antagonism may only distantly replicate these conditions.
Probably more important than whether an antibiotic is bacteriostatic or bactericidal in vitro is whether its antimicrobial effect is concentration-dependent or h'me-dependent. Examples of the former include the quinolones and aminoglycosides in which the outcome is related to the peak antibiotic concentration achieved at the site of infection in relation to the minimum concentration necessary to inhibit multiplication of the organism (the Minimum Inhibitory Concentration, or MIC). These antimicrobials produce a prolonged inhibitory effect on bacterial multiplication (the Post-Antibiotic Effect, or PAE) which suppresses growth until the next dose is given. In contrast, agents such as the (ii-lactams and macrolides have more modest PAEs and exhibit time-dependent killing; for optimal efficacy, their concentrations should be kept above the MIC for a high proportion of the time between each dose (Fig. 11.1).
Figure 11.1 shows the results of an experiment in which a culture broth initially containing 106 bacteria per ml is exposed to various concentrations of two antibiotics one of which exhibits concentration- and the other time-dependent killing. The 'Control' series contains no antibiotic, and the other series contain progressively higher antibiotic concentrations from 0.5 x to 64 x the MIC. Over 6 hours incubation, the time-dependent antibiotic exhibits killing but there is no difference between the 1 x MIC and 64 x MIC. The additional cidal effect of rising concentrations of the antibiotic which has concentration-dependent killing can be clearly seen.
It should always be remembered that drugs are seldom the sole instruments of cure but act together with the natural defences of the body. Antimicrobials act at different sites in the target organism as follows:
The cell wall. This gives the bacterium its characteristic shape and provides protection against the much lower osmotic pressure of the environment. Bacterial multiplication involves breakdown and extension of the wall; interference with these processes prevents the organism from resisting osmotic pressures, so that it bursts. As the cells of higher, e.g. human, organisms do not possess this type of wall, drugs that act here may be especially selective; obviously, the drugs are effective only against growing cells. They include: penicillins, cephalosporins, vancomycin, bacitracin, cycloserine.
The cytoplasmic membrane inside the cell wall is the site of most of the microbial cell's biochemical activity. Drugs that interfere with its function include: polyenes (nystatin, amphotericin), azoles (fluconazole, itraconazole, miconazole), polymyxins (colistin, polymyxin B).
Protein synthesis. Drugs that interfere at various points with the build-up of peptide chains on the ribosomes of the organism include: chloramphenicol, erythromycin, fusidic acid, tetracyclines, aminoglycosides, quinupristin/dalfopristin, linezolid.
Nucleic acid metabolism. Drugs may interfere
• directly with microbial DNA or its replication or repair, e.g. quinolones, metronidazole, or with RNA, e.g. rifampicin
• indirectly on nucleic acid synthesis, e.g. sulphonamides, trimethoprim.
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