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Antibiotic regimens for the empirical treatment of newborn infants with necrotising enterocolitis

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Authors

Dharmesh Shah1, John KH Sinn2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Neonatal Intensive Care Unit, Westmead Hospital, Sydney, Australia [top]
2Department of Neonatology, Royal North Shore Hospital, The University of Sydney, Sydney, Australia [top]

Citation example: Shah D, Sinn JKH. Antibiotic regimens for the empirical treatment of newborn infants with necrotising enterocolitis. Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD007448. DOI: 10.1002/14651858.CD007448.pub2.

Contact person

Dharmesh Shah

Neonatal Intensive Care Unit
Westmead Hospital
Sydney
NSW 2145
Australia

E-mail: dharmeshparul@yahoo.com

Dates

Assessed as Up-to-date: 18 February 2012
Date of Search: 13 February 2012
Next Stage Expected: 18 February 2014
Protocol First Published: Issue 4, 2008
Review First Published: Issue 8, 2012
Last Citation Issue: Issue 8, 2012

Abstract

Background

Although the exact aetiology of necrotising enterocolitis (NEC) remains unknown, research suggests that it is multifactorial; suspected pathophysiological mechanisms include immaturity, intestinal ischaemia, disruption of intestinal mucosal integrity, formula feeding, hyperosmolar load to the intestine, infection and bacterial translocation. Various antibiotic regimens have been widely used in the treatment of NEC.

Objectives

To compare the efficacy of different antibiotic regimens on mortality and the need for surgery in neonates with NEC.

Search methods

Searches were made of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2012), Oxford Database of Perinatal Trials, MEDLINE (1966 to February 2012), EMBASE (1980 to February 2012) and CINAHL (1982 to February 2012).

Selection criteria

All randomised and quasi-randomised controlled trials where antibiotic regimens were used for treatment of NEC.

Data collection and analysis

Eligibility of studies for inclusion was assessed independently by each review author. The criteria and standard methods of the Cochrane Neonatal Review Group were used to assess the methodological quality of the included trials.

Results

Two trials met the inclusion criteria. Faix 1988 randomised 42 premature infants with radiological diagnosis of NEC. Infants were randomised to receive either intravenous ampicillin and gentamicin or ampicillin, gentamicin and clindamycin. Hansen 1980 randomised 20 infants with NEC to receive intravenous ampicillin and gentamicin with or without enteral gentamicin.

In the study by Faix 1988, there were no statistical differences in mortality (RR 1.10; 95% CI 0.32 to 3.83) or bowel perforation (RR 2.20; 95% CI 0.45 to 10.74) between the two groups although there was a trend towards higher rate of strictures in the group that received clindamycin (RR 7.20; 95% CI 0.97 to 53.36).

The Hansen 1980 study showed no statistically significant difference in death, bowel perforation or development of strictures.

Authors' conclusions

There was insufficient evidence to recommend a particular antibiotic regimen for the treatment of NEC. There were concerns about adverse effects following the usage of clindamycin, related to the development of strictures. To address this issue a large randomised controlled trial needs to be performed.

Plain language summary

Antibiotic usage for necrotising enterocolitis in newborn infants

Necrotising enterocolitis (NEC) is a gastrointestinal disease that primarily affects premature infants. Infants who have developed NEC could rapidly become very sick, leading to various morbidities and even death. The cause of NEC is uncertain and possibly multifactorial, but an infectious agent is most commonly suspected. Various antibiotic combinations are commonly used as treatment in such infants. Certain antibiotic regimens could lead to drug side effects and even antibiotic resistance. The authors of this study reviewed the medical literature to ascertain the best antibiotic combination for the treatment of this condition. Four eligible studies were identified and only two of these studies were found to be suitable for analysis. Both these studies were performed before 1988. The two studies included 62 infants with NEC and compared one antibiotic regimen to another. There was no difference between the two groups. The authors concluded that there was insufficient evidence to recommend a particular antibiotic regimen for NEC.

