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 itraconazole associated with HIV infection is . 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. 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 , are extremely uncommon but resistant Candida 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 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 , and attention to the medical community. There was widespread infections caused by species, uncertainty whether potential opportunists like Candida zygomycetes, and less commonly 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 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, 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 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 to be associated only with concurrent bicarbonate excretion. We have attempted to minimize severe leukopenia, one sees a reemergence of the the former by infusion of a liter of normal saline prior to “neutropenia” pathogens, Candida species and each amphotericin B dose, and we have treated the latter Aspergillus (20,21). Candidemia has been blamed on the with potassium and bicarcarbonate replacement. While intravenous 0 V) catheters so common in late stage AIDS renal toxicity is largely responsive to interruption of the patients, whether used for nutrition or to treat cancers of amphotericin B dose (should be considered when cytomegalovirus. creatinine raises above 2.5 to 3) eventually this may be Aspergillosis was initially associated only with irreversible. It is important to note that a patient receiving neutropenia, but is clearly occurring in many patients concurrent renally excreted drugs, such as 5FC, will w'hose leukocyte counts arc not severely depressed. It is have marked increases of serum concentration and my strong impression that aspergillosis is on the increase, resultant toxicity. and will become even more of a problem in the patients AMB is diluted in 5% glucose and administered with AIDS. intravenously over 1-4 h. Rapid administration is preferred Add to these infections scattered patients with zygo­ by some patients because of shortening the time of fever mycetes, hyalohyphomycetes, and phaeohyphomycetes, and chills, but this is disputed by some (23). There is also and the menu for fungal opportunism becomes truly a riskof rapid administration causing acute rises in serum large. potassium, especially in patients with renal failure. A variety of lipid associated forms of AMB are under Management of Mycoses in AIDS: development. The purpose of most of these is to bypass General Considerations the kidneys and reduce the nephrotoxicity. There is also the desire of raising concentrations in macrophage and At present, there are available a variety of topical sites of infection, and also avoiding systemic toxicities medications for dermatophyte and for mucosal associated with administration of the drug. These have candidiasis. Of these, we have found topical clotrimazole been less well realized than the clear reduction of to be particularly helpful in oropharyngeal candidiasis, nephrotoxicity. Anemia docs seem to be minimized, but and have often recommended this as an agent of first patients still have fevers and chills with all three forms of choice, as troches given 10 mg five times per day. drug now used. The forms now include amphotericin B However, this is less convenient for some to take than lipid complex (ABLC, Bristol Myers Squibb, Princeton, systemic agents, is less effective against esophageal NJ, USA), in which the drug is as high as 30% in the disease, and is ineffective forother than topical infections. lipids, and morphologically appears in a form consisting The systcmically administered antifungals include the of ribbon or leaflike polymorphic bits. This preparation polyenes amphotericin B and a variety of alternatives has seen the widest clinical use in controlled trials (24). prepared in lipid vehicles, 5 fluorocytosine (5FC), and AmBisome (Vestar, San Dimas, CA, USA) is a true the azoles ketoconazole, fluconazole, and itraconazole. liposomal form of drug and has been used in controlled Saperconazole is a potent difluoronated derivative of fashion in Europe with 82% “cures” among 29 patients itraconazole now' entering clinical trials (22). Other treated. However, some of these pulmonary infections potent azole and nonazole antifungals are under were caused by Candida, which is a difficult diagnosis to consideration or in prcclinical development. A brief confirm. comparison of the major drugs appears in Table 2. No patients were reported to have AIDS (25). The preparations are extremely expensive and difficult to Polyenes prepare for administration, though more uniform than ABLC. Finally there is amphotericin B colloidal Of the polyenes, amphotericin B deoxycholate (AMB, dispersion (ABLC) which is a very uniform preparation Fungizone) has been the most broadly used derivative. of amphotericin B intercalated with lipid in disclike AMB is associated wilh multiple toxicities, including structures only a few molecules thick(26). The preparation fever, chills, nausea and vomiting and thrombophlebitis is stable, easily handled, and is now undergoing trials in during administration. These can be minimized by aspergillosis. Which of these preparations will gain premedication with meperidine, 25 mg per dose widespread use is at yet uncertain. intravenously, acetaminophen (23). AMB also causes anemia from depression of erythropoietin and would Flucytosine (5FC, Roche Laboratories) presumably respond to recombinant erythropoietin. The most dangerous toxicity of amphotericin B is 5FC is a highly soluble agent which is effective in the nephrotoxicity, which is manifested both by glomerulo- limited spectrum of Candida and Cryptococcus tubular blood flow imbalance, causing decreased infections, with anecdotal suggestions of efficacy in glomerular flow and azotemia, and also distal renal aspergillosis and . Resistance 406 GRAYBILL

