NOSO-5O2 is the first clinical candidate of a new antimicrobial class, the odilorhabdins. The pharmacodynamics of NOSO-502 was studied to establish the magnitude of the pharmacodynamic index (PDI) and make human dose predictions. In vitro experiments using different types of media were performed in time-kill curves and a pharmacokinetic model. In vivo experiments were conducted in the neutropenic murine thigh infection model. Six E. coli (MIC 1-8 mg/L) and two K. pneumoniae (MIC 1-2 mg/L) strains were used. 24 h bacteriostatic and 1- and 2-log10 kill effects were related to fAUC0-24/MIC and fAUC0-24/MIC per length of dosing interval (fAUC0-24/MIC·1/tau). Human pharmacokinetic parameters were predicted using interspecies allometric scaling and used to simulate the dose needed to reach the bacteriostatic PDI target for E. coli. The in vitro activity of NOSO-502 was dependent on the media and the strength of Mueller-Hinton Broth II (MHBII) used such that fAUC0-24/MIC ratios were higher when measured in 100% MHBII than 50% MHBII. In vivo for E. coli, the fAUC0-24/MIC for bacteriostatic effect and 1-log10 reduction in bacterial count were 10.7 ± 10.9 and 18.2 ± 16.5, respectively. The final human predicted parameters of the model had CV values of <20%. The human dose required to achieve the bacteriostatic fAUC0-24/MIC for each E. coli strain varied from 149 to 1717 mg/day. A combination of the use of PDI targets and prediction of human pharmacokinetics allowed effective doses of NOSO-502 in man to be estimated.
To evaluate the penetration of olorofim, a novel antifungal agent into the tissues of the rat. Quantitative whole-body autoradiography was used to assess the distribution and tissue penetration in male and female rats following a single 2-hour IV infusion of [14C]-olorofim. Radioactivity was rapidly and extensively distributed throughout many tissues in both sexes with maximal concentrations observed soon after start of the infusion. Thereafter radioactivity declined and at 336 h (final timepoint), concentrations of radioactivity in most tissues were below the limit of quantification. The pattern of radioactive distribution was similar at all timepoints with concentrations greatest in liver, kidney cortex, adrenal cortex, abdominal and brown fat; the lowest concentrations were observed in the whole eye and at the bone surface (with levels similar to plasma in bone marrow and uveal tract/retina). Tissue:plasma radioactivity concentration ratios for most tissues were above unity during the period 2.25 to 72 h post-start of infusion. Radioactivity was detected in tissues frequently reported as sites of systemic fungal infections such as the lung, brain, kidney, bone and eye. Pharmacokinetic analyses showed that at early timepoints >75% of circulating radiolabelled material was intact olorofim confirming that olorofim is present in these key tissues at levels similar to or exceeding those seen in plasma. Olorofim distributes widely into rat tissues including those frequently infected by fungi, indicating its potential to treat systemic fungal infections caused by susceptible species, a finding in agreement with recent clinical reporting from a Phase 2 trial.
Polymyxin B has been used for many years to treat Acinetobacter baumannii, but little is known about its pharmacodynamics (PD). We aimed to describe the PD of polymyxin B in treating A. baumannii infections. Using the murine neutropenic thigh and lung infection models we determined the magnitude of the pharmacokinetic (PK)/PD index correlating with efficacy for eight A. baumannii strains. PD was analysed using the Emax model to determine PD targets. Using published human PK data the PTAs were calculated. In the thigh infection model, stasis, 1-log10 and 2-log10 kill were reached for all strains. Median (range) fAUC/MIC (area under the unbound concentration-time curve divided by the MIC) targets for stasis, 1-log10 kill and 2-log10 kill were 2.1 (1.0-11), 2.9 (1.0-15) and 4.0 (1.1-20), respectively. In contrast, in the lung model, 2-log10 kill was reached in 2/8 strains only, and there was insufficient killing at tolerated exposures to determine PD fAUC/MIC targets. For the standard human dosing regimen, PTAs derived from the thigh model were inadequate at the USCAST (United States Committee on Antimicrobial Susceptibility Testing) clinical breakpoint and a protein binding of 90%. Whereas polymyxin B treatment had good efficacy in the murine thigh infection model, in the lung infection model its effect was limited. PD targets, with MICs of circulating A. baumannii isolates of ≤2 mg/L, are not reached with a standard human dosing regimen and will probably exceed threshold values for toxicity. These data suggest that the efficacy of polymyxin B as monotherapy for A. baumannii infections is questionable.
