Itraconazole Therapy for Chronic Coccidioidal Meningitis Richard M. Tucker, M D ; David W. Denning, M B ; Bertrand Dupont, M D ; a n d D a v i d A. Stevens, M D
Study Objective: To assess the efficacy of orally administered itraconazole in the treatment of coccidioidal meningitis. Design: Prospective, nonrandomized open trial. Setting: Multicenter trial at an urban county hospital, a university referral center, and referring institutions. Patients: Ten patients with culture or serologic evidence of coccidioidal meningitis refractory to standard therapy. Patients receiving other systemic antifungal therapy were excluded. Intervention: Itraconazole was administered orally at doses of 300 to 400 m g / d for a median duration of 10 months. Disease activity and drug efficacy were evaluated at initiation of therapy and at the most recent follow-up using a standardized scoring system.
l ^ o c c i d i o i d o m y c o s i s is a s y s t e m i c m y c o s i s e n d e m i c t o t h e s o u t h w e s t U n i t e d S t a t e s a n d t o p a r t s of C e n t r a l a n d S o u t h A m e r i c a . I n f e c t i o n w i t h Coccidioides immitis r e s u l t s in a n a s y m p t o m a t i c o r insignificant illness in m o s t infected h u m a n s b u t c a n o c c a s i o n a l l y c a u s e d i s e a s e in v a r i o u s sites, p r e d o m i n a n t l y t h e l u n g s , b o n e s , a n d skin. A p p r o x i m a t e l y 1 6 % of p a t i e n t s w i t h disseminated coccidioidomycosis develop meningitis, its m o s t m a l i g n a n t m a n i f e s t a t i o n ( 1 ) . If left u n t r e a t e d , c o c c i d i o i d a l m e n i n g i t i s is u n i v e r s a l l y fatal. T h e r a p y w i t h s y s t e m i c a n d i n t r a c e r e b r o s p i n a l fluid a m p h o t e r i cin B is c o n v e n t i o n a l a n d h a s l o w e r e d m o r t a l i t y t o a n estimated 3 0 % ( 2 ) . In addition to the well-recognized toxicities of i n t r a v e n o u s t h e r a p y , i n t r a c e r e b r o s p i n a l fluid a m p h o t e r i c i n p r o d u c e s significant n e u r o l o g i c t o x icity ( 1 ) .
Measurements and Main Results: Eight of ten patients are evaluable. Of five patients receiving itraconazole as sole therapy, four have responded. All three patients receiving intrathecal amphotericin B have had that therapy discontinued and have no evidence of active disease in the absence of intrathecal therapy. Toxicity has been minimal; one patient had mild nausea.
I t r a c o n a z o l e is a n e w , o r a l l y a c t i v e t r i a z o l e t h a t is a c t i v e in v i t r o a n d clinically a g a i n s t a w i d e v a r i e t y of fungal p a t h o g e n s i n c l u d i n g C. immitis ( 3 , 4 ) . T h e initial s u c c e s s of i t r a c o n a z o l e in t h e t r e a t m e n t of a single p a t i e n t a t o u r i n s t i t u t i o n led t o t h i s m o r e e x t e n s i v e e v a l u a t i o n of its efficacy in c o c c i d i o i d a l m e n i n g i t i s .
Conclusions: Itraconazole shows impressive activity in this series of patients with refractory coccidioidal meningitis. Itraconazole in this and other fungal meningitides should be evaluated further.
Annals of Internal Medicine.
1990;112:108-112.
F r o m the Santa Clara Valley Medical Center and Institute for Medical Research, San Jose, California; Stanford University School of Medicine, Stanford, California; and the Pasteur Institute Hospital, Paris, France. For current author addresses, see end of text.
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P a t i e n t s and M e t h o d s Patients The patients we report here represent all those patients with coccidioidal meningitis who were entered into a larger open trial of itraconazole in the treatment of systemic mycoses; details of that protocol have been described previously (3) and are briefly summarized below. All patients had chronic active coccidioidal meningitis as evidenced by positive cerebrospinal fluid cultures for C. immitis or the detection of complement-fixing antibody to C. immitis antigen in the cerebrospinal fluid. The patients were evaluated with history, physical examination, radiographs, scans, and cultures for extrameningeal disease. Systemic antifungal chemotherapy precluded participation but intracerebrospinal fluid therapy was allowed. Itraconazole was selected over other oral azole therapy because of our previous favorable experience with it in the treatment of coccidioidal meningitis and its ready availability at our institutions at the time these patients were enrolled. Patients were evaluated at frequent intervals for clinical and laboratory evidence of toxicity as previously detailed ( 3 ) . Evaluation of drug efficacy included assessment of clinical symptoms of meningitis; examination of cerebrospinal fluid leukocyte count, glucose, and protein; fungal culture of cerebrospinal fluid; measurement of C. immitis complement-fixing antibody titers in cerebrospinal fluid and serum; and clinical evaluation of disease activity at extrameningeal sites where appropriate. Serologic assays included testing of the preceding sample and present sample concurrently so that changes in titer were reproducible. Samples of cerebrospinal fluid were drawn from the site (lumbar, cisternal, or ventricular) of maximal disease activity (greatest perturbation of cerebrospinal fluid leukocyte count, glucose, and protein from normal for site, highest
antibody titer). Treatment results were quantified using a previously described (5) scoring system for coccidioidal meningitis, modified from a system commonly used for evaluation of nonmeningeal coccidioidomycosis (6). Points were ascribed to clinical, serologic, and radiologic abnormalities and to cerebrospinal fluid, hematologic, chemical, and culture studies to provide a numeric summary of disease activity. Severity, reversibility, objectivity, and how directly the measure reflected disease activity were criteria used in assigning of points to entities (6). One point was thus assigned to fever, photophobia, fatigue, nausea or vomiting or anorexia, and meningismus. One point was assigned to headache if mild and two points if severe. Confusion, obtundation, and coma were assigned two, three, and four points, respectively. Incontinence was assigned one point; paresis or plegia, two; and cranial nerve palsies, two points. Mild to moderate hydrocephalus was assigned one point and severe hydrocephalus, three points. A positive cerebrospinal fluid culture was assigned three points. Cerebrospinal fluid leukocytes (X 10VL) of 21 to 99, 100 to 199, and 200 or more were assigned one, two, and three points, respectively. A cerebrospinal fluid glucose level of 31 % to 49% of the serum value was assigned one point and 30% or less of serum value, three points. A cerebrospinal fluid protein level of 1 g/L or more was assigned one point. Cerebrospinal fluid antibody titers of 1:1 to 1:2, 1:4 to 1:8, and 1:16 or greater were assigned one, two, and three points, respectively. Concomitant intracerebrospinal fluid therapy was assigned two points. Evaluations were made before treatment, during