Zinc as adjunct treatment in infants aged between 7 and 120 days with
probable serious bacterial infection: a randomised, double-blind, placebocontrolled trial
Shinjini Bhatnagar, Nitya Wadhwa, Satinder Aneja, Rakesh Lodha, Sushil Kumar Kabra, Uma Chandra Mouli Natchu, Halvor Sommerfelt,
Ashok Kumar Dutta, Jagdish Chandra, Bimbadhar Rath, Mamta Sharma, Vinod Kumar Sharma, Mohini Kumari, Tor A Strand
Summary
Background Serious bacterial infections are a major cause of death in early infancy in developing co untries. Inexpensive
and accessible interventions that can add to the effect of standard antibiotic treatment could reduce infant mortality. We
measured the effect of zinc as an adjunct to antibiotics in infants with probable serious bacterial infection.
Methods In this randomised, double-blind, placebo-controlled trial, we enrolled infants aged 7–120 days with probable
serious bacterial infection at three hospitals in New Delhi, India, between July 6, 2005, and Dec 3, 2008. With computergenerated sequences, we randomly assigned infants in permuted blocks of six, stratified by whether patients were
underweight or had diarrhoea at enrolment, to receive either 10 mg of zinc or placebo orally every day in addition to standard
antibiotic treatment. The primary outcome was treatment failure, which was defined as a need to change antibiotics within 7
days of randomisation, or a need for intensive care, or death at any time within 21 days. Participants and investigators were
masked to treatment allocation. All analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov,
number NCT00347386.
Findings 352 infants were randomly assigned to receive zinc and 348 to placebo. 332 given zinc and 323 given placebo could
be assessed for treatment failure. Significantly fewer treatment failures occurred in the zinc group (34 [10%]) than in the
placebo group (55 [17%]; relative risk reduction 40%, 95% CI 10–60, p=0·0113; absolute risk reduction 6·8%, 1·5–12·0,
p=0·0111). Treatment of 15 (95% CI eight to 67) infants with zinc would prevent one treatment failure. Ten infants receiving
zinc died compared with 17 given placebo (relative risk 0·57, 0·27–1·23, p=0·15).
Interpretation Zinc could be given as adjunct treatment to reduce the risk of treatment failure in infants aged 7–120 days with
probable serious bacterial infection.
Funding Department of Biotechnology, Government of India; the European Commission; the Meltzer Foundation; and the
Research Council of Norway.
Introduction
Of the 7·8 million deaths a year in children younger than 5 years in Africa, southeast Asia, and the eastern Mediterranean, more than 3 million
are in neonates.1 Sepsis and pneumonia—responsible for 25% of these deaths1—are often clinically difficult to distinguish in young infants. Of
the 1 million neonatal deaths that occur annually in India, more than a quarter are attributed to serious bacterial infections, such as pneu-monia,
sepsis, and meningitis.2 Many young in-fants in hospital have been admitted because of these severe infections.3 Despite advances in
antimicrobial treatment, outcomes remain poor.4 Development of inexpensive and accessible interventions that could improve treatment
outcomes and reduce case fatality is important.
Several animal and human studies 5–7 have shown that zinc is crucial for immune function. Zinc given orally during an episode of
childhood diarrhoea reduces duration and severity of illness. 8–11 In a community-based trial of infants and children with diarrhoea in North
India,12 zinc supplements reduced diarrhoeal morbidity, raised the number of circulating T cells (especially CD4 cells), and improved the
cutaneous delayed hypersensitivity reaction.
A reduced risk of treatment failure will shorten time in hospital, lower use of high-generation antimicrobials and treatment cost, and possibly
reduce mortality. We aimed to estimate the efficacy of 10 mg of oral zinc daily combined with standard antibiotic treatment in infants aged
between 7 and 120 days with probable serious bacterial infection.
