RESEARCH/PRACTICE REPORTS

PARENTERAL AND ORAL FLUCONAZOLE FORACUTE CRYPTOCOCCAL MENINGITIS IN AIDS: EXPERIENCE WITH THIRTEEN PATIENTS John J. Stern, Nancy A. Pietroski, R. MichaelBuckley, Michael N. Braffman, and Michael G. Rinaldi

OBJECTIVE: Cryptococcus

neoformans infections of the central nervous systemaffect up to ten percentof AIDS patients. Standard therapy with amphotericin B with or without5-flucytosine has a high rate of failure, relapse, and toxicity. fluconazole is a new triazole antifungal agent available in both oral and intravenous formsthat has shownefficacy in the primaryand maintenance treatment of cryptococcal meningitis in AIDSpatients. In this open, noncomparative trial,we evaluated the safetyand efficacyof intravenous fluconazole followed by oral fluconazole in the treatment of acutecryptococcal meningitis in AIDSpatients. METIlOVS: Thirteen AIDSpatients with acutecryptococcal meningitis, or relapse aftersuccessful primary therapy, received400 mg of intravenous fluconazole daily for 12-16 days followed by oral fluconazole 400 mgld for the durationof primary therapy. If cerebrospinal fluid (CSF)culturesconverted to negativewithin32 weeksof treatment, the fluconazole dose was decreased to 200 mgld as maintenance therapy. RESULTS: fluconazole therapy was successful in six patients (46 percent) and unsuccessful in seven(54 percent). Of the seven patients considered unsuccessful, one demonstrated clinical improvement but remained CSF-eulture positive, five were clinical failures and were switched to amphotericin B therapy, and one died aftertwo weekssecondary to cryptococcal meningitis. No patient experienced any adverse reactions necessitating discontinuation of therapy. CONCLUSIONS: In this smallgroupof patients, moderate dosesof parenteral and oral fluconazole for acutecryptococcal meningitis in AIDSpatients demonstrated failure rates similarto those reportedin other studieswith fluconazole and with amphotericin B. As there JOHN J. STERN, M.D.• is a Clinical Assistant Professor of Medicine. Infectious Disease Section. The University of Pennsylvania School of Medicine, The Pennsylvania Hospital; NANCY A. PIETROSKI, Phann.D.• is an Assistant Clinical Professor, Philadelphia College of Pharmacy and Science; R. MICHAEL BUCKLEY, M.D., is a Clinical Professor of Medicine, Infectious Disease Section, The University of Pennsylvania School of Medicine, The Pennsylvania Hospital; MICHAEL N. BRAFFMAN, M.D., is a Clinical Assistant Professor of Medicine, Infectious Disease Section, The University of Pennsylvania School of Medicine, The Pennsylvania Hospital, Philadelphia, PA; and MICHAEL G, RINALDI, Ph.D., is a Professor of Pathology and Medicine, The Department of Pathology, The University of Texas Health Science Center, San Antonio, TX. Reprints: John J. Stern, M.D., 822 Pine St., Suite 3A, Philadelphia, PA 19107. Adapted from a presentation at the 30th International Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 23, 1990. This work was supported by a grant from Pfizer Central Research, Groton, CT.

876 •

was no difference in initialKarnofsky scoresor the severity of diseasein treatment successes versusfailures, it is difficult to determine who mightrespondto fluconazole as initialtherapy or who should be treatedinitially with anotheragent. Furtherstudies and clinical experience are needed.

Ann Pharmacother 1992;26:876-82.

causes a common life-threatening central nervous system infection in patients with AIDS, affecting up to ten percentof this population.'> Although C. neoformans infections can be widely disseminated to involve the lung, skin, and genitourinary tract, meningitis without meningoencephalitis is most frequently

CRYPTOCOCCUS NEOFORMANS

observed.'

The cornerstone of therapy for cryptococcal meningitis has been amphotericin B plus 5-flucytosine. 3 However, in AIDS patients, the additionof 5-flucytosine to amphotericin B therapy neither enhances patient survival nor prevents relapse. The use of 5-flucytosine often may add to the toxicity of treatingcryptococcal meningitis by causing neutropenia, which AIDS patients are already at risk for because of their disease state and the administration of bone-marrow suppressing drugs.4,S Additionally, AIDS patients are at continued risk for relapse after their initial therapy and therefore require chronic, life-long maintenance therapy.-" Becauseof the frequently observed toxicities of amphotericin B, especially nephrotoxicity (associated with extended use) and the associated fevers and chills experienced during parenteral infusions, alternative antifungal agentsare now being activelyinvestigated. Fluconazole, a new triazole antifungal agent, with a prolonged serum halflife of 30 hours, achieves concentrations in the cerebrospinalfluid (CSF)that are 70-80 percentof the serumconcentrations.' Fluconazole has shown efficacyin AIDS patients with acute cryptococcal meningitis who had either received amphotericin B first or were receiving fluconazole for the first time.S,9 When compared with amphotericin B in the treatment of acute cryptococcal meningitis in AIDS, fluconazole has shownsimilarresponse rates." Au-

