Antimicrobial Chemotherapy, 4th Edition

General properties of antimicrobial agents

2

Inhibitors of bacterial protein synthesis

  1. Greenwood

The remarkable process by which proteins are manufactured on the ribosomal conveyor belt according to a blueprint provided by the cell nucleus is so fundamentally important and intrinsically fascinating that no one who has studied any aspect of modern biology can fail to have encountered it.

For the present purpose it is sufficient to outline the main features of the process. The first step is the formation of an initiation complex, consisting of messenger RNA (mRNA), transcribed from the appropriate area of a DNA strand; the two ribosomal subunits; and methionyl transfer RNA (tRNA) (N-formylated in bacteria) which occupies the ‘peptidyl donor’ site (P site) on the larger ribo-somal subunit. Aminoacyl tRNA appropriate to the next codon to be read slots into place in the aminoacyl ‘acceptor’ site (A site), and an enzyme called peptidyl transferase attaches the methionine to the new amino acid with the formation of a peptide bond. The mRNA and the ribosome now move with respect to one another so that the dipeptide is translocated from the A to the P site and the next codon of the mRNA is aligned with the A site in readiness for the next aminoacyl tRNA. The process continues to build up amino acids in the nascent peptide chain according to the order dictated by mRNA until a ‘nonsense’ codon is encountered, which signals chain termination.

Although the general mechanism of protein synthesis is thought to be universal, the process as it occurs in bacterial cells is sufficiently different from mammalian protein synthesis to offer scope for the selective toxicity required of therapeutically useful antimicrobial agents. The chief difference that is exploited involves the actual structure of the ribosomal workshop in both protein and RNA components. These structural differences are reflected in the sedimentation characteristics of the two types of ribosome when they are subjected to ultracentrifugation analysis. Bacterial ribosomes exhibit a sedimentation coefficient of 70 Svedberg units (70 S) and dissociate into 50 S and 30 S subunits; mammalian ribosomes, on the other hand, display an 80 S sedimentation coefficient and are composed of 60 S and 40 S subunits.

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The selective activity of therapeutically useful inhibitors of protein synthesis is far from absolute. Some, such as tetracyclines and clindamycin, have suffi-cient activity against eukaryotic ribosomes to be of value against certain protozoa. Moreover, the mitochondria of mammalian and other eukaryotic cells (which may have been derived from endosymbiotic bacteria during the course of evolution) carry out protein synthesis that is susceptible to some antibiotics used in therapy. The selectivity of these antibiotics is, therefore, a product not only of structural differences in the ribosomal targets, but also of access to, and affinity for, those targets.

Inhibitors of bacterial protein synthesis with sufficient selectivity to be useful in human therapy include aminoglycosides, chloramphenicol, tetracyclines, fusidic acid, macrolides, lincosamides, streptogramins, and mupirocin. With the upsurge of concern over multi-resistant strains of staphylococci and enterococci there has been renewed interest in agents with anti-Gram-positive activity. Among these are two groups of protein synthesis inhibitors that were investigated in earlier years, but not then developed for clinical use: the oxazolidinones and the everninomicins.

Aminoglycosides

The discovery of the first aminoglycoside, streptomycin, in 1943 extended the scope of chemotherapy to embrace one of the major microbial scourges—tuberculosis. It was later found that streptomycin was just one of a large family of related antibiotics produced by various species of Streptomyces and Micromonospora. Those derived from the latter genus, such as gentamicin and sissomicin, are distinguished in their spelling by an ‘i’ rather than a ‘y’ in the ‘mycin’ suffix.

Structurally, most aminoglycosides consist of a linked ring system composed of aminosugars and an aminosubstituted cyclic polyalcohol (aminocyclitol). One antibiotic usually included with the group, spectinomycin, contains no amino-glycoside substituent and is properly regarded as a pure aminocyclitol. Astro-mycin (fortimicin A), an aminoglycoside used in Japan, and apramycin, which is used in veterinary practice, also exhibit unusual structural features.

