The prevalence of Carbapenem-Resistant Gram-Negative Bacteria (CR-GNB) is rapidly escalating, presenting a significant global public health concern. This study aims to evaluate the survival rate of early appropriate therapy with polymyxin B (PMB), and adverse drug reactions of PMB in treating severe burn sepsis caused by CR-GNB infections.

We retrospectively analyzed 72 patients with severe burn sepsis caused by CR-GNB infections from January 1, 2018, to December 30, 2023. These patients received a treatment regimen based on PMB for at least three days. We collected data on the patient's clinical characteristics, microbiological results, details of PMB treatment, adverse drug reactions with PMB, and mortality. We compared the 30-day mortality rates between patients who received early appropriate therapy (the timely administration of an active antimicrobial agent within 48 h after the onset of infection) and those who underwent non-early appropriate therapy, multivariate Cox regression analysis was employed to evaluate factors impacting the 30-day survival rate of patients, and the adverse drug reactions caused by PMB were also analyzed.

Among the 72 patients with severe burn sepsis, the clinical effective rate was 69.4% (50/72), the 30-day all-cause mortality rate was 31.9% (23/72) and the 30-day sepsis-associated mortality rate was 27.8% (20/72). The adverse drug reactions of PMB included nephrotoxicity and skin pigmentation, with an incidence of 19.4% (14/72) and 15.3% (11/72), respectively. The patients who received early appropriate therapy had a lower mortality rate, lower SOFA scores and more wound infections compared to those who underwent non-early appropriate therapy (all P < 0.05). The univariate Cox regression analysis showed that age, hypertension, SOFA score at the time of sepsis diagnosis, and early appropriate therapy with PMB were associated with both 30-day all-cause mortality and sepsis-associated mortality in severely burned patients (all P < 0.05). Additionally, In the multivariate Cox regression analysis, early appropriate therapy with PMB was identified as an independent protective factor for both 30-day all-cause mortality (HR = 0.183 [95% CI 0.071-0.468], P < 0.001) and sepsis-associated mortality (HR = 0.150 [95% CI 0.054-0.414], P < 0.001) in severely burned patients.

Polymyxin B is an effective option for burn sepsis patients in treating CR-GNB infections. Early appropriate therapy with PMB significantly improved the survival rate of severe burn sepsis patients infected with CR-GNB.

Acinetobacter baumannii has become an increasingly urgent public health concern among global health agencies due to high rates of carbapenem resistance. Carbapenem-resistant A. baumannii (CRAB) that express both oxacillinases and MBLs is especially problematic due to resistance to all β-lactams.

Two clinical A. baumannii isolates, AR-0033 and AR-0083, harbouring bla NDM-1 (for both isolates MICaztreonam >64 mg/L, MICceftazidime/avibactam >128/4 mg/L, MICpolymyxin B = 1 mg/L, MICcefiderocol  ≥16 mg/L) were treated with mono- or combination therapies of aztreonam/ceftazidime/avibactam and polymyxin B (PMB) in static time-kill studies over 24 h. Replicate time-kills were analysed by integrating the area under the cfu/mL-versus-time curve using the linear-trapezoidal method and normalizing to the growth control to produce the log-ratio area (LRA). The LRA was mathematically modelled as a function of aztreonam concentrations using a Hill-type function to identify the IC50 values for aztreonam.

Treatment with aztreonam/ceftazidime/avibactam achieved <2 log10 cfu/mL reduction by 24 h for all concentrations in both isolates. Monotherapies of PMB at 0.75, 1.5, 3.0 and 6.0 mg/L displayed maximum killing by 6 h against AR-0033. Monte Carlo simulations of human pharmacokinetics of aztreonam showed that package insert dosing resulted in a average free steady-state concentration above the target aztreonam IC50 values for AR-0033 ≥96% of time when in combination with ceftazidime/avibactam and PMB.

This study supports the potential utility of low-dose PMB therapy in combination with β-lactams to combat NDM-producing CRAB.

As the last defense against multidrug-resistant gram-negative bacteria, colistin sulfate's clinical use, which is often empirical, risks resistance and adverse reactions. This study aimed to develop a population pharmacokinetic (PPK) model of colistin sulfate for critically ill patients and determine the optimal dosing regimen. This retrospective study included 204 critically ill patients. We used a validated LC-MS/MS method to measure its plasma concentrations and RIFLE criteria for nephrotoxicity evaluation. NONMEM developed PPK models. Monte Carlo simulations set dosing regimens based on the probability of target attainment (PTA). A two-compartment model adequately described the data, creatinine clearance and weight were covariates for elimination rate and central volume, respectively. Only 11.8% had nephrotoxicity. With Monte Carlo simulations, all regimens except the maintenance dose of 0.5 MU administered every 12 h achieved > 90% PTA at the minimum inhibitory concentration (MIC) ≤ 0.5 mg/L. However, at MIC > 0.5 mg/L, the routine regimen resulted in insufficient exposure. Based on our PPK model, the dose of intravenous colistin sulfate should be adjusted according to creatinine clearance (CrCL) and weight. For critically ill patients with infections, under the conventional treatment regimens, when the MIC is ≥ 1 mg/L, it is difficult for patients to achieve the ideal therapeutic effect in terms of exposure dose. When CrCL is below 10 ml/min, the regimen of 1 MU every 8 h used could cause the potential for increasing nephrotoxicity risk, which is significantly concerned.

Although colistin (administered as colistin methanesulphonate [CMS]) is used to treat infections in critically-ill patients undergoing sustained low-efficiency dialysis (SLED), there is a paucity of information on appropriate dosing regimens. This study aimed to characterize the population pharmacokinetics (popPK) of colistin during SLED and evaluate the likelihood of antibacterial benefit and colistin nephrotoxicity for different regimens.

A prospective popPK study included 13 critically-ill patients (six females) treated with CMS and receiving SLED (6-8h). For each subject, the PK of formed colistin was studied on a nonSLED day and a SLED day (n=8 studied during SLED day first). A single intravenous daily dose [150mg colistin base activity (CBA)] was administered on a nonSLED day. On a SLED day, patients received 150mg CBA 12-hourly. Serial blood, urine and dialysate samples were collected over 24h on both days. Colistin plasma concentrations were measured by high-performance liquid chromatography. PopPK modeling and Monte Carlo Simulations were performed.

A linear one-compartment disposition model well-described the data. The population mean apparent colistin body clearance, excluding SLED clearance, was 1.69 L/h (20% interindividual variability [IIV], 42.1% interoccasion variability). The apparent colistin SLED clearance was 3.49 L/h (41.7% IIV), i.e. 67.4% of total colistin clearance on a SLED day. The apparent volume of distribution was 50.2 L (23.0% IIV).

Colistin clearance was substantially higher during SLED; therefore, SLED should be accounted for in CMS dosing regimens. This project generated clinically applicable regimens, including loading doses, to achieve required probabilities of target attainment in patients undergoing SLED.

Treatment options for carbapenem-resistant Enterobacteriaceae (CRE) infections are limited, with polymyxin B (PMB) and ceftazidime-avibactam (CZA) being among the available choices. However, research on these options is scarce and significantly heterogeneous. This study aims to analyze the efficacy, safety, and cost-effectiveness of PMB and CZA within a standardized target trial emulation (TTE) framework.

This retrospective study emulated a target trial to evaluate the efficacy, safety, and cost-effectiveness of CZA versus PMB for treating CRE infections. Conducted at Nanjing Drum Tower Hospital, this study included adult patients treated with CZA or PMB from July 2020 to December 2022. Data on demographics, treatment outcomes, and costs were collected. The primary outcomes included clinical cure, incidence of adverse drug reactions (ADRs), and cost-effectiveness. Secondary outcomes assessed 28-day all-cause mortality, microbiological eradication rates, incidence of acute kidney injury (AKI), and gastrointestinal events. The outcomes were assessed using the modified intention-to-treat (mITT) effects, per-protocol effects, and propensity score overlap weighting (PSOW) methods.

