 even

when only a single dose is given. Not only is there a substantial

mortality directly attributable to the infection, C. difficile-

associated morbidity increases the length of hospital stay by

8e21 days.5 The increasing prevalence of CDAD has led to the

review of antimicrobial policy in many hospitals, with a switch to

narrow-spectrum agents such as gentamicin and flucloxacillin, in

an attempt to lessen the negative impact of antibiotic use.

Antibiotic choice

Does choosing the correct antibiotic make a difference?

Overall, patients in whom appropriate antibiotic therapy is

delayed are more likely to experience complications, have

a longer hospital stay and have a higher mortality rate.6 In

surgery, this is illustrated by the finding that patients with peri-

tonitis, who received antibiotics to which at least one pathogen

was resistant were 2e3 times more likely to experience

re-operation, abscess formation and further infection than those

who received antibiotics correctly targeting the infecting

species.7 The effect of inappropriate antibiotics on mortality is

similar; a 42% mortality rate was seen when the antibiotics

prescribed did not cover the causative organisms, compared to

17.7% in those whose antibiotics were effective against the

pathogens isolated.8

How do I choose the correct antibiotic?

It is useful to have a logical approach to antibiotic prescribing.

Antibiotic use for prophylaxis should be distinguished from that

for therapy. Allocation to the wrong category is a significant

cause of irrational antibiotic use.

The need for therapy should be firmly established, guided by

the following features:

� clinical picture

� relevant radiology

� inflammatory markers (white cell count, CRP, procalcitonin).

In order to eradicate the organism causing the infection, the

correct antibiotic given by the correct route for the correct

duration must be chosen. This ensures the antibiotic concentra-

tions at the site of infection are optimal but that side effects are

avoided and costs minimized. However, it can be difficult to

diagnose infection, particularly in the absence of an overt focus,

and clinical progress can be unpredictable, regardless of the

antibiotic used and the in vitro sensitivity results. Some infec-

tions resolve spontaneously, whilst others continue unabated

despite appropriate therapy. Targeted therapy (when the causa-

tive organism and its sensitivities are known) is ideal. However

empirical therapy (when the pathogen has not yet been defini-

tively identified) aimed at a suspected focus of infection is more

commonly given. In both scenarios, appropriate microbiological

samples (e.g. blood cultures, sputum, urine, wound swab, stool)

should be obtained prior to antibiotics being commenced.

Cultures may be negative if taken during or after a course of

antibiotics.

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Empirical regimens e Having identified a likely focus of infec-

tion (e.g. surgical-site infection with cellulitis, post-operative

pneumonia) an appropriate empirical regimen relies on knowl-

edge of the likely causative organisms and their local suscepti-

bility patterns. The latter will also be required if a pathogen has

been cultured, but sensitivity results are pending. This informa-

tion is often built into local antibiotic prescribing guidelines;

alternatively the Microbiology Department can offer advice. A

range of factors must be considered when choosing a regimen,

and answers should be available before phoning

a microbiologist:

� Recent or relevant microbiology results.

� Does the patient have a history of antibiotic resistant organ-

isms (e.g. MRSA) or C. difficile infection?

� What other antibiotics, including those used for prophylaxis,

has the patient received recently? Prior antibiotic therapy is

a major risk factor for the acquisition of resistant bacteria.

� Where has the patient been admitted from, for how long have

they been an inpatient and what kind of ward are they on?

Those patients admitted from a nursing home or transferred

from another hospital are at higher risk of resistant organisms

than those admitted from home. Acquisition of resistant

pathogens is more likely with increasing length of stay, and

specifically stays on ICU or Burns Units, and on wards where

outbreaks are in progress or background rates of resistant

organisms are high.1

� Is the patient allergic to any classes of antibiotic, and what is

the nature of the allergy?

� Are there any physiological factors that may influence which

antibiotics can be administered e such as abnormalities of

renal or liver function, pregnancy?

