Chemotherapy of infections

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Chapter 12 Chemotherapy of infections

History

Many substances that we now know to possess therapeutic efficacy were first used in the distant past. The Ancient Greeks used male fern, and the Aztecs Chenopodium, as intestinal anthelminthics. The Ancient Hindus treated leprosy with Chaulmoogra. For hundreds of years moulds have been applied to wounds, but, despite the introduction of mercury as a treatment for syphilis (16th century), and the use of cinchona bark against malaria (17th century), the history of modern rational chemotherapy did not begin until Ehrlich1 developed the idea from his observation that aniline dyes selectively stained bacteria in tissue microscopic preparations and could selectively kill them. He invented the word ‘chemotherapy’ and in 1906 he wrote:

The antimalarials pamaquin and mepacrine were developed from dyes and in 1935 the first sulfonamide, linked with a dye (Prontosil), was introduced as a result of systematic studies by Domagk.2 The results obtained with sulfonamides in puerperal sepsis, pneumonia and meningitis were dramatic and caused a revolution in scientific and medical thinking.

In 1928, Fleming3 accidentally rediscovered the long-known ability of Penicillium fungi to suppress the growth of bacterial cultures, but put the finding aside as a curiosity. His Nobel lecture in 1945 was prophetic for our current times: ‘It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.’

In 1939, principally as an academic exercise, Florey4 and Chain5 undertook an investigation of antibiotics, i.e. substances produced by microorganisms that are antagonistic to the growth or life of other microorganisms.6 They prepared penicillin and confirmed its remarkable lack of toxicity.7 When the preparation was administered to a policeman with combined staphylococcal and streptococcal septicaemia there was dramatic improvement; unfortunately the manufacture of penicillin in the local pathology laboratory could not keep pace with the requirements (it was also extracted from the patient’s urine and re-injected); it ran out and the patient later succumbed to infection.

In recent years, however:

(See the review by Morel and Mossialos9 on how this perverse economic incentive could be turned around.)

Classification of antimicrobial drugs

Antimicrobial agents may be classified according to the type of organism against which they are active and in this book we follow the sequence:

A few antimicrobials have useful activity across several of these groups. For example, metronidazole inhibits obligate anaerobic bacteria as well as some protozoa that rely on anaerobic metabolic pathways (such as Trichomonas vaginalis).

Antimicrobial drugs have also been classified broadly into:

The classification is in part arbitrary because most bacteriostatic drugs are bactericidal at high concentrations, under certain incubation conditions in vitro, and against some bacteria. However, there is some clinical evidence for use of conventionally bactericidal drugs for infective endocarditis and meningitis.

Bactericidal drugs act most effectively on rapidly dividing organisms. Thus a bacteriostatic drug, by reducing multiplication, may protect the organism from the killing effect of a bactericidal drug. Such mutual antagonism of antimicrobials may be clinically important, but the matter is complex because of the multiple factors that determine each drug’s efficacy at the site of infection. In vitro tests of antibacterial synergy and antagonism may only distantly replicate these conditions.

Probably more important is whether its antimicrobial effect is concentration-dependent or time-dependent. Examples of the former include the quinolones and aminoglycosides in which the outcome is related to the peak antibiotic concentration achieved at the site of infection in relation to the minimum concentration necessary to inhibit multiplication of the organism (the minimum inhibitory concentration, or MIC). These antimicrobials produce a prolonged inhibitory effect on bacterial multiplication (the post-antibiotic effect, or PAE) which suppresses growth until the next dose is given. In contrast, agents such as the β-lactams and macrolides have more modest PAEs and exhibit time-dependent killing; their concentrations should be kept above the MIC for a high proportion of the time between each dose (Fig. 12.1).

Figure 12.1 shows the results of an experiment in which a culture broth initially containing 106 bacteria per mL is exposed to various concentrations of two antibiotics, one of which exhibits concentration-dependent and the other time-dependent killing. The ‘control’ series contains no antibiotic, and the other series contain progressively higher antibiotic concentrations from 0.5 × to 64 × the MIC. Over 6 h incubation, the time-dependent antibiotic exhibits killing, but there is no difference between the 1 × MIC and 64 × MIC. The additional cidal effect of rising concentrations of the antibiotic which has concentration-dependent killing can be clearly seen.

