7 Days Versus 14 Days of Antibiotics for Neonatal Sepsis

Indian Council of Medical Research (ICMR)

Status and phase: Completed; Phase 3

Conditions: Infant, Newborn; Anti-bacterial Agents; Recurrence; Neonatal SEPSIS

Treatments: Drug: 14-day course of antibiotics; Drug: 7-day course of antibiotics

Study type: Interventional

Funder types: Other

Identifiers

NCT03280147

5/7/329/2009-RHN

Details and patient eligibility

About

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.

Full description

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 7%, 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 at 1/3rd and 2/3rd of expected recruitment. 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.

Enrollment: 261 patients

Sex: All

Ages: 1 hour to 28 days old

Volunteers: No Healthy Volunteers

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 or equal to1000 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. Central Nervous System infection (Central Nervous System infection (meningitis will be defined as CSF Cells >25 per uL with polys >60% OR [(CSF glucose <20 mg/dL OR CSF:blood* glu ratio <0.6) AND (CSF protein >150 mg/dL in term OR >180 mg/dL in preterm)]
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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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261 participants in 2 patient groups

7-day course of antibiotics

Experimental group

Description:

Randomization of subjects will be performed at the end of 7 days of sensitive intravenous antibiotic administration, provided the subjects meet randomization criteria. Those who are randomized to the 7-day group will not receive any further antibiotics.

Treatment:

Drug: 7-day course of antibiotics

14-day course of antibiotics

Active Comparator group

Description:

Randomization of subjects will be performed at the end of 7 days of sensitive intravenous antibiotic administration, provided the subjects meet randomization criteria. Those who are randomized to the 14-day group will receive 7 more days of the same antibiotics, to make it a total of 14 days.

Treatment:

Drug: 14-day course of antibiotics