Chapter 12 Chemotherapy of infections
Infection is a major category of human disease and skilled management of antimicrobial drugs is of the first importance. The term chemotherapy is used for the drug treatment of infections in which the infecting agents (viruses, bacteria, protozoa, fungi, worms) are destroyed or removed without injuring the host. The use of the term to cover all drug or synthetic drug therapy needlessly removes a distinction which is convenient to the clinician and has the sanction of long usage. By convention the term is also used to include therapy of cancer. This chapter will examine:
• Classification of antimicrobial drugs.
• Principles of optimal antimicrobial therapy.
• Use of antimicrobial drugs: choice; combinations; chemoprophylaxis and pre-emptive suppressive therapy; chemoprophylaxis in surgery.
• Special problems with antimicrobial drugs: resistance; superinfection; masking 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:
In order to use chemotherapy successfully, we must search for substances which have an affinity for the cells of the parasites and a power of killing them greater than the damage such substances cause to the organism itself … This means … we must learn to aim, learn to aim with chemical substances.
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.
the magic bullets have lost some of their magic. One solution may be to find alternatives to antibiotics when resistance appears, but there is also an urgent need for new antibiotics to be developed. Few pharmaceutical companies are now involved in antibiotic development … The high cost of development, the prolonged safety evaluation, and the probable short duration of field use and the present tendency for any new compound to induce resistance all militate against major investment in new compounds.8
(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:
• Bacteriostatic, i.e. those that act primarily by arresting bacterial multiplication, such as sulfonamides, tetracyclines and chloramphenicol.
• Bactericidal, i.e. those which act primarily by killing bacteria, such as penicillins, aminoglycosides and rifampicin.
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).
Fig. 12.1 Efficacy of antimicrobials: examples of concentration-dependent and time-dependent killing (see text) (cfu = colony-forming units).
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.
How antimicrobials act – sites of action
It should always be remembered that drugs are seldom the sole instruments of cure but act together with the natural defences of the body. Antimicrobials may act at different sites in the target organism, and these are characteristically structures or metabolic pathways that differ from those in the human host – this allows for ‘selective toxicity’:
The cell wall
Bacterial multiplication involves breakdown and extension of the cell wall; interference with these processes prevents the organism from resisting osmotic pressures, so that it bursts. Obviously, the drugs are effective principally against growing cells. They include: penicillins, cephalosporins, vancomycin, bacitracin, cycloserine.
The cytoplasmic membrane
Drugs that interfere with its structure include: polyenes (nystatin, amphotericin), azoles (fluconazole, itraconazole), polymyxins (colistin, polymyxin B) and daptomycin.
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.
Make a diagnosis
as precisely as is possible and define the site of infection, the organism(s) responsible and their susceptibility to a range of antimicrobial agents (to give several therapeutic options to cater for different sites of infection and the possibility of allergies or other drug sensitivities in the infected individual). This objective will be more readily achieved if all relevant samples for laboratory culture are taken before treatment is begun. Once antimicrobials have been administered, isolation of the underlying organism by culture may be inhibited and its place in diagnostic samples may be taken by resistant, colonising bacteria which obscure the true causative pathogen. New diagnostic methods that rely on detecting specific microbial nucleic acids (e.g. the polymerase chain reaction, PCR), lipids or proteins allow detection of the causative pathogen in patients who have already received antimicrobial therapy, although it is currently usually not possible simultaneously to determine the antimicrobial susceptibility patterns of these microbes.
It is inconsistent that the assessment of new antibiotics for therapeutic use is very much more rigorously controlled than is the introduction of diagnostic tests that direct their use – Gluud and Gluud propose a harmonised approach to the assessment and regulation of new diagnostic procedures in clinical microbiology.10
Remove barriers to cure,
e.g. drain abscesses, remove obstruction in the urinary tract and infected intravenous catheters.
Decide whether chemotherapy is really necessary
Chronic abscesses or empyemata respond poorly to antibiotics alone and require surgical drainage, although chemotherapeutic cover may be essential if surgery is undertaken in order to avoid dissemination of infection during the operation. Even some acute infections are better managed symptomatically than by antimicrobials; thus the risks of adverse drug reactions for previously healthy individuals might outweigh the modest clinical benefits that follow antibiotic therapy of salmonella gastroenteritis and streptococcal sore throat.