Principles of antimicrobial chemotherapy

The following principles, many of which apply to drug therapy in general, are a guide to good practice with antimicrobial agents.

Use of antimicrobial drugs

Choice

Identification of the microbe and performing susceptibility tests take time, and therapy at least of the more serious infections must usually be started on the basis of the informed ‘best guess’ (i.e. ‘empirical’ therapy). Especially in critically ill patients, choosing initial therapy to which the infecting microbes are susceptible has been shown to improve the outcome – with the worldwide rise in prevalence of multiply resistant bacteria during the past decade, knowledge of local antimicrobial resistance rates is therefore an essential prerequisite. Publication of these rates (and corresponding guidelines for choice of empirical therapy for common infections) is now an important role for clinical diagnostic microbiology laboratories. Such guidelines must be reviewed regularly to keep pace with changing resistance patterns.

When considering ‘best guess’ therapy, infections may be categorised as those in which:

Particularly in the second and third categories, choice of an antimicrobial may be guided by:

Rapid diagnostic tests

Rapid detection of markers of infection such as C-reactive protein (CRP) and procalcitonin assays are now available, and evidence is accruing as to how they should best be used. Both CRP and procalcitonin concentrations rise in the serum within a few hours of the commencement of serious bacterial infections, and it appears that clinical decisions on antimicrobial use based on algorithms that include the results of such assays may be more accurate, and may spare some patients from antibiotic exposure.

Use of tests of this type to diagnose involvement of specific pathogens has undergone a revolution with the widespread introduction of affordable, sensitive and specific assays. Increasingly, reliable tests are being introduced which can be used at the patient’s bedside (‘point of care’ tests, POC). Classically, antimicrobials were selected after direct microscopy of smears of body secretions or tissues – thus flucloxacillin may be indicated when clusters of Gram-positive cocci are found (indicating staphylococci), but vancomycin would be preferred in those hospitals with a high prevalence of methicillin-resistant Staphylococcus aureus (MRSA).

Light microscopy will remain useful in this way for many years to come, but use of PCR to detect DNA sequences specific for individual microbial species or resistance mechanisms greatly speeds up the institution of definitive, reliable therapy. These methods are already widely used for diagnosing meningitis (detecting Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae), tuberculosis (including detection of rifampicin resistance) and most viral infections. Quantitative PCR allows monitoring the response to therapy (e.g. monitoring copy numbers of circulating cytomegalovirus (CMV) DNA in a transplant recipient being treated with ganciclovir). Several other novel, rapid non-culture techniques are being assessed for laboratory application, such as proteomics by mass spectroscopy, which allow speciation of bacteria and fungi within a few minutes of their culture in broth or on solid media.

Modification of treatment can be made later if necessary, in the light of conventional culture and susceptibility tests. Treatment otherwise should be changed only after adequate trial, usually 2–3 days, because over-hasty alterations cause confusion and encourage the emergence of resistant organisms.

Route of administration

Parenteral therapy (which may be i.m. or i.v.) is preferred for therapy of serious infections because high therapeutic concentrations are achieved reliably and rapidly. Initial parenteral therapy should be switched to the oral route whenever possible once the patient has improved clinically and as long as a suitable oral antibiotic is available and they are able to absorb it (i.e. not with vomiting, ileus or diarrhoea). Many antibiotics are well absorbed orally, and the long-held assumption that prolonged parenteral therapy is necessary for adequate therapy of serious infections (such as osteomyelitis) is often not supported by the results of clinical trials.

Although i.v. therapy is usually restricted to hospital patients, continuation parenteral therapy of certain infections, e.g. cellulitis, in patients in the community is sometimes performed by specially trained nurses. The costs of hospital stays and some risks of health-care-associated infections are avoided, but this type of management is suitable only when the patient’s clinical state is stable, oral therapy is not suitable, and the infection is amenable to once-daily administration of a suitable antibiotic (usually one having a prolonged half-life).

Oral therapy of infections is usually cheaper and avoids the risks associated with maintenance of intravenous access; on the other hand, it may expose the gastrointestinal tract to higher local concentrations of antibiotic with consequently greater risks of antibiotic-associated diarrhoea. Some antimicrobial agents are available only for topical use to skin, anterior nares, eye or mouth; in general it is better to avoid antibiotics that are also used for systemic therapy because topical use may be especially likely to select for resistant strains. Topical therapy to the conjunctival sac is used for therapy of infections of the conjunctiva and the anterior chamber of the eye.

