New Antibiotics in Pulmonary and Critical Care Medicine

†, * University of the Pacific, School of Pharmacy Stockton, California, and Kendle International, Inc.;   †Maine Medical Center, Portland, Maine, and University of Vermont, College of Medicine, Burlington, Vermont

Semin Respir Crit Care Med. 2000;21(1) 

In This Article

Current Treatment Options

Currently available ß-lactams able to resist the class C ß-lactamases and ESBLs include the fourth-generation cephalosporins (e.g., cefepime and cef-pirome) and the carbapenems (e.g., imipenem and meropenem). The fluoroquinolones remain highly active against many of these ß-lactamase-producing bacteria and are likely to result in good outcomes; however, ESBL-producing strains can often confer multidrug resistance, so therapy should be modified when susceptibility data become available. As discussed in earlier sections, pharmacodynamic indices may be used not only to optimize patient outcome but also to minimize the development of resistance. Specifically, against inducibly resistant strains of E. cloacae and P. aeruginosa, Aronoff and Shlaes[71] demonstrated that the frequency of bacterial mutation under antimicrobial pressure was directly related to the ratio of drug concentration to the MIC of the bacteria. Furthermore, the time the drug concentration remains in excess of the MIC at the site of infection has been shown to be predictive of clinical and bacteriologic outcome for ß-lactam antibiotics.[72] Familiarity with these concepts allows the practicing clinician to compare agents for potential efficacy based on pharmacodynamic indices (e.g., time above MIC, Cp:MIC ratio, and AUC:MIC ratio) resulting in the selection of regimens that will maximize bacterial killing. Consequently, it was shown recently that patients receiving antibacterial therapy yielding suboptimal pharmacodynamic indices were more likely to select for resistant bacterial populations during therapy.[73]

These data further emphasize the need for clinicians to optimize both antibacterial selection and its dosing regimen based on known pharmaco-dynamic principles. The fourth-generation cephalosporins and the carbapenems both reach concentrations well in excess of typical bacterial MICs in lung tissue and epithelial lining fluid for a significant period of the dosing interval. Furthermore, Sanders and colleagues have reported the successful treatment of patients with cefepime that were infected with multiply-resistant Enterobacter species, including ceftazidime-resistant strains.[74] Included in this group were chronically infected patients who had responded poorly to imipenem, aminoglycosides, and ciprofloxacin. The success rate of cefepime in this group of patients was 88.2%, and the development of resistance was not reported to occur during therapy.

The use of combination therapy in the treatment of infection has been controversial, and the results of clinical studies are often contradictory.[73,74,75,76] Compounding the difficulty in the interpretation of combination therapy studies is the fact that resistance mechanisms continue to evolve, patient populations (e.g., immune system status) vary, the end-points of such studies can be questionable, and knowledge of optimal antibiotic dosing strategies (e.g., once-daily aminoglycoside administration) are emerging. With this in mind, it is difficult to prospectively study rational antibiotic combinations in a controlled fashion that employs optimal dosing strategies against a large enough sample of a variety of infecting organisms on which to base firm conclu- sions from these studies. So in clinical practice, some clinicians continue to treat infections due to organisms with a propensity to develop resistance quickly with combination therapy, if based on nothing else but circumstantial evidence. A distillation of the data from studies evaluating combination therapy has revealed a benefit when treating systemic infection caused specifically by P. aeruginosa. Examining the patient populations within these studies in greater detail further emphasizes the benefit of combination antipseudomonal therapies in neutropenic patients. For infection due to gram-negative bacilli other than P. aeruginosa, combination therapy has not been shown to have a significant impact on patient outcome. When combination therapy targeted against gram-negative bacilli is felt to be clinically indicated, an aminoglycoside or fluoroquinolone is optimally combined with a -lacta-mase- stable ß-lactam (e.g., fourth-generation cephalosporin, carbapenem). In proven ß-lactam- intolerant patients, aztreonam could be substituted for the ß-lactam and combined with either an aminoglycoside or a fluoroquinolone. Quinolone-aminoglycoside combinations, although popular in certain geographic regions, are infrequently synergistic against gram-negative bacteria in direct contrast with ß-lactam-aminoglycoside and ß-lactam- quinolone combinations.[79,80,81]


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