The effect of a comprehensive typhoid conjugate vaccine campaign on antimicrobial prescribing in children in Harare, Zimbabwe: a mixed methods study.

BACKGROUND: Vaccines prevent infections and could subsequently reduce antimicrobial use. A 1-week mass vaccination campaign was done with Typbar-TCV (Bharat Biotech, Hyderabad, India) between Feb 25 and March 4, 2019. We investigated whether this typhoid conjugate vaccine campaign could affect antimicrobial prescribing in children presenting to primary care in Harare, Zimbabwe. METHODS: In this mixed methods study, data for acute paediatric outpatient consultations between Jan 1, 2018, and March 31, 2020, were collected from five clinics in Harare. Interrupted time series analysis was done to compare prescription data before and after the campaign. To contextualise findings, qualitative data were collected between April 20, 2021, and July 20, 2022, comprising ethnographic research (ie, workshops, surveys, observations, and interviews) in 14 clinics. Ethnographic data were used for thematic analysis. The primary outcome was monthly antimicrobial prescriptions in children aged 6 months to 15 years, normalised by the number of trauma events in all age groups. FINDINGS: In the data collection period, 27 107 paediatric consultations were recorded. 17 951 (66·2%) of 27 107 children were prescribed antimicrobials. Despite the perceived reduction in typhoid cases and a decreasing trend in the prescription of antimicrobials commonly used to treat typhoid (ie, ciprofloxacin and azithromycin), mass vaccination with Typbar-TCV did not affect the total rate of antimicrobials (adjusted rate ratio, 1·20, 95% CI 0·70-2·05, p=0·51) or the rate of typhoid antimicrobials prescribed (0·93, 0·44-1·96, p=0·85). Unsafe water sources and insufficient diagnostic services were reported to contribute to the continued disease burden and antimicrobial prescription. INTERPRETATION: Non-specific febrile illness caused by confirmed or suspected typhoid is a common cause of antimicrobial use in endemic areas. Although effective in preventing typhoid fever, we were unable to identify any effect of Typbar-TCV on antimicrobial prescribing. Ethnographic research showed the effect of contextual factors on antimicrobial prescribing, including concerns regarding safe water access, appropriate sewage disposal, health-care and diagnostic availability. To realise effects beyond disease burden reduction, holistic approaches addressing these concerns are needed so that the value of vaccines mitigating the effects of antimicrobial use as a driver of antimicrobial resistance is fully achieved. FUNDING: Wellcome Trust. TRANSLATION: For the Shona translation of the abstract see Supplementary Materials section.

COVID-19 and HIV viral load suppression in children andadolescents in Durban, South Africa

Background: The coronavirus disease 2019 (COVID-19) pandemic poses challenges to paediatric and adolescent HIV treatment programme. Modelling exercises raised concerns over potential impact of disruptions. Objectives: To describe the impact of the COVID-19 pandemic on viral load (VL) testing among infants, children and adolescents on antiretroviral treatment (ART) in Durban, South Africa. Method: Routinely collected, aggregated data of monthly VL counts done on all those less than 19 years old from January 2018 to January 2022 was analysed. An interrupted time series analysis using a Prais-Winsten linear regression model, including terms for lockdowns and excess mortality determined VL trends. Results: The unadjusted mean VL was 2166 (confidence interval [CI]: 252.2) and 2016 (CI: 241.9), P = 0.039, and percentage VL suppression rates (72.9%, CI: 2.4% vs 73.6%, CI: 1.8%) across COVID and pre-COVID periods, showing no significant difference, P = 0.262. In the interrupted time series analysis, modelled monthly VL counts did not differ significantly by lockdown level (e.g., level 5 lockdown: ­210.5 VLs, 95% CI: ­483.0 to +62.1, P = 0.138) or excess mortality (­0.1, 95% CI: ­6.3 to 6.1, P = 0.969). A significant downward trend in VL testing over time, including during the pre-COVID-19 period (­6.6 VL per month, 95% CI: ­10.4 to ­2.7, P = 0.002), was identified. Conclusion: Viral load suppression for children and adolescents were not negatively affected by COVID-19. A trend of decrease in VL testing predated COVID-19. What this study adds: Evidence presented that HIV VL testing and suppression rates in children and adolescents in a high burden setting were sustained through the COVID pandemic.

Healthcare Seeking and Access to Care for Pneumonia, Sepsis, Meningitis, and Malaria in Rural Gambia.

Children with acute infectious diseases may not present to health facilities, particularly in low-income countries. We investigated healthcare seeking using a cross-sectional community survey, health facility-based exit interviews, and interviews with customers of private pharmacies in 2014 in Upper River Region (URR) The Gambia, within the Basse Health & Demographic Surveillance System. We estimated access to care using surveillance data from 2008 to 2017 calculating disease incidence versus distance to the nearest health facility. In the facility-based survey, children and adult patients sought care initially at a pharmacy (27.9% and 16.7% respectively), from a relative (23.1% and 28.6%), at a local shop or market (13.5% and 16.7%), and on less than 5% of occasions with a community-based health worker, private clinic, or traditional healer. In the community survey, recent symptoms of pneumonia or sepsis (15% and 1.5%) or malaria (10% and 4.6%) were common in children and adults. Rates of reported healthcare-seeking were high with families of children favoring health facilities and adults favoring pharmacies. In the pharmacy survey, 47.2% of children and 30.4% of adults had sought care from health facilities before visiting the pharmacy. Incidence of childhood disease declined with increasing distance of the household from the nearest health facility with access to care ratios of 0.75 for outpatient pneumonia, 0.82 for hospitalized pneumonia, 0.87 for bacterial sepsis, and 0.92 for bacterial meningitis. In rural Gambia, patients frequently seek initial care at pharmacies and informal drug-sellers rather than community-based health workers. Surveillance underestimates disease incidence by 8-25%.

