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Antifungal prophylaxis: To prevent or not
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EDITORIAL
Antifungal Prophylaxis: To Prevent or Not JOHN R. PERFECT, M.D., Durham,NorthCarolina
D
eep-seated fungal infections have increased in importance over the last decade. This increase is directly linked to a variety of new immunocompromised cases attributable to advances in medical care and infection with the human immunodeficiency virus (HIV). Unfortunately, the diagnosis of these deep-seated mycoses can be fatally delayed and even when identified, the limited group of antifungal drugs to treat infections in these immunocompromised hosts makes the outcome uncertain in many cases. Therefore, clinicians have identified certain high-risk groups for mycoses, such as febrile neutropenic patients, and start empiric antifungal therapy before the burden of organisms becomes too great. This empiric practice of antifungal drug use treats many patients without mycoses but has become established in many medical centers as routine care. The next frontier in clinical management of mycoses is to determine if true antifungal prophylaxis or prevention, prior to any signs of infection, would be successful. In this issue of the journal, Ampel et al [1] have taken an important step in identifying a high-risk population for study of antifungal prophylaxis. This prospective, cohort analysis of HIV-infected subjects living in an endemic area for coccidioidomycosis showed an estimated cumulative incidence of 24.6% in 41 months for developing active fungal infection. This infection was associated with risk factors of a CD4 lymphocyte count of less than 0.250 X 109/L and a diagnosis of acquired immunodeficiency syndrome. This study identifies a high risk of disease in a large identifiable population. Although the investigators do not discuss it, they are now in a position to evaluate the value of antifungal prophylaxis in both a reasonable length of time and with a manageable number of patients. In my opinion, this article is linked to an even larger question. What are the clinical criteria for institution of antifungal prophylaxis? The concept of antifungal prophylaxis has been revitalized with From the Division of Infectious Diseases. Duke University Medical Center, Durham. North Carolina. Requests for reprints should be addressed to John R. Perfect, M.D., Division of Infectious Diseases. Duke University Medical Center, P.O. Box 3353. Durham. North Carolina 27710. Manuscript submitted November 9. 1992, and accepted November 19, 1992.
the advent of safe azole drugs and thus a series of new studies have recently appeared [2-10]. However, I suggest that all clinicians consider at least six criteria before justifying antifungal prophylaxis: (1) safety, (2) efficacy, (3) cost, (4) consequence, (5) prevalence, and (6) resistance. Mter examining each criterion carefully, clinicians must judge the potential cost-benefit ratio in their own patient population. A review of the criteria can be made in the following manner. The prophylactic drug must be safe. With the new triazoles, this issue has become less important than with the polyenes such as amphotericin B, but these drugs may have interactions with other drugs that these seriously ill patients receive. It is also essential that one uses proper placebo-controlled, randomized studies with well-described endpoints and patient populations to make judgments on efficacy. Any lesser study is unacceptable. Despite these obvious criteria, studies continue to appear in the literature without this rigorous but basic design and without any cost-benefit analysis. The cost is particularly high if expensive drugs are used for long periods of time without survival benefits. On the other hand, prophylactic use of these agents could prevent fungal infections and save not only immense costs associated with prolonged hospitalization due to these fungal infections but also prevent suffering and save lives. We also need to understand the consequences of the prophylaxis on both the primary infection and the underlying disease. Does it really make a difference in the final outcome of the patient, reduce pain and suffering, and/or increase quality of life, or simply make us feel better because it should work? The clinician must identify and/or select a group of patients in whom the known frequency of fungal infection is high to detect a clinical difference with prophylaxis if successful. For most institutions, it is likely that the frequency of fungal infections would need to be over 10% of the at-risk population to detect a local reduction in the number of infections seen with prophylaxis. Therefore, all clinicians should know or reliably estimate the prevalence of fungal infections in their own patients prior to using these prophylaxis regimens. Finally, we must monitor for development of fungal resistance to the prophylactic drugs. For example, widespread azole use
March 1993 The American Journal of Medicine Volume 94
233
ANTIFUNGAL PROPHYLAXIS / PERFECT
in immunocompromised hosts for prolonged periods can potentially select for drug-resistant yeast and mold infections. We should not be fooled into complacency; these resistant strains are already present in certain patient populations [11-14] and they will likely continue to expand. We must protect our present antifungal drugs with careful prophylactic and therapeutic selections, since the immediate pharmaceutical horizon is not full of new and wonderful antifungal agents for treatment of deep-seated mycoses. We should continue to encourage the concept and study of antifungal prophylaxis in certain identified high-risk groups and in some cases use it, but not blindly adopt or extrapolate it to other groups without a favorable review of the above criteria for each patient population. "An ounce of prevention is worth a pound of cure" is only true when you know the true weight of the prevention.
