OBJECTIVES: This study assessed the real-world clinical impact of rapid antimicrobial susceptibility testing (RAST) compared with conventional susceptibility testing (AST) in critically ill patients with Gram-negative bl...OBJECTIVES: This study assessed the real-world clinical impact of rapid antimicrobial susceptibility testing (RAST) compared with conventional susceptibility testing (AST) in critically ill patients with Gram-negative bloodstream infections (GNB BSIs), focusing on early optimization of therapy and clinical outcomes in a high multidrug-resistant (MDR) setting. METHODS: We conducted a retrospective, observational study including adult patients with GNB BSIs who were stratified according to the susceptibility testing strategy used (RAST or conventional AST). The primary outcome was 30-day all-cause mortality. Secondary outcomes included administration of early active antimicrobial therapy, clinical failure and length of both intensive care unit (ICU) and hospital stay. RESULTS: A total of 133 patients were included (RAST: 37; AST: 96). Thirty-day mortality was observed in 4/37 patients (10.8%) in the RAST group and in 30/96 (31.3%) in the AST group (P = 0.015). Early active therapy was administered to 32/37 (86.5%) RAST patients versus 44/96 (45.8%) in the AST group (P < 0.001). Clinical failure occurred in 0/37 RAST patients versus 20/96 (20.8%) AST patients (P = 0.003). Mean ICU stay was 30.3 ± 22.9 days (RAST) versus 36.9 ± 25.6 days (AST), P = 0.17. In Cox regression analysis, RAST-guided management (HR = 0.16, 95% CI 0.04-0.62) and early active therapy (HR = 0.51, 95% CI 0.19-0.94) were independently associated with survival. CONCLUSIONS: RAST may represent a valuable tool to optimize antimicrobial therapy in critically ill patients with GNB BSIs, particularly considering the increasing prevalence of MDR pathogens.
Therapeutic drug monitoring (TDM) is essential for optimizing systemic antifungal therapy, particularly for agents with narrow therapeutic windows, variable pharmacokinetics (PK) or established exposure-response relation...Therapeutic drug monitoring (TDM) is essential for optimizing systemic antifungal therapy, particularly for agents with narrow therapeutic windows, variable pharmacokinetics (PK) or established exposure-response relationships. By enabling individualized dosing, TDM improves efficacy, reduces toxicity and helps prevent resistance. This review synthesizes current evidence and recommendations for antifungal TDM across available and emerging agents, including triazoles, flucytosine, echinocandins, amphotericin B, and novel therapies such as ibrexafungerp, olorofim and fosmanogepix. Voriconazole, posaconazole and itraconazole exhibit substantial interpatient variability and concentration-dependent toxicity, supporting routine TDM. Fluconazole is generally predictable but may warrant monitoring in critically ill patients, those on renal replacement therapy, or with central nervous system infections, though empiric dose escalation is often more practical. Isavuconazole has more stable PK, limiting TDM to select high-risk scenarios. Flucytosine requires TDM due to its narrow therapeutic index and resistance risk, particularly in renal impairment. Echinocandins are safe, but critically ill or obese patients may be underexposed, warranting empiric dose adjustments over routine TDM. Liposomal amphotericin B exhibits complex PK with plasma concentrations poorly reflecting active drug, precluding reliable TDM. Emerging antifungals lack sufficient data to support routine TDM. Despite strong justification, real-world utilization remains inconsistent, constrained by access, logistics and interpretive challenges. Expanding timely access, standardizing protocols and developing consensus-driven guidance, while using empiric dosing strategies where appropriate, are essential to ensure safe, effective and individualized antifungal therapy.
