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Carbapenem-resistant Enterobacterales (CRE) have become a global threat, with colistin being the last resort for treatment. CLSI and EUCAST recommend broth microdilution (BMD) as the reference method for colistin susceptibility testing. Nordmann and Poirel have developed a simple and rapid Polymyxin NP test as an alternative to BMD for screening of colistin-resistant Enterobacterale (CoRE) isolates. This study aimed to evaluate the performance of the colistin rapid NP (CRNP) test for the detection of colistin resistance. CRNP test was performed on thirty-one clinical Enterobacterales isolates [ Klebsiella pneumoniae (21), Enterobacter spp , (9) and Escherichia coli (1), which were resistant to Colistin by the reference BMD method. The results of the NP test were interpreted after 4hr by the change in color of NP solution (original orange to yellow as a result of bacterial growth) and compared with that of BMD. The CRNP test could accurately detect 26/31 of the colistin resistant Enterobacterale isolates, and thus had an overall categorical agreement of 83.8%. Out of thirty-one CoRE isolates, five Enterobacter spp. 5/31 (16.1%) could not be detected by the CRNP test giving a false-negative result. Excluding those five Enterobacter spp. the categorical agreement (CA) of the CRNP test with BMD was 100%. The overall very major error (VME) of the CRNP test was 16% but decreased to < 3% when Enterobacter spp. (5) were excluded. The CRNP test is technically less demanding, yields faster results compared to the reference BMD method, and has 100% agreement with reference BMD in Enterobacterales except for Enterobacter spp. [ABSTRACT FROM AUTHOR]

Development of multi-, extensively-, and pandrug-resistant (MDR, XDR, and PDR) strains of Pseudomonas aeruginosa remains a major problem in medical care. The present study evaluated the effect of antimicrobial photodynamic therapy (aPDT) as a monotherapy and in combination with colistin against P. aeruginosa isolates. Two P. aeruginosa isolates recovered from patients with respiratory tract infections were examined in this study. Minimum inhibitory concentration (MIC) of colistin was determined by the colistin broth disk elution (CBDE) and the reference broth microdilution (rBMD) methods. aPDT was performed using the photosensitizer (Ps) riboflavin at several concentrations and a light-emitting diode (LED) emitting blue light for different irradiation times with or without colistin at 1/2 × MIC concentration. Both PA1 and PA2 isolates were identified as colistin-resistant P. aeruginosa with a MIC ≥4 μg/mL by the CBDE and MICs of 512 μg/mL and 256 μg/mL, respectively, by the rBMD. In aPDT, neither riboflavin nor LED light alone had antibacterial effects. The values of colony forming units per milliliter (CFU/mL) in both isolates were significantly reduced by LED + Ps treatments in a time-dependent manner (LED irradiation time) and dose-dependent manner (Ps concentration). In comparison with control, treatment with Ps (50 μM) + LED (120 s) and Ps (100 μM) + LED (120 s) resulted in 0.27 log 10 CFU/mL and 0.43 log 10 CFU/mL reductions in PA1, and 0.28 log 10 CFU/mL and 0.34 log 10 CFU/mL reductions in PA2, respectively, (P < 0.01). The best results were obtained after the combination of aPDT followed by colistin, which increased bacterial reduction, resulting in a 0.41−0.7 log 10 CFU/mL reduction for PA1 and 0.35−0.83 log 10 CFU/mL reduction for PA2 (P = 0.001). This study suggests the potential implications of aPDT in combination with antibiotics, such as colistin for treatment of difficult-to-treat P. aeruginosa infections. [ABSTRACT FROM AUTHOR]

Carbapenem-resistant organisms (CROs) are a significant public health threat globally, particularly in countries like India with high antibiotic resistance rates. The current study investigates the prevalence of CROs, detects resistance mechanisms using phenotypic methods and assesses the efficacy of newer antibiotics against CROs. A prospective study conducted at a tertiary care hospital in India during 2021–23. Clinical specimens were processed and bacterial identification was performed using MALDI-TOF mass spectrometry followed by antimicrobial susceptibility testing using CLSI guidelines against a plethora of newer antibiotics for CROs. Carbapenemase production was detected using phenotypic methods, and the presence of the mcr-1 gene was assessed by real-time PCR. During the study period, predominantly (70 %) Gram-negative bacteria were isolated; amongst which 5692 strains were carbapenem-resistant, wherein resistance to different carbapenems ranged from 34.1% to 79 %. Majority of the carbapenemase producers were metallo-β-lactamases (MBL) producers (75 %). Colistin resistance was noted in 5.4 % of selected carbapenem-resistant isolates. Among newer antibiotics, cefiderocol demonstrated the lowest resistance rates (0–14 %), while resistance to newer β-lactam/β-lactamase inhibitor combinations was very high in carbapenem-resistant isolates. Fosfomycin, minocycline and tigecycline, each showing variable efficacy depending on the site of infection. Moreover, newer β-lactam/β-lactamase inhibitor combinations offer restricted benefits due to widespread prevalence of MBL in the region. The escalating prevalence of CROs in India underscores the urgency for alternative treatment options beyond colistin. Hence, highlighting the critical importance of developing effective strategies to combat carbapenem resistance. [ABSTRACT FROM AUTHOR]

To assess the effectiveness of colistin (administered as colistimethate sodium-CMS) and polymyxin B (PMB) for the treatment of bloodstream infections (BSIs) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). This retrospective cohort included hospitalized adult patients with CRKP BSIs from a single tertiary-care hospital. A univariate analysis comparing CMS and PMB groups was carried out and an inverse-probability propensity score (IPPS) was created. An IPPS-adjusted Cox regression model for 30-day mortality was performed including covariates potentially associated with mortality. A total of 100 patients with CRKP BSI (87 were KPC-producing isolates) were included. The 30-day mortality was 42.0 %:17/46 (38.8 %) and 25/54 (44.6 %) patients of CMS and PMB groups, respectively, P = 0.54 (incidence rate, 18.9 and 21.7/1000 patients-day in CMS and PMB groups, respectively, P = 0.62). No statistically significant difference in 30-day mortality rate was observed in a model adjusted for Pitt bacteremia score, high-risk primary site and IPPS, which included age, intensive care unit admission, minimal inhibitory concentration, previous colonization by CRKP, diabetes mellitus, malignancy, neutropenia, meropenem use before BSI, adjuvant therapy with meropenem and amikacin, and time to start polymyxin. Acute kidney injury (AKI) occurred in 52.0 % of patients, with no significant differences between groups (47.8 % and 57.4 % for CMS and PMB, respectively, P = 0.83). In-hospital mortality was 47,7 % and 50.0 % in CMS and PMB groups, respectively, P = 0.82. There was no difference in 30-day mortality and AKI rates among patients with CRKP BSI treated with PMB or CMS. [ABSTRACT FROM AUTHOR]

Bacteriophage (phage) therapy is a promising anti-infective option to combat antimicrobial resistance. However, the clinical utilization of phage therapy has been severely compromised by the potential emergence of phage resistance. Although certain phage resistance mechanisms can restore bacterial susceptibility to certain antibiotics, a lack of knowledge of phage resistance mechanisms hinders optimal use of phages and their combination with antibiotics. Genome-wide transposon screening was performed with a mutant library of Klebsiella pneumoniae MKP103 to identify phage pKMKP103_1-resistant mutants. Phage-resistant phenotypes were evaluated by time-kill kinetics and efficiency of plating assays. Phage resistance mechanisms were investigated with adsorption, one-step growth, and mutation frequency assays. Antibiotic susceptibility was determined with broth microdilution and population analysis profiles. We observed a repertoire of phage resistance mechanisms in K pneumoniae , such as disruption of phage binding (fhuA ::Tn and tonB ::Tn), extension of the phage latent period (mnmE ::Tn and rpoN ::Tn), and increased mutation frequency (mutS ::Tn and mutL ::Tn). Notably, in contrast to the prevailing view that phage resistance re-sensitizes antibiotic-resistant bacteria, we observed a bidirectional steering effect on bacterial antibiotic susceptibility. Specifically, rpoN ::Tn increased susceptibility to colistin while mutS ::Tn and mutL ::Tn increased resistance to rifampicin and colistin. Our findings demonstrate that K pneumoniae employs multiple strategies to overcome phage infection, which may result in enhanced or reduced antibiotic susceptibility. Mechanism-guided phage steering should be incorporated into phage therapy to better inform clinical decisions on phage-antibiotic combinations. [Display omitted] [ABSTRACT FROM AUTHOR]

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a great public health problem and is associated with many disease outbreaks and high mortality rates. Alarmingly, K. pneumoniae has been isolated from food in several recent studies. This study aimed to investigate the prevalence and characteristics of CRKP in food samples from Egypt. A total of 311 food samples (including 116 minced meat, 92 chicken meat, 75 diced meat, and 28 mutton) were collected from local markets in Egypt and were screened for CRKP with the determination of their antimicrobial resistance profiles. The whole genome sequence was done for 23 CRKP isolates to clarify the relationship between CRKP from food and human cases in Egypt using the SNP core genome. The conjugation probability of the bla NDM-5 harboring plasmid was identified using oriTfinder CRKP was isolated from 11% (35/311) of the samples, with 45.71% (16/35) of them showing resistance to colistin, one of the last-resort options for treating CRKP-mediated infections. In addition to the carbapenem and colistin resistance, the CRKP isolates frequently exhibited resistance to multiple antimicrobials including β-lactams, fluoroquinolones, aminoglycosides, tetracyclines, and chloramphenicol. In addition, most of the CRKP were potentially hypervirulent K. pneumoniae (HvKP) identified as phylogroup Kp1 and of high-risk groups as detected in STs reported in many human outbreaks globally, such as ST383 and ST147. The core-genome phylogeny showed similarities between the isolates from this study and those previously isolated from clinical human samples in Egypt. In addition, analysis of the plasmid on which bla NDM is encoded revealed that several antimicrobial resistance genes such as bla OXA-9 , bla CTX-M-15 , aac(6′)-Ib, qnrS1, and several virulence genes are encoded on the same plasmid. This study is significant for food safety and public health and is important to further identify the change in the epidemiology of CRKP infections, especially the consumption of contaminated food products. [ABSTRACT FROM AUTHOR]