therapy, at the end of therapy, and, for patients on continuing therapy, at the most recent clinical assessment. Response to therapy was classified into the following categories: response, 60% or less of the pretreatment score and negative cerebrospinal fluid culture; partial response, 6 1 % to 80% of pretreatment score and a negative culture; nonresponse, 81 % or greater of the pretreatment score or a positive cerebrospinal fluid culture in a patient treated for more than 2 months; unevaluable, patients treated for less than 2 months or in whom therapy cannot be assessed due to noncompliance or lack of follow-up information. One patient (Patient 1) was previously included (3) in a report of the efficacy of itraconazole therapy for deep mycoses; this report updates his status on continuing therapy with itraconazole. Participants began therapy between 8 August 1985 and 18 August 1988. Treatment results are current as of 8 April 1989. This study was performed in accordance with the guidelines for human experimentation of the U.S. Department of Health and Human Services and the institutional review boards of the respective institutions. Informed consent was obtained from each participant. Pharmacokinetic Studies Samples of serum were drawn at specified intervals after a dose whenever possible. Concentrations of itraconazole were measured in these samples by an agar bioassay using Candida pseudotropicalis as a test organism as previously described (3). Results Patient Characteristics Ten patients have been enrolled in the protocol; their clinical characteristics at initiation of itraconazole therapy are summarized in the Appendix Table. Two patients are female and 8 are male. The mean age at entry was 38.4 years (range, 13 to 79 years). The median duration of disease was 20 months (range, 5 to 194 months; mean, 51 months). The duration of previous therapy was co-extensive with the duration of disease in these patients with chronic active disease. All
patients had received previous therapy with intracerebrospinal fluid and intravenous amphotericin B, seven of ten had received ketoconazole, two had received miconazole, and one had received fluconazole. Nine of ten had meningitis as a sole site of active infection; one patient (Patient 9) had both meningitis and skin infection. None of the participants had concurrent illness or immunodeficiency that was felt to be contributory to the meningitis. Two patients began therapy because of progressive meningitis while receiving concurrent intracerebrospinal fluid therapy and five began because they wanted to avoid intracerebrospinal fluid amphotericin treatment. Three patients who showed minimal evidence of disease on chronic intracerebrospinal fluid amphotericin treatment began itraconazole therapy with the goal of discontinuing this intracerebrospinal fluid therapy; all had shown a progression of disease with several previous attempts at tapering the frequency of intracerebrospinal fluid amphotericin administration. Thus, five of ten patients began treatment while receiving intracerebrospinal fluid amphotericin; the remainder received itraconazole as sole therapy. Eight patients had cerebrospinal fluid devices in place at initiation of therapy: five had ventriculoperitoneal or ventriculo-atrial shunts and six had Ommaya reservoirs; three patients had both devices. Clinical Results Eight of ten patients are evaluable; one patient is unevaluable due to noncompliance and another was lost to follow-up. Table 1 summarizes the treatment results among evaluable patients; Figure 1 shows the score of disease in individual evaluable patients before therapy and at the most recent follow-up. The median duration of treatment is 10 months (range, 6 to 42 months; mean, 15.1 months); all eight remain on therapy. Seven of eight patients have received 400 m g / d of itraconazole throughout their treatment; Patient 10 has received 300 to 400 m g / d . Seven of eight evaluable patients have shown a response to therapy. Among patients receiving concurrent therapy with intracerebrospinal fluid amphotericin (Patients 1, 2, and 5), all three have responded and have had that therapy discontinued for the first time since their original diagnosis. The cerebrospinal fluid antibody titer declined in the one patient (Patient 2) in whom it was initially positive and cerebrospinal fluid leukocyte counts remain normal in all three patients on itraconazole alone. Among the five patients receiving itraconazole as sole therapy, four have responded. All four responders have shown a decline in their cerebrospinal fluid antibody titer; one patient's titer became negative. The cerebrospinal fluid leukocyte count declined in all three responders in whom it was initially abnormal; cerebrospinal fluid cultures became negative in both responders with initially positive cultures. All four have no clinical evidence of active disease. The single patient with extrameningeal site disease has shown a complete response at that skin site. One patient (Patient 8) initially responded to itra-
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Table 1. Results of Treatment with Itraconazole Patient
Duration Itraconazole Therapy
Intracerebrospinal Fluid Therapy Discontinued
Cerebrospinal Fluid Leukocyte Count Before Therapy Most Recent
mo
X 1&/L
42 17 9 20 12 10 6
It 2t 5t 6t
n n n
lot
Yes Yes Yes Not Not Not Not
6
applicable applicable applicable applicable
33 66 54 1100 62 8 63
0 10 10 67 21 0 31
Not applicable
1055
650
* Reciprocal of last > 3 + dilution. t Patient was on concurrent intracerebrospinal fluid therapy. % Patient treated with itraconazole therapy alone.
conazole therapy with a conversion of the cerebrospinal fluid culture to negative and a return to normal of the cerebrospinal fluid leukocyte count and cerebrospinal fluid antibody titer. After 8 months of therapy he became noncompliant for 2 weeks and had a recrudescence of disease with a new headache and a rise in cerebrospinal fluid leukocyte count. These abnormalities disappeared within 1 month of restarting itraconazole; he remains free of active disease after an additional 2 months of therapy. The single patient failing therapy (Patient 10) had previously responded to treatment with intracerebrospinal fluid amphotericin but had this therapy discontinued because of drug-associated myelopathy ( 7 ) . He failed therapy with fluconazole (100 m g / d ) and intracerebrospinal fluid miconazole (20 m g / d ) . Itraconazole therapy was begun; however, after 2 months he became noncompliant. During this interval his cerebrospinal fluid leukocyte count and cerebrospinal fluid antibody titer rose. Two months later itraconazole therapy was restarted. After 4 additional months of itraconazole as sole therapy, his cerebrospinal fluid grew C. immitis and intracerebrospinal fluid miconazole was restarted. Although he is receiving both itraconazole and miconazole, his cerebrospinal fluid fungal culture remains positive, his cerebrospinal fluid leukocyte count remains elevated, his cerebrospinal fluid antibody titer has risen, and he has developed progressive hydrocephalus.
