Reply

Guy W. Amsden

Clinical Pharmacology Research Center, Bassett Healthcare, 1 Atwell Road, Cooperstown, NY 13326-1394, USA

Sir,

I thank Dr Pérez-Trallero for his comments and appreciate the in vitro studies he undertook to illustrate his concerns about my recent article in the Journal.1 Although I acknowledged in the article that different laboratory methods may yield varying MICs for the same bacterium, I do not believe I implied that these differences negate the high MICs that have been reported in the literature, nor did I minimize the importance of these results. I wholly agree that the incidence of macrolide resistance among pneumococci is increasing globally. The purpose of the article was to stimulate thought and to offer explanations to account for the absence of large numbers of reports of clinical failures in patients with infections caused by these bacteria who had been treated with macrolides, despite the growing laboratory evidence of this resistance trend. Although Dr Pérez-Trallero is clearly fluent in the background of pneumococcal resistance, other readers of the Journal may not be so familiar with the idiosyncrasies of this particular type of resistance. The article also served to bring together all of the literature on the various aspects of this topic. Too often, a lack of such knowledge has been used against us and our fellow clinicians, either in error or by design, to initiate formulary changes.

With regard to Dr Pérez-Trallero's criticism of the clinical trial data that I used to support my hypotheses, I agree that some of the studies reported in the literature did not use the most appropriate comparator agents and that patients with some types of infection may have responded equally well to symptomatic treatment only. However, it is indisputable that in these clinical trials, and in the literature in general, there are fewer reports of clinical failures than would be anticipated from the results of in vitro studies. The paucity of clinical failures is a mystery. My article espouses hypotheses extrapolated from the literature. Although Dr Pérez-Trallero validated the work of Gerardo et al.2 in terms of the variability of MICs determined by different susceptibility testing methods, he failed to provide any alternative hypotheses to those that I proposed. His demonstration of high MICs of clarithromycin and azithromycin for pneumococci, although performed according to standard laboratory methods, failed to take account of the effects of host defences. Therein lie the chronic friction and misunderstanding between clinical and laboratory medicine.

Standard susceptibility testing methods fail to take account of the bactericidal activity of human serum, the potential for phagocytes to enhance the antibacterial effects of antibiotics intracellularly and the effects of certain antibiotics on bacterial virulence factors—all of which may prevent a potential pathogen from initiating or extending an infectious process.3–5 If the MIC were the sole criterion for predicting the response to antibiotic therapy, then it is obvious from the published data for in vitro pneumococcal resistance that the use of ß-lactams as treatment for patients with infections caused by these bacteria would have been abandoned years ago in many countries where rates of resistance to these drugs are very high. On the contrary, it has been demonstrated clinically that higher dosages of ß-lactams are associated with favourable clinical outcomes despite the in vitro trends.6,7 Faith in these concepts was recently affirmed when the Centers for Disease Control in the USA and the Drug-resistant Streptococcus pneumoniae (DRSP) Therapeutic Working Group recommended in the acute otitis media treatment guidelines that the standard dosage of amoxycillin should be doubled in order to overcome DRSP.8

Whether or not the hypotheses and arguments that I advanced in my article are correct, I believe that the dichotomy between the in vitro resistance and clinical trial data, not only for the macrolides, but for other antimicrobial classes too, should be thoroughly re-evaluated. The current methods of predicting whether or not an antibiotic will be effective against a bacterial pathogen in vivo and determining the optimal dosage of an antimicrobial are crude. Until we take account of inherent host defences and how antibiotics react with pathogens at the sites of infection, the way we choose one antimicrobial agent over another will continue to be flawed.

Notes

J Antimicrob Chemother 2000; 45: 402–403

Tel: +1-607-547-3399; Fax: +1-607-547-6914; E-mail: guy.amsden{at}bassett.org

References

1 . Amsden, G. W. (1999). Pneumococcal macrolide resistance—myth or reality? Journal of Antimicrobial Chemotherapy 44, 1–6.[Free Full Text]

2 . Gerardo, S. H., Citron, D. M., Claros, M. C. & Goldstein, E. J. C. (1996). Comparison of Etest to broth microdilution method for testing Streptococcus pneumoniae susceptibility to levofloxacin and three macrolides. Antimicrobial Agents and Chemotherapy 40, 2413–5.[Abstract]

3 . Gomez-Lus, M. L., Giménez, M. J., Prieto, J., Martin, M., Frias, J. & Aguilar, L. (1998). Effect of polymorphonuclear neutrophils on serum bactericidal activity against Streptococcus pneumoniae after amoxicillin administration. European Journal of Clinical Microbiology and Infectious Diseases 17, 40–3.[ISI][Medline]

4 . Meyer, A. P., Bril-Bazuin, C., Mattie, H. & van den Broek, P. J. (1993). Uptake of azithromycin by human monocytes and enhanced intracellular antibacterial activity against Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 37, 2318–22.[Abstract]

5 . Shryock, T. R., Mortensen, J. E. & Baumholtz, M. (1998). The effects of macrolides on the expression of bacterial virulence mechanisms. Journal of Antimicrobial Chemotherapy 41, 505–12.[Abstract]

6 . Pallares, R., Linares, J., Vadillo, M., Cabellos, C., Manresa, F., Viladrich, P. F. et al. (1995). Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. New England Journal of Medicine 333, 474–80.[Abstract/Free Full Text]

7 . Friedland, I. R. (1995). Comparison of the response to antimicrobial therapy of penicillin-resistant and penicillin-susceptible pneumococcal disease. Pediatric Infectious Disease Journal 14, 885–90.[ISI][Medline]

8 . Dowell, S. F., Butler, J. C., Giebink, G. C., Jacobs, M. R., Jernigan, D., Musher, D. M. et al. (1999). Acute otitis media: management and surveillance in an era of pneumococcal resistance—a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatric Infectious Disease Journal 18, 1–9.[ISI][Medline]





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