Immunocompromised animal models for the study of antibiotic combinations.

ABSTRACT

Studies of various models of Pseudomonas aeruginosa infections in neutropenic animals have demonstrated the superiority of the combination of beta-lactam and aminoglycoside antibiotics when compared with a single drug alone. A limited number of studies carried out in models of Klebsiella pneumoniae infections in neutropenic animals have shown similar results. The efficacy of double beta-lactam combinations for the treatment of gram-negative bacillary infections has not been studied as extensively; the few available reports did not show any benefit over a single beta-lactam treatment. Most studies of combined therapy in gram-positive infections have been performed in the experimental endocarditis model. Experiments in Staphylococcus aureus, Streptococcus viridans, and Streptococcus faecalis endocarditis have shown a clear-cut advantage for combined beta-lactam/aminoglycoside treatment over single beta-lactam therapy, as predicted by in vitro tests. The enhanced efficacy of combined beta-lactam/aminoglycoside treatment in both gram-negative bacillary and gram-positive coccal infections appears to result in most studies in increased and faster killing of the bacteria. With P. aeruginosa infections, however, experiments in neutropenic mice suggest that in addition to increased killing, the beta-lactam arm of the combined treatment prevents the emergence of the small colony variants that lead to treatment failures during therapy with aminoglycoside alone. For both gram-negative bacillary and gram-positive coccal infections, in vitro tests that demonstrated synergism for the combined antibiotics generally predicted enhanced therapeutic efficacy in vivo. Conversely, when no synergism was demonstrated in vitro, there was generally no increased efficacy of combined treatment in vivo. Animal models add a dimension to our understanding of the efficacy of antibiotics, both singly and in combination, that is not always apparent from the results of in vitro tests alone. These in vivo tests can be of value when planning clinical trials.