Antimicrobial Chemotherapy, 5th Edition
Part 3 - General Principles of Usage of Antimicrobial Agents
No antimicrobial agent is totally free from unwanted side effects, and about 5% of patients prescribed antimicrobial therapy will develop an adverse reaction of some sort. Most are trivial; some merely inconvenient. Others may require admission to hospital for specialist management, but a few are life threatening or fatal. Adverse drug reactions are not unique to antimicrobial agents and may have major implications for the patient and add to the costs of healthcare delivery, while due caution should always be exercised before a patient is placed on antimicrobial therapy, to see whether there is an identifiable contraindication to the use of the agent. Unnecessary or inappropriate prescribing is to be deplored for several reasons, but in particular for unjustifiably running the risk of avoidable adverse reactions.
Adverse reactions range from the allergic to the toxic. Others are unpredictable and defined as idiosyncratic, and alterations to the microbial flora can result in complicating disease. However, it is important to keep a proper perspective on the relative frequency of adverse events and this is indicated in Table 16.1.
Determinants of toxicity
A few adverse reactions are genetically determined. For example, patients deficient in the enzyme glucose-6-phosphate dehydrogenase are at risk of developing acute haemolysis when prescribed sulphonamides, nitrofurantoin, or the antimalarial primaquine. Occasionally, the use of chloramphenicol, or nalidixic acid, may be similarly complicated. This reaction may be avoided by screening for this X-linked erythrocyte enzyme defect, which is more common among people of Mediterranean, Far Eastern, or African stock. Similarly, the ability to acetylate the antituberculosis drug isoniazid is genetically determined. In slow acetylators, isoniazid toxicity may occur.
Table 16.1 Relative frequency of selected adverse reactions to antimicrobial agents (The more serious or important adverse drug reactions are shown in bold type). Reproduced by Davey P., ‘Antimicrobial Chemotherapy’ in DJ Weatherall, JGG Ledingham, and DA Warrell (eds.) Oxford Textbook of Medicine, Third edn., Vol. 1 (1996), with permission from Oxford University Press.
Many intravenously administered drugs, including antimicrobial agents, produce local irritation and frank phlebitis. To overcome this it may be necessary to adjust the pH of an intravenous infusion by suitable buffering. Similarly, pain may accompany the intramuscular injection of a drug. For example, cefoxitin is given with a local anaesthetic, lignocaine, to counter the pain at the injection site.
Many drugs may produce gastrointestinal symptoms due to a local chemical irritation of the gastric and intestinal mucosa. Here again, suitable buffering, enteric coating, or slow-release formulations may diminish these symptoms and increase the acceptability of a drug.
Drugs usually undergo oxidation, reduction, hydrolysis, or conjugation to a greater or lesser degree before excretion. The liver is the major site of this metabolism, although other organs such as the kidneys are also involved. When disease impairs renal or hepatic function there is the risk of accumulation of the drug, or a metabolite, which may reach toxic concentrations in the tissues.
Similarly, in the premature or full-term neonate both renal and hepatic functions are physiologically immature so that some adjustments of dosaging may have to be made (see Chapter 15).
Certain drugs may cause hepatic enzyme induction or the synthesis of a new enzyme. Rifampicin is a powerful inducer, decreasing the half-lives of many drugs such as prednisone, warfarin, digoxin, ketoconazole, and the sulphonylureas. Women simultaneously prescribed rifampicin and the contraceptive pill may conceive owing to inadequate circulating hormone concentrations that result from the induction of hepatic enzymes by rifampicin. Likewise, simultaneous administration of certain quinolones (e.g. ciprofloxacin) may result in the accumulation of toxic concentrations of theophyllines.
Certain antibiotics such as piperacillin and ticarcillin, being relatively inactive, are prescribed in large doses. Each 1 g of these agents contains 4.7 mmol sodium. This can result in sodium overloading and congestive cardiac failure, particularly in patients with impaired renal function.