Between July 1, 2020, and December 31, 2022, 492 hospitalized patients treated with CZA or PMB were screened at Nanjing Drum Tower Hospital. Following inclusion and exclusion criteria, 176 patients were included in the mITT analysis, and 153 in the per-protocol analysis. The clinical cure rate was significantly higher in the CZA group compared to the PMB group across all analyses. The 28-day mortality was similar between groups, while the microbial eradication rate was significantly higher in the CZA group compared to the PMB group across all analyses. The incidence of ADRs was consistent between groups, but AKI occurred more frequently in PMB patients, while gastrointestinal events were more common in the CZA group. The CZA strategy demonstrated a 28.1% increase in efficacy, with an incremental cost-effectiveness ratio of 71,651.76 yuan. Sensitivity analyses confirmed the robustness of these findings.

This study demonstrates that CZA has a higher clinical cure rate compared to PMB within a standard TTE framework. However, the overall incidence of ADRs was similar between the two treatments. Pharmacoeconomic analysis also indicated that CZA is cost-effective.

https://www.chictr.org.cn ; identifier, ChiCTR2300067946.

Background: Antimicrobial resistance (AMR) is a global threat in the public healthcare sector. The emergence of carbapenem-resistant Enterobacterales (CRE) has become a serious public health threat in South Africa. The spread of CRE has led to the use of colistin for treating severe infections. Colistin is a cationic, lipopeptide antibacterial agent that is effective against most Gram-negative bacteria through its disruption of the bacterial cell membrane. This study aims to determine the colistin resistance (MIC) and mobile colistin resistance (mcr-1) gene in clinical isolates from healthcare facilities in Mthatha and its surrounding areas. Methods: Fifty-three CRE isolates were collected from health facilities between January 2019 and June 2021 and stored in skim milk 10% and 5% inositol broth. The carbapenemase confirmatory test involved a RESIST-4 O.K.N.V assay (Coris BioConcept, Gembloux, Belgium), which was conducted following manufacturer protocol. Broth microdilution was performed according to the ISO standard method (20776-1) using A ComAspTM colistin 0.25-16 μg/mL MIC Broth. Conventional polymerase reaction (PCR) was performed for the detection of mcr-1. Results: N = 53 (100%) isolates were used. A total of 53% were defined as Klebsiella pneumoniae, Escherichia coli constituted 8%, Enterobacter cloacae 8%, Serratia marcescens 8%, Serratia fonticola 2%, Enterobacter aerogenes 2%, Klebsiella oxytoca 2%, Citrobacter koseri 2%, and Citrobacter freundii 2%. The specimens were from the following wards: Pediatric and Neonatal 38%, Medical 30%, Gynecology, Labour, and Maternity 11%, OPD and A&E 11%, ENT 4%, and Others-Male TB ward, Trauma, and adult ICU 6%. In total, 13% of the isolates were resistant and 86% were sensitive to colistin. The common CRE genes detected were OXA-48 at 47%, NDM at 13%, VIM at 1%, and a combination of OXA-48 and NDM at 5%. Of the isolates, 66% were positive for the production of carbapenamase. In this study, we found that all N = 53 (100%) isolates did not have the mobile colistin resistance gene (mcr-1). Conclusions: Antimicrobial resistance is associated with the emergence of carbapenemases genes. Increasing resistance to colistin in clinical settings can lead to difficulties in treating CRE infections, which may lead to clinical failure. In our study, 13% of isolates were phenotypically resistant to colistin.

Polymyxins are the last line of defense against carbapenem-resistant Gram-negative bacilli infections. However, the efficacy of polymyxins against the independent risk factor of bacterial species is unknown. We aimed to compare the efficacy and safety of colistin sulfate (CS) and polymyxin B (PMB) for carbapenem-resistant Acinetobacter baumannii (CRAB) infections.

We carried out a retrospective multicenter study that included patients with CRAB infections at three tertiary hospitals in Guizhou province, China, from 1 Jan 2020 to 30 Jun 2024. Patients were grouped into the CS group and PMB group. The main outcomes were all-cause 28-day mortality and clinical failure rate. The secondary outcomes included the microbiological cure rate, duration of CS or PMB treatment, and length of hospital stay. Safety was evaluated based on the rates of adverse drug reactions.

A total of 140 patients were included, with 58 patients in the CS group and 82 patients in the PMB group. All-cause 28-day mortality was 32.8% in the CS group and 37.8% in the PMB group (adjusted HR = 0.73, 95% CI 0.38-1.37, p = 0.316), and the clinical failure rate was 48.3% and 56.1% (adjusted OR = 0.64, 95% CI 0.29-1.39, p = 0.262) in the CS group and PMB group, respectively. There were no significant differences in any of the secondary outcomes. The incidence of acute kidney injury (AKI) in the CS group was lower than that in the PMB group (5.2% vs. 19.5%). Compared to the PMB group, the adjusted odds ratio of AKI was 0.24 (95% Cl 0.06-0.96, p = 0.044) for the CS group.

Our results suggest that CS is similarly effective to PMB for CRAB infections but it is associated with fewer safety concerns than PMB. This clinical research provides significant information on the efficacy and safety of CS and PMB for CRAB infections.

Difficult-to-treat resistant (DTR) Pseudomonas aeruginosa infections have emerged as a significant global public health threat, characterized by limited treatment options and a heightened mortality risk. This study aimed to assess the appropriateness of initial antibiotic therapy, estimate 30-day all-cause mortality, and determine the impact of DTR P. aeruginosa infections on mortality.

A retrospective, multicenter study was conducted at four teaching hospitals in Beirut, Lebanon, between January 2021 and December 2023. The primary outcome was 30-day all-cause mortality. Kaplan-Meier survival analysis was used to assess time-to-mortality, and the log-rank test was applied to compare survival outcomes relative to DTR infections and the appropriateness of initial antibiotic therapy. Multivariable logistic regression was performed to identify predictors of mortality.

Out of 2,639 screened cases, 477 patients met the inclusion criteria. Respiratory tract infections accounted for 38.8% of cases. Carbapenem-resistant P. aeruginosa (CRPA) comprised nearly one-third of isolates, and 15.3% were categorized as DTR. The most common empirical antibiotics were piperacillin-tazobactam (33.9%) and meropenem (24.5%). Inappropriate initial antibiotic therapy was observed in 43.8% of cases, with 33.8% of patients receiving antibiotics to which the pathogen was resistant. DTR infections were significantly more likely to be associated with inappropriate therapy (odds ratio [OR] = 4.21, 95% CI = 2.43-7.32, P < 0.001). The 30-day all-cause mortality rate was 14.8%, with a mean time-to-mortality of 13.29 ± 9.81 days. Patients who received inappropriate therapy had a shorter time-to-mortality (11.76 ± 8.80 days) compared to those receiving appropriate therapy (15.46 ± 10.90 days, P = 0.03). Predictors of mortality included DTR P. aeruginosa infection (adjusted odds ratio [AOR] = 2.48, 95% CI = 1.32-4.63, P < 0.01), and inappropriate initial therapy (AOR = 1.40, 95% CI = 1.04-2.35, P < 0.01).

DTR P. aeruginosa infections and inappropriate initial antibiotic therapy are associated with increased mortality risk in hospitalized patients.

