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Colistin is one of the last-resort antibiotics in treating infections caused by multidrug-resistant (MDR) pathogens. Unfortunately, the emergence of colistin-resistant gram-negative strains limit its clinical application. Here, we identify an FDA-approved drug, valnemulin (Val), exhibit a synergistic effect with colistin in eradicating both colistin-resistant and colistin-susceptible gram-negative pathogens both in vitro and in the mouse infection model. Furthermore, Val acts synergistically with colistin in eliminating intracellular bacteria in vitro. Functional studies and transcriptional analysis confirm that the combinational use of Val and colistin could cause membrane permeabilization, proton motive force dissipation, reduction in intracellular ATP level, and suppression in bacterial motility, which result in bacterial membrane disruption and finally cell death. Our findings reveal the potential of Val as a colistin adjuvant to combat MDR bacterial pathogens and treat recalcitrant infections. A colistin adjuvant valnemulin is identified to circumvent MDR bacterial pathogens and treat recalcitrant infections by causing membrane permeabilization, proton motive force dissipation, and reduction in intracellular ATP level. [ABSTRACT FROM AUTHOR]

Due to the lack of other treatment options, a rebirth of polymyxins is urgently required. Colistin (also called polymyxin E) and polymyxin B are the only two examples of this antibiotic class that were effectively employed in such critical situations. In the present work, both of the two studied medications were quantified via a simple, green, and non-extracting spectrophotometric approach based on the formation of ion-pair complexes with Erythrosine B. Without using any organic solvents, the pink color of the created complexes was detected at wavelength = 558 nm. To achieve the highest intensity of absorbance, optimum conditions were established by the screening of many experimental factors such as pH, buffer volume, the volume of Erythrosine B, and the time consumed to undergo the reaction. For Colistin and Polymyxin B respectively, Beer-Lambert's law was observed at the concentration ranges of 1–6, 1–9 µg mL− 1. The technique was approved and validated following ICH recommendations. Lastly, the suggested approach has been successfully implemented to quantify the cited medications colorimetrically, for the first time, in their parenteral dosage forms with excellent recoveries. Also, Content uniformity testing was implemented. [ABSTRACT FROM AUTHOR]

This retrospective study aimed to assess the effectiveness and safety of colistin used in combination therapy for treating nosocomial bloodstream infections caused by multi-drug resistant gram-negative pathogens in pediatric patients. Patients aged between 1 month and 18 years consecutively hospitalized with healthcare-associated bloodstream infections necessitating the administration of intravenous colistin at Dr. Sami Ulus Training and Research Hospital between January 2015 and January 2020 were included in the study. Patient-specific detailed clinical information, prognoses, and laboratory findings on days 1, 3, and 7 of colistin treatment were obtained from medical records. The study included 45 pediatric patients receiving intravenous colistin; 26 (57.8%) were male and 19 (42.2%) were female, with a median age of 18 months. While the clinical response was observed at 82.2% and microbiological response at 91.1% with colistin treatment, two patients (4.4%) discontinued treatment due to side effects without assessing treatment response. The most common adverse effect associated with the use of colistin was nephrotoxicity, which occurred in eight patients (17.8%). Among these patients, only one had pre-existing chronic kidney failure. Conclusion: Colistin used in combination therapy may be effective and safe for treating nosocomial infections caused by multi-drug resistant gram-negative bacteria in pediatric patients, who often have high mortality rates and limited treatment options. What is Known: • Colistin is an antibacterial agent used in the treatment of infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) and is associated with significant adverse effects such as nephrotoxicity. • The increasing prevalence of hospital-acquired infections has led to the expanded use of colistin in clinical practice. What is New: • The study demonstrates a high clinical and microbiological response rate to combination therapy with colistin in the treatment of infections caused by MDR-GNB. • The study highlights the importance of monitoring nephrotoxicity in pediatric patients receiving colistin, showing that these effects can be reversible after treatment cessation. [ABSTRACT FROM AUTHOR]

Colistin is a polymyxin antibiotic currently experiencing renewed clinical interest due to its efficacy in the treatment of multidrug resistant (MDR) bacterial infections. The frequent onset of acute dose-dependent kidney injury, with the potential of leading to long-term renal damage, has limited its use and hampered adequate dosing regimens, increasing the risk of suboptimal plasma concentrations during treatment. The mechanism of colistin-induced renal toxicity has been postulated to stem from mitochondrial damage, yet there is no direct evidence of colistin acting as a mitochondrial toxin. The aim of this study was to evaluate whether colistin can directly induce mitochondrial toxicity and, if so, uncover the underlying molecular mechanism. We found that colistin leads to a rapid permeability transition of mitochondria isolated from mouse kidney that was fully prevented by co-incubation of the mitochondria with desensitizers of the mitochondrial transition pore cyclosporin A or L-carnitine. The protective effect of L-carnitine was confirmed in experiments in primary cultured mouse tubular cells. Consistently, the relative risk of colistin-induced kidney damage, calculated based on histological analysis as well as by the early marker of tubular kidney injury, Kim-1, was halved under co-administration with L-carnitine in vivo. Notably, L-carnitine neither affected the pharmacokinetics of colistin nor its antimicrobial activity against relevant bacterial strains. In conclusion, colistin targets the mitochondria and induces permeability transition thereof. L-carnitine prevents colistin-induced permeability transition in vitro. Moreover, L-carnitine co-administration confers partial nephroprotection in mice treated with colistin, without interfering with its pharmacokinetics and antibacterial activity. [ABSTRACT FROM AUTHOR]

Colistin remains an important antibiotic for the therapeutic management of drug-resistant Klebsiella pneumoniae. Despite the numerous reports of colistin resistance in clinical strains, it remains unclear exactly when and how different mutational events arise resulting in reduced colistin susceptibility. Using a bioreactor model of infection, we modelled the emergence of colistin resistance in a susceptible isolate of K. pneumoniae. Genotypic, phenotypic and mathematical analyses of the antibiotic-challenged and un-challenged population indicates that after an initial decline, the population recovers within 24 h due to a small number of "founder cells" which have single point mutations mainly in the regulatory genes encoding crrB and pmrB that when mutated results in up to 100-fold reduction in colistin susceptibility. Our work underlines the rapid development of colistin resistance during treatment or exposure of susceptible K. pneumoniae infections having implications for the use of cationic antimicrobial peptides as a monotherapy. A combined microbiological and mathematical approach to study colistin resistance in antibiotic sensitive K. pneumoniae reveals a rapid emergence and selection of genetic variants generated by spontaneous mutations in key regulatory genes. [ABSTRACT FROM AUTHOR]

The increasing incidence of multidrug-resistant (MDR) Pseudomonas aeruginosa is a worldwide problem, particularly among critically ill patients. Since it is not anticipated that any new treatments will be available in the near feature, our research aims to assess the efficacy and safety of colistin in the treatment of infections caused by P. aeruginosa in neutropenic leukemia patients. A study was conducted at two hospitals (i.e., Beit-Jala Hospital/Bethlehem; n = 78 and Augusta Victoria Hospital/Jerusalem; n = 61) over a period of 18 months. Using a confidence interval of 95%, a margin of error of 5%, and a response rate of 50%, demographic and clinical characteristics were analyzed. One of the major results of our study was that colistin-treated patients had a favorable clinical response at day six and less nephrotoxicity outcomes compared to the control group. Data analyses revealed a high incidence (50–63%; n = 79) of leukemia in both hospital groups. Microbiologic response, infection-related mortality, and relapse rates were not statistically significant between both groups. Our study demonstrated that colistin is highly useful and effective in the treatment of MDR P. aeruginosa in blood cancer patients. Colistin has proven superior to control group in terms of clinical response at day six. Our study has also shown lower nephrotoxicity rates, which is further encouraging and could support the potential of using colistin as an alternative therapy for such infections. As multidrug resistance continues to be a worldwide concern, the need for effective therapies such as colistin remains of great importance. [ABSTRACT FROM AUTHOR]

Under the "One Health" concept, this paper aims to explore the occurrence of antimicrobial resistance in Enterobacterales (i.e., Escherichia coli and Salmonella enterica) among the South American Sea Lions on Argentina's northern Patagonian coast. From 177 fecal samples collected, conventional protocols were used to isolate E. coli and S. enterica. Antimicrobials classified as critically important by the WHO were evaluated by disk diffusion and agar spot (colistin) methods. Molecular tools were used to detect mcr genes as needed. A total of 176 antimicrobial-susceptible E. coli strains and 14 S. enterica strains were recovered. Twelve E. coli strains were colistin resistant (agar spot positive) but PCR negative for the mcr-1 to mcr-5 genes. Whole-genome sequencing revealed a chromosomal mutation, coding for Val161Gly change in PmrB protein, as the colistin resistance mechanism in one of these isolates. This study provides knowledge on AMR surveillance in wildlife associated with the marine environment in South America. [ABSTRACT FROM AUTHOR]

