Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity.

The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.

Assessment of safety in newborns of mothers participating in clinical trials of vaccines administered during pregnancy.

A panel of experts convened by the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, developed proposed guidelines for the evaluation of adverse events in newborns of women participating in clinical trials of maternal immunization in the United States.

Appropriate antibiotic therapy improves Ureaplasma sepsis outcome in the neonatal mouse.

BACKGROUND: Ureaplasma causes sepsis in human neonates. Although erythromycin has been the standard treatment, it is not always effective. No published reports have evaluated Ureaplasma sepsis in a neonatal model. We hypothesized that appropriate antibiotic treatment improves Ureaplasma sepsis in a neonatal mouse model. METHODS: Two ATCC strains and two clinical strains of Ureaplasma were evaluated in vitro for antibiotic minimum inhibitory concentration (MIC). In addition, FVB albino mice pups infected with Ureaplasma were randomly assigned to saline, erythromycin, or azithromycin therapy and survival, quantitative blood culture, and growth were evaluated. RESULTS: MICs ranged from 0.125 to 62.5 µg/ml and 0.25 to 1.0 µg/ml for erythromycin and azithromycin, respectively. The infecting strain and antibiotic selected for treatment appeared to affect survival and bacteremia, but only the infecting strain affected growth. Azithromycin improved survival and bacteremia against each strain, whereas erythromycin was effective against only one of four strains. CONCLUSION: We have established a neonatal model of Ureaplasma sepsis and observed that treatment outcome is related to infecting strain and antibiotic treatment. We speculate that appropriate antibiotic selection and dosing are required for effective treatment of Ureaplasma sepsis in neonates, and this model could be used to further evaluate these relationships.

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

BACKGROUND: Candida is a common nosocomial infection and is associated with increased healthcare costs. In neonates, candida infection is associated with high mortality and morbidity and is transmitted by direct and indirect contact. Patient isolation measures, i.e. single room isolation or cohorting, are usually recommended for infections that 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 METHODS: Relevant trials in any language were searched in the following databases in July 2011: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2011), MEDLINE, BIOSIS, EMBASE and CINAHL. Proceedings of the Pediatric Academic Societies (from 1987) and ongoing trials were searched. 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 used to identify studies and to assess the methodological quality of eligible cluster-randomized trials. 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 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. Well designed trials randomizing clusters of units or hospitals to a type of patient isolation method intervention are needed.

Phase 1/2 double-blind, placebo-controlled, dose escalation, safety, and pharmacokinetic study of pagibaximab (BSYX-A110), an antistaphylococcal monoclonal antibody for the prevention of staphylococcal bloodstream infections, in very-low-birth-weight neonates.

Staphylococcal sepsis is a major cause of morbidity and mortality in very-low-birth-weight (VLBW) infants. A human chimeric monoclonal antibody, pagibaximab, was developed against staphylococcal lipoteichoic acid. We evaluated the safety, tolerability, and pharmacokinetics of pagibaximab in VLBW neonates. A phase 1/2, randomized, double-blind, placebo-controlled, dose escalation study was conducted in VLBW infants (700 to 1,300 g) 3 to 7 days old. Patients received two doses 14 days apart of intravenous pagibaximab (10, 30, 60, or 90 mg/kg of body weight) or placebo in a 2:1 ratio. Blood and urine samples were obtained pre- and postinfusion for analysis of safety and pharmacokinetics, and data on adverse events were gathered. Staphylococcal organisms causing sepsis were collected and evaluated. Fifty-three patients received at least one dose of pagibaximab or placebo. The average gestational age was 27.6 weeks; the average birth weight was 1,003 g. All serious adverse events were deemed unrelated or probably not drug related. Morbidity and mortality were similar across treatment groups. No evidence of immunogenicity of pagibaximab was detected. Pagibaximab pharmacokinetics was linear. The mean clearance (CL), volume of distribution, and elimination half-life of pagibaximab were independent of dose. The serum half-life was 20.5 +/- 6.8 days. Pagibaximab enhanced serum opsonophagocytic activity. All staphylococci causing sepsis were opsonizable by pagibaximab. Two infusions of pagibaximab, administered 2 weeks apart to high-risk neonates appeared safe and tolerable, and pharmacokinetics were linear. Evaluation of more frequent doses, at the highest doses tested, in neonates at high-risk of staphylococcal sepsis, is warranted.

