Caspofungin Dose Escalation for Invasive Candidiasis Due to Resistant Candida albicans (original) (raw)
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Mycopathologia, 2014
It was previously demonstrated that brief (≤1 h) exposures to echinocandins are as effective to kill Candida albicans cells as continuous 24-h exposure. However, killing rates after continuous and short (1 h) echinocandin exposures to C. albicans have not yet been evaluated in RPMI-1640 with and without 50 % serum. We evaluated four echinocandin susceptible C. albicans bloodstream isolates, ATCC 10231 type strain and an echinocandin-resistant isolate (DPL20, FKS F645P). Caspofungin MICs, time-kill and postantifungal effect (PAFE) tests were performed in RPMI-1640 with and without 50 % serum. Killing rates (k values) in time-kill and PAFE experiments were determined for each strain and concentration. In time-kill experiments, colony count decreases were isolate- and concentration-dependent at 0.25, 1, 4, 8, 16 and 32 mg/L in RPMI-1640, but concentration-independent at 1, 4, 8, 16 and 32 mg/L in 50 % serum. One-hour caspofungin exposure at 4, 16 and 32 mg/L resulted in CFU decreases c...
Infection and Drug Resistance
Background: Echinocandins are the first-line therapy for treatment of invasive Candida infections, but the mortality rate remains high, calling for novel strategies. Giving single larger echinocandin doses infrequently is an alternative regimen. Our aim was to test this novel approach in a neutropenic murine model. Materials and methods: We compared the in vivo efficacy of single 10 and 40 mg/kg of caspofungin (2.5× and 10× the normal humanized dose) to that of the same cumulative doses of daily 2 and 8 mg/kg doses for 5 days against 2 each of wild-type C. albicans and C. dubliniensis as well as echinocandin resistant C. albicans. As a comparator, we tested daily 1 mg/kg amphotericin B. Results: In lethality experiments, all caspofungin and amphotericin B regimens improved survival against wild-type C. albicans and C. dubliniensis clinical isolates (P<0.0001) and decreased the mean fungal kidney burdens of both species compared to controls. However, fungal kidney burden decreases were not always statistically significant, especially with single 10 or 40 mg/kg caspofungin doses. Amphotericin B was the least active drug against wild-type C. albicans. Against echinocandin-resistant strains, monodose 40 mg/kg caspofungin and 1 mg/kg of daily amphotericin B were effective in lethality experiments. Although, significant kidney CFU decreases were never found, except for amphotericin B against one of the isolates (p<0.05 at day 3 and p<0.001 at day 6). Conclusion: Single 40 mg/kg caspofungin and 1 mg/kg amphotericin B proved to be effective in the lethality experiments against wild-type and echinocandin-resistant C. albicans and wild-type C. dubliniensis. This was not always shown regarding fungal tissue burdens. Single caspofungin doses used in mice in this study are attainable in humans as well, suggesting a potential place of this dosing strategy not only in prevention but also in curative treatment of evolved invasive Candida infections.
Effects of Caspofungin against Candida guilliermondii and Candida parapsilosis
Antimicrobial Agents and Chemotherapy, 2006
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Dose escalation studies with caspofungin against Candida glabrata
Journal of Medical Microbiology, 2015
Echinocandins are recommended as first-line agents against invasive fungal infections caused by Candida glabrata, which still carry a high mortality rate. Dose escalation of echinocandins has been suggested to improve the clinical outcome against C. glabrata. To address this possibility, we performed in vitro and in vivo experiments with caspofungin against four WT C. glabrata clinical isolates, a drug-susceptible ATCC 90030 reference strain and two echinocandinresistant strains with known FKS mutations. MIC values for the clinical isolates in RPMI 1640 were #0.03 mg l 21 but increased to 0.125-0.25 mg l 21 in RPMI 1640+50 % serum. In RPMI 1640+50 % serum, the replication of C. glabrata was weaker than in RPMI 1640.Caspofungin in RPMI 1640 at 1 and 4 mg l 21 showed a fungicidal effect within 7 h against three of the four clinical isolates but was only fungistatic at 16 and 32 mg l 21 (paradoxically decreased killing activity). In RPMI 1640+50 % serum, caspofungin at ¢1 mg l 21 was rapidly fungicidal (within 3.31 h) against three of the four isolates. In a profoundly neutropenic murine model, all caspofungin doses (1, 2, 3, 5 and 20 mg kg 21 daily) decreased the fungal tissue burdens significantly (P,0.05-0.001) without statistical differences between doses, but the mean fungal tissue burdens never fell below 10 5 cells (g tissue) 21 .The echinocandin-resistant strains were highly virulent in animal models and all doses were ineffective. These results confirm the clinical experience that caspofungin dose escalation does not improve efficacy.
