Correspondence
Posaconazole Prophylaxis in Hematologic Cancer
N Engl J Med 2007; 356:2214-2218May 24, 2007
- Article
To the Editor:
Ullmann et al. and Cornely et al. (Jan. 25 issue)1,2 report on posaconazole prophylaxis in patients with hematologic cancers. Ullmann et al. found that posaconazole was superior to fluconazole for protection against invasive aspergillosis, and Cornely et al. found that posaconazole was superior to fluconazole and also to itraconazole in preventing fungal infections. After the widespread use of fluconazole and voriconazole as prophylaxis3 and antifungal treatment, an increase in the risk of infections with resistant fungi was observed.4,5 Selection pressure due to continuous exposure to azoles appears to play a crucial role in the emergence of resistance to these drugs. Prophylactic use of such a highly active and broad-spectrum antifungal agent as posaconazole, even in high-risk patients, could favor the emergence and amplification of resistant strains. In addition, such use might be associated with a risk of cross-resistance with other azoles, reducing their efficacy in the treatment of life-threatening fungal infections.
Stefan Weiler, M.D.
Romuald Bellmann, M.D.
Innsbruck Medical School, A-6020 Innsbruck, Austria
romuald.bellmann@i-med. ac. at Dr. Weiler reports receiving salary support from Pfizer and Torrex-Chiesi. No other potential conflict of interest relevant to this letter was reported.
5 References1
Ullmann AJ ,Lipton JH ,Vesole DH , et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007;356:335-347
Full Text | Web of Science | Medline2
Cornely OA ,Maertens J ,Winston DJ , et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356:348-359
Full Text | Web of Science | Medline3
Goodman JL ,Winston DJ ,Greenfield RA , et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992;326:845-851
Full Text | Web of Science | Medline4
Wingard JR ,Merz WG ,Rinaldi MG ,Johnson TR ,Karp JE ,Saral R . Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl J Med 1991;325:1274-1277
Full Text | Web of Science | Medline5
Marty FM ,Cosimi LA ,Baden LR . Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants. N Engl J Med 2004;350:950-952
Full Text | Web of Science | Medline
To the Editor:
Aspergillosis and infection with not-uncommon opportunistic fungi were the most frequent breakthrough infections in the studies of posaconazole prophylaxis reported by Ullmann et al. and Cornely et al. One point mutation in aspergillus cytochrome P-450 (CYP) demethylase could result in posaconazole resistance.1 It is unclear whether the cases of aspergillosis occurred because aspergillus isolates developed resistance or tolerance to posaconazole or because some patients with mucositis, poor oral intake, or both had suboptimal posaconazole levels. Since another triazole, voriconazole, has emerged as the preferred treatment for aspergillosis,2 it will be important to determine whether preexposure of molds colonizing the respiratory tract (especially aspergillus) to posaconazole would result in a lack of fungicidal activity of subsequent voriconazole-based treatment for breakthrough aspergillosis. Risk stratification based on host characteristics, description of the outcomes of treatment for breakthrough aspergillosis in the setting of posaconazole prophylaxis, and analysis of cost-effectiveness are needed to identify the subgroup of high-risk patients with hematologic cancer who may benefit from posaconazole as primary prophylaxis.
Dimitrios P. Kontoyiannis, M.D.
University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
dkontoyi@mdanderson.org Russell E. Lewis, Pharm.D.
University of Houston, Houston, TX 77030Dr. Kontoyiannis reports receiving research support and honoraria from and serving on speakers' bureaus for Merck, Fujisawa, and Enzon and serving on an advisory board for Schering–Plough. Dr. Lewis reports receiving research support from Merck, Fujisawa, and Pfizer and serving on advisory boards for Pfizer and Schering–Plough. No other potential conflict of interest relevant to this letter was reported.
2 References1
Mann PA ,Parmegiani RM ,Wei SQ , et al. Mutations in Aspergillus fumigatus resulting in reduced susceptibility to posaconazole appear to be restricted to a single amino acid in the cytochrome P450 14alpha-demethylase. Antimicrob Agents Chemother 2003;47:577-581
CrossRef | Web of Science | Medline2
Herbrecht R ,Denning DW ,Patterson TF , et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408-415
Full Text | Web of Science | Medline
To the Editor:
With regard to the study by Ullmann et al., it would be useful to know whether the numbers of patients with any hepatic adverse events and any hepatic serious adverse events in the posaconazole group exceeded those in the fluconazole group, and whether the patients with increased hepatic enzymes in the posaconazole group had levels that exceeded three times the upper limit of the normal range. Such findings may be harbingers of serious hepatic injury.1
David S. Krause, M.D.
