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Background Individuals with cryptococcal antigenemia are at high risk of developing cryptococcal meningitis if untreated. The progression and timing from asymptomatic infection to cryptococcal meningitis is unclear. We describe a subpopulation of individuals with neurologic symptomatic cryptococcal antigenemia but negative cerebral spinal fluid (CSF) studies. Methods We evaluated 1201 human immunodeficiency virus–seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Baseline characteristics and clinical outcomes of participants with neurologic–symptomatic cryptococcal antigenemia and negative CSF cryptococcal antigen (CrAg) were compared to participants with confirmed CSF CrAg+ cryptococcal meningitis. Additional CSF testing included microscopy, fungal culture, bacterial culture, tuberculosis culture, multiplex FilmArray polymerase chain reaction (PCR; Biofire), and Xpert MTB/Rif. Results We found 56% (671/1201) of participants had confirmed CSF CrAg+ cryptococcal meningitis and 4% (54/1201) had neurologic symptomatic cryptococcal antigenemia with negative CSF CrAg. Of those with negative CSF CrAg, 9% (5/54) had Cryptococcus isolated on CSF culture (n = 3) or PCR (n = 2) and 11% (6/54) had confirmed tuberculous meningitis. CSF CrAg-negative patients had lower proportions with CSF pleocytosis (16% vs 26% with ≥5 white cells/μL) and CSF opening pressure >200 mmH2O (16% vs 71%) compared with CSF CrAg-positive patients. No cases of bacterial or viral meningitis were detected by CSF PCR or culture. In-hospital mortality was similar between symptomatic cryptococcal antigenemia (32%) and cryptococcal meningitis (31%; P =.91). Conclusions Cryptococcal antigenemia with meningitis symptoms was the third most common meningitis etiology. We postulate this is early cryptococcal meningoencephalitis. Fluconazole monotherapy was suboptimal despite Cryptococcus -negative CSF. Further studies are warranted to understand the clinical course and optimal management of this distinct entity. Clinical Trials Registration NCT01802385. [ABSTRACT FROM AUTHOR]

Background: Cryptococcal meningitis can occur in persons with less-apparent immunosuppression. We evaluated clinical characteristics and outcomes of persons with HIV-related Cryptococcus presenting with higher CD4 counts.Methods: We enrolled 736 participants from 2 prospective cohorts in Uganda and South Africa from November 2010 to May 2017. We compared participants with CD4 <50, 50-99, or ≥100 cells/μL by clinical characteristics, cerebrospinal fluid (CSF) parameters, and 18-week survival.Results: Among first episode of cryptococcosis, 9% presented with CD4 ≥100 cells/μL. Participants with CD4 ≥100 cells/μL presented more often with altered mental status (52% vs 39%; P = .03) despite a 10-fold lower initial median CSF fungal burden of 7850 (interquartile range [IQR] 860-65500) versus 79000 (IQR 7400-380000) colony forming units/mL (P < .001). Participants with CD4 ≥100 cells/μL had higher median CSF levels of interferon-gamma, interleukin (IL)-6, IL-8, and IL-13, and lower monocyte chemokine, CCL2 (P < .01 for each). Death within 18 weeks occurred in 47% with CD4 <50, 35% with CD4 50-99, and 40% with CD4 ≥100 cells/μL (P = .04).Conclusion: HIV-infected individuals developing cryptococcal meningitis with CD4 ≥100 cells/μL presented more frequently with altered mental status despite having 10-fold lower fungal burden and with greater Th2 (IL-13) immune response. Higher CD4 count was protective despite an increased propensity for immune-mediated damage, consistent with damage-response framework.Clinical Trial Registration: NCT01075152 and NCT01802385. [ABSTRACT FROM AUTHOR]