The aminocyclitol moiety of most aminoglycosides consists of one of two derivatives of streptamine: streptidine (present in streptomycin and its relatives) or deoxystreptamine (present in most other therapeutically useful aminoglyco-sides) (Fig. 2.1). Deoxystreptamine-containing aminoglycosides can, in their turn, be subdivided into two major groups: the neomycin group and the kanamycin group. The aminoglycosides most commonly used in medicine, including gentam-icin and tobramycin, belong to the kanamycin group. The designation ‘kanamycin’, ‘gentamicin’, or ‘neomycin’ indicates a family of closely related compounds and commercial preparations usually contain a mixture of these. For example, gentamicin, as used therapeutically, is a mixture of several structural variants of the gentamicin C complex (Fig. 2.2).

 

Fig. 2.1 Grouping of therapeutically useful aminoglycosides according to characteristics of the aminocyclitol ring. In most aminoglycosides the aminocyclitol moiety is either streptidine or deoxystreptamine, both derivatives of streptamine. The deoxy-streptamine group can be subdivided into those in which sugar substituents are linked at the 4- and 5-hydroxyls, and those substituted at the 4- and 6-hydroxyl positions.

 

Fig. 2.2 Structure of the gentamicin C complex, showing the ring numbering system and variations in structure of the different gentamicins.

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General properties of aminoglycosides

The aminoglycosides are potent, broad-spectrum bactericidal agents that are very poorly absorbed when given orally and are therefore administered by injection. They lack useful activity against streptococci and anaerobes, but the activity against streptococci can often be improved by using them in conjunction with penicillins, with which they interact synergically (p. 119). They penetrate poorly into mammalian cells and are of limited value in infections caused by intracel-lular bacteria. Some members of the group display important activity against Mycobacterium tuberculosis or Pseudomonas aeruginosa (Table 2.1).

Table 2.1 Summary of the antibacterial spectrum and toxicity of some aminoglycosides

 

 

Pseudomonas aeruginosa

Mycobacterium tuberculosis

Relative degrees of:

Aminoglycoside

Staphylococci

Streptococci

Enterobacteria

Ototoxicity

Nephrotoxicity

 

Streptomycin

Good

Poor

Good

Poor

Good

+++

+

Kanamycin

Good

Poor

Good

Poor

Good

++

++

Gentamicin

Good

Fair

Good

Good

Poor

++

++

Tobramycin

Good

Poor

Good

Good

Poor

++

++

Sissomicin

Good

Poor

Good

Good

Poor

++

++

Netilmicin

Good

Poor

Good

Good

Poor

+

+

Amikacin

Good

Poor

Good

Good

Good

++

+

Neomycin

Good

Poor

Good

Poor

Fair

+++

+++

 

As a group the aminoglycosides display considerable toxicity, affecting both the ear and the kidney, and their use requires careful laboratory monitoring. In the laboratory the activity of aminoglycosides is markedly affected by pH and other variables.

Mode of action

Most of the work on the mode of action of aminoglycosides has concentrated on streptomycin, which binds to a particular protein in the 30 S ribosomal subunit. Alteration of this protein results in streptomycin resistance, but aminoglycosides of the kanamycin and neomycin groups, which bind at a different site on the 30 S subunit and also to the 50 S subunit, are generally unaffected. Several effects of the binding of streptomycin and other aminoglycosides have been noted, including a tendency to cause misreading of certain codons of mRNA resulting in the production of defective proteins, some of which may affect membrane integrity. Other evidence suggests that the primary site of action lies in the formation of non-functioning initiation complexes, or inhibition of the translocation step in polypeptide synthesis. None of these hypotheses fully explains the potent bactericidal activity of aminoglycosides compared with other inhibitors of protein synthesis. Definitive solutions to these and other paradoxical aspects of aminoglycoside action are still the subject of dispute.

Aminoglycosides enter bacteria by an active transport process involving respiratory quinones. Since these are absent in streptococci and anaerobes, this accounts for the relative insusceptibility of those organisms.

Streptomycin

The use of streptomycin has declined with the appearance of other aminogly-cosides, although it is still a component of several antituberculosis regimens recommended by the World Health Organization (WHO; see Chapter 26). It has also been used in the treatment of some rarer conditions, including plague, brucellosis, bartonellosis, and tularaemia, possibly for want of adequate evidence that more modern agents might be effective.

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Neomycin group

Neomycin is the most ototoxic of the aminoglycosides and it is now little used, except in topical preparations; even this use is discouraged because of the risk of promoting the emergence of aminoglycoside resistance. It has also been given orally together with other agents to sterilize the gut before abdominal surgery, but the inactivity of aminoglycosides against anaerobes ensures that most of the gut flora escapes, and the procedure is not without risk of systemic toxicity. Framycetin, a common component of topical preparations, is identical to neomycin B.

