Penicillin and gentamicin are used globally for treating sepsis and presumed sepsis in the neonatal age group and the second month of life.15,27,28 Extended-interval (24-hourly) gentamicin regimens using doses ranging from 4 to 5 mg/kg/day have been shown to be as effective as traditional dosing regimens for treating neonatal sepsis.29–31 The combination of penicillin/amoxicillin and gentamicin targets common neonatal pathogens such as Escherichia coli, other enteric gram-negative rods, streptococci and pneumococci.
Benzyl penicillin and ampicillin need to be given 4 times a day, which is impractical in the outpatient setting. Based on recommendations from the 2007 London consultation on community-based strategies for management of severe infections in young infants born in high mortality settings,12 the pharmacologic profile of antibiotics32,33 and experience of their use,3–5 we decided to use a combination of procaine penicillin and gentamicin delivered by intramuscular (IM) injection as the reference arm to treat clinically diagnosed severe infection because both can be given in once daily dosing and together can successfully treat vast majority of bacterial infections in young infants.
For the simplified experimental regimens, amoxicillin was selected as the oral agent. Oral antibiotics have successfully been used in community-based management of neonatal pneumonia, resulting in significant reduction in pneumonia and overall neonatal mortality.6,24 There is extensive experience with use of oral amoxicillin in newborns and young infants, and safety of this drug is well-established in this age group.27,34 In full-term neonates, the bioavailability of oral amoxicillin is high at approximately 80%.35 Similar serum amoxicillin concentrations were achieved in neonates in the first 4 days of life with intravenous and oral routes, with the exception of the first 30 minutes after dosing when levels were lower with oral administration.36,37
All the simplified experimental arms in these studies employ oral amoxicillin, yet in varying ways (Table 2). Arm D (injection gentamicin for 2 days and oral amoxicillin for 7 days) is being undertaken only in the African sites because of reservations by the Technical Advisory Group about achieving an adequate sample size in Pakistan and Bangladesh within the funding period. The study comparing reference therapy with oral amoxicillin alone in infants who have only fast breathing is also being conducted in African young infants.
Amoxicillin has been recommended for use in doses ranging from 50 to 150 mg/kg/day. Higher doses are recommended to achieve minimum inhibitory concentrations that can overcome pneumococcal resistance. High-dose oral amoxicillin (80–90 mg/kg/day) is the therapy of choice for young children with otitis media and pneumonia due to suspected drug-resistant pneumococcal infection.38–40 The recommended intravenous dose of amoxicillin for neonates in the first week of life is 100 mg/kg divided every 12 hours, whereas 150 mg/kg/day divided every 8 hours is recommended for older neonates.27 In the African and South Asian trials, amoxicillin is given in doses ranging from 80 to 100 mg/kg/day based on 1 of 6 weight bands in which the infant falls.
The duration of antibiotic therapy is based on achievement of cure for an infection. The WHO recommendation of 10 or more days duration of therapy for antibiotic treatment is not based on strong evidence. Studies in Bangladesh and India have used 10 days of antibiotic therapy,4,5 whereas in Pakistan, 7 days of procaine penicillin and gentamicin once daily was found to be effective in the management of possible serious bacterial infection in young infants when families refused referral care.3 Very severe pneumonia in older children has been treated with 7 days of injectable antibiotics with good results,41 whereas severe pneumonia has been treated with 5 days of oral antibiotics.42 Switch therapy of injectable to oral antibiotics has been demonstrated to be efficacious for treatment of serious infections in neonates18 and in older children.43 For young infants with clinical severe infection included in this study, IM procaine penicillin will be used in a dose of 50,000 units/kg once daily IM and IM gentamicin in a 4–7.5 mg/kg/day once daily dose IM (depending on weight band of the young infant). Duration of all regimens in this study will be 7 days.
The trials are designed to be open-label because of the difficulty in ethically justifying use of placebo injections in the population under study and because acceptability of simplified regimens with lower number of injections is an important secondary outcome for the trials.
The current standard of care for young infants with clinical signs suggestive of severe infection is hospitalization and parenteral antibiotic therapy for 10 or more days.23 As discussed elsewhere in this supplement44 and previously reported,4,45 this standard of care is rarely practiced in developing countries with high neonatal mortality rates. For ethical reasons, in the design of these trials, we felt compelled to only include sites where neonatal mortality rates and hospitalization refusal rates were known to be high,8–10 and those young infants whose families refused referral advice for hospitalization for their sick young infants. Documented refusal of hospital admission thus forms an important inclusion criterion for enrolment of study subjects. The Bangladesh and Pakistan investigators have reported their experience with family acceptance for hospitalization.22,45 Other site characteristics are reported in the site-specific articles in this supplement. The African trial sites in Democratic Republic of Congo, Kenya and Nigeria were chosen to be broadly representative of central, eastern and western sub-Saharan African countries with neonatal mortality rates exceeding 40 per 1000 live births and remote locations making access to hospital facilities difficult for many families.2
Despite the effect on study generalizability, we are excluding young infants with clinical signs of critical illness (unconscious, convulsions, apnea, unable to feed, unable to cry, cyanosed, bulging fontanelle, persistent vomiting), infants with weight less than 1500 g and infants with surgical comorbidities because we cannot ethically justify random allocation of such infants to therapeutic options with oral antibiotics.
Treatment failure on or before 7 days of therapy has been chosen as the primary study outcome in these trials and defined as a composite of death, clinical deterioration, serious adverse event, hospitalization or persistence of clinical signs beyond specified days. Death, although a hard outcome, has not by itself been selected as a primary outcome because we expect the number of deaths to be low (around 2%) based on prior experience3 as rescue therapy is going to be provided and it will be unethical to withhold such therapy. Therefore, using the comparatively rare outcome of death will inflate the sample size to unfeasible levels. Because of the subjective nature of clinical signs of deterioration, their definitions and determination have been standardized across sites and are described further in the site-specific articles.8–10
This article describes the scientific rationale for the study designs of 3 trials of simplified antibiotic therapy for the management of clinically diagnosed severe infections and a trial of management of fast breathing in newborns and young infants currently being conducted in Bangladesh, Pakistan, Democratic Republic of Congo, Kenya and Nigeria. Although designed as independent studies, extensive collaboration between study sponsors and among study investigators has resulted in harmonization of study protocols wherever possible, which will allow subsequent pooled analyses by providing sufficient power to address important policy questions regarding outcomes in subgroups such as newborns with early-onset sepsis, and infants with multiple clinical signs (indicating more severe illness) versus single signs. These trials will inform the development of policies and guidelines regarding community case management of newborns and young infants with clinically diagnosed severe infections as well as for infants with fast breathing alone.
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