Paradoxical Effect of Caspofungin: Reduced Activity against Candida albicans at High Drug Concentrations

Abstract

Resistance problems with caspofungin, an echinocandin inhibitor of fungal cell wall glucan synthesis, have been rare. We noted paradoxical turbid growth of Candida albicans isolates in broth in some high (supra-MIC) concentrations. Among isolates submitted for susceptibility testing and screened at drug concentrations up to 12.5 g/ml, the frequency was 16%. Analysis of the turbid growth indicated slowing of growth in the presence of drug but with numbers of CFU up to 72% those of drug-free controls. Clearing of growth again by the highest drug concentrations produced a quadriphasic pattern in a tube dilution series. Cells growing at high drug concentrations were not resistant on retesting but showed the paradoxical effect of the parent. Among a selected series of isolates tested at concentrations up to 50 g/ml, an additional 53% showed a "mini-paradoxical effect": no turbid growth but incomplete killing at high concentrations (supra-minimum fungicidal concentration). These effects were reproducible; medium dependent in extent; noted in macro-and microdilution, in the presence or absence of serum, and on agar containing drug (but not when drug concentrations were not constant, as in agar diffusion); not seen with other echinocandins and less commonly in other Candida species; and not due to destruction of drug in tubes showing the effect. Cooperative enhancement of inhibition by a second drug could eradicate the effect. We postulate that high drug concentrations derepress or activate resistance mechanisms. The abilities of subpopulations to survive at high drug concentrations could have in vivo consequences.Caspofungin is an antifungal drug of the echinocandin class. Agents of this class can be produced by several fungi. This newly introduced agent has as its mechanism of action noncompetitive inhibition of synthesis of (1,3)-␤-D-glucan, a principal constituent of fungal cell walls (4). It has been shown to be fungicidal in vitro against Candida species and efficacious in animal models of candidiasis and in clinical trials (4). Development of resistance is rare, even after prolonged treatment (4). We recently observed resistance to growth inhibition and killing among some clinical Candida isolates, but only at high concentrations of caspofungin, and here we report those observations in detail.(This paper was presented in part at the 14th European Congress of Clinical Microbiology and Infectious Diseases, Prague, Czech Republic, 1 to 4 May 2004.) MATERIALS AND METHODSIsolates. Isolates were identified to species level by standard methods reported previously (12, 17), with molecular genotyping performed for a subset of the isolates (22).Susceptibility testing. Broth macrodilution and microdilution testing (13) utilizing an 80% turbidity endpoint (6), determination of the minimum fungicidal concentration (MFC) (20), incorporation of drug into agar (2), assays of drug diffusion into agar containing organisms (16), and macrodilution checkerboardtype drug interaction studies (3) were performed as detailed elsewhere. Th...

High-dose caspofungin combination antifungal therapy in patients with hematologic malignancies and hematopoietic stem cell transplantation

“…8,25 This paradoxical effect is similar to that described for Gram-positive bacteria in response to increasing b-lactam drug concentrations (the 'Eagle effect'). 26,27 Interestingly, this resistance to drug-induced inhibition of growth at higher concentrations of CAP is reversible and is more pronounced among Candida species; 25 the echinocandin-pneumocandin-Eagle effect is less pronounced with filamentous molds, although in experimental animal models of brain zygomycosis lower CAP concentration favorable effect was reversed by increasing the concentration of the drug leading to reduced High-dose caspofungin therapyresponse.…”

Paradoxical Effect of Caspofungin against Candida Bloodstream Isolates Is Mediated by Multiple Pathways but Eliminated in Human Serum

“…Paradoxical growth of Candida isolates at echinocandin concentrations that exceed the MIC is well recognized in vitro (23,25). In the present study, we characterized echinocandin par- The ranges of drug concentrations tested were as follows: caspofungin (0.06 to 64 g/ml), cyclosporine (0.0025 to 10.25 g/ml), nikkomycin Z (2 to 128 g/ml), and tacrolimus (0.0025 to 10.25 g/ml).…”

“…Along these lines, concerns have been expressed about the possible therapeutic implications of an in vitro paradoxical effect, in which certain Candida isolates exhibit increased growth in the presence of echinocandin concentrations above the minimum inhibitory concentration (MIC). Although the paradoxical effect is typically apparent in vitro at concentrations that are achievable in human serum with conventional dosing strategies, the clinical relevance of the phenomenon in the treatment of patients with candidiasis is unproven.To date, paradoxical effects have been demonstrated against Candida albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. dubliniensis isolates (3,5,10,16,23,25,28). Moreover, they have been described with all three commercially available echinocandins (5), although rates differ among these agents.…”

“…To date, paradoxical effects have been demonstrated against Candida albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. dubliniensis isolates (3,5,10,16,23,25,28). Moreover, they have been described with all three commercially available echinocandins (5), although rates differ among these agents.…”

Frequency of paradoxical effect with caspofungin in Candida albicans

“…To the editor, In their article regarding the paradoxical growth effect with echinocandins, Fleischhacker et al [1], discussing their findings with caspofungin, state: "Stevens et al did not demonstrate [a paradoxical effect, i.e., growth in concentrations above an apparent MIC] in a … group of C. albicans isolates…," citing two of our papers [2,3]. However, in our original description of the paradoxical effect with caspofungin [2], we reported the phenomenon in two sets of C. albicans isolates, 16% of 25 isolates and 18% of 17 isolates, and in the later paper studying the mechanism [3], we had expanded the study of frequency to 65 isolates, of which 22% had shown the effect.…”