Petit PR, Touret F, Driouich JS
… +11 more, Paré A, de Lamballerie X, Marlin R, Contreras V, Relouzat F, Gallouët AS, Pascal Q, Guedj J, Le Grand R, Nougairède A, Solas C
J Antimicrob Chemother
· 2026 Jul · PMID 42396859
·
Full text
OBJECTIVES: Favipiravir (T-705) shows potent in vitro activity but inconsistent in vivo efficacy. We assessed how plasma exposure and tissue distribution shape antiviral coverage using a tissue-based PK/PD framework. MET...OBJECTIVES: Favipiravir (T-705) shows potent in vitro activity but inconsistent in vivo efficacy. We assessed how plasma exposure and tissue distribution shape antiviral coverage using a tissue-based PK/PD framework. METHODS: Favipiravir and its hydroxylated metabolite (M1) were quantified in plasma and multiple organs of Syrian golden hamsters after single and repeated dosing and compared with a non-human primate dataset. We derived tissue penetration factors (TPFs), metabolic ratios (MR) and inhibitory quotients (IQ) against published EC50 values for representative RNA viruses and integrated these results with available human pharmacokinetic data. RESULTS: Favipiravir absorbed rapidly and distributed heterogeneously, reaching highest levels in kidney, gut and respiratory organs with limited brain access; M1 was enriched in liver and kidney. Organ exposure ranking was broadly similar across species. Tissue IQs were often lower than plasma IQs, indicating that plasma monitoring can overestimate target-organ coverage. IQ analysis suggested favourable coverage for influenza and RSV, heterogeneous, dose-dependent coverage for chikungunya, Rift Valley fever viruses and Orthohantavirus andesense (ANDV), intermediate coverage for Zika virus, and limited coverage for SARS-CoV-2, ebolavirus and West Nile virus. For some viruses, coverage may require higher exposures, prompting dose reassessment and safety data. The IQ patterns aligned with reported preclinical efficacy, and human pharmacokinetics suggested robust exposure margins for influenza but insufficient margins for SARS-CoV-2 and ebolavirus. CONCLUSIONS: Tissue-based IQs refine the interpretation of exposure-response relationships and help explain favipiravir's variable in vivo performance. The same framework can be refined and applied to other antiviral candidates to support preparedness strategies.
Goodman AL, Easom N, Bielopolski D
… +16 more, Sutherland RK, Marks M, Hensgens MPM, Bonten M, Bostock J, Walls G, Lye D, Boyles T, Yahav D, Cheng MP, Legg A, Paul M, Lescure FX, Lee TC, Tong SYC, Davis JS
J Antimicrob Chemother
· 2026 Jul · PMID 42396858
·
Full text
Current guidelines for the management of meticillin-susceptible Staphyloccocus aureus bloodstream infection/bacteraemia (SAB) recommend intravenous (flu)cloxacillin as the first-line treatment. This is based on decades o...Current guidelines for the management of meticillin-susceptible Staphyloccocus aureus bloodstream infection/bacteraemia (SAB) recommend intravenous (flu)cloxacillin as the first-line treatment. This is based on decades of clinical practice. The high acute kidney injury rates seen with (flu)cloxacillin in the recently published SNAP trial, which is the largest randomized clinical trial ever in S. aureus bacteraemia (SAB), shows us the need to regularly test and question our usual clinical practice. Acute kidney injury is common in SAB when high doses of (flu)cloxacillin are used. The contribution of (flu)cloxacillin to developing or exacerbating acute kidney injury is likely to have been under recognized until now. Caution needs to be taken with (flu)cloxacillin. Cefazolin provides a safer and equally efficacious treatment for SAB. We discuss how this new evidence might be combined with our existing knowledge and the results of the CloCeBa trial to guide us how to appropriately manage our patients.
