Genomic characterization of multi drug resistant ESBL-producing Escherichia coli isolates from patients and patient environments in a teaching hospital in Ghana.

BACKGROUND: ESBL-producing Escherichia coli pose a growing health risk in community and healthcare settings. We investigated the resistome, virulome, mobilome, and genetic relatedness of multidrug-resistant (MDR) E. coli isolates from patients and their environment in a Ghanaian teaching hospital. MATERIALS AND METHODS: Twenty-three MDR ESBL-producing or carbapenem-resistant E. coli isolates from a collection of MDR Gram-negative bacteria (GNB) from patients and environments were selected for genomic analyses. Whole genome sequencing and bioinformatics tools were used to analyze genomic characteristics and phylogeny. RESULTS: The prevalence and incidence of rectal carriage of ESBL E. coli among patients were 13.65% and 11.32% respectively. The ß-lactamase genes, blaTEM-1B (10 isolates) and blaCTX-M-15 (12 isolates) were commonly associated with IncFIB plasmid replicons and co-occurred with aminoglycoside, macrolide, and sulfamethoxazole/trimethoprim resistance. Insertion sequences, transposons, and class I integrons were found with blaCTX-M-15. Carriage and environmental isolates carried multiple virulence genes, with terC being the most prevalent in 21 isolates. Seventeen sequence types (STs) were identified, including a novel ST (ST13846). Phylogenetic analysis grouped the isolates into four main clusters, with one outlier. High genetic relatedness was observed between two carriage isolates of ST940 and between a carriage isolate and an environmental isolate of ST648. Isolates with different STs, collected at different times and locations, also showed genetic similarities. CONCLUSION: We identified ESBL-producing E. coli with diverse genomic characteristics circulating in different hospital directorates. Clonal relatedness was observed among isolates from patients and the environment, as well as between different patients, suggesting transmission within and between sources.

Genome analysis of multidrug resistant Enterococcus faecium and Enterococcus faecalis circulating among hospitalized patients in uMgungundlovu District, KwaZulu-Natal, South Africa.

BACKGROUND: Vancomycin-resistant enterococci (VRE) are important pathogens categorized as high-priority bacteria in the Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics published by the World Health Organization. The aim of this study was to determine the risk factors, resistance, virulence, mobilomes associated with multidrug-resistant and clonal lineages of Enterococcus faecium and faecalis circulating among hospitalized patients following the health system in South Africa, using whole genome sequencing (WGS). METHODS: A cross-sectional study was conducted during a two-month periods among hospitalized patients in 2017. Rectal swabs were collected from patients admitted to medical and surgical wards in an urban tertiary hospital, and a rural district hospital in uMgungundlovu district, South Africa. Enterococci were screened for vancomycin resistance on bile esculin azide agar supplemented with 6 mg/L of vancomycin and confirmation of VRE was done using ROSCO kits. Conventional and real-time PCR methods were used to ascertain the presence of VanA, VanB, VanC-2/3 and VanC-1 genes. All six multidrug-resistant Enterococcus faecalis and faecium selected were identified using multiplexed paired-end libraries (2 × 300 bp) with the Nextera XT DNA sample preparation kit (Illumina, San Diego, CA, USA) and genome sequencing was done using Illumina MiSeq instrument with 100× coverage at the National Institute of Communicable Diseases Sequencing Core Facility, South Africa. Antibiotic resistance genes, virulence factors, plasmids, integrons and CRISPR were characterized using RAST, ResFinder, VirulenceFinder, PlasmidFinder, PHAST and ISFinder respectively. RESULTS: Sequencing analysis revealed that these strains harbouring numerous resistance genes to glycopeptides (vanC[100%], vex3[100%], vex2[83,33%] and vanG[16,66%]), macrolides, lincosamides, sterptogramine B (ermB[33,32%], Isa[16,66%], emeA[16,66%]) and tetracyclines (tetM[33,32%]) in both district and tertiary hospitals. Multidrug efflux pumps including MATE, MFS and pmrA conferring resistance to several classes of antibiotics were also identified. The main transposable elements observed were in the Tn3 family, specifically Tn1546. Four single sequence types (STs) were identified among E. faecium in the district hospital, namely ST822, ST636, ST97 along with a novel ST assigned ST1386, while one lineage, ST29 was detected in the tertiary hospital. CONCLUSION: The study reveals the genetic diversity and high pathogenicity of multidrug-resistant Enterococcus faecalis and faecium circulating among hospitalized patients. It underlines the necessity to implement routine screening of admitted patients coupled with infection control procedures, antimicrobial stewardship and awareness should be strengthened to prevent and/or contain the carriage and spread of multidrug resistant E. faecium and E. faecalis in hospitals and communities in South Africa.