Tabic 2 Comparison of the Major Amifungals Drugs Used in Different Mycoses

Polyenes Azoles 5FC A.MB ABLC KETO ITRA FLU

Spectrum

Candida ++++ UNK +++ ++ ++ ++

Torulopsis ++ UNK ++ ± UNK +

Aspergillus +++ UNK o +++ o

Cryptococciis ++++ +++ +++ UNK ++++ +4++

Histoplasma ++++ UNK o +++ ++++ +++

Coccidioides +++ +++ o 4* +++

Phaeohypho mycoses +++ UNK ± + +++ UNK

P. marneffei

Route of administration IV IV ORA ORAL ORAL ORAL, IV

Acid needed N7A N/A NO YES YES NO

Highest dose {in mg/kg) 1.5 5 150 30 9 >30

Excretion R>II R>H R H HR

Toxicities

Fever +++ ++ O 0 0 O

Nausea ++++ +++ +++ +++ + +

Renal ++++ ± O O 0 O

Hepatic + UNK ± +++ ± ±

Endocrin OO O ++++ 0 0

Myelosup 0 0 ++++ 0 o o

Drug Interactions \\ hich Reduce Level of Antifungal;

H2 Blocker 0 o o ++++ ++++ ++

Rifampin o o 0 ++++ ++++ +

Phenytoin 0 o o +++ +++ +

Raise Drug Concentration: Cyclosporine 0 0 0 ++++ ++ + Unk = unknown; IV = intravenous; R = renal; H = hepatic. emerges rapidly, and for this reason 5FC is used only in complications. On the basis of some promising animal conjunction with other agents. Generally this has been investigations, which show additive benefit of fluconazole amphotericin B. However, 5FC is excreted rcnally, and and 5FC, some investigators arc studying the clinical nephrotoxicity from concurrent AMB causes 5FC combination of fluconazole and 5FC in cryptococca! retention, and this in turn increases myelotoxicity, the meningitis (27). Such a combination would have the major problem when using this drug. This is a problem potential of an entirely oral regimen that is not when 5FC is used for a prolonged period of time in nephrotoxic. patients already neutropenic from AIDS and its MYCOSES TREATMENT IN' AIDS PATIENTS 407 Azolcs associated with HIV infection, including the phacohypho- mycetes (36). At the onset of the AIDS pandemic, ketoconazole was the major systemic azoic in use. Ketoconazole isabsorhed Recommendations for Specific Mycoses optimally after oral administration to patients with an acid gastric milieu (28). Patients with AIDS are relatively Candidiasis achlorhydric, and ketoconazolc absorption is markedly As shown in Table 1, the severity of illness correlates depleted in them. Further, drugs such as rifampin and closely with the immunologic status of the host. The other cytochrome p-450 enzyme inducers can accclcratc most common forms are oropharyngel and esophageal; degradation of the drug such that it is undetectable. vaginal disease appears less frequently associated with These problems, and the lack of clinical experience in immune defect. cryptococcal meningitis, coupled with the very high Disseminated candidiasis is rare, in one series seen in doses needed to treat coccidioidal meningitis, and the only 13 of 903 patients with AIDS (37). This was high failure rates seen in histoplasmosis (in the setting of confirmed in a study of446 cases, in which 28 fungemias AIDS) combined to make ketoconazole a poor choice for were diagnosed, but only four blood cultures, all done in patients with AIDS (29). Further, ketoconazole has more patients near death, yielded useful diagnostic information gastrointestinal intolerance than the newer triazoles, and (38). Candidemia generally occurs as a complication of when well absorbed it can suppress adrenal function, prolonged catheterization or in patients neutropenic in which may be already depressed in patients with the last phases of disease (37). histoplasmosis, tuberculosis* or cytomegalovirus For mild forms of oropharyngeal thrush clotrimazole infection. We use ketoconazole minimally