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Antistaphylococcal immunoglobulins to prevent staphylococcal infection in very low birth weight infants

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Authors

Prakeshkumar S Shah1, David A Kaufman2

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


1Department of Paediatrics and Department of Health Policy, Management and Evaluation, Rm 775A, University of Toronto, Toronto, Canada [top]
2Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia, USA [top]

Citation example: Shah PS, Kaufman DA. Antistaphylococcal immunoglobulins to prevent staphylococcal infection in very low birth weight infants. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD006449. DOI: 10.1002/14651858.CD006449.pub2.

Contact person

Prakeshkumar S Shah

Department of Paediatrics and Department of Health Policy, Management and Evaluation, Rm 775A
University of Toronto
600 University Avenue
Toronto Ontario M5G 1XB
Canada

E-mail: pshah@mtsinai.on.ca

Dates

Assessed as Up-to-date: 09 February 2009
Date of Search: 09 February 2009
Next Stage Expected: 09 February 2011
Protocol First Published: Issue 2, 2007
Review First Published: Issue 2, 2009
Last Citation Issue: Issue 2, 2009

What's new

Date / Event Description

History

Date / Event Description
09 January 2008
Amended

Converted to new review format.

Abstract

Background

Nosocomial infection is a major problem affecting the immediate health and long-term outcome of preterm and very low birth weight neonates. More than half of these infections are caused by staphylococci. Various type specific antibodies targeted at different antigenic markers of Staphylococcus have been developed and have shown promise in animal studies.

Objectives

To evaluate the efficacy and safety of antistaphylococcal immunoglobulins in the prevention of Staphylococcal infection in very low birth weight infants.

Search methods

Medline, Embase, CINAHL, Cochrane Central Register of Controlled Trials (The Cochrane Library) were searched from their inception until February 2009. In addition, abstracts of major pediatric meetings of last seven years were searched.

Selection criteria

Randomized and quasi-randomized studies of antistaphylococcal immunoglobulins for the prevention of staphylococcal infections in preterm or very low birth weight neonates were reviewed by both authors for their eligibility for inclusion. Studies of any dose and/or route were included. Quality of studies was evaluated using criteria of masking of randomization, masking of intervention, completeness of follow-up and masking of outcome assessment by both review authors.

Data collection and analysis

Data from the primary author were obtained where published data provided inadequate information for the review or where relevant data could not be abstracted. Data were abstracted independently by both review authors. Statistical methods included calculation of relative risk (RR), risk difference (RD), number needed to treat (NNT) and weighted mean difference (WMD) when appropriate. Ninety five percent confidence intervals (CI) was used for these estimates of treatment effects. A fixed effect model was used for meta-analyses.

Results

Three eligible studies were included (two studies of INH A-21 and one study of Altastaph involving a total of 2, 701 neonates). Three reports of Pagibaximab were published as abstracts and will be considered for inclusion when further information is obtained. There were no significant differences noted in the risk of Staphylococcal infection between INH A-21 vs. placebo (typical RR 1.07, 95% CI 0.94, 1.22) or Altastaph vs. placebo (RR 0.86, 95% CI 0.32, 2.28); the risk of other bacterial infection between INH A-21 vs. placebo (typical RR 0.87, 95% CI 0.72, 1.06) or Altastaph vs. placebo (RR 0.93, 95% CI 0.53, 1.64); or the risk of any infection between INH A-21 vs. placebo (RR 1.00, 95% CI 0.91, 1.09) or Altastaph vs. placebo (RR 0.93, 95% CI 0.54, 1.62).There was no significant difference in the incidence of relevant secondary outcomes (chronic lung disease at 28 days, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity or duration of antibiotic and vancomycin use).

Authors' conclusions

Antistaphylococcal immunoglobulins (INH A-21 and Altastaph) are not recommended for prevention of staphylococcal infections in preterm or VLBW neonates. Further research to investigate the efficacy of other products such as Pagibaximab is needed.

Plain language summary

Antistaphylococcal immunoglobulins to prevent staphylococcal infection in very low birth weight infants

Babies born at earlier gestation and who are born with low birth weight are at significant risk of sepsis. This is in part due to the immaturity of the immune defence system, including low levels of immunoglobulins. Researchers attempted to boost the immune system by artificially providing antibodies specific to the most common bacteria causing such infections. Three studies reviewed here (two of which are pilot studies) revealed neither benefit nor risk associated with the preventative use of specific antibodies to common bacterial infections.

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Background

Nosocomial infections are reported in approximately 20 - 25% of very low birth weight neonates (Stoll 2002). The incidence is higher at lower gestational age and lower birth weights, reaching 50% in infants with birth weight < 750 g. Approximately half of these infections are caused by Staphylococcus Epidermidis and another 5 - 8% of infections are caused by Staphylococcus Aureus (Stoll 2002). Reduced amount of fetal antibodies, structural limitations reducing affinity of these antibodies to antigens, and functional deficiency of B and T lymphocytes have been proposed as mechanisms for compromised host defenses in the neonate (Splawski 1991; Schroeder 1995). Presence of central venous catheters, multiple intravenous attempts, poor skin integrity and the use of total parenteral nutrition including lipids are considered significant predisposing factors (Stoll 2002). The systemic inflammatory response secondary to infection may increase the risk of death and severe neurological handicap (Gray 1995; Adams-Chapman 2006; Stoll 2004). Sepsis is associated with increased length of stay, severe intraventricular hemorrhage, periventricular leukomalacia, neurodevelopmental impairment, chronic lung disease, increased number of days on ventilator support and increased cost to health care systems (Fanaroff 1998; Graham 2004; Stoll 2004; Stoll 2002).

Practices that have shown to reduce nosocomial infections include appropriate hand hygiene, nutrition, skin care, vascular access care and improving the "culture" of intensive care (Horbar 2001). Other strategies to reduce infection including administration of prophylactic antibiotics, antifungal agents, colony stimulating factors, immunoglobulin and topical emollient ointments have met with variable success (Kaufman 2004; Banerjea 2002; Conner 2004). Multiple clinical trials have evaluated the role of pooled generic human immunoglobulins in the prevention and treatment of nosocomial infections. A systematic review of generic immunoglobulin administration to prevent infections demonstrated only a 3% reduction in the incidence of infections without any significant change in mortality (Ohlsson 2004; Ohlsson 2004a). This may be due to the low titre of type specific antibodies (Schroeder 1995; Splawski 1991; Kaufman 2006) and variable activity of these preparations against the common infective agent Staphylococcus Epidermidis (Weisman 2004). This concern is supported by "batch to batch" variation in the amount of antibodies against Staphylococcus Epidermidis (Weisman 1994).