Inhalational antibiotics are of proven benefit for pseudomonas colonisation of the lungs in children with cystic fibrosis (twice-daily tobramycin), monthly pentamidine for pneumocystis prophylaxis and zanamivir for influenza A and B (if commenced within 48 h). In addition, there is probable benefit for colistin in cystic fibrosis and as an adjunct to parenteral antibiotics for Gram-negative pneumonia, for aminoglycosides in bronchiectasis, and for ribavirin for RSV infection in children.

Other routes used for antibiotics on occasion include rectal (as suppositories), intra-ophthalmic, intrathecal (to the CSF), and by direct injection or infusion to infected tissues.

Chemoprophylaxis and pre-emptive suppressive therapy

It is sometimes assumed that what a drug can cure it will also prevent, but this is not necessarily so. The basis of effective chemoprophylaxis is the use of a drug in a healthy person to prevent infection by one organism of reliable and predictable susceptibility, e.g. benzylpenicillin against a Group A streptococcus. However, the term chemoprophylaxis is commonly extended to include suppression of existing infection.

It is essential to know the organisms causing infection and their local resistance patterns, and the period of time the patient is at risk. A narrow-spectrum antibiotic regimen should be administered only during this period – ideally for a few minutes before until a few hours after the risk period. It is therefore much easier to define chemotherapeutic regimens for short-term exposures (e.g. surgical operations) than it is for longer-term and less well-defined risks. The main categories of chemoprophylaxis may be summarised as follows:

Long-term prophylaxis of bacterial infection can be achieved often by doses that are inadequate for therapy once the acute infection has been fully treated.

Attempts to use drugs routinely to prevent infection when a wide and unpredictable range of organisms may be involved, e.g. pneumonia in the unconscious patient and urinary tract infection in patients with long-term urinary catheters, have not only failed but have sometimes encouraged infections with less susceptible organisms. Attempts routinely to prevent bacterial infection secondary to virus infections, e.g. in respiratory tract infections and measles, have also not been sufficiently successful to outweigh the disadvantages. In these situations it is generally better to be alert for complications and then to treat them promptly and vigorously rather than to try to prevent them.

Chemoprophylaxis in surgery

The principles governing use of antimicrobials in this context are as follows.

Chemoprophylaxis is justified:

In the UK, controversy followed the publication in 2006 of the updated guidelines of the British Society for Antimicrobial Chemotherapy’s working party on the prevention of infective endocarditis (see the Guide to further reading for illustrative articles). The new guidelines advocated a much more restricted policy of administering antimicrobial prophylaxis at the time of medical interventions, including dentistry. This was based on the lack of convincing evidence for the efficacy of this time-honoured practice, with the exception of those patients at highest risk (for example, those with prosthetic heart valves or who had previously suffered episodes of infective endocarditis). This policy was supported by the subsequent publication of evidence-based guidelines from the National Institute for Health and Clinical Excellence (NICE) in England, and similar guidelines have subsequently been promoted in other countries, including the USA.

Antimicrobials should be given

i.v., i.m. or occasionally rectally at the beginning of anaesthesia and for no more than 48 h. A single preoperative dose, given at the time of induction of anaesthesia, has been shown to give optimal cover for most operations. Vancomycin is often included in prophylactic regimens when the patient is known to be a carrier of MRSA or its local prevalence is high (ask microbiological advice).

Specific instances are:

1. Colorectal surgery: there is a high risk of infection with Escherichia coli, Clostridium spp., streptococci and Bacteroides spp. which inhabit the gut (co-amoxiclav or piperacillin).

2. Gastroduodenal surgery: colonisation of the stomach with gut organisms occurs especially when acid secretion is low, e.g. in gastric malignancy, following use of a histamine H2-receptor antagonist or following previous gastric surgery (co-amoxiclav).

3. Gynaecological surgery: because the vagina contains Bacteroides spp. and other anaerobes, streptococci and coliforms (co-amoxiclav).

