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Published Ahead of Print 23 July 2007. 10.1128/AAC.00296-07. 2007, 51(10):3599. DOI:Antimicrob. Agents Chemother. Cuenca-Estrella Johan W. Mouton, Albert Pahissa and Manuel Rodríguez-Pardo, Fernando Laguna, J. Peter Donnelly, Juan L. Rodríguez-Tudela, Benito Almirante, Dolors Candidiasis and Candidemia Response of Patients with Mucosal of Fluconazole to the Therapeutic Correlation of the MIC and Dose/MIC Ratio http://aac.asm.org/content/51/10/3599 Updated information and services can be found at: These include: REFERENCES http://aac.asm.org/content/51/10/3599#ref-list-1at: This article cites 29 articles, 18 of which can be accessed free CONTENT ALERTS more»articles cite this article), Receive: RSS Feeds, eTOCs, free email alerts (when new http://journals.asm.org/site/misc/reprints.xhtmlInformation about commercial reprint orders: http://journals.asm.org/site/subscriptions/To subscribe to to another ASM Journal go to: o n N ovem ber 27, 2013 by guest http://aac.asm .org/ D ow nloaded from o n N ovem ber 27, 2013 by guest http://aac.asm .org/ D ow nloaded from ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Oct. 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� Juan L. Rodrı´guez-Tudela,1* Benito Almirante,2 Dolors Rodrı´guez-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 Hebro´n, Barcelona,2 and Servicio de Medicina Interna, Hospital Carlos III, Madrid,3 Spain; Department of Haematology, Radboud University Nijmegen Medical Centre, and Nijmegen University Centre for Infectious Diseases, Radboud University Nijmegen, Nijmegen, The Netherlands4; and 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 theMIC 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 oropha- ryngeal 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. The setting of breakpoints for antimicrobial agents has evolved considerably in recent years. However, the development of break- points for antifungals has received less attention than that for antibacterials partly due to the complex nature of invasive fungal diseases and partly due to the lack of a proper standard for susceptibility tests. Publication M27-A2 of the CLSI (formerly the NCCLS) for testing the susceptibilities of yeasts to antifungal agents, including fluconazole, was an important step (24); but the process was not in line with the process for setting breakpoints established by the European Committee on Antimicrobial Sus- ceptibility Testing (EUCAST), which takes into account pharma- cokinetic (PK)-pharmacodynamic (PD) data and other factors, such as dosing regimens, toxicology, resistance mechanisms, wild type MIC distributions, and clinical outcome data (15). The Antifungal Susceptibility Testing Subcommittee (AFST) of EUCAST was charged with applying this process to antifungal drugs and recently achieved the first step in publishing a standard method (29) that differs slightly from that of the CLSI but that results in essentially the same MICs (9, 8, 30). Both methods produce MICs up to 2 mg/liter. Above this value, the CLSI method generates MICs twofold higher than those generated by the EUCAST AFST method (30). The interpatient variability in population PK parameter esti- mates has only recently been recognized as a key factor in pre- dicting the outcome for individual patients and establishing breakpoints and targets for clinical susceptibility. Monte Carlo simulation is used to address this (5), as it can be used to deter- mine the probability of target attainment for PD indices by taking the inherent variation within different populations into account (2, 11, 12, 20, 22, 23). Indeed, this statistical technique forms an integral part of the breakpoint-setting process for antibacterials of both the CLSI and the EUCAST. Mouton used Monte Carlo simulation to determine the variations in exposure for fluconazole (21), but the PD target required to attain the breakpoint was not clear. The aim of the current study was to determine the corre- lation of MICs to the clinical outcomes for patients with candi- demia and oropharyngeal candidiasis (OPC) who had been treated with fluconazole and also to determine the PK-PD pa- rameter relation that best predicted this outcome. We then used these data to establish a PD target and subsequently determine the probability of target attainment for fluconazole and the clin- ical breakpoint for fluconazole by way of proving the concept for establishing the clinical breakpoints of antifungals. MATERIALS AND METHODS Patients. (i) Candidemia. One hundred twenty-six candidemia patients treated with fluconazole were recruited from a population-based surveillance study per- * Corresponding author. Mailing address: Servicio de Micologı´a, Centro Nacional de Microbiologı´a, 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@isciiii.es. � Published ahead of print on 23 July 2007. 