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The emergence and spread of Acinetobacter baumannii pose a severe threat to public health, highlighting the urgent need for the next generation of therapeutics due to its increasing resistance to existing antibiotics. BfmR, a response regulator modulating virulence and antimicrobial resistance, shows a promising potential as a novel antimicrobial target. Developing BfmR inhibitors may propel a new therapeutic direction for intractable infection of resistant strains. In this study, we conducted a structure-based hierarchical virtual screening pipeline combining molecular docking, molecular dynamic simulation, and MM/GBSA calculation to sift the Specs chemical library and finally discover three novel potential BfmR inhibitors. The three hits can reduce the MIC of meropenem for the carbapenem-resistant Acinetobacter baumannii (CRAB) strain ZJ06. Similar to the BfmR knockout strain, Cmp-98 was demonstrated to downregulate the expression of K locus genes, indicating it as a BfmR inhibitor. Bacteria underwent harmful morphological changes after treatment with these inhibitors. Molecular dynamic simulations found that all the hits tend to dynamically bind to different positions of the phosphorylation site of BfmR. Wherein we identified a potential inhibitory-binding cleft, beside a possible activated binding cleft at the edge of the phosphorylation site. Restraining the ligand binding poses may help exert inhibitory effects. This study reports a group of new scaffold BfmR inhibitors, offering new insights for novel antibiotic therapeutics against CRAB.

Carbapenem-Resistant Acinetobacter baumannii (CRAB) outbreak in intensive care units (ICUs) is a significant problem for healthcare facilities. In this study, we aimed to investigate the occurrence of CRAB isolates among ICU-admitted patients during the three waves of the COVID-19 pandemic in Iran using Multiple-Locus Variable Number Tandem-Repeat Analysis (MLVA). We obtained 50 (A) baumannii isolates from tracheal aspirate and blood culture samples. In the disc diffusion method, all isolates were cefotaxime, ceftriaxone, and cefepime-resistant, while 98% (49/50) of isolates were resistant to piperacillin, piperacillin-tazobactam, ceftazidime, and ciprofloxacin. Levofloxacin and tobramycin resistance was found in 76% (38/50) of isolates. In the microbroth dilution test all isolates were resistant to imipenem, 98% (49/50) to meropenem, 68% (34/50) to colistin, and 20% (10/50) to polymyxin (B) Based on the PCR findings, all isolates harbored bla OXA-40 , ISAba-1, and int-2 genes. There were no isolates found that have the bla OXA-58 , bla OXA-143 , bla VEB-1 , bla VIM , and int-3 genes. Among Extended-spectrum beta-lactamases (ESBL) genes, bla CTX-M , bla TEM , bla SHV , bla GES , and bla PER-1 have a prevalence of 42% (21/50), 84% (42/50), 58% (29/50), 78% (39/50), and 54% (27/50), respectively. 74% (37/50) of the isolates had the bla OXA-23 gene, while all of the isolates carried the bla OXA-40 gene. Among MBL genes, bla IPM , bla GIM , bla SIM , and bla NDM-1 have a prevalence of 20% (10/50), 8% (4/50), 22% (11/50), and 60% (30/50), respectively. The prevalence of int-1 was documented as 74% (37/50). Accordingly, all isolates were identified as CRAB. The co-existence of bla OXA-23 /int-2 and bla OXA-23 /isaba-1 was 74% (37/50). The co-existence of bla NDM-1 /ISAba-1 was observed in 30 (60%) isolates. Using an 80% similarity threshold on the dendrogram constructed through MLVA typing, all isolates were grouped into two clusters: cluster A with 9 isolates from wave 3, and cluster B with 41 isolates from waves 3, 4, and 5. Our study confirms a clonal transmission of CRAB during the study period and suggests using molecular typing methods like MLVA in healthcare settings to identify dominant clones, antibiotic resistance patterns, and transmission routes. This will help to better manage the emergence and spread of antibiotic-resistant strains in future outbreaks., (© 2024. The Author(s).)