Zinc as an adjunct therapy in the management of severe pneumonia among Gambian children: randomized controlled trial.

BACKGROUND: The benefit of zinc as an adjunct therapy for severe pneumonia is not established. We assessed the benefit of adjunct zinc therapy for severe pneumonia in children and determined whether the study children were zinc deficient. METHODS: This was a randomized, parallel group, double-blind, placebo-controlled trial with an allocation ratio of 1:1 conducted in children with severe pneumonia to evaluate the efficacy of daily zinc as an adjunct treatment in preventing 'treatment failure' (presence of any sign of severe pneumonia) on day-5 and day-10 and in reducing the time to resolution of signs of severe pneumonia. Six hundred and four children 2-59 months of age presenting with severe pneumonia at six urban and rural health care facilities in The Gambia were individually randomised to receive placebo (n = 301) or zinc (n = 303) for seven days. To determine if the study children were zinc deficient, supplementation was continued in a randomly selected subgroup of 121 children from each arm for six months post-enrolment, and height-gain, nutritional status, plasma zinc concentrations, and immune competence were compared. RESULTS: Percentage of treatment failure were similar in placebo and zinc arms both on day 5 (14.0% vs 14.1%) and day 10 (5.2% vs 5.9%). The time to recovery from lower chest wall indrawing and sternal retraction was longer in the placebo compared to zinc arm (24.4 vs 23.0 hours; P = 0.011 and 18.7 vs 11.0 hours; P = 0.006 respectively). The time to resolution for all respiratory symptoms of severity was not significantly different between placebo and zinc arms (42.3 vs 30.9 hours respectively; P = 0.242). In the six months follow-up sub-group, there was no significant difference in height gain, height-for-age and weight-for-height Z-scores, mid upper arm circumference, plasma zinc concentrations, and anergy at six months post-enrolment. CONCLUSIONS: In this population, zinc given as an adjunct treatment for severe pneumonia showed no benefit in treatment failure rates, or clinically important benefit in time to recovery from respiratory symptoms and showed marginal benefit in rapidity of resolution of some signs of severity. This finding does not support routine use of zinc as an adjunct treatment in severe pneumonia in generally zinc replete children. TRIAL REGISTRATION: ISRCTN33548493.

Long-term Impact of Oral Azithromycin Taken by Gambian Women During Labor on Prevalence and Antibiotic Susceptibility of Streptococcus pneumoniae and Staphylococcus aureus in Their Infants: Follow-up of a Randomized Clinical Trial.

Background: Oral azithromycin given to women in labor decreases maternal and neonatal bacterial carriage but increases azithromycin-resistant bacteria during at least 4 weeks following the intervention. We assessed the prevalence of bacterial carriage and azithromycin resistance 12 months after treatment among study infants. Methods: Nasopharyngeal swabs (NPSs) were collected between November 2014 and May 2015 from children aged 11-13 months whose mothers had received azithromycin or placebo during labor. Streptococcus pneumoniae and Staphylococcus aureus were isolated using conventional microbiological methods. Antibiotic susceptibility was determined by disk diffusion and confirmed by Etest or VITEK-2. Results: NPSs were collected from 461 children. The prevalence of S. pneumoniae and S. aureus was similar between children from the azithromycin and placebo arms (85.0% vs 82.1%; odds ratio [OR], 1.23 [95% confidence interval {CI}, .73-2.08] for S. pneumoniae and 21.7% vs 21.3%; OR, 1.02 [95% CI, .64-1.64] for S. aureus). Prevalence of azithromycin-resistant S. pneumoniae was similar in both arms (1.8% vs 0.9% in children from the azithromycin and placebo arms, respectively; OR, 2.10 [95% CI, .30-23.38]); resistance to other antibiotics was also similar between arms. For S. aureus, there was no difference in azithromycin resistance between children in the azithromycin (3.1%) and placebo (2.6%) arms (OR, 1.22 [95% CI, .35-4.47]) or resistance to any other antibiotics. Conclusions: The higher prevalence of S. aureus azithromycin resistance observed among women treated during labor and their babies 4 weeks after treatment had waned 12 months after delivery. Azithromycin intervention did not induce other antibiotic resistance to S. pneumoniae or S. aureus. Clinical Trials Registration: NCT01800942.

Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis.

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 µmol/liter (95% CI, 30 to 45 µmol/liter) by day 7 and by 49 µmol/liter (95% CI, 35 to 64µmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 µmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.

Age at menarche in relation to maternal use of tobacco, alcohol, coffee, and tea during pregnancy.

To investigate the potential effects of common early life exposures on age at menarche, the authors examined data collected in a follow-up study of pregnancies that occurred during the 1960s in California. Among 994 female offspring interviewed as adolescents, 98% had started their menstrual periods at a mean age of 12.96 years. After adjustment, the mean age at menarche was a few months earlier among girls whose mothers smoked a pack or more of cigarettes daily during pregnancy compared with unexposed girls (difference = -0.22 years, 95% confidence interval (CI): -0.49, 0.05) and more so among girls who were not White (difference = -0.52 years, 95% CI: -1.1, 0.08). Girls with both high prenatal and childhood passive smoke exposure had an adjusted mean age at menarche about 4 months earlier than those unexposed. The daughter's mean age at menarche varied little by maternal prenatal alcohol consumption. Daughters of tea consumers had a later mean age (difference = 0.41 years at >/= 3 cups (0.7 liter)/day, 95% CI: 0.03, 0.80) and were more likely to start menarche later (>13 years) (odds ratio = 1.7, 95% CI: 0.91, 3.2), but daughters of coffee consumers did not. These suggestive findings, which merit further investigation, may be related to hormonal effects.