Pharmacodynamics of antibiotics in the therapy of meningitis: Infection model observations

Abstract

Detailed studies of pharmacodynamic principles relevant to the therapy of bacterial meningitis are difficult to perform in man, while the rabbit model of bacterial meningitis has proved to be extremely valuable and has led to insights that appear relevant for the treatment of humans. Most importantly in the light of the restricted penetration of antibiotics into the CSF, animal studies have shown that in meningitis there is a dose-response curve between the CSF concentrations achieved by antibiotics and their bactericidal activity. This appears to be true for all classes of antibiotics thus far examined, including the beta-lactams, which do not show such a dose-response behaviour in other infections. Only CSF concentrations that exceed the MBC of the infecting organism by at least 10-30-fold achieve consistent and rapid bactericidal activity. Such rapid bactericidal activity is a requirement for successful therapy with beta-lactams and can be impaired with certain antibiotics by the specific conditions in infected CSF (protein content; acidic pH; slow-growing bacteria). However, rapid antibiotic killing of the infecting organisms may not be without adverse effects either. Some antibiotics, particularly beta-lactams lead to the brisk liberation of bacterial cell wall components (e.g. endotoxin, in the case of Gram-negative organisms) which have an inflammatory effect on the host and can lead to a temporary deterioration of the disease. Dexamethasone, when administered with the antibiotic, can prevent some of the adverse effects of rapid bacterial lysis.

Antimicrobial chemotherapy of human infection due toListeria monocytogenes

“…The combination of penicillin plus tetracycline was no more effective than penicillin alone (19). Combinations including rifampicin are probably antagonistic (48,51), and combinations including ciprofloxacin, although antagonistic in chequerboard tests, were more promising in time-kill curve experiments (51). Ciprofioxacin combinations may be worth further clinical or animal investigation.…”

“…The MBC of Listeria monocytogenes when tested against ampicillin is often greater than 64 mg/1, and it has been proposed that CSF antimicrobial concentration should exceed the MBC by tenfold for effective therapy (51). Therefore, it is dif-ficult to understand how ampicillin monotherapy even at doses of greater than 6 g/day can achieve reliable clinical cure as CSF ampicillin concentrations above the MBC cannot be pharmacologically achieved.…”

“…One group demonstrated synergy between penicillin or ampicillin plus rifampicin with bactericidal activity occurring at lower concentrations of both drugs but only bacteriostatic activity at higher concentrations (63). Others have recommended the use of co-trimoxazole and rifampicin combinations (48), but more recent in vitro testing using time-kill curves and chequerboard studies has clearly shown rifampicin to be antagonistic in combination with the beta-lactams, co-trimoxazole or trimethoprim (51,93). When rifampicin was used alone in mouse models, resistance did not develop during therapy (25), and other animal studies have shown that rifampicin was superior to all other regimens in the removal of organisms from the spleen (43).…”

“…Various combinations of antibiotics have been tested, but the most bactericidal combinations in vitro appear to be ampicillin plus gentamicin, trimethoprim plus gentamicin, vancomycin plus gentamicin and trimethoprim plus sulphamethoxazole (co-trimoxazole) (51). Apart from trimethoprim plus gentamicin, the other combinations have been used successfully to treat limited numbers of clinical infections.…”

Pathogenesis of pneumococcal infection

“…This was thought to be due to the release of cell-wall products and pneumolysin [69]. Organisms with high cell-wall turnover, resulting in a greater release of teichoic acid components, induce a greater in¯ammatory response in the rabbit meninges [70].…”