J Antimicrob Chemother
· 2026 Mar · PMID 41778969
·
Full text
BACKGROUND: Plasma pharmacokinetic/pharmacodynamic (PK/PD) targets are a surrogate of pulmonary exposures for pneumonia, despite potential differences in exposures. This study defined free plasma and pulmonary epithelial...BACKGROUND: Plasma pharmacokinetic/pharmacodynamic (PK/PD) targets are a surrogate of pulmonary exposures for pneumonia, despite potential differences in exposures. This study defined free plasma and pulmonary epithelial lining fluid (ELF) PK/PD targets for different antibiotics against Klebsiella pneumoniae (KP) in a preclinical pneumonia model, and assessed the predicted cfu/lung response of human exposures relative to MIC breakpoints. METHOD: Secondary analyses were performed on previously published in vivo cfu/lung data generated using 17 KP after administration of different dosing regimens of meropenem, cefiderocol, levofloxacin and tobramycin. Efficacy was evaluated as change in log10 cfu/lung at 24 h. Emax models were fitted to composite cfu data, and plasma and ELF targets were calculated using the Hill equation. The average human plasma and ELF exposures achieved clinically relative to MIC breakpoints were overlaid on the Emax curve to predict corresponding cfu/lung efficacy. RESULTS: All Emax models had an R2 > 0.85. ELF targets differed from plasma targets and were generally lower (meropenem, cefiderocol and tobramycin), but higher for levofloxacin. Based on average human ELF exposures, the predicted cfu/lung responses of all four antibiotics were ≥1 log10 cfu/lung reduction at susceptible MICs, variable at intermediate MICs and limited at resistant MICs. Based on plasma targets, both meropenem and cefiderocol predicted cfu reduction at resistant breakpoints, whereas ELF exposures predicted net growth. CONCLUSION: These data demonstrate the clinical translation of the pneumonia model relative to established breakpoints and emphasizes the potential limitations of relying solely on plasma exposure targets in predicting clinical efficacy for pneumonia.
OBJECTIVES: Pretreatment drug resistance (PDR) compromises antiretroviral therapy (ART) efficacy and is a major concern in HIV care, yet its consequences for key treatment outcomes are not well-defined. We therefore syst...OBJECTIVES: Pretreatment drug resistance (PDR) compromises antiretroviral therapy (ART) efficacy and is a major concern in HIV care, yet its consequences for key treatment outcomes are not well-defined. We therefore systematically investigated the prevalence of PDR and its impact on mortality, attrition and viral suppression amongst patients starting ART. METHODS: An observational cohort study was conducted in Southwest China, 2014-2022. PDR was analysed using the Stanford HIV Drug Resistance Database. Molecular transmission networks were constructed with HIV-TRACE. Cox and logistic regression evaluated the impact of PDR. RESULTS: Amongst 3478 eligible patients, the overall prevalence of PDR was 6.4%. PDR rates to non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors and protease inhibitors were 4.1%, 1.3% and 1.1%, respectively. The overall mortality and attrition rates were 4.58 and 2.40 per 100 person-years, respectively. Whilst PDR showed no significant association with mortality, it was associated with increased attrition. Compared to those without resistance, the adjusted HR (95% CI) for attrition was 1.67 (1.11-2.52) in the overall drug-resistant group, 2.16 (1.36-3.43) in the NNRTI-resistant group and 2.09 (1.10-3.97) in the efavirenz/nevirapine-resistant group. Viral suppression was significantly lower in the drug-resistant group [adjusted odds ratio (AOR): 0.46; 95% CI: 0.27-0.77], the NNRTI-resistant group (AOR: 0.42; 95% CI: 0.22-0.78) and the efavirenz/nevirapine-resistant group (AOR: 0.41; 95% CI: 0.21-0.81). CONCLUSIONS: Our study reveals a moderate prevalence of PDR in Southwest China, significantly associated with increased risk of attrition and virologic failure, particularly amongst patients with resistance to efavirenz/nevirapine. Our findings strongly advocate for routine PDR testing prior to ART initiation to guide optimal first-line treatment strategies.