Olorofim is an antifungal agent with a novel mechanism of action against Aspergillus spp., rare moulds and dimorphic fungi. Preclinical studies reported unidirectional antagonism between olorofim and mould-active azoles (e.g. azoles other than fluconazole) against Aspergillus fumigatus in which the azole reduces the antifungal effect of olorofim. To assess the potential clinical impact of this preclinical finding, we compared outcomes of olorofim with and without concomitant azoles from a Phase 2b salvage study in patients with invasive fungal diseases with few or no treatment options. Analyses are limited by the study size but outcomes were similar for olorofim with and without an azole in combination (whether mould-active or not) at Days 42 (the primary study endpoint) and 84 for both Mycoses Study Group-European Organization for Research and Treatment of Cancer (MSG-EORTC) responses and for all-cause mortality in patients with aspergillosis (77 not receiving an azole, 24 receiving an azole in combination), in patients with coccidioidomycosis (11 not receiving an azole, 30 receiving an azole in combination) and in patients with other fungal infections (50 not receiving an azole, 10 receiving an azole in combination). In addition, the rate of drug-induced liver injury was not increased in patients receiving combination with an azole. Although limited by small numbers of patients for individual fungi, this analysis did not demonstrate a pattern of reduced clinical efficacy or tolerability of olorofim when given in combination with either the mould-active azoles or with fluconazole.Trial registration number. NCT03583164.
The incidence of bloodstream infection (BSIs) due to extended-spectrum β-lactamase (ESBL) producing Escherichia coli is increasing worldwide. There is controversy as to whether ESBL production in itself is associated with higher mortality. The aim of this study is to evaluate the impact of ESBL production on mortality in BSIs due to E. coli considering the effect of confounders. PROBAC study is a prospective, multicentre, cohort study performed in 26 Spanish hospitals (October 2016-March 2017). All patients with E. coli BSIs were included. The outcome variable was all-cause 30-day mortality. Confounding was controlled by calculating a propensity score (PS) for ESBL production using baseline variables. PS were used as covariable, for matching, for inverse probability of treatment weight analysis and for stratified analysis within the PS quartiles. A total of 2394 cases were included, of which 322 (13.5%) were ESBL-producing isolates. The frequency of appropriate empirical treatment, in ESBL-producing and non-ESBL-producing isolates, was 53.7% and 92.0%, respectively. Thirty-day mortality was 14.6% in ESBL-producing isolates versus 9.6% in non-ESBL-producing isolates (P = 0.006), for a crude OR of 1.61 (95% CI: 1.14-2.27; P = 0.006). When we adjusted by PS and appropriate empirical treatment, the OR changed to 1.12 (95% CI: 0.75-1.67; P = 0.584). Other PS applications provided similar results. BSIs due to ESBL-producing E. coli were associated with higher mortality in the crude analyses; however, the estimate of the association is reduced after adjustment for baseline variables and empirical therapy, and is not significant in matched analysis.
