Emma C. Wall

Dose Response Effect of High-Dose Fluconazole for HIV-Associated Cryptococcal Meningitis in Southwestern Uganda

BACKGROUND Therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis in many centers in Africa is fluconazole administered at a dosage of 400-800 mg per day. However, higher dosages of fluconazole have been used to treat patients without resulting in serious toxicity. Pharmacokinetic and pharmacodynamic considerations suggest that higher dosages might be associated with greater efficacy. METHODS Sixty HIV-seropositive, antiretroviral therapy-naive patients with first-episode cryptococcal meningitis in Mbarara, Uganda, were treated with fluconazole: the first 30 patients received 800 mg per day, and the second 30 patients received 1200 mg per day. After 2 weeks, the dosage was reduced to 400 mg per day for an additional 8 weeks. The primary outcome measure was rate of clearance of infection, or early fungicidal activity, as determined by serial quantitative cerebrospinal fluid cryptococcal cultures during the first 2 weeks. Secondary outcome measures were safety and mortality through 10 weeks. RESULTS Forty-seven percent of patients had a reduced level of consciousness at presentation. Early fungicidal activity was significantly greater for patients receiving fluconazole at a dosage of 1200 mg per day than it was for patients receiving 800 mg per day (early fungicidal activity +/- standard deviation, -0.18+/-0.11 vs. -0.07+/-0.17 log colony-forming units/mL per day; P=.007). Fluconazole administered at a dosage of 1200 mg per day appeared to be well tolerated, and no liver function disturbance was observed. Two-week and 10-week mortality were 30% and 54%, respectively, with no statistically significant difference between the groups. CONCLUSIONS Fluconazole is more rapidly fungicidal when administered at a dosage of 1200 mg per day than when administered at a dosage of 800 mg per day. In resource-limited settings, additional studies are needed to test the addition of flucytosine or short-duration amphotericin B to high-dose fluconazole and to test strategies to facilitate earlier presentation, diagnosis, and treatment of patients with cryptococcal meningitis.

Bacterial Meningitis in Malawian Adults, Adolescents, and Children During the Era of Antiretroviral Scale-up and Haemophilus influenzae Type b Vaccination, 2000–2012

Culture positive bacterial meningitis has fallen over a 12-year period in urban Malawi following Hib vaccination. Hib, NTS, and pneumococcal meningitis have fallen significantly in children. Pneumococcal meningitis has not fallen in adults; NTS and pneumococcal meningitis are seasonal.

High mortality amongst adolescents and adults with bacterial meningitis in sub-Saharan Africa: an analysis of 715 cases from Malawi.

Mortality from bacterial meningitis in African adults is significantly higher than those in better resourced settings and adjunctive therapeutic interventions such as dexamethasone and glycerol have been shown to be ineffective. We conducted a study analysing data from clinical trials of bacterial meningitis in Blantyre, Malawi to investigate the clinical parameters associated with this high mortality. Methods We searched for all clinical trials undertaken in Blantyre investigating bacterial meningitis from 1990 to the current time and combined the data from all included trial datasets into one database. We used logistic regression to relate individual clinical parameters to mortality. Adults with community acquired bacterial meningitis were included if the CSF culture isolate was consistent with meningitis or if the CSF white cell count was >100 cells/mm3 (>50% neutrophils) in HIV negative participants and >5 cells/mm3 in HIV positive participants. Outcome was measured by mortality at discharge from hospital (after 10 days of antibiotic therapy) and community follow up (day 40). Results Seven hundred and fifteen episodes of bacterial meningitis were evaluated. The mortality rate was 45% at day 10 and 54% at day 40. The most common pathogens were S.pneumoniae (84% of positive CSF isolates) and N.meningitidis (4%). 607/694 (87%) participants tested were HIV antibody positive. Treatment delays within the hospital system were marked. The median presenting GCS was 12/15, 17% had GCS<8 and 44.9% had a seizure during the illness. Coma, seizures, tachycardia and anaemia were all significantly associated with mortality on multivariate analysis. HIV status and pneumococcal culture positivity in the CSF were not associated with mortality. Adults with community acquired bacterial meningitis in Malawi present with a severe clinical phenotype. Predictors of high mortality are different to those seen in Western settings. Optimising in-hospital care and minimising treatment delays presents an opportunity to improve outcomes considerably.