OBJECTIVES: Biapenem is used to treat bacterial infections in various populations. However, no dosing recommendations exist for renal impairment and elderly populations. This study aimed to simulate the pharmacokinetics...OBJECTIVES: Biapenem is used to treat bacterial infections in various populations. However, no dosing recommendations exist for renal impairment and elderly populations. This study aimed to simulate the pharmacokinetics of biapenem in special populations using physiologically based pharmacokinetic (PBPK) modelling and to optimize dosing regimens. METHODS: A whole-body PBPK model for biapenem was developed and evaluated in healthy adults. Then the model was extrapolated to renal impairment and elderly populations. Box-whisker analysis and Monte Carlo simulation were performed to optimize the dosing regimen. RESULTS: The developed PBPK models incorporating glomerular filtration and hydrolase metabolism accurately characterized biapenem pharmacokinetics in healthy adults and in renal impairment and elderly populations. For moderate, severe and end-stage renal impairment populations, we recommend reducing the biapenem dose to 67%, 50% and 30% of that for healthy adults, respectively, to achieve comparable therapeutic efficacy. No dose adjustment is necessary for individuals with mild renal impairment. The elderly population with renal impairment should follow the same dosage adjustments as those recommended for general renal impairment. Against Escherichia coli and Klebsiella pneumoniae, most simulated dosage regimens achieved cumulative fraction of response (CFR) values exceeding 80% for targets of 40%, 60% and 80% of time that free drug concentrations exceed the minimum inhibitory concentration (%fT > MIC) in healthy adults and in renal impairment and elderly populations. However, none of the simulated regimens produced satisfactory CFR values against Pseudomonas aeruginosa or Acinetobacter baumannii in these populations. CONCLUSIONS: Biapenem PBPK models were successfully developed to optimize dosing regimens for special populations.
OBJECTIVES: Age-related pathophysiological changes may impact the pharmacokinetics and pharmacodynamics (PK/PD) of ß-lactam antibiotics, potentially resulting in suboptimal concentrations in older adults. This study eval...OBJECTIVES: Age-related pathophysiological changes may impact the pharmacokinetics and pharmacodynamics (PK/PD) of ß-lactam antibiotics, potentially resulting in suboptimal concentrations in older adults. This study evaluated PK/PD target attainment with current intravenous amoxicillin-clavulanate and piperacillin-tazobactam dosing regimens in older adults, identified risk factors for target non-attainment, and assessed the prevalence of toxic concentrations. METHODS: This was a prospective, observational PK study in geriatric inpatients (≥75 years) who were treated intravenously with amoxicillin-clavulanate (1 g/0.2 g q6h as a 30-minute infusion) or piperacillin-tazobactam (4 g/0.5 g q6h as a 3-hour infusion). Trough blood samples were collected in steady-state conditions. Target attainment was evaluated against a 100%fT > MIC target. Risk factors for target non-attainment were identified by multivariable logistic regression analysis. Toxicity thresholds were defined as total Cmin concentrations of 80 mg/L for amoxicillin and 157.2 mg/L for piperacillin. RESULTS: Seventy-four patients (median age (IQR): 87 years (83-90)) were included. The PK/PD target was achieved in 15 of 35 and 33 of 39 patients for amoxicillin-clavulanate and piperacillin-tazobactam, respectively. Multivariable logistic regression analysis revealed an effect of comorbidity burden, assessed by the Cumulative Illness Rating Scale-Geriatric (CIRS-G), and estimated glomerular filtration rate that explained 23.8% of target non-attainment (P < 0.05). Receiver operator characteristic curves identified an eGFR of 67 mL/min/1.73m2 as a threshold associated with an increased risk of target non-attainment. Toxicity thresholds were never exceeded in this study. CONCLUSIONS: Health status and renal function, rather than chronological age, play a significant role in target non-attainment among older adults. Further research is required to delineate predictors for interpatient variability in PK and develop evidence-based dosing strategies. TRIAL REGISTRATION: Registration in ClinicalTrials.govTrial registration number: NCT04436991Registration date: 16/06/2020.
