Antibody for the prevention of neonatal noscocomial staphylococcal infection: a review of the literature.

Staphylococci, especially coagulase negative staphylococci (CONS), are responsible for over 75 % of late-onset infections in very low birth weight infants. These infections cause increased length of hospital stay, need for antibiotics, and cost of medical care. Several drug companies have developed and evaluated hyperimmune polyclonal and monoclonal antibodies for the prevention of neonatal staphylococcal infection including 1) Altastaph by North American Biologics Inc., 2) Veronate by Inhibitex Inc., and 3) Pagibaximab by Biosynexus Inc, and Glaxo Smith Kline Inc. We will review the development and status of these potential products. Altastaph is a S. aureus serotype 5 and 8 vaccine induced hyperimmune polyclonal antibody whose development has been placed on hold due to its failure to demonstrate any trend toward efficacy in a recently completed Phase II study. Veronate is a polyclonal antibody obtained by plasmapheresis from donors with high titers of MSCRAMM (microbial surface components recognizing adhesion matrix molecules) activity against CONS whose development has been placed on hold due to its failure to demonstrate effectiveness in a recently completed Phase III study. Pagibaximab is a humanized mouse chimeric monoclonal antibody (previously known as BSYX-A110) directed against lipoteichoic acid (LTA), a major cell wall component of gram-positive bacteria, that has recently completed a Phase II study suggesting efficacy and is being developed further for clinical investigation.

Patient isolation measures for infants with candida colonization or infection for preventing or reducing transmission of candida in neonatal units.

BACKGROUND: Candida is one of the most common nosocomial infections in the intensive care setting worldwide and is associated with increased healthcare costs. In neonates, candida infection is associated with high mortality and morbidity. Candida is transmitted by direct and indirect contact. Routine infection control measures that include standard precautions are routinely employed to prevent spread of nosocomial infections. Patient isolation measures, i.e. single room isolation or cohorting, are usually recommended for infections spread by contact. OBJECTIVES: To determine the effect of patient isolation measures (single room isolation and/or cohorting) for infants with candida colonization or infection as an adjunct to routine infection control measures on the transmission of candida to other infants in the neonatal unit. SEARCH STRATEGY: Relevant trials in any language were searched in the following databases in Jan 2007: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2006), MEDLINE (1966 - Jan 2007) and PREMEDLINE, EMBASE (1980 - Jan 2007), CINAHL (1982 - Jan 2007). Proceedings of the Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research) and the European Society for Pediatric Research (1987 - Jan 2007) were also searched in Jan 2007. Authors or other experts were contacted for more information on relevant published or unpublished trials. Additional searches were also made in the reference lists of relevant journal articles and in the reviewer's personal files. SELECTION CRITERIA: Types of studies: Cluster randomized trials (where clusters may be defined by hospital, ward, or other subunits of the hospital). TYPES OF PARTICIPANTS: Neonatal units caring for infants colonized or infected with candida. Types of interventions: A policy of patient isolation measures (single room isolation or cohorting of infants with candida colonization or infection) compared to routine isolation measures. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Neonatal Review Group (CNRG) were to be used to identify studies and to assess the methodological quality of eligible trials. The statistical package (RevMan 4.2) provided by the Cochrane Collaboration was to be used. In cluster-randomized trials, if the unit of analysis of the trial was the cluster (not individuals) and analysis took into account the correlation between clusters, the inverse variance method was to be used for meta-analysis. If this was not the case, a narrative synthesis was to be made without meta-analysis. Infection rates and colonization rates were to be expressed as rate ratios for each trial and if appropriate for meta-analysis, the generic inverse variance method in RevMan was to be used. MAIN RESULTS: No eligible trials were identified. AUTHORS' CONCLUSIONS: The review found no evidence to either support or refute the use of patient isolation measures (single room isolation or cohorting) in neonates with candida colonization or infection. Despite the evidence for transmission of candida by direct or indirect contact and evidence of cross-infection by health care workers, no standard policy of patient isolation measures beyond routine infection control measures exists in the neonatal unit. There is an urgent need to research the role of patient isolation measures for preventing transmission of candida in the neonatal unit. Cluster randomized trials involving multiple units or hospitals with randomized allocation of one type of patient isolation measure or the other (i.e. single room isolation or cohorting) with careful consideration for determining an appropriate sample size and analysis would be the most appropriate method to research this intervention.

Level of maternal antibody required to protect neonates against early-onset disease caused by group B Streptococcus type Ia: a multicenter, seroepidemiology study.