Toxicity Eight patients are evaluable for evidence of drug toxicity; a total of 122 patient-months of therapy have been administered. Toxicity has been minimal. Only one patient has experienced any toxicity attributable to itraconazole: mild nausea without vomiting that was tolerated with symptomatic treatment without dosage reduction. Discussion The options for the treatment of coccidioidal meningitis are, at present, less than optimal. Standard therapy utilizes both intravenous and intracerebrospinal fluid amphotericin; this therapy is associated with substantial neurologic toxicity that limits therapy and may mimic disease ( 1 ) . Some patients, however, may be cured, even in the presence of intracerebrospinal fluid devices such as reservoirs and shunts. Experience with azoles in the treatment of coccidioidal meningitis is limited. Miconazole and ketoconazole, the azoles currently available for treatment of
Pharmacokinetic Studies Sera for pharmacokinetic analysis were available from four of eight evaluable patients. Mean serum concentrations of itraconazole varied from 3.4 to 15.4 /xmol/ L with wide variation among patients. These values are consistent with our previously reported results (3) in a larger series of patients with various systemic mycoses. Three samples of cerebrospinal fluid were available from two patients at a time of steady-state pharmacokinetics (2 weeks or more after starting therapy); itraconazole was not detected in any sample.
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Figure 1. Response to itraconazole therapy in eight evaluable patients using a standard scoring system. Data are given as the percentage of baseline abnormality at the most recent follow-up.
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Table 1. (Continued) Cerebrospinal Fluid Antibody Titer* Before Therapy Most Recent
Cerebrospinal Fluid Culture Before Therapy Most Recent
Assessment (% Pretherapy Score)
0 32 0 512 16 8 8
0 0 0 8 4 0 4
Negative Negative Negative Positive Negative Positive Negative
Negative Negative Negative Negative Negative Negative Negative
Response Response Response Response Response Response Response
8
16
Positive
Positive
Nonresponse (120)
systemic mycoses, have been used with limited success. Miconazole must be given by intracerebrospinal fluid administration and is sometimes poorly tolerated; treatment is marked by high rates of relapse ( 8 ) . Ketoconazole has been effective in selected patients, particularly when used in high doses (9); this therapy, however, is associated with substantial gastrointestinal and endocrine toxicity (10). Fluconazole, like itraconazole, an experimental triazole, is distinguished from other azoles by its high cerebrospinal fluid penetration as documented in experimental animals (11) and humans (12). It is effective in murine coccidioidal (13) and rabbit cryptococcal (14) meningitis, and it shows great promise in the treatment of human fungal meningitis (15). The early experience with fluconazole in the treatment of coccidioidal meningitis has been promising ( 5 ) . We have treated 18 patients with chronic coccidioidal meningitis with 50 to 400 m g / d of fluconazole. Responses were seen in 67% of patients after a mean treatment duration of 9.8 months. Response or partial response was seen in 63% of patients receiving fluconazole as sole therapy. These results can be contrasted with those of the present study. Fluconazole was well tolerated by all participants. Continued experience with larger patient groups and more extensive follow-up will be important to fully define the potential of fluconazole in the treatment of coccidioidal meningitis. Itraconazole is highly active against C. immitis in vitro; minimum inhibitory concentrations ranged from 0.025 to 7.0 juimol/L (median, 0.025 /imol/L) and minimum fungicidal concentrations varied from 0.025 to more than 14 /imol/L (median, 0.10 ]j.mol/L) in 52 clinical isolates ( 4 ) . Achievable serum concentrations are substantially higher; a mean peak serum concentration of 8.3 /xmol/L is achieved at 7 hours after dosage in patients on chronic therapy ( 3 ) . However, susceptibility testing may be method dependent. Itraconazole appears to be quite effective in treating nonmeningeal coccidioidomycosis. We have reported (3) complete responses in 63% of patients treated with itraconazole for a mean of 7.1 months. Unlike fluconazole, itraconazole has negligible cerebrospinal fluid penetration in both animal models and
(30) (6) (25) (40) (50) (21) (33)
Comment
N o evidence of disease N o evidence of disease N o evidence of disease Asymptomatic Asymptomatic N o evidence of disease Asymptomatic; nasal skin lesion resolved Progressive disease: persistent positive cerebrospinal fluid cultures; worsening hydrocephalus
in humans (3, 11). Despite this, it has shown success (14, 16) in the treatment of both experimental and human cryptococcal meningitis. In this respect, itraconazole shares characteristics with amphotericin B; the latter drug also penetrates cerebrospinal fluid poorly after systemic administration but is effective by that route in cryptococcal (although not in coccidioidal) meningitis. Itraconazole is not presently available for other than oral therapy. Our experience suggests that itraconazole offers substantial benefit in the treatment of human coccidioidal meningitis. The patients reported here were refractory to standard therapy; the high rate of response to itraconazole is impressive in this setting. The single patient who failed therapy also failed to respond to fluconazole and intracerebrospinal fluid miconazole. Our favorable results suggest that penetration into the meninges, a compartment that cannot be sampled in patients, occurs with itraconazole and is more important than the penetration into cerebrospinal fluid. This theory would be consistent with the observation that cerebrospinal fluid cultures in coccidioidal meningitis are