International Journal of Antimicrobial Agents

ObjectivesTo provide real-world evidence on piperacillin exposure and outcomes in critically ill patients following the implementation of pharmacokinetic (PK)/pharmacodynamic (PD)-guided dosing in routine care. MethodsThis retrospective observational study included critically ill adults who received continuous piperacillin/tazobactam infusion between 2011 and 2019. Empiric doses were individualized using dosing software based on renal function and subsequently adjusted according to therapeutic drug monitoring (TDM) results. Drug exposure was defined as subtherapeutic (<32 mg/L), therapeutic (32-64 mg/L), moderately high (64-96 mg/L), or supratherapeutic (>96 mg/L). ResultsA total of 1538 critically ill patients with severe infections and sepsis of varying severity were included, and 3,090 piperacillin serum concentrations were analysed. Median daily piperacillin dose was 8,000 mg, median steady-state concentration 55 mg/L, and median clearance 6.25 L/h. At the first measurement, individualized empiric dosing resulted in 45.7% of patients being within the therapeutic range; after TDM-guided adjustment, target attainment increased to 62.4%. Subtherapeutic and supratherapeutic concentrations were uncommon among all TDM samples collected during individualized dosing (<32 mg/L: 12.8%; < 16 mg/L: 0.8%; > 96 mg/L: 11%). ICU mortality was 21.1 % in patients within the therapeutic range, 30.3 % in those with moderately high concentrations, and 44.1 % in those with supratherapeutic concentrations (p = 0.05). Women were 1.8 times more likely to present supratherapeutic concentrations. ConclusionsA multimodal approach combining individualized empiric dosing, TDM, and continuous infusion ensured target attainment while reducing drug consumption. These findings support the integration of individualized, PK/PD-guided dosing into routine care for critically ill patients and highlight the need for further studies addressing sex-related pharmacokinetic variability.

BackgroundThe emergence of multidrug-resistant (MDR) infections represents one of the most critical challenges faced by contemporary medical practice. The World Health Organization (WHO) has identified antibiotic resistance as a significant threat to global health, with MDR bacteria leading to increased morbidity, mortality, and healthcare costs [1]. Objective (PICOS)This review examines (P) MDR infection patients receiving (I) short-term (0-14 day) phage therapy versus (C) long-term/antibiotic treatments, assessing (O) efficacy (eradication rates) and safety (adverse events) through (S) clinical trial/case study analysis. Primary & Secondary Outcome MeasuresEfficacy (bacterial eradication) and safety (adverse events) of 0-14 day phage therapy, compared to conventional antibiotics or longer phage regimens. InterventionApplication of bacteriophages (viruses that infect and lyse bacteria) as targeted antimicrobial agents. MethodsA comprehensive review of clinical trials, case studies, and experimental models from peer-reviewed literature. ResultsPhage therapy demonstrates high bacterial specificity, adaptability to resistance, and synergistic effects with antibiotics. Article SummaryWhile phage therapy offers a promising alternative to antibiotics, its clinical integration faces regulatory, logistical, and safety challenges. Strengths and limitations of this studyThe strengths include detailed analysis of phage mechanisms, clinical applications, and therapeutic potential. The limitations are limited large-scale randomized controlled trials (RCTs) and standardized treatment protocols & last is This review was not registered in PROSPERO. ConclusionPhage therapy holds transformative potential in combating MDR infections but requires further research, regulatory standardization, and clinical validation.

