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BACKGROUND: The Cryptococcus neoformans polysaccharide capsule is a well-characterized virulence factor with immunomodulatory properties. The organism and/or shed capsule is postulated to raise intracranial pressure (ICP) in cryptococcal meningitis (CM) by mechanical obstruction of cerebrospinal fluid (CSF) outflow. Little is known regarding capsule phenotype in human cryptococcosis. We investigated the relationship of ex vivo CSF capsular phenotype with ICP and CSF immune response, as well as in vitro phenotype. METHODS: In total, 134 human immunodeficiency virus (HIV)-infected Ugandan adults with CM had serial lumbar punctures with measurement of CSF opening pressures, quantitative cultures, ex vivo capsule size and shedding, viscosity, and CSF cytokines; 108 had complete data. Induced capsular size and shedding were measured in vitro for 48 C. neoformans isolates. RESULTS: Cryptococcal strains producing larger ex vivo capsules in the baseline (pretreatment) CSF correlated with higher ICP (P = .02), slower rate of fungal clearance (P = .02), and paucity of CSF inflammation, including decreased CSF white blood cell (WBC) count (P < .001), interleukin (IL)-4 (P = .02), IL-6 (P = .01), IL-7 (P = .04), IL-8 (P = .03), and interferon γ (P = .03). CSF capsule shedding did not correlate with ICP. On multivariable analysis, capsule size remained independently associated with ICP. Ex vivo capsular size and shedding did not correlate with that of the same isolates grown in vitro. CONCLUSIONS: Cryptococcal capsule size ex vivo is an important contributor to virulence in human cryptococcal meningitis.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Cryptococcus neoformans/citologia , Cryptococcus neoformans/imunologia , Cápsulas Fúngicas/imunologia , Meningite Criptocócica/microbiologia , Infecções Oportunistas Relacionadas com a AIDS/líquido cefalorraquidiano , Infecções Oportunistas Relacionadas com a AIDS/imunologia , Adulto , Análise de Variância , Antifúngicos/farmacologia , Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/microbiologia , Citocinas , Feminino , Cápsulas Fúngicas/química , Cápsulas Fúngicas/microbiologia , Humanos , Pressão Intracraniana/imunologia , Masculino , Meningite Criptocócica/líquido cefalorraquidiano , Meningite Criptocócica/imunologia , Fenótipo , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Uganda , ViscosidadeRESUMO
Background: Antibiotic resistance (ABR) is a global challenge, and its control depends on robust evidence primarily derived from surveillance systems. Methods: We utilised a national surveillance data set to demonstrate how such evidence can be systematically generated. In doing so, we characterised the ABR profiles of priority clinical pathogens, identified associated factors, and drew inferences on antibiotic usage in Uganda. Results: Of the 12 262 samples collected between 2019-21, we analysed 9033 with complete metadata. ABR was steadily increasing at a rate of 0.5% per year, with a surge in 2021 and the highest and lowest levels of penicillin and carbapenems detected in the northern (odds ratio (OR) = 2.26; P < 0.001) and the northeast (OR = 0.28; P < 0.001) regions of Uganda respectively. ABR was commonly observed with Escherichia coli (OR = 1.18; P < 0.001) and Klebsiella pneumoniae (OR = 1.25; P < 0.001) among older and male patients (61-70 years old) (OR = 1.88; P = 0.005). Multi-drug resistance (MDR) and ABR were disproportionately higher among bloodstream infections than respiratory tract infections and urinary tract infections, often caused by Acinetobacter baumannii. Co-occurrence of ABR suggests that cephalosporins such as ceftriaxone are in high use all over Uganda. Conclusions: ABR is indeed a silent pandemic, and our results suggest it is increasing at 0.5% per year, with a notable surge in 2021 likely due to coronavirus disease 2019 (COVID-19). Of concern, ABR and MDR are mainly associated with bloodstream and surgical wound infections, with a gender and age dimension. However, it is encouraging that carbapenem resistance remains relatively low. Such evidence is critical for contextualising the implementation and evaluation of national action plans.
