Successful Treatment of Coccidioidal Meningitis with Voriconazole

Meningitis is a potentially lethal complication of coccidioidomycosis. Fluconazole is the drug of choice in the treatment of this condition, and therapy is continued indefinitely [1, 2]. Patients who experience treatment failure receive intrathecal amphotericin B [2]. We report a previously healthy man who had fluconazole treatment failure but responded completely to voriconazole. Intense photosensitivity occurred, but discontinuation of therapy was not required.

Case report. In June 1999, this 47-year-old man from Baltimore developed malaise, severe headaches, diplopia, night sweats, chills, weight loss of 7 kg, and a fever (temperature of 39°C). Immediately before the development of these symptoms, he had been feeling well. Examination of CSF obtained through lumbar puncture showed pleocytosis and high protein content (figure 1, day -180). He received empiric intravenous ceftriaxone for 3 weeks without demonstrating any clinical response. Examination of CSF from a second lumbar puncture showed an increase in the leukocyte count to 828 cells/mm³ with 30% eosinophils. Complement-fixing antibody titers to Coccidioides species were 1 : 16 in serum and 1 : 4 in CSF. Coccidioidal meningitis was diagnosed, and daily administration of 400 mg of fluconazole was started.

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Figure 1

A, The course of treatment with fluconazole and voriconazole for a patient with coccidioidal meningitis is shown. B, Levels of glucose and protein and leukocyte counts in CSF obtained through lumbar puncture from 180 days before the institution of voriconazole therapy through day 837 of treatment.

The patient's condition improved and he remained asymptomatic for 4 months while taking fluconazole, but he then developed diplopia, nausea, vomiting, dizziness, and progressive hearing loss in the right ear. Examination of CSF from a lumbar puncture performed on day 131 of fluconazole treatment found modest improvement over pretreatment values: the glucose level had increased from 29 to 38 mg/dL, the protein level had decreased from 165 to 90 mg/dL, and the leukocyte count remaining high (273 cells/mm³ with 29% eosinophils). The fluconazole dosage was increased to 800 mg/day, and the patient was referred to the Clinical Center at the National Institutes of Health (NIH; Bethesda, MD) on 16 December 1999 for further evaluation.

In the 24 h before the patient was evaluated at the NIH, he developed a right facial droop. The findings of a physical examination were remarkable for right third, sixth, and peripheral seventh cranial nerve palsies; decreased sensation of taste; decreased sensation on the right side of the face; profound hearing loss in the right ear, with no response to pure tones or speech; moderate high-frequency hearing loss in the left ear; moderate ataxia, with a broad gait; positive Romberg's sign; equivocal left Babinski's reflex; paresthesias in both lower extremities; and left pronator drift, despite normal muscle tone bilaterally and strength on the right side. Vital signs were within normal ranges. The patient's only travel to an area where coccidioidomycosis is endemic was a helicopter trip to the Grand Canyon while visiting Las Vegas in March 1998, more than 1 year before the onset of the illness.

Cytologic examination of CSF from a lumbar puncture showed acute and chronic inflammatory changes. Cryptococcal antigen was undetectable in serum and CSF. Coccidioidal complement-fixing antibody titers in specimens obtained on 16 December 1999 were 1 : 4 in serum and 1 : 2 in CSF (specimens were tested at D. Pappagianis' laboratory at the University of California, Davis). Cultures of CSF were negative for fungus. The fluconazole dosage was increased to 1200 mg/day. In the next 5 days, the patient's symptoms worsened. Severe dizziness, nausea, and vomiting ensued. Moreover, the patient's ataxia had progressed, rendering him unable to walk. A physical examination had new findings, including left-sided deviation of the uvula, drooping right soft palate, hoarseness, and left pronator drift. There was hyperreflexia in all extremities and tingling in the left side of his body and right face. Other findings of the examination were unchanged from those of 5 days before. The results of hematologic, liver function, and renal function tests remained normal. Although no unusual findings had been seen on a brain MRI with gadolinium enhancement 25 days previously, a second MRI showed an intense signal in the pons, near the pontinomedullary junction, with an adjacent inflammatory mass in the pontine cistern. Meningeal enhancement was also evident (figure 2).

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Figure 2

Fluid-attenuated inversion recovery MRI of the brain after injection of gadolinium demonstrates an enhancing lesion involving the right pontinomedullary junction (arrow). There is an adjacent mass in the pontine cistern. Meningeal thickening and enhancement are also present.

The patient was admitted on 21 December 1999 to the Clinical Center for treatment with voriconazole on a protocol approved by the National Institute of Allergy and Infectious Diseases institutional review board. After informed consent was obtained, the patient was given intravenous voriconazole every 12 h (6 mg/kg for the first 2 doses and 4 mg/kg every 12 h thereafter). The patient reported photopsia during the first infusion of voriconazole, perceived in the lower half of vision in his left eye, but that resolved in a few hours and did not recur.

The patient continued to improve over the course of the next 6 days, and therapy was changed to 300 mg of voriconazole orally every 12 h. Another brain MRI performed on day 27 revealed decreased pontine edema and meningeal inflammation. New and persistent lower back pain and sporadic symptoms of “electric shocks” over the patient's chest prompted an MRI of the spinal cord on day 54 of voriconazole therapy. The study showed meningeal enhancement at T5–S2, extending down the cauda equina. Examination of CSF from a lumbar puncture showed decreasing pleocytosis.