Methods
Study design and participants
We undertook a randomised, double-blind, placebo-controlled trial from July 6, 2005, to Dec 3, 2008, at three tertiary hospitals in New Delhi, India
(Kalawati Saran Children’s Hospital, Deen Dayal Upadhyay Hospital, and All India Institute of Medical Sciences). We screened infants aged 7–120
days in emergency depart-ments for any of the following clinical symptoms or signs of possible serious bacterial infection: convulsions, fast
breathing, severe chest indrawing, grunting, bulging fontanelle, axillary temperature 37·5°C or higher or lower than 35·5°C, refusal to feed or drink,
uncon-sciousness or lethargy, no attachment to or suckling at breast (in breastfed infants), excessive crying or irritability, diarrhoea, or cyanosis
(appendix). These criteria were adapted from the definitions used by the Integrated Management of Neonatal and Childhood Illnesses strategy.13
We included preterm infants (≤32 weeks of gestation) only when they were older than 2 months at screening. We excluded infants who
weighed 1500 g or less; needed mechanical ventilation, inotropic drugs, or exchange transfusion; had major congenital anomalies, inborn errors
of metabolism, severe birth asphyxia, renal failure, surgical or other disorders interfering with oral feeding, pre-existing seizure disorders, or any
other serious underlying medical problems; were born to HIV-infected mothers; or had received zinc during the present episode of infection.
We measured serum C-reactive protein concentra-tion with a semi-quantitative latex agglutination assay (Plasmatec Laboratory Products,
Bridport, Dorset, UK) immediately after eligibility was established. Infants with a concentration of 12 mg/L or higher were judged to have
probable serious bacterial infection and were eligible for the trial. Study physicians were present 24 h a day and obtained written informed
consent from the guardians of these patients (or with a thumbprint from those who were illiterate) in the presence of a witness. Patients were
then randomly assigned to receive zinc or placebo. Infants who could not be fed orally were observed for up to 24 h of stabilisation and
randomly assigned only when they were able to tolerate oral feeding. The ethics com-mittees of all hospitals and WHO’s Ethics Review
Committee approved the study protocol.
Randomisation and masking
We stratified patients by whether they were underweight (ie, weight-for-age Z scores14 <–2) or had diarrhoea at enrolment. A scientist not
involved in the study generated allocation sequences with STATA (version 9.0). Within each hospital and stratum, patients were randomly
assigned equally in permuted blocks of six to receive zinc or placebo. WHO provided identical blister packs that contained dispersible tablets
with or without zinc sulphate (10 mg of elemental zinc; Nutriset, Malaunay, France). Each pack had been labelled with a unique serial number
according to the randomisation list, which was not available to investigators until data had been obtained, entered, and locked. Participants and
investigators were masked to treatment allocation. We maintained masking during data analysis by coding treatment allocation with two letters.
Procedures
After randomisation, the study physician gave every infant half a dispersible tablet of zinc (ie, 5 mg of elemental zinc) or placebo dissolved in
2·5 mL expressed breastmilk or distilled water orally every 12 h until recovery—ie, end of a 2 day period with no symptoms or signs of
probable serious bacterial infection and a daily weight gain of at least 10 g with exclusive oral feeding—or until the completion of 21 days’
treatment, whichever was earlier. Treatment was repeated in infants who vomited within 15 min of receiving the tablet.
Study physicians examined patients for all relevant clinical features every 6 h or more often when clinically indicated until recovery or end of
day 21. They repeated the respiratory rate count when it was 60 or more breaths per min in infants younger than 2 months or 50 or more breaths
per min in those older than 2 months, and recorded the second count. 13 Study staff recorded weights of naked infants at randomisation and every
24 h until recovery or end of day 21. The site supervisor (a paediatrician) oversaw at least one daily assessment done by every study physician.
Infants were treated according to a standardised protocol with recommended doses (appendix) of intra-venous ampicillin and an
aminoglycoside (intra-venous gentamicin or amikacin) when infants were not receiving antibiotic treatment at admission, or of a thirdgeneration cephalosporin and one of the amino-glycosides when patients had already been treated with antibiotics. Intravenous cloxacillin
was given when staphylo-coccal infection was suspected. Patients who had not recovered by the end of 21 days were no longer monitored
by the study staff but were managed by hospital physicians.
Researchers in the laboratory at the All India Institute of Medical Sciences cultured blood specimens at admission with BACTEC (Becton
Dickinson, Sparks, MD, USA; model PEDS PLUS/F). Study physicians obtained blood specimens at baseline, 72 h, and the end of the study.
Serum was stored at –20°C. We measured serum concentrations of zinc with a flame furnace atomic absorption spectrophotometer (GBC Avanta,
Dandenong, VIC, Australia) as per standard procedures,15 C-reactive protein concentrations with a commercial ELISA (Biocheck, Foster City,
CA, USA), and procalcitonin concentrations with a chemi-immuno-luminescence assay (BRAHMS, Hennigsdorf, Germany).