Treatment of methicillin-resistant Staphylococcus aureus in neonatal mice: lysostaphin versus vancomycin.

S. aureus is a significant cause of late-onset sepsis in neonates. Increasing antibiotic resistance, however, requires additional treatment options. Lysostaphin, an endopeptidase, has that potential. The objective of this study is to compare lysostaphin versus vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) in a neonatal mouse model. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against MRSA strain USA300 were determined using standard methods. To determine pharmacokinetics, neonatal pups received either vancomycin or lysostaphin intraperitoneal and serum samples were obtained. To evaluate efficacy, pups were infected s.c. and littermates randomized to receive either saline, vancomycin, or lysostaphin intraperitoneal. Pups were observed for survival and growth. Quantitative blood cultures were obtained 24 h after infection. The MIC/MBC for vancomycin and lysostaphin were 0.71/1.19 microg/mL and <0.008/0.015 microg/mL, respectively. Mean lysostaphin concentrations ranged from 2.34 to 8.92 microg/mL. Mean vancomycin concentrations ranged from 1.72 to 11.2 microg/mL. Lysostaphin improved survival compared with placebo (p < 0.00001) and vancomycin (p < 0.03). There was no significant difference in growth among the groups. All treatment regimens resulted in less bacteremia compared with placebo (p < 0.0001). Lysostaphin appears to be more effective than vancomycin in treating MRSA in a neonatal model.

Antibiotic prophylaxis improves Ureaplasma-associated lung disease in suckling mice.

Ureaplasma infection is associated with increased lung disease in high-risk neonates. Our goal was to determine the impact of antibiotic prophylaxis on Ureaplasma and oxygen-induced lung disease in newborn mice. In animal model development and prophylaxis experiments, pups were randomly assigned to either 0.8 or 0.21 inspired oxygen concentration [fraction of inspired oxygen (FiO2)] from 1 to 14 d of age and either Ureaplasma or 10 B media daily from 1 to 3 d. All pups were observed for growth and survival. Surviving pups had culture and PCR evaluated for blood, bronchoalveolar lavage, and lung, and lung weights, pathology, morphometry, histology, and immunohistochemistry were determined. In prophylaxis experiments, erythromycin, azithromycin, or normal saline was given for the first 3 d, and minimum inhibitory concentration and pharmacokinetics were determined. In model development, 0.8 FiO2 and Ureaplasma infection survival and growth were significantly decreased and lung edema and inflammation were significantly increased. In prophylaxis experiments, we observed significantly improved survival and growth with azithromycin versus normal saline controls, whereas erythromycin was not significantly different from controls, and decreased inflammatory response with azithromycin versus normal saline and erythromycin. In a neonatal mouse model of Ureaplasma and oxygen-induced lung disease, appropriate antibiotic prophylaxis improves survival and morbidity and decreases lung inflammation.

Guidelines on CMV congenital infection.

Congenital cytomegalovirus (CMV) infection occurs in 0.6-0.7% of all newborns and is the most prevalent infection-related cause of congenital neurological handicap. Vertical transmission occurs in around 30% of cases, but the fetus is not always affected. Symptomatic newborns at birth have a much higher risk of suffering severe neurological sequelae. Detection of specific IgG and IgM and IgG avidity seem to be the most reliable tests to identify a primary infection but interpretation in a clinical context may be difficult. If a seroconversion is documented or a fetal infection is suspected by ultrasound markers, an amniocentesis should be performed to confirm a vertical transmission. In the absence of a confirmed fetal infection with fetal structural anomalies, a pregnancy termination should be discouraged. Fetal prognosis is mainly correlated to the presence of brain damage. Despite promising results with the use of antiviral drugs and CMV hyperimmune globulin (HIG), results have to be interpreted with caution. Pregnant women should not be systematically tested for CMV during pregnancy. Managing CMV screening should be restricted to pregnancies where a primary infection is suspected or among women at high risk. The magnitude of congenital CMV disease and the value of interventions to prevent its transmission or to decrease the sequelae need to be established before implementing public health interventions. In this paper, aspects of CMV infection in the pregnant woman and her infant are reviewed.

Population structure of invasive and colonizing strains of Streptococcus agalactiae from neonates of six U.S. Academic Centers from 1995 to 1999.

