Long-term administration of quarterly IV ibandronate is effective and well tolerated in postmenopausal osteoporosis: 5-year data from the DIVA study long-term extension.

UNLABELLED: Long-term bone mineral density (BMD) gains, bone marker levels, and safety of 3 mg quarterly intravenous (IV) ibandronate were studied in this 3-year extension to the Dosing IntraVenous Administration (DIVA) trial. Quarterly IV ibandronate consistently increased lumbar spine bone mineral density measured with dual-energy X-ray absorptiometry (DXA-BMD) over 5 years (8.1%) and was well tolerated in women with postmenopausal osteoporosis. INTRODUCTION: Treatment with IV ibandronate regimens, 2 mg bimonthly and 3 mg quarterly, has been studied for up to 5 years in a long-term extension (LTE) to the 2-year DIVA trial. METHODS: DIVA LTE is an open-label extension to a 2-year randomized, double-blind, double-dummy, noninferiority, phase III study (DIVA core). DIVA LTE involved postmenopausal women who had completed 2 years of DIVA core, comparing daily oral and IV ibandronate (≥75% adherence with IV ibandronate in year 2 of DIVA). Patients previously treated with 2 mg bimonthly or 3 mg quarterly IV ibandronate continued on the same regimen; patients who had received 2.5 mg daily oral ibandronate and placebo IV in DIVA core were switched to IV ibandronate. RESULTS: Pooled analysis of 497 intent-to-treat (ITT) patients receiving IV ibandronate from DIVA core baseline showed consistent increases over 5 years in lumbar spine DXA-BMD (8.4% [95% confidence interval (CI) = 7.5, 9.3] with 2 mg bimonthly and 8.1% [95% CI = 7.2, 8.9] with 3 mg quarterly). Three-year data relative to DIVA LTE baseline in the full ITT population (756 patients randomized or reallocated from DIVA, including those previously on daily treatment) showed maintenance of DXA-BMD gains from DIVA core with further gains in lumbar spine DXA-BMD. These benefits are supported by sustained reductions in markers of bone metabolism. No tolerability concerns or new safety signals were observed. CONCLUSIONS: Treatment with IV ibandronate 2 mg bimonthly or 3 mg quarterly is effective and well tolerated for up to 5 years in women with postmenopausal osteoporosis.

Intravenous ibandronate injections given every three months: a new treatment option to prevent bone loss in postmenopausal women.

OBJECTIVE: To investigate the efficacy, safety, and dose response of three doses of ibandronate, given intermittently by intravenous (IV) injection every three months, in preventing postmenopausal osteoporosis. PATIENTS AND METHODS: 629 postmenopausal women, categorised according to time since menopause and baseline lumbar spine (L1-4) bone mineral density (BMD), were enrolled into a multicentre, double blind, placebo controlled trial. They were randomly allocated to receive IV ibandronate 0.5 mg, 1 mg or 2 mg, or placebo every three months. All women received daily calcium supplementation. RESULTS: One year's treatment with intermittent IV ibandronate injections produced a dose dependent gain in mean (SD) lumbar spine BMD from baseline of 2.5 (2.5)%, 1.8 (2.6)%, and 1.0 (2.8)% in the groups receiving 2 mg, 1 mg, and 0.5 mg ibandronate, respectively, compared with a loss of BMD of 0.4 (2.4)% in the women in the placebo group; p=0.0001 for each ibandronate dose v placebo. Highest BMD gains occurred in women with osteopenia receiving 2 mg ibandronate. Similarly, at the hip, all three doses of ibandronate produced significantly better gains in BMD than placebo (p<0.05), with the greatest gains in the women with osteopenia receiving the 2 mg dose. Ibandronate concomitantly and dose dependently suppressed markers of bone turnover in comparison with placebo, and injections were well tolerated. CONCLUSION: IV ibandronate injections, given every three months, may be an effective alternative to oral bisphosphonates and hormonal therapy in the prevention of bone loss in postmenopausal women.

Oral weekly ibandronate prevents bone loss in postmenopausal women.