To determine the frequency of cyp51A variants among a contemporary collection of triazole-resistant Aspergillus fumigatus clinical isolates from the USA and compare their specific contribution to reduced triazole susceptibility. The genomes of 87 isolates with decreased susceptibility to at least one mould-active triazole antifungal collected between 2007 and 2020 were sequenced. The cyp51A variants were identified and genetically introduced into a cyp51A-null strain. Antifungal susceptibilities for the mould-active triazole antifungals were determined following CLSI guidelines, and variant positions were mapped after protein homology modelling. Most clinical isolates (60%) carried one of 15 variants that reduced susceptibilities to short-chain (G448S, Y121F, TR46/Y121F/T289A and TR46/Y121F/T289A/N512), long-chain (P216L, F219S and substitutions in the G54 and M220 residues) or multiple (TR34/L98H and TR34/L98H/S297T/F495I) triazoles. While TR34/L98H and TR46/Y121F/T289A were among the most common variants affecting susceptibility, occurring in 13 and 9 isolates, respectively, variants exclusively affecting the coding region and influencing susceptibility were most common, occurring in 31 isolates. A total of 14 isolates (16%) exhibited reduced susceptibility that could not be explained by variants in any known resistance determinants (cyp51A, hmg1 or hapE). Our findings demonstrate the range of mutations affecting triazole resistance among US isolates and provide a much-needed side-by-side comparison of the impact of these variants on the most currently used mould-active triazole antifungals. Moreover, they underscore the extent to which triazole resistance remains unexplained by known genetic determinants and the need for further discovery.
To evaluate the long-term sustainability and impact of an integrated electronic medical record-driven antimicrobial stewardship (AMS) ward round in an ICU at a tertiary referral hospital. The study assessed antimicrobial prescribing patterns, acceptance of stewardship recommendations, and antimicrobial consumption over 7 years. A prospective review commenced with implementation of the ICU-AMS ward round at Austin Health in 2017. When AMS recommendations were given, data were collected including patient demographics, antimicrobial prescribing, classification of recommendation, and acceptance. Antimicrobial use was assessed via DDDs per occupied bed day per month and analysed using interrupted time series analysis. Logistic regression examined patient and clinician factors associated with recommendation acceptance. Over 7 years, 9163 AMS recommendations were made for 4610 patients. Recommendation acceptance was high, with antibiotic escalation the most accepted (95%) and discontinuation least accepted (82%). Recommendations were more likely to be accepted in immunocompromised (OR 1.31, P = 0.003) and non-surgical patients (OR 1.31, P < 0.001). Recommendations provided by AMS physicians who identified as men were more likely to be accepted (OR 1.23, P = 0.003). Antimicrobial consumption trends showed significant decreases in piperacillin/tazobactam, meropenem, ciprofloxacin and vancomycin use post-implementation. Amoxicillin/clavulanate use increased, suggesting potential compensatory prescribing. This study demonstrates the long-term effectiveness and sustainability of an ICU-AMS programme, achieving high recommendation acceptance and sustained reductions in broad-spectrum antimicrobial use. Continued efforts should focus on optimizing stewardship practices, addressing barriers to acceptance, and evaluating compensatory prescribing patterns.
To search for colistin heteroresistance (CHR) prevalence in Acinetobacter baumannii bloodstream isolates, and to investigate potential molecular contributors to CHR using WGS. A total of 267 A. baumannii isolates were recovered from bloodstream infections between January 2014 and July 2018 at a tertiary care hospital in Türkiye. Antimicrobial susceptibility to colistin was assessed using the broth microdilution method. CHR was evaluated by population analysis profiling (PAP). WGS was performed on a representative heteroresistant strain (A325) to investigate putative CHR-associated mechanisms. Thirty-five isolates (13.9%) were classified as colistin-resistant. CHR was identified in 86 of 267 isolates (32.2%) using PAP. Comparative genomic analysis of the colistin-susceptible main population and the colistin-resistant subpopulation of isolate A325 revealed identical mutational profiles in known resistance-associated genes, with the exception of a partial deletion in the lpxD gene between codons 2 and 75, identified exclusively in the resistant subpopulation. Notably, tetracyclines, macrolides and aminoglycosides were fully inactive in the colistin-susceptible main population, whereas an inhibition zone around these antibiotic discs was observed with the colistin-resistant subpopulation. This study demonstrates a high prevalence of both colistin resistance and CHR among A. baumannii bloodstream isolates. The identification of a partial lpxD deletion in the resistant subpopulation of the colistin-heteroresistant isolate suggests a potential contributory role of LPS-related alterations in CHR. Inverse antimicrobial activity profiles between populations highlight distinct resistance mechanisms potentially shaped by evolutionary trade-offs and collateral sensitivity.
