Epidemiology of adult meningitis during antiretroviral therapy scale-up in southern Africa: Results from the Botswana national meningitis survey.

OBJECTIVES: Data on meningitis epidemiology in high HIV-prevalence African settings following antiretroviral therapy scale-up are lacking. We described epidemiology of adult meningitis in Botswana over a 16-year period. METHODS: Laboratory records for adults undergoing lumbar puncture (LP) 2000-2015 were collected, with complete national data 2013-2014. Cerebrospinal fluid (CSF) findings and linked HIV-data were described, and national incidence figures estimated for 2013-2014. Temporal trends in meningitis were evaluated. RESULTS: Of 21,560 adults evaluated, 41% (8759/21,560) had abnormal CSF findings with positive microbiological testing and/or pleocytosis; 43% (3755/8759) of these had no confirmed microbiological diagnosis. Of the 5004 microbiologically-confirmed meningitis cases, 89% (4432/5004) were cryptococcal (CM) and 8% (382/5004) pneumococcal (PM). Seventy-three percent (9525/13,033) of individuals undergoing LP with identifiers for HIV registry linkage had documented HIV-infection. Incidence of LP for meningitis evaluation in Botswana 2013-2014 was 142.6/100,000 person-years (95%CI:138.3-147.1); incidence of CM was 25.0/100,000 (95%CI:23.2-26.9), and incidence of PM was 2.7/100,000 (95%CI:2.4-3.1). In contrast to previously reported declines in CM incidence with ART roll-out, no significant temporal decline in pneumococcal or culture-negative meningitis was observed. CONCLUSIONS: CM remained the predominant identified aetiology of meningitis despite ART scale-up. A high proportion of cases had abnormal CSF with negative microbiological evaluation.

Causes of Pediatric Meningitis in Botswana: Results From a 16-Year National Meningitis Audit.

BACKGROUND: Central nervous system infections are an important cause of childhood morbidity and mortality in high HIV-prevalence settings of Africa. We evaluated the epidemiology of pediatric meningitis in Botswana during the rollout of antiretroviral therapy, pneumococcal conjugate vaccine and Haemophilus influenzae type B (HiB) vaccine. METHODS: We performed a cross-sectional study of children (<15 years old) evaluated for meningitis by cerebrospinal fluid (CSF) examination from 2000 to 2015, with complete national records for 2013-2014. Clinical and laboratory characteristics of microbiologically confirmed and culture-negative meningitis were described and incidence of Streptococcus pneumoniae, H. influenzae and cryptococcal meningitis was estimated for 2013-2014. RESULTS: A total of 6796 unique cases were identified. Median age was 1 year [interquartile range 0-3]; 10.4% (435/4186) of children with available HIV-related records were known HIV-infected. Overall, 30.4% (2067/6796) had abnormal CSF findings (positive microbiologic testing or CSF pleocytosis). Ten percent (651/6796) had a confirmed microbiologic diagnosis; including 26.9% (175/651) Cryptococcus, 18.9% (123/651) S. pneumoniae, 20.3% (132/651) H. influenzae and 1.1% (7/651) Mycobacterium tuberculosis. During 2013-2014, national cryptococcal meningitis incidence was 1.3 cases per 100,000 person-years (95% confidence interval, 0.8-2.1) and pneumococcal meningitis incidence 0.7 per 100,000 person-years (95% confidence interval, 0.3-1.3), with no HiB meningitis diagnosed. CONCLUSIONS: Following HiB vaccination, a marked decline in microbiologically confirmed cases of H. influenzae meningitis occurred. Cryptococcal meningitis remains the most common confirmed etiology, demonstrating gaps in prevention-of-mother-to-child transmission and early HIV diagnosis. The high proportion of abnormal CSF samples with no microbiologic diagnosis highlights limitation in available diagnostics.

High Mortality in HIV-Associated Cryptococcal Meningitis Patients Treated With Amphotericin B-Based Therapy Under Routine Care Conditions in Africa.

BACKGROUND: Cryptococcal meningitis (CM) causes 10%-20% of HIV-related deaths in Africa. Due to limited access to liposomal amphotericin and flucytosine, most African treatment guidelines recommend amphotericin B deoxycholate (AmB-d) plus high-dose fluconazole; outcomes with this treatment regimen in routine care settings have not been well described. METHODS: Electronic national death registry data and computerized medical records were used to retrospectively collect demographic, laboratory, and 1-year outcome data from all patients with CM between 2012 and 2014 at Botswana's main referral hospital, when recommended treatment for CM was AmB-d 1 mg/kg/d plus fluconazole 800 mg/d for 14 days. Cumulative survival was estimated at 2 weeks, 10 weeks, and 1 year. RESULTS: There were 283 episodes of CM among 236 individuals; 69% (163/236) were male, and the median age was 36 years. All patients were HIV-infected, with a median CD4 count of 39 cells/mm3. Two hundred fifteen person-years of follow-up data were captured for the 236 CM patients. Complete outcome data were available for 233 patients (99%) at 2 weeks, 224 patients (95%) at 10 weeks, and 219 patients (93%) at 1 year. Cumulative mortality was 26% (95% confidence interval [CI], 20%-32%) at 2 weeks, 50% (95% CI, 43%-57%) at 10 weeks, and 65% (95% CI, 58%-71%) at 1 year. CONCLUSIONS: Mortality rates following HIV-associated CM treated with AmB-d and fluconazole in a routine health care setting in Botswana were very high. The findings highlight the inadequacies of current antifungal treatments for HIV-associated CM and underscore the difficulties of administering and monitoring intravenous amphotericin B deoxycholate therapy in resource-poor settings.