On day 61, the dosage of voriconazole was increased to 432 mg (6 mg/kg) every 12 h intravenously. Back pain and chest dysesthesias gradually disappeared, and the patient resumed full-time employment. An MRI on day 83 showed no edema of the brain stem and decreased meningeal enhancement. The patient tolerated voriconazole well, except for the appearance of marked photosensitivity, which necessitated the use of sunscreen and protective clothing.

On day 103, the patient's treatment regimen was changed to 400 mg of voriconazole orally every 12 h. On day 115, complement-fixing antibody to Coccidioides species was undetectable in CSF. Except for brief periods during which the patient received 300 or 450 mg of voriconazole, he continued to receive 400 mg twice daily until day 383. Photosensitivity remained intense, with regular peeling of the skin, but this was restricted to the face and dorsa of both hands. Neurological examination showed complete resolution of third, sixth, seventh, and ninth cranial nerve palsies and almost complete resolution of the tenth cranial nerve palsy. He had residual right-sided persistent hearing loss. An audiogram showed mild, unchanged high-frequency hearing loss in the left ear and a recovery of at least 50 dB on the right ear. The voriconazole dosage was decreased to 350 mg twice daily on day 384 and to 300 mg twice daily on day 460. The patient was referred back to his local physician on day 571. On day 837 of voriconazole therapy, the patient was asymptomatic, except for decreased hearing in the right ear; was working full-time; and had normal results of testing of CSF and no complement-fixing antibody in serum or CSF (as determined at D. Pappagianis' laboratory). The voriconazole dosage was reduced on day 837 to 250 mg twice daily. The patient reported that photosensitivity improved markedly over the course of the next several weeks.

Voriconazole concentrations were measured by high-performance liquid chromatography on 9 occasions in serum obtained between 1.5 and 4 h after administration of doses of 300–450 mg. The average value was 2.6 μg/mL (range, 0.27–4.55 μg/mL). These values were confirmed in the same samples at Pfizer (Sandwich, UK). The average level of voriconazole in CSF samples obtained on 8 occasions was 2.1 μg/mL (range, 0.91–3.03 μg/mL).

Because plasma retinoid levels have been reported to be high in patients with voriconazole photosensitivity [3], our patient was tested twice while receiving 400 mg of voriconazole twice daily. His retinol levels were 1300 μg/L on day 260 and 1747 μg/L on day 291. These values exceed the upper limit of normal for our laboratory (1100 μg/mL). The patient was not taking multivitamins or alternative medicines that might have provided a dietary source of retinoids.

Discussion. Brief exposures in areas where coccidioidomycosis is endemic can lead to onset of disease many months later. Our patient's exposure in Las Vegas and northern Arizona preceded the onset of illness by 15 months, an unusually long but not unknown incubation period. The diagnosis of coccidioidal meningitis appears to be relatively secure, based on the specificity of the test for complement-fixing antibody in CSF [4]. Failure to isolate Coccidioides species from multiple cultures of CSF is common. The response of coccidioidal meningitis to fluconazole is often slow and may be incomplete, requiring administration of intraventricular amphotericin B [2].

Voriconazole is a wide-spectrum triazole antifungal agent recently approved for primary treatment of invasive aspergillosis and for treatment of nonresponsive infections due to Scedosporium apiospermum or Fusarium species. We have not found reports of experience with voriconazole in treatment of coccidioidal meningitis. The recommended twice-daily intravenous dosage is 6 mg/kg for 2 doses and then 4 mg/kg. Oral therapy (200 mg twice daily) is administered later in the course of treatment to adults weighing at least 40 kg. The dosage can be increased to 300 mg twice daily if insufficient response is obtained. We chose higher oral voriconazole dosages because of the severity of the patient's illness and because fluconazole therapy had failed to prevent profound progression, despite escalation of dosage over the course of 155 days. Whether our patient's illness required these high dosages is unknown, but treatment did result in readily detectable levels of voriconazole in CSF, which was also found by bioassay in a patient with CNS aspergillosis [5]. Our patient's serum voriconazole concentrations, measured by high-performance liquid chromatography, were somewhat below the mean values of 3–5 μg/mL reported in volunteers 1–4 h after receipt of 300–400 mg on a twice-daily schedule [6].

Our patient developed severe photosensitivity after 10 weeks of therapy, and these symptoms continued for 2 years. When the voriconazole dose was reduced to 250 mg, which is close to the recommended dose of 200 mg, symptoms improved but did not disappear. Photosensitivity was accompanied by elevated plasma retinol levels, as has been reported elsewhere [3], although no causal relationship can be implied. It is likely that the effect of voriconazole on P-450–dependent enzymes slowed retinol metabolism, as occurs with ketoconazole and retinoic acid [7].

Meningeal enhancement on MRI of the brain is a common finding in coccidioidal meningitis, although, as in our patient, it may not be present on the initial examination [8]. MRI findings consistent with inflammation or edema in the brain stem, which were also noted in our patient, were present in 2 of 14 patients in one series [8], and a brain-stem abscess, confirmed at autopsy, was found in 1 of 12 patients in another series [9]. One patient in the latter series had spinal meningeal enhancement, as did our patient. Gratifyingly, the brain-stem lesion and adjacent inflammatory mass in the pontine cistern, as well as the radicular pain, cleared completely in our patient.

Judging by this single case, voriconazole may be an alternative to intrathecal amphotericin B for treatment of patients with coccidioidal meningitis that does not respond to high doses of fluconazole. Photosensitivity may require even more precautions in the sunlit areas of the southwestern United States than were needed for our patient in Baltimore.

• Received January 14, 2003.
• Revision received February 14, 2003.
• Accepted June 9, 2003.

• © 2003 by the Infectious Diseases Society of America