OBJECTIVES: We report on our initial clinical experience and identify factors associated with subtherapeutic cefazolin levels among patients with severe infections. METHODS: This was an observational study of patients tr...OBJECTIVES: We report on our initial clinical experience and identify factors associated with subtherapeutic cefazolin levels among patients with severe infections. METHODS: This was an observational study of patients treated with cefazolin guided by therapeutic drug monitoring (TDM) for severe infections. Cefazolin trough levels were collected and considered subtherapeutic when total drug concentrations were <40 mg/L. Hypoalbuminemia was defined as an albumin level of <3 g/dL within 72 h of cefazolin TDM. Trough levels were drawn within 90 min of the next scheduled dose for intermittent regimens. Steady state levels were drawn after at least 8 h of cefazolin via continuous infusion. RESULTS: Seventy patients were included. Overall, 76% (53/70) of patients had bloodstream infections, of whom 60% (32/53) had definitive endocarditis. MSSA was the underlying pathogen in 86% (60/70) of cases. Subtherapeutic levels were observed in 39% (27/70) of patients. The total median (IQR) daily cefazolin dose was similar among patients who received dosing by continuous and intermittent infusions [6 g (6-8) versus 6 g (6-6), P = 0.271]; however, those who received continuous infusions had a higher median (IQR) cefazolin level [61 mcg/mL) (38-80) versus 38 (19-71), P = 0.012]. Among those with measured albumin levels (n = 55), hypoalbuminemia was associated with endocarditis [OR = 11.9; 95% CI: 2.4-59.1; P = 0.002] and a lower cefazolin concentration [OR = 0.97; 95%CI: 0.95-0.99; P = 0.026]. CONCLUSIONS: Despite standard dosing with cefazolin, subtherapeutic levels were commonly observed. Factors associated with subtherapeutic levels included hypoalbuminemia and administration by intermittent infusion. Future studies are imperative to validate or refute current therapeutic targets for cefazolin.
J Antimicrob Chemother
· 2026 Jun · PMID 42372046
·
Full text
BACKGROUND AND OBJECTIVES: Dalbavancin, a lipoglycopeptide with a half-life of 150-200 h, is a promising treatment option for prosthetic joint infections (PJIs) and other orthopaedic implant-associated infections (IAIs)...BACKGROUND AND OBJECTIVES: Dalbavancin, a lipoglycopeptide with a half-life of 150-200 h, is a promising treatment option for prosthetic joint infections (PJIs) and other orthopaedic implant-associated infections (IAIs) caused by multidrug-resistant staphylococci. However, in vitro studies have shown that when exposed to low concentrations of dalbavancin, staphylococcal strains resistant to dalbavancin can emerge, potentially affecting its effectiveness in cases of recurrent infection. To investigate whether dalbavancin-resistant staphylococci emerge in vivo following long-term dalbavancin treatment for PJIs or orthopaedic IAIs. PATIENTS AND METHODS: Nineteen patients who had received long-term dalbavancin treatment (≥12 weeks) following PJI or orthopaedic IAI and 25 control patients scheduled for elective prosthetic joint surgery were sampled from the nares and perineum. Each sample was subcultured on Mueller-Hinton II agar plates containing various concentrations of dalbavancin (0.0, 0.125, 0.5, and 2.0 mg/L). The growth of staphylococcal colonies was analysed using MALDI-TOF, and the MIC values of dalbavancin were determined using the gradient test method. RESULTS: Among dalbavancin-treated patients, 4 out of 19 displayed staphylococcal species resistant to dalbavancin (MIC value >0.25 mg/L according to EUCAST breakpoint tables). These four were all Staphylococcus epidermidis isolates, three from the nares and one from the perineum, and displayed MIC values of 0.38, 0.38, 0.5, and 0.75 mg/L. No resistant staphylococci were detected in the samples from the control group (P = 0.029, Fisher's exact test). CONCLUSIONS: The present study demonstrated the emergence of dalbavancin-resistant staphylococci following long-term treatment.
