-Lactam/ -lactamase inhibitor combinations: pharmacodynamic considerations and possible role in the management of bacterial infections in the neutropenic host

The choice of effective empirical treatment of fever in the neutropenic host requires a sound knowledge of the local microbial epidemiology and the susceptibility patterns of pathogens. Since the list of possible pathogens can, at best, only be narrowed to a few most likely organisms, the use of empirical broad-spectrum antibiotic therapy in such situations is warranted. Indeed, the empirical use of broad-spectrum antimicrobial agents is further supported by the observation that the types of organisms that cause infections in the neutropenic host have changed over time. Amongst other factors, acquisition of resistance by microorganisms to the antimicrobial agents used for prophylaxis and therapy, has led to the need for continuous revision of empirical regimens. Bacterial resistance to -lactam antibiotics mediated by the production of drug inactivating enzymes has also influenced the selection of therapy. Various approaches towards empirical therapy in the neutropenic host have been adopted based on trends in bacterial resistance. One successful approach has been the development of potent agents such as the aminothiazolyl cephalosporins, monobactams and carbapenems that are relatively resistant to hydrolysis by the -lactamases. These agents have been used as single agents or in combination with an aminoglycoside. Most combination antimicrobial regimens for empirical therapy include an aminoglycoside, but because of the untoward effects associated with these agents, coupled with the need for continued serum drug monitoring during therapy and the shift of infecting organisms towards Gram-positive bacteria, aminoglycosides have often been replaced by other agents. An additional strategy to overcome drug resistance and expand the coverage against Gram-positive bacteria involves the use of -lactamase inhibitors in combination with -lactam antibiotics. The search for inhibitors of bacterial -lactamases resulted in the discovery of clavulanic acid followed by other inhibitors such as sulbactam, olivanic acid, BRL 42715, penems, carbapenems and tazobactam. Structurally, tazobactam is a sulbactam derivative that has demonstrated highly potent activity against