Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 13) ppt

SECTION 3 INFECTION AND INFLAMMATION This page intentionally left blank Chemotherapy of infections SYNOPSIS 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 parasitic infections in which the parasites (viruses, bacteria, protozoa, fungi, worms) are destroyed or removed without injuring the hostThe 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. • Classification of antimicrobial drugs • How antimicrobials act • Principles of optimal antimicrobial therapy • Use of antimicrobial drugs: choice; combinations; chemoprophylaxis and pre- emptive suppressive therapy • Problems with antimicrobial drugs: resistance; opportunistic infection; masking of infections • Antimicrobial drugs of choice (Reference table) 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 chaul- moogra. 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 chemo- therapy did not begin until Ehrlich 1 developed the idea from his observation that aniline dyes selec- tively stained bacteria in tissue microscopic prepa- rations 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 sulphonamide, linked with a dye (Prontosil), was introduced as a result of systematic studies by Domagk. 2 The results obtained with sulphonamides 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. 201 II 11 CHEMOTHERAPY OF INFECTIONS in puerperal sepsis, pneumonia and meningitis were dramatic and caused a revolution in scientific and medical thinking. In 1928, Fleming 3 accidentally rediscovered the long-known ability of Penicillium fungi to suppress the growth of bacterial cultures but put the finding aside as a curiosity. In 1939, principally as an academic exercise, Florey 4 and Chain 5 undertook an investigation of antibiotics, i.e. substances produced by microorgan- isms 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 strepto- coccal septicaemia there was dramatic improve- ment; 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. 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. 4 Howard Walter Florey (1898-1969), Professor of Pathology at Oxford University. 5 Ernest Boris Chain (1906-79). 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). Subsequent development amply demonstrated the remarkable therapeutic efficacy of penicillin. Classification of antimicrobial drugs Antimicrobial agents may be classified according to the type of organism against which they are active and in this book follow the sequence: Antibacterial drugs Antiviral drugs Antifungal drugs Antiprotozoal drugs Anthelminthic drugs. A few antimicrobials have useful activity across several of these groups. For example, metronida- zole inhibits obligate anaerobic bacteria (such as Clostridium perfringens) 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 sulphonamides, tetracyclines and chloramphenicol • bactericidal, i.e. those which act primarily by killing bacteria, such as penicillins, cephalosporins, aminoglycosides, isoniazid and rifampicin. Less used in modern clinical practice, the classi- fication is somewhat arbitrary because most bact- eriostatic drugs can be shown to be bactericidal at high concentrations, under certain incubation conditions in vitro and against some bacteria. 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 and changing factors that determine each drug's efficacy at the site of infection. In vitro tests of antibacterial synergy and 202 PRINCIPLES OF ANTIMICROBIAL CHEMOTHERAPY 11 antagonism may only distantly replicate these conditions. Probably more important than whether an anti- biotic is bacteriostatic or bactericidal in vitro is whether its antimicrobial effect is concentration- dependent or h'rae-dependent. Examples of the former include the quinolones and aminoglyco- sides 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 inhibi- tory 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 f3-lactams and macrolides have more modest PAEs and exhibit time-dependent killing; for optimal efficacy, their concentrations should be kept above the MIC for a high proportion of the time between each dose (Fig. 11.1). Figure 11.1 shows the results of an experiment in which a culture broth initially containing 10 6 bacteria per ml is exposed to various concentrations of two antibiotics one of which exhibits concentra- tion- and the other time-dependent killing. The 'Control' series contains no antibiotic, and the other series contain progressively higher antibiotic con- centrations from 0.5 x to 64 x the MIC. Over 6 hours incubation, the time-dependent antibiotic exhibits killing but there is no difference between the 1 x MIC and 64 x MIC. The additional cidal effect of rising concentrations of the antibiotic which has concen- tration-dependent killing can be clearly seen. How antimicrobials act It should always be remembered that drugs are seldom the sole instruments of cure but act together with the natural defences of the body. Antimicro- bials act at different sites in the target organism as follows: The cell wall. This gives the bacterium its charac- teristic shape and provides protection against the much lower osmotic pressure of the environment. Bacterial multiplication involves breakdown and extension of the wall; interference with these pro- cesses prevents the organism from resisting osmotic pressures, so that it bursts. As the cells of higher, e.g. human, organisms