The current array of traditional antibacterial agents targeting Gram-negative infections are failing to meet the clinical need. Here we present a novel, bifunctional immunotherapy (CTX-09) with the ability to harness endogenous anti-galactose-alpha-1,3-galactosyl-beta-1,4-N-acetyl-glucosamine (anti-αGal) antibodies to drive immune-mediated clearance of Gram-negative bacteria. In addition, CTX-09 has direct-acting broad-spectrum bactericidal activity equivalent to colistin and meropenem against 1952 Gram-negative clinical isolates. In vitro, CTX-09 demonstrated immune-mediated efficacy through recruitment of anti-αGal antibodies and engagement of antibody effector mechanisms that enhanced bacterial clearance at sub-bactericidal concentrations. In vivo, at sub-bactericidal doses, CTX-09 demonstrated anti-αGal antibody driven clearance of susceptible and multidrug-resistant (MDR) strains. In the presence of anti-αGal antibody, bacterial burden was reduced by >99.9% (3-log10) in neutropenic mouse thigh and pneumonia infection models. This data suggest that CTX-09 or other antibody-recruiting molecules have potential to address the urgent clinical need of patients with gram-negative infections using a novel immunotherapeutic mechanism.

Bloodstream infections (BSIs) are amongst the leading healthcare-associated infections (HCAIs), and their comprehensive evaluation and management are of global and regional importance. This narrative review examines and reports data on BSIs from the Gulf Cooperation Council (GCC) region covering the period between 2013 and 2023. The reviewed literature demonstrated that BSIs were frequently associated with critical care settings such as the Intensive Care Unit (ICU) and were often associated with invasive lines and devices [such as central-line associated BSI (CLABSI)]. Fever was the main presenting symptom, while diabetes mellitus and hypertension were the common associated comorbidities. High mortality rates were reported for BSIs, particularly when caused by multidrug-resistant (MDR) Gram-negative pathogens. There was a wide range of antimicrobial resistance rates reported across the region; however, carbapenem-resistance rates exceeding 30% were reported for Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Few publications included molecular mechanisms of carbapenem resistance; however, when mechanisms were reported they were dominated by OXA-48. In conclusion, the lack of structured surveillance programs and networks to monitor microbiological phenotypic and genotypic patterns as well as clinical outcomes across the region means there is paucity of uniform data on BSIs across the GCC region. To bridge this gap, we recommend timely surveillance programs for the monitoring of resistance and outcomes.

Various population pharmacokinetic studies have suggested controversial optimal dosing regimens for polymyxin B in recent years. The objective of this study was to examine the real-world performance of various dosing regimens in therapeutic target attainment.

This is a secondary analysis of a large prospective multicenter cohort (ChiCTR2200056667). Patients were retrospectively included from the cohort, and patient demographic characteristics, polymyxin B dosing regimens and corresponding 24-hour areas under the curve (AUCs) were collected. Patients were categorized into various groups according to the dosage regimens, and the corresponding AUC target attainment was analyzed. The target AUC ratio was defined as 50-100 mg/L·h.

A total of 304 AUC data from 247 patients were included in this study. Only 55.3% of the AUCs were in the range of 50-100 mg/L·h. Differences in subgroups stratified by fixed-dosing regimens, weight-based regimens, and renal function-based dosing regimens. Moreover, the differences among the highest target dose strategies (fixed dose of 50 mg/12 h, weight-adjusted dose of 1-1.25 mg/kg/12 h, and CRRT unadjusted dose) were also insignificant.

No polymyxin B dosing strategy is superior in terms of target attainment, which highlights the importance of TDM in the clinical application of polymyxin B.

Polymyxin B (PMB) remains a last-line therapeutic agent for multidrug-resistant gram-negative bacteria (MDR-GNB) infections. However, reliable pharmacokinetic (PK) data to guide nebulized PMB dosing regimens in critically ill patients are limited. This study aimed to establish a population pharmacokinetic (PopPK) model for PMB in both epithelial lining fluid (ELF) and plasma of critically ill patients with MDR-GNB pneumonia and to optimize dosing regimens. A prospective PK study was conducted in 76 adult patients receiving nebulized PMB either as monotherapy or in combination with intravenous administration. PK data were analyzed using non-linear mixed-effect modeling, with PMB concentration-time profiles described by a coupled model integrating separate two-compartment models for plasma and ELF. The final model identified albumin levels and age as significant covariates influencing PK variability. Monte Carlo simulations demonstrated that nebulization therapy either alone or combined with intravenous administration significantly enhances ELF concentration and the probability of target attainment. Additionally, Pseudomonas aeruginosa requires higher nebulized doses than Klebsiella pneumoniae and Acinetobacter baumannii. This study develops a PopPK model of PMB in ELF and plasma, providing critical insights to optimize PMB treatment strategies for patients with MDR-GNB pneumonia.

The pharmacokinetics of polymyxins are highly variable and conventional dosing regimens may likely lead to sub-optimal exposures and outcomes, particularly in critically ill patients with multi-drug-resistant infections. The aim of this systematic review is to describe the published pharmacokinetic data and to investigate variables that have been shown to affect the pharmacokinetics of colistimethate sodium, colistin, and polymyxin B in adult populations.

Sixty studies were identified. A total of 27 and 33 studies described the pharmacokinetics of colistin and polymyxin B, respectively.

The most common dosing regimen for colistimethate sodium was a loading dose of 9 MIU, followed by 9 MIU/day in two to three divided doses, while for polymyxin B, a loading dose of 100-200 mg, followed by 50-100 mg every 12 h was given. Studies that used colistin sulfate instead of colistimethate sodium reported lower inter-individual variability, which may be attributed to the formulation of colistin sulfate being an active drug. The volume of distribution for colistin is typically lower in healthy individuals than in critically ill patients, owing to variations in physiological and pathological conditions. The clearance of colistimethate sodium in critically ill patients not undergoing dialysis was higher, around 13 L/h, compared with those receiving continuous renal replacement therapy, where clearance ranged from 2.31 to 8.23 L/h. In patients receiving continuous renal replacement therapy, clearance of colistin was higher compared with colistimethate sodium (2.06-6.63 L/h and 1.57-3.85 L/h, respectively). Colistin protein binding in critically ill patients ranged from 51% to 79%. The volume of distribution of polymyxin B was similar between critically ill and acutely ill patients, with range of 6.3-33.1 L and 6.22-38.6 L, respectively. Clearance of polymyxin B was also almost similar between critically ill and acutely ill patients (range of 1.27-2.32 L/h). There were two studies that reported free drug concentrations instead of the total drug concentrations of polymyxin B. In critically ill patients, protein binding ranged from 48.8% to 92.4% for polymyxin B. Creatinine clearance was the most common patient characteristic associated with altered clearance of colistimethate sodium and/or colistin, and polymyxin B.

Critically ill patients exhibit complex pharmacokinetics for colistin and polymyxin B, influenced by renal function, body weight, and clinical factors such as acute kidney injury, augmented renal clearance, serum albumin, and liver function. These factors necessitate individualized dosing adjustments to avoid toxicity and achieve therapeutic efficacy. Model-informed precision dosing provides a promising approach to optimize their use by integrating population pharmacokinetic parameters, patient-specific variables, and therapeutic drug monitoring, ensuring a balance between efficacy, safety, and resistance prevention.

This study aimed to investigate the associated factors predicting 30-day mortality of carbapenem-resistant Gram-negative bacilli (CR-GNB) infections, with focus on polymyxin B AUCss,24h/MIC.

This prospective cohort study included patients with CR-GNB infections from January 2022 to January 2024. The primary outcome was 30-day mortality. Classification and regression tree (CART) analysis was used to calculate the AUCss,24h/MIC threshold for 30-day mortality. Multivariate analysis was conducted to assess risk factors affecting this outcome.

