Correlation of anti-fungal susceptibility with clinical outcomes in patients with cryptococcal meningitis

BMC Infectious Diseases

Cheng-Hsien Lu³  Ya-Fen Tang¹  Chun-Chih Chien¹  Fang-Ju Chen²  Jien-Wei Liu²  Tzu-Yao Chang²  Chen-Hsiang Lee² 

[1]Department of Laboratory Medicine, Kaohsiung, Taiwan

[2]Division of Infectious Diseases, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan

[3]Department of Biological Science, National Sun Yat-Sen University, Kaohsiung, Taiwan

关键词: Susceptibility;    Outcome;    Fluconazole;    Cryptococcal meningitis;   

Others  :  1158682
DOI  :  10.1186/1471-2334-12-361

 received in 2012-05-17, accepted in 2012-12-18,  发布年份 2012

【 摘 要 】

Background

This study aimed to investigate the correlation of minimum inhibiting concentrations (MICs), obtained by broth micro-dilution, and clinical response in patients with cryptococcal meningitis.

Methods

Using retrospective analyses covering the period 2001–2010, factors affecting clinical therapeutic cure in patients with cryptococcal meningitis 10 weeks after the start of anti-fungal therapy were identified. Specific emphasis was placed on the role of anti-fungal susceptibility.

Results

Of 46 patients with cryptococcal meningitis identified, 21 were cured after 10 weeks of treatment. Overall, 12 strains (26.1%) were resistant to fluconazole (>8 μg/ml) and 8 (17.4%) had an MIC >1 μg/ml for amphotericin B. Twenty-three patients received combination amphotericin B and fluconazole as their initial antifungal therapy, 17 were given amphotericin B only, five received fluconazole only, and one received a combination of amphotericin B and flucytosine. After 2 weeks, all patients received fluconazole (400–600 mg daily for 8 weeks at least, then 200 mg daily thereafter). The presence of isolates resistant to fluconazole (MIC >8 μg/ml; 4.8% vs. 44%, p < 0.01) were statistically significant among patients who were cured. Anti-fungal susceptibility, reflected by fluconazole MIC >8 μg/ml, was an independent predictor of therapeutic cure at 10-week evaluation (OR = 15.7; 95% CI: 1.8-135.9; p = 0.01), but higher MIC of amphotericin B (>1 μg/ml) was not.

Conclusions

The MICs of fluconazole, determined by the CLSI method, may be a potential predictor of therapeutic cure in patients with cryptococcal meningitis.