BACKGROUND AND OBJECTIVES: Self-administration of outpatient parenteral antimicrobial therapy (S-OPAT) aligns with the growing emphasis on patient and caregiver engagement in healthcare. Despite its potential benefits, S...BACKGROUND AND OBJECTIVES: Self-administration of outpatient parenteral antimicrobial therapy (S-OPAT) aligns with the growing emphasis on patient and caregiver engagement in healthcare. Despite its potential benefits, S-OPAT use varies widely, suggesting that many eligible patients are not offered this option. Insight into S-OPAT decision-making is needed to improve its broader implementation and quality. The objectives of this study were to identify determinants that (i) influence healthcare professionals' (HCPs) decisions to offer S-OPAT and (ii) affect patients' and caregivers' acceptance or refusal of S-OPAT. METHODS: Semi-structured interviews were performed with HCPs involved in S-OPAT and with patients and caregivers who either self-administered OPAT or declined S-OPAT. Participants were recruited from four hospitals and six home care organizations. Transcripts were analysed using thematic analysis. RESULTS: Fifty-one interviews were conducted with HCPs, patients and caregivers. The determinants reported were related to cognitions or affect (e.g. emotions or personality traits, such as patients' reluctance to accept help), skills and capabilities (e.g. patients' perceived skills for S-OPAT, or the ability of HCPs to explain what S-OPAT entails) and collaboration and communication (e.g. between healthcare organizations and between patients and caregivers). CONCLUSIONS: Decisions regarding S-OPAT are influenced by cognitive, skill-related, and collaborative determinants shaping inter-stakeholder cooperation. Addressing these determinants may help create a more person-centred approach and support further expansion of S-OPAT. We recommend increasing HCP awareness of S-OPAT, discussing S-OPAT with all patients or their caregivers, emphasizing the freedom to try S-OPAT, and tailoring the content, timing, and location of the S-OPAT offer to individual needs.
OBJECTIVES: Perioperative antibiotic prophylaxis is crucial for preventing detrimental postoperative prosthetic joint infections (PJIs). Guidelines aim to prevent infection with methicillin-susceptible staphylococci-in S...OBJECTIVES: Perioperative antibiotic prophylaxis is crucial for preventing detrimental postoperative prosthetic joint infections (PJIs). Guidelines aim to prevent infection with methicillin-susceptible staphylococci-in Sweden through administering cloxacillin, at fixed doses with minimal consideration to kidney function or patient weight. Over- and under-dosing could have adverse effects, negative effects on the microbiome, or increase the risk of PJI. We aimed primarily to evaluate whether the current uniform prophylactic regimen of cloxacillin in hip and knee arthroplasty is adequate. PATIENTS AND METHODS: Patients subjected to elective prosthetic joint surgery (N = 204) were included in a prospective study. Free plasma concentrations of cloxacillin were measured on three occasions throughout arthroplasty surgery. Samples were analysed using a validated HPLC-MS/MS method. A free concentration of <2 mg/L was deemed a theoretically appropriate concentration to suppress growth of methicillin-susceptible staphylococci in bone. A sensitivity analysis with values of 1 and 4 mg/L was included. RESULTS: Potentially subtherapeutic concentrations (≤2 mg/L) at the end of surgery were found in 31 cases (15%). The corresponding numbers for 1 and 4 mg/L were 3 and 88 (1% and 43%). In multivariable logistic regression analysis, an ASA (American Association of Anesthesiologists physical status) score of I (relatively healthy patients), estimated glomerular filtration rate >90 mL/min/1.73 m2, body weight >100 kg and long duration of surgery significantly predicted suboptimal concentrations. CONCLUSIONS: Current cloxacillin dosing in hip and knee arthroplasty surgery results in a risk for subtherapeutic levels in patients with high body weight and preserved renal function. Therefore, dosing guidelines for cloxacillin prophylaxis in arthroplasty should be reviewed.
