Anna-Bettina Haidich

Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis

BACKGROUND Multidrug resistance among bacteria increases the need for new antimicrobial drugs with high potency and stability. Tigecycline is one candidate drug, and a previous meta-analysis of only published randomised controlled trials suggested that it might as effective as comparator treatments; we did a meta-analysis to include new and unpublished trials to assess its efficacy for the treatment of adult patients with serious bacterial infection. METHODS We searched PubMed, Cochrane Central Register, and Embase up to March 30, 2011, to identify published studies, and we searched clinical trial registries to identify completed unpublished studies, the results of which were obtained through the manufacturer. Eligible studies were randomised trials assessing the clinical efficacy, safety, and eradication efficiency of tigecycline versus other antimicrobial agents for any bacterial infection. The primary outcome was treatment success in patients who received at least one dose of the study drug, had clinical evidence of disease, and had complete follow-up (the clinically assessable population). Meta-analysis was done with random-effects models because of heterogeneity across the trials. FINDINGS 14 randomised trials, comprising about 7400 patients, were included. Treatment success was lower with tigecycline than with control antibiotic agents, but the difference was not significant (odds ratio 0·87, 95% CI 0·74-1·02). Adverse events were more frequent in the tigecycline group than in the control groups (1·45, 1·11-1·88), with significantly more vomiting and nausea. All-cause mortality was higher in the tigecycline group than in the comparator groups, but the difference was not significant (1·28, 0·97-1·69). Eradication efficiency did not differ between tigecycline and control regimens, but the sample size for these comparisons was small. INTERPRETATION Tigecycline is not better than standard antimicrobial agents for the treatment of serious infections. Our findings show that assessment with unpublished studies is needed to make appropriate decisions about new agents. FUNDING None.

Any casualties in the clash of randomised and observational evidence?: No—recent comparisons have studied selected questions, but we do need more data

Randomised controlled trials and observational studies are often seen as mutually exclusive, if not opposing, methods of clinical research. Two recent reports, however, identified clinical questions (19 in one report,1 five in the other2) where both randomised trials and observational methods had been used to evaluate the same question, and performed a head to head comparison of them. In contrast to the belief that randomised controlled trials are more reliable estimators of how much a treatment works, both reports found that observational studies did not overestimate the size of the treatment effect compared with their randomised counterparts. The authors say that the merits of well designed observational studies may need to be re-evaluated: case-control and cohort studies may need to assume more respect in assessing medical therapies and largescale observational databases should be better exploited. 1 2 The first claim flies in the face of half a century of thinking, so are these authors right? The combined results from the two reports indeed show a striking concordance between the estimates obtained with the two research designs. A correlation analysis we performed on their combined databases found that the correlation coefficient between the odds ratio of randomised trials and the odds ratio of observational designs is 0.84 (P<0.001). This represents excellent concordance …

Increase in Oxidative Stress but Not in Antioxidant Capacity with Advancing Stages of Chronic Kidney Disease

Background/Aims: Increased oxidative stress in chronic kidney disease (CKD) was suggested to be both a cause and an effect of renal injury. However, the evolution of oxidant stress from early stages of renal function decline is not fully clear. This study aimed to determine the oxidant-antioxidant balance across the whole range of renal function. Methods: A total of 116 patients with CKD (85 predialysis patients divided into groups according to CKD stage, and 31 patients with end-stage renal disease (ESRD) on hemodialysis treatment), as well as 29 healthy subjects were evaluated. Plasma levels of 15-F2t-isoprostane (15-F2t-IsoP), a valid marker of oxidant stress, as well as total antioxidant capacity (TAC) and serum levels of vitamin E were measured in all participants. Results: Plasma 15-F2t-IsoP levels were higher in predialysis and ESRD patients compared to healthy subjects and were progressively increasing with advancing CKD stages (p < 0.001). In contrast, plasma TAC was similar between healthy subjects and predialysis patients, and presented a small reduction in ESRD patients (p < 0.001). Vitamin E levels were higher in healthy subjects compared to any other group (p < 0.001) and slightly higher in ESRD patients compared to predialysis patients (p < 0.01), but did not differ significantly between the groups of predialysis patients. Plasma 15-F2t-IsoP levels were inversely correlated with estimated glomerular filtration rate in predialysis patients (r = –0.65, p < 0.001). Conclusions: This study shows that 15-F2t-IsoP levels increase progressively with advancing CKD stages, whereas TAC and vitamin E levels remain rather stable with the loss of renal function and change only in patients with ESRD.

Patterns of patient enrollment in randomized controlled trials.

