The burden of hospital-acquired infections (HAI) in sub-Saharan Africa: a systematic review and meta-analysis.

Background: Hospital-acquired infections (HAI) are a leading cause of morbidity and mortality globally. These infections are diverse, but the majority are lower respiratory tract infection (LRTI), surgical site infection (SSI), bloodstream infection (BSI), and urinary tract infection (UTI). For most sub-Saharan African countries, studies revealing the burden and impact of HAI are scarce, and few systematic reviews and meta-analysis have been attempted. We sought to fill this gap by reporting recent trends in HAI in sub-Saharan Africa (SSA) with attention to key patient populations, geographic variation, and associated mortality. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a literature search of six electronic databases (Web of Science, Pubmed, APA PsycInfo, CINAHL, Embase, and the Cochrane Library) to identify studies assessing the prevalence of HAI in SSA countries. Studies published between 01 January 2014 and 31 December 2023 were included. We applied no language or publication restrictions. Record screening and data extractions were independently conducted by teams of two or more reviewers. Using the R software (version 4.3.1) meta and metafor packages, we calculated the pooled prevalence estimates from random-effect meta-analysis, and further explored sources of heterogeneity through subgroup analyses and meta-regression. This study is registered with PROSPERO, CRD42023433271. Findings: Forty-one relevant studies were identified for analysis, consisting of 15 from West Africa (n = 2107), 12 from Southern Africa (n = 2963), 11 from East Africa (n = 2142), and 3 from Central Africa (n = 124). A total of 59.4% of the patient population were associated with paediatric admissions. The pooled prevalence of HAI was estimated at 12.9% (95% CI: 8.9-17.4; n = 7336; number of included estimates [k] = 41, p < 0.001). By subregions, the pooled current prevalence of HAI in the West Africa, Southern Africa, East Africa and Central Africa were estimated at 15.5% (95% CI: 8.3-24.4; n = 2107; k = 15), 6.5% (95% CI: 3.3-10.7; n = 2963; k = 12), 19.7% (95% CI: 10.8-30.5; n = 2142; k = 11) and 10.3% (95% CI: 1.1-27.0; n = 124; k = 3) of the patient populations respectively. We estimated mortality resulting from HAI in SSA at 22.2% (95% CI: 14.2-31.4; n = 1118; k = 9). Interpretation: Our estimates reveal a high burden of HAI in SSA with significant heterogeneity between regions. Variations in HAI distribution highlight the need for infection prevention and surveillance strategies specifically tailored to enhance prevention and management with special focus on West and East Africa, as part of the broader global control effort. Funding: No funding was received for this study.

Yeast mannan rich fraction positively influences microbiome uniformity, productivity associated taxa, and lay performance.

BACKGROUND: Alternatives to antibiotic as growth promoters in agriculture, such as supplemental prebiotics, are required to maintain healthy and high performing animals without directly contributing to antimicrobial resistance bioburden. While the gut microbiota of broiler hens has been well established and successfully correlated to performance, to our knowledge, a study has yet to be completed on the effect of prebiotic supplementation on correlating the mature laying hen productivity and microbiota. This study focused on establishing the impact of a yeast derived prebiotic, mannan rich fraction (MRF), on the cecal microbiota of late laying hens. This study benefitted from large sample sizes so intra- and intergroup variation effects could be statistically accounted for. RESULTS: Taxonomic richness was significantly greater at all taxonomic ranks and taxonomic evenness was significantly lower for all taxonomic ranks in MRF-supplemented birds (P < 0.005). Use of principal coordinate analyses and principal component analyses found significant variation between treatment groups. When assessed for compositional uniformity (an indicator of flock health), microbiota in MRF-supplemented birds was more uniform than control birds at the species level. From a food safety and animal welfare perspective, Campylobacter jejuni was significantly lower in abundance in MRF-supplemented birds. In this study, species associated with high weight gain (an anticorrelator of performance in laying hens) were significantly lower in abundance in laying hens while health-correlated butyrate and propionate producing species were significantly greater in abundance in MRF-supplemented birds. CONCLUSIONS: The use of prebiotics may be a key factor in controlling the microbiota balance limiting agri-food chain pathogen persistence and in promoting uniformity. In previous studies, increased α- and ß-diversity indices were determinants of pathogen mitigation and performance. MRF-supplemented birds in this study established greater α- and ß-diversity indices in post-peak laying hens, greater compositional uniformity across samples, a lower pathogenic bioburden and a greater abundance of correlators of performance.