Enterococcal contamination of hospital environments in KwaZulu-Natal, South Africa.

AIMS: Enterococci are implicated in hospital-acquired infections and show high tenacity on inanimate objects in the hospital environment. This study investigated the prevalence of Enterococcus spp. in selected wards in public hospitals at four levels of healthcare from a district in KwaZulu-Natal, South Africa. METHODS AND RESULTS: Swabs were collected from frequently touched areas in the paediatric wards and intensive care units (ICUs). Presumptive Enterococcus spp. were isolated and confirmed to genus and species levels, followed by Kirby-Bauer disk diffusion against 14 antibiotics. The results showed that enterococci were recovered from all 11 surfaces tested with the highest contamination rate observed on occupied beds and mops used to clean floors. A total number of 295 Enterococcus was identified. Polymerase chain reaction identified Enterococcus faecalis 83.1% (245/295) and Enterococcus faecium 12.9% (38/295), while whole genome sequencing identified Enterococcus gallinarum 2.0% (6/295) and Enterococcus casseliflavus 2.0% (6/295). Significant prevalence was observed in paediatric wards 64.1% (189/295) compared with the ICUs 35.9% (106/295), p < 0.05, in central, regional and district hospitals. Collectively, 82.0% (242/295) of enterococcal isolates were multidrug resistant, and 80 different antibiograms were observed. The most prominent antibiogram for E. faecium was CIP-RIF-NIT-TET-ERY and for E. faecalis CIP-TET-ERY. CONCLUSION: E. faecalis was the most frequent enterococcal species isolated in all the hospitals investigated and correlates with studies conducted elsewhere. A substantially greater number of isolates were recovered from the paediatric wards compared with ICUs, and thus improved standards should be developed for infection control practices. It is suggested that the elevated use of antibiotics contributed to the increased nonsusceptible isolates observed from ICUs. This study highlighted the high recovery rate of enterococci in the hospital environment even in a nonoutbreak setting. SIGNIFICANCE AND IMPACT OF THE STUDY: Enterocci had a high prevalence rate on the surfaces within the hospitals studied. This study gives an insight into the possible roles all healthcare staff may play in infection control intervention, including proper handling of hospital cleaning equipment and lack of knowledge about the potential for bacteria dissemination.

Genomic analysis of antibiotic-resistant Enterococcus spp. reveals novel enterococci strains and the spread of plasmid-borne Tet(M), Tet(L) and Erm(B) genes from chicken litter to agricultural soil in South Africa.