To determine whether mortality is lower in patients with Klebsiella pneumoniae bloodstream infection (BSI) who receive combination antimicrobial therapy than in those who receive monotherapy. Two authors independently searched for relevant articles in the PubMed, Embase, Web of Science, and Cochrane Library databases through to August 10, 2023. Risk of bias was evaluated using the ROBINS-I tool. Possible sources of heterogeneity were evaluated by meta-regression using a mixed-effects model. Among 8044 articles screened, there were 23 studies (3443 patients) that were eligible for meta-analysis. Meta-regression analysis identified the proportion of patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) BSI to be a potential source of heterogeneity. Subgroup analysis showed that mortality on monotherapy was significantly higher when the proportion of patients with CRKP BSI was ≥50% (OR 1.75, 95% CI 1.33–2.30) and significantly lower when this proportion was <50% (OR 0.55, 95% CI 0.24–1.24). Overall mortality was significantly higher on tigecycline monotherapy (OR 2.86, 95% CI 1.46–5.59) than on combination therapy containing both these agents. There was a trend in favor of colistin/polymyxin B-containing combination therapy (OR 1.37, 95% CI 0.83–2.28). Combination antimicrobial therapy can lower mortality in patients with CRKP but may not show a survival advantage over monotherapy when the proportion of patients with CRKP BSI is <50%. High-quality prospective observational studies are needed because of the high risk of bias and limited data in the studies performed to date. • The studies reported to date have shown that combination therapy, most commonly tigecycline-containing, colistin/polymyxin B-containing is associated with lower mortality when treating CRKP. • A trend of higher mortality was observed on combination therapy in the <50% CRKP group. • In addition, we found that mortality was lower on tigecycline-based combination therapy than on tigecycline monotherapy (four studies, 206 patients). [ABSTRACT FROM AUTHOR]

Colistin is a viable option for multidrug resistant gram-negative bacteria emerged from inappropriate antibiotic use. Nonetheless, suboptimal colistin concentrations and nephrotoxicity risks hinder its clinical use. Thus, the aim of this study is to investigate clinical outcomes in correlation with pharmacokinetic differences and infection types in critically ill patients on intravenous colistin methanesulfornate sodium (CMS). A systematic literature search of Embase, Google Scholars, and PubMed was performed to identify clinical trials evaluating pharmacokinetic parameters along with clinical outcomes of CMS treatment from inception to July 2023. The pooled analyses of clinical impact of CMS on nephrotoxicity, mortality, clinical cure, and colistin concentration at steady state (C ss,avg) were performed. This study was registered in the PROSPERO (CRD 42023456120). Total of 695 critically ill patients from 17 studies were included. The mortality was substantially lower in clinically cured patients (OR 0.05; 95% CI 0.02 – 0.14), whereas the mortality rate was statistically insignificant between nephrotoxic and non-nephrotoxic patients. Inter-patient variability of pharmacokinetic parameters of CMS and colistin was observed in critically ill patients. The standard mean differences of C ss,avg were statistically insignificant between clinically cure and clinically failure groups (standard mean difference (SMD) −0.25; 95% CI −0.69 – 0.19) and between nephrotoxic and non-nephrotoxic groups (SMD 0.67; 95% CI −0.27–1.61). The clinical cure rate is substantially lower in pneumonia patients (OR 0.09; 95% CI 0.01 – 0.56), and pharmacokinetic parameters pertaining to microbiological cure were different among strains. The mortality rate was substantially lower in clinically cured patients with CMS. However, no significant differences in C ss,avg of colistin were examined to determine the impact of pharmacokinetic differences on clinical outcomes including mortality rate and nephrotoxicity risk. Nevertheless, the clinical cure rate is substantially lower in patients with respiratory infection than patients with urinary tract infection. [ABSTRACT FROM AUTHOR]

Carbapenem-resistant Enterobacteriaceae (CRE) infections pose a significant threat to global health due to limited treatment options and high mortality rates. Colistin-based regimens have emerged as a primary treatment approach, but the effectiveness and mortality outcomes of colistin monotherapy versus colistin-fosfomycin combination therapy remain uncertain. This study aims to compare the effectiveness and mortality of colistin monotherapy and colistin-fosfomycin combination therapy for CRE infections. Notably, our study is the first to undertake a comprehensive examination of the effectiveness and mortality outcomes between colistin monotherapy and colistin-fosfomycin combination therapy in the context of CRE infections. A retrospective cohort study was conducted using data from patients diagnosed with carbapenem-resistant Enterobacteriaceae (CRE) infections at Nakornping Hospital during 2015 to 2022. Inverse probability weighting (IPW) was employed to create balanced cohorts of patients receiving either colistin monotherapy or colistin-fosfomycin combination therapy. The primary outcome measure was treatment effectiveness, assessed by 30-day mortality. Secondary outcome measures included clinical response, mortality at the end of treatment, and microbiologic response. Univariate and multivariate logistic regression analysis were employed after applying propensity score weighting using inverse probability of weighting (IPW). A total of 220 patients were included in the analysis, with 67 receiving colistin monotherapy and 153 receiving colistin-fosfomycin combination therapy. Propensity score weighting using IPW balanced the baseline characteristics between the two groups. The effectiveness of treatment, as measured by 30-day mortality, was not significantly different between the colistin monotherapy group and the colistin-fosfomycin combination therapy group (adjusted odds ratio [aOR] = 1.51, 95% confidence interval [CI]: 0.60–3.78, p = 0.383). Similarly, no significant difference was observed in the mortality at the end of treatment between the two groups (aOR = 1.26, 95% CI: 0.55–2.90, p = 0.576). The clinical response (aOR = 1.48, 95% CI: 0.61–3.59, p = 0.383) and microbiologic response (aOR = 0.66, 95% CI: 0.18–2.38, p = 0.527) were similar between the colistin monotherapy and colistin-fosfomycin combination therapy groups. The propensity score analysis among 220 matched patients showed comparable treatment effectiveness and mortality between colistin monotherapy and colistin-fosfomycin combination therapy for CRE infections. These results suggest that colistin monotherapy may be as effective as combination therapy. More prospective randomized controlled trials are needed to confirm these findings and establish optimal CRE treatment strategies. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii , a common carbapenem-resistant gram-negative bacillus, usually causes nosocomial infections. Colistin has been used for carbapenem-resistant A. baumannii (CRAB) infections; however, only a few studies have evaluated colistin as a treatment option compared to appropriate controls. We investigated the effectiveness of colistin monotherapy in treating CRAB pneumonia compared to those treated without an active drug. Adult patients (≥ 18 years) with CRAB isolated from respiratory specimens were screened from September 2017 to August 2022. Only patients with pneumonia treated with colistin monotherapy (colistin group) were included and compared to those without any active antibiotics (no active antibiotics [NAA] group). The primary and secondary outcomes were 30-day all-cause mortality and acute kidney injury within 30 days. The inverse probability of the treatment-weighted Cox proportional hazard model was used to compare mortality between groups. Among the 826 adult patients with CRAB in their respiratory specimens, 45 and 123 patients were included in the colistin and NAA groups, respectively. Most of the CRAB pneumonia (91.1%) cases were hospital-acquired pneumonia. The 30-day all-cause mortality rates in the colistin and NAA groups were 58.3% and 56.1%, respectively, and no difference was observed after adjustments (adjusted hazard ratio, 0.74; 95% CI, 0.47–1.17). The incidence of acute kidney injury was higher in the colistin group (65.3%) compared to the NAA group (39.0%) (P = 0.143). Colistin monotherapy did not significantly improve treatment outcomes for CRAB pneumonia. The development and evaluation of new antimicrobials for CRAB pneumonia should be advocated in clinical practice. [ABSTRACT FROM AUTHOR]

Mobile colistin resistance (MCR) is the primary mechanism for colistin resistance and has been disseminated worldwide; this has gained substantial attention and led to policy changes for the use of colistin in food animals in many countries. The global spread of mcr was attributed to the high selective pressure of colistin used in livestock, and the acquisition of mcr by low-copy-number and highly conjugative plasmids. The dramatic decrease of mcr after the colistin-banning policy could be associated with the fitness cost mediated by MCR. Besides mediating resistance to both polymyxins and antimicrobial peptides, MCR is thought to enhance the virulence of bacteria and affect the host immune response. To combat colistin-resistant bacteria, MCR inhibitors have been developed based on the structure of MCR, and other strategies targeting mcr -positive plasmids/strains have also been exploited. Colistin is regarded as a last-line drug against serious infections caused by multidrug-resistant Gram-negative bacterial pathogens. Therefore, the emergence of mobile colistin resistance (mcr) genes has attracted global concern and led to policy changes for the use of colistin in food animals across many countries. Currently, the distribution, function, mechanism of action, transmission vehicles, origin of mcr , and new treatment strategies against MCR-producing pathogens have been extensively studied. Here we review the prevalence, structure and function of mcr , the fitness cost and persistence of mcr -carrying plasmids, the impact of MCR on host immune response, as well as the control strategies to combat mcr -mediated colistin resistance. Colistin is regarded as a last-line drug against serious infections caused by multidrug-resistant (MDR) Gram-negative bacterial pathogens. Therefore, the emergence of mobile colistin resistance (mcr) genes has attracted global concern and led to policy changes for the use of colistin in food animals across many countries. Currently, the distribution, function, mechanism of action, transmission vehicles, origin of mcr , and new treatment strategies against MCR-producing pathogens have been extensively studied. Here we review the prevalence, structure, and function of mcr , the fitness cost and persistence of mcr -carrying plasmids, the impact of MCR on host immune response, as well as the control strategies to combat mcr -mediated colistin resistance. [ABSTRACT FROM AUTHOR]

• Repeated use of antibiotics to treat pulmonary exacerbations may lead to kidney injury. • We lack early urinary biomarkers to recognize kidney injury. • Using a kidney-on-a-chip and a CF cohort, we identify new urinary biomarkers of kidney injury. • Urinary soluble Fas, a marker of apoptosis, was associated with chronic kidney disease in CF. Our objective was to discover novel urinary biomarkers of antibiotic-associated nephrotoxicity using an ex-vivo human microphysiological system (MPS) and to translate these findings to a prospectively enrolled cystic fibrosis (CF) population receiving aminoglycosides and/or polymyxin E (colistin) for a pulmonary exacerbation. We populated the MPS with primary human kidney proximal tubule epithelial cells (PTECs) from three donors and modeled nephrotoxin injury through exposure to 50 µg/mL polymyxin E for 72 h. We analyzed gene transcriptional responses by RNAseq and tested MPS effluents. We translated candidate biomarkers to a CF cohort via analysis of urine collected prior to, during and two weeks after antibiotics and patients were followed for a median of 3 years after antibiotic use. Polymyxin E treatment resulted in a statistically significant increase in the pro-apoptotic Fas gene relative to control in RNAseq of MPS: fold-change = 1.63, FDR q -value = 7.29 × 10−5. Effluent analysis demonstrated an acute rise of soluble Fas (sFas) concentrations that correlated with cellular injury. In 16 patients with CF, urinary sFas concentrations were significantly elevated during antibiotic treatment, regardless of development of AKI. Over a median of three years of follow up, we identified seven cases of incident chronic kidney disease (CKD). Urinary sFas concentrations during antibiotic treatment were significantly associated with subsequent development of incident CKD (unadjusted relative risk = 2.02 per doubling of urinary sFas, 95 % CI = 1.40, 2.90, p < 0.001). Using an ex-vivo MPS, we identified a novel biomarker of proximal tubule epithelial cell injury, sFas, and translated these findings to a clinical cohort of patients with CF. [Display omitted] [ABSTRACT FROM AUTHOR]