TheAnnalsofPharmacotherapy • 1992 July/August, Volume 26

conazole has also shown efficacy in preventing relapse in patients successfully treated for acute disease.8,9,11 In this open, nonrandomized study, we describe our experience with parenteral fluconazole followed by oral fluconazole in the treatment of AIDS patients with acute cryptococcal meningitis. Methods Patients with AIDS were eligible for entry into this open-label trial from March 1989 through March 1990, if they had clinical and CSF findings consistent with cryptococcal meningitis. Clinical findings associated with cryptococcal infection of the CSF included headache, fever, nausea, vomiting, malaise, mental status changes, photophobia, meningismus, and less frequently, neck stiffness. CSF findings consistent with cryptococcal meningitis included a normal or mildly abnormal protein, glucose, and white blood cell count. Patients also had to have a positive culture of C. neoformans from the CSF. Patients were also eligible for the study if they had experienced a relapse of cryptococcal meningitis (documented by a positive CSF culture) after having received previous successful treatment for acute cryptococcal meningitis with amphotericin B (documented by a negative follow-up culture). Patients who had relapsed after prior amphotericin B therapy must not have received more than I mg/kg/wk of amphotericin B in the four weeks prior to entry into this study. Patients were excluded if they were younger than 18 years old, pregnant or lactating, or using illicit drugs. Laboratory values that excluded patients were aspartate aminotransferase and alanine aminotransferase elevated more than five times the upper limit of normal, alkaline phosphatase greater that two times the upper limit of normal, and prothrombin time greater than five seconds over control. Patients who were unlikely to survive more than two weeks (by clinical judgment of the investigators) were also excluded from the study. The study protocol was reviewed and approved by the institutional review board at the Pennsylvania Hospital. All patients signed a written informed consent form before entry into the study. Treatment consisted of a loading dose of fluconazole 400 mg iv infused over two hours, which was then repeated 12 hours later (total dose 800 mg). This was followed by a single intravenous dose of 400 mg given on a daily basis for 12-16 days. The length of intravenous therapy was determined by clinical response. Patients were then switched to fluconazole 400 mg/d po (given as four 100-mg capsules once daily) for the duration of primary therapy. Primary therapy included the initial period of intravenous fluconazole and the ensuing period of oral therapy. The duration of this primary therapy with intravenous and oral fluconazole extended for 12 weeks beyond the date of the first of two consecutive negative CSF cultures. Primary therapy ranged from a minimum of 20 weeks to a maximum of 32 weeks. Parenteral therapy could be reinitiated if clinically indicated. For patients successfully completing primary therapy, treatment was continued with a maintenance dose of fluconazole 200 mg/d po. Renal function was assessed by 24-hour urine creatinine clearance (CI,,) collections during intravenous therapy and by serum creatinine during oral therapy. Patients with renal impairment had their primary or maintenance dose of fluconazole reduced according to the following schedule: CI" >50 mL/min, full dose; CI" 20-50 mL/min, dose decreased by 50 percent; CI" 50 mL/min, and did not require a dosage reduction. SUCCESSFUL RESPONSE

Six patients were successfully treated with fluconazole, including one patient who had relapsed while on maintenance amphotericin B (Table I). Entry Kamofsky scores for this group ranged from 20 to 90 (mean 60), and entry CSF cryptococcal antigens ranged from 1:64 to ~I: 16 000. After 12-16 days of parenteral fluconazole all six patients were switched to oral fluconazole, and after culture conversion, these patients remained free of active cryptococcal disease. Tune to CSF culture conversion was 4-5 weeks in four patients (2, 3, 4, 6), 8 weeks in one patient (I), and 18 weeks in one patient (5). Patient I died at 27 weeks of fluconazole therapy from AIDS-related causes not believed to be a result of cryptococcal disease. Patient 5 died at 13 months while receiving maintenance fluconazole therapy secondary to AIDS-related causes. Four patients (2, 3, 4, 6) were alive at the conclusion of the study, and continued on a maintenance dose of oral fluconazole 200 mg/d. UNSUCCESSFUL RESPONSE