BACKGROUND: Voriconazole is recommended as first-line therapy for invasive fungal infections but exhibits substantial pharmacokinetic (PK) variability and hepatotoxicity. Although CYP2C19 polymorphisms partially explain...BACKGROUND: Voriconazole is recommended as first-line therapy for invasive fungal infections but exhibits substantial pharmacokinetic (PK) variability and hepatotoxicity. Although CYP2C19 polymorphisms partially explain this variability, evidence regarding additional genetic determinants remains inconsistent. Studies integrating genetic and clinical factors for voriconazole PK and hepatotoxicity are limited. OBJECTIVES: To assess the association between 10 genetic variants and voriconazole trough concentrations in CYP2C19 normal (NM) and intermediate (IM) metabolizers and to identify predictors of PK variability and hepatotoxicity. METHODS: This observational study included 114 adult Chinese patients receiving voriconazole between July 2022 and May 2023. Associations between genetic variants and voriconazole trough concentrations were assessed within CYP2C19 NMs and IMs. Generalized linear models (GLMs) identified predictors of PK variability, and binary logistic regression assessed hepatotoxicity risk. RESULTS: Voriconazole trough concentrations varied over 40-fold (0.2-9 μg/mL). Nominal associations were observed for CYP3A4 (rs4646437) and NR1I2 (rs7643645, rs3814055) in NMs and for SLCO1B3 (rs4149117), SLCO2B1 (rs3781727) and NR1I2 (rs3814055) in IMs, but none remained significant after Bonferroni correction. GLM analysis identified SLCO1B3 (rs4149117), NR1I2 (rs3814055), albumin, C-reactive protein (CRP) and daily dose as predictors of PK variability. Hepatotoxicity occurred in 27.2% of patients and was associated with higher trough concentrations, whereas the NR1I2 (rs7643645) GG genotype and higher baseline platelet count were associated with reduced risk. CONCLUSIONS: Marked interindividual variability in voriconazole exposure persists among CYP2C19 NMs and IMs. Integrating therapeutic drug monitoring (TDM) with genetic and clinical factors may optimize dosing and reduce hepatotoxicity risk. Larger multicentre studies are still needed.
INTRODUCTION: Surgical site infections (SSIs) are a leading cause of healthcare-associated infections, particularly in abdominal surgery. In patients allergic to beta-lactams, gentamicin is often used for surgical antibi...INTRODUCTION: Surgical site infections (SSIs) are a leading cause of healthcare-associated infections, particularly in abdominal surgery. In patients allergic to beta-lactams, gentamicin is often used for surgical antibiotic prophylaxis (SAP), but its efficacy is questioned due to limited tissue-level pharmacokinetic/pharmacodynamic (PK/PD) data. MATERIALS AND METHODS: We conducted a monocentric prospective study involving eight adult patients undergoing major abdominal surgery who received gentamicin (5 mg/kg IV) for SAP. Subcutaneous unbound gentamicin concentrations were measured using microdialysis over 6 h. Plasma and tissue PKs were analysed using nonlinear mixed-effects modelling. Monte Carlo simulations assessed the probability of target attainment (PTA) for Cmax/MIC >8 at doses of 5 and 8 mg/kg, using EUCAST MIC distributions for Escherichia coli and Staphylococcus aureus. RESULTS: A total of 246 samples were collected (100 plasma and 146 microdialysate). Subcutaneous gentamicin concentrations were lower than plasma concentrations throughout the 0-6 h interval. Mean Cmax values were 43.7 ± 4.5 mg/L in plasma and 17.8 ± 11.5 mg/L in subcutaneous tissue. Given the lack of defined tissue PK/PD targets in surgical prophylaxis, a plasma-based Cmax/MIC > 8 target was used for PTA simulations. At 5 mg/kg, PTA was suboptimal for MIC ≥1 mg/L in subcutaneous tissue. Simulations showed that increasing the dose to 8 mg/kg improved the cumulative fraction of response against E. coli and S. aureus from 70% and 79% to 80% and 87%, respectively. DISCUSSION: This study highlights insufficient subcutaneous gentamicin exposure with standard SAP dosing. An 8 mg/kg dose improved tissue PK/PD target attainment, supporting updated dosing recommendations for beta-lactam-allergic patients. Further research is needed to validate safety and efficacy in broader populations.
