Cryptococcal meningitis accounts for 20 to 25% of acquired immunodeficiency syndrome-related deaths in Africa. Antiretroviral therapy (ART) is essential for survival; however, the question of when ...ART should be initiated after diagnosis of cryptococcal meningitis remains unanswered.
We assessed survival at 26 weeks among 177 human immunodeficiency virus-infected adults in Uganda and South Africa who had cryptococcal meningitis and had not previously received ART. We randomly assigned study participants to undergo either earlier ART initiation (1 to 2 weeks after diagnosis) or deferred ART initiation (5 weeks after diagnosis). Participants received amphotericin B (0.7 to 1.0 mg per kilogram of body weight per day) and fluconazole (800 mg per day) for 14 days, followed by consolidation therapy with fluconazole.
The 26-week mortality with earlier ART initiation was significantly higher than with deferred ART initiation (45% 40 of 88 patients vs. 30% 27 of 89 patients; hazard ratio for death, 1.73; 95% confidence interval CI, 1.06 to 2.82; P=0.03). The excess deaths associated with earlier ART initiation occurred 2 to 5 weeks after diagnosis (P=0.007 for the comparison between groups); mortality was similar in the two groups thereafter. Among patients with few white cells in their cerebrospinal fluid (<5 per cubic millimeter) at randomization, mortality was particularly elevated with earlier ART as compared with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P=0.008). The incidence of recognized cryptococcal immune reconstitution inflammatory syndrome did not differ significantly between the earlier-ART group and the deferred-ART group (20% and 13%, respectively; P=0.32). All other clinical, immunologic, virologic, and microbiologic outcomes, as well as adverse events, were similar between the groups.
Deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebrospinal fluid. (Funded by the National Institute of Allergy and Infectious Diseases and others; COAT ClinicalTrials.gov number, NCT01075152.).
WHO recommends Xpert MTB/RIF as initial diagnostic testing for tuberculous meningitis. However, diagnosis remains difficult, with Xpert sensitivity of about 50–70% and culture sensitivity of about ...60%. We evaluated the diagnostic performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis.
We prospectively obtained diagnostic cerebrospinal fluid (CSF) specimens during screening for a trial on the treatment of HIV-associated cryptococcal meningitis in Mbarara, Uganda. HIV-infected adults with suspected meningitis (eg, headache, nuchal rigidity, altered mental status) were screened consecutively at Mbarara Regional Referral Hospital. We centrifuged CSF, resuspended the pellet in 2 mL of CSF, and tested 0·5 mL with mycobacteria growth indicator tube culture, 1 mL with Xpert, and cryopreserved 0·5 mL, later tested with Xpert Ultra. We assessed diagnostic performance against uniform clinical case definition or a composite reference standard of any positive CSF tuberculous test.
From Feb 27, 2015, to Nov 7, 2016, we prospectively evaluated 129 HIV-infected adults with suspected meningitis for tuberculosis. 23 participants were classified as probable or definite tuberculous meningitis by uniform case definition, excluding Xpert Ultra results. Xpert Ultra sensitivity was 70% (95% CI 47–87; 16 of 23 cases) for probable or definite tuberculous meningitis compared with 43% (23–66; 10/23) for Xpert and 43% (23–66; 10/23) for culture. With composite standard, we detected tuberculous meningitis in 22 (17%) of 129 participants. Xpert Ultra had 95% sensitivity (95% CI 77–99; 21 of 22 cases) for tuberculous meningitis, which was higher than either Xpert (45% 24–68; 10/22; p=0·0010) or culture (45% 24–68; 10/22; p=0·0034). Of 21 participants positive by Xpert Ultra, 13 were positive by culture, Xpert, or both, and eight were only positive by Xpert Ultra. Of those eight, three were categorised as probable tuberculous meningitis, three as possible tuberculous meningitis, and two as not tuberculous meningitis. Testing 6 mL or more of CSF was associated with more frequent detection of tuberculosis than with less than 6 mL (26% vs 7%; p=0·014).
Xpert Ultra detected significantly more tuberculous meningitis than did either Xpert or culture. WHO now recommends the use of Xpert Ultra as the initial diagnostic test for suspected tuberculous meningitis.
National Institute of Neurologic Diseases and Stroke, Fogarty International Center, National Institute of Allergy and Infectious Disease, UK Medical Research Council/DfID/Wellcome Trust Global Health Trials, Doris Duke Charitable Foundation.