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Background

Necrotising enterocolitis (NEC) is the most common emergency involving the gastrointestinal tract occurring in the neonatal period. Two to five per cent of all infants admitted to the neonatal intensive care unit (NICU) develop NEC (Stoll 1994). Of these patients, 90% are born preterm (Kliegman 1984). NEC occurs in 2% to 5% of very low birth weight (VLBW) infants (Newell 2005) and approximately 20% to 40% of these infants require surgical intervention (Engum 1998). The mortality rate varies from 20% to 35% (Kliegman 1994) and 25% of survivors experience long-term sequelae (Berseth 1998), such as poor growth, short bowel syndrome and intestinal strictures. There are also reports of poor neurodevelopmental outcome in VLBW infants with NEC, especially in babies requiring surgery (Simon 1994; Salhab 2004; Hintz 2005).

Description of the condition

The aetiology of NEC is unknown. The pathogenesis of NEC appears to be multifactorial with no unifying hypothesis explaining its cause or prevention (Bauer 1992). Suspected pathophysiological mechanisms include immaturity, intestinal ischaemia, disruption of intestinal mucosal integrity, formula feeding, hyperosmolar load to the intestine, infection and bacterial translocation (Caplan 2001).

Infections, whether systemic or localised to the intestinal tract, precipitate NEC in a subset of affected infants. It is unclear if a local enteric infection is necessary for the development of NEC (Willoughby 1994). Several lines of evidence have been used to support the hypothesis that infection is necessary for the development of NEC. These include the isolation of infectious agents from infants with NEC, epidemiological characteristics of outbreaks suggestive of an infectious process and decreased incidence of NEC associated with interventions aimed at decreasing spread of infectious agents (Kliegman 1979a; Rotbart 1983a). The organisms involved in the aetiology of NEC are both pathogenic bacteria and normal gut flora. Organisms isolated from stool cultures of affected infants are also isolated from healthy babies. Blood cultures are positive in 30% to 35% of infants with NEC (Kliegman 1979b). The most common organisms include Escherichia coli and Staphylococcus epidermidis, and Clostridium, Klebsiella, Pseudomonas, Salmonella and Enterococcus species (Coit 1999). There are also reports of sporadic outbreaks of NEC associated with viral infections, including corona virus (Chany 1982) and rota virus (Rotbart 1983b).

NEC can present as mild feeding intolerance or as a fulminant surgical condition. According to the modified Bell Staging NEC is classified into three stages (Bell 1978):

  • stage IA: suspected NEC;
  • stage IB: suspected NEC with blood from rectum;
  • stage IIA: confirmed NEC, mildly ill with pneumatosis intestinalis;
  • stage IIB: confirmed NEC, moderately ill with portal vein gas;
  • stage IIIA: advanced NEC with organ dysfunction;
  • stage IIIB: advanced NEC with pneumoperitoneum.

Description of the intervention

Prevention of continuing injury to the mucosal lining of the gastrointestinal tract is an important goal of treatment for NEC. Antibiotics treat systemic infection and may stop disease progression and injury to the mucosa of the gastrointestinal tract. Administration of systemic antibiotics after obtaining appropriate cultures is considered standard treatment as soon as the diagnosis of NEC is suspected (Kliegman 1987).

There is a range of antibiotics regimens used as initial treatment in the NICUs around the world. These include ampicillin, gentamicin, flucloxacillin, vancomycin, clindamycin and metronidazole (Kanto 1994). Even though therapy with broad-spectrum antibiotics is standard in all cases of NEC, there is wide variation in the choice and duration of administration of antibiotics. Little is known about the efficacy of different antibiotics or antibiotic regimens with respect to the primary aim of treating the infection and stopping disease progression.

How the intervention might work

Antibiotic treatment should prevent enteric organisms from spreading into the blood stream and this should lead to a decrease in mortality, less need for surgery, decreased secondary blood stream infection, decreased duration of mechanical ventilation, shortened time to establish full enteral feeds, better weight gain and improved neurodevelopmental outcome.

Objectives

To compare the efficacy of different antibiotic regimens (antibiotic monotherapy, monotherapy with combination therapy and combination therapies) on mortality and the need for surgery in the empirical treatment of neonates with NEC.