The purpose of this study was to describe the population structure of group B streptococci (GBS) isolated from infected and colonized neonates during a prospective active-surveillance study of early-onset disease in six centers in the United States from July 1995 to June 1999 and to examine its relationship to bovine strains of GBS. The phylogenetic lineage of each GBS isolate was determined by multilocus sequence typing, and isolates were clustered into clonal complexes (CCs) using the eBURST software program. A total of 899 neonatal GBS isolates were studied, of which 129 were associated with invasive disease. Serotype Ia, Ib, and V isolates were highly clonal, with 92% to 96% of serotype Ia, Ib, and V isolates being confined to single clonal clusters. In contrast, serotype II and III isolates were each comprised of two major clones, with 39% of serotype II and 41% of serotype III isolates in CC 17 and 41% of serotype II and 54% of serotype III isolates in CC 19. Further analysis demonstrates that the CC 17 serotype II and III GBS are closely related to a previously described "ancestral" lineage of bovine GBS. While 120 (93%) of invasive GBS were confined to the same lineages that colonized neonates, 9 (7%) of the invasive GBS isolates were from rare lineages that comprised only 2.7% of colonizing lineages. These results are consistent with those for other geographic regions that demonstrate the highly clonal nature of GBS infecting and colonizing human neonates.

Optimum Detection of Ureaplasma in Premature Infants.

BACKGROUND: Ureaplasma spp. is a known risk factor for bronchopulmonary dysplasia in premature infants. Emerging research suggests treatment with azithromycin or clarithromycin in the first days of life (DOLs) reduces bronchopulmonary dysplasia in Ureaplasma spp. positive infants. Side effects of these antibiotics make it imperative to optimize reliable noninvasive screening procedures to identify infants who would benefit from treatment. METHODS: The aim of this study was to determine the best site and time to screen for Ureaplasma spp. in 24- to 34-week premature infants. Oral, nasal, gastric and tracheal cultures were collected and placed immediately in 10B broth media. Polymerase chain reaction verified culture results and identified the Ureaplasma spp. RESULTS: Cultures yielded a Ureaplasma spp. incidence of 80/168 = 47.6% [95% confidence interval (CI): 40-56]. Nasal cultures had greater sensitivity to detect Ureaplasma spp. than oral cultures (P = 0.008): however, a significant proportion of infants with Ureaplasma spp. would have been missed (12/79 = 15.2%, 95% CI: 8%-25%, P < 0.001) if oral cultures were not obtained. For all sites, the collection at DOL 7-10 were more likely to be positive than the collection at DOL 1-2: however, a significant proportion (5/77 = 6.5%, 95% CI: 2-15, P < 0.001) of infants with Ureaplasma spp. would have been missed if the DOL 1-2 cultures were not obtained. CONCLUSIONS: For optimal Ureaplasma spp. detection in 24- to 34-week premature infants, cultures need to be taken both early and late in the first 10 DOLs both from nasal and oral secretions.

Prophylaxis with lactoferrin, a novel antimicrobial agent, in a neonatal rat model of coinfection.

Lactoferrin has broad-spectrum antimicrobial activity, and the authors hypothesized that recombinant human lactoferrin (Talactoferrin alfa [TLF]) would reduce mortality and morbidity in a coinfection model. The MIC 50 (minimum inhibitory concentration required to inhibit the growth of 50% of organisms) of TLF against Candida albicans and Staphylococcus epidermidis was determined. Neonatal Wistar rats were infected with C albicans or S epidermidis or both, at doses of 2 x10(8) colony-forming units (CFUs) given subcutaneously. Rat pups in each group were randomly given TLF intraperitoneally at 40 mg/kg/dose or 300 mg/kg/dose, or saline in 0.2 mL, once a day for 4 d and were monitored for mortality, weight gain, and blood culture positivity. Trough serum levels of TLF were measured at 24, 48, 72, 96, and 144 h. MIC 50 of TLF was 30 microg/mL and 500 microg/mL for C albicans and S epidermidis, respectively. TLF prophylaxis significantly improved survival in the coinfection group at 40 mg/kg/dose (by 16.1%; P=.019) and at 300 mg/kg/dose (by 15.1%; P=.027) and in the S epidermidis group at a dose of 40 mg/kg/dose (by 18.6%; P=.04). Weight gain was not affected by TLF prophylaxis. Serum trough levels of TLF were 1000-fold lower than in vitro MIC 50. The authors conclude that lactoferrin prophylaxis significantly enhanced survival in coinfection and in the subgroup of S epidermidis infection (40 mg/kg/dose) through indirect mechanisms.