Background: There are multiple antibiotic regimens for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) in clinical practice. We conducted this meta-analysis to compare the efficacy and safety of cefiderocol-based regimens and colistin-based regimens in the treatment of CRAB infections., Methods: Two authors independently searched the PubMed, Web of Science, Embase, and Cochrane databases from their establishment to April 15, 2024, to search for randomized controlled trials (RCTs) or cohort studies, and compared the clinical efficacy and safety of cefiderocol-based regimens and colistin-based regimens in the treatment of CRAB infections. The Newcastle Ottawa Scale (NOS) checklist was used to evaluate the quality of the included studies. The primary outcome was all-cause mortality, and subgroup analysis was conducted on the basis of the site of infection and the risk of bias in the studies. Trial sequential analysis (TSA) was then conducted., Results: Six observational studies were included, with 251 cases in the cefiderocol-based group and 372 cases in the colistin-based group. Compared to the colistin-based group, the cefiderocol-based group had lower all-cause mortality (RR = 0.71, 95% CI: 0.54-0.92, P = 0.01) and 30-day mortality (RR = 0.64, 95% CI: 0.43-0.95, P = 0.03). However, for the 14-day and 28-day mortality rates, there was no statistically significant difference between two groups. According to the subgroup analysis, among patients with bloodstream infection (BSI), the cefiderocol-based group had lower all-cause mortality, but it did not reduce the mortality of ventilator-associated pneumonia (VAP) patients. The result of TSA showed that our conclusions are reliable. There was no significant statistical difference in the microbiological cure rate, clinical cure rate, or duration of hospitalization. In addition, the cefiderocol-based group did not have an increased incidence of acute kidney injury (AKI)., Conclusions: Compared with the colistin-based regimens, the cefiderocol-based regimens were significantly associated with a lower risk of mortality in CRAB-infected patients, especially for patients with BSI. However, they did not show any advantages in terms of the clinical cure rate or microbiological cure rate, nor did they reduce the incidence of AKI., Prospero Registration Number: CRD42023487213., (© 2024. The Author(s).)

Carbapenem-resistant Acinetobacter baumannii (CRAB) poses a significant threat to hospitalized patients as effective therapeutic options are scarce. Based on the genomic characteristics of the CRAB strain AB2877 harboring chromosome-borne bla OXA-23 , which was isolated from the bronchoalveolar lavage fluid (BALF) of a patient in a respiratory intensive care unit (RICU), we systematically analyzed antibiotic resistance genes (ARGs) and the genetic context associated with ARGs carried by CRAB strains harboring chromosome-borne bla OXA-23 worldwide. Besides bla OXA-23 , other ARGs were detected on the chromosome of the CRAB strain AB2877 belonging to ST208/1806 (Oxford MLST scheme). Several key genetic contexts associated with the ARGs were identified on the chromosome of the CRAB strain AB2877, including (1) the MDR region associated with bla OXA-23 , tet(B)-tetR(B ), aph(3'')-Ib, and aph(6)-Id (2); the resistance island AbGRI3 harboring armA and mph(E)-msr(E ) (3); the Tn 3 -like composite transposon containing bla TEM-1D and aph(3')-Ia ; and (4) the structure "IS Aba1-bla ADC-25 ." The first two genetic contexts were most common in ST195/1816, followed by ST208/1806. The last two genetic contexts were found most frequently in ST208/1806, followed by ST195/1816.IMPORTANCEThe bla OXA-23 gene can be carried by plasmid or chromosome, facilitating horizontal genetic transfer and increasing carbapenem resistance in healthcare settings. In this study, we focused on the genomic characteristics of CRAB strains harboring the chromosome-borne bla OXA-23 gene, and the important genetic contexts associated with bla OXA-23 and other ARGs were identified, and their prevalent clones worldwide were determined. Notably, although the predominant clonal CRAB lineages worldwide containing the MDR region associated with bla OXA-23 , tet(B)-tetR(B ), aph(3'')-Ib, and aph (6)-Id was ST195/1816, followed by ST208/1806, the CRAB strain AB2877 in our study belonged to ST208/1806. Our findings contribute to the knowledge regarding the dissemination of CRAB strains and the control of nosocomial infection., Competing Interests: The authors declare no conflict of interest.

We investigated the activity of cefiderocol/β-lactamase inhibitor combinations against clinical strains with different susceptibility profiles to cefiderocol to explore the potentiality of antibiotic combinations as a strategy to contain the major public health problem of multidrug-resistant (MDR) pathogens. Specifically, we evaluated the synergistic activity of cefiderocol with avibactam, sulbactam, or tazobactam on three of the most "Critical Priority" group of MDR bacteria (carbapenem-resistant Enterobacterales , Pseudomonas aeruginosa , and Acinetobacter baumannii ). Clinical isolates were genomically characterized by Illumina iSeq 100. The synergy test was conducted with time-kill curve assays. Specifically, cefiderocol/avibactam, /sulbactam, or /tazobactam combinations were analyzed. Synergism was assigned if bacterial grow reduction reached 2 log 10 CFU/mL. We reported the high antimicrobial activity of the cefiderocol/sulbactam combination against carbapenem-resistant Enterobacterales , P. aeruginosa , and A. baumannii ; of the cefiderocol/avibactam combination against carbapenem-resistant Enterobacterales ; and of the cefiderocol/tazobactam combination against carbapenem-resistant Enterobacterales and P. aeruginosa. Our results demonstrate that all β-lactamase inhibitors (BLIs) tested are able to enhance cefiderocol antimicrobial activity, also against cefiderocol-resistant isolates. The cefiderocol/sulbactam combination emerges as the most promising combination, proving to highly enhance cefiderocol activity in all the analyzed carbapenem-resistant Gram-negative isolates, whereas the Cefiderocol/tazobactam combination resulted in being active only against carbapenem-resistant Enterobacterales and P. aeruginosa, and cefiderocol/avibactam was only active against carbapenem-resistant Enterobacterales.