Tetracyclines are taken up by developing bones and teeth. In the former this causes no significant long-term complications, but staining of the teeth is unsightly and ranges from patchy cream to extensive brown deposits. Enamel hypoplasia may also result. The ability to cause dental staining varies among the tetracyclines, being least with oxytetracycline. However, avoidance of all tetracyclines in children under 12 years of age will prevent staining of the permanent dentition.
Too-rapid infusion of vancomycin can result in the release of histamine, which in turn, can produce acute flushing, tachycardia, and hypotension—a reaction descriptively known as ‘red man’ syndrome.
Drugs may interact with other agents in vitro when mixed before administration, or in vivo once the drugs are ingested or injected. The study of drug interactions has become increasingly important and complex as new therapeutic agents become available. In general, incompatibilities can be avoided by mixing the agents separately and administering them by a different route or at different times.
Table 16.2 In-vitro incompatibilities of selected antimicrobial agents
Table 16.2 indicates the variety of in-vitro incompatibilities associated with antimicrobial agents. This list is far from complete. Pharmaceutical advice should be sought or the relevant section of the British National Formulary consulted whenever there is doubt.
In-vivo drug interactions include competition for plasma protein-binding sites and inhibition or induction of liver enzymes, thus interfering with or potentiating other therapeutic effects. Table 16.3 indicates the variety of effects that have been described. Among the more important is interference with anticoagulant drugs, a problem that is commonly, but not exclusively, caused by antimicrobial agents. For example, rifampicin and griseofulvin impair anticoagulation by enzyme induction, whereas sulphonamides, co-trimoxazole, erythromycin, metronidazole, and the azole antifungals increase anticoagulation by enzyme inhibition, so that bleeding may occur.
Among the antibiotics the β-lactam compounds have the greatest potential to produce hypersensitivity reactions. Because of the similar structure of the penicillins, hypersensitivity to one agent is usually accompanied by hypersensitivity to the whole group. Moreover, structural similarities between cephalosporins and penicillins are accompanied by a degree of cross-hypersensitivity: about 10% of patients who are hypersensitive to penicillins show cross-hypersensitivity to cephalosporins. This is much more likely to occur in patients who have experienced a previous anaphylactic response to a penicillin, when the subsequent use of all β-lactam antibiotics (see Chapter 1) must be avoided. The monobactam agent aztreonam is less allergenic and may be given to patients with a history of hypersensitivity to other β-lactam antibiotics. This suggests that the β-lactam ring is not the sensitizing moiety of these drugs.
Table 16.3 In-vivo incompatibilities of selected antimicrobial agents
Immediate hypersensitivity reactions to penicillins and cephalosporins can, within minutes, produce nausea, vomiting, pruritus, urticaria, wheezing, laryngeal oedema, and cardiovascular collapse. In extreme cases the patient may die unless the attack is controlled with adrenaline and attention to the integrity of the airways. The estimated frequency for anaphylaxis is 1-5 for every 10 000 courses of penicillin prescribed.
Delayed hypersensitivity reactions include drug fever, erythema nodosum, and a serum-sickness-like syndrome. Hypersensitivity rashes are particularly common with semisynthetic penicillins such as ampicillin and its analogues and to a lesser degree, cephalosporins. The rashes are usually maculopapular and pruritic but may also be vesicular, bullous, urticarial, or scarlatiniform.
The use of ampicillin is associated with a generalized maculopapular eruption in more than 90% of patients suffering from infectious mononucleosis (glandular fever) and, less frequently, in association with cytomegalovirus infection. The exact reason for these hypersensitivity rashes is uncertain, although both infections are characterized by intense polyclonal antibody responses. The response is short lived and does not reflect long-lasting penicillin hypersensitivity, so that future use of penicillins is not contra-indicated in these patients.
Other antimicrobial agents that commonly produce hypersensitivity drug rashes are the sulphonamides and clindamycin. The sulphonamides and co-trimoxazole are responsible for a wide variety of eruptions that range from urticarial to maculopapular to erythema multiforme and its more severe variant, the Stevens-Johnson syndrome in which there is both cutaneous and mucous membrane involvement and a significant mortality rate.