One aminoglycoside of the neomycin group, paromomycin, is unusual in exhibiting activity against the protozoa causing amoebic dysentery and leishmaniasis as well as some tapeworms. However, other drugs are preferred in the treatment of these parasitic diseases (see Chapter 5).

Kanamycin group

Important members of this large group include kanamycin itself, gentamicin, tobramycin, netilmicin, and a semi-synthetic derivative of kanamycin A, amikacin.

In its naturally occurring form kanamycin is a mixture of three closely related compounds, kanamycin A, B, and C. Pharmaceutical preparations consist almost exclusively of kanamycin A, although kanamycin B (bekanamycin) is available in some countries. The spectrum of activity is similar to that of streptomycin (and includes M. tuberculosis), but it retains activity against streptomycin-resistant strains and is less likely to cause vestibular damage.

Kanamycin has largely been superseded by gentamicin and tobramycin (deoxykanamycin B), which are more active against many enterobacteria and, more importantly, include Ps. aeruginosa in their spectrum. This has been a major factor in the popularity of these agents for the ‘blind’ therapy of serious infection before the results of laboratory tests are known. The relative merits of gentamicin and tobramycin have been the subject of much debate. Tobramycin appears to be marginally less toxic and slightly more active against Ps. aerug-inosa; against other susceptible bacteria, gentamicin probably has the edge.

Other agents of the kanamycin group, including sissomicin, dibekacin, micro-nomicin (gentamicin C2B), ribostamycin, and the fortimicin A derivative astromicin, seem to offer little advantage over gentamicin or tobramycin, although some of these compounds offer stability to certain aminoglycoside-modifying enzymes (see p. 148). Netilmicin (N-acetyl sissomicin) also exhibits this feature, and is is somewhat less toxic than its predecessors.

Amikacin and arbekacin are semi-synthetic derivatives of kanamycin A and dibekacin respectively, in which an α-aminobutyric acid substituent has been added to an amino group on the deoxystreptamine ring; isepamicin is similarly derived from gentamicin B. These compounds were specifically developed to resist most aminoglycoside-modifying enzymes, although they have lower intrinsic activity

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than gentamicin or tobramycin. Amikacin, the most widely available of these drugs, has been popular in units troubled by gentamicin resistance. Strains of bacteria that are resistant to gentamicin by non-enzymic mechanisms are cross-resistant to amikacin and other aminoglycosides.

Spectinomycin

Spectinomycin exhibits properties that separate it from the true aminoglycosides. It displays inferior antibacterial activity against most species and generally achieves a bacteristatic rather than a bactericidal effect. Its sole use is in the treatment of gonorrhoea in patients who are either hypersensitive to penicillin, or infected with gonococci that are resistant to penicillin.

Chloramphenicol

Chloramphenicol was one of the first therapeutically useful antibiotics to appear from systematic screening of Streptomyces strains in the wake of the discovery of streptomycin in the 1940s. Although it is a naturally occurring compound it is a relatively simple molecule (Fig. 2.3) and can readily be synthesized. Attempts to modify the structure have generally resulted in a marked loss of activity, but thiamphenicol, a compound in which a sulphomethyl group replaces the nitro group of chloramphenicol, displays antibacterial activity comparable to that of chloramphenicol itself. A fluorinated derivative, florfenicol, is used in veterinary practice.

 

Fig. 2.3 Structure of chloramphenicol.

Pure chloramphenicol is very insoluble in water and tastes extremely bitter. These problems have been overcome by prodrug forms of the antibiotic: chloramphenicol palmitate and stearate to improve palatability and chloramphenicol succinate to improve solubility for injection. These prodrugs lack antibacterial activity, but serve to release chloramphenicol in the body; they should not be used for laboratory tests of bacterial sensitivity.

Chloramphenicol acts by inhibiting the peptidyl transferase reaction—the step at which the peptide bond is formed—on 70S ribosomes. The spectrum of activity embraces most Gram-positive and Gram-negative bacteria, and also extends to chlamydiae and rickettsiae, those strictly intracellular bacteria that

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cause a variety of infections, including trachoma, psittacosis, and typhus (Table 2.2). Resistance when it occurs is usually due to bacterial enzymes that acetylate the two hydroxyl groups.