4. Leg amputation: because there is a risk of gas gangrene in an ischaemic limb and the mortality is high (benzylpenicillin, or metronidazole for the patient with allergy to penicillin).

5. Insertion of prostheses – joints, heart valves, vessels: chemoprophylaxis is justified because infection (Staphylococcus aureus, coagulase-negative staphylococci and coliforms are commonest) often means that the artificial joint, valve or vessel must be replaced. Single perioperative doses of appropriate antibiotics with plasma elimination half-lives of several hours (e.g. cefotaxime) are adequate, but if short half-life agents are used (e.g. flucloxacillin) several doses should be given during the first 24 h.

6. General surgery: clearance of Staphylococcus aureus from the anterior nares of carriers with mupirocin is known to reduce the incidence of wound infection by about a half, and this treatment has recently been shown in one high-quality trial to be effective when targeted only at staphylococcal nasal carriers who were detected by screening nasal swabs with a rapid real-time PCR assay. This strategy is much more potentially attractive than the alternative of treating all patients preoperatively, which has been demonstrated not to reduce infection rates significantly while maximising unnecessary mupirocin exposure.

Problems with antimicrobial drugs

Resistance

Microbial resistance to antimicrobials is a matter of great importance; if sensitive strains are supplanted by resistant ones, then a valuable drug may become useless. Just as ‘some are born great, some achieve greatness, and some have greatness thrust upon them’,12 so microorganisms may be naturally (‘born’) resistant, ‘achieve’ resistance by mutation or have resistance ‘thrust upon them’ by transfer of plasmids and other mobile genetic elements.

Resistance may become more prevalent by spread of microorganisms containing resistance genes, and also by dissemination of the resistance genes among different microbial species. Because resistant strains are encouraged (selected) at the population level by use of antimicrobial agents, antibiotics are the only group of therapeutic agents which can alter the actual diseases suffered by other, untreated individuals. About 50% of antimicrobial use is in human medicine – the remainder being given to animals – and 80% of human use occurs in domiciliary practice, out of hospitals.

Problems of antimicrobial resistance have burgeoned during the past few decades in most countries of the world, both in and out of hospital, and fortunately a number of international bodies have been established devoted to the reduction of resistance worldwide: ‘Our mission is clear: we must work together to preserve the power of antimicrobials and to return these miracle agents to their rightful position as effective treatments of disease’ (Dr Stuart Levy, http://www.tufts.edu/med/apua/).

Some resistant microbes are currently mainly restricted to hospital patients or to those who have recently been in hospital, e.g. MRSA, vancomycin-resistant enterococci (VRE). Others more commonly infect patients in the community, e.g. penicillin- and macrolide-resistant Streptococcus pneumoniae and multiply resistant Mycobacterium tuberculosis, whereas some (such as coliforms that produce ‘extended spectrum β-lactamases’ (ESBLs)) are commoner in hospital but occur also quite commonly in individuals who have never been inpatients.

This is a rapidly changing field, and our technical abilities to detect novel resistance mechanisms and to type resistant strains of microbe have recently improved. As a result, a continuing series of different antimicrobial resistant and virulent microorganisms have been recognised to have emerged recently in Europe and North America. These include: community-acquired, toxin-producing MRSA (primarily affecting previously well young adults and intravenous drug users); multiply resistant Acinetobacter baumanii (including strains introduced by transfer of tsunami victims and Gulf War casualties to hospitals in their home countries); and New Delhi metallo-beta-lactamase (NDM-1) producing strains of coliforms (introduced to hospitals in the West via international air travel of patients who had received medical care in the Indian subcontinent). These problems have spawned a new nomenclature for beta-lactamase resistance mechanisms, and for Gram-negative rod resistance in general – ‘multidrug-resistant’ (MDR) strains are resistant to at least three different antimicrobial drug classes, ‘extensively drug-resistant’ (XDR) strains are susceptible to only one or two antimicrobial options, while ‘pan-drug resistant’ (PDR) strains are no longer amenable to antimicrobial treatment.