• This work proposed a novel, integrated experimental and QSP modeling strategy to distinguish between inducible and non-inducible resistance. • At low inocula, the resistant bacterial population was lacking. Colistin caused rapid killing, but 3 to 6 log10 of bacterial regrowth occurred. • The QSP model explained this by an inducible formation of a less susceptible population in response to colistin, which assured bacterial survival. • We developed a novel cutoff filter approach to only allowed inter-conversion of bacterial populations, if enough bacteria converted per time. • Simultaneous modeling of the total population and of resistant bacteria considerably strengthened the proposed QSP model and its conclusions. Colistin is a polymyxin and peptide antibiotic that can yield rapid bacterial killing, but also leads to resistance emergence. We aimed to develop a novel experimental and Quantitative and Systems Pharmacology approach to distinguish between inducible and non-inducible resistance. Viable count profiles for the total and less susceptible populations of Pseudomonas aeruginosa ATCC 27853 from static and dynamic in vitro infection models were simultaneously modeled. We studied low and normal initial inocula to distinguish between inducible and non-inducible resistance. A novel cutoff filter approach allowed us to describe the eradication and inter-conversion of bacterial populations. At all inocula, 4.84 mg/L of colistin (sulfate) yielded ≥4 log 10 killing, followed by >4 log 10 regrowth. A pre-existing, less susceptible population was present at standard but not at low inocula. Formation of a non-pre-existing, less susceptible population was most pronounced at intermediate colistin (sulfate) concentrations (0.9 to 5 mg/L). Both less susceptible populations inter-converted with the susceptible population. Simultaneously modeling of the total and less susceptible populations at low and standard inocula enabled us to identify the de novo formation of an inducible, less susceptible population. Inducible resistance at intermediate colistin concentrations highlights the importance of rapidly achieving efficacious polymyxin concentrations by front-loaded dosage regimens. [ABSTRACT FROM AUTHOR]

An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii–calcoaceticus complex (ABC). Sulbactam–durlobactam is a β-lactam–β-lactamase inhibitor combination with activity against Acinetobacter , including multidrug-resistant strains. In a phase 3, pathogen-specific, randomised controlled trial, we compared the efficacy and safety of sulbactam–durlobactam versus colistin, both in combination with imipenem–cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bloodstream infections were randomised 1:1 using a block size of four to sulbactam–durlobactam (1·0 g of each drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7–14 days. All patients received imipenem–cilastatin (1·0 g of each drug in combination over 1 h every 6 h) as background therapy. The primary efficacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference was less than +20%. The primary safety endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at ClinicalTrials.gov , NCT03894046. Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam–durlobactam or colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC isolates were included in the primary efficacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam–durlobactam group and 20 (32%) of 62 in the colistin group, a difference of –13·2% (95% CI –30·0 to 3·5), which met criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0·001) lower with sulbactam–durlobactam than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the sulbactam–durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam–durlobactam group and 14 (16%) of 86 patients in the colistin group. Our data show that sulbactam–durlobactam was non-inferior to colistin, both agents given in combination with imipenem–cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam–durlobactam was well tolerated and could be an effective intervention to reduce mortality from serious infections caused by carbapenem-resistant ABC, including multidrug-resistant strains. Entasis Therapeutics and Zai Lab. [ABSTRACT FROM AUTHOR]

Rising prevalence of antibiotic resistance and the unavailability of newer drugs to tackle this menace is one of the major hindrances to the goal of health and well-being set up by the General Assembly of the United Nations. The genes responsible for this resistance are often disseminated from hospitals to different environmental sources. In 2015, for the first time, resistance to Colistin was detected caused by chromosomal genetic mutations. Later, plasmid-mediated colistin resistance (MCR-1 to MCR-10) was detected, first from China and then from various other countries. As per Clinical and Laboratory Standards Institute (CLSI), commonly available diffusion techniques cannot detect colistin resistance appropriately. Even commercial susceptibility systems fail in this regard. Keeping in mind the importance of surveillance of colistin-resistant bugs, we present an update on the prevalence, mechanism of resistance, and detection. [ABSTRACT FROM AUTHOR]

Polymyxin B and polymyxin E (colistin) are presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales , Acinetobacter baumannii , and Klebsiella pneumoniae. Yet resistance to this last-line drugs is a major public health threat and is rapidly increasing. Polymyxin S 2 (S 2) is a polymyxin B analogue previously synthesized in our institute with obviously high antibacterial activity and lower toxicity than polymyxin B and colistin. To predict the possible resistant mechanism of S 2 for wide clinical application, we experimentally induced bacterial resistant mutants and studied the preliminary resistance mechanisms. Mut-S, a resistant mutant of K. pneumoniae ATCC BAA-2146 (Kpn2146) induced by S 2 , was analyzed by whole genome sequencing, transcriptomics, mass spectrometry and complementation experiment. Surprisingly, large-scale genomic inversion (LSGI) of approximately 1.1 Mbp in the chromosome caused by IS 26 mediated intramolecular transposition was found in Mut-S, which led to mgrB truncation, lipid A modification and hence S 2 resistance. The resistance can be complemented by plasmid carrying intact mgrB. The same mechanism was also found in polymyxin B and colistin induced drug-resistant mutants of Kpn2146 (Mut-B and Mut-E, respectively). This is the first report of polymyxin resistance caused by IS 26 intramolecular transposition mediated mgrB truncation in chromosome in K. pneumoniae. The findings broaden our scope of knowledge for polymyxin resistance and enriched our understanding of how bacteria can manage to survive in the presence of antibiotics. An inversion of approximately 1.1 Mbp due to IS 26 intramolecular transposition caused mgrB truncation in chromosome of K. pneumoniae , which led to LPS modifications, and hence resistance to polymyxins. [Display omitted] [ABSTRACT FROM AUTHOR]

Carbapenem-resistant Acinetobacter baumannii (CRAB) is one of the most commonly found nosocomial infections in critically ill patients. However, the appropriate treatment period for a specific group of critically ill patients with CRAB infection is currently being debated. Therefore, our study aimed to evaluate the optimal courses of therapy for critically ill patients with CRAB infection by comparing the outcomes of colistin therapy of short duration (<14 days) versus long duration (≥ 14 days). A retrospective cohort study was conducted at Nakornping Hospital on critically ill patients with CRAB infection who received either a short or long course of colistin treatment between 2015 and 2022. The primary outcome was the 30-day mortality rate while secondary outcomes were clinical response, microbiological response, and nephrotoxicity. Propensity score matching with a 1: 1 ratio was performed to reduce potential biases. Furthermore, a logistic regression model was used to estimate the odds ratio (OR). A total of 374 patients met the inclusion criteria. Two hundred and forty-eight patients were recruited after utilizing propensity scores to match patients at a 1: 1 ratio. The results from the propensity score matching analysis demonstrated that the long-course therapy group had a lower 30-day mortality rate compared to the short-course therapy group (adjusted OR (aOR) = 0.46, 95% CI: 0.26–0.83, p = 0.009). The clinical response and microbiological response rates were higher in patients who received the long course of colistin therapy compared to those receiving the short course (aOR = 3.24, 95% CI: 1.78–5.92, p = 0.001; aOR = 3.01, 95% CI: 1.63–5.57, p = 0.001). There was no significant different in the occurrence of nephrotoxicity (aOR = 1.28, 95% CI: 0.74–2.22, p = 0.368) between the two treatment groups. A long course of colistin therapy resulted in a lower 30-day mortality rate in critically ill patients, and better clinical and microbiological outcomes, but similar nephrotoxicity as compared to a short course of colistin therapy. Therefore, a specific subset of critically ill patients who had CRAB infection needed to be considered for a long course of therapy. [ABSTRACT FROM AUTHOR]

Colistin is considered as a last resort therapy for multidrug-resistant gram-negative organisms. It is widely used despite the significant risk of nephrotoxicity. Experimental studies showed the nephroprotective effect of dexmedetomidine, a sedative agent, against colistin toxicity. This study was performed to show the possible nephroprotective effect of dexmedetomidine among critically ill patients who received colistin. Adult (>17 years) patients who were admitted to our surgical and medical intensive care unit (ICU) from March 2018 through March 2021, and who received colistin were included. Patients who receive Colistin therapy or intensive care unit follow-up of <72 h (discharge or death) and Acute kidney injury (AKI) or need hemodialysis prior to colistin therapy at the same hospitalization were excluded. AKI risk factors were examined by grouping patients with and without AKI. Patients, receiving colistin concomitantly with dexmedetomidine were also evaluated. Of the 139 patients included, 27 (17.8%) patients received dexmedetomidine. Sixty-five patients (47%) had AKI, at a median 5 (4-7) days after the initiation of colistin. Older age, lower baseline estimated glomerular filtration rate, and vasopressor use were associated with a higher risk of AKI, while dexmedetomidine use was associated with a lower risk. In the multivariate regression model, dexmedetomidine use was independently associated with a lower risk of AKI development (OR 0.20 95% CI 0.07–0.59, p = 0.003). In respect to these findings, dexmedetomidine may provide protection against AKI during colistin therapy in critically ill patients. [ABSTRACT FROM AUTHOR]