Because of the difficulty of conducting efficacy trials of vaccines against group B streptococcus (GBS), the licensure of these vaccines may have to rely on studies that measure vaccine-induced antibody levels that correlate with protection. This study estimates the level of maternal antibody required to protect neonates against early-onset disease (EOD) caused by GBS type Ia. Levels of maternal serum IgG GBS Ia antibodies, measured by ELISAs in 45 case patients (neonates with EOD caused by GBS Ia) and in 319 control subjects (neonates colonized by GBS Ia but without EOD) born at > or =34 weeks gestation were compared. The probability of developing EOD declined with increasing maternal levels of IgG GBS Ia antibody (P = .03). Neonates whose mothers had levels of IgG GBS Ia antibody > or =5 microg/mL had an 88% lower risk (95% confidence interval, 7%-98%) of developing type-specific EOD, compared with those whose mothers had levels < 0.5 microg/mL. A vaccine that induces IgG GBS Ia antibody levels > or =5 microg/mL in mothers can be predicted to confer a high degree of type-specific immunity to EOD to their infants.

The effectiveness of risk-based intrapartum chemoprophylaxis for the prevention of early-onset neonatal group B streptococcal disease.

OBJECTIVE: Our purpose was to evaluate the effectiveness of a risk-based intrapartum antibiotic prophylaxis strategy for the prevention of early-onset neonatal group B streptococcal disease. STUDY DESIGN: Cases and controls were selected from infants born to women with one or more risk factors: preterm labor or rupture of membranes, prolonged rupture of membranes (>18 hours), fever during labor, or previous child with group B streptococcal disease. Cases were matched with controls by birth hospital and gestational age. Data abstracted from medical records were analyzed to estimate the effectiveness of intrapartum antibiotic prophylaxis. RESULTS: We analyzed data from 109 cases and 207 controls. Nineteen (17%) case versus 69 (33%) control mothers received an acceptable regimen of intrapartum antibiotic prophylaxis. In adjusted analyses, the effectiveness of intrapartum antibiotic prophylaxis was 86% (95% confidence interval, 66%-94%). When the first dose of antibiotics was given > or =2 hours before delivery, the effectiveness increased to 89% (95% confidence interval, 70%-96%); when it was given within 2 hours of delivery, the effectiveness was 71% (95% confidence interval, -8%-92%). Effectiveness was lowest in mothers with intrapartum fever (72%, 95% confidence interval, -9%-93%). On the basis of a 70% prevalence of maternal risk factors expected among cases in the absence of intrapartum antibiotic prophylaxis, we estimate that the risk-based strategy could reduce early-onset group B streptococcal disease by 60%. CONCLUSIONS: The risk-based approach to intrapartum antibiotic prophylaxis is effective in preventing early-onset group B streptococcal disease. To achieve the maximum preventive effect, the first dose of antibiotics should be administered at least 2 hours before delivery.

Antibiotic susceptibility profiles for group B streptococci isolated from neonates, 1995-1998.

Antibiotic susceptibility profiles were analyzed for 119 invasive and 227 colonizing strains of group B streptococci isolated from neonates at 6 US academic centers. All strains were susceptible to penicillin, vancomycin, chloramphenicol, and cefotaxime. The rate of resistance to erythromycin was 20.2% and to clindamycin was 6.9%. Resistance to erythromycin increased in 1997. Type V strains were more resistant to erythromycin than were type Ia (P=.003) and type Ib (P=.004) strains and were more resistant to clindamycin than were type Ia (P<.001), type Ib (P=.01), and type III (P=.001) strains. Resistance rates varied with geographic region: in California, there were high rates of resistance to erythromycin and clindamycin (32% and 12%, respectively), and low rates in Florida (8.5% and 2.1%, respectively). Penicillin continues to be the drug of choice for treatment of group B streptococcus infection. For women who are penicillin intolerant, however, the selection of an alternative antibiotic should be guided by contemporary resistance patterns observed in that region.

Treatment of obstructive jaundice in erythroblastosis fetalis with ursodeoxycholic acid (UDCA): a case report.

OBJECTIVE: To report a significant improvement of direct hyperbilirubinemia values, in an infant with cholestasis secondary to erythroblastosis fetalis, after treatment with ursodeoxycholic acid (UDCA). STUDY DESIGN: Case report. RESULTS: A full term infant, with total and direct bilirubin values of 26 mg/dl (445 micromol/l) and 24.5 mg/dl (419 micromol/l), respectively, on the third day of life, had total and direct bilirubin values of 8.2 mg/dl (140 micromol/l) and 6.9 mg/dl (118 micromol/l), respectively, after 2 days of treatment with UDCA. Because the natural course of this cholestasis takes several weeks to resolve, the observed improvement is highly suggestive of a direct effect of UDCA on the disease course. CONCLUSION: This treatment may add a new therapeutic option to the limited measures available for this condition, although further studies regarding safety and its mechanism of action are needed before it can be routinely recommended.

