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Antimicrobial Agents and Chemotherapy, July 2007, p. 2656-2657, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01583-06

LETTERS TO THE EDITOR

Relationship of Blood Level and Susceptibility in Voriconazole Treatment of Histoplasmosis

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Monitoring of voriconazole serum levels has been advocated by Smith et al. as a method of ensuring adequate drug exposure in treating invasive mycoses (9). Voriconazole blood levels may vary considerably between subjects as a consequence of genetic polymorphisms that dictate variable clearance and nonlinear elimination (4, 5, 7, 8, 10). Among patients taking 200 mg twice a day, trough voriconazole concentrations range from below 0.100 µg/ml to nearly 10 µg/ml in several studies (2, 4, 5, 6). Although clinical trial data are lacking, voriconazole is occasionally used to treat Histoplasma capsulatum infections. In this report, we determined blood levels in patients treated with voriconazole as a secondary therapy for histoplasmosis, usually because of intolerance of other antifungal therapies, mostly amphotericin B or itraconazole.

Serum specimens from nine patients with disseminated histoplasmosis that had been submitted for antigen testing were later tested for serum levels of voriconazole (3). All nine patients were considered to have improved clinically during secondary oral voriconazole treatment at a dose of 200 mg twice daily. All patients had received voriconazole for at least 2 weeks before blood concentrations were determined, but the exact timing of the blood specimens obtained following the oral administration of voriconazole was not recorded. Specimens had been frozen for up to 4 years prior to the determination of serum drug levels. Our experience with a similar compound, itraconazole, showed no loss of activity after 4 years at –20°C. Furthermore, the levels observed in the patients in this study are consistent with levels obtained in real-time testing of fresh specimens. Isolates of H. capsulatum for this patient cohort were unavailable for voriconazole susceptibility testing; therefore, archived H. capsulatum isolates from AIDS patients who had either primary or relapsed histoplasmosis were employed for this testing by a modified CLSI (formerly NCCLS) method as described previously (1). A comparison of voriconazole susceptibilities (by MIC measurements) of these archived H. capsulatum isolates from patients with both primary and relapsed disease (Fig. 1) was made with the random voriconazole blood levels measured from the nine patients who were being treated with the drug for disseminated histoplasmosis (Fig. 1).

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FIG. 1. Comparison of antifungal susceptibilities of primary and relapse isolates of H. capsulatum to voriconazole and random voriconazole blood levels in patients receiving voriconazole for the treatment of histoplasmosis. The left-hand axis depicts the MIC scale for the primary and relapse isolates, included in the left-hand section of the figure. The median MIC was 0.015 µg/ml for the primary and 0.030 µg/ml for the relapse isolates. The right-hand axis depicts voriconazole blood levels for the histoplasmosis cases, included in the right-hand section of the figure. The three specimens with blood levels shown below the 0.125-µg/ml voriconazole blood level designation demonstrated a zone of inhibition in the bioassay, which was below the lowest standard. None Detected, no inhibition was observed for the specimen.

Among 20 samples for the nine patients, voriconazole concentrations ranged from undetectable to 8.00 µg/ml (Fig. 1). Voriconazole blood levels were highly variable and possibly inadequate in several of our patients, with two random blood levels clearly falling below the median MIC for primary (0.015 µg/ml) and relapsed (0.030 µg/ml) isolates. Three other levels fell below the lowest calibrator (0.125 µg/ml) for serum voriconazole levels, and therefore we do not know if they were below these MIC medians. There were questions about medication compliance in three patients, two of whom had levels of <0.125 µg/ml. Nonetheless, all nine patients had already improved in response to amphotericin B or itraconazole before voriconazole was started, and no patient relapsed while receiving voriconazole, despite the documented low drug levels.

Pascual et al. reported a 90% response for patients with aspergillosis or candidiasis with voriconazole trough levels of >1.0 mg/ml and only a 54% response for patients with lower troughs (6). Smith et al. reported findings for 28 patients with invasive mycoses, mostly aspergillosis, and observed favorable responses for 100% (10/10) of patients with random serum levels, >2.05 µg/ml, compared with unfavorable responses for 44% of patients with lower concentrations (9). Among our nine patients with histoplasmosis, random levels were <2.05 µg/ml in 60%, <1.0 µg/ml in 45%, and <0.125 µg/ml in 30%. Although we cannot establish a "subtherapeutic level" from our cases, since all appear to have responded to the therapies given, we suggest that levels that measure below the calibrator level of 0.125 µg/ml might be considered subtherapeutic. This task is further complicated by the paucity of voriconazole MIC data for histoplasmosis. Given the variability in serum levels in patients receiving voriconazole for histoplasmosis, the relatively high MIC₉₀ of voriconazole for H. capsulatum noted herein, and the lack of prospective trials establishing the effectiveness of voriconazole for the treatment of histoplasmosis, we suggest that it may be prudent to measure trough concentrations of voriconazole in patients receiving it for treatment of histoplasmosis to ensure detectable drug levels.