Recently, various type specific antibodies targeted at different antigenic markers of Staphylococcus have been developed and have shown promise in animal studies and phase one studies (Kaufman 2006; Patti 2005). These include Altastaph (antibody against capsular polysaccharide antigen type 5 and 8), Staphvax (Staphylococcus polysaccharide conjugate vaccine), BSYX-A110 (anti-lipoteichoic acid monoclonal antibody), Veronate or INH-A21 (antibody against "microbial surface components recognizing adhesive matrix molecules" [MSCRAMMS]), and Aurexis (monoclonal antibody to clumping factorA) (Patti 2005; Kaufman 2006). In a neonatal rat model, Veronate was shown to increase phagocytic activity and had both prophylactic and therapeutic effects (Vernachio 2006). Veronate was well tolerated and had a safety profile similar to generic immunoglobulin (Capparelli 2005). Phase 1 studies of Veronate demonstrated increased antibody titre in human recipients (Capparelli 2005). However, these preparations are also likely to have side effects similar to those of generic immunoglobulin, including allergic reactions, potential for transmission of blood-borne infections, and infusion related side effects due to the their large volume (Kaufman 2006; Singh-Grewal 2006). These side effects could potentially contribute to increased incidence of intracranial hemorrhage, patent ductus arteriosus, necrotizing enterocolitis and bronchopulmonary dysplasia. Additionally, in preterm and very low birth weight infants, these specific products may not be effective due to other aspects of poor innate immunologic response, such as immature white blood cells and deficient complement system (Kaufman 2006).

This review evaluates the effects of administration of organism specific antistaphylococcal immunoglobulin on preventing late-onset sepsis in very low birth weight infants or infants less than/or equal to 32 weeks gestation.

Objectives

To evaluate the efficacy and safety of antistaphylococcal immunoglobulins in the prevention of Staphylococcal infection in preterm and very low birth weight infants.

Comparison will include:

  1. Any antistaphylococcal immunoglobulin compared to placebo or no treatment
  2. Different types of antistaphylococcal immunoglobulins compared to placebo or no treatment
  3. One type of antistaphylococcal immunoglobulin compared to another type of antistaphylococcal immunoglobulin.

Within each category subgroup analyses are planned according to birth weight (a) among extremely low birth weight infants (< 1000 g) and (b) different types of immunoglobulins.

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Methods

Criteria for considering studies for this review

Types of studies

Randomized or quasi-randomized controlled trials of any type of antistaphylococcal immunoglobulin vs. placebo or no intervention for prevention of Staphylococcal infection in very low birth weight infants were included. Cluster trials were not included. Studies reporting on any primary or secondary outcomes were included.

Types of participants

Very low birth weight (< 1500 g) infants who received placebo, no intervention or antistaphylococcal immunoglobulins before 28 days of age. Only studies in which subjects received antistaphylococcal immunoglobulin at the time when they were clinically deemed free of infection were included. If the study enrolled patients based on gestational age alone, we included only patients less than/or equal to 32 weeks gestational age.

Types of interventions

Antistaphylococcal immunoglobulins are defined as immunoglobulins with enriched activity against one of the antigenic component of the organism Staphylococcus. Studies of antistaphylococcal immunoglobulin (of any type) used for the prevention of infection were included. Any route of administration of antistaphylococcal immunoglobulin (intravenous, intramuscular, subcutaneous or oral) was considered. Studies of any duration of administration were considered. Eligible control interventions included placebo, no treatment or another type of antistaphylococcal immunoglobulin. Any study in which participants received antistaphylococcal immunoglobulins for therapeutic purpose was not included.

Types of outcome measures

Primary outcomes:
  1. Incidence of Staphylococcal infections after intervention (clinical signs of infection and isolation of Staphylococci from either blood, CSF, urine or other sterile body sites)
  2. Incidence of other bacterial infection after intervention (clinical signs of infection and isolation of other bacteria from either blood, CSF, urine or other sterile body sites)
  3. Incidence of any infection after intervention (clinical signs of infection and isolation of bacteria/fungi from either blood, CSF, urine or other sterile body sites)
  4. Mortality prior to discharge from NICU
    1. Infection related mortality
    2. All cause mortality

All primary outcomes will be measured until discharge from NICU.

Secondary outcomes:
  1. Chronic lung disease (defined as oxygen requirement at 36 weeks postmenstrual age [ Shennan 1988])
  2. Patent ductus arteriosus (PDA) (clinically diagnosed with or without echocardiogram)
    1. PDA treated medically
    2. PDA treated surgically
  3. Necrotizing enterocolitis (NEC) according to Bell 1978 classification
    1. Stage 1 NEC
    2. Stage 2 NEC
    3. Stage 3 NEC
  4. Intraventricular hemorrhage (according to Papile 1978 classification)
    1. Any grade of intraventricular hemorrhage
    2. Grade 3 or grade 4 intraventricular hemorrhage
  5. Periventricular leukomalacia (PVL)
  6. Retinopathy of prematurity (ROP)
    1. Any stage of retinopathy of prematurity
    2. Stage 3 or 4 retinopathy of prematurity
  7. Length of hospitalization (days)
  8. Neurodevelopmental disability at 18 - 24 months (including cerebral palsy, cognitive impairment, deafness and blindness)
  9. Change in the titre of antistaphylococcal antibody levels (as reported by authors)
  10. Incidences of allergic reaction (skin rash, anaphylaxis)
  11. Incidence of transmission of blood borne disease (cytomegalovirus infection, hepatitis B infection, HIV infection)
  12. Duration of any antibiotic use prior to discharge (days)
  13. Duration of Vancomycin use prior to discharge (days)
  14. Clinically important adverse effects reported by authors (pulmonary edema, hypertension, hypoglycemia)
  15. Any clinically important outcome or adverse effects reported by authors (not pre-specified)

Search methods for identification of studies

As per Cochrane Neonatal Review Group search strategy:

MEDLINE was searched (1966 to February 2009) using the following terms which will be combined by "AND".

Population: Infant-Newborn (MeSH) OR Infant-premature (MeSH) OR Infant, Low Birth Weight (MeSH) OR Infant, Very Low Birth Weight (MeSH) OR Infant, Small for Gestational Age (MeSH) OR Infant, Premature, Disease (MeSH) OR Infant, Newborn, Diseases (MeSH) OR newborn (text word) OR infant (text word) OR neonate (text word)
Intervention: Immunoglobulins, intravenous (MeSH); Intravenous immunoglobulins (MeSH); Intravenous immune globulin (MeSH); Immune globulin, intravenous (MeSH) Immunologic factors (MeSH); Immunological factors (MeSH); Factors, immunologic (MeSH); Factors, immunological (MeSH)
Comparison: Clinical trials (MeSH) OR Controlled Clinical Trials (MeSH) OR Randomized Controlled Trials (MeSH) OR Random Allocation (MeSH) OR Multicenter studies (MeSH) OR Control groups (MeSH) OR Evaluation studies (MeSH)

Other databases that were searched include: EMBASE (1980 to February 2009); CINAHL (1982 to February 2009); the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4, 2008, The Cochrane Library) with appropriate terms. We searched the reference lists of identified articles. The reference lists of identified trials, abstracts from the annual meetings of the Society for Pediatric Research, American Pediatric Society and Pediatric Academic Societies published in Pediatric Research (2001 - 2007) were searched. No language restrictions were applied. Authors were contacted in the event of clarification of the data, obtaining relevant data and obtaining data on the outcomes not reported in the manuscript.

The following types of articles were excluded: letters, editorials/commentaries, reviews, lectures.

Data collection and analysis

All published articles identified as potentially relevant by the literature search were assessed for inclusion in the review by both review authors. In order to be included the trial had to meet the following criteria: 1) the study population had to be very low birth weight neonates; 2) the intervention had to be one of the specific immunoglobulin preparations against Staphylococcal infections; 3) the study had to be a randomized or quasi randomized controlled trial and 4) one or more primary or secondary outcome measures have been reported.

