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Dose escalation studies with caspofungin against Candida glabrata
Marianna Domán1, Renátó Kovács1, David S Perlin2
1Department of Medical Microbiology, University of Debrecen, Hungary.
Journal of Medical Microbiology
|August 23, 2015
Summary
Increasing caspofungin dosage does not improve treatment outcomes for invasive Candida glabrata infections. This study found higher doses were not more effective in vitro or in a murine model, confirming current clinical observations.
Area of Science:
- Medical Mycology
- Infectious Diseases
- Pharmacology
Background:
- Invasive fungal infections caused by Candida glabrata have high mortality rates.
- Echinocandins are first-line treatments, and dose escalation is considered for improved outcomes.
- Caspofungin efficacy against C. glabrata, particularly with dose escalation, requires further investigation.
Purpose of the Study:
- To evaluate the in vitro and in vivo efficacy of caspofungin against Candida glabrata.
- To determine if caspofungin dose escalation improves outcomes in a murine model of invasive candidiasis.
- To assess caspofungin activity against both wild-type and echinocandin-resistant C. glabrata strains.
Main Methods:
- In vitro susceptibility testing (MIC determination) of caspofungin against C. glabrata isolates in RPMI 1640 and serum-supplemented media.
- Time-kill kinetic assays to assess caspofungin's fungicidal/fungistatic activity.
- In vivo efficacy study in a neutropenic murine model using various caspofungin doses against C. glabrata infection.
Main Results:
- Caspofungin MICs increased in serum-supplemented media, where C. glabrata replication was slower.
- In vitro, caspofungin showed fungicidal activity at lower concentrations but fungistatic activity at higher concentrations (paradoxical effect).
- In vivo, all caspofungin doses reduced fungal burden but showed no dose-dependent improvement, and resistant strains were unaffected.
Conclusions:
- Caspofungin dose escalation does not enhance efficacy against Candida glabrata infections.
- The paradoxical fungistatic effect at higher in vitro concentrations warrants further study.
- Echinocandin-resistant C. glabrata strains remain a significant therapeutic challenge.
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