Single vs Multiple Antibiotics in Community-Acquired Pneumonia

By Richard G. Wunderink, MD, FCCP; and Grant W. Waterer, MBBS, FCCP

Other investigators have noted a similar trend. Mufson and Stanek²⁰ have demonstrated a mortality benefit for addition of a macrolide to a cephalosporin for bacteremic pneumococcal pneumonia (Fig 5). The differences have persisted over a multiyear observation period in the same institution.

The findings of Waterer et al¹⁹ and Mufson and Stanek²⁰ challenge popular teaching that, in documented cases of pneumococcal pneumonia, monotherapy with a b-lactam, including penicillin, is the treatment of choice. Their findings do support the recommendations of both the Infectious Diseases Society of America² and the American Thoracic Society¹ regarding severe CAP. Both societies' guidelines recommended combination therapy with a cephalosporin and either a macrolide or a quinolone for severe CAP cases, despite no evidence of superiority at the time these recommendations were formulated.

There are at least five potential reasons for the beneficial effect of initial combination therapy for bacteremic S pneumoniae. First, the possibility of a polymicrobial etiology with only the pneumococcal bacteremia diagnosed is very real. Studies that document polymicrobial CAP rely on serologic conversion for detection of atypical microorganisms and, in all studies, the pneumococcus is the most common usual bacterial etiology. No systematic search for atypical microorganisms was performed in either study. In support of this possibility, the mortality rate associated with quinolone monotherapy, which does provide atypical coverage, was closest to the predicted mortality. A second possibility is that the combination antibiotics had a synergistic effect on killing pathogens. Some data exist to suggest synergy for several of the combinations but not for the two most common—a cephalosporin plus either a macrolide or a quinolone. The third possibility is an immunomodulatory effect of certain antibiotics. Cell wall-active agents like cephalosporins may cause more mediator release than other antibiotics. More interesting is the immunomodulatory effect of macrolides on cytokine production, including tumor necrosis factor.²¹ Because 46% of the combinations involved a macrolide and because the cephalosporin/macrolide group had the lowest actual mortality and greatest reduction compared with predicted mortality, this is an attractive hypothesis. The fourth possibility is the possibility of antibiotic tolerance, especially to the cephalosporins and other b-lactams. Because only bacteremic pneumonia cases were studied, the authors of both studies were able to exclude the possibility of inappropriate treatment based on sensitivity testing.^19,20 With antibiotic tolerance, the microorganism appears to be sensitive to an antibiotic based on the minimum inhibitory concentration (MIC). However, the bacteriocidal concentration is markedly greater than the MIC, rendering the antibiotic bacteriostatic at best. Pneumococcal tolerance can occur in up to 20% of isolates.²² The last possibility is that the monotherapy is deficient rather than that the combination is beneficial. The primary fluoroquinolone used in the study was levofloxacin. The MICs for pneumococcus are higher for levofloxacin than for the newer quinolones (gatifloxacin or moxifloxacin), and antibiotic failures have begun to be reported for levofloxacin.

Most likely, each of these potential reasons may contribute to the overall benefit. It should also be noted that, as both of these studies are retrospective, the findings may also be due to chance or bias involving unrecognized factors.^19,20 This issue will remain unresolved until a prospective, randomized, double-blind trial is conducted in patients with severe CAP.

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