BACKGROUND: Heteroresistance (HR) in Pseudomonas aeruginosa causes misclassification as 'susceptible (S)' on routine antibiotic susceptibility techniques, potentially contributing to subsequent treatment failure. This st...BACKGROUND: Heteroresistance (HR) in Pseudomonas aeruginosa causes misclassification as 'susceptible (S)' on routine antibiotic susceptibility techniques, potentially contributing to subsequent treatment failure. This study aimed to explore clinically relevant risk factors for HR compared with S (S-HR), and resistant (R) compared with HR (HR-R) phenotypes. Additionally, we explored whether integrating medical history and laboratory data can enable rapid and accurate identification of HR and R phenotypes in this pathogen. METHODS: This retrospective study included 420 P. aeruginosa strains collected from 2011 to 2024 in China. The strains were categorized into three groups according to their sensitivity to meropenem: non-heteroresistant susceptible, heteroresistant and non-heteroresistant resistant. Logistic regression, random forest and XGBoost models were constructed using variables identified through LASSO (least absolute shrinkage and selection operator) regression. The models' performance was evaluated via 10-fold cross-validation comparing area under the receiver operating characteristic curve (AUROC), sensitivity and specificity. RESULTS: Multivariate analyses identified central venous catheters as an independent risk factor for S-HR, and malignant solid tumours, pulmonary infections, mechanical ventilation and carbapenem use for HR-R. A discriminating diagnostic model, combining clinical and laboratory data, showed an AUROC of 0.919 for HR-R and 0.856 for S-HR. The calibration plots indicated good alignment between the estimated and observed probabilities. CONCLUSIONS: This study presents a validated two-stage risk assessment model to discriminate the two phases of meropenem heteroresistance in P. aeruginosa. By identifying novel stage-specific risk factors and delivering a practical tool compatible with clinical workflows, this model facilitates the early identification and targeted intervention of HR, offering novel insights into the mechanistic dissection of HR.
Pezzati L, Conti F, Gennari W
… +14 more, Mussini C, Pontali E, Volpe A, Vicenti I, Saracino A, Rossetti B, Bruzzone B, Shallvari A, Forcina G, Albini L, Corsini D, Cozzi-Lepri A, Zazzi M, Rusconi S
OBJECTIVES: To estimate the prevalence of NRTI and integrase strand transfer inhibitor (INSTI), drug resistance mutations (DRMs) in antiretroviral therapy (ART)-experienced people with HIV-1 (PWH) switched to bictegravir...OBJECTIVES: To estimate the prevalence of NRTI and integrase strand transfer inhibitor (INSTI), drug resistance mutations (DRMs) in antiretroviral therapy (ART)-experienced people with HIV-1 (PWH) switched to bictegravir/emtricitabine/tenofovir alafenamide fumarate (B/F/TAF) and among those with HIV-RNA ≤50 copies/mL to assess the association with risk of viral rebound (VR). METHODS: Data from the ARCA cohort were used to estimate resistance prevalence assuming a binomial distribution; 95% confidence intervals (CIs) were reported. Standard survival analysis with time-fixed covariate measured at B/F/TAF initiation was used to evaluate the association between detected resistance and risk of confirmed VR >50 copies/mL (2 consecutive values). FINDINGS: We included 1414 PWH (973-69%-in the VR analysis). Overall, 27% were female, median age was 53 years (IQR 44-59). Major NRTI-DRMs were detected in 25% (95% CI: 22.5, 27.1). Major INSTI-DRMs affecting bictegravir were rare (0.6%, 95% CI: 0.2, 1.4). The overall rate of VR by 36 months was 5.3% (95% CI: 3.7-6.9%), confirming that viral rebound on B/F/TAF is a rare event. After controlling for confounding, NRTI resistance was not associated with VR, whereas a history of INSTI virological failure (VF) and major INSTI-DRMs were associated with VR (aRH 2.68, 95% CI: 1.40, 5.12; and aRH 4.21, 95% CI: 1.18, 15.02, respectively). CONCLUSIONS: In our cohort of PWH who were switched to B/F/TAF, NRTI-DRMs were common, but B/F/TAF remained effective in maintaining viral suppression despite their presence. However, previous failure to INSTI-based regimens and major INSTI-DRMs were risk factors for VR.