OBJECTIVES: To (1) assess the prevalence and patterns of HIV drug resistance (HIVDR) mutations, (2) identify correlations between different HIVDR mutations within drug classes, and (3) examine the association between res...OBJECTIVES: To (1) assess the prevalence and patterns of HIV drug resistance (HIVDR) mutations, (2) identify correlations between different HIVDR mutations within drug classes, and (3) examine the association between resistance mutations and high HIV viral load. METHODS: We conducted a secondary analysis of retrospective data collected through the Population-based HIV Impact Assessment (PHIA) surveys conducted between 2015 and 2019 in 13 African countries. We included participants aged ≥15 years with available HIVDR genotyping. The primary outcomes were (1) prevalence of HIVDR mutations, categorized by drug class into non-nucleoside reverse transcriptase inhibitors (NNRTIs), Nucleoside Reverse Transcriptase Inhibitors (NRTIs), and Protease inhibitors (PIs); (2) high HIV viral load (VL), (HIV RNA ≥1000 copies/mL). RESULTS: The analysis included 2292 participants, with a median age range between 31 and 41 years. More than one-third of participants were not receiving ART. Of all participants, 1949 (85%) had high VL. Resistance to NNRTIs and NRTIs was the most prevalent in most countries, ranging from 43% to 60%, and 37% to 53%, respectively. Resistance to PI ranges from 0.2% to 5%. Multiple drug resistance mutations across all ART classes were strongly associated with high VL. Among NNRTIs, 16/39 mutations (e.g. K103N, Y181C) and 18/34 NRTI mutations (e.g. M184V, K65R) showed strong associations with high VL in ≥10 countries. For PIs, Q58E and L33F emerged as key mutations strongly associated with high VL across multiple nations. CONCLUSIONS: Strengthening resistance surveillance, optimising ART regimens, and improving adherence are crucial to curb resistance and sustain HIV epidemic control.
HIV/AIDS remains a global health challenge with significant disparities in access to prevention strategies, particularly among underserved populations. Pre-exposure prophylaxis (PrEP) has proven to be an effective interv...HIV/AIDS remains a global health challenge with significant disparities in access to prevention strategies, particularly among underserved populations. Pre-exposure prophylaxis (PrEP) has proven to be an effective intervention in reducing HIV transmission, yet its uptake remains suboptimal in Europe. This report examines the current state of PrEP implementation in Spain, identifies key barriers to its access and proposes strategies for overcoming these obstacles, with a focus on equity and innovation. Despite PrEP being available since 2019, challenges such as centralized, hospital-based distribution, stigmatization, rigid eligibility criteria, excess medicalization and insufficient healthcare provider education persist. This study highlights the disproportionate underutilization of PrEP among populations with difficulty accessing prevention programmes, including women, migrants, sex workers, transgender individuals and people who inject drugs. Moreover, the introduction of long-acting injectables (LAI) and their endorsement by WHO represent a promising solution to improve PrEP efficacy, adherence and reduce the burden of frequent clinic visits. Drawing on successful international models, such as the 56 Dean Street clinic in London, this paper advocates for a decentralized, de-medicalized, community-based approach to PrEP delivery alongside policy reforms to simplify eligibility criteria and integrate PrEP into broader healthcare services. These solutions aim to address geographical and socio-cultural barriers, ultimately facilitating more equitable access to HIV prevention across Europe. The findings emphasize the importance of flexibility, community engagement and innovation to ensure that those most at need are ultimately offered PrEP, contributing to global efforts to close the HIV prevention gap.
