Antibiotics in the medical and surgical treatment of necrotizing enterocolitis. A systematic review

The study was registered in the PROSPERO register (CRD42020162193) January 15th, 2020.

Studies with documented NEC according to Bell’s classification stage II or III, treatment with at least one type of antibiotic and with reported progression of the disease defined as surgery and/or death as an outcome were included. Exclusion criteria were 1) inability to obtain the full text and insufficient data on primary outcomes, 2) studies with overlapping data, 3) case reports 4) non-original articles such as reviews 5) articles not available in English or Scandinavian languages (Danish, Norwegian or Swedish).

The following databases were searched: Embase, Medline (both through Ovid) and Cochrane. Clinicaltrials.​gov and Prospero were searched for any relevant ongoing trials or reviews. Opengrey.eu was searched to locate relevant grey literature within the area.

Relevant search terms were identified in Embase and Medline. The following search was conducted in Embase and adjusted to fit Medline and Cochrane format:

(prematurity [Emtree] or extremely low birthweight [Emtree] or very low birth weight [Emtree] or low birthweight [Emtree] or newborn [Emtree] or infant [Emtree] or Infant* or extremely premature infant*or premature infant* or premature neonate or pre-mature infant or pre-term bab* or pre-term child* or pre-term infant* or pre-term neonate or pre-term newborn or premature or premature bab* or premature child* or premature neonate* or premature newborn* or prematuritas or preterm bab* or preterm child* or preterm infant* or preterm neonate* or preterm newborn* or human neonate* or human newborn* or human infant* or Neonate* or Newborn child* or Newborn bab* or Neonatal Prematurity or Prematurity or Extremely Premature Infant* or Extremely Preterm Infant* or Extremely Premature Infant* or extremely low birthweight infant or extremely low birthweight infant or ELBW or very low birthweight infant or very low birth weight infant or VLBW or low birthweight infant or low birth weight infant or LBW) AND (necrotizing enterocolitis [Emtree] or necrotising enterocolitis or necrotizing enterocolis) AND (antiinfective agent [Emtree] or antibiotic agent [Emtree] or antibiotic prophylaxis [Emtree] or amoxycillin or amoxicillin or ampicillin or azithromycin or augmentin or benzylpenicillin or b-lactam or beta-lactam or beta-lactams or clarithromycin or cefuroxime or cotrimoxazole or co-trimoxazole or cefotaxime or ceftriaxone or ceftriaxone or cefditoren or chloramphenicol or cefpodoxime or cephradine or cephalexin or cefetamet or cefaclor or cephalosporin* or erythromycin or gentamicin or gentamycin or levofloxacin or minocycline or metronidazole or moxifloxacin or penicllin* or quinolone* or roxithromycin or sulphamethoxazole or sulfamethoxazole or trimethoprim or Antibiotic* or folate antagonists or combined antibiotic* or antibiotic or antibiotic prophylaxis or anti bacterial agent* or anti infective agent* or antibacterial agent* or antibacterial drug* or antibacterial spectrum or antiinfective* or antimicrobial* or antiseptic* or microbiological agent* or Anti-Bacterial agent* or Antibacterial Agent* or Anti-Bacterial Compound* or Anti Bacterial Compound* or Bacteriocidal Agent* or Bacteriocide* or Anti-Mycobacterial Agent* or Anti Mycobacterial Agent* or Antimycobacterial Agent*)The search was finalized by excluding conference abstracts from the search. A third search was performed by manually checking the references listed in the included studies. All relevant studies were included in the original search.

Covidence¹⁴ was used for the screening process. The initial screening was carried out by the authors EMG and KJ. Included studies were screening based on title and abstract. If conflicts occurred, reasons for exclusion were discussed until agreement. Full text screening was carried out by the same two authors. In case of conflict, the article was discussed until a mutual agreement among all authors were obtained.

Data collection was conducted with a standardized piloted form within Covidence [14] and on an external platform allowing for extraction in duplicate by both authors. All extracted data was reviewed by both authors to ensure consistency in agreement. When information was missing from the included articles the author [15] was contacted.

The list of study items to be extracted was made according to the Cochrane handbook chapter 5 [16] and modified according to relevance for this review. Extracted items included: Author name, title, publication year, study method, number of included infants, type of antibiotics used, doses, frequency, and route of administration. The number of infants who died or underwent surgery was retrieved. For the group of patients that underwent surgery the postoperative use of antibiotics was registered and the number of postoperative deaths or reported reoperation for NEC was retrieved.

RCTs were analyzed for bias using the Risk of Bias tool RoB2 [17]. RoB2 evaluates the risk of bias in a study based on 5 domains of bias: 1) the randomization process 2) deviations from the intended intervention 3) missing outcome data 4) measurement of the outcome 5) selection of the reported result. Each domain is graded low, high, some concerns or no information according to a set of signaling questions, and later summed in an algorithm to determine bias level. The n-RCTs included were analyzed using ROBINS-I [18]. ROBINS-I evaluate how well the n-RCT study handles bias spread across 7 domains compared to a well performed RCT. The 7 domains are: 1) confounding 2) Selection of participants 3) Classification of interventions 4) Deviations from intended interventions 5) Missing data 6) Measurement of outcomes 7) Selection of reported results. A n-RCT might therefore have been without major risks of bias compared to other studies of the same type, but compared to a RCT have issues, e.g., arising from randomization. All analyses were conducted at study level.