Quality of included trials were evaluated independently by both review authors using the following criteria:

  1. Masking of randomization
  2. Masking of intervention
  3. Completeness of follow-up
  4. Masking of outcome assessment

The possible answers to these questions could be: yes, no and can't tell.

Data from the primary author were obtained where published data provided inadequate information for the review or where relevant data could not be abstracted. Retrieved articles were assessed and data were abstracted independently by both review authors.

Statistical methods included calculation of relative risk (RR), risk difference (RD), number needed to treat (NNT) and weighted mean difference (WMD) when appropriate. Ninety five percent confidence intervals (CI) was used for these estimates of treatment effects. A fixed effect model was used for meta-analyses. Tests for between study heterogeneity including the I-squared (I2) test was applied.

Comparison included:

  1. Any antistaphylococcal immunoglobulin preparations vs. placebo or no treatment
  2. Different types of antistaphylococcal immunoglobulin preparations vs. placebo or no treatment
  3. One type of antistaphylococcal immunoglobulin vs. another type of antistaphylococcal immunoglobulin preparation. Within each category subgroup, analyses are planned according to birth weight
    1. among extremely low birth weight infants (< 1000 g)
    2. different types of immunoglobulin preparations

It is likely that these immunoglobulin preparations may have differential function depending upon their specificity against particular antigens.

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Results

Description of studies

A total of six reports eligible for inclusion were identified. Three reports have been published in an abstract form only. The authors of the three abstracts indicated that two studies have been submitted for publication and third would be submitted soon. As no further information other than what was available in the abstracts was provided, we have not abstracted the details of studies and have placed these studies in the section of studies awaiting further assessment (Weisman 2003 [trial details ClinicalTrials.gov Identifier: NCT00631878]; Weisman 2004; Thackray 2006).

A total of three reports are currently eligible for inclusion in this review (Benjamin 2006; Bloom 2005; DeJonge 2007). Two studies (Bloom 2005; DeJonge 2007) used pooled generic antistaphylococcal immunoglobulin (INH-A21) and the third study (Benjamin 2006) used antibody against type 5 and type 8 capsular polysachraide antigen (Altastaph). Clinical details regarding the participants, interventions and outcomes are given in the table "Characteristics of Included Studies" and are detailed below. Two studies (Capparelli 2005; Mandy 2000) were excluded from the review and the reason for exclusion are reported in the table “Characteristics of Excluded Studies”.

Benjamin 2006 compared the effects of solution of IgG containing high concentrations of type 5 and type 8 capsular polysaccharide antigens of staphylococcal aureus (Altastaph) to placebo. This was a randomized controlled trial of 206 VLBW neonates from 18 NICUs. The infants were randomized to two groups: Group 1: received up to two doses of 1000 mg/kg (20 ml/kg) on study days 1 and 14; Group 2: received placebo in the form of 0.45% saline at similar volume and interval. All infusions were administered over 3 - 5 hours. All patients were followed for up to 28 days after second infusion or until discharge from nursery or death. The primary outcome was safety as assessed by proportion of neonates with adverse events and serious adverse events including mortality, hypoglycemia, and hypertension. Secondary outcomes included invasive Staphylococcal aureus infection (positive culture from sterile body fluid), definitive coagulase negative staphylococcal (CoNS) infection (two positive cultures on the same day or three or more positive cultures in less than/or equal to 5 days), probable CoNS infection (two positive cultures in less than/or equal to 5 days) and possible CoNS infection (one positive culture from sterile body fluid or positive cultures separated by > 5 days). All patients were monitored for potential side effects (hypertension, hypoglycemia or glucose instability, respiratory compromise, discontinuation of infusion due to adverse effects) and common neonatal morbidities (PDA, NEC or gastrointestinal perforation).

Bloom 2005 compared the effects donor-selected antistaphylococcal human immunoglobulin INH-A21 (Veronate®) to placebo in a group sequential dose ranging randomized study. This was a randomized controlled trial of 512 neonates between 501 to 1250g birth weight. Of these 512 neonates, 505 infants received at least one dose of study medication. The infants were randomized to four groups: Group 1: received up to four doses of 250 mg/kg/dose of INH-A21 on study days 1, 8, 22 and 36 provided intravenous access was available; Group 2: received up to four doses of 500 mg/kg/dose of INH-A21 on study days 1, 8, 22 and 36 provided intravenous access was available; Group 3: received up to four doses of 750 mg/kg/dose of INH-A21 on study days 1, 8, 22 and 36 provided intravenous access was available; Group 4: received placebo in the form of 0.45% saline at similar dose and interval. The volume for all doses was 15 ml/kg/dose. All infusions were administered according to dose escalation protocol. All patients were followed for up to 70 days after admission or until discharge home or to another institution or death. Investigators assessed at protocol-defined intervals efficacy and futility boundaries set by group-sequential bounds. It was planned that if a treatment effect of an arm crossed the futility boundary, randomization to that arm would stop and the remaining patients were to be enrolled in the subsequent treatment arms. This resulted in imbalance. For the purpose of this review, data from all three intervention groups were combined as the treatment group. The primary outcome was incidences of adverse events and serious adverse events and proportion of neonates with late-onset sepsis. Sepsis was diagnosed when, in addition to clinical features, one positive culture was identified from usually sterile culture sites. However, for coagulase negative staphylococcal sepsis, positive culture from two sites obtained within 72 hours was required. Probable sepsis was diagnosed when only one positive culture was identified and infant received > 4 days of antibiotics. All patients were monitored for potential side effects and common neonatal morbidities. These included anemia, hyperbilirubinemia, PDA, NEC, ROP, IVH, PVL, hydrocephalus and spontaneous intestinal perforation. Data on certain patient characteristics and outcomes (gestational age, birth weight, number of infants with culture proven bacterial infection, chronic lung disease at 28 days, incidences of medically and surgically treated PDA, incidences of stage 1, 2 and 3 NEC, grade 3 or 4 IVH, stage 3 or 4 ROP, incidence of ROP surgery, duration of antibiotic use, duration of vancomycin use and incidences of pulmonary edema, hypertension and hypoglycemia) were obtained by contacting Veronate study group at Inhibitex Inc.

DeJonge 2007 compared the effect of donor-selected antistaphylococcal human immunoglobulin INH-A21 (Veronate®) to placebo. This was a randomized controlled trial of 1983 VLBW neonates from 95 NICUs. The infants were randomized to 2 groups: Group 1: received up to four doses of 1.5 ml/kg (750 mg/kg) on study days 1, 3, 8 and 15 provided intravenous access was available; Group 2: received placebo in the form of 0.45% saline at similar volume and interval. All infusions were administered according to dose escalation protocol. All patients were followed for up to 70 days after admission or until discharge home or to another institution or death. The primary outcome was proportion of neonates with late-onset sepsis due to staphylococcal aureus. Sepsis was diagnosed when, in addition to clinical features, one positive culture was identified from usually sterile culture sites. However, for CoNS sepsis positive culture from two sites obtained within 24 hours was required. Probable sepsis was diagnosed when only one positive culture was identified and the infant received > 4 days of antibiotics. All patients were monitored for potential side effects and common neonatal morbidities. These included anemia, hyperbilirubinemia, PDA, NEC, ROP, IVH, PVL, hydrocephalus and spontaneous intestinal perforation. Data on certain outcomes (number of infants with culture proven bacterial infection, chronic lung disease at 28 days, incidences of medically and surgically treated PDA, incidences of stage 2 and 3 NEC, grade 3 or 4 IVH, stage 3 or 4 ROP, incidence of ROP surgery, duration of antibiotic use, duration of vancomycin use and incidences of pulmonary edema, hypertension and hypoglycemia) were obtained by contacting the Veronate study group at Inhibitex Inc.