Phage-encoded endolysins have emerged as a potential substitute to conventional antibiotics due to their exceptional benefits including host specificity, rapid host killing, least risk of resistance. In addition to their antibacterial potency and biofilm eradication properties, endolysins are reported to exhibit synergism with other antimicrobial agents. In this study, the synergistic potency of endolysins was dissected with antimicrobial peptides to enhance their therapeutic effectiveness. Recombinantly expressed and purified bacteriophage endolysin [T7 endolysin (T7L); and T4 endolysin (T4L)] proteins have been used to evaluate the broad-spectrum antibacterial efficacy using different bacterial strains. Antibacterial/biofilm eradication studies were performed in combination with different antimicrobial peptides (AMPs) such as colistin, nisin, and polymyxin B (PMB) to assess the endolysin’s antimicrobial efficacy and their synergy with AMPs. In combination with T7L, polymyxin B and colistin effectively eradicated the biofilm of Pseudomonas aeruginosa and exhibited a synergistic effect. Further, a combination of T4L and nisin displayed a synergistic effect against Staphylococcus aureus biofilms. In summary, the obtained results endorse the theme of combinational therapy consisting of endolysins and AMPs as an effective remedy against the drug-resistant bacterial biofilms that are a serious concern in healthcare settings. [ABSTRACT FROM AUTHOR]

Background: We assessed the clinical effectiveness of cefiderocol (CFDC) in comparison with colistin (COL) for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infections (BSI). Materials/methods: Retrospective cohort study including adults with CRAB-BSI. Outcomes were mortality, clinical cure and adverse events during therapy. The average treatment effect of CFDC compared to COL was weighted with the inverse-probability treatment weight (IPTW). Results: Overall, 104 patients were included (50 CFDC, 54 COL), median age 66.5 years, median Charlson Comorbidity Index 5, septic shock in 33.6% of patients. Primary BSI accounted for 43.3% of cases, followed by ventilator-associated pneumonia (VAP) (26%), catheter-related BSI (20.2%) and hospital-acquired pneumonia (HAP) (9.6%). Although not significantly, mortality at all time points was lower for CFDC than COL, while clinical cure was higher in CFDC than COL (66% vs. 44.4%, p = 0.027). Adverse events were more frequent in COL than CFDC-group (38.8% vs. 10%, p < 0.0001), primarily attributed to acute kidney injury (AKI) in the COL group. Patients with bacteremic HAP/VAP treated with CFDC had a significant lower 30-d mortality and higher clinical cure than COL (p = 0.008 and p = 0.0008, respectively). Increment of CCI (p = 0.005), ICU (p = 0.025), SARS-CoV2 (p = 0.006) and ECMO (p < 0.0001) were independently associated with 30-d mortality, while receiving CFDC was not associated with survival. Conclusions: CFDC could represent an effective and safe treatment option for CRAB BSI, especially in patients with bacteremic HAP/VAP and frail patients where the risk of acute renal failure during therapy should be avoided. Key summary points: Increasing real-life data support the clinical effectiveness and safety of cefiderocol (CFDC) for carbapenem resistant Acinetobacter baumannii (CRAB) infections. We investigated CFDC in comparison with colistin (COL) for the treatment of CRAB bloodstream infections (BSI). Clinical cure was higher in CFDC than COL group. Patients with hospital acquired/ventilator-associated pneumonia treated with CFDC had a statistically significant lower 30-d mortality and higher clinical cure than those treated with COL. Adverse events were more frequent in COL than in CFDC-group. CFDC could be an effective and safe treatment option for CRAB BSI, especially in patients with HAP/VAP and frail patients where the risk of acute renal failure during therapy should be avoided. [ABSTRACT FROM AUTHOR]

Klebsiella pneumoniae is considered as the most common pathogen of hospital-acquired pneumonia. K. pneumoniae has emerged as the superbug which had shown multidrug resistance (MDR) as well as extensively drug resistance. Carbapenem resistant K. pneumoniae (CRKP) has become a menace for the treatment with monotherapy of the patients mainly admitted in intensive care units. Hence, in the present study we collected total 187 sputum isolates of K. pneumoniae and performed the antimicrobial susceptibility testing by using the automated Vitek-2 system and broth micro-dilution method (67 CRKP). The combination study of solithromycin with meropenem, colistin, cefotaxime, piperacillin and tazobactam, nitrofurantoin, tetracycline, levofloxacin, curcumin and nalidixic acid was performed by using checkerboard assay. We observed the high rate of resistance towards ampicillin, cefotaxime, ceftriaxone, cefuroxime and aztreonam. The colistin and tigecycline were the most sensitive drugs. The CRKP were 36%, maximum were from the patients of ICUs. The best synergistic effect of solithromycin was with meropenem and cefotaxime (100%), colistin and tetracycline (80%). So, these combinations can be a choice of treatment for the infections caused by MDR CRKP and other Gram-negative bacteria where the monotherapy could not work. [ABSTRACT FROM AUTHOR]

Polymyxin E or colistin is an effective antibiotic against MDR Gram-negative bacteria. Due to unwanted side effects, the use of this antibiotic has been limited for a long time, but in recent years, the widespread of MDR Gram-negative bacteria infections has led to its reintroduction. Neurotoxicity and nephrotoxicity are the significant dose-limiting adverse effects of colistin. Several agents with anti-inflammatory and antioxidant properties have been used for the prevention of colistin-induced neurotoxicity. This study aims to review the preclinical studies in this field to prepare guidance for future human studies. The data was achieved by searching PubMed, Scopus, and Google Scholar databases. All eligible pre-clinical studies performed on neuroprotective agents against colistin-induced neurotoxicity, which were published up to September 2023, were included. Finally, 16 studies (ten in vitro and eight in vivo) are reviewed. Apoptosis (in 13 studies), inflammatory (in four studies), and oxidative stress (in 14 studies) pathways are the most commonly reported pathways involved in colistin-induced neurotoxicity. The assessed compounds include non-herbal (e.g., ascorbic acid, rapamycin, and minocycline) and herbal (e.g., curcumin, rutin, baicalein, salidroside, and ginsenoside) agents. Besides these compounds, some other measures like transplantation of mitochondria and the use of nerve growth factor and mesenchymal stem cells could be motivating subjects for future research. Based on the data from experimental (in vitro and animal) studies, a combination of colistin with neuroprotective agents could prevent or decrease colistin-induced neurotoxicity. However, well-designed randomized clinical trials and human studies are essential for demonstrating efficacy. [ABSTRACT FROM AUTHOR]

Colistin- and carbapenem-resistant Acinetobacter baumannii is a serious multidrug resistant (MDR) bacterium in clinical settings. Discovery of new antibacterial drugs against MDR is facing multiple challenges in drug development. Combination of known antibiotics with a robust adjuvant might be an alternative effective strategy for MDR treatment. In the study herein, we report an antibiotic adjuvant activity of a natural compound panduratin A from fingerroot (Boesenbergia rotunda) as a potent adjuvant to colistin. The present study investigated the antibiotic adjuvant effect of panduratin A against 10 colistin- and carbapenem-resistant A. baumannii. Antibacterial activities were tested by broth microdilution method. Biofilm assay was used to determine the efficacy of panduratin A in biofilm formation inhibition on two representative strains Aci46 and Aci44. Genomic and transcriptomic analyses of colistin- and carbapenem-resistant A. baumannii strains were used to identify potential resistance and tolerance mechanism in the bacteria. Panduratin A-colistin combination showed an increased effect on antibacterial in the A. baumannii. However, panduratin A did not improve the antibacterial activity of imipenem. In addition, panduratin A improves anti-biofilm activity of colistin against Aci44 and Aci46, the colistin- and carbapenem-resistant A. baumannii. Panduratin A markedly enhances bactericidal and anti-biofilm activity of colistin against colistin- resistant A. baumannii. Based on genome comparisons, single nucleotide polymorphism (SNP) patterns in six genes encoding biofilm and lipid A biosynthesis were shared in Aci44 and Aci46. In Aci44, we identified a partial sequence of pmrB encoding a polymyxin resistant component PmrB, whereas a full length of pmrB was observed in Aci46. RNA-seq analyses of Aci44 revealed that panduratin A-colistin combination induced expression of ribosomal proteins and oxidative stress response proteins, whereas iron transporter and MFS-type transporter systems were suppressed. Panduratin A-colistin combination could promote intracellular reactive oxygen species (ROS) accumulation could lead to the cidal effect on colistin-resistant A. baumannii. Combination of panduratin A and colistin showed a significant increase in colistin efficacy against colistin- resistant A. baumannii in comparison of colistin alone. Genomic comparison between Aci44 and Aci46 showed mutations and SNPs that might affect different phenotypes. Additionally, based on RNA-Seq, panduratin A-colistin combination could lead to ROS production and accumulation. These findings confirmed the potency of panduratin as colistin adjuvant against multidrug resistant A. baumannii. [ABSTRACT FROM AUTHOR]