 
Published ahead of print on 16 April 2007.

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1
1. Connolly, P., J. Wheat, C. Schnizlein-Bick, M. Durkin, S. Kohler, M. Smedema, J. Goldberg, E. Bridendine, and D. Loebenberg. 1999. Comparison of a new triazole antifungal agent, Schering 56592, with itraconazole and amphotericin B for treatment of histoplasmosis in immunocompetent mice. Antimicrob. Agents Chemother. 43:322-328.[Abstract/Free Full Text]
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2. Denning, D. W., P. Ribaud, N. Milpied, D. Caillot, R. Herbrecht, E. Thiel, A. Haas, M. Ruhnke, and H. Lode. 2002. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin. Infect. Dis. 34:563-571.[CrossRef][Medline]
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3. Freifeld, A. G., P. C. Iwen, B. L. Lesiak, R. K. Gilroy, R. B. Stevens, and A. C. Kalil. 2005. Histoplasmosis in solid organ transplant recipients at a large Midwestern university transplant center. Transpl. Infect. Dis. 7:109-115.[CrossRef][Medline]
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4. Lazarus, H. M., J. L. Blumer, S. Yanovich, H. Schlamm, and A. Romero. 2002. Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: a dose escalation study. J. Clin. Pharmacol. 42:395-402.[Abstract]
5
5. Leveque, D., Y. Nivoix, F. Jehl, and R. Herbrecht. 2006. Clinical pharmacokinetics of voriconazole. Int. J. Antimicrob. Agents 27:274-284.[CrossRef][Medline]
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6. Pascual, A. A., S. Bolay, and O. Marchetti. 2006. Documentation of low voriconazole blood levels followed by dose adjustment in patients with invasive fungal infections not responding to therapy, abstr. M-1304. Abstr. 46th Intersci. Conf. Antimicrob. Agents Chemother., San Francisco, CA, 27 to 30 September 2006.
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7. Purkins, L., N. Wood, K. Greenhalgh, M. J. Allen, and S. D. Oliver. 2003. Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety. Br. J. Clin. Pharmacol. 56(Suppl. 1):10-16.[CrossRef][Medline]
8
8. Purkins, L., N. Wood, K. Greenhalgh, M. D. Eve, S. D. Oliver, and D. Nichols. 2003. The pharmacokinetics and safety of intravenous voriconazole—a novel wide-spectrum antifungal agent. Br. J. Clin. Pharmacol. 56(Suppl. 1):2-9.[CrossRef][Medline]
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9. Smith, J., N. Safdar, V. Knasinski, W. Simmons, S. M. Bhavnani, P. G. Ambrose, and D. Andes. 2006. Voriconazole therapeutic drug monitoring. Antimicrob. Agents Chemother. 50:1570-1572.[Abstract/Free Full Text]
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10. Trifilio, S., R. Ortiz, G. Pennick, A. Verma, J. Pi, V. Stosor, T. Zembower, and J. Mehta. 2005. Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 35:509-513.[CrossRef][Medline]

						Alison Freifeld* University of Nebraska Medical Center Omaha, Nebraska 68198-5400 Sandra Arnold University of Tennessee Health Science Center Le Bonheur Children's Medical Center 50 N. Dunlap St. Memphis, Tennessee 38103 Winnie Ooi Travel and Tropical Medicine Clinic Department of Infectious Diseases Lahey Clinic 41 Mall Road Burlington, Massachusetts 01805 Fabian Chen Royal Berkshire Hospital Reading RG1 5AN, United Kingdom Thomas Meyer Arnett Clinic Lafayette, Indiana L. Joseph Wheat Melinda Smedema Ann Lemonte Patricia Connolly MiraVista Diagnostics 4444 Decatur Blvd., Suite 300 Indianapolis, Indiana 46241
						* Phone: (402) 559-8650, Fax: (402) 559-5581, E-mail: afreifeld{at}unmc.edu

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Antimicrobial Agents and Chemotherapy, July 2007, p. 2656-2657, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01583-06

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Freifeld, A. Articles by Connolly, P. Search for Related Content PubMed PubMed Citation Articles by Freifeld, A. Articles by Connolly, P.