Coagulase-negative staphylococcal infections in the neonate and child: an update.

Coagulase-negative staphylococcus (CONS) infection is the most common bloodstream infection treated in neonatal and pediatric intensive care units and significantly impacts patient mortality and morbidity. Staphylococcus epidermidis is the most common CONS species isolated clinically and investigated for its pathogenicity and virulence. Difficulties exist in the differentiation of CONS infection from culture contamination in clinical specimens, as CONS is a common skin commensal. Most CONS isolates have the mecA gene and exhibit beta-lactam resistance. The glycopeptide antibiotics, such as vancomycin, are the mainstay in therapy, although resistance has been reported. Arbekacin, linezolid, and streptogramins are newer antibiotics being evaluated as alternatives to glycopeptides. Monoclonal and polyclonal antibodies have been developed against the cell-wall components of staphylococcus and may hold promise for immune prophylaxis and treatment of CONS infection.

Late-onset sepsis in preterm infants: update on strategies for therapy and prevention.

Late-onset sepsis occurs in 15-25% of very low birth weight neonates. Early diagnosis and therapy optimize patient outcomes. Despite these efforts, mortality remains high (18-36%) and survivors suffer significant neurological and pulmonary morbidity. Although rapid diagnostics are improving, more are needed. Current therapy remains antibiotics and supportive care. Adjunctive therapies have either limited data (e.g., pentoxifylline) or have been found ineffective (e.g., granulocyte transfusions, granulocyte macrophage colony-stimulating factor/granulocyte colony-stimulating factor, and intravenous immunoglobulin). Preventive strategies that have proven beneficial include infection control measures (e.g., hand hygiene and universal precautions), early enteral feeds with human milk, early removal of central lines, catheter infection prevention bundles, antibiotic stewardship and focused quality improvement measures. Promising strategies to prevent late-onset sepsis include oral lactoferrin, and pathogen-specific monoclonal antibodies but more evidence is required to make practice recommendations.

Populations at risk for developing respiratory syncytial virus and risk factors for respiratory syncytial virus severity: infants with predisposing conditions.

According to National Vital Statistics Reports, premature infants (< 36 weeks gestation) account for approximately 7.4% of all births. During the 8 years from 1989 to 1997, multiple births steadily increased across all categories from twin to quintuplet and higher orders. During that same period low birth weight (< 2500 g) births increased almost 12%, and very low birth weight (< 1500 g) births increased approximately 20%.Attendant to these national trends in multiple and preterm births, overall gestation-specific survival rates have improved substantially. This improved outcome can be attributed in large measure to advances in neonatal care and technology. Despite the encouraging statistics on survival, infants born prematurely, at low or very low birth weights and/or with chronic conditions that predispose to lower respiratory tract illness, continue to incur serious risk of long term morbidity and the consumption of inpatient hospital services. In a recent 2-year study of US children, low and very low birth weights were found to be independent risk factors for bronchiolitis-associated mortality. In the past 14 years what defines bronchopulmonary dysplasia (BPD)/chronic lung disease (CLD) has shifted away from clinical, radiographic and pathologic findings in the preterm infant toward the pathophysiology of arrested lung development and the need for supportive care beyond 36 weeks corrected gestational age. The incidence of BPD/CLD ranges from 14 to 43%, with higher rates observed among infants of lower gestational age and birth weight. The health care team approach to the management of BPD directs its efforts toward minimizing pulmonary vascular resistance, alleviating airway obstruction and improving short term lung mechanics. Measures to prevent BPD/CLD attempt to forestall both acute and chronic lung function abnormalities. To that end researchers have investigated the early use of continuous positive airway pressure, vitamin supplementation and recombinant human copper/zinc superoxide dismutase. Despite significant gains in the survival of infants born at lower gestational ages, prematurity, low birth weight and/or underlying chronic pulmonary disease put the pediatric patient at risk for increased frequency and severity of respiratory syncytial virus lower respiratory tract illness and the potential for its long term sequelae.

Dexamethasone effects on group B streptococcal infection in newborn rats.