147 Sawgrass Dr., Blue Bell, PA 19422
dskmd@aol.com Dr. Krause reports serving as a consultant for Nektar Therapeutics. No other potential conflict of interest relevant to this letter was reported.
1 References1
Food and Drug Administration Working Group. Clinical white paper. November 2000. (Accessed May 3, 2007, at http://www.fda.gov/cder/livertox/clinical.pdf.)
To the Editor:
Cornely et al. state that in patients undergoing chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome, posaconazole improved overall survival and was more effective in preventing invasive fungal infections than either fluconazole or itraconazole. Patients were randomly assigned to receive posaconazole or either fluconazole or itraconazole, but only one of the two comparison drugs was used at each center. This protocol implies two separate randomized trials: one comparing posaconazole (in 239 patients) with fluconazole (in 240 patients), and the second comparing posaconazole (in 65 patients) with itraconazole (in 58 patients). In the Supplementary Appendix (available with the full text of the article at www.nejm.org), the authors partly present the results in this way, and we agree with them that there is not sufficient statistical power to draw any conclusion from the latter comparison. The statement that posaconazole is better than itraconazole is therefore not upheld by the results of this trial.
Cees van Nieuwkoop, M.D.
Jaap T. van Dissel, M.D., Ph.D.
Leiden University Medical Center, 2300 RC Leiden, the Netherlands
c.van_nieuwkoop@lumc. nl Author/Editor Response
Both Weiler and Bellmann and Kontoyiannis and Lewis raise questions regarding the development of resistance in the setting of prophylaxis. In the posaconazole group and the fluconazole group, the most frequent pathogens causing breakthrough infections were aspergillus and candida species. No aspergillus isolates from patients with breakthrough aspergillosis were available for susceptibility testing, since breakthrough aspergillosis in the posaconazole group was identified by means of the galactomannan assay, not by culture. Therefore, we were unable to determine whether decreased susceptibility to azoles was a factor in these breakthrough infections. Molecular modeling has shown that posaconazole has modes of binding to the CYP51 target enzyme that differ from those of the other azoles. The models are supported by analyses of mutant strains of candida and aspergillus for which cross-resistance is not observed and show reciprocal activity of posaconazole and voriconazole.1,2 Obviously, we cannot speculate on the attributes of mutations that may arise as a result of posaconazole prophylaxis. Nevertheless, we agree with Weiler and Bellmann and with Kontoyiannis and Lewis that longitudinal surveillance studies are warranted.
As noted by Krause, hepatobiliary disorders are a known side effect of azole therapy, but they are also caused by graft-versus-host disease (GVHD). Patients with GVHD, and especially hepatic GVHD, were allowed to enter our trial with aminotransferase levels that were up to 10 times the upper limit of the normal range, regardless of serum bilirubin levels — values higher than those permitted in other trials.3 Owing to the randomized, double-blind design of our study, evaluation of changes in liver function in the posaconazole group as compared with the fluconazole group can be considered unbiased. The distribution of treatment-emergent adverse events affecting liver function was similar in the posaconazole and fluconazole groups in our study, as well as in the study of patients with neutropenia by Cornely et al. (Table 1Table 1
Treatment-Emergent Hepatic Adverse Events.). Post hoc analysis of changes in aminotransferase levels and total bilirubin levels during the exposure period showed similar rates of change in the posaconazole and fluconazole groups (Table 2Table 2
Selected Results of Liver-Function Tests during the Exposure Period in Patients with Graft-versus-Host Disease.). The change in both groups reflects the complicated underlying disease, azole use in general, or both.3 ReferencesAndrew J. Ullmann, M.D.
Johannes Gutenberg University, 55101 Mainz, Germany
ullmann@uni-mainz.de Pranatharthi Chandrasekar, M.D.
Harper Hospital, Detroit, MI 48201Hernando Patino, M.D.