The primary outcome was treatment failure, which was defined as a need to change antimicrobial treat-ment within 7 days of randomisation, or
a need for intensive care (mechanical ventilation or vasoactive drug infusion, or both), or death at any time within 21 days of randomisation.
According to this definition, the worst outcome was reported. The decision to change antimicrobial drugs was made by two senior paedia-tricians
(site investigators) on the basis of a priori guidelines—ie, persistence beyond 72 h of random-isation of any clinical symptom or sign suggestive of
probable serious bacterial infection identified at enrolment, worsening of an initial symptom or sign of the disorder, or identification of one or
more new symptoms or signs any time after the initial 24 h (appendix).
Secondary outcomes were time to clinical recovery (ie, to the end of a 2 day period with no symptoms or signs of probable serious bacterial
infection), time to achieve exclusive oral feeding (ie, to the end of a 2 day period on exclusive oral feeding), time to weight gain (ie, to the end of a 2
day period with daily weight gain of at least 10 g on exclusive oral feeding), and time to overall recovery (ie, to the end of a 2 day period with no
symptoms or signs of probable serious bacterial infection and daily weight gain of at least 10 g on exclusive oral feeding).
To ensure uniformity between hospitals, the site super-visors underwent training in patient assessment and outcomes, according to our standard
operating procedures. We standardised the study procedures and did regular exercises of clinical outcomes and laboratory procedures to minimise
intra-observer and inter-observer variability within and across the three hospitals. An independent data and safety monitoring board com-posed of a
paediatrician, a paediatric surgeon, a medical intensive care specialist, and a biostatistician reviewed every serious adverse event (death or need for
intensive care) and met every 6 months to ensure that the study was done according to protocol.
Statistical analysis
On the basis of an audit of the participating hospitals, we estimated that the risk of treatment failure in the placebo group would be 25%. With
the assumption of a 5% loss to follow-up, we needed to recruit 700 infants (350 in each group) to identify an efficacy of 40% or more against
treatment failure with 90% power and 95% confidence. 16
Site supervisors checked all case report forms twice before they were sent for double data entry in Microsoft Access (2007 version) with inbuilt logic, range, and consistency checks. For intention-to-treat analyses, we used STATA (version 11.0) to calculate the proportion of
treatment failures in the two trial groups and the corresponding relative risk (RR) and risk difference (RD). Irrespective of whether treatment
had failed and with censoring of children at the time of withdrawal of consent, we used Cox proportional hazards regression to compare the
time to recovery between the trial groups. A hazard ratio greater than 1 indicated a beneficial effect of zinc. We censored patients who did not
recover by 504 h (day 21) at that time. We censored infants who died at 505 h (ie, 1 h longer than 21 days). We compared the change in serum
zinc concentration from baseline to recovery between the two groups with the Student’s t test. The effect of zinc on laboratory markers of
inflammation (C-reactive protein and pro-calcitonin) at 72 h and at recovery was compared with the Mann-Whitney test.
We did predefined subgroup analyses to assess whether diarrhoea or infants being underweight at enrolment modified the effect of zinc.
Interactions were assessed with interaction terms in generalised linear models of the binomial family with log links to estim ate RRs and
identity links for RDs. We also did a post-hoc analysis restricted to infants aged 7 to 60 days.
This trial is registered with ClinicalTrials.gov, number NCT00347386.
Role of the funding source
The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. SB, NW, TAS,
RL, UCMN, and HS had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Results
Figure 1 shows the trial profile. Table 1 shows baseline charac-teristics. 148 (42%) of 352 in the zinc group versus 137 (39%) of 348 given
placebo received ampicillin and an amino-glycoside; 163 (46%) versus 163 (47%) received a third-generation cephalosporin and an
aminoglycoside; and 41 (12%) versus 48 (14%) were given intravenous cloxacillin.
Concentrations of C-reactive protein and procalcitonin at baseline were high in both groups (table 1). Median concentration of C-reactive
protein was lower in infants with diarrhoea (28·7 mg/L, IQR 15·2–53·8) than in those without diarrhoea (37·3 mg/L, 20·2–64·2). 44% of all
patients (302 of 681) had serum zinc concentrations of less than 9·2 µmol/L at baseline. Median serum zinc concentrations were 10·2 µmol/L
(IQR 8·1–12·9) in children with diarrhoea compared with 9·3 µmol/L (7·4–11·7) in those without diarrhoea. No protocol devia-tions were
recorded in either group.
