Unexplained Benefits of Antibiotics in Childhood: Empiricism in Need of Enlightenment

Infections remain relentless causes of morbidity and mortality, particularly in the developing world. Pneumonia, diarrhea, and malaria kill 3.5 million, 2.5 million, and 655 000 people annually, respectively, and disproportionately injure children less than 5 years of age [1]. Any reduction in thisburdentochildrenshouldbewelcomed. In this issue of The Journal of Infectious Diseases, Gilliams et al [2] report that by adding azithromycin to chloroquine to treat childhood malaria, the incidences of subsequent respiratory and gastrointestinal infections are lowered, and times to next pulmonary and diarrheal illness are prolonged. For every 7 children treated with chloroquine-azithromycin for malaria, 1 case of respiratory-tract infection and 1 case of gastrointestinal-tract infection were apparently averted. This work extends prior efforts in Ethiopia, demonstrating that mass azithromycin treatment for trachoma reduced all-cause and infectious childhood mortality [3] and that azithromycin was associated with reduced mortality in a cluster-randomized trial for trachoma control [4]. The data of Gilliams et al also complement those of Trehan et al, who demonstrated a 40% reduction in mortality in Malawian children by adding amoxicillin or cefdinir to readyto-use therapeutic food regimens for the outpatient treatment of acute severe malnutrition [5]. Why might the addition of azithromycin to chloroquine reduce gut and respiratory infections? It is possible that the illnesses averted in the azithromycin antibiotic group were, in reality, unusual presentations of malaria [6, 7]. However, these children had no smear evidence of malaria when they had these gut and lung infections, making this explanation less likely. Alternatively, the azithromycin could have fortuitously inhibited growth of a specific pathogen acquired by a susceptible child before or during the course of the antibiotic treatment, thereby prohibiting pathogen population expansion or preventing colonization. The nonplasmodial, nonchlamydial target(s) of azithromycin in this cohort might have been Streptococcus pneumoniae, Haemophilus influenzae, Salmonella typhi, nontyphoidal salmonella, other gramnegative bacilli, group B streptococcus, and even mycobacteria, based on studies of childhood sepsis in Africa [8–13]. Another potential explanation for the success of azithromycin is that it altered the host’s commensal microbial population such that a yet to be encountered pulmonary or intestinal pathogen did not take hold. Finally, azithromycin might have had a nonspecific antiinflammatory effect that ameliorated the manifestations of illnesses that resemble lower-respiratory-tract infections or gastroenteritis [14]. There are precedents for antibiotics conferring unintended benefits. For example, 4 decades ago, Steigman et al, at Mount Sinai Hospital in New York, reported the complete absence of earlyonset group B Streptococcus (GBS) infections in their newborns, which they associated with universal use of intramuscular penicillin to prevent opthalmia neonatorum [15].They stated “ . . . we believe there is an urgent need to encourage appropriate, carefully designed prospective alternate case studies in order to determine whether a serendipitous observation can or cannot prevent deaths due to early-onset invasive GBS disease. . . . ” Intrapartum antibiotic prophylaxis of women, prompted by controlled studies and guided by diagnostic microbiology [16], is now established as an intervention to reduce the morbidity and mortality of early-onset GBS infections [17]. Sometimes the benefit of antibiotics is demonstrated before the etiology of a disease is Received 28 February 2014; accepted 13 March 2014; electronically published 20 March 2014. Correspondence: Lori R. Holtz, MD, Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8208, St. Louis, MO 63110 (holtz_l@kids.wustl.edu). The Journal of Infectious Diseases 2014;210:514–6 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/infdis/jiu172