Seven patients had unsuccessful outcomes with fluconazole therapy (Table 2). Entry Kamofsky scores for this group ranged from 20 to 90 (mean 50), and entry CSF

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877

cryptococcal antigens ranged from 1:16 to ~ 1:16 000. While receiving fluconazole, patient 7 demonstrated improvement in his clinical status, with resolution of fever and headaches. However, no sterile CSF cultures were obtained despite 28 weeks of therapy (clinically quiescent disease), and he died at that time of AIDS-related causes not believed to be related to cryptococcal disease. Patient 8 had visual deterioration and progressive papilledema throughout the course of fluconazole therapy. After 7 weeks of fluconazole therapy, he was switched to amphotericin B and responded clinically. The remaining five patients failed to respond both clinically and mycologically to fluconazole therapy. Two patients (9, 10) improved clinically and their CSF was transiently sterilized on weeks 6 and 11 of therapy, respectively. However, these patients subsequently developed recurrent signs and symptoms of cryptococcal meningitis with posi-

tive C. neoformans CSF cultures while they were receiving fluconazole 400 mg orally (primary therapy). Both patients were started on amphotericin B at week 16 with resolution of cryptococcal meningitis. Both subsequently died from noncryptococcal AIDS-related causes. Two patients (11, 13) demonstrated clinical improvement initially while receiving parenteral fluconazole and remained stable for brief periods of time, although C. neoformans could not be cleared from the CSF in the patient. After 15 and 13 weeks, respectively, each of these patients developed progressive neurologic deterioration on oral fluconazole and were then successfully treated with amphotericin B. Patient 11 continued to do well at the conclusion of the study, and patient 13 died after 13 months secondary to noncryptococcal AIDSrelated causes. Patient 12 entered the study with a Karnofsky score of 20 and evidence of disseminated cryptococcus, including

Table 1. Successful Response to Fluconazole Therapy ENTRY KARNOFSKY SCORE

(mean60)

ENTRY CSF CRYPTOCOCCAL ANTIGEN TITER

90

~16000

negative at 8 wk

2

20

NA

negative at 4 wk

3

50

64

negative at 5 wk

4

70

64

negative at 4 wk

5

70

4096

negative at 18 wk

6

80

2048

negative at 4 wk

PATIENT

CM

CSF CULTURES DURING THERAPY

OUTCOME

response; death from non-CM causes at 27 wk response; on maintenance fluconazole 200 mg/d response; on maintenance fluconazole 200 mg/d response; on maintenance fluconazole 200 mg/d response; on maintenance fluconazole; death from non-CM causes at 13 mo response; on maintenance fluconazole 200 mg/d

= cryptococcal meningitis; CSF = cerebrospinal fluid; NA = not available. Table 2. Unsuccessful Response to Fluconazole Therapy ENTRY KARNOFSKY SCORE

PATIENT

(mean50)

ENTRY CSF CRYPTOCOCCAL ANTIGEN TITER

7

40

~16000

persistently positive

8

70

2048

persistently positive

9

90

4096

10

70

~16000

II

40

16

positive for 6 wk. negative for 6 wk. then positive again positive for II wk. negative for 5 wk. then positive again persistently positive

12

20

2048

persistently positive

13

50

~16000

persistently positive

CM

CSF CULTURES DURING THERAPY

=cryptococcal meningitis; CSF =cerebrospinal fluid.

878 •

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OUTCOME

clinical response; death from non-CM causes at 28 wk of fluconazole therapy progressive papilledema; successful salvage with amphotericin B at 7 wk; alive clinical and mycologic failure; salvage with amphotericin B; death from non-CM causes clinical and mycologic failure; successful salvage with amphotericin B; death from non-CM causes clinically stable. then neurologic deterioration at 15 wk; successful salvage with amphotericin B; alive disseminated cryptococcus; rapid decline after II d of fluconazole; death after 7 d of amphotericin B and 5-f1ucytosine clinically stable. then progressive neurologic deterioration at 13 wk; successful salvage with amphotericin B; death from non-CM causes

Research/Practice

positive cultures of the CSF, sputum, blood, skin, and urine. He rapidly declined after receiving a total of 11 days of fluconazole therapy. He was started on amphotericin B and 5-flucytosine therapy, but died after an additional 7 days of therapy. FLUCONAZOLE CONCENTRAnONS