Schering–Plough Research Institute, Kenilworth, NJ 070331
Xiao L ,Madison V ,Chau AS ,Loebenberg D ,Palermo RE ,McNicholas PM . Three-dimensional models of wild-type and mutated forms of cytochrome P450 14alpha-sterol demethylases from Aspergillus fumigatus and Candida albicans provide insights into posaconazole binding. Antimicrob Agents Chemother 2004;48:568-574
CrossRef | Web of Science | Medline2
Chau AS ,Mendrick CA ,Sabatelli FJ ,Loebenberg D ,McNicholas PM . Application of real-time quantitative PCR to molecular analysis of Candida albicans strains exhibiting reduced susceptibility to azoles. Antimicrob Agents Chemother 2004;48:2124-2131
CrossRef | Web of Science | Medline3
Herbrecht R ,Denning DW ,Patterson TF , et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408-415
Full Text | Web of Science | Medline
Author/Editor Response
Weiler and Bellmann point out that selective pressure accompanying prolonged antifungal exposure may cause shifts toward primary resistant organisms. At baseline in our study, the primary colonizing organism was Candida albicans in the posaconazole group (in 37% of patients) and in the fluconazole or itraconazole group (32%). At week 6, colonization rates declined to 6% in both groups. Colonization rates for C. glabrata increased from 6% in both groups at baseline to 9% in the posaconazole group and 7% in the fluconazole or itraconazole group at week 6. There was no difference in the emergence of candida species between the two groups and no change in the 90th percentile of the minimum inhibitory concentration after more than two tube dilutions for all yeasts. In addition, the study by Ullmann et al. did not show reduced sensitivity to posaconazole in the candida strains colonizing the patients during the study. Shifts toward resistance in colonizing organisms may occur over longer periods than the duration of our study, so they may be found in the future.
Kontoyiannis and Lewis hypothesize that mucositis and suboptimal drug exposure are potential reasons for the 2% failure rate in the posaconazole group. Analysis of their well-taken point reveals that none of the 10 patients with grade 3 or 4 mucositis at baseline had an invasive fungal infection. Average and maximum plasma levels of posaconazole in patients with proven or probable breakthrough infection were not different from those in the overall population. Thus, the occurrence of invasive fungal infection does not appear to be associated with a particular plasma level of posaconazole.
In a large, randomized clinical trial comparing fluconazole with itraconazole as prophylaxis in high-risk patients, the efficacy results for the oral solutions of the two drugs did not differ significantly.1 Thus, there was no good evidence to support a recommendation for the use of a specific systemic prophylaxis in patients undergoing remission-induction chemotherapy.2,3 In the absence of clinical trials that proved the superior efficacy of any comparison drug in this high-risk population, we did not agree on a single drug to compare with posaconazole and instead left the choice to each participating hospital. This approach allowed us to compare posaconazole with drugs used in current clinical practice.
3 ReferencesOliver A. Cornely, M.D.
University of Cologne, 50924 Cologne, Germany
oliver.cornely@uni-koeln. de Andrew J. Ullmann, M.D.
Johannes Gutenberg University, 55101 Mainz, GermanyCathy Hardalo, M.D.
Schering–Plough Research Institute, Kenilworth, NJ 070331
Glasmacher A ,Cornely O ,Ullmann AJ , et al. An open-label randomized trial comparing itraconazole oral solution with fluconazole oral solution for primary prophylaxis of fungal infections in patients with haematological malignancy and profound neutropenia. J Antimicrob Chemother 2006;57:317-325
CrossRef | Web of Science | Medline2
Kish MA . Guide to development of practice guidelines. Clin Infect Dis 2001;32:851-854
CrossRef | Web of Science | Medline3
Cornely OA ,Bohme A ,Buchheidt D , et al. Prophylaxis of invasive fungal infections in patients with hematological malignancies and solid tumors -- guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2003;82:Suppl 2:S186-S200
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Celalettin Ustun, David L. DeRemer, John C.H. Steele, Caralee Forseen, John F. Fisher, Anand P. Jillella. (2008) Fatal Aspergillus fumigatus and Candida glabrata infections with posaconazole prophylaxis after stem cell transplantation. International Journal of Antimicrobial Agents 32:4, 365-366
CrossRef2
Shelley S Magill, Tom M Chiller, David W Warnock. (2008) Evolving strategies in the management of aspergillosis. Expert Opinion on Pharmacotherapy 9:2, 193-209
CrossRef3
James E Frampton, Lesley J Scott. (2008) Posaconazole. Drugs 68:7, 993-1016
CrossRef