uncommonly positive (1). Itraconazole was effective both as sole therapy and when administered with concurrent intracerebrospinal fluid amphotericin. Further experience will determine its full potential as an adjunct to intracerebrospinal fluid therapy; allowing an enhanced response to and a more rapid discontinuation of intracerebrospinal fluid amphotericin would do much to limit the substantial toxicity of that treatment. Because all our patients remain on itraconazole, we cannot evaluate the risk of relapse after apparently successful therapy. However, the lethality of untreated disease and the deficiencies of presently licensed therapy make the present information extremely important for these patients despite the absence as yet of observation after therapy. The rapid relapse in Patient 8 and the rapid progression of disease in Patient 10 after each became noncompliant suggest that itraconazole is fungistatic rather than fungicidal and implies a need for prolonged therapy. However, given the mild and infrequent toxicity of itraconazole and the toxicity and difficulty in administration of the present conventional
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Appendix Table. Characteristics of Patients with Meningitis Just before Treatment with Itraconazole Patient
Sex, Age
Race or Ethnic Group
M, 36 M, 13 F, 16 M, 27 F, 20 M, 24 M, 79 M, 35 M, 41 M, 57
Previous Azole Therapy
White White Hispanic Hispanic White Arab White Black Filipino Korean
194 60 30 12 20 9 10 102 5 68
ketoconazole, miconazole ketoconazole ketoconazole None None ketoconazole None ketoconazole ketoconazole ketoconazole, fluconazole, miconazole
intracerebrospinal fluid amphotericin therapy, an oral therapy which would only suppress disease would be an advance, even if it required treatment for many years or for the rest of the patient's life. Our data do not allow a direct comparison of itraconazole with high-dose ketoconazole or fluconazole, the alternative oral agents for coccidioidal meningitis. We have seen minimal toxicity with itraconazole at doses up to 400 m g / d ( 3 ) . Ketoconazole had substantial gastrointestinal and endocrine toxicity at the doses that have appeared to have some efficacy in coccidioidal meningitis. The relatively low toxicity of itraconazole is a clear advantage over ketoconazole. Fluconazole, because of its higher cerebrospinal fluid penetration, has a theoretic advantage over itraconazole. The two drugs are, however, roughly equivalent in animal models of fungal meningitis (14). A comparative trial of these two agents may be indicated.
2.
3. 4.
5. 6.
7.
8. 9.
10. Acknowledgments: The authors thank Eduardo G. Arathoon, MD; Steven Helvie, MD; George Skaff, MD; Thomas L. Fife, MD; Richard J. Hamill, MD; Michael Palestine, MD; Elmer Palitang, MD; and Paul L. Williams, M D for referring patients and providing data on those patients. Requests for Reprints: David A. Stevens, M D , Department of Medicine, Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128. Current Author Addresses: Dr. Tucker: Department of Medicine, Wenatchee Valley Clinic, 820 North Chelan Street, Wenatchee, WA 98807. Drs. Denning and Stevens: Department of Medicine, Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128. Dr. Dupont: Pasteur Institute, 25 rue du Docteur Roux, F-75724 Paris, France.
11.
12.
13. 14.
15. 16.
References 1. Kelly PC. Coccidioidal meningitis. In: Stevens DA, ed. Coccidioido-
112
Intracerebrospinal Fluid Amphotericin
Central Nervous System Device
Yes Yes Yes Yes Yes No No No No No
None Reservoir, shunt None Shunt Reservoir Reservoir, shunt Shunt Reservoir Reservoir Reservoir, shunt
mo
y 1 2 3 4 5 6 7 8 9 10
Duration of Disease
mycosis: A Text. New York: Plenum Medical Book Co.; 1980:16394. Pappagianis D, Crane R. Survival in coccidioidal meningitis since the introduction of amphotericin B. In: Ajello L, ed. Coccidioidomycosis: Current Clinical and Diagnostic Status. Miami: Symposia Specialists; 1977:223-37. Tucker RM, Williams PL, Arathoon EG, Stevens DA. Treatment of mycoses with itraconazole. Ann NY Acad Sci. 1988;544:451-70. Tucker RM, Denning DW, Rinaldi MG, Hanson LH, Stevens DA. Itraconazole therapy of progressive coccidioidomycosis [Abstract 573]. In: Abstracts of the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1988:210. Tucker RM, Galgiani JN, Denning DW, et al. Treatment of coccidioidal meningitis with fluconazole. Rev Infect Dis. 1990 [In press]. Stevens DA, Stiller RL, Williams PL, Sugar AM. Experience with ketoconazole in three major manifestations of progressive coccidioidomycosis. Am J Med. 1983;74:58-63. Carnevale NT, Galgiani JN, Stevens DA, Herrick MK, Langston JW. Amphotericin B-induced myelopathy. Arch Intern Med. 1980;140:1189-92. Stevens DA. Miconazole in the treatment of coccidioidomycosis. Drugs. 1983;26:347-54. Graybill JR, Stevens DA, Galgiani JN, et al. Ketoconazole treatment of coccidioidal meningitis. Ann NY Acad Sci. 1988;544:488-96. Sugar AM, Alsip SG, Galgiani JN, et al. Pharmacology and toxicity of high-dose ketoconazole. Antimicrob Agents Chemother. 1987;31:1874-8. Perfect JR, Durack DT. Penetration of imidazoles and triazoles into cerebrospinal fluid of rabbits. J Antimicrob Chemother. 1985; 16:816. Tucker RM, Williams PL, Arathoon EG, et al. Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis. Antimicrob Agents Chemother. 1988;32:369-73. Graybill JR, Sun SH, Ahrens J. Treatment of murine coccidioidal meningitis with fluconazole ( U K 49,858). / Med Vet Mycol. 1986;24:113-9. Perfect JR, Savani DV, Durack DT. Comparison of itraconazole and fluconazole in treatment of cryptococcal meningitis and Candida pyelonephritis in rabbits. Antimicrob Agents Chemother. 1986;29:579-83. Dismukes WE. Azole antifungal drugs: old and new. Ann Intern Med. 1988;109:177-9. Denning DW, Tucker RM, Hanson LH, Hamilton JR, Stevens DA. Itraconazole therapy for cryptococcal meningitis and cryptococcosis. Arch Intern Med. 1989;149:2301-8.