in patients a! 10 mg five times per day is commonly used. For more with HIV infection. extensive disease fluconazole at 50 to 100 mg per day is Of the major antifungal triazoles, SCH39304 was used (39-40). Some clinicians favor ketoconazole but perhaps the most potent in animal studies, and was problems with gastrointestinal tolerance and poor highly effective in initial clinical studies (30). However, absorption have made this unattractive to me. the discovery of animal carcinogenicity caused its Remission rates for fluconazole, at >80%, appear to be termination from clinical studies. Saperconazole also similar or superior to clotrimazole, but there is a more looked very potent in animals, but ovarian tumors in rapid recolonization (and relapse) in patients treated rodent suggested that it too might be discontinued. with clotrimazole. In a small series of 36patients Kolelar However, these may be species specific, and clinical et al. (39) found fluconazole to be 100% efficacious in studies arc resumed at this time. These developments thrush, vs. only 65% for clotrimazole (39). Fluconazole leave two major triazoles in clinical use. Fluconazole has is clearly more effective than ketoconazolc in a large the advantages of water solubility (permitting IV study with esophagitis (41). There were 129 administration) and excellent tissue penetration, and endoscopically evaluated patients randomized to renal excretion, permitting evaluation for urinary tract ketoconazole 200 mg per day or fluconazole 1 (X) mg per infections (28). It also may be less susceptible to p-450 day. Of fluconazole recipients 91 % were cured, vs. 52% enzyme inducers than itraconazole, [traconazole requires of ketoconazolc recipients (p <0.001). One criticism of intragastric acid, and is hepatically degraded, which are that study is that the ketoconazole dose, only 200 mg per potential disadvantages (31). However, a new day, was too low to be efficacious, but higher doses of cyclodextrinoral formation may avoid some of the ketoconazole approach the cost of fluconazole, losing absorption problems and provide higher blood levels, one advantage, and arc less well tolerated. Fluconazole though intravenous dosing is not yet possible (32). The treatment should be probably 100 mg/day minimally, advantages of itraconazole lie in its excellent potency and 200 mg per day may be more effective. How long to against all of the agents covered by fluconazole and also treat is unclear. Some treat only until the disease is a much larger experience with agents covered by suppressed, which may be 4 or 5 days to a few weeks. fluconazole and a much larger experience with One small report of 23 patients documented favorable , against which it is extremely responses to a single 150 mg dose of fluconazole with effective (Reference 33, Wheat LJ, unpublished five relapses at 3 weeks post treatment, and another four observations for the AIDS Clinical Trials Group). relapses at 42 days (42). However, Denning et al. (34) have found itraconazole The experience with itraconazole is quite small. The relatively less potent in patients with aspergillosis in the dose is 50 to 400 mg per day, depending on severity of setting of AIDS than in other patients (34). Itraconazole illness. is also effective against Aspergillus and perhaps has Failures and relapses will undoubtedly become larger greater potency against Sporothrixschenckii (35). There problems. There is some evidence that relapses arc is also some experience with the less common pathogens caused by new' isolates (43). Whether it is these new 408 GRAYBILL