Manure from food animals exposed to antibiotics is often used as soil fertiliser, potentially releasing antibiotic-resistant bacteria (ARB) with diverse antibiotic-resistance genes (ARGs) into the soil. To determine the impact of chicken litter application on the soil resistome, Enterococcus spp. isolated from chicken litter and soil samples collected before and after the soil amendment were characterised, using whole-genome sequencing and bioinformatics tools. Nineteen Enterococcus spp. isolates from the three sources were sequenced on Illumina Miseq platform to ascertain the isolates' resistome, mobilome, virulome, clonality, and phylogenomic relationships. Multilocus sequence typing (MLST) analysis revealed eight novel sequence types (STs) (ST1700, ST1752, ST1753, ST1754, ST1755, ST1756, ST1004, and ST1006). The isolates harboured multiple resistance genes including those conferring resistance to inter alia macrolides-lincosamide-streptogramin (erm(B), lnu(B), lnu(G), lsaA, lsaE, eat(A), msr(C)), tetracycline (tet(M), tet(L), tet(S)), aminoglycosides (aac(6')-Ii, aac(6')-Iih, ant(6)-Ia, aph(3')-III, ant(9)-Ia), fluoroquinolones (efmA, and emeA), vancomycin (VanC {VanC-2, VanXY, VanXYC-3, VanXYC-4, VanRC}), and chloramphenicol (cat). The litter-amended soil harboured new ARB (particularly E. faecium) and ARGs (ant(6)-Ia, aac(6')-Ii, aph(3')-III), lnu(G), msr(C), and eat(A), efmA) that were not previously detected in the soil. The identified ARGs were associated with diverse mobile genetic elements (MGEs) such as insertion sequences (IS6, ISL3, IS256, IS30), transposons (Tn3 and Tn916) and plasmids (repUS43, repUS1, rep9b, and rep 22). Twenty-eight virulence genes encoding adherence/biofilm formation (ebpA, ebpB, ebpC), antiphagocytosis (elrA) and bacterial sex pheromones (Ccf10, cOB1, cad, and camE), were detected in the genomes of the isolates. Phylogenomic analysis revealed a close relationship between a few isolates from litter-amended soil and the chicken litter isolates. The differences in the ARG and ARB profiles in the soil before and after the litter amendment and their association with diverse MGEs indicate the mobilisation and transmission of ARGs and ARB from the litter to the soil.

Carbapenem Resistance Determinants Acquired through Novel Chromosomal Integrations in Extensively Drug-Resistant Pseudomonas aeruginosa.

Two novel blaDIM-1- or blaIMP-1-containing genomic islands (GIs) were discovered by whole-genome sequence analyses in four extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates from inpatients at a tertiary hospital in Ghana. The strains were of sequence type 234 (ST234) and formed a phylogenetic clade together with ST111, which is recognized as a global high-risk clone. Their carbapenem resistance was encoded by two Tn402-type integrons, In1592 (blaDIM-1) and In1595 (blaIMP-1), both carrying complete tni mobilization modules. In1595 was bound by conserved 25-bp inverted repeats (IRs) flanked by 5-bp direct repeats (DRs) associated with target site duplication. The integrons were embedded in two GIs that contained cognate integrases and were distinguished by a lower GC content than the chromosomal average. PAGI-97A (52.659 bp; In1592), which encoded a P4-type site-specific integrase of the tyrosine recombinase family in its 3' border, was integrated into tRNA-Pro(ggg) and bracketed by a 49-bp perfect DR created by 3'-end target duplication. GIs with the same structural features, but diverse genetic content, were identified in 41/226 completed P. aeruginosa genomes. PAGI-97B (22,636 bp; In1595), which encoded an XerC/D superfamily integrase in its 5' border, was inserted into the small RNA (sRNA) PrrF1/PrrF2 locus. Specific insertions into this highly conserved locus involved in iron-dependent regulation, all leaving PrrF1 intact, were identified in an additional six phylogenetically unrelated P. aeruginosa genomes. Our molecular analyses unveiled a hospital-associated clonal dissemination of carbapenem-resistant ST234 P. aeruginosa in which the XDR phenotype resulted from novel insertions of two GIs into specific chromosomal sites.

BSAC Vanguard Series: From treatment options to precision medicine: the future of 'omics-based' antibiotic resistance surveillance data.

Conventional culture-based phenotypic and genomic surveillance has drawbacks and may not necessarily reflect the true burden of antibiotic resistance. The integration of metagenomic surveillance with transcriptomics and proteomics will yield a step change in the utility of surveillance data from treatment options to precision medicine.

High prevalence of multidrug resistant ESBL- and plasmid mediated AmpC-producing clinical isolates of Escherichia coli at Maputo Central Hospital, Mozambique.

