THE OI REPORT: A Critical Review of the Treatment & Prophylaxis of AIDS-Related Opportunistic Infections (OIs)

CRYPTOCOCCAL MENINGITIS
by Mark Harrington

MICROBIOLOGY & EPIDEMIOLOGY
Cryptococcus neoformans is fungal organism found worldwide. There are four serotypes; types A and D are most commonly found in immunosuppressed persons. The organism can be found in bird droppings, in the soil, and on vegetables or fruit. Aside from isolated anecdotes (Fessel 1993), there have been no identified environmental outbreaks of cryptococcal disease (cryptococcosis).

Cryptococcosis is the most common life-threatening AIDS related fungal infection, and the second most common overall (after Candida). Five to 10% of people with AIDS (PWAs) develop cryptococcosis, with two thirds of them developing cryptococcal meningitis (CM), in which the organism infects the meninges -- the fluid-filled membranes lining the brain, including the spinal fluid (cerebrospinal fluid or CSF). Cryptococcal pneumonia is common among people with chemotherapy or organ-transplant-related immunosuppression, but not among people with AIDS. Among PWAs, CM is most common among those with fewer than 50, most often fewer than 25, CD4 cells. Cryptococcosis decreased as a cause of death among PWAs from 7.7% to 5.0% between 1987-1993, probably due to improved antifungal treatment and prophylaxis (Selik 1995).

In 1996 the CDC reported on a population-based surveillance study conducted in Atlanta, San Francisco, Alabama and Houston which assessed rates of cryptococcal infections between 1992-1994. 1,075 cases were detected, of which 924 (86%) were among HIV-infected persons. The average annual incidence of cryptococcal disease was 6.6 per 100,000 in San Francisco, 4.2 and 4.8 in Houston and Atlanta, respectively, and 1.8 in Alabama. Of the 151 patients without AIDS, 68% had underlying conditions ranging from diabetes (25%), cancer (23%) and steroid therapy (16%). Among PWAs, the incidence of cryptococcosis was much higher -- 40 per 1,000 PWAs in Atlanta, 23 in San Francisco, 22 in Houston and 20 in Alabama. (Why was the rate of cryptococcosis so much higher in Atlanta (p<0.001), right in the CDC's own back yard?) Between 1992 and 1994, the incidence of cryptococcosis decreased significantly in both Atlanta and San Francisco (p<0.001), which the authors speculated was related to the increasing use of azole drugs (Hajjeh 1996b).

Another study by the same team analyzed risk factors for cryptococcosis among HIV-infected persons in San Francisco and Atlanta. 158 cryptococcosis cases were matched with 423 controls by CD4 count and primary physician. 93% of the cases were male 89% had fewer than 100 CD4 cells. Risk factors for CM included being in a warehouse during the previous month (OR 2.92, 95% CI 1.26-6.76) and sexual contact with an intravenous drug user (OR 2.02, CI 1.09-3.74). Patients receiving fluconazole within the past three months were less likely to develop cryptococcosis (OR 0.34, CI 0.16-0.72). The study included just 11 women. Thirteen patients died; risk factors for death included being an IDU (OR 3.8, 1.1-14.3) or having a seizure the week of diagnosis (OR 9.2, 1.7-52.7) (Hajjeh 1996a).

To assess risk factors, Oursler and colleagues conducted a case-control study comparing 37 incident cases of cryptococcal meningitis and 74 matched controls at Johns Hopkins University from a cohort followed since 1988. While there were no differences in age, sex, race, HIV risk factors or stage of AIDS, a history of fluconazole use was associated with a 47% risk reduction for cryptococcosis (OR = 0.53, p=0.15). A two-week course of fluconazole was associated with at 25% reduction in risk (OR = 0.75, p=0.02). History or duration of steroid use did not increase the risk of cryptococcosis. There was no difference in survival between cases and controls, presumably due to the successful use of therapeutic strategies described below (Oursler 1997).