isolates or persistent “educated” isolates, in the past few relapse rate was confirmed in a large Mycoses Study years there has been increasing informal experience with Group trials of suppression therapy, in which fluconazole patients failing both clotrimazole and fluconazole. The recipients (200 mg per day) had 8% relapses or protocol former may relate to factors of drug penetration into noncompliance, vs. 37% of those randomized to weekly involved tissues, but the latter appears to be increasing AMB at 1 mg/kg/dose (53). There were also more drug resistance. Fluconazole resistance has emerged in bacteremias i n patients with intravenous catheters placed increasing numbers of laboratory isolates (Rinaldi M, for long term administration of amphotericin B. Thus personal communication). Because pretreatmentisolates chronic suppression with fluconazole at 200 mg per day are generally not available for testing, it is yet unclear is the regimen of choice for both efficacy and tolerance. whether the failures arc mutations to resistance of the There is now ongoing a trial comparing itraconazole original strains, or whether they arc new isolates. When (200 mg per day) with fluconazole for chronic resistant isolates extend to esophagitis, severe dysphagia suppression. and malnutrition can follow, so the consequences are For primary cryptococcal meningitis the choices are significant. The in vitro studies and smaller clinical less clear. As recently as 1988, Dismukes (54) experience with itraconazole do not have resistance recommended amphotericin B as primary therapy for emerging yet, but this may be only a matter of lesser use cryptococcal meningitis (54). At about the same time as of itraconazole and delays in reporling. Accordingly this recommendation, others were reporting responses in there persist questions as to whether azole resistance will over hal f of the patients given fluconazole at 200-400 mg be limited to fluconazole, how great a problem it will be, per day (55-57). The first comparison of amphotericin B and whether moderate degrees of resistance will cross to and fluconazole was done in a small study by Larsen et other azoles in the future. The nonstandardized in vitro al. (58), in which 6 patients were randomized to high study methods further compound guidance in selection dose AMB (0.7 mg/kg/day for 1 week then continued at of drugs. three times per week) and 5FC (150 mg/kg/day) vs. fluconazole (400 mg per day) found 0/6 AMB/5FC failures vs. 8/14 failures (persistent positive cultures or Patients with cryptococcal meningitis outside of the clinical failures) on fluconazole (58). setting or AIDS respond well to amphotericin B and 5FC The difference was significant but the study was so given for either 4 weeks (uncomplicated patients) or 6 small as to have little power, A much larger study in weeks (more complicated patients) and fewer than 30% which fluconazole (200to400 mg per day) was com pared relapse in the yearfol lowing treatment (44). Cryptococcus with a lower dose of AMB (minimum 0.3 mg/kg/day, tends to be more widely disseminated in patients with usually without accompanying 5FC) had only 34% of AIDS than in non-HIV infected patients (33,45). In one fluconazole recipients and 40% of AMB recipients culture series of 68 patients 68% of those cultures had positive negative in the cerebrospinal fluid at 10 weeks (59). Of cultures of blood, 54% for sputum, 30% of bone marrow, the culture positive patients at 10 weeks, 27% of the and 57% from urine (46). The prostate appears to be not amphotericin B recipients and 34% of the fluconazole only a major site for extramcningeal disease, but also a recipients had positive cerebrospinal fluid cultures but primary site for relapse after treatment with amphotericin were clinically improved. Thesewere called “quiescent” B (47); and relapse is a major problem after amphotericin patients and were grouped as failures, but as followup B initial therapy. Initial reports by Kovacsctal. (48) had was terminated at that point, it is not known whether they a failure rate above 60%, with a relapse rate also as high would have eventually worsened clinically or converted as 60% in those who initially responded to a Fixed course to negative cultures. Additionally, deaths in the first 2 of amphotericin B and 5FC (48). Kovacs ct al. (48) also weeks among fluconazole recipents (15%) were more noted great problems with myelotoxicity due to 5FC. commonly seen than in AMB recipients (59) and the Chuck and Sande (49), in reviewing their experience cerebrospinal fluid cultured turned negative more rapidly with 106 patients, found that 5FC had to be stopped in AMB recipients than fluconazole recipients. However, because of toxicity in half of the 49 recipients. Also, 5FC the differences were not statistically significant. In this added no apparent survival benefit (49). study, prctreatment factors predicting early death included Chronic suppression with amphotericin B was then cerebrospinal fluid antigen titer >1:1024 (p=0.01) and examined in open studies. Zugeret al. (50) confirmed the fewer than 20 leukocyte per mm3 of cerebrospinal fluid. value of maintenance suppression with amphotericin B Otherregimens for treatment ofcryptoeoccal meningitis (50). Those relapses which occurred appeared to originate arc under consideration. Combined fluconazole/ from the prostate (51). Relapses were systematically flucytosine is a regimen which offers an all oral therapy examined in a study by Bozzctte et al. (52). Relapse rates without nephrotoxicity, and in a small pilot study appears were above 30% in patients randomized to placebo after promising (27). In addition to fluconazole there has been completing a course of AMB+5FC. and were 4% in some interest in itraconazole. The drug does not appear patients continued on fluconazole prophylaxis. This low in cerebrospinal fluid, but it is efficacious in rabbits with MYCOSES TREATMENT IN AIDS PATIENTS 409