BACKGROUND: Epidemiological data of cephalosporin-resistant Enterobacterales in Sub-Saharan Africa is still restricted, and in particular in Mozambique. The aim of this study was to detect and characterize extended-spectrum ß-lactamase (ESBL) - and plasmid-mediated AmpC (pAmpC)-producing clinical strains of Escherichia coli at Maputo Central Hospital (MCH), a 1000-bed reference hospital in Maputo, Mozambique. METHODS: A total of 230 clinical isolates of E. coli from urine (n = 199) and blood cultures (n = 31) were collected at MCH during August-November 2015. Antimicrobial susceptibility testing was performed by the disc diffusion method and interpreted according to EUCAST guidelines. Isolates with reduced susceptibility to 3rd generation cephalosporins were examined further; phenotypically for an ESBL-/AmpC-phenotype by combined disc methods and genetically for ESBL- and pAmpC-encoding genes by PCR and partial amplicon sequencing as well as genetic relatedness by ERIC-PCR. RESULTS: A total of 75 isolates with reduced susceptibility to cefotaxime and/or ceftazidime (n = 75) from urine (n = 58/199; 29%) and blood (n = 17/31; 55%) were detected. All 75 isolates were phenotypically ESBL-positive and 25/75 (33%) of those also expressed an AmpC-phenotype. ESBL-PCR and amplicon sequencing revealed a majority of blaCTX-M (n = 58/75; 77%) dominated by blaCTX-M-15. All AmpC-phenotype positive isolates (n = 25/75; 33%) scored positive for one or more pAmpC-genes dominated by blaMOX/FOX. Multidrug resistance (resistance ≥ three antibiotic classes) was observed in all the 75 ESBL-positive isolates dominated by resistance to trimethoprim-sulfamethoxazole, ciprofloxacin and gentamicin. ERIC-PCR revealed genetic diversity among strains with minor clusters indicating intra-hospital spread. CONCLUSION: We have observed a high prevalence of MDR pAmpC- and/or ESBL-producing clinical E. coli isolates with FOX/MOX and CTX-Ms as the major ß-lactamase types, respectively. ERIC-PCR analyses revealed genetic diversity and some clusters indicating within-hospital spread. The overall findings strongly support the urgent need for accurate and rapid diagnostic services to guide antibiotic treatment and improved infection control measures.

Quantitative microbial risk assessment for waterborne pathogens in a wastewater treatment plant and its receiving surface water body.

BACKGROUND: Access to safe water for drinking and domestic activities remains a challenge in emerging economies like South Africa, forcing resource-limited communities to use microbiologically polluted river water for personal and household purposes, posing a public health risk. This study quantified bacterial contamination and the potential health hazards that wastewater treatment plant (WWTP) workers and communities may face after exposure to waterborne pathogenic bacteria in a WWTP and its associated surface water, respectively. RESULTS: Escherichia coli (Colilert®-18/ Quanti-Tray® 2000) and enterococci (Enterolert®/ Quanti-Tray® 2000) were quantified and definitively identified by real-time polymerase chain reaction targeting the uidA and tuf genes, respectively. An approximate beta-Poisson dose-response model was used to estimate the probability of infection (Pi) with pathogenic E. coli. Mean E. coli concentration ranged from 2.60E+ 02/100 mL to 4.84E+ 06/100 mL; enterococci ranged from 2.60E+ 02/100 mL to 3.19E+ 06/100 mL across all sampled sites. Of the 580 E. coli isolates obtained from this study, 89.1% were intestinal, and 7.6% were extraintestinal pathogenic E. coli. The 579 enterococci obtained were 50.4% E. faecalis (50.4%), 31.4% E. faecium, 3.5%, E. casseliflavus and 0.7% E. gallinarum. The community health risk stemming from the use of the water for recreational and domestic purposes revealed a greater health risk (Pi) from the ingestion of 1 mL of river water from upstream (range, 55.1-92.9%) than downstream (range, 26.8-65.3%) sites. The occupational risk of infection with pathogenic E. coli for workers resulting from a once-off unintentional consumption of 1 mL of water was 0% (effluent) and 23.8% (raw influent). Multiple weekly exposures of 1 mL over a year could result in a Pi of 1.2 and 100% for the effluent and influent, respectively. CONCLUSION: Our findings reveal that there is a potentially high risk of infection for WWTP workers and communities that use river water upstream and downstream of the investigated WWTP.