The increase of multidrug-resistant Enterobacteriaceae bacteria has led to the reintroduction of colistin for clinical treatments, and colistin has become a last resort for infections caused by multidrug-resistant bacteria. Enterobacteriaceae bacteria carrying the mcr-1 gene are majorly related to colistin resistance, which may be the main reason for the continued increase in the colistin resistance rate of Enterobacteriaceae. The study aimed to investigate the sequence type and prevalence of Escherichia coli (E. coli) harboring the mcr-1 gene in the gut flora of children in southern China. Fecal samples (n = 2632) of children from three medical centers in Guangzhou were cultured for E. coli. The mcr-1 -harboring isolates were screened via polymerase chain reaction (PCR). The colistin resistance transfer frequency was studied by conjugation experiments. DNA sequencing data of seven housekeeping genes were used for multi-locus sequence typing analysis (MLST). PCR indicated that 21 of the 2632 E. coli (0.80%) isolates were positive for mcr-1 ; these strains were resistant to colistin. Conjugation experiments indicated that 18 mcr-1 -harboring isolates could transfer colistin resistance phenotypes to E. coli J53. MLST analysis revealed that the 21 isolates were divided into 18 sequence types (STs); E. coli ST69 was the most common (14.3%), followed by E. coli ST58 (9.5%). These results demonstrate the colonization dynamics and molecular epidemiology of E. coli harboring mcr-1 in the gut flora of children in southern China. The mcr-1 gene can be horizontally transmitted within species; hence, it is necessary to monitor bacteria that harbor mcr-1 in children. [ABSTRACT FROM AUTHOR]

• SM2 (10 and 100 mg/L) enhanced the conjugative transfer of ARGs between E. coli. • SM2 (>10 mg/L) increased the permeability of the cell membrane. • SM2 could affect the activities or content of antioxidants in bacteria. • SM2 affected the transfer of ARGs by regulating cell membrane and gene expression. As a new type of environmental pollutant, antibiotic resistance genes (ARGs) pose a huge challenge to global health. Horizontal gene transfer (HGT) represents an important route for the spread of ARGs. The widespread use of sulfamethazine (SM2) as a broad-spectrum bacteriostatic agent leads to high residual levels in the environment, thereby increasing the spread of ARGs. Therefore, we chose to study the effect of SM2 on the HGT of ARGs mediated by plasmid RP4 from Escherichia coli (E. coli) HB101 to E. coli NK5449 as well as its mechanism of action. The results showed that compared with the control group, SM2 at concentrations of 10 mg/L and 200 mg/L promoted the HGT of ARGs, but transfer frequency decreased at concentrations of 100 mg/L and 500 mg/L. The transfer frequency at 200 mg/L was 3.04 × 10−5, which was 1.34-fold of the control group. The mechanism of SM2 improving conjugation transfer is via enhancement of the mRNA expression of conjugation genes (trbBP, trfAP) and oxidative stress genes, inhibition of the mRNA expression of vertical transfer genes, up regulation of the outer membrane protein genes (ompC, ompA), promotion of the formation of cell pores, and improvement of the permeability of cell membrane to promote the conjugation transfer of plasmid RP4. The results of this study provide theoretical support for studying the spread of ARGs in the environment. [Display omitted] [ABSTRACT FROM AUTHOR]

• Multidrug resistance in important food pathogens abounds. • Antimicrobial potential of extracts of Loxostylis alata was explored. • L. alata reduced bacterial cell attachment and biofilm biomass. • Anti-biofilm activity is an alternative mechanism to overcome bacterial infection. Bacterial biofilms pose health challenges both in clinical environments and the food industry. Major foodborne bacterial pathogens form biofilms on surfaces and persist, causing infections in humans that may be difficult to treat. Conventional use of antibiotics is fast becoming ineffective due to emerging resistance of pathogens to antibiotics. Previous studies have demonstrated the antimicrobial potential of Loxostylis alata A. Spreng. ex Rchb. extracts against a range of bacterial pathogens. The inhibitory effects of methanol and aqueous extracts of L. alata and an antibacterial compound (5-demethyl sinensetin) isolated from the leaves on the growth and development of microbial biofilms was investigated against clinical isolates of Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and reference strains of Bacillus cereus, Salmonella Enteritidis and Salmonella Typhimurium using the crystal violet (CV) assay. The Kirby-Bauer disk diffusion method was utilized to determine antibiotic susceptibility and resistance profiles of the four clinical and three reference isolates. E. cloacae was resistant to tetracycline and doxycycline and P. mirabilis was resistant to colistin while E. coli and K. pneumoniae were pan-susceptible to all the antibiotics screened. The hot water extract reduced biofilm adhesion from 7% to >50% for the clinical isolates and the ATCC strains, except for S. Typhimurium. The methanol extract inhibited the growth of preformed biofilms of S. Enteritidis and S. Typhimurium by >50% and also reduced the biofilm biomass in S. Enteritidis and E. coli by >50%. The plant extracts and compound were able to reduce initial cell attachment and biofilm biomass, although inhibition of growth in a preformed biofilm was not attained. [ABSTRACT FROM AUTHOR]

Heteroresistance refers to subpopulation-mediated differential antimicrobial susceptibility within a clonal bacterial population. Usually, it designates a resistant subpopulation identified within an isolate considered susceptible by classical antimicrobial susceptibility testing. Heteroresistance lacks a uniform microbiological definition for diagnostic laboratories, and its clinical impact remains unclear for most bacterial species. This narrative review aims to provide a practical overview on the latest developments in the field of heteroresistance for both clinical microbiologists and physicians, with a particular focus on ESKAPE pathogens. A literature search was performed on Pubmed and Google with the key words heteroresistance (heterogeneity OR heterogeneous) AND antibiotic resistance. Among the 836 publications selected based on their abstracts, the most relevant for the detection, epidemiology and clinical impact of heteroresistance in ESKAPE pathogens are discussed here. Heteroresistance is only clearly defined for heterogeneous vancomycin intermediate Staphylococcus aureus. We compiled a larger microbiological definition to be applicable to other bacterial species and antibiotics in the clinical context. We highlighted the key technical points of population analysis profile, which is the reference standard for detecting heteroresistance. Heteroresistance to polymyxins, β-lactams (carbapenems, cefiderocol), fosfomycin, tigecycline and aminoglycosides is frequently reported in multidrug-resistant gram-negative pathogens. Treatment failure due to heteroresistance has been described in case reports or retrospective studies, so far confirmed by meta-analyses in the case of heterogeneous vancomycin intermediate S. aureus only. Finally, to treat pandrug-resistant bacterial infections, the option of targeting susceptible subpopulations of resistant isolates using tailored antibiotic combinations is also discussed. Systematic heteroresistance screening by clinical laboratories is not currently recommended. Nevertheless, we should be aware of this phenomenon, and in specific cases, such as treatment failure, heteroresistance should be tested by reference laboratories. Additional studies using standardized methods are needed to improve our understanding of heteroresistance and further assess its clinical impact. [ABSTRACT FROM AUTHOR]

The stomach acid degradation, mucus clearance and intestinal epithelial impermeability severely limit the oral delivery of polypeptide drugs. To simultaneously address the three major barriers, novel self-assembled core-shell nanosystems (CA-NPs) were designed. The fabricated shell of citric acid cross-linked carboxymethyl cellulose (CA-CMC) wrapped on core nanoparticles (HA-NPs) maintained the integrity of CA-NPs in the stomach. When CA-NPs passed through the stomach, the CA-CMC shell was gradually degraded to release the core HA-NPs in the intestine. HA-NPs with numerous hydrophilic groups and mannose side chains rapidly penetrated through the mucus layer and efficiently transcellular transported via the glucose transporter (GLUT)-mediated and paracellular transport through reversible opening of tight junctions (TJs) by CA-CMC. The oral bioavailability and therapeutic effects of CA-NPs-loaded polypeptide colistin against Escherichia coli (E. coli) bacteremia in mice were significantly increased compared with the native colistin, respectively. Good safety was observed following oral daily delivery for 14 consecutive days. Thus, CA-NPs may offer a promising strategy for the oral delivery of polypeptide drugs. [Display omitted] • Maintained the integrity of core-shell nanoparticles in the stomach. • Rapid penetration of the mucus layer and efficient transepithelial transport. • Achieve efficient oral absorption through multiple transport pathways. • Achieve more effective bacteremia therapeutic effects. • Exhibited excellent long-term safety in mice. [ABSTRACT FROM AUTHOR]

Colistin is considered a valuable and last-resort therapeutic option for MDR gram-negative bacteria. Nephrotoxicity is the most clinically pertinent adverse effect of colistin. Vivo studies suggest that administering oxidative stress-reducing agents, such as ascorbic acid, is a promising strategy to overcome colistin-induced nephrotoxicity (CIN). However, limited clinical data explores the potential benefit of adjunctive ascorbic acid therapy for preventing CIN. Therefore, this study aims to assess the potential nephroprotective role of ascorbic acid as adjunctive therapy against CIN in critically ill patients. This was a retrospective cohort study at King Abdulaziz Medical City (KAMC) for all critically ill adult patients who received IV colistin. Eligible patients were classified into two groups based on the ascorbic acid use as concomitant therapy within three days of colistin initiation. The primary outcome was CIN odds after colistin initiation, while the secondary outcomes were 30-day mortality, in-hospital mortality, ICU, and hospital LOS. Propensity score (PS) matching was used (1:1 ratio) based on the patient's age, SOFA score, and serum creatinine. A total of 451 patients were screened for eligibility; 90 patients were included after propensity score matching based on the selected criteria. The odds of developing CIN after colistin initiation were similar between patients who received ascorbic acid (AA) as adjunctive therapy compared to patients who did not (OR (95 %CI): 0.83 (0.33, 2.10), p-value = 0.68). In addition, the 30-day mortality, in-hospital mortality, ICU, and hospital LOS were similar between the two groups. Adjunctive use of Ascorbic acid during colistin therapy was not associated with lower odds of CIN. Further studies with a larger sample size are required to confirm these findings. [ABSTRACT FROM AUTHOR]

[Display omitted] • Utility of heavy water in identifying colistin resistant microbes. • Live tracking of bacterial growth and early detection of antibiotic-resistant by C-D peak. • Validation of the sensitivity of C-D peak at low biomass bacteria sample in an artificial urine medium. The impact of microbial infections is increasing over time, and it is one of the major reasons for death in both developed and developing countries. colistin is considered as the antibiotic of last choice for infections brought by major multidrug-resistant (MDR), gram-negative bacteria such as Enterobacter species, Acinetobacter species, and Pseudomonas aeruginosa. Existing approaches to diagnose these resistant species are relatively slow and take up to 2 to 3 days. In this work, we propose a novel interdisciplinary method based on Raman spectroscopy and heavy water to identify colistin-resistant microbes. Our hypothesis is based on the fact that resistant bacteria will be metabolically active in the culture medium containing antibiotics and heavy water, and these bacteria will take up deuterium instead of hydrogen to newly synthesized lipids and proteins. This effect will generate a 'C − D' bond-specific Raman spectral marker. Successful identification of this band in the spectral profile can confirm the presence of colistin-resistant bacteria. We have validated the efficacy of this approach in identifying colistin-resistant bacteria spiked in artificial urine and have compared sensitivity at different bacterial concentrations. Overall findings suggest that heavy water can potentially serve as a suitable Raman probe for identifying metabolically active colistin-resistant bacteria via urine under clinically implementable time and can be used in clinical settings after validation. [ABSTRACT FROM AUTHOR]