Cefepime is widely used in the intensive care unit (ICU) for the treatment of complicated Gram-negative infections. Cefepime is a candidate for therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD), especially in critically ill patients, notably because of its concentration-dependent neurological toxicity. In this study, we aimed to evaluate the impact of the implementation of cefepime MIPD on PK/PD targets attainment in intensive care. We performed a monocentric, retrospective, before-after study, including all adult patients hospitalized in our ICU and for whom at least two cefepime plasma through concentrations (Cmin) were measured on separate days. The main endpoint was a Cmin between 4xMIC (or 10mg/L if the MIC was unavailable) and 20mg/L. We modelled the odds of target attainment via a mixed-effect logistic model and the rate of target attainment with a spline of time. A total of 281 patients were included, of whom 121 were in the MIPD group and 160 in the control group. Median age, weight and follow-up duration were 65 years, 76 kg and 3 days respectively. The two most common infections were pneumonia (n=239) and peritonitis (n=16). A total of 728 cefepime through concentrations were collected. MIPD was non-significantly associated with higher odds of being in the therapeutic range (aOR 1.40 [0.88 - 2.22]) and significantly associated with lower odds of being over-exposed (aOR 0.58 [0.35 - 0.96]). HR of target attainment was 1.1 [0.7 - 1.9] at day 1 and 1.6 [0.9 - 2.9] at day 7. In summary, we demonstrated that cefepime MIPD in the ICU reduces the risk of over-exposure, and may be beneficial on the odds and on the rate of PK/PD targets attainment. What is already known about this subjectO_LICefepime is a candidate for TDM/MIPD programs, with established PK/PD targets for both antimicrobial efficacy and neurological toxicity (100% f T >4xMIC and Cmin>20mg/L, respectively). C_LIO_LIPrevious randomized controlled trials (RCT) of beta-lactams model-informed precision dosing (MIPD) versus standard dosing approaches failed to demonstrate a superiority of MIPD in clinical endpoints attainment, and provided conflicting results on pharmacokinetic target attainment. C_LI What this study addsO_LICefepime MIPD in the intensive care units reduces the odds of being over-exposed, and thus, possibly, the risk of elicit dose-dependent neurological toxicity. C_LIO_LIFurther RCT evaluating MIPD efficacy should focus on evaluating target attainment rate instead of probability alone. C_LI

ObjectivesLinezolid is highly valuable for treating infections caused by Gram-positive bacteria that are resistant to first-line agents. Severe infections require empirical therapy, where treatment is initiated before the pathogen and its susceptibility are identified. This evaluation aims to compare different dosing strategies for empirical dosing of linezolid in an intensive care unit (ICU) setting, with the goal of optimising pathogen eradication while minimising toxicities. MethodsThree dosing strategies were compared, all based on two previously published datasets of prospective clinical studies: (i) standard dosing, (ii) therapeutic drug monitoring (TDM) guided dosing, and (iii) a theoretical model-informed precision dosing (MIPD) guided by a population pharmacokinetic model using a Bayesian approach. Each scenario was combined with an ICU-specific minimal inhibitory concentration (MIC) distribution sampled over ten years and containing over 19,000 pathogens. The pharmacokinetic-pharmacodynamic target for pathogen eradication was defined as the minimum concentration above the MIC, and the toxicity limit was set at minimum concentrations exceeding 8 mg/L. ResultsData from 117 critically ill patients with 2184 TDM samples were available. Within the past 10 years, the rate of resistance to linezolid has increased significantly among intensive care patients, rising from 6.3% in 2015 to 11.4-15% between 2021 and 2024. Using standard dosing, only 35.7% of patients were within the target range. This number increased slightly to 46.3% when dose adaptations with TDM were possible. In contrast, MIPD projected target attainment in 70.9-81.3% of patients. ConclusionsIn the era of increasing antimicrobial resistance, particularly against linezolid, novel dosing strategies such as MIPD become urgently necessary. Our results suggest that empirical linezolid dosing based on standard regimens as well as dose adaptation based on TDM failed to achieve sufficient target concentrations in ICU patients. Dosing guided by MIPD should therefore be further explored and implemented in future clinical practice.

Multi-drug resistance in Pseudomonas aeruginosa is often associated with overexpression of drug efflux pumps which limit antibiotics exposure. So far, successful development of efflux pump inhibitors (EPIs) has been plagued by undesirable toxicities and inconsequential in vivo efficacy. TAXIS Pharmaceuticals Inc. has discovered an effective anti-pseudomonal therapy involving a novel indole carboxamide class of EPI, TXA11114, with a fluorine substituted diamine sidechain, as an adjunctive to levofloxacin. TXA11114 has demonstrated excellent potentiation of levofloxacin MIC by [&ge;] 8-fold in 90% of Walter-Reed and CDC multi-drug resistant (MDR) isolates. Biophysical and genetic studies with TXA11114 support efflux inhibition while ruling out membrane disruption as a mechanism of action. TXA11114 enhanced the levofloxacin killing and diminished the frequency of resistance emergence to levofloxacin to undetectable levels. Moreover, in murine thigh and lung P. aeruginosa infection models, the TXA11114-levofloxacin combination showed pronounced killing compared to levofloxacin alone, achieving a validated in vivo efficacy milestone that previous EPIs could not. Most importantly, TXA11114 exhibits a safe toxicology profile when screened for cytotoxicity, hERG channel inhibition, in vitro nephrotoxicity, and acute toxicity. Further, pharmacokinetic (PK) parameters of TXA11114 have a complementary profile with that of levofloxacin in plasma and bronchoalveolar lavage fluid (BALF) samples of infected mice, maximizing pharmacodynamic (PD) benefits. Overall, studies on the TXA11114-levofloxacin combination highlight its potential as an anti-pseudomonal agent for combating multidrug-resistant infections.