do not possess this type of wall, drugs that act here may be especially selective; obviously, the drugs are effective only against grow- ing cells. They include: penicillins, cephalosporins, vancomycin, bacitracin, cycloserine. The cytoplasmic membrane inside the cell wall is the site of most of the microbial cell's biochemical activity. Drugs that interfere with its function include: polyenes (nystatin, amphotericin), azoles (fluconazole, itraconazole, miconazole), polymyxins (colistin, polymyxin B). Protein synthesis. Drugs that interfere at various points with the build-up of peptide chains on the ribosomes of the organism include: chlorampheni- col, erythromycin, fusidic acid, tetracyclines, amino- glycosides, quinupristin/dalfopristin, linezolid. Nucleic acid metabolism. Drugs may interfere • directly with microbial DNA or its replication or repair, e.g. quinolones, metronidazole, or with RNA, e.g. rifampicin • indirectly on nucleic acid synthesis, e.g. sulphonamides, trimethoprim. 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) respons- ible and their sensitivity to drugs. This objective will be more readily achieved if all relevant biolo- gical samples for the laboratory are taken before treatment is begun. Once antimicrobials have been administered, isolation of the underlying organism may be inhibited and its place in diagnostic samples may be taken by resistant, colonizing bacteria which obscure the true causative pathogen. 203 11 CHEMOTHERAPY OF INFECTIONS Concentration dependent killing Fig. I I. I Efficacy of antimicrobials: examples of concentration- dependent and time-dependent killing (see text) (cfu = colony- forming units). Remove barriers to cure, e.g. lack of free drainage of abscesses, obstruction in the urinary or respira- tory tracts, infected intravenous catheters. Decide whether chemotherapy is really necessary. As a general rule, acute infections require chemo- therapy whilst other measures may be more impor- tant for resolution of chronic infections. For example, chronic abscess or empyema respond poorly to antibiotics alone, although chemothera- peutic cover may be essential if surgery is undertaken in order to avoid a flare-up of infection or its dissemination during the breaking down of tissue barriers. Even some of the acute infections are better managed symptomatically than by antimicrobials; thus the risks of adverse drug reactions for previously healthy individuals may outweigh the modest clinical benefits that follow antibiotic therapy of salmonella gastroenteritis and streptococcal sore throat. Select the best drug. This involves consideration of: — specificity; ideally the antimicrobial activity of the drug should match that of the infecting organisms. Indiscriminate use of broad- spectrum drugs promotes antimicrobial resistance and encourages opportunistic infections (see p. 210). At the beginning of treatment, empirical 'best guess' chemotherapy of reasonably broad spectrum must often be given because of the absence of precise identification of the responsible microbe. The spectrum of cover should be narrowed once the causative organisms have been identified. — 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 antimicrobials or whose routes of elimination may be impaired, e.g. by renal disease. Administer the drug in optimum dose and fre- quency and by the most appropriate route(s). Inadequate dose may encourage the development of microbial resistance. In general, on grounds of practicability, intermittent dosing is preferred to continuous infusion. Plasma concentration monitor- ing can be performed to optimise therapy and reduce adverse drug reactions (e.g. aminoglycosides, vancomycin, 5-flucytosine). 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 endo- carditis, in which relapse is possible long after apparent clinical cure and so the drugs are continued for a longer time, 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 204 USE OF ANTIMICROBIAL DRUGS 11 proof of cure is desirable because disappearance of symptoms and signs occurs before the organisms are eradicated. This is generally restricted to espe- cially susceptible hosts e.g. urinary tract infection in pregnancy. Microbiological culture must be done, of course, after withdrawal of chemotherapy. Prophylactic chemotherapy for surgical and dental procedures should be of very limited dura- tion, often only a single large dose being given. It should start at the time of surgery to reduce the risk of selecting resistant organisms prior to surgery (see p. 207). Carriers of pathogenic or resistant organisms, in general, 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 The general rule is that selection of antimicrobials should be based on identification of the microbe and sensitivity tests. All appropriate specimens (blood, pus, urine, sputum, cerebrospinal fluid) must therefore be taken for examination before administering any antimicrobial. This process inevitably takes time and therapy at least of the more serious infections must usually be started on the basis of the 'best guess'. With the worldwide rise in prevalence of multiply-resistant bacteria during the past decade, knowledge of local antimicrobial resistance rates is an essential pre- requisite to guide the choice of local 'best guess' (or 'empirical') antimicrobial therapy. Publication of these rates (and corresponding guidelines for choice of empirical antibiotic therapy for common infec- tions) is now an important role for clinical diag- nostic microbiology laboratories. Such guidelines must be reviewed regularly to keep pace with changing resistance rates. 