We enrolled 107 patients, among which 30-day mortality occurred in 31 (29.0%) cases. The CART-derived AUCss,24h/MIC breakpoint was 51.3, and patients in the below-breakpoint group had 3.4-fold higher 30-day mortality than those in the above-breakpoint group (58.1% vs 17.1%, P < 0.001). On multivariate analysis, polymyxin B AUCss,24h/MIC of ≥51.3 (aOR 0.08, P = 0.001) predicted a lower risk for 30-day mortality. In subgroup analysis, the survival benefit of AUCss,24h/MIC target attainment remained in patients with high risk of mortality or carbapenem-resistant Acinetobacter baumannii infections.

Polymyxin B AUCss,24h/MIC of ≥51.3 independently predicted lower 30-day mortality in treating CR-GNB infections. Further studies should verify the AUCss,24h/MIC target associated with survival outcomes in larger randomized controlled trials.

To evaluate the efficacy of intravenous colistin sulfate (CS) in the treatment of carbapenem-resistant Gram-negative bacilli (CR-GNB) infections in real-world clinical settings and to identify factors influencing its therapeutic outcomes, with the aim of promoting the rational use of CS.

A retrospective analysis was conducted on the clinical characteristics and treatment outcomes of 174 patients diagnosed with CR-GNB infection who received intravenous CS at our center between January 2021 and December 2023. The study evaluated both clinical efficacy and adverse drug reactions (ADRs).

Among the 174 patients, 118 cases (67.8%) demonstrated clinical improvement, and the bacterial clearance rate was 53.9%. Multivariate logistic regression analysis identified several factors significantly associated with treatment efficacy: neurological disease (OR [95% CI]: 0.100 [0.019-0.541]; p = 0.006), admission to a surgical ward (OR [95% CI]: 0.136 [0.023-0.801]; p = 0.027), septic shock (OR [95% CI]: 5.147 [1.901-14.096]; p = 0.001), and empirical use of CS (OR [95% CI]: 4.250 [1.109-16.291]; p = 0.035). Additionally, 10 cases (5.8%) of acute kidney injury (AKI) were attributed to nephrotoxicity from CS, with 2 cases recovering after discontinuation of the drug.

Our findings suggest that intravenous colistin sulfate may be an effective treatment option for CR-GNB infections when used appropriately. However, further studies are required to better understand its real-world efficacy and safety profile.

Carbapenem-resistant Gram-negative (CRGN) bacterial infections are an urgent health threat, especially in low-income and middle-income countries (LMICs), where they are rarely detected and might not be treated appropriately given inadequate health system capacity. To understand this treatment gap, we estimated the total number of CRGN bacterial infections requiring an active agent and the number of individuals potentially initiated on appropriate treatment in eight large LMICs.

For eight selected countries (Bangladesh, Brazil, Egypt, India, Kenya, Mexico, Pakistan, and South Africa), we estimated deaths associated with CRGN bacterial infections (that were not susceptible to other antibiotics) in 2019 using data from the Global Burden of Disease 2021 study on antimicrobial resistance. We used estimates from the literature to establish infection type-specific case fatality rates and an overall case fatality rate for CRGN bacterial infections. The total number of CRGN bacterial infections requiring an active agent could then be calculated by dividing the total number of CRGN bacterial infection-related deaths by the overall case fatality rate. We estimated the treatment gap (ie, the number of individuals with CRGN bacterial infections who were not appropriately treated) by subtracting from the total number of infections the number of individuals who initiated appropriate treatment, which was estimated using 2019 IQVIA sales data for six antibiotics active against CRGN bacteria, corrected to account for IQVIA's partial data coverage for each country and dose-adjusted by age.

In 2019, in the eight selected countries, we estimated that there were 1 496 219 CRGN bacterial infections (95% CI 1 365 392-1 627 047) but that only 103 647 treatment courses were procured. The resulting treatment gap (1 392 572 cases [95% CI 1 261 745-1 523 400]) meant that only 6·9% of patients were treated appropriately. The treatment gap persisted even when we used more restrictive assumptions. The most-procured antibiotic was tigecycline (intravenous; 47 531 [45·9%] of 103 647 courses). India procured most of the treatment courses (83 468 [80·5%] courses), with 7·8% of infections treated appropriately (treatment gap 982 848 cases [95% CI 909 291-1 056 405]). The rates of appropriate treatment coverage were highest in Mexico (5634 [5·4%] courses procured; treatment gap 32 141 cases [30 416-33 867]) and Egypt (7572 [7·3%] courses procured; treatment gap 43 258 cases [38 742-47 774]), both with 14·9% of infections treated appropriately.

Infections caused by CRGN bacteria are likely to be significantly undertreated in LMICs. To close this treatment gap, improved access to diagnostics and antibiotics, strengthening of health systems, and research to identify gaps in the treatment pathway are needed.

Global Antibiotic Research and Development Partnership, supported by the Governments of Canada, Germany, Japan, Monaco, the Netherlands, Switzerland, and the UK, and by the Canton of Geneva, the EU, the Bill & Melinda Gates Foundation, Global Health EDCTP3, GSK, the RIGHT Foundation, the South African Medical Research Council, and Wellcome.

Differences exist between Infectious Diseases Society of America guidance and European Society of Clinical Microbiology and Infectious Diseases guidelines on treating pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB). This study compared the outcomes of colistin-based and high-dose ampicillin/sulbactam-based combination therapies in patients with CRAB nosocomial pneumonia. A retrospective cohort study was conducted at a university-affiliated hospital in South Korea. Patients received either a colistin-based regimen with a loading dose followed by a maintenance dose (June 2021-May 2022) or a high-dose ampicillin/sulbactam-based regimen with sulbactam 9 g/day (October 2022-September 2023). The primary outcome was 28-day all-cause mortality; secondary outcomes included 14-day/28-day clinical success rates and 14-day/28-day kidney injury based on the Risk, Injury, Failure, Loss, End-stage renal disease score. Logistic and Poisson regression analyses were used to compare outcomes between groups. Among 179 patients enrolled in the study, 84 received the colistin-based regimen and 95 received the high-dose ampicillin/sulbactam-based regimen. The ampicillin/sulbactam group showed significantly lower 28-day mortality (20% vs. 61%; adjusted relative risk [aRR] = 0.16, 95% CI 0.08-0.32). Clinical success rates were higher in the ampicillin/sulbactam group at both 14 days (39% vs. 23%; aRR = 2.19, 95% CI 1.10-4.37) and 28 days (55% vs. 32%; aRR = 2.71, 95% CI 1.14-5.20). Additionally, 28-day kidney injury was lower in the ampicillin/sulbactam group (0.63 ± 1.16 vs. 1.06 ± 1.35; aRR = 0.56, 95% CI 0.40-0.79). High-dose ampicillin/sulbactam-based combination therapy demonstrates superior outcomes over colistin-based combination therapy for CRAB nosocomial pneumonia, including lower mortality, higher clinical success rates, and reduced kidney injury.

Colistin is an antimicrobial used as a last resort in the treatment of resistant gram-negative infections associated with high morbidity and mortality. Therefore, the rapid and accurate detection of colistin susceptibility is of vital importance. However, the current methods used to determine colistin susceptibility face various challenges. The purpose of this study was to evaluate two novel rapid colistin susceptibility methods, namely resazurin-based rapid modified colistin disk elution (RrmCBDE) and nitrate reductase-based rapid modified colistin disk elution (NRrmCBDE), alongside the established modified colistin broth disk elution (mCBDE), against the reference broth microdilution (BMD) method for determining colistin susceptibility in Enterobacterales isolates.

The colistin susceptibility of 215 multidrug-resistant or extensively drug-resistant Enterobacterales isolates was determined using RrmCBDE and NRrmCBDE with 0.5 and 3 McFarland variations, and mCBDE test. The RrmCBDE and NRrmCBDE tests yielded results in approximately 6 h, whereas the mCBDE test required 16-20 h. The findings were then compared with the reference BMD method.