【 授权许可】

   
2012 Lee et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Mitchell TG, Perfect JR: Cryptococcosis in the era of AIDS-100 years after the discovery of Cryptococcus neoformans. Clin Microbiol Rev 1995, 8:515-548.
• [2]Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG, Powderly WG, Singh N, Sobel JD, Sorrell TC: Practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2010, 50:291-322.
• [3]Brandt ME, Pfaller MA, Hajjeh RA, Hamill RJ, Pappas PG, Reingold AL, Rimland D, Warnock DW, Cryptococcal Disease Active Surveillance Group: Trends in anti-fungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998. Antimicrob Agents Chemother 2001, 45:3065-3069.
• [4]Armengou A, Porcar C, Mascaró J, García-Bragado F: Possible development of resistance to fluconazole during suppressive therapy for AIDS-associated cryptococcal meningitis. Clin Infect Dis 1996, 23:1337-1338.
• [5]Paugam A, Camet-Dupouy J, Blanche P, Gangneux JP, Tourte-Schaefer C, Sicard D: Increased fluconazole resistance of Cryptococcus neoformans isolated from a patient with AIDS and recurrent meningitis. Clin Infect Dis 1994, 19:975-976.
• [6]Berg J, Clancy CJ, Nguyen MH: The hidden danger of primary fluconazole prophylaxis for patients with AIDS. Clin Infect Dis 1998, 26:186-187.
• [7]Clinical and Laboratory Standards Institute (CLSI): Reference method for broth dilution anti-fungal susceptibility testing of yeasts; approved standard. 3rd edition. CLSI document M27–A3, CLSI, Wayne, PA; 2008.
• [8]Dannaoui E, Abdul M, Arpin M, Michel-Nguyen A, Piens MA, Favel A, Lortholary O, Dromer F, French Cryptococcosis Study Group: Results obtained with various anti-fungal susceptibility testing methods do not predict early clinical outcome in patients with cryptococcosis. Antimicrob Agents Chemother 2006, 50:2464-2470.
• [9]Witt MD, Lewis RJ, Larsen RA, Milefchik EN, Leal MA, Haubrich RH, Richie JA, Edwards JE Jr, Ghannoum MA: Identification of patients with acute AIDS-associated cryptococcal meningitis who can be effectively treated with fluconazole: the role of anti-fungal susceptibility testing. Clin Infect Dis 1996, 22:322-328.
• [10]Aller AI, Martin-Mazuelos E, Lozano F, Gomez-Mateos J, Steele-Moore L, Holloway WJ, Gutiérrez MJ, Recio FJ, Espinel-Ingroff A: Correlation of fluconazole MICs with clinical outcome in cryptococcal infection. Antimicrob Agents Chemother 2000, 44:1544-1548.
• [11]American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992, 20:864-874.
• [12]Liliang PC, Liang CL, Chang WN, Chen HJ, Su TM, Lu K, Lu CH: Shunt surgery for hydrocephalus complicating cryptococcal meningitis in human immuno-deficiency virus-negative patients. Clin Infect Dis 2003, 37:673-678.
• [13]Lan SH, Chang WN, Lu CH, Lui CC, Chang HW: Cerebral infarction in chronic meningitis: a comparison of tuberculous meningitis and cryptococcal meningitis. QJM 2001, 94:247-253.
• [14]Ito-Kuwa S, Nakamura K, Aoki S, Vidotto V: Serotype identification of Cryptococcus neoformans by multiplex PCR. Mycoses 2007, 50:277-281.
• [15]Nguyen MH, Yu CY: In vitro comparative efficacy of voriconazole and itraconazole against fluconazole-susceptible and -resistant Cryptococcus neoformans isolates. Antimicrob Agents Chemother 1998, 42:471-472.
• [16]Lozano-Chiu M, Paetznick VL, Ghannoum MA, Rex JH: Detection of resistance to amphotericin B among Cryptococcus neoformans clinical isolates: performances of three different media assessed by using E-test and National Committee for Clinical Laboratory Standards M27-A methodologies. J Clin Microbiol 1998, 36:2817-2822.
• [17]Yu YL, Lau YN, Woo E, Wong KL, Tse B: Cryptococcal infection of the nervous system. Q J Med 1988, 66:87-96.
• [18]Sun HY, Chen MY, Hsiao CF, Hsieh SM, Hung CC, Chang SC: Endemic fungal infections caused by Cryptococcus neoformans and Penicillium marneffei in patients infected with human immuno-deficiency virus and treated with highly active anti-retroviral therapy. Clin Microbiol Infect 2006, 12:381-388.
• [19]Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK, Thompson SE, Sugar AM, Tuazon CU, Fisher JF, Hyslop N, Jacobson JM, Hafner R, Dismukes WE, The NIAID Mycoses Study Group and the AIDS Clinical Trials Group: Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. N Engl J Med 1992, 326:83-89.
• [20]Zuger A, Louie E, Holzman RS, Simberkoff MS, Rahal JJ: Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1986, 104:234-240.
• [21]Clark RA, Greer D, Atkinson W, Valainis GT, Hyslop N: Spectrum of Cryptococcus neoformans infection in 68 patients infected with human immuno-deficiency virus. Rev Infect Dis 1990, 12:768-777.
• [22]Anaissie E, Shawar R, Paetznick V, Ensign LG, Witte Z, LaRocco M: Two-site comparison of broth micro-dilution and semi-solid agar dilution methods for susceptibility testing of Cryptococcus neoformans in three media. J Clin Microbiol 1993, 31:1370-1372.
• [23]Franzot SP, Hamdan JS: In vitro susceptibilities of clinical and environmental isolates of Cryptococcus neoformans to five anti-fungal drugs. Antimicrob Agents Chemother 1996, 40:822-824.
• [24]Sionov E, Chang YC, Garraffo HM, Kwon-Chung KJ: Hetero-resistance to fluconazole in Cryptococcus neoformans is intrinsic and associated with virulence. Antimicrob Agents Chemother 2009, 53:2804-2815.
• [25]Larsen RA, Bauer M, Brouwer AE, Sanchez A, Thomas AM, Rajanuwong A, Chierakul W, Peacock SJ, Day N, White NJ, Rinaldi MG, Harrison TS: In vitro clinical correlation for amphotericin B susceptibility in AIDS-associated cryptococcal meningitis. Antimicrob Agents Chemother 2007, 51:343-345.
• [26]Larsen RA, Bauer M, Pitisuttithum P, Sanchez A, Tansuphaswadikul S, Wuthiekanun V, Peacock SJ, Simpson AJ, Fothergill AW, Rinaldi MG, Bustamante B, Thomas AM, Altomstone R, Day NP, White NJ: Correlation of susceptibility of Cryptococcus neoformans to amphotericin B with clinical outcome. Antimicrob Agents Chemother 2011, 55:5624-5630.
• [27]Chang WN, Huang CR, Lei CB, Lee PY, Chien CC, Chang HW, Chang CS, Lu CH: Serotypes of clinical cerebrospinal fluid Cryptococcus neoformans isolates from southern Taiwan and their in vitro susceptibilities to amphotericin B, fluconazole, and voriconazole. Jpn J Infect Dis 2004, 57:113-115.
• [28]Brouwer AE, Rajanuwong A, Chierakul W, Griffin GE, Larsen RA, White NJ, Harrison TS: Combination anti-fungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004, 363:1764-1767.