3599 o n N ovem ber 27, 2013 by guest http://aac.asm .org/ D ow nloaded from formed in Barcelona, Spain, during 2002 and 2003 (1). A case was defined by the recovery of any Candida species from blood cultures. A case of candidemia that occurred �30 days after the initial case was considered a new case. Cure was defined by eradication of the candidemia and resolution of the associated signs and symptoms. Failure was defined as persistent candidemia, despite 4 days of fluconazole treatment. The recommended dose of fluconazole for candidemia is 400 mg/day, but the dose was adjusted to 200 mg/day when the creatinine clearance was between 10 and 50 ml/min and to 100 mg/day when the creatinine clearance was �10 ml/min. (ii) OPC. One hundred ten patients with human immunodeficiency virus (HIV) infection had been treated in another study with fluconazole for a total of 132 episodes of oral thrush caused by Candida albicans (16). Clinical resolution was defined as the absence of lesions compatible with oral thrush after 10 days of therapy. Mycological cure was not evaluated. All episodes were used to evaluate the clinical outcome, irrespective of the dose of fluconazole given. Hence, a total of 258 episodes of Candida infection were available for analysis. Antifungal susceptibility testing. All isolates were sent to the Mycology Ref- erence Laboratory, National Centre for Microbiology, Madrid, Spain, for species confirmation and antifungal susceptibility testing. The MICs of fluconazole for each of the isolates were determined by the standard of the AFST of EUCAST for fermentative yeasts (AFST-EUCAST discussion document 7.1 [29]). Briefly, fluconazole was distributed in RPMI supplemented with 2% glucose in flat- bottomed microtitration trays which were inoculated with 105 CFU/ml of yeast, incubated at 35°C, and then read after 24 h at 530 nm by use of a spectropho- tometer. The end point was defined as the concentration that resulted in 50% inhibition of growth compared with the growth in the control well. Candida krusei ATCC 6258 and C. parapsilosis ATCC 22019 were included for quality control. These results were not available to any of the participants until the end of the clinical studies. Statistical analysis. When required, data were transformed to log2 or log10 to approximate a normal distribution. The area under the curve (AUC) at 24 h (AUC24) and the corresponding dose were obtained from selected references (6, 10, 13, 14, 19, 26). Linear regression analysis was undertaken to determine the correlation coefficient and the relationship between the dose administered to each patient and the corresponding AUC24. This enabled us to calculate the exact equivalencies between dose/MIC, AUC/ MIC, and the unbound fraction (f) of fluconazole AUC versus the MIC (fAUC/ MIC) by considering an unbound fraction of 88%. All these parameters were correlated with the outcomes for the two patient cohorts (Fig. 1; see also Table 3) (6, 10, 13, 14, 19, 26). A sigmoidal dose-response curve (maximum-effect model) with variable slope (Prism software, version 3.0; Graphpad Inc., San Diego, CA) was fitted to the outcome data for the OPC patients. The goodness of fit of the curve was judged by the R2 value. R2 is a fraction between 0.0 and 1.0 and has no units. Higher values indicate that the curve comes closer to the data. The dose/MIC that provokes a response halfway between the baseline and the maximum effect is called the 50% effective concentration (EC50). Logistic regression analysis was performed with SAS software (SAS, Cary, NC), and classification and regression tree (CART) analysis was undertaken by using WEKA software (32). Briefly, the program determines the optimal CART analysis-derived value that discriminates between patients with a higher likelihood of success and those with a likelihood of a poor outcome. Since failures may still occur when the values are above this value, we also determined the value that