We aimed to describe enrollment patterns in a large cohort of randomized controlled trials (RCTs) and evaluate whether early recruitment predicts the ability of RCTs to reach their target enrollment. We considered all 77 efficacy RCTs initiated by the AIDS Clinical Trials Group between 1986 and 1996 (28,992 patients enrolled until November 1999). Thirteen RCTs (17%) failed to reach half their target recruitment. Enrollment trajectories showed that the initial rate of accrual determined the subsequent rates of enrollment. The target sample size was attained by 7/8, 11/14, 15/35 and 4/20 of trials with very rapid, rapid, moderate and slow enrollment during the first 3 months, respectively (P < 0.001). Enrollment during the first month or two strongly correlated with subsequent accrual (P < 0.001). The patient pool, the eligibility criteria, the attractiveness of a trial and adequacy of the network of clinical sites may influence RCT enrollment. Early enrollment offers strong evidence on the feasibility of a trial and is indicative of its future pace of recruitment.

A combination of the IPAG questionnaire and PiKo-6® flow meter is a valuable screening tool for COPD in the primary care setting.

AIMS To investigate the validity of the International Primary Care Airways Guidelines (IPAG) questionnaire and PiKo-6® (Ferraris Respiratory Europe Ltd.) flow meter as screening tools for diagnosing chronic obstructive pulmonary disease (COPD) in the primary care setting. METHODS The first 50 patients in 25 general practice offices completed the IPAG questionnaire and underwent spirometry with the handheld PiKo-6® flow meter. The results were compared with official spirometry parameters after bronchodilation. All participants had no previous medical diagnosis of respiratory diseases. RESULTS Data from 1,078 out of 1,250 subjects (462 males, mean age 65.3 ± 11.4 years) were analysed. The percentage of smokers was 48.4% (38 ± 29 pack-years). COPD was diagnosed in 111 (10.3%) patients. In the subgroup of smokers the sensitivity and specificity for COPD diagnosis were 91% and 49%, respectively, for the IPAG questionnaire; 80% and 95% respectively for the PiKo-6® spirometer; and 72% and 97% for their combination. The negative predictive value of the questionnaire was 97%, whereas the positive predictive value of the questionnaire/ PiKo-6® combination was 82%. Using a cut-off score of 19 points for the IPAG questionnaire, we calculated the best combination of sensitivity (75%) and specificity (72%). CONCLUSIONS The IPAG questionnaire and the hand-held PiKo-6® spirometer can be used in combination to increase the possibility of an early and accurate diagnosis of COPD in the primary care setting.

The quality of safety reporting in trials is still suboptimal: Survey of major general medical journals

OBJECTIVE To evaluate whether the quality of reporting harms improved after the publication of the Extension of the Consolidated Standards of Reporting Trials (CONSORT) statement and predictors that influence the safety reporting in randomized controlled trials (RCTs) STUDY DESIGN AND SETTING Systematic survey of published RCTs assessing drugs. In MEDLINE, we identified 228 RCTs published in Annals of Internal Medicine, British Medical Journal, Journal of American Medical Association, The Lancet, and The New England Journal of Medicine in 2003 and 2006. RESULTS The reporting of harms have improved over time both in quality and extent of space. However, the mean score as an overall measure of adequacy in reporting harms was 0.58 in 2003 and increased to 0.67 in 2006, indicating a moderate safety reporting. Safety was more adequate in trials with statistically significant results for efficacy, private funding, primary harms outcome, and anti-infective, antineoplasmatic, or immunosuppressive agents. CONCLUSION The use of the Extension of the CONSORT statement may be associated with improving the quality of safety reporting in RCTs, but there are still deficiencies that need to be corrected to use quantitative objective evidence for harms in performing meta-analyses and making therapeutic decisions.

Twenty-four-hour intraocular pressure control with bimatoprost and the bimatoprost/timolol fixed combination administered in the morning, or evening in exfoliative glaucoma

Aim To compare 24 h intraocular pressure (IOP) control of morning and evening administered bimatoprost/timolol fixed combination (BTFC) and evening administered bimatoprost in exfoliative glaucoma (XFG). Methods One eye of 60 XFG patients was included in this prospective, observer-masked, crossover comparison. Following wash-out, all patients received bimatoprost monotherapy for 6 weeks. They were then randomised to morning, or evening, administered BTFC for 3 months and then switched to the opposite therapy. Results At baseline, mean 24 h pressure was 29.0 mm Hg. Bimatoprost reduced the mean IOP by 8.1 mm Hg (27.8%, p<0.001). The evening administration of BTFC reduced 24 h IOP to a statistically lower level than morning administration (10.2 mm Hg (35.3%) vs 9.8 mm Hg (33.8%); p=0.005). Both dosing regimens reduced IOP significantly more than bimatoprost (p≤0.006, for all time points). A 24 h IOP reduction ≥30% was seen in 43 patients (72%) with evening BTFC compared with 39 patients (65%) with morning BTFC (p=0.344) and only 24 patients (40%) with bimatoprost monotherapy (p<0.001 vs both BTFC regimens). Conclusion Both BTFC dosing regimens significantly reduce 24 h IOP in XFG compared with bimatoprost monotherapy. The evening dosing gives rise to statistically better 24 h IOP control and could be considered in these patients.