According to BMD results, the mCBDE method showed 98.6% categorical agreement (CA) with 1.39% very major errors (VME). It demonstrated 97.86% sensitivity and 100% specificity. For RrmCBDE, the 0.5 McFarland variation had 91.2% CA, 8.8% VME, 86.4% sensitivity, and 100% specificity, while the 3 McFarland variation achieved 97.2% CA, 2.79% VME, 95.7% sensitivity, and 100% specificity. Similarly, NRrmCBDE, the 0.5 McFarland variation exhibited 88.37% CA and 11.6% VME, 82.1% sensitivity, and 100% specificity, while the 3 McFarland variation demonstrated 98.6% CA, 1.39% VME, 97.86% sensitivity, and 100% specificity.

Based on these results, it was concluded that the novel RrmCBDE and NRrmCBDE tests, particularly with the 3 McFarland variation, provided results within approximately 6 h, making them a rapid alternative to conventional methods.

Background: Achieving pharmacokinetic/pharmacodynamic (PK/PD) targets is critical for improving treatment success, particularly in critically ill patients. This study investigates the role of inflammatory biomarkers and their influence on the PK/PD characteristics of polymyxin B (PMB) in patients with extensively drug-resistant Gram-negative (XDR-GN) bacterial nosocomial pneumonia. Methods: Serial blood and/or bronchoalveolar lavage fluid (BALF) samples were collected at specified time points and analyzed for PMB and/or inflammatory biomarkers, including IL-6 and IL-10. Clinical data were also recorded, and their correlations with PK parameters were further analyzed. Results: Among the 27 enrolled patients, 22 (81.5%) achieved treatment success. The pharmacokinetic parameters of PMB included a maximum plasma concentration (Cmax) of 8.3 µg/mL, clearance (CL) of 1.55 L/h, volume of distribution (Vd) of 30.44 L, half-life (t1/2) of 19.56 h, steady-state area under the plasma concentration-time curve from time 0 to 24 h (AUCss,0-24h) of 110.08 h·µg/mL, and a plasma protein-binding ratio of 85.53%. The AUCss,0-24h metric was identified as a robust predictor of clinical efficacy, with an optimal cutoff value of 77.27 h·µg/mL. Notably, 48.15% of patients achieved the target AUCss,0-24h range of 50-100 h·µg/mL, with 76.95% of these patients attaining treatment success. Another 48.15% of patients exceeded this target, and 92.31% of this subgroup achieved treatment success. PMB demonstrated limited pulmonary penetration, with an epithelial lining fluid (ELF)/plasma ratio of 15.69% [16.86, 18.15]. Furthermore, TNF-α and the IL-6/IL-10 ratio were significantly correlated with PMB PK parameters. Conclusions: Our and others' studies suggest heterogeneity of PMB PK parameters in critically ill patients. The majority of critically ill patients achieved or surpassed the recommended PK/PD targets and attained treatment success through intravenous administration of PMB at a simplified fixed dose. However, PMB did not achieve satisfactory pulmonary concentrations, suggesting that its efficacy may involve alternative mechanisms. The modulation of inflammatory responses may play a pivotal role in the treatment of severe infections, highlighting the potential for biomarker-guided therapeutic strategies.

The global dissemination of carbapenemase-producing Klebsiella pneumoniae (CPKP) has been occurring at an alarming pace, especially for the metallo-β-lactamase (MBL) group. Current clinical data suggest that carbapenem is still irreplaceable in terms of safety and efficacy. For MBL-producing Klebsiella pneumoniae (MBL-KP), how to use carbapenem judiciously in the context of advocating carbapenem-sparing strategies remains largely undetermined.

Four strains carrying different MBLs (two IMPs and two NDMs) were collected. The genome sequence, drug resistance phenotype, and synergistic effect of different meropenem-based antimicrobial combinations were tested. Dynamics in vitro pharmacokinetic/pharmacodynamic (PK/PD) model was used to optimize the dosage. The selected combination regimens were verified in a murine model of peritoneal sepsis.

Meropenem in combination with fosfomycin or colistin was effective against MBL-KP strains. Meropenem in combination with colistin had a better bactericidal effect compared with fosfomycin, while such a combination was prone to cause colistin-dependent heterogeneous resistance, especially for IMP-KP. For NDM-KP extremely resistant to meropenem, ultra-high dose up to 2.75 g q6h meropenem in combination with fosfomycin or colistin was needed. For IMP-KP, high-dose meropenem monotherapy (2 g q8h) or low-dose meropenem (1 g q8h) in combination with fosfomycin were both feasible.

Meropenem in combination with fosfomycin or colistin was an effective choice for MBL-KP. The combination regimen and dosage optimization should be assessed based on not only the type of enzyme but also the specific value of minimum inhibitory concentration (MIC).

Acinetobacter baumannii is a high-priority organism for the development of new antibacterial treatments. We found that the antimalarial medication mefloquine (MFQ) permeabilized the bacterial cell membrane of A. baumannii, decreased membrane fluidity, and caused physical injury to the membrane. MFQ also maintained activity across different pH conditions (pH range: 5-8). Structure-activity relationship analysis using MFQ analogs demonstrated that piperidin-2-yl methanol is required for antibacterial activity. Scanning and transmission electron microscopy demonstrated the compromised morphological and membrane integrity in MFQ-treated cells. MFQ synergized with the membrane permeabilizers polymyxin B and colistin and the MFQ + polymyxin B combination killed bacterial cells more effectively than either treatment alone. MFQ + polymyxin B was effective against other gram-negative bacteria including Escherichia coli, Burkholderia pseudomallei, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Bodipy-cadaverine displacement assays confirmed the active interaction of MFQ with other membrane lipid components, such as lipopolysaccharide, lipid A, lipoteichoic acids, and fatty acids. In all-atom molecular dynamics simulations, lipid interactions facilitated the permeation of MFQ into the simulated Gram-negative membrane. Additionally, positively charged nitrogen in the piperidine group of MFQ seems to enhance interactions with the negatively charged components of the bacterial membrane. MFQ + polymyxin B caused significantly greater curvature in the simulated membrane, indicating greater damage than standalone drug treatment. Finally, in vivo assays showed that MFQ + polymyxin B rescued Galleria mellonella larvae infected with A. baumannii. In conclusion, membrane-active agents such as MFQ may warrant further investigation as a potential components of gram-negative infection treatment, particularly in combination with polymyxin B.

Antimicrobial resistance is a threat globally, and new treatments are urgently needed to combat the rise of multidrug-resistant bacteria. However, the development of anti-infectives has declined over the last two decades due to regulatory, financial and long-term requirement related challenges. In this study, we examined the membrane interactions of the antiparasitic agent mefloquine (MFQ) in combination with polymyxin B, using both in vitro and in silico approaches to evaluate their potential efficacy against gram-negative bacterial infections. We investigated the interaction of MFQ with lipid bilayers to understand the mechanism through which antibacterial activity is exerted. The piperidine moiety of MFQ plays a critical role in its interaction with the lipid bilayer and facilitates membrane permeabilization. In contrast, the membrane permeabilizer polymyxin B is associated with significant neurotoxicity and nephrotoxicity. Our findings highlight the potential of membrane-acting compounds, such as MFQ, to enhance combinatorial activity while mitigating polymyxin B-associated toxicity.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is an emerging and important major cause of nosocomial infections, posing a significant challenge to clinicians worldwide. The intrinsic and acquired resistance mechanisms exhibited by CRAB, associated with its ability to persist in healthcare environments, have transformed it into a critical public health concern. The clinical implications of CRAB infections include severe manifestations, like ventilator-associated pneumonia and bloodstream infections. These infections are often associated with increased morbidity and mortality, particularly in critically ill patients, such as those in intensive care units, immunocompromised, and those undergoing invasive procedures. Considering these characteristics, the therapeutic armamentarium for the treatment of CRAB infections is increasingly limited, as these strains exhibit resistance to a broad range of antibiotics, including carbapenems and the new β-lactam inhibitors, which are considered last-line agents for many bacterial infections. An important role is represented by cefiderocol and data from real-world evidence. The aim of this narrative review is to discuss the main topics of CRAB infection and strategies for prevention, management, and therapy.

