Robert Lupinacci

Global Distribution and Outcomes for Candida Species Causing Invasive Candidiasis: Results from an International Randomized Double-Blind Study of Caspofungin Versus Amphotericin B for the Treatment of Invasive Candidiasis

AbstractIn a randomized study, caspofungin was compared with amphotericin B for the treatment of invasive candidiasis in a total of 239 adults from 56 sites in 20 countries. This study provided a unique opportunity to assess the frequency and outcome of invasive candidiasis caused by different Candida species worldwide, and the results are presented here. Efficacy was primarily assessed at the end of intravenous therapy using a modified intent-to-treat (MITT) analysis. This analysis was performed on 224 of the 239 patients enrolled in the study. Attempts were made to collect baseline Candida isolates from all patients for species identification at a central laboratory. Yeasts were identified to the species level using two commercial systems and microscopic examination. Viable baseline isolates were recovered from 210 of the 224 (94%) patients included in the MITT analysis. Candida albicans was the most frequently isolated species in all regions and was responsible for 45% of cases overall. Nevertheless, the majority of cases of infection were caused by non-albicans Candida species. In the USA and Canada, Candida glabrata was the second most commonly isolated pathogen (18%). In contrast, Candida parapsilosis and Candida tropicalis accounted for 55% of cases in Latin America. Outcomes were comparable for patients treated with caspofungin (74% overall; 64% and 80% for infections due to Candida albicans and non-albicans species) and amphotericin B (62% overall; 58% and 68% for infections due to Candida albicans and non-albicans species), and were generally similar across continents. The distribution of Candida species isolated from patients enrolled in a clinical trial may not be representative of pathogens causing invasive candidiasis in the general population. Nevertheless, our findings may affect the regional choice of empirical antifungal therapy for seriously ill patients with suspected or documented invasive candidiasis since different Candida species have varying susceptibility to conventional antifungal drugs.

Randomized Clinical Trial of the Efficacy and Safety of Preservative-free Tafluprost and Timolol in Patients With Open-Angle Glaucoma or Ocular Hypertension

PURPOSE To compare the efficacy and safety of tafluprost, a preservative-free (PF) prostaglandin analogue, with PF timolol in patients with open-angle glaucoma or ocular hypertension. DESIGN Randomized, double-masked, multicenter clinical trial. METHODS After discontinuation and washout of existing ocular hypotensive treatment, patients who had intraocular pressure (IOP) ≥23 and ≤36 mm Hg in at least 1 eye at the 08:00 hour time point were randomized 1:1 to 12 weeks of treatment with either PF tafluprost 0.0015% or PF timolol 0.5%. IOP was measured 3 times during the day (08:00, 10:00, 16:00 hours) at baseline and at weeks 2, 6, and 12. It was hypothesized that PF tafluprost would be noninferior to PF timolol over 12 weeks with regard to change from baseline IOP. The trial was powered for a noninferiority margin of 1.5 mm Hg at each of the 9 time points assessed. RESULTS A total of 643 patients were randomized and 618 completed (PF tafluprost = 306, PF timolol = 312). IOPs at the 3 time points assessed during the baseline visit ranged from 23.8 to 26.1 mm Hg in the PF tafluprost group and 23.5 to 26.0 mm Hg in the PF timolol group. IOPs at the 3 time points assessed during the 12-week visit ranged from 17.4 to 18.6 mm Hg for PF tafluprost and 17.9 to 18.5 mm Hg for PF timolol. At all 9 time points, the upper limits of the 2-sided 95% confidence intervals for the difference between treatments in IOP lowering were less than the prespecified noninferiority margin. Similar percentages of PF tafluprost and PF timolol patients reported ocular pain/stinging/irritation (4.4% vs 4.6%) and pruritus (2.5% vs 1.5%). The percentages of PF tafluprost and PF timolol patients reporting conjunctival hyperemia were 4.4% vs 1.2% (nominal P = .016). CONCLUSIONS The IOP-lowering effect of PF tafluprost was noninferior to that of PF timolol. PF tafluprost is an efficacious and generally well-tolerated ocular hypotensive agent.