Providing care to multi-drug resistant organisms (MDRO) carriers has a profound impact on healthcare providers (HCPs), potentially challenging their personal and professional values. Understanding HCPs' experiences is key to addressing challenges in providing care to carriers and to support HCPs when providing this care. This review aims to examine experiences of HCPs with a focus on moral dimensions of care. We systematically searched Cochrane library, CINAHL, EMBASE, PsycINFO, PubMed and Web of Science. Experiences were analysed using a thematic analysis approach. This review was registered in PROSPERO (CRD42023418340). Eighteen studies were included, primarily conducted in hospitals and nursing homes. Experiences were categorized into three levels: the individual HCP, the care practice and the institutional setting. First, HCPs are uncertain about personal health and safety, have different knowledge levels and question proportionality of infection prevention and control (IPC) measures. Second, HCPs say that wearing PPE limits connection with carriers and note various other challenges regarding the care relationship such as considering how often to enter an isolation room. Third, HCPs face shortages in resources such as time, experience poor infrastructure making it difficult to adhere to IPC measures and specify a need for management support regarding caring for carriers. Moral dimensions of care received limited attention. An example is that HCPs do not want to betray colleagues who ignore IPC measures, but simultaneously fear transmission due to poor compliance. The diverse experiences provide input for future interventions to support HCPs in caring for MDRO carriers. The limited attention to moral dimensions of care restricts understanding of HCPs' values and challenges. Strengthening support requires further research, particularly qualitative studies led by ethics experts.
Oritavancin is a lipoglycopeptide with sustained bactericidal activity against Gram-positive bacteria due to its prolonged half-life. This Systematic Review aimed to extrapolate, from in vitro/in vivo or clinically study, the most relevant PK/PD target to inform therapeutic drug monitoring-guided oritavancin dose optimization in clinical practice. Following the PRISMA 2020 Statement and adopting the PICO strategy, a comprehensive search was conducted in PubMed, Scopus and Cochrane databases up to September 2025. Of 186 articles screened, 52 were considered eligible for full-text assessment. Nine studies were included and proceeded with data extraction and synthesis steps. In vitro studies showed a marked concentration-dependent bactericidal activity at fCmax > 4-16 mg/L against different bacterial strains, further confirmed by in vivo animal models (fCmax/MIC > 6 to 14). However, the only identified in-human daily repeated doses study supported the findings of an exposure-response relationship with %fT > MIC as predictive of microbiological and clinical success. The peculiar pharmacokinetics profile of oritavancin results in a borderline collinearity between the two PK/PD indices fCmax/MIC and %fT > MIC in relation to microbiological and clinical success rates. On the basis of available in vitro/in vivo data supporting concentration-dependent killing activity, a single 1200 mg oritavancin dose should be adequate for most infections. In special patient populations, or when multidose oritavancin regimens are adopted for long-term antibiotic treatment, therapeutic drug monitoring supported by expert clinical pharmacological advice may be valuable to optimize the initial and next-dose strategy (1200 mg or 800 mg) and to define the timing of re-administration.