BACKGROUND: Dalbavancin is a promising option for the treatment of complex gram-positive infections. However, the optimal dosing regimen to ensure adequate drug exposure during prolonged treatment courses remains debate....BACKGROUND: Dalbavancin is a promising option for the treatment of complex gram-positive infections. However, the optimal dosing regimen to ensure adequate drug exposure during prolonged treatment courses remains debate. OBJECTIVES: To evaluate whether an intravenous dalbavancin regimen of 1500 mg administered on days 1, 15 and 43 achieves validated serum concentration targets for infections requiring 12 weeks of treatment. METHODS: We conducted a retrospective bicentric study including patients who received three 1500 mg doses of dalbavancin intended to provide 12 weeks of treatment coverage between January 2020 and May 2024. Patients' characteristics, microbiological data, and dalbavancin concentrations measured before reinjection on days 15, 43 and 90 were collected. We targeted a total dalbavancin plasma concentration of ≥8.04 mg/L, validated for Staphylococcus spp. strains with a MIC ≤0.125 mg/L. Concentrations were compared according to body mass index (≥30 kg/m2) and albumin level (≥30 g/L). RESULTS: Forty-two patients (39 bone and joint infections and three vascular infections) were included. Dalbavancin serum trough concentrations exceeded 8.04 mg/L for all available measurements (76/76) across the different monitored time points during the 12-week treatment period. Although lower concentrations were observed in patients with hypoalbuminemia or obesity, all measured values remained above the target threshold. CONCLUSIONS: These results suggest that a three-dose dalbavancin regimen administered on days 1, 15, and 43 may achieve validated pharmacokinetic targets and maintain therapeutic exposure over a 12-week period for staphylococcal infections with a dalbavancin MIC ≤0.125 mg/L. Therapeutic drug monitoring should be performed for patients with hypoalbuminemia or obesity until larger studies confirm these findings, and for strains with an MIC >0.125 mg/L.
Hsue PY, Waters L, Orkin C
… +10 more, Tiraboschi JM, Avihingsanon A, Marongiu A, Whiteman AS, Tian Y, Nielson CM, Aizen K, Cohen C, Hindman JT, Rockstroh JK
BACKGROUND: People with HIV have a greater risk of cardiovascular disease than the general population. Current literature suggests that some ARTs may exacerbate this risk. OBJECTIVES: To estimate the risk of hypertension...BACKGROUND: People with HIV have a greater risk of cardiovascular disease than the general population. Current literature suggests that some ARTs may exacerbate this risk. OBJECTIVES: To estimate the risk of hypertension in treatment-naïve people with HIV receiving integrase strand transfer inhibitor (INSTI)/tenofovir alafenamide (TAF) or INSTI/non-TAF versus NNRTI/non-TAF regimens. METHODS: Post hoc pooled analysis evaluating data from US participants in five Phase 3 randomized studies. Adjusted prevalence of Stage 1 and 2 hypertension (American College of Cardiology/American Heart Association criteria) and conditional odds of higher blood pressure ratios were estimated using proportional odds mixed-effect regression through 108 weeks after ART initiation. Time to incident hypertension through 96 weeks was modelled using Cox proportional-hazards regression. RESULTS: In total, 2411 participants were included (528, 749 and 1134 received NNRTI/non-TAF, INSTI/non-TAF and INSTI/TAF regimens, respectively). Nearly half of participants had hypertension (Stage ≥1) at baseline. The Week 96 adjusted estimates of risk of hypertension (95% CI) were 1.06 (0.99, 1.13) and 1.12 (0.98, 1.27) for Stages ≥1 and ≥2 hypertension, respectively, for NNRTI/non-TAF versus INSTI/non-TAF, and 1.01 (0.95, 1.08) and 1.02 (0.91, 1.17) for Stages ≥1 and ≥2 hypertension, respectively, for NNRTI/non-TAF versus INSTI/TAF. There were no significant differences in conditional odds of high blood pressure between treatment groups. No significant differences were identified in time to incident composite hypertension for INSTI/non-TAF and INSTI/TAF versus NNRTI/non-TAF regimens; estimated hazard ratios (approximate 95% CI) were 0.88 (0.66, 1.17) and 0.98 (0.75, 1.28), respectively. CONCLUSIONS: Results suggest the risk of hypertension is not significantly different across INSTI/TAF, INSTI/non-TAF and NNRTI/non-TAF regimens.