It is to be hoped that our abilities to treat and prevent such infections will continue to increase in parallel with our abilities to recognise them (laboratory testing methodology also needs to be developed continually because, for example, some of the new coliform beta-lactamases (such as ‘AmpC’-producing strains) can be difficult to detect with conventional techniques). Considerable hope is given by the remarkable reductions in MRSA bacteraemia rates reported from English hospitals in the past 5 years, which have apparently resulted from mandated enforcement of conventional but stringent screening, clearance and infection control measures: there was a 46% fall in the 2 years from July 2008 to September 2010. Hence rising resistance rates are not inevitable.

In well-controlled observational studies, the outcomes of infections with antibiotic-resistant bacteria are generally significantly poorer than those with susceptible strains, and the costs of therapy and associated length of hospital stay are greater.

Mechanisms of resistance

act as follows:

Resistance is mediated most commonly by the production of enzymes that modify the drug, e.g. aminoglycosides are phosphorylated, β-lactamases hydrolyse penicillins. Other mechanisms include decreasing the passage into or increasing the efflux of drug from the bacterial cell (e.g. meropenem resistance in Pseudomonas aeruginosa), modification of the target site so that the antimicrobial binds less effectively (e.g. methicillin resistance in staphylococci), and bypassing of inhibited metabolic pathways (e.g. resistance to trimethoprim in many bacteria). More is becoming known of the complex molecular systems which control expression of antimicrobial resistance, and this knowledge should soon lead to novel compounds that inhibit resistance mechanisms at the genetic and phenotypic levels (see Stix13 for an example).

Limitation of resistance

to antimicrobials may be achieved by ‘antibiotic stewardship’ which includes:

Avoidance of indiscriminate use by ensuring that the indication for, and the dose and duration of treatment are appropriate; studies of hospital and domiciliary prescribing have shown that up to 35% of antimicrobial courses administered in the UK may be inappropriate – either not indicated at all, or administered for too long. Performing ward rounds on areas of the hospital with high rates of antibiotic use (e.g. intensive care units, acute surgical wards) to assess the justification for treatment of individual patients and to educate other doctors in limiting unnecessary courses of antibiotics has recently become an important role for clinical microbiologists.

Restricting use of antimicrobial combinations to appropriate circumstances, e.g. tuberculosis.

Constant monitoring of resistance patterns in a hospital or community (changing recommended antibiotics used for empirical treatment when the prevalence of resistance becomes high), and good infection control in hospitals (e.g. isolation of carriers, hand hygiene practices for ward staff) to prevent the spread of resistant bacteria.

Restricting drug use, e.g. delaying the emergence of resistance by limiting the use of the newest member of a group of antimicrobials so long as the currently used drugs are effective; restricting use of a drug may become necessary where it promotes the proliferation of resistant strains.

Avoiding transmission of multiply resistant bacteria among patients and staff in hospital, by health-care workers performing careful hand hygiene between each patient contact, and through identification and isolation of carriers.

‘The over-riding principle of medicine is “do no harm”, yet, in the case of antibiotics, harm is inevitable, for use (even appropriate usage) selects for resistance, complicating the treatment of future patients.’14

Antibiotic policies are agreed among clinicians, microbiologists and pharmacists which guide prescribing towards a limited range of agents which provide adequate choice to cover therapy of important infections while limiting confusion and maximising the opportunities for economical purchase in bulk. Analysis of the many trials of ‘antibiotic cycling’, where first-choice antibiotics for commonly treated infections in a hospital or ward are formally rotated with a periodicity of several months or years, has shown that this strategy does not reduce overall resistance rates or total antibiotic usage. Use of ‘delayed prescriptions’ in primary health care management of less serious infections, where a prescription is given to patients for them to take to the pharmacy only if their symptoms fail to improve in 24–48 h, has been shown to reduce antibiotic usage and not impair outcomes in upper and lower respiratory tract infection.

Doctors are encouraged to avoid use of antimicrobial agents whenever possible, and international efforts are being made to educate the general public not to expect an antibiotic prescription for minor ailments such as coughs and colds (see, for example, http://www.biomedcentral.com/1471-2296/10/20 and http://ecdc.europa.eu/en/EAAD/Pages/Home.aspx/).

Recent prospective studies have shown that initial broad-spectrum empirical therapy given to acutely ill patients in hospital can be safely ‘de-escalated’ to narrower spectrum and cheaper antimicrobial agents as soon as the results of initial cultures have been obtained (i.e. usually after 48 h).