Ten patients had fluconazole concentrations drawn during intravenous therapy after the loading dose of 800 mg followed by 400 mg/d. An attempt was made to draw fluconazole concentrations in all patients, but there were difficulties experienced in drawing reliable sets of concentrations in three patients. Therefore, no data for these patients are presented here, including the patient whose fluconazole dose was decreased because of renal impairment. The mean age of the patients who had fluconazole concentrations drawn was 38 ± 8 years and the mean weight was 72 ± 12 kg. The mean 24-hour Cl., during intravenous therapy was 93 ± 20 rnL/min. Estimated Cl., in all patients was greater than 50 rnL/min for the duration of oral therapy. No patients were receiving any concomitant medications that have been shown to affect the pharmacokinetics of fluconazole (e.g., cimetidine, rifampin)." Mean serum peak and trough concentrations on days I, 7, and the last day of intravenous therapy are shown for ten patients in Table 3 and Figure 1. Mean trough concentrations on day I were 5.0 llg/mL, increasing to l2.61lg/rnL on day 7 and reaching l3.21lg/rnL on day 14. Mean peak concentrations were 10.0 ug/ml. on day 1, l7.61lg/rnL on

day 7, and 20.11lg/rnL on day 14. From these data, it can be seen that steady-state concentrations were essentially achieved by day 7 (despite the loading dose of 800 mg); this is consistent with the reported half-life of fluconazole of 25-30 hours.' Nine patients had simultaneous serum and CSF concentrations drawn during therapy with oral fluconazole 400 mg/d. Mean concentrations and serum to CSF concentration ratios at weeks 4, 6, 8, 10, and 12 are shown in Table 3 and Figure 2. The mean serum fluconazole concentration was 25.9 ug/ml, (range 22.4-29.5) and the mean cerebrospinal fluid concentration was 18.3 Ilg/mL (range 13.8-21.9). CSF to serum fluconazole ratios in the paired serurn/CSF samples were consistent throughout the course of oral therapy. Although the numbers were small, the CSF to serum concentration ratios ranged from 62.9 to 79.1 percent (mean 71.0 percent) (Figure 3). From our data in this small number of patients, we can conclude that fluconazole serum concentrations with oral therapy were equal to those with intravenous therapy. This indicates excellent bioavailability of the oral form of the drug, even in AIDS patients who might be expected to have malabsorption problems with oral medication. There was no significant difference in serum or CSF concentrations between patients who had a successful response to fluconazole and those who had an unsuccessful response.

35

~g/mL

,---~~~~~~~~~~~~~~~~~~-

30

Table 3. Fluconazole Concentrations" Intravenous therapy Peaks Troughs

DAY I

DAY 7

END OF THERAPY

10.0± 3.0 5.0±1.1

17.6±4.1 12.6±4.5

20.1 ± 4.8 13.2±4.3

Oral therapy

j

Serum

20

CSF

Q)

so 15

WEEK 6

WEEK 8

WEEK 10

WEEK 12

10

27.0 ± 4.0 24.5 ± 0.1 22.4 ± 10.9 29.5 ± 5.2 26.3 ± 10.5 17.0±2.6 18.3±0.1 13.8±5.6 21.9±3.0 20.7±9.3 63.0 ± 3.0 74.5 ± 0.1 62.9 ± 5.4 74.4 ± 2.9 79.1 ± 13.5

5

o L-~~--,---~~-'---~_--'-~~----'~_~-'-----_ _

(%)

2

'Data expressed as mean concentration in ug/ml, ± SD. CSF =cerebrospinal fluid.

25

25

o WEEK 4

Serum CSF CSF/serum

.,c:

6

4

8 Week of Therapy

10

M

12

Figure 2. Simultaneous serum and CSF fluconazole concentrations drawn during oral therapy of 400 mg/d. See text for further details. CSF = cerebrospinal fluid.

~g/mL ,---~~~~~~~~~~~~~~~~~~~

CSF/Serum'llo

.,100 0

:5 ~ c

20

8

15

:'cS

~ c: 0

~

1l

"0

Trough

~

c

c: 0 60 0 Q)

10

"0 N

5

u; E

'8" c;

u::

E

40

:>

:>

Jj

80

c

Q)

8:>

N·.

a:

2Q) 20

o L-~-'--~~-'-----~-'--~~-'-----~-L~~--'---~--'-~.-------J , Day of Therapy

14

~ (j) 0

0 4

Figure I. Mean serum fluconazole peak and trough concentrations drawn during intravenous therapy on days 1.7,14 after 800-mg loading dose, then 400 mg/d iv. See text for further details.

