Simplified antibiotic regimens for community management of neonatal sepsis

Although child survival has improved substantially in the past 15 years, the decline in neonatal mortality (particularly deaths related to neonatal sepsis) has been more modest, which has contributed to the overall non-attainment of Millennium Development Goal 4 (to reduce child mortality).1Liu L Oza S Hogan D et al.Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals.Lancet. 2016; (published online Nov 10.)http://dx.doi.org/10.1016/S0140-6736(16)31593-8Summary Full Text Full Text PDF Scopus (1715) Google Scholar WHO recommends admission to hospital for any young infant (neonates and those aged 28–59 days) with clinically severe infections.2WHOPocket book of hospital care for children. second edn. World Health Organization, Geneva2013Google Scholar However, access to hospital care and lack of willingness (mostly on the part of parents) to admit a young infant with possible bacterial infection are some of the many factors that have contributed to neonatal sepsis continuing to account for about 7% of all child mortality. In The Lancet Global Health, Fatima Mir and colleagues report results from the Simplified Antibiotic Therapy Trial (SATT) in Pakistan,3Mir F Nisar I Tikmani SS et al.Simplified antibiotic regimens for treatment of clinical severe infection in the outpatient setting when referral is not possible for young infants in Pakistan (Simplified Antibiotic Therapy Trial [SATT]): a randomised, open-label, equivalence trial.Lancet Glob Health. 2016; (published online Dec 14.)http://dx.doi.org/10.1016/S2214-109X(16)30335-7PubMed Google Scholar in which three antibiotic regimens were compared for treatment of neonatal infections: procaine benzylpenicillin and gentamicin; amoxicillin and gentamicin; and procaine benzylpenicillin, gentamicin, and amoxicillin. These findings add to evidence already available from the AFRINEST and Projahnmo studies (table).4Baqui AH Saha SK Ahmed ASMNU et al.for the Projahnmo Study Group in BangladeshSafety and efficacy of alternative antibiotic regimens compared with 7 day injectable procaine benzylpenicillin and gentamicin for outpatient treatment of neonates and young infants with clinical signs of severe infection when referral is not possible: a randomised, open-label, equivalence trial.Lancet Glob Health. 2015; 3: e279-e287Summary Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 5Tshefu A Lokangaka A et al.African Neonatal Sepsis Trial (AFRINEST) groupSimplified antibiotic regimens compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with clinical signs of possible serious bacterial infection when referral is not possible: a randomised, open-label, equivalence trial.Lancet. 2015; 385: 1767-1776Summary Full Text Full Text PDF PubMed Scopus (98) Google Scholar The findings of these three studies, which together provide data for more than 8500 young infants, show that a substantial proportion of neonatal infections can be managed in the community when referral is not possible. The individual and combined results of these trials show that simplified antibiotic regimens (which include oral amoxicillin) are equally effective when compared with the standard 7-day course of injectable penicillin and gentamicin.TableComparison of baseline characteristics and treatment outcomes in SATT, AFRINEST, and Projahnmo trialsSATT3Mir F Nisar I Tikmani SS et al.Simplified antibiotic regimens for treatment of clinical severe infection in the outpatient setting when referral is not possible for young infants in Pakistan (Simplified Antibiotic Therapy Trial [SATT]): a randomised, open-label, equivalence trial.Lancet Glob Health. 2016; (published online Dec 14.)http://dx.doi.org/10.1016/S2214-109X(16)30335-7PubMed Google ScholarAFRINEST*Excludes 890 infants who were given gentamicin and oral amoxicillin for 2 days followed by oral amoxicillin for 5 days.5Tshefu A Lokangaka A et al.African Neonatal Sepsis Trial (AFRINEST) groupSimplified antibiotic regimens compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with clinical signs of possible serious bacterial infection when referral is not possible: a randomised, open-label, equivalence trial.Lancet. 2015; 385: 1767-1776Summary Full Text Full Text PDF PubMed Scopus (98) Google ScholarProjahnmo4Baqui AH Saha SK Ahmed ASMNU et al.for the Projahnmo Study Group in BangladeshSafety and efficacy of alternative antibiotic regimens compared with 7 day injectable procaine benzylpenicillin and gentamicin for outpatient treatment of neonates and young infants with clinical signs of severe infection when referral is not possible: a randomised, open-label, equivalence trial.Lancet Glob Health. 