distinguished between those who had an almost 100% probability of cure and those who had a lower probability of cure. Monte Carlo simulations were performed by using the MicLab program (ver- sion 2.35; Medimatics, Maastricht, The Netherlands), as described earlier (22, 23). Briefly, a dosing regimen of 400 mg/day was simulated by using a population of 10,000 subjects and a lognormal distribution of pharmacokinetic parameters, assuming a volume of distribution of 45 liters (coefficient of variation [CV], 12%) and a half-life of 32 h (CV, 15%) of fluconazole. f was assumed to be 0.88 and was not varied (6, 10, 13, 14, 19, 26). The output consisted of a probability distribution, a cumulative probability distribution, and selected confidence inter- vals for the fAUC/MIC ratios. The fAUC/MIC probability distribution was determined for MICs of 1 to 32 mg/liter (see Fig. 3). RESULTS Patients. The cohort with oral thrush has been described previously (16). Briefly, these were HIV-positive patients with OPC due to C. albicans. The demographics and clinical data for the candidemia pa- tients were as follows. Eighty-one patients (64.3%) were males, and 45 (35.7%) were females. Their ages ranged from 16 to 90 years, with a mean � standard deviation age of 62.1 � 15.8 years. Forty-seven patients (37.3%) had cancer (34 with solid cancers, 7 with lymphoma, 4 with leukemia, and 2 with multiple myeloma), 6 had HIV infection, 27 (21.4%) had diabetes, and FIG. 1. Linear regression of dose versus AUC24. Data were obtained from previous reports (6, 10, 13, 14, 19, 26). 3600 RODRI´GUEZ-TUDELA ET AL. ANTIMICROB. AGENTS CHEMOTHER. o n N ovem ber 27, 2013 by guest http://aac.asm .org/ D ow nloaded from 71 (56.3%) had undergone surgery in the 3 months before they developed candidemia. Four patients had received a solid or- gan transplant, and three had received a hematopoietic stem cell transplant. Only nine patients (7.1%) were neutropenic. These patients experienced a total of 126 (40.5%) episodes of candidemia. The mortality rate was 30.8%, but death was at- tributed to candidemia in only 6.9% of the cases. Microorganisms. Table 1 shows the etiologic agents of can- didemia and mucosal candidosis. C. albicans was responsible for 79.4% of the episodes. Doses. Sixty-five episodes of OPC were treated with 100 mg/ day fluconazole, 44 with a dose of 200 mg/day, and 23 with 400 mg/day. Four episodes of candidemia were treated with 100 mg/ day, 25 with 200 mg/day, 92 with 400 mg/day, 2 with 600, and 3 with 800 mg/day. The doses were considered to be equivalent to the AUC, even though some patients had renal dysfunction. Exposure-response analysis. Overall, 93.7% (136 of 145 ep- isodes) of the infections due to isolates with fluconazole MICs �2 mg/liter responded to fluconazole treatment (Table 2). A response of 66% (8 of 12 episodes) was observed when the infections were caused by isolates with MICs of 4 mg/liter, and a response of 11.8% (12 of 101 episodes) was observed when the infection was caused by isolates with fluconazole MICs �8 mg/liter. However, when the dose administered was taken into consideration, 93.4% (114 of 122) of the patients infected with isolates with fluconazole MICs of �4 mg/liter responded to �100 mg/day fluconazole, whereas only 17.9% (12 of 67 epi- sodes) of those episodes caused by strains with fluconazole MICs �8 mg/liter were cured. The results were similar when the data were analyzed ac- cording to the disease entity (Table 2). In total, 93.9% (140 of 149) of the patients were cured when the dose/MIC was �100, whereas when the dose/MIC was a lower value, only 14.6% (16 of 109) of the patients were cured. For a dose/MIC of 50, 50% (5 of 10 episodes) (Table 3) were cured. However, the response rate for a dose/MIC of �50 was 91.2% (145 of 159). The number of episodes of OPC and the comparable numbers of successes and failures in this group made a separate analysis possible. The relationship between the dose/MIC and the prob- ability of cure showed that all patients were cured when the dose/MIC was �100 and all failed when it was �10 (Fig. 2). An EC50 of 43.7 (95% confidence interval, 33.8 to 56.6) was esti- mated, and CART analysis indicated that 35.5 was the value that best separated the groups into those who were cured and those who were not. However, a number of failures occurred when the dose/MIC was greater than 35.5, although all patients were cured when