We present our findings on interpatient transmission, epidemic control measures, and the outcomes of a series of ten critically ill burn patients who were either colonized or infected with carbapenem-resistant Acinetobacter baumannii (CRAB). None of the five infected patients achieved clinical cure, and all experienced relapses. Microbiological failure was observed in 40% of the infected patients. The isolated CRAB strains were found to carry bla OXA-23 and armA resistance genes. Despite the lack of clinical cure, all five infected patients survived and were discharged from the Burn Intensive Care Unit., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: 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., Methods: 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., Results: 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., Conclusions: Different antibiotic regimens containing fosfomycin in combination can be used for treatment of severe infections caused by CRAB., (Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

This study aimed to characterize carbapenem-resistant Acinetobacter baumannii (CRAB) isolates from Jiangxi patients using whole-genome sequencing (WGS). We subjected 100 clinical CRAB strains isolated from the three local largest teaching hospitals to WGS and antimicrobial susceptibility testing. Molecular epidemiology was investigated using multilocus sequence typing, core genome multilocus typing, core genome single-nucleotide polymorphism phylogeny, and pulsed-field gel electrophoresis. The most prevalent acquired carbapenemase was bla OXA-23 , predominant in all isolates (100%). Isolates belonging to the dominating international clone IC2 accounted for 92% of all isolates. International IC11 (ST164 Pas /ST1418 Ox ) clone was found in an additional 8% (eight isolates), with seven isolates (87.5%) carrying an acquired additional bla NDM-1 carbapenemase. The oxa23 -associated Tn 2009 , either alone or in a tandem repeat structure containing four copies of bla OXA-23 , was discovered in 62% (57 isolates) of IC2. The oxa23 -associated Tn 2006 was identified in 38% (35 isolates) of IC2 and all IC11 isolates. A putative conjugative RP-T1 (formerly RepAci6) plasmid with bla OXA-23 in Tn 2006 within AbaR4, designated pSRM1.1, was found in IC2 A. baumannii strain SRM1. The bla NDM-1 gene found in seven IC11 isolates was located on a novel Tn 6924 -like transposon, a first-time report in IC11. These findings underscore the significant importance of real-time surveillance to prevent the further spread of CRAB., Importance: Carbapenem-resistant Acinetobacter baumannii (CRAB) is notorious for causing difficult-to-treat infections. To elucidate the molecular and clinical epidemiology of CRAB in Jiangxi, clinical CRAB isolates were collected and underwent whole-genome sequencing and antibiotic susceptibility phenotyping. Key findings included the predominance of OXA-23-producing IC2 A. baumannii , marked by the emergence of OXA-23 and NDM-1-producing IC11 strains., Competing Interests: The authors declare no conflict of interest.

Background: We assessed the clinical effectiveness of cefiderocol (CFDC) in comparison with colistin (COL) for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infections (BSI)., Materials/methods: Retrospective cohort study including adults with CRAB-BSI. Outcomes were mortality, clinical cure and adverse events during therapy. The average treatment effect of CFDC compared to COL was weighted with the inverse-probability treatment weight (IPTW)., Results: Overall, 104 patients were included (50 CFDC, 54 COL), median age 66.5 years, median Charlson Comorbidity Index 5, septic shock in 33.6% of patients. Primary BSI accounted for 43.3% of cases, followed by ventilator-associated pneumonia (VAP) (26%), catheter-related BSI (20.2%) and hospital-acquired pneumonia (HAP) (9.6%). Although not significantly, mortality at all time points was lower for CFDC than COL, while clinical cure was higher in CFDC than COL (66% vs. 44.4%, p = 0.027). Adverse events were more frequent in COL than CFDC-group (38.8% vs. 10%, p < 0.0001), primarily attributed to acute kidney injury (AKI) in the COL group. Patients with bacteremic HAP/VAP treated with CFDC had a significant lower 30-d mortality and higher clinical cure than COL (p = 0.008 and p = 0.0008, respectively). Increment of CCI (p = 0.005), ICU (p = 0.025), SARS-CoV2 (p = 0.006) and ECMO (p < 0.0001) were independently associated with 30-d mortality, while receiving CFDC was not associated with survival., Conclusions: CFDC could represent an effective and safe treatment option for CRAB BSI, especially in patients with bacteremic HAP/VAP and frail patients where the risk of acute renal failure during therapy should be avoided., (© 2024. The Author(s).)