Evidence is accumulating that resistance rates do not rise inevitably and irreversibly (see page 169). In both hospital and domiciliary practice, reductions in antibiotic usage are often shown to be followed by reductions in the prevalence of microbial resistance, although there can be a ‘lag’ of months or years. The situation is sometimes complicated by the phenomenon of ‘linked multiple resistance’ whereby the genes coding resistance mechanisms to several antibiotics are carried on the same genetic elements (e.g. plasmid). In this case, use of any of these antibiotics will select for increased resistance via all the mechanisms carried by the plasmid.

Although clinical microbiology laboratories report microbial susceptibility test results as ‘sensitive/susceptible’ or ‘resistant’ to a particular antibiotic, this is not an absolute predictor of clinical response. In a given patient’s infection, variables such as absorption of the drug, its penetration to the site of infection, and its activity once there (influenced, for example, by protein binding, pH, concentration of oxygen, metabolic state of the pathogen, intracellular location and concentration of microbes) profoundly alter the likelihood that effective therapy will result.

Superinfection

When any antimicrobial drug is used, there is usually suppression of part of the normal bacterial flora of the patient which is susceptible to the drug. Often, this causes no ill effects, but sometimes a drug-resistant organism, freed from competition, proliferates to an extent which allows an infection to be established. The principal organisms responsible are Candida albicans and pseudomonads. But careful clinical assessment of the patient is essential, as the mere presence of such organisms in diagnostic specimens taken from a site in which they may be present as commensals does not necessarily mean they are causing disease.

Antibiotic-associated (or Clostridium difficile-associated) colitis

is an example of a superinfection. It is caused by alteration of the normal bowel flora, which allows multiplication of Clostridium difficile which releases several toxins that damage the mucosa of the bowel and promote excretion of fluid. Almost any antimicrobial may initiate this condition, but the drugs most commonly reported today are cephalosporins and quinolones (e.g. ciprofloxacin). It takes the form of an acute colitis (pseudomembranous colitis) with diarrhoeal stools containing blood or mucus, abdominal pain, leucocytosis and dehydration. A history of antibiotic use in the previous 3 weeks, even if the drug therapy has been stopped, should alert the physician to the diagnosis which is confirmed by detection of C. difficile toxin in the stools and typical appearances on proctosigmoidoscopy. Mild cases usually respond to discontinuation of the offending antimicrobial, allowing re-establishment of the patient’s normal bowel flora, but more severe cases merit treatment with oral metronidazole. Some strains have been associated with particularly severe disease and have caused large outbreaks in hospitals – combined therapy with oral vancomycin and parenteral metronidazole plus intensive care support is required for the most serious cases. Other therapeutic and preventative measures of unproven efficacy include intracolonic instillation of vancomycin, intravenous immunoglobulin and oral probiotics. A variety of investigational antibiotics is also being assessed, such as rifaximin and fidaxomicin (an RNA polymerase inhibitor), and several compounds taken by mouth that may bind and inactivate faecal toxin. Diarrhoea in some cases can be intractable, and desperate measures have included instillation of microbiologically screened donor faeces in an attempt to restore a normal balance of the gut flora – in some cases with surprisingly good response rates of over 80% in therapeutic trials.15

C. difficile may be spread among hospitalised patients on the unwashed hands of health-care workers and also survives well in the environment – symptomatic patients should be isolated and the ward cleaned carefully. Hospital outbreaks have responded to combinations of control measures (‘care bundles’), especially involving severe restriction of the use of cephalosporin and quinolone antibiotics. Antimicrobial agents used instead that seem to carry a lower risk of causing colitis have included co-amoxiclav and piperacillin-tazobactam.

Guide to further reading

Ada G. Vaccines and vaccination. N. Engl. J. Med.. 2001;345:1042–1053.

Alliance for the Prudent Use of Antibiotics (APUA), The APUA website has a wide range of articles and useful links relating to the control of antimicrobial resistance worldwide. Available at: http://www.tufts.edu/med/apua/ (accessed October 2011)

Anon. Antibacterial prophylaxis for orthopaedic surgery. Drug Ther. Bull. 2001;39:43–46.

Anon. Antibacterial prophylaxis in surgery: 1. Gastrointestinal and biliary surgery. Drug Ther. Bull.. 2003;41:84–86.