Response and Relapse Rates of Candidal Esophagitis in HIV-Infected Patients Treated with Caspofungin

Caspofungin is a new antifungal drug of the echinocandin class. We analyzed the clinical efficacy of caspofungin (50 mg/day) in the treatment of HIV-infected adults with endoscopically documented Candida esophagitis and enrolled in four clinical trials of caspofungin. Symptoms were evaluated daily; a favorable outcome required complete resolution of all esophageal symptoms assessed at the time of discontinuation of therapy. Relapse was defined as recurrent symptoms during the subsequent 2 weeks. A multivariate logistic regression model was developed to identify potential factors (including severity of symptoms at presentation, CD4(+) cell count on entry, extent of disease [assessed endoscopically at baseline], causative Candida species, duration of therapy [overall and after resolution of symptoms], time on treatment before symptom resolution, and antifungal prophylaxis) that might predict symptomatic relapse in the 2 weeks following completion of therapy. The median CD4(+) lymphocyte count for the entire population was 31/mm(3). Candida albicans was isolated from 109 of 110 patient samples cultured for the pathogen and constituted the sole isolate in 77%. Extensive esophageal involvement was present in 55% of patients at the time of pretreatment endoscopy. The duration of therapy ranged from 7 to 20 days (median, 12 days). Symptoms resolved in 117 of 123 patients (95%; 95% confidence interval, 90-98%) with a median time of ~4 days. Response rates were 43 of 46 (93%) and 70 of 73 (96%) for patients with greater or fewer than 50 CD4(+) cells/mm(3), and 80 of 85 (94%) and 23 of 24 (96%) in infections caused by C. albicans alone or in association with non-albicans isolates, respectively. Symptoms recurred within 2 weeks of stopping caspofungin in 19 of 115 evaluable patients (17%), including 3 of 16 (19%) receiving antifungal prophylaxis. Relapse rates were similar for patients with greater or fewer than 50 CD4(+) cells/mm(3). In this relatively small number of patients, only symptom severity and extent of disease judged endoscopically at baseline were significantly (p < 0.10) associated with early relapse in the multivariate model.

Caspofungin Use in Patients with Invasive Candidiasis Caused by Common Non-albicans Candida Species: Review of the Caspofungin Database

ABSTRACT Increasing rates of invasive candidiasis caused by non-albicans Candida species have been reported worldwide. Particular concerns have been raised for C. parapsilosis because of reduced in vitro susceptibility to echinocandins. We identified 212 patients with invasive candidiasis due to non-albicans Candida species (≥5 cases per species) in 5 clinical trials of caspofungin monotherapy from the pharmaceutical sponsors (Merck and Co., Inc.) database: 71 cases were caused by C. parapsilosis, 65 by C. tropicalis, 54 by C. glabrata, 10 by C. krusei, 9 by C. guilliermondii, and 5 by C. lusitaniae. One hundred sixty-seven cases caused by C. albicans were also identified. Efficacy was assessed at the end of caspofungin therapy. Success (favorable overall response) required favorable clinical and microbiological responses. The mean APACHE II scores were 16.5 in the non-albicans group and 15.7 in the C. albicans group. Neutropenia at study entry was more common in the non-albicans group (12%) than in the C. albicans group (5%). The median duration of caspofungin therapy was 14 days in both groups. The success rates were 77% in both groups and at least 70% for each non-albicans species: 74% for C. parapsilosis, 71% for C. tropicalis, 85% for C. glabrata, 70% for C. krusei, 89% for C. guilliermondii, and 100% for C. lusitaniae. The times to negative blood culture were similar for the various species. The overall mortality rates were 26% in the non-albicans group and 29% in the C. albicans group. Drug-related serious adverse events and discontinuations due to caspofungin toxicity were uncommon. Although the sample sizes were limited, caspofungin demonstrated favorable efficacy and safety profiles in the treatment of invasive candidiasis caused by the following non-albicans Candida species: C. parapsilosis, C. tropicalis, C. glabrata, C. krusei, C. guilliermondii, and C. lusitaniae.