Cryptococcal meningitis is common in sub-Saharan Africa. Given the need for data for a rapid, point-of-care cryptococcal antigen (CRAG) lateral flow immunochromatographic assay (LFA), we assessed ...diagnostic performance of cerebrospinal fluid (CSF) culture, CRAG latex agglutination, India ink microscopy, and CRAG LFA for 832 HIV-infected persons with suspected meningitis during 2006-2009 (n = 299) in Uganda and during 2010-2012 (n = 533) in Uganda and South Africa. CRAG LFA had the best performance (sensitivity 99.3%, specificity 99.1%). Culture sensitivity was dependent on CSF volume (82.4% for 10 μL, 94.2% for 100 μL). CRAG latex agglutination test sensitivity (97.0%-97.8%) and specificity (85.9%-100%) varied between manufacturers. India ink microscopy was 86% sensitive. Laser thermal contrast had 92% accuracy (R = 0.91, p<0.001) in quantifying CRAG titers from 1 LFA strip to within <1.5 dilutions of actual CRAG titers. CRAG LFA is a major advance for meningitis diagnostics in resource-limited settings.
Introduction. Cryptococcal meningitis is the most common cause of adult meningitis in sub-Saharan Africa. Raised intracranial pressure (ICP) is common in cryptococcosis. Prior studies suggest ...elevated ICP is associated with mortality, and guidelines recommend frequent lumbar punctures (LPs) to control ICP. However, the magnitude of the impact of LPs on cryptococcal-related mortality is unknown. Methods. In sum, 248 individuals with human immunodeficiency virus (HIV)-associated cryptococcal meningitis, screened for the Cryptococcal Optimal ART Timing (COAT) trial in Uganda and South Africa, were observed. Individuals received an LP to diagnose meningitis, and subsequent therapeutic LPs were recommended for elevated ICP (>250 mmH2O) or new symptoms. We compared survival, through 11 days, between individuals receiving at least 1 therapeutic LP with individuals not receiving therapeutic LPs. The COAT trial randomized subjects at 7–11 days; thus, follow-up stopped at time of death, randomization, or 11 days. Results. Seventy-five (30%) individuals had at least 1 therapeutic LP. Individuals receiving therapeutic LPs had higher cerebrospinal fluid (CSF) opening pressures, higher CSF fungal burdens, and were more likely to have altered mental status at baseline than those with no therapeutic LPs. Thirty-one deaths (18%) occurred among 173 individuals without a therapeutic LP and 5 deaths (7%) among 75 with at least 1 therapeutic LP. The adjusted relative risk of mortality was 0.31 (95% confidence interval: .12–.82). The association was observed regardless of opening pressure at baseline. Conclusions. Therapeutic LPs were associated with a 69% relative improvement in survival, regardless of initial intracranial pressure. The role of therapeutic LPs should be reevaluated.
Urinary tract infections (UTIs) in pregnant women contribute about 25% of all infections and are among the most frequent clinical bacterial infections. Pregnancy changes in women that include ...anatomical, physiological and hormonal make them susceptible to develop UTI. Left untreated, UTI in pregnancy is associated with grave complications to the mother and fetus. These complications can be decreased by prompt and proper diagnosis and appropriate treatment that also reduces the emergency of drug resistance. Antimicrobial resistance is a major health problem in the treatment of UTI. We determined the prevalence, bacteriology and antimicrobial susceptibility of symptomatic urinary tract infection among pregnant women at Mbarara Regional Referral Hospital.
We conducted a cross-sectional study from November 2019 to February 2020 involving 400 pregnant women with symptomatic UTI. Patient information was obtained using a structured questionnaire. We collected clean-catch midstream urine specimens for culture and performed antimicrobial susceptibility testing following Clinical and Laboratory Standards Institute standards. Data was entered into RED-cap Version 8.2 software and then exported to Stata Version 14.1 for analysis.
The proportion of culture-positive UTI was 140/400 (35%). Gram-negative bacteria were more prevalent (73%): Klebsiella pneumoniae 52(37.41%), Escherichia coli 40(28.78%), Pseudomonas aeruginosa and Proteus mirabilis 7(5.04% each), Citrobacter freundii 1(1%). Staphylococcus aureus 33(23.57%) was the only gram-positive isolate. All the isolates were resistant to ampicillin, amoxicillin, amoxicillin/clavulanic acid and ceftazidime/clavulanic acid (95.7, 95.0, 72.9 and 50.7% respectively). Prevalence of extended-spectrum beta-lactamases producing Enterobacteriaceae was 29.0% while that of methicillin-resistant Staphylococcus aureus was 33.3%. All cultures demonstrated resistance to more than one drug. Majority of the bacterial isolates were sensitive to ciprofloxacin, ceftriaxone, nitrofurantoin, cefotaxime and gentamicin at 82.9, 81.4, 79.3, 78.6, 66.4 and 65.7% respectively.