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Study Objective: To assess the efficacy of orally administered itraconazole in the treatment of coccidioidal meningitis. Design: Prospective, nonrandomized open trial. Setting: Multicenter trial at an urban county hospital, a university referral center, and referring institutions. Patients: Ten patients with culture or serologic evidence of coccidioidal meningitis refractory to standard therapy. Patients receiving other systemic antifungal therapy were excluded. Intervention: Itraconazole was administered orally at doses of 300 to 400 m g / d for a median duration of 10 months. Disease activity and drug efficacy were evaluated at initiation of therapy and at the most recent follow-up using a standardized scoring system.
l ^ o c c i d i o i d o m y c o s i s is a s y s t e m i c m y c o s i s e n d e m i c t o t h e s o u t h w e s t U n i t e d S t a t e s a n d t o p a r t s of C e n t r a l a n d S o u t h A m e r i c a . I n f e c t i o n w i t h Coccidioides immitis r e s u l t s in a n a s y m p t o m a t i c o r insignificant illness in m o s t infected h u m a n s b u t c a n o c c a s i o n a l l y c a u s e d i s e a s e in v a r i o u s sites, p r e d o m i n a n t l y t h e l u n g s , b o n e s , a n d skin. A p p r o x i m a t e l y 1 6 % of p a t i e n t s w i t h disseminated coccidioidomycosis develop meningitis, its m o s t m a l i g n a n t m a n i f e s t a t i o n ( 1 ) . If left u n t r e a t e d , c o c c i d i o i d a l m e n i n g i t i s is u n i v e r s a l l y fatal. T h e r a p y w i t h s y s t e m i c a n d i n t r a c e r e b r o s p i n a l fluid a m p h o t e r i cin B is c o n v e n t i o n a l a n d h a s l o w e r e d m o r t a l i t y t o a n estimated 3 0 % ( 2 ) . In addition to the well-recognized toxicities of i n t r a v e n o u s t h e r a p y , i n t r a c e r e b r o s p i n a l fluid a m p h o t e r i c i n p r o d u c e s significant n e u r o l o g i c t o x icity ( 1 ) .
Measurements and Main Results: Eight of ten patients are evaluable. Of five patients receiving itraconazole as sole therapy, four have responded. All three patients receiving intrathecal amphotericin B have had that therapy discontinued and have no evidence of active disease in the absence of intrathecal therapy. Toxicity has been minimal; one patient had mild nausea.
I t r a c o n a z o l e is a n e w , o r a l l y a c t i v e t r i a z o l e t h a t is a c t i v e in v i t r o a n d clinically a g a i n s t a w i d e v a r i e t y of fungal p a t h o g e n s i n c l u d i n g C. immitis ( 3 , 4 ) . T h e initial s u c c e s s of i t r a c o n a z o l e in t h e t r e a t m e n t of a single p a t i e n t a t o u r i n s t i t u t i o n led t o t h i s m o r e e x t e n s i v e e v a l u a t i o n of its efficacy in c o c c i d i o i d a l m e n i n g i t i s .
Conclusions: Itraconazole shows impressive activity in this series of patients with refractory coccidioidal meningitis. Itraconazole in this and other fungal meningitides should be evaluated further.
Annals of Internal Medicine.
1990;112:108-112.
F r o m the Santa Clara Valley Medical Center and Institute for Medical Research, San Jose, California; Stanford University School of Medicine, Stanford, California; and the Pasteur Institute Hospital, Paris, France. For current author addresses, see end of text.
108
©1990 American College of Physicians
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P a t i e n t s and M e t h o d s Patients The patients we report here represent all those patients with coccidioidal meningitis who were entered into a larger open trial of itraconazole in the treatment of systemic mycoses; details of that protocol have been described previously (3) and are briefly summarized below. All patients had chronic active coccidioidal meningitis as evidenced by positive cerebrospinal fluid cultures for C. immitis or the detection of complement-fixing antibody to C. immitis antigen in the cerebrospinal fluid. The patients were evaluated with history, physical examination, radiographs, scans, and cultures for extrameningeal disease. Systemic antifungal chemotherapy precluded participation but intracerebrospinal fluid therapy was allowed. Itraconazole was selected over other oral azole therapy because of our previous favorable experience with it in the treatment of coccidioidal meningitis and its ready availability at our institutions at the time these patients were enrolled. Patients were evaluated at frequent intervals for clinical and laboratory evidence of toxicity as previously detailed ( 3 ) . Evaluation of drug efficacy included assessment of clinical symptoms of meningitis; examination of cerebrospinal fluid leukocyte count, glucose, and protein; fungal culture of cerebrospinal fluid; measurement of C. immitis complement-fixing antibody titers in cerebrospinal fluid and serum; and clinical evaluation of disease activity at extrameningeal sites where appropriate. Serologic assays included testing of the preceding sample and present sample concurrently so that changes in titer were reproducible. Samples of cerebrospinal fluid were drawn from the site (lumbar, cisternal, or ventricular) of maximal disease activity (greatest perturbation of cerebrospinal fluid leukocyte count, glucose, and protein from normal for site, highest
antibody titer). Treatment results were quantified using a previously described (5) scoring system for coccidioidal meningitis, modified from a system commonly used for evaluation of nonmeningeal coccidioidomycosis (6). Points were ascribed to clinical, serologic, and radiologic abnormalities and to cerebrospinal fluid, hematologic, chemical, and culture studies to provide a numeric summary of disease activity. Severity, reversibility, objectivity, and how directly the measure reflected disease activity were criteria used in assigning of points to entities (6). One point was thus assigned to fever, photophobia, fatigue, nausea or vomiting or anorexia, and meningismus. One point was assigned to headache if mild and two points if severe. Confusion, obtundation, and coma were assigned two, three, and four points, respectively. Incontinence was assigned one point; paresis or plegia, two; and cranial nerve palsies, two points. Mild to moderate hydrocephalus was assigned one point and severe hydrocephalus, three points. A positive cerebrospinal fluid culture was assigned three points. Cerebrospinal fluid leukocytes (X 10VL) of 21 to 99, 100 to 199, and 200 or more were assigned one, two, and three points, respectively. A cerebrospinal fluid glucose level of 31 % to 49% of the serum value was assigned one point and 30% or less of serum value, three points. A cerebrospinal fluid protein level of 1 g/L or more was assigned one point. Cerebrospinal fluid antibody titers of 1:1 to 1:2, 1:4 to 1:8, and 1:16 or greater were assigned one, two, and three points, respectively. Concomitant intracerebrospinal fluid therapy was assigned two points. Evaluations were made before treatment, during therapy, at the end of therapy, and, for