DIAGNOSIS & PROGNOSIS
Presentation of cryptococcosis may be indolent and non-specific, with symptoms including fever, headache, nausea and vomiting. Rigidity in the neck, photophobia, cough and altered mental status are also observed. Patients sometimes present with cryptococcal pneumonia, whose symptoms include cough, fever, and infiltrates or mass in the lobes (Driver 1995). This condition is often misdiagnosed as Pneumocystis carinii pneumonia (PCP). Such misdiagnosis is dangerous, as treatment of PCP with prednisone will encourage the outgrowth of C. neoformans. Cryptococcosis may also occur in the skin as oral lesions or sinusitis, nodules, molluscum-like lesions or erythematous plaques (Schmidt-Westhausen 1995, Dimino-Emme 1995), in the prostate gland (Larsen 1989), and rarely in the eyes, bones, joints, liver, kidneys or adrenal glands (van der Horst 1997).

Antibody and skin tests are unreliable, so a definitive diagnosis requires isolation of C. neoformans from serum or sterile body fluids such as cerebrospinal fluid (CSF). Fungal cultures may be taken from urine, blood or CSF. Diagnostic stains for cryptococcal antigens include alcian blue, mucicarmine or India ink, which is positive in 80% of AIDS cases. Cryptococcal antibodies are 95% sensitive, but cross-react with antibodies to Trichosporon beigelii, a fungal organism found in the healthy human gut. CSF findings may also include low glucose levels and elevated protein and lymphocyte concentrations. Lumbar punctures (LP) are essential to measure opening pressure (OP) in CSF and initiate the algorithm to reduce elevated intracranial pressure (ICP) if indicated (see below).

Patients with high initial CSF pressure, decreased CSF glucose, low CSF leukocyte count , no cryptococcal antibody or high cryptococcal antigen titers tend to have a poor prognosis. Patients with low initial CSF pressure, higher CSF leukocyte counts, cryptococcal antibodies and low cryptococcal antigen levels tend to fare better (Isada 1994). Elevated intracranial pressure (ICP) at baseline reduces the probability of two-week CSF clearance, increasing the risk of relapse and early mortality (Saag 1995a). Researchers from USC and Los Angeles County Hospital examined case records of all subjects diagnosed with AIDS and cryptococcal meningitis between 1986 and 1993. 237 of 410 patients (58%) with AIDS-related CM received amphotericin B and flucytosine. Of these 237, 205 (86%) survived to day 14, by which point 76 (37%) were CSF C. neoformans culture negative, and 129 (63%) were still CSF culture positive. 85% of patients who became CSF culture negative at day 14 survived and remained culture negative to day 70, while only 50% of the 129 who remained culture positive at day 14 survived and became culture negative by day 70 (p<0.001). Thus, the early mycological response to induction therapy appears to predict the chances of recurrence and survival at ten weeks. The authors recommended that induction therapy "be designed to maximize the proportion of subjects with sterile CSF cultures at two weeks" (Robinson 1995).

TREATMENT OVERVIEW

Three major groups of antifungal compounds are in clinical use: the polyene antibiotics, the azole derivatives, and the allylamines-thiocarbamates. All interact with or inhibit ergesterol, the major sterol in the fungal plasma membrane. [These drugs are thus ineffective against P. carinii, which has cholesterol instead of ergesterol in its membrane.] (Georgopapadakou 1994).

Amphotericin B and nystatin are both polyene antibiotics. The azole antifungals fluconazole, itraconazole, ketoconazole and miconazole inhibit ergesterol synthesis. Trimethoprim, sulfamethoxazole and flucytosine (5-FC) inhibit fungal nucleic acid synthesis. Newer antifungal compounds such as the nikkomycins and echinocandins inhibit cell wall synthesis (Georgopapadakou 1994).

Treatment for cryptococcal meningitis has improved greatly since the early days of the AIDS epidemic, due to the introduction of the broad-spectrum antifungal drugs known as azoles, and to the focused efforts of a number of researchers who developing a firmly-grounded standard-of-care by carrying out a series of studies which built logically upon previous studies and have cumulatively reduced mortality from CM by more than half. The major elements of this improved standard of care have been 1) using higher doses of amphotericin B (with or without flucytosine) for induction, 2) using fluconazole rather than amphotericin B for maintenance, and 3) reducing intracranial pressure in patients presenting with dangerously high opening pressures in their CSF. Reducing ICP by repeated LP and draining of CSF reduces symptoms such as headache, nausea, vomiting, cranial nerve palsy and visual changes.