BackgroundTrans Sodium Crocetinate (TSC) is a bipolar synthetic carotenoid under development as a drug to enhance oxygenation to hypoxic tissue in addition to standard of care. TSC acts via a novel mechanism of action, improving the diffusivity of oxygen in blood plasma. Thus, it is based on physical-chemical principles, unlike most drugs which are based on biochemistry-based mechanisms. We explored the use of escalating doses and multiple daily dosing of TSC as a potential therapeutic for patients suffering from hypoxemia due to SARS-CoV-2 infection. MethodsIndividuals [&ge;]18 years who were hospitalized with confirmed SARS-CoV-2 infection and hypoxemia, defined as SpO2 < 94% on room air or requiring supplemental oxygen, WHO ordinal scale 3 through 7 (exclusive of Extra Corporeal Membrane Oxygenation [ECMO]) were enrolled in cohorts of six subjects, each of whom received the same dose (0.25, 0.5, 1.0, or 1.5 mg/kg) of TSC via intravenous bolus every 6 hours in addition to standard of care (SOC). This report describes the safety and efficacy results from the lead-in phase of the study and the population pharmacokinetics (PK) analyses. Safety was assessed as the number of serious adverse events and dose-limiting toxicities (DLTs) observed with each dose. Several efficacy parameters were examined in the lead-in phase and descriptive statistics of efficacy parameters are provided. No formal statistical analyses were performed. The population PK analyses were based on previous analyses and examination of the concentration profiles, and two-compartment linear pharmacokinetic models were evaluated and validated. Covariates, including body size, age, sex, organ function, and dose level, were evaluated for inclusion into the model. ResultsTSC was well tolerated. There were no treatment emergent adverse events (TEAEs) reported. There were 2 serious adverse events (SAEs) reported during the study, neither were considered treatment-related. A total of 24 (96%) subjects survived. One subject (4.0%) died during the study as a result of an SAE (respiratory failure), and that event was determined to be due to COVID-19 complications and not related to study drug. There was an observed reduction in the time to improvement in WHO Ordinal Scale with increasing dose. The median time to 1-point reduction in subjects receiving 0.25 mg/kg was 11.5 days versus 7.5 days in the 1.5 mg/kg treatment cohort. The overall range across all doses was 1 day to 28 days. A total of 36.0% of subjects had a 1-point improvement in WHO Ordinal Scale to Day 7. The 1.5 mg/kg dose resulted in observed superior outcomes for multiple secondary clinical outcomes: time to 1-point WHO Ordinal Score improvement through Day 29/discharge, 1-point improvement by Day 7, days to return to room air, and hospital length of stay. The PK results showed that the two-compartment model fit the data well. Clearance decreased with increasing dose level and there was no evidence that clearance was affected by covariates other than dose level. ConclusionsThese findings suggest that TSC administration every 6 hours at doses up to 1.5 mg/kg for up to 15 days is safe and well tolerated with predictable pharmacokinetics and demonstrated an observed clinical benefit in the treatment of COVID-19-related hypoxemia. (ClinicalTrials.gov number, NCT04573322)

Enterococcal bacteremia is associated with high mortality and long-term hospitalization. Here, we aimed to investigate the clinical outcomes and evaluate risk factors for mortality in adult patients treated with vancomycin (VCM) for penicillin-resistant Enterococcus faecium (E. faecium) bacteremia. Data were collected from inpatients at a single university hospital between January 2009 and December 2020. The area under the curve (AUC) of VCM was calculated using the Bayesian approach. The primary outcome was 30-day in-hospital mortality. Univariate analysis showed significant differences in the combined use of vasopressors, history of the use of inactive antimicrobial agents against E. faecium, VCM plasma trough concentration, and renal dysfunction during VCM administration between 30-day mortality and survival groups. However, the AUC/minimum inhibitory concentration (MIC) was not significantly different. Multivariate analysis revealed that concomitant vasopressors were an independent risk factor for 30-day all-cause mortality (odds risk, 7.81; 95% confidence interval, 1.16-52.9; P = 0.035). VCM plasma trough concentrations and AUC/MIC in the mortality group were higher than those in the surviving group. Depending on the drug-susceptibility results of E. faecium, it is considered that the AUC/MIC is calculated at a double AUC value. No association between AUC/MIC and treatment effect in E. faecium bacteremia was assumed because the known target AUC/MIC was sufficiently achieved in the mortality group. When an immunocompromised host develops E. faecium bacteremia with septic shock, especially in situations where the hemodynamics of using a pressor agent is unstable, treating it exclusively by sufficient exposure to antibacterial agents may be difficult.

