Anti-bacterial Agents, Infant, Newborn, Neonatal SEPSIS, Recurrence
Conditions
Keywords
Neonate, Sepsis, Antibiotics, Duration
Brief summary
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.
Detailed 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.
Interventions
DRUG7-day course of antibiotics
Subjects in the 7-day course of antibiotics arm of the study will receive no further antibiotics after randomization as they would have already received 7 days of sensitive antibiotics before randomization. The choice of antibiotics would be guided by the blood culture and sensitivity report. Thus, subjects in this arm of the study could get a variety of antibiotics, depending on the sensitivity reports. Hence, names of specific antibiotics and/or their brand names have not been mentioned.
DRUG14-day course of antibiotics
Subjects in the 14-day course of antibiotics arm of the study will receive 7 more days of antibiotics after randomization as they would have already received 7 days of sensitive antibiotics before randomization. The choice of antibiotics would be guided by the blood culture and sensitivity report. Thus, subjects in this arm of the study could get a variety of antibiotics, depending on the sensitivity reports. Hence, names of specific antibiotics and/or their brand names have not been mentioned.
Sponsors
Post Graduate Institute of Medical Education and Research, Chandigarh
Chacha Nehru Bal Chikitsalaya, New Delhi
Lady Hardinge Medical College
Indira Gandhi Institute of Child Health, Bangalore
Institute of Obstetrics and Gynecology, Chennai
King George's Medical University
Pandit Bhagwat Dayal Sharma, PGIMS, Rohtak
St Johns Medical College Hospital, Bangalore, India
Indian Council of Medical Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Outcome assessor will be provided objective clinical information related to episodes of all illnesses during follow-up with all patient identifiers removed and the record identified only by a unique code number. All imaging films and investigation reports provided to the outcome assessor will be similarly bereft of patient identifiers and coded by a unique code number. The outcome assessor will not be involved in the rest of the study. The outcome assessor will adjudicate whether the given episode of illness is a relapse.
Intervention model description
Randomized, outcome-assessor blinded, active-controlled, multi-centric, non-inferiority trial
Eligibility
Sex/Gender
ALL
Age
1 Hours to 28 Days
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Definite or probable relapse within 21 days post-antibiotic completion as per protocol | From 0-21 days after the end of the planned antibiotic therapy | Among participants who adhered to study protocol- Definite relapse: Episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode, Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
| Definite or probable relapse within 21 days post-antibiotic completion as per intention to treat | From 0-21 days after the end of the planned antibiotic therapy | Among all randomized patients- Definite relapse: Episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode, Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Definite relapse within 28 days post-antibiotic completion, as per protocol | From 0-28 days after the end of the planned antibiotic therapy | Among participants who adhered to study protocol Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode |
| Definite relapse within 28 days post-antibiotic completion, as per intention-to-treat | From 0-28 days after the end of the planned antibiotic therapy | Among all randomized patients Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode |
| Definite relapse within 28 days post-randomization, as per protocol | From 0-28 days after randomization | Among participants who adhered to study protocol Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode |
| Definite relapse within 28 days post-randomization, as per Intention-to-treat | From 0-28 days after randomization | Among all randomized patients Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode |
| Definite relapse within 35 days post-randomization, as per protocol | From 0-35 days after randomization | Among participants who adhered to study protocol Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode |
| Definite relapse within 35 days post-randomization, as per intention to treat | From 0-35 days after randomization | Among all randomized patients Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode |
| Probable relapse within 21 days post-antibiotic completion, as per protocol | From 0-21 days after the end of the planned antibiotic therapy | Among participants who adhered to study protocol Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
| Probable relapse within 21 days post-antibiotic completion, as per intention-to-treat | From 0-21 days after the end of the planned antibiotic therapy | Among all randomized patients Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
| Probable relapse within 28 days post-antibiotic completion, as per protocol | From 0-28 days after the end of the planned antibiotic therapy | Among participants who adhered to study protocol Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
| Probable relapse within 28 days post-antibiotic completion, as per intention-to-treat | From 0-28 days after the end of the planned antibiotic therapy | Among all randomized patients Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
| Definite relapse within 21 days post-antibiotic completion, as per protocol | From 0-21 days after the end of the planned antibiotic therapy | Among participants who adhered to study protocol Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode |
| Probable relapse within 28 days post-randomization, as per intention-to-treat | From 0-28 days after randomization | Among all randomized patients Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
| Probable relapse within 35 days post-randomization, as per protocol | From 0-35 days after randomization | Among participants who adhered to study protocol Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
| Probable relapse within 35 days post-randomization, as per intention-to-treat | From 0-35 days after randomization | Among all randomised patients Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
| Definite relapse or probable relapse within 28 days post-randomization, as per protocol | From 0-28 days after randomization | Among participants who adhered to study protocol Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
| Definite relapse or probable relapse within 28 days post-randomization, as per Intention-to-treat | From 0-28 days after randomization | Among all randomized patients Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
| Definite relapse or probable relapse within 35 days post-randomization, as per protocol | From 0-35 days after randomization | Among participants who adhered to study protocol Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
| Definite relapse or probable relapse within 35 days post-randomization, as per intention-to-treat | From 0-35 days after randomization | Among all randomised patients Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
| Secondary sepsis | From 0-35 days after randomization | Sepsis due to bacterial organisms other than the original etiologic bacteria or with a different antibiogram or with a fungal organism |
| Adverse events | From 0-35 days after randomization | Adverse events as per a list of adverse events, graded as per severity, and defined a priori |
| Probable relapse within 28 days post-randomization, as per protocol | From 0-28 days after randomization | Among participants who adhered to study protocol Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis. |
| Definite relapse within 21 days post-antibiotic completion, as per intention-to-treat | From 0-21 days after the end of the planned antibiotic therapy | Among all randomized patients Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode |
Countries
India
Outcome results
None listed