Caspofungin for invasive candidiasis at a tertiary care medical center
The American journal of medicine, 2006
Caspofungin is emerging as first-line therapy for invasive candidiasis. Data on the use of caspofungin for treatment for invasive candidiasis are limited to clinical trials and case reports. We report a single-center experience with 104 consecutive courses of caspofungin for the treatment of invasive candidiasis to evaluate a real-world performance of this drug. A retrospective chart review of patients receiving caspofungin at a tertiary care medical center was performed. Patient information and microbiologic data were abstracted from patient charts and electronic medical records. Of 241 patients receiving caspofungin for all indications, 122 (51%) had proven invasive candidiasis. There were 104 treatment courses for candidiasis in 99 patients available for review. Bloodstream (66%) and abdominal infections (25%) were the most common sites of infection. Most infections were non-albicans (80/104, 77%; including patients infected with more than one species). Clinical cure rates at the...
Clinical Infectious Diseases, 2009
Background. The standard caspofungin treatment regimen (50 mg/day after a 70-mg dose on day 1) is effective and well tolerated for the treatment of invasive candidiasis, but experience with higher doses of caspofungin is limited. We evaluated the safety and efficacy of caspofungin at 3 times the standard dosing regimen. Methods. Patients with proven invasive candidiasis were randomized to receive a standard or high-dose (150 mg/day) caspofungin treatment regimen. Safety was assessed in all patients as treated. Efficacy was assessed as a secondary objective in a full-analysis-set population. A favorable overall response was defined as symptom resolution and microbiological clearance at the end of caspofungin therapy. Results. A total of 204 patients were included in the safety analysis (104 received the standard regimen, and 100 received the high-dose regimen), and 197 were included in the efficacy analysis (102 and 95 in the standard and high-dose treatment groups, respectively). Patient demographic characteristics, neutropenia status (6.7% and 8.0% had neutropenia, respectively), and Acute Physiology and Chronic Health Evaluation II scores (mean, 16.5 and 17, respectively) were similar between treatment groups. Significant drug-related adverse events occurred in 1.9% of patients receiving the standard regimen and 3.0% of patients receiving the high-dose regimen (difference, 1.1%; 95% confidence interval, Ϫ4.1% to 6.8%). The most-common drug-related adverse events in the standard and high-dose treatment groups were phlebitis (3.8% and 2.0%, respectively), increased alkaline phosphatase level (6.9% and 2.0%, respectively), and increased aspartate transaminase level (4.0% and 2.0%, respectively). Overall, 71.6% of patients who received the standard regimen and 77.9% of patients who received the high-dose regimen had favorable overall responses (difference, 6.3%; 95% confidence interval, Ϫ5.9% to 18.4%; not statistically significant). Mortality at 8 weeks after therapy was similar between groups. Conclusions. Both caspofungin dosing regimens were effective and well tolerated in patients with invasive candidiasis. No safety concerns were found for caspofungin at a dosage of 150 mg/day. The incidence and clinical importance of serious Candida infections have increased dramatically during the