Background & aimsAn extensively-drug resistant (XDR) NDM and OXA-48 producing E. coli contributing to repeat episodes of biliary sepsis was isolated from the blood stream of a 45-55 year-old male with a background of IgG4 related sclerosing cholangitis. The patient was awaiting orthotopic liver transplant (OLT). There is no standardized antibiotic prophylaxis regimen however in line with the Infectious Diseases Society of America (IDSA) guidance an antibiotic prophylactic regimen of Ceftazidime-Avibactam (CZA) 2.5g TDS with Aztreonam (ATM) 2g TDS IV was proposed. MethodsTo inform the individualised pharmacodynamic outcome likelihood prior to prophylaxis dosing the hollow fibre infection model (HFIM) was applied to simulate the in vivo antibiotic exposures of the CZA-ATM regimen. The HFIM was inoculated with [~]10 x 105 bacterial CFU/mL of the XDR E. coli strain and CFUs/mL were measured for a total of 120 hours to determine the in vitro PK/PD killing dynamics. ResultsA 4-log reduction in CFU/mL in the first ten hours of the regimen exposure was observed however the killing dynamics were slow and six eight-hourly infusions were required to reduce bacterial cells to below the limit of quantification. Thus, the HFIM supported the use of the regimen for infection clearance however highlighted the need for several infusions. Standard local practise is to administer prophylaxis antibiotics at induction of OLT however the HFIM provided data to rationalise earlier dosing therefore the patient was dosed at 24 hours prior to their OLT induction. The patient was subsequently discharged 8 days after surgery. ConclusionsThe HFIM provides a dynamic culture solution for informing individualised medicine by testing antibiotic combinations and exposures against the bacterial isolates cultured from the patients infection.

This paper proposes both a rationale and potential study design for evaluation of low dose doxycycline (20mg BID) for the prevention of COVID-19 infection in exposed health care workers. More generally, it provides a potential study design blueprint to other investigators for any interventional COVID-19 study looking to evaluate interventions for prevention or treatment of COVID-19 infection. This specific study described is a randomized, double blind, placebo controlled study to evaluate the efficacy and safety of doxycycline for the prevention of COVID-19 infection and disease in healthcare workers with ongoing high risk exposure to COVID-19. This study would consist of a 50-day Treatment Period (Day 0-Day 50), followed by an End of Study Visit, approximately 30 days after completion of study drug dosing. Initially, for approximately the first 4 to 6 weeks, an initial open-label arm would be enrolled with up to 1938 subjects who will be assigned to take 20mg doxycycline BID. In the double blind, placebo controlled arms approximately 3,692 participants would be randomized to either doxycycline or placebo for 50 days. Doxycycline is a rational candidate drug to be evaluated for repurposing against SARS-CoV-2. Doxycycline is a generally safe tetracycline derivative that has been available for decades, most commonly dosed at 100mg BID to treat bacterial infections. However, in addition to its antimicrobial properties, doxycycline (and more generally tetracycline derivatives) may have a role as an effective anti-viral agent and as an anti-inflammatory drug. Early studies indicate potential efficacy of minocycline against respiratory syncytial virus (RSV) [12], and doxycycline against Dengue and Chikungunya infection[9, 10]. In addition, doxycycline is known or proposed to target several pathways that regulate viral replication. [13, 14, 15]. Doxycycline is a particularly attractive candidate as a COVID-19 prophylactic given it has been used in clinical practice for decades and maintains an excellent safety profile as demonstrated in multiple clinical studies. Any effective prophylaxis for COVID-19 should be able to demonstrate high efficacy at preventing infection and/or lowering severity of disease. Equally important, it should demonstrate this efficacy at dosing levels that are highly unlikely to precipitate any untoward severe side effects. Doxycycline has been selected based on its ability to: 1) inhibit metalloproteinases (MMPs), implicated in initial viral entry into the cell as well as in acute respiratory distress syndrome (ARDS) associated with severe COVID-19 infection [13, 16]; 2) potential to inhibit Papain-like proteinase (PLpro) responsible for proteolytic cleavage of the replicase polyprotein to release non-structural proteins 1, 2 & 3 (Nsp1, Nsp2 and Nsp3) all essential for viral replication. [19]; 3) potential to inhibit 3C-like main protease (3CLpro) or Nsp5 which is cleaved from the polyproteins causes further cleavage of Nsp4-16 and mediates maturation of Nsps which is essential in the virus lifecycle. [19]; 4) act as an ionophore help transport Zinc intracellularly, increasing cellular concentrations of Zinc to inhibit viral replication. [6, 15]; 5) inhibit Nf-kB which may lower inflammatory response to COVID-19 infection, and lower risk of viral entry due to decreasing DPP4 cell surface receptor. [20, 21]; 6) inhibits (specifically low-dose doxycycline) expression of CD147/EMMPRIN that may be necessary for SARS-CoV-2 entry into T lymphocytes [22, 23].

