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Antimicrobial Agents and Chemotherapy, October 2007, p. 3599-3604, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00296-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Correlation of the MIC and Dose/MIC Ratio of Fluconazole to the Therapeutic Response of Patients with Mucosal Candidiasis and Candidemia{triangledown}

Juan L. Rodríguez-Tudela,1* Benito Almirante,2 Dolors Rodríguez-Pardo,2 Fernando Laguna,3 J. Peter Donnelly,4 Johan W. Mouton,5 Albert Pahissa,2 and Manuel Cuenca-Estrella1

Servicio de Micologia, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Majadahonda, Madrid,1 Servicio de Enfermedades Infecciosas, Hospital Universitario Valle de Hebrón, Barcelona,2 Servicio de Medicina Interna, Hospital Carlos III, Madrid, Spain,3 Department of Haematology, Radboud University Nijmegen Medical Centre, and Nijmegen University Centre for Infectious Diseases, Radboud University Nijmegen, Nijmegen, The Netherlands,4 Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands5

Received 1 March 2007/ Returned for modification 14 April 2007/ Accepted 12 July 2007

We report on the correlation of the outcomes for two cohorts of patients who had been treated for candidemia (126 episodes) or oropharyngeal candidiasis (110 episodes) with various doses of fluconazole and the MIC of fluconazole obtained by using the EUCAST standard for fermentative yeasts. Of 145 episodes caused by an isolate with a fluconazole MIC ≤2 mg/liter, 93.7% (136 of 145) responded to fluconazole treatment. The response for those infected with a strain with a MIC of 4 mg/liter was 66% but reached 100% when the dose was greater than 100 mg/day, whereas the response for those infected with strains with MICs ≥8 mg/liter was only 12%. Hence, a MIC of 2 mg/liter or 4 mg/liter was able to predict successful treatment. A cure rate of 93.9% (140 of 149) was achieved when the dose/MIC ratio was ≥100 but fell to 14.6% (16 of 109) when the ratio was less. The dose/MIC required to achieve a response rate of 50% (the 50% effective concentration) was 43.7 for the cohort of patients with oropharyngeal candidiasis. Classification and regression analysis indicated that a dose/MIC of 35.5 was the threshold for the prediction of cure or failure. However, an increase in exposure above this threshold further increased the probability of cure, and all patients were cured when the dose/MIC exceeded 100. Monte Carlo simulations showed a probability of target attainment of 99% at MICs ≤2 mg/liter and a pharmacodynamic target of a dose/MIC ratio of 100, which was equivalent to an unbound fraction of the fluconazole area under the curve versus the MIC of 79.

* Corresponding author. Mailing address: Servicio de Micología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Ctra. Majadahonda Pozuelo km 2, 28220 Majadahonda, Spain. Phone: 34 91 8223919. Fax: 34 91 5097966. E-mail: juanl.rodriguez-tudela{at}isciiii.es

{triangledown} Published ahead of print on 23 July 2007.

Antimicrobial Agents and Chemotherapy, October 2007, p. 3599-3604, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00296-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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