Polymyxin B, a last resort for carbapenem-resistant gram-negative bacteria (CRGNB) infections, has infection site-specific pharmacokinetic/pharmacodynamic (PK/PD) properties. However, there is little clinical evidence to support optimal exposures of polymyxin B for different site infections. We performed a prospective, observational, multicenter study to evaluate the clinical outcomes and PK/PD of intravenous polymyxin B treatment for various site CRGNB infections. The main clinical outcomes were 14-day all-cause mortality and nephrotoxicity, and the secondary outcomes were 28-day mortality and clinical response. The area under curves (AUCs) of polymyxin B were determined, and their associations with clinical outcomes were analyzed by stratification based on the infection site. A total of 312 patients were ultimately enrolled from 10 research centers. The overall 14-day mortality was 29.5%, and those of patients with lower respiratory tract infection (LRTI), intra-abdominal infection (IAI), and bloodstream infection (BSI) were 32.3%, 19.7%, and 30.3%, respectively. The 28-day mortality rate was 38.1%, while LRTI patients had the highest mortality (41.4%) and IAI patients lowest (34.8%). The clinical response rate was 46.2%, which was similar among the subgroups. The overall AKI rate was 60.9%. An AUC greater than 50 mg∙h/L was related to lower mortality in IAI patients but not in LRTI patients, which led to a lower but not significant difference in the overall analysis. The AUC of polymyxin B was an independent risk factor for 14-day mortality in IAI patients, and the cutoff value was 76 mg∙h/L. The results would be helpful for personalized dosing and monitoring of polymyxin B.CLINICAL TRIALSThis study is registered with the Chinese Clinical Trial Registry as ChiCTR2200056667.

Polymyxins, including colistin and polymyxin B, are the final resort against Gram-negative bacterial infections. However, its clinical application is restricted due to concerns related to neurotoxicity. Despite the similar antibacterial spectrum and mode of action shared between colistin and polymyxin B, there is still a lack of definitive evidence to support the idea that their neurotoxicity profiles are identical. To comprehensively compare the neurotoxicity between colistin and polymyxin B both in vivo and in vitro and establish a theoretical foundation to guide the rational use of polymyxins within clinical settings. in vitro experiments simulated nerve damage by exposing N2a and RSC96 cells to colistin and polymyxin B. The evaluation of nerve injury included assessments of cell viability and apoptosis. To discern the variance in the mechanisms of nerve injury between colistin and polymyxin B, oxidative stress levels were examined, such as SOD, CAT, GSH, and malondialdehyde (MDA). In in vivo experiments, a rat nerve injury model was created by intraventricular injections of colistin and polymyxin B, respectively. The impact of these drugs on brain injury in rats, particularly within the hippocampus and medulla oblongata, was measured using HE and Nissl staining. The potential influence of polymyxins on the ferroptosis pathway was evaluated by assessing LPO and Fe2+ levels and the degree of mitochondrial impairment. At equivalent doses, colistin demonstrated a reduced level of neurotoxicity compared to polymyxin B, both in vitro and in vivo. in vitro experiments revealed greater cell viability and a lower apoptosis rate after colistin treatment than after polymyxin B treatment. This variance in outcomes could be attributed to the comparatively lower levels of oxidative stress associated with colistin administration. In a rat model, nerve injury resulted in observable damage to both the hippocampus and the medulla oblongata. A comprehensive assessment of the extent of damage in the CA1 to CA4 regions of the hippocampus, and the solitary tract nucleus of the medulla oblongata underscored that the neurotoxic effects of colistin remained milder compared to those elicited by polymyxin B. Even when evaluated at equivalent multiples of clinically recommended doses, colistin exhibited lower neurotoxicity in vivo than polymyxin B. For the first time, this study demonstrated the role of ferroptosis in polymyxin B-induced nerve damage. The activation levels observed within the ferroptosis pathway due to polymyxin B exceeded those triggered by colistin. Colistin exhibited a marked reduction in neurotoxicity compared to polymyxin B, evident in both the equivalent and clinically recommended doses. These findings suggest that, from the perspective of neurotoxicity, colistin presents a more favorable option for clinical use.

Aerosolized polymyxin B delivery was a promising approach for the treatment of ventilator-associated pneumonia (VAP). However, there were little data on the concentrations of polymyxin B in epithelial lining fluid (ELF), which impedes the optimal use of aerosolized polymyxin B in clinics.

We present four cases of patients diagnosed with VAP caused by Gram-negative bacteria, who enrolled in a prospective, therapeutic drug monitoring (TDM) study of polymyxin B. The patients were treated with aerosolized and intravenous administration of polymyxin B. Polymyxin B concentrations in both ELF and plasma were determined using validated LC-MS/MS methods.

All four patients achieved bacterial eradication, with three of them reaching clinical improvement or cure. Following aerosol administration (25 or 50 mg, q12h) and intravenous infusion (50-100 mg, q12h) of polymyxin B, it was observed that the concentrations of polymyxin B in ELF were significantly higher in ELF (20.6-97.6 mg/L) compared to those in plasma (1.19-5.16 mg/L) during the steady sate. The area under the concentration-time curve for 24 h (AUC24h,ELF) ranged from 283.6 to 1872.9 mg•h/L.

This study presented polymyxin B concentrations in ELF following aerosolized delivery, supporting its clinical use from a PK/PD perspective. Following combined aerosol and intravenous administration, polymyxin B achieved notably higher concentrations in ELF than those observed in plasma.

Colistin, has reinstated as a last-resort antibiotic despite its known nephrotoxicity. The aim of this study was to determine the potential nephroprotective effects of Magnesium (Mg) Sulfate during colistin therapy. This study was an open-label, placebo-controlled, block-randomized clinical trial conducted from January 2023 to February 2024 involving 87 patients eligible for colistin therapy. Patients were randomly assigned to receive either Mg sulfate (16 mEq in 100 mL of normal saline) or 100 mL of normal saline as placebo before each dose of colistin. The primary outcome of the study was the incidence of Acute Kidney Injury (AKI) during the first week of colistin therapy, while the secondary outcomes included colistin dose adjustments, length of stay in the ICU and hospital, and overall mortality. This study was registered in The Iranian Registry of Clinical Trials (IRCT20130917014693N15; 2023-01-12). A total of 87 patients (46 in Mg and 41 in control group) completed the study. Fourteen patients (30.43%) in the Mg group and twenty-one patients (51.21%) in the control group developed AKI during the first week of colistin therapy (p = 0.048). Although AKI incidence was not statistically different between the groups in unadjusted Cox regression model (HR =0.51, 95% CI =0.26-1.01, P =0.057), it became significant after adjusting for confounding factors (HR =0.40,95% CI =0.18-0.86, P =0.021). The length of hospital stay was 48.62 ± 18.82 and 44.82 ± 20.23 days for Mg and control groups respectively (p=0.373). In the Mg group, 25 out of 46 patients (54.34 %) and in the control group, 24 out of 41 patients (58.53%) eventually expired (p=0.694). This study indicates that Mg sulfate significantly reduces AKI rates and prevents hypomagnesemia, optimizing dosing and enhancing patient safety during colistin therapy.

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections pose a critical clinical challenge. Although ceftazidime/avibactam (CAZ/AVI) and polymyxin B (PMB) are frontline therapies, their comparative effectiveness in terms of 30-day survival, renal safety profiles, and clinical success rates remains poorly characterized. To address this knowledge gap, a multicenter real-world study was conducted.