cryptococcal meningitis, and more recently there have ACTG, in which itraconazole was given to patients with been open trials confirming efficacy in humans (60). In both primary infection, and for suppression after an the open itraconazole study the best responses appeared induction course of amphotericin B. The drug was given to occur in patients who had received even a few days of initially at 600 mg per day, and then continued for amphotericin B before the azoic was started. suppression at 400 mg per day (Wheat JL, unpublished Based in part on these studies there is now ongoing a observations). Itraconazole has been extremely effective large Mycoses Study Group/ACTG trial in which patients in treatment of histoplasmosis, with above 80% responses, are randomized to 2 weeks of amphotericin B (0.7 mg/ even in patients who were quite ill when they started the kg/day) with or without flucytosine (100 mg/kg/day) drug. Given its excellent tolerance and high efficacy, and this is followed by randomization toeither fluconazole itraconazole is recommended as the drug of choice for (200 mg per day) or itraconazole (400 mg per day) for histoplasmosis in the setting of AIDS. Drug should be prolonged suppressive therapy. The study is being continued indefinitely. conducted in a double blind fashion. There has also been a largely anecdotal and unpublished Finally, there has been interest in reducing polyene scries of patients treatment with fluconazole. One’s toxicity by using lipid associated amphotericin B for impression is that fluconazole given in low doses is not initial therapy. ABLC has been explored in a pilot study, very effective, but at 400 mg per day fluconazole is also but does not appear more effective than amphotericin B, quite effective in histoplasmosis. Much of the “evidence” though it is somewhat better tolerated (22). has not been submitted to peer-reviewed publications, One complicating factor in cryptococcal meningitis and the role of fluconazole vs. itraconazole is not clearly has been the discovery (or perhaps rediscovery) of as elucidated. many as 4% of patients who appear to improve and then after days to weeks develop sudden intracranial Coccidioidomycosis hypertension (61). This has high mortality if untreated, Coccidioidomycosis tends to present rather late in the and the regimen we and others have used most effect ively course of HIV infection, with CD4 cell count similar to is repeated lumbar fluid aspirations, using a large bore or below 200 (15,69-70). The disease may take a focal needle, to lower the pressure. form, such as meningitis or bone/joint disease, or a more widely disseminated one associated with diffuse Histoplasmosis pulmonary infiltrates. The lower the CD4 count, the Histoplasmosis in non-AIDS patients responds well to more diffuse and widespread the disease. amphotericin B, kctoconazole, or itraconazole (62-65). Treatment for coccidioidomycosis has been varied, Patients with disseminated histoplasmosis in the setting with a number of patients receiving amphotericin B, of AIDS also respond well to histoplasmosis, with over others kctoconazole, and far fewer either itraconazole or 80% remissions (11). Patients respond frequently within fluconazole (15,69). In one study of 14 patients with 2 weeks of initiation of amphotericin B, with rapid meningitis, 55% of 9 patients treated with amphotericin resolution of fever, weight gain, and return of sense of B or kctoconazole died, vs. none of 5 treated with well being. In addition to clinical response, histoplasma fluconazole (71). Coccidioidal meningitis appears to capsular polysaccharide antigen titers can be