Background: Multiple randomized controlled studies have compared numerous antibiotic regimens, including new, recently commercialized antibiotics in the treatment of nosocomial pneumonia (NP). The objective of this Bayesian network meta-analysis (NMA) was to compare the efficacy and the safety of different antibiotic treatments for NP. Methods: We conducted a systematic search of PubMed, Medline, Web of Science, EMBASE and the Cochrane Library databases from 2000 through 2021. The study selection included studies comparing antibiotics targeting Gram-negative bacilli in the setting of NP. The primary endpoint was 28 day mortality. Secondary outcomes were clinical cure, microbiological cure and adverse events. Results: Sixteen studies encompassing 4993 patients were included in this analysis comparing 13 antibiotic regimens. The level of evidence for mortality comparisons ranged from very low to moderate. No significant difference in 28 day mortality was found among all beta-lactam regimens. Only the combination of meropenem plus aerosolized colistin was associated with a significant decrease of mortality compared to using intravenous colistin alone (OR = 0.43; 95% credible interval [0.17–0.94]), based on the results of the smallest trial included. The clinical failure rate of ceftazidime was higher than meropenem with (OR = 1.97; 95% CrI [1.19–3.45]) or without aerosolized colistin (OR = 1.40; 95% CrI [1.00–2.01]), imipemen/cilastatin/relebactam (OR = 1.74; 95% CrI [1.03–2.90]) and ceftazidime/avibactam (OR = 1.48; 95% CrI [1.02–2.20]). For microbiological cure, no substantial difference between regimens was found, but ceftolozane/tazobactam had the highest probability of being superior to comparators. In safety analyses, there was no significant difference between treatments for the occurrence of adverse events, but acute kidney failure was more common in patients receiving intravenous colistin. Conclusions: This network meta-analysis suggests that most antibiotic regimens, including new combinations and cefiderocol, have similar efficacy and safety in treating susceptible Gram-negative bacilli in NP. Further studies are necessary for NP caused by multidrug-resistant bacteria. Registration PROSPERO CRD42021226603 [ABSTRACT FROM AUTHOR]

Bacterial resistance surveillance is one of the main outputs of microbiological laboratories and its results are important part of antimicrobial stewardship (AMS). In this study, the susceptibility of specific bacteria to selected antimicrobial agents was tested. The susceptibility of 90 unique isolates of pathogens of critical priority obtained from clinically valid samples of ICU patients in 2017–2021 was tested. 50% of these fulfilled difficult-to-treat resistance (DTR) criteria and 50% were susceptible to all antibiotics included in the definition. 10 Enterobacterales strains met DTR criteria, and 2 (20%) were resistant to colistin (COL), 2 (20%) to cefiderocol (FCR), 7 (70%) to imipenem/cilastatin/relebactam (I/R), 3 (30%) to ceftazidime/avibactam (CAT) and 5 (50%) to fosfomycin (FOS). For Enterobacterales we also tested aztreonam/avibactam (AZA) for which there are no breakpoints yet. The highest MIC of AZA observed was 1 mg/l, MIC range in the susceptible cohort was 0.032–0.064 mg/l and in the DTR cohort (incl. class B beta-lactamase producers) it was 0.064–1 mg/l. Two (13.3%) isolates of Pseudomonas aeruginosa (15 DTR strains) were resistant to COL, 1 (6.7%) to FCR, 13 (86.7%) to I/R, 5 (33.3%) to CAT, and 5 (33.3%) to ceftolozane/tazobactam. All isolates of Acinetobacter baumannii with DTR were susceptible to COL and FCR, and at the same time resistant to I/R and ampicillin/sulbactam. New antimicrobial agents are not 100% effective against DTR. Therefore, it is necessary to perform susceptibility testing of these antibiotics, use the data for surveillance (including local surveillance) and conform to AMS standards. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii is an opportunistic pathogen that is responsible for nosocomial infections. Imipenem and colistin are drugs that are commonly used to treat severe infections caused by A. baumannii, such as sepsis, ventilator-associated pneumonia, and bacteremia. However, some strains of A. baumannii have become resistant to these drugs, which is a concern for public health. Biofilms produced by A. baumannii increase their resistance to antibiotics and the cells within the inner layers of biofilm are exposed to sub-inhibitory concentrations (sub-MICs) of antibiotics. There is limited information available regarding how the genes of A. baumannii are linked to biofilm formation when the bacteria are exposed to sub-MICs of imipenem and colistin. Thus, this study’s objective was to explore this relationship by examining the genes involved in biofilm formation in A. baumannii when exposed to low levels of imipenem and colistin. The study found that exposing an isolate of A. baumannii to low levels of these drugs caused changes in their drug susceptibility pattern. The relative gene expression profiles of the biofilm-associated genes exhibited a change in their expression profile during short-term and long-term exposure. This study highlights the potential consequences of overuse and misuse of antibiotics, which can help bacteria become resistant to these drugs. [ABSTRACT FROM AUTHOR]

Introduction: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections commonly cause hospital-acquired infections. The study aimed to compare the outcomes of CRKP infections between patients receiving ceftazidime avibactam +/− aztreonam and polymyxins in a hospital setting with a high prevalence of New Delhi Metallo Beta Lactamase production. Methods: We conducted a retrospective cohort study from January 2020 to September 2022 in critically ill adult patients admitted to a non-COVID-19 medical intensive care unit with CRKP infection. The patients were followed up for a total of 30 days or death, whichever was later. Results: Of a total of 106 patients included in the study, 65 patients received polymyxins and 41 patients received ceftazidime–avibactam +/− aztreonam. Higher 30-day mortality was noted in the polymyxin group (56.9% vs. 29.2%, P = 0.005). The mean time to event (mortality) in ceftazidime–avibactam +/− aztreonam was 23.9 + 1.5 days which was significantly higher compared to polymyxins (17.9 + 1.2 days, p = 0.006). On Cox regression analysis, after adjusting for the covariates, the hazard ratio for time to event with the use of polymyxin was 2.02 (95% CI: 1.03–3.9). Conclusion: Ceftazidime–avibactam + aztreonam is possibly associated with better clinical outcomes in patients infected with CRKP. [ABSTRACT FROM AUTHOR]

Colistin remains one of the last-resort therapies for combating infections caused by multidrug-resistant (MDR) Enterobacterales, despite its adverse nephro- and neuro-toxic effects. This study elucidates the mechanism of action of a non-antibiotic 4-anilinoquinazoline-based compound that synergistically enhances the effectiveness of colistin against Salmonella enterica. The quinazoline sensitizes Salmonella by deactivating intrinsic, mutational, and transferable resistance mechanisms that enable Salmonella to counteract the antibiotic impact colistin, together with an induced disruption to the electrochemical balance of the bacterial membrane. The attenuation of colistin resistance via the combined treatment approach also proves efficacious against E. coli, Klebsiella, and Acinetobacter strains. The dual therapy reduces the mortality of Galleria mellonella larvae undergoing a systemic Salmonella infection when compared to individual drug treatments. Overall, our findings unveil the potential of the quinazoline-colistin combined therapy as an innovative strategy against MDR bacteria. [ABSTRACT FROM AUTHOR]

Respiratory tract infections caused by multi-drug-resistant (MDR) bacteria have been a severe risk to human health. Colistin is often used to treat the MDR Gram-negative bacterial infections as a last-line therapy. Inhaled colistin can achieve a high concentration in the lung but none of aerosolized colistin products has been approved in the USA. Liposome has been reported as an advantageous formulation strategy for antibiotics due to its controlled release profile and biocompatibility. We have developed colistin liposomal formulations in our previous study. In the present study, the cellular uptake and transport of colistin in colistin liposomes were examined in two human lung epithelium in vitro models, Calu-3 monolayer and EpiAirway 3D tissue models. In both models, cellular uptake (p < 0.05) and cellular transport (p < 0.01) of colistin were significantly reduced by the colistin liposome compared to the colistin solution. Our findings indicate that inhaled colistin liposomes could be a promising treatment for extracellular bacterial lung infections caused by MDR Pseudomonas aeruginosa (P. aeruginosa). [ABSTRACT FROM AUTHOR]