Empirical regimens usually provide broad-spectrum Gram-posi-

tive, Gram-negative and anaerobic cover. This may be through

the administration of a single agent, or multiple narrow-spectrum

combination antibiotic therapy.1 In general, broad-spectrum

agents are more problematic than narrow-spectrum ones.

Therefore, strategies must be in place that decrease broad

empirical therapy whilst maintaining effective cover. When

microbiological results are available, ‘de-escalating’ to a narrow-

spectrum antibiotic or discontinuing an agent may be possible

and is encouraged (e.g. switching a cephalosporin to fluclox-

acillin when a flucloxacillin-sensitive S. aureus is grown from

a wound swab). Advice from pharmacists and microbiologists

can help with this process, and it may be incorporated into

a hospital antimicrobial guidelines. Examples of empirical regi-

mens are shown in Table 1.

Targeted therapy e Targeted therapy is possible if the choice of

antibiotic is guided by the microbiology data. This may also

influence the duration of treatment. An agent with as narrow

spectrum as possible (to which the patient is not allergic) should

be chosen.

Route of administration e It is common practice in the UK to

treat life-threatening infections with parenteral antibiotics

because delivery to tissues is guaranteed. If absorption is unim-

paired, oral treatment is usually adequate for less serious infec-

tions. Quinolones, fusidic acid, linezolid, clindamycin and

metronidazole have good oral bioavailability and the intravenous

� 2009 Elsevier Ltd. All rights reserved.

Examples of empirical antibiotic choices in surgery

Infection Initial empirical choice Penicillin allergy (non-anaphylaxis) Route Duration (approximate) Cautions

Peritonitis Co-amoxiclav

or

Amoxicillin þ metronidazole þ aminoglycoside

(e.g. gentamicin)

Cefuroxime þ metronidazole i.v. 5e7 days Risk of multi-resistant Gram-negative

organisms

Biliary infections Co-amoxiclav

or

Amoxicillin þ metronidazole þ aminoglycoside

(e.g. gentamicin)

Cefuroxime þ metronidazole i.v. 7e10 days Risk of multi-resistant Gram-negative

organisms

Osteomyelitis Flucloxacillin þ fusidic acid/rifampicin Clindamycin Initially i.v. 6 weeks in total Biopsy before treatment if possible

Never use rifampicin or fusidic acid

monotherapy

Necrotizing infections of

soft tissue

Amoxicillin þ metronidazole þ aminoglycoside

(e.g. gentamicin)

or

Piperacillin/tazobactam þ clindamycin

Clindamycin þ ciprofloxacin i.v. Depends upon clinical

response/severity

An adjunct to surgery

Surgical-site infection Clean surgery: Flucloxacillin

Contaminated/dirty: Co-amoxiclav

Clindamycin

Doxycycline

Initially i.v. Depends upon clinical

response/severity

Consider likelihood of MRSA. Prophylactic

antibiotics may have altered flora

Acute pyelonephritis Aminoglycoside (e.g. gentamicin)

or

Co-amoxiclav

Aminoglycoside (e.g. gentamicin) Initially i.v. 10e14 days Risk of multi-resistant Gram-negative

organisms

Epiglottitis Cefuroxime/cefotaxime

or ciprofloxacin

Cefuroxime/cefotaxime Initially i.v. 7e10 days Seek advice on prophylaxis for contacts of

invasive Haemophilus influenzae infection

These examples are provided as a guide. Where available, local prescribing guidelines should be followed. For doses, refer to the British National Formulary or the Renal Drug Handbook (in cases of renal dysfunction).

Contact the microbiologist if there is no response, physical condition deteriorates, if there is a possibility of allergy to the empirical agents or if there is a history of MRSA infection or colonization.

Table 1

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route offers little advantage in administration. Oral administra-

tion may avoid the need for intravenous access, thereby reducing

the risks of nosocomial bacteraemia.