Risk of bias in included studies

The methodological qualities of the reviewed studies are given in the table "Characteristics of Included Studies." The information was extracted from the published paper and by contacting investigators. All three included studies were of high methodological quality.

Benjamin 2006: The study was described as blinded and randomized. Detailed information on methodological quality was provided by authors. The randomization was done centrally by computerized numbers. Allocation of eligible patients was concealed and placebo and study medication were identical in appearance and volume. Investigators were not aware of randomization. Masking of outcome assessment was maintained and the follow-up was complete. Patients were followed up for 42 days or discharge/transfer from NICU or mortality. This may have resulted in incomplete data for certain long-term outcomes.

Bloom 2005: The study was described as blinded and randomized. Detailed information on methodological quality was provided by authors. The randomization was done centrally by computerized numbers. Allocation of eligible patients was concealed and placebo and study medication were identical in appearances and volume and investigators were not aware of randomization. A total of 512 patients were randomized, but only 505 received at least one dose of the study medication. Authors have only reported on these 505 patients. Masking of outcome assessment was maintained. Patients were followed up for 70 days or discharge/transfer from NICU or mortality. This may have resulted in incomplete data for certain long-term outcomes.

DeJonge 2007: The study was described as blinded and randomized. Detailed information on methodological quality was provided by authors. The randomization was done centrally by computerized numbers. Allocation of eligible patients was concealed and placebo and study medication were identical in appearances and volume and investigators were not aware of randomization. Masking of outcome assessment was maintained. Patients were followed up for 70 days or discharge/transfer from NICU or mortality. This may have resulted in incomplete data for certain long-term outcomes.

Effects of interventions

Two chemically and immunogenically different products have been compared in these three studies (two studies of INH A-21 and one study of Altastaph). Due to differences in the products, differences in their mechanism of action, differences in the host response to the products and differences in the population studied (lower mean birth weight and longer duration of hospitalization for patients in INH A-21 studies), we have not combined data from both these products together and reported them separately.

ANTISTAPHYLOCOCCAL IMMUNOGLOBULIN VS. PLACEBO OR NO TREATMENT (COMPARISON 1):

Primary outcomes:

All three studies reported results of infection as infection rate during the study period in their studies. None of the studies reported the outcome as infection/days of hospitalization or time to infection.

Incidence of Staphylococcal infections after intervention (Outcome 1.1):

Any probable or definite CONS sepsis as defined in the original studies were included. When INH A-21 was compared to placebo there was no statistically significant difference in the risk of Staphylococcal infections (typical RR 1.07, 95% CI 0.94, 1.22). When Altastaph was compared to placebo there was no statistically significant difference in the risk of Staphylococcal infections (RR 0.86, 95% CI 0.32, 2.28).

Incidence of other bacterial infection after intervention (Outcome 1.2):

When INH A-21 was compared to placebo there was no statistically significant difference in the risk of other bacterial infections (typical RR 0.87, 95% CI 0.72, 1.06). When Altastaph was compared to placebo there was no statistically significant difference in the risk of other bacterial infections (RR 0.93, 95% CI 0.53, 1.64).

Incidence of any infection after intervention (Outcome 1.3):

This outcome includes bacterial, fungal or viral infections. When INH A-21 was compared to placebo there was no statistically significant difference in the risk of any infection (typical RR 1.00, 95% CI 0.91, 1.09). When Altastaph was compared to placebo there was no statistically significant difference in the risk of any infection (RR 0.93, 95% CI 0.54, 1.62).

Mortality prior to discharge from NICU:
a. Infection related mortality (Outcome 1.4):

When INH A-21 was compared to placebo there was no statistically significant difference in the risk of mortality due to infections (RR 2.73, 95% CI 0.33, 22.50).

b.All cause mortality (Outcomes 1.5.1 and 1.5.2):

When INH A-21 was compared to placebo there was no statistically significant difference in the risk of mortality due to any cause (typical RR 0.80, 95% CI 0.59, 1.08). When Altastaph was compared to placebo there was no statistically significant difference in the risk of mortality due to any cause (RR 1.31, 95% CI 0.30, 5.70).

Secondary outcomes:
Chronic lung disease (Outcome 1.6):

Data on chronic lung disease were available from investigators of INH A-21 at 28 days only and not at 36 weeks postmenstrual age as defined in the current review. There was no statistically significant difference in the risk of chronic lung disease at 28 days between INH A-21 vs. placebo (typical RR 0.99, 95% CI 0.95, 1.04).

Patent ductus arteriosus (Outcome 1.7):

Between group treated with INH A-21 vs. group treated with placebo, there was no statistically significant difference in the risk of patent ductus arteriosus treated medically (typical RR 1.06, 95% CI 0.94, 1.19), patent ductus arteriosus treated surgically (typical RR 1.01, 95% CI 0.83, 1.22), patent ductus arteriosus treated medically or surgically (typical RR 1.04, 95% CI 0.96, 1.14). Between group treated with Altastaph vs. group treated with placebo there was no statistically significant difference in the risk of patent ductus arteriosus (RR 0.98, 95% CI 0.0.46, 2.08).

Necrotizing enterocolitis (Outcome 1.8):

Between group treated with INH A-21 vs. group treated with placebo, there was no statistically significant difference in the risk of stage 1 NEC (RR 0.63, 95% CI 0.26, 1.53), stage 2 NEC (typical RR 1.00, 95% CI 0.73, 1.38) or stage 3 NEC (typical RR 0.80, 95% CI 0.46, 1.40). Between group treated with Altastaph vs. group treated with placebo there was no statistically significant difference in the risk of NEC or gastrointestinal perforation (combined outcome reported not pre-specified in the protocol of this review) (RR 1.37, 95% CI 0.45, 4.19).

Intraventricular hemorrhage (Outcome 1.9):
a.Any grade of intraventricular hemorrhage (Outcomes 1.1.1 and 1.1.2):

When INH A-21 was compared to placebo there was no statistically significant difference in the risk of any grade of intraventricular hemorrhage (typical RR 0.93, 95% CI 0.83, 1.04). When Altastaph was compared to placebo there was no statistically significant difference in the risk of any grade of intraventricular hemorrhage (RR 0.75, 95% CI 0.35, 1.25).

b.Grade 3 or grade 4 intraventricular hemorrhage (Outcome 1.9.3):

When INH A-21 was compared to placebo there was no statistically significant difference in the risk of grade 3 or 4 intraventricular hemorrhage (typical RR 0.98, 95% CI 0.77, 1.25).