6

8 Week 01 Therapy

10

12

Figure 3. CSF/serum fluconazole concentration ratios during oral therapy with 400 mg/d. See text for further details. CSF = cerebrospinal fluid.

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ADVERSE REACTIONS

Table 4. Adverse Reactions to Fluconazole

Adverse reactions during both intravenous and oral fluconazole therapy were mild and reversible and are reported in Table 4. No patient had fluconazole therapy discontinued secondary to an adverse reaction. Because of the numerous concomitant medications in this ill group of AIDS patients, identifying fluconazole-induced drug reactions was difficult. Fluconazole has been shown to increase the area under the curve of phenytoin when the two drugs are administered concomitantly"; in this study, two patients (4, 10) received fluconazole and phenytoin therapy concurrently without a significant change in serum phenytoin concentrations.

Discussion Cryptococcal meningitis is a relatively common, lifethreatening infection in AIDS patients. Given the known toxicities and limited effectiveness of amphotericin B,2.4.6 great interest has emerged in fmding new, less toxic antifungal agents effective in treating this illness. Fluconazole, because of its excellent pharmacokinetics and spectrum of activity, is being evaluated in several other clinical studies as therapy for acute cryptococcal meningitis. These studies have used a variety of fluconazole doses and dosing schedules of fluconazole, making comparison between each study and our own somewhat difficult. We used a relatively high dose of parenteral fluconazole, and our failure rate was 54 percent 0/13). This is somewhat lower than the failure rate of a large, multicenter study comparing amphotericin B (with or without 5-flucytosine) in the treatment of AIDS-associated cryptococcal meningitis. In this study, patients were randomized to receive either amphotericin B (with or without 5-flucytosine, at the discretion of the investigator) or fluconazole (400mg loading dose followed by a 200-mg maintenance dose). The dose of fluconazole was increased to 400 mg/d if the CSF cultures for C. neoformans remained positive after two weeks of therapy. Fluconazole was administered either intravenously or orally at the discretion of the investigator. Success rates were 40 percent for amphotericin B (n=63; failure rate 60 percent) and 34 percent for fluconazole (n=131; failure rate 66 percent). These rates were comparable, although there were more earlier deaths and a longer period to culture conversion in the fluconazole group. 10 Larsen et al. compared amphotericin B with 5-flucytosine (n=6) and fluconazole 400 mg/d (n=14). Fifty-seven percent of the patients did not respond to fluconazole therapy and all responded to amphotericin B/5-flucytosine), although the number of patients is very small." Our observation that six patients demonstrated initial clinical improvement, with two achieving transient sterilization of their CSF, suggests that fluconazole, a fungistatic triazole, may be inadequate in the doses currently used to maintain clinical resolution in the setting of ongoing, cellmediated immunosuppression in AIDS. Adequate fluconazole CSF and serum concentrations at the time of relapses l6 suggest that neither poor absorption nor compliance explains these failures. The emergence of resistant organisms may contribute to this observation. However, serial minimum inhibitory concentrations for each patient's or880

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The Annals ofPharmacotherapy

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NUMBER OF REPORTS"

Probable eosinophilia nausea/vomiting liver function test elevations Doubtful liver function test elevations thrombocytopenia rash/pruritus

2 2 4 4 I 2

"Multiple adverse drug reactions occurred in some patients.