The effect of tenofovir and amphotericin coadministration on kidney function is poorly characterized. We measured creatinine during induction therapy and at 4 weeks after diagnosis in Ugandans undergoing cryptococcal meningitis therapy and classified as not receiving antiretroviral therapy (ART), receiving nontenofovir ART or receiving tenofovir-based ART. Longitudinal creatinine changes and grade 2-4 creatinine adverse events were evaluated across groups. Creatinine concentrations were similar across ART groups. At 4 weeks after diagnosis, creatinine was 0.25 mg/dL higher than at diagnosis, but similar across groups. Adverse event incidence was also similar across ART groups. Tenofovir and amphotericin coadministration did not increase the risk of kidney dysfunction. [ABSTRACT FROM AUTHOR]

Background Increased antiretroviral therapy (ART) availability has been associated with more patients developing cryptococcosis after ART initiation. Despite this changing epidemiology, data regarding cryptococcal meningitis in those already receiving ART are limited. We compared clinical presentations and outcomes among ART-naïve and ART-experienced Ugandans. Methods We prospectively enrolled 605 HIV-infected persons with first-episode cryptococcal meningitis from August 2013 to May 2017 who received amphotericin-based combination therapy. We classified participants by ART status and ART duration and compared groups for 2-week survival. Results Overall, 46% (281/605) of participants were receiving ART at presentation. Compared with those not receiving ART, those receiving ART had higher CD4 counts (P <.001) and lower cerebrospinal fluid fungal burdens (P <.001). Of those receiving ART, 56% (156/281) initiated ART within 6 months, and 18% (51/281) initiated ART within 14 days. Two-week mortality did not differ by ART status (27% in both ART-naïve and ART-experienced%; P >.99). However, 47% (24/51) of those receiving ART for ≤14 days died within 2 weeks, compared with 19% (20/105) of those receiving ART for 15–182 days and 26% (32/125) of those receiving ART for >6 months (P <.001). Among persons receiving ART for >6 months, 87% had HIV viral loads >1000 copies/mL. Conclusions Cryptococcosis after ART initiation is common in Africa. Patients initiating ART who unmask cryptococcal meningitis are at a high risk of death. Immune recovery in the setting of central nervous system infection is detrimental, and management of this population requires further study. Implementing pre-ART cryptococcal antigen screening is urgently needed to prevent cryptococcal meningitis after ART initiation. [ABSTRACT FROM AUTHOR]

