β-lactams

the structure of which contains a β-lactam ring. The major subdivisions are:

Other subcategories of β-lactams include:

Other inhibitors of cell wall synthesis include vancomycin and teicoplanin.

Aminoglycosides

The names of those that are derived from streptomyces end in ‘mycin’, e.g. tobramycin. Others include gentamicin (from Micromonospora purpurea which is not a fungus, hence the spelling as ‘micin’) and semi-synthetic drugs, e.g. amikacin.

Tetracyclines,

as the name suggests, are four-ringed structures and their names end in ‘-cycline’.

Macrolides:

e.g. erythromycin. Clindamycin, structurally a lincosamide, has a similar action and overlapping antibacterial activity.

Other drugs that act by inhibiting protein synthesis include quinupristin-dalfopristin, linezolid, chloramphenicol and sodium fusidate.

Sulfonamides

Usually their names contain ‘sulpha’ or ‘sulfa’. These drugs and trimethoprim, with which they may be combined, inhibit synthesis of nucleic acid precursors.

Quinolones

are structurally related to nalidixic acid; the names of the most recently introduced members of the group end in ‘-oxacin’, e.g. ciprofloxacin. They act by preventing DNA replication.

Azoles

all contain an azole ring and the names end in ‘-azole’, e.g. metronidazole. They act by the production of short-lived intermediates toxic to DNA of sensitive organisms. Rifampicin inhibits bacterial DNA-dependent RNA polymerase.

Antimicrobials that are restricted to certain specific uses, i.e. tuberculosis, urinary tract infections, are described with the treatment of these conditions in Chapter 14.

Mode of action

Penicillins act by inhibiting the enzymes (penicillin binding proteins, PBPs) involved in the cross-linking of the peptidoglycan layer of the cell wall, which is weakened, and this leads to osmotic rupture. Penicillins are thus bactericidal and are ineffective against resting organisms which are not making new cell wall. The main defence of bacteria against penicillins is to produce enzymes, β-lactamases, which hydrolyse the β-lactam ring. Other mechanisms that have been described include modifications to PBPs to render them unable to bind β-lactams, reduced permeability of the outer cell membrane of Gram-negative bacteria, and pumps in the outer membrane which remove β-lactam molecules. Some particularly resistant bacteria may possess several mechanisms that act in concert. The remarkable safety and high therapeutic index of the penicillins is due to the fact that human cells, while bounded by a cell membrane, lack a cell wall. They exhibit time-dependent bacterial killing (see p.164).

Pharmacokinetics

Benzylpenicillin is destroyed by gastric acid and is unsuitable for oral use. Others, e.g. phenoxymethylpenicillin, resist acid and are absorbed in the upper small bowel. The plasma t_½ of penicillins is usually < 2 h. They are distributed mainly in the body water and enter well into the CSF if the meninges are inflamed. Penicillins are organic acids and their rapid clearance from plasma is due to secretion into renal tubular fluid by the anion transport mechanism in the kidney. Renal clearance therefore greatly exceeds the glomerular filtration rate (127 mL/min). The excretion of penicillin can be usefully delayed by concurrently giving probenecid which competes successfully for the transport mechanism. Dosage of penicillins may need to be reduced for patients with severely impaired renal function.

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.

Uses

Benzylpenicillin is highly active against Streptococcus pneumoniae and the Lancefield Group A, β-haemolytic streptococcus (Streptococcus pyogenes). Viridans streptococci are usually sensitive unless the patient has recently received penicillin. Enterococcus faecalis is less susceptible and, especially for endocarditis, penicillin should be combined with an aminoglycoside, usually gentamicin. This combination is synergistic unless the enterococcus is highly resistant to the aminoglycoside (minimal inhibitory concentration (MIC) of 128 mg/L or above); such strains are becoming more frequent in hospital patients and present major difficulties in therapy. Over 90% of Staphylococcus aureus are now resistant in hospital and domiciliary practice. Benzylpenicillin is a drug of choice for infections due to Neisseria meningitidis (meningococcal meningitis and septicaemia), Bacillus anthracis (anthrax), Clostridium perfringens (gas gangrene) and tetani (tetanus), Corynebacterium diphtheriae (diphtheria), Treponema pallidum (syphilis), Leptospira spp. (leptospirosis), Actinomyces israelii (actinomycosis) and for Borrelia burgdorferi (Lyme disease) in children. Penicillin resitance rates in Neisseria gonorrhoeae are high in many parts of the world.

Adverse effects

are in general uncommon, apart from allergy (above). It is salutary to reflect that the first clinically useful true antibiotic (1942) is still in use and remains among the least toxic.