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. The infecting organism is not identified by the clinical diagnosis, e.g. in urinary tract infection or abdominal surgical wound infection. In the second and third categories particularly, 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 cephalexin may be a reasonable first choice for lower urinary tract infection (coliform organisms — depending on the prevalence of resistance locally), and benzylpeni- cillin for meningitis in the adult (meningococcal or pneumococcal). Rapid diagnostic tests. Use of tests of this type is about to undergo a revolution with the widespread introduction of affordable, sensitive and specific nucleic acid detection assays (especially those based on the Polymerase Chain Reaction, PCR). Classi- cally, antimicrobials were selected in the knowledge that the organism was a Gram-positive or Gram- negative coccus or bacillus, observed by direct staining of body secretions or tissues. It is necessary to know the current local sensitivities to anti- microbial drugs for organisms so classified. Thus flucloxacillin may be indicated when clusters of Gram-positive cocci are found (indicating staphylo- cocci), but vancomycin is preferred in many hospitals with a high prevalence of methicillin- resistant Staphylococcus aureus (MRSA). The use of Ziehl-Neelsen staining may reveal acid-fast tubercle bacilli. Light microscopy will remain useful in this 205 11 CHEMOTHERAPY OF INFECTIONS way for many years to come, but use of PCR to detect DNA sequences specific for individual micro- bial species or resistance mechanisms greatly speeds up the institution of definitive, reliable therapy. These methods are already widely used for diag- nosing meningitis (detecting Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae) and tuberculosis (including detection of rifampicin resistance). Modification of treatment can be made later if necessary, in the light of culture and sensitivity tests. Treatment otherwise should be changed only after adequate trial, usually 2-3 days, for 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 concen- trations 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 they are able to absorb the drug i.e. not with vomiting, ileus or diarrhoea. Many antibiotics are, however, 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 are avoided, but this type of management is suitable only when the patient's clinical state is stable and oral therapy is not suitable. 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 con- centrations of antibiotic with consequently greater risks of antibiotic-associated diarrhoea. Some anti- microbial 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 espe- cially 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. Other routes used for antibiotics on occasion include inhalational, 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; full doses of each drug are needed. • 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. flueytosine plus amphotericin B for Cryptococcus neoformans meningitis. Selection of agents. A bacteriostatic drug, by red- ucing multiplication, may protect the organism from a bactericidal drug (see above, Antagonism). When a combination must be used blind, it is theo- retically preferable to use two bacteriostatic or two bactericidal drugs, lest there be antagonism. 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. 206 USE OF ANTIMICROBIAL DRUGS 11 The basis of effective, true, chemoprophylaxis is the use of a drug in a healthy person to prevent infection by one organism of virtually uniform susceptibility, e.g. benzylpenicillin against a group A streptococcus. But the term chemoprophylaxis is commonly extended to include suppression of existing infection. To design effective chemopro- phylaxis 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 can be seen that it is 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, 8 recurrent urinary tract infection. • Prevention of opportunistic infections, e.g. due to commensals getting into the wrong place (bacterial endocarditis after dentistry 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 chemoprophylaxis, e.g. prophylaxis 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, animal bites, trauma. • Prevention of acute exacerbations of a chronic infection, e.g. bronchitis, in cystic fibrosis. 