This article highlights a label-free point-of-care detection of colistin (Polymyxin B) with modified immunosensor in chicken eggs. The manufacturing of screen-printed gold electrodes (Au-SPEs) is claimed to improve the sensor's sensitivity and point-of-care diagnostics, outperforming the outputs in terms of time and accuracy. The sensor attached a specific colistin antibody to a conventional Au-SPE that had been polyethyleneimine (PEI) modified by a carbodiimide-mediated amide coupling procedure. Using cyclic voltammetry (CV) and (K3Fe (CN)6)− as a redox probe during each stage of fabrication, this immunosensor captured the electrochemical changes in the sample laced with colistin. Characterization of Au-SPEs was done with AFM for surface morphology and topographic data and FTIR for the functional group confirmation. Limit of Detection (LOD) of 1.539 µg/kg of egg with high specificity toward antigen against other antibiotics was observed. Therefore, the proposed immunosensor based on Au-SPEs has potential applicability for early detection of colistin which could be a promising tool for its rapid detection. [ABSTRACT FROM AUTHOR]

Objective: To establish a high-performance liquid chromatography–tandem mass spectrometry method (HPLC–MS/MS) to simultaneously determine colistin sulfate and tigecycline in human plasma. Methods: Polymyxin B1 internal standard (20 µL) was added into 200 µL of plasma sample. The samples were treated with methanol-5% trichloroacetic acid (50:50, V/V) solution, and the protein precipitation method was adopted for post-injection analysis. The chromatographic column was a Dikma C18 (4.6 mm × 150 mm, 5 μm). For the mobile phase, 0.1% formic acid in aqueous solution was used for phase A, 0.1% formic acid in acetonitrile solution for phase B, and gradient elution was also applied. The flow rate was 0.8 mL/min, the column temperature was 40 °C, and the injection volume was 10 µL; Electrospray ionization and multiple reaction ion monitoring were adopted and scanned by the HPLC–MS/MS positive ion mode. Results: The endogenous impurities in the plasma had no interference in the determination of the analytes. There existed a good linear relationship of colistin sulfate within the range of 0.1–10 µg/mL (R2 = 0.9986), with the lower limit of quantification (LLOQ) of 0.1 µg/mL. There existed a good linear relationship of tigecycline within the range of 0.05–5 µg/ mL (R2 = 0.9987), with the LLOQ of 0.05 µg/mL. The intra- and inter-day relative standard deviations of colistin sulfate and tigecycline were both less than 15%, and the accuracy was between 88.21% and 108.24%. The extraction had good stability, the extraction recovery rate was 87.75–91.22%, and the matrix effect was 99.40–105.26%. Conclusion: This study successfully established a method for simultaneously detecting colistin sulfate and tigecycline plasma concentrations. The method was simple, rapid, and highly sensitive and could be applied for therapeutic medication monitoring. [ABSTRACT FROM AUTHOR]

Introduction: Carbapenem-resistant organisms (CRO) have emerged as a significant worldwide issue. However, the availability of efficacious antibiotics for treating CRO infections remains limited. Polymyxins, including colistin sulfate, represent the last-line therapeutic option against CRO infections. This study aims to retrospectively evaluate the clinical effectiveness and safety of colistin sulfate in managing CRO infections among patients with hematological diseases. Methods: Between April 2022 and January 2023, a total of 118 hematological patients diagnosed with CRO infection were treated with colistin sulfate at Suzhou Hongci Hospital of Hematology. The assessment encompassed the clinical efficacy, bacterial clearance rate, adverse reactions, and 30-day all-cause mortality. Results: The study found that the total effective rate of colistin sulfate in the treatment of CRO infection was 74.6%, with a bacterial clearance rate of 72.6%. Throughout the treatment, nephrotoxicity occurred in 7.6% of cases, neurotoxicity in 2.5% of cases, and the 30-day all-cause mortality rate was 22.9%. Multivariate logistic analysis revealed that the treatment course and combination medication with other antimicrobials were independent factors affecting the clinical efficacy of colistin sulfate. Conclusion: Our study demonstrates that the treatment of colistin sulfate can achieve high clinical efficacy and microbial responses, with a low risk of nephrotoxicity. This study provides evidence of the positive clinical efficacy and safety of colistin sulfate treatment in these patients. High-quality randomized controlled trials are still needed to further confirm the beneficial role of colistin sulfate. [ABSTRACT FROM AUTHOR]

The dosage of colistin for the treatment of enteric E. coli in animals necessitates considering the heteroresistant (HR) nature of the targeted inoculum, described by the presence of a major susceptible population (S1, representing 99.95% of total population) mixed with an initial minor subpopulation of less susceptible bacteria (S2). Herein, we report the 1-compartment population pharmacokinetics (PK) of colistin in chicken intestine (jejunum and ileum) and combined it with a previously established pharmacodynamic (PD) model of HR in E. coli. We then computed probabilities of target attainment (PTA) with a pharmacodynamic target (AUC24h/MIC) that achieves 50% of the maximal kill of bacterial populations (considering inoculums of pure S1, S2 or HR mixture of S1 + S2). For an MIC of 1 mg/L, PTA > 95% was achieved with the registered dose (75,000 IU/kg BW/day in drinking water) for the HR mixture of S1 + S2 E. coli, whether they harboured mcr or not. For an MIC of 2 mg/L (ECOFF), we predicted PTA > 90% against the dominant susceptible sub-population (S1) with this clinical dose given (i) over 24 h for mcr-negative isolates or (ii) over 6 h for mcr-positive isolates (pulse dosing). Colistin clinical breakpoint S ≤ 2 mg/L (EUCAST rules) should be confirmed clinically. [ABSTRACT FROM AUTHOR]

Due to the wide use of antibiotics, intensive aquaculture farms have been recognized as a significant reservoir of antibiotic resistomes. Although the prevalence of colistin resistance genes and multidrug-resistant bacteria (MDRB) has been documented, empirical evidence for the transmission of colistin and multidrug resistance between bacterial communities in aquaculture farms through horizontal gene transfer (HGT) is lacking. Here, we report the prevalence and transmission risk of colistin and multidrug resistance in 27 aquaculture water samples from 9 aquaculture zones from over 5000 km of subtropical coastlines in southern China. The colistin resistance gene mcr−1, mobile genetic element (MGE) intl1 and 13 typical antibiotic resistance genes (ARGs) were prevalent in all the aquaculture water samples. Most types of antibiotic (especially colistin) resistance are transmissible in bacterial communities based on evidence from laboratory conjugation and transformation experiments. Diverse MDRB were detected in most of the aquaculture water samples, and a strain with high-level colistin resistance, named Ralstonia pickettii MCR, was isolated. The risk of horizontal transfer of the colistin resistance of R. pickettii MCR through conjugation and transformation was low, but the colistin resistance could be steadily transmitted to offspring through vertical transfer. The findings have important implications for the future regulation of antibiotic use in aquaculture farms globally to address the growing threat posed by antibiotic resistance to human health. [ABSTRACT FROM AUTHOR]

Introduction: This study examines the role of mesenchymal stem cells (MSCs) in an experimental sepsis model developed with colistin-resistant Acinetobacter baumannii (CRAB). Materials and methods: BALB-c mice were divided into treatment groups (MSC, MSC + colistin (C)-fosfomycin (F), and C-F and control groups (positive and negative)). CRAB was administered to mice through intraperitoneal injection. Three hours later, C, F, and MSC were given intraperitoneally to the treatment groups. Colistin administration was repeated every 12 h, F administration was done every 4 h, and the second dose of MSC was administered after 48 h. Mice were sacrificed at 24 and 72 h. The bacterial load was determined as colony-forming units per gram (cfu/g). Histopathological examination was conducted on the left lung, liver, and both kidneys. IL-6 and C-reactive protein (CRP) levels in mouse sera were determined by enzyme-linked immunosorbent assay. Results: Among the treatment groups, the C-F group had the lowest colony count in the lung (1.24 ± 1.66 cfu/g) and liver (1.03 ± 1.08 cfu/g). The highest bacterial clearance was observed at 72 h compared to 24 h in the MSC-treated groups (p = 0.008). The MSC + C-F group showed the lowest histopathological score in the liver and kidney (p = 0.009). In the negative control group, the IL-6 level at the 24th hour was the lowest (p < 0.001). Among the treatment groups, the CRP level was the lowest in the MSC + C-F group at 24 and 72 h. Conclusion: In a CRAB sepsis model, adding MSCs to a colistin-fosfomycin treatment may be beneficial in terms of reducing bacterial loads and preventing histopathological damage. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) infection poses a severe threat to global public health due to its high mortality. Currently, polymyxins are mainly used for the treatment of Gram-negative bacterial-related infection, while exhibiting limited antibacterial activities against Staphylococcus aureus (S. aureus). However, the combination of antibiotics with antibiotic adjuvants is a feasible strategy for the hard-treated infection and toxicity reducing. We will investigate the antibacterial activity of simeprevir (SIM), which treated for genotype 1 and 4 chronic hepatitis C, combined with polymyxins against MRSA through high-throughput screening technology. In our study, the synergistic antibacterial effect of SIM and polymyxins against S. aureus in vitro was found by checkerboard assay and time-growth curve. The cytotoxicity of SIM combined with polymyxin B sulfate [PB(S)] or polymyxin E (PE) in vitro was evaluated using CCK-8, human RBC hemolysis and scratch assays. In addition, we investigated the eradication of biofilm formation of S. aureus by biofilm inhibition assay and the killing of persister cells. Moreover, we evaluated the therapeutic effect and in vivo toxicity of the combination against MRSA in murine subcutaneous abscess model. Furthermore, it was preliminarily found that SIM significantly enhanced the destruction of MRSA membrane by SYTOX Green and DISC3(5) probes. In summary, these results reveal that the therapy of SIM combined with polymyxins (especially PE) is promising for the treatment of MRSA infection. [ABSTRACT FROM AUTHOR]