Table 2.2 Summary of the antibacterial spectrum of inhibitors of protein synthesis in common use

 

Antibiotic

Staphylococci

Streptococci

Neisseria spp.

Haemophilus influenzae

Enterobacteria

aeruginosa

Pseudomonas Anaerobes

Rickettsiae and chlamydiae

Mycoplasmas

 

Aminoglycosides

Good

Poor

Fair

Fair

Good

Variable

Fair

Chloramphenicol

Good

Good

Good

Good

Good

Poor

Good

Good

Fair

Clindamycin

Very good

Good

Good

Fair

Variable

Fusidic acid

Very good

Fair

Good

Fair

Macrolides

Very good

Very good

Good

Good

Fair

Good

Variable

Mupirocin

Very good

Very good

Good

Good

Streptogramins

Very good

Very good

Good

Good

Fair

Tetracyclines

Good

Good

Good

Good

Gooda

Poor

Fair

Good

Good

 

–, no useful activity;…, no information.

NB: Individual strains of susceptible species may be resistant to any of these agents.

aPoor activity against Proteus spp.

The action of chloramphenicol against enterobacteria is largely bacteristatic, but against some bacteria, including the Gram-positive cocci, chloramphenicol may display quite potent bactericidal activity. The drug also possesses the important properties of diffusing well into cerebrospinal fluid (CSF) and of penetrating into cells—a very useful feature in the treatment of diseases such as typhoid, typhus, and other conditions where intracellular bacteria are involved. Resistance to chloramphenicol is generally uncommon, although resistant strains ofSalmonella enterica, serotype Typhi cause serious problems in areas of the world where typhoid is endemic. Strains of Haemophilus influenzae that are resistant to chloramphenicol are also being encountered with increasing frequency.

Given its attractive qualities it is a great pity that chloramphenicol displays one grave drawback: potentially fatal aplastic anaemia (p. 211). This rare side-effect has relegated chloramphenicol to the role of a reserve drug. Use of thiamphenicol is also commonly associated with bone marrow depression, but the irreversible effects have not been reported with this drug. Chloramphenicol is sometimes still used in typhoid fever and meningitis, including neonatal meningitis when, however, the other potentially fatal side-effect of the antibiotic (‘grey baby syndrome’; p. 195) may follow if the dosage is not properly adjusted.

Tetracyclines

The first tetracycline, chlortetracycline (Fig. 2.4), was described in 1948 as a product of Streptomyces aureofaciens. Oxytetracycline and tetracyline itself (so-called because it lacks both the chlorine of chlortetracycline and the hydroxyl of oxytetracycline) quickly followed. These, and other members of the group including demeclocycline, doxycycline, lymecycline, methacycline, and minocy-cline, are closely related structural variants of the same tetracyclic molecule.

 

Fig. 2.4 Structure of chlortetracycline.

The tetracyclines are among the most broad-spectrum of all antimicrobial agents, displaying good activity against most Gram-positive and Gram-negative bacteria, rickettsiae, chlamydiae, mycoplasmas, and spirochaetes (Table 2.2). They do not differ much in their antibacterial activity and are distinguished more

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by their pharmacokinetic behaviour. Doxycycline and minocycline are the most widely used. They are more completely absorbed when given orally and, unlike the others, they do not aggravate renal failure so that they can be used in patients suffering renal impairment; they also exhibit marginally better antibacterial activity, and they display sufficiently long serum half-lives to allow them to be given only once or twice daily. Tetracyclines should not be given to young children (see p. 202).

Susceptible bacteria concentrate tetracyclines by an active transport process. In the cell they interact with the 30 S ribosomal subunit and thereby interfere with the binding of aminoacyl tRNA to the A site on the ribosome. Like chlo-ramphenicol, the tetracyclines are predominantly bacteristatic. The therapeutic importance of the group as a whole has declined over the years with the upsurge of resistant strains, particularly among enterobacteria and streptococci. The mechanism of the most common form of resistance is unusual in that a new protein is produced which appears to prevent uptake of the drug (p. 153). There is almost complete cross-resistance between tetracyclines, although minocycline may retain activity against some tetracycline-resistant strains. The glycylcyclines, which are presently under development, appear to be active against many strains resistant to the earlier compounds.

