Long-term Serologic Follow-up of Children Vaccinated with a Pediatric Formulation of Virosomal Hepatitis A Vaccine Administered With Routine Childhood Vaccines at 12-15 Months of Age.

BACKGROUND: The aim of this open-label, active-controlled, parallel group, phase 2 follow-up study was to assess the long-term immunogenicity of Epaxal Junior, the pediatric dose of an aluminum-free virosomal inactivated hepatitis A virus (HAV) vaccine, in children receiving routine childhood vaccines (RCV). METHODS: Healthy children (12-15 months old, ≥8 kg weight) were randomized (1:1:1) to group A: Epaxal Junior + RCV (day 1); group B: Epaxal Junior (day 1) + RCV (day 29) and group C: Havrix 720 + RCV (day 1). All 3 groups received 2 doses of HAV vaccines 6 months apart. Children who completed the primary study were followed up from 18 months to 7.5 years post booster. RESULTS: Of 291/327 randomized children who had completed the primary study, 157 were followed for the 7.5-year analysis (group A: 50; group B: 54; and group C: 53). Of these, 152 children had protective levels of anti-HAV antibodies [≥10 mIU/mL; 98% (group A); 96.3% (group B); 96.2% (group C)]. Anti-HAV geometric mean concentrations were similar in groups A and B at all the time points (1.5-, 2.5-, 3.5-, 5.25- and 7.5-year time point) but slightly lower in group C. Predictions of the median duration of persistence of seroprotective antibody levels, using the linear mixed model were similar in all groups: (group A: 19.1 years, group B: 18.7 years, group C: 17.3 years). CONCLUSIONS: Immunization with Epaxal Junior administered with RCVs at 12 months elicited protective response beyond 7.5 years in almost all children. Assessing the kinetic of anti-HAV antibody titers decline over time, the moment to reach antibody concentrations below the accepted protective level may occur earlier than previously estimated.

Comparison of the immunogenicity and safety of pentavalent vaccine Quinvaxem in a compact prefilled auto-disabled (cPAD) injection system versus single-dose vials in healthy infants: a phase 3, open-label, randomized, parallel-group, non-inferiority study.

OBJECTIVE: To evaluate non-inferiority of three doses of Quinvaxem in a compact prefilled auto-disabled (cPAD) injection system versus Quinvaxem in a single-dose vial administered with conventional syringe in terms of seroconversion/seroprotection rates for all antibodies (anti-hepatitis B (HB), anti-Haemophilus influenzae type b polyribosylribitol phosphate (Hib PRP), anti-diphtheria, anti-tetanus, anti-Bordetella pertussis) at 1 month after primary vaccination. METHODS: Four hundred healthy infants aged 42-65 days were randomized (1:1) to receive Quinvaxem in cPAD or single-dose vial at 6, 10, and 12 weeks of age. Blood samples were collected before vaccination and at 1 month after the third dose to determine seroconversion/seroprotection rates. Safety was assessed from solicited and unsolicited adverse events and serious adverse events (SAEs). RESULTS: Of the 400 infants randomized, 395 (98.8%) received all three vaccine doses. In the cPAD vs. single-dose vial groups, seroprotection rates against Hib PRP (both 98.5%), HB (92.9% vs. 93.4%), diphtheria (100% vs. 99%), and tetanus toxoids (both 100%), and seroconversion against B. pertussis (95.4% vs. 97%) were ≥92% at 1 month after the third vaccination (lower limits of 95% confidence intervals simultaneously greater than -10%). Geometric mean concentrations exceeded seroprotection/seroconversion thresholds by large margins. The incidences of induration and erythema were comparable between the groups; tenderness was slightly higher in the cPAD group (85.5% vs. 76.5%). No vaccine-related SAEs occurred. CONCLUSIONS: Quinvaxem in cPAD was non-inferior to single-dose vial with respect to seroprotection/seroconversion rates for all antibodies. Both presentations were well-tolerated.

Pharmacodynamic profiling of ceftobiprole for treatment of complicated skin and skin structure infections.

Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin (meticillin)-resistant staphylococci, was statistically noninferior to a combination of vancomycin plus ceftazidime in patients with complicated skin and skin structure infections (cSSSI). This analysis used data from this clinical trial to determine the relationship between therapeutic outcome and the percentage of time that the unbound ceftobiprole concentration exceeds the MIC (percent T>MIC). From the trial of ceftobiprole (500 mg every 8 h, 2-h infusion) for cSSSI due to gram-positive and/or gram-negative bacteria, data from 309 patients in the microbiological intent-to-treat analysis set with measured ceftobiprole concentrations and baseline MICs were used to assess the relationship between percent T>MIC and therapeutic outcome. Individual pharmacokinetic (PK) profiles were obtained from a three-compartment population PK model. The relationship between percent T>MIC and a clinical cure was determined. For the clinical trial dosing regimen, individual percent T>MICs were used to calculate fractional target attainment rates (TARs) for >or=30 and >or=50% T>MIC targets at various MICs. There was a statistically significant relationship between achieving a >or=30 or >or=50% T>MIC and a clinical cure (P = 0.003 and P = 0.007, respectively; Pearson's chi(2) test). The fractional TAR was greater than 90% at a MIC of MIC and a clinical cure with ceftobiprole was demonstrated. A ceftobiprole regimen of 500 mg every 8 h as a 2-h infusion has a high probability of achieving a target of >or=30 or >or=50% T>MIC for patients with cSSSI due to gram-positive and gram-negative pathogens.