Carbapenemase-producing Enterobacterales (CPE) represent a serious health care concern and their spread in animals has become alarming. Following several cases of CPE infections in a companion animal clinic, the role of the clinic backyard lawn used for dog relief walks of hospitalized dogs as a CPE reservoir has been investigated over a 4-year period (2020-2023). Soil surface samples were taken through application of sterile wipes. After enrichment in Mueller-Hinton broth and selection on CHROMID® (OXA-48, CARBA) agar plates, isolates were identified by MALDI-TOF MS. CPE isolates were submitted to microdilution antimicrobial susceptibility testing and sequenced with short (Illumina) and long (ONT) read technologies to obtain complete circular genomes to perform antimicrobial resistance gene screening, phylogenetic (cgMLST, cgSNPs) and plasmid analyses. A total of 32 CPE representing eight different species were isolated, with E. coli (n = 15) and E. hormaechei (n = 7) being predominant. Genome-wide typing identified 11 different subtypes of E. coli and three of E. hormaechei, highlighting bacterial diversity. Thirty CPE contained an identical 63 589-bp IncL plasmid only differing by inversion of the blaOXA-48-containing transposon (Tn1999.2, invTn1999.2), and two CPE contained a 51 479-bp blaOXA-181-containing IncX3 plasmid. Strains associated with infections or carriage in hospitalized pets were also present in the lawn. The canine relief area of a veterinary clinic was identified as a long-term environmental reservoir for CPE, mainly due to the hyperepidemic blaOXA-48-positive IncL plasmid spreading between various bacterial species, emphasizing the urgent need for an extended hygiene concept including the outdoor environment.
Acquired resistance to last-line linezolid has emerged in Enterococcus spp. and can be conferred by the optrA gene. Here, we study the global genomic context of optrA in E. faecalis and E. faecium, to understand its dissemination pattern. We identified 565 enterococcal genomes from NCBI and 86 optrA-containing enterococcal plasmids from the plasmid database, PLSDB. We characterized the plasmid replication and antimicrobial resistance genes of optrA-containing plasmids and the plasmid pangenome. To identify prevalent optrA genetic contexts, we mapped the genomes against PLSDB plasmid and transposon Tn6674 (prevalent in E. faecalis) sequences using minimap2. A greater proportion of E. faecium (47.3%: n = 70/149) carried the optrA gene on plasmids than E. faecalis (28.9%: n = 120/416). In E. faecalis, the major optrA contexts were represented either by a Tn6674 transposon (28.0%) or a plasmid-associated MDR fexA-optrA-erm(A) genetic unit (32.9%), and were associated with distinct E. faecalis phylogroups. In E. faecium, the dominant optrA contexts were the optrA-erm(A)/(B) genetic unit (24.2%), the fexA-optrA-erm(A) unit (16.8%), and the Tn6261 transposon (14.1%). We observed that in some E. faecalis and E. faecium plasmids, the fexA-optrA-erm(A) unit was flanked by IS1216E elements on both sides, suggesting the mobilization of this MDR gene cassette by IS1216E-like elements into diverse plasmid backgrounds. This is the first study to investigate the genomic context of optrA in a phylogeographically diverse enterococcal genome collection. We demonstrated that mobile genetic elements play a key role in the global expansion of optrA and highlighted the underlying public health concern imposed by plasmids in drug-resistant enterococcal dissemination.
Effective alternatives to standard of care treatment for E. faecalis infective endocarditis (EFIE) are needed. Some in vitro studies have suggested daptomycin and ceftaroline have synergistic activity against E. faecalis. We aimed to assess the in vitro and in vivo activity of daptomycin in combination with ceftaroline against E. faecalis clinical isolates with and without high-level of aminoglycoside resistance (HLAR). A panel of six endocarditis-associated E. faecalis isolates were used for time-kill assays at initial standard and high inocula. Daptomycin (10 mg/kg/day intravenously) and daptomycin (10 mg/kg/day iv) plus ceftaroline (600 mg q12 hours intravenous) were compared in vivo using a human-like pharmacokinetic model in two treatment groups using the experimental EFIE model in rabbits. The combination of daptomycin plus ceftaroline achieved synergy against all three HLAR and all three non-HLAR strains in time-kill assays at initial standard inoculum. A bactericidal effect was observed in two of the three HLAR E. faecalis isolates. For HLAR EFAE-188, the use of daptomycin plus ceftaroline significantly decreased the bacterial density in vegetations compared with daptomycin alone (median density 5.2 versus 6.7 log10 cfu/g; P = 0.028). For non-HLAR EFAE-468, the bacterial density in vegetations was lower with the combination therapy than with daptomycin alone (median density 5.2 versus 6.8 log10 cfu/g; P = 0.072). Adding ceftaroline prevented the development of daptomycin-resistant E. faecalis isolates in all cases. Daptomycin plus ceftaroline represents a promising alternative for treating EFIE. Further clinical studies are needed to confirm these findings.
