Hendrickx S, Ilbeigi K, Thoré ESJ
… +17 more, Bertram MG, Calvo-Alvarez E, Cintesun S, Olías-Molero AI, Corral MJ, Mateo-Barrientos M, Estaquier J, Pomel S, Alunda JM, Gul S, Van Bocxlaer K, Frézard F, Tavares J, Da Silva AC, Costi MP, Maes L, Caljon G
J Antimicrob Chemother
· 2026 Apr · PMID 42085493
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Given the impact of kinetoplastid diseases, the limited therapeutic options and risk of treatment failure, continued research efforts to discover novel drug entities are required. The ambition to deliver drug development...Given the impact of kinetoplastid diseases, the limited therapeutic options and risk of treatment failure, continued research efforts to discover novel drug entities are required. The ambition to deliver drug development candidates has mainly been taken on board by academia and public private partnerships, but remains highly challenging because of the lack of adequate funding and standardized laboratory procedures. Establishing a systematic roadmap of experiments and decision criteria to attain high-quality leads and drug candidates with lower risk profiles remains the logical path to deliver more compelling proof-of-concepts for impactful diseases, such as African trypanosomiasis, Chagas disease and visceral and cutaneous leishmaniasis. In a three-part series, a structured roadmap from 'hit finding' to 'drug development candidate' is presented with a focus on the minimal essential data package, laboratory experimental models and endpoints. Part 1 introduces the concept of a pragmatic framework with reference to specific preclinical R&D stages: (i) hit finding, (ii) hit profiling, (iii) lead definition and (iv) drug development candidate to support a more focused early development path that remains accessible to engaged stakeholders. The experiment-oriented roadmap is presented in the next parts addressing the discovery and characterization of confirmed hits (Part 2) and the lead discovery phase towards identification of a drug development candidate (Part 3). Although specifically focusing on kinetoplastid diseases, the principles also apply to small-molecule preclinical R&D against other microbial diseases, evidently with specific adaptation of the primary pharmacology models.
Porlier A, Nadeau M, Laflamme J
… +8 more, Pilote S, Gervais P, Drolet B, Tchernof A, Biertho L, Marceau S, Simard C, Julien F
J Antimicrob Chemother
· 2026 Apr · PMID 42085492
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BACKGROUND AND OBJECTIVES: Optimal cefazolin dosing for surgical prophylaxis in patients with severe obesity remains controversial, particularly regarding tissue exposure at the surgical site. Plasma concentrations may n...BACKGROUND AND OBJECTIVES: Optimal cefazolin dosing for surgical prophylaxis in patients with severe obesity remains controversial, particularly regarding tissue exposure at the surgical site. Plasma concentrations may not reliably reflect pharmacologically active antibiotic levels in target tissues. This study aims to characterize total and calculated unbound concentrations of cefazolin in subcutaneous adipose tissue, dermis and plasma in patients with severe obesity undergoing bariatric surgery, and to assess pharmacodynamic target attainment across clinically relevant MIC thresholds. METHODS: In this prospective observational study, patients undergoing sleeve gastrectomy received cefazolin prophylaxis according to current guidelines (2 or 3 g intravenously). Plasma, dermis and adipose tissue samples were collected at incision (T0), 30 min (T30) and end of surgery (Tend). Total cefazolin concentrations were quantified using validated HPLC methods. Concentration-time profiles were analysed using linear mixed-effects models adjusted for age, BMI and creatinine clearance. Target attainment was evaluated at MIC thresholds of 2, 4 and 8 mg/L. RESULTS: Dermis and plasma total cefazolin concentrations consistently exceeded all MIC thresholds in both dosing groups, whereas adipose tissue concentrations were more variable, with reduced attainment at higher MICs. Calculated unbound cefazolin concentrations demonstrated marked matrix-dependent differences: plasma unbound levels consistently exceeded all targets, dermal unbound concentrations increased significantly from T0 to Tend and adipose tissue unbound concentrations remained low across all time points. Increasing the dose from 2 to 3 g modestly improved total adipose tissue target attainment but did not substantially enhance unbound adipose tissue exposure. No surgical site infections occurred. CONCLUSIONS: In patients with severe obesity, guideline-recommended cefazolin dosing provides adequate plasma and dermis exposure but fails to ensure reliable unbound adipose tissue concentrations. These findings highlight the limitations of plasma-based assessments and support tissue-informed, individualized prophylactic strategies in bariatric surgery.