• The isolation rates of carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) were 6.31% (332/5265), 62.95% (440/699) and 15.20% (152/1000), respectively. Aztreonam/avibactam, colistin and eravacycline exhibited high antimicrobial activity against different species producing various carbapenemases. • The two highest isolation rates for CRPA were found in respiratory and central nervous system (CNS) infections. For CRAB, the highest isolation rate was in CNS infections, followed by bloodstream infections, and skin and soft tissue infections. For CRE, the highest isolation rates were in CNS infections and urinary tract infections. • In CRE, aztreonam/avibactam exhibited higher antimicrobial activity than ceftazidime/avibactam. However, in CRPA, aztreonam/avibactam showed lower antibacterial activity than ceftazidime/avibactam. In a comparison of antimicrobial activity between tigecycline and eravacycline, eravacycline maintained higher antimicrobial activity in CRE and CRAB. • The association between different resistance mechanisms and antimicrobial activity was analysed, which is less commonly addressed in existing research. Carbapenem-resistant bacteria (CRB), including carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA) and carbapenem-resistant Enterobacterales (CRE), pose a considerable threat to public health in China. Eravacycline, aztreonam/avibactam and colistin are important antimicrobial agents for the treatment of serious infections caused by CRB. This study aimed to evaluate the prevalence of CRB strains, and the susceptibility of commonly used clinical antimicrobial agents against strains with different carbapenemase genes. In total, 7194 gram-negative bacteria strains were collected from different regions of China, and 924 carbapenem-resistant strains were identified. All strains were from confirmed infections. Antimicrobial susceptibility testing, covering 21 antimicrobial agents including aztreonam/avibactam, eravacycline, colistin and other comparators, was performed using the broth microdilution method. Carbapenemase genes (bla KPC , bla NDM , bla OXA , bla IMP and bla VIM) were screened using polymerase chain reaction amplification and sequence analysis. All statistical analyses were performed using Statistical Package for the Social Sciences Version 23.0. The isolation rates of CRE, CRAB and CRPA were 6.31% (332/5265), 62.95% (440/699) and 15.20% (152/1000), respectively. The predominant carbapenemase in carbapenem-resistant Escherichia coli (CRECO) was NDM, while in carbapenem-resistant Klebsiella pneumoniae (CRKP), it was KPC. All CRAB produced OXA-23, and 85.52% of CRPA did not produce any of the following carbapenemases: NDM, KPC, VIM, IMP and OXA. Aztreonam/avibactam, colistin and eravacycline exhibited high antimicrobial activity against different species producing various carbapenemases. Compared with ceftazidime/avibactam, aztreonam/avibactam demonstrated superior antimicrobial activity, particularly pronounced in CRECO and strains producing metallo-beta-lactamases. In comparisons between tigecycline and eravacycline, the latter maintained higher antimicrobial activity across different species. Antimicrobial agents exhibited varying levels of activity against strains with different resistance mechanisms. Using aztreonam/avibactam, eravacycline and colistin to treat infections caused by CRB offers significant advantages. These findings will guide clinical practice and optimize antimicrobial administration. [Display omitted] [ABSTRACT FROM AUTHOR]

Multi-drug resistant (MDR) Klebsiella pneumoniae is a public health concern due to its presence in Bangladeshi poultry products and its ability to spread resistance genes. This study genetically characterizes a distinct MDR K. pneumoniae isolate from the gut of poultry in Noakhali, Bangladesh, offering insights into its resistance mechanisms and public health impact. Klebsiella pneumoniae isolates from broiler and layer poultry were identified using biochemical and molecular analyses. Eleven isolates were tested for antibiotic sensitivity and categorized by their Multiple Antibiotic Resistance Index (MARI) profiles. The isolate with the highest MARI was selected for whole-genome sequencing using Illumina technology. The sequencing data were analyzed for genome annotation, pan-genome analysis, genome similarities, sequence type identification, and the identification of genetic determinants of resistance and virulence genes. We identified 10 MARI profiles among 11 K. pneumoniae isolates, with values ranging from 0.64 to 0.94. The highest MARI of 0.94 was found in an isolate from a layer poultry. This isolate's genome, 5401,789 base pairs long with 89.6 % coverage, showed potential inter-species dissemination, as indicated by core genome phylogenetic analysis. It possessed genes conferring resistance to fluoroquinolones, aminoglycosides, β-lactams, folate pathway antagonists, fosfomycin, macrolides, quinolones, rifamycin, tetracyclines, and polymyxins, including colistin. Poultry serve as reservoirs for MDR K. pneumoniae , which can spread to other species and pose significant health risks. Rigorous monitoring of antibiotic use and genetic characterization of MDR bacterial isolates are essential to mitigate this threat. • Isolated Klebsiella pneumoniae from poultry showed MARI values between 0.64 and 0.94. • One isolate resisted 16 of 17 antibiotics tested and underwent whole genome sequencing. • Possible inter-species transmission observed, with same sequence type crossing hosts and varying AMR.. • Poultry chickens are emerging as reservoirs of multi-drug resistant bacteria. [ABSTRACT FROM AUTHOR]

This study was conducted to evaluate the effects of walnut green husk extract (WGHe) on the growth performance, meat quality, antioxidative status, gut morphology, and microbiota diversity of broilers. A total of 216 one-day-old broilers were divided into 4 groups, each consisting of 9 replicates (6 birds per replicate) as follows: 1) control group, basal diet; 2) antibiotic group, basal diet supplemented with enduracidin and colistin sulfate; 3) low-dose group, basal diet supplemented with 5.0 g/kg WGHe; and 4) high-dose group, basal diet supplemented with 10.0 g/kg WGHe. The results revealed that the percentage of abdominal fat decreased, and the ratio of the duodenal villus length to crypt depth (V/C), as well as the α-diversity of the ileal microbiota, increased with 10.0 g/kg WGHe supplementation (P < 0.05). The shear force of the breast muscle and plasma malondialdehyde (MDA) concentration decreased, whereas the plasma peroxidase (POD) activity, Trolox equivalent antioxidant capacity (TEAC), and jejunal villus length increased in response to WGHe supplementation (P < 0.05). Compared with the antibiotic diet, the addition of 5.0 g/kg WGHe resulted in a significant increase in the relative abundances of Candidatus Arthromitus, Eubacterium coprostanoligenes , and Ruminococcaceae UCG-014 (P < 0.01). Furthermore, the addition of 10.0 g/kg WGHe increased the relative abundances of Candidatus Arthromitus and Lachnoclostridium , whereas the relative abundance of unidentified Chloroplast decreased (P < 0.05). In conclusion, dietary supplementation with 10.0 g/kg WGHe is advantageous for intestinal health, meat quality, and antioxidant status in broilers, suggesting its potential as a functional additive in poultry production. [ABSTRACT FROM AUTHOR]

Carbapenems and colistin are vital antimicrobials used to treat Enterobacteriaceae -caused infections. The present study aimed to characterize the coexistence mechanism of carbapenem and colistin resistance in an Escherichia coli isolated from retail chicken meat. A total of 4 E. coli isolates co-harboring carbapenem resistance gene bla NDM (2 E. coli isolates with bla NDM-5 and 2 with bla NDM-9) and colistin resistance gene mcr-1. Antimicrobial susceptibility testing exhibited that all the 4 E. coli strains had multidrug resistance profile and consistent with the resistance genes they carried. MLST showed that 3 E. coli isolates belonged to a pathogenic E. coli lineage ST354, which is closely associated with human infections and pose a serious threat to public health. Whole genome sequencing (WGS) showed that 4 mcr-1 -positive plasmids with sizes of 60.4 kb to 67.4 kb all belonged to the IncI2 type. A total of 5 bla NDM -harboring plasmids ranged from 99.0 kb to 138.3 kb, among which 4 plasmids belonged to unknow type and only pCS5L-NDM belonged to IncFIA/IncFIB group of hybrid plasmids, a novel carrier for bla NDM. Comparative analysis exhibited that the mcr-1 or bla NDM -carrying plasmids of E. coli strains from chicken meat showed high identity with that from Enterobacteriaceae of human origin, which indicated the risk of mcr-1 or bla NDM dissemination from retail meat to human. The simultaneous occurrence of mcr-1 and bla NDM in E. coli emphasizes the significant of antimicrobial resistance surveillance in retail meat. [ABSTRACT FROM AUTHOR]

Polymyxin B (PB) and Polymyxin E (PE, also called colistin) are used as the last treatment resort for multidrug-resistant Gram-negative bacterial infections. The nephrotoxicity and neurotoxicity of polymyxins limit their clinical use, and guidelines recommend therapeutic drug monitoring (TDM) to optimize efficacy and reduce toxicity. However, there are limited analytical methods available for the determination of PB and PE. This study aimed to develop a simple and robust liquid chromatography with tandem mass spectrometry (LC-MS/MS) analytical method for determining the main compounds of PB and PE, namely PB1, PB2, ile-PB1, PE1, and PE2, in human plasma and to investigate of their pharmacokinetics in critically ill patients with the use of PB and PE, respectively. Plasma PB1, PB2, ile-PB1, PE1, and PE2 were chromatographically separated on a Welch LP-C18 column and detected using electrospray ionization mode coupled with multiple reaction monitoring. The calibration curve showed acceptable linearity over 20–10,000 ng/mL for PB1, PE1, and PE2 and 10–5000 ng/mL for PB2 and ile-PB1 in the plasma, respectively. After validation following approved guidelines, this method was successfully applied for PB and PE pharmacokinetic analysis and TDM in critically ill patients. Additionally, the composition of PB1, PB2, ile-PB1, PE1, and PE2 remains unchanged from 0 to 12 h after entering the patient's body. [Display omitted] • First method for simultaneous determination of PB1, PB2, ile-PB1, PE1, and PE2. • The quantitative method is rapid, inexpensive, sensitive, precise, and accurate. • The method has been successfully used in clinical TDM and PK studies. • The proportions of each component remain unchanged during in vivo metabolism. [ABSTRACT FROM AUTHOR]

