7 Days Versus 14 Days of Antibiotics for Neonatal Sepsis
7 Days Versus 14 Days of Antibiotics for Neonatal Sepsis
The optimum duration of intravenous antibiotic therapy for culture-proven neonatal bacterial
 sepsis is not known. Current practices, ranging from 7 days to 14 days of antibiotics, are
 not evidence-based. This is a randomized, active -controlled, multi-centric, non-inferiority
 trial to compare the efficacy of a 7-day course of intravenous antibiotics versus a 14-day
 course among neonates weighing > 1000 g at birth with culture-proven bacterial sepsis that is
 uncomplicated by meningitis, bone or joint infections deep-seated abscesses. The primary
 outcome measure is a definite or probable relapse within 21 days after stoppage of
 antibiotics.
The optimum duration of intravenous antibiotic therapy for uncomplicated neonatal bacterial
 septicemia is not known. Pediatricians administer anywhere between 7 to 14 days of
 antibiotics, but these practices are not evidence based. C reactive protein (CRP) guided
 antibiotic duration is based on limited data and serial quantitative CRP is both cumbersome
 and not universally available. If it could be demonstrated that a 7-day course of antibiotics
 is not inferior to a 14-day course of antibiotics in terms of relapse rates of infection,
 then a 7 day course of antibiotics could be uniformly adopted, resulting in economic savings,
 shorter duration of hospitalization, less chances of hospital acquired infections, less
 chances of antibiotic induced adverse events and less antibiotic resistance. To test this
 hypothesis, a randomized, active-controlled, multi-centric, non-inferiority trial to compare
 the efficacy of a 7-day course of intravenous antibiotics with a 14-day course has been
 planned. Subjects weighing more than 1000 g at birth with suspected sepsis will be enrolled
 and observed for a 7-day period to see if they meet eligibility criteria for randomization.
 Subjects will be randomized on the 7th day of antibiotics, if the initial blood culture grows
 a non-Staphylococcus aureus bacterial organism, if they have no meningitis, osteomyelitis,
 septic arthritis or deep seated abscess and if the sepsis goes into clinical remission by the
 5th day and remains in remission up to the 7th day of sensitive antibiotics. Subjects in the
 14-day group will receive 7 more days of antibiotics after randomization, whereas those in
 the 7-day group will receive no further antibiotics after randomization. Subjects will be
 followed up for a 35-day period after randomization. The key outcome will be treatment
 failure as measured by "definite or probable relapse" within a 21-day period after completion
 of antibiotic therapy. Secondary outcomes will include definite relapse within 21 and 28 days
 after antibiotic completion and within 28 and 35 days after randomization; and probable
 relapse at similar time points. Other secondary outcomes will include secondary infections
 and adverse events. A total sample size of 700 (350 in each arm) will be required to detect a
 non-inferiority margin of 5%, assumed event rate of 10%, with 90% power, one-sided alpha
 error of 5% and loss to follow-up of approximately 10%. Data safety monitoring board will
 monitor serious adverse events in the trial and will perform one mid-term analysis when about
 50% of the expected primary outcomes have occurred or when 50% of the subjects have completed
 their follow-up as per protocol, whichever is earlier. At the time of interim analysis, the
 DSMB will revisit the sample size of the study. O'Brien Fleming's stopping criteria will be
 used for the primary outcome while Pocock's stopping rule will be used for the serious
 adverse events.
Inclusion Criteria:

 Inclusion criteria for the initial observation part of study preceding randomization

 1. Neonates aged 0-28 days, either inborn or outborn, who are currently admitted in the
 Neonatal Unit of the centre.

 2. Whose birth weight is greater than 1000 grams (it should be reliably ascertained from
 records of a hospital)

 3. Whose residence is within approximately 15 kms from the center, so that the infant can
 be brought back to the center for follow-up

 4. Who have suspected septicemia for which a conventional or BACTEC/BACTALERT blood
 culture is sent and for which the treating physician decides to start antibiotics

 Inclusion criteria for Randomization applicable after 7 days of therapy of above patients
 with sensitive antibiotics:

 1. Positive blood culture other than Staphylococcus aureus

 2. No signs and symptoms of sepsis from end of day 5 through end of day 7 of starting
 sensitive antibiotics

 Exclusion Criteria:

 Exclusion criteria for the initial observation part of study preceding randomization:

 1. Suspected meniingitis (meningitis will be defined as one or more of CSF cell count
 more than or equal to 25 per microliter with > 60% neutrophils; glucose 180 mg/dL in
 preterm or positive gram stain report)

 2. Septic arthritis, osteomyelitis or deep-seated abscess as clinically judged by the
 treating team

 3. Life threatening congenital malformations as judged by the principal investigator of
 the centre

 Exclusion criteria for randomization applicable after 7 days of therapy of above patients
 with sensitive antibiotics:

 1. Sterile blood culture

 2. Suspected contaminants in blood culture.

 3. Growth of Staphylococcus aureus in blood culture

 4. Growth of fungal organism in blood culture

 5. Diagnosis of meningitis, septic arthritis, osteomyelitis, abscess

 6. Has not gone into remission on day 5 or have recurrence of symptoms from day 5 through
 day 7

 7. If the empiric antibiotic is resistant but neonate has shown improvement of signs and
 symptoms of sepsis and there is ambiguity regarding in vivo sensitivity of antibiotic
 use