Borjabad B, Rojas J, Inciarte A
… +18 more, Sempere A, Chivite I, González-Cordón A, Mosquera MM, Torres B, Calvo J, de la Mora L, Martinez-Rebollar M, Laguno M, Foncillas A, Ambrosioni J, Alcami J, Miró JM, Blanco JL, Sanchez-Palomino S, Blanch J, de Lazzari E, Martinez E
BACKGROUND: Following a successful pilot study of a three-day-per-week regimen of efavirenz, emtricitabine, and tenofovir disoproxil fumarate, we hypothesized that this strategy would sustain virological efficacy and red...BACKGROUND: Following a successful pilot study of a three-day-per-week regimen of efavirenz, emtricitabine, and tenofovir disoproxil fumarate, we hypothesized that this strategy would sustain virological efficacy and reduce long-term toxicities. METHODS: After a 24-week randomized phase, participants in the A-TRI-WEEK trial (ClinicalTrials.gov NCT01778413) were offered the three-day-per-week regimen. The extension was approved by the Institutional Review Board, and participants provided informed consent; follow-up continued until further participation no longer offered additional clinical or research value. HIV-RNA, CD4 and CD8 cells, blood and urine chemistries, and bone mineral density (BMD) were assessed every 6 months. Treatment failure was defined a priori as virological failure (HIV RNA >1000 copies/mL once or ≥50 copies/mL confirmed), discontinuation, or loss to follow-up. Secondary outcomes included changes in lipids, estimated glomerular filtration rate (eGFR), urine protein/creatinine, and BMD. RESULTS: Of 61 participants completing the 24-week phase, 59 (97%) entered the extension. After 7 years, 37 (63%) remained free of treatment failure. Only one participant experienced virological failure, following an unintentional treatment interruption, with no resistance mutations detected. All other failures were due to discontinuations (CNS symptoms, n = 7; BMD decline, n = 7; drug interactions, n = 2; regimen preference, n = 2; cancer, n = 1; death unrelated, n = 1; loss to follow-up, n = 1). Laboratory parameters showed biphasic patterns, with initial stability followed by modest late declines in eGFR and BMD and increases in triglycerides and proteinuria. Most discontinuations occurred in the latter half of follow-up (years 4-7). CONCLUSIONS: A three-day-per-week regimen of efavirenz, emtricitabine, and tenofovir disoproxil fumarate maintained durable long-term viral suppression, while mitigating but not fully preventing toxicities associated with EFV/TDF/FTC. These findings support reduced-exposure antiretroviral therapy and warrant evaluation of similar strategies with modern integrase inhibitor-based regimens.
OBJECTIVES: To investigate the species distribution and antifungal susceptibility profiles of clinical mould isolates from China to olorofim, manogepix, amphotericin B, triazoles and echinocandins. METHODS: Isolates were...OBJECTIVES: To investigate the species distribution and antifungal susceptibility profiles of clinical mould isolates from China to olorofim, manogepix, amphotericin B, triazoles and echinocandins. METHODS: Isolates were collected from patients at 10 tertiary hospitals across China between 2019 and 2024. Species identification was performed by sequence analysis. Antifungal susceptibility testing was performed according to the CLSI reference methods. The cyp51A, cyp51B and hmg1 genes from triazole-resistant isolates were amplified to identify mutations associated with resistance. RESULTS: Aspergillus spp. (92.02%) remained the most prevalent pathogens, followed by Fusarium spp. (4.18%) and Mucorales (1.90%). The proportion of non-A. fumigatus isolates showed an increasing trend. The majority of Aspergillus spp. were susceptible/WT to triazoles (97.52%), with posaconazole showing the highest potency. Among the triazole-resistant Aspergillus isolates, two harboured cyp51A mutations (TR46/Y121F/T289A, G441S) and one carried an hmg1 mutation (V827L). Notably, the novel antifungals olorofim and manogepix were highly potent against most tested moulds, including triazole-resistant Aspergillus isolates. For Fusarium spp., manogepix showed low MECs, whereas olorofim and triazoles showed higher and more species-specific MICs. Both novel agents showed high MIC/MECs against Mucorales isolates, and triazole MIC distributions varied markedly between species. CONCLUSIONS: A. fumigatus sensu stricto remained the predominant pathogen while non-A. fumigatus moulds became increasingly prevalent. Triazole resistance among clinical Aspergillus isolates was uncommon but was associated with cross-resistance and target gene mutations. Novel antifungals olorofim and manogepix demonstrated potent in vitro activity against a broad range of clinical moulds, including triazole-resistant Aspergillus isolates.