Treatment of CM has two phases, induction and maintenance. While patients without AIDS may clear their infection after initial therapy (induction), patients with HIV disease require lifelong suppressive therapy (maintenance). For induction, amphotericin B (0.7 mg/kg/day) is given, with or without oral flucytosine (5-FC, 25 mg/kg every six hours) for two weeks. There is some evidence that adding flucytosine to amphotericin B increases the rate of clearance of CSF. For maintenance, fluconazole (400 mg/day for eight weeks, followed by 200 mg/day) is preferred, appearing somewhat superior to itraconazole. Patients intolerant to fluconazole may benefit from itraconazole maintenance at 400 mg/day. If relapse occurs, patients may be reinduced with amphotericin B. According to ACTG 159/MSG 017, this regimen is associated with 5% early mortality and 9% overall mortality, a two-week culture conversion rate of 60% and a ten-week culture conversion rate of 72% (Saag 1995a; van der Horst 1995, 1997). The addition of flucytosine does not increase toxicity, and by multivariate analysis, is associated with better initial and long-term responses (Saag 1995a, 1995b). For maintenance therapy, fluconazole is superior to placebo (Bozzette 1991), to amphotericin B (Powderly 1992) and to itraconazole (Saag 1995b).

Induction Therapy
Amphotericin B (Fungizone) is a broad-spectrum antifungal agent that works by binding to ergesterol, making the fungal cell wall leak and leading to collapse of the cell. Because it is poorly absorbed orally, amphotericin B is given intravenously. It is highly toxic and is contraindicated with cyclosporin, aminoglycoside antibiotics and corticosteriods. There are also significant interactions with intravenous pentamidine and foscarnet. Over 10% of patients develop nausea, vomiting, fever, chills, malaise, generalized pain and kidney toxicity, and a smaller proportion develop cardiac arrhythmias, rigors, anemia and phlebitis. Patients should take lots of water when receiving amphotericin B to minimize damage to the kidneys. For obvious reasons, these toxicities limit amphotericin B's use as maintenance therapy. Newer liposomal formulations of amphotericin B are being studied to see if they are less toxic.

Induction regimens for patients with cryptococcal meningitis, but without AIDS, using amphotericin B, with or without flucytosine, were studied in the 1970s, but controversy remains about whether the addition of flucytosine was helpful (Bennett 1979). Initially used amphotericin B doses (0.3 mg/kg/day) were lower than doses used today (0.7 mg/kg/day), suggesting that lower response rates seen in early studies were due to inadequate doses (Powderly 1995).

Three studies compared amphotericin B induction regimens with fluconazole (two studies) or itraconazole (one study) in PWAs with CM. Amphotericin B was a superior induction treatment in all three studies; initial responses to azole-containing regimens averaged only about 50% (Larsen 1990, de Gans 1990, Saag 1992). One such study, ACTG 059, found 8% mortality within 2 weeks of starting therapy and 14% mortality at 10 weeks on the amphotericin B regimen. 194 patients with acute AIDS-associated cryptococcal meningitis were randomized to receive either fluconazole (200 mg/day) or amphotericin B (0.5 mg/kg/day). Only nine patients received flucytosine with their amphotericin B. Forty percent of those assigned to amphotericin B achieved two negative cultures within ten weeks, compared with 34% on fluconazole. Overall survival was similar between the two groups (86% on amphotericin B and 82% on fluconazole), but 19 of the 24 fluconazole deaths occurred within the first two weeks of treatment, compared with just 5 of 9 on amphotericin. Patients receiving amphotericin B appeared to become culture negative faster than those on fluconazole. For these reasons, amphotericin B is generally preferred as first-line induction therapy. (Saag 1992).

