ArticlesCombination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial
Introduction
Cryptococcal meningitis is a common and often fatal opportunistic infection in HIV-infected individuals, especially in Africa and Asia. In northeast Thailand, cryptococcal disease is second only to tuberculosis as an AIDS-defining illness.1 In a Bangkok hospital, mortality of patients with HIV-associated cryptococcal meningitis was 43% with a mean time to death of 14 days, despite treatment with full conventional doses of amphotericin B.2
At least two factors might explain this high acute mortality: raised intracranial pressure and only moderately effective antifungal regimens, which frequently take more than 2 weeks to sterilise CSF. In a multicentre trial,3 the proportion of patients with negative CSF culture at 2 weeks was only 51% for amphotericin B and 60% for amphotericin B plus flucytosine (difference borderline p=0·06). In a separate study,4 2 week CSF culture status was an important determinant of outcome at 10 weeks by multivariate analysis. In-vitro and animal studies of the treatment of cryptococcosis have lent support to the use of antifungal combinations, including amphotericin B plus fluconazole.5, 6 Fluconazole is now widely available and affordable. Therefore, we examined whether initial drug combinations that include fluconazole lead to more rapid CSF sterilisation without additional toxicity. We measured CSF sterilisation rates using a new primary endpoint, the rate of reduction in CSF colony forming units (CFU) defined by serial quantitative CSF cultures.
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Participants and procedures
The study was done at Sappasitprasong Hospital, Ubon Ratchathani, northeast Thailand, and approved by the ethical and scientific review subcommittee of the Thai Ministry of Public Health and by the research ethics committee of St George's Hospital, London, UK. Between May and December, 2002, after obtaining written informed consent, we enrolled 64 adults with a first episode of cryptococcal meningitis, diagnosed by CSF India ink and cryptococcal antigen tests (figure 1). Exclusion criteria were
Results
The table shows baseline clinical and laboratory characteristics and clinical outcomes. At time of presentation with cryptococcal meningitis, 40 (63%) patients were known to be HIV-seropositive and 28 (44%) had a previous diagnosis of AIDS. The most common previous AIDS-defining illnesses were wasting syndrome, tuberculosis, and Pneumocystis carinii pneumonia. The median CD4 count was 9×109/L. All treatments were well tolerated and no drug treatment had to be withdrawn within the first 2 weeks
Discussion
Our study confirms the greater fungicidal activity of amphotericin plus flucytosine compared with amphotericin B alone in cryptococcal meningitis, as suggested by the Mycoses Study Group trial,3 and shows that flucytosine can be used safely in the setting of a provincial hospital in Thailand. Concern over combining amphotericin B and fluconazole has been based on their related effects on fungal membrane ergosterol. Our results are consistent with previous in-vitro and animal data, suggesting
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2022, IDCasesCitation Excerpt :Lumbar puncture is recommended when the open pressure is more than 250, and the goal should be to keep open pressure <200 this has been described to decrease mortality and improve outcomes. The frequency is unclear and should be based on the clinical assessment [34,33,31,40,12]. Alternative therapeutics approaches such as CSF shunting through a lumbar drain or ventriculostomy are available and should be considered for patients when LP is not well tolerated, or symptoms worsen even with repetitive LP, sudden decline in mental status, or evidence of hydrocephalus [41–44].
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