Anon. Antibacterial prophylaxis in surgery: 3. Arterial surgery in the abdomen, pelvis and lower limbs. Drug Ther. Bull.. 2004;42:43–47.

Anon. Antibacterial prophylaxis in surgery: 2. Urogenital, obstetric and gynaecological surgery. Drug Ther. Bull.. 2004;42:9–12.

Anon. Major changes in endocarditis prophylaxis for dental, GI and GU procedures. Medical Letter. 2007;49:99–100.

Arias C.A., Murray B.E. Antibiotic-resistant bugs in the 21st century – a clinical super-challenge. N. Engl. J. Med.. 2009;360:439–443.

Aymes S. Treatment of staphylococcal infection. Prescriptions must be part of a package that includes infection control. Br. Med. J.. 2005;330:976–977.

Beynon R.P., Bahl V.K., Prendergast B.D. Infective endocarditis. Br. Med. J.. 2006;333:334–339. Available at: http://www.bmj.com/content/333/7563/334.full.pdf+html (accessed 30.10.2011)

Bode L.G., Kluytmans J.A., Wertheim H.F., et al. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N. Engl. J. Med.. 2010;362:9–17.

Boudma L., Luyt C.E., Tubach F., et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomized controlled trial. Lancet. 2010;375:463–474.

Colebrook I., Kenny M. Treatment with prontosil for puerperal infections. Lancet. 1939;2:1319. (a classic paper)

Connaughton M., Commentary: controversies in NICE guidance on infective endocarditis. 2008. Available at http://www.bmj.com/content/336/7647/771.full.pdf (accessed October 2011)

Corwin P., Toop L., McGeoch G., et al. Randomised controlled trial of intravenous antibiotic treatment for cellulitis at home compared with hospital. Br. Med. J.. 2005;330:129–132.

Dancer S.J. How antibiotics can make us sick: the less obvious adverse effects of antimicrobial chemotherapy. Lancet Infect. Dis.. 2004;4:611–619.

Deleo F.R., Otto M., Kreiswirth B.N., Chambers H.F. Community-acquired meticillin-resistant Staphylococcus aureus. Lancet. 2010;375:1557–1568.

Fishman J.A. Infection in organ-transplant recipients. N. Engl. J. Med.. 2007;357:2601–2614.

Fletcher C. First clinical use of penicillin. Br. Med. J.. 1984;289:1721–1723. (a classic paper)

Gluud C.G., Gluud L.L. Evidence based diagnostics. Br. Med. J.. 2005;330:724–726.

Health Protection Agency. The ‘Antimicrobial Resistance’ section of the website of the UK Health Protection Agency (http://www.hpa.org.uk/infections/topics_az/antimicrobial_resistance/menu.htm (accessed October 2011)) is a valuable resource of contemporary background information on the prevalence and epidemiology of infectious diseases and antimicrobial resistance in the UK. Also on the HPA website, quarterly-updated reports on MRSA bacteraemia and Clostridium difficile diarrhoea rates in England and Wales can be found at: http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1259151891722 (accessed October 2011)

Kluytmans J., Struelens M. Meticillin resistant Staphylococcus aureus in the hospital. Br. Med. J.. 2009;338:532–537.

Kwiatkowski D. Susceptibility to infection. Br. Med. J.. 2000;321:1061–1065.

Leibovici L., Shraga B., Andreassen S., et al. How do you choose antibiotic treatment? Br. Med. J.. 1999;318:1614–1616.

Livermore D.M. Minimising antibiotic resistance. Lancet Infect. Dis.. 2005;5:450–459.

Loudon I. Puerperal fever, the streptococcus, and the sulphonamides, 1911–1945. Br. Med. J.. 1987;295:485–490.

Morel C., Mossailos. Stoking the antibiotic pipeline. Br. Med. J.. 2010;340:1115–1118.

Pitout J.D. The latest threat in the war on antimicrobial resistance (NMD beta-lactamases). Lancet Infect. Dis.. 2010;10:578–579.

Pitout J.D. Infections with extended-spectrum beta-lactamase-producing Enterobacteriaceae: changing epidemiology and drug treatment choices. Drugs. 2010;70:313–333.

Queenan A.M., Bush K. Carbapenemases: the versatile beta-lactamases. Clin. Microbiol. Rev.. 2007;20:440–458.