Bone and joint infections (BJIs) due to third-generation cephalosporin-resistant (3GC-R) Enterobacterales are particularly challenging-to-treat infections, and their treatment often relies on carbapenems. Due to its stability towards various beta-lactamases, as well as its limited spectrum of activity, temocillin could be a promising alternative. This study evaluated the in vitro activity of temocillin against a collection of 3GC-R Enterobacterales isolates from BJIs and modelled the probability of PK/PD target attainment according to the dosage regimen used. MICs of temocillin and seven comparators (ertapenem, imipenem, meropenem, levofloxacin, delafloxacin, doxycycline and tigecycline) were determined using gradient strips for 104 3GC-R Enterobacterales isolates from BJIs in three French hospitals. Isolates were characterized about their mechanism of resistance to 3GC (ESBL or hyperproduced cephalosporinase). PK/PD simulations were performed with six dosage regimens and different stages of renal function in order to calculate PTA according to temocillin MIC. Temocillin showed a susceptibility rate of 92.3% (96/104) in 3GC-R isolates from BJIs: 95.3% (61/64) in ESBL producers and 87.5% (35/40) in AmpC hyperproducers. Temocillin was the only alternative to carbapenems for 25% (26/104) of isolates. PTA values increased with declining renal function. In normorenal patients, none of the tested regimen achieved adequate PTA up to the Enterobacterales breakpoint (16 mg/L). This study demonstrated the high in vitro efficacy of temocillin against 3GC-R Enterobacterales from BJIs, regardless of the underlying resistance mechanism. However, dosage adjustments based on the strain's MIC and the patient's renal function are crucial for optimal efficacy.
This study aims to elucidate the molecular mechanism of enhanced florfenicol resistance mediated by the resistance-enhanced RE-CmeABC in Campylobacter, with a focus on the evolution of its efflux function. The complex models of FFC with wild-type CmeB and RE-CmeB are constructed by molecular modelling methods, and the efflux channels and corresponding bottleneck residues are predicted by CAVER program. Then mutants are constructed on the basis of predicted amino acid residues by natural transformation and functional confirmation is performed by antimicrobial susceptibility testing and accumulation assay. Channel P1 is identified as the optimal FFC efflux channel, and the specific residues composed are illustrated. The corresponding bottleneck residues are S615, S616, Q87, T614, K89, S47 and S84. Among them, mutations of Q87 and K89 are non-conserved, having a particularly pronounced effect on efflux function. Decreased (8-fold) MIC and increased FFC accumulation were observed in MU-11168-RE-CmeABC (with mutated RE-CmeB) compared with that in 11168-RE-CmeABC (with RE-CmeB), respectively, which verifies the predicted FFC efflux tunnel is reliable. This demonstrates that the P1 channel in RE-CmeB has evolved into a dominant and specialized extrusion pathway with minimal functional redundancy, fundamentally underpinning its enhanced resistance. Our findings reveal that the enhanced resistance is primarily due to a functional specialization of the P1 efflux channel in RE-CmeB. This elucidation, strongly supported by the concordance between computational predictions and experimental data, provides a mechanistic basis and high-value targets (Q87/K89) for the development of efflux pump inhibitors against multidrug-resistant Campylobacter.