Actuarial survival in the premature infant less than 30 weeks' gestation.

OBJECTIVE: Because survival from admission to discharge does not provide parents and physicians information about future life expectancy in the premature neonate, we characterized the actuarial survival, defined as the future life expectancy from a given postnatal age, in a large inborn population of premature infants < 30 weeks' gestation. STUDY DESIGN: We determined daily actuarial survival of 1925 inborn infants (23 to 29 weeks' gestation) admitted to the Baylor Affiliated Nurseries from July 1986 through December 1994, stratified by 100-g birth weight and by 1-week gestational-age intervals. RESULTS: In the 501- to 600-g birth weight stratum, actuarial survival improved from 31% at birth, to 61% on day of life 7, and then to 75% on day of life 28; in the 901- to 1000-g birth weight stratum, actuarial survival improved from 88%, to 94%, and then to 98% throughout the same times, respectively. Similar trends were obtained when data were stratified by gestational age. CONCLUSIONS: Survival in the smallest infants improves dramatically during the first few days of life, but there is a significant risk for late death in the smallest of these infants.

Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. MEDI-493 Study Group.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants. MEDI-493 (palivizumab) is a humanized monoclonal antibody to the fusion protein of RSV and is active in animal models for prevention of pulmonary RSV replication. OBJECTIVE: To describe the safety, tolerance, immunogenicity and pharmacokinetics of repeat intravenous doses of MEDI-493 in premature infants or infants with bronchopulmonary dysplasia. DESIGN: Phase I/II multicenter, randomized, double blind, placebo-controlled, dose escalation trial. PATIENT POPULATION: Infants born prematurely (< or = 35 weeks of gestation) who were < or = 6 months of age and infants with bronchopulmonary dysplasia who were < or = 24 months of age were eligible for study participation. STUDY AGENTS: Participants received 3, 10 or 15 mg/kg MEDI-493 or 0.9% saline intravenously every 30 days for up to five doses. RESULTS: MEDI-493 was safe and well-tolerated and did not induce a specific anti-MEDI-493 response. The mean half-life of 20 days was comparable with that of other immunoglobulin G preparations. Mean trough serum concentrations 30 days after Infusion 1 were 6.8, 36.1 and 60.6 microg/ml for the 3-, 10- and 15-mg/kg dose groups, respectively. After Infusion 2 the trough concentrations were 11.9, 45.2 and 70.7 microg/ml. After subsequent doses the mean trough values ranged from 14 to 18 microg/ml in those given 3 mg/kg and were > 40 microg/ml for patients who received 10 or 15 mg/kg MEDI-493 (46 to 72 microg/ml and 88 to 96 microg/ml, respectively). CONCLUSIONS: MEDI-493 was safe and well-tolerated in this high risk pediatric population. Mean serum concentrations of MEDI-493 that have been shown to produce a 2-log reduction in pulmonary RSV titer in cotton rats were maintained when 10 or 15 mg/kg MEDI-493 was given every 30 days to pediatric patients at high risk for serious RSV disease. Monthly doses of 15 mg/kg maintained concentrations of > 40 microg/ml for the majority of patients.

Capsular polysaccharide types of group B streptococcal isolates from neonates with early-onset systemic infection.

The distribution of serotypes of group B streptococci (GBS) isolated from 67 infants with early-onset sepsis are described. Case-infants were assembled from 13 hospitals across the United States from 15 July 1995 to 5 February 1997 through prospective active surveillance. The distribution of GBS serotypes was Ia, 40%; Ib, 9%; II, 6%; III, 27%; V, 15%; and nontypeable, 3%. Type V occurred more frequently in the northeast region (New York and New Jersey) than in other regions (29% vs. 9%, P = .06). Conversely, type III occurred significantly less frequently in the northeast region than other regions (10% vs. 35%, P = .04). GBS types Ia, III, and V accounted for 82% of the isolates. This report supports previous observations about the emergence of GBS type V, but our data caution that conclusions about serotype distributions based on one geographic location or on a small number of patients may not be generally applicable. Continued monitoring seems necessary for the design of a GBS vaccine.

Resource utilization among neonatologists in a university children's hospital.