Tetracyclines are still widely used for the treatment of respiratory infections, particularly chronic bronchitis and mycoplasma pneumonia. They have been the drugs of choice for rickettsial and chlamydial infections of all types but their position may be eroded by the newer macrolides (see below). Tetracyclines are active against malaria parasites and some other protozoa. They are used in combination with quinine in the treatment of Plasmodium falciparum infections. Doxycycline is also sometimes recommended for antimalarial prophylaxis.

Fusidic acid

Fusidic acid is the only therapeutically useful member of a group of naturally occurring antibiotics that display a steroid-like structure (Fig. 2.5). The antibiotic acts to prevent the translocation step in bacterial protein synthesis by inhibiting one of the substances (factor G) essential for this reaction.

 

Fig. 2.5 Structure of fusidic acid.

Fusidic acid is active in vitro against Gram-positive and Gram-negative cocci, M. tuberculosisNocardia asteroides, and many anaerobes; the ribosomes of Gram-negative bacilli are susceptible to the action of the drug, but access is denied by the Gram-negative cell wall.

Staphylococcus aureus is particularly susceptible to fusidic acid and the compound is usually regarded simply as an antistaphylococcal agent. It penetrates well into infected tissues, including bone, and it is favoured by some authorities for the treatment of staphylococcal osteomyelitis. A potential drawback is the presence in any large staphylococcal population of a small number of fusidic acid resistant variants which might proliferate during therapy. For this

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reason, fusidic acid is usually administered together with another antibiotic, often a penicillin.

Fusidic acid is usually free from side-effects when given orally. Intravenous administration of the diethanolamine salt is sometimes accompanied by a reversible jaundice. Topical preparations are available, but their use risks encouraging the emergence of resistance.

Macrolides

The earliest macrolide, erythromycin, was discovered in 1952 as a product of Streptomyces erythreus. This and related antibiotics share a similar molecular structure characterized by a 14-, 15-, or 16-membered macrocyclic lactone ring substituted with some unusual sugars (Fig. 2.6). All members of the group are thought to act by causing the growing peptide chain to dissociate from the ribo-some during the translocation step in bacterial protein synthesis.

 

Fig. 2.6 Structure of erythromycin A.

Macrolides are most notable for their antistaphylococcal and antistreptococcal activity, though the spectrum encompasses other important pathogens, including chlamydiae, mycoplasmas, legionellae, and some mycobacteria (Table 2.2). Resistance is common among staphylococci, but less so in streptococci. However, erythromycin-resistant Streptococcus pyogenes strains are increasing in prevalence.

Macrolides have many attractive properties as well-tolerated oral compounds that display good tissue penetration. Their spectrum of activity makes them particularly suitable for the treatment of respiratory and soft-tissue disease and for infections caused by susceptible intracellular bacteria.

Erythromycin

Erythromycin, the oldest and most widely used macrolide antibiotic, exists in four forms: erythromycin A, B, C, and D. Erythromycin A (Fig. 2.6) is the most

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active and predominates in pharmaceutical preparations. The native form is broken down in the acid conditions of the stomach and is administered in the form of enteric-coated tablets which protect the antibiotic until it reaches the absorption site in the duodenum. Alternatively, the stearate salt or esterified pro-drug forms are used for oral administration. Two ester formulations are in general use: the ethylsuccinate and the estolate. Erythromycin lactobionate and erythromycin gluceptate are available for intravenous use. The estolate is generally regarded as the most toxic formulation because of its propensity to cause reversible cholestatic jaundice. However, this uncommon complication can arise with any of the preparations.

Erythromycin was originally discovered at a time when resistance of staphylococci to penicillin was first becoming a serious problem. In the fear that its usefulness might be similarly compromised, erythromycin was mainly used as a reserve antistaphylococcal agent, or as a second-line antistreptococcal agent for use in patients allergic to penicillin. Erythromycin is liable to cause nausea and abdominal cramps and this has also limited its popularity.

In common with other macrolides, the antibiotic lacks useful activity against enterobacteria and Ps. aeruginosa, but is active againstMycoplasma pneumoniae. Erythromycin is also used in campylobacter enteritis if the severity of infection warrants antimicrobial treatment, and in Legionella pneumophila pneumonia.