OBJECTIVES: To determine the PK of the pro-drug colistimethate sodium (CMS) and colistin in adult patients admitted to a South African critical care unit and to compare the PK with historical data. MATERIALS AND METHODS:...OBJECTIVES: To determine the PK of the pro-drug colistimethate sodium (CMS) and colistin in adult patients admitted to a South African critical care unit and to compare the PK with historical data. MATERIALS AND METHODS: We conducted a prospective, observational, PK study in critically ill adult patients receiving intravenous colistin as part of standard of care. CMS was administered as a loading dose of either 9 million units (MU) or 12 MU followed by maintenance doses dependent on creatinine clearance (CrCl) at either 12- or 8-hourly. PK samples were collected at 1, 2, 4, 8, 12, 24 and 48 hours post-loading dose. CMS and colistin concentrations were analysed using liquid chromatography-tandem mass spectrometry. The PK of CMS and colistin were described using non-compartmental analysis in Phoenix WinNonlin. RESULTS: We enrolled 24 participants, 50% (12/24) were admitted with burns. Mean age was 42 years (SD ± 16.3) and mean CrCl was 140 mL/min (SD ± 58.7). The PK parameters following a loading dose of 9 MU were comparable to published data. Colistin AUC showed a negative correlation with white cell count (r = -0.63) and eGFR (r = -0.44). Probability of target attainment was acceptable at Acinetobacter baumannii minimum inhibitory concentrations <1 mg/L. CONCLUSION: Our results are comparable to previously published literature. Notably, increasing eGFR and WCC decreased colistin AUC. Future work will adopt a population pharmacokinetic modelling approach to quantify and account for sources of variability, with the aim of informing individualized dosing strategies for this South African population.
Lapadula G, Soria A, Antolini L
… +9 more, Rugova A, Colella E, Sabbatini F, Squillace N, Mezzadri L, Limonta S, Cappelletti A, Ranzani A, Bonfanti P
J Antimicrob Chemother
· 2026 Feb · PMID 41665334
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BACKGROUND: Switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) has been associated with reduced transaminase level among people with HIV (PWH), with and without HBV. It is unclear whether t...BACKGROUND: Switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) has been associated with reduced transaminase level among people with HIV (PWH), with and without HBV. It is unclear whether the effect is mediated by HBV serostatus. METHODS: We conducted a longitudinal observational study of PWH who switched from TDF to TAF between 2016 and 2023. A mixed-effects model with random intercepts assessed the effect of the switch on transaminases, including an interaction term for HBV status: chronic hepatitis B (HBsAg+), possible occult HBV infection (pOBI; HBsAg-/HBcAb+) and no HBV. RESULTS: Among 727 individuals, 7% had chronic hepatitis B and 35% had pOBI. Switching to TAF was associated with a significant ALT decrease (β -3.5 UI/mL, 95%CI: -5.2 to -1.9). Compared to HBV-negative individuals, individuals with chronic hepatitis B experienced steeper ALT reduction (β -7.5, 95%CI: -11.8 to -3.2), while pOBI was associated with a non-significant reduction (β -1.9; 95%CI: -4.4-0.6; P = 0.133). These findings persisted after adjusting for other predictors of transaminase levels. TAF was also associated with accelerated weight gain (+0.75 kg/year, 95% CI: 0.63-0.87) and a transient drop in the Hepatic Steatosis Index (-0.22; 95% CI: -0.38 to -0.06) followed by an annual increase thereafter (+0.18/year; 95% CI: 0.10-0.27). CONCLUSIONS: Switching from TDF to TAF is associated with modest but statistically significant ALT reduction in PWH, especially in HBsAg + individuals. Our findings suggest that TAF may represent a favourable option in this subgroup, although potential metabolic consequences warrant close monitoring.