Neurotoxicity and nephrotoxicity are the major dose-limiting factors for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the neurotoxic and nephrotoxic effects of colistin formulated with in-house synthesized sodium deoxycholate sulfate (SDCS) in a mouse model. Male mice C57BL/6 were randomly divided into four groups: control (saline solution), colistin (15 mg/kg/day), colistin:SDCS 1:1, and colistin:SDCS 1:2. In the colistin:SDCS treatment groups, the dosage was 15 mg/kg/day colistin equivalent; all mice were treated for 7 successive days. The thermal tolerance, body weight gain and organ weights were measured. The levels of serum blood urea nitrogen (BUN), creatinine (Cr), superoxide dismutase (SOD), and catalase (CAT) were assessed. Histopathological damages were assessed on mice organ. The colistin:SDCS formulations significantly improved thermal pain response of the mice comparable to the control group. The administration did not impair kidney function as evidence from BUN and Cr results; however, the oxidative stress biomarkers decreased in the colistin and colistin-SDCS treated mice. Several abnormalities were observed in the kidney, liver, spleen, and sciatic nerve tissues following colistin treatment, which indicated evidence of toxicity. The colistin-SDCS formulations were associated with less acute toxicity and fewer nephrotoxic and neurotoxic changes compared with the colistin alone group which indicated that SDCS attenuated colistin nephrotoxicity and neurotoxicity. This study highlights the potential application of colistin formulated with SDCS for safer clinical use against MDR Gram-negative bacteria. [ABSTRACT FROM AUTHOR]

Purpose of Review: Antimicrobial resistance continues to increase throughout the world, with the impact on critically ill children in low- and middle-income paediatric intensive care units largely unknown. Recent Findings: There has been a global shift indicating a predominance of Gram-negative bacilli among multidrug-resistant isolates. A 4-year review (2019 to 2022) found a progressive and substantial increase in the incidence of carbapenem-resistant Klebsiella pneumoniae (29% to 51%) alongside high levels of carbapenem-resistant Acinetobacter baumannii (93%) within the paediatric intensive care unit at the Chris Hani Baragwanath Academic Hospital in South Africa. The pharmacological treatment of these infections relies heavily on the continued use of carbapenems, often in combination with colistin. Summary: The burden of antimicrobial resistance is disproportionately borne, particularly within sub-Saharan Africa and South Asia. The resource-constrained South African public healthcare system, already significantly burdened by both HIV and TB, continues to face several challenges in combating the growth in antimicrobial resistance. Limited access, largely driven by prohibitive costs, to sophisticated laboratory techniques and newer pharmacological agents, leaves the implementation of effective infection prevention and control and antimicrobial stewardship programmes as the most pragmatic options to address the problem. [ABSTRACT FROM AUTHOR]

The single-component colistin E2, with superior antibacterial activity and lower toxicity, was being developed as the latest generation of polymyxin drugs. However, colistin E2 has not been tested quantitatively in biological matrices. In this study, based on the quantitative detection of colistin methanesulphonate (CMS) and colistin by Zhao et al., 15N-labeled colistin E2 was used as an internal standard (IS) for a more accurate quantitative detection of CMS E2 in human plasma. A rapid ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC–MS/MS) assay method was developed for determination of CMS E2 and colistin E2 in human plasma. After pretreatment of plasma samples by 96-well SPE Supra-Clean Weak Cation Exchange (WCX) plate, the formed colistin E2 was detected and quantified by UHPLC–MS/MS system. All plasma lots were found to be free of interferences with the analyte. The matrix has no effect on the quantitation of the analyte. No significant effect of the carryover was observed. The dilution integrity was demonstrated in plasma samples without the loss of accuracy and precision. The lower limit of quantification (LLOQ) was 0.0300 mg/L for colistin E2 in plasma with accuracy (relative error, 5.1–12.7%) and precision (relative standard deviation, − 5.7–9.3%). Stability of CMS E2 and colistin E2 was demonstrated in biological samples before and during sample treatment, and in the extract. Furthermore, this method was successfully applied to the analysis of plasma samples obtained from Chinese healthy volunteers receiving a single intravenous CMS E2 dose of 5 mg/kg. In conclusion, the detection method was characterized by speed and high accuracy, which laid a solid foundation for the subsequent development of CMS E2 drug. [ABSTRACT FROM AUTHOR]

Owing to the emergence of antibiotic resistance, the polymyxin colistin has been recently revived to treat acute, multidrug-resistant Gram-negative bacterial infections. Positively charged colistin binds to negatively charged lipids and damages the outer membrane of Gram-negative bacteria. However, the MCR-1 protein, encoded by the mobile colistin resistance (mcr) gene, is involved in bacterial colistin resistance by catalysing phosphoethanolamine (PEA) transfer onto lipid A, neutralising its negative charge, and thereby reducing its interaction with colistin. Our preliminary results showed that treatment with a reference pyrazolone compound significantly reduced colistin minimal inhibitory concentrations in Escherichia coli expressing mcr-1 mediated colistin resistance (Hanpaibool et al. in ACS Omega, 2023). A docking-MD combination was used in an ensemble-based docking approach to identify further pyrazolone compounds as candidate MCR-1 inhibitors. Docking simulations revealed that 13/28 of the pyrazolone compounds tested are predicted to have lower binding free energies than the reference compound. Four of these were chosen for in vitro testing, with the results demonstrating that all the compounds tested could lower colistin MICs in an E. coli strain carrying the mcr-1 gene. Docking of pyrazolones into the MCR-1 active site reveals residues that are implicated in ligand–protein interactions, particularly E246, T285, H395, H466, and H478, which are located in the MCR-1 active site and which participate in interactions with MCR-1 in ≥ 8/10 of the lowest energy complexes. This study establishes pyrazolone-induced colistin susceptibility in E. coli carrying the mcr-1 gene, providing a method for the development of novel treatments against colistin-resistant bacteria. [ABSTRACT FROM AUTHOR]

Multi-drug resistance poses a serious threat to the public health worldwide. The situation becomes worse when multidrug-resistant bacteria develop resistance against last resort antibiotics such as colistin attributed to plasmid-borne mcr genes. Humans and non-human animals including pigs and chickens are the main reservoirs of these mcr genes harboring bacteria which have now disseminated globally, thus, causing difficulties in treating bacterial infections. Several mcr-gene-containing bacterial (MGCB) species have been found in diverse ecosystems, including aquatic, soil, botanical, wildlife, animal, and public environments. Environmental samples have shown to contain the mcr-1, mcr-2, mcr-3, mcr-5, mcr-7, and mcr-8 genes variants. The genes are found in Escherichia coli, Enterobacter, Klebsiella, Proteus, Salmonella, Citrobacter, Pseudomonas, Acinetobacter, Kluyvera, Aeromonas, Providencia, and Raulotella isolates. The routes of transmission of MGCB are contact with reservoirs that contain mcr, consumption of contaminated animal-/plant-based foods or water, trade and travel that involve animal-/plant-based foods. An updated and precise estimation of prevelance as well as mechanism of colistin resistance mediated by mcr genes is inevitable to regulate the spread of colistin resistance by implementing effective strategies. Hence, this review presents a comprehensive overview of epidemiology and the various mechanisms of colistin resistance that are currently not clearly understood. [ABSTRACT FROM AUTHOR]