Penicillin allergy e Allergy to penicillin is the most commonly

reported antibiotic reaction. The nature of the allergy should be

carefully explored and then documented in the medical notes and

on the drug chart. Many ‘allergies’ consist of gastrointestinal

upset (nausea, diarrhoea), which are common reactions to anti-

biotic administration and can be disregarded. True IgE-mediated

allergy is characterized by urticaria, laryngeal oedema, bron-

chospasm, hypotension or local swelling (including colic and

vomiting) within 1e2 h of administration. However, only

a minority of patients who claim to be penicillin allergic have

true IgE-mediated allergy. StevenseJohnson syndrome and toxic

epidermal necrolysis are more dangerous than anaphylaxis and

also require avoidance of penicillins. Delayed reactions have

many other causes. Many late-onset macular/papular rashes are

not IgE-mediated, but may be related to the drug and may still

require avoidance. It should be noted that mild previous reac-

tions do not guarantee mild reactions in the future. In general,

penicillins (including extended-spectrum agents such as co-

amoxiclav and piperacillin/tazobactam) should be avoided in

patients who report penicillin allergy. In patients without IgE-

mediated reactions, cephalosporins and other beta-lactams (e.g.

carbapenems and aztreonam) may be used with caution. Most

guidelines give options for penicillin-allergic patients but where

there is doubt, advice should be sought from pharmacy or

a microbiologist.

What are the next steps?

Having decided on the antibiotic and the route of administration,

the clinical response and inflammatory markers should be

monitored closely.

Duration e Establishing the duration of treatment is important in

order to maintain a favourable balance between adequately

treating the infection and minimizing the development of adverse

effects (e.g. resistance, CDAD). Antibiotics should be given for

the shortest duration possible and many infections can be

effectively treated with short-duration therapy (one week or less)

e particularly when an infective focus has been drained, or

source control is effective. For example, patients with compli-

cated intra-abdominal infections (e.g. peritonitis) can be safely

treated with 5e7 days of antibiotics, or even less if the infection

is localized (e.g. localized appendix perforation).8 Five days of

antibiotic therapy are adequate for most post-operative chest

infections, and three days for uncomplicated urinary tract

infections.

A review or stop date should be clearly stated on the

prescription chart and the need for continuing therapy should be

reviewed daily. Microbiological specimens taken before

commencing antibiotics that fail to grow any pathogens may be

reassuring when making a decision to stop treatment.

Switching from the IV to oral route e Many UK hospitals have

incorporated a switch from intravenous to oral antibiotics into

their prescribing guidelines. This allows parenteral therapy to be

limited to the early phase of treatment, with the course

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completed via the oral route once the patient has clinically

improved. This has several advantages including earlier

discharge from hospital, reduced risk of cannula-site infection

and reduced cost.9 The criteria for switching to oral therapy

usually include:9

� clinical response

� defervescence

� improvement in inflammatory markers

� absence of co-morbidity/immunosuppression that would

necessitate intravenous treatment

� appropriate oral agent(s) being available that cover the

pathogen(s) causing the infection and that achieve adequate

penetration at the infection site

� absence of gastrointestinal problems causing reduced

absorption.

A switch to oral therapy is often appropriate after 48 h of

intravenous treatment, but this depends on the individual and

local policy. It is important to continue to monitor the clinical

response and inflammatory markers after a switch has been made.

Other measures e Antibiotics form only one part of the

treatment of surgical infection. The penetration of antibiotics

into enclosed spaces is poor and pus may render the agent

inactive. It is therefore imperative that collections are drained

and free drainage restored (adequate source control). In

a patient not clinically responding to appropriate antibiotic

therapy, imaging should be considered to search for a hidden

collection. Foreign bodies also reduce the effectiveness of

antibiotics and should be removed wherever possible, partic-

ularly if the clinical response is poor. This also applies to

intravascular devices; blood cultures from each lumen of a long

catheter (in addition to peripheral cultures) should be taken as

part of the investigation of fever in a surgical patient. Whilst

some line infections can be managed with the catheter kept in

place, others, such as S. aureus and Candida spp., almost

always necessitate line removal.

How do I take into account local epidemiology?