Periventricular leukomalacia (Outcome 1.10):

When INH A-21 was compared to placebo there was no statistically significant difference in the risk of periventricular leukomalacia (typical RR 1.11, 95% CI 0.74, 1.65).

Retinopathy of prematurity (Outcome 1.11):
a.Any stage of retinopathy of prematurity (Outcome 1.11.1):

When INH A-21 was compared to placebo there was no statistically significant difference in the risk of any stage of retinopathy of prematurity (typical RR 1.00, 95% CI 0.91, 1.10).

b.Stage 3 or 4 retinopathy of prematurity (Outcome 1.11.2):

When INH A-21 was compared to placebo there was no statistically significant difference in the risk of Stage 3 or 4 retinopathy prematurity (typical RR 0.81, 95% CI 0.59, 1.10).

Length of hospitalization (in days):

None of the studies has reported on this outcome.

Neurodevelopmental disability at 18 - 24 months:

None of the studies has reported on this outcome.

Change in the titre of antistaphylococcal antibody levels:

Benjamin 2006 reported on antibody titre and showed a significant increase in the antibody titre through out the study period in the Altastaph group and no detectable antibody levels in the placebo group.

Incidences of allergic reaction (skin rash, anaphylaxis) (Outcome 1.14):

There was no allergic reactions noted in either group in studies by Bloom 2005 and DeJonge 2007).

Incidence of transmission of blood borne disease:

None of the studies has reported on this outcome.

Duration of any antibiotic use prior to discharge (days) (Outcome 1.12):

When INH A-21 was compared to placebo there was no statistically significant difference in the duration of antibiotic use (WMD 0.02 days, 95% CI -1.15 days, 1.19 days).

Duration of Vancomycin use prior to discharge (days) (Outcome 1.13):

When INH A-21 was compared to placebo there was no statistically significant difference in the duration of Vancomycin use (WMD 0.05 days, 95% CI -0.68 days, 0.78 days).

Clinically important adverse effects reported by authors:
a. Pulmonary edema (Outcome 1.15):

When INH A-21 was compared to placebo there was no statistically significant difference in the risk of pulmonary edema (typical RR 1.46, 95% CI 0.94, 2.26).

b. Hypertension (Outcome 1.16.1 and 1.16.2):

When INH A-21 was compared to placebo there was no statistically significant difference in the risk of hypertension (typical RR 1.16, 95% CI 0.84, 1.61). When Altastaph was compared to placebo there was no statistically significant difference in the risk of hypertension (RR 1.47, 95% CI 0.63, 3.45).

c. Hypoglycemia (Outcome 1.17.1 and 1.17.2):

When INH A-21 was compared to placebo there was no statistically significant difference in the risk of hypoglycemia (typical RR 1.15, 95% CI 0.90, 1.47). When Altastaph was compared to placebo there was no statistically significant difference in the risk of hypoglycemia (RR 1.40, 95% CI 0.55, 3.54).

Any clinically important outcome or adverse effects reported by authors (not pre-specified) (Outcome 1.18):
a. Discontinuation of study medication due to adverse events (Outcome 1.18.1 and 1.18.2):

When INH A-21 was compared to placebo there was no statistically significant difference in the risk of discontinuation of study medication due to adverse events (RR 0.68, 95% CI 0.25, 1.89). When Altastaph was compared to placebo there was no statistically significant difference in the risk of discontinuation of study medication due to adverse events (RR 1.18, 95% CI 0.37, 3.74).

b. Serious adverse events (Outcomes 1.18.3 and 1.18.4):

When INH A-21 was compared to placebo there was no statistically significant difference in the risk of serious adverse events (RR 1.04, 95% CI 0.72, 1.51). When Altastaph was compared to placebo there was no statistically significant difference in the risk of serious adverse events (RR 1.18, 95% CI 0.37, 3.74).

Discussion

Three different pharmacological agents of antistaphylococcal immunoglobulins have been tested for prevention of staphylococcal infections in VLBW neonates. Results of two of these agents (INH A-21 and Altastaph) are published. The results of the trials of Pagibaximab have been published as abstracts and are awaiting full publication. Of the three studies included in this review, two were Phase II trials (one of INH A-21 and one trial of Altastaph) and one for INH A21 was a Phase III trial of adequate sample size. Analyses of these agents failed to demonstrate any significant difference in any of the primary or secondary outcomes of this review. There was no reduction in the risk of infections (staphylococcal or non-staphylococcal), mortality or important secondary outcomes related to VLBW infants. Only preliminary reports of Pagibaximab (Thackray 2006; Weisman 2003; Weisman 2004) are available and based on these results, a plan for phase II/III trials is underway (Weisman 2007).

Efforts have been made to boost the level of circulating immunoglobulins in preterm and very low birth weight infants due to the low levels of IgG antibodies at birth and the anticipated decline of immunoglobulins in the first 4 - 8 weeks after birth. Standard IVIG reduced sepsis by 3% without any other benefits. Our review failed to identify benefits of specific hyperimmune globulins against staphylococci. However, these results are from two preliminary trials (one of dose finding and another of establishing safety) and only one phase three study. The products studied are also quite dissimilar in their mechanisms of action. Studies of INH A-21 (Bloom 2005; DeJonge 2007) enrolled smaller and more immature neonates and followed them for a longer period of time (72 days) compared to study of Altastaph (Benjamin 2006), where infants were more mature and studied for 42 days. This may have an important effect on the results as the risk of infection is greater in smaller more immature infants and the chance of finding an infection increases the longer the subjects are followed. None of the studies reported the incidence of infection as a function of time (in the unit of per 1000 admissions or as per 1000 days of study or hospitalization) so one could not directly compare results in a standardized fashion. It is also unclear from the description of studies whether a single neonate who had multiple infections were counted more than once. Suggested definition of definitive infection include signs of sepsis and two positive cultures obtained from blood or normally sterile body fluids within 24 hours. This is not consistent among included studies and may have affected results. These are important features that need to be understood in the context of future clinical trials.

Important components of the immune system in addition to opsonizing antibody include complement, phagocyte signalling and function, and cytokines.Antibodies interact with complement and phagocytic cells and in preterm infants and complement levels and toll-like receptors are lower compared to full term infants and adults (Strunk 2007). Phagocytic cells including neutrophils, monocytes and macrophages have diminished function of chemotaxis, adherence, activation, phagocytosis, the oxidative burst and release of antimicrobial products in the phagosome. These functions may be critical after interaction with antibody and complement and may partially explain the lack of efficacy in these antibody products in the preterm infant. As these components work in concert leading to phagocytosis and lysis of microbes, successful preventative therapies in an immunocompromised host may involve more than an antibody approach.

From these studies some observations can be made.While antibody levels are low during the time period, the underdeveloped immune system of the preterm infant may need more than one component to aid its defense against systemic infection.It is unknown whether different antibodies or a combination of these and other immune factors would be efficacious in the prevention of staphylococcal infections. All these studies lacked appropriate animal models similar to the preterm host.None of the antibody preparations were tested in immunocompromised animal models. Research in this area would help to answer unknown questions regarding efficacy of specific antibody preparations prior to the onset of further human clinical trials.In addition, the role of cytokines, colony stimulating factors, complement and other components of the immune system working in concert with antibodies in attenuating colonization, proliferation and invasive infection of these micro-organisms in the preterm infant can be ascertained.