Safety of Single High-Dose Liposomal Amphotericin B for Induction Treatment of Cryptococcal Meningitis and Histoplasmosis in People With HIV: A Systematic Review and Meta-analysis.

Background: Evidence for efficacy of single, high-dose liposomal amphotericin B (LAmB) in HIV-associated cryptococcal meningitis and histoplasmosis is growing. No systematic review has examined the safety of this regimen across multiple studies. Methods: We systematically searched Medline, Scopus, and the Cochrane Library from inception to April 2023 for studies reporting grade 3 and 4 adverse events (AEs) with single high-dose LAmB vs traditional amphotericin regimens for HIV-associated fungal infections. Results: Three trials (n = 946) were included. Compared with traditional regimens, single high-dose LAmB was associated with equivalent risk of grade 3 and 4 AEs (risk ratio [RR], 0.75; 95% CI, 0.53-1.06) and lower overall risk of grade 4 AEs (RR, 0.68; 95% CI, 0.55-0.86), grade 4 renal (RR, 0.43; 95% CI, 0.20-0.94) and grade 4 hematological AEs (RR, 0.46; 95% CI, 0.32-0.65). Conclusions: Single, high-dose LAmB is associated with a lower risk of life-threatening AEs compared with other World Health Organization-endorsed amphotericin B-based regimens in invasive HIV-related fungal infection.

What clinic closure reveals about care for drug-resistant TB: a qualitative study.

BACKGROUND: There have been calls for "person-centered" approaches to drug-resistant tuberculosis (DR-TB) care. In 2020, Charles James Hospital in South Africa, which incorporated person-centered care, was closed. Patients were referred mid-course to a centralized, tertiary hospital, providing an opportunity to examine person-centered DR-TB and HIV care from the perspective of patients who lost access to it. METHODS: The impact of transfer was explored through qualitative interviews performed using standard methods. Analysis involved grounded theory; interviews were assessed for theme and content. RESULTS: After switching to the centralized site, patients reported being unsatisfied with losing access to a single clinic and pharmacy where DR-TB, HIV and chronic disease care were integrated. Patients also reported a loss of care continuity; at the decentralized site there was a single, familiar clinician whereas the centralized site had multiple, changing clinicians and less satisfactory communication. Additionally, patients reported more disease-related stigma and less respectful treatment, noting the loss of a "special place" for DR-TB treatment. CONCLUSION: By focusing on a DR-TB clinic closure, we uncovered aspects of person-centered care that were critical to people living with DR-TB and HIV. These perspectives can inform how care for DR-TB is operationalized to optimize treatment retention and effectiveness.

ATR-FTIR spectroscopy as a method for the determination of mineral chelation in high concentration manganese and zinc proteinates used as animal feed additives.

Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy is an essential tool for the determination of mineral chelation in proteinates used as animal feed additives. With advances in feed formulations and stringent regulatory requirements to confirm the degree of chelation in animal feed supplements, the aim of this work was to further refine the method and demonstrate its applicability to newly formulated, higher concentration (20% (w/w)) manganese and zinc proteinates of industrial relevance. Calibration and prediction models were created using multivariate analysis with R2 > 0.99 for both mineral proteinates tested. Root mean square error of calibration (RMSEC) values were found to be 1.7% and 2.1% respectively for the manganese and zinc products. The refined method produced reliable data for various applications with excellent specificity, selectivity, and reproducibility. Consequently, the proposed refinements are expected to be of interest from a regulatory perspective and for those in the feed industry for conclusively determining the percentage chelation of minerals in high concentration proteinate products.

Decentralized, Integrated Treatment of RR/MDR-TB and HIV Using a Bedaquiline-Based, Short-Course Regimen Is Effective and Associated With Improved HIV Disease Control.