Hughes GA, Jorissen RN, Wondimkun YA
… +8 more, Inacio MC, Lang C, Bennett N, Worth LJ, Thursky K, Clark M, James R, Sluggett JK
J Antimicrob Chemother
· 2026 Jun · PMID 42367138
·
Full text
BACKGROUND AND OBJECTIVES: While microbiology tests can guide management of infectious diseases, little is known about the prevalence of testing around the time of antibiotic initiation in long-term care facilities (LTCF...BACKGROUND AND OBJECTIVES: While microbiology tests can guide management of infectious diseases, little is known about the prevalence of testing around the time of antibiotic initiation in long-term care facilities (LTCFs). The objectives of this study were to investigate prevalence and factors associated with microbiology testing around the time of antibiotic initiation, and subsequent treatment pathways in LTCFs. METHODS: This retrospective cohort study included individuals aged ≥65 years who entered a LTCF in three Australian states between 1 January 2017 and 30 June 2019, and received a systemic antibiotic (n = 36 977). Prevalence of microbiology testing in the 14 days pre- and 7 days post-antibiotic initiation, and treatment pathways 14 days post-initiation, were determined. Multivariable logistic regression determined adjusted odds ratios (aORs) and 95% confidence intervals (95%CIs) for factors associated with testing. RESULTS: In total 15 407 (41.7%) individuals were tested around the time of antibiotic initiation, ranging from 22.9% (n = 585/2551 residents) of macrolide initiators to 79.3% (n = 413/521) of nitrofurantoin initiators. Individuals with urinary tract infections on LTCF entry (aOR 1.24, 95%CI 1.10-1.40) or initiating trimethoprim (aOR 2.80, 95%CI 2.50-3.13) were more likely to be tested. Males (aOR 0.81, 95%CI 0.77-0.85), and residents who received cephalosporins (aOR 0.75, 95%CI 0.68-0.84), penicillins (aOR 0.49, 95%CI 0.45-0.55), or with airways disease (aOR 0.87, 95%CI 0.82-0.91) had lower odds of testing. Among those tested, 14.5% (n = 2238) had a second dispensing of the same antibiotic, 11.4% (n = 1 751) switched antibiotic therapy and 5.9% (n = 904) were hospitalized within 14 days. CONCLUSIONS: With four in ten residents tested, and lower prevalence within certain resident subgroups, this study suggests a high dependence on initiating empiric therapy in LTCFs.
J Antimicrob Chemother
· 2026 Jun · PMID 42333448
·
Full text
BACKGROUND: Enterococcus faecalis is a common cause of healthcare-associated infections. They characteristically exhibit reduced susceptibility to penicillins and elevated MICs for aminoglycosides, limiting these drugs a...BACKGROUND: Enterococcus faecalis is a common cause of healthcare-associated infections. They characteristically exhibit reduced susceptibility to penicillins and elevated MICs for aminoglycosides, limiting these drugs as single-agent therapies. Combinations of cell wall synthesis inhibitors and aminoglycosides have a synergistic effect, resulting in bactericidal activity. The mechanism behind this synergism is not fully understood. OBJECTIVES: The present study was performed to explore the relationship between synergistic activity between cell wall-active agents/aminoglycoside combinations and cell membrane energetics in E. faecalis. METHODS: Analysis was performed using reference broth microdilution MIC testing, checkerboard assays, time-kill assays and fluorescent microscopy. RESULTS: We observed that cell wall remodelling agents promoted aminoglycoside uptake facilitated by antibiotic-induced decreases in the intracellular pH (pHi). CONCLUSIONS: Drugs that inhibit cell wall synthesis induce a decrease in the pHi, suggesting that cell wall remodelling is linked to ion transport and cytoplasmic acidification. Our study supports a model in which inhibition of peptidoglycan synthesis produces membrane stress-associated intracellular acidification that promotes ΔpH-dependent aminoglycoside uptake in E. faecalis.
OBJECTIVES: Current guidelines recommend at least 14 days of antifungal therapy for uncomplicated candidaemia after blood culture clearance, despite limited supporting evidence. We evaluated whether antifungal treatment...OBJECTIVES: Current guidelines recommend at least 14 days of antifungal therapy for uncomplicated candidaemia after blood culture clearance, despite limited supporting evidence. We evaluated whether antifungal treatment duration was associated with clinical outcomes. METHODS: This multicentre retrospective study in Taiwan (January 2014 to June 2024) included adults with uncomplicated candidaemia (microbiological clearance within 5 days, adequate source control, and no deep-seated or metastatic infection) completing 7-20 days of antifungal therapy. Patients were classified into short-course (7-13 days) and long-course (14-20 days) groups. Primary outcomes were all-cause mortality within 14 days and recurrence within 90 days after the end of treatment (EOT) and secondary outcomes were EOT 90-day mortality and EOT 1-year recurrence. Inverse probability of treatment weighting (IPTW) was applied to adjust for confounders. RESULTS: Among 203 patients, 72 (35.5%) received short-course and 131 (64.5%) long-course therapy. Overall, EOT 14-day mortality was 7.4% (5.6% versus 8.4% in short-course and long-course groups, respectively). Short-course therapy was not associated with increased EOT 14-day mortality in crude (OR 0.64, 95% CI 0.17-1.95), multivariable (aOR 0.33, 95% CI 0.06-1.35), or IPTW-weighted analyses (aOR 0.42, 95% CI 0.11-1.55). The EOT 90-day recurrence rate was 4.4%, with no significant differences across analyses. IPTW-weighted Kaplan-Meier and subgroup analyses showed consistent findings. No significant differences were observed in secondary outcomes, including EOT 90-day mortality and EOT 1-year recurrence. CONCLUSIONS: Short-course antifungal therapy was not associated with increased mortality or recurrence compared with long-course therapy among patients with uncomplicated candidaemia who achieved adequate source control and microbiological clearance.