CRPA-infected patients treated with PMB or CAZ/AVI-based regimens were enrolled from five hospitals between January 1, 2021, to July 31, 2023. Propensity score matching (PSM) and binary logistic regression analysis were performed to evaluate efficacy and acute renal injury (AKI) occurrence, and a multivariable COX proportional hazards regression of the 30-day all-cause mortality was performed.

170 CRPA-infected patients were enrolled, among whom 124 (72.9%) had difficult-to-treat resistant P. aeruginosa (DTR-PA) infections and 77 (45.3%) received CAZ/AVI-based regimens. After 1:1 PSM, the results demonstrated that the CRPA clearance rate was significantly higher in the CAZ/AVI group compared to the PMB group (61.0% vs. 24.4%, p = 0.001); however, no significant differences were observed in clinical success rates (55.6% vs. 44.4%), incidence of AKI (26.8% vs. 39.0%), or 30-day all-cause mortality (7.3% vs. 12.2%) between the two groups (all p > 0.05). Compared with the PMB-based regimens, CAZ/AVI-based regimens were significantly associated with CRPA clearance success (OR 0.185, 95%CI 0.061-0.564, p < 0.001); additionally, multi-site infection (OR 0.295, 95%CI 0.097-0.899, p = 0.032) and the number of combined anti-PA antibiotics (OR 0.435, 95%CI 0.213-0.888, p = 0.022) were associated with enhanced CRPA clearance. The occurrence of AKI in patients with CRPA infection was associated with underlying diseases, including sepsis/septic shock (OR 3.405, 95%CI 1.007-11.520, p = 0.049), and diabetes mellitus (OR 3.600, 95%CI 1.018-12.733, p = 0.047). In addition, other CREs infection (HR 40.849, 95%CI 3.323-502.170, p = 0.004), APACHE II score (HR 1.072, 95%CI 1.032-1.114, p < 0.001) were found to be independent predictors of 30-day all-cause mortality.

In conclusion, CAZ/AVI-based regimens demonstrated superior efficacy in clearing CRPA compared to PMB-based regimens. Furthermore, several factors associated with AKI and mortality in CRPA-infected patients were identified, highlighting the need for further research to optimize treatment strategies.

To analyze and compare the incidence of adverse events (AEs) associated with different administration routes of colistin, with the aim of providing a reference for its safe and effective clinical use.

Adverse event (AE) reports related to colistin were retrieved from the FDA Adverse Event Reporting System (FAERS) database. The reporting trends were analyzed, and the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) for colistin-associated AEs were calculated. A comparative analysis was conducted to examine the occurrence of AEs under different administration routes of colistin.

A total of 13,043 AE reports were extracted from the FAERS database. Further analysis of 176 key AEs associated with colistin indicated a significant increase in the number of reports after 2021. The year and country of the reports showed heterogeneity across different administration routes. Intravenous (IV) administration of colistin was associated with the highest proportion of AEs, and heterogeneity was also observed in the types of AEs reported for inhaled and oral (PO) administration routes.

Compared to inhaled and PO administration routes, IV administration of colistin is more likely to result in AEs such as nephrotoxicity and drug ineffectiveness. Additionally, there are significant differences in the types of AEs associated with colistin across different administration routes.

Multidrug-resistant Acinetobacter baumannii emerged as a threatening "superbug" with significant morbidity and mortality and limited antimicrobial therapy options. The results of different antibiotic combination studies are heterogeneous and controversial. Further comparative studies are crucial to overcome such difficult-to-treat infections and to improve patient outcomes. This study investigates the mortality and outcomes of colistin versus colistin-based combination therapy for infections caused by Multidrug-resistant Acinetobacter baumannii in critically ill patients.

A retrospective observational study was conducted at an academic tertiary hospital in Khobar City, Eastern Province, Saudi Arabia. Patients who fulfilled the inclusion criteria and were admitted from January 1, 2017, to December 31, 2022, were included. The investigated primary outcome was 30-day mortality, while secondary outcomes were one-year all-cause mortality, clinical cure, microbiologic eradication, and recurrence of Acinetobacter infections. Statistical comparisons were employed, and a P-value of ≤ .05 was considered significant.

Of the 178 patients who fulfilled the inclusion criteria, 47 received colistin only, and 131 received colistin in combinations (55 with carbapenems, 53 with tigecycline, and 23 with both). The estimated 30-day mortality rate of the study population was 22.5%, with statistically insignificant differences in 30-day mortality rates when the colistin group compared to cumulative colistin-based combination (23.4% vs. 22.1%; difference, 1.3 percentage points; 95% confidence interval [CI], 0.487-2.371; P = 0.858) or subgroups. However, colistin-based combination groups showed better secondary outcomes, with significantly less all-cause mortality and better clinical cure in colistin combination with carbapenems or tigecycline and less Acinetobacter infection recurrence in combination with carbapenems.

The study findings demonstrate the benefits of investigated colistin combination options that result in less one-year all-cause mortality, better clinical cure, higher microbiologic response, and less infection recurrence. However, no significant differences were observed regarding 30-day mortality. In addition, the study highlights the limitations of the available antimicrobial options and the crucial need for new effective antimicrobials and more successful combinations.

Infection with Carbapenem-resistant Gram-negative bacteria (CR-GNB) poses further challenges in treating stroke-associated pneumonia (SAP) patients. This multicenter retrospective study aimed to evaluate the efficacy of polymyxin B (PMB) in CR-GNB-infected SAP patients and to identify factors that may influence its effectiveness.

From 1 September 2019, and 30 December 2022, a total of 196 CR-GNB-infected SAP patients from five hospitals in China were included in the study based on specific criteria. Demographics and clinical data were obtained from the electronic medical records. Propensity score matching (PSM) was used to minimize the effect of potential confounding variables. Univariate analysis and multivariate logistic analysis were performed to identify risk factors affecting microbial efficacy.

Among the 196 SAP patients infected with CR-GNB, 24.5% received PMB combined inhalation and 75.5% received non-combined inhalation treatment. The clinical success rate was 68.9%, with 25.5% achieving microbial efficacy within 7 days and 37.8% achieving microbial cure. The 30-day all-cause mortality rate was 14.8%. The incidence of acute kidney injury was 34.7%. After adjustment by propensity score matching, the PMB combined inhalation group exhibited significantly higher microbial efficacy compared to the non-combined inhalation group (46.7% vs. 26.7%, p = 0.049). Multivariate logistic analysis identified multi-site infections and Carbapenem-resistant Pseudomonas aeruginosa infection as independent risk factors for microbial efficacy.

Combined inhalation of PMB demonstrated superior effectiveness in microbial clearance compared to non-combined inhalation in treating CR-GNB-infected SAP patients. We recommend aerosol combined inhalation of PMB and suggest developing personalized PMB-based regimens for individual patients to enhance treatment outcomes.