Endolysins (lysins), a novel class of antibacterial agents derived from bacteriophages, efficiently lyse bacteria by degrading the peptidoglycan layer within the bacterial wall. Colistin, a classic peptide antibiotic with the ability to permeabilize the outer membrane, has recently shown great promise in synergizing with lysins against gram-negative bacteria. However, the exact mechanisms responsible for their synergy remain unclear. Here, we first demonstrated the synergistic bacterial killing of various lysin and colistin combinations. With a model lysin, LysAB2, we then confirmed that there is a threshold concentration of colistin causing sufficient permeabilization of the outer membrane for lysin to access the peptidoglycan layer and subsequently exert its lytic ability. The threshold colistin concentrations were found to range 0.2−0.8 μM for the tested bacteria, with the exact value largely depending on the density of lipopolysaccharides on the outer membrane. Beyond the threshold colistin level, LysAB2 could synergize with colistin at a concentration as low as 0.31 μM. Next, we proved for the first time that lysin-induced degradation of the peptidoglycan layer facilitated the disruption of cytoplasmic membrane by colistin, elevated the level of reactive oxygen species in bacterial cells, and boosted the killing effect of colistin. Additionally, the colistin-lysin combination could effectively eliminate established biofilms due to the biofilm dispersal ability of lysin. The in-vivo efficacy was preliminary confirmed in a Galleria mellonella infection model for combination with colistin doses (≥ 1.8 μg/larvae), which could reach beyond the threshold concentration, and a fixed LysAB2 dose (10 μg/larvae). In summary, our study provided the first experimental evidence unravelling the mechanisms behind the synergy of colistin and lysins. All these findings provided important insights in guiding the dosing strategy for applying this combination in future development. [ABSTRACT FROM AUTHOR]

• AS101 is a Phase II clinical immunomodulator that exhibits synergistic antimicrobial and antibiofilm effects against colistin (COL)-resistant Escherichia coli and Klebsiella pneumoniae both in vitro and in vivo in combination with COL. • The combination of AS101 with COL reduces the expression of inflammatory cytokines IL-1β and IL-6 at combined application concentrations. • AS101 enhances the antimicrobial efficacy of COL by disrupting outer membrane permeability and promoting ROS accumulation. Colistin (COL) was once considered to be the last line of defence against multidrug-resistant bacteria belonging to the family Enterobacteriaceae. Due to the misuse of COL, COL-resistant (COL-R) Enterobacteriaceae have emerged. To address this clinical issue and combat COL resistance, novel approaches are urgently needed. In this study, the in vitro and in vivo antimicrobial and antibiofilm effects of the immunomodulator AS101 were investigated in combination with COL against COL-R Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae). Checkerboard assay, time-kill assay, and scanning electron microscopy confirmed the in vitro antimicrobial phenotype, whereas, crystal violet staining and multidimensional confocal laser scanning microscopy with live/dead staining confirmed the antibiofilm capability of the combination therapy. Moreover, the Galleria mellonella infection model and the mouse infection model indicated the high in vivo efficacy of the combination therapy. Additionally, cytotoxicity experiments performed using human kidney-derived HK-2 cells and haemolysis assays performed using human erythrocytes collectively demonstrated safety at effective combination concentrations. Furthermore, quantification of the expression of inflammatory cytokines via enzyme-linked immunosorbent assay confirmed the anti-inflammatory advantage of combination therapy. At the mechanistic level, changes in outer and inner membrane permeability and accumulation of ROS levels, which might be potential mechanisms for synergistic antimicrobial effects. This study found that AS101 can restore COL susceptibility in clinical COL-R E. coli and K. pneumoniae and also has synergistic antibiofilm and anti-inflammatory capabilities. This study provided a novel strategy to combat clinical infections caused by COL-R E. coli and K. pneumoniae. [Display omitted] [ABSTRACT FROM AUTHOR]

Non-typhoidal Salmonella represents a significant global concern for food safety and One Health. Despite the United Arab Emirates (UAE) being a leading consumer of chicken meat globally, there is a lack of comprehensive understanding regarding the prevalence and genomic characteristics of Salmonella within the country. This study aims to address this gap by conducting a thorough analysis of Salmonella prevalence, antimicrobial resistance, and genomic profiles of isolates obtained from whole broiler carcasses retailed under chilled conditions in the UAE. Our findings reveal that Salmonella was detected in 41.2 % (130/315) of the sampled chilled broiler carcasses, with notable variability observed among samples sourced from six different companies. Phenotypic antimicrobial resistance (AMR) testing, among 105 isolates, highlighted high resistance rates to tetracycline (97.1 %), nalidixic acid (93.3 %), ampicillin (92.4 %), azithromycin (75.2 %), ciprofloxacin (63.8 %), and ceftriaxone (54.3 %). Furthermore, a concerning 99 % (104/105) of the isolates exhibited multidrug resistance. Whole-genome sequencing (WGS) of 60 isolates identified five serovars, with S. infantis /Sequence Type (ST) 32 (55 %) and S. Minnesota/ST-458 (28.3 %) being the most prevalent. WGS analysis unveiled 34 genes associated with antimicrobial resistance, including mcr - 1.1 (only in two isolates), conferring resistance to colistin. The two major serovars, Infantis and Minnesota, exhibited significant variation (P -values <0.001) in the distribution of major AMR genes (aadA1 , bla CMY-2 , bla SHV-12 , qnrB19 , qnrS1 , sul1 , and sul2). Notably, the gene qacEdelta , conferring resistance to quaternary ammonium compounds commonly found in disinfectants, was universally present in all S. Infantis isolates (n = 33), compared to only one S. Minnesota isolate. Additionally, all S. Infantis isolates harbored the IncFIB (pN55391) plasmid replicon type. Major serovars exhibited distinct distributions of antimicrobial resistance genes, underscoring the importance of serovar-specific surveillance. These findings emphasize the critical need for continuous surveillance and intervention measures to address Salmonella contamination risks in poultry products, providing valuable insights for public health and regulatory strategies not only in the UAE but also globally. • The first survey and genomic characterization of Salmonella in the UAE produced chicken. • Salmonella was detected in 41.2 % (130/315) of the sampled chilled broiler carcasses. • A concerning 99 % (104/105) of the isolates exhibited multidrug resistance. • WGS of 60 isolates identified S. Infantis (55 %) and S. Minnesota as the most prevalent. • Infantis and Minnesota serovars exhibited variation in the antimicrobial resistance genes. [ABSTRACT FROM AUTHOR]

In this study, it was aimed to reveal the in vitro interactions of combinations of colistin with meropenem, rifampicin and tigecycline in colistin-resistant, biofilm-forming Klebsiella pneumonia. A total of 30 isolates, 15 of which formed biofilms and 15 did not form biofilms, were randomly selected from K. pneumoniae isolates growing in blood samples. The synergy rates of colistin-meropenem, colistin-tigecycline, colistin-rifampicin combinations in planktonic/sessile bacteria are; It was determined as 83,3%/73,3%, 66,6%/33,3%, 100%/60% respectively. Biofilm inhibitory concentration (BIC) of colistin, meropenem, tigecycline, and rifampicin significantly increased after biofilm formation. The synergistic activity seen in the sessile form was independent of the planktonic form. Although a high synergistic effect was observed in the meropenem-colistin combination on sessile bacteria, colistin had very high BIC ​​in all combinations. Large-scale studies are needed in which the number of isolates studied is large, bacterial resistance profiles are evaluated genomically, and various antimicrobial groups are included. [ABSTRACT FROM AUTHOR]

Colistin (CST) is considered as "agent of last resort" against gram-negative bacteria as feed additive. Its clinical effectiveness has reduced since the emergence of mcr-1 gene in ducks. Isopropoxy benzene guanidine (IBG), a new guanidine derivative, showed positive effects on improving animal weights and alleviating intestinal pathogens, therefore, the objective of this study was to evaluate the effect of this compound supplement with CST in ducks and explore the possibilities in feed additive. A total of fifteen duck-origin Escherichia coli carrying the mcr-1 gene were included in this study. A checkerboard microdilution assay was used to evaluate the in vitro antibacterial activity of IBG combined with CST against mcr-1 -positive E. coli. A 3-by-2 time–kill array of IBG (16, 32, and 64 μg/mL) and CST (1/2 MIC and 1/4 MIC) over 24 hours was utilized to characterize the activity of the agents alone and in combination against E. coli strain 1 in vitro. The intestinal colonization model was used to evaluate the in vivo effect of IBG combined with CST. These results indicated that the combination of IBG plus CST showed a synergistic effect against all clinical isolates (FICI < 0.5). The bacterial burden was reduced by more than 2 log 10 CFU/mL when E. coli strain 1 was tested with 1/2 MIC CST plus 64 μg/mL IBG for 24 h. Further experiments in vivo demonstrated that the CST combined with IBG was able to increase duck weights, reduced intestinal pathogenic E. coli and showed a synergistic antibacterial effect. Combination of CST (4 mg/kg b.w.) plus IBG (32 or 64 mg/kg b.w.) achieved 1.84 to 3.29 log 10 CFU/g killing after 7 d of therapy, which was significantly different from that in the challenge control group (p <0.05). In summary, our study demonstrated the potential use of IBG as feed additive for veterinary purposes in ducks and provided new insights into overcoming resistance in the future. [ABSTRACT FROM AUTHOR]

• We analysed raw manure samples, mesophilic anaerobic digestates and post-digestates. • Plasmids were transferred from raw manure but not from digestates or post-digestates. • Conjugative Enterobacterales plasmids conferred resistance to various antibiotics. • Mesophilic AD processes lead to fewer conjugative Enterobacterales plasmids. • Care must be taken to avoid re-contamination during storage. Manure is a major source of antimicrobial-resistant bacteria and resistance genes carried by mobile genetic elements such as plasmids. In France, the number of on-farm biogas plants has increased significantly in recent years. Our study investigated the impact of mesophilic anaerobic digestion (AD) and the post-treatment of digestates on the fate of conjugative plasmids, along with their potential transfer of antimicrobial resistance. Samples of raw manure, digestates and post-treated digestates were collected from three on-farm biogas plants. Conjugative plasmids were captured using the Escherichia coli CV601 recipient strain and media supplemented with rifampicin and kanamycin — to which the recipient strain is resistant — and tetracycline, sulfamethoxazole, gentamicin, trimethoprim, amoxicillin, cefotaxime, ciprofloxacin or colistin. Putative transconjugants were identified and characterised by disc diffusion and whole genome sequencing. The results showed that the antimicrobial resistance genes transferred from the different matrices conferred resistance to tetracyclines, sulphonamides, trimethoprim, and/or streptomycin. Transconjugants were obtained from raw manure samples but not from digestates or post-digestates, suggesting that mesophilic AD processes may produce fewer conjugative plasmids potentially able to be transferred to Enterobacterales. [ABSTRACT FROM AUTHOR]