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Methods

Criteria for considering studies for this review

Types of studies

Randomised and quasi-randomised controlled trials, published and unpublished, were considered for this review.

Types of participants

Newborn infants of any gestational age requiring treatment for confirmed or suspected NEC.

NEC was defined according to modified Bell's criteria (Walsh 1988):

  • suspected: stage 1A and 1B;
  • confirmed: stages 2 and 3.

Types of interventions

  • Any intravenous or oral antibiotic treatment.
  • Single antibiotic versus placebo.
  • Single antibiotic versus single antibiotic.
  • Single antibiotic versus combination antibiotics.
  • Different combinations of antibiotics.

Types of outcome measures

Primary outcomes
  • Mortality up to the time of discharge from hospital.
  • Need for surgical intervention (any surgical intervention including peritoneal drainage).
Secondary outcomes
  • Duration of mechanical ventilation (days).
  • Duration of time to establish full enteral feeds (days).
  • Need to change antibiotics following the stool or blood culture results.
  • Long-term neurodevelopmental outcome (validated scales of neurodevelopment e.g., Griffiths Neurodevelopmental Scale, Bayley Scale for Infant Development).
  • Formal hearing testing.
  • Formal visual acuity.

Search methods for identification of studies

See Cochrane Neonatal Review Group (CNRG) search strategy (CNRG 2011).

We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2012), MEDLINE (1966 to February 13, 2012), EMBASE (1980 to February 13, 2012), CINAHL (1982 to February 13, 2012) and the Oxford Database of Perinatal Trials, using the following MeSH terms or text words:

  • enterocolitis, Necrotizing OR enterocolitis OR NEC AND
  • anti-bacterial agents OR antibiotics AND
  • therapeutics OR therapy AND
  • infant, newborn/OR infant, low birth weight/OR infant, very low birth weight/OR infant, premature/OR Infant, Premature, Diseases OR (neonate: OR prematur*: OR newborn) AND
  • controlled clinical trial OR randomised controlled trial OR cohort studies.

Searching other resources

We searched abstracts of Academic Paediatric Society (1996 to 2011), Perinatal Society of Australia and New Zealand (PSANZ, 1997 to 2011) and European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPHGAN, 1987 to 2011) annual conferences.

We searched unpublished trials from the International Clinical Trials Registry Platform, Australia and NZ Clinical Trial Registry.

We searched previous reviews, including cross-references and abstracts. We did not limit the search to the English language; all efforts were made to have reports in foreign languages translated.

We assessed the title and abstract of each trial for eligibility. We reviewed the full report if there was uncertainty.

Data collection and analysis

Selection of studies

Each review author independently assessed the eligibility of studies for inclusion. We used the criteria and standard methods of the CNRG (CNRG 2011) to assess the methodological quality of the included trials.

Data extraction and management

We evaluated the quality of the trials included in terms of allocation concealment; adequate randomisation; blinding of parents, carers and assessors to intervention; and completeness of assessment (intention to treat). In all randomised individuals this was defined as yes, no or unsure for each category. We performed a sensitivity analysis was according to the quality of the included trials.

We requested additional information from the authors of each trial to clarify methodology and results as necessary. We used a data collection form to aid extraction of relevant information and data from each included study. Each review author extracted the data independently, compared data and resolved differences by consensus.

Assessment of risk of bias in included studies

We employed the standard methods of the CNRG (CNRG 2011). We assessed the methodological quality of the studies using the following key criteria: allocation concealment (blinding of randomisation), blinding of intervention, completeness of follow-up and blinding of outcome measurement/assessment. For each criterion, assessment was yes, no, or unclear. Two review authors separately assessed each study. We resolved any disagreement by discussion. The information is presented in the ' Characteristics of Included Studies' table. In addition, the following issues were evaluated and entered into the 'Risk of bias' table:

  1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?For each included study, we categorised the method used to generate the allocation sequence as:
    1. adequate (any truly random process e.g. random number table; computer random number generator);
    2. inadequate (any non-random process e.g. odd or even date of birth; hospital or clinic record number);
    3. unclear.
  2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed? For each included study, we categorised the method used to conceal the allocation sequence as:
    1. adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
    2. inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
    3. unclear.
  3. Blinding (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment? For each included study, we categorised the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or classes of outcomes. We categorised the methods as:
    1. adequate, inadequate or unclear for participants;
    2. adequate, inadequate or unclear for personnel;
    3. adequate, inadequate or unclear for outcome assessors.
  4. Incomplete outcome data (checking for possible attrition bias through withdrawals, drop-outs, protocol deviations). Were incomplete outcome data adequately addressed? For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported and whether missing data were balanced across groups or were related to outcomes.Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorised the methods as:
    1. adequate (< 20% missing data);
    2. inadequate (greater than/or equal to 20% missing data);
    3. unclear.
  5. Selective reporting bias. Were reports of the study free of suggestion of selective outcome reporting? For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:
    1. adequate (where it is clear that all of the study's pre-specified outcomes and all expected outcomes of interest to the review have been reported);
    2. inadequate (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study failed to include results of a key outcome that would have been expected to have been reported);
    3. unclear.
  6. Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias? For each included study, we described any important concerns we had about other possible sources of bias (e.g. whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:
    1. yes;
    2. no;
    3. unclear.

If needed, we planned to explore the impact of the level of bias by undertaking sensitivity analyses.

Measures of treatment effect

We used the standard methods of the CNRG to synthesise the data (CNRG 2011). We expressed categorical data as risk ratio (RR), risk difference (RD) and 95% confidence intervals (CI) and continuous data as weighted mean difference (WMD) and 95% CI. We used the fixed-effect model for meta-analysis. The number needed to treat for an additional beneficial outcome (NNTB) based on 1/RD was calculated for significant differences.

Assessment of heterogeneity

The treatment effects of individual trials was estimated and heterogeneity between trial results examined by inspecting the forest plots and quantifying the impact of heterogeneity in any meta-analysis using a measure of the degree of inconsistency in the studies' results (I2 statistic).

If statistical heterogeneity was detected the possible causes were explored. A fixed-effect model was used for meta-analyses. Publication bias was examined using a funnel plot, and a regression approach to assess funnel plot asymmetry (Egger 1997).

Subgroup analysis and investigation of heterogeneity

The subgroup analysis was performed based on:

  • birth weight (less than/or equal to 1500 g or > 1500 g);
  • gestational age (less than/or equal to 32 weeks or > 32 weeks);
  • type of feeding (formula, mother's own milk or banked human milk);
  • duration of antibiotics (< one week or > one week).

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Results

Description of studies

See: Characteristics of Included Studies; Characteristics of excluded studies

Results of the search

We identified four potentially relevant studies.

Included studies

We included two studies for analysis, which involved 62 infants with NEC.

Faix 1988 randomised 42 premature infants with radiological diagnosis of NEC. Infants were randomised either to receive intravenous ampicillin and gentamicin or ampicillin, gentamicin and clindamycin. Antibiotics were administered for 10 to 14 days. The mean gestational age in the clindamycin group was 29.2 ± 2.7 weeks and mean birth weight was 1290 ± 560 g. For the control group the mean gestational age was 29.6 ± 3.7 weeks and mean birth weight was 1310 ± 560 g. The mean age at diagnosis was 29.6 ± 23.2 days in the clindamycin group and 26.6 ± 24.7 in the control group. The severity of NEC was staged according to the criteria of Bell et al (Bell 1978), in which pneumatosis intestinalis or portal gas is classified as stage II and those who also had shock, marked gastrointestinal haemorrhage or perforation were classified as stage III. The primary outcomes studied were death and bowel necrosis. The secondary outcomes were time to resolution of pneumatosis/portal gas, time to re-institution of enteral feeds and development of strictures.

Hansen 1980 randomised 20 infants with NEC to receive intravenous ampicillin and gentamicin with or without enteral gentamicin. The mean gestational age was 34.7 ± 1.3 weeks in the study group with a mean birth weight of 2220 ± 295 grams. In the control group the mean gestational age was 35.6 ± 1.1 weeks and mean birth weight was 2180 ± 198 grams. The mean age at diagnosis was 5.9 ± 1.3 days in both groups. The severity of NEC was judged according to the Bell Staging (Bell 1978). Outcomes studied were death, perforation, strictures, prolonged ileus and days with pneumatosis.