Klebsiella pneumoniae is a major cause of hospital-acquired pneumonia and a critical global threat due to its escalating multidrug resistance. This review highlights current advancements in therapeutic strategies, includ...Klebsiella pneumoniae is a major cause of hospital-acquired pneumonia and a critical global threat due to its escalating multidrug resistance. This review highlights current advancements in therapeutic strategies, including double and triple drug combinations, and evaluates their clinical efficacy and limitations. We discuss the global dissemination of resistance determinants such as blaKPC, blaNDM and mcr genes, and the complex mechanisms, including porin mutations, efflux pump overexpression and enzymatic degradation. The regional variation in these mechanisms undermines treatment success. Evidence for antibiotic combination therapy, including the double (colistin/meropenem) and triple (polymyxin B/meropenem/rifampicin) regimens, is analysed, along with controversies regarding their superiority over monotherapy. Finally, we highlight inhaled antibiotic delivery, particularly dry powder inhalers, as a promising strategy to achieve targeted, effective pulmonary drug concentrations and reduced systemic toxicity. Despite progress, significant barriers remain, including formulation stability, regulatory hurdles and the continued shortage of clinical trials. Future research should prioritize optimizing inhaled drug therapies and innovative delivery platforms to combat multidrug-resistant K. pneumoniae lung infections.
BACKGROUND: Carbapenem antibiotics are critical therapies for multidrug-resistant infections, but their comparative haematologic safety profiles remain poorly characterized. We systematically evaluated haematologic adver...BACKGROUND: Carbapenem antibiotics are critical therapies for multidrug-resistant infections, but their comparative haematologic safety profiles remain poorly characterized. We systematically evaluated haematologic adverse events associated with meropenem, ertapenem, imipenem and doripenem using pharmacovigilance data. METHODS: We analyzed the FDA Adverse Event Reporting System (FAERS) database from January 2013 to July 2025. Disproportionality analysis was performed using reporting odds ratios (RORs) with 95% confidence intervals for haematologic adverse events. RESULTS: Sixteen distinct haematologic adverse events were identified. Meropenem demonstrated the most extensive toxicity profile with significant signals for 15 adverse events, including severe conditions: thrombocytosis (ROR = 24.941), eosinophilia (ROR = 24.663), bone marrow failure (ROR = 13.113), agranulocytosis (ROR = 11.57) and pancytopenia (ROR = 11.131). Imipenem demonstrated signals for nine events, notably thrombocytopenia and eosinophilia. Ertapenem demonstrated nine events: leucopenia (ROR = 3.843) and neutropenia (ROR = 2.469). No reports were identified for doripenem. CONCLUSIONS: Significant differences exist in haematologic safety profiles among carbapenems. Meropenem shows the broadest spectrum of severe toxicity, while other carbapenems demonstrate fewer reports. demonstrates fewer reported haematologic safety signals and not a most favourable haematologic safety profile. These differential safety profiles should inform further studies on carbapenem selection, including patients with baseline haematologic disorders.
OBJECTIVES: This study investigated whether extracorporeal membrane oxygenation (ECMO) alters the pharmacokinetics or tissue penetration of vancomycin and linezolid, assessed the need for dose adjustments during ECMO sup...OBJECTIVES: This study investigated whether extracorporeal membrane oxygenation (ECMO) alters the pharmacokinetics or tissue penetration of vancomycin and linezolid, assessed the need for dose adjustments during ECMO support and evaluated the suitability of each drug for different infection sites. METHODS: Each Landrace pig underwent two sequential experiments, one without ECMO and one with ECMO, separated by more than 4 weeks. Blood samples were collected before and after intravenous infusion of vancomycin and linezolid and tissue samples were obtained immediately after the ECMO period. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using a non-compartmental model and tissue penetration rates were determined by comparing tissue concentrations with serum levels before euthanasia. RESULTS: ECMO did not significantly influence the pharmacokinetics of vancomycin or linezolid. Vancomycin penetration was highest in the kidney (390%) and alveolar epithelial lining fluid (120%), with lower levels in the lung, liver, spleen and skin (10%-20%) and minimal penetration in the small intestine and muscle (<10%). Linezolid demonstrated stronger tissue penetration, reaching 236% in alveolar epithelial lining fluid and 20%-30% in the kidney and liver. CONCLUSIONS: ECMO does not affect the pharmacokinetics of vancomycin or linezolid, suggesting that dose adjustments are unnecessary. Both drugs demonstrate wide tissue distribution during ECMO and are suitable treatment options in this setting.