Ceftolozane-tazobactam is an emerging ‎treatment for severe infections caused by multidrug-resistant (MDR) Pseudomonas ‎aeruginosa. However, limited ‎data support its use in bacteremia treatment. This study aimed to assess the effectiveness of the treatment of MDR P. aeruginosa bacteremia using ceftolozane-‎tazobactam-based or colistin-based regimens. ‎ This retrospective, cohort, multicentre study included adult patients with ‎ MDR P. aeruginosa bacteremia treated with either ceftolozane-tazobactam or ‎colistin, between September 2018 and August 2021, at four hospitals in Saudi ‎Arabia. The primary endpoint was the 30-day risk-adjusted mortality. Secondary endpoints included the 14-day risk of mortality, bacterial eradication, and clinical ‎success. Cox proportional hazards ‎regression and relative risk estimation were used for analysis, as appropriate. ‎ In total, 46 patients were included; 17 patients received ceftolozane-‎tazobactam-based regimen, and 29 received a colistin-based regimen. There was no association with the use of ‎ceftolozane-tazobactam compared to colistin and the 30-day risk-adjusted mortality ‎‎(hazard ratio [HR] ‎0.58, 95% confidence interval [CI] 0.16–2.13, P = 0.42). Also, the ‎‎14-day risk of mortality and bacterial eradication were not different between the ‎ceftolozane-tazobactam and colistin regimens, HR 2.1, 95% CI 0.42–10.48; P = 0.36; and ‎relative risk (RR) 0.65; 95% CI 0.28–1.52; P = 0.30; respectively. On the other hand, ‎ceftolozane-tazobactam use was associated with higher clinical success than colistin ‎‎(RR 1.84, 95% CI 1.11–3.06: P = 0.021).‎ The risk of mortality of MDR P.aeruginosa bacteremia was ‎similar when treated with ceftolozane-tazobactam-based or colistin-based antimicrobial regimens. A higher clinical success was observed with the ceftolozane-‎tazobactam-based regimen compared to the colistin-based regimen. ‎ [ABSTRACT FROM AUTHOR]

The development of nanotechnology-based antibiotic delivery systems (nanoantibiotics) is an important challenge in the effort to combat microbial multidrug resistance. These systems have improved biopharmaceutical characteristics by increasing local bioavailability and reducing systemic toxicity and the number and frequency of drug side effects. Conjugation of low -molecular -weight antibacterial agents with natural polysaccharides is an effective strategy for developing optimal targeted delivery systems with programmed release and reduced cytotoxicity. This study describes the synthesis of conjugates of colistin (CT) and hyaluronic acid (HA) using carbodiimide chemistry to conjugate the amino groups of CT with the carboxyl groups of HA. The obtained polysaccharide carriers had a degree of substitution (DS) with CT molecules of 3–10 %, and the CT content was 129–377 μg/mg. The size of the fabricated particles was 300–600 nm; in addition, there were conjugates in the form of single macromolecules (30–50 nm). The ζ-potential of developed systems was about −20 mV. In vitro release studies at pH 7.4 and pH 5.2 showed slow hydrolysis of amide bonds, with a CT release of 1–5 % after 24 h. The conjugates retained antimicrobial activity depending on the DS: at DS 8 %, the minimum inhibitory concentration (MIC) of the conjugate corresponded to the MIC of free CT. The resulting systems also reduced CT nephrotoxicity by 20–50 %. These new conjugates of CT with HA are promising for the development of nanodrugs for safe and effective antimicrobial therapy. [ABSTRACT FROM AUTHOR]

The widespread emergence of antibiotic resistance poses a substantial challenge to global health. While polymyxin E serves as a final option in treatment, its effectiveness is hindered by dose-related toxicity. A crucial strategy for addressing this issue involves incorporating an antibiotic adjuvant to enhance the antibiotic's efficacy and decrease the required dosage. Here, we reported a multifunctional antibacterial compound A33 , containing a 2-aminothiazole scaffold. In vitro studies demonstrated that A33 in combination with polymyxin E inhibited the growth of various Gram-negative bacteria, meanwhile with minimum inhibitory concentrations (MICs) of 0.5–4 μg/mL against twenty-three Gram-positive bacteria, including two drug-resistant strains. In vivo studies showed significant efficacy of the combined treatment of A33 and polymyxin E in a mouse infection model. The mice treated with compound A33 (64 mg/kg) and polymyxin E (0.5 mg/kg) in combination had a 100 % survival rate. Mechanistic studies suggested that A33 might exert its synergistic effect by targeting the outer membrane of Gram-negative bacteria. The ADMET data demonstrated that A33 possessed good pharmacokinetic profiles and drug-likeness properties. Overall, the optimized compound A33 assisted polymyxin E in combating various Gram-negative bacteria and exhibited bactericidal effects against drug-resistant Gram-positive bacteria, offering a new potential therapeutic approach for managing mixed bacterial infections. [Display omitted] • Discovery of 41 novel 2-aminothiazole derivatives enhances polymyxin E efficacy in Gram-negative bacteria and resists MDR Gram-positive strains. • Optimized compound A33 provides a promising therapeutic strategy for mixed bacterial infections • Structural modification of compound 1 yielded A33, which shows excellent antibacterial activity and improved drug-like properties. • In vivo studies reveal significant efficacy of A33 combined with polymyxin E in a mouse infection model. • Mechanistic studies indicate A33 targets Gram-negative bacteria's outer membrane, enhancing polymyxin E's bactericidal effect. [ABSTRACT FROM AUTHOR]

Colistin is a polymyxin antimicrobic mainly used to treat infection caused by multi-drug resistant Gram-negative bacteria. Mechanisms of colistin resistance are linked to the mobile colistin resistance (mcr) genes, which are transferable within mobile plasmids. Currently, there is limited research on the environmental dissemination of these genes. The behavioural and morphological characteristics of Apis mellifera L. make honey bees effective environmental bioindicators for assessing the prevalence of antimicrobial-resistant bacteria. This study aims to evaluate the colistin phenotypic and genotypic resistance in environmental Gram-negative bacteria isolated from foraging honey bees, across a network of 33 colonies distributed across the Emilia-Romagna region in Italy. Phenotypic resistances were determined through a microdilution assay using the minimum inhibitory concentration (MIC) with dilutions ranging from 0.5 μg/ml to 256 μg/ml. Strains with MIC values gather than 2 μg/ml were classified as resistant. Also, the identification of the nine mcr genes was carried out using two separate multiplex PCR assays. The study found that 68.5% of isolates were resistant and the genus with the higher resistance rates observed in Enterobacter spp. (84.5%). At least one mcr gene was found in 137 strains (53.3%). The most detected gene was mcr5 (35.3%), which was the most frequently detected gene in the seven provinces, while the least observed was mcr4 (4.8%), detected only in two provinces. These results suggested the feasibility of detecting specific colistin resistance genes in environmentally spread bacteria and understanding their distribution at the environmental level, despite their restricted clinical use. In a One-Health approach, this capability enables valuable environmental monitoring, considering the significant role of colistin in the context of public health. [Display omitted] • AMR environmental monitoring is essential to protect ecosystem health. • Honey bee colonies are crucial in environmental biomonitoring. • Colistin is an antimicrobic used to treat MDR Gram-negative bacteria. • 68.5% of isolates were colistin-resistant and mcr genes were found in 53.3% of them. • The most detected gene was mcr5 (35.3%), while the least found was mcr4 (4.8%). [ABSTRACT FROM AUTHOR]

Efficient tools for rapid antibiotic susceptibility testing (AST) are crucial for appropriate use of antibiotics, especially colistin, which is now often considered a last resort therapy with extremely drug resistant Gram-negative bacteria. Here, we developed a rapid, easy and miniaturized colistin susceptibility assay based on microfluidics, which allows for culture and high-throughput analysis of bacterial samples. Specifically, a simple microfluidic platform that can easily be operated was designed to encapsulate bacteria in nanoliter droplets and perform a fast and automated bacterial growth detection in 2 h, using standardized samples. Direct bright-field imaging of compartmentalized samples proved to be a faster and more accurate detection method as compared to fluorescence-based analysis. A deep learning powered approach was implemented for the sensitive detection of the growth of several strains in droplets. The DropDeepL AST method (Droplet and Deep learning-based method for AST) developed here allowed the determination of the colistin susceptibility profiles of 21 fast-growing Enterobacterales (E. coli and K. pneumoniae), including clinical isolates with different resistance mechanisms, showing 100 % categorical agreement with the reference broth microdilution (BMD) method performed simultaneously. Direct AST of bacteria in urine samples on chip also provided accurate results in 2 h, without the need of complex sample preparation procedures. This method can easily be implemented in clinical microbiology laboratories, and has the potential to be adapted to a variety of antibiotics, especially for last-line antibiotics to optimize treatment of patients infected with multi-drug resistant strains. [Display omitted] • Simplified workflow for bacteria encapsulation and detection in nanoliter droplets. • Automated and deep learning powered approach for droplet classification. • Digital susceptibility testing for colistin using clinical isolates in 2 hours. • Categorization of bacteria strains in complete agreement with the reference method. • Direct urine analysis on chip for rapid detection of antimicrobial resistance. [ABSTRACT FROM AUTHOR]