J Antimicrob Chemother
· 2026 Jun · PMID 42333446
·
Full text
OBJECTIVES: Selective digestive decontamination (SDD) is routinely applied in Dutch ICUs to prevent colonization by potentially pathogenic microorganisms. In the R-GNOSIS ICU study, conducted outside of the Netherlands,...OBJECTIVES: Selective digestive decontamination (SDD) is routinely applied in Dutch ICUs to prevent colonization by potentially pathogenic microorganisms. In the R-GNOSIS ICU study, conducted outside of the Netherlands, SDD consisted of a mix of an oropharyngeal paste and a gastric suspension containing colistin, tobramycin and nystatin. Although SDD improves patient outcomes, its impact on the pangenome and resistome of colonizing Escherichia coli remains poorly understood. This study aimed to determine whether SDD influences the genomic composition and resistance repertoire of E. coli isolates from ICU patients. METHODS: We compared 129 genomes of E. coli isolates from patients that received SDD and patients that did not receive SDD, but standard care only (baseline patients) in five ICUs located across three European countries (R-GNOSIS ICU study). Comparative analyses were performed to assess differences in the pangenome, plasmidome and antibiotic resistance gene content between groups. RESULTS: The overall pangenome compositions of E. coli isolates from SDD-treated and baseline patients were highly similar. Accessory genome variation was strongly associated with phylogeny, but not with SDD exposure. Plasmidome differences were explained by the interaction of ICU location and phylogroup. A tobramycin resistance gene, flanked by IS26 elements and frequently co-occurring with blaCTX-M-15, was more prevalent in isolates from SDD patients. No mcr genes associated with transferable colistin resistance were detected. CONCLUSIONS: SDD did not significantly alter the overall pangenome or plasmidome composition of colonizing E. coli in ICU patients. However, a potentially mobile tobramycin resistance gene was more prevalent in E. coli from SDD patients.
BACKGROUND AND OBJECTIVES: Because antimicrobial resistance is one of the most pressing global health challenges of our time, it is crucial to find and develop new antimicrobial compounds, especially molecules with new t...BACKGROUND AND OBJECTIVES: Because antimicrobial resistance is one of the most pressing global health challenges of our time, it is crucial to find and develop new antimicrobial compounds, especially molecules with new targets and mechanisms of action. Among those, trans-translation, the main quality control system responsible for rescuing bacterial ribosomes present in non-stop complexes, is an appealing target. The objective of this study was to use in vitro and in vivo screening assays to evaluate organic compounds from the French Essential Chemical Library (Chimiothèque Nationale Essentielle, CNE) as trans-translation inhibitors. METHODS: In vitro cell-free assays and whole-cell in vivo trans-translation assays were performed to screen compounds from the chemical library. MIC and chequerboard assays were performed to assess the compounds' inhibition of bacterial cell growth in ESKAPE pathogens, alone or in combination with current antibiotics. RESULTS: Our initial results revealed a new family of γ-carboline compounds capable of inhibiting trans-translation in both in vitro and in vivo Escherichia coli-based assays, without affecting canonical translation. One molecule from the γ-carboline family, namely compound 404, presented high activity and specificity. CONCLUSIONS: These findings raise the prospect of further optimization of γ-carboline compounds' activity in order to use them in combination with currently available antibiotics to combat resistant pathogenic bacteria.
Calvez V, Charpentier C, Alidjinou EK
… +12 more, Wirden M, Bouvier-Alias M, De Monte A, Maillard A, Montes B, Trabaud MA, Raymond S, Teyssou E, Soulie C, Peytavin G, Descamps D, Marcelin AG
BACKGROUND: Doravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with moderate plasma protein binding and good potential for anatomical sanctuary penetration. MATERIALS AND METHODS: Adding doravirine to...BACKGROUND: Doravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with moderate plasma protein binding and good potential for anatomical sanctuary penetration. MATERIALS AND METHODS: Adding doravirine to existing antiretroviral therapy (ART) regimens has led to virological success in two groups of people living with HIV (PLWHIV): those with recent virological rebound (n = 84) and those with prolonged low-level viremia (LLV, n = 39). Doravirine was added without any modification to the other ART drugs. RESULTS: After 6 months, 88% of PLWHIV in the recent failure group had achieved virological success, compared to 33% of those in the LLV group. Efficacy was closely tied to the genotypic susceptibility score (GSS), with higher success rates in patients whose regimens retained two or more active drugs. Doravirine resistance mutations were uncommon but occurred more frequently in the LLV group. No significant associations were found between treatment response and CD4 count, nadir, VL zenith or duration of suppression. CONCLUSIONS: These findings support the use of doravirine add-on strategies to rescue virological control without changing the full regimen, particularly when a full regimen change is not feasible and when GSS is favourable. The study highlights the potential of doravirine in tailored salvage therapy strategies.