Klebsiella pneumoniae was the most prevalent isolate followed by E. coli. These two organisms were highly resistant to the commonly used antibiotics. Our study recorded a higher prevalence of culture-positive UTI in pregnancy than all the studies in Uganda. Empirical treatment of UTI should be minimized as sensitivity varies for each organism, for each drug and over time.
HIV-infected individuals with CD4 count >100 cells/μL with cryptococcal meningitis presented more frequently with altered mental status despite having a 10-fold lower fungal burden. The survival by ...extremes of low and high CD4 are consistent with the damage-response framework theory.
Abstract
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.
Loss to follow-up (LTFU) deprives HIV-exposed infants the lifesaving care required and results in exposing HIV free infants to virus requisition risk. We aimed to determine the rate of LTFU, ...postnatal mother-to-child HIV-transmission (MTCT) and to identify maternal factors associated with LTFU among HIV-exposed infants enrolled at Mbarara Regional Referral Hospital PMTCT clinic.
Study participants were infants born to HIV-positive mothers enrolled in the PMTCT clinic for HIV care at Mbarara Regional Referral Hospital. While access database in the Early Infant Diagnosis (EID) clinic provided data on infants, the open medical record system database at the ISS clinic provided that for mothers. Infants were classified as LTFU if they had not completed their follow-up schedule by 18 months of age. At 18 months, an infant is expected to receive a rapid diagnostic test before being discharged from the PMTCT clinic. Postnatal MTCT of HIV was calculated as a proportion of infants followed and tested from birth to 18 months of age. Logistic regression was used to determine possible associations between mothers' characteristics and LTFU. In-depth interviews of mothers of LTFU infants and health workers who attend to the HIV-exposed infants were carried out to identify factors not captured in the electronic database.
Out of 1624 infants enrolled at the clinic, 533 (33%) were dropped for lack of mother's clinic identification number, 18 (1.1%) were either dead or transferred out. Out of 1073 infants analysed, 515 (48%) were LTFU by 18 months of age while out of the 558 who completed their follow-up schedule, 20 (3.6%) tested positive for HIV. Young age of mother, far distance to hospital and non-use of family planning were identified as outstanding factors responsible for LTFU. In addition, in-depth interviews revealed facility-level factors such as "waiting time" which would not be found in routine client databases.
This study has revealed a high rate of loss to follow up among HIV-exposed infants enrolled at Mbarara Regional Referral hospital PMTCT clinic. Young maternal age, long distance to health facility and failure to use family planning were significantly associated with LTFU. Incorporating family planning services in the ART and PMTCT clinics could reduce loss to follow-up of HIV exposed infants. Young mothers should be targeted with information on the importance of completing the EID follow-up schedule and also, their clinic identification number be gotten at each visit.
Neonatal septicaemia is one of the most common leading causes of neonatal morbidity and mortality in developing countries. It is estimated to affect more than 30 million people worldwide annually, ...potentially leading to 6 million deaths.
To determine the prevalence, bacteriological profile, antibiotic susceptibility and factors associated with neonatal septicaemia among neonates suspected to sepsis at Kilembe mines hospital.
We conducted a descriptive cross-sectional study, where purposive sampling technique was used and blood was drawn from 122 neonates suspected to sepsis attending Kilembe Mines Hospital during the period (July to November 2020). Specimens were inoculated in Brain heart infusion broth, transported to Fortportal Regional Referral Hospital, plated daily up to 7 days on blood, chocolate, MacConkey agar and incubated in aerobic and 5% carbondioxide. Pure colonies were identified by Gram stain, biochemical tests and antibiotic sensitivities obtained by Kirby Bauer disc diffusion method. Associations were tested using Chi square with Fisher's exact or Yates correction tests where necessary and statistical significance was set at P < 0.05. Stata (version 14) used for statistical analysis.