Advanced Human Immunodeficiency Virus Disease in Botswana Following Successful Antiretroviral Therapy Rollout: Incidence of and Temporal Trends in Cryptococcal Meningitis.

Background: Botswana has a well-developed antiretroviral therapy (ART) program that serves as a regional model. With wide ART availability, the burden of advanced human immunodeficiency virus (HIV) and associated opportunistic infections would be expected to decline. We performed a nationwide surveillance study to determine the national incidence of cryptococcal meningitis (CM), and describe characteristics of cases during 2000-2014 and temporal trends at 2 national referral hospitals. Methods: Cerebrospinal fluid data from all 37 laboratories performing meningitis diagnostics in Botswana were collected from the period 2000-2014 to identify cases of CM. Basic demographic and laboratory data were recorded. Complete national data from 2013-2014 were used to calculate national incidence using UNAIDS population estimates. Temporal trends in cases were derived from national referral centers in the period 2004-2014. Results: A total of 5296 episodes of CM were observed in 4702 individuals; 60.6% were male, and median age was 36 years. Overall 2013-2014 incidence was 17.8 (95% confidence interval [CI], 16.6-19.2) cases per 100000 person-years. In the HIV-infected population, incidence was 96.8 (95% CI, 90.0-104.0) cases per 100000 person-years; male predominance was seen across CD4 strata. At national referral hospitals, cases decreased during 2007-2009 but stabilized during 2010-2014. Conclusions: Despite excellent ART coverage in Botswana, there is still a substantial burden of advanced HIV, with 2013-2014 incidence of CM comparable to pre-ART era rates in South Africa. Our findings suggest that a key population of individuals, often men, is developing advanced disease and associated opportunistic infections due to a failure to effectively engage in care, highlighting the need for differentiated care models.

Microbiology of urinary tract infections in Gaborone, Botswana.

OBJECTIVE: The microbiology and epidemiology of UTI pathogens are largely unknown in Botswana, a high prevalence HIV setting. Using laboratory data from the largest referral hospital and a private hospital, we describe the major pathogens causing UTI and their antimicrobial resistance patterns. METHODS: This retrospective study examined antimicrobial susceptibility data for urine samples collected at Princess Marina Hospital (PMH), Bokamoso Private Hospital (BPH), or one of their affiliated outpatient clinics. A urine sample was included in our dataset if it demonstrated pure growth of a single organism and accompanying antimicrobial susceptibility and subject demographic data were available. RESULTS: A total of 744 samples were included. Greater than 10% resistance was observed for amoxicillin, co-trimoxazole, amoxicillin-clavulanate, and ciprofloxacin. Resistance of E. coli isolates to ampicillin and co-trimoxazole was greater than 60% in all settings. HIV status did not significantly impact the microbiology of UTIs, but did impact antimicrobial resistance to co-trimoxazole. CONCLUSIONS: Data suggests that antimicrobial resistance has already emerged to most oral antibiotics, making empiric management of outpatient UTIs challenging. Ampicillin, co-trimoxazole, and ciprofloxacin should not be used as empiric treatment for UTI in this context. Nitrofurantoin could be used for simple cystitis; aminoglycosides for uncomplicated UTI in inpatients.

An epidemiologic review of enteropathogens in Gaborone, Botswana: shifting patterns of resistance in an HIV endemic region.

BACKGROUND: The epidemiology of diarrheal disease in Botswana, an HIV endemic region, is largely unknown. Our primary objective was to characterize the prevalent bacterial and parasitic enteropathogens in Gaborone, Botswana. Secondary objectives included determining corresponding antimicrobial resistance patterns and the value of stool white and red blood cells for predicting bacterial and parasitic enteropathogens. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective cross-sectional study examined laboratory records of stool specimens analyzed by the Botswana National Health Laboratory in Gaborone, Botswana from February 2003 through July 2008. In 4485 specimens the median subject age was 23 [interquartile range 1.6-34] years. Overall, 14.4% (644 of 4485) of samples yielded a pathogen. Bacteria alone were isolated in 8.2% (367 of 4485), parasites alone in 5.6% (253 of 4485) and both in 0.5% (24 of 4485) of samples. The most common bacterial pathogens were Shigella spp. and Salmonella spp., isolated from 4.0% (180 of 4485) and 3.9% (175 of 4485) of specimens, respectively. Escherichia coli (22 of 4485) and Campylobacter spp. (22 of 4485) each accounted for 0.5% of pathogens. Comparing antimicrobial resistance among Shigella spp. and Salmonella spp. between two periods, February 2003 to February 2004 and July 2006 to July 2008, revealed an increase in ampicillin resistance among Shigella spp. from 43% to 83% (p<0.001). Among Salmonella spp., resistance to chloramphenicol decreased from 56% to 6% (p<0.001). The absence of stool white and red blood cells correlated with a high specificity and negative predictive value. CONCLUSIONS/SIGNIFICANCE: Most gastroenteritis stools were culture and microscopy negative suggesting that viral pathogens were the majority etiologic agents in this Botswana cohort. Shigella spp. and Salmonella spp. were the most common bacteria; Isospora spp. and Cryptosporidium spp. were the most common parasites. Resistance to commonly used antimicrobials is high and should be closely monitored.