Richie R., Wray D., Stoken T., Prophylaxis against infective endocarditis: summary of NICE guidance. Available online:. 2008. http://www.bmj.com/content/336/7647/770.full.pdf (accessed October 2011)

Ryan E.T., Wilson M.E., Kain K.C. Illness after international travel. N. Engl. J. Med.. 2002;347:505–516.

Safdar N., Handelsman J., Maki D.G. Does combination antimicrobial chemotherapy reduce mortality in Gram-negative bacteraemia? A meta-analysis. Lancet Infect. Dis.. 2004;4:519–527.

Shannon-Lowe J., Matheson N.J., Cooke F.J., Aliyu S.H. Prevention and medical management of Clostridium difficile infection. Br. Med. J.. 2010;340:641–646.

Stix G. An antibiotic resistance fighter. New Sci.. 2006:80–83. April

1 Paul Ehrlich (1854–1915), the German scientist who was the pioneer of chemotherapy and discovered the first cure for syphilis (Salvarsan).

2 Gerhard Domagk (1895–1964), bacteriologist and pathologist, who made his discovery while working in Germany. Awarded the 1939 Nobel prize for Physiology or Medicine, he had to wait until 1947 to receive the gold medal because of Nazi policy at the time.

3 Alexander Fleming (1881–1955). He researched for years on antibacterial substances that would not be harmful to humans. His findings on penicillin were made at St Mary’s Hospital, London. See http://nobelprize.org/nobel_prizes/medicine/laureates/1945/fleming-lecture.pdf (accessed October 2011).

4 Howard Walter Florey (1898–1969), Professor of Pathology at Oxford University.

5 Ernest Boris Chain (1906–1979), biochemist. Fleming, Florey and Chain shared the 1945 Nobel prize for Physiology or Medicine.

6 Strictly, the definition should refer to substances that are antagonistic in dilute solution because it is necessary to exclude various common metabolic products such as alcohols and hydrogen peroxide. The term ‘antibiotic’ is now commonly used for antimicrobial drugs in general, and it would be pedantic to object to this. Today, many commonly used antibiotics are either fully synthetic or are produced by major chemical modification of naturally produced molecules: hence, ‘antimicrobial agent’ is perhaps a more accurate term, but ‘antibiotic’ is much the commoner usage.

7 The importance of this discovery for a nation at war was obvious to these workers but the time, July 1940, was unpropitious, for invasion was feared. The mood of the time is shown by the decision to ensure that, by the time invaders reached Oxford, the essential records and apparatus for making penicillin would have been deliberately destroyed; the productive strain of Penicillium mould was to be secretly preserved by several of the principal workers smearing the spores of the mould into the linings of their ordinary clothes where it could remain dormant but alive for years; any member of the team who escaped (wearing the right clothes) could use it to start the work again (Macfarlane G 1979 Howard Florey, Oxford).

8 Lord Soulsby of Swaffham Prior 2005 Resistance to antimicrobials in humans and animals. British Medical Journal 331:1219.

9 Morel C M, Mossialos E 2010 Stoking the antibiotic pipeline. British Medical Journal 340:1115–1118

10 Gluud C G, Gluud L L 2005 Evidence based diagnostics. British Medical Journal 330:724–726

11 Rheumatic fever is caused by a large number of types of Group A streptococci and immunity is type-specific. Recurrent attacks are commonly due to infection with different strains of these, all of which are sensitive to penicillin and so chemoprophylaxis is effective. Acute glomerulonephritis is also due to Group A streptococci but only a few types cause it, so that natural immunity is more likely to protect and second attacks are rare. Therefore, chemoprophylaxis is not used (see also p. 168).

12 Malvolio in Twelfth Night, act 2 scene 5, by William Shakespeare (1564–1616).

13 Stix G 2006 An antibiotic resistance fighter. New Scientist April: 80–83

14 Livermore D M 2006 Minimising antibiotic resistance. Lancet Infectious Diseases 5:450–459.

15 Garborg K, Waagsbø B, Stallemo A et al 2010 Results of faecal donor instillation therapy for recurrent Clostridium difficile-associated diarrhoea. Scandinavian Journal of Infectious Diseases 42:857–861.

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