Blood cultures were positive in 59.0% cases with 55.5% male and 44.4% female. EOS was present in 56.9% and LOS 43.1% of the cases. Gram negative (56.9%) organisms were most implicated with neonatal septicaemia than Gram positives ones (43.1%). Gram positive organisms exhibited better susceptibility to amikacin, linezolid and vancomycin but more resistant to ampicillin and gentamicin. Of the aminoglycosides, amikacin exhibited a verge over netilmicin and gentamicin against Gram negative isolates. Risk factors of neonatal septicaemia were mother's age of ≥25 years, employed mothers, tertiary-level of education, SVD, ANC attendance of ≥4 times, UTI during pregnancy, PROMS, foul Smelling liquor, urban residence, neonatal birth weight of ≥2500 g, Apgar score 1st and 5th min ≥6 and resuscitation.
Multi-drug resistant organisms were isolated. Therefore caution is required in selection of antibiotic therapy and avoid empirical treatment.
Abstract
Background
Abnormal vaginal discharge is a common complaint among women of reproductive age, affecting about one- third of all women. In resource-limited settings where access to laboratory ...services is limited, treatment is usually syndromic. This approach may result in ineffective treatment, with high recurrence rates and a potential of developing antibiotic resistance. This study aimed to determine the bacterial isolates and antibiotic susceptibility among women with an abnormal vaginal discharge attending the gynecology clinic at a tertiary hospital in Southwestern Uganda.
Methods
We conducted a hospital based cross-sectional study among 361 women aged 15–49 years, presenting with abnormal vaginal discharge at the gynecology clinic of Mbarara Regional Referral Hospital from December 2020 to June 2021. Demographic characteristics were collected using a structured questionnaire. We collected cervical and vaginal sterile swabs and subjected them to wet preparation and gram stain. The specimens were cultured for bacterial isolates. Susceptibility testing was performed on samples with bacterial isolates using the Kirby-Bauer disc diffusion method, on the commonly prescribed antibiotics in this setting. We summarized and described the bacterial isolates and antibiotic susceptibility patterns as frequencies and percentages.
Results
We enrolled 361 women with abnormal vaginal discharge. Bacteria were isolated in 29.6% (107/361) of the women, and the commonest isolates included;
Staphylococcus aureus
48.6% (52/107),
Klebsiella pneumoniae
29.9% (32/107) and
Enterococcus faecalis
15% (16/107). Yeast cells were found in 17.7% (64/361) of the women with abnormal vaginal discharge. Cefuroxime (90.7%) and Ciprofloxacin (81.3%) had a high level of sensitivity while high levels of resistance were observed for Doxycycline (86.0%) and Azithromycin (67.0%).
Conclusion
The common bacterial isolates were
Staphylococcus aureus
,
Klebsiella pneumoniae
and
Enterococcus faecalis
. The isolated bacteria were most sensitive to Cefuroxime and Ciprofloxacin but resistant to Doxycycline and Azithromycin. There is need for routine culture and susceptibility testing of women with abnormal vaginal discharge so as to guide treatment, minimize inappropriate antibiotic use and consequently reduce antibiotic resistance.
Abstract Introduction The optimal resuscitation strategy for patients with severe sepsis in resource-limited settings is unknown. Therefore, we determined the association between intravenous fluids, ...changes in vital signs and lactate after the first 6 hours of resuscitation from severe sepsis, and in-hospital mortality at a hospital in Uganda. Materials and methods We enrolled patients admitted with severe sepsis to Mbarara Regional Referral Hospital and obtained vital signs and point-of-care blood lactate concentration at admission and after 6 hours of resuscitation. We used logistic regression to determine predictors of in-hospital mortality. Results We enrolled 218 patients and had 6 hour postresuscitation data for 202 patients. The median (interquartile range) age was 35 (26-50) years, 49% of patients were female, and 57% were HIV infected. The in-hospital mortality was 32% and was associated with admission Glasgow Coma Score (adjusted odds ratio aOR, 0.749; 95% confidence interval CI, 0.642-0.875; P < .001), mid-upper arm circumference (aOR, 0.876; 95% CI, 0.797-0.964; P = .007), and 6-hour systolic blood pressure (aOR, 0.979; 95% CI, 0.963-0.995; P = .009) but not lactate clearance of 10% or greater (aOR, 1.2; 95% CI, 0.46-3.10; P = .73). Conclusions In patients with severe sepsis in Uganda, obtundation and wasting were more closely associated with in-hospital mortality than lactate clearance of 10% or greater.
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