Purpose: Although the proportion of immunocompromised patients admitted to the ICU is increasing, data regarding specific management, including acquired infection (ICU-AI) prophylaxis, in this setting are lacking. We aim to investigate the effect of multiple-site decontamination regimens (MSD) in immunocompromised patients. Methods: We conducted a prospective pre-/post-observational study in 2 ICUs in Bretagne, western France. Adults who required mechanical ventilation for 24 h or more were eligible. During the study period, MSD was implemented in participating ICUs in addition to standard care. It consists of the administration of topical antibiotics (gentamicin, colistin sulfate, and amphotericin B), four times daily in the oropharynx and the gastric tube, 4% chlorhexidine bodywash once daily, and a 5-day nasal mupirocin course. Results: Overall, 295 immunocompromised patients were available for analysis (151 in the post-implementation group vs 143 in the pre-implementation group). Solid organ cancer was present in 77/295 patients while immunomodulatory treatments were noticed in 135/295. They were 35 ICU-AI in 29/143 patients in the standard-care group as compared with 10 ICU-AI in 9/151 patients in the post-implementation group (p < 0.001). In a multivariable Poisson regression model, MSD was independently associated with a decreased incidence of ICU-AI (incidence rate ratio = 0.39; 95%CI [0.20–0.87] p = 0.008). There were 35/143 deaths in the standard-care group as compared with 22/151 in the post-implementation group (p = 0.046), this difference remained in a multivariable Cox model (HR = 0.58; 95CI [0.34–0.95] p = 0.048). Conclusion: In conclusion, MSD appeared to be associated with improved outcomes in critically ill immunocompromised patients. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii is a Gram-negative priority pathogen that can readily overcome antibiotic treatment through a range of intrinsic and acquired resistance mechanisms. Treatment of carbapenem-resistant A. baumannii largely relies on the use of colistin in cases where other treatment options have been exhausted. However, the emergence of resistance against this last-line drug has significantly increased amongst clinical strains. In this study, we identify the phytochemical kaempferol as a potentiator of colistin activity. When administered singularly, kaempferol has no effect on growth but does impact biofilm formation. Nonetheless, co-administration of kaempferol with sub-inhibitory concentrations of colistin exposes bacteria to a metabolic Achilles heel, whereby kaempferol-induced dysregulation of iron homeostasis leads to bacterial killing. We demonstrate that this effect is due to the disruption of Fenton's reaction, and therefore to a lethal build-up of toxic reactive oxygen species in the cell. Furthermore, we show that this vulnerability can be exploited to overcome both intrinsic and acquired colistin resistance in clinical strains of A. baumannii and E. coli in vitro and in the Galleria mellonella model of infection. Overall, our findings provide a proof-of-principle demonstration that targeting iron homeostasis is a promising strategy for enhancing the efficacy of colistin and overcoming colistin-resistant infections. The phytochemical kaempferol reduces the minimum inhibitory concentration of colistin against the pathogen Acinetobacter baumannii by dysregulating iron homeostasis, which in turn causes a lethal accumulation of reactive oxygen species in cells. [ABSTRACT FROM AUTHOR]

Due to multi-drug resistance, physicians increasingly use the last-resort antibiotic colistin to treat infections with the Gram-negative bacterium Klebsiella pneumoniae. Unfortunately, K. pneumoniae can also develop colistin resistance. Interestingly, colistin resistance has dual effects on bacterial clearance by the immune system. While it increases resistance to antimicrobial peptides, colistin resistance has been reported to sensitize certain bacteria for killing by human serum. Here we investigate the mechanisms underlying this increased serum sensitivity, focusing on human complement which kills Gram-negatives via membrane attack complex (MAC) pores. Using in vitro evolved colistin resistant strains and a fluorescent MAC-mediated permeabilization assay, we showed that two of the three tested colistin resistant strains, Kp209_CSTR and Kp257_CSTR, were sensitized to MAC. Transcriptomic and mechanistic analyses focusing on Kp209_CSTR revealed that a mutation in the phoQ gene locked PhoQ in an active state, making Kp209_CSTR colistin resistant and MAC sensitive. Detailed immunological assays showed that complement activation on Kp209_CSTR in human serum required specific IgM antibodies that bound Kp209_CSTR but did not recognize the wild-type strain. Together, our results show that developing colistin resistance affected recognition of Kp209_CSTR and its killing by the immune system. [ABSTRACT FROM AUTHOR]

Introduction: Bloodstream infections (BSI) caused by carbapenem-resistant Acinetobacter baumannii (CRAB) are associated with high mortality with limited treatment. The aim of this study is to compare effectiveness and safety of colistin-based versus cefiderocol-based therapies for CRAB-BSI. Methods: This is a retrospective observational study enrolling patients with monomicrobial CRAB-BSIs treated with colistin or cefiderocol from 1 January 2020, to 31 December 2022. The 30-day all-cause mortality rate was the primary outcome. A Cox regression analysis was performed to identify factors independently associated with mortality. A propensity score analysis using inverse probability of treatment weighting (IPTW) was also performed. Results: Overall 118 patients were enrolled, 75 (63%) and 43 (37%) treated with colistin- and cefiderocol-based regimens. The median (q1–q3) age was 70 (62–79) years; 70 (59%) patients were men. The 30-day all-cause mortality was 52%, significantly lower in the cefiderocol group (40% vs 59%, p = 0.045). By performing a Cox regression model, age (aHR = 1.03, 95% CI 1.00–1.05), septic shock (aHR = 1.93, 95% CI 1.05–3.53), and delayed targeted therapy (aHR = 2.42, 95% CI 1.11–5.25) were independent predictors of mortality, while cefiderocol-based therapy was protective (aHR = 0.49, 95% CI 0.25–0.93). The IPTW-adjusted Cox analysis confirmed the protective effect of cefiderocol (aHR = 0.53, 95% CI 0.27–0.98). Conclusions: Cefiderocol may be a valuable treatment option for CRAB-BSI, especially in the current context of limited treatment options. [ABSTRACT FROM AUTHOR]

Metallo-β-lactamases (MBL) are a threat to public health, since they dramatically limit the use of β-lactams. We report the isolation of a multidrug-resistant Hafnia paralvei strain from urine and a rectal swab of a female patient after allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome. Antimicrobial susceptibility testing yielded resistance to trimethoprim/sulfamethoxazole, colistin, fosfomycin and all β-lactams, except cefiderocol. Whole genome sequencing revealed the presence of plasmid-encoded NDM-1 and VIM-1 carbapenemases. This finding highlights the importance of epidemiological surveillance and new therapeutic options for MBL. [ABSTRACT FROM AUTHOR]

Carbapenemases-producing K. pneumoniae are challenging antimicrobial therapy of hospitalised patients, which is further complicated by colistin resistance. The aim of this study was to investigate the molecular epidemiological insights into carbapenemases-producing and colistin-resistant clinical K. pneumoniaeA total of 162 colistin resistant clinical strains of K. pneumoniae were collected during 2017–2019. Antimicrobial susceptibility and the colistin minimum inhibitory concentration were determined. Using PCR assay, the prevalence of resistance-associated genes including blaKPC, blaIMP, blaVIM, blaOXA-48, blaNDM-1 and mcr-1 to -9 was examined. Additionally, a PCR assay was used to examine the mgrB gene in colistin-resistant bacteria. 94.4% of the tested strains were resistant to imipenem and 96.3% were resistant to meropenem. Colistin resistance (MIC > 4 µg/L) was observed in 161 isolates (99.4%) by Colistin Broth Disk Elution method. The KPC enzyme was the most common carbapenemase and was identified in 95 strains (58.6%), followed by the IMP, VIM and OXA-48 detected in 47 (29%), 23 (14.2%) and 12 (7.4%) isolates, respectively. However, no NDM-1 gene was detected. Additionally, none of the studied isolates harbored mcr variants, while mgrB gene was observed in 152 (92.6%) isolates. Colistin resistance of K. pneumoniae isolates may be associated with mgrB gene mutation. To stop the spread of resistant K. pneumoniae, surveillance must be improved, infection prevention protocols must be followed, and antibiotic stewardship must be practised. [ABSTRACT FROM AUTHOR]

Resistance of Acinetobacter baumannii to multiple clinically important antimicrobials has increased to very high rates in Greece, rendering most of them obsolete. The aim of this study was to determine the molecular epidemiology and susceptibilities of A. baumannii isolates collected from different hospitals across Greece. Single-patient A. baumannii strains isolated from blood cultures (n = 271), from 19 hospitals, in a 6-month period (November 2020–April 2021) were subjected to minimum inhibitory concentration determination and molecular testing for carbapenemase, 16S rRNA methyltransferase and mcr gene detection and epidemiological evaluation. 98.9% of all isolates produced carbapenemase OXA-23. The vast majority (91.8%) of OXA-23 producers harbored the armA and were assigned mainly (94.3%) to sequence group G1, corresponding to IC II. Apramycin (EBL-1003) was the most active agent inhibiting 100% of the isolates at ≤16 mg/L, followed by cefiderocol which was active against at least 86% of them. Minocycline, colistin and ampicillin-sulbactam exhibited only sparse activity (S <19%), while eravacycline was 8- and 2-fold more active than minocycline and tigecycline respectively, by comparison of their MIC50/90 values. OXA-23-ArmA producing A. baumannii of international clone II appears to be the prevailing epidemiological type of this organism in Greece. Cefiderocol could provide a useful alternative for difficult to treat Gram-negative infections, while apramycin (EBL-1003), the structurally unique aminoglycoside currently in clinical development, may represent a highly promising agent against multi-drug resistant A. baumanni infections, due to its high susceptibility rates and low toxicity. [ABSTRACT FROM AUTHOR]