Hypersensitivity reactions may also involve individual organs. For example, the penicillins occasionally produce an interstitial nephritis. Nitrofurantoin may affect the lungs, and erythromycin estolate is associated with hypersensitivity cholestasis. Haemolytic anaemia, neutropenia, and thrombocytopenia may occasionally occur with the penicillins, cephalosporins, and sulphonamides.
This is difficult. Some individuals have a strong family history of drug allergy or of allergic disease such as asthma or atopic eczema. Skin testing is occasionally carried out, but is unfortunately poorly predictive. It is therefore imperative to inquire about any previous episodes of hypersensitivity. When reactions occur they should be carefully documented and explained to the patient, so that serious hypersensitivity reactions can be avoided in the future.
Altered microbial flora
Antimicrobial drugs cannot distinguish between pathogenic organisms and those that make up the normal flora of the host. Even so-called ‘narrow-spectrum’ antibiotics such as penicillin have a profound effect on the normal flora of the mouth and gut to eliminate or suppress penicillinsensitive strains of streptococci and anaerobic bacteria. As a rule this alteration of the normal flora is without clinical consequence and is rapidly reversed on stopping treatment.
Some agents have a greater potential to suppress the normal flora, which may be complicated by the overgrowth of drug-resistant organisms, which in turn may give rise to superinfection. In general, the worst culprits are broad-spectrum antibiotics such as the tetracyclines, aminopenicillins (ampicillin, amoxicillin), and cephalosporins. Their use is occasionally associated with the overgrowth of yeasts, particularly within the oral cavity or in the vagina, where they may result in candidiasis (thrush).
Of greater importance is the syndrome of antibiotic-associated colitis caused by toxin-producing strains of Clostridium difficile. This may follow the use of various agents, although clindamycin, ampicillin, and the cephalosporins are most commonly incriminated. It is thought, but not proven, that antibiotic use selectively favours proliferation of the causative organism. The colitis caused by the toxin may be severe, even life threatening. Outbreaks of C. difficile colitis in hospitals are frequent. Oral metronidazole or vancomycin are successfully used to control the condition when it arises.
Finally, patients treated with antimicrobial agents are at risk of acquiring organisms from the environment. Because of the intensive selection pressure operating in many hospital units, organisms acquired in hospital are often more virulent and frequently exhibit resistance to a variety of antibiotics, putting the patient at increased risk.
Tissue- and organ-specific toxicity
Antimicrobial agents are commonly administered orally provided that absorption from the bowel is satisfactory. It is scarcely surprising, therefore, that a variety of gastrointestinal side effects are associated with their use. Nausea, vomiting, and increased bowel movement, sometimes amounting to diarrhoea, are common, but are generally of minor inconvenience and do not interrupt treatment. Diarrhoea occurs in about 5-10% of patients taking oral ampicillin or clindamycin. However, the most serious gastrointestinal complications are overgrowth ofCandida spp. or toxigenic strains of Cl. difficile (see above).
Skin rashes are among the more frequent adverse reactions caused by antimicrobial drugs. Most reactions are caused by hypersensitivity, but a wide variety of other eruptions may occur, including maculopapular, vesicular, and bullous eruptions, exfoliation, and erythema multiforme. Delayed hypersensitivity reactions with sulphonamides may result in erythema nodosum, which may be part of a serum-sickness-like syndrome with drug fever and arthralgia.
Photosensitivity occurs with long-acting sulphonamides, tetracyclines (particularly demeclocycline), and quinolones. The skin becomes red, oedematous, and vesicular. This is more common in hot climates.
Hypersensitivity manifested by bronchial asthma and pulmonary eosinophilia occurs usually in sensitized individuals. Asthmatic reactions are most likely in people with an underlying bronchospastic tendency. Nitrofurantoin, sulphonamides, and β-lactam agents may cause such reactions. Long-term use of nitrofurantoin has also been associated with a chronic interstitial pneumonitis progressing to fibrosis. The changes may be only partially reversible on stopping the drugs.
