Antibacterial drugs

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Chapter 13 Antibacterial drugs

Classification

Inhibition of cell wall synthesis

β-lactams

Penicillins

Benzylpenicillin (1942) is produced by growing one of the penicillium moulds in deep tanks. In 1957 the penicillin nucleus (6-amino-penicillanic acid) was synthesised and it became possible to add various side-chains and so to make semi-synthetic penicillins with different properties. Penicillins differ widely in antibacterial spectrum. A general account of the penicillins follows and then of the individual drugs in so far as they differ.

Adverse effects

The main hazard with the penicillins is allergic reactions. These include itching, rashes (eczematous or urticarial), fever and angioedema. Rarely (about 1 in 10 000) there is anaphylactic shock, which can be fatal (about 1 in 50 000–100 000 treatment courses). Allergies are least likely when penicillins are given orally and most likely with topical application. Metabolic opening of the β-lactam ring creates a highly reactive penicilloyl group which polymerises and binds with tissue proteins to form the major antigenic determinant. The anaphylactic reaction involves specific IgE antibodies which can be detected in the plasma of susceptible persons.

There is cross-allergy between all the various forms of penicillin, probably due in part to their common structure, and in part to the degradation products common to them all. Partial cross-allergy exists between penicillins and cephalosporins (a maximum of 10%), which is of particular concern when the reaction to either group of antimicrobials has been angioedema or anaphylactic shock. Carbapenems (meropenem and imipenem-cilastatin) and, especially, the monobactam aztreonam apparently have a lower risk of cross-reactivity. One experimental study estimated the rate of reactivity to meropenem in patients with a previous history of immediate penicillin hypersensitivity reaction as a maximum of 5.2%.

When attempting to predict whether a patient will have an allergic reaction, a reliable history of a previous adverse response to penicillin is valuable. Immediate-type reactions such as urticaria, angioedema and anaphylactic shock can be taken to indicate allergy, but interpretation of maculopapular rashes is more difficult. Since an alternative drug can usually be found, a penicillin is best avoided if there is suspicion of allergy, although the condition is undoubtedly overdiagnosed and may be transient (see below).

When the history of allergy is not clear cut and it is necessary to prescribe a penicillin, the presence of IgE antibodies in serum is a useful indicator of reactions mediated by these antibodies, i.e. immediate (type I) reactions. Additionally, an intradermal test for allergy may be performed using standard amounts of a mixture of a major determinant (metabolite) (benzylpenicilloyl polylysine) and minor determinants (such as benzylpenicillin) of the allergic reaction; appearance of a flare and wheal reaction indicates a positive response. The fact that only about 10% of patients with a history of ‘penicillin allergy’ respond suggests that many who are so labelled are not, or are no longer, allergic to penicillin.

Other adverse effects include diarrhoea due to alteration in normal intestinal flora, which may progress to Clostridium difficile-associated diarrhoea. Neutropenia is a risk if penicillins (or other β-lactam antibiotics) are used in high dose and usually for a period of longer than 10 days. Rarely the penicillins cause anaemia, sometimes haemolytic, and thrombocytopenia or interstitial nephritis. Sometimes patients receiving parenteral β-lactams may develop fever with no other signs of an adverse reaction except occasionally for a modestly raised CRP: this should always be considered in the investigation of such patients who seem otherwise well, and cautiously stopping antibiotic therapy usually produces a prompt resolution. Penicillins are presented as their sodium or potassium salts which are inevitably taken in significant amounts for patients with renal or cardiac disease if high dose of antimicrobial is used. Extremely high plasma penicillin concentrations cause convulsions. Co-amoxiclav and flucloxacillin given in high doses for prolonged periods in the elderly may cause hepatic toxicity.

Narrow-spectrum penicillins

Benzylpenicillin

Benzylpenicillin (t½ 0.5 h) (penicillin G) has to be given with spaced doses that have to be large to maintain a therapeutic concentration, but the large therapeutic ratio of penicillin allows the resulting fluctuations to be tolerable.1 Benzylpenicillin is eliminated by the kidney, with about 80% being actively secreted by the renal tubule and this can be blocked by probenecid.