patients on continuing therapy, at the most recent clinical assessment. Response to therapy was classified into the following categories: response, 60% or less of the pretreatment score and negative cerebrospinal fluid culture; partial response, 6 1 % to 80% of pretreatment score and a negative culture; nonresponse, 81 % or greater of the pretreatment score or a positive cerebrospinal fluid culture in a patient treated for more than 2 months; unevaluable, patients treated for less than 2 months or in whom therapy cannot be assessed due to noncompliance or lack of follow-up information. One patient (Patient 1) was previously included (3) in a report of the efficacy of itraconazole therapy for deep mycoses; this report updates his status on continuing therapy with itraconazole. Participants began therapy between 8 August 1985 and 18 August 1988. Treatment results are current as of 8 April 1989. This study was performed in accordance with the guidelines for human experimentation of the U.S. Department of Health and Human Services and the institutional review boards of the respective institutions. Informed consent was obtained from each participant. Pharmacokinetic Studies Samples of serum were drawn at specified intervals after a dose whenever possible. Concentrations of itraconazole were measured in these samples by an agar bioassay using Candida pseudotropicalis as a test organism as previously described (3). Results Patient Characteristics Ten patients have been enrolled in the protocol; their clinical characteristics at initiation of itraconazole therapy are summarized in the Appendix Table. Two patients are female and 8 are male. The mean age at entry was 38.4 years (range, 13 to 79 years). The median duration of disease was 20 months (range, 5 to 194 months; mean, 51 months). The duration of previous therapy was co-extensive with the duration of disease in these patients with chronic active disease. All
patients had received previous therapy with intracerebrospinal fluid and intravenous amphotericin B, seven of ten had received ketoconazole, two had received miconazole, and one had received fluconazole. Nine of ten had meningitis as a sole site of active infection; one patient (Patient 9) had both meningitis and skin infection. None of the participants had concurrent illness or immunodeficiency that was felt to be contributory to the meningitis. Two patients began therapy because of progressive meningitis while receiving concurrent intracerebrospinal fluid therapy and five began because they wanted to avoid intracerebrospinal fluid amphotericin treatment. Three patients who showed minimal evidence of disease on chronic intracerebrospinal fluid amphotericin treatment began itraconazole therapy with the goal of discontinuing this intracerebrospinal fluid therapy; all had shown a progression of disease with several previous attempts at tapering the frequency of intracerebrospinal fluid amphotericin administration. Thus, five of ten patients began treatment while receiving intracerebrospinal fluid amphotericin; the remainder received itraconazole as sole therapy. Eight patients had cerebrospinal fluid devices in place at initiation of therapy: five had ventriculoperitoneal or ventriculo-atrial shunts and six had Ommaya reservoirs; three patients had both devices. Clinical Results Eight of ten patients are evaluable; one patient is unevaluable due to noncompliance and another was lost to follow-up. Table 1 summarizes the treatment results among evaluable patients; Figure 1 shows the score of disease in individual evaluable patients before therapy and at the most recent follow-up. The median duration of treatment is 10 months (range, 6 to 42 months; mean, 15.1 months); all eight remain on therapy. Seven of eight patients have received 400 m g / d of itraconazole throughout their treatment; Patient 10 has received 300 to 400 m g / d . Seven of eight evaluable patients have shown a response to therapy. Among patients receiving concurrent therapy with intracerebrospinal fluid amphotericin (Patients 1, 2, and 5), all three have responded and have had that therapy discontinued for the first time since their original diagnosis. The cerebrospinal fluid antibody titer declined in the one patient (Patient 2) in whom it was initially positive and cerebrospinal fluid leukocyte counts remain normal in all three patients on itraconazole alone. Among the five patients receiving itraconazole as sole therapy, four have responded. All four responders have shown a decline in their cerebrospinal fluid antibody titer; one patient's titer became negative. The cerebrospinal fluid leukocyte count declined in all three responders in whom it was initially abnormal; cerebrospinal fluid cultures became negative in both responders with initially positive cultures. All four have no clinical evidence of active disease. The single patient with extrameningeal site disease has shown a complete response at that skin site. One patient (Patient 8) initially responded to itra-
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Table 1. Results of Treatment with Itraconazole Patient
Duration Itraconazole Therapy
Intracerebrospinal Fluid Therapy Discontinued
Cerebrospinal Fluid Leukocyte Count Before Therapy Most Recent
mo
X 1&/L
42 17 9 20 12 10 6
It 2t 5t 6t
n n n
lot
Yes Yes Yes Not Not Not Not
6
applicable applicable applicable applicable
33 66 54 1100 62 8 63
0 10 10 67 21 0 31
Not applicable
1055
650
* Reciprocal of last > 3 + dilution. t Patient was on concurrent intracerebrospinal fluid therapy. % Patient treated with itraconazole therapy alone.
conazole therapy with a conversion of the cerebrospinal fluid culture to negative and a return to normal of the cerebrospinal fluid leukocyte count and cerebrospinal fluid antibody titer. After 8 months of therapy he became noncompliant for 2 weeks and had a recrudescence of disease with a new headache and a rise in cerebrospinal fluid leukocyte count. These abnormalities disappeared within 1 month of restarting itraconazole; he remains free of active disease after an additional 2 months of therapy. The single patient failing therapy (Patient 10) had previously responded to treatment with intracerebrospinal fluid amphotericin but had this therapy discontinued because of drug-associated myelopathy ( 7 ) . He failed therapy with fluconazole (100 m g / d ) and intracerebrospinal fluid miconazole (20 m g / d ) . Itraconazole therapy was begun; however, after 2 months he became noncompliant. During this interval his cerebrospinal fluid leukocyte count and cerebrospinal fluid antibody titer rose. Two months later itraconazole therapy was restarted. After 4 additional months of itraconazole as sole therapy, his cerebrospinal fluid grew C. immitis and intracerebrospinal fluid miconazole was restarted. Although he is receiving both itraconazole and miconazole, his cerebrospinal fluid fungal culture remains positive, his cerebrospinal fluid leukocyte count remains elevated, his cerebrospinal fluid antibody titer has risen, and he has developed progressive hydrocephalus.