A randomized comparative study of levofloxacin versus amoxicillin/clavulanate for treatment of infants and young children with recurrent or persistent acute otitis media.

BACKGROUND: The need for alternative antimicrobial therapy for recurrent and persistent acute otitis media (AOM) in children has raised interest in assessing the efficacy and safety of fluoroquinolones for treatment of these infections. METHODS: In an evaluator-blinded, active-comparator, noninferiority, multicenter study, children (6 months to <5 years) were randomized 1:1 to receive levofloxacin (10 mg/kg twice daily) or amoxicillin/clavulanate (14:1; amoxicillin 45 mg/kg twice daily) for 10 days, with evaluations 4-6 days of therapy (visit 2), 2-5 days after completing therapy (visit 3), and 10-17 days after last dose (visit 4). Primary outcome was clinical cure at visit 3 based on resolution of clinical signs and symptoms of AOM. RESULTS: A total of 1650 children were randomized and 1305 were clinically evaluable at visit 3 (630 levofloxacin, 675 comparator). Clinical cure rates were 72.4% (456 of 630) in levofloxacin-treated and 69.9% (472 of 675) in amoxicillin/clavulanate-treated children. Cure rates were also similar for levofloxacin and comparator for each age group (< or =24 months: 68.9% versus 66.2%; >24 months: 76.9% versus 75.1%; respectively). Cure rates at visit 4 were 74.9% and 73.8% in levofloxacin and amoxicillin/clavulanate groups, respectively. The upper limits of the confidence intervals were less than the noninferiority margin of 10% indicating that levofloxacin treatment is noninferior to comparator treatment overall and in both infants (6 months to 2 years) and children 2-5 years. No differences between treatment groups regarding the frequency or type of adverse events were apparent. CONCLUSIONS: Levofloxacin was not inferior to amoxicillin/clavulanate for the treatment of recurrent and/or persistent AOM in infants and children.

A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skin-structure infections.

BACKGROUND: A randomized, double-blind, multicenter trial involving patients with a broad range of complicated skin and skin-structure infections due to either gram-positive or gram-negative bacteria was conducted to compare ceftobiprole monotherapy with treatment with vancomycin plus ceftazidime. METHODS: Patients were randomized 2:1 to receive ceftobiprole or to receive vancomycin plus ceftazidime. Outcomes were determined at a test-of-cure visit (7-14 days after completion of therapy) and were analyzed for all patients with complicated skin and skin-structure infections, as well as for subgroups, on the basis of major types of infections and severity of disease. RESULTS: Among the clinically evaluable and the intent-to-treat populations, clinical cure rates at the test-of-cure visit were similar in the ceftobiprole and comparator treatment arms (clinical cure rate, 90.5% [439 of 485 patients] and 90.2% [220 of 244 patients] in the clinically evaluable population, respectively; 81.9% [448 of 547 patients] and 80.8% [227 of 281 patients] in the intent-to-treat population, respectively). Clinical cure rates in ceftobiprole-treated patients ranged from 86.2% (125 of 145 patients) among those with diabetes who had foot infections to 93.0% (80 of 86 patients) among those with cellulitis. Among patients treated with ceftobiprole, clinical cure rates were similar among patients from whom gram-negative bacteria were isolated (87.9% [109 of 124 patients]) and among patients from whom gram-positive bacteria were isolated (91.8% [292 of 318 patients]) and were not statistically different from the clinical cure rates among comparator-treated patients (89.7% [61 of 68 patients] and 90.3% [149 of 165 patients], respectively). Rates of adverse events and serious adverse events in the 2 treatment groups were similar. CONCLUSIONS: Ceftobiprole monotherapy is as effective as vancomycin plus ceftazidime for treating patients with a broad range of complicated skin and skin-structure infections and infections due to gram-positive and gram-negative bacteria.

Comparative safety profile of levofloxacin in 2523 children with a focus on four specific musculoskeletal disorders.

BACKGROUND: Fluoroquinolones, including levofloxacin, have not been recommended for use in children largely because studies in juvenile laboratory animals suggest there may be an increased risk of fluoroquinolone-associated cartilage lesions. A large prospective trial is needed to assess the risks associated with using levofloxacin in children. OBJECTIVE: Assess the safety and tolerability of levofloxacin therapy in children based on observations for 1 year after therapy. METHODS: Safety data were collected in children who participated in 1 of 3 efficacy trials (N = 2523) and a subset of these children who also subsequently participated in a long-term 1-year surveillance trial (N = 2233). Incidence of adverse events in children randomized to receive levofloxacin versus nonfluoroquinolone antibiotics was compared. Based on assessments by treating physicians and an independent data safety monitoring committee, events related to the musculoskeletal system were further categorized as 1 of 4 predefined musculoskeletal disorders (arthralgia, arthritis, tendinopathy, gait abnormality) considered most likely clinical correlates of fluoroquinolone-associated cartilage lesions observed in laboratory animals. RESULTS: Levofloxacin was well tolerated during and for 1 month after therapy as evidenced by similar incidence and character of adverse events compared with nonfluoroquinolone antibiotics. However, incidence of at least 1 of the 4 predefined musculoskeletal disorders (largely due to reports of arthralgia) was greater in levofloxacin-treated compared with nonfluoroquinolone-treated children at 2 months (2.1% vs. 0.9%; P = 0.04) and 12 months (3.4% vs. 1.8%; P = 0.03) after starting therapy. CONCLUSIONS: The incidence of 1 or more of the 4 predefined musculoskeletal disorders identified in nonblinded, prospective evaluations, was statistically greater in levofloxacin-treated compared with comparator-treated children.