Purpose: Colistin is an antibiotic which is increasingly used as a last-resort therapy in critically-ill patients with multidrug resistant Gram-negative infections. The purpose of this study was to evaluate the mechanisms underlying colistin's pharmacokinetic (PK) behavior and to characterize its hepatic metabolism. Methods: In vitro incubations were performed using colistin sulfate with rat liver microsomes (RLM) and with rat and human hepatocytes (RH and HH) in suspension. The uptake of colistin in RH/HH and thefraction of unbound colistin in HH (fu,hep) was determined. In vitro to in vivo extrapolation (IVIVE) was employed to predict the hepatic clearance (CLh) of colistin. Results: Slow metabolism was detected in RH/HH, with intrinsic clearance (CLint) values of 9.34± 0.50 and 3.25 ± 0.27 mL/min/kg, respectively. Assuming the well-stirred model for hepatic drug elimination, the predicted rat CLh was 3.64± 0.22 mL/min/kg which could explain almost 70% of the reported non-renal in vivo clearance. The predicted human CLh was 91.5 ± 8.83 mL/min, which was within two-fold of the reported plasma clearance in healthy volunteers. When colistin was incubated together with the multidrug resistance-associated protein (MRP/Mrp) inhibitor benzbromarone, the intracellular accumulation of colistin in RH/HH increased significantly. Conclusion: These findings indicate the major role of hepatic metabolism in the non-renal clearance of colistin, while MRP/Mrp-mediated efflux is involved in the hepatic disposition of colistin. Our data provide detailed quantitative insights into the hereto unknown mechanisms responsible for non-renal elimination of colistin. [ABSTRACT FROM AUTHOR]

Colistin is a last resort drug for the treatment of multiple drug-resistant (MDR) Gram-negative bacterial infections. Rapid methods to detect resistance are highly desirable. Here, we evaluated the performance of a commercially available MALDI-TOF MS-based assay for colistin resistance testing in Escherichia coli at two different sites. Ninety clinical E. coli isolates were provided by France and tested in Germany and UK using a MALDI-TOF MS-based colistin resistance assay. Lipid A molecules of the bacterial cell membrane were extracted using the MBT Lipid Xtract Kit™ (RUO; Bruker Daltonics, Germany). Spectra acquisition and evaluation were performed by the MBT HT LipidART Module of MBT Compass HT (RUO; Bruker Daltonics) on a MALDI Biotyper® sirius system (Bruker Daltonics) in negative ion mode. Phenotypic colistin resistance was determined by broth microdilution (MICRONAUT MIC-Strip Colistin, Bruker Daltonics) and used as a reference. Comparing the results of the MALDI-TOF MS-based colistin resistance assay with the data of the phenotypic reference method for the UK, sensitivity and specificity for the detection of colistin resistance were 97.1% (33/34) and 96.4% (53/55), respectively. Germany showed 97.1% (33/34) sensitivity and 100% (55/55) specificity for the detection of colistin resistance by MALDI-TOF MS. Applying the MBT Lipid Xtract™ Kit in combination with MALDI-TOF MS and dedicated software showed excellent performances for E. coli. Analytical and clinical validation studies must be performed to demonstrate the performance of the method as a diagnostic tool. [ABSTRACT FROM AUTHOR]

Multidrug-resistant bacteria are emerging as a major global threat to public health. Bacteriophages are an important source of antimicrobial enzymes and could be developed as an alternative antibiotic candidate. This study investigates the antibacterial capacity of the endolysin LysE against Aeromonas hydrophila. The endolysin LysE gene was cloned and expressed in Escherichia coli BL21 (DE3) cells. Purified recombinant LysE protein was tested for its antimicrobial activity against A. hydrophila. The study reveals that recombinant LysE protein was highly effective against Gram-negative bacteria when combined with antimicrobials that alter the permeability of the outer membrane. Specifically, the enzyme had the highest muralytic activity at pH 4, and maintained over 50% of the activity at pH 10. Moreover, endolysin displayed more than 50% activity even after 30 min of incubation at 100 °C. Also, endolysin LysE resulted in one log reduction in CFU/mL in 30 min and demonstrated antibiofilm capabilities when combined with EDTA. Interestingly, checkerboard assay showed its synergistic effects in combination with lower concentrations of colistin against A. hydrophila. Additionally, in vitro tests with Channa striatus kidney (CSK) cell lines do not show cytotoxic effects. Taken together, these findings suggest that LysE can be employed with outer membrane permeabilizers to expand the arsenal repertoire against Gram-negative bacteria in the aquaculture, food, and medical industries. [ABSTRACT FROM AUTHOR]

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Phage lytic enzymes are promising antimicrobial agents. In this study, an endolysin derived from vB_AbaM_PhT2 (vPhT2), was identified. This endolysin represented the conserved lysozyme domain. Recombinant endolysin (lysAB- vT2) and hydrophobic fusion endolysin (lysAB-vT2-fusion) were expressed and purified. Both endolysins showed lytic activity against bacterial crude cell wall of Gram-negative bacteria. The MIC of lysAB-vT2-fusion was 2 mg/ml corresponding to 100 µM, while the MIC of lysAB-vT2 was more than 10 mg/ml (400 µM). Combination of lysAB-vT2-fusion with colistin, polymyxin B or copper was synergistic against A. baumannii (FICI value as 0.25). Antibacterial activity of lysAB-vT2-fusion plus colistin at the fractional inhibitory concentrations (FICs) revealed that it can inhibit Escherichia coli, Klebsiella pneumoniae and various strains of extremely drug-resistant A. baumannii (XDRAB) and phage resistant A. baumannii. The lysAB- vT2-fusion still retained its antibacterial activity after incubating the enzyme at 4, 20, 40 and 60 °C for 30 min. The lysAB-vT2-fusion could inhibit the mature biofilm, and incubation of lysAB-vT2-fusion with T24 human cells infected with A. baumannii led to a partial reduction of LDH release from T24 cells. In summary, our study highlights the antimicrobial ability of engineered lysAB-vT2-fusion endolysin, which can be applied for the control of A. baumannii infection. [ABSTRACT FROM AUTHOR]

S. 4,[5],12:i:-, a monophasic variant of S. enterica serovar Typhimurium, is an important multidrug resistant serovar. Strains of colistin-resistant S. 4,[5],12:i:- have been reported in several countries with patients occasionally had recent histories of travels to Southeast Asia. In the study herein, we investigated the genomes of S. 4,[5],12:i:- carrying mobile colistin resistance (mcr) gene in Thailand. Three isolates of mcr-3.1 carrying S. 4,[5],12:i:- in Thailand were sequenced by both Illumina and Oxford Nanopore platforms and we analyzed the sequences together with the whole genome sequences of other mcr-3 carrying S. 4,[5],12:i:- isolates available in the NCBI Pathogen Detection database. Three hundred sixty-nine core genome SNVs were identified from 27 isolates, compared to the S. Typhimurium LT2 reference genome. A maximum-likelihood phylogenetic tree was constructed and revealed that the samples could be divided into three clades, which correlated with the profiles of fljAB-hin deletions and plasmids. A couple of isolates from Denmark had the genetic profiles similar to Thai isolates, and were from the patients who had traveled to Thailand. Complete genome assembly of the three isolates revealed the insertion of a copy of IS26 at the same site near iroB, suggesting that the insertion was an initial step for the deletions of fljAB-hin regions, the hallmark of the 4,[5],12:i:- serovar. Six types of plasmid replicons were identified with the majority being IncA/C. The coexistence of mcr-3.1 and blaCTX-M-55 was found in both hybrid-assembled IncA/C plasmids but not in IncHI2 plasmid. This study revealed possible transmission links between colistin resistant S. 4,[5],12:i:- isolates found in Thailand and Denmark and confirmed the important role of plasmids in transferring multidrug resistance. [ABSTRACT FROM AUTHOR]