Trimethoprim-sulfamethoxazole (TMP-SMX) is an effective treatment for Pneumocystis jirovecii pneumonia (PCP); however, a high incidence of adverse events has been observed. Low-dose TMP-SMX is a potentially effective treatment with fewer adverse events; however, evidence is limited. We aimed to evaluate the efficacy and safety of low-dose TMP-SMX after adjusting for patient background characteristics. In this multicentre retrospective cohort study, we included patients diagnosed with non-human immunodeficiency virus (HIV) PCP and treated with TMP-SMX between June 2006 and March 2021 at three institutions. The patients were classified into low-(TMP equivalent <12.5 mg/kg) and conventional-dose groups (TMP equivalent 12.5-20 mg/kg/day). The primary endpoint was 30-day mortality, and the secondary endpoints were 180-day mortality, adverse events of grade 3 or greater per the Common Terminology Criteria for Adverse Events Version 5.0, and initial treatment completion rates. The background characteristics were adjusted using the overlap weighting method with propensity scores. Fifty-five patients in the low-dose and 81 in the conventional-dose groups were evaluated. There was no significant difference in 30-day mortality (7.6% vs. 14.9%, P = 0.215) or 180-day mortality (18.1% vs. 24.0%, P = 0.416) after adjusting for patient background characteristics. The incidence of adverse events, especially nausea and hyponatremia, was significantly lower in the low-dose group (27.3% vs. 58.6%, P = 0.001). The initial treatment completion rates were 43.8% and 27.7% in the low-dose and conventional-dose groups, respectively. Low-dose TMP-SMX did not alter survival but reduced the incidence of adverse events in patients with non-HIV PCP, compared with conventional-dose TMP-SMX.

ObjectivesTo develop a population pharmacokinetic (PPK) model of polymyxin B (PMB) for intravenous (IV) and combined intravenous plus inhaled (IV+IH) administration in critically ill patients, and evaluate the association between the 24-h steady-state area under concentration-time curve to minimum inhibitory concentration ratio (AUCss,24h/MIC) and clinical outcomes. MethodsThis prospective cohort was conducted in the ICU of the Third Xiangya Hospital, Central South University (ethics R19048; ChiCTR1900028602). Adults with multidrug-resistant Gram-negative bacterial infections receiving PMB [&ge;]48 h were enrolled and assigned to IV or IV+IH groups. Serial plasma samples were analyzed by validated LC-MS/MS. The PPK model was developed with NONMEM(R). Clinical efficacy at end of treatment was blindly assessed. ResultsForty-three patients were enrolled (IV, n=22; IV+IH, n=21), with an overall clinical success rate of 66.7%. A two-compartment PPK model best described the data, with typical values of clearance (2.6 L/h), central volume (13.6 L), and peripheral volume (17.6 L). Clearance was influenced by creatinine clearance and total bile acids. In the overall cohort, neither AUCss,24h nor AUCss,24h/MIC differed significantly between clinical success and failure (p=0.591 and 0.143). In the IV group, AUCss,24h/MIC was significantly higher in responders (p=0.005) with an ROC-derived efficacy threshold of 94.37; AUCss,24h showed a non-significant trend (p=0.076). No exposure- response relationship was observed in the IV+IH group (p=0.398 and 0.495). ConclusionsPlasma AUCss,24h/MIC appears to be associated with clinical efficacy during IV monotherapy but not in IV+IH regimens, likely due to high pulmonary exposure. Plasma-based PK/PD targets should be applied cautiously when inhalation is added.

