Hilde Giezek

Bowel colonization with resistant gram-negative bacilli after antimicrobial therapy of intra-abdominal infections: observations from two randomized comparative clinical trials of ertapenem therapy

The selection of resistant gram-negative bacilli by broad-spectrum antibiotic use is a major issue in infection control. The aim of this comparative study was to assess the impact of different antimicrobial regimens commonly used to treat intra-abdominal infections on the susceptibility patterns of gram-negative bowel flora after completion of therapy. In two international randomized open-label trials with laboratory blinding, adults with complicated intra-abdominal infection requiring surgery received piperacillin-tazobactam (OASIS 1) or ceftriaxone/metronidazole (OASIS II) versus ertapenem for 4–14 days. Rectal swabs were obtained at baseline, end of therapy, and 2 weeks post-therapy. Escherichia coli and Klebsiella spp. were tested for production of extended-spectrum β-lactamase (ESBL). Enterobacteriaceae resistant to the agent used were recovered from 19 of 156 (12.2%) piperacillin-tazobactam recipients at the end of therapy compared to 1 (0.6%) patient at baseline (p<0.001) in OASIS I, and from 33 of 193 (17.1%) ceftriaxone/metronidazole recipients at the end of therapy compared to 5 (2.6%) patients at baseline (p<0.001) in OASIS II. Ertapenem-resistant Enterobacteriaceae were recovered from 1 of 155 and 1 of 196 ertapenem recipients at the end of therapy versus 0 and 1 ertapenem recipients at baseline in OASIS I and II, respectively. Resistant Enterobacteriaceae emerged significantly less often during treatment with ertapenem than with the comparator in both OASIS I (p<0.001) and OASIS II (p<0.001). The prevalence of ESBL-producers increased significantly during therapy in OASIS II among 193 ceftriaxone/metronidazole recipients (from 4 [2.1%] to 18 [9.3%]) (p<0.001), whereas no ertapenem recipient was colonized with an ESBL-producer at the end of therapy in either study. Selection for imipenem-resistant Pseudomonas aeruginosa was uncommon in all treatment groups. In these studies, the frequency of bowel colonization with resistant Enterobacteriaceae substantially increased in patients treated with either piperacillin-tazobactam or ceftriaxone/metronidazole, but not in patients treated with ertapenem.

Once-Weekly Oral Alendronate 70 mg in Patients with Glucocorticoid-Induced Bone Loss: A 12-Month Randomized, Placebo-Controlled Clinical Trial

Objective. Glucocorticoid-induced osteoporosis is the most common iatrogenic form of osteoporosis. We evaluated the efficacy and safety of once-weekly bisphosphonate therapy for prevention and treatment of bone loss in patients on glucocorticoid therapy. Methods. We conducted a 12-month, multicenter, randomized, double-blind, placebo-controlled trial with 114 and 59 patients in the treatment and placebo arms, respectively. Participants were stratified according to the duration of prior oral glucocorticoid therapy at randomization. Participants received alendronate 70 mg once weekly (ALN OW) or placebo; all received supplemental daily calcium (1000 mg) and 400 IU vitamin D. Clinical evaluations were performed at baseline, 3, 6, 9, and 12 months. Results. At 12 months, there was a significant mean percentage increase from baseline in the ALN OW group for lumbar spine (2.45%), trochanter (1.27%), total hip (0.75%), and total body (1.70%) bone mineral density (BMD). Comparing ALN OW versus placebo at 12 months, a significant treatment difference for the mean percentage change from baseline was observed for lumbar spine (treatment difference of 2.92%; p ≤ 0.001), trochanter (treatment difference 1.66%; p = 0.007), and total hip (treatment difference 1.19; p = 0.008) BMD. Biochemical markers of bone remodeling also showed significant mean percentage decreases from baseline. Conclusion. Over 12 months ALN OW significantly increased lumbar spine, trochanter, total hip, and total body BMD compared with baseline among patients taking glucocorticoid therapy. A significant treatment difference versus placebo was observed at 12 months for the mean percentage change from baseline for lumbar spine, trochanter, and total hip.

Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial.

(Headache 2011;51:73‐84)

Efficacy and safety of ertapenem versus piperacillin-tazobactam for the treatment of intra-abdominal infections requiring surgical intervention

Complicated intra-abdominal infections usually mandate prompt surgical intervention supplemented by appropriate antimicrobial therapy. The aim of this study was to demonstrate that ertapenem was not inferior to piperacillin-tazobactam for the treatment of community-acquired intra-abdominal infections. A randomized open-label active-comparator clinical trial was conducted at 48 medical centers on four continents from December 2001 to February 2003. Adult patients with intra-abdominal infections requiring surgery were randomized to receive either ertapenem 1 g daily or piperacillin/tazobactam 13.5 g daily in 3–4 divided doses. The primary analysis of efficacy was the clinical response rate in clinically and microbiologically evaluable patients at the test-of-cure assessment 2 weeks after completion of therapy. All treated patients were included in the safety analysis. Patient demographics, disease characteristics, and treatment duration in both treatment groups were generally similar. The most commonly isolated pathogens at baseline were E coli (greater than 50% of cases in each group) and B fragilis (~9%). Favorable clinical response rates were 107/119 (90%) for ertapenem recipients and 107/114 (94%) for piperacillin/tazobactam recipients. The frequencies of drug-related adverse events, most commonly diarrhea and elevated serum alanine aminotransferase levels, were similar in both treatment groups. Six of 180 ertapenem recipients (3%) and two of 190 piperacillin/tazobactam recipients (1%) had serious drug-related adverse experiences. In this study, ertapenem and piperacillin/tazobactam were comparably safe and effective treatments for adult patients with complicated intra-abdominal infections.

