Treatments for invasive fungal infections remain unsatisfactory. We evaluated the efficacy, tolerability, and safety of voriconazole as salvage treatment for 273 patients with refractory and ...intolerant-to-treatment fungal infections and as primary treatment for 28 patients with infections for which there is no approved therapy. Voriconazole was associated with satisfactory global responses in 50% of the overall cohort; specifically, successful outcomes were observed in 47% of patients whose infections failed to respond to previous antifungal therapy and in 68% of patients whose infections have no approved antifungal therapy. In this population at high risk for treatment failure, the efficacy rates for voriconazole were 43.7% for aspergillosis, 57.5% for candidiasis, 38.9% for cryptococcosis, 45.5% for fusariosis, and 30% for scedosporiosis. Voriconazole was well tolerated, and treatment-related discontinuations of therapy or dose reductions occurred for <10% of patients. Voriconazole is an effective and well-tolerated treatment for refractory or less-common invasive fungal infections.
Susceptibility testing can yield variable results because it is method (commercial or reference), agent, and species dependent. Therefore, in order for results to be clinically relevant, MICs ...(minimal inhibitory concentrations) or MECs (minimal effective concentrations) should help in selecting the best treatment agent in the clinical setting. This is accomplished by categorical endpoints, ideally, breakpoints (BPs) and/or ECVs/ECOFFs (epidemiological cutoff values). BPs and ECVs are available by the reference methods (CLSI Clinical and Laboratory Standards Institute and EUCAST European Committee on Antifungal Susceptibility Testing) for a variety of species/agent combinations. The lack of clinical data precludes establishment of BPs for susceptibility testing by the commercial methods and ECVs have only been calculated for the Etest and SYO assays. The goal of this review is to summarize the variety of commercial methods for antifungal susceptibility testing and the potential value of Etest and SYO ECVs for detecting mutants/non-wild type (NWT)
isolates. Therefore, the literature search focused on publications where the commercial method, meaning MICs and ECVs, were reported for specific NWT isolates; genetic mutations have also been listed. For the Etest, the best performers recognizing the NWT were anidulafungin ECVs: 92% for the common species; 97% for
and fluconazole ECVs, mostly for
(45 NWT isolates). By the SYO, posaconazole ECVs recognized 93% of the
and 96% of the
NWT isolates and micafungin ECVs 94% (mostly
and
). Smaller sets, some with clinical data, were also listed. These are promising results for the use of both commercial methods to identify antifungal resistance (NWT isolates). However, ECVs for other species and methods need to be defined, including the
complex and emerging species.
Antifungal susceptibility testing is an important tool for managing patients with invasive fungal infections, as well as for epidemiological surveillance of emerging resistance. For routine testing ...in clinical microbiology laboratories, ready-to-use commercial methods are more practical than homemade reference techniques. Among commercially available methods, the concentration gradient Etest strip technique is widely used. It combines an agar-based diffusion method with a dilution method that determinates a minimal inhibitory concentration (MIC) in µg/mL. Many studies have evaluated the agreement between the gradient strip method and the reference methods for both yeasts and filamentous fungi. This agreement has been variable depending on the antifungal, the species, and the incubation time. It has also been shown that the gradient strip method could be a valuable alternative for detection of emerging resistance (non-wild-type isolates) as Etest epidemiological cutoff values have been recently defined for several drug-species combinations. Furthermore, the Etest could be useful for direct antifungal susceptibility testing on blood samples and basic research studies (e.g., the evaluation of the in vitro activity of antifungal combinations). This review summarizes the available data on the performance and potential use of the gradient strip method.