The follow-up study, ACTG 169/Mycoses Study Group (MSG) 087, therefore, looked to optimize the induction regimen (amphotericin B with or without flucytosine) and to compare different azole maintenance regimens. It had two steps. The first, induction, step will be discussed here, and the maintenance step later. Step one, presented in fall 1995, asked whether adding flucytosine (5-FC) to amphotericin B as induction therapy for cryptococcal meningitis improve 2- or 10-week survival compared to induction with amphotericin B alone. Amphotericin B was administered at 0.7 mg/kg intravenously with or without 25 mg/kg oral flucytosine every six hours for two weeks. Participants were then re-randomized to their maintenance regimen. The study enrolled 381 participants with acute first episode CM, and had 99% power to detect a 20% increase or decrease in CSF clearance of cryptococcal antigen. Starting CD4 counts averaged around 20. 60% were culture positive for Cryptococcus neoformans. 50% were African-American (van der Horst 1995, 1997).

(van der Horst 1997)

There were no significant differences in either the percentage who became culture negative in their CSF or in the rate of clinical resolution. The study did not support the hypothesis that adding flucytosine to amphotericin B improves acute outcomes for induction therapy of CM. The death rate in step one was just 5.5%, a significant reduction from the 8% death-rate in ACTG 059, suggesting that the regimens to reduce intracranial pressure (which were used in both arms) may have reduced mortality levels.

Decreasing Elevated Intracranial Pressure (ICP) Reduces Mortality
In ACTG 159/MSG 017, elevated intracranial pressure (ICP) at baseline affected the probability of CSF clearance at two weeks. For those who cleared CSF, median opening pressure at baseline was 220 mm water, and for those with positive cultures at two weeks it was 280 mm water. Of the fourteen early deaths, 13 occurred among patients whose opening pressure was over 250 mm water at the most recent lumbar puncture; only six of these had clinical signs of elevated ICP (Saag 1995a).

Although this part of the study was not randomized, it may be the most important "new" result of ACTG 159. Both induction regimens included measures to reduce intracranial pressure (ICP) in patients with the worst symptoms. These measures were developed in collaboration between ACTG infectious disease specialists and neurologists such as David Clifford. About 200 of the participants in ACTG 159 had their opening pressure measured. If the intracranial pressure was above 250 ml of water the investigators recommended taking measures, which were mandatory if the ICP was over 350 or if the patient displayed related symptoms -- severe nausea, severe headache, particularly when moving, or papilledema. The three steps were as follows:

1. Daily removal by lumbar puncture of 25-30 cc's of CSF fluid by putting in a drain;
2. Administration of acetazolamide (Diamox, a drug which reduces fluid retention) which is believed to inhibit the production of CSF; it's a mild diuretic also used for glaucoma;
3. Inserting an intraventricular shunt, although no one needed it.

Of the 200 patients whose ICP was measured, 30-40% had abnormally high ICP. It may be possible to use information on outcomes in this population to develop new guidelines for the management of high ICP during acute cryptococcal meningitis. MSG and ACTG researchers have been discussing a consensus conference on the optimal management of AIDS-related fungal diseases. Thus, if high ICP were managed properly according to this algorithm, mortality from acute cryptococcal meningitis should be no greater than 5.5% of all cases of meningitis.

Recent case series support the efficacy of reducing elevated ICP. At Vancouver, Bach and colleagues presented a case series of five patients who each had an opening pressure greater than 380 mm water, but no evidence of hydrocephalus by CT scan. One patient was blind in one eye, two had decreased vision and three had cranial nerve findings. Despite dexamethasone treatment and multiple lumbar punctures, none improved until they received lumbo-peritoneal or ventriculo-peritoneal shunts, after which all symptoms, including blindness and cranial nerve palsies, completely resolved (Bach 1996).

Two liposomal formulations of amphotericin B have also been studied in pilot, open-label, uncontrolled trials. Initial uncontrolled studies of liposomal amphotericin B (AmBisome, 3 mg/kg/day) were favorable, with 67% of patients experiencing a mycological response and 74% a clinical response. The compound was well-tolerated (Coker 1993). Amphotericin B lipid complex (ABLC) or amphotericin B were given to 55 patients with AIDS-associated cryptococcal meningitis, the former at doses ranging from 1.2-5 mg/kg, for six weeks. 86% of patients had a clinical response, though mycological activity was a modest 42%. ABLC was less toxic to the blood and kidneys than amphotericin B (Sharkey 1996).