The emergence and spread of hypervirulent Klebsiella pneumoniae (hvKp) poses a serious and growing challenge to public health worldwide. However, the knowledge regarding hvKp of animal origin remains very limited. In this study, we characterized a colistin-resistant hvKp isolate obtained from healthy chicken faeces and gained insight into the molecular basis of hypervirulence and colistin resistance. Antimicrobial susceptibility testing was conducted by broth microdilution. The hypermucoviscous phenotype was determined by string tests. Whole-genome sequencing (WGS) was performed using a combination of Illumina NovaSeq/Oxford Nanopore PromethION platforms. Sequence alignment and complement assays were used to identify the mutations conferring colistin resistance. The virulence was investigated using both Galleria mellonella larvae and mice infection models. This strain KP20 displayed a hypermucoviscous phenotype and strong biofilm-forming capacity. WGS revealed that strain KP20 carried a pLVPK-like virulence plasmid with a novel replicon profile (IncFIB/RepB), harbouring key hypervirulence-associated genes, including iucABCD-iutA, iroBCDN, peg-344 and rmpA/rmpA2. Moreover, a plasmid harbouring the trimethoprim resistance gene dfrA50, pKP20-2, was identified as a member of the phage-like plasmids: genetic elements that function both as phages and plasmids. Sequence analysis and functional confirmation suggested that mutations in the crrB gene contributed to the colistin resistance observed in this strain. The virulence of KP20 was confirmed in the animal infection models. In this study, a high-risk ST412-K57 colistin-resistant hvKp of animal origin was identified and characterized. According to the One Health concept, our findings highlight the critical need for implementing enhanced molecular surveillance of hvKp in animals.
Therapeutic drug monitoring (TDM) may help optimize beta-lactam antibiotic dosing in patients with deep-seated infections. However, its impact on clinical outcomes remains unclear. The objective of this review was to evaluate the existing evidence on the role of TDM and pharmacokinetic/pharmacodynamic (PK/PD)-guided optimization of beta-lactam antibiotic dosing in achieving PK/PD targets, and improving clinical outcomes in patients with deep-seated infections. We conducted a systematic review of studies reporting on beta-lactam TDM, PK/PD target attainment, and clinical outcomes in adult (≥18 years) patients with confirmed deep-seated infections, including complex bacteraemias with a suspected or proven deep-seated source, infective endocarditis, bone and joint infection, and epidural abscess. The search was conducted using MEDLINE (via PubMed), Embase, CINAHL and CENTRAL from inception to June 2025. Twelve studies were included in the final analysis. Considerable variability was observed in PK/PD target definitions and attainment, dosing adjustments and outcome reporting. Eleven of the twelve studies were rated as poor quality on the Newcastle-Ottawa Scale due to lack of comparability. Only one study included a non-TDM comparator group and the authors reported no significant difference in clinical outcomes. Three studies showed a trend towards improved clinical outcomes with TDM-guided dosing. TDM frequently led to dose reductions due to concerns of beta-lactam antibiotic toxicity with standard dosing. Current evidence supporting beta-lactam antibiotic TDM in deep-seated infections is limited by methodological heterogeneity and poor study quality. Well-designed trials are needed to establish the clinical utility of TDM in this setting.
Neomycin is widely used in livestock to control colibacillosis. Resistance among clinical Escherichia coli is increasing, likely driven by the use of this aminoglycoside following the European restrictions on zinc oxide and colistin. The aim of this study was to investigate the genetic epidemiology of neomycin-resistant E. coli across six animal species and five European countries. A total of 750 neomycin-resistant E. coli isolates were included, combining retrospectively identified genomes with prospectively isolated and sequenced strains from multiple animal species. Genomic analyses, based on short reads (n = 529), long reads (n = 177), or hybrid assemblies (n = 44), included phylogenetic comparison, and identification of neomycin resistance genes and their genetic contexts. Neomycin resistance was mediated by aph(3')-Ia in 98.2% of the isolates, which were distributed across 28 clonal complexes, predominantly CC10, which was frequently detected in all countries and hosts. aph(3')-Ia was primarily carried by conjugative plasmids of diverse replicon types (70.3%) and embedded in two transposons (Tn903 and Tn4352) and three newly identified genetic elements, while a chromosomally integrated element accounted for the remaining 29.7%. Plasmids carrying aph(3')-Ia frequently co-harboured tetracycline and trimethoprim-sulfamethoxazole resistance genes, with IncX1 plasmids additionally containing chloramphenicol and quinolone resistance determinants. Phylogenetic analysis revealed dissemination of plasmid-borne elements across multiple lineages, while the chromosomal element was mostly restricted to ST117, ST88, and ST189. The spread of neomycin resistance in E. coli from European livestock is primarily driven by the mobility of aph(3')-Ia embedded in diverse genetic contexts and plasmid backbones, promoting co-transfer of other resistance determinants.