Sulaiman H, Wölky SA, Rozali MA
… +11 more, Adiraju SKS, Hasan MS, Hernandez-Mitre MP, Liu X, Mat-Nor MB, Mazlan MZ, Salmuna ZN, Wallis SC, Xie J, Roberts JA, Abdul-Aziz MH
J Antimicrob Chemother
· 2026 Jun · PMID 42318924
·
Full text
OBJECTIVES: To characterize the population pharmacokinetics and pharmacokinetic/pharmacodynamic target attainment of piperacillin and tazobactam in critically ill patients with sepsis or septic shock in Malaysian intensi...OBJECTIVES: To characterize the population pharmacokinetics and pharmacokinetic/pharmacodynamic target attainment of piperacillin and tazobactam in critically ill patients with sepsis or septic shock in Malaysian intensive care units and to use the population pharmacokinetic model to estimate individual target attainment and explore associations with clinical outcomes. METHODS: Serial blood samples were collected on days 1 and 3 of therapy in this prospective multicentre study. Total plasma piperacillin and tazobactam concentrations were quantified using a validated chromatographic assay. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Monolix. Therapeutic exposure was defined as achieving 100% fT>16 mg/L for piperacillin and 85% fT>2 mg/L for tazobactam while remaining below the piperacillin toxicity threshold (<160 mg/L). RESULTS: Forty-five critically ill adults with sepsis or septic shock were recruited (median age, 61 years [range: 18-88]; median creatinine clearance (CLcr) 70 mL/min [range: 30-161]; 20 females). A one-compartment model with first-order elimination best described the pharmacokinetics for both drugs. Estimated CLcr significantly influenced drug clearance. Pre-defined therapeutic exposures were achieved in 54% and 44% on days 1 and 3, respectively. Patients attaining exposures were older and had lower CLcr. Clinical cure and ICU survival were numerically different across exposure groups, although these exploratory comparisons were not statistically significant. Simulations indicated that a 4.5 g loading dose followed by 4.5 g every 6 h as a continuous infusion achieved effective and safe exposures in patients with CLcr 50 to 130 mL/min. CONCLUSION: Continuous infusion is the most reliable strategy for achieving early piperacillin/tazobactam therapeutic exposures in patients with sepsis or septic shock.
Abraham S, Lee ZZ, Jordan D
… +8 more, Stegger M, Saidenberg ABS, Lugsomya K, Lee T, Mukerji S, Price L, Nairn K, Abraham RJ
J Antimicrob Chemother
· 2026 Jun · PMID 42318923
·
Full text
OBJECTIVES: Livestock are recognized reservoirs of antimicrobial resistance (AMR). However, current surveillance often overlooks key ecological aspects such as spatial-temporal patterns and quantification of shedding lev...OBJECTIVES: Livestock are recognized reservoirs of antimicrobial resistance (AMR). However, current surveillance often overlooks key ecological aspects such as spatial-temporal patterns and quantification of shedding levels of resistant bacteria. In particular, early detection of low-level shedding of resistance to critically important antimicrobials (CIAs), including extended-spectrum cephalosporins (ESCs) and fluoroquinolones (FQs), remains limited. Using commensal Escherichia coli as an indicator, we applied a high-throughput Robotic Antimicrobial Susceptibility Platform (RASP) to assess phenotypic resistance in isolates from 900 samples collected across 10 pig herds over 3 years. METHODS: Quantitative assessments of antimicrobial resistance (cfu/g) were performed using selective agars containing antimicrobials, with plating and data capture (colony counting) automated on the RASP. Broth microdilution and whole-genome sequencing were performed on CIA-R E. coli using RASP. RESULTS: Persistent resistance to ampicillin and tetracycline (∼5.8 log10 cfu/g) showed minimal variation between herds and years. Gentamicin resistance declined significantly (-0.23 log10 cfu/g/year, P < 0.0001), while ESC resistance rose significantly (0.16 log10 cfu/g/year, P = 0.015), although some herds showed no ESC shedding. Ciprofloxacin resistance was detected in 58% of samples but generally at lower levels (∼2.1 log10 cfu/g) with herd-level variability. Genomic analysis identified FQ-resistant sequence types ST744 and ST167 with global phylogenetic links, and ESC resistance was associated with blaCTX-M-1 on IncI1 plasmids. CONCLUSIONS: These findings reveal the ecological complexity of AMR in livestock and highlight limitations of standard surveillance in detecting rare resistances. Our study demonstrates how high-throughput robotics integrated with robust field design can enhance AMR monitoring and inform One Health strategies for mitigation.