Monitoring for cryptococcal antigen in serum and CSF is essential to assess the efficacy of therapy (Powderly 1994). Patients who fail to clear their cryptococcal antigen at two weeks of treatment have a higher risk of recurrence and ultimate clinical failure, raising the as-yet-unanswered question of whether induction therapy should be continued longer in this population, whether they should be switched to alternative induction regimens, or whether doses of amphotericin B should be increased (Powderly 1996).

Maintenance Therapy
In the days before azole antifungals, amphotericin B was used as maintenance therapy for cryptococcal meningitis in people with AIDS. The drug's toxicity limited its efficacy, however. Activists began importing fluconazole, which was then available overseas, in the late 1980s until the drug was approved by the FDA in 1990, based on small studies such as ACTG 026, which showed that fluconazole was effective at long-term suppression of cryptococcosis (Powderly 1992). Later, with the introduction of itraconazole, questions arose about the most cost-effective azole maintenance regimen, and several studies were designed to optimize maintenance therapy.

ACTG 159/MSG 017 step two addressed this question, asking whether itraconazole is as effective as fluconazole in suppressing relapse of cryptococcal meningitis during the maintenance phase of treatment. Michael Saag presented step II of ACTG 159/MSG 017 in fall 1995. Of the 381 participants who entered step one, 306 (80%) were able to enroll in step two, the maintenance phase of the study. Participants were randomized to fluconazole or itraconazole. Endpoints were CSF culture negativity and resolution of symptoms at week ten (Saag 1995a).

(Saag 1995a)

The null hypothesis (that fluconazole was at least 15% better than itraconazole) could not be rejected for CSF culture negativity, but it was rejected for clinical outcomes; itraconazole recipients did at least as well clinically as those maintained on fluconazole. There were no statistically significant differences in mortality at 10 weeks or at 12 months. They looked at patients according to both randomizations together. The following proportions of patients who entered the study CSF positive and became CSF negative at ten weeks were observed.

(Saag 1995a)

There appeared to be a trend to greater ten-week conversion to culture negativity among patients who received itraconazole maintenance (Saag 1995a).

Whereas ACTG 159 looked at 2- and 10-week clearance of acute cryptococcal meningitis, MSG 025 looked at time-to-relapse after treatment of an acute episode. 107 people with AIDS who had survived a bout of acute CM were randomized to receive fluconazole or itraconazole as maintenance. Median follow-up was nine months. 107 patients who had been successfully treated for AIDS-related CM were randomized to 200 mg/day of either itraconazole (N=55) or fluconazole (N=52) and followed for documented CSF-culture-positive relapses. No differences were observed in mortality or toxicity between the two arms (Saag 1995b).

(Saag 1995b)

There was no mortality difference here because no one died of a cryptococcal relapse. Interestingly, there were two separate predictors of failure in MSG 025: not getting flucytosine in the induction period, and getting itraconazole during the maintenance period. Thus, with longer-term follow-up in MSG 025, the apparent inefficacy of flucytosine and the apparent efficacy of itraconazole seen in ACTG 159 were both brought into question.

Assessing the two studies together leads to the conclusion that the greater initial microbiological efficacy of fluconazole as compared to itraconazole (72% versus 60%) may confer a deferred benefit by suppressing the organism more completely.

PROPHYLAXIS
ACTG 981 randomized 428 patients with CD4 counts below 200 to receive fluconazole or clotrimazole troches and followed them for a median of 35 months. The primary endpoint was development of a serious or life-threatening invasive fungal infection. Fluconazole reduced the incidence of such infections (mainly CM) from 10% to 2.5%, a 75% reduction in relative risk (Powderly 1995a).

* Episodes of OC = episodes of oral candida per 100 patient years of follow-up. (Powderly 1995a)

78% of the invasive fungal infections occurred in people with fewer than 50 CD4 cells. Both drugs were well tolerated. Nineteen patients discontinued treatment because of side effects, 13 on fluconazole and 6 in clotrimazole (p=0.11). Rash developed in three on fluconazole. Liver toxicity occurred in six fluconazole patients and two clotrimazole patients (p=0.6).