Aligning national standard treatment guidelines (STGs) with WHO AWaRe Book recommendations where appropriate is a key antimicrobial stewardship goal. Antibiotic recommendations in national STGs vary significantly, creating gaps that require evaluation to help address rising AMR rates. We analysed adult STGs from 24 countries in six WHO regions for 11 infections commonly seen across countries in the primary care section of the WHO AWaRe Book. These included acute otitis media (AOM), pharyngitis, sinusitis, community-acquired pneumonia (CAP), chronic obstructive pulmonary disease, lower urinary tract infections, gastroenteritis (bloody and non-bloody), oral and dental infections, skin and soft tissue infections and enteric fever. National STGs were compared with WHO AWaRe recommendations to assess alignment of first-line antibiotic recommendations. 522 different first-line oral antibiotic regimens were collected from the different STGs in 24 countries across 6 WHO regions. Access antibiotics were recommended in 65.7% of the regimens, while Watch antibiotics accounted for 34.3% of first-line recommendations globally, with limited recommendations of Reserve antibiotics. The Western Pacific Region (76.4%), showed the highest proportions of Access group antibiotic recommendations. Infection-specific analysis showed significant variation in alignment, with a higher alignment for enteric fever, non-bloody gastroenteritis and cystitis, and a lower alignment for CAP, oral and dental infections, and AOM (P = 0.0089). First-line antibiotic recommendations in adult STGs showed moderate alignment with WHO AWaRe Book treatment guidance, with regional variability. Aligning first-line recommendations with the WHO AWaRe Book guidance in primary care would assist stewardship programmes.
Syphilis remains a global public health concern, particularly in pregnancy due to the risk of congenital syphilis. The WHO recommends benzathine penicillin G (BPG) as the standard treatment in pregnant women, whilst the optimal dosing strategy has not been established, particularly in relation to the impact of gestational age. This study sought to characterize the pharmacokinetics (PK) of a three-dose regimen of intramuscular BPG, given at weekly intervals, in pregnant women with syphilis. A prospective PK study was undertaken in 30 pregnant Ethiopian women (second (n = 15) and third (n = 15) trimester) with syphilis (late or of unknown duration) who received three, once-weekly doses of intramuscular BPG (2.4 million units per dose). Dried blood spot samples were collected for up to 8 weeks after the first dose and benzylpenicillin concentrations quantified by liquid chromatography-mass spectrometry. Population PK analysis was performed using nonlinear, mixed-effects modelling. The PK model demonstrated biphasic absorption with a second-phase absorption half-life of 18 days. Gestational age did not impact apparent clearance or volume of distribution. Benzylpenicillin concentrations remained above the target threshold (18 ng/mL) for at least 28 days after the second dose in all women (median total cumulative time >18 ng/mL was 46 days [interquartile range 41-52 days)]. However, six participants (21%) exhibited subtherapeutic concentrations before the scheduled second injection (Day 7). A three-dose, once-weekly intramuscular BPG regimen maintained therapeutic concentrations for at least 4 weeks, suggesting potentially simpler, single- or two-dose BPG regimens in pregnant women with syphilis should be evaluated for both PK exposure and clinical outcomes.