Broad-spectrum penicillins

The activity of these semi-synthetic penicillins extends to include many Gram-negative bacilli. They do not resist β-lactamases, and their usefulness has reduced markedly in recent years because of the increased prevalence of organisms that produce these enzymes.

These agents are less active than benzylpenicillin against Gram-positive cocci, but more active than the β-lactamase-resistant penicillins (above). They have useful activity against Enterococcus faecalis and many strains of Haemophilus influenzae. Enterobacteriaceae are unreliably susceptible. Members of this group differ more pharmacologically than antibacterially.

Cephalosporins

Cephalosporins were first obtained from a filamentous fungus Cephalosporium cultured from the sea near a Sardinian sewage outfall in 1945; their molecular structure is closely related to that of penicillin, and many semi-synthetic forms have been introduced. They now comprise a group of antibiotics having a wide range of activity and low toxicity. The term cephalosporins will be used here in a general sense although some are strictly cephamycins, e.g. cefoxitin and cefotetan.

Adverse effects

Cephalosporins are well tolerated. The most usual unwanted effects are allergic reactions of the penicillin type, and gastrointestinal upset. Overall the rate of cephalosporin skin reactions such as urticarial rashes and pruritis lies between 1% and 3%. There is cross-allergy between penicillins and cephalosporins involving up to 10% of patients; if a patient has had a severe or immediate allergic reaction or if serum or skin testing for penicillin allergy is positive (see p. 176), then a cephalosporin should not be used. Pain may be experienced at the sites of i.v. or i.m. injection. If cephalosporins are continued for more than 2 weeks, reversible thrombocytopenia, haemolytic anaemia, neutropenia, interstitial nephritis or abnormal liver function tests may occur. The broad spectrum of activity of the third generation cephalosporins may predispose to opportunist infection with resistant bacteria or Candida albicans and to Clostridium difficile diarrhoea. In the UK, reduction of broad-spectrum cephalosporin use is one component of the bundle of measures aimed to reduce the incidence of Clostridium difficile-associated diarrhoea. Ceftriaxone achieves high concentrations in bile and, as the calcium salt, may precipitate to cause symptoms resembling cholelithiasis (biliary pseudolithiasis).

Ceftobiprole is an interesting new investigational parenteral cephalosporin which binds avidly to the mutated penicillin binding protein 2′ responsible for methicillin resistance in staphylococci. It has good activity in vitro and in animal models against MRSA and vancomycin-resistant strains and better activity than ceftriaxone against penicillin-resistant pneumococci. Clinical trials are underway in skin and soft tissue infection and pneumonia.

Other β-lactam antibacterials

Other inhibitors of cell wall synthesis and membrane function

Vancomycin

Vancomycin (t½ 8 h), a ‘glycopeptide’ or ‘peptolide’, acts on multiplying organisms by inhibiting cell wall formation at a site different from the β-lactam antibacterials. It is bactericidal against most strains of clostridia (including Clostridium difficile), almost all strains of Staphylococcus aureus (including those that produce β-lactamase and methicillin-resistant strains), coagulase-negative staphylococci, viridans group streptococci and enterococci. Frankly resistant Staphylococcus aureus strains have been exceptionally rarely reported, although isolates with raised (but still formally susceptible) vancomycin MICs around 2–3 mg/L have been increasingly recognised and have a somewhat poorer outcome when the drug is used to treat serious, systemic infections such as endocarditis and bacteraemia. Detecting these borderline-susceptible strains reliably in the microbiology laboratory can be technically challenging. Combining vancomycin with linezolid, daptomycin or rifampicin may give better results in such cases, and therapeutic drug monitoring is important to keep trough concentrations at the upper end of the acceptable scale.

Vancomycin is poorly absorbed from the gut and is given i.v. for systemic infections as there is no satisfactory i.m. preparation. It distributes effectively into body tissues and is eliminated by the kidney.