BACKGROUND: Antibiotic resistance and tolerance pose dual challenges to clinical antibiotic therapy, with tolerance potentially accelerating resistance evolution. LYSC98, a candidate drug that has just received clinical...BACKGROUND: Antibiotic resistance and tolerance pose dual challenges to clinical antibiotic therapy, with tolerance potentially accelerating resistance evolution. LYSC98, a candidate drug that has just received clinical approval in China, has been reported to have bactericidal activity against antibiotic-resistant Staphylococcus aureus. However, its mechanism and activity against antibiotic-resistant bacteria in tolerant state remains unexplored. OBJECTIVES: To evaluate the antibacterial activity of LYSC98 against antibiotic-resistant bacteria in different metabolite states, and to elucidate its mechanism of action. MATERIALS AND METHODS: MIC values of antimicrobial agents were determined using broth microdilution. Time-kill assays were used to evaluate the bactericidal effect. SEM and TEM were conducted to visualize the morphological changes. Membrane permeability was determined by propidium iodide. RESULTS: LYSC98 showed potent antibacterial activity against Gram-positive pathogens, with MICs ranging from 0.06 to 2 mg/L. It demonstrated a rapid bactericidal effect against antibiotic-resistant pathogens, irrespective of their growth phase or tolerant state, and conferred an extended post-antibiotic effect. Significantly, LYSC98 displayed a low potential for resistance development. It targeted both bacterial cell wall and membrane, with in vitro membrane assays indicating selective damage to these structures and no observed harm to mammalian cells. CONCLUSIONS: LYSC98's rapid bactericidal activity, selective disruption of bacteria without harming mammalian cells and low propensity for resistance development make it a novel promising candidate for combating chronic, clinically recalcitrant infections.
OBJECTIVES: Pseudomonas aeruginosa is a common microorganism in chronic infections due to biofilm formation and antibiotic resistance. This study aimed to compare the synergistic effects of antibiotic combinations agains...OBJECTIVES: Pseudomonas aeruginosa is a common microorganism in chronic infections due to biofilm formation and antibiotic resistance. This study aimed to compare the synergistic effects of antibiotic combinations against carbapenem-resistant P. aeruginosa (CRPA) in planktonic and biofilm-embedded states. METHODS: Twelve CRPA bloodstream isolates from the Asian Bacterial Bank (2016-2018) were analysed. The minimum biofilm eradication concentrations (MBECs) were determined using the peg lid system, and antimicrobial interactions were assessed using biofilm checkerboard assays, testing three double combinations (colistin-rifampin, colistin-imipenem, and rifampin-ceftazidime/avibactam) and two triple combinations (colistin-rifampin-imipenem and colistin-rifampin-ceftazidime/avibactam). RESULTS: The MBEC values of all four antimicrobial agents (rifampin, colistin, imipenem, and ceftazidime/avibactam) were significantly higher than their corresponding minimum inhibitory concentration values (P < 0.001). Although single agents required markedly elevated concentrations to eradicate CRPA biofilms, approximately half of the double and triple antimicrobial combinations demonstrated synergistic activity. In the biofilm phase, synergism rates were comparable between triple combinations (colistin-rifampin-ceftazidime/avibactam, 50%; colistin-rifampin-imipenem, 66%) and double combinations (colistin-rifampin, 42%; rifampin-ceftazidime/avibactam, 42%; colistin-imipenem, 66%). The triple combinations showed lower FBEC indices (colistin-rifampin-imipenem: median 0.17; colistin-rifampin-ceftazidime/avibactam: 0.34) than the corresponding double combinations (colistin-rifampin: 0.53; colistin-imipenem: 0.20; rifampin-ceftazidime/avibactam: 0.78), although these differences were not statistically significant. CONCLUSIONS: Our study provides experimental evidence that antimicrobial combination therapy may offer advantages over single agents for CRPA biofilm eradication, supporting further investigation into the role of such regimens in biofilm-associated infections.