1,4,7-Triazacyclononane Restores the Activity of ß-Lactam Antibiotics against Metallo-ß-Lactamase-Producing Enterobacteriaceae: Exploration of Potential Metallo-ß-Lactamase Inhibitors.

Metallo-ß-lactamase (MBL)-producing Enterobacteriaceae are of grave clinical concern, particularly as there are no metallo-ß-lactamase inhibitors approved for clinical use. The discovery and development of MBL inhibitors to restore the efficacy of available ß-lactams are thus imperative. We investigated a zinc-chelating moiety, 1,4,7-triazacyclononane (TACN), for its inhibitory activity against clinical carbapenem-resistant Enterobacteriaceae MICs, minimum bactericidal concentrations (MBCs), the serum effect, fractional inhibitory concentration indexes, and time-kill kinetics were determined using broth microdilution techniques according to Clinical and Laboratory Standards Institute (CSLI) guidelines. Enzyme kinetic parameters and the cytotoxic effects of TACN were determined using spectrophotometric assays. The interactions of the enzyme-TACN complex were investigated by computational studies. Meropenem regained its activity against carbapenemase-producing Enterobacteriaceae, with the MIC decreasing from between 8 and 64 mg/liter to 0.03 mg/liter in the presence of TACN. The TACN-meropenem combination showed bactericidal effects with an MBC/MIC ratio of ≤4, and synergistic activity was observed. Human serum effects on the MICs were insignificant, and TACN was found to be noncytotoxic at concentrations above the MIC values. Computational studies predicted that TACN inhibits MBLs by targeting their catalytic active-site pockets. This was supported by its inhibition constant (Ki ), which was 0.044 µM, and its inactivation constant (Kinact), which was 0.0406 min-1, demonstrating that TACN inhibits MBLs efficiently and holds promise as a potential inhibitor.IMPORTANCE Carbapenem-resistant Enterobacteriaceae (CRE)-mediated infections remain a significant public health concern and have been reported to be critical in the World Health Organization's priority pathogens list for the research and development of new antibiotics. CRE produce enzymes, such as metallo-ß-lactamases (MBLs), which inactivate ß-lactam antibiotics. Combination therapies involving a ß-lactam antibiotic and a ß-lactamase inhibitor remain a major treatment option for infections caused by ß-lactamase-producing organisms. Currently, no MBL inhibitor-ß-lactam combination therapy is clinically available for MBL-positive bacterial infections. Hence, developing efficient molecules capable of inhibiting these enzymes could be a promising way to overcome this phenomenon. TACN played a significant role in the inhibitory activity of the tested molecules against CREs by potentiating the activity of carbapenem. This study demonstrates that TACN inhibits MBLs efficiently and holds promises as a potential MBL inhibitor to help curb the global health threat posed by MBL-producing CREs.

Topical (local) antibiotics for respiratory infections with sore throat: An antibiotic stewardship perspective.