An indirect side effect of antibiotic therapy is opportunistic lung infection following modification of the normal flora. This usually occurs in patients with underlying malignant disease and those receiving cytotoxic or immunosuppressive therapy. Patients who are artificially ventilated are particularly vulnerable.
Antibiotics may affect the liver to produce an acute hepatitis or cholestasis. Such reactions are often unpredictable, although pre-existing liver disease suggests caution in prescribing potentially hepatotoxic drugs.
Several antimicrobial drugs, including cephalosporins, clindamycin, and intravenously administered fusidic acid, may produce minor elevations of liver enzymes which uncommonly progress to a frank hepatitis with nausea, vomiting, and a tender enlarged liver. Cholestasis may be seen in association with nitrofurantoin, erythromycin derivatives, and prolonged use of flucloxacillin, especially in the elderly.
Isoniazid is a frequent cause of hepatitis, which is uncommon below the age of 20 years, but increases significantly in people of middle age and beyond. Symptoms usually develop within the first 2 months of treatment and subside on stopping treatment. Transient asymptomatic elevation of liver enzymes is common but of little significance. Routine testing of liver function is not justified unless symptoms develop.
Rifampicin may also produce elevation of liver enzymes, although when used in combination with isoniazid—as it may be in the treatment of tuberculosis—clinical hepatotoxicity appears to be no more frequent than when isoniazid is used alone.
A more serious variety of liver toxicity may follow the use of intravenous tetracycline in patients with pre-existing liver disease or during pregnancy. Under these circumstances liver necrosis may prove fatal.
Central nervous system
Ototoxicity is an important side effect of aminoglycoside antibiotics. However, their individual potential for either vestibulotoxicity or cochleotoxicity varies and is least for tobramycin. Vestibulotoxicity is recognized by unsteadiness of gait and nystagmus; cochleotoxicity is recognized by a hearing loss that initially affects high frequencies that may only be detected by audiography. Deafness may also occasionally complicate the use of intravenous erythromycin.
Although penicillins are (setting aside penicillin allergy) the least toxic of antibiotics, encephalitic reactions may occur with massive parenteral doses of penicillin G (12 g or more per day). There is no conceivable therapeutic benefit in such heroic doses, which should be avoided.
Other β-lactam antibiotics such as the cephalosporins and imipenem may also be associated with convulsions and encephalopathy when given in high doses. High doses of quinolones may also produce convulsions. The phenomenon of benign intracranial hypertension may follow the use of nalidixic acid, tetracycline, and, occasionally, penicillin. This is reversible on stopping treatment. Optic neuritis is a rare complication of the use of chloramphenicol; ethambutol is also associated with dose-related optic nerve damage and retinopathy.
Peripheral nervous system
Several agents may be associated with a peripheral neuropathy, although the mechanisms are not well understood. Isoniazid is known to interfere with pyridoxine metabolism. Nitrofurantoin competes with thiamine pyrophosphate and thus interferes with pyruvate oxidation. Metronidazole may produce a reversible peripheral neuropathy with prolonged use.
The nucleoside analogues used in the treatment of HIV disease are all associated with peripheral neuropathy.
Neuromuscular blockade, although rare, is potentially serious and occurs in association with the use of aminoglycosides and tetracyclines. The aminoglycosides produce neuromuscular blockade by a curare-like anticholinesterase effect and by competing with calcium; this is more likely to be seen following the use of muscle relaxants during anaesthesia.
Since the kidneys are the major route of drug excretion, it is not surprising that nephrotoxicity is relatively frequent. It is often dose related and is more common either in those with pre-existing renal failure or in those receiving other nephrotoxic agents.
Some early sulphonamides, which were rapidly excreted and poorly soluble, were prone to deposit crystals within the urinary tract, sometimes causing tubular damage and ureteric obstruction. This is uncommon with later sulphonamides, which are generally more soluble and more slowly excreted. A similar complication has been linked to the protease inhibitors indinavir and ritonavir, used in the treatment of HIV infection.
These may occasionally be nephrotoxic, particularly in patients with pre-existing renal insufficiency and older people with physiological renal impairment. The degree of renal failure varies, but is usually reversible. An explanation of the phenomenon may lie in the anti-anabolic effect of tetracyclines.