Overview of safety experience with caspofungin in clinical trials conducted over the first 15 years: a brief report

Safety experience is available from 32 completed clinical studies (17 Phase I and 15 Phase II-III) of caspofungin (CAS) conducted between 1995 and 2010 in adult and paediatric patients. Clinical and laboratory adverse events (AEs) were collected from all enrolled subjects and patients. Investigators identified the seriousness, causality and result of all AEs noted during study therapy and for up to 28 days post therapy. Up to 31 December 2010, full safety data are available from 1951 individuals who have received at least one dose of CAS in Phase I-III clinical studies, including 171 paediatric patients, 394 volunteer adult subjects and 1386 adult patients (276 with oropharyngeal/oesophageal candidiasis, 366 with invasive candidiasis, 180 with invasive aspergillosis and 564 with persistent fever and neutropenia). CAS was administered for up to 196 days at daily doses ranging from 5mg to 210 mg. Overall, 41.8% of CAS recipients had an AE that was classified as drug-related. The most frequently reported drug-related AEs were fever (9.3%), chills (5.2%), increased alanine aminotransferase (6.5%), increased aspartate aminotransferase (6.0%) and increased alkaline phosphatase (5.2%). Serious AEs were reported in 27.3% of CAS recipients overall but were attributed to CAS in only 0.8%, and discontinuation of CAS due to a drug-related AE was infrequent (2.7%). Dose-related CAS toxicity was not observed. In conclusion, CAS has demonstrated a favourable safety profile in 1951 adult and paediatric patients enrolled in clinical trials.

Sugammadex efficacy for reversal of rocuronium- and vecuronium-induced neuromuscular blockade: A pooled analysis of 26 studies

STUDY OBJECTIVE To summarize and compare efficacy of sugammadex with neostigmine or placebo for reversal of rocuronium- or vecuronium-induced neuromuscular blockade (NMB), and to demonstrate consistency of sugammadex results across various patient populations. DESIGN Pooled analysis on data from 26 multicenter, randomized, Phase II and III studies. SETTING Operating room. PATIENTS 1855 adults undergoing surgery under general anesthesia and receiving rocuronium or vecuronium for NMB. INTERVENTIONS Sugammadex (2.0mg/kg at second twitch reappearance [T2; moderate NMB], 4.0mg/kg at 1-2 post-tetanic counts [PTC; deep NMB] or 16.0mg/kg at 3min after rocuronium 1.2mg/kg), neostigmine or placebo. MEASUREMENTS Time to recovery of the train-of-four (TOF) ratio to 0.9. MAIN RESULTS Geometric mean (95% CI) times to recovery to TOF ratio of 0.9 were 1.9 (1.8-2.0) min following sugammadex 2.0mg/kg and 10.6 (9.8-11.6) min following neostigmine administration at T2 after rocuronium, and 2.9 (2.5-3.4) min and 17.4 (13.4-22.6) min, respectively, after vecuronium. Recovery times were 2.2 (2.1-2.3) min following sugammadex 4.0mg/kg and 19.0 (14.8-24.6) min following neostigmine administered at a target of 1-2 PTC after rocuronium, and 3.8 (3.0-5.0) min and 67.6 (56.3-81.2) min after vecuronium. Sugammadex administered 3min after rocuronium 1.2mg/kg resulted in rapid recovery (1.7 [1.5-2.0] min). Modest increases in mean recovery time were associated with vecuronium use (+1.6min [78%; (61%-98%)] versus rocuronium), mild-to-moderate renal impairment (+0.4min [20%; (9%-32%)] versus normal renal function) and geographic location (+1.0min [38%; (25%-52%)] in subjects in USA/Canada versus Europe/Japan). CONCLUSIONS Sugammadex administered at recommended doses provides rapid and predictable reversal of rocuronium and vecuronium-induced moderate and deep NMB, and effective reversal 3min after rocuronium 1.2mg/kg. Robust recovery was seen across various patient factors, providing further confirmation of labeled dose recommendations.

Preservative-free tafluprost in the treatment of open-angle glaucoma or ocular hypertension in India: a phase III clinical trial.

The aim of this study was to evaluate the efficacy and safety of preservative‐free (PF) tafluprost compared with PF timolol in Indian subjects with open‐angle glaucoma (OAG) or ocular hypertension.