Background: Appropriate antimicrobial use is essential for antimicrobial stewardship (AMS). Ugandan hospitals are making efforts to improve antibiotic use, but improvements have not been sufficiently documented and evaluated., Methods: Six Ugandan hospitals implemented AMS interventions between June 2019 and July 2022. We used the WHO AMS toolkit to set-up hospital AMS programmes and implemented interventions using continuous quality improvement (CQI) techniques and targeting conditions commonly associated with antibiotic misuse, that is, urinary tract infections (UTIs), upper respiratory tract infections (URTIs) and surgical antibiotic prophylaxis (SAP). The interventions included training, mentorship and provision of clinical guidelines to support clinical decision-making. Quarterly antibiotic use surveys were conducted., Results: Data were collected for 7037 patients diagnosed with UTIs. There was an increase in the proportion of patients receiving one antibiotic for the treatment of UTI from 48% during the pre-intervention to 73.2%, p<0.01. There was a 19.2% reduction in the number of antimicrobials per patient treated for UTI p<0.01. There was an increase in use of nitrofurantoin, the first-line drug for the management of UTI. There was an increase in the use of Access antibiotics for managing UTIs from 50.4% to 53.8%. The proportion of patients receiving no antimicrobials for URTI increased from 26.3% at pre-intervention compared with 53.4% at intervention phase, p<0.01. There was a 20.7% reduction in the mean number of antimicrobials per patient for URTI from the pre-intervention to the intervention phase, from 0.8 to 0.6, respectively, p<0.001 and reduction in the number of treatment days, p=0.0163. Among patients undergoing surgery, 49.5% (2212) received SAP during the pre-intervention versus 50.5% (2169) during the intervention., Conclusions: Using CQI approaches to focus on specific causes of inappropriate antibiotic use led to desirable overall reductions in antibiotic use for URTI and UTI., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The emergence of multidrug-resistant Neisseria gonorrhoeae (NG) is a major global health threat necessitating response and control measures. NG antimicrobial resistance (AMR) surveillance data from sub-Saharan countries is exceedingly limited. This paper aims to describe the establishment, design and implementation of a standardised and quality-assured gonococcal surveillance programme and to describe the susceptibility patterns of the cultured gonococcal isolates in Kampala, Uganda., Methods: From March 2018 to September 2019, using the WHO Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP) protocol, consecutive males with urethral discharge syndrome were recruited from 10 surveillance sites in Kampala City, Uganda, in collaboration with the Ministry of Health. Males completed a questionnaire and provided a urethral swab specimen. Culture, identification and antimicrobial susceptibility testing (Etest) were performed., Results: Of the 1013 males recruited, 73.1% (740/1013) had a positive Gram stain and 51.1% (n=518) were culture-positive for NG. Using Etest (458 isolates), the resistance to ciprofloxacin was 99.6%. Most isolates were susceptible to azithromycin, cefoxitin and gentamicin, that is, 99.8%, 98.5% and 92.4%, respectively, and all isolates were susceptible to ceftriaxone and cefixime., Conclusions: We established a standardised, quality-assured WHO EGASP. Using Etest, 458 isolates were characterised, with associated epidemiological surveillance data, in 1.5 years, which by far exceed the minimum 100 isolates per year and country requested in the WHO Global GASP, to detect AMR levels with confidence. These isolates with the epidemiological data can be used to develop population level interventions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Infection prevention and control (IPC) in health care facilities is essential to protecting patients, visitors, and health care personnel from the spread of infectious diseases, including Ebola virus disease (Ebola). Patients with suspected Ebola are typically referred to specialized Ebola treatment units (ETUs), which have strict isolation and IPC protocols, for testing and treatment (1,2). However, in settings where contact tracing is inadequate, Ebola patients might first seek care at general health care facilities, which often have insufficient IPC capacity (3-6). Before 2014-2016, most Ebola outbreaks occurred in rural or nonurban communities, and the role of health care facilities as amplification points, while recognized, was limited (7,8). In contrast to these earlier outbreaks, the 2014-2016 West Africa Ebola outbreak occurred in densely populated urban areas where access to health care facilities was better, but contact tracing was generally inadequate (8). Patients with unrecognized Ebola who sought care at health care facilities with inadequate IPC initiated multiple chains of transmission, which amplified the epidemic to an extent not seen in previous Ebola outbreaks (3-5,7). Implementation of robust IPC practices in general health care facilities was critical to ending health care-associated transmission (8). In August 2018, when an Ebola outbreak was recognized in the Democratic Republic of the Congo (DRC), neighboring countries began preparing for possible introduction of Ebola, with a focus on IPC. Baseline IPC assessments conducted in frontline health care facilities in high-risk districts in Uganda found IPC gaps in screening, isolation, and notification. Based on findings, additional funds were provided for IPC, a training curriculum was developed, and other corrective actions were taken. Ebola preparedness efforts should include activities to ensure that frontline health care facilities have the IPC capacity to rapidly identify suspected Ebola cases and refer such patients for treatment to protect patients, staff members, and visitors., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

The effect of tenofovir and amphotericin coadministration on kidney function is poorly characterized. We measured creatinine during induction therapy and at 4 weeks after diagnosis in Ugandans undergoing cryptococcal meningitis therapy and classified as not receiving antiretroviral therapy (ART), receiving nontenofovir ART or receiving tenofovir-based ART. Longitudinal creatinine changes and grade 2-4 creatinine adverse events were evaluated across groups. Creatinine concentrations were similar across ART groups. At 4 weeks after diagnosis, creatinine was 0.25 mg/dL higher than at diagnosis, but similar across groups. Adverse event incidence was also similar across ART groups. Tenofovir and amphotericin coadministration did not increase the risk of kidney dysfunction.