Based on findings of this review, we can conclude that antistaphylococcal immunoglobulins in the forms of INH A-21 and Altastaph revealed no significant effects, either benefits or risks, when used for prevention of staphylococcal infections in VLBW preterm neonates.

Authors' conclusions

Implications for practice

This review of two preliminary trials and one definitive trials identified no significant effects, either benefits or risks, of the antistaphylococcal immunoglobulin preparations INH A-21 or Altastaph, for the prevention of staphylococcal infections in very low birth-weight infants.

Implications for research

Further research to investigate the efficacy of other products such as Pagibaximab may reveal efficacy and safety profile appropriate for neonates. Preterm or immunocompromised animal models are needed to evaluate efficacy of new products or combination therapies. Additionally, adjunctive therapy augmenting neutrophil and monocyte function may be needed for antibody preparations to have efficacy in preterm infants.

Acknowledgements

We would like to thank investigator group at Inhibitex Corp. for providing results of their studies for certain outcomes.

Contributions of authors

P Shah
Writing of the protocol and review
Editing of the protocol and review

Data collection and data check

D Kaufman
Editing and review of the protocol and review

Data collection and data check

Declarations of interest

Dr Kaufman was investigator for Bloom 2005; Benjamin 2006 and DeJonge 2007 studies.

Differences between protocol and review

Two chemically and immunogenically different products have been compared in three included studies of this review (two studies of INH A-21 and one study of Altastaph). Due to the variability in the products, their mechanisms of action and difference in the host responses to them, and differences in the population studied (lower mean birth weight and longer duration of hospitalization for patients in INH A-21 studies) we have not combined data from both these products together as mentioned in the protocol but we have reported them separately.

Additional tables

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Benjamin 2006

Methods

Randomized controlled trial.

Masking of randomization - yes

Masking of intervention - yes

Masking of outcome assessment - yes

Completeness of follow up - yes

Participants

206 VLBW neonates from 18 NICUs.

Group 1: Median (SD) BW 1018 (269) grams

Male: Female - 57:57

Group 2: Median (SD) BW 1055 (268) grams

Male: Female - 56:56

Interventions

Group 1: received up to two doses of 1000 mg/Kg (20 ml/Kg) on study days 1 and 14; Group 2: received placebo in the form of 0.45% saline at similar dose and interval.

All infusions were administered over 3-5 hours.

Outcomes

Safety as assessed by proportion of neonates with adverse events and serious adverse events including mortality, hypoglycemia, and hypertension, Discontinuation of infusion due to adverse effects, Respiratory compromise, hypoglycemia, hypertension, glucose instability, gastrointestinal perforation were reported. efficacy outcomes included Invasive Staphylococcal aureus infection, Definitive CoNS infection,

Probable CoNS infection and Possible CoNS infection.

Notes

All patients were followed for up to 28 days after second infusion or until discharge from nursery or death.

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes
Allocation concealment? Yes
Blinding? Yes
Incomplete outcome data addressed? Unclear

Data for only 28 days after second infusion provided.

Free of selective reporting? Yes
Free of other bias? Yes

Bloom 2005

Methods

Randomized controlled trial

  1. Masking of randomization - yes
  2. Masking of intervention - yes
  3. Masking of outcome assessment - yes
  4. Completeness of follow up ? no
  5. Intention to treat analyses: No
Participants

A total of 512 neonates < 1250g BW were randomized from 20 NICUs.

505 patients received one dose of study medication

Group 1: Mean (SD) BW 920 (202) grams; Mean (SD) GA 26.9 (2.0) weeks; Male: Female - 47:47

Group 2: Mean (SD) BW 889 (204) grams; Mean (SD) GA 26.6 (2.0) weeks; Male: Female - 49:47

Group 3: Mean (SD) BW 909 (179) grams; Mean (SD) GA 27.1 (2.4) weeks; Male: Female - 85:72

Group 4: Mean (SD) BW 900 (190) grams; Mean (SD) GA 26.9 (2.0) weeks; Male: Female - 71:87

Interventions

Group 1: received up to four doses of 250 mg/kg/dose of INH-A21

Group 2: received up to four doses of 500 mg/kg/dose of INH-A21

Group 3: received up to four doses of 750 mg/kg/dose of INH-A21

Group 4: received placebo in the form of 0.45% saline at similar dose and interval

All study medications were given on study days 1, 8, 22 and 36 provided intravenous access was available. The volume for all doses was 15 ml/kg/dose. All infusions were administered according to dose escalation protocol.

Outcomes

Data on outcomes reported in the publication were Sepsis, CoNS sepsis, Probable CoNS sepsis, Anemia, Hyperbilirubinemia, PDA, NEC, ROP, IVH, PVL, Hydrocephalus, and Spontaneous intestinal perforation.

Data on outcomes of culture proven bacterial infection, Chronic lung disease at 28 days, Incidences of medically and surgically treated PDA, Incidences of stage 1, 2 and 3 NEC, Grade 3 or 4 IVH, Stage 3 or 4 ROP, Incidence of ROP surgery, Duration of antibiotic use Duration of vancomycin use, Incidences of pulmonary edema, hypertension and hypoglycemia were obtained by contacting authors

Notes

All patients were followed for up to 70 days after admission, or until discharge home or to another institution or death.

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes
Allocation concealment? Yes
Blinding? Yes
Incomplete outcome data addressed? Unclear

Data for maximum of 70 days after randomization are provided.

Free of selective reporting? Yes
Free of other bias? Yes

DeJonge 2007

Methods

Randomized controlled trial

  1. Masking of randomization - yes
  2. Masking of intervention - yes
  3. Masking of outcome assessment - yes
  4. Completeness of follow up - yes
Participants

A total of 1983 VLBW neonates from 95 NICUs.

Group 1: Mean (SD) BW 891 (204) grams; Mean (SD) GA 26.8 (2.2) weeks; Male: Female - 487:507

Group 2: Mean (SD) BW 896 (197) grams; Mean (SD) GA 26.8 (2.2) weeks; Male: Female - 504:485

Interventions

Group 1: received up to four doses of 1.5 ml/Kg (750 mg/Kg) on study days 1, 3, 8 and 15 provided intravenous access was available;

Group 2: received placebo in the form of 0.45% saline at similar dose and interval. All infusions were administered according to dose escalation protocol.

Outcomes

Data on the outcomes reported in the publication were late-onset sepsis by staphylococcal aureus, CoNS

Probable infection, Anemia, Hyperbilirubinemia, PDA, NEC, ROP, IVH, PVL, Hydrocephalus, and Spontaneous intestinal perforation.

Data on outcomes of infants with culture proven bacterial infection, chronic lung disease at 28 days, incidences of medically and surgically treated PDA, incidences of stage 2 and 3 NEC, grade 3 or 4 IVH, stage 3 or 4 ROP, incidence of ROP surgery, duration of antibiotic use, duration of vancomycin use and incidences of pulmonary edema, hypertension, and hypoglycemia were obtained from the authors.

Notes

All patients were followed for up to 70 days after admission, or until discharge home or to another institution or death.

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes
Allocation concealment? Yes
Blinding? Yes
Incomplete outcome data addressed? Unclear

Data for maximum of 70 days after randomization are provided.