OBJECTIVES: Cefoperazone-sulbactam, a β-lactam/β-lactamase inhibitor combination, is widely used against ESBL-producing Gram-negative pathogens. This study investigated the in vivo pharmacokinetics/pharmacodynamics (PK/P...OBJECTIVES: Cefoperazone-sulbactam, a β-lactam/β-lactamase inhibitor combination, is widely used against ESBL-producing Gram-negative pathogens. This study investigated the in vivo pharmacokinetics/pharmacodynamics (PK/PD) of 1:1 and 2:1 cefoperazone-sulbactam formulations in neutropenic murine thigh and lung infection models. METHODS: Eleven ESBL-producing Gram-negative isolates with varying MICs were used to establish murine thigh and lung infection models. The plasma and epithelial lining fluid (ELF) pharmacokinetics of cefoperazone and sulbactam were evaluated over a wide dose range. Five dose-fractionation experiments were conducted to identify the PK/PD index most correlated with efficacy, and dose-escalation to determine PK/PD targets. RESULTS: All isolates exhibited cefoperazone MICs ≥ 64 mg/L, reduced by 8- to 16-fold by sulbactam at a 1:1 or 2:1 ratio. Cefoperazone and sulbactam showed linear pharmacokinetics across the dose range, well described by a two-compartmental model. Plasma protein binding was 57% for cefoperazone and 3% for sulbactam. ELF penetration was 0.12 for cefoperazone and 0.21 for sulbactam, which were used to determine the ELF-based targets. PK/PD targets reflecting the primary active component against each pathogen were reported. Cefoperazone %fT > MIC was used as the PK/PD index for E. coli and K. pneumoniae, the magnitude for 1-log10 cfu bacterial reduction was 50.3% (1:1) and 51.3% (2:1) in the thigh infection model, 52.4% (1:1) and 75.6% (2:1) in the lung infection model. For A. baumannii, sulbactam was identified as the primary active component, and the 1-log10 cfu %fT > MIC target for sulbactam was 68.7%. CONCLUSIONS: Cefoperazone-sulbactam demonstrated strong in vivo antibacterial activity against the 11 tested isolates. This study established PK/PD targets under varied conditions, providing a valuable foundation for optimizing the clinical application of cefoperazone-sulbactam.
BACKGROUND: Prosthetic joint infections (PJI) of the hip and knee are most often caused by Staphylococcus spp. and require long-term treatment with rifampicin and fluoroquinolone as first-line treatment. However, resista...BACKGROUND: Prosthetic joint infections (PJI) of the hip and knee are most often caused by Staphylococcus spp. and require long-term treatment with rifampicin and fluoroquinolone as first-line treatment. However, resistance, contraindications or intolerance highlight the need for effective oral alternatives. Tetracyclines, with favourable bioavailability and bone penetration, represent a potential option. METHODS: CYCLIOS, a multicentre retrospective matched case-control study, included adult patients with staphylococcal hip or knee PJI treated with curative intent. Cases received doxycycline as part of their antibiotic regimen, and controls were matched 1:2 on infection site, age, pathogen and date of multidisciplinary meeting. The primary endpoint was a composite of death or treatment failure at 2 years. RESULTS: Sixty-seven patients were analysed (23 doxycycline group, 44 control). The two groups were comparable except for immunosuppression (17% (4/23) versus 2% (1/44); P = 0.04). The median duration of doxycycline was 75 days (interquartile range [IQR]: 47-83). The primary endpoint occurred in 43% (10/23 and 19/44) of both groups (odds ratio [OR] 1.01, 95% confidence interval [CI] [0.36-2.84]; P = 0.98). Treatment-related adverse events were reported in 35% (8/23) versus 20% (9/44); P = 0.24, but premature discontinuation remained rare (4% (1/23) versus 5% (2/44); P = 1.00). In the conditional logistic regression model, doxycycline exposure was not associated with an increased risk of unfavourable outcome (univariate OR 1.06, 95% CI [0.40-2.81]; P = 0.91 and multivariate OR 0.97, 95% CI [0.23-4.25]; P = 0.97). CONCLUSION: In this multicentre real-life study, doxycycline-based regimen, no significant difference was observed between doxycycline-based regimens and comparator strategies, with acceptable tolerability. Given the observational design and limited sample size, these findings should be considered exploratory. Tetracyclines may represent a pragmatic therapeutic alternative when first-line options are not feasible.