Toxicity Eight patients are evaluable for evidence of drug toxicity; a total of 122 patient-months of therapy have been administered. Toxicity has been minimal. Only one patient has experienced any toxicity attributable to itraconazole: mild nausea without vomiting that was tolerated with symptomatic treatment without dosage reduction. Discussion The options for the treatment of coccidioidal meningitis are, at present, less than optimal. Standard therapy utilizes both intravenous and intracerebrospinal fluid amphotericin; this therapy is associated with substantial neurologic toxicity that limits therapy and may mimic disease ( 1 ) . Some patients, however, may be cured, even in the presence of intracerebrospinal fluid devices such as reservoirs and shunts. Experience with azoles in the treatment of coccidioidal meningitis is limited. Miconazole and ketoconazole, the azoles currently available for treatment of
Pharmacokinetic Studies Sera for pharmacokinetic analysis were available from four of eight evaluable patients. Mean serum concentrations of itraconazole varied from 3.4 to 15.4 /xmol/ L with wide variation among patients. These values are consistent with our previously reported results (3) in a larger series of patients with various systemic mycoses. Three samples of cerebrospinal fluid were available from two patients at a time of steady-state pharmacokinetics (2 weeks or more after starting therapy); itraconazole was not detected in any sample.
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Figure 1. Response to itraconazole therapy in eight evaluable patients using a standard scoring system. Data are given as the percentage of baseline abnormality at the most recent follow-up.
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Table 1. (Continued) Cerebrospinal Fluid Antibody Titer* Before Therapy Most Recent
Cerebrospinal Fluid Culture Before Therapy Most Recent
Assessment (% Pretherapy Score)
0 32 0 512 16 8 8
0 0 0 8 4 0 4
Negative Negative Negative Positive Negative Positive Negative
Negative Negative Negative Negative Negative Negative Negative
Response Response Response Response Response Response Response
8
16
Positive
Positive
Nonresponse (120)
systemic mycoses, have been used with limited success. Miconazole must be given by intracerebrospinal fluid administration and is sometimes poorly tolerated; treatment is marked by high rates of relapse ( 8 ) . Ketoconazole has been effective in selected patients, particularly when used in high doses (9); this therapy, however, is associated with substantial gastrointestinal and endocrine toxicity (10). Fluconazole, like itraconazole, an experimental triazole, is distinguished from other azoles by its high cerebrospinal fluid penetration as documented in experimental animals (11) and humans (12). It is effective in murine coccidioidal (13) and rabbit cryptococcal (14) meningitis, and it shows great promise in the treatment of human fungal meningitis (15). The early experience with fluconazole in the treatment of coccidioidal meningitis has been promising ( 5 ) . We have treated 18 patients with chronic coccidioidal meningitis with 50 to 400 m g / d of fluconazole. Responses were seen in 67% of patients after a mean treatment duration of 9.8 months. Response or partial response was seen in 63% of patients receiving fluconazole as sole therapy. These results can be contrasted with those of the present study. Fluconazole was well tolerated by all participants. Continued experience with larger patient groups and more extensive follow-up will be important to fully define the potential of fluconazole in the treatment of coccidioidal meningitis. Itraconazole is highly active against C. immitis in vitro; minimum inhibitory concentrations ranged from 0.025 to 7.0 juimol/L (median, 0.025 /imol/L) and minimum fungicidal concentrations varied from 0.025 to more than 14 /imol/L (median, 0.10 ]j.mol/L) in 52 clinical isolates ( 4 ) . Achievable serum concentrations are substantially higher; a mean peak serum concentration of 8.3 /xmol/L is achieved at 7 hours after dosage in patients on chronic therapy ( 3 ) . However, susceptibility testing may be method dependent. Itraconazole appears to be quite effective in treating nonmeningeal coccidioidomycosis. We have reported (3) complete responses in 63% of patients treated with itraconazole for a mean of 7.1 months. Unlike fluconazole, itraconazole has negligible cerebrospinal fluid penetration in both animal models and
(30) (6) (25) (40) (50) (21) (33)
Comment
N o evidence of disease N o evidence of disease N o evidence of disease Asymptomatic Asymptomatic N o evidence of disease Asymptomatic; nasal skin lesion resolved Progressive disease: persistent positive cerebrospinal fluid cultures; worsening hydrocephalus
in humans (3, 11). Despite this, it has shown success (14, 16) in the treatment of both experimental and human cryptococcal meningitis. In this respect, itraconazole shares characteristics with amphotericin B; the latter drug also penetrates cerebrospinal fluid poorly after systemic administration but is effective by that route in cryptococcal (although not in coccidioidal) meningitis. Itraconazole is not presently available for other than oral therapy. Our experience suggests that itraconazole offers substantial benefit in the treatment of human coccidioidal meningitis. The patients reported here were refractory to standard therapy; the high rate of response to itraconazole is impressive in this setting. The single patient who failed therapy also failed to respond to fluconazole and intracerebrospinal fluid miconazole. Our favorable results suggest that penetration into the meninges, a compartment that cannot be sampled in patients, occurs with itraconazole and is more important than the penetration into cerebrospinal fluid. This theory would be consistent with the observation that cerebrospinal fluid cultures in coccidioidal meningitis are uncommonly positive (1). Itraconazole