OBJECTIVES: To investigate the efficacy, safety, and dose-response of once-weekly oral ibandronate in the prevention of postmenopausal bone loss. DESIGN: This was a multi-centre, placebo-controlled, double-blind, randomized, 24-month phase II/III dose-finding study. SETTING: Primary care units in 14 osteoporosis centres. SUBJECTS: A total of 630 women were stratified into four strata according to time since menopause (TSM, 1-3 vs. >3 years) and baseline bone mineral density (BMD; normal: T-score > or =1 vs. osteopenic: -2.5 < or = T-score < or = 1) of the lumbar spine. INTERVENTIONS: Within each stratum women were further randomized to receive once-weekly ibandronate (5, 10, or 20 mg week-1) or placebo for 24 months. MAIN OUTCOME MEASURES: Efficacy parameters were the relative changes from baseline in spine (L1-4) and hip BMD, and biochemical markers of bone turnover (serum and urinary C-telopeptide of collagen type I (CTx), osteocalcin, and alkaline phosphatase) measured by dual energy X-ray absorptiometry and enzyme immunoassays, respectively. RESULTS: Once-weekly therapy with ibandronate induced dose-dependent increases in spine and hip BMD. At month 24, differences between the relative changes in spine and hip BMD induced by 20 mg ibandronate and placebo was 4.0 and 2.7%, respectively. Similar or more pronounced differences were seen in osteopenic women of TSM 1-3 years (5.3 and 3.5%) and of TSM >3 years (3.5 and 2.9%), respectively. A dose-dependent suppression of all biochemical markers of bone turnover was observed with significant decreases in the 20 mg dose groups of all strata at month 24. The overall safety results indicated that once-weekly oral ibandronate was well-tolerated at all three doses. CONCLUSION: Once-weekly oral therapy with 20 mg ibandronate provides an effective and safe therapy for the prevention of postmenopausal bone loss.

Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients.

OBJECTIVE: Phase III study to confirm a trend observed in a previous phase II study showing that a single dose of lenercept, human recombinant p55 tumor necrosis factor receptor-immunoglobulin G1 (TNFR55-IgG1) fusion protein, decreased mortality in patients with severe sepsis or early septic shock. DESIGN: Multicenter, double-blind, phase III, placebo-controlled, randomized study. SETTING: A total of 108 community and university-affiliated hospitals in the United States (60), Canada (6) and Europe (42). PATIENTS: A total of 1,342 patients were recruited who fulfilled the entry criteria within the 12-hr period preceding the study drug administration. INTERVENTION: After randomization, an intravenous dose of 0.125 mg/kg lenercept or placebo was given. The patient was monitored for up to 28 days, during which standard diagnostic, supportive, and therapeutic care was provided. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was 28-day all-cause mortality. Baseline characteristics were as follows: a total of 1,342 patients were randomized; 662 received lenercept and 680 received placebo. The mean age was 60.5 yrs (range, 17-96 yrs); 39% were female; 65% had medical admissions, 8% had scheduled surgical admissions, and 27% had unscheduled surgical admissions; 73% had severe sepsis without shock, and 27% had severe sepsis with early septic shock. Lenercept and placebo groups were similar at baseline with respect to demographic characteristics, simplified acute physiology score II-predicted mortality, profiles of clinical site of infection and microbiological documentation, number of dysfunctioning organs, and interleukin-6 (IL-6) plasma concentration. Lenercept pharmacokinetics were similar in severe sepsis and early septic shock patients. Tumor necrosis factor was bound in a stable manner to lenercept as reflected by the accumulation of total serum tumor necrosis factor alpha concentrations. There were 369 deaths, 177 on lenercept (27% mortality) and 192 on placebo (28% mortality). A one-sided Cochran-Armitage test, stratified by geographic region and baseline, predicted 28-day all-cause mortality (simplified acute physiology score II), gave a p value of .141 (one-sided). Lenercept treatment had no effect on incidence or resolution of organ dysfunctions. There was no evidence that lenercept was detrimental in the overall population. CONCLUSION: Lenercept had no significant effect on mortality in the study population.

Frequency and transferability of trimethoprim and sulfonamide resistance in methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis.