In a California Collaborative Treatment Group (CCTG) study, two prophylactic regimens of fluconazole were compared - 200 mg daily versus 400 mg weekly. Participants were enrolled in an ongoing Mycobacterium avium study. Median follow-up was one year, and there were no significant differences in cryptococcal infections between the two groups, though the once-weekly fluconazole group had more Candida. Fluconazole resistance was infrequent (Havlir 1996).

Despite encouraging results from the CCTG study and the dramatic reduction in serious and invasive fungal infections seen with fluconazole in ACTG 981, routine antifungal prophylaxis is not yet recommended for everyone with CD4 counts below 200, for several reasons:

1. In ACTG 981, most serious or invasive fungal infections occurred in patients with fewer than 25 CD4 cells, and almost all in patients with counts below 50. Therefore, the efficacy of using fluconazole at higher CD4 levels remains unclear.
2. Widespread fluconazole use selects for the development of fluconazole-resistant Candida species, many of which become resistant to all azoles and can only be treated with weekly amphotericin B. Promiscuous or inappropriately early use of fluconazole prophylaxis might cause an epidemic of resistant Candida and or encourage the emergence of resistant Cryptococcus species.
3. Fluconazole prophylaxis is outrageously expensive. New York state's ADAP, for example, spent over $3 million on fluconazole in 1995, more than for any other drug aside from Neupogen. Pfizer does not give New York's ADAP the Medicaid discount.
4. Like other azoles, fluconazole may cause complicated interactions with other drugs widely used by people with HIV and AIDS, such as the rifamycins, including rifabutin, as well as antihistamines, concomitant use of which can cause cardiac arrythmias.

The main reason many people with HIV take fluconazole chronically is not to prevent serious and invasive fungal infections, but to suppress chronic, recurrent Candida infections, a setting where the risk of drug resistance appears much more likely. To assess the overall risk-benefit ratio of fluconazole suppressive therapy, ACTG 323/MSG 040 will enroll 914 participants with fewer than 150 CD4 cells and randomize them to receive either continuous fluconazole (400 mg weekly) or intermittent oral fluconazole (200 mg daily) for one week during episodes of oral candidiasis or for three weeks during episodes of esophageal candidiasis. Patients who develop more than three episodes of OC or one episode of EC at a fluconazole dose of 400 mg weekly will be crossed-over to continuous suppression at 200 mg/day. Endpoints include episodes of candidiasis, invasive fungal infections and the development of drug-resistant fungi.

CURRENT CONTROVERSIES
Induction. Despite a handful of studies in the last twenty years, the efficacy of flucytosine when added to amphotericin B appears unclear. In a recent review, Bill Powderly opined, that "Most clinicians would choose initial therapy with amphotericin, followed by maintenance therapy with an azole. Many [emphasis added] would include flucytosine with the initial regimen." (Powderly 1996). Powderly himself felt that initial 5FC in MSG 025 appeared to have lowered the risk of relapse (William Powderly, personal communication). Others have proposed using liposome-encapsulated amphotericin B (AmBisome) as induction rather than amphotericin B itself. However, AmBisome is more expensive than amphotericin B, and its allegedly lower toxicities remain unproved (Powderly 1996). If AmBisome's sponsor wanted to, it could sponsor a study of AMB versus AmBisome, with a factorial design adding 5FC or not. In a letter to The New England Journal of Medicine following the publication of ACTG 159, Robert Larsen from USC questioned the authors' conclusion that switching to azole maintenance at ten weeks was warranted for all patients; he suggested that for those who were CSF culture positive at week two, a longer period of amphotericin B induction may be warranted (Larsen 1997). The authors of ACTG 159 replied that there was "no difference in long-term outcome with regard to relapse or survival based on culture positivity at week two" (Saag 1997).

Maintenance. As for maintenance, fluconazole appears superior to itraconazole. However, this may reflect different degrees of absorption of the drug, rather than different efficacy or resistance. Higher dose itraconazole (400 mg/day), or the oral cyclodextrin liquid suspension, which is more orally bioavailable, could prove better than 200 mg did in MSG 025. Janssen, the sponsor, should conduct such a study.