Excluded studies

We excluded two trials from the final analysis.

Scheifele 1987 was not a randomised or a quasi-randomised trial. They compared 90 infants during two different study periods. During 1982 to 1983 ampicillin and gentamicin was prescribed for NEC and between 1984 to 1985 cefotaxime and vancomycin were used. Diagnosis was clinical and radiological with staging according to the Bell staging (Bell 1978). Mean birth weight in the ampicillin/gentamicin group was 1828 g and age of onset was 12.3 ± 1.8 days. The outcome measures compared included early (thrombocytopenia, surgery for peritonitis, protracted illness, death) and late (feed intolerance, strictures, recurrent NEC, death) complications. They reported a significant difference (Fisher's exact test P = 0.004) in major complications (peritonitis, strictures, feed intolerance, recurrent NEC) favouring the group managed with cefotaxime and vancomycin. There was a significant difference in mortality favouring the group receiving cefotaxime and vancomycin (Fisher's exact test P = 0.048).

Bell 1973 had insufficient data for analysis. They reported retrospective data on 23 infants with NEC. If the diagnosis was achieved prior to perforation, infants received intravenous penicillin (50, 000 units/kg/24 h) and either intravenous kanamycin (15 mg/kg/day) or intravenous gentamicin (3 to 7.5 mg/kg/day) and oral kanamycin or gentamicin by gavage. Fourteen infants with NEC without perforation all had resolution of clinical and radiological signs of the disease. None of the 14 infants treated with topical antibiotics developed perforation.

Risk of bias in included studies

Allocation (selection bias)

In both of the trials random allocation to treatment group was used. Faix 1988 used random allocation (method of generation of random sequence not stated) and concealed the allocation treatment assignment using sealed envelopes. Hansen 1980 used a random number table.

Blinding (performance bias and detection bias)

Neither of the trials reported blinding of intervention.

Blinding of outcome measures were not performed in both the trials.

Incomplete outcome data (attrition bias)

Neither of the trials reported exclusions after randomisation.

Selective reporting (reporting bias)

  • None noted.

Other potential sources of bias

  • None noted.

Effects of interventions

  • Any intravenous or oral antibiotic treatment: no studies identified.
  • Single antibiotic versus placebo: no studies identified.
  • Single antibiotic versus single antibiotic: no studies identified.
  • Single antibiotic versus combination antibiotics: no studies identified.
  • Different combinations of antibiotics: two studies identified (Hansen 1980; Faix 1988).

Parenteral ampicillin and gentamicin vs parenteral ampicillin, gentamicin and clindamycin (Comparison 1)

In the study by Faix 1988, there was no statistical difference in mortality or bowel perforation between the two groups. There was a trend towards higher rate of strictures in the group that received clindamycin.

Death (Outcome 1.1)

There was no difference in death rates between the two groups (RR 1.10; 95% CI 0.32 to 3.83; Analysis 1.1).

Strictures (among survivors) (Outcome 1.2)

A statistically increased risk of strictures in infants randomised to the clindamycin group (Fisher exact test, P = 0.022) was identified in this study. All strictures were surgically resected in this group (RR 7.20; 95% CI 0.97 to 53.36; Analysis 1.2).

Bowel perforation (Outcome 1.3)

The administration of parenteral clindamycin made no statistical reduction in the incidence of bowel perforation (RR 2.20; 95% CI 0.45 to 10.74; Analysis 1.3).

Time to resolution of pneumatosis/portal gas/air fluid levels

There was no statistical difference in the antibiotic and control group.

Time to successful re-institution of enteral feeding (among survivors)

There was no statistical difference between the two groups.

Parenteral ampicillin and gentamicin vs parenteral ampicillin, gentamicin and enteral gentamicin (Comparison 2)

In the study performed by Hansen 1980, there was no statistically significant difference in mortality, bowel perforation or strictures between the two study groups.

Mortality (Outcome 2.1)

There was no statistically significant difference in mortality between the two groups (RR 0.50; 95% CI 0.05 to 4.67; Analysis 2.1).