Salmonella enterica serovar Kentucky is a frequent cause for clinical infections in human patients. They are isolated and reported with multidrug resistance from the foods of animal origin from various countries. However, studies inferring the colistin resistance are limited. Hence, the current study reports the genetic factors and genomic analysis of the colistin-resistant Salmonella enterica serovar Kentucky strain COL-R for better understanding of its pathogenic potential and phylogenetic relatedness. The S. Kentucky strain COL-R was successfully isolated from chicken meat during ongoing surveillance of food of animal origin. Antimicrobial susceptibility testing revealed resistance to cefoxitin, erythromycin, gentamicin, tetracycline, and most disturbingly to ciprofloxacin and colistin (broth microdilution method). Whole-genome sequence of the COL-R strain was subjected to various in silico analysis to identify the virulence factors, antimicrobial resistance genes, pathogenicity islands and sequence type. The S. Kentucky COL-R strain belonged to sequence type (ST) 198 with a high probability (0.943) of being a human pathogen. Besides presence of integrated phage in the S. Kentucky COL-R genome, 38 genes conferring resistance to various antimicrobials and disinfectants were also identified. Nucleotide Polymorphism analysis indicated triple mutations in gyrA and parC genes conferring fluoroquinolone resistance. Phylogenomic analysis with 31 other S. Kentucky genomes revealed discernible clusters with S. Kentucky COL-R strain latching onto a cluster of high diversity (geographic location and isolation sources). Taken together, our results document the first occurrence of colistin resistance in a fluoroquinolone resistant S. Kentucky COL-R strain isolated from retail chicken and provide crucial information on the genomic features of the strain. [ABSTRACT FROM AUTHOR]

Morganella morganii, a non-negligent opportunistic pathogen of the family Enterobacteriaceae, enlisted recently in the global priority pathogens by WHO for its swift propensity to acquire drug-resistant genes, engendering enhanced death rates. A combination of diverse antimicrobials could be recycled to overcome the ongoing acquisition of resistance mechanisms by M. morganii. Herein, we investigated the in vitro synergistic effect of colistin with meropenem, rifampicin, minocycline and linezolid against three intrinsic colistin-resistant M. morganii strains collected from critical departments of tertiary care hospitals. The strains were identified and tested for antimicrobial susceptibility by VITEK 2 automated system. The 16S rRNA sequencing was used to reconfirm the species identification. Minimum inhibitory concentrations (MICs) of colistin, meropenem, rifampicin, minocycline and linezolid were determined by the broth microdilution method. Synergistic interactions were studied by checkerboard and time-kill assay. The VITEK 2 identification and 16S rRNA sequencing confirmed that the strains were M. morganii. The automated antimicrobial susceptibility test revealed that all three isolates were multi-drug resistant. The checkerboard analysis demonstrated the synergy of all four combinations with FICI values ranging from 0.06 to 0.31 in all three isolates. These results suggest a potential role of meropenem as an adjuvant for treating M. morganii infections. The current work presented the first evidence of synergy between colistin and other antibiotics against M. morganii infection, which needs validation through in vitro and in vivo studies using a larger number of isolates. [ABSTRACT FROM AUTHOR]

In this study, genomic and plasmid characteristics of Escherichia coli were determined with the aim of deducing how mcr genes may have spread on a colistin withdrawn pig farm. Whole genome hybrid sequencing was applied to six mcr-positive E. coli (MCRPE) strains isolated from pigs, a farmworker and wastewater collected between 2017 and 2019. Among these, mcr-1.1 genes were identified on IncI2 plasmids from a pig and wastewater, and on IncX4 from the human isolate, whereas mcr-3 genes were found on plasmids IncFII and IncHI2 in two porcine strains. The MCRPE isolates exhibited genotypic and phenotypic multidrug resistance (MDR) traits as well as heavy metal and antiseptic resistance genes. The mcr-1.1-IncI2 and IncX4 plasmids carried only colistin resistance genes. Whereas, the mcr-3.5-IncHI2 plasmid presented MDR region, with several mobile genetic elements. Despite the MCRPE strains belonged to different E. coli lineages, mcr-carrying plasmids with high similarities were found in isolates from pigs and wastewater recovered in different years. This study highlighted that several factors, including the resistomic profile of the host bacteria, co-selection via adjunct antibiotic resistance genes, antiseptics, and/or disinfectants, and plasmid-host fitness adaptation may encourage the maintenance of plasmids carrying mcr genes in E. coli. [ABSTRACT FROM AUTHOR]

Antimicrobial misuse is a worldwide issue, and antimicrobial resistance is considered the most challenging aspect of health care. It has been reported that as much as 30–50% of antimicrobials prescribed in hospitals are deemed unnecessary or inappropriate. Antibiotic stewardship programs (ASPs) include policies that apply continuous management of judicious anti-infectious treatment in the clinical setting. Therefore, the objectives of this study were to evaluate the effect of ASPs on antibiotic consumption, the costs of antibiotic expenditure, and the sensitivity of antimicrobials. A retrospective, quasi-experimental study was performed to assess the effect of ASP at An-Najah National University Hospital, a tertiary care hospital in the West Bank, Palestine, over a period of 20 months before and 17 months after the implementation of the ASP. Data on antibiotic consumption were reported monthly as days of therapy per 1000 patient-days and monthly costs (USD/1000 patient-days). A total of 2367 patients who received one or more of the targeted antibiotics (meropenem, colistin and tigecycline) during their hospital stay were included in the study. They have split into two groups: 1710 patients in the pre-ASP group, and 657 patients in the post ASP group. The most significant reduction in DOT per 1000 patient-days was seen with tigecycline, with a percentage of change of − 62.08%. Furthermore, the mean cost of the three antibiotics decreased significantly by 55.5% in the post-ASP phase compared to the pre-ASP phase. After the implementation of ASP, there was a statistically significant increase in susceptibility to meropenem, piperacillin and piperacillin/tazobactam with respect to Pseudomonas aeruginosa. However, changes in mortality rates were not statistically significant (p = 0.057). ASP positively reduced costs and antimicrobial consumption, with no statistically significant effect on the overall mortality rate. However, a long-term evaluation of the ASP's impact is needed to conclude its lasting impact on infection-related mortality and antimicrobial susceptibility pattern. [ABSTRACT FROM AUTHOR]

The emergence and rapid spread of the mobile colistin resistance gene mcr-1 among bacterial species and hosts significantly challenge the efficacy of "last-line" antibiotic colistin. Previously, we reported silver nitrate and auranofin serve as colistin adjuvants for combating mcr-1-positive bacteria. Herein, we uncovered more gold-based drugs and nanoparticles, and found that they exhibited varying degree of synergisms with colistin on killing mcr-1-positive bacteria. However, pre-activation of the drugs by either glutathione or N-acetyl cysteine, thus releasing and accumulating gold ions, is perquisite for their abilities to substitute zinc cofactor from MCR-1 enzyme. X-ray crystallography and biophysical studies further supported the proposed mechanism. This study not only provides basis for combining gold-based drugs and colistin for combating mcr-1-positive bacterial infections, but also undoubtedly opens a new horizon for metabolism details of gold-based drugs in overcoming antimicrobial resistance. [ABSTRACT FROM AUTHOR]

Antimicrobial susceptibility was determined for clinical gram-negative isolates from Czech Republic, Hungary, and Poland, where published data for ceftolozane/tazobactam (C/T) and imipenem/relebactam (IMI/REL) is scarce. C/T was active against 94.3% of Enterobacterales, 10–18% higher than the tested cephalosporins and piperacillin/tazobactam. IMI/REL was the most active tested agent against non-Morganellaceae Enterobacterales (99.7% susceptible). C/T was the most active among all studied agents except colistin against Pseudomonas aeruginosa (96.0% susceptible); susceptibility to IMI/REL was 90.7%. C/T maintained activity against 73.7–85.3% of β-lactam-resistant or multidrug-resistant P. aeruginosa subsets. C/T and IMI/REL could represent important treatment options for patients from these countries. [ABSTRACT FROM AUTHOR]

Infectious diseases are still the major issue not only due to antibiotic resistance but also causing deaths if not diagnosed at early-stages. Different approaches including nanosized drug delivery systems and theranostics are researched to overcome antibiotic resistance, decrease the side effects of antibiotics, improve the treatment response, and early diagnose. Therefore, in the present study, nanosized, radiolabeled with 99mTc, colistin encapsulated, neutral and cationic liposome formulations were prepared as the theranostic agent for Pseudomonas aeruginosa infections. Liposomes exhibited appropriate physicochemical properties thanks to their nano-particle size (between 173 and 217 nm), neutral zeta potential value (about − 6.5 and 2.8 mV), as well as encapsulation efficiency of about 75%. All liposome formulations were radiolabeled with over 90% efficiency, and the concentration of stannous chloride was found as 1 mg.mL−1 to obtain maximum radiolabeling efficiency. In alamar blue analysis, neutral liposome formulations were found more biocompatible compared with the cationic formulations. Neutral colistin encapsulated liposomes were found to be more effective against P. aeruginosa strain according to their time-dependent antibacterial effect, in addition to their highest bacterial binding capacity. As conclusion, theranostic, nanosized, colistin encapsulated, neutral liposome formulations were found as promising agents for the imaging and treating of P. aeruginosa infections. [ABSTRACT FROM AUTHOR]