Treatment failure could be assessed in 655 infants (figure 1). Four patients (one given zinc; three placebo) who had treatment failure left the
study before recovery could be recorded. Treatment efficacy—ie, reduction in relative risk of treatment failure—was 40% (95% CI 10–60;
p=0·0113; table 2). The absolute risk reduction was 6·8% (1·5–12·0; p=0·0111); therefore, 15 (eight to 67) infants with probable serious
bacterial infection would need to be treated with zinc in addition to antibiotics to prevent one treatment failure. A similar efficacy (54%, 20–74;
p=0·0045) was noted when analysis was restricted to infants aged between 7 and 60 days.
Cause of treatment failure was assigned by worst outcome and first cause (table 2). Of 89 infants who had treatment failure, 76 had their
antibiotics changed within 7 days (table 2). Although we classed death as a treatment failure at any time up to day 21, seven of eight who died
after 7 days of treatment had a change of antibiotics in the first week and therefore fulfilled criteria for treat-ment failure even before they
died. Nearly two-thirds of decisions to change antibiotics (17 of 29 in zinc group; 33 of 47 in placebo group) occurred within 96 h of
randomisation. 15 (5%) of the 332 infants given zinc and 17 (5%) of the 323 given placebo needed a second change in antibiotics within the
21 days.
The efficacy of zinc was higher in infants with diarrhoea at enrolment than in those without diarrhoea (p=0·0260; figure 2). Three children
(one in the zinc group; two in the placebo group) needed a change of antibiotics for persistence of diarrhoea of the 27 children whose treatment
failed because symptoms present at enrolment persisted. Treatment efficacy did not differ between underweight infants and those not
underweight (p=0·39; figure 2). Case fatality did not vary significantly (table 2). Time to overall recovery and other forms of recovery also did
not differ (table 3).
The mean change in serum zinc concentration from enrolment to recovery was higher in the children given zinc (3·3 µmol/L, SD 6·9) than in
those receiv-ing placebo (1·2 µmol/L, 5·2), with a difference of 2·0 µmol/L (95% CI 1·1–3·0; p<0·0001). The effect of zinc on laboratory
markers of inflammation (C-reactive protein and procalcitonin) did not differ between the two groups (appendix). The risk of adverse events that
were not components of the clinical outcomes was also alike in the two groups (appendix). Table 4 shows the symp-toms and signs of probable
serious bacterial infection recorded at the time of treatment failures.
Discussion
We have reported that zinc reduced treatment failure in infants younger than 120 days with probable serious bacterial infection by 40%. Use of
zinc also reduced the number of deaths, although the difference between the groups was not significant. When analysis was restricted to infants
60 days or younger, we still recorded a bene-ficial effect. Time to recovery, weight gain, or exclusive oral feeding was not affected by zinc
supple-ments, and weight at recovery did not differ significantly. As far as we are aware, zinc as adjunct treatment in infants with probable
serious bacterial infection has not been reported previously (panel).
Treatment failure in children with probable serious bacterial infection diagnosed with clinical criteria and measurements of C-reactive protein
concentrations is likely to be even more common than in a study set-ting. In high-burden, resource-limited settings, routine clinical care is often
less intensive than during studies with additional personnel and resources. Therefore, the absolute risk reduction from zinc treatment could be
larger than the value we have reported, and fewer than the estimated 15 children would need to be treated to prevent one treatment failure.
