Beta-lactam/beta-lactamase inhibitor combinations: pharmacodynamic considerations and possible role in the management of bacterial infections in the neutropenic host.
Morbidity and mortality in febrile neutropenic patients result mainly from complications attributable to infectious diseases. Both Gram-negative and Gram-positive bacterial infections have been implicated. The use of antibiotics in combating bacterial infections has been hampered by production by many bacterial pathogens of beta-lactamases that render them resistant to beta-lactam antibiotics. Since susceptibility to the beta-lactam appears crucial in attaining a clinical response in Gram-negative bacteraemia in febrile neutropenic patients, regimens that inhibit the activity of beta-lactamases are desirable. Although many beta-lactamase inhibitors, such as tazobactam, can result in irreversible inhibition of bacterial beta-lactamase in vitro, careful selection of dosage, as well as testing in models of infection mimicking that in patients, is required. Experimental studies in in-vitro models of infection that mimic conditions of absent host response, show that tazobactam restores the activity of piperacillin against beta-lactamase-producing bacteria. Optimal dosage regimens of beta-lactamase inhibitors will provide mean concentrations of beta-lactamase inhibitor at or above those used in in-vitro testing.
Okereke
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C
Anti-infective Pharmacology Research Unit, University of Rhode Island College of Pharmacy and Brown University Medical School, Roger Williams Medical Center, Providence 02908, USA.
Dudley
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MN
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001424:Bacterial Infections / Q000188:drug therapy*; D004359:Drug Therapy, Combination / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D009503:Neutropenia / Q000276:immunology*; D009894:Opportunistic Infections / Q000188:drug therapy* / Q000276:immunology; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D010878:Piperacillin / Q000493:pharmacokinetics / Q000494:pharmacology; D000078142:Tazobactam; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors
D000900:Anti-Bacterial Agents; D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid; D000078142:Tazobactam; D010878:Piperacillin