The Efficacy of Montelukast during the Allergy Season in Pediatric Patients with Persistent Asthma and Seasonal Aeroallergen Sensitivity

Objective. To determine the effect of montelukast on asthma during the allergy season in children with persistent asthma and seasonal aeroallergen sensitivity. Design. This 3-week double-blind, placebo-controlled, parallel-group multicenter study compared daily montelukast 5 mg chewable tablets and placebo in patients 6–14 years of age with forced expiratory volume in 1 second (FEV1) ≥ 60 and ≤ 85% predicted, persistent asthma that is also active during allergy season, and documented sensitivity to seasonal allergens. Concomitant inhaled corticosteroid use was permitted in up to 40% of enrolled patients. The primary endpoint was the percentage change from baseline in FEV1 over 3 weeks of treatment. Additional endpoints included the percentage change from baseline in β -agonist use, average changes in daytime and nighttime symptom score, AM and PM peak expiratory flow rate (PEFR), investigators global asthma evaluation, and parent/guardian global asthma evaluation at the end of the treatment period. Adverse experiences (AEs) were collected to assess safety and tolerability. Results. A total of 421 patients were randomized to montelukast (N = 203) or placebo (N = 218). For the primary endpoint, the percentage change from baseline FEV1, montelukast was not significantly different from placebo (least squares mean 9.53% vs. 9.15%, respectively; p = 0.810). Compared with placebo, montelukast was associated with significantly lower (better) investigators global asthma evaluation (LS mean 2.71 vs. 2.98; p < 0.05) and parent/guardian global asthma evaluation (LS mean: 2.63 vs. 2.90; p < 0.05) scores. There were no significant differences between treatment groups for the other efficacy evaluations. Both treatments were well tolerated, with no significant differences observed in AE rates. Conclusion. Montelukast did not significantly improve FEV1 compared with placebo over three weeks of treatment during the allergy season in pediatric patients with seasonal allergen sensitivity. (ClinicalTrials.gov identifier: NCT00289874)

Extended-release niacin/laropiprant effects on lipoprotein subfractions in patients with type 2 diabetes mellitus.

BACKGROUND A potentially atherogenic lipid profile often found in patients with type 2 diabetes mellitus (T2DM) includes increased concentrations of small, low-density lipoprotein (LDL) and intermediate-density lipoprotein (IDL) and decreased concentration of medium/large high-density lipoprotein (HDL) particles. Extended-release niacin/laropiprant (ERN/LRPT) lowers LDL-cholesterol (LDL-C) and triglycerides (TG), and raises HDL cholesterol (HDL-C) levels with attenuation of niacin-induced flushing. METHODS Plasma HDL, LDL, IDL, very-low-density lipoprotein (VLDL), and chylomicron particle concentration and size at were evaluated at baseline and week 12 using nuclear magnetic resonance (NMR). The data were acquired from a randomized, multicenter, double-blind, placebo-controlled study including 796 patients with T2DM treated with either 1 tablet of ERN 1 gram/LRPT 20 mg or matching placebo daily, increased after 4 weeks to 2 tablets daily. RESULTS ERN/LRPT significantly (P≤0.001 for all) reduced LDL-C 17.9% and TG 23.1%, and increased HDL-C levels 23.2%. Compared to placebo, ERN/LRPT decreased LDL, IDL, VLDL, and chylomicron particle concentrations [median concentration of smallest LDL particles decreased 16.6%, 95% confidence interval (CI) -22.3, -10.9, whereas the largest LDL particles decreased 11.0%, 95% CI -18.7, -3.2, and total VLDL/chylomicron mean plasma particle concentration decreased 34.7%, 95% CI -41.3, -28.1]. Compared to placebo, ERN/LRPT shifted the distribution of HDL particle diameter from smaller to larger (median concentration of the largest HDL particles increased 32.7% (95% CI 25.30, 40.58), whereas concentration of the smallest HDL particles decreased 8.2% (95% CI -11.29, -5.06). CONCLUSIONS Compared with placebo in patients with T2DM, ERN/LRPT shifted the lipoprotein profile toward a potentially less atherogenic pattern with reduced atherogenic LDL and IDL particle concentrations, and increased large HDL plasma particle concentrations. (ClinicalTrials.gov: NCT00485758).

Predictors of asthma following severe respiratory syncytial virus (RSV) bronchiolitis in early childhood

We sought to identify predictors of asthma development following severe early childhood RSV bronchiolitis. Different definitions of asthma were also compared.