WHAT IS KNOWN AND OBJECTIVE: The overuse and misuse of antibiotics, especially for viral, and self-limiting, respiratory tract infections such as sore throat, increases the risk of the development and spread of antimicrobial resistance within communities. Up to 80% of sore throat cases have a viral aetiology, and even when the infection is bacterial, most cases resolve without antibiotics. However, antibiotics are still frequently and often inappropriately prescribed for the treatment of sore throat. Furthermore, topical (local) antibiotics for treatment of sore throat are widely available over the counter. The objective of this systematic review was to establish the evidence for the benefits, risk of harm and antimicrobial resistance associated with topical (local) antibiotics used for patients with sore throat. METHODS: Eligible studies included those in patients with sore throat of any aetiology receiving the topical (local) antibiotics tyrothricin, bacitracin, gramicidin or neomycin where the antibiotic was topically/locally applied via the nasal cavity or throat. Nasal applications were included as these are occasionally used to treat upper respiratory tract infections that may involve sore throat. There was no restriction or requirement regarding comparator. The outcomes of interest included efficacy, safety, and in vitro culture and antimicrobial resistance data. RESULTS AND DISCUSSION: This systematic review found sparse and mainly poor-quality evidence relating to the use of topical (local) antibiotics for sore throat, and it was not possible to establish the benefits, risk of harm or impact of use on antimicrobial resistance. WHAT IS NEW AND CONCLUSIONS: Further research is necessary to ascertain the risks and benefits of topical (local) antibiotics, their contribution to antimicrobial resistance and the risk of harm. We do, however, question whether it is appropriate and rational to use topical (local) antibiotics for the treatment of sore throat caused by respiratory tract infections in the absence of robust evidence.

Spread of Plasmid-Encoded NDM-1 and GES-5 Carbapenemases among Extensively Drug-Resistant and Pandrug-Resistant Clinical Enterobacteriaceae in Durban, South Africa.

Whole-genome sequence analyses revealed the presence of blaNDM-1 (n = 31), blaGES-5 (n = 8), blaOXA-232 (n = 1), or blaNDM-5 (n = 1) in extensively drug-resistant and pandrug-resistant Enterobacteriaceae organisms isolated from in-patients in 10 private hospitals (2012 to 2013) in Durban, South Africa. Two novel NDM-1-encoding plasmids from Klebsiella pneumoniae were circularized by PacBio sequencing. In p19-10_01 [IncFIB(K); 223.434 bp], blaNDM-1 was part of a Tn1548-like structure (16.276 bp) delineated by IS26 The multireplicon plasmid p18-43_01 [IncR_1/IncFIB(pB171)/IncFII(Yp); 212.326 bp] shared an 80-kb region with p19-10_01, not including the blaNDM-1-containing region. The two plasmids were used as references for tracing NDM-1-encoding plasmids in the other genome assemblies. The p19-10_01 sequence was detected in K. pneumoniae (n = 7) only, whereas p18-43_01 was tracked to K. pneumoniae (n = 4), Klebsiella michiganensis (n = 1), Serratia marcescens (n = 11), Enterobacter spp. (n = 7), and Citrobacter freundii (n = 1), revealing horizontal spread of this blaNDM-1-bearing plasmid structure. Global phylogeny showed clustering of the K. pneumoniae (18/20) isolates together with closely related carbapenemase-negative ST101 isolates from other geographical origins. The South African isolates were divided into three phylogenetic subbranches, where each group had distinct resistance and replicon profiles, carrying either p19-10_01, p18-10_01, or pCHE-A1 (8,201 bp). The latter plasmid carried blaGES-5 and aacA4 within an integron mobilization unit. Our findings imply independent plasmid acquisition followed by local dissemination. Additionally, we detected blaOXA-232 carried by pPKPN4 in K. pneumoniae (ST14) and blaNDM-5 contained by a pNDM-MGR194-like genetic structure in Escherichia coli (ST167), adding even more complexity to the multilayer molecular mechanisms behind nosocomial spread of carbapenem-resistant Enterobacteriaceae in Durban, South Africa.

Diversity and Proliferation of Metallo-ß-Lactamases: a Clarion Call for Clinically Effective Metallo-ß-Lactamase Inhibitors.