OBJECTIVES: This study aimed to investigate the anti-virulence effects of subinhibitory concentration of clarithromycin on Staphylococcus aureus and to explore the underlying molecular mechanism. METHODS: Haemolytic acti...OBJECTIVES: This study aimed to investigate the anti-virulence effects of subinhibitory concentration of clarithromycin on Staphylococcus aureus and to explore the underlying molecular mechanism. METHODS: Haemolytic activity was measured using rabbit erythrocytes. α-haemolysin production was assessed by Western blot analysis. Transcriptional changes were analysed by RT-qPCR and promoter activity assays. To verify the target mechanism, a ΔsaeR mutant and a complemented strain were constructed. Molecular docking and DARTS assay were employed to evaluate the potential clarithromycin-SaeR interaction. Substitution of a single residue, Arg154, with alanine was performed to determine its functional role. In vivo efficacy of clarithromycin was assessed using the Galleria mellonella infection model. RESULTS: Clarithromycin at 1/8MIC reduced haemolytic activity in methicillin-resistant S. aureus strains MR200 and MR271 from 83.61% ± 0.86% to 9.05% ± 4.13% and from 85.12% ± 1.95% to 45.24% ± 1.06%, respectively, and significantly decreased α-haemolysin production. Clarithromycin selectively downregulated saeR, with a 1.87-fold reduction in MR200 and 1.54-fold reduction in MR271, while the agr pathway remained largely unaffected. Promoter activity assays confirmed suppression of the saeR-P1 promoter. Haemolytic activity and α-haemolysin production were significantly reduced in the ΔsaeR mutant, and clarithromycin caused no additional inhibition, and these effects were restored upon saeR complementation. Molecular docking and DARTS assay suggested a potential SaeR-clarithromycin binding. Arg154 substitution eliminated both SaeR regulatory activity and drug-mediated virulence suppression. In vivo, 1/8MIC clarithromycin improved larval survival to over 90%. CONCLUSIONS: This study demonstrated that clarithromycin exerted an anti-virulence effect against S. aureus by targeting the SaeR, highlighting a potential strategy for repurposing antibiotics to mitigate bacterial pathogenicity.
Trinh NTH, Fukasawa T, Yanai T
… +6 more, Okura T, Takayama A, Sakai T, Reiakvam OM, Nordeng HME, Kawakami K
J Antimicrob Chemother
· 2026 Jun · PMID 42313421
·
Full text
OBJECTIVES: Quantification of prescription of antimicrobial agents and use of paediatric outpatient services before, during and after the COVID-19 pandemic. METHODS: We conducted a population-based study using Norwegian...OBJECTIVES: Quantification of prescription of antimicrobial agents and use of paediatric outpatient services before, during and after the COVID-19 pandemic. METHODS: We conducted a population-based study using Norwegian linked health registries and Japanese claims (2018-2023). Paediatric antibiotic prescription rates, broad-spectrum use, and proportion of antibiotic prescriptions with prior presumed bacterial infection diagnoses were analysed monthly, overall and by age groups and sex. Interrupted time series analyses were performed to evaluate pandemic-related changes, expressed in rate ratio (RR) and its CI, using March 2020 as the interruption point and the pre-pandemic trend/level as reference. RESULTS: Data on 5.5 million children and 19.5 million antibiotic prescriptions were analysed. Before the pandemic, antibiotic prescribing was higher in Japan (120-200/1000 children/month) than in Norway (10-20/1000). At pandemic onset, rates fell by 45% in Norway (RR = 0.55; 95% CI, 0.45-0.67) and by 53% in Japan (RR = 0.47; 95% CI, 0.41-0.55), then by 2023 had returned to expected levels. Broad-spectrum antibiotic use was much higher in Japan (70%) compared with Norway (10%) before the pandemic. However, Norway experienced a sharp 20% increase whereas Japan remained largely unchanged post-pandemic. The proportion of prescriptions with a prior presumed bacterial diagnosis was between 50% and 65% before the pandemic then decreased modestly by 5%-10% at pandemic onset, followed by gradual rebound in both countries. CONCLUSIONS: The COVID-19 pandemic significantly altered paediatric antibiotic prescribing in both countries. Sustained antibiotic stewardship efforts are needed to ensure appropriate paediatric antibiotic use in the post-pandemic era.