A total of 374 Staphylococcus aureus and 126 Staphylococcus epidermidis strains from 14 countries were studied for their resistance to methicillin, trimethoprim (Tp) and sulfonamides (Su), alone and combined (TpSu). The frequency of resistance to Tp, Su and TpSu was much higher in methicillin-resistant S. epidermidis (MRSE) than in methicillin-resistant S. aureus (MRSA). Considerable differences, however, existed in isolates from different countries. Resistance to Tp, Su or TpSu in MRSA was low or absent in isolates from Switzerland, Spain, Japan, Mexico, Argentina and Chile, but high in isolates from Germany and Brazil. High level Tp resistance mostly resided on large plasmids. It could be transferred in 17 out of 97 strains. Su resistance was never cotransferred. Strains cured of their large Tp resistance plasmids remained Su-resistant, which suggests a chromosomal location of Su resistance.

Effectiveness of cefetamet pivoxil in the treatment of pyelonephritis in children.

Cefetamet pivoxil was investigated in an open, randomized comparative study involving a total of 37 children with acute pyelonephritis, whose ages ranged from 2 to 14 years. The patients received either 10 mg/kg (n = 18) or 20 mg/kg (n = 8) cefetamet pivoxil twice daily, or 30-50 mg/kg amoxycillin/clavulanic acid three times daily (n = 11) for a period of 7-10 days. Escherichia coli was the main causative agent isolated in 28 (75.7%) of the patients; other pathogens included Proteus mirabilis (three patients). Proteus species (one patient), Klebsiella pneumoniae (two patients), Pseudomonas diminuta (one patient) and mixed infections (three patients). No differences in the overall treatment outcome could be observed between the treatment regimens used and, at the end of treatment, all pathogens were eradicated with neither relapse, nor persistence of the isolated pathogen, nor reinfection occurring. The clinical signs and symptoms had subsided in all patients at treatment end and the tolerability of the trial drugs was found to be satisfactory with no premature treatment withdrawal required. It is concluded that cefetamet pivoxil in the standard twice-daily dose of 10 mg/kg was equally effective and as well tolerated as 20 mg/kg cefetamet pivoxil given twice daily or 30-50 mg/kg amoxycillin/clavulanic acid given three times daily.

Identical genes for trimethoprim-resistant dihydrofolate reductase from Staphylococcus aureus in Australia and central Europe.

The nucleotide sequence of a 1.25 kb BglII/EcoRI fragment from the 34 kb trimethoprim (Tp)-resistant plasmid pABU1 of Staphylococcus aureus 157/4696, isolated in Zürich, was determined. It contained the entire Tp-resistant dihydrofolate reductase gene, 197 bp of the thymidylate synthetase, 395 bp of a truncated gene and 111 bp of IS257R1. With the exception of one single base pair at position of 862 the sequence of the whole fragment was identical to nucleotides 1633 to 2885 of the Tp-resistant transposon Tn4003 in plasmid pSK1 from an Australian S. aureus isolate. This suggests the worldwide dissemination of Tn4003 in multiresistant Staphylococci.

Clinical consequences of development of resistance to third generation cephalosporins.

Eighteen patients are described in whom initially sensitive microorganisms were replaced by resistant isolates during administration of ceftriaxone (n = 8), cefoperazone (n = 5), moxalactam (n = 4), cefotaxime (n = 2) or ceftazidime (n = 1), despite combination with aminoglycosides. All patients had documented gram-negative infections; in 12 patients underlying haematological diseases were present. Resistant strains of Enterobacter cloacae (14), Serratia marcescens (4), Klebsiella oxytoca (3), Pseudomonas aeruginosa (2) and Citrobacter freundii (2) emerged within 2 to 19 (mean 9) days after the beginning of treatment. In 12 patients relapse or secondary infections occurred. Seven of the patients with haematological disorders died. Resistance development was seen in 8 of 29 patients on ceftriaxone and 4 of 10 patients on moxalactam during prospective evaluations; the other drugs were used sporadically. Thus, selection of resistant bacteria is relatively frequent and may have serious clinical consequences in patients with impaired host-defense mechanisms.