used for respond well, either with or without concurrent HIV both diagnosis and assessing response to treatment and infection, to fluconazole at 400 mg per day (68,70-72). in predicting later relapse (66). However, if amphotericin However, the mortality for all forms of coccidio­ Bis discontinued many patients relapse within the ensuing idomycosis in one large study of 77 patients was 43%, months, and as with Cryptococcus, chronic suppression and it was not clear that any drug was consistently is necessary (50,52-53,66-68). As recently reported in a superior (69). In particular, diffuse pulmonary disease large experience, suppression with amphotericin B can had a mortality of 60%. Our impression is that be accomplished readily, but the morbidity of weekly coccidioidomycosis associated with AIDS may respond amphotericin B is considerable, in addition to the initially to fluconazole, amphotericin B, or kctoconazole, complications associated with long term intravenous but that it relapses, and may do so explosively. For 18 catheter placement. Amphotericin B is not my drug of patients with rcticulonodular disease given amphotcricin choice for histoplasmosis in the setting of AIDS. B, 70% died, with a median survival of 1 month (15). Ketoconazole has been used for both initial treatment Thus there is no clear drug of choice. and as suppression therapy, and in neithcrcasc is the drug very satisfactory. With failures and relapses exceeding Penicilliosis 50% each, a small experience with kctoconazole has not Penicillium mameffei infects residents (or emigrants been further developed (29). from) predominantly of southeast Asia (19). Given the A small but positive experience with eight of nine dramatic increase of HIV infection, especially in women, patients responding to itraconazole was published by and the tendency for certain groups of businessmen to Graybill (67). This led to a much larger study by the “holiday” in endemic areas, one must consider this a real 410 CRAYBILL risk for the traveler to Thailand and its environs. The 2. Gould E, Kory WP, Raskin JB. Ibe MJ, Redhammer DE. disease is slowly progressive, and responds to Esophageal biopsy findings in the acquired immunodeficiency amphotcricin B and azoles, to which it is broadly syndrome (AIDS): clinicopathologic findings in 20 patients. susceptible (17-19). South Med J 1988; 81:1392. 3 Phelan JA, Saltxmann BR, FriedlandGH, Klein RS. Oral findings Aspergillosis in patients with acquired immunodeficiency syndrome. Oral Surg Oral Med Oral Pathol 1987: 64:50. Aspergillus may colonize the respiratory tract in up to 4, Odds FC. Schmid J. So! 1 DR. Epidemiology of Candida infections 10% of patients with AIDS, but of these only about 10% in AIDS. In van den Bossche H, Mackensie DWR, Cauwenbergh develop invasive disease (20). The majority of such G. van Cutsem J. Drouhet E, Dupont B, Eds. Mycoses in AIDS patients develop pulmonary disease (21,31). The lungs Patients. New York: Plenum Press, 1990:67. were the sole site of disease in 18 of 37 patients in one 5, Klein RS, HarrisCA, Small KB,Mol! B, Lesser N.Friedland GH. series (21). The brain was also invaded in five of these in high-risk patients as the initial manifestation patients. Most patients ultimately failed therapy. of the acquired immunodeficiency syndrome. New Engl J Med Aspergillosis was thought initially to be a disease of the 1984;3U:354. late AIDS patient with leukopenia, and to depend more 6, Whelan WL. Kirsch DR. Kwon-Chung KJ, Wahl SM, Smith PD. on neutropenia than the depression of cell mediated inpatients with the acquired immunodeficiency syndrome: absenceof a novel or hypervirulent