Schwartz KL, Bai L, Brown KA
… +21 more, Tadrous M, Grimshaw JM, Witteman HO, Friedman L, Langford BJ, Leung V, Gomes T, Garber G, Taljaard M, Shuldiner J, Gushue S, Silverman M, Daneman N, Brehaut J, Presseau J, Leis JA, Lacroix M, Zwarenstein M, Masucci L, Thavorn K, Ivers N
J Antimicrob Chemother
· 2026 Jun · PMID 42313420
·
Full text
BACKGROUND: We previously demonstrated in a randomized controlled trial that antibiotic prescribing feedback to family physicians reduced antibiotic use. However, that trial did not evaluate for patient harms from potent...BACKGROUND: We previously demonstrated in a randomized controlled trial that antibiotic prescribing feedback to family physicians reduced antibiotic use. However, that trial did not evaluate for patient harms from potential under-prescribing of antibiotics. OBJECTIVES: To evaluate the safety of an antibiotic audit and feedback intervention. METHODS: We performed a post hoc secondary analysis of a randomized controlled trial that compared an intervention group, who received a mailed antibiotic prescribing peer comparison feedback letter, compared with a control group who did not receive a letter. The initial trial was limited to patients aged 65 years or older due to availability of pharmacy claims data. The primary outcome was an emergency department visit or hospital admission for a bacterial infection. The outcome was assessed at 6 months post-intervention using administrative data claims data and multivariable linear regression models. The initial trial was registered (NCT04594200). RESULTS: We included 4879 physicians-3909 intervention physicians and 970 control physicians. There were 37 345 severe infection events in the 6 month post-intervention period. The observed mean (SD) of all severe infection events per physician was 7.73 (12.42) for control and 7.64 (11.91) for intervention groups. The model-based adjusted mean difference was -0.23 (95% CI, -0.92 to 0.45; P = 0.505). CONCLUSIONS: In this post hoc analysis of a randomized controlled trial comparing antibiotic prescribing feedback versus no feedback to physicians in primary care, there was no evidence of severe bacterial infection complications associated with reduced antibiotic prescribing. These findings support antibiotic peer comparison feedback as a safe and effective tool to reduce unnecessary antibiotic prescribing.
INTRODUCTION: Antimicrobial resistance is recognized by the WHO as one of the leading global public health challenges. Antimicrobial Stewardship Programmes (ASPs) aim to promote the rational and efficient use of antimicr...INTRODUCTION: Antimicrobial resistance is recognized by the WHO as one of the leading global public health challenges. Antimicrobial Stewardship Programmes (ASPs) aim to promote the rational and efficient use of antimicrobials, although their implementation faces various limitations. Digital tools and artificial intelligence (AI) emerge as strategies to improve the efficiency and outcomes of these programmes. OBJECTIVE: To analyse the role of digital tools and AI in hospital-based ASP interventions and their impact on clinical, microbiological and antimicrobial use indicators. MATERIAL AND METHODS: A systematic review was conducted following PRISMA methodology. A bibliographic search was performed in PubMed, Scopus and Cochrane Library (2014-25), as well as grey literature. Articles on hospitalized patients requiring antimicrobial treatment were included according to PICOS criteria. Risk of bias and methodological quality were assessed according to the type of study. Two independent researchers conducted the selection, evaluation and data extraction. A third researcher resolved discrepancies. RESULTS: Thirty-one studies met the inclusion criteria. The most commonly used tools were Clinical Decision Support Systems (58%), followed by alerts in electronic health records, machine learning models, telemedicine and mobile applications. Most studies showed improvements in therapeutic appropriateness and reduction in antibiotic consumption. However, the impact on clinical and microbiological indicators was heterogeneous and of low quality. CONCLUSION: Digital tools applied in ASPs improve prescription quality indicators and reduce antimicrobial consumption. Nevertheless, their impact on clinical and microbiological outcomes remains limited. Standardized indicators and robust methodological studies are needed to confirm their real impact on ASP outcomes. PROTOCOL REGISTRATION: This protocol has been registered in PROSPERO with the ID: CRD42024601221.