OBJECTIVE: We studied factors affecting length of hospital stay and resulting hospital charges among patients managed by two separate groups of neonatologists in the same academic health science center. DESIGN: Retrospective analysis of clinical and financial data base information. METHODS: Neonatal intensive care was provided in the same acute care nursery in a large university children's hospital by: (1) neonatologists in a full-time academic division (group A) and (2) a group associated with a private managed care organization (group B). Clinical and financial parameters of all neonates admitted in fiscal year 1994 were compared for the two provider groups. Stepwise regression analysis was used to evaluate factors influencing hospital charges and length of hospital stay (LOS) and to adjust for differences in clinical variables between the two groups. RESULTS: Group A physicians provided care for 340 infants, while 137 were treated by those of group B. Group A included older patients, more outborns, more level III patients, more sepsis, more intermittent positive pressure ventilation, and more patent ductus arteriosus. The incidence of transient tachypnea of the newborn was higher among group B patients. Hospital charges were primarily determined by LOS, which was similar for the two groups. When the data were corrected for differences in risk and patient acuity, however, a significant relationship between physician group and LOS was demonstrated, with LOS being an average of 7.8 days shorter for group A. A net reduction of $3 114 969 in hospital charges might have been realized had group A physicians provided care for all study patients. CONCLUSIONS: Hospital charges were determined by LOS. In this setting, academic neonatologists produced shorter LOS and comparable clinical outcomes, despite caring for a population at greater risk. The reduction in LOS could have resulted in more than $3.1 million in annualized savings had the academic group provided care for all of the study patients.

Novel approaches to the prevention and therapy of neonatal bacterial sepsis.

A variety of adjunctive treatments have been shown to offer potential benefits for neonates with sepsis. Most are not available clinically and those that are available still should be considered experimental or limited in their use; however, these efforts are far from complete and should continue to evolve in the coming years. Efforts toward the rapid diagnosis of bacterial infections are a necessary component in the eventual implementation of these potential novel strategies. As a better understanding of the intricate mechanisms of neonatal sepsis is developed, it will be possible to provide patients with an increasingly effective array of treatment and prevention strategies.

Premature rupture of the membranes: neonatal consequences.

Premature rupture of the membranes (PROM), membrane rupture before the onset of labor, occurs in 2% to 18% of pregnancies. The time from PROM to delivery (latency) is usually less than 48 hours in term pregnancy. Therefore, the risks of PROM at term are related to fetal distress, prolapsed cord, abruptio placenta, and rarely, infection. Preterm PROM (pPROM), PROM before 37 weeks' gestation, accounts for 20% to 40% of PROM, and the incidence is doubled in multiple gestations. The latency period in pPROM is inversely related to the gestational age thereby increasing the risks of oligohydramnios and infection in very premature infants and their mothers. Because pPROM is associated with 30% to 40% of premature births, pPROM is also responsible for the neonatal problems resulting from prematurity. This review examines the impact of PROM on the neonate including fetal distress, prematurity, infection, pulmonary hypoplasia, and restriction deformations.

Mature micromegakaryocytes: an unusual developmental pattern in term infants.

We sought to gain perspective on platelet production in the fetus and the newborn by counting and characterizing megakaryocytes from available cord blood. Elutriation was used to isolate circulating megakaryocytes from umbilical arteries and veins obtained at scheduled caesarean sections of nine normal term fetuses. Megakaryocytes were identified by established criteria, their diameters measured, and maturation stages recorded. Large numbers of megakaryocytes, mostly mature, were found in both the umbilical arteries and veins, many times more than previously observed circulating in adult blood. In term infants more than a third of the mature megakaryocytes had unusually decreased nuclear lobation and were dwarf cells with diameters as small as 13 microns, which we considered to be micromegakaryocytes. The atypicality of these small but mature cells is seen as merely a leftward skewing in the development of megakaryocyte ploidies. We believe that in normal fetuses the extent of megakaryocyte ploidization and development is distinctive and probably regulated differently to the adult pattern.

Teaching newborn medicine to third-year medical students. Use of a checklist.

OBJECTIVE: To determine if use of a checklist during the third-year medical student's newborn medicine rotation within the pediatric clerkship affected grades, end-of-course examination scores, or perceptions of the new-born clinical experience before and after use of this teaching aid. METHODS: The checklist contained 46 newborn medicine-related skills and concepts and required staff review. A postclerkship questionnaire was used to assess the student's perception of all components of the clinical clerkship. A standardized test was used to assess clinical knowledge. The clerkship grade was based on test scores (30%) and clinical performance (70%). RESULTS: All students (N = 321) returned the postclerkship questionnaire from July 1, 1988, to June 30, 1990, and the checklist plus questionnaire (N = 294) from July 1, 1990, to June 30, 1992. During both periods, the curriculum and clinical experience remained unchanged. Although there was no change in grade distribution, mean final examination score (P < .011) and student perception of the nursery portion of the clerkship (P < .01) improved significantly after we began using the checklist. "Poor" ratings of the nursey experience decreased from 12% (1988 to 1989) to 3% (1991 to 1992), and "excellent" ratings increased from 13% to 24%. In addition, examination performance on specific examination questions appeared related to completion of checklist items (r = .68, P < .016). CONCLUSIONS: Use of a readily available checklist, to remind students and faculty of the skills and concepts to be mastered during the nursey portion of the clerkship, did not impact final grades, although information transfer and student perception of the clinical experience improved. We speculate that clear delineation of readily available objectives focuses students and staff, decreases anxiety, and provides a sense of accomplishment.