ganism were not performed. Further studies will require this analysis. In all of our 13 patients, parenteral fluconazole was employed as initial therapy and was extremely well tolerated. As reported elsewhere," fluconazole was relatively free of hepatotoxicity, with none of our patients requiring discontinuation of the drug because of drug toxicities. Serum and CSF concentrations were comparable after both intravenous and oral administration, suggesting that the bioavailability of oral fluconazole is high. CSF to serum concentration ratios were approximately 70 percent, similar to those reported in other studies.v" The major limitation of our study is the lack of a randomized, comparative design. Because of small numbers, it is not statistically possible to compare the responder and nonresponder groups directly. Consequently, we were unable to determine characteristics that may have predicted a favorable response to fluconazole therapy. Although the nonresponders had slightly lower entrance Karnofsky scores and mean cryptococcal antigen titers, we did not believe that these values were clinically meaningful. The ranges of entrance cryptococcal antigen titers for both groups were similar. The rate of fall of antigen titers was not consistent with the time to culture conversion in either group; in fact, in most patients in both groups, the cryptococcal antigen titers rose and fell repeatedly during therapy, and little correlation could be made between clinical status, rate of culture conversion, and cryptococcal antigen titer value. Finally, as mentioned earlier, there was essentially no difference in the serum and CSF concentrations of fluconazole between responders and nonresponders. In conclusion, high-dose oral and parenteral fluconazole for acute cryptococcal meningitis in 13 AIDS patients demonstrated a relatively high failure rate (54 percent). This rate was lower than that experienced in a large, multicenter comparative trial of fluconazole versus amphotericin B (60 percent)'? and similar to that experienced in a smaller study (57 percent)." Saag et al. stated that fluconazole may be an alternative to amphotericin B for the treatment of acute cryptococcal meningitis." However, the relatively high failure rates for both fluconazole and amphotericin Bin Saag et al.'s study as well as in ours and in Larsen et al.'s, IS underscore the refractory nature of cryptococcal meningitis with both new and conventional therapy in AIDS patients. Higher doses of fluconazole, perhaps with the addition of 5-flucytosine,19,20 the routine use of 5-flucytosine with amphotericin B, or the use of the new triazole itraconazole" or amphotericin B lipid complex-' may provide better outcomes for this difficult disease, and are receiving further study. ~

1992 July/August, Volume 26

Research/Practice We thank the medical housestaff of the Pennsylvania Hospital for taking excellent care of the patients included in this study, and for their help in obtaining the large number of required clinical specimens.

photericin B lipidcomplex(ABLC)in cryptococcal meningitis in normal or immunocompromised mice(abstract 166). Twenty-ninth AnnuaIlnterscience Conference on Antimicrobial Agentsand Chemotherapy, Houston, September 1989.

References 1. Armstrong D, Gold JWM, Dryjanski J, Whimbey HE, Polsky B, Hawkins C, et al, Treatment of infections in patients withthe acquired immunodeficiency syndrome. Ann Intern Med 1985; 103:738-43. 2. KovacsJA, Kovacs AA, Wright WC, Gill VJ, Tuazon CV, Gelmann EP, et al. Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med 1985; 103:533-8. 3. Bennett JE, Dismukes WE, Duma RJ, Medoff G, Sande MA, Gallis H, et aI. A comparison of amphotericin B alone and combined with f1ucytosine in the treatmentof cryptococcal meningitis. N Eng/ J Med 1979;301: 126-31. 4. Dismukes WE, Cloud G, Gallis HA, Kerkering TM, Medoff G, Craven PC, et al. Treattnent of cryptococcal meningitis withcombination amphotericin B and f1ucytosine for four as compared to six weeks. N Eng/] Med 1987;317:334-41. 5. Chuck SL, Sande MA. Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome. N Engl J Med 1989;321:794-9. 6. Zuger A, Louie E, Holzman RS, SimberkotTMSS, Rahal JJ. Cryptococcal disease in patients with the acquired immunodeficiencysyndrome. Diagnostic features and outcomeof treattnent. Ann Intern Med 1986; 104:234-40. 7. Brammer KW, Farrow PR, Faulkner JK. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis 1990; 12(suppl 3):S318-26. 8. Stern JJ, Hartman BJ, Sharkey P, Rowland V, Squires KE, Murray HW, et aI. Oral fluconazole therapy for patients withacquired immunodeficiency syndromeand cryptococcosis: experiencewith 22 patients. Am] Med 1988;85:477-80. 9. Sugar AM, Saunders C. Oral fluconazole as suppressive therapyof disseminated cryptococcosis in patients with acquiredimmunodeficiency syndrome. Am] Med 1988;85:481-9. 10. Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK, et al. Comparison of amphotericin B withfluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. N Eng/] Med 1992;326:83-9. II. Powderly WG, Saag MS, Cloud GA, Robinson P, Meyer RD, Jacobson JM, et al. A randomizedclinical trial of fluconazole versus amphotericin B as maintenance therapyfor prevention of relapseof cryptococcal meningitis in patients with AIDS. N Engl J Med 1992;326: 793-8. 12. Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The use of the nitrogen mustards in the palliative treatment of carcinoma. Cancer 1948; I:634-56. 13. Harris SC, Wallace JE, Fould G, Rinaldi MG. Assayof fluconazole by megabore capillary gas chromotography with nitrogen selective detection. AntimicrobAgents Chemother 1989;33:714-6. 14. Lazar JD, Wilner KD. Drug interactions with fluconazole. Rev Infect Dis 1990;12(suppI3):327-33. 15. Larsen RA, Leal MAE, Chan LS. Fluconazole compared withamphotericin B plus flucytosine for cryptococcal meningitis in AIDS: a randomized trial. Ann Intern Med 1990;113:183-7. 16. Perfect JR, Savani DV, Durack DT. Comparisonof itraconazole and fluconazole in treatment of cryptococcal meningitis and candidapyelonephritis in rabbits. AntimicrobAgents Chemother 1986;29:579-83. 17. Graybill JR. New antifungal agents. Eur.l Clin Microbio/lnfect Dis 1989;8:402-12. 18. Chin T, Fong IW, Vandenbroucke A. Pharmacokinetics of fluconazole in serumand cerebrospinal fluid in a patientwith AIDSand cryptococcal meningitis. Pharmacotherapy 1990; 10:305-7. 19. Berry A, Graybill J, Audie L. The use of high dose fluconazole in cryptococcal meningitis in AIDS (abstract). SeventhInternational Conference on AIDS; 1991, no. W.B.2287. 20. Jones BE, Larsen RA, Bozzette S, Haghighat D, Leedom JM, McCutchan JA. A Phase II trial of fluconazole plus flucytosine for cryptococcal meningitis (abstract). Seventh International Conference on AIDS; 1991, no. W.B. 2337. 21. Denning DW, Tucker RM, Hanson H, Hamilton JR, Stevens DA. Itraconazoletherapy for cryptococcalmeningitisand cryptococcosis. Arch Intern Med 1989;149:2301-8. 22. Whitney RR, Kunselman L, Clark JM, Bonner DP. Efficacyof am-