Free of selective reporting? Yes
Free of other bias? Yes
Footnotes

SD = standard deviation, BW = birth weight, GA = gestational age, PDA = patent ductus arteriosus, NEC = necrotizing enterocolitis, ROP = retinapathy of prematurity, IVH = intraventricular hemorrhage, PVL = periventricular leukomalacia, CoNS infection = Coagulase negative staphylococcal infection

Characteristics of excluded studies

Capparelli 2005

Reason for exclusion

Phase 1 open label dose escalation study

Mandy 2000

Reason for exclusion

No comparative group

Characteristics of studies awaiting classification

Thackray 2006

Methods

Phase 2 double blind randomized controlled trial

Participants

Very Low Birth Weight neonates

Interventions

Pagibaximab or placebo

Outcomes

Safety, pharmacokinetics, pharmacodynamics, clinical activity

Notes

Abstract only, authors were contacted and advised that the report was under consideration for publication, no further details were provided

Weisman 2003

Methods

Safety and pharmacokinetic study

Participants

Very Low Birth Weight neonates

Interventions

Pagibaximab

Outcomes

Safety, pharmacokinetics

Notes

Abstract only, authors were contacted and advised that the report was under consideration for publication, no further details were provided

Weisman 2004

Methods

Phase 1/2 double blind placebo controlled dose escalation study

Participants

Very Low Birth Weight neonates

Interventions

Pagibaximab

Outcomes

Safety, efficacy, immunogenicity

Notes

Abstract only, authors were contacted and advised that the report was under consideration for publication, no further details were provided

Characteristics of ongoing studies

Summary of findings tables

  • None noted.

Additional tables

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References to studies

Included studies

Benjamin 2006

Published and unpublished data

Benjamin DK, Schelonka R, White R, Holley HP, Bifano E, et al. A blinded, randomized, multicenter study of an intravenous Staphylococcus aureus immune globulin. Journal of Perinatology 2006;26:290-5.

Bloom 2005

Published and unpublished data

Bloom B, Schelonka R, Kueser T, Walker W, Jung E, Kaufman D, et al. Multicenter study to assess safety and efficacy of INH-A21, a donor-selected human staphylococcal immunoglobulin, for prevention of nosocomial infections in very low birth weight infants. The Pediatric Infectious Disease Journal 2005;24(10):858-66.

DeJonge 2007

Published and unpublished data

DeJonge M, Burchfield D, Bloom B, Duenas M, Walker W, Polak M, et al. Clinical trial of safety and efficacy of INH-A21 for the prevention of nosocomial staphylococcal bloodstream infection in premature infants. Journal of Pediatrics 2007;151:260-5.

Excluded studies

Capparelli 2005

* Capparelli EV, Bloom BT, Kueser TJ, Oelberg DG, Bifano EM, White RD, et al. Multicenter study to determine antibody concentrations and assess the safety of administration of INH-A21, a donor-selected human Staphylococcal immune globulin, in low-birth-weight infants. Antimicrobial Agents and Chemotherapy 2005;49:4121-7.

Mandy 2000

Mandy GT, Weisman LE, Horwith G, Fuller S, Fanaroff AA. Safety of a Staphylococcus Aureus (SA) Intravenous Human Immune Globulin (AltaStaph) in Very-Low-Birth-Weight (VLBW) Neonates. Pediatric Research 2000;47:4.

Studies awaiting classification

Thackray 2006

Thackray H, Lassiter H, Walsh W, Brozanski B, Steinhorn R, Dhanireddy R, et al. Phase II Randomized, Double Blind, Placebo-Controlled, Safety, Pharmacokinetics (PK), and Clinical Activity Study in Very Low Birth Weight (VLBW) Neonates of Pagibaximab, a Monoclonal Antibody for the Prevention of Staphylococcal Infection. Pediatric Research E-PAS 2006;59:3724.6.

Weisman 2003

Weisman LE, Mandy GT, Garcia-Prats JA, Nesin M, Schneider JH, Johnson KE, et al. Safety and Pharmacokinetics of a Human Chimeric Anti-Staphylococcal Monoclonal Antibody for Prevention of Coagulase Negative Staphylococcal Infection in Very Low Birth Weight Infants: Preliminary Report. Pediatric Research 2003;53.

Weisman 2004

Weisman LE, Thackray HM, Gracia-Prats JA, Nesin M, Mond J, Schneider JH, et al. Phase I/II Double Blind, Placebo Controlled, Dose Escalation, Safety and Pharmacokinetics Study in Very Low Birth Weight Neonates of BSYX-A110, an Anti-Staphylococcal Monoclonal Antibody for the Prevention of Staphylococcal Bloodstream Infections. Pediatric Research 2004;55:4.

Ongoing studies

Other references

Additional references

Adams-Chapman 2006

Adams-Chapman I, Stoll BJ. Neonatal infection and long-term neurodevelopmental outcome in the preterm infant. Current Opinion in Infectios Diseases 2006;19:290-7.

Banerjea 2002

Banerjea MC, Speer CP. The current role of colony-stimulating factors in prevention and treatment of neonatal sepsis. Seminars in Neonatology 2002;7:335-49.

Bell 1978

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

Capparelli 2005

Capparelli EV, Bloom BT, Kueser TJ, Oelberg DG, Bifano EM, White RD, et al. Multicenter study to determine antibody concentrations and assess the safety of administration of INH-A21, a donor-selected human Staphylococcal immune globulin, in low-birth-weight infants. Antimicrobial Agents and Chemotherapy 2005;49:4121-7.

Conner 2004

Conner JM, Soll RF, Edwards WH. Topical ointment for preventing infection in preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD001150. DOI: 10.1002/14651858.CD001150.pub2.

Fanaroff 1998

Fanaroff AA, Korones SB, Wright LL, Verter J, Poland RL, Bauer CR, et al. Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants. The National Institute of Child Health and Human Development Neonatal Research Network. Pediatric Infectious Disease Journal 1998;17:593-8.

Graham 2004

Graham EM, Holcroft CJ, Rai KK, Donohue PK, Allen MC. Neonatal cerebral white matter injury in preterm infants is associated with culture positive infections and only rarely with metabolic acidosis. American Journal of Obstetric and Gynecology 2004;191:1305-10.

Gray 1995

Gray JE, Richardson DK, McCormick MC, Goldmann DA. Coagulase-negative staphylococcal bacteremia among very low birth weight infants: relation to admission illness severity, resource use, and outcome. Pediatrics 1995;95:225-30.

Horbar 2001

Horbar JD, Rogowski J, Plsek PE, Delmore P, Edwards WH, Hocker J, et al. Collaborative quality improvement for neonatal intensive care. NIC/Q Project Investigators of the Vermont Oxford Network. Pediatrics 2001;107:14-22.

Kaufman 2004

Kaufman D, Fairchild KD. Clinical microbiology of bacterial and fungal sepsis in very-low-birth-weight infants. Clinical Microbiological Review 2004;17:638-80.

Kaufman 2006

Kaufman D. Veronate (Inhibitex). Current Opinion on Investigational Drugs 2006;7:172-9.

Ohlsson 2004

Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD001239. DOI: 10.1002/14651858.CD001239.pub2.