Preparations and dosage for injection

Benzylpenicillin may be given i.m. or i.v. (by bolus injection or by continuous infusion). For a sensitive infection, benzylpenicillin² 600 mg 6-hourly is enough.

For relatively insensitive infections and where sensitive organisms are sequestered within avascular tissue (e.g. infective endocarditis) 7.2 g is given daily i.v. in divided doses. When an infection is controlled, a change may be made to the oral route with phenoxymethylpenicillin (amoxicillin is more reliably absorbed in adults).

Procaine penicillin, given i.m. only, liberates benzylpenicillin over 12–24 h, but it will not give therapeutic blood concentrations for some hours after injection, and peak concentrations are low.

Preparations and dosage for oral use

Phenoxymethylpenicillin (penicillin V), is resistant to gastric acid and so is moderately well absorbed, sometimes erratically in adults. It is less active than benzylpenicillin against Neisseria gonorrhoeae and meningitidis, and so is unsuitable for use in gonorrhoea and meningococcal meningitis, although satisfactory against Streptococcus pneumoniae and Streptococcus pyogenes, especially after the acute infection has been controlled by intravenous therapy. The dose is 500 mg 6-hourly.

All oral penicillins are best given on an empty stomach to avoid the absorption delay caused by food.

Amoxicillin

(t_½ 1 h; previously known as amoxycillin) is a structural analogue of ampicillin (below) and is better absorbed from the gut (especially after food), and for the same dose achieves approximately double the plasma concentration. Diarrhoea is less frequent with amoxicillin than with ampicillin. The oral dose is 250 mg 8-hourly; a parenteral form is available but offers no advantage over ampicillin.

Co-amoxiclav

(Augmentin). Clavulanic acid is a β-lactam molecule which has little intrinsic antibacterial activity but binds irreversibly to β-lactamases. Thereby it competitively protects the penicillin against bacterial β-lactamases, acting as a ‘suicide’ inhibitor. It is formulated in tablets as its potassium salt (equivalent to 125 mg of clavulanic acid) in combination with amoxicillin (250 or 500 mg), as co-amoxiclav, and is a satisfactory oral treatment for infections due to β-lactamase-producing organisms, notably in the respiratory or urogenital tracts. These include many strains of Staphylococcus aureus, Escherichia coli and an increasing proportion of Haemophilus influenzae. It also has useful activity against β-lactamase-producing Bacteroides spp. The t_½ is 1 h and the dose one tablet 8-hourly.

Ampicillin

(t_½ 1 h) is acid-stable and is moderately well absorbed when swallowed. The oral dose is 250 mg–1 g 6–8-hourly; or i.m. or i.v. 500 mg 4–6-hourly. Approximately one-third of a dose appears unchanged in the urine. The drug is concentrated in the bile.

Adverse effects

Ampicillin may cause diarrhoea but the incidence (12%) is less with amoxicillin. Ampicillin and amoxicillin are commonly associated with Clostridium difficile diarrhoea, related to the frequency of their use rather than to high innate risk of causing the disease. Ampicillin and its analogues may cause a macular rash resembling measles or rubella, usually unaccompanied by other signs of allergy, and seen in patients with disease of the lymphoid system, notably infectious mononucleosis and lymphoid leukaemia. A macular rash should not be taken to imply allergy to other penicillins, which tend to cause a true urticarial reaction. Patients with renal failure and those taking allopurinol for hyperuricaemia also seem more prone to ampicillin rashes. Cholestatic jaundice has been associated with use of co-amoxiclav even up to 6 weeks after cessation of the drug; the clavulanic acid may be responsible.

Ticarcillin

(t_½ 1 h) is presented in combination with clavulanic acid (as Timentin), so to provide greater activity against β-lactamase-producing organisms. It is given by i.m. or slow i.v. injection or by rapid i.v. infusion.

Piperacillin

(t_½ 1 h) is available as a combination with the β-lactamase inhibitor tazobactam (as Tazocin).

Mode of action

is that of the β-lactams, i.e. cephalosporins impair bacterial cell wall synthesis and hence are bactericidal. They exhibit time-dependent bacterial killing (see p. 164).

Addition of various side-chains on the cephalosporin molecule confers variety in pharmacokinetic and antibacterial activities. The β-lactam ring can be protected by such structural manoeuvring, which results in compounds with improved activity against Gram-negative organisms, but less anti-Gram-positive activity. The cephalosporins resist attack by some β-lactamases, but resistance is mediated by other means.