The worldwide proliferation of life-threatening metallo-ß-lactamase (MBL)-producing Gram-negative bacteria is a serious concern to public health. MBLs are compromising the therapeutic efficacies of ß-lactams, particularly carbapenems, which are last-resort antibiotics indicated for various multidrug-resistant bacterial infections. Inhibition of enzymes mediating antibiotic resistance in bacteria is one of the major promising means for overcoming bacterial resistance. Compounds having potential MBL-inhibitory activity have been reported, but none are currently under clinical trials. The need for developing safe and efficient MBL inhibitors (MBLIs) is obvious, particularly with the continuous spread of MBLs worldwide. In this review, the emergence and escalation of MBLs in Gram-negative bacteria are discussed. The relationships between different class B ß-lactamases identified up to 2017 are represented by a phylogenetic tree and summarized. In addition, approved and/or clinical-phase serine ß-lactamase inhibitors are recapitulated to reflect the successful advances made in developing class A ß-lactamase inhibitors. Reported MBLIs, their inhibitory properties, and their purported modes of inhibition are delineated. Insights into structural variations of MBLs and the challenges involved in developing potent MBLIs are also elucidated and discussed. Currently, natural products and MBL-resistant ß-lactam analogues are the most promising agents that can become clinically efficient MBLIs. A deeper comprehension of the mechanisms of action and activity spectra of the various MBLs and their inhibitors will serve as a bedrock for further investigations that can result in clinically useful MBLIs to curb this global menace.

Effect of rifampicin and efavirenz on moxifloxacin concentrations when co-administered in patients with drug-susceptible TB.

Objectives: We compared the pharmacokinetics of moxifloxacin during rifampicin co-treatment or when dosed alone in African patients with drug-susceptible recurrent TB. Methods: Patients in the intervention arm of the Improving Retreatment Success (IMPRESS) randomized controlled TB trial received 400 mg of moxifloxacin, with rifampicin, isoniazid and pyrazinamide in the treatment regimen. Moxifloxacin concentrations were measured in plasma during rifampicin-based TB treatment and again 4 weeks after treatment completion, when given alone as a single dose. Moxifloxacin concentration-time data were analysed using non-linear mixed-effects models. Results: We included 58 patients; 42 (72.4%) were HIV co-infected and 40 (95%) of these were on efavirenz-based ART. Moxifloxacin pharmacokinetics was best described using a two-compartment disposition model with first-order lagged absorption and elimination using a semi-mechanistic model describing hepatic extraction. Oral clearance (CL/F) of moxifloxacin during rifampicin-based TB treatment was 24.3 L/h for a typical patient (fat-free mass of 47 kg), resulting in an AUC of 16.5 mg·h/L. This exposure was 7.8% lower than the AUC following the single dose of moxifloxacin given alone after TB treatment completion. In HIV-co-infected patients taking efavirenz-based ART, CL/F of moxifloxacin was increased by 42.4%, resulting in a further 30% reduction in moxifloxacin AUC. Conclusions: Moxifloxacin clearance was high and plasma concentrations low in our patients overall. Moxifloxacin AUC was further decreased by co-administration of efavirenz-based ART and, to a lesser extent, rifampicin. The clinical relevance of the low moxifloxacin concentrations for TB treatment outcomes and the need for moxifloxacin dose adjustment in the presence of rifampicin and efavirenz co-treatment need further investigation.

Building an antimicrobial stewardship model for a public-sector hospital: a pre-implementation study.

Introduction. Antimicrobial resistance (AMR) is recognized as an important global health risk, associated with increased mortality, morbidity and healthcare costs. Antimicrobial stewardship (AMS) involves a coherent set of processes that promote the rational use of antimicrobials.Gap statement. An AMS programme should be adapted and developed according to the available resources of a facility. This requires an analysis of the core AMS elements that are already in place and the resources available.Aim. This study aimed to assess the readiness of a tertiary healthcare facility and staff towards implementing an antimicrobial stewardship programme (ASP).Methodology. This study focused on two aspects during an AMS pre-implementation phase. A situational or strengths, weaknesses, opportunities, and threats analysis was conducted based on (1) a questionnaire on attitudes and perceptions of pharmacists, clinicians and nurses towards AMR and AMS and (2) a situational analysis on the readiness of the facility.Results. The questionnaire, which was available for completion between September 2021 and December 2021, was sent to a total of 3100 healthcare professionals (HCPs). Thirty-two (1.0 %) HCPs comprising 2 pharmacists, 16 clinicians and 14 nurses completed the questionnaire. Of the total participants, 31 (96.9 %) viewed AMR as a problem in South African hospitals and 29 (90.6 %) perceived AMR as a problem at their facility. The majority (n = 29, 90.6 %) of the participants were familiar with the term AMS, and 26 (81.3 %) participants agreed to willingly participate in any initiatives involving antimicrobial use at the facility. The situational analysis depicted existing strengths in terms of AMS structures such as the formation of an AMS committee and information and technology systems at the HCP's disposal. Weaknesses included the limited number of AMS activities being carried out and poor participation from HCPs within the AMS team.Conclusion. A pre-implementation phase in the building of an ASP can greatly assist in finding gaps for improvement, which can then be addressed in the implementation phase. Furthermore, the pre-implementation phase provides a baseline to measure improvements once the implementation phase has been instituted.