BACKGROUND: We previously published that human neutrophil-mediated bacterial killing of group B Streptococcus (GBS) in vitro was dependent on the timing and concentration of dexamethasone exposure. HYPOTHESIS: Dexamethasone treatment would affect neutrophil mediated killing of GBS in an animal model. METHODS: Wistar rat pups were randomly allocated to receive placebo or dexamethasone before, early or late after GBS infection. Suckling rats were infected with 104 or 105 colony-forming units of GBS or nothing. Pups were followed for survival, quantitative bacteremia, growth and neutrophil-mediated bacterial killing. Neutrophils for bacterial killing were obtained via cardiac puncture before infection. Statistics included chi square for survival, Mann-Whitney U test for bacteremia, analysis of variance for growth and paired Student's t test for bacterial killing analyses. RESULTS: Dexamethasone treatment before invasive GBS infection decreases quantitative bacteremia, improves survival and improves neonatal neutrophil-mediated bacterial killing in suckling rats, whereas dexamethasone treatment after infection increases bacteremia and decreases survival. Regardless of timing of dexamethasone treatment, before or after invasive GBS infection, growth was significantly impaired in all suckling rats receiving dexamethasone compared with controls. CONCLUSION: Treatment with dexamethasone before invasive GBS infection improves survival and decreases bacteremia in suckling rats; this appears in part to be mediated by improved neonatal neutrophil-mediated bacterial killing. We speculate that this improvement in outcome may be a result of improved number or function of neutrophil cell surface receptors.

Necrotizing enterocolitis and gastrointestinal complications after indomethacin therapy and surgical ligation in premature infants with patent ductus arteriosus.

BACKGROUND: Indomethacin is the most frequently used pharmacological agent for closure of a patent ductus arteriosus (PDA) in premature infants. However, reports of complications, particularly, necrotizing enterocolitis (NEC) and isolated gastrointestinal perforation have generated concerns about the use of this medication. OBJECTIVES: A retrospective study to compare the incidence of NEC, NEC-related gastrointestinal complications and isolated gastrointestinal perforation among premature infants treated for a PDA with either, indomethacin alone (I), surgical ligation alone (L), or indomethacin followed by surgical ligation (I-L). METHODS: The medical records of 224 infants that underwent treatment, either pharmacological or surgical, for a PDA, confirmed by echocardiography, over a 4-year period (1995 to 1998) were analyzed. Treatment history and gastrointestinal complications were reviewed. RESULTS: Of the 224 infants, 108 (48.2%) were treated with I, 50 (22.3%) by L, 66 (29.5%) with I-L. The clinical characteristics of the three treatment groups were similar and no differences in the incidence of NEC were observed between groups. NEC occurred in 14 (13%) of the I group, seven (14%) of the L group, and eight (12%) of the I-L group. The rate of NEC related gastrointestinal complications and isolated gastrointestinal perforation were also similar among groups. CONCLUSION: In this large retrospective study, indomethacin treatment for a significant PDA in premature infants was not associated with a greater risk for NEC or NEC-related gastrointestinal complications than surgical ligation.

Assessment of intrapartum antibiotic prophylaxis for the prevention of early-onset group B Streptococcal disease.

BACKGROUND: Most early-onset group B streptococcal (GBS) disease in recent years has occurred in newborns of prenatally GBS-negative mothers who missed intrapartum antibiotic prophylaxis (IAP). We aimed to assess the accuracy of prenatal culture in predicting GBS carriage during labor, the IAP use, and occurrence of early-onset GBS disease. METHODS: We obtained vaginal-rectal swabs at labor for GBS culture from 5497 women of ≥ 32 weeks' gestation and surface cultures at birth from newborns between February 5, 2008 and February 4, 2009 at 3 hospitals in Houston, TX and Oakland, CA. Prenatal cultures were performed by a healthcare provider during routine care, and culture results were obtained from medical records. The accuracy of prenatal culture in predicting intrapartum GBS carriage was assessed by positive and negative predictive values. Mother-to-newborn transmission of GBS was assessed. Newborns were monitored for early-onset GBS disease. RESULTS: GBS carriage was 24.5% by prenatal and 18.8% by labor cultures. Comparing prenatal with labor GBS cultures of 4696 women, the positive predictive value was 50.5% and negative predictive value was 91.7%. IAP, administered to 93.3% of prenatally GBS-positive women, was 83.7% effective in preventing newborn's GBS colonization. Mother-to-newborn transmission of GBS occurred in 2.6% of elective cesarean deliveries. Two newborns developed early-onset GBS disease (0.36/1000 births); the prenatal GBS culture of one was negative, the other's was unknown. CONCLUSIONS: IAP was effective in interrupting mother-to-newborn transmission of GBS. However, approximately 10% of prenatally GBS-negative women were positive during labor and missed IAP, whereas approximately 50% of prenatally GBS-positive women were negative during labor and received IAP. These findings emphasize the need for rapid diagnostics during labor.