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Antibacterianos , Humanos , Uganda/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Pré-Escolar , Idoso , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Criança , Lactente , Adolescente , Adulto Jovem , Recém-Nascido , COVID-19/epidemiologia , Farmacorresistência Bacteriana , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Farmacorresistência Bacteriana MúltiplaRESUMO
Background: In low-resource settings, antimicrobial resistance (AMR) is detected by traditional culture-based methods and ensuring the quality of such services is a challenge. The AMR Scorecard provides laboratories with a technical assessment tool for strengthening the quality of bacterial culture, identification, and antimicrobial testing procedures. Objective: To evaluate the performance of the AMR Scorecard in 11 pilot laboratory evaluations in three countries also assessed with the Stepwise Laboratory Quality Improvement Process Towards Accreditation (SLIPTA) checklist. Methods: Pilot laboratory evaluations were conducted in Cameroon, Ethiopia and Kenya between February 2019 and March 2019. Assessors with previous SLIPTA and microbiology experience were trained. Assessors performed the laboratory assessments using the SLIPTA and AMR Scorecard tools. Results: Weaknesses in technical procedures and the quality management systems were identified in all areas and all laboratories. Safety had the highest mean performance score (SLIPTA: 68%; AMR Scorecard: 73%) while management review had the lowest (SLIPTA: 32%; AMR Scorecard: 8%) across all laboratories. The AMR Scorecard scores were generally consistent with SLIPTA scores. The AMR Scorecard identified technical weaknesses in AMR testing, and SLIPTA identified weaknesses in the quality management systems in the laboratories. Conclusion: Since the AMR Scorecard identified important gaps in AMR testing not detected by SLIPTA, it is recommended that microbiology laboratories use SLIPTA and the AMR Scorecard in parallel when preparing for accreditation. Expanding the use of the AMR Scorecard is a priority to address the need for quality clinical microbiology laboratory services in support of optimal patient care and AMR surveillance.
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Background: Antimicrobial resistance (AMR) is becoming a critical public health issue globally. The World Health Organization launched the Global Antimicrobial Resistance and Use Surveillance System (GLASS) to support the strengthening of the AMR evidence base. Objective: The article describes the evolution of national AMR surveillance systems and AMR data reporting of countries in the African continent between 2017 and 2019, and the constraints, perceived impact and value of the participation in GLASS. Methods: Data on implementation of national surveillance systems and AMR rates were submitted to GLASS between 2017 and 2019 and summarised though descriptive statistics. The information on constraints and perceived impact and value in GLASS participation was collected though a set of questionnaires. Results: Between 2017 and 2019, Egypt, Ethiopia, Madagascar, Malawi, Mali, Mozambique, Nigeria, South Africa, Sudan, Tunisia, Uganda and Zambia submitted data to GLASS. The main constraints listed are linked to scarce laboratory capacity and capability, limited staffing, budget issues, and data management. Moreover, while the data are not yet nationally representative, high resistance rates were reported to commonly-used antibiotics, as the emerging resistance to last treatment options. Conclusion: Despite the limitations, more and more countries in the African continent are working towards reaching a status that will enable them to report AMR data in a complete and systematic manner. Future improvements involve the expansion of routine surveillance capacity for several countries and the implementation of surveys that allow to effectively define the magnitude of AMR in the continent.
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OBJECTIVES: To assess baseline prevalence of cryptococcal antigen (CrAg) positivity; and its contribution to reductions in all-cause mortality, deaths from cryptococcus and unknown causes, and new cryptococcal disease in the REALITY trial. DESIGN: Retrospective CrAg testing of baseline and week-4 plasma samples in all 1805 African adults/children with CD4+ cell count less than 100 cells/µl starting antiretroviral therapy who were randomized to receive 12-week enhanced-prophylaxis (fluconazole 100âmg/day, azithromycin, isoniazid, cotrimoxazole) vs. standard-prophylaxis (cotrimoxazole). METHODS: Proportional hazards models were used to estimate the relative impact of enhanced-prophylaxis vs. standard-cotrimoxazole on all, cryptococcal and unknown deaths, and new cryptococcal disease, through 24 weeks, by baseline CrAg positivity. RESULTS: Excluding 24 (1.4%) participants with active/prior cryptococcal disease at enrolment (all treated for cryptococcal disease), 133/1781 (7.5%) participants were CrAg-positive. By 24 weeks, 105 standard-cotrimoxazole vs. 78 enhanced-prophylaxis participants died. Of nine standard-cotrimoxazole and three enhanced-prophylaxis cryptococcal deaths, seven and two, respectively, were CrAg-positive at baseline. Among deaths of unknown cause, only 1/46 standard-cotrimoxazole and 1/28 enhanced-prophylaxis were CrAg-positive at baseline. There was no evidence that relative reductions in new cryptococcal disease associated with enhanced-prophylaxis varied between baseline CrAg-positives [hazard-ratioâ=â0.36 (95% confidence interval 0.13-0.98), incidence 19.5 vs. 56.5/100 person-years] and CrAg-negatives [hazard-ratioâ=â0.33 (0.03-3.14), incidence 0.3 vs. 0.9/100 person-years; Pheterogeneityâ=â0.95]; nor for all deaths, cryptococcal deaths or unknown deaths (Pheterogeneityâ>â0.3). CONCLUSION: Relative reductions in cryptococcal disease/death did not depend on CrAg status. Deaths of unknown cause were unlikely to be cryptococcus-related; plausibly azithromycin contributed to their reduction. Findings support including 100âmg fluconazole in an enhanced-prophylaxis package at antiretroviral therapy initiation where CrAg screening is unavailable/impractical.