The postantibiotic effect induced by antimicrobial combinations.

Antimicrobial combinations are frequently needed for the successful treatment of serious infections. Generally, the same dosing schedules are employed irrespective of whether the drugs are used singly or in combination. A postantibiotic effect (PAE) has been described for all antibiotics used singly against Gram-positive cocci, but only for non-beta-lactams against Gram-negative bacilli with the exception of carbapenems against Pseudomonas aeruginosa. The major clinical relevance of the PAE pertains to its impact on antimicrobial dosing, where agents inducing a long PAE may be administered with longer dosing intervals than currently employed, without loss of efficacy. The purpose of this study was to examine whether PAEs induced by drug combinations differed from the PAEs induced by the drugs alone, and whether a pattern of synergism, addition or antagonism could be defined in this regard. The study organisms, 7 strains of Staphylococcus aureus, 4 strains of Escherichia coli, 4 strains of Klebsiella pneumoniae and 6 strains of Ps. aeruginosa, were exposed to several beta-lactams, aminoglycosides, rifampin and ciprofloxacin singly and in combination. The antimicrobial combinations used against S. aureus affected the PAE in either an additive or an indifferent manner when compared to the PAEs induced by the drugs as single agents. Enhancement of PAEs against Gram-negative bacilli was primarily dependent on the ability of each individual drug to induce a PAE. Thus, for a combination of drugs where both agents induced a PAE individually, the final PAE was a rough mathematical sum of the individual PAEs (addition). When only one of the agents induced a PAE, the final result was similar to the PAE of that particular drug (indifference). Ciprofloxacin seemed to be an exception to this rule, since it did not increase the PAE of a PAE producing drug, despite exhibiting a PAE itself. Rifampin was unique in that it prolonged the PAE in a marked synergistic fashion, when employed with one or more other PAE-producing agents. Further studies in vivo are clearly needed to confirm these observations, but they could have significant impact on the design of dosing regimens for antimicrobial combinations.