8 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, in fact, second attacks are rare. Therefore, chemoprophylaxis is not used (see also p. 239). • Prevention of spread amongst contacts (in epidemics and/or sporadic cases). Spread of influenza A can be partially prevented by amantadine; in an outbreak of meningococcal meningitis, or when there is a case in the family, rifampicin may be used; very young and fragile nonimmune child contacts of pertussis might benefit from erythromycin Long-term prophylaxis of bacterial infection can be achieved often by doses that are inadequate for therapy, although prophylaxis of infection asso- ciated with surgical procedures should always employ high doses to ensure eradication of the high bacterial numbers that may be introduced to normally sterile sites. Details of the practice of chemoprophylaxis are given in the appropriate sections. Attempts to use drugs routinely in groups specially at risk to prevent infection by a range of organisms, e.g. pneumonia in the unconscious or in patients with heart failure, in the newborn after prolonged labour, and in patients with long-term urinary catheters, have not only failed but have sometimes encouraged infections with less suscept- ible organisms. Attempts routinely to prevent bacterial infection secondary to virus infections, e.g. in respiratory tract infections, measles, have not been sufficiently successful to outweigh the dis- advantages of drug allergy and infection with drug- resistant bacteria. In these situations it is generally better to be alert for complications and then to treat them vigorously, 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 the presence of large numbers of bacteria in the viscus which is being operated on, e.g. 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, or of abnormal heart valves following the transient bacteraemia of dentistry 207 11 CHEMOTHERAPY OF INFECTIONS — when the risks of infection are low but randomised controlled trials in large numbers of patients have shown the benefits of prophylaxis to outweigh the risks, e.g. single- dose antistaphylococcal prophylaxis for uncomplicated hernia and breast surgery. This indication remains controversial. Antimicrobials should be selected with a know- ledge of the likely pathogens at the sites of surgery and their prevailing antimicrobial susceptibility. Antimicrobials should be given i.v., i.m. or occa- sionally 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 many diff- erent operations. Specific instances are: 1. Colorectal surgery, because there is a high risk of infection with Escherichia coli, Clostridium spp, streptococci and Bacteroides spp which inhabit the gut (a cephalosporin plus metronidazole, or benzylpenicillin plus gentamicin plus metronidazole are commonly used) 2. Gastroduodenal surgery, because colonisation of the stomach with gut organisms occurs especially when acid secretion is low, e.g. in gastric malignancy, following use of a histamine H 2 -receptor antagonist or following previous gastric surgery (usually a cephalosporin will be adequate) 3. Gynaecological surgery, because the vagina contains Bacteroides spp and other anaerobes, streptococci and coliforms (metronidazole and a cephalosporin are often used). 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 prosthetic joints. Chemoprophylaxis is justified because infection (Staphylococcus aureus, coagulase-negative staphylococci and coliforms are commonest) almost invariably means that the artificial joint, valve or vessel must be replaced (various regimens are used, with inclusion of vancomycin when the local MRSA prevalence is high). 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 hours. 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. 9 so microorganisms may be naturally Cborn') 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 in a human population by spread of microorganisms containing resistance genes, and this may also occur 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 untreated individuals. Problems of antimicrobial resistance have bur- geoned during the past decade in most countries of the world. Some resistant microbes are currently mainly restricted to patients in the hospital, e.g. MRSA, vancomycin-resistant enterococci (VRE), and coliforms that produce 'extended spectrum (3- lactamases'. Others more commonly infect patients in the community, e.g. penicillin-resistant Strepto- coccus pneumoniae and multiply-resistant My co- bacterium tuberculosis. Evidence is accruing that the outcomes of infections with antibiotic resistant bacteria are generally poorer than those with 9 Malvolio in Twelfth Night, Act 2 Scene 5, by William Shakespeare (1564-1616). 208 [...]... restricting use of a drug may become necessary where it promotes the proliferation of resistant strains Although clinical microbiology laboratories report microbial susceptibility test results as 'sensitive' 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... 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... phagocytic cellular defences have been reduced by disease (e.g AIDS, hypogammaglobulinaemia, leukaemia) or drugs (e.g cytotoxics, adrenal steroids) Such infections involve organisms that rarely or never cause clinical disease in normal hosts Treatment 212 of possible infections in such patients should be prompt, initiated before the results of bacteriological tests are known and usually involving combinations... prontosil for puerperal infections Lancet 2:1319 (a classic paper) Fishman J A, Rubin R H 1998 Infection in organtransplant recipients New England Journal of Medicine 338:1741-1751 Fletcher C 1984 First clinical use of penicillin British Medical Journal 289:1721-1723 (a classic paper) Lowy F D 1998 Staphylococcus aureus infections New England Journal of Medicine 339: 520-532 Kwiatkowski D 2000 Susceptibility . penicillins, cephalosporins, aminoglycosides, isoniazid and rifampicin. Less used in modern clinical practice, the classi- fication is somewhat arbitrary because most. a bactericidal drug. Such mutual antagonism of antimicrobials may be clinically important, but the matter is complex because of the multiple