Intravenous immune globulin prophylaxis of late-onset sepsis in premature neonates.

To determine whether a single dose of intravenously administered immune globulin (IVIG) decreases late-onset sepsis in premature infants, we prospectively entered 753 neonates with birth weight 500 to 2000 gm, gestation < or = 34 weeks, and age < or = 12 hours into a multicenter, double-blind, controlled trial. Infants were randomly selected to receive a single intravenous infusion, 10 ml/kg, of either IVIG (500 mg/kg) or albumin (5 mg/kg) and were observed for 8 weeks for infection. Maternal and neonatal risk factors for infection did not differ between groups. Although serum IgG values before infusion were related to gestation (R = 0.62), the change in serum IgG or half-life of IgG after IVIG infusion was not (R < or = 0.09). The serum IgG concentration was increased (p < 0.05) in IVIG-treated patients for 8 weeks. There were 88 episodes of late-onset sepsis in 79 neonates (10.5%). Causative organisms included the following: Staphylococcus epidermidis (37 episodes), Enterococcus (9), Staphylococcus aureus (7), Candida (6), Escherichia coli (6), and multiple organisms (11). Sepsis, death, and death as a result of infection were unaffected by treatment. We conclude that a single infusion of IVIG, 500 mg/kg, shortly after birth was not effective prophylaxis for late-onset infection in premature neonates. Future studies of late-onset sepsis prophylaxis should consider IVIG with known pathogen-specific antibody concentrations against organisms causing these infections, in particular S. epidermidis.

Opsonic activity of commercially available standard intravenous immunoglobulin preparations.

Several standard intravenous immunoglobulin G (IVIG) products are available in the United States and have been used with the intent to treat or prevent infections in neonates. We evaluated more than 100 lots of IVIG, from 6 products, to determine the amount of opsonic antibody against neonatal pathogens. Neutrophil-mediated opsonophagocytosis was used to determine opsonic activity in these preparations for Staphylococcus epidermidis; Haemophilus influenzae type b; Streptococcus pneumoniae serotypes 3, 14 and 19; Group B Streptococcus serotypes Ia, Ib, Ia/c, II and III; and Escherichia coli (K1). Pathogen-specific opsonic activity of the lots tested ranged from undetectable to 1:80 and was detectable in < 10% to > 90% of lots tested depending on the organism and manufacturer. Within an IVIG lot there was variable opsonic activity against different strains or serotypes of the same organism. Opsonic activity was significantly (P < or = 0.05) affected by the manufacturer's donor pool and less so by the manufacturing method. We conclude that the pathogen-specific opsonic antibody activity of an IVIG lot is: (1) highly variable for several common neonatal pathogens; (2) predominantly dependent on the donor pool and not the manufacturing method. Clinicians may more appropriately select therapy if the pathogen-specific antibody content of IVIG products by lot are known. In the future neonatal IVIG research should focus on using preparations with known pathogen-specific antibody activity.

Opsonic antibodies to Staphylococcus epidermidis: in vitro and in vivo studies using human intravenous immune globulin.

Staphylococcus epidermidis is a major cause of nosocomial infections, including sepsis in premature infants. Intravenous immune globulin (IVIG) has been used to prevent neonatal sepsis, but efficacy has varied in different clinical trials. The role of IgG antibody in immunity to S. epidermidis was studied using an opsonophagocytic assay and a lipid-emulsion-induced lethal model of neonatal S. epidermidis sepsis. Opsonic antibody to S. epidermidis varied between IVIG preparations and between lots: Lots with > or = 90% opsonic activity promoted bacterial clearance from blood and significantly enhanced survival when compared with lots with < or = 50% opsonic activity. Absorption of IVIG with S. epidermidis removed in vitro opsonic and in vivo protective activity. These studies suggest that opsonic antibody may play an important role in S. epidermidis immunity in immunocompromised patients, such as premature infants. Standard IVIG, however, may not provide therapy effective in preventing S. epidermidis infections, as many IVIG lots contain insufficient levels of opsonic S. epidermidis antibody.