The fluoroquinolone antibiotics are relatively new agents with long serum half lives, a high degree of bioavailability, and a broad spectrum of activity against many gram-negative and some ...gram-positive organisms. They are useful in a range of clinical settings but should not be considered as first-line treatment of many infections. Specific indications include chronic osteomyelitis caused by multiple-resistant gram-negative bacilli, chronic bacterial prostatitis refractory to other oral antibiotics, complicated urinary tract infections, and empiric therapy of suspected bacterial GI infections. Quinolones may also be considered when patients are allergic to a conventional agent, when infections are caused by multiple-resistant gram-negative bacilli, or when the toxicity of an alternate therapy is greater.
Caspofungin is an echinocandin antifungal agent administered once daily as an intravenous infusion. Relationships between caspofungin exposure and clinical efficacy and safety were investigated. ...End‐of‐infusion (CEOI) and trough (C24 hours) concentrations were obtained in 218 patients with mucosal (i.e., esophageal and/or oropharyngeal) candidiasis (MC) receiving caspofungin 35, 50, or 70 mg/day and 278 patients with invasive candidiasis (IC) receiving 50, 100, or 150 mg/day. Area under the plasma concentration–time curve (AUC0–24 hours) was obtained in a subset of MC patients (n = 99). Odds ratios were estimated for the association between log‐transformed PK and efficacy response and the occurrence of common adverse events. No pharmacokinetic or hybrid parameter (ratio of AUC:MIC, CEOI:MIC, C24 hours:MIC) was significantly correlated with overall treatment outcome in either MC or IC, although this patient population may exhibit confounding factors which masked a potential pharmacokinetic/pharmacodynamic relationship. An exploratory evaluation of MC identified significant pharmacokinetic correlations with endoscopic response, but not symptom response. Statistically significant associations were identified for IC patients with C. parapsilosis infections. Occurrence of clinical adverse events and/or laboratory abnormalities did not appear to be increased by higher caspofungin plasma concentrations. Caspofungin concentrations achieved with 50 mg/day are generally within the therapeutic window for the treatment of candidiasis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background: In a double-blind randomized trial of empirical antifungal Rx for persistently febrile neutropenic pts, CAS was as effective as and better tolerated than L-AmB. We now examine the results ...of this study in the subgroup of pts with AML.
Methods: Randomization to CAS (70 mg x 1, then 50 mg/d) or L-AmB (3 mg/kg/d) was stratified by risk category high risk = allogeneic hematopoietic stem cell transplant or relapsed acute leukemia and use of antifungal prophylaxis. The primary efficacy endpoint was % of treated pts with documented fever and neutropenia who had a successful outcome defined by all the following: successful Rx of baseline (BL) invasive fungal infection (IFI) (if any), no breakthrough (BT) IFI to 7 d post-Rx, survival @7d post-Rx, no premature discontinuation (DC) due to lack of efficacy or study drug toxicity, and fever resolution x 48 hr during neutropenia.
Results: 703/1095 (64%) of the treated pts had AML, including 364/556 (65%) and 339/539 (63%) in the CAS and L-AmB groups, respectively. Demographic characteristics were similar in AML pts in both Rx groups. 27% of CAS and 22% of L-AmB pts with AML were high risk. Median days of Rx were: CAS, 12; L-AmB, 11. The table shows % AML pts with a successful outcome by Rx group.
% AML pts with a successful outcome by Rx group
CAS (N=364)L-AmB (N=339)Difference (CAS - L-AmB)95% CI for difference between treatment groupsSuccess Rx of BL IFI †503119(−16, 53)No BT IFI9395−2(−5, 2)Suvival @ 7d post-Rx92884(0, 8)No premature DC87862(−3, 7)Fever resolution48462(−5, 9)All of the above40382(−5, 10)† 7/14 CAS and 5/16 L-AmB pts had successful Rx of BL IFI.
The composite success rates for the high risk AML pts were 46/99 (46%) for CAS and 31/76 (41%) for L-AmB.
Conclusions: In this post hoc subgroup analysis, CAS provided an effective and generally well-tolerated option for the empirical Rx of persistently febrile neutropenic pts with AML.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background A data monitoring committee (DMC) is often employed to assess trial progress and review safety data and efficacy endpoints throughout a trail. Interim analyses performed for the DMC should ...use data that are as complete and verified as possible. Such analyses are complicated when data verification involves subjective study endpoints or requires clinical expertise to determine each subject's status with respect to the study endpoint. Therefore, procedures are needed to obtain adjudicated data for interim analyses in an efficient manner. In the past, methods for handling such data included using locally reported results as surrogate endpoints, adjusting analysis methods for unadjudicated data, or simply performing the adjudication as rapidly as possible. These methods all have inadequacies that make their sole usage suboptimal.
Purpose For a study of prophylaxis for invasive candidiasis, adjudication of both study eligibility criteria and clinical endpoints prior to two interim analyses was required. Because the study was expected to enroll at a moderate rate and the sponsor required adjudicated endpoints to be used for interim analyses, an efficient process for adjudication was required.
Methods We created a web-based endpoint adjudication system (WebEAS) that allows for expedited review by the endpoint adjudication committee (EAC). This system automatically identifies when a subject's data are complete, creates a subject profile from the study data, and assigns EAC reviewers. The reviewers use the WebEAS to review the subject profile and submit their completed review form. The WebEAS then compares the reviews, assigns an additional review as a tiebreaker if needed, and stores the adjudicated data.
Results The study for which this system was originally built was administratively closed after 10 months with only 38 subjects enrolled. The adjudication process was finalized and the WebEAS system activated prior to study closure. Some website accessibility issues presented initially. However, once these issues were resolved, the reviewers found the system user-friendly and easy to navigate.
Limitations Web-based data adjudication depends upon expeditious data collection and verification. Further, ability to use web-based technologies, in addition to clinical expertise, must be considered in selecting EAC members.
Conclusion The automated nature of this system makes it a practical mechanism for ensuring timely endpoint adjudication. The authors believe a similar approach could be useful for handling endpoint adjudication for future clinical trials. Clinical Trials 2009; 6: 60—66. http://ctj.sagepub.com
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK, VSZLJ
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