Download Unexplained Benefits of Antibiotics in Childhood

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.