Newer derivatives of erythromycin

Efforts to modify the properties of erythromycin have been more successful in generating compounds with improved pharmacological features rather than enhanced antibacterial activity. Much interest has centred on altering the molecule

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in such a way that the reactive groups responsible for the acid lability are modi-fied. Such changes increase the bioavailability and often extend the plasma half-life. Any improvement in antibacterial activity is generally modest, but enhanced tissue penetration may render these compounds more effective. Acid-stable derivatives of erythromycin also appear to be less prone to cause gastrointestinal upset. Macrolides of this type include azithromycin, clarithromycin, dirithromycin, and roxithromycin.

A new class of erythromycin derivatives, the ketolides, is under development. They have been obtained by introducing a keto function into the macrolactone ring of erythromycin after removal of one of the sugars. These compounds share the Gram-positive spectrum of the earlier macrolides, but retain activity against macrolide-resistant strains.

Azithromycin

In this semi-synthetic macrolide, a methyl-substituted nitrogen atom has been inserted into the lactone ring of erythromycin to produce a 15-membered ring structure that is described as an azalide. Azithromycin has a considerably improved bioavailability and a much extended plasma half-life compared with erythromycin. The antibacterial spectrum is similar to that of erythromycin, although it is somewhat more active against some important respiratory pathogens such as H. influen-zae and L. pneumophila; there is also some improvement in activity against enteric Gram-negative bacilli, but this is unlikely to be of therapeutic benefit. A long terminal half-life enables azithromycin to be administered once a day, and a single dose is effective in chlamydial and gonococcal infections of the genital tract.

Clarithromycin

This compound is the 6-O-methyl derivative of erythromycin; it is metabolized in the body to yield the 14-hydroxy metabolite, which retains antibacterial activity, but has altered pharmacokinetic properties. The activities of clarithromycin and its hydroxy metabolite are similar to that of erythromycin, although concentrations required to inhibit legionellae and chlamydiae are generally lower.

There have been claims of much enhanced penetration into pulmonary sites, beneficial interactions between the parent compound and the hydroxy metabo-lite, and other minor advantages. It is doubtful whether these translate into significantly improved therapeutic efficacy, but it is better absorbed and less prone to cause abdominal discomfort than other macrolides. It has been successfully used in combination regimens for the treatment of infections with Helicobacter pylori and some mycobacteria, notably those of the M. avium group.

Dirithromycin

Dirithromycin is an oral prodrug of the erythromycin derivative, erythromycy-clamine. Although it is less active than than erythromycin against most organisms within the spectrum, it has a much extended plasma half-life and has been

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successfully used for once-daily treatment of respiratory tract, skin, and soft-tissue infections.

Roxithromycin

Roxithromycin is another erythromycin A derivative and, not surprisingly, exhibits activity very similar to the older drug. It differs, however, in having an extended plasma half-life, a feature that may be related to extensive binding to plasma proteins. It is used in various countries (but not the UK) as an alternative to erythromycin.

Other macrolides

Other macrolides that have been used in various parts of the world include olean-domycin (or its better absorbed derivative triacetyloleandomycin) and a series of compounds with a 16-membered ring, including spiramycin, josamycin, mide-camycin (and its diacetyl derivative, miocamycin), kitasamycin, and rokitamycin. None of them seems to offer much therapeutic advantage over erythromycin. Spiramycin is sometimes used as an alternative to pyrimethamine in infections caused by the protozoan parasite, Toxoplasma gondii. Hope that it might be of value in cryptosporidiosis has not been substantiated.

Lincosamides

The original lincosamide, lincomycin, a naturally occurring product of Streptomyces lincolnensis, has been superseded by clindamycin (7-chloro-7-deoxylincomycin; Fig. 2.7), which exhibits improved antibacterial activity.

 

Fig. 2.7 Structure of clindamycin.

Lincosamides interfere with the process of peptide elongation in a way that has not been precisely defined. The ribosomal binding site is probably similar to that of erythromycin, since resistance to erythromycin caused by an inducible methylation of the ribosomal binding site affects lincosamides as well.

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Lincomycin and clindamycin possess good antistaphylococcal and antistrep-tococcal activity and have also proved therapeutically useful in the treatment of infections due to Bacteroides fragilis and some other anaerobes. Enterobacteria and Ps. aeruginosa lie outside the spectrum of activity (Table 2.2). Clindamycin exhibits some activity against parasitic protozoa and has been used in toxo-plasmosis, malaria, and babesiosis.