Persistence of Pneumolysin in the Cerebrospinal Fluid of Patients With Pneumococcal Meningitis Is Associated With Mortality

Poor prognosis in Pneumococcal meningitis may be associated with high pneumolysin levels in cerebrospinal fluid (CSF). In patient samples we showed that pneumolysin levels in CSF remained high after 48 hours in nonsurvivors of meningitis compared with survivors. Selective antipneumolysin treatment may present a novel therapeutic option.

Prediction of Outcome From Adult Bacterial Meningitis in a High-HIV-Seroprevalence, Resource-Poor Setting Using the Malawi Adult Meningitis Score (MAMS)

Summary The Malawi Adult Meningitis Score prediction tool accurately estimates risk of clinical outcome from bacterial meningitis in sub-Saharan Africa. Clinical trial analysis by risk stratification reveals more severe outcomes in low-risk groups receiving adjunctive glycerol compared to placebo.

Genomic pneumococcal load and CSF cytokines are not related to outcome in Malawian adults with meningitis

Summary Objective Bacterial meningitis in sub-Saharan Africa is predominantly caused by Streptococcus pneumoniae, is often associated with HIV co-infection and mortality rates are double those seen in better resourced settings. Methods To investigate the cause of this excessive mortality we quantified the pneumococcal DNA load and six common pro-inflammatory cytokines in the cerebrospinal fluid (CSF) of Malawian adults with culture proven pneumococcal meningitis and correlated the results to clinical parameters and outcome. There are currently no published data relating bacterial load to outcome in adults with pneumococcal meningitis. Results The mean age of patients was 32 years, 82% were HIV infected and 49% had died by day 40. CSF bacterial loads were high (median 6.5 × 105 copies/ml CSF) and there was no significant variation in bacterial load between survivors and non-survivors. All pro-inflammatory CSF cytokines were elevated in the CSF, with no clinically important differences between survivors and non-survivors. HIV status did not affect the CSF bacterial load or cytokine response. Conclusion Mortality from pneumococcal meningitis in adults in sub-Saharan Africa is not related to pneumococcal bacterial load. More research is needed to understand the very high mortality from meningitis in this region.

Goal directed therapy for suspected acute bacterial meningitis in adults and adolescents in sub-Saharan Africa

Background Mortality from acute bacterial meningitis (ABM) in sub-Saharan African adults and adolescents exceeds 50%. We tested if Goal Directed Therapy (GDT) was feasible for adults and adolescents with clinically suspected ABM in Malawi. Materials and methods Sequential patient cohorts of adults and adolescents with clinically suspected ABM were recruited in the emergency department of a teaching hospital in Malawi using a before/after design. Routine care was monitored in year one (P1). In year two (P2), nurses delivered protocolised GDT (rapid antibiotics, airway support, oxygenation, seizure control and fluid resuscitation) to a second cohort. The primary endpoint was composite mean number of clinical goals attained. Secondary endpoints were individual goals attained and death or disability from proven or probable ABM at day 40. Results 563 patients with suspected ABM were enrolled in the study; 273 were monitored in P1; 290 patients with suspected ABM received GDT in P2. 61% were male, median age 33 years and 90% were HIV co-infected. ABM was proven or probable in 132 (23%) patients. GDT attained more clinical goals compared to routine care: composite mean number of goals in P1 was 0·55 vs. 1·57 in P2 GDT (p<0·001); Death or disability by day 40 from proven or probable ABM occurred in 29/57 (51%) in P1 and 38/60 (63%) in P2 (p = 0·19). Conclusion Nurse-led GDT in a resource-constrained setting was associated with improved delivery of protocolised care. Outcome was unaffected. Trial registration www.isrctn.com ISRCTN96218197

845Prediction of Outcome from Adult Bacterial Meningitis in a High HIV Seroprevelence, Resource-Poor Setting Using a New Severity Scoring Tool, the Malawi Adult Meningitis Score (MAMS)

Seroprevelence, Resource-Poor Setting Using a New Severity Scoring Tool, the Malawi Adult Meningitis Score (MAMS) Emma Wall, MBChB, MRCP, DTM&H, MRes; Mavuto Mukaka, PhD; Matthew Scarborough, PhD; Katherine M.B. Ajdukiewicz, MD; Katharine Cartwright, MRCPath; Brian Faragher, PhD; David Lalloo, MB, BS, MD; Robert Heyderman, PhD; Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi; John Radcliffe Hospital, Oxford, United Kingdom; Department of Medicine, North Manchester General Hospital, Manchester, United Kingdom; University Hospitals of Leicestershire NHS Trust, Leicester, United Kingdom; Liverpool School of Tropical Medicine, Liverpool, United Kingdom