OBJECTIVE: The objective of this study is to elucidate the phenotypic and genetic basis of carbapenem tolerance in Klebsiella pneumoniae species complex bloodstream isolates lacking carbapenemase genes, with a focus on m...OBJECTIVE: The objective of this study is to elucidate the phenotypic and genetic basis of carbapenem tolerance in Klebsiella pneumoniae species complex bloodstream isolates lacking carbapenemase genes, with a focus on multicellular behaviours. MATERIALS AND METHODS: Fifty clinical K. pneumoniae species complex isolates from bloodstream infections were screened for reduced susceptibility to meropenem. Five strains (MIC 1-2 mg/L) lacking carbapenemase genes were analysed using whole-genome sequencing, time-kill assays, plasmid-based gene expression assays and phenotypic assays, including autoaggregation and biofilm formation. RESULTS: The results of the time-kill assay showed that three strains were carbapenem tolerant. Two strains carrying blaDHA-1 exhibited reduced meropenem activity and enhanced survival following drug exposure. One isolate showed sustained survival and carried a frameshift mutation in mrkH, leading to downregulation of mrkA expression and enhanced autoaggregation. Complementation with wild-type mrkH reduced tolerance. Disruption of cellular aggregates significantly decreased survival, indicating that aggregation provides physical protection against meropenem. CONCLUSIONS: This study identified mrkH-linked autoaggregation as a novel mechanism of carbapenem tolerance in Klebsiella isolates. Overall, the findings underscore the role of multicellular behaviours in antibiotic resilience and highlight the potential clinical relevance of non-carbapenemase-mediated tolerance mechanisms.
OBJECTIVES: To assess the biliary pharmacokinetic/pharmacodynamic (PK/PD) of continuous infusion (CI) ceftazidime-avibactam in a series of critical orthotopic liver transplant (OLT) recipients having pre-emptive therapy...OBJECTIVES: To assess the biliary pharmacokinetic/pharmacodynamic (PK/PD) of continuous infusion (CI) ceftazidime-avibactam in a series of critical orthotopic liver transplant (OLT) recipients having pre-emptive therapy during OLT because of carbapenemase-producing Enterobacterales (CPE) rectal colonization or targeted therapy of CPE intra-abdominal (IAIs) and/or biliary tract infections (BTIs). METHODS: We performed an exploratory, hypothesis-generating prospective case series including critical OLT recipients carrying a Kehr's tube and undergoing therapeutic drug monitoring of ceftazidime and avibactam in both bile and plasma simultaneously while receiving CI ceftazidime-avibactam pre-emptive or targeted therapy. Biliary aggressive joint PK/PD target attainment [defined as a free ceftazidime steady-state concentrations fCss/MIC ratio >4 coupled with an avibactam fCss/target concentration (CT = 4 mg/L) ratio >1] was selected as optimal threshold of ceftazidime-avibactam efficacy, given this was previously shown to be independently associated with lower rates of microbiological failure and resistance development. Bile-to-plasma fCss ratios were calculated. RESULTS: Overall, four critical OLT recipients were included. Aggressive biliary ceftazidime-avibactam joint PK/PD target during treatment with CI 2 g/0.5 g q8 h over 8 h was attained in 2/4 cases (quasi-optimal and suboptimal in one case each). Median (range) fCss bile-to-plasma ratios were 0.28 (0.22-0.38) for ceftazidime and 0.24 (0.11-0.52) for avibactam. CONCLUSIONS: Our limited cases series suggested that both ceftazidime and avibactam showed a moderate and broadly similar biliary penetration. Administration by CI may be helpful in attaining an aggressive biliary joint PK/PD target of ceftazidime-avibactam against pathogens with an MIC up to 8 mg/L.