Archives of Medical Research Volume 24. No. 4, pp. 403-412,1993 Printed in Mexico Treatment of Systemic Mycoses in Patients with AIDS JOHN R. GRAYBILL Infectious Diseases Section, Audit Murphy \’A Hospital, San Antonio, Texas, USA Abstract Far and away the most common funga! infection also be effective. For histoplasmosis itraconazole associated with HIV infection is candidiasis. This appears to be the most advantageous drug, with tends to produce mucosal topical infections and excellent clinical response within 2 weeks. A role for local treatment may be enough to control them. fluconazole is unclear. Coccidioidomycosis is Generally we prefer courses of 1-2 weeks rather uncommon, but difficult. I cannot offer any than chronic suppression, for fear of eliciting suggestions on “ideal” therapy here. Other diseases, overgrowth of resistant isolates. Fluconazole such as aspergillosis, are extremely uncommon but resistant Candida species may be an increasing still are AIDS associated mycoses. It is my personal problem over the next decade. For cryptococcoses fear that as we go along identifying the AIDS virus the problem is both simpler and more complicated. and its complications, aspergillosis and zygomycosis Fluconazole is highly effective for chronic may establish themselves as the future “black hats” suppression, but not very effective for initial therapy. for which we will need to pull something out of the Here a short course of amphotericin B, just 2 weeks “ box”. What to pull is not very clear. (Arch Med Res in length, is followed by chronic azole suppression. 1993; 24:403) Fluconazole appears excellent, butitraconazole may KEY WORDS: Systemic mycoses; AIDS; Treatments. Introduction suppress bacterial infections in these neutropenic patients. A variety of fungal pathogens have moved into this Until the 1970s, systemic mycoses were regarded as niche, and as a result we have seen sharp increases of interesting, obscure illnesses worthy of relatively little fungemia caused by Candida species and Fusarium, and attention to the medical community. There was widespread infections caused by Aspergillus species, uncertainty whether potential opportunists like Candida zygomycetes, and less commonly Trichosporon and species were commensals or pathogenic, and for the dematiaceous fungi. The niche offered by AIDS is that of “always" pathogenic fungi causing theendemic mycoses, depressed cell mediated immunity. A number of mycoses infection was common but illness so rare as to be of have sharply increased to fill this need (1). The AIDS relatively minor concern. Since the 1970s there have mycotic opportunists have generally had different been three major events which have reshaped and identities, but more recently some of the exploiters of dramatically enlarged the role of fungi in clinical neutropenia have also come to infect patients with AIDS. medicine. All three events are still ongoing. They include: We shall concentrate on these organisms for the remainder 1) the markedly increased spectrum of antibacterial of this discussion. drugs, 2) thcsharply increasing use of immunosuppressive medications and cytotoxic drugs, and 3) the spread of the The Setting AIDS pandemic throughout the world. Cancer chemotherapy has predominantly targeted the HIV infection appears as a depression of CD4 hematopoietic cclls of the neutrophil lineage, and a lymphocyte counts, initially unassociated with infection, variety of antibacterial agents have acted effectively to but as CD4 counts slowly decline, at a rate of about 70 per year, in 6 to 10 years one eventually reaches a level below 500 cells, at which time the consequences of Correspondence to: Dr. John R. Graybill, Infectious Diseases Section, Audio Murphy VA immunologic perturbation gradually become evident. Hospital. 7400 Merton Minter Blvd. San Antonio, TX 78284, USA Among these are feelings of malaise, lymphadenopathy, Tel. (512)617-51-II or567-48-23,Fax(512)614-61 -97 anorexia, and thrush. Thrush is so common in HIV 403 404 GRAYBILL infected patients that it has bccome a clear clinical aggressive variety that may present to acutely as to be marker for HIV infection (in the absence of other confuscd with bacteria! sepsis, or more obscurely as predisposing factors) and the extension of Candida adrenal insufficiency or colonic masses (11,12). The first infection into the esophagus isaclinical defining condition cases were scattered, among immigrants from the endemic for AIDS (1-5). Although thrush may be confused with foci in the Caribbean Islands who later developed AIDS hairy leukoplakia, and although Candida esophagoptosis while living in New York or California, and then reac­ may clinically mimic esophagoptosis causcd by tivated endogenous foci from infection long ago (13,14). cytomegalovirus, the implications of advancing immune However, as AIDS has moved into the midwestern USA depression are clear in all of these AIDS associated primary histoplasmosis has been turning up in as many conditions. By the time a patient reaches the late phases as 20-25% of patients with AIDS in Indianapolis, Kansas of AIDS, his chances of experiencing Candida infection City and other mid western cities (11). arc over 90%. Over 90% of the Candida infections are This is a dramatic development which has made caused by C. albicans, serotype B (4). Isolates are not histoplasmosis truly a household word in these areas. unique or hypervirulent in patients with AIDS (6). Similar increases arc now being experienced in other Along with thrash, there may be infections of other homelands of H. capsulatum, namely, Colombia, Brazil, mucous membranes, and vaginal candidiasis has also Argentina and other Latin American countries. It is been reported to be common by some, though less so by unclear why H. capsulation is increasing not only in others (7). Vaginal infection occurs without a reduction these areas but also in areas such as Africa, whereas H in CD4 counts, and is followed in order by oropharyngeal capsulatum variety duboisia, so called African candidiasis, and finally esophageal disease, the latter histoplasmosis, has not increased. when the CD4 counts arc very low (Table 1). Along with histoplasmosis in the midwestcm United Associated with mucosal Candida infection there may States and South Amcrica there has been a rise in be dermatophyte infection which is commonly extensive coccidioidomycosis (15). Coccidioidomycosis is still and varied in etiology (8-10). Seborrheic keratitis, argued fairly uncommon in patients with AIDS, but like by some to be of fungal etiology, is seen in a majority of histoplasmosis tends to occur in patients with severe patients by the time they reach severe stages of AIDS. depressions of the CD4 counts. The disease is more These infections are troublesome but not lethal. variable than histoplasmosis, and may present as focal Unfortunately, as the immune deficit associated with pulmonary lesions, meningitis, focal disseminated lesions, HIV infection progresses, so docs the risk of life- or widespread disease, the worst form, and associated threatening fungal infection rise. Although the systcmic with the lowest CD4 counts. Coccidioidomycosis is still mycoses may present as often as 50% of the time as the much less common than histoplasmosis, and it is yet initial clinical AIDS defining infections, they commonly uncertain whether it will evolve into a major scourge like appear only when the CD4 count is less than 200, and its midwestcm relative H capsulatum. usually are associated with counts below 100/mm3 (1). It It is curious that while there is some increase in is not widely appreciated, but the mycoses one encounters coccidioidomycosis in the desert areas of the southwest depend considerably upon the residence of the patient. United States, there has been little increase in Worldwide, Cryptococcus neoformans leads the list, cryptococcoses in these areas. Perhaps this is because C. with 6-9% in the United States, and 20-30% in Africa (1). neoformans needs morerainfallorother factors unknown. Europe and South America are also experiencing many It is also unclear why Blastomyces dermatitidis, endemic patients with cryptococcoses, usually cryptococcal in the United States over much of the H. capsulatum meningitis. I lowever, in addition to cryptococcal disease cndemic region, has only rarely affected patients with there has been a dramatic increase in patients with AIDS (16). It is also unclear why Paracoccidioides histoplasmosis, almost uniformly the widely disseminated brasiliensis, resident in much of the H. capsulatum endemic area of South America, has also not been a problem of patients with AIDS (17). Table 1 Recently we have begun to appreciate yet another Infection in Women' endemic mycoses, caused by Penicillium mameffei, Mean CD4 count which is yet confincd largely to certain regions of Asia Form of disease N per mm ’ (18,19). Patients with this infection can develop None 31 741 pulmonary or disseminated disease, with isolation of P. marnejfei in blood of 14, bone marrow of 15, and skin of Vaginal to 516 9 of a total 21 patients. There is a characteristic skin Oropharyngeal 16 230 lesion which has the umbilicated shape of molluscum contagiosum. Elliptical shaped yeast cells loosely Esophagitis 9 30 resembling H. capsulatum may be seen in the 'From Reference 7. macrophages. The frequency appears to be increasing. MYCOSES TREATMENT IN AIDS PATIENTS 405 Finally, when the CD4 counts fall to very low levels, tubular acidoses, manifested by hypokalemia and excess and initially thought