Background: The World Health Organization (WHO) recommends systematic symptom screening for tuberculosis (TB). However, TB prevalence surveys suggest that this strategy does not identify millions of TB patients, globally. Undiagnosed or delayed diagnosis of TB contribute to TB transmission and exacerbate morbidity and mortality. We conducted a cluster-randomized trial of large urban and rural primary healthcare clinics in 3 provinces of South Africa to evaluate whether a novel intervention of targeted universal testing for TB (TUTT) in high-risk groups diagnosed more patients with TB per month compared to current standard of care (SoC) symptom-directed TB testing. Methods and findings: Sixty-two clinics were randomized; with initiation of the intervention clinics over 6 months from March 2019. The study was prematurely stopped in March 2020 due to clinics restricting access to patients, and then a week later due to the Coronavirus Disease 2019 (COVID-19) national lockdown; by then, we had accrued a similar number of TB diagnoses to that of the power estimates and permanently stopped the trial. In intervention clinics, attendees living with HIV, those self-reporting a recent close contact with TB, or a prior episode of TB were all offered a sputum test for TB, irrespective of whether they reported symptoms of TB. We analyzed data abstracted from the national public sector laboratory database using Poisson regression models and compared the mean number of TB patients diagnosed per clinic per month between the study arms. Intervention clinics diagnosed 6,777 patients with TB, 20.7 patients with TB per clinic month (95% CI 16.7, 24.8) versus 6,750, 18.8 patients with TB per clinic month (95% CI 15.3, 22.2) in control clinics during study months. A direct comparison, adjusting for province and clinic TB case volume strata, did not show a significant difference in the number of TB cases between the 2 arms, incidence rate ratio (IRR) 1.14 (95% CI 0.94, 1.38, p = 0.46). However, prespecified difference-in-differences analyses showed that while the rate of TB diagnoses in control clinics decreased over time, intervention clinics had a 17% relative increase in TB patients diagnosed per month compared to the prior year, interaction IRR 1.17 (95% CI 1.14, 1.19, p < 0.001). Trial limitations were the premature stop due to COVID-19 lockdowns and the absence of between-arm comparisons of initiation and outcomes of TB treatment in those diagnosed with TB. Conclusions: Our trial suggests that the implementation of TUTT in these 3 groups at extreme risk of TB identified more TB patients than SoC and could assist in reducing undiagnosed TB patients in settings of high TB prevalence. Trial registration: South African National Clinical Trials Registry DOH-27-092021-4901.

Whole-genome sequence (WGS) analyses were employed to investigate the genomic epidemiology of extensively drug-resistant Klebsiella pneumoniae strains, focusing on the carbapenem resistance-encoding determinants, mobile genetic support, clonal and epidemiological relationships. A total of ten isolates were obtained from patients admitted to the intensive care unit (ICU) in a public hospital in South Africa. Five isolates were from rectal swabs of colonized patients and five from blood cultures of patients with invasive carbapenem-resistant infections. Following microbial identification and antibiotic susceptibility tests, the isolates were subjected to WGS on the Illumina MiSeq platform. All the isolates showed genotypic resistance to tested β-lactams (NDM-1, OXA-1, CTX-M-15, TEM-1B, SHV-1) and other antibiotics. All but one isolate belonged to the ST152 with a novel sequence type, ST3136, differing by a single-locus variant. The isolates had the same plasmid multilocus sequence type (IncF[K12:A-:B36]) and capsular serotype (KL149), supporting the epidemiological linkage between the clones. Resistance to carbapenems in the 10 isolates was conferred by the bla_NDM-1 mediated by the acquisition of multi-replicon [ColRNAI, IncFIB(pB171), Col440I, IncFII, IncFIB(K) and IncFII(Yp)] p18-43_01 plasmid. These findings suggest that the acquisition of bla_NDM-1-bearing plasmid structure (p18-43_01), horizontal transfer and clonal dissemination facilitate the spread of carbapenemases in South Africa. This emphasizes the importance of targeted infection control measures to prevent dissemination.

National sentinel site surveillance for antimicrobial resistance in Klebsiella pneumoniae isolates in South Africa, 2010 - 2012