REFERENCES 1. Ampel NM. Dols CL. Galgiani IN. CoccidioidomycosIs dUring human immunodeficiency virus infection: results of a prospective study in acoccidioidal endemic area. Am J Med 1993; 94: 235--40. 2. Samonis G. Rolston K. Karl C. Miller P. Bodey GP. Prophylaxis of oropharyngeal candidiasis with fluconazole. Rev Infect Dis 1990; 12: 369-73. 3. Arska-Rozenberg M. Dekker AW. Branger J. Verhoef J. Arandomized study to compare oral fluconazole to amphotericin B in the prevention of fungal infections with acute leukemia. J Antimicrob Chemother 1991; 27: 369-76. 4. Just-Nubling C. Gentschew G. Meibner K. et al. Fluconazole prophylaxis of
234
recurrent oral candidiaSIS in HIV-posltlve patients. Eur J Clin Microbiollnfect Dis 1991; 10: 917-21. 5. Leen CLS, Dunbar EM, Ellis ME, Mandai BK. Once-weekly fluconazole to prevent recurrence of oropharyngeal candidiasis In patients with AIDS and AIDSrelated complex: a double-blind placebo-eontrolled study. J Infect 1990; 21: 55--60. 6. Stevens DA. Greene I. Lang OS. Thrush can be prevented in patients with acquired immunodeficiency syndrome and the acqUired immunodeficiency syndrome-related complex. Arch Intern Med 1991; 151: 2458-64. 7. Nightingale SO, Cal SX. Peterson OM. et al. Primary prophylaxis with fluconazole against systemic fungal infections in HIV-positive patients. AIDS 1992; 6: 191-4. 8. Brammer KW. Management of fungal Infection In neutropenic patients with fluconazole. Hamatol Bluttransfus 1990; 33: 546-50. 9. Goodman JL. Winston OJ, Greenfield RA. et al. Acontrolled trial offluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992; 326: 845-51. 10. Perfect JR. Klotman ME, Gilbert CC, et al. Prophylactic intravenous amphotericin Bin neutropenic autologous bone marrow transplant recipients. J Infect Dis 1992; 165: 891-7. 11. Wingard JR. Merz WG, Rinaldi MG, Johnson TR. Karp JE, Saral R. Increase in Candidakruseiinfection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. NEng! J Med 1991; 325: 1274-7. 12. Troillet N. Durussel C. Bille J, Glauser MP. Chave JP. Fluconazole-resistant oral candidiasis in human immunodeficiency virus-infected patients: in vitro-in vivocorrelation [abstract 1202]. Thirty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, Anaheim. CA. 1992. 13. Dupont B. Improvisi L. Eliaszewicz M. Pialoux G. Resistance of Candida albicansto fluconazole in AIDS patients [abstract 1203). Thirty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, Anaheim. CA. 1992. 14. Rodriquez-Tudela JL, Laguna F, Martinez-Suarez JV, Chaves F. Dronda F. Fluconazole resistance of Candidaalbicansisolates from AIDS patients receiving prolonged antifungal therapy [abstract 1204]. Thirty-second Intersclence Conference on Antimicrobial Agents and Chemotherapy, Anaheim. CA. 1992.