Clindamycin hydrochloride, like chloramphenicol, is extremely bitter. For oral administration the drug is formulated in capsules or as the biologically inactive palmitate, which liberates the parent compound in vivo. Clindamycin phosphate, the soluble form used for intravenous administration, is similarly inactive in the test-tube, but is hydrolysed to the active drug in the body.

Patients treated with clindamycin (or lincomycin) commonly experience diarrhoea caused by a clostridial toxin, which occasionally develops into a potentially fatal pseudomembranous colitis (see p. 251). Other antibiotics, notably ampi-cillin and broad-spectrum cephalosporins, may also cause this side-effect, but the incidence of toxin-associated colitis appears to be somewhat higher following clindamycin therapy.

Streptogramins

Each member of the streptogramin family is not one antibiotic, but two: they are produced as synergic mixtures by various species ofStreptomyces. One of these compounds, virginiamycin, has been extensively used as a growth promoter in animal husbandry. Another streptogramin, pristinamycin, is sometimes used as an antistaphylococcal agent in continental Europe, but plasma concentrations after oral administration do not greatly exceed inhibitory levels and solubility problems have militated against parenteral use. A formulation consisting of the water-soluble derivatives, quinupristin and dalfopristin, is, however, suitable for infusion and is now in use in human therapy.

The two components of streptogramin antibiotics are both macrolactones, but they are structurally different. Alone they exhibit feeble bacteristatic activity, but in combination the effect is bactericidal. Component A is a polyunsaturated peptolide that causes distortion of the aminoacyl-tRNA binding site, hindering further growth of the peptide chain. The action of component B, a hexadep-sipeptide, is less well understood, but it is proposed that it binds to an adjacent site and that the combined effect is to constrict the channel through which the nascent peptide is extruded from the ribosome. Protein synthesis is completely blocked and the consequences are lethal to the bacterial cell.

The activity of streptogramins is virtually restricted to Gram-positive organisms. Their major claim to attention is that they retain activity against multi-resistant staphylococci and some enterococci, notably Enterococcus faecium. Unfortunately, E. faecalis, which is more commonly encountered, is often resistant.

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Mupirocin

Mupirocin (formerly known as pseudomonic acid) is a component of the antibiotic complex produced by the bacterium Ps. fluorescens. The novel structure consists of monic acid with a short fatty acid side-chain (Fig. 2.8). The terminal portion of the molecule distal to the fatty acid resembles iso-leucine, and mupirocin inhibits protein synthesis by blocking incorporation of the amino acid into polypeptides. The analogous process in mammalian cells is unaffected.

 

Fig. 2.8 Structure of mupirocin.

The spectrum of activity embraces staphylococci and streptococci, but excludes most enteric Gram-negative bacilli (Table 2.2). Hopes that mupirocin might be useful in systemic therapy were thwarted by the realization that the compound is inactivated in the body. Consequently, its use is restricted to topical preparations. Mupirocin has proved particularly useful in the eradication of staphylococci from nasal carriage sites (see p. 372).

Oxazolidinones

Several oxazolidinones have been investigated over the years as possible antimicrobial agents. Two, linezolid and eperezolid, have received particular attention owing to their activity against Gram-positive organisms, including multi-resistant staphylococci, pneumococci and enterococci. They are well absorbed by the oral route and exhibit bacteristatic activity. They act at an early stage in protein synthesis by blocking the formation of the 70 S initiation complex. A principal attraction of these compounds is that they do not show cross-resistance to other classes of drugs. Linezolid has been most widely investigated in clinical trials and is soon to be marketed. Although early indications are that it is safe and effective, it is too early to assess its true place in treatment.

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Everninomicins

Concern about multiresistant Gram-positive cocci has stimulated fresh interest in the everninomicins, a family of naturally occurring oligosaccharide antibiotics that interfere with protein synthesis by blocking attachment of aminoacyl-tRNA to the smaller ribosomal subunit. These compounds have useful activity against staphylococci, streptococci, enterococci and clostridia. One member of the group, avilamycin, has been used as a growth promoter in food animals and resistance is known to develop through such use. As with the streptogramins, this has led to concerns about cross-resistance to related agents developed for human therapy.