Prophylaxis. The question of whether and when to use antifungal prophylaxis to prevent serious and invasive fungal infections in AIDS remains controversial, despite the clear results of ACTG 981. Concern about the expense of fluconazole prophylaxis and about the dangers of encouraging antifungal drug resistance, especially with Candida, have induced many physicians to take a cautious approach. This question calls out for a randomized trial comparing different strategies, such as ACTG 323.

Resistance. While fluconazole-resistant Candida species have been well-known for quite some time, only recently have reports begun to emerge of fluconazole-resistant Cryptococcus. In 1995, Koletar and colleagues at Ohio State University reported the emergence of fluconazole-resistant C. neoformans between 1991 and 1994 in patient isolates at their unit. While there was no increase in resistance to amphotericin B or flucytosine, in 1991 all eleven pre-treatment C. neoformans isolates had an MIC to fluconazole below 16 µg/ml, but by 1994, only 9/16 isolates were below this level, and 11/20 had MICs over 32 µg/ml. Thirteen of 14 isolates with high MICs came from patients with previous fluconazole therapy (Koletar 1995). A CDC study of DNA subtypes and antifungal susceptibilities in recurrent (relapsed) cryptococcosis showed that 73% of C. neoformans isolates from patients with recurrent meningitis were still susceptible to fluconazole, however, and only one patient each experienced increasing MICs to amphotericin B, flucytosine and fluconazole, respectively (Brandt 1995). Fears of widespread azole-resistant cryptococcal infections remain unconfirmed by extensive data, though the possibility exists for the resistant organisms identified in case series mentioned above to spread.