EXTRACfO Infecciones por Cryptococcus neoformans en el sistema nervioso central afectan hasta el diez por ciento de pacientes con SIDA La terapia estandar con anfotericina B con 6 sin 5-flucitosina tiene una alta incidencia de fallo, relapso, y toxicidad. Fluconazole es un nuevo antifungal tipo triazole y disponible en forma oral y endovenosa que ha dernostrado ser efectivo en el tratarnientoprirnario y de mantenimiento de meningitis por criptococo en pacientes de SIDA En este estudio abierto y no-comparativo se evahia eficacia y seguridad de fluconazole intravenoso seguido por la ruta oral en el tratarnientode meningitis aguda por criptococo en pacientes de SIDA

OBJETIVO:

PACIENTF.s Y METODOS: Trece pacientes de SIDA con meningitis aguda por criptococo, 0 relapso luego de terapia prirnaria exitosa, recibieron 400 mg diarios de fluconazole intravenoso por 12-16 dfas, seguido por 400 mg diarios de fluconazole oral por la duraci6n de la terapia primaria. Si los cultivos dellfquido cefalorraqufdeoconvertfana negativo en 32 semanas de tratarniento,la dosis de fluconazole se reducfa a 200 mg diarios como terapia de mantenimiento.

La terapia con fluconazole fue exitosa en 7/13 de los pacientes (46 por ciento) y no-exitosa en 7/13 (54 por ciento). De los 7 pacientes que no respondieron, un paciente demostr6 mejoria clfnica pero permaneci6 con cultivos positivos en ellfquido cefalorraqufdeo,5 pacientes fueron fallas clfnicas y se cambi6 la terapia a anfotericina B, y un paciente muri6 despues de dos semanas debido a meningitis por criptococo. Ningun paciente tuvo reacciones adversas que requirieran descontinuar la terapia. RESULTADOS:

CONCLUSIONES: En este pequefio grupo, dosis moderadas de fluconazole endovenoso y oral para meningitis por criptococo en pacientes de SIDA demostraron una incidencia de falla similar a los reportados con anfotericina B y otros estudios con fluconazole. Debido a que no hubo diferencia en los valores iniciales de Kamofsky 0 en severidad de la enfermedad entre los que fallaron la terapia y los que se curaron, es diffcil determinar quien va a responder a la terapia inicial con fluconazole 6 quien debe ser tratado inicialmentecon otra terapia. Se requiere mas estudio y experiencia clinica para llegar a una conclusi6n defmitiva.

