No abstract

We retrospectively compared the clinical manifestations, laboratory features, and outcome of cryptococcal meningitis in 44 human immunodeficiency virus (HIV)-positive and 21 HIV-negative patients in Durban, South Africa, and contrasted our findings with those in the developed world. Cryptococcal meningitis was the initial AIDS-defining illness in 84% of patients. Headache, fever, convulsions, neck stiffness, and neurological signs were more common in HIV-positive patients. We detected neurological abnormalities in 50% of the HIV-positive group. Seventeen percent of HIV-positive patients had completely normal CSF indices. HIV-positive patients with cryptococcal meningitis frequently had oral candidiasis and tuberculosis as coexistent illnesses. Prognostic factors identified in the West do not appear to be applicable in Africa. Death during hospitalization was significantly higher in the HIV-positive group. HIV-associated cryptococcal meningitis in Africa is apparently associated with higher rates of neurological complications and death than is such disease in developed countries of the world.

Fluconazole (FLZ) has emerged as a highly successful agent in the management of systemic infections of Candida. Cure rates for symptomatic candidiasis following single 150-mg FLZ dose therapy exceed 90%. In vitro, however, FLZ is fungistatic only in a narrow pH range and is not effective at vaginal pH, 4.2. This study evaluated the effect of FLZ on Candida albicans under in vitro conditions resembling the vaginal microenvironment, using vagina-simulative medium (VS). We found that FLZ was fungicidal for C. albicans in VS, but not in other media at the same pH, 4.2. In VS, FLZ was fungicidal at concentrations of >8 g/ml and reduced viability by greater than 99.9%. Analysis of the components of VS indicated that 17 mM acetic acid, a concentration achieved in the vagina, was responsible for the synergistic, fungicidal effect. This effect was not seen at neutral pH. Other substrates were not effective substitutes for acetic acid; however, short-chained carboxylic acids, glyoxylate and malonate, were effective. Most strains of C. albicans that were resistant to FLZ under standard conditions were killed by FLZ plus acetate. Other species of Candida were also killed, except C. krusei and C. glabrata. This study shows that FLZ has fungicidal activity for Candida species under in vitro conditions that mimic the vaginal microenvironment. This raises the possibility that FLZ may also have fungicidal effects during treatment of vaginal candidiasis. Elucidating the mechanism by which FLZ and acetate interact may disclose vulnerable pathways that could be exploited in drug development.

Introduction Rationale for guideline updateSix years after the Southern African HIV Clinicians Society cryptococcal disease guideline was published in 2013, cryptococcal meningitis (CM) remains an important cause of mortality among antiretroviral treatment (ART)-naïve and ART-experienced HIV-seropositive adults in South Africa. 1,2 Several important practice-changing developments led us to update the guideline to diagnose, prevent and manage this common fungal opportunistic infection. The World Health Organization (WHO) published a guideline for advanced HIV disease in 2017 and a guideline relevant to resource-limited settings for HIV-associated CM in 2018. 3,4 Cryptococcal antigen (CrAg) screening and pre-emptive treatment reduced all-cause mortality among ambulatory participants in a randomised clinical trial in Zambia and Uganda. 5 Following an evaluation of reflex versus provider-initiated screening, national reflex laboratory CrAg screening was implemented in South Africa in 2016. 6,7 Recently completed clinical trials conducted in resourcelimited settings have provided evidence for the best first-line antifungal regimens for CM and the

The diagnostic gold standard for active tuberculosis (TB) is the detection of Mycobacterium tuberculosis (MTB) by culture or molecular methods. However, despite its limited sensitivity, sputum smear microscopy is still the mainstay of TB diagnosis in resource-limited settings. Consequently, diagnosis of smear-negative pulmonary and extrapulmonary TB remains challenging in such settings. A number of novel or alternative techniques could provide adjunctive diagnostic use in the context of difficult-to-diagnose TB. These may be especially useful in certain patient groups such as persons infected with human immunodeficiency virus (HIV) and children, who are disproportionably affected by smear-negative and extrapulmonary disease and who are also most adversely affected by delays in TB diagnosis and treatment. We review a selection of these methods that are independent of nucleic acid amplification techniques and could largely be implemented in resource-limited settings in current or adapted versions. Specifically, we discuss the diagnostic use and potential of serologic tests based on detection of antibodies to MTB antigens; interferon gamma release assays using site-specific lymphocytes; detection of lipoarabinomannan, a glycolipid of MTB, in urine; the string test, a novel technique to retrieve lower respiratory tract samples; and fine needle aspiration biopsy of lymph nodes.