*

Bach MC, Tally PS.: Ventricular shunting in patients with cryptococcal meningitis and uncontrollable intracranial hypertension. Abstract MoB1231, XI Intl Conf on AIDS, Vancouver, 1996.
Bennett JE, Dismukes WE, Duma RJ et al.: A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 1979;301:126-131.
Bozzette SA, Larsen RA, Chiu J, et al.: A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the acquired immunodeficiency syndrome. N Engl J Med 1991;324:580-4.
Brandt ME, Pfaller MA, Hajjeh RA, Pinner RW and the CDC Fungal Active Surveillance Group. DNA subtypes and antifungal susceptibilities in recurrent cryptococcosis. Abstract E77, 35th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, 1995.
Coker RJ, Viviani M, Gazzard BG, et al.: Treatment of cryptococcosis with liposomal amphotericin B (AmBisome) in 23 patients with AIDS. AIDS 1993;7:829-35.
de Gans J, Portegies P, Tiessens G, et al.: Itraconazole compared with amphotericin B plus flucytosine in AIDS patients with cryptococcal meningitis. AIDS 1992;6:185-90.
Dimino-Emme L, Gurevitch AW. Cutaneous manifestations of disseminated cryptococcosis. J Am Acad Dermatol 1995, 32:5(2):844-50.
Driver JA, Saunders CA, Heinze-Lacey B et al.: Cryptococcal pneumonia in AIDS. JAIDS 1995;9:168-71.
Fesel WJ. Cryptococcal meningitis after unusual exposures to birds. N Engl J Med 1993;328:1354-5.
Hajjeh R, Stephens D, Baughman W et al.: A case-control study of risk factors for cryptococcosis in HIV-infected persons. Abstract TuB186, XI Intl Conf on AIDS, Vancouver, 1996a.
Hajjeh R, Farley M, Baughman W, et al.: Multistate population-based surveillance for cryptococcal disease: 1992-1994. Abstract I053, 36th ICAAC, New Orleans, 1996b.
Havlir DV, Bozzette SA, McCutchan JA et al.: A double-blind, randomized study of weekly versus daily fluconazole for the prevention of fungal infections in 568 AIDS patients. Abstract, 3rd Conf Retroviruses and Opportunistic Infections, Washington, DC, 1996.
Isada CM, Kasten BL, Goldman MP, Gray LD, Aberg JA, Infectious Diseases Handbook 1994-1995, American Pharmaceutical Association, Lexi-Comp, Hudson, OH, 1994, pp. 76-77.
Koletar SL, Buesching WF, Fass RJ. Emerging resistance to fluconazole among blood and CSF Cryptococcus neoformans isolates. Abstract E70, 35th ICAAC, San Francisco, 1995.
Larsen RA, Bozzette S, McCutchan JA, et al.: Persistent Cryptococcus neoformans of the prostate after successful treatment of meningitis. Ann Intern Med 1989;111:125-8.
Larsen RA, Leal MA, Chan LS. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. Ann Intern Med 1990:113:183-7.
Larsen, RA. Treatment of cryptococcal meningitis [letter]. N Engl J Med 337:21, 1997.
Nguyen MH, Barchiesi F, McGough DA, et al.: In vitro evaluation of combination of fluconazole and flucytosine against Cryptococcus neoformans var. neoformans. Antimicrob Agents Chemother 1995;39:1691-5.
Oursler KK, Moore RD, Chaisson RE, et al.: Risk factors for cryptococcal meningitis in HIV-infected patients [abstract], 35th IDSA Meeting, San Francisco, 1997.
Physician's Desk Reference 49, 1995, Medical Economics Press, Montvale, NJ, p. 1255-56.
Powderly WG, Finkelstein DM, Feinberg J, Frame P, He W, van der Horst C, Koletar SL, Eyster EM, Carey J, Waskin H, Hooton TM, Hyslop N, Spector SA, Bozzette SA for the NIAID AIDS Clinical Trials Group. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. N Engl J Med 332(11); 700-5, 1995.
Powderly WG, Saag MS, Cloud GA et al.: A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. N Engl J Med 1992;326:793-8.
Powderly, WG. Cryptococcal meningitis and AIDS. Clin Infect Dis 1993;17:837-42.
Powderly WG, Cloud GA, Dismukes WE, Saag MS. Measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of AIDS-associated cryptococcal meningitis. Clin Infect Dis 1994;18:789-92.
Powderly WG: Editorial response: management of cryptococcal meningitis -- have we answered all the questions? Clin Infect Dis 1996;22:329-30.
Robinson P, Leal M, Evans S, Bauer M, Hotom P, Larsen R. Rapid mycologic response in AIDS-associated cryptococcal meningitis results in improved survival. Abstract F-121, Abstr Gen Meet Am Soc Microbiol 95:1996.
Saag MS, Powderly WG, Cloud GA, et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. (ACTG 059) N Engl J Med 1992;326:83-9.
Saag MS, van der Horst C, Cloud G, et al.: Randomized double blind comparison of amphotericin B plus flucytosine to AMB alone (STEP 1) followed by a comparison of fluconazole to itraconazole (STEP 2) in the treatment of acute cryptococcal meningitis in patients with AIDS: part 2. Abstract I217, 35th ICAAC, San Francisco, 1996a.
Saag MS, Cloud GC, Graybill JR et al.: Comparison of fluconazole versus itraconazole as maintenance therapy of AIDS-associated cryptococcal meningitis. Abstract I218, 35th ICAAC, San Francisco, 1995b.
Saag, MS, van der Horst C. Treatment of cryptococcal meningitis [letter]. N Engl J Med 337:21, 1997.
Schmidt-Westhausen A, Grünewald T, Reichart PA, Pohle HD. Oral cryptococcosis in a patient with AIDS. Oral Dis 1995;1:2:77-9
Selik RM et al. Changing trends in AIDS-related deaths. Abstract I22, 35th ICAAC, San Francisco, 1995.
Sharkey PK, Graybill JR, Johnson ES et al.: Amphotericin B lipid complex compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis 1996;22:315-21.
van der Horst C, et al.: A randomized double-blind comparison of amphotericin B (AMB) plus flucytosine to AMB alone (step 1) followed by a comparison of fluconazole to itraconazole (step 2) in the treatment of acute cryptococcal meningitis in patients with AIDS. Abstract I216, 35th ICAAC, San Francisco, 1995.
van der Horst CM, Saag MS, Cloud GA, et al.: Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med 337:15-21, 1997.

TAG home page

Last modified: 5/22/98
Treatment Action Group
350 Seventh Avenue, Suite 1603
New York, NY 10001
phone: (212) 971-9022
fax: (212) 971-9019
copyright © 1998 TAG