The development of novel therapeutics for infectious diseases remains a global health priority. To accelerate the treatment development, innovative strategies through new approach methodology (NAM) are needed to bridge speed of in vitro with predictive power of in vivo studies, while reducing mammalian experiments. The zebrafish (Danio rerio), particularly the embryo/larva, has been established as a valuable non-mammalian in vivo model in biomedical research. We developed a standardized and streamlined workflow for the zebrafish as NAM, which consisted of 3 steps: drug selection and efficacy evaluation, internal exposure assessment, and PKPD modelling. Compounds with higher tolerated doses than minimum inhibitory concentration were selected. Drug efficacy was quantified through longitudinal individual fluorescence microscopy at baseline and 24 and 48h on treatment. Drug exposure was quantified in larval homogenates and exposure medium from 0-48h on treatment. The PKPD relationship was quantified by non-linear mixed effects modelling. For case study bedaquiline, PKPD was quantified using a one-compartment model with age-depending elimination, and an Emax concentration-response relationship on the delayed logistic bacterial growth function, with an EC50 of 26.6 {micro}g/mL and an Emax of 1.07-1.37. In the case of clarithromycin, in contrast, negligible internal exposure after waterborne treatment were observed, illustrating the risk of false negatives without internal exposure assessments. Bactericidal efficacy was confirmed by intravenous drug injections, showing a clear dose dependent antimycobacterial effect. The standardized zebrafish NAM workflow presented here facilitates the translation of drug efficacy to higher vertebrates, reducing rodent studies to confirmatory or replacing them completely, thus accelerating drug development.

BackgroundThere is debate on whether cefazolin or antistaphylococcal penicillins should be the first-line treatment for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. Ongoing trials are investigating whether cefazolin is non-inferior to (flu)cloxacillin, but it remains uncertain whether these findings would apply to other antistaphylococcal penicillins. ObjectiveWe conducted a systematic review and meta-analysis comparing cefazolin to each of the individual antistaphylococcal penicillins for MSSA bacteremia. MethodsO_ST_ABSData SourcesC_ST_ABSWe updated a 2019 systematic review but specifically focused on evaluating outcomes by individual antistaphylococcal penicillins. Study Eligibility CriteriaComparative observational studies. ParticipantsPatients with MSSA bacteremia. InterventionsCefazolin versus the antistaphylococcal penicillins. Assessment of Risk of BiasThe risk of bias in non-randomized studies of interventions tool. Methods of Data SynthesisThe primary outcome was 30-day all-cause mortality, and we assessed for non-inferiority of cefazolin using a prespecified non-inferiority margin of a pooled odds ratio (OR) <1.2. Secondary outcomes were 90-day mortality, treatment-related adverse events (TRAEs), discontinuation due to toxicity, and nephrotoxicity. ResultsNo randomized data have been published. 30 observational studies at moderate or high risk of bias were included, which comprised 3869 patients who received cefazolin and 11644 patients who received antistaphylococcal penicillins (flucloxacillin=6721, unspecified=2440, nafcillin=1305, cloxacillin=1258, and oxacillin=120). Cefazolin was associated with a reduced odds of 30-day all-cause mortality (OR=0.73, 95%CI=0.62-0.85) compared to antistaphylococcal penicillins, meeting pre-specified non-inferiority as well as superiority. This effect was consistent versus flucloxacillin (OR=0.92, 95%CI=0.73-1.16), nafcillin (OR=0.58, 95%CI=0.28-1.17), cloxacillin (OR=0.42, 95%CI=0.11-1.58), and oxacillin (OR=0.31, 95%CI=0.03-2.75). Point estimates favored cefazolin for 90-day mortality, TRAEs, nephrotoxicity, and discontinuation due to toxicity overall and in each comparison with individual antistaphylococcal penicillins, except for TRAEs versus cloxacillin. ConclusionsIn moderate to low quality observational data, cefazolin was associated with superior effectiveness and safety as compared to antistaphylococcal penicillins overall and individually.

BackgroundCurrent FDA-approved label recommends polymyxin B dosing should be adjusted according to renal function, despite several studies proved poor correlation between polymyxin B PK and creatinine clearance. The study aims to assess the impact of renal function on polymyxin B metabolism and identify an alternate dosing strategy by population analysis. MethodsBlood samples from adult patients were collected at steady state during routine therapeutic drug monitoring. Nonlinear mixed effects modeling was employed to build a population PK model of polymyxin B. Monte Carlo simulations were performed to design polymyxin B dosing regimens across various renal function. ResultsPharmacokinetic analyses included 112 polymyxin B concentrations at steady state from 32 adult patients aged 37-93 received intravenous polymyxin B (100-200 mg/d). The creatinine clearance in patients was 5.91-244 mL/min. In the final population PK model, CrCL was the significant covariate on CL (typical value, 1.59 L/hr; between-subject variability, 13%). Mean (SD) individual empirical Bayesian estimates of CL was 1.75 (0.43) L/hr. A new dosing strategy combining the PK/PD targets and Monte Carlo simulation indicated that polymyxin B dose reductions improved the probability of achieving optimal exposures in simulated patients with renal insufficiency. For severe infections caused by organisms with MIC of [&ge;] 2 mg/L, though a high daily dose (e.g. 200mg/day) would possible for bacterial eradication, the risk of nephrotoxicity is significantly increased. ConclusionA population PK model was established to develop individualized polymyxin B dosage regimens that the dose of polymyxin B should be adjusted according to CrCL.