GISELLE RiVERA

RESUME

Jusqu'a dix pourcent des sideens sont affectes par une infection du systeme nerveux central it Cryptococcus neoformans. Le traiternentstandard 11 l'amphotericine B, avec ou sans 5-flucytosine,est associe it un taux d'echec et de rechute eleve et est souvent toxique. Le fluconazole est un nouvel antifongique de type triazole disponible sous forme orale et intraveineuse et dont I'efficacite a ete demontree dans Ie traitement et la prevention de la meningite it cryptocoques chez les sideens, Cette etude ouverte, non comparative, avait pour but d'evaluer la securite et I' efficacite du fluconazole intraveineux puis oral dans Ie traitement aigu de la meningite it cryptocoques chez les patients victimes du SIDA

OBJECTIF:

PATIENTS ET METHODOLOGIE: Treize sideens atteints d'une meningite aigue it cryptocoques, ou victirnesd'une rechute apres un traitement initialement efficace, ont recu une dose quotidienne unique de 400 mg de fluconazole par voie intraveineuse pour 12-16 jours. Le traitement etait ensuite poursuivi avec Ie fluconazole oral 400 mg par jour pour la duree du traitement prirnaire defini cornrne une therapie intraveineuseet orale s'etendant du diagnostic jusqu'a 12 semaines apres la premiere de deux culture negative du liquide cephalo-rachidien (LCR). Si la culture du LCR s'averait negative en 32 semaines de traitement, la dose etait alors reduite it 200 mg par jour comme therapie de maintien.

Le traitement au fluconazole s'est avere efficace chez 6/13 patients (46 pourcent) et inefficace chez 7/13 (54 pourcent). Parmi les 7 echecs therapeutiques, I patient a demontre une amelioration clinique RESULTATS:

The Annals ofPharmacotherapy •

1992 July/August, Volume 26 • 881

mais les culturesdu LCR sont demeureespositives, 5 patientsfurent consideres comme des echecsc1iniques et durent etre transferes 11 l'arnphotericine B, et I patientest decede des suitesde la rneningite apres deux semaines. Aucun patient n' a presente de reaction indesirable necessitant l'arret de la therapie, CONCLUStONS: Malgre la faible taillede l'echantillon,cette etude demontreque des doses modereesde fluconazole parenteral et oral conduisent11 un taux d'echec comparable11 celui rapporteavec d'autres etudes portantsur Ie fluconazole ou l'amphotericineB dans Ie traitement

de la meningite 11 cryptocoques chez les sideens. Puisqu'aucune difference n'a ete observeepour Ie scorede Kamofsky ou la severitede la maladieentre les succeset les echecs therapeutiques, il est done difficile de predirequels patientspourrontrepondrefavorablement au fluconazole comme therapie initialepar rapport11 ceux qui devraientetre traitesavec d'autres medicaments. Des etudes supplementaires permettront de cumuler l'experiencec1inique requisepour repondre 11 ces questions. MARC PARENT

POSSffiLE CORRELATION BETWEEN GLYCEMIA AND BLOOD PRESSURE IN BLACK, DIABETIC, HYPERTENSIVE PATIENTS Linda A. Jaber, Wayne R. Melchior, and David R. Rutledge

OBJECTIVE: To determine if there is any association between glycemia and blood pressure in black patients with hypertension and diabetes mellitus whose antihypertensive medications had been unchanged for six months. DESIGN: Retrospective, from March 1990 through February 1991. SElTING: Internal medicine ambulatory clinic at Detroit Receiving Hospital/University Health Center. PATIENTS:

Patients seen during this period with hypertension and

type II diabetes. Of the 639 possible subjects, 124 met the following

criteria: (I) no change in antihypertensive medications for six months, (2) absence of secondary hypertension, and (3) weight change (if any) was less than five percent. Changes in antihypertensive medication(s) excluded 388 patients, secondary hypertension excluded 3, weight changes of more than five percent excluded 94, and lack of matching postprandial capillary blood glucose (PCBG) values excluded 30. The mean age of the subjects was 66.8 years, mean diabetes duration was 12.0 years, mean PCBG was 10.7 mmol, mean systolic blood pressure (SBP) was 154.3 mm Hg, mean diastolic blood pressure (DBP) was 90.1 mm Hg. There were 28 men in the study and 96 women; 90 were obese (body mass index >25 kg/m-) and 34 were nonobese. The diabetes was managed with insulin in 67 patients, with sulfonylureas in 50, and with diet in 7. INTERVENTION: None MAIN OUTCOME

MEASURES: SBP and DBP versus PCBG at matching times both at baseline and at six months. RESULTS: There was a positive association between blood pressure measurements and glycemia. Overall change in SBP was strongly correlated with PCBG changes (r=O.745, p