Background. Nosocomial infections are a major cause of morbidity in the critically injured, and the incidence of resistant strains of bacteria is increasing. Management requires a strategy that achieves accurate empiric cover without antibiotic overuse − a goal that may be achieved by surveillance and antibiotic stewardship. Objectives. With the aim of minimising the use of empirical ultrabroad-spectrum combination antimicrobial prescriptions and reducing bacterial resistance, the level I Trauma Intensive Care Unit (TICU) at Inkosi Albert Luthuli Central Hospital (IALCH) in Durban employs stewardship and an antimicrobial policy based on surveillance. This study was undertaken with three aims: (i) to describe the spectrum and sensitivities of nosocomial pathogens in a level I TICU; (ii) to ascertain, based on surveillance data, how frequently initial empiric choice of antimicrobials was correct; and (iii) to determine how frequently ultrabroad-spectrum antimicrobials were prescribed and were actually necessary. Methods. Over a 12-month period, all critically injured patients who underwent mechanical ventilation in the TICU were identified from a prospectively gathered database. Information regarding every specimen submitted to the National Health Laboratory Services (NHLS) situated at IALCH was extracted from the laboratory computer database. For each patient, bacterial isolates and antimicrobial susceptibility were identified using standard laboratory techniques. Empiric prescriptions for presumed nosocomial sepsis were identified from the hospital’s computerised patient record system and compared with culture results. Acinetobacter species were regarded as colonisers and treatment not offered unless this was the sole isolate in the presence of signs of severe sepsis. Results. Of 227 patients, 106 (46.6%) had 136 culture-positive isolates with a total of 323 pathogens (201 Gram-negative, 119 Gram-positive, 3 Candida albicans). There were 19 species of Gram-negative pathogens, of which 56% comprised Enterobacteriaceae. Extended spectrum beta-lactamase (ESBL) production was found in 6/31 (19%) Escherichia coli coli and 6/24 (25%) Klebsiella isolates. Staphyloccocal species accounted for 60% of the Gram-positive isolates, of which 18 were methicillin-resistant Staphylococcus aureus (MRSA). All Candida isolates were sensitive to fluconazole. One hundred and one empiric and 14 directed prescriptions were issued. Despite positive cultures, antimicrobials were not prescribed for 21 patients who had no evidence of sepsis. Excluding multidrug-resistant Acinetobacter isolates, there were 87 (93.5%) appropriate and 6 (6.5%) incorrect prescriptions. Ultrabroad-spectrum combination therapy (U-bSCT) was employed for 11 patients but was necessary in only 2. Conclusions. When combined with regular bacterial surveillance, antimicrobial stewardship allows accurate empiric antimicrobial prescription with minimal need for ultrabroad-spectrum combination therapy. This policy can potentially reduce the emergence of multidrug-resistant pathogens, precluding the need for broad-spectrum antimicrobials and the attendant problems of overuse.

Drug resistant Acinetobacter baumannii (A. baumannii) poses serious treatment challenges and is on the rise worldwide. The Infectious Diseases Society of America/Society for Healthcare Epidemiology of America recommends preauthorization of antibiotics to ensure successful antibiotic stewardship programs (ASWPs). This study estimates and analyzes the microbiological and clinical characteristics of A. baumanii strains with differentiating criteria for sepsis versus colonization, in order to support preauthorization and assist ASWPs at the patient level. A retrospective observational study was performed from 2008 to 2014. The clinical and microbiological characteristics of A. baumannii strains were correlated to assess pathogenic status and antibiotic resistance patterns. A flow chart was produced to differentiate between sepsis and colonization amongst patient groups. A. baumannii was cultured in 2656 cases, with a prevalence of 0.9-2.4% during 7 years study periods. There was a statistically significant difference between the sepsis and colonization groups (P=0.02). Sepsis accounted for 37-51% of A. baumanii isolates and colonisation for 49-63% (P=<0.01). Multidrug resistant (MDR), extensive drug resistant (XDR) and pandrug resistant (PDR) A. baumannii was detected in 53-60%, 1-19% and 1% of cultures in the sepsis group, and 75%, 8-23% and 1% in the colonized group. There was a high percentage of polymicrobial infection in the sepsis group and pure growth was not always significant for sepsis. Cases of MDR and XDR A. baumannii increased over the seven-year study, while PDR strains emerged. For a successful ASWP, both clinical and microbiological information should be interpreted when establishing preauthorization/decision to treat.

Background. In South Africa (SA), the National Department of Health has developed an Antimicrobial Resistance National Strategy Framework document to manage antimicrobial resistance (AMR). One of the strategic objectives is to optimise surveillance and early detection of AMR. At the National Institute for Communicable Diseases (NICD), an analysis of selected organisms and antimicrobial agents from both the public and the private sectors was conducted. Objectives. The relevance of surveillance for AMR is increasingly recognised in the light of global action plans to combat resistance. In this report, we present an overview of ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.) organisms and Escherichia coli reported from public and private sector laboratories in SA for the period 2016 - 2017. Methods. Antimicrobial susceptibility testing (AST) profiles on selected ESKAPE organisms and E. coli isolated from blood cultures from the public and private sectors in 2016 and 2017 were analysed. AST data were extracted from a web-based electronic platform created by the NICD. Drug-bug combinations following the World Health Organization’s Global Antimicrobial Surveillance System guidelines were included in the analysis. Results. A total of 28 920 ESKAPE organisms and E. coli were reported in 2016 and 32 293 in 2017 across the two health sectors. Proportions of some organisms differed between the two health sectors, such as E. coli (19% in the public sector and 36% in the private sector), A. baumannii (14% public and 4% private), P. aeruginosa (7% public and 11% private) and S. aureus (27% public and 17% private). Susceptibility data indicated changing patterns in both sectors towards an increase in non-susceptibility to carbapenems in K. pneumoniae (p<0.01). However, we demonstrated an increase in susceptibility to cloxacillin in S. aureus (p<0.01) in both sectors. Conclusions. The key clinically important finding is the rapidly decreasing carbapenem susceptibility among Enterobacteriaceae reported in SA, irrespective of sector. In addition, the analysis provides information that could be used to monitor the effectiveness of interventions implemented at a national level under the guidance and direction of the national AMR framework.