was effective both as sole therapy and when administered with concurrent intracerebrospinal fluid amphotericin. Further experience will determine its full potential as an adjunct to intracerebrospinal fluid therapy; allowing an enhanced response to and a more rapid discontinuation of intracerebrospinal fluid amphotericin would do much to limit the substantial toxicity of that treatment. Because all our patients remain on itraconazole, we cannot evaluate the risk of relapse after apparently successful therapy. However, the lethality of untreated disease and the deficiencies of presently licensed therapy make the present information extremely important for these patients despite the absence as yet of observation after therapy. The rapid relapse in Patient 8 and the rapid progression of disease in Patient 10 after each became noncompliant suggest that itraconazole is fungistatic rather than fungicidal and implies a need for prolonged therapy. However, given the mild and infrequent toxicity of itraconazole and the toxicity and difficulty in administration of the present conventional
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Appendix Table. Characteristics of Patients with Meningitis Just before Treatment with Itraconazole Patient
Sex, Age
Race or Ethnic Group
M, 36 M, 13 F, 16 M, 27 F, 20 M, 24 M, 79 M, 35 M, 41 M, 57
Previous Azole Therapy
White White Hispanic Hispanic White Arab White Black Filipino Korean
194 60 30 12 20 9 10 102 5 68
ketoconazole, miconazole ketoconazole ketoconazole None None ketoconazole None ketoconazole ketoconazole ketoconazole, fluconazole, miconazole
intracerebrospinal fluid amphotericin therapy, an oral therapy which would only suppress disease would be an advance, even if it required treatment for many years or for the rest of the patient's life. Our data do not allow a direct comparison of itraconazole with high-dose ketoconazole or fluconazole, the alternative oral agents for coccidioidal meningitis. We have seen minimal toxicity with itraconazole at doses up to 400 m g / d ( 3 ) . Ketoconazole had substantial gastrointestinal and endocrine toxicity at the doses that have appeared to have some efficacy in coccidioidal meningitis. The relatively low toxicity of itraconazole is a clear advantage over ketoconazole. Fluconazole, because of its higher cerebrospinal fluid penetration, has a theoretic advantage over itraconazole. The two drugs are, however, roughly equivalent in animal models of fungal meningitis (14). A comparative trial of these two agents may be indicated.
2.
3. 4.
5. 6.
7.
8. 9.
10. Acknowledgments: The authors thank Eduardo G. Arathoon, MD; Steven Helvie, MD; George Skaff, MD; Thomas L. Fife, MD; Richard J. Hamill, MD; Michael Palestine, MD; Elmer Palitang, MD; and Paul L. Williams, M D for referring patients and providing data on those patients. Requests for Reprints: David A. Stevens, M D , Department of Medicine, Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128. Current Author Addresses: Dr. Tucker: Department of Medicine, Wenatchee Valley Clinic, 820 North Chelan Street, Wenatchee, WA 98807. Drs. Denning and Stevens: Department of Medicine, Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128. Dr. Dupont: Pasteur Institute, 25 rue du Docteur Roux, F-75724 Paris, France.
11.
12.
13. 14.
15. 16.
References 1. Kelly PC. Coccidioidal meningitis. In: Stevens DA, ed. Coccidioido-
112
Intracerebrospinal Fluid Amphotericin
Central Nervous System Device
Yes Yes Yes Yes Yes No No No No No
None Reservoir, shunt None Shunt Reservoir Reservoir, shunt Shunt Reservoir Reservoir Reservoir, shunt
mo
y 1 2 3 4 5 6 7 8 9 10
Duration of Disease
mycosis: A Text. New York: Plenum Medical Book Co.; 1980:16394. Pappagianis D, Crane R. Survival in coccidioidal meningitis since the introduction of amphotericin B. In: Ajello L, ed. Coccidioidomycosis: Current Clinical and Diagnostic Status. Miami: Symposia Specialists; 1977:223-37. Tucker RM, Williams PL, Arathoon EG, Stevens DA. Treatment of mycoses with itraconazole. Ann NY Acad Sci. 1988;544:451-70. Tucker RM, Denning DW, Rinaldi MG, Hanson LH, Stevens DA. Itraconazole therapy of progressive coccidioidomycosis [Abstract 573]. In: Abstracts of the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1988:210. Tucker RM, Galgiani JN, Denning DW, et al. Treatment of coccidioidal meningitis with fluconazole. Rev Infect Dis. 1990 [In press]. Stevens DA, Stiller RL, Williams PL, Sugar AM. Experience with ketoconazole in three major manifestations of progressive coccidioidomycosis. Am J Med. 1983;74:58-63. Carnevale NT, Galgiani JN, Stevens DA, Herrick MK, Langston JW. Amphotericin B-induced myelopathy. Arch Intern Med. 1980;140:1189-92. Stevens DA. Miconazole in the treatment of coccidioidomycosis. Drugs. 1983;26:347-54. Graybill JR, Stevens DA, Galgiani JN, et al. Ketoconazole treatment of coccidioidal meningitis. Ann NY Acad Sci. 1988;544:488-96. Sugar AM, Alsip SG, Galgiani JN, et al. Pharmacology and toxicity of high-dose ketoconazole. Antimicrob Agents Chemother. 1987;31:1874-8. Perfect JR, Durack DT. Penetration of imidazoles and triazoles into cerebrospinal fluid of rabbits. J Antimicrob Chemother. 1985; 16:816. Tucker RM, Williams PL, Arathoon EG, et al. Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis. Antimicrob Agents Chemother. 1988;32:369-73. Graybill JR, Sun SH, Ahrens J. Treatment of murine coccidioidal meningitis with fluconazole ( U K 49,858). / Med Vet Mycol. 1986;24:113-9. Perfect JR, Savani DV, Durack DT. Comparison of itraconazole and fluconazole in treatment of cryptococcal meningitis and Candida pyelonephritis in rabbits. Antimicrob Agents Chemother. 1986;29:579-83. Dismukes WE. Azole antifungal drugs: old and new. Ann Intern Med. 1988;109:177-9. Denning DW, Tucker RM, Hanson LH, Hamilton JR, Stevens DA. Itraconazole therapy for cryptococcal meningitis and cryptococcosis. Arch Intern Med. 1989;149:2301-8.
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