BACKGROUND: In decentralized sites, with fewer resources and a high prevalence of advanced HIV, the effectiveness of the new short-course, bedaquiline-based regimen for rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) is not well-described. SETTING: Adults with pulmonary RR/MDR-TB initiating the short-course regimen in KwaZulu-Natal, South Africa were prospectively enrolled at a decentralized program that integrated person-centered TB care. METHODS: In addition to standard of care monitoring, study visits occurred at enrollment and months 1, 2, 4, 6, and 9. Favorable RR/MDR-TB outcome was defined as cure or treatment completion without loss to follow-up, death, or failure by treatment. In patients with HIV, we assessed antiretroviral therapy (ART) uptake, virologic and immunologic outcomes. RESULTS: Among 57 patients, HIV was present in 73.7% (95% CI: 60.3-84.5), with a median CD4 count of 170 cells/mm 3 (intraquartile range 49-314). A favorable RR/MDR-TB outcome was achieved in 78.9% (CI: 67.1-87.9). Three deaths occurred, all in the setting of baseline advanced HIV and elevated viral load. Overall, 21.1% (95% CI: 12.1-32.9) experienced a severe or life-threatening adverse event, the most common of which was anemia. Among patients with HIV, enrollment resulted in increased ART uptake by 24% (95% CI: 12.1%-39.4%), a significant improvement from baseline ( P = 0.004); virologic suppression during concomitant treatment was observed in 71.4% (n = 30, 95% CI: 55.4-84.3). CONCLUSION: Decentralized, person-centered care for RR/MDR-TB in patients with HIV using the short-course, bedaquiline-based regimen is effective and safe. In patients with HIV, enrollment led to improved ART use and reassuring virologic outcomes.

Effect of Mannan-rich fraction supplementation on commercial broiler intestinum tenue and cecum microbiota.

BACKGROUND: The broiler gastrointestinal microbiome is a potent flock performance modulator yet may also serve as a reservoir for pathogen entry into the food chain. The goal of this project was to characterise the effect of mannan rich fraction (MRF) supplementation on microbiome diversity and composition of the intestinum tenue and cecum of commercial broilers. This study also aimed to address some of the intrinsic biases that exist in microbiome studies which arise due to the extensive disparity in 16S rRNA gene copy numbers between bacterial species and due to large intersample variation. RESULTS: We observed a divergent yet rich microbiome structure between different anatomical sites and observed the explicit effect MRF supplementation had on community structure, diversity, and pathogen modulation. Birds supplemented with MRF displayed significantly higher species richness in the cecum and significantly different bacterial community composition in each gastrointestinal (GI) tract section. Supplemented birds had lower levels of the zoonotic pathogens Escherichia coli and Clostridioides difficile across all three intestinum tenue sites highlighting the potential of MRF supplementation in maintaining food chain integrity. Higher levels of probiotic genera (eg. Lactobacillus and Blautia) were also noted in the MRF supplemented birds. Following MRF supplementation, the cecum displayed higher relative abundances of both short chain fatty acid (SFCA) synthesising bacteria and SCFA concentrations. CONCLUSIONS: Mannan rich fraction addition has been observed to reduce the bioburden of pathogens in broilers and to promote greater intestinal tract microbial biodiversity. This study is the first, to our knowledge, to investigate the effect of mannan-rich fraction supplementation on the microbiome associated with different GI tract anatomical geographies. In addition to this novelty, this study also exploited machine learning and biostatistical techniques to correct the intrinsic biases associated with microbiome community studies to enable a more robust understanding of community structure.

Quantitative Proteomic Analysis Reveals Yeast Cell Wall Products Influence the Serum Proteome Composition of Broiler Chickens.

With an ever-growing market and continual financial pressures associated with the prohibition of antibiotic growth promoters, the poultry industry has had to rapidly develop non-antibiotic alternatives to increase production yields. A possible alternative is yeast and its derivatives, such as the yeast cell wall (YCW), which have been proposed to confer selected beneficial effects on the host animal. Here, the effect of YCW supplementation on the broiler chicken was investigated using a quantitative proteomic strategy, whereby serum was obtained from three groups of broilers fed with distinct YCW-based Gut Health Products (GHP) or a control basal diet. Development of a novel reagent enabled application of ProteoMiner™ technology for sample preparation and subsequent comparative quantitative proteomic analysis revealed proteins which showed a significant change in abundance (n = 167 individual proteins; p < 0.05); as well as proteins which were uniquely identified (n = 52) in, or absent (n = 37) from, GHP-fed treatment groups versus controls. An average of 7.1% of proteins showed changes in abundance with GHP supplementation. Several effects of these GHPs including immunostimulation (via elevated complement protein detection), potential alterations in the oxidative status of the animal (e.g., glutathione peroxidase and catalase), stimulation of metabolic processes (e.g., differential abundance of glyceraldehyde-3-phosphate dehydrogenase), as well as evidence of a possible hepatoprotective effect (attenuated levels of serum α-glutathione s-transferase) by one GHP feed supplement, were observed. It is proposed that specific protein detection may be indicative of GHP efficacy to stimulate broiler immune status, i.e., may be biomarkers of GHP efficacy. In summary, this work has developed a novel technology for the preparation of high dynamic range proteomic samples for LC-MS/MS analysis, is part of the growing area of livestock proteomics and, importantly, provides evidential support for beneficial effects that GHP supplementation has on the broiler chicken.