Spahr Y, Fernandez JE, Endimiani A
… +3 more, Schuller S, Rohrbach H, Perreten V
J Antimicrob Chemother
· 2026 Apr · PMID 42057444
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OBJECTIVES: 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,...OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: To investigate the emergence of cefiderocol resistance in a clinical Klebsiella oxytoca isolate and to identify the underlying mechanism. METHODS: A clinical isolate of K. oxytoca susceptible to cefiderocol wa...OBJECTIVE: To investigate the emergence of cefiderocol resistance in a clinical Klebsiella oxytoca isolate and to identify the underlying mechanism. METHODS: A clinical isolate of K. oxytoca susceptible to cefiderocol was exposed to stepwise increasing cefiderocol concentrations via broth microdilution in iron-depleted CAMHB (ID-CAMHB) to select spontaneous mutants. WGS identified potential resistance-associated mutations. CRISPR-Cas9 genome editing was used to confirm causality. Growth curves in CAMHB and ID-CAMHB were performed to assess potential growth alterations. RESULTS: A spontaneous mutant with elevated cefiderocol MIC (16 mg/L) carried a Q1008L substitution in the miniconductance mechanosensitive channel MscM. CRISPR-edited strains reproduced this phenotype. Growth kinetics did not reveal an obvious growth defect under the tested in vitro conditions. CONCLUSION: This is the first report linking cefiderocol resistance to a mutation in MscM in K. oxytoca. Although observed in a single isolate, the lack of an apparent growth defect under the tested conditions suggests that this resistance mechanism may persist in the absence of antibiotic pressure.
BACKGROUND: 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,...BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
OBJECTIVES: 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...OBJECTIVES: 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). MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: Daptomycin plus ceftaroline represents a promising alternative for treating EFIE. Further clinical studies are needed to confirm these findings.
Gómez Londoño LF, Souza ACO, Burt B
… +8 more, Das S, Ge W, Meza-Perez V, Wiederhold NP, Shelat AA, Cuomo CA, Fortwendel JR, Rogers PD
J Antimicrob Chemother
· 2026 Apr · PMID 42011663
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OBJECTIVES: 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 tria...OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
Pirolo M, Abuoun M, Duggett N
… +9 more, Haenni M, Fritz MK, Nilsson O, Veldman KT, Brouwer MSM, Davies J, Stubberfield E, Damborg P, Guardabassi L
J Antimicrob Chemother
· 2026 Apr · PMID 41995000
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BACKGROUND AND OBJECTIVES: 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...BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Korvin K, Goutelle S, Laffont-Lozes P
… +6 more, Villa F, Martin A, Chiaruzzi M, Loubet P, Sotto A, Larcher R
J Antimicrob Chemother
· 2026 Apr · PMID 41994999
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BACKGROUND: Cefepime is a key carbapenem-sparing agent due to its stability against AmpC β-lactamases. However, high plasma concentrations are associated with cefepime-induced neurotoxicity (CIN). Following 2019 EUCAST r...BACKGROUND: Cefepime is a key carbapenem-sparing agent due to its stability against AmpC β-lactamases. However, high plasma concentrations are associated with cefepime-induced neurotoxicity (CIN). Following 2019 EUCAST reclassification of 'intermediate' as 'susceptible, increased exposure', higher doses (6 g/day) are often recommended. Pharmacokinetic/pharmacodynamic (PK/PD) simulations suggest that a reduced daily dose of cefepime 4 g/day administered by continuous infusion may achieve adequate target attainment while limiting toxicity, but real-world clinical data are scarce. METHODS: We conducted a prospective, single-centre observational study including adult inpatients treated with cefepime administered as a 2 g loading dose followed by continuous infusion of 4 g/day. Therapeutic drug monitoring was performed to assess steady-state free cefepime concentrations (ƒCss). The primary endpoint was pharmacodynamic target attainment (100% ƒT > MIC) for EUCAST 'susceptible, increased exposure' breakpoints. RESULTS: Among 46 included patients, median ƒCss was 26.2 mg/L (IQR 18.4-33.2). Pharmacodynamic targets were achieved in 96% of patients for Enterobacterales (MIC 4 mg/L) and 93% for Pseudomonas aeruginosa (MIC 8 mg/L). Clinical efficacy was observed in 96% of cases. Signs consistent with CIN occurred in three patients (6.5%), mainly in the context of renal function deterioration or pre-existing neurological vulnerability. CONCLUSION: A reduced-dose cefepime regimen consisting of 4 g/day administered by continuous infusion achieves high pharmacodynamic target attainment with a favourable efficacy-toxicity balance in real-life clinical practice. This strategy represents a promising alternative to higher-dose regimens and supports individualized dosing guided by renal function and therapeutic drug monitoring.