Ohlsson 2004a

Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD000361. DOI: 10.1002/14651858.CD000361.pub2.

Papile 1978

Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1, 500 gm. Journal of Pediatrics 1978;92:529-34.

Patti 2005

Patti JM. Vaccines and immunotherapy for staphylococcal infections. International Journal of Artificial Organs 2005;28:1157-62.

Schroeder 1995

Schroeder HW, Jr., Mortari F, Shiokawa S, Kirkham PM, Elgavish RA, Bertrand FE 3rd. Developmental regulation of the human antibody repertoire. Annals of New York Academy of Science 1995;764:242-60.

Shennan 1988

Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82:527-32.

Singh-Grewal 2006

Singh-Grewal D, Kemp A, Wong M. A prospective study of the immediate and delayed adverse events following intravenous immunoglobulin infusions. Archives of Disease of Childhood 2006;91:651-4.

Splawski 1991

Splawski JB, Jelinek DF, Lipsky PE. Delineation of the functional capacity of human neonatal lymphocytes. Journal of Clinical Investigations 1991;87:545-53.

Stoll 2002

Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002;110:285-91. [MEDLINE: 1]

Stoll 2004

Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. Journal of the American Medical Association 2004;292:2357-65. [MEDLINE: 1]

Strunk 2007

Strunk T, Richmond P, Simmer K, Currie A, Levy O, Burgner D. Neonatal immune responses to coagulase-negative staphylococci. Current Opinion in Infectious Diseases 2007;20(4):370-5.

Vernachio 2006

Vernachio JH, Bayer AS, Ames B, Bryant D, Prater BD, Syribeys PJ, Gorovits EL, Patti JM. Human immunoglobulin G recognizing fibrinogen-binding surface proteins is protective against both Staphylococcus aureus and Staphylococcus epidermidis infections in vivo. Antimicrobial Agents and Chemotherapy 2006;50:511-8.

Weisman 1994

Weisman LE, Cruess DF, Fischer GW. Opsonic activity of commercially available standard intravenous immunoglobulin preparations. Pediatric Infectious Disease Journal 1994;13:1122-5.

Weisman 2004

Weisman LE. Coagulase-negative staphylococcal disease: emerging therapies for the neonatal and pediatric patient. Current Opinion in Infectious Diseases 2004;17:237-41.

Weisman 2007

Weisman LE. Antibody for teh prevention of neonatal nosocomial staphylococcal infection: a review of the literature. Archives de Pediatrie 2007;14:S31-S34.

Other published versions of this review

  • None Noted.

Classification pending references

  • None Noted.

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Data and analyses

1 Antistaphylococcal immunoglobulin vs. placebo or no treatment

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Incidence of staphylococcal infection after intervention 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1.1 INH A-21 vs. placebo 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.94, 1.22]
1.1.2 Altastaph vs. placebo 1 206 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.32, 2.28]
1.2 Incidence of other bacterial infections after intervention 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.2.1 INH A-21 vs. placebo 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.72, 1.06]
1.2.2 Altastaph vs. placebo 1 206 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.53, 1.64]
1.3 Incidence of any infection after intervention 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.3.1 INH A-21 vs. placebo 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.91, 1.09]
1.3.2 Altastaph vs. placebo 1 206 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.54, 1.62]
1.4 Infection related mortality prior to discharge 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.4.1 INH A-21 vs. placebo 1 505 Risk Ratio (M-H, Fixed, 95% CI) 2.73 [0.33, 22.50]
1.5 All cause mortality prior to discharge 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.5.1 INH A-21 vs. placebo 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.59, 1.08]
1.5.2 Altastaph vs. placebo 1 206 Risk Ratio (M-H, Fixed, 95% CI) 1.31 [0.30, 5.70]
1.6 Chronic lung disease 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.6.1 Chronic lung disease at 28 days (INH A-21 vs. placebo) 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.95, 1.04]
1.7 Patent ductus arteriosus 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.7.1 PDA treated medically (INH A-21 vs. placebo) 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.94, 1.19]
1.7.2 PDA treated surgically (INH A-21 vs. placebo) 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.83, 1.22]
1.7.3 PDA treated medically or surgically (INH A-21 vs. placebo) 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.96, 1.14]
1.7.4 PDA treated medically or surgically (Altastaph vs. placebo) 1 206 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.46, 2.08]
1.8 Necrotising enterocolitis 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.8.1 NEC stage 1 (INH A21 vs. placebo) 1 505 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.26, 1.53]
1.8.2 NEC stage 2 (INH A-21 vs. placebo) 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.73, 1.38]
1.8.3 NEC stage 3 (INH A-21 vs. placebo) 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.46, 1.40]
1.8.4 NEC any stage or gastrointestinal perforation (not pre-specifed outcome of review) 1 206 Risk Ratio (M-H, Fixed, 95% CI) 1.37, [0.45, 4.19]
1.9 Intraventricular hemorrhage 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.9.1 Any grade of IVH (INH A-21 vs. placebo) 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.83, 1.04]
1.9.2 Any grade of IVH (Altastaph vs. placebo) 1 206 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.35, 1.64]
1.9.3 Grade 3 or grade 4 IVH (INH A-21 vs. placebo) 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.77, 1.25]
1.10 Periventricular leukomalacia 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.10.1 INH A-21 vs. placebo 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.74, 1.65]
1.11 Retinopathy of prematurity 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.11.1 Any stgae of ROP (INH A-21 vs. placebo) 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.91, 1.10]
1.11.2 Stage 3 or 4 ROP (INH A-21 vs. placebo) 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.59, 1.10]
1.12 Duration of antibiotic use prior to discharge 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.12.1 INH A-21 vs. placebo 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 0.02 [-1.15, 1.19]
1.13 Duration of Vancomycin use before discharge 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.13.1 INH A-21 vs. placebo 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 0.05 [-0.68, 0.78]
1.14 Allergic reactions 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.14.1 INH A-21 vs. placebo 2 2488 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.15 Pulmonary edema 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.15.1 INH A-21 vs. placebo) 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 1.46 [0.94, 2.26]
1.16 Hypertension 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.16.1 INH A-21 vs. placebo 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 1.16 [0.84, 1.61]
1.16.2 Altastaph vs. placebo 1 206 Risk Ratio (M-H, Fixed, 95% CI) 1.47 [0.63, 3.45]
1.17 Hypoglycemia 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.17.1 INH A-21 vs. placebo 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 1.15 [0.90, 1.47]
1.17.2 Altastaph vs. placebo 1 206 Risk Ratio (M-H, Fixed, 95% CI) 1.40 [0.55, 3.54]
1.18 Other adverse effects 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.18.1 Discontinuation of study medication due to adverse event (INH A21 vs. placebo) 1 505 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.25, 1.89]
1.18.2 Discontinuation of study medication due to adverse effects (Altastaph vs. placebo) 1 206 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.37, 3.74]
1.18.3 Serious adverse events (INH A-21 vs. placebo) 2 2488 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.72, 1.51]
1.18.4 Serious adverse events (Altastaph vs. placebo) 1 206 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.37, 3.74]

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Sources of support

Internal sources

  • Department of Paediatrics, Mount Sinai Hospital, University of Toronto, Canada
  • Department of Pediatrics, University of Virginia Medical School, USA

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 2, 2009 (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.