Shooting hoops: globetrotting plasmids spreading more than just antimicrobial resistance genes across One Health.

Our study provides novel insights into the global nature of antimicrobial resistance (AMR) plasmids across the food chain. We provide compelling evidence of the globetrotting nature of AMR plasmids and the need for surveillance to sequence plasmids with a template of analyses for others to expand these data. The AMR plasmids analysed were detected in 63 countries and in samples from humans, animals and the environment. They contained a combination of known and novel AMR genes, metal resistance genes, virulence factors, phage and replicon types.

Relative Bioavailability of Trace Minerals in Production Animal Nutrition: A Review.

The importance of dietary supplementation of animal feeds with trace minerals is irrefutable, with various forms of both organic and inorganic products commercially available. With advances in research techniques, and data obtained from both in-vitro and in-vivo studies in recent years, differences between inorganic and organic trace minerals have become more apparent. Furthermore, differences between specific organic mineral types can now be identified. Adhering to PRISMA guidelines for systematic reviews, we carried out an extensive literature search on previously published studies detailing performance responses to trace minerals, in addition to their corresponding relative bioavailability values. This review covers four of the main trace minerals included in feed: copper, iron, manganese and zinc, and encompasses the different types of organic and inorganic products commercially available. Their impact from environmental, economic, and nutritional perspectives are discussed, along with the biological availability of various mineral forms in production animals. Species-specific sections cover ruminants, poultry, and swine. Extensive relative bioavailability tables cover values for all trace mineral products commercially available, including those not previously reviewed in earlier studies, thereby providing a comprehensive industry reference guide. Additionally, we examine reasons for variance in reported relative bioavailability values, with an emphasis on accounting for data misinterpretation.

Detection of HIV Virologic Failure and Switch to Second-Line Therapy: A Systematic Review and Meta-analysis of Data From Sub-Saharan Africa.

Background: The late recognition of virologic failure (VF) places persons with HIV in Sub-Saharan Africa at risk for HIV transmission, disease progression, and death. We conducted a systematic review and meta-analysis to determine if the recognition and response to VF in the region has improved. Methods: We searched for studies reporting CD4 count at confirmed VF or at switch to second-line antiretroviral therapy (ART). Using a random-effects metaregression model, we analyzed temporal trends in CD4 count at VF-or at second-line ART switch-over time. We also explored temporal trends in delay between VF and switch to second-line ART. Results: We identified 26 studies enrolling patients with VF and 10 enrolling patients at second-line ART switch. For studies that enrolled patients at VF, pooled mean CD4 cell count at failure was 187 cells/mm3 (95% CI, 111 to 263). There was no significant change in CD4 count at confirmed failure over time (+4 cells/year; 95% CI, -7 to 15). Among studies that enrolled patients at second-line switch, the pooled mean CD4 count was 108 cells/mm3 (95% CI, 63 to 154). CD4 count at switch increased slightly over time (+10 CD4 cells/year; 95% CI, 2 to 19). During the same period, the mean delay between confirmation of VF and switch was 530 days, with no significant decline over time (-14 days/year; 95% CI, -58 to 52). Conclusions: VF in Africa remains an event recognized late in HIV infection, a problem compounded by ongoing delays between VF and second-line switch.

A surprising complication of breast augmentation surgery.

Infections caused by opportunistic fungal organisms such as Scedosporium spp. have been increasingly recognized over the last few decades. Most affected patients are immunocompromised or critically ill, but Scedosporium spp. infections have also been described in immunocompetent patients, such as localized disease from direct inoculation or in near-drowning events. We describe a case of a patient with no known underlying immune impairment who experienced significant infection with Scedosporium apiospermum at both sites of breast augmentation. Once identified, the choice of therapeutics can be challenging given the intrinsic resistance and variable activity of different antifungal agents; however, other factors also impact the outcome of this infection such as the host immune status. Thus, both the recognition and treatment of Scedosporium infections can be challenging.