J Antimicrob Chemother
· 2026 Apr · PMID 41988658
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OBJECTIVES: The macrolide resistance in Bordetella pertussis cannot be fully explained by 23S rRNA mutations, underscoring the need for comprehensive methods to detect resistant isolates and clarify mechanisms. METHODS:...OBJECTIVES: The macrolide resistance in Bordetella pertussis cannot be fully explained by 23S rRNA mutations, underscoring the need for comprehensive methods to detect resistant isolates and clarify mechanisms. METHODS: Whole-genome sequencing data from 556 isolates with macrolide resistance information, including 398 resistant and 158 sensitive strains, were retrieved from the National Center for Biotechnology Information (NCBI). A k-mer-based genome-wide k-mer-based association studies using Pyseer identified 1322 resistance-associated k-mers. Refinement with Scoary2, least absolute shrinkage and selection operator (LASSO) and variable selection using random forests (VSURF) yielded six key k-mers, enabling the construction of a simplified model for predicting resistance. RESULTS: A total of 1322 different k-mers were involved in resistance. In the further simplified model, only six k-mers were included, in which a DHCW motif cupin fold protein (odds ratio [OR]: 25.84, 95% confidence interval [CI]: 15.58-44.03) and an IS481 insertion sequence located near infA (OR: 28.96, 95% CI: 7.64-243.86) showed strong associations with resistance. Despite the reduced feature set, the simplified model achieved classification performance comparable to the initial model, with similar sensitivity (97.7% versus 98.7%), specificity (92.1% versus 99.5%), and accuracy (93.4% versus 99.3%). Notably, it maintained a robust area under the receiver operating characteristic curve (area under the curve = 0.98), indicating strong predictive capability. CONCLUSIONS: This study developed a simplified k-mer-based model for accurately identifying macrolide-resistant B. pertussis isolates and uncovered novel resistance features.
Vale C, Sime FB, Cotta MO
… +4 more, Eriksson L, Roberts JA, Horvath R, Abdul-Aziz MH
J Antimicrob Chemother
· 2026 Apr · PMID 41982169
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BACKGROUND: 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. OBJECTIVE: The objective of...BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Murakami K, Ida M, Suzuki Y
… +11 more, Kobayashi M, Konishi N, Kato R, Ariyoshi T, Kobayashi K, Mitobe M, Kubota H, Yokoyama K, Suzuki J, Miyake H, Sadamasu K
Luque Paz D, Cañas MA, Cuervo G
… +12 more, Espasa M, Hernandez-Meneses M, Quintana E, Falces C, Tolosana JM, Vidal B, Perissinotti A, Llopis J, Moreno A, García-de-la-Mària C, Miró JM, Hospital Clinic Endocarditis Study Group
OBJECTIVES: Aminopenicillin associated with parenteral cephalosporins provides synergistic activity against Enterococcus faecalis. Oral consolidation treatment is an option for infective endocarditis E. faecalis (EFIE),...OBJECTIVES: Aminopenicillin associated with parenteral cephalosporins provides synergistic activity against Enterococcus faecalis. Oral consolidation treatment is an option for infective endocarditis E. faecalis (EFIE), but optimal oral regimen remains under debate. We aimed to assess the in vitro activity of combinations based on amoxicillin plus an oral cephalosporin, namely, cephalexin or cefixime, against E. faecalis strains. METHODS: MIC and MBC values were determined against 6 clinical isolates of endocarditis-associated E. faecalis. Time-kill (TK) experiments were performed using amoxicillin (½MIC) plus cephalexin or cefixime at different concentrations (Cmax, ½Cmax and Cmin). Comparator regimens were amoxicillin/cefazolin and amoxicillin/ceftriaxone. TK experiments were carried out at standard (∼5 × 105 cfu/mL) and high inoculum (∼108 cfu/mL). RESULTS: Using amoxicillin combined with Cmax, ½Cmax or Cmin of oral cephalosporin at standard inoculum, synergy or additivity was observed in 66, 33 and 0% of E. faecalis isolates with adjunctive cephalexin; and in 83, 50 and 33% of isolates with adjunctive cefixime, respectively. In comparator regimens, synergy was found in all isolates at standard inoculum. At high inoculum, amoxicillin/cefixime at Cmax had similar efficacy to amoxicillin/ceftriaxone, showing synergy in 50% of E. faecalis isolates, while amoxicillin/cephalexin at Cmax and amoxicillin/cefazolin only achieved synergy in 17% of isolates. CONCLUSIONS: The combination of amoxicillin/cefixime exhibits synergy in most E. faecalis strains at standard inoculum. Cefixime could represent an interesting adjunctive therapy to amoxicillin for oral consolidation treatment of EFIE.