A randomized study of a monoclonal antibody (pagibaximab) to prevent staphylococcal sepsis.

BACKGROUND: Pagibaximab, a human chimeric monoclonal antibody developed against lipoteichoic acid, was effective against staphylococci preclinically and seemed safe and well tolerated in phase 1 studies. OBJECTIVE: To evaluate the clinical activity, pharmacokinetics, safety, and tolerability of weekly pagibaximab versus placebo infusions in very low birth weight neonates. PATIENTS AND METHODS: A phase 2, randomized, double-blind, placebo-controlled study was conducted at 10 NICUs. Patients with a birth weight of 700 to 1300 g and 2 to 5 days old were randomly assigned to receive 3 once-a-week pagibaximab (90 or 60 mg/kg) or placebo infusions. Blood was collected for pharmacokinetics, bacterial killing, and safety analyses. Adverse event and clinical outcome data were collected. RESULTS: Eighty-eight patients received pagibaximab at 90 (n = 22) or 60 (n = 20) mg/kg or placebo (n = 46). Groups were not different in demography, mortality, or morbidity. Pagibaximab demonstrated linear pharmacokinetics, a 14.5-day half-life, and nonimmunogenicity. Definite staphylococcal sepsis occurred in 0%, 20%, and 13% (P < .11) and nonstaphylococcal sepsis occurred in 0%, 10%, and 15% (P < .15) of patients in the 90 mg/kg, 60 mg/kg, and placebo groups, respectively. In all patients with staphylococcal sepsis, estimated or observed pagibaximab levels were <500 µg/mL (target level) at infection. CONCLUSIONS: Three once-a-week 90 or 60 mg/kg pagibaximab infusions, in high-risk neonates, seemed safe and well tolerated. No staphylococcal sepsis occurred in infants who received 90 mg/kg. Target levels were only consistently achieved after 2 to 3 doses. Dose optimization should enhance protection.

Motavizumab, a second-generation humanized mAb for the prevention of respiratory syncytial virus infection in high-risk populations.

Evolved from palivizumab, motavizumab is a second-generation humanized mAb that is in development by MedImmune for the prevention of respiratory syncytial virus (RSV) infection in high-risk populations; the drug is also under investigation for the same indication by Abbott Laboratories. Motavizumab targets a highly conserved epitope in the A antigenic site of the RSV fusion (F) protein, which is important in the invasion of RSV from cell to cell. Motavizumab, which differs from palivizumab by just 13 amino acids, has exhibited a 70-fold enhancement in binding to the RSV F protein compared with the first-generation mAb, with an 11-fold faster association rate and 6-fold slower disassociation rate. Motavizumab was approximately 20-fold more potent than palivizumab in vitro, and was more effective at lower doses in vivo. In phase III clinical trials, motavizumab was non-inferior [corrected] to palivizumab in reducing the incidence [corrected] of RSV-related hospitalizations and was superior to palivizumab in reducing the incidence [corrected] of RSV-related medically attended [corrected] outpatient visits for lower respiratory tract infections in high-risk infants. In terms of safety, motavizumab has been demonstrated to be comparable with palivizumab. Until an effective prophylactic vaccine is developed, motavizumab could potentially become the first-line preventive agent against RSV disease in specific high-risk patients.

Respiratory syncytial virus (RSV) prevention and treatment: past, present, and future.

Respiratory syncytial virus (RSV) is a very important pathogen worldwide. It occurs and recurs naturally throughout life. Both short and long term morbidity, and mortality are particularly significant for infants, especially those infants with underlying conditions and risk factors. Current treatment strategies for these patients (e.g Ribavirin) are limited but several new interventions (e.g. RSV604, BTA9881, ALN-RSV01) are under investigation. Several preventive agents and strategies have been developed (e.g. RSV-IGIV, palivizumab) and others are in the pipeline (e.g. motavizumab) and under development (e,g, Medi-557). In this article, we review the RSV clinical condition with a focus on the highest risk populations. In addition we review prevention and treatment strategies of the past, present and future for these high-risk patients. This review should provide a single valuable source of information to clinicians and investigators.