the dose/MIC exceeded 100. Monte Carlo simulations were performed by use of a 400-mg dose of fluconazole per day. The formula AUC � 0.99 � dose � 9.2 was used to calculate the corresponding AUC/MIC and fAUC/MIC of the dose/MICs obtained in this work (Fig. 2 and Table 3). These Monte Carlo simulations showed a probability of target attainment of 99% at MICs �2 mg/liter and a dose/ MIC ratio of 100 (equivalent to fAUC/MIC of 79) to be the optimum PD target. For MICs �4 mg/liter, a PD target of 50 (equivalent to a fAUC/MIC of 40) would be attained with a 99% probability. DISCUSSION The results presented here showed that there was a corre- lation between the outcome and the results of antifungal sus- ceptibility testing, as others have found previously (7, 17, 27, 28, 31). However, as 79.4% of the isolates were C. albicans, the results should be interpreted with this limitation in mind. More than 90% of the patients responded to fluconazole when the isolate had a fluconazole MIC�2 mg/liter. For those isolates with fluconazole MICs of 4 mg/liter the response was 66%, although this reached 100% when �100 mg/day flucon- azole was given. Only 11.8% (12 of 101) patients responded when the fluconazole MIC was �8 mg/liter. However, since few such isolates were responsible for candidemia, the data from this population were useful only as support of the results obtained for patients with OPC. In fact, an MIC of either 2 mg/liter or 4 mg/liter could be used to discriminate the success and the failure of fluconazole treatment. The PDs of fluconazole for Candida infections have been investigated and have demonstrated that there is a correlation between the dose, the MIC of the yeast, and outcome (4, 18, 19). AUC divided by MIC, i.e., AUC/MIC, is the PD param- TABLE 1. Species causing fungal infections Species No. (%) of species causing: Candidemia OPC All Candida albicans 73 132 205 (79.4) Candida parapsilosis 27 27 (10.4) Candida tropicalis 12 12 (4.6) Candida glabrata 9 9 (3.4) Other yeastsa 5 5 (1.9) All 126 (48.8) 132 (51.2) 258 a Other yeasts comprised one isolate each of the following species: C. krusei, C. guilliermondii, C. kefyr, C. dubliniensis, and Geotrichum capitatum. TABLE 2. Correlation of MIC data with fluconazole treatment adjusted by dose administered MIC (mg/liter) % Clinical success (no. cured/total no.) for the following doses of fluconazole and patients with the indicated conditions: 100 mg/day �100 mg/day All doses All cases Candidemia OPC Candidemia OPC Candidemia OPC �0.5 75 (3/4) 100 (21/21) 92 (95/103) 100 (5/5) 91 (98/107) 100 (26/26) 93 (124/133) 1 100 (4/4) 100 (6/6) 100 (6/6) 100 (4/4) 100 (10/10) 2 100 (1/1) 100 (1/1) 100 (1/1) 100 (1/1) 100 (2/2) 4 20 (1/5) 100 (3/3) 100 (4/4) 100 (3/3) 69 (5/9) 66 (8/12) 8 0 (0/15) 40 (2/5) 41 (7/17) 40 (2/5) 26 (7/32) 24 (9/37) �16 0 (0/19) 75 (3/4) 0 (0/41) 75 (3/4) 2 (0/60) 4 (3/64) VOL. 51, 2007 FLUCONAZOLE MIC AND THERAPEUTIC RESPONSE 3601 o n N ovem ber 27, 2013 by guest http://aac.asm .org/ D ow nloaded from eter that best predicts efficacy (4, 18, 19). However, the dose of fluconazole can be used as a surrogate for AUC, as the dose and AUC have been shown to be virtually equivalent (19) (Fig. 1). However, Monte Carlo simulations were performed for the fAUC/MIC of a 400-mg/day dose. Therefore, the interpreta- tion of the data in the same units would make the exercise straightforward (Table 3). Thus, the AUC24 and the corre- sponding dose were obtained from selected references (6, 10, 13, 14, 19, 26). A linear regression was calculated, and then the equation obtained was used to calculate with accuracy of the equivalencies between the dose and the AUC. Then, fAUC/ MIC was calculated by assuming that f was 88% (6, 10, 13, 14, 19, 26). A dose/MIC of �50 achieved a response rate above 90% (145 of 159 patients) (Table 3). However, 5 of the 10 cases for which the dose/MIC was exactly 50 failed treatment (Table 3). This represents a high failure rate, albeit for a small number of patients. The probability of cure was shown to be a function of the dose/MIC and the EC50 was 43.7, but nonetheless, a dose/ MIC just short of 100 was required to achieve a probability of cure of 90% (Fig. 2). In murine models of systemic candidosis, the AUC24/MIC required to achieve 50% of the maximum effect varied from 25 to 44 (4, 18), although an AUC/MIC of �500 was required to attain a 2-log10 reduction in the numbers of CFU (