Influence of the Chelation Process on the Stability of Organic Trace Mineral Supplements Used in Animal Nutrition.

The effect of the chelation process on the pH-dependent stability of organic trace minerals (OTMs) used as mineral supplements in animal nutrition was assessed using analytical techniques such as potentiometry, Fourier Transform Infrared Spectroscopy (FTIRS) and amino acid profiling. The aim was to understand the influence and relative importance of the manufacturing conditions on mineral chelation and the subsequent pH stability of OTMs. A selection of OTMs were assessed over a wide pH range to account for the typical environmental changes encountered in the gastrointestinal (GI) tract. In the case of proteinate type products, the potentiometric assessment of free mineral concentration indicated that the hydrolysis procedure used to generate the chelating peptides was the major influencer of the pH stability of the products. Many products are available under the umbrella term "OTMs", including amino acid complexes, amino acid chelates, polysaccharide complexes and proteinates. Significant differences in the pH-dependent stability of a range of commercially available OTMs were observed.

Time to embrace access programmes for medicines: lessons from the South African flucytosine access programme.

BACKGROUND: Cryptococcal meningitis (CM) is estimated to cause 181 000 deaths annually, with the majority occurring in Sub-Saharan Africa. Flucytosine is recommended by the World Health Organization as part of the treatment for CM. Widespread use of flucytosine could reduce mortality in hospital by as much as 40% compared to the standard of care, yet due to market failure, quality-assured flucytosine remains unregistered and largely inaccessible throughout Africa. METHODS: The recently established South African flucytosine clinical access programme is an attempt to address the market failure that led to a lack of public sector access to flucytosine for CM, by making the medicine freely available to tertiary hospitals in South Africa. RESULTS: Between November 2018 and September 2019, 327 CM patients received flucytosine through this programme, with efforts to support sustainable national scale-up presently ongoing. We describe why this programme was needed, its catalytic potential, what is still required to ensure widespread access to flucytosine, and observations from this experience that may have wider relevance. CONCLUSIONS: The South African flucytosine access programme illustrates how access programmes may be one part of the solution to addressing the vicious cycle of perceived low demand, limiting manufacturer interest in specific product markets.

Increased Mortality With Delayed and Missed Switch to Second-Line Antiretroviral Therapy in South Africa.

BACKGROUND: After failure of first-line antiretroviral therapy (ART) in the public sector, delayed or missed second-line ART switch is linked with poor outcomes in patients with advanced HIV. SETTING: We investigated delayed or missed second-line ART switch after confirmed virologic failure in the largest private sector HIV cohort in Africa. METHODS: We included HIV-infected adults with confirmed virologic failure after 6 months of nonnucleoside reverse-transcriptase inhibitor-based ART. We estimated the effect of timing of switch on the hazard of death using inverse probability of treatment weighting of marginal structural models. We adjusted for time-dependent confounding of CD4 count, viral load, and visit frequency. RESULTS: Five thousand seven hundred forty-eight patients (53% female) with confirmed virologic failure met inclusion criteria; the median age was 40 [interquartile range (IQR): 35-47], advanced HIV was present in 48% and the prior duration of nonnucleoside reverse-transcriptase inhibitor-based ART was 1083 days (IQR: 665-1770). Median time to confirmation of virologic failure and to second-line switch was 196 (IQR: 136-316) and 220 days (IQR: 65-542), respectively. Switching to second-line ART after confirmed failure compared with remaining on first-line ART reduced risk of subsequent death [adjusted hazard ratio: 0.47 (95% confidence interval: 0.36 to 0.63)]. Compared with patients who experienced delayed switch, those switched immediately had a lower risk of death, regardless of CD4 cell count. CONCLUSIONS: Delayed or missed switch to second-line ART after confirmed first-line ART failure is common in the South African private sector and associated with mortality. Novel interventions to minimize switch delay should be tested and not limited to those with advanced disease at treatment failure.

Simplifying switch to second-line antiretroviral therapy in sub Saharan Africa: predicted effect of using a single viral load to define efavirenz-based first-line failure.

