aDepartment of Medical Microbiology, University Medical Center, Nijmegen, the Netherlands; and bDepartment of Medical Microbiology, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands.
Sponsorship: This study was supported by the EC-TMR-EUROFUNG network (ERBFMXR-CT970145).
Received: 25 October 2000; accepted: 1 February 2001.
Because invasive aspergillosis is encountered relatively infrequently in HIV-infected patients, we hypothesized that prophylaxis for Pneumocystis carinii pneumonia (PCP) might also prevent invasive Aspergillus infections.
Invasive aspergillosis is a significant cause of morbidity and death in immunocompromised patients, including those with AIDS. Although the incidence of this infection is low, the risk is increased in those with low counts of CD4 T lymphocytes, neutropenia and during corticosteroid treatment. Sulfonamides, especially trimethoprim–sulfamethoxazole (TMP–SMZ), are antimicrobial agents that have frequently been employed to prevent PCP, toxoplasmic encephalitis and bacterial respiratory infections in HIV-infected patients. During prophylaxis with TMP–SMZ, 13.9% of patients develop adverse events that necessitate discontinuation , and alternative regimens such as dapsone, or aerosolized pentamidine are considered . Because Pneumocystis is now believed to belong to the fungal kingdom, we investigated whether these drugs were active against Aspergillus spp. This is of relevance because patients at risk of PCP are often also at risk of developing invasive aspergillosis.
The literature was reviewed for cases of invasive aspergillosis in HIV-infected persons or those with AIDS, which had also documented the drug that was used to prevent PCP. Only 18 cases have been described in the literature that met these criteria [3–5]. Among these, 14 patients had received dapsone or pentamidine prophylaxis and four TMP–SMZ. The largest series was published by Denning et al., in which 13 patients with AIDS were described who developed invasive aspergillosis, of whom 12 (92%) had received PCP prophylaxis with pentamidine. Taking into account the proportion of patients who receive either TMP–SMZ or alternative regimens, the probability of developing invasive aspergillosis in patients who received alternative PCP prophylaxis is much higher than for those on prophylaxis with TMP–SMZ (relative risk 21.5). This suggests that TMP–SMZ might show activity against Aspergillus as opposed to pentamidine or dapsone. Therefore, the in-vitro activity of TMP–SMZ, dapsone and pentamidine was determined against a collection of 20 clinical Aspergillus fumigatus isolates and 10 Aspergillus flavus isolates. The in-vitro activity was determined according to the proposed guidelines of the National Committee for Clinical Laboratory Standards for the susceptibility testing of conidium-forming fungi (M38-P) using a broth microdilution format . The minimal inhibitory concentration (MIC) was read at 50% inhibition of growth compared with that of the drug-free well. TMP–SMZ was active in vitro against A. fumigatus (geometric mean MIC 54.6 μg/ml, range 40–160 μg/ml), and trimethoprim alone was inactive (geometric mean MIC > 8 μg/ml) (Table 1). The antifungal activity of TMP–SMZ appeared to be fungistatic based on MIC/MFC ratios. Dapsone and pentamidine were inactive in vitro against all Aspergillus isolates at therapeutic concentrations. The recommended dose of TMP–SMZ for the prevention of PCP pneumonia in patients with HIV infection is 160/800 mg a day , which results in peak blood levels of sulfamethoxazole that range between 40 and 60 μg/ml. These blood levels are equal to or above the MIC of 19 out of 20 A. fumigatus isolates, but are too low to inhibit any of the A. flavus isolates.
The results of the literature review and the in-vitro findings suggest that PCP prophylaxis with TMP–SMZ may prevent invasive aspergillosis in HIV-infected patients when it is caused by A. fumigatus, although the concentrations achieved in the blood are sub-optimal compared with the MIC of the isolates. Further studies are required to confirm this observation, and to establish whether sulfonamides also show activity against other fungal pathogens such as Cryptococcus and Histoplasma.
Jacques F. G. M. Meisab
Johan W. Moutonb
Paul E. Verweija
1. El-Sadr WM, Luskin-Hawk R, Yurik TM. et al
. A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention ofPneumocystis cariniipneumonia in human immunodeficiency virus-infected persons. Terry Beirn Community Programs for Clinical Research on AIDS.
Clin Infect Dis 1999, 29: 775 –783.
2. Kaplan JE, Masur H, Holmes KK. et al
. An overview of the 1999 US Public Health Service/Infectious Diseases Society of America guidelines for preventing opportunistic infections in human immunodeficiency virus-infected persons. Clin Infect Dis 2000, 30 (Suppl. 1) : S15 –S28.
3. Mylonakis E, Mileno MD, Flanigan T, De Orchis DF, Rich J. Pulmonary invasive aspergillosis in patients infected with the human immunodeficiency virus: report of two cases. Heart Lung 1998, 27: 63 –66.
4. Pursell KJ, Telzak EE, Armstrong D. Aspergillus
species colonization and invasive disease in patients with AIDS. Clin Infect Dis 1992, 14: 141 –148.
5. Denning DW, Follansbee SE, Scolaro M, Norris S, Edelstein H, Stevens DA. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med 1991, 324: 654 –662.
6. National Committee for Clinical laboratory Standards. Reference method for broth dilution antifungal susceptibility testing of conidiun-forming filamentous fungi.
Proposed standard M38-P. Wayne, PA: National Committee for Clinical Laboratory Standards; 1998.
© 2001 Lippincott Williams & Wilkins, Inc.