Multidrug resistant bacterial and fungal pathogens are resistant to a number of significant front-line drugs, hence, identification of new inhibitory agents to combat them is crucial. In this study, we aim to evaluate the activity of Pandemic Box compounds from Malaria Medicines Venture (MMV) against A. baumannii and P. aeruginosa bacterial, C. auris, C. albicans and A. niger fungal clinical isolates. Isolates were initially screened with 201 antibacterial and 46 antifungal compounds (10 μM) using a microbroth dilution in triplicates to determine MIC. A persister assay was performed for bacterial pathogens. Out of 201 antibacterial compounds, twenty-nine and seven compounds inhibited the growth of A. baumannii and P. aeruginosa at 10 μM, respectively. MMV1580854, MMV1579788, eravacycline and epetraborole inhibited both the bacterial test isolates. In a persister assay, MMV1634390 showed complete bactericidal effect against A. baumannii. With antifungal activity compounds, C. auris responded to15 compounds, Six compounds inhibited C. albicans and one was effective against A. niger at 10 μM. The ratio of Minimum Fungicidal Concentration (MFC): Minimum Inhibitory Concentration (MIC) of MMV1782110 was 2 against C. auris. Eberconazole, amorolfine and luliconazole are fungicidal targeting C. albicans at a MFC: MIC ratio of 2. Five compounds from MMV Pandemic Box were found to be inhibiting colistin and ceftazidime resistant A. baumannii clinical isolate, also against colistin and β-lactam resistant P. aeruginosa clinical isolate. MMV1634390 showed complete bactericidal effect against A. baumannii in a persister assay. MMV1782110, Eberconazole, amorolfine and luliconazole exhibited potent anti-fungal activity. Further investigations are warranted to identify the targets and mechanism. • MMV Pandemic Response Box compounds were evaluated against MDR bacterial and fungal pathogens isolated from patients. • MMV1634390 compound was highly bactericidal against A. baumannii , whereas eravacycline and epetraborole were against both A. baumannii and P. aeruginosa. • Few compounds were fungicidal against MDR Candida and Aspergillus fungal species. • A novel compound MMV1782110 showed excellent inhibitory activity against Candida auris. [ABSTRACT FROM AUTHOR]

• Glabridin targets and inhibits enoyl-acyl carrier protein reductase, also called 'FabI', in E. coli. • Glabridin synergistically enhances antimicrobial activities of colistin on E. coli in vitro and in vivo. • Glabridin synergistically suppressed E. coli biofilms formation and eradication with colistin. The increase in antimicrobial resistance leads to complications in treatments, prolonged hospitalization, and increased mortality. Glabridin (GLA) is a hydroxyisoflavan from Glycyrrhiza glabra L. that exhibits multiple pharmacological activities. Colistin (COL), a last-resort antibiotic, is increasingly being used in clinic against Gram-negative bacteria. Previous reports have shown that GLA is able to sensitize first line antibiotics such as norfloxacin and vancomycin on Staphylococcus aureus , implying that the use of GLA as an antibiotic adjuvant is a promising strategy for addressing the issue of drug resistance. However, the adjuvant effect on other antibiotics, especially COL, on Gram-negative bacteria such as Escherichia coli has not been studied. The objective of our study was to investigate the targets of GLA and the synergistic effect of GLA and COL in E. coli , and to provide further evidence for the use of GLA as an antibiotic adjuvant to alleviate the problem of drug resistance. We first investigated the interaction between GLA and enoyl-acyl carrier protein reductase, also called "FabI", through enzyme inhibition assay, differential scanning fluorimetry, isothermal titration calorimetry and molecular docking assay. We tested the transmembrane capacity of GLA on its own and combined it with several antibiotics. The antimicrobial activities of GLA and COL were evaluated against six different susceptible and resistant E. coli in vitro. Their interactions were analyzed using checkerboard assay, time-kill curve and CompuSyn software. A series of sensitivity tests was conducted in E. coli overexpressing the fabI gene. The development of COL resistance in the presence of GLA was tested. The antimicrobial efficacy of GLA and COL in a mouse model of urinary tract infection was assessed. The anti-biofilm effects of GLA and COL were investigated. In this study, enzyme kinetic analysis and thermal analysis provided evidence for the interaction between GLA and FabI in E. coli. GLA enhanced the antimicrobial effect of COL and synergistically suppressed six different susceptible and resistant E. coli with COL. Overexpression experiments showed that targeted inhibition of FabI was a key mechanism by which GLA synergistically enhanced COL activity. The combination of GLA and COL slowed the development of COL resistance in E. coli. Combined GLA and COL treatment significantly reduced bacterial load and mitigated urinary tract injury in a mouse model of E. coli urinary tract infection. Additionally, GLA + COL inhibited the formation and eradication of biofilms and the synthesis of curli. Our findings indicate that GLA synergistically enhances antimicrobial activities of COL by targeting inhibition of FabI in E. coli. GLA is expected to continue to be developed as an antibiotic adjuvant to address drug resistance issues. [Display omitted] [ABSTRACT FROM AUTHOR]

The transmission of antibiotic-resistant bacteria among wild animal species may hold significant epidemiological implications. However, this issue is seldom explored due to the perceived complexity of these systems, which discourages experimental investigation. To address this knowledge gap, we chose a configuration of birds and mammals coexisting in an urban green area as a research model: the rook Corvus frugilegus and the striped field mouse Apodemus agrarius. The indirect transmission of antimicrobial-resistant bacteria between these species is possible because rodents inhabiting rook colonies frequently come into contact with the birds' faeces and pellets. The study was conducted in two cities in eastern Poland (Central Europe) – Lublin and Chełm. Among 71 Escherichia (E.) coli isolates studied, 19.7% showed resistance to from one to six of the antibiotics tested, with much higher prevalence of antibiotic-resistant bacteria in the birds (32%) than in the rodents (7%). Whole genome sequencing was performed on 10 selected E. coli isolates representing similar resistance phenotypes. The following antimicrobial resistance genes were detected: bla TEM-1b , tet (A), tet (B), aph(6)-Id, aph(3'')-Ib , aadA1 , aadA2 , catA1 , floR , cmlA , sul2 , sul3 , dfrA14 , and dfrA2. Birds from the same city and also from both neighbouring cities shared E. coli bacteria with the same sequence types, whereas isolates detected in birds were not found to have been transferred to the mammalian population, despite close contact. This demonstrates that even intensive exposure to sources of these pathogens does not necessarily lead to effective transmission of antibiotic-resistant E. coli strains between birds and mammals. Further efforts should be dedicated to investigating actual transmission of antimicrobial-resistant bacteria in various ecological systems, including those that are crucial for public health, such as urban environments. This will facilitate the development of more accurate models for epidemiological threats and the formulation of well-balanced decisions regarding the coexistence of humans and urban wildlife. • Mechanisms of transmission of drug-resistant bacteria in wildlife are poorly understood. • We studied such transfer between birds and mammals in an urban environment. • Phenotypic drug resistance testing and whole genome sequencing of E.coli were used. • Birds shared the same E. coli STs, but no transmission to mammals was observed. • Developing better strategies for human-wildlife coexistence were discussed. [ABSTRACT FROM AUTHOR]

• The machine learning model can be a prediction tool for colistin-induced acute kidney injury (AKI). • The top risk factors were days of colistin used, cumulative dose, and daily dose. • The positive interactions among colistin dose, blood urea nitrogen level, and chronic kidney disease were observed. • A lower cutoff colistin dose was suggested for patients with a higher risk of AKI. Colistin-induced nephrotoxicity prolongs hospitalisation and increases mortality. The study aimed to construct machine learning models to predict colistin-induced nephrotoxicity in patients with multidrug-resistant Gram-negative infection. Patients receiving colistin from three hospitals in the Clinical Research Database were included. Data were divided into a derivation cohort (2011–2017) and a temporal validation cohort (2018–2020). Fifteen machine learning models were established by categorical boosting, light gradient boosting machine and random forest. Classifier performances were compared by the sensitivity, F1 score, Matthews correlation coefficient (MCC), area under the receiver operating characteristic (AUROC) curve, and area under the precision-recall curve (AUPRC). SHapley Additive exPlanations plots were drawn to understand feature importance and interactions. The study included 1392 patients, with 360 (36.4%) and 165 (40.9%) experiencing nephrotoxicity in the derivation and temporal validation cohorts, respectively. The categorical boosting with oversampling achieved the highest performance with a sensitivity of 0.860, an F1 score of 0.740, an MCC of 0.533, an AUROC curve of 0.823, and an AUPRC of 0.737. The feature importance demonstrated that the days of colistin use, cumulative dose, daily dose, latest C-reactive protein, and baseline haemoglobin were the most important risk factors, especially for vulnerable patients. A cutoff colistin dose of 4.0 mg/kg body weight/d was identified for patients at higher risk of nephrotoxicity. Machine learning techniques can be an early identification tool to predict colistin-induced nephrotoxicity. The observed interactions suggest a modification in dose adjustment guidelines. Future geographic and prospective validation studies are warranted to strengthen the real-world applicability. [Display omitted] [ABSTRACT FROM AUTHOR]

• Severe infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) have been reported increasingly. • Many in-vivo and in-vitro studies suggest a possible role of intravenous fosfomycin for the treatment of CRAB infections. • Cefiderocol-containing regimens were independently associated with survival and clinical success, whilst colistin-based regimens were associated with death and clinical failure. • The study data showed clinical features and use of different antibiotic regimens with a possible role for fosfomycin in combination for treatment of severe infections caused by CRAB. Severe infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) have been reported increasingly over the past few years. Many in-vivo and in-vitro studies have suggested a possible role of intravenous fosfomycin for the treatment of CRAB infections. This multi-centre, retrospective study included patients treated with intravenous fosfomycin for severe infections caused by CRAB admitted consecutively to four hospitals in Italy from December 2017 to December 2022. The primary goal of the study was to evaluate the risk factors associated with 30-day mortality in the study population. A propensity score matched analysis was added to the model. One hundred and two patients with severe infections caused by CRAB treated with an intravenous fosfomycin-containing regimen were enrolled in this study. Ventilator-associated pneumonia (VAP) was diagnosed in 59% of patients, primary bacteraemia in 22% of patients, and central-venous-catheter-related infection in 16% of patients. All patients were treated with a regimen containing intravenous fosfomycin, mainly in combination with cefiderocol (n =54), colistin (n =48) or ampicillin/sulbactam (n =18). Forty-eight (47%) patients died within 30 days. Fifty-eight (57%) patients experienced clinical therapeutic failure. Cox regression analysis showed that diabetes, primary bacteraemia and a colistin-containing regimen were independently associated with 30-day mortality, whereas adequate source control of infection, early 24-h active in-vitro therapy, and a cefiderocol-containing regimen were associated with survival. A colistin-based regimen, A. baumannii colonization and primary bacteraemia were independently associated with clinical failure. Conversely, adequate source control of infection, a cefiderocol-containing regimen, and early 24-h active in-vitro therapy were associated with clinical success. Different antibiotic regimens containing fosfomycin in combination can be used for treatment of severe infections caused by CRAB. [ABSTRACT FROM AUTHOR]