Zinc is important for mucosal barrier function and components of innate and adaptive immunity, such as lytic activity of phagocytes and natural
killer cells, and expres-sion of cytokines.5–7,19 Oral zinc supplementation increases serum thymulin and CD4 counts and decreases the occurrence
of opportunistic infections in clinical immuno-suppressive disorders.20 Reduced incidence of infections has also been reported in patients with
sickle cell disease, in whom zinc supplementation increased interleukin 2 production.21 Heightened activity of com-plement C3 and phagocytes
and the ratio of naive to memory T cells in children with diarrhoea caused by enterotoxigenic Escherichia coli given zinc indicates that this
supplement enhances innate immunity.22 In a murine polymicrobial sepsis model,23,24 short-term zinc supplementation decreased the bacterial load
and reduced the NF-κB activity in vital organs. The researchers postu-lated that zinc modulates innate immune responses to polymicrobial sepsis
through the regulation of NF-κB.23,24
The higher efficacy of zinc in infants who had diarrhoea at enrolment than in those who did not merits further investigation. Serum
concentrations of C-reactive protein were lower in infants with diarrhoea at admission than in those without diarrhoea, sug-gesting that they
could have had milder disease. Another explanation is that zinc supplementation replenishes stores depleted by stool losses, with zinc thereby
becoming available for protective mechanisms to respond to bacterial infection. In our study, the reduced risk of treatment failure in infants
with diarrhoea at enrolment was not because of a quick resolution of diarrhoea, indicating that zinc treatment contributed to the resolution of
probable serious bacterial infection rather than to resolution of any one symptom or sign.
Our study was not powered to assess the effect of zinc on case fatality and did not include neonates in the first week of life. We used a
symptom-based definition of probable serious bacterial infection, but such criteria are often applied in settings like ours. 13 We extended the
WHO definition to infants 60 days or older, because similar infections continue to occur in these children. Additionally, we enhanced the
specificity of the diagnosis with the additional criterion of a C-reactive protein concentration of 12 mg/L or higher. 25 Concentrations of
procalcitonin were greater than 0·5 µg/L in more than 70% of participants and greater than 0·3 µg/L in more than 90%, further suggesting that
they did indeed have serious bacterial infection.26,27 The loss to follow-up was small and is unlikely to have biased our efficacy estimates.
Future trials need to measure the efficacy of zinc treatment for probable serious bacterial infection in other settings—specifically, other studies
should meas-ure the effect of zinc supplementation on important outcomes in children who are diagnosed with serious bacterial infections
without measurements of concen-trations of C-reactive protein. If such trials show improve-ment in treatment outcomes, the use of zinc as an
adjunct to antibiotic treatment might lead to sub-stantial reductions in infant mortality, particularly in resource-constrained settings where
second-line anti-biotics and appropriate intensive care might be unavailable. Care providers at small health-care facilities can be trained to
initiate treatment of probable serious bacterial infection with antibiotics and zinc before transferring infants to appropriately equipped facilities.
Zinc syrup or dis-persible tablets are already available in the public and private health-care systems for treatment of acute diarrhoea in many
countries of low and middle income and the incremental costs to make this intervention available for young infants with probable serious
bacterial infection would be small.
Contributors
SB formulated the research question and designed the study. SB, HS, and TAS wrote research grants. SB, NW, SA, RL, SKK, UCMN, AKD, JC, BR, MS, VKS, MK, and TAS
developed the standard operating procedures. SB, NW, RL, SKK, AKD, JC, BR, MS, VKS, and MK implemented the trial. SB, NW, SA, and TAS supervised clinical and data
management. SB, NW, SA, RL, UCMN, HS, and TAS analysed data. SB, NW, RL, UCMN, HS, and TAS interpreted the findings. SB, NW, SA, RL, SKK, UCMN, HS, and TAS wrote
the report.
Conflicts of interest
We declare that we have no conflicts of interest.
Acknowledgments
The study was funded by the Department of Biotechnology, Ministry of Science and Technology, Government of India (BT/PR5238/MED/14/610/2004). We also received funding from
the European Commission (EU-INCO-DC contract number INCO-FP6-003740), the Meltzer Foundation (Bergen, Norway), and the Research Council of Norway (project number 172226). We
thank the medical and nursing staff of the three hospitals for their contribution; the patients and their parents; Ritu Chawla, Uday Pal Singh Kainth, Anil Gulati, Arvind Bagga, and
Madhulika Kabra for providing clinical support to patients enrolled in the study at the Deen Dayal Upadhyay Hospital and All India Institute of Medical Sciences; Arti Kapil for
supervising the blood cultures; Anil Kumar Sharma for assisting in quality assurance and supervision of the research staff; Savita Saini for undertaking the micronutrient assays and
providing technical support for all other laboratory work; Mukesh Juyal for secretarial support; Dharmendra Sharma for data management support and analysis of data; and Olivier
Fontaine (WHO) for providing the intervention (zinc and placebo tablets from Nutriset) and periodic reviews of study procedures.
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