Select the best drug
This involves consideration of the following factors:
• Specificity: indiscriminate use of broad-spectrum drugs promotes antimicrobial resistance and encourages opportunistic infections, e.g. with yeasts (see p. 167). At the beginning of treatment, empirical ‘best guess’ chemotherapy of reasonably broad spectrum must often be given because the susceptibility and identity of the responsible microbe is uncertain. The spectrum may be narrowed once these are microbiologically confirmed.
• Pharmacokinetic factors: to ensure that the chosen drug is capable of reaching the site of infection in adequate amounts, e.g. by crossing the blood–brain barrier.
• The patient: who may previously have exhibited allergy to a group of antimicrobials or whose routes of elimination may be impaired, e.g. by renal disease.
Administer the drug
in optimum dose and frequency and by the most appropriate route(s). Inadequate doses may encourage the development of microbial resistance. In general, on grounds of practicability, intermittent dosing is preferred to continuous infusion. Plasma concentration monitoring can be performed to optimise therapy and reduce adverse drug reactions (e.g. aminoglycosides, vancomycin).
Continue therapy
until apparent cure has been achieved; most acute infections are treated for 5–10 days. There are many exceptions to this, such as typhoid fever, tuberculosis and infective endocarditis, in which relapse is possible long after apparent clinical cure and so the drugs are continued for a longer period determined by comparative or observational trials. Otherwise, prolonged therapy is to be avoided because it increases costs and the risks of adverse drug reactions.
Test for cure
In some infections, microbiological proof of cure is desirable because disappearance of symptoms and signs occurs before the organisms are eradicated. This is generally restricted to especially susceptible hosts, e.g. urinary tract infection in pregnancy. Confirmatory culture must be done, of course, after withdrawal of chemotherapy.
Prophylactic chemotherapy
for surgical and dental procedures should be of very limited duration, often only a single large dose being given (see p. 167).
Carriers of pathogenic or resistant organisms
should not routinely be treated to remove the organisms for it may be better to allow natural re-establishment of a normal flora. The potential benefits of clearing carriage must be weighed carefully against the inevitable risks of adverse drug reactions.
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:
1. Choice of antimicrobial follows automatically from the clinical diagnosis because the causative organism is always the same, and is virtually always sensitive to the same drug, e.g. meningococcal septicaemia (benzylpenicillin), some haemolytic streptococcal infections, e.g. scarlet fever, erysipelas (benzylpenicillin), typhus (tetracycline), leprosy (dapsone with rifampicin).
2. The infecting organism is identified by the clinical diagnosis, but no safe assumption can be made as to its sensitivity to any one antimicrobial, e.g. tuberculosis.
3. A single infecting organism is not identified by the clinical diagnosis, e.g. in urinary tract infection or abdominal surgical wound infection.
Particularly in the second and third categories, choice of an antimicrobial may be guided by:
Knowledge of the likely pathogens
(and their current local susceptibility rates to antimicrobials) in the clinical situation. Thus co-amoxiclav might be a reasonable first choice for lower urinary tract infection (coliform organisms – depending on the prevalence of resistance locally), and benzylpenicillin for meningitis in the adult (meningococcal or pneumococcal).
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.
Combinations
Treatment with a single antimicrobial is sufficient for most infections. The indications for use of two or more antimicrobials are:
• To avoid the development of drug resistance, especially in chronic infections where many bacteria are present (hence the chance of a resistant mutant emerging is high), e.g. tuberculosis.
• To broaden the spectrum of antibacterial activity: (1) in a known mixed infection, e.g. peritonitis following gut perforation, or (2) where the infecting organism cannot be predicted but treatment is essential before a diagnosis has been reached, e.g. septicaemia complicating neutropenia or severe community-acquired pneumonia.
• To obtain potentiation (or ‘synergy’), i.e. an effect unobtainable with either drug alone, e.g. penicillin plus gentamicin for enterococcal endocarditis.
• To enable reduction of the dose of one component and hence reduce the risks of adverse drug reactions, e.g. flucytosine plus amphotericin B for Cryptococcus neoformans meningitis.
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:
• True prevention of primary infection: rheumatic fever,11 recurrent urinary tract infection.
• Prevention of opportunistic infections, e.g. due to commensals getting into the wrong place (coagulase-negative staphylococcal prosthetic joint infection from the patient's skin during the operation, and peritonitis after bowel surgery). Note that these are both high-risk situations of short duration; prolonged administration of drugs before surgery would result in the areas concerned (mouth and bowel) being colonised by drug-resistant organisms with potentially disastrous results (see below). Immunocompromised patients can benefit from longer-term chemoprophylaxis, e.g. of Gram-negative septicaemia complicating neutropenia with an oral quinolone, or of Pneumocystis carinii pneumonia with co-trimoxazole.
