Antibiotics in patients on chemotherapy; aspects on pharmacokinetic and pharmacodynamic interactions with antineoplastic drugs

Abstract: The aims of these studies were to investigate the pharmacokinetics of two beta-lactam antibiotics in patients with fever and cytostatic-induced neutropenia and the influence of cytostatic-induced gastrointestinal damage on the absorption of co-trimoxazole. Furthermore to study the pharmacodynamic interactions between antibiotics and antineoplastic drugs and the impact of antineoplastic drugs on the intestinal microflora. Methods: Kinetic data were obtained by model-independent methods for the beta-lactam antibiotics and by population-based methods for co-trimoxazole. Bacterial killing curves and postantibiotic effects (PAE) of different antibiotics alone and in combination with antineoplastic drugs were studied in vitro. Faecal samples were obtained from patients with acute leukaemia on different cytostatic regimens before, during and after treatment and were cultured quantitatively and qualitatively. Results and Discussion: The faster elimination of meropenem and ceftazidime in our patients compared to historical controls results in shorter times above MIC for the most common pathogens. A dose interval of 6 h seems safer than the commonly used 8 h interval, since serum concentrations should stay above MIC for most of a dose interval in these immunocompromised patients. No correlation was found between the degree of cytostatic-induced gastrointestinal damage and the bioavailability of co-trimoxazole, indicating that the dose of co-trimoxazole needs not be adjusted in these patients.Antibacterial effect and PAEs of the combinations of antibiotics and antineoplastic drugs did not differ markedly from the effects of the antibiotics alone. In the presence of 5-FU and doxorubicin, the antibacterial effect of tobramycin was increased against S. aureus. The PAEs of meropenem and ciprofloxacin against S. epidermidis were synergistically prolonged by 5-FU. This might be due to inhibition of slime production in these strains by 5-FU. The antineoplastic regimens caused only minor changes of the intestinal microflora.