Bacterial topoisomerases are enzymes critical for maintaining genomic DNA integrity and ensuring bacterial cell survival, making them ideal targets for antibacterial agents. Bacterial topoisomerase inhibitors, such as qu...Bacterial topoisomerases are enzymes critical for maintaining genomic DNA integrity and ensuring bacterial cell survival, making them ideal targets for antibacterial agents. Bacterial topoisomerase inhibitors, such as quinolones and fluoroquinolones, target two enzymes, DNA gyrase and topoisomerase IV, and inhibit the control of DNA supercoiling/decatenation, leading to impaired DNA replication and bacterial cell death. Since their initial discovery, many quinolones and fluoroquinolones have been developed with activity against a wide range of bacterial species, contributing significantly to the treatment of various infectious diseases worldwide. Fluoroquinolones such as levofloxacin and ciprofloxacin remain important and effective therapeutic options today due to their broad-spectrum antibacterial activity, chemical stability and high bioavailability. However, side effects of fluoroquinolones have become a concern, leading to warnings being issued in the United States, Europe and the United Kingdom. Furthermore, in many countries, the prevalence of fluoroquinolone-resistant bacteria has been steadily increasing each year, which poses a serious threat to public health. The clinical development of new non-quinolone bacterial topoisomerase inhibitors (for example, zoliflodacin, gepotidacin and fobrepodacin) offers a promising solution to these issues and has the potential to play a crucial role in combating the growing problem of antimicrobial resistance. This review article will discuss the evolution of quinolone and fluoroquinolone antibacterial agents as key topoisomerase inhibitors, examine their current clinical applications and challenges to future development, and explore the potential of new topoisomerase inhibitors.
Han WM, Apornpong T, Chuaypen N
… +8 more, Aung TPP, Amornritvanich P, Hiranburana N, Lwin HMS, Hiransuthikul A, Kerr S, Tangkijvanich P, Avihingsanon A
BACKGROUND: Limited data exist on whether the presence of type-2 diabetes mellitus (T2DM) increases the risk of significant liver fibrosis (LF) among people with HIV (PWH) and metabolic dysfunction-associated steatotic l...BACKGROUND: Limited data exist on whether the presence of type-2 diabetes mellitus (T2DM) increases the risk of significant liver fibrosis (LF) among people with HIV (PWH) and metabolic dysfunction-associated steatotic liver disease (MASLD). This study examined liver stiffness progression and significant LF risk according to T2DM status in PWH with MALSD (PWH-MASLD) diagnosed via vibration-controlled transient elastography (VCTE). METHODS: PWH who had MASLD and had ≥2 VCTE measurements during the follow-up (median duration 4 years) were included. Change in liver stiffness measurement (LSM) from baseline (ΔLSM) was evaluated using a linear mixed-effects model. Multivariable Poisson regression was used to evaluate association between baseline T2DM and significant LF incidence (LSM ≥7.5 kPa). RESULTS: Among 345 PWH with MASLD (35% female), 97 (28%) had T2DM at baseline. In adjusted analysis, LSM declined modestly over time [mean -0.15 kPa/year (95% CI -0.28, -0.01)]. The ΔLSM over time was not associated with baseline T2DM (Pinteraction = 0.40). Among 253 PWH-MASLD without LF at baseline, the incidence of LF was 3.89 [95% CI 2.79-5.41]/100 person-years. Participants with baseline T2DM had a >3-fold higher risk of significant LF compared with those without T2DM [adjusted incidence risk ratio (aIRR): 3.35, 95% CI: 1.67-6.75). Time-updated BMI (per kg/m2 increase) was also associated with significant LF (aIRR, 1.10, 95% CI 1.03-1.18). CONCLUSIONS: Despite stable LSM over 4 years of follow-up, PWH with MASLD and T2DM have a significantly higher risk of LF. Prioritizing this population for intensive monitoring and treatments interventions may help mitigate liver disease progression.