Interprofessional education in antimicrobial stewardship, a collaborative effort.

Introduction: Antimicrobial stewardship (AMS) education and interprofessional collaboration are integral to the success of a stewardship programme. An interactive interprofessional AMS workshop, designed to encourage workplace interprofessional collaboration was piloted in a tertiary hospital. Objectives: To obtain feedback to determine the suitability and sustainability of the AMS workshop. Methods: Feedback was elicited through a predesigned questionnaire containing both open-ended and closed questions on the content and structure of the workshop. Results: The survey had a 70% (n = 16) overall response rate. All participants agreed that the goals of the workshop were met and that the knowledge and skills gained from the workshop would help them in their AMS roles. All participants indicated that the workshop content, and the level at which it was pitched, met their expectations and that it had improved their knowledge and skills. All agreed that they found it advantageous and enjoyed learning as an interprofessional group. Open feedback showed that the workshop was found to be useful and would potentially result in improved patient care, dissemination of knowledge, improved teamwork and organizational culture. Conclusions: The positive feedback and changes made following the workshop demonstrated that a targeted AMS educational workshop adds value to an antimicrobial stewardship programme.

Evaluation of intermittent antimicrobial infusion documentation practices in intensive care units: A cross-sectional study.

OBJECTIVE: To observe nurse administration of carbapenem antibiotics, in the context of medication safety measures, in intensive care units. RESEARCH METHODOLOGY/DESIGN: A quantitative study was conducted using observation principles. SETTING: Three adult private and public Intensive Care Units in the health district of a capital city in KwaZulu-Natal, South Africa. MAIN OUTCOME MEASURES: Nurse practices were observed for double-checking of the medication order, medication vial, and method of preparation and administration. Infusion bags were inspected for nurse labelling of medication and patient details. Patient medication treatment charts were inspected for nurse signature. RESULTS: Carbapenem infusion administrations (n = 223) to twenty patients were observed. Adherence to the scheduled time occurred in 34.9% administrations, 5.4% doses were not given, and an incorrect dose given on 1.4% administrations. One hundred and forty-four (64.6%) infusion bags were inspected during the administrations: there was no medication label affixed to 21.5% bags, and only 8.3% of bags were labelled with essential details; the patient's name, drug, dose, date, time, signature of the nurse mixing and administering the dose, and signature of the secondary nurse. CONCLUSION: There was a lack of compliance with accepted medication risk mitigation measures. Sub-optimal double-checking resulted in the incorrect dose given, missed dose, and non-adherence to scheduled administration time. This has implications for the optimal administration of antimicrobial medications, raising concerns about the efficacy of treatment for critically ill patients. IMPLICATIONS FOR CLINICAL PRACTICE: Parenteral administration errors pose a challenge in acute care areas. Risk mitigation measures include double-checking of medications. If antimicrobial treatment is not administered at the prescribed dosing intervals, this may have implications for the efficacy of time-dependent broad-spectrum antibiotics such as carbapenems. Medication administration errors involving antimicrobial medications should therefore be considered as high-risk errors, with the potential to contribute towards antimicrobial resistance.