A specific effect of demeclocycline is the production of nephrogenic diabetes insipidus, a phenomenon that has been put to therapeutic advantage in the management of the syndrome of inappropriate antidiuretic hormone secretion.
Among tetracyclines, doxycycline is unique in being devoid of nephrotoxicity, reflecting its primary hepatobiliary route of excretion.
These are the antibiotics most frequently associated with nephrotoxicity. Their nephrotoxic potential varies and occurs in decreasing order of frequency with gentamicin, tobramycin, amikacin, and netilmicin. Nephrotoxicity is potentiated by pre-existing renal disease, prolonged or repeated courses of treatment, or the simultaneous administration of other nephrotoxic agents. Renal damage is often reversible, although permanent impairment including renal failure does occur.
Nephrotoxicity is the leading complication of the use of amphotericin B. This results from a combination of a reduction in glomerular filtration, renal tubular acidosis, and decreased concentrating ability. Careful monitoring of renal function is a prerequisite to the use of this agent. Lipid formulations of amphotericin B (p. 70) are less nephrotoxic.
Bone marrow toxicity may be selective and affect one cell line, or be unselective and produce pancytopenia and marrow aplasia. Immunemediated haemolysis, in which Coombs' antibodies are detected, may also occur. Bleeding may occur from platelet dysfunction or from thrombocytopenia. Eosinophilia may represent a hypersensitivity reaction.
The penicillins may rarely produce a primary haemolytic anaemia and Coombs' antibody-positive disease. Selective white cell depression has been described with ampicillin and flucloxacillin. Similarly, the cephalosporins may be associated with a positive Coombs' test, although frank haemolysis is uncommon. Eosinophilia occurs with variable frequency, as does the selective depression of white cells, and occasionally platelets, following the development of platelet antibodies. A vitamin K-dependent bleeding disorder has been associated with cephalosporins possessing a thiotetrazole side-chain, such as cefamandole, cefotetan, and cefoperazone. Although uncommon, bleeding occurs in elderly or malnourished patients undergoing major surgery. It is both treated and prevented by the administration of vitamin K.
Among the more important groups of agents to produce haematological side effects are the sulphonamides and sulphonamide-containing mixtures such as co-trimoxazole. Marrow toxicity may result in aplastic anaemia, or a selective neutropenia, or thrombocytopenia. In addition, haemolysis may be either primary or related to glucose-6-phosphate dehydrogenase deficiency. Co-trimoxazole may produce megaloblastic bone marrow changes or, less commonly, a peripheral megaloblastic anaemia. This tends to occur with prolonged therapy and is related to the joint antifolate action of the two components of co-trimoxazole.
This has achieved notoriety for inducing marrow depression, which is manifested in two ways. The more common dose-related bone marrow depression is seen when the daily dose exceeds 4 g. There is a progressive anaemia, neutropenia, and sometimes thrombocytopenia, which is reversible on either discontinuing treatment or reducing the dosage. A more serious reaction is that of total bone marrow depression and aplastic anaemia. This is unpredictable but is estimated to occur with a frequency of 1 in 24 000 to 1 in 40 000 treatment courses. Mortality from aplastic anaemia is in excess of 50%. Thiamphenicol, a derivative of chloramphenicol available in some parts of the world, appears to be devoid of the irreversible toxic effects on the bone marrow.
Adverse reactions to antiviral drugs
The past decade has seen the licensing of many new antiviral drugs, largely for the treatment of herpesviruses and HIV infections. Inevitably this has led to the recognition of a range of adverse reactions, some of which are unique to this class of agents.
Aciclovir has proved remarkably free from serious toxicity. However, if administered in high dosage crystal deposition in the renal tubules can occur, occasionally leading to renal failure, unless patients are kept adequately hydrated. Neurotoxicity manifested by tremor, ataxia, and seizures can also complicate high dosage treatment or administration to patients with renal impairment. These side effects usually resolve on stopping treatment.
