In vivo studies with a Candida tropicalis isolate exhibiting paradoxical growth in vitro in the presence of high concentration of caspofungin

Abstract

We investigated the activity of caspofungin against a Candida tropicalis clinical isolate showing paradoxical growth in vitro. BALB/c mice immunosuppressed by cyclophosphamide were infected intraperitoneally using 10(7) CFU/mouse. Caspofungin was administered intraperitoneally once daily for 5 days or as a single dose using the following doses: 0.12, 0.25, 1, 2, 3, 5, and 15 mg/kg. The single dose of caspofungin was effective only at 5 and 15 mg/kg concentrations (100% survival). Five-day caspofungin treatment led to 100% survival at doses of 1 mg/kg or higher. Caspofungin treatment significantly decreased the number of viable yeasts in the peritoneal lavage samples as well as in the infected abscesses at doses 1, 3, 5, and 15 mg/kg caspofungin as compared to the untreated control (P<0.001 in all cases), and even to the group treated with 0.12 mg/kg caspofungin (P<0.05 in all cases). At 2 mg/kg caspofungin dose, sterilization of the internal organs was reproducibly incomplete, suggesting that the role of paradoxical growth in the late clinical failure cannot be excluded.

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

“…The apparent paradoxical growth was not reproducible in subsequent experiments (7). To date, the latter study remains the only one to suggest paradoxical growth of Candida in vivo, since other mouse models of C. tropicalis and C. dubliniensis infections have yielded negative results (3,16). Of further note, our findings were consistent with earlier reports demonstrating an increase in MICs in the presence of serum (11,12,18,19).…”

“…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.…”

Paradoxical Growth of Candida albicans in the Presence of Caspofungin Is Associated with Multiple Cell Wall Rearrangements and Decreased Virulence

“…The significance of the reduced virulence of cells exhibiting paradoxical growth remains to be elucidated, but we think that this finding provides insights into some clinical aspects. First, this finding could explain the failed attempts to reproduce the paradoxical effect in vivo because it could be confused with success in treatment (7,9,48). This finding may also have special relevance for virulence factors such as biofilm formation.…”

“…In particular, paradoxical growth (PG) (also known as the Eagle effect) is observed in vitro and occurs when yeast cells can grow in the presence of high antifungal concentrations but remain fully susceptible at intermediate-to-low concentrations (8). Paradoxical growth in the presence of echinocandins has been observed for Candida albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. dubliniensis (8)(9)(10)(11)(12)(13)(14). This phenomenon is echinocandin and species specific.…”