March 1993 The American Journal of Medicine Volume 94
-----'1
EDITORIAL
Antifungal Prophylaxis: To Prevent or Not JOHN R. PERFECT, M.D., Durham,NorthCarolina
D
eep-seated fungal infections have increased in importance over the last decade. This increase is directly linked to a variety of new immunocompromised cases attributable to advances in medical care and infection with the human immunodeficiency virus (HIV). Unfortunately, the diagnosis of these deep-seated mycoses can be fatally delayed and even when identified, the limited group of antifungal drugs to treat infections in these immunocompromised hosts makes the outcome uncertain in many cases. Therefore, clinicians have identified certain high-risk groups for mycoses, such as febrile neutropenic patients, and start empiric antifungal therapy before the burden of organisms becomes too great. This empiric practice of antifungal drug use treats many patients without mycoses but has become established in many medical centers as routine care. The next frontier in clinical management of mycoses is to determine if true antifungal prophylaxis or prevention, prior to any signs of infection, would be successful. In this issue of the journal, Ampel et al [1] have taken an important step in identifying a high-risk population for study of antifungal prophylaxis. This prospective, cohort analysis of HIV-infected subjects living in an endemic area for coccidioidomycosis showed an estimated cumulative incidence of 24.6% in 41 months for developing active fungal infection. This infection was associated with risk factors of a CD4 lymphocyte count of less than 0.250 X 109/L and a diagnosis of acquired immunodeficiency syndrome. This study identifies a high risk of disease in a large identifiable population. Although the investigators do not discuss it, they are now in a position to evaluate the value of antifungal prophylaxis in both a reasonable length of time and with a manageable number of patients. In my opinion, this article is linked to an even larger question. What are the clinical criteria for institution of antifungal prophylaxis? The concept of antifungal prophylaxis has been revitalized with From the Division of Infectious Diseases. Duke University Medical Center, Durham. North Carolina. Requests for reprints should be addressed to John R. Perfect, M.D., Division of Infectious Diseases. Duke University Medical Center, P.O. Box 3353. Durham. North Carolina 27710. Manuscript submitted November 9. 1992, and accepted November 19, 1992.
the advent of safe azole drugs and thus a series of new studies have recently appeared [2-10]. However, I suggest that all clinicians consider at least six criteria before justifying antifungal prophylaxis: (1) safety, (2) efficacy, (3) cost, (4) consequence, (5) prevalence, and (6) resistance. Mter examining each criterion carefully, clinicians must judge the potential cost-benefit ratio in their own patient population. A review of the criteria can be made in the following manner. The prophylactic drug must be safe. With the new triazoles, this issue has become less important than with the polyenes such as amphotericin B, but these drugs may have interactions with other drugs that these seriously ill patients receive. It is also essential that one uses proper placebo-controlled, randomized studies with well-described endpoints and patient populations to make judgments on efficacy. Any lesser study is unacceptable. Despite these obvious criteria, studies continue to appear in the literature without this rigorous but basic design and without any cost-benefit analysis. The cost is particularly high if expensive drugs are used for long periods of time without survival benefits. On the other hand, prophylactic use of these agents could prevent fungal infections and save not only immense costs associated with prolonged hospitalization due to these fungal infections but also prevent suffering and save lives. We also need to understand the consequences of the prophylaxis on both the primary infection and the underlying disease. Does it really make a difference in the final outcome of the patient, reduce pain and suffering, and/or increase quality of life, or simply make us feel better because it should work? The clinician must identify and/or select a group of patients in whom the known frequency of fungal infection is high to detect a clinical difference with prophylaxis if successful. For most institutions, it is likely that the frequency of fungal infections would need to be over 10% of the at-risk population to detect a local reduction in the number of infections seen with prophylaxis. Therefore, all clinicians should know or reliably estimate the prevalence of fungal infections in their own patients prior to using these prophylaxis regimens. Finally, we must monitor for development of fungal resistance to the prophylactic drugs. For example, widespread azole use
March 1993 The American Journal of Medicine Volume 94
233
ANTIFUNGAL PROPHYLAXIS / PERFECT
in immunocompromised hosts for prolonged periods can potentially select for drug-resistant yeast and mold infections. We should not be fooled into complacency; these resistant strains are already present in certain patient populations [11-14] and they will likely continue to expand. We must protect our present antifungal drugs with careful prophylactic and therapeutic selections, since the immediate pharmaceutical horizon is not full of new and wonderful antifungal agents for treatment of deep-seated mycoses. We should continue to encourage the concept and study of antifungal prophylaxis in certain identified high-risk groups and in some cases use it, but not blindly adopt or extrapolate it to other groups without a favorable review of the above criteria for each patient population. "An ounce of prevention is worth a pound of cure" is only true when you know the true weight of the prevention.