Reporting of conflicts of interest in guidelines of preventive and therapeutic interventions

BackgroundGuidelines published in major medical journals are very influential in determining clinical practice. It would be essential to evaluate whether conflicts of interests are disclosed in these publications. We evaluated the reporting of conflicts of interest and the factors that may affect such disclosure in a sample of 191 guidelines on therapeutic and/or preventive measures published in 6 major clinical journals (Annals of Internal Medicine, BMJ, JAMA, Lancet, New England Journal of Medicine, Pediatrics) in 1979, 1984, 1989, 1994 and 1999.ResultsOnly 7 guidelines (3.7%) mentioned conflicts of interest and all were published in 1999 (17.5% (7/40) of guidelines published in 1999 alone). Reporting of conflicts of interest differed significantly by journal (p=0.026), availability of disclosure policy by the journal (p=0.043), source of funding (p < 0.001) and number of authors (p=0.004). In the entire database of 191 guidelines, a mere 18 authors disclosed a total of 24 potential conflicts of interest and most pertained to minor issues.ConclusionsDespite some recent improvement, reporting of conflicts of interest in clinical guidelines published in influential journals is largely neglected.

Twenty-four hour efficacy with preservative free tafluprost compared with latanoprost in patients with primary open angle glaucoma or ocular hypertension

Aim To compare 24 h intraocular pressure (IOP) control obtained with preservative free (PF) tafluprost 0.0015% versus branded preservative containing latanoprost 0.005% administered as first choice monotherapy in patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT). Methods This prospective, observer-masked, crossover study included consecutive newly diagnosed patients with POAG or OHT, and baseline IOP between 24 and 33 mm Hg. Qualifying patients underwent baseline untreated 24 h IOP monitoring in habitual positions, with Goldmann tonometry at times 10:00, 14:00, 18:00 and 22:00, and Perkins supine tonometry at times 02:00 and 06:00. They were then randomised to either latanoprost or tafluprost, administered in the evening, for 3 months and then switched to the opposite therapy for another 3 months. 24 h monitoring was repeated at the end of each treatment period. Results 38 patients completed the study. Mean untreated 24 h IOP (24.9 mm Hg) was significantly reduced with both prostaglandins (p<0.001). Tafluprost demonstrated similar mean 24 h efficacy compared with latanoprost (17.8 vs 17.7 mm Hg; p=0.417). Latanoprost demonstrated significantly better 24 h trough IOP (15.9 vs 16.3 mm Hg; p=0.041) whereas tafluprost provided significantly lower 24 h IOP fluctuation (3.2 vs 3.8 mm Hg; p=0.008). No significant difference existed between the two prostaglandins for any adverse event. Conclusions PF tafluprost achieved similar 24 h IOP reduction to branded latanoprost. The current study highlights the importance of complete assessment of efficacy over 24 h. Clinical trials registration NCT01162603.

Twenty-four-hour intraocular pressure control with the travoprost/timolol maleate fixed combination compared with travoprost when both are dosed in the evening in primary open-angle glaucoma

Objective: To evaluate the 24 h efficacy and safety of the travoprost/timolol maleate fixed combination (TTFC) versus travoprost when both are dosed in the evening in primary open-angle glaucoma patients. Methods: Prospective, double-masked, crossover, active-controlled, randomised 24 h comparison. After a 6 week medicine-free period, patients were randomised to either TTFC or travoprost for 8 weeks and were then switched to the opposite treatment for another 8 weeks. At the end of the washout and treatment periods, a 24 h pressure curve was performed. Results: Thirty-two patients completed the study. The TTFC group demonstrated a lower absolute intraocular pressure level (2.4 mm Hg) for the 24 h curve and at all time points, compared with travoprost (p⩽0.047). The pressure reduction from untreated baseline was significantly different between treatments for all time points (p = 0.018). The mean 24 h pressure fluctuation was lower with TTFC (3.0 mm Hg) compared with travoprost (4.0 mm Hg, p = 0.001). No statistical difference existed between the two treatment groups for any adverse event (p>0.05). Conclusions: This study suggests that when both drugs are dosed in the evening the TTFC provides improved intraocular pressure reduction, compared with travoprost, over the 24 h curve and for each individual time point in primary open-angle glaucoma patients.