Background/Objectives: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is an important pathogen associated with high mortality and treatment failure rates. We aimed to assess the susceptibility of CRPA to antipseudomonal agents, identify its resistance mechanisms, and evaluate clinical outcomes in a sample of CRPA isolates. Methods: This was an in vitro study of a clinical isolate of CRPA from hospitalized patients with CRPA infection and a retrospective observational study of these patients, who were diagnosed between 14 February 2021 and 10 August 2023 at Songklanagarind Hospital in Songkhla, Thailand. In vitro experiments were conducted to determine the minimum inhibitory concentrations (MICs) of the antipseudomonal agents using the broth microdilution method. Resistance mechanisms were assessed using the modified carbapenem inactivation method, combined disk tests, and quantitative real-time reverse transcription polymerase chain reaction. Results: A total of 140 CRPA isolates were analyzed. Both traditional and novel β-lactams had high MICs. The most common resistance mechanism was the upregulation of the MexAB-OprM efflux pump (81.3%), followed by the downregulation of the OprD porin (48.9%) and metallo-β-lactamase (MBL) production (45.0%), and the overexpression of blaAmpC (41.0%). The 30-day all-cause mortality rate was 30.5%. The risk factors associated with 30-day mortality included a Charlson Comorbidity Index of ≥5 (OR: 3.43; 95% CI: 1.07-10.99; p = 0.03), sepsis (OR: 10.62; 95% CI: 1.26-89.44; p = 0.03), and septic shock (OR: 4.39; 95% CI: 1.67-11.55; p < 0.01). In contrast, receiving active documented therapy was significantly associated with reduced mortality (OR: 0.17; 95% CI: 0.04-0.74; p = 0.01). Conclusions: This study revealed higher MIC values of all β-lactams for CRPA, while colistin and amikacin remained effective. The resistance mechanisms included MexAB-OprM overexpression, OprD downregulation, MBL production, and blaAmpC overexpression, with a higher prevalence of MBL than in other regions of Thailand. High 30-day mortality was associated with comorbidities, sepsis, and septic shock, but active therapy reduced mortality.

To establish a population pharmacokinetic (PopPK) model of polymyxin B (PMB) in critically ill patients based on steady-state trough (Ctrough,ss) and peak (Cpeak,ss) concentrations, optimize the dosing regimen, and evaluate the consistency of 24-hour steady-state area under the concentration-time curve (AUCss,24h) estimation between model-based and the two-point (Ctrough,ss and Cpeak,ss) methods.

PopPK modeling was performed using NONMEM, Monte Carlo simulations were used to optimize PMB dosing regimens. Bland-Altman analysis was used to evaluate the consistency between the two AUCss,24h estimation methods.

A total of 95 patients, contributing 214 blood samples, were included and categorized into a modeling group (n = 80) and a validation group (n = 15). A one-compartment model was developed, with creatinine clearance (CrCL) and platelet count (PLT) identified as significant covariates influencing PK parameters. Simulation results indicated that when a Minimum Inhibitory Concentration (MIC) ≤ 0.5 mg·L-1, a probability of target attainment (PTA) ≥ 90% was achieved in all groups except for the 50 mg every 12 h (q12h) maintenance dose group. PTA decreased as CrCL increased, with slight variations observed across different PLT levels. The 75 mg and 100 mg q12h groups showed a higher proportion of AUCss,24h within the therapeutic window. Bland-Altman analysis revealed a mean bias of 12.98 mg·h·L-1 between the two AUCss,24h estimation methods. The Kappa test (κ = 0.51, P < 0.001) and McNemar's test (P = 0.33) demonstrated moderate agreement, reflecting overall consistency with minor discrepancies in classification outcomes.

The PopPK model of PMB is well-suited for critically ill patients. The 75 mg q12h and 100 mg q12h regimens are appropriate for critically ill patients, with CrCL levels guiding individualized dosing. A two-point sampling strategy can be used for routine therapeutic drug monitoring (TDM) of PMB.

To expand a translational pharmacokinetic-pharmacodynamic (PK/PD) modelling approach for assessing the combined effect of polymyxin B and minocycline against Klebsiella pneumoniae.

A PK/PD model developed based on in vitro static time-kill experiments of one strain (ARU613) was first translated to characterize that of a more susceptible strain (ARU705), and thereafter to dynamic time-kill experiments (both strains) and to a murine thigh infection model (ARU705 only). The PK/PD model was updated stepwise using accumulated data. Predictions of bacterial killing in humans were performed.

The same model structure could be used in each translational step, with parameters being re-estimated. Dynamic data were well predicted by static-data-based models. The in vitro/in vivo differences were primarily quantified as a change in polymyxin B effect: a lower killing rate constant in vivo compared with in vitro (concentration of 3 mg/L corresponds to 0.05/h and 57/h, respectively), and a slower adaptive resistance rate (the constant in vivo was 2.5% of that in vitro). There was no significant difference in polymyxin B-minocycline interaction functions. Predictions based on both in vitro and in vivo parameters indicated that the combination has a greater-than-monotherapy antibacterial effect in humans, forecasting a reduction of approximately 5 and 2 log10 colony-forming units/mL at 24 h, respectively, under combined therapy, while the maximum bacterial load was reached in monotherapy.

This study demonstrated the utility of the PK/PD modelling approach to understand translation of antibiotic effects across experimental systems, and showed a promising antibacterial effect of polymyxin B and minocycline in combination against K. pneumoniae.

The human body gets exposed to a variety of toxins intentionally or unintentionally on a regular basis from sources such as air, water, food, and soil. Certain toxins can be synthetic, while some are biological. The toxins affect the various parts of the body by activating numerous pro-inflammatory markers, like oxidative stresses, that tend to disturb the normal function of the organs ultimately. Nowadays, people use different types of herbal treatments, viz., herbal drinks that contain different spices for detoxification of their bodies. One such example is turmeric, the most commonly available spice in the kitchen and used across all kinds of households. Turmeric contains curcumin, which is a natural polyphenol. Curcumin is a medicinal compound with different biological activities, such as antioxidant, antineoplastic, anti-inflammatory, and antibacterial. Hence, this review gives a comprehensive insight into the promising potential of curcumin in the detoxification of heavy metals, carbon tetrachloride, drugs, alcohol, acrylamide, mycotoxins, nicotine, and plastics. The review encompasses diverse animal-based studies portraying curcumin's role in nullifying the different toxic effects in various organs of the body (especially the liver, kidney, testicles, and brain) by enhancing defensive signaling pathways, improving antioxidant enzyme levels, inhibiting pro-inflammatory markers activities and so on. Furthermore, this review also argues over curcumin's safety assessment for its utilization as a detoxifying agent.

There are limited comparative studies of ceftazidime/avibactam (CAZ/AVI) vs. polymyxin B (PMB) for carbapenem-resistant organisms (CRO) infections. The aim of this study was to compare the efficacy and safety of CAZ/AVI and PMB in treating CRO infections.

This single-centre, retrospective cohort study with propensity score-matching (PSM) involved adult patients with CRO infections. Patients who received the CAZ/AVI-based regimen were included in the cohort group; those prescribed with the PMB-based regimen were included in the control group. The primary outcome was 28-day all-cause mortality.

Among 298 eligible patients, 96 patients in each group were included in the PSM cohort. The CAZ/AVI group showed no improvement in 28-day or 14-day all-cause mortality, nor in 14-day clinical response, compared to the PMB group. However, the CAZ/AVI-based regimen was associated with higher 14-day clinical response rates than the PMB-based regimen in subgroups with carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections and monotherapy. The CAZ/AVI group achieved greater CRO eradication than the PMB group (crude odds ratio [OR], 1.658; 95% confidence interval [CI], 1.108-2.480; P = 0.014; adjusted OR, 1.718; 95% CI, 1.055-2.798; P = 0.030). This advantage in CRO eradication with CAZ/AVI was consistent in most subgroups, including septic shock, bloodstream infection and lower respiratory tract infection. The CAZ/AVI and PMB groups had comparable nephrotoxicity (crude OR, 0.577; 95% CI, 0.306-1.089; P = 0.090; adjusted OR, 0.741; 95% CI, 0.361-1.521; P = 0.414).

CAZ/AVI-based and PMB-based regimens demonstrated similar clinical efficacy and nephrotoxicity in treating CRO infections. However, CAZ/AVI was superior to PMB in CRO eradication and treating CRPA infections. CAZ/AVI monotherapy was more effective than PMB monotherapy for CRO infections.

ChiCTR2300078790 prospectively registered on 19 Dec 2023 (https://www.chictr.org.cn).