Strictures (Outcome 2.2)

There was no difference in stricture rate between the study groups (RR 0.50; 95% CI 0.05 to 4.67; Analysis 2.2).

Bowel perforation (Outcome 2.3)

No statistically significant difference was identified between the study groups (RR 0.20; 95% CI 0.01 to 3.70; Analysis 2.3).

Time to resolution of pneumatosis

No statistically significant differences identified between the study groups.

Time to successful re-institution of enteral feeding (among survivors)

This outcome was not reported.

Discussion

Summary of main results

Although four potential studies were identified, only two were included for analysis. All studies were trials comparing different antibiotic regimens and none were placebo controlled. All studies identified were done more than two decades ago. One of the included study (Hansen 1980) was a relatively small trial. The included studies used different antibiotics in their treatment arm and Hansen 1980 used enteral gentamicin as the treatment group.

In the trial by Faix 1988, oral gentamicin showed no statistical difference in mortality or bowel perforation. Parenteral clindamycin was found to be associated with trend towards increased risk of strictures (RR 7.20; 95% CI 0.97 to 53.36). Hansen 1980 similarly demonstrated nil significant differences in mortality, bowel perforation or strictures between groups.

Among the excluded studies, Scheifele 1987 compared parenteral ampicillin and gentamicin with parenteral vancomycin and cefotaxime, used during two different era. Their comparison showed a significant difference in outcomes (mortality, strictures, recurrent NEC and peritonitis) in the group managed with broad-spectrum antibiotics (ampicillin and gentamicin). Similarly the retrospective report by Bell 1973 showed that infants with NEC who received enteral antibiotics did not develop perforation.

Thus, antibiotics remain the main stay of conservative treatment for NEC, but there was no evidence from present randomised trials to suggest that any antibiotic regimen is superior to another, despite their widespread usage.

NEC can be potentially life threatening and infection is one of the causative agents implicated. Aerobic and anaerobic organisms have been identified in infants with NEC. Antibiotics are one of the primary treatments in these infants. This review clearly highlights the lack of evidence into benefits and risks of a particular antibiotic regimen in the treatment of NEC. The role of enteral antibiotics needs to be examined further in randomised controlled trials.

Overall completeness and applicability of evidence

More trials are needed comparing one antibiotic regimen against another or placebo. Case-control studies are required to investigate the possible association between the use of clindamycin and bowel stricture in neonates with NEC.

Quality of the evidence

Both the studies were randomised, but there was no blinding of the intervention or the outcomes. These studies did not meet all the set criteria for methodological quality in the review.

Potential biases in the review process

  • None noted.

Agreements and disagreements with other studies or reviews

  • None noted.

Authors' conclusions

Implications for practice

There was insufficient evidence to recommend a particular antibiotic regimen for treatment of NEC.

Implications for research

Further randomised trials are needed to compare the efficacy of various antibiotic regimens for the treatment of NEC.

Risk of strictures with usage of intravenous clindamycin needs to be explored in future case-control studies.

Contributions of authors

Dharmesh Shah (DS) performed the literature search, selected relevant studies, assessed the methodological quality of studies, entered the data into Review Manager (RevMan 2011) and write the discussion.

John Sinn (JS) performed the literature search, selected relevant studies, assessed the methodological quality of studies, checked the data entered into RevMan by DS, corresponded with authors of the studies, revised and edited the draft of the review.

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Faix 1988

Methods

Randomised controlled trial

Single unit

Blinding of randomisation: yes (concealed envelopes)

Blinding of intervention: no

Complete follow-up: yes

Blinding of outcome: yes (radiologists interpreting the reports were unaware of the treatment assigned)

Participants

42 infants with a diagnosis of NEC that was defined as 2 of the 3 clinical signs (abdominal distension, frankly bloody stools, gastric residuals less than/or equal to 5 mL) and radiographic documentation of pneumatosis intestinalis or portal gas)

Interventions

IV ampicillin (100-150 mg/kg/day divided every 8 h) + IV gentamicin (5 mg/kg initially and then 2.5-7.5 mg/kg/day in 3 divided doses) vs