• Suppression of existing infection before it causes overt disease, e.g. tuberculosis, malaria.
• Prevention of acute exacerbations of a chronic infection, e.g. bronchitis, cystic fibrosis.
• Prevention of spread among contacts (in epidemics and/or sporadic cases). Spread of influenza A can be partially prevented by amantadine; rifampicin may be used when there is a case of meningococcal meningitis in a family.
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:
• When the risk of infection is high because of large numbers of bacteria at the operative site, e.g. in operations on the large bowel.
• When the risk of infection is low but the consequences of infection would be disastrous, e.g. infection of prosthetic joints or prosthetic heart valves.
• When the risks of infection are low but randomised controlled trials have shown the benefits of prophylaxis to outweigh the risks, e.g. single-dose antistaphylococcal prophylaxis for uncomplicated hernia and breast surgery.
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 selected
in the light of knowledge of the likely pathogens at the sites of surgery and their locally prevalent antimicrobial susceptibility.
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).
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
• Naturally resistant strains. Some bacteria are innately resistant to certain classes of antimicrobial agent, e.g. coliforms and many other Gram-negative bacteria possess outer cell membranes which protect their cell walls from the action of certain penicillins and cephalosporins. Facultatively anaerobic bacteria (such as Escherichia coli) lack the ability to reduce the nitro group of metronidazole which therefore remains in an inactive form.
• Spontaneous mutation brings about organisms with novel antibiotic resistance mechanisms. If these cells are viable, in the presence of the antimicrobial agent selective multiplication of the resistant strain occurs so that it eventually dominates.
• Transmission of genes from other organisms is the commonest and most important mechanism. Genetic material may be transferred, e.g. in the form of plasmids which are circular strands of DNA that lie outwith the chromosomes and contain genes capable of controlling various metabolic processes including formation of β-lactamases (that destroy some penicillins and cephalosporins), and enzymes that inactivate aminoglycosides. Alternatively, genetic transfer may occur through bacteriophages (viruses which infect bacteria), particularly in the case of staphylococci.
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.
Opportunistic infection
arises in patients whose immune systems are compromised or whose phagocytic cellular defences have been reduced by disease (e.g. AIDS, hypogammaglobulinaemia, leukaemia) or drugs (e.g. cytotoxics). Such infections may involve organisms that rarely or never cause clinical disease in normal hosts. Treatment of possible infections in such patients should be prompt, initiated before the results of bacteriological tests are known, and usually involve combinations of bactericidal drugs administered parenterally. Infections of this type include Pneumocystis carinii pneumonia, and ‘primary’ septicaemia in neutropenic patients with gut organisms such as Escherichia coli and Klebsiella spp. which cross the mucosa of the gut and invade the bloodstream directly. Local defences may also be compromised and allow opportunistic infection with lowly pathogens even in otherwise healthy hosts: the best example is Staphylococcus epidermidis infection of intravenous catheters.
Masking of infections
Masking of infections by chemotherapy is an important possibility. For example, a course of penicillin adequate to cure gonorrhoea may prevent simultaneously contracted syphilis from showing primary and secondary stages without effecting a cure, and a serological test for syphilis should therefore be done 3 months after treatment for gonorrhoea.
Drugs of choice
For detailed guidance on the choice of antimicrobial drugs for particular infections the reader is referred to Chapters 13 and 14, and to a variety of contemporary clinical sources, including textbooks of microbiology and infectious diseases.
In previous editions we have referred to the current ‘Medical Letter on Drugs and Therapeutics’ and ‘Treatment Guidelines from the Medical Letter’ (USA) editions from 2000 to 2010 (current version available online at: http://www.medicalletter.org/downloads/t94-1.pdf), and this is still valuable although it is of most relevance to North American practice.
Detailed guidance, intended for use by primary care physicians in England and including evidence-based recommendations on antibiotic choice for particular infections and extensive reference lists, is available via the Health Protection Agency website (http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1279888711402). We also recommend section 5 of the Electronic British National Formulary (http://bnf.org/bnf/bnf/current/2071.htm)
Tables on drugs for viruses, fungi, protozoa and helminths are provided in Chapter 15.
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