Development of a PIV-vectored RSV vaccine: preclinical evaluation of safety, toxicity, and enhanced disease and initial clinical testing in healthy adults.

MEDI-534 is a bivalent live attenuated vaccine candidate against human respiratory syncytial virus (hRSV) and human parainfluenza virus type 3 (hPIV3) that was previously shown to be immunogenic and to protect rodents and African green monkeys from wild-type (wt) hRSV challenge. We performed further preclinical evaluations to address the safety of MEDI-534 prior to human testing. MEDI-534 did not predispose rodents to enhanced RSV disease following wt-RSV challenge, and the tissue tropism of the chimeric virus was confined to the respiratory tract. Representative clinical trial material did not produce toxicity in rats. In adults, MEDI-534 was highly restricted in replication, did not boost RSV and PIV3 antibody titers, and produced no medically significant vaccine-related adverse events thereby warranting further evaluation in pediatric populations.

Safety and immunogenicity of concurrent administration of live attenuated influenza vaccine with measles-mumps-rubella and varicella vaccines to infants 12 to 15 months of age.

OBJECTIVE: This study evaluated the safety, tolerability, and immunogenicity of live attenuated influenza vaccine administered concurrently with measles-mumps-rubella vaccine and varicella vaccine to healthy children 12 to 15 months of age. METHODS: Children were assigned randomly to receive (1) measles-mumps-rubella vaccine, varicella vaccine, and intranasal placebo on day 0, followed by 1 dose of live attenuated influenza vaccine on days 42 and 72; (2) measles-mumps-rubella, varicella, and live attenuated influenza vaccines on day 0, followed by a second dose of live attenuated influenza vaccine on day 42 and intranasally administered placebo on day 72; or (3) 1 dose of live attenuated influenza vaccine on days 0 and 42, followed by measles-mumps-rubella and varicella vaccines on day 72. Serum samples were collected before vaccination on days 0, 42, and 72. Reactogenicity events and adverse events were collected through day 41 after concurrent vaccinations and through day 10 after administration of live attenuated influenza vaccine or placebo alone. RESULTS: Among 1245 (99.5%) evaluable children, seroresponse rates and geometric mean titers for measles-mumps-rubella vaccine and varicella vaccine were similar with concurrent administration of live attenuated influenza vaccine or placebo (seroresponse rates of > or = 96% for measles-mumps-rubella vaccine and > or = 82% for varicella vaccine in both groups). Hemagglutinin-inhibiting antibody geometric mean titers and seroconversion rates to influenza strains in live attenuated influenza virus vaccine were similar after the vaccine was administered alone (seroconversion rates of 98%, 92%, and 44% for H3, B, and H1 strains, respectively) or with measles-mumps-rubella and varicella vaccines (seroconversion rates of 98%, 96%, and 43%). The incidences of reactogenicity events and adverse events were similar among treatment groups. CONCLUSIONS: Concurrent administration of live attenuated influenza vaccine with measles-mumps-rubella vaccine and varicella vaccine provided equivalent immunogenicity, compared with separate administration, and was well tolerated.

Linezolid versus cefadroxil in the treatment of skin and skin structure infections in children.

BACKGROUND: Skin and skin structure infections are common reasons for visits to pediatricians, accounting for up to 18%. Staphylococcus aureus and Streptococcus pyogenes are the most frequently isolated Gram-positive pathogens in uncomplicated skin infections. Increasingly outpatient infections involve antibiotic-resistant Gram-positive pathogens including methicillin-resistant S. aureus. METHODS: This randomized, blinded, comparator-controlled, multinational trial compared the efficacy and safety of linezolid and cefadroxil for treatment of uncomplicated skin/skin structure infections in pediatric patients. Children ages 5 to 11 years were to receive linezolid suspension [10 mg/kg (up to 600 mg)] or cefadroxil suspension [15 mg/kg (up to 500 mg)] every 12 h. Patients ages 12 to 17 years were to receive linezolid tablets (600 mg) or cefadroxil capsules (500 mg) every 12 h. Therapy lasted 10 to 21 consecutive days with a follow-up visit 10 to 21 days posttherapy. RESULTS: Linezolid and cefadroxil were consistently effective treatments across all primary and secondary efficacy assessments. At follow-up cure rates were 88.7% (205 of 231) for linezolid-treated and 86.2% (193 of 224) for cefadroxil-treated intent-to-treat patients; cure rates were 91.0% (201 of 221) for linezolid-treated and 90.0% (189 of 210) for cefadroxil-treated clinically evaluable patients. S. aureus was eradicated in 89.6% (120 of 134) linezolid-treated and 88.8% (111 of 125) cefadroxil-treated microbiologically evaluable patients. Gastrointestinal complaints were the most common adverse events reported, without significant differences between treatment groups, and myelosuppression was not observed in this study. CONCLUSIONS: Linezolid is well-tolerated and as effective as cefadroxil in treating uncomplicated skin infections in pediatric patients. Linezolid effectively treated infections caused by S. aureus, methicillin-resistant S. aureus and S. pyogenes.

Bacterial toxins and enteral feeding of premature infants at risk for necrotizing enterocolitis.

Bacterial translocation and enteral feeding are factors implicated in neonatal necrotizing enterocolitis (NEC) in the preterm infant. A cohort of 60 preterm low birth-weight (LBW) infants (600-1,600 g at birth) consecutively admitted to the neonatal intensive care unit (NICU; N = 183) were prospectively followed to evaluate the role of bacterial endotoxins (lipopolysaccharides) and enteral feeding in the development of NEC. Stage I NEC was identified in 14/60 (23%) infants. In all, 15% (9/60) of infants followed, which represented roughly 5% of higher risk, LBW infants admitted to the NICU, progressed to Stage II or III NEC disease. Infants not enterally fed (nothing by mouth [NPO]) were at greatest risk of developing NEC. No infant who was breast milk fed progressed to Stage II or III NEC. The protective effect of breast milk was most evident when compared with the combined group of NPO or formula-feeding infants per person-week at risk (RR = .15, P < .04). Toxin-producing bacteria and endotoxin levels in stool filtrates predicted early and advanced stages of NEC disease. Cytokine concentrations (interleukin-6 [IL-6]) in stool appeared of limited value in reflecting mucosally limited disease in the gastrointestinal tract. Overgrowth of toxin-producing bacteria and their toxin products may adversely affect gut barrier function; monitoring endotoxin concentrations in stool filtrates may be most clinically useful in NPO and formula-fed infants identified at risk of developing NEC. Am. J. Hum. Biol. 10:211-219, 1998. © 1998 Wiley-Liss, Inc.