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The Impact of Primary Prophylaxis for Cryptococcosis on Fluconazole Resistance in Candida Species

Apisarnthanarak, Anucha MD*; Mundy, Linda M MD

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 15th, 2008 - Volume 47 - Issue 5 - p 644-645
doi: 10.1097/QAI.0b013e31815bad0c
Letters to the Editor

*Division of Infectious Diseases, Thammasart University Hospital, Pratumthani, Thailand, †Saint Louis University School of Public Health, Saint Louis, MO

To the Editor:

Primary anticryptococcal prophylaxis in advanced HIV infection is generally not recommended, given no evidence for improved survival, associated excess costs, and the potential risk for emerging drug resistance.1 In Thailand, however, the prevalence of cryptococcosis is high, primary fluconazole prophylaxis has been associated with reduced invasive fungal infections and mortality, and primary cryptococcal prophylaxis is recommended in national HIV treatment guidelines.2,3 Although primary prophylaxis has not been shown to select for fluconazole resistance among patients who subsequently developed cryptococcal meningitis,4 the impact of primary anticryptococcal prophylaxis on the emergence of fluconazole resistance in Candida species among patients with HIV infection has not been evaluated.

Thammasart University is a 450-bed tertiary care referral hospital in central Thailand. Infectious diseases consultative services and care formally began in January 2003, with an annual increase in the number of HIV-related admissions from the year 2002 (N = 125) to the year 2006 (N = 405). Most HIV-related admissions were for the evaluation of fever; 45% of cases had CD4 counts <100 cells/μL.5 Since 2003, primary anticryptococcal prophylaxis has been routinely prescribed to patients with advanced HIV infection (CD4 counts <100 cells/μL), as recommended by the Thai National HIV Treatment Guideline.3 We conducted a drug utilization and antimicrobial resistance correlation analysis of inpatient antifungal consumption and the prevalence of fluconazole-resistant Candida spp. among hospitalized adults with HIV infection for the calendar years 2002 to 2006. The rate of inpatients' antifungal use was recorded as the total number of grams of drug, converted into defined daily doses (DDDs) per 1000 patient-days, in accordance with the recommendations of the World Health Organization.6 Oral and parenteral drug expenditures were included for analysis. Antimicrobial susceptibility patterns of Candida spp., and the proportion of resistant isolates, were derived from existing data in the Microbiology Department. Correlations between antifungal consumption and resistance were assessed by Pearson correlation analyses.

There was an incremental increase in oral fluconazole consumption (from 6 to 35 DDDs per 1000 patient-days) during the years 2002 to 2006, whereas the consumption of oral itraconazole and other parenteral antifungal agents (eg, fluconazole, amphotericin B) remained unchanged (Table 1). Notably, 86% of oral fluconazole prescriptions were for primary anticryptococcal prophylaxis, and 36% of the patients prescribed oral fluconazole had CD4 counts >100 cells/μL for at least 6 months. During the same 5-year period that the prevalence of fluconazole-resistant Candida spp. increased from 2% to 33%, detection of Candida albicans significantly declined from 95% to 54% (see Table 1). A significant correlation between oral fluconazole consumption and fluconazole-resistant Candida spp. (r = 0.71, P < 0.001) was noted. No correlation was evident for fluconazole-resistant Candida spp. and other antifungal drugs.



Our study findings have significant implications for clinical and laboratory practices. The incremental increase in oral fluconazole consumption was temporally attributed to the national HIV prevention policy for opportunistic infections. Notably, this increase in fluconazole use correlated with increased fluconazole-resistant Candida spp. Our findings suggest that systematic surveillance for fluconazole-resistant Candida spp. is judicious in countries where primary anticryptococcal prophylaxis is given to persons with advanced HIV infection. In addition, our findings imply potential benefit from interventions that minimize inappropriate antifungal use in developing countries. Focused educational interventions aimed at improving guideline compliance with prophylaxis against opportunistic infections are needed.

Anucha Apisarnthanarak, MD*

Linda M. Mundy, MD†

*Division of Infectious Diseases Thammasart University Hospital Pratumthani, Thailand

†Saint Louis University School of Public Health Saint Louis, MO

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1. Masur H, Kaplan JE, Holmes KKUS, Public Health Service, Infectious Diseases Society of America. Guidelines for preventing opportunistic infections among HIV-infected persons-2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. Ann Intern Med. 2002;137:435-478.
2. Chetchotisakd P, Sungkanuparph S, Thinkhamrop B, et al. A multicentre, randomized, double-blind, placebo-controlled trial of primary cryptococcal meningitis prophylaxis in HIV-infected patients with severe immune deficiency. HIV Med. 2004;5:140-143.
3. Royal College of Physician of Thailand. Guidelines for the use of antiretroviral agents and opportunistic infection prophylaxis in HIV-1-infected adults. 2003 revision. Available at: Accessed August 1, 2007.
4. Manosuthi W, Sungkanuparph S, Thongyen S, et al. Antifungal susceptibilities of Cryptococcus neoformans cerebrospinal fluid isolates and clinical outcomes of cryptococcal meningitis in HIV-infected patients with/without fluconazole prophylaxis. J Med Assoc Thai. 2006;89:795-802.
5. Kitkungvan D, Apisarnthanarak A, Plengpart P, et al. Fever of unknown origin in patients with human immunodeficiency virus infection in Thailand: an observation study and review of the literature. Int J STD AIDS. (In press).
6. World Health Organization. Collaborating Centre for Drug Statistics Methodology. ATC Index with DDDs. Oslo, Norway: WHO; 2004. Available at: Accessed August 1, 2007.
© 2008 Lippincott Williams & Wilkins, Inc.