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EDITORIAL COMMENTARY Unexplained Benefits of Antibiotics in Childhood: Empiricism in Need of Enlightenment Lori R. Holtz and Phillip I. Tarr Washington University School of Medicine, St. Louis, Missouri (See the major article by Gilliams et al on pages 585–92.) Keywords. antibiotics; children; disease control. 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 this burdento children should bewelcomed. 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 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 ([email protected]). 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. [email protected]. DOI: 10.1093/infdis/jiu172 514 • JID 2014:210 (15 August) • 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]. EDITORIAL COMMENTARY 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 known. Enterotoxigenic E. coli were identified as the cause of traveler’s diarrhea in 1975 [18], but over a decade earlier, Kean et al demonstrated that antibiotics prevented or ameliorated this entity [19]. These authors cautioned “ . . . it requires no great medical sagacity to predict that if such drugs are administered without adequate precautions . . . toxic symptoms will occur.” They were prescient: current guidelines do not recommend antibiotics for the prevention of traveler’s diarrhea because of the adverse effects of these drugs, and concern about selecting resistant bacteria [20]. Moreover, and most pertinent to the work of Gilliams et al, there is an effective alternate strategy to prophylaxis for traveler’s diarrhea that involves halting incipient episodes by early syndrome recognition and treatment with antibiotics. Azithromycin has a good safety profile, but no drug is harmless. Like other macrolides, azithromycin might be associated with sudden cardiac death [21], and has a low rate of hepatic, gastrointestinal [22], and ototoxic side effects [23]. The resistance of nasopharyngeal isolates of S. pneumoniae increases after mass azithromycin distribution for trachoma [24], and susceptibility increases after macrolide pressure is released [25]. Nonetheless, despite our ignorance as to the reason for their effectiveness, children in lowincome settings at risk for life-threatening infections do seem to benefit from short courses of antibiotics. It is likely that antibiotics used inappropriately have, to this point in history, saved more lives than they have cost. This gilded therapeutic era is probably in its twilight, but the current side-effect “price” of potentially helpful antibiotics (eg, azithromycin and β-lactams) is low, and their “value” (ie, aversion of death or of potentially serious gastrointestinal or pulmonary infections) is high. The low numbers needed to treat or to avert cases of pneumonia and of diarrhea, as calculated by Gilliams et al, reflect the high frequency of such illnesses and the continued susceptibility to antibiotics of their putative causative agents. These antimicrobial “market conditions” are unlikely to persist, and we cannot continue to rely on microbiologically unenlightened empiricism. It is now time to learn why and how fortuitously timed azithromycin and β-lactam antibiotics prevent deaths, acute lower-respiratory-tract infections, and gastrointestinal illnesses in children in Malawi and elsewhere. Specifically, it is crucial to determine what etiologic agents are being inhibited by antibiotics, and what illnesses are unlikely to respond [13]. Diagnostic, treatment, and preventive strategies should then be built on such knowledge, as was done for neonatal GBS infection and traveler’s diarrhea. If expanded use of antibacterial agents is adopted to prevent severe childhood infections without knowing their exact targets, side effects and resistance might soon thwart the advantages they confer on recipient populations. Notes Financial support. This work was supported by Children’s Discovery Institute (MD-FR-2013292). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. World Health Report World Health Organization, 2011. 2. Gilliams EA, Jumare J, Claassen CW, et al. Chloroquine-azithromycin combination antimalarial treatment decreases risk of respiratory- and gastrointestinal-tract infections in Malawian children. J Infect Dis 2014; 210:585–92. 3. Keenan JD, Ayele B, Gebre T, et al. Childhood mortality in a cohort treated with mass azithromycin for trachoma. Clin Infect Dis 2011; 52:883–8. 4. Porco TC, Gebre T, Ayele B, et al. Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial. JAMA 2009; 302:962–8. 5. Trehan I, Goldbach HS, LaGrone LN, et al. Antibiotics as part of the management of severe acute malnutrition. N Engl J Med 2013; 368:425–35. 6. Nayak KC, Mohini , Kumar S, et al. A study on pulmonary manifestations in patients with malaria from northwestern India (Bikaner). J Vector Borne Dis 2011; 48: 219–23. 7. Sowunmi A, Ogundahunsi OA, Falade CO, Gbotosho GO, Oduola AM. Gastrointestinal manifestations of acute falciparum malaria in children. Acta Trop 2000; 74:73–6. 8. Reddy EA, Shaw AV, Crump JA. Community-acquired bloodstream infections in Africa: a systematic review and meta-analysis. Lancet Infect Dis 2010; 10:417–32. 9. Dhanoa A, Fatt QK. Non-typhoidal Salmonella bacteraemia: epidemiology, clinical characteristics and its’ association with severe immunosuppression. Ann Clin Microbiol Antimicrob 2009; 8:15. 10. Kiratisin P. Bacteraemia due to nontyphoidal Salmonella in Thailand: clinical and microbiological analysis. Trans R Soc Trop Med Hyg 2008; 102:384–8. 11. Deen J, von Seidlein L, Andersen F, Elle N, White NJ, Lubell Y. Community-acquired bacterial bloodstream infections in developing countries in south and southeast Asia: a systematic review. Lancet Infect Dis 2012; 12:480–7. 12. Biggs HM, Lester R, Nadjm B, et al. Invasive salmonella infections in areas of high and low malaria transmission intensity in Tanzania. Clin Infect Dis 2014; 58:638–47. 13. D’Acremont V, Kilowoko M, Kyungu E, et al. Beyond malaria—causes of fever in outpatient Tanzanian children. N Engl J Med 2014; 370:809–17. 14. Giamarellos-Bourboulis EJ. Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents 2008; 31:12–20. 15. Steigman AJ, Bottone EJ, Hanna BA. Intramuscular penicillin administration at birth: prevention of early-onset group B streptococcal disease. Pediatrics 1978; 62:842–4. 16. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC. MMWR Recomm Rep 2002; 51: 1–22. 17. Verani JR, McGee L, Schrag SJ, Division of Bacterial Diseases NCfI, Respiratory Diseases CfDC, Prevention. Prevention of perinatal group B streptococcal disease—revised guidelines from CDC, 2010. MMWR Recomm Rep 2010; 59:1–36. 18. Gorbach SL, Kean BH, Evans DG, Evans DJ Jr, Bessudo D. Travelers’ diarrhea and toxigenic Escherichia coli. N Engl J Med 1975; 292:933–6. 19. Kean BH, Schaffner W, Brennan RW. The diarrhea of travelers. V. Prophylaxis with phthalylsulfathiazole and neomycin sulphate. JAMA 1962; 180:367–71. 20. DuPont HL. Travelers’ diarrhea: antimicrobial therapy and chemoprevention. Nat Clin Pract Gastroenterol Hepatol 2005; 2:191–8; quiz 1 p following 8. EDITORIAL COMMENTARY • JID 2014:210 (15 August) • 515 21. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012; 366:1881–90. 22. Azithromycin safety information. http://www. fda.gov/Safety/MedWatch/SafetyInformation/ ucm225814.htm. Accessed 28 February 2014. 516 • JID 2014:210 (15 August) • 23. Ress BD, Gross EM. Irreversible sensorineural hearing loss as a result of azithromycin ototoxicity. A case report. Ann Otol Rhinol Laryngol 2000; 109:435–7. 24. Leach AJ, Shelby-James TM, Mayo M, et al. A prospective study of the impact of community-based azithromycin treatment of trachoma EDITORIAL COMMENTARY on carriage and resistance of Streptococcus pneumoniae. Clin Infect Dis 1997; 24: 356–62. 25. Haug S, Lakew T, Habtemariam G, et al. The decline of pneumococcal resistance after cessation of mass antibiotic distributions for trachoma. Clin Infect Dis 2010; 51:571–4.