strain. J Infect Dis immunity (20). Denninget al. (34) reported a discouraging 1990; 162:513. experience with 13 AIDS patients who had pulmonary 7 Imam N, Carpenter CCJ, Mayer KH, Fisher A, Stein M.Danforth aspergillosis (34). Even though patients were treated SB. Hierarchical pattern of mucosal Candida infections in HIV aggressively, most went on to die of progressive disease. seropositive women. Am J Med 1990; 89:142. Denning et al. report “responses” in 9 of 13 patients, but 8. DeVroey C, Song M. Dermatophyte and Pityrosporum in AIDS these are generally transient. Ten of their patients died, patients. In van den Bossche H, Mackensie DWR. Cauwenbergh with a median survival of only 3 months after the G. van Cutsem J, Drouhet E, Dupont B Eds. Mycoses in AIDS diagnosis. We have treated also two patients with Patients. New York: Plenum Press, 1990:135. disseminated disease; one patient with sinusitis of the 9. Hay RJ. Clinical aspects of dermatomyeoses in AIDS patients. In maxilla progressed despite decompression, high dose van den Bossche H, Mackensie DWR, Cauwenbergh G, van amphotcricin B, SCH39304, and itraconazole therapy. Cutsem I, Drouhet E, Dupont B, Eds. Mycoses in AIDS Patients. New York: Plenum Press. 1990:141. Another with sinusitis also succumbed to aspergillosis 10. deGreef H. Treatment of derniatomycosis in AIDS patients. In despite aggressive antifungal therapy. Therefore, while van den Bossche H, Mackensie DWR, Cauwenbergh G, van amphotericin B or itraconazole may be utilized, the Cutsem J. Drouhet E. Dupont B, Eds. Mycoses in AIDS Patients. overall response for invasive aspergillosis is poor in New York: Plenum Press. 1990:325. patients with AIDS, and novel approaches arc needed. 11. Wheat LJ, Connoly-Springfield PA, Backer RL, Curfman MF, Eads ME, Israel K. Norris SA, Webb D.Zeckel ML. Disseminated Other Fungal Pathogens histoplasmosis in the acquired immunodeficiency syndrome: Trichosporon beigelii is a common commensal of the clinical findings, diagnosis and treatment, and review of the anal mucosa, and a rare pathogen of AIDS patients. It has literature. Medicine 1990; 69:361. caused at least one case of catheter sepsis (73). Even 12. Graybill JR, Sharkey PK, Johnson P, Nightingale S The major mushroom fungi can cause invasive sinusitis, and endemic mycoses in the setting of AIDS: clinical manifestations. In van den Bossche H. Mackensie DWR, Cauwenbergh G, van fortunately one patient reported responded well to Cutsem J, Drouhet F., Dupont B. Eds. Mycoses in AIDS Patients. amphotcricin B (74). New York: Plenum Press, 1990:179. Zygomycetes and phaeohyphomycetes occasionally 13. Mamiel! W, Goldberg DM, Neu IIC. Histoplasmosis in patients infect patients with AIDS (17). There are insufficient with the acquired immune deficiency syndrome. Am J Med 1986; numbers of patients to make any recommendations other 81:974. than “usual” therapy. In the case of zygomycetes, this is 14. Bartholomew C. Raju C, Patrick A. Penco F, Jankey N. AIDS on high dose (1 to 1.5 mg/kg) amphotericin B and Trinidad. Lancet 1984; 1:103. debridement if at all possible. In the case of 15. Galgiani IN, Ampel NM. Coccidioidomycosis in human phaeohyphomycetes this may be amphotericin B or immunodeficiency virus-infected patients, J Infect Dis 1990; itraconazole (36). I would be inclined to use itraconazole, 162:1165 which has about a two thirds response rate, even in 16 Pappas PG, Pottage JC, Tapper ML, Shafer RW, Blum RM, Bonebrake FC. Klein B, Chmel II. Stratton CW. Powderly W, patients who have failed amphotcricin B. Dismukes WE. in AIDS patients. 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