BackgroundResistance to colistin, a last-reserve antibiotic used for treating drug-resistant infections, is increasing globally. This study evaluated six diagnostic tests designed to detect colistin-resistant pathogens. MethodsPCR and broth microdilution assays (BMD) were used to respectively characterize the molecular mechanisms and phenotypic colistin resistance of 142 Gram-negative bacterial isolates and controls. The sensitivity, specificity, positive- and negative-predictive values, major (ME) and very major errors (VME), categorical and essential agreements (EA) of ComASP Colistin, CHROMagar COL-APSE, Rapid NP Test, Sensititre, MicroScan, and Vitek 2 were determined with these isolates; the BMD was used as gold standard. ResultsThe Vitek 2, Sensititre, and ComASP tests were more efficient, albeit with concerning ME and VMEs and low EAs. Sensititre was 100% specific with 0% ME and 3.61% VME; Vitek 2 had the least VME (1.25% and 0%) and a low EA (57.50%). ComASP had an EA of 75.35%. MicroScan was highly sensitive (96.55%) but less specific (87.50%), with very below-accetable EAs (48.11%). The CHROMAgar COL-APSE efficiently identified the species with their unique colours but was the least specific (67.80%), with the highest ME (32.20%) and high VME (7.23%). The Rapid NP test had the highest VME (7.84%), producing results within 4 hours with 92.16% sensitivity and 96.08% specificity. ConclusionVitek 2, MicroScan, ComASP colistin, and Sensititre are good for determining colistin resistance; the latter two tests are recommendable for low-resourced laboratories. The in-house Rapid NP test has short turnaround time with high efficiency for initial resistance screening.

Linezolid is an alternative to vancomycin for treating Gram-positive central nervous system (CNS) healthcare-associated infections. The recommended dosing regimen remains debated. PK-Pop-LCR is a prospective population pharmacokinetic-pharmacodynamic multicenter study which included brain injured patients with an external ventricular drainage receiving linezolid at different dosing regimens. The cerebrospinal fluid (CSF) penetration of linezolid was investigated and a population pharmacokinetic model developed using plasma and CSF data. Monte Carlo simulations were conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) in CSF against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), for different dosing regimens. The plasma pharmacodynamic target, AUC/MIC > 100, was used in CSF. Over 25 patients included, blind adjudication confirmed 14 cases of CNS infections. The mean AUCCSF/fAUCplasma ratio was close to 80% with no difference between patients with and without CNS infection, despite higher CSF cytokines levels in CNS-infected patients. The recommended dose of 1200 mg/24h allowed to reach PTAs [&ge;] 90% only for MICs [&le;] 0.5 mg/L, and CFR of 3.2% and 40% for MRSA and MRSE, respectively. 2 700 mg/24h would allow to achieve PTA > 90% for MIC up to 1 mg/L and CFR of 90% for MRSE but none of dosing regimens tested was appropriate for MRSA infections. We confirmed the extensive CSF distribution of linezolid. Higher doses than those recommended should be considered to treat CNS infection in critically brain injured patients. However, pharmacodynamic target for CNS infections should be further investigated to confirm these findings. FundingsFrench Ministry of Health.

ObjectivesThe coexistence of TB and DM (TB-DM) has been associated with an increased risk of treatment failure, death, delayed culture conversion and drug resistance. As plasma concentrations may influence clinical outcomes, we evaluated the evidence on the PK of TB drugs in DM individuals to guide management. MethodsWe performed a systematic review and meta-analysis through searches of major databases from 1946 to 6 July 2023. PROSPERO (CRD42022323566). ResultsOut of 4173 potentially relevant articles, we identified 16 studies assessing rifampicin PK, 9 on isoniazid, 8 on pyrazinamide and 3 on ethambutol. Two studies reported on second line anti-TB drugs. According to our analysis, RIF Tmax was significantly prolonged in patients with DM compared to non-DM patients. We found no significant differences for RIF Cmax, AUC 0-24 or C2hr, INH C2hr, PZA C2hr, PZA Tmax and ETB Tmax. While RIF C2hr was slightly reduced in TB-DM patients, this finding was not statistically significant. ConclusionsThis review comprehensively examines the impact of DM on the PK of TB drugs. We observed significant heterogeneity among studies. Given the association between lower plasma concentrations and poor clinical outcomes among DM patients, we recommend a higher dose limit to correct for larger bodyweight of patients with DM.