IV ampicillin (same dose) + IV gentamicin (same dose) + IV clindamycin (20 mg/kg/day divided every 8 h) given for 10-14 days

Outcomes

Bowel perforation

Death

Among survivors: time to resolution of pneumatosis, portal gas and intestinal air fluid levels

Time to successful re-institution of enteral feeding after NPO discontinued

Stricture

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Information about random sequence generation not available

Allocation concealment (selection bias) Low risk

Blinding of randomisation: yes (concealed envelopes)

Blinding (performance bias and detection bias) High risk

Blinding of intervention: no (clinicians were aware of the treatment regimen)

Blinding of outcome: yes (radiologists interpreting the reports were unaware of the treatment assigned)

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes

Selective reporting (reporting bias) Low risk

All events mentioned

Other bias Unclear risk

-

Hansen 1980

Methods

Randomised controlled trial

Single unit

Blinding of randomisation: yes

Blinding of intervention: yes

Blinding of outcome: unclear

Participants

20 infants with NEC diagnosed by abdominal distension, gastrointestinal bleeding and radiological evidence of pneumatosis intestinalis

Interventions

IV ampicillin (150 mg/kg/day in 4 divided doses) + IV gentamicin (7.5 mg/kg/day, IM, every 8 h) vs

IV ampicillin (same dose) + IV gentamicin (same dose) + gentamicin orally (15 mg/kg/day, via nasogastric tube, every 4 h for 4 days)

Outcomes

Perforation

Stricture

Prolonged ileus

Death

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Random number table

Allocation concealment (selection bias) Low risk

Blinding of randomisation: yes

Blinding (performance bias and detection bias) Unclear risk

Blinding of intervention: yes (control group received equal volume of placebo in form of sterile water)

Blinding of outcome: unclear

Incomplete outcome data (attrition bias) Low risk

-

Selective reporting (reporting bias) Unclear risk

-

Other bias Unclear risk

-

Footnotes

IV: intravenous; NEC: necrotising enterocolitis; NPO: nil by mouth

Characteristics of excluded studies

Bell 1973

Reason for exclusion

Insufficient data for analysis

Scheifele 1987

Reason for exclusion

Not a randomised or quasi-randomised trial

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References to studies

Included studies

Faix 1988

Faix RG, Polley TZ, Grasela TH. A randomized, controlled trial of parenteral clindamycin in neonatal necrotizing enterocolitis. The Journal of Pediatrics February 1988;112(2):271-7.

Hansen 1980

Hansen TN, Ritter DA, Speer ME, Kenny JD, Rudolph AJ. A randomized, controlled study of oral gentamicin in the treatment of neonatal necrotizing enterocolitis. The Journal of Pediatrics 1980;97(5):836-9.

Excluded studies

Bell 1973

Bell MJ, Kosloske AM, Benton C, Martin LW. Neonatal necrotizing enterocolitis: prevention of perforation. Journal of Pediatric Surgery 1973;8(5):601-5.

Scheifele 1987

Scheifele DW, Ginter GL, Olsen E, Fussell S, Pendray M. Comparison of two antibiotic regimens for neonatal necrotizing enterocolitis. Journal of Antimicrobial Chemotherapy 1987;20(3):421-9.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Bauer 1992

Bauer CR. Effective care of newborn. Oxford University Press, 1992.

Bell 1978

Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Annals of Surgery 1978;187(1):1-7.

Berseth 1998

Berseth CL, Abrams SA. Avery's Disease of the Newborn. WB Saunders Company, 1998.

Caplan 2001

Caplan MS, Jilling T. New concepts in necrotizing enterocolitis. Current Opinion in Pediatrics 2001;13(2):111-5.

Chany 1982

Chany C, Moscovici O, Lebon P. Association of coronavirus infection with neonatal necrotizing enterocolitis. Pediatrics 1982;69(2):209.

CNRG 2011

Soll RF, Bracken MB, Horbar JD, Ohlsson A, Suresh G, Haughton DE. Cochrane Neonatal Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)) 2011, Issue 3. Art. No.: NEONATAL.