2015; 3: e279-e287Summary Full Text Full Text PDF PubMed Scopus (73) Google ScholarAge 0–6 days1083/2453 (44%)1160/3564 (33%)253/2490 (10%)Male sex1309/2453 (53%)1901/3564 (53%)1530/2490 (61%)Weight-for-age <–2 SD940/2453 (38%)611/3564 (17%)N/AOne clinical sign alone2141/2453 (87%)3111/3564 (87%)1543/2490 (62%)FeverAlone905/2453 (37%)N/A584/2490 (23%)In combination with other signs1015/2453 (41%)1648/3564 (46%)1035/2490 (42%)Severe chest indrawingAlone717/2453 (29%)N/A791/2490 (32%)In combination with other signs818/2453 (33%)1553/3564 (44%)1478/2490 (59%)Poor feedingAlone356/2453 (15%)N/A131/2490 (5%)In combination with other signs606/2453 (25%)578/3564 (16%)920/2490 (37%)HypothermiaAlone144/2453 (6%)N/A34/2490 (1%)In combination with other signs233/2453 (9%)191/3564 (5%)52/2490 (2%)Movement only when stimulatedAlone19/2453 (1%)N/A3/2490 (<1%)In combination with other signs122/2453 (5%)99/3564 (3%)57/2490 (2%)Death within 7 days28/2251 (1%)35/2516 (1%)28/2367 (1%)Treatment failure265/2251 (12%)183/2516 (7%)207/2367 (9%)Admission51/265 (19%)8/183 (4%)54/207 (26%)Persistence of signs on day 462/265 (23%)82/183 (45%)34/207 (16%)Appearance of new signs on or after day 322/265 (8%)17/183 (9%)21/207 (10%)Recurrence of signs on or after day 544/265 (17%)19/183 (10%)37/207 (18%)Treatment failure risk difference (95% CI)Arm B vs arm A*Excludes 890 infants who were given gentamicin and oral amoxicillin for 2 days followed by oral amoxicillin for 5 days.†Difference between amoxicillin and gentamicin (arm B), and procaine benzylpenicillin and gentamicin (arm A).−1·9 (−5·1 to 1·3)−1·9 (−4·4 to 0·1)−1·5 (−4·3 to 1·3)Arm C vs arm A‡Difference between procaine benzylpenicillin, gentamicin, and amoxicillin (arm C), and procaine benzylpenicillin and gentamicin (arm A).1·1 (−2·3 to 4·5)−0·6 (−3·1 to 2·0)−1·7 (−4·5 to 1·1)Data are number of patients/total number of patients (%), unless otherwise indicated. N/A=not available.* Excludes 890 infants who were given gentamicin and oral amoxicillin for 2 days followed by oral amoxicillin for 5 days.† Difference between amoxicillin and gentamicin (arm B), and procaine benzylpenicillin and gentamicin (arm A).‡ Difference between procaine benzylpenicillin, gentamicin, and amoxicillin (arm C), and procaine benzylpenicillin and gentamicin (arm A). Open table in a new tab Data are number of patients/total number of patients (%), unless otherwise indicated. N/A=not available. SATT addresses some of the key limitations of the other two trials. First, 1083 (44%) of 2453 neonates enrolled in the study were aged 0–6 days, reflecting the substantial contribution of this age group to infection-related neonatal mortality.6Oza S Lawn JE Hogan DR Mathers C Cousens SN Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000–2013.Bull World Health Organ. 2015; 93: 19-28Crossref PubMed Scopus (213) Google Scholar Although Mir and colleagues do not present data for treatment outcomes separately for this age group, it is anticipated that a pooled analysis—including data from all three studies—would address this evidence gap. These results would be of great interest to public health professionals and policy makers. Second, in SATT, blood cultures were obtained from 2067 (84%) enrolled infants and tests for antimicrobial susceptibility were done in positive samples, which is very impressive for a community-based study. But, as Aristotle said, “The more you know, the more you don't know”. Only 81 (4%) samples were positive for a pathogen: 18 (22%) were Campylobacter species; 13 (16%) were pseudomonads, 12 (15%) were enteric Gram-negative organisms, and eight (10%) were Streptococcus pyogenes. These results differ from those reported in multicentre hospital-based studies in developing countries, both in terms of culture positivity and the microbes isolated, which are not unexpected in such a study.7Investigators of the Delhi Neonatal Infection Study (DeNIS) collaborationCharacterisation and antimicrobial resistance of sepsis pathogens in neonates born in tertiary care centres in Delhi, India: a cohort study.Lancet Glob Health. 2016; 4: e752-e760Summary Full Text Full Text PDF PubMed Scopus (190) Google Scholar, 8Hamer DH Darmstadt GL Carlin JB et al.Etiology of bacteremia in young infants in six countries.Pediatr Infect Dis J. 2015; 34: e1-e8Crossref PubMed Scopus (75) Google Scholar However, what is perplexing is the high frequency of campylobacter bacteraemia (18/81 [22%])noted (in the absence of diarrhoea) and bacteraemic treatment failure (9/18 [50%]), which has not been reported previously (even in the six-country study that includes this Pakistan study site).8Hamer DH Darmstadt GL Carlin JB et al.Etiology of bacteremia in young infants in six countries.Pediatr Infect Dis J. 2015; 34: e1-e8Crossref PubMed Scopus (75) Google Scholar This finding deserves further attention in future studies on the cause of neonatal sepsis. Even though SATT and other studies have provided rich data with which to make an evidence-based decision about community management of neonatal infections using simplified antibiotic regimens, some concerns remain about this study. First, as in the other two trials, most children (2141/2453 [87%]) enrolled in SATT had only one of the five clinical signs of severe infection, which provides poor sensitivity (72%) and specificity (75%).9Weber MW Carlin JB Gatchalian S Lehmann D Muhe L Mulholland EK Predictors of neonatal sepsis in developing countries.Pediatr Infect Dis J. 2003; 22: 711-717Crossref PubMed Scopus (110) Google Scholar Additionally, only 1015 (41%) participants had fever in combination with another sign (this combination has a specificity of 92%).9Weber MW Carlin JB Gatchalian S Lehmann D Muhe L Mulholland EK Predictors of neonatal sepsis in developing countries.Pediatr Infect Dis J. 2003; 22: 711-717Crossref PubMed Scopus (110) Google Scholar This finding begs the question, did all participants have severe infection? Probably not, because case fatality was around 1% (28/2251 died within 7 days), which is very low even if participants with critical illness were excluded (ie, those at highest risk of death). Second, about a quarter of patients labelled as having treatment failure had persistence of clinical signs on day 4 (62/265 [23%]). This endpoint has not been shown to be a valid measure of treatment failure or poor prognosis and is likely to be subject to observer bias in such non-blinded studies. Third, although community health workers are good at screening young infants for referral, their specificity remains low (69%) compared with doctors (100%).10Lee AC Chandran A Herbert HK et al.Treatment of infections in young infants in low- and middle-income countries: a systematic review and meta-analysis of frontline health worker diagnosis and antibiotic access.PLoS Med. 2014; 11: e1001741Crossref PubMed Scopus (30) Google Scholar Therefore, at least 31% of the children in this trial might have received antibiotics unnecessarily. It is heartening to observe that 32 (86%) of 37 specimens tested for antimicrobial susceptibility were sensitive to amoxicillin and gentamicin. However, concerns about antibiotic overuse and resistance,11Laxminarayan R Duse A Wattal C et al.Antibiotic resistance—the need for global solutions.Lancet Infect Dis. 2013; 13: 1057-1098Summary Full Text Full Text PDF PubMed Scopus (2537) Google Scholar particularly to amoxicillin and gentamicin, are growing; these drugs are part of the simplified regimen.7Investigators of the Delhi Neonatal Infection Study (DeNIS) collaborationCharacterisation and antimicrobial resistance of sepsis pathogens in neonates born in tertiary care centres in Delhi, India: a cohort study.Lancet Glob Health. 2016; 4: e752-e760Summary Full Text Full Text PDF PubMed Scopus (190) Google Scholar, 8Hamer DH Darmstadt GL Carlin JB et al.Etiology of bacteremia in young infants in six countries.Pediatr Infect Dis J. 2015; 34: e1-e8Crossref PubMed Scopus (75) Google Scholar Moreover, the frequency of surveillance visits noted in this study (ten over a 15-day period) are not attainable in programme settings, and results in practice are unlikely to be as impressive as those reported by Mir and colleagues. Therefore, until biomarkers (to reliably identify children with bacterial infections) that can be used by frontline health workers are developed, this strategy for community management of neonatal infections must be reserved for instances when referral is not possible. Limitations notwithstanding, Mir and colleagues (along with the investigators in AFRINEST and Projahnmo) must be congratulated for successfully running a complex clinical trial to a high standard (with high rates of treatment adherence and follow-up). These studies represent a serious effort to address important but difficult clinical questions, with careful attention to a standardised study design and data quality. The findings of these trials show the need for continuing investment to develop point-of-care tests to identify children with bacterial infection at community or first-facility level, and for development of improved measures of treatment failure that are shown to be valid predictors of mortality or poor outcome. Until then, the challenge for policy makers today is to move forward based on a critical review of the best available data, such as these. I have received research grants from the Bill & Melinda Gates Foundation and WHO, outside the submitted work. Simplified antibiotic regimens for treatment of clinical severe infection in the outpatient setting when referral is not possible for young infants in Pakistan (Simplified Antibiotic Therapy Trial [SATT]): a randomised, open-label, equivalence trialTwo simplified antibiotic regimens requiring fewer injections are equivalent to a reference treatment for young infants with signs of clinical severe infection but without signs of critical illness. The use of these simplified regimens has the potential to increase access to treatment for sick young infants who cannot be referred to hospital. Full-Text PDF Open Access

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