Objectives: To perform a systematic review with meta-analysis to assess the clinical efficacy of cefiderocol-based regimens for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) infections., Methods: Two authors independently searched PubMed-MEDLINE, Scopus, and Cochrane databases, from inception to 02 July 2023, for randomised controlled trials (RCTs) or observational studies comparing clinical efficacy of cefiderocol-based vs. non-cefiderocol-based regimens in patients with CRAB infections. Data were extracted by the two authors independently, and the quality of included studies was independently assessed using ROB 2.0 or ROBINS-I tools. Primary outcome was mortality rate. Meta-analysis was performed by pooling odds ratios (ORs) retrieved from studies providing adjustment for confounders using a random-effects model with the inverse variance method. Multiple subgroups and sensitivity analyses were conducted to investigate the source of heterogeneity., Results: A total of 530 articles were screened, and 6 studies (1 RCT and 5 observational; N=561; 247 cefiderocol-based vs. 314 non-cefiderocol-based regimens) were included. Cefiderocol did not significantly reduce in-hospital mortality compared to alternative therapies (predominantly colistin-based), but the confidence intervals around the effect estimate included clinically important benefit (N=5; OR 0.64; 95%CI 0.40-1.04; I 2 =57.5%). When only observational studies providing adjustment for confounders were considered, a lower risk of mortality was found in patients treated with cefiderocol-based regimens (N=4; OR 0.53; 95%CI 0.39-0.71; I 2 =0.0%)., Conclusions: Cefiderocol-based regimens were associated with a significantly lower risk of mortality in patients with CRAB infections in observational studies providing proper adjustment for confounders., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Introduction . Colonization by carbapenem-resistant Acinetobacter baumannii (CRAB) causes therapeutic and economic problems for critically ill patients. Gap Statement . The analysis of CRAB in China was limited to certain regions. Aims . To investigate the antibiotic susceptibility, molecular characterization and clonal relationship among CRAB isolates from multiple hospitals of eastern China. Methodology . Isolates from 29 tertiary hospitals from September 2015 to September 2018 were recovered. All strains were analysed using antimicrobial susceptibility testing to detect their tolerance. PCR was also used to detect multiple β-lactamase genes. After multilocus sequence typing (MLST) of seven house-keeping genes. eBURST was used to assess clonal complexes and explore evolutionary relationships. Results . All isolates showed resistance to carbapenems, while remaining susceptible to colistin and tigecycline. All isolates were detected with bla OXA-51 gene by PCR, and 80.1 % harboured the bla OXA-23 gene. The prevalence of bla OXA-23 gene was remarkably increased from 50.7 % in 2015 to 90.5 % in 2018. Other genes such as bla OXA-24 , bla OXA-58 , bla IMP-2/4 , bla VIM-2 , bla SHV , bla AmpC and bla TEM were also obtained. While bla KPC , bla NDM-1 , bla IMP-4 and bla SIM-1 were not found in these strains. MLST showed all isolates could be divided into 26 known sequence types (STs) and ten novel STs and 47.2 % isolates belong to ST195 and ST208. eBURST revealed clonal complex 92 as the major clonal complex (98.4 %), which includes 88.5 % (23/26) of known STs and 80 % (8/10) of unknown STs. Phylogenetic analysis also found that almost all CRAB isolates could cluster into one lineage, suggesting an epidemic of this CRAB lineage. This indicated severe nosocomial infections of CRAB in multiple hospitals of eastern China. Conclusion . An outbreak of ST195 and ST208 CRAB-resistant clones with bla OXA-23 gene might be happening in multiple hospitals in eastern China.

Objectives: Mortality among patients with carbapenem-resistant Acinetobacter baumannii (CRAB) infections varies between studies. We examined whether in vivo fitness of CRAB strains is associated with clinical outcomes in patients with CRAB infections., Methods: Isolates were collected from patients enrolled in the AIDA trial with hospital-acquired pneumonia, bloodstream infections and/or urinary tract infections caused by CRAB. The primary outcome was 14-day clinical failure, defined as failure to meet all criteria: alive; haemodynamically stable; improved or stable Sequential Organ Failure Assessment (SOFA) score; improved or stable oxygenation; and microbiological cure of bacteraemia. The secondary outcome was 14-day mortality. We tested in vivo growth using a neutropenic murine thigh infection model. Fitness was defined based on the CFU count 24 hours after injection of an inoculum of 10 5  CFU. We used mixed-effects logistic regression to test the association between fitness and the two outcomes., Results: The sample included 266 patients; 215 (80.8%) experienced clinical failure. CRAB fitness ranged from 5.23 to 10.08 log CFU/g. The odds of clinical failure increased by 62% for every 1-log CFU/g increase in fitness (OR 1.62, 95% CI 1.04-2.52). After adjusting for age, Charlson score, SOFA score and acquisition in the intensive