Hughes S, Cheong J, Snape J
… +22 more, Jethwa S, Ng SH, Thangarajah R, Escayo T, Mcintyre B, Chong SW, Stone A, Oakley R, Frost K, Watson C, Brandish C, Martin D, Lewis N, Liu A, Patel R, Ahmad D, Patel A, Agravedi N, Hussain N, May S, Newby K, Hamilton R
BACKGROUND: Teicoplanin exhibits complex pharmacokinetics with substantial inter-patient variability. Therapeutic drug monitoring (TDM) is recommended to ensure adequate exposure, yet contemporary data on real-world pres...BACKGROUND: Teicoplanin exhibits complex pharmacokinetics with substantial inter-patient variability. Therapeutic drug monitoring (TDM) is recommended to ensure adequate exposure, yet contemporary data on real-world prescribing practices are scarce. We evaluated current teicoplanin dosing and monitoring practices across UK and Irish hospitals. METHODS: We conducted a multicentre, retrospective cohort study (Teicoplanin in UK: Study of Hospital Practice; TUcK-SHOP) across 21 hospitals. Adults receiving ≥5 days of intravenous/intramuscular teicoplanin with at least one TDM sample were included. Primary outcome was adherence to local or national dosing guidelines. Secondary outcomes included initial trough level attainment (≥20 mg/L) and laboratory-confirmed toxicity. Multivariable linear regression identified predictors of first trough concentrations. RESULTS: A total of 391 patients met inclusion criteria (median age 69 years; 57.5% male). Guideline adherence was 66% overall but varied widely between sites (5%-100%). Most patients received three-dose loading (61.3%) with median maintenance dosing of 10.6 mg/kg daily (IQR 7.3-12.1). Median first trough level was 24.6 mg/L (IQR 17.9-33.2); only 40.8% of patients on 6 mg/kg maintenance achieved ≥20 mg/L versus 86.6% on 12 mg/kg (P < 0.001). Independent predictors of higher trough levels included lower creatinine clearance, longer time to TDM sampling, higher loading and maintenance doses, and greater body weight (adjusted R2 = 0.26, P < 0.001). Dose adjustments were required in 30% of patients. CONCLUSIONS: Teicoplanin prescribing demonstrates significant variation across UK and Irish hospitals. Higher maintenance dosing (10-12 mg/kg) predicts therapeutic target attainment. These real-world data support the need for standardized dosing protocols to optimize teicoplanin therapy.
OBJECTIVES: The COVID-19 pandemic impacted healthcare use, with mixed reports regarding impacts on antimicrobial resistance. The aim was to identify changes in healthcare utilisation and antibiotic prescribing related to...OBJECTIVES: The COVID-19 pandemic impacted healthcare use, with mixed reports regarding impacts on antimicrobial resistance. The aim was to identify changes in healthcare utilisation and antibiotic prescribing related to the COVID-19 pandemic and quantify subsequent impacts on antibiotic resistance in clinical Escherichia coli isolates in Scotland. METHODS: Data involving ∼490 000 people from January 2018 to March 2022 were analysed. Joinpoint regression analyses identified trend changes in healthcare encounters, and antibiotic use in community and hospital settings. Using these joinpoints as an 'intervention' timepoint, interrupted time series analysis quantified associated changes in proportions of E. coli blood and urine culture isolates that were antibiotic resistant and multidrug resistant (MDR). RESULTS: January 2020 was identified as the intervention point. From 26% resistant (not MDR) and 35% MDR among urine E. coli isolates immediately pre-intervention, there were changes in level of +2.5% (95%CI -0.4% to 5.4%) and trend of +0.3% (95%CI 0.1% to 0.5%) per month for resistant (not MDR), and level change of +0.4% (95%CI -2.0% to 2.8%) but trend change of -0.3% (95%CI -0.5% to -0.1%) per month for MDR. By 9 month post-intervention, compared with predicted levels without intervention, resistant (not MDR) proportions increased while MDR proportions decreased. Similar changes occurred among blood culture isolates, but with less certainty around estimates. CONCLUSION: Small but significant reductions in MDR E. coli resulted from COVID-19-related changes in healthcare and antibiotic use. The findings are critical for antimicrobial stewardship and infection control interventions and evaluation.