Chemotherapy of infections

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Chapter 12 Chemotherapy of infections

Mark Farrington

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 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.

• How antimicrobials act.

• 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.

• Antimicrobial drugs of choice.

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.

In recent years, however:

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:

• Antibacterial drugs.

• Antiviral drugs.

• Antifungal drugs.

• Antiprotozoal drugs.

• Anthelminthic drugs.

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).

image

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.

Protein synthesis

Drugs that interfere at various points with the build-up of peptide chains on microbial ribosomes include: chloramphenicol, erythromycin, fusidic acid, tetracyclines, aminoglycosides, 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. sulfonamides, 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) 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

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