Coit 1999

Coit AK. Necrotizing enterocolitis. The Journal of Perinatal and Neonatal Nursing 1999;12(4):53-66.

Egger 1997

Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical research ed.) 1997;315:629-34.

Engum 1998

Engum SA, Grosfeld JL. Necrotizing enterocolitis. Current Opinion in Pediatrics 1998;10(2):123-30.

Hintz 2005

Hintz SR, Kendrick DE, Stoll BJ, Vohr BR, Fanaroff AA, Donovan EF. Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics 2005;115(3):696-703.

Kanto 1994

Kanto WP Jr, Hunter JE, Stoll JB. Recognition and medical management of necrotizing enterocolitis. Clinics in Perinatology 1994;21(2):335-46.

Kliegman 1979a

Kliegman RM. Neonatal necrotizing enterocolitis: implications for an infectious disease. Pediatric Clinics of North America 1979;26(2):327-44.

Kliegman 1979b

Kliegman RM, Pittard WB, Fanaroff AA. Necrotizing enterocolitis in neonates fed human milk. Journal of Pediatrics 1979;95(3):450-3.

Kliegman 1984

Kliegman RM, Fanaroff AA. Necrotizing enterocolitis. New England Journal of Medicine 1984;310(17):1093-103.

Kliegman 1987

Kliegman RM, Walsh MC. Neonatal necrotizing enterocolitis: pathogenesis, classification and spectrum of illness. Current Problems in Pediatrics 1987;17(4):213-88.

Kliegman 1994

Kliegman RM, Walker WA, Yolken RH. Necrotizing enterocolitis. Clinics in Perinatology 1994;21(2):437-55.

Newell 2005

Newell SJ. Roberton's Textbook of Neonatology. Churchill Livingstone, 2005.

RevMan 2011

Review Manager (RevMan) [Computer program]. Version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.

Rotbart 1983a

Rotbart HA, Levin MJ. How contagious is necrotizing enterocolitis? Pediatric Infectious Disease Journal 1983;2:406.

Rotbart 1983b

Rotbart HA, Levin MJ, Yolken RH. An outbreak of rotavirus-associated neonatal necrotizing enterocolitis. Journal of Pediatrics 1983;103(3):454-9.

Salhab 2004

Salhab WA, Perlman JM, Silver L, Sue Broules R. Necrotizing enterocolitis and neurodevelopmental outcome in extremely low birth weight < 1000 grams. Journal of Perinatology 2004;24(9):531-3.

Simon 1994

Simon NP. Follow-up for infants with necrotizing enterocolitis. Clinics in Perinatology 1994;21(2):411-24.

Stoll 1994

Stoll BJ. Epidemiology of necrotizing enterocolitis. Clinics in Perinatology 1994;21(2):205-18.

Walsh 1988

Walsh MC, Kliegman RM, Fanaroff AA. Necrotizing enterocolitis: a practitioners perspective. Pediatric Review 1988;9(7):219-26.

Willoughby 1994

Willoughby RE Jr, Pickering LK. Necrotizing enterocolitis and infection. Clinics in Perinatology 1994;21(2):307-15.

Other published versions of this review

  • None noted.

Classification pending references

  • None noted.

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Data and analyses

1 Parenteral ampicillin and gentamicin vs ampicillin, gentamicin and clindamycin

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Mortality 1 42 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.32, 3.83]
1.2 Stricture 1 33 Risk Ratio (M-H, Fixed, 95% CI) 7.20 [0.97, 53.36]
1.3 Bowel perforation 1 42 Risk Ratio (M-H, Fixed, 95% CI) 2.20 [0.45, 10.74]

2 Parenteral ampicillin and gentamicin vs parenteral ampicillin, gentamicin and enteral gentamicin

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Mortality 1 20 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.05, 4.67]
2.2 Stricture 1 20 Risk Ratio (M-H, Fixed, 95% CI) 0.20 [0.01, 3.70]
2.3 Bowel perforation 1 20 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.05, 4.67]

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Sources of support

Internal sources

  • No sources of support provided.

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA
  • Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

This review is published as a Cochrane review in The Cochrane Library, Issue 8, 2012 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.