Pharmacokinetics

Usually, cephalosporins are excreted unchanged in the urine, but some, including cefotaxime, form a desacetyl metabolite which possesses some antibacterial activity. Many are actively secreted by the renal tubule, a process which can be blocked with probenecid. As a rule, the dose of cephalosporins should be reduced in patients with poor renal function. Cephalosporins in general have a t_½ of 1–4 h although there are exceptions (e.g. ceftriaxone, t_½ 8 h). Wide distribution in the body allows treatment of infection at most sites, including bone, soft tissue, muscle and (in some cases) CSF. Data on individual cephalosporins appear in Table 13.1.

Table 13.1 The cephalosporins

Classification and uses

The cephalosporins are conventionally categorised by ‘generations’ sharing broadly similar antibacterial and pharmacokinetic properties; newer agents have rendered this classification less precise but it retains sufficient usefulness to be presented in Table 13.1.

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.

Adverse effects

It may cause gastrointestinal upset including nausea, blood disorders, allergic reactions, confusion and convulsions.

Meropenem

(t_½ 1 h) is similar to imipenem, but is stable to renal dihydropeptidase and can therefore be given without cilastatin. It penetrates into the CSF and is not associated with nausea or convulsions.

Ertapenem

(t_½ 4 h) is given as a single daily injection; because of this it has found a niche indication for parenteral therapy of multiply resistant Gram-negative bacteria out of hospital, such as ESBL-producing coliforms. It is, however, much less active against Pseudomonas aeruginosa, Acinetobacter and their relatives. Adverse events are uncommon, but include diarrhoea (4.8%), infusion vein phlebitis (4.5%) and nausea (2.8%).

Uses

Vancomycin is effective in cases of antibiotic-associated pseudomembranous colitis (caused by Clostridium difficile or, less commonly, staphylococci) in a dose of 125 mg 6-hourly by mouth. Combined with an aminoglycoside, it may be given i.v. for streptococcal endocarditis in patients who are allergic to benzylpenicillin and for serious infection with multiply resisant staphylococci. It is not as effective as flucloxacillin for serious infections caused by methicillin-susceptible S. aureus. Dosing is guided by plasma concentration monitoring with the aim of achieving trough concentrations between 10 and 20 mg/L (15–20 mg/L in patients being treated for infective endocarditis). Trough concentrations of up to 25 mg/L of recent vancomycin formulations have not been associated with significant toxicity, and may give better outcomes for the most severe infections and those with less-susceptible strains. There is actually no strong evidence that monitoring peak and/or trough serum vancomycin concentrations reduces the incidence of renal or ototoxicity. However, achieving adequate serum concentrations clearly correlates with both outcome and avoidance of rises in isolates’ vancomycin MICs, so initial doses should be calculated on total body-weight even in obese subjects, and dose adjustments should be based on measured serum concentrations performed at least weekly in subjects with stable renal function (and more often in those with reduced or varying renal function).

Adverse effects

Tinnitus and deafness may occur, but may improve if the drug is stopped. Nephrotoxicity and allergic reactions also occur. Rapid i.v. infusion may cause a maculopapular rash, possibly due to histamine release (the ‘red person’ syndrome).

Teicoplanin

is structurally related to vancomycin and is active against Gram-positive bacteria. The t_½ of 50 h allows once daily i.v. or i.m. administration. It is less likely than vancomycin to cause oto- or nephrotoxicity, but serum monitoring is required to assure adequate serum concentrations for severely ill patients and those with changing renal function.

Daptomycin

(t_½ 9 h) is a recently released lipopeptide antibiotic, naturally produced by the bacterium Streptomyces roseosporus which was first isolated from a soil sample from Mount Ararat in Turkey.³ It has activity against virtually all Gram-positive bacteria, including penicillin-resistant Streptococcus pneumoniae and MRSA, regardless of vancomycin resistance phenotype. It is unable to cross the Gram-negative outer membrane, rendering these bacteria resistant.

Daptomycin demonstrates concentration-dependent bactericidal activity, including moderately so against most enterococci (for which vancomycin is generally bacteriostatic). Initial binding to the Gram-positive cell membrane is followed by a variety of effects including membrane depolarisation (probably via the drug forming an ion channel across the membrane: this seems to be the main cidal mechanism) and reduced lipoteichoic acid and protein synthesis. A few Clostridium species appear innately resistant, but resistance has proved difficult to induce in vitro and reduction in susceptibility during clinical use has rarely been reported to date. The underlying mechanisms of resistance seem to involve a variety of physiological effects including an altered membrane potential. Staphylococci with increased vancomycin MICs are also less susceptible to daptomycin, and resistance to both agents is acquired progressively in a stepwise fashion.

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