Many UK hospitals have local policies to direct antimicrobial use

in order to:10

� provide appropriate empirical choices for a wide range of

infections

� limit further evolution of bacterial resistance

� consider local epidemiology and resistance patterns

� control costs1

� limit the risk of healthcare-associated infections9 (e.g. CDAD).

Antibiotic prescribing guidelines are reviewed regularly so

that up-to-date resistance patterns are reflected in the recom-

mendations. An increasing national prevalence of CDAD with

several large and well-publicized outbreaks has resulted in

changes to many antibiotic policies. Cephalosporins, previ-

ously a mainstay of surgical prescribing, have been removed

from many surgical protocols due to their association with

CDAD. Replacements include co-amoxiclav, piperacilline

tazobactam and amoxicillin/gentamicin combinations,

although it should be remembered that almost all antibiotics

can result in CDAD.

To further promote prudent antibiotic prescribing, some

hospitals have introduced a list of ‘restricted’ antimicrobials.10

� 2009 Elsevier Ltd. All rights reserved.

Antibiotic therapy

Is the antibiotic for prophylaxis or treatment?

Yes

Yes

No

Yes

Yes

No

No

Is there good clinical evidence of infection?Send data (cultures, WBC, CRP, imaging) to assist diagnosis

Do previous microbiology data existto guide therapy?

Can you wait formicrobiology data?

Follow prophylaxis guidelinesappropriate for the procedure

Are adjunctive measures required?

Antibiotics are not indicatedEnsure regular review of patient and laboratory results

Complicated patient or infection?Contact microbiologist

Targeted therapy is possible; base antibiotic choice on sensitivity data

Set a stop or review dateReview need for antibiotics dailySwitch to oral therapy as soon as appropriateKeep courses of antibiotic short

Empirical regimenUse local guidelines (if available), but consider:• likely focus of infection• carriage of resistant organisms (e.g. MRSA)• type of ward/outbreaks• previous use of antibiotics• allergies; liver/renal function

Set a stop or review dateReview need for antibiotics dailyNarrow the spectrum when data is available,then move to targeted therapySwitch to oral therapy as soon as appropriateKeep courses of antibiotic short

• drainage of abscess or collection• relief of obstruction• removal of foreign body• removal of catheter

WBC: White blood cell

CRP: C-reactive protein

MRSA: Methicillin-resistant Staphylococcus aureus

Figure 1

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Such antibiotics cannot be prescribed without discussion with

a microbiologist, and their use is warranted only when no

alternative agent is available. Antibiotics that are commonly

restricted include those that are particularly broad-spectrum (e.g.

carbapenems), expensive (e.g. linezolid) or associated with the

promotion of CDAD (e.g. cephalosporins).

Guidelines never cover all eventualities and in difficult cases

(e.g. those with complex histories, previous exposure to multiple

antibiotics, multiple allergies or unusual or complicated infec-

tions) microbiological advice should always be sought. Advice

on appropriate specimens and investigations may also be vital in

these patients.

Specialist areas e Intensive care (ICU) and high-dependency

(HDU) units often appear to have their own unique bacterial flora

and the prevalence of antibiotic-resistant organisms is usually

significantly higher than on other hospital wards. This is largely

because patients usually arrive with a substantial ‘antibiotic

history’ and these units are heavy users of antibiotics, particu-

larly empirically given, broad-spectrum agents. Unusual bacterial

species and increased resistance may necessitate the use of

antimicrobials infrequently encountered elsewhere in the

hospital, and this may make appropriate antibiotic choice diffi-

cult. Advice from a microbiologist who is familiar with the

ecology of the unit is indispensable. Once returned to a regular

ward, an ex-ITU or HDU patient remains at increased risk of

SURGERY 27:10 439

resistant and unusual organisms and this should be considered

when choosing empirical antibiotics for them.

Summary

The rational use of antimicrobial agents is crucial if the effective-

ness of antibiotics is to be maintained. Figure 1 illustrates an

example of an algorithm that could be used to aid antibiotic therapy

and highlights many of the key decision areas discussed. A

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