Thomas C. Darton

Low- and middle-income countries (LMIC) continue to experience a high burden of infectious diseases and disparities in access to and use of antimicrobials, yet data on antibiotic prescribing in outpatient settings, where the majority of global prescriptions occur, remain scarce. The objective of this study is to provide data on diagnoses and antibiotic prescriptions among primary care patients in Harare, Zimbabwe. We conducted a retrospective study of medical records from eight primary care clinics in Harare, Zimbabwe. Clinics were selected based on the population they served and the availability of records. Patient consultations conducted between January 2016 and December 2022 were included. Antibiotic prescriptions were categorised into groups according to the AWaRe (Access, Watch and Reserve) classification. During the study period, 199,880 patient consultations were recorded. The median patient age was 9 years and 52.5% (105,035/199,880) were female. The most common causes of presentation were due to infectious diseases including, in order of frequency, gastroenteritis (15.2%; 30,352/199,880), acute respiratory infections (10.9%; 21,381/199,880) and pneumonia (10.5%; 20,889/199,880). Overall, antibiotics were prescribed in 70.5% (117,674/166,858) of patients who were not referred to hospital. Antibiotics commonly prescribed were amoxicillin (39.4%; 65,825/166,858), ciprofloxacin (10.3%; 17,162/166,858), metronidazole (9.4%; 15,681/166,858). Among those who were prescribed antibiotics and not referred, 70.6% (83,034/117,674) were prescribed ‘Access’ and 29.3% (34,472/117,674) ‘Watch’ group antibiotics. Patients with respiratory infections, including those with upper respiratory infections, and gastroenteritis were frequently prescribed antibiotics. This study shows that infectious diseases remain a common reason for primary care presentation and antibiotics were frequently prescribed. These findings highlight the need for increasing access to diagnostics in primary care, and for antibiotic stewardship and other context-adapted interventions aimed at optimising patient management and reducing unnecessary antibiotic prescriptions.

Summary: Salmonella Typhi secretes typhoid toxin that activates cellular DNA damage responses (DDR) during acute typhoid fever. Human infection challenge studies revealed that the toxin suppresses bacteraemia via unknown mechanisms. Using quantitative proteomic analysis on the plasma of bacteraemic participants, we demonstrate that wild-type toxigenic Salmonella induced secretion of lysozyme (LYZ) and apolipoprotein C3 (APOC3). Recombinant typhoid toxin or infection with toxigenic Salmonella recapitulate LYZ and APOC3 secretion in cultured cells, which involved ATM/ATR-dependent DDRs and confirmed observations in typhoid fever. LYZ alone inhibited secretion of virulence effector proteins SipB and SopE. LYZ caused loss of Salmonella morphology characterised by spheroplast formation. Spheroplast formation was mediated by LYZ and enhanced by lactoferrin, which was identified by proteomics in participants with typhoid fever. Our findings may indicate that toxin-induced DDRs elicit antimicrobial responses, which suppress Salmonella bacteraemia during typhoid fever.

Streptococcus pyogenes–related skin infections are increasingly implicated in the development of rheumatic heart disease (RHD) in lower-resource settings, where they are often associated with scabies. The true prevalence of S pyogenes–related pyoderma may be underestimated by bacterial culture. A multiplex quantitative polymerase chain reaction (qPCR) assay for S pyogenes, Staphylococcus aureus, and Sarcoptes scabiei was applied to 250 pyoderma swabs from a cross-sectional study of children aged emm-typing was used to supplement previous whole genome sequencing (WGS) of cultured isolates. Pyoderma lesions with S pyogenes increased from 51% (127/250) using culture to 80% (199/250) with qPCR. Compared to qPCR, the sensitivity of culture was 95.4% for S pyogenes (95% confidence interval {CI}, 77.2%–99.9%) in samples with S pyogenes alone (22/250 [9%]), but 59.9% (95% CI, 52.3%–67.2%) for samples with S aureus coinfection (177/250 [71%]). Direct PCR-based emm-typing was successful in 50% (46/92) of cases, identifying 27 emm-types, including 6 not identified by WGS (total 52 emm-types). Bacterial culture significantly underestimates the burden of S pyogenes in pyoderma, particularly with S aureus coinfection. Molecular methods should be used to enhance the detection of S pyogenes in surveillance studies and clinical trials of preventive measures in RHD-endemic settings.

Protracted bacterial bronchitis (PBB) causes chronic wet cough for which seasonal azithromycin is increasingly used to reduce exacerbations. We investigated the impact of seasonal azithromycin on antimicrobial resistance and the nasopharyngeal microbiome. In an observational cohort study, 50 children with PBB were enrolled over two consecutive winters; 25/50 at study entry were designated on clinical grounds to take azithromycin over the winter months and 25/50 were not. Serial nasopharyngeal swabs were collected during the study period (12–20 months) and cultured bacterial isolates were assessed for antimicrobial susceptibility. 16S rRNA-based sequencing was performed on a subset of samples. Irrespective of azithromycin usage, high levels of azithromycin resistance were found; 73% of bacteria from swabs in the azithromycin group vs. 69% in the comparison group. Resistance was predominantly driven by azithromycin-resistant S. pneumoniae, yet these isolates were mostly erythromycin susceptible. Analysis of 16S rRNA-based sequencing revealed a reduction in within-sample diversity in response to azithromycin, but only in samples of children actively taking azithromycin at the time of swab collection. Actively taking azithromycin at the time of swab collection significantly contributed to dissimilarity in bacterial community composition. The discrepancy between laboratory detection of azithromycin and erythromycin resistance in the S. pneumoniae isolates requires further investigation. Seasonal azithromycin for PBB did not promote antimicrobial resistance over the study period, but did perturb the microbiome.