Can the third-generation cephalosporins eliminate the need for antimicrobial combinations?

Abstract

Antimicrobial combinations have been widely utilized since the beginning of the chemotherapeutic era. This is true despite the fact that the use of such combinations has a number of potential disadvantages, including (1) antibiotic antagonism; (2) an increased incidence of toxicity; (3) the emergence of multi-resistant organisms; (4) promotion of a false sense of security; and (5) increased expense. The reasons generally given for the use of such combinations include (1) antimicrobial synergism, (2) suppression of antimicrobial resistance, (3) decreased toxicity, and (4) broader coverage. Although there are clearly some situations in which synergistic combinations have been shown to be useful (such as in the treatment of enterococcal endocarditis and severe Pseudomonas infections), the use of combination therapy to reduce the emergence of resistance (excluding the treatment of mycobacterial infections and of infections in which rifampin is used) or to reduce toxicity has not met with widespread success. Indeed, most combinations are used simply to broaden the spectrum of antimicrobial coverage. The development of new penicillins and cephalosporins with broader spectra of activity has raised the distinct possibility that these drugs could be used as single agents for the treatment of most serious infections. Although comparative studies performed to date suggest that the new broad-spectrum penicillins and cephalosporins may be useful as single agents in the treatment of infections in a variety of clinical situations in which combinations are now commonly employed, additional studies enrolling greater numbers of patients are necessary to determine whether these agents can replace combination therapy. The use of single-drug therapy in the management of febrile episodes and documented infections in neutropenic patients remains problematic because of the greater likelihood of infections with organisms such as Pseudomonas aeruginosa, in which case combination therapy is often required. Earlier studies have clearly documented that combinations of antibiotics that are synergistic are more effective in treating bacteremias and other serious infections in neutropenic patients than are combinations that have failed to demonstrate synergism. Because of the increased activity of some of the newer drugs, such as ceftazidime, against P. aeruginosa it is possible that such agents could be used as monotherapy for patients with severe neutropenia. This possibility is an attractive one, but it should be studied carefully to make certain that it will not be associated with significant failure due to the emergence of resistant organisms.