Background. In previous studies, itraconazole was revealed to be an effective therapy and was considered to be the gold standard treatment for mild-to-moderate acute and chronic clinical forms of ...paracoccidioidomycosis. A pilot study was conducted to investigate the efficacy, safety, and tolerability of voriconazole for the long-term treatment of acute or chronic paracoccidioidomycosis, with itraconazole as the control treatment. Methods. A randomized, open-label study was conducted at 3 Brazilian tertiary care hospitals. Patients were randomized (at a 2 : 1 ratio) to receive oral therapy with voriconazole or itraconazole for 6 months. Patients receiving ⩾1 dose of study drug were evaluated for safety; patients with confirmed paracoccidioidomycosis who completed ⩾6 months of therapy (treatment-evaluable patients) were evaluated for treatment efficacy. Satisfactory global response was assessed at the end of treatment. Results. Fifty-three patients were evaluated for treatment safety (35 received voriconazole, and 18 received itraconazole). Both drugs were well tolerated. The most common treatment-related adverse events in the voriconazole group included abnormal vision, chromatopsia, rash, and headache; the most common treatment-related adverse events in the itraconazole group included bradycardia, diarrhea, and headache. Liver function test values were slightly higher in patients receiving voriconazole than in those receiving itraconazole; 2 patients in the voriconazole group were withdrawn from treatment because of increased liver function test values. In the intent-to-treat populations, the satisfactory response rate (i.e., complete or partial global response) was 88.6% among the voriconazole group and 94.4% among the itraconazole group. The response rate among treatment-evaluable patients was 100% for both treatment groups; no relapses were observed after 8 weeks of follow-up. Conclusions. This is, to our knowledge, the first study to demonstrate that voriconazole is as well tolerated and effective as itraconazole for the long-term treatment of paracoccidioidomycosis.
This mini-review summarizes the clinical outcomes and antifungal susceptibility results, where available, for three new antifungals, including fosmanogepix, ibrexafungerp, and rezafungin, against
...isolates cultured from patients in clinical trials. When reported, most of the data were generated by the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method or by both the CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodologies. For fosmanogepix, we summarize the in vitro data for
isolates from 9 patients and for
spp. cultured from 20 patients in two clinical trials. Ibrexafungerp has also been evaluated in several clinical trials. From conference proceedings, a total of 176
isolates were evaluated in the FURI and CARES studies, including 18
isolates (CARES study). However, MIC data are not available for all clinical isolates. Results from the ReSTORE rezafungin phase 3 clinical study also included in vitro results against
spp., but no patients with
infections were included. In conclusion, this mini-review summarizes insights regarding clinical outcomes and the in vitro activity of three new antifungals against
spp. cultured from patients in clinical trials.
Commercial tests are often employed in clinical microbiology laboratories for antifungal susceptibility testing of filamentous fungi. Method-dependent epidemiological cutoff values (ECVs) have been ...defined in order to detect non-wild-type (NWT) isolates harboring resistance mechanisms. We reviewed the literature in order to find studies where commercial methods were used to evaluate for in vitro susceptibility of filamentous fungi and assess their ability to detect NWT isolates according to the available ECVs. Data were found for the gradient concentration strips Etest and MIC Test Strips (MTS), broth microdilution Sensititre YeastOne (SYO), Micronaut-AM and the agar dilution VIPcheck assays. Applying itraconazole, voriconazole and posaconazole Etest ECVs for
, Etest was able to detect 90.3% (84/93), 61.2% (90/147) and 86% (31/36) of isolates with known
mutations, respectively. Moreover, Etest also was able to detect 3/3
mutants using caspofungin ECVs and 2/3 micafungin mutant isolates. Applying the voriconazole and posaconazole SYO ECVs, 57.7% (67/116) and 100% (47/47) of mutants with known
substitutions were classified as NWT, respectively. VIPcheck detected 90.3% (159/176), 80.1% (141/176) and 66% (141/176)of mutants via itraconazole, voriconazole and posaconazole, respectively, whereas Micronaut-AM detected 88% (22/25). In conclusion, Etest posaconazole and itraconazole, as well as micafungin and caspofungin ECVs, detected
mutants. On the other hand, while the posaconazole SYO ECV was able to detect
mutants, similar data were not observed with the SYO voriconazole ECV.
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