Ganciclovir, in contrast to aciclovir, is a more toxic drug. The major complication of use is bone marrow suppression, particularly neutropenia. This can prove difficult to manage since the drug is often required to treat cytomegalovirus infection in bone marrow and organ transplanted patients. Such patients are already extremely immunosuppressed and any additional drug-induced bone marrow suppression is undesirable. Foscarnet is an alternative to ganciclovir for the treatment of cytomegalovirus infections. While it is not associated with bone marrow suppression, its major adverse effect is dose related renal impairment. This requires careful monitoring of renal function during treatment, with dose reduction and sometimes cessation of therapy. An unusual complication is genital ulceration.
This group of agents has expanded rapidly over the past 15 years. The clinical trials programme has often been accelerated resulting in early licensing before the full range of adverse reactions has been defined. Furthermore, the potential for interaction both between these agents and between other classes of drugs, is high and they therefore require considerable caution and expertise in their use. A selection of side effects to commonly used agents is provided.
Nucleoside reverse transcriptase inhibitors
Zidovudine (AZT) was the first antiretroviral drug to be approved and is still in widespread use. Bone marrow suppression primarily causing mild to moderate anaemia is the most common side effect. This tends to be macrocytic in nature since the drug is less suppressive to early immature forms of erythrocytes, than the mature red cell. Other side effects include myopathy, hepatotoxicity, and pigmentation of the nails.
Didanosine and stavudine can both cause a sensory neuropathy, often starting in the feet. Unless detected early, it can progress to produce severe paraesthesiae and sensory loss. Another unusual yet serious adverse effect of these drugs is acute pancreatitis. Careful monitoring and measurement of serum amylase can avoid this complication. Bone marrow toxicity may also occur.
Abacavir is a potent drug but may cause a severe hypersensitivity reaction, which precludes continued use. Skin rashes can also be troublesome.
Lamivudine is widely prescribed and generally safe. Pancreatitis occurs rarely.
Non-nucleoside reverse transcriptase inhibitors
Nevirapine is most commonly linked to early onset skin rashes. These occur in approximately 20% of patients within the first month of treatment and in a small number are severe and life threatening especially causing the Stevens-Johnson syndrome. Nevirapine is a potent inducer of the cytochrome P-450 enzymes; drugs such as rifampicin and rifabutin require dose adjustment if co-administered.
Efavirenz frequently causes mild to moderate neuropsychiatric side effects in the first few weeks of treatment. These include anxiety, insomnia, vivid dreams, depression and, rarely, a suicidal response.
Saquinavir is generally well tolerated but notorious for interactions with other agents. It increases the plasma concentrations of terfenamide and astemizole, while other drugs either reduce plasma concentrations of saquinavir (rifampicin, rifabutin) or increase them (ketoconazole, ritonavir). The interaction with ritonavir has been exploited pharmaceutically, since it is often co-marketed in fixed dose formulations of other protease inhibitors (e.g. lopinavir + ritonavir) to boost their plasma concentrations to therapeutic advantage.
Nelfinavir is associated with dose-related mild to moderate diarrhoea.
Prevention of adverse reactions
There are major difficulties in preventing adverse drug reactions. Patients frequently respond idiosyncratically to antimicrobial agents, as to other drugs; the chief problem, especially with the rarer side effects, is their unpredictability. Awareness of the possibility of adverse effects is obviously important, and a close working relationship with either a clinical pharmacist or a specialist in the use of antimicrobial agents will help to overcome problems as they arise.
When toxic effects develop or are suspected, the decision has to be made whether to stop or change the patient's treatment. The drug may often be continued provided the dose is adjusted by reducing each individual dose or by prolonging the interval between doses.
Antibiotic assays are important in determining whether dosage adjustment is necessary, particularly in the case of aminoglycosides, in which the leeway between effective and toxic levels is small.
Finally, the reporting of adverse drug reactions, whether caused by antimicrobial agents or other drugs, remains the responsibility of all practising doctors. In the UK the Medicines and Healthcare Products Regulatory Agency's Committee on Safety of Medicines operates a voluntary adverse reactions reporting system (see Postscript, p. 452).