REFERENCES 1. Ampel NM. Dols CL. Galgiani IN. CoccidioidomycosIs dUring human immunodeficiency virus infection: results of a prospective study in acoccidioidal endemic area. Am J Med 1993; 94: 235--40. 2. Samonis G. Rolston K. Karl C. Miller P. Bodey GP. Prophylaxis of oropharyngeal candidiasis with fluconazole. Rev Infect Dis 1990; 12: 369-73. 3. Arska-Rozenberg M. Dekker AW. Branger J. Verhoef J. Arandomized study to compare oral fluconazole to amphotericin B in the prevention of fungal infections with acute leukemia. J Antimicrob Chemother 1991; 27: 369-76. 4. Just-Nubling C. Gentschew G. Meibner K. et al. Fluconazole prophylaxis of
234
recurrent oral candidiaSIS in HIV-posltlve patients. Eur J Clin Microbiollnfect Dis 1991; 10: 917-21. 5. Leen CLS, Dunbar EM, Ellis ME, Mandai BK. Once-weekly fluconazole to prevent recurrence of oropharyngeal candidiasis In patients with AIDS and AIDSrelated complex: a double-blind placebo-eontrolled study. J Infect 1990; 21: 55--60. 6. Stevens DA. Greene I. Lang OS. Thrush can be prevented in patients with acquired immunodeficiency syndrome and the acqUired immunodeficiency syndrome-related complex. Arch Intern Med 1991; 151: 2458-64. 7. Nightingale SO, Cal SX. Peterson OM. et al. Primary prophylaxis with fluconazole against systemic fungal infections in HIV-positive patients. AIDS 1992; 6: 191-4. 8. Brammer KW. Management of fungal Infection In neutropenic patients with fluconazole. Hamatol Bluttransfus 1990; 33: 546-50. 9. Goodman JL. Winston OJ, Greenfield RA. et al. Acontrolled trial offluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992; 326: 845-51. 10. Perfect JR. Klotman ME, Gilbert CC, et al. Prophylactic intravenous amphotericin Bin neutropenic autologous bone marrow transplant recipients. J Infect Dis 1992; 165: 891-7. 11. Wingard JR. Merz WG, Rinaldi MG, Johnson TR. Karp JE, Saral R. Increase in Candidakruseiinfection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. NEng! J Med 1991; 325: 1274-7. 12. Troillet N. Durussel C. Bille J, Glauser MP. Chave JP. Fluconazole-resistant oral candidiasis in human immunodeficiency virus-infected patients: in vitro-in vivocorrelation [abstract 1202]. Thirty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, Anaheim. CA. 1992. 13. Dupont B. Improvisi L. Eliaszewicz M. Pialoux G. Resistance of Candida albicansto fluconazole in AIDS patients [abstract 1203). Thirty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, Anaheim. CA. 1992. 14. Rodriquez-Tudela JL, Laguna F, Martinez-Suarez JV, Chaves F. Dronda F. Fluconazole resistance of Candidaalbicansisolates from AIDS patients receiving prolonged antifungal therapy [abstract 1204]. Thirty-second Intersclence Conference on Antimicrobial Agents and Chemotherapy, Anaheim. CA. 1992.
March 1993 The American Journal of Medicine Volume 94