Antimicrobial resistance remains a global challenge threatening the ability to control diseases caused by bacterial infections. Here, we explored the antimicrobial activity of 2,3-N,N-diphenyl quinoxaline derivatives against representative Gram-positive, Gram-negative and Mycobacterium species. Two quinoxaline derivatives (compounds 25 and 31) demonstrated particularly potent activity against most Staphylococcus aureus, Enterococcus faecium and Enterococcus faecalis strains tested (MIC values between 0.25 to 1 mg/l). These compounds also demonstrated potent antibacterial activity against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecium/E. faecalis (VRE) strains. Against an extensive panel of clinically relevant isolates, they further showed comparable or better activity to four currently used antibiotics (vancomycin, teicoplanin, daptomycin and linezolid). Finally, they performed better in preventing S. aureus and E. faecalis biofilm formation when compared to several other antibiotics. In conclusion, these two quinoxaline derivatives have promising activities that could be further explored as part of efforts to identify urgently needed new antibacterial agents.

Development of a novel inhibitor targeting Gyrase B and Topoisomerase IV offers a potential opportunity to combat the drug resistance. In the present study, we extensively investigated the efficacy of RBx 10080758, a novel fluorobenzothiazole, against skin and respiratory infections caused by Staphylococci and Streptococci in in vitro and in vivo models. RBx 10080758 showed a potent IC50 of 0.06 M against Gyrase and Topoisomerase IV and also exhibited a strong whole cell in vitro activity with MIC ranges of 0.015-0.06, 0.015-0.03, 0.008-0.03, 0.008-0.03, 0.008-0.0.06, 0.015-0.06 g/ml against Staphylococcus. aureus, Streptococcus pneumoniae, Coagulase negative Staphylococci, Streptococcus viridans, Streptococcus pyogenes and Enterococcus, respectively. As expected from the novel class of molecule, it retains potent even against linezolid and vancomycin resistant strains. Interesting, in mouse systemic infection 10 mg/kg, IV dose protected 100% mice from lethal infections. In rat thigh infection model with MRSA WCUH29 at 45 mg/kg exhibited >3-log10 cfu reduction in thigh muscles. RBx 10080758 displayed potent in vitro and in vivo activity against a panel of MDR Gram-positive bacteria. As a novel chemical class, the fluorobenzothiazoles have the potential to become clinically viable antibiotics, to address the drug resistance problem by its unique dual targeting mechanism of action.

IntroductionApramycin is an aminoglycoside antimicrobial that has been used in veterinary medicine since the 1980s but not licensed for human medicine. Because it is not impacted by common aminoglycoside resistance mechanisms, there is interest in repurposing the drug for use in humans, as a treatment of multidrug resistant Gram negative bacterial infections. Gap StatementThe prevalence and factors associated with apramycin resistance in bacteria isolated from humans has received limited study but is important foundational information for considering repurposing apramycin for use in humans. AimTo systematically review and analyze data pertaining to apramycin resistance in bacteria isolated from humans and to identify knowledge gaps, to inform work evaluating the potential for re-purposing of apramycin for clinical use in humans. MethodologyA systematic review was performed to evaluate apramycin resistance in bacteria isolated from humans. ResultsA total of 1626 references were identified during the search, with 34 studies were deemed eligible for inclusion. Pooled estimates for apramycin resistance were 6% (95% CI 1-12%) for E. coli, 1% (0-3%) for Acinetobacter spp, 2% (0-5%) for Enterobacter spp, 7% (2-15%) for Klebsiella spp, 4% (0-13%) for Pseudomonas and 0% (0-0%) for Salmonella spp. Multivariable mixed-effects meta-regression identified no effect of year (P=0.36), bacterial species (all P>0.19), geographic region (all P>0.13) or enrollment of known carbapenem-resistant isolates (P=0.44). The only significant variable was datasets that used known gentamicin-resistant isolates (P=0.003). ConclusionDespite nearly 50 years of apramycin use in animals, apramycin resistance was identified in bacteria of human origin but was rare, supporting the potential value of re-purposing this drug for use in humans and suggesting that there is limited spillover of resistance from veterinary and agricultural use of apramycin.