Risk of bias across studies was analyzed using Robvis plot diagram [19] . Risk ratios (RR) were calculated to investigate trends.

The search resulted in 115 references from Cochrane library, 2063 from Embase, 534 from Medline and 13 from Cochrane trials. A total of 2715 references. No relevant ongoing studies were identified on clinicaltrials.​gov nor was any material found on Opengrey.eu at the time of search (updated February 24th, 2021).

EndNote initially removed 379 duplicates. The remaining 2336 references were uploaded to Covidence for screening (Fig. 1). During the initial screening all titles were available in English. A total of 5 studies with 375 infants were included, 2 RCTs and 3 cohort studies (Table 1). The two RCTs have previously been included in a Cochrane review [7],

On September 12th, 2020, the search was repeated. A total of 264 new references was added (Endnote initially removed 2 duplicates). The new references were screened by the author EMG, and none fulfilled the inclusion criteria.

None of the studies investigated a specific postoperative antibiotic regimen in children undergoing surgery. All infants continued the study specific treatment they had received before surgery.

Both of the included RCTs [20, 21]) raised some concern for bias in domain 5 (bias due to selection of reported result) as shown in Fig. 2. No pre-specified plan for study analysis was available and outcome measures were not presented in advance according to the criteria stated in Rob2 [17]. For the study by Hansen et al. [20] domain 4 gave rise to some concern for bias because the outcome assessors role in the study was unclear. No meta-analysis of the two RCTs was carried out because of too different treatment regimens to obtain reliable data.

As for the cohort studies, one study [23] was performed in a methodological manner comparable to a RCT. Two studies [10, 22] had one or more areas that gave reason to concern for bias.

In the study by Vermeylen et al. [22] information about statistical analysis of differences between the two groups compared were missing (domain 1). Scheifele et al. [10] provided well analyzed information about possible confounders, but according to standards specified by the ROBINS-I [18] tool it cannot be compared to a well performed RCT.

All the cohort studies [10, 22, 23] had a low risk of bias regarding bias due to deviation from intended intervention (D4), missing data (D5), measurement of outcomes (D6) and selection of reported results (D7). Only the study by Luo et al. [23] could receive a low risk of bias equal to a well performed RCT.

With the limited number of studies and difference in study setup it was decided not to calculate the weight of each individual study. Only one study was judged to be of overall low risk of bias [23], and it was decided there was no substance for a generalization (Fig. 3). No synthesis of studies was conducted due to the clinical heterogeneity of the studies (Table 1).

For both the RCTs, the mortality rate in the intervention group varied from 10 to 20% and 18–20% in the control group with no significant differences. The values for surgery were 10–30% and 18–40%, respectively, and with no significant difference. In the three cohort studies the mortality rate varied from 0 to 15% in the intervention group and 10–32% in the control group. The values for surgery were 15–71% and 8–33%, respectively. The only significant difference found was in the surgical rate in the study by Vermeylen et al. [22] with the lowest rate in the group who received metronidazole but there was no difference in the mortality rates.

In the study by Luo et al. [23] 17 infants deteriorated from Bell’s stage II to III in a population of 143 infants. Eleven of these had received metronidazole and 6 had not. There was a lower mortality rate in the group receiving metronidazole, but the difference was not statistically significant.

Two studies specified the number of deaths for Bell’s stage III NEC. Vermeylen et al. [22] reported 5/30 deaths in the intervention group (metronidazole), compared to 4/4 deaths in the control group. In the study by Luo et al. [23] 1/11 infants receiving metronidazole died compared to 2/6 without metronidazole.

For the secondary outcomes no reliable data could be retrieved.

In the study by Faix et al. [21] there was no significant difference in the rate of bowel necrosis (perforation and gangrene) between the two groups (ampicillin+ gentamicin vs. ampicillin+gentamin + clindamycin). Hansen et al. [20] showed no significant differences regarding perforation, strictures, or death between the two groups of regimens (ampicillin+ gentamicin vs ampicillin+ gentamicin + oral gentamicin).

In the study by Scheifele et al. [10] children with a birthweight > 2200 g had better outcomes regardless of treatment. No infants in this group died, but had a similar risk of surgery as the children with a birthweight below 2200 g. For the group of infants with a BW < 2200 g, the group receiving standard treatment (ampicillin and gentamicin) had a significantly higher risk (p = 0.004) for surgery, peritonitis, strictures, but not for re-NEC (4/34 infants, p = 0.07 compared to the intervention with cefotaxime and vancomycin. No infants < 2200 g treated with cefotaxime/vancomycin died compared to 5/38 in the control group (p = 0.048).