BACKGROUND: Many individuals failing first-line antiretroviral therapy (ART) in sub-Saharan Africa never initiate second-line ART or do so after significant delay. For people on ART with a viral load more than 1000 copies/ml, the WHO recommends a second viral load measurement 3 months after the first viral load and enhanced adherence support. Switch to a second-line regimen is contingent upon a persistently elevated viral load more than 1000 copies/ml. Delayed second-line switch places patients at increased risk for opportunistic infections and mortality. METHODS: To assess the potential benefits of a simplified second-line ART switch strategy, we use an individual-based model of HIV transmission, progression and the effect of ART which incorporates consideration of adherence and drug resistance, to compare predicted outcomes of two policies, defining first-line regimen failure for patients on efavirenz-based ART as either two consecutive viral load values more than 1000 copies/ml, with the second after an enhanced adherence intervention (implemented as per current WHO guidelines) or a single viral load value more than 1000 copies/ml. We simulated a range of setting-scenarios reflecting the breadth of the sub-Saharan African HIV epidemic, taking into account potential delays in defining failure and switch to second-line ART. FINDINGS: The use of a single viral load more than 1000 copies/ml to define ART failure would lead to a higher proportion of persons with nonnucleoside reverse-transcriptase inhibitor resistance switched to second-line ART [65 vs. 48%; difference 17% (90% range 14-20%)], resulting in a median 18% reduction in the rate of AIDS-related death over setting scenarios (90% range 6-30%; from a median of 3.1 to 2.5 per 100 person-years) over 3 years. The simplified strategy also is predicted to reduce the rate of AIDS conditions by a median of 31% (90% range 8-49%) among people on first-line ART with a viral load more than 1000 copies/ml in the past 6 months. For a country of 10 million adults (and a median of 880 000 people with HIV), we estimate that this approach would lead to a median of 1322 (90% range 67-3513) AIDS deaths averted per year over 3 years. For South Africa this would represent around 10 215 deaths averted annually. INTERPRETATION: As a step towards reducing unnecessary mortality associated with delayed second-line ART switch, defining failure of first-line efavirenz-based regimens as a single viral load more than 1000 copies/ml should be considered.

Antimicrobial treatment practices among Ugandan children with suspicion of central nervous system infection.

Acute central nervous system (CNS) infections in children in sub-Saharan Africa are often fatal. Potential contributors include late presentation, limited diagnostic capacity and inadequate treatment. A more nuanced understanding of treatment practices with a goal of optimizing such practices is critical to prevent avoidable case fatality. We describe empiric antimicrobial treatment, antibiotic resistance and treatment adequacy in a prospective cohort of 459 children aged two months to 12 years hospitalised for suspected acute CNS infections in Mbarara, Uganda, from 2009 to 2012. Among these 459 children, 155 had a laboratory-confirmed diagnosis of malaria (case-fatality rate [CFR] 14%), 58 had bacterial infections (CFR 24%) and 6 children had mixed malaria and bacterial infections (CFR 17%). Overall case fatality was 18.1% (n = 83). Of 219 children with laboratory-confirmed malaria and/or bacterial infections, 182 (83.1%) received an adequate antimalarial and/or antibiotic on the day of admission and 211 (96.3%) within 48 hours of admission. The proportion of those receiving adequate treatment was similar among survivors and non-survivors. All bacterial isolates were sensitive to ceftriaxone except one Escherichia coli isolate with extended-spectrum beta-lactamase (ESBL). The observed high mortality was not a result of inadequate initial antimicrobial treatment at the hospital. The epidemiology of CNS infection in this setting justifies empirical use of a third-generation cephalosporin, however antibiotic resistance should be monitored closely.

High-Dose Fluconazole Consolidation Therapy for Cryptococcal Meningitis in Sub-Saharan Africa: Much to Gain, Little to Lose.

Cryptococcal meningitis accounts for an estimated 25% of AIDS-associated mortality in sub-Saharan Africa. Accumulating animal and human evidence suggest that a higher, more fungicidal, dose of fluconazole during consolidation therapy could be more effective in controlling residual infection and may help significantly reduce posthospitalization mortality. Although the potential for toxicity is low, the use of fluconazole at a dose of 800 mg/day during consolidation therapy requires examination in a randomized clinical trial. In the interim, within countries where postdischarge mortality from cryptococcal meningitis is high and amphotericin-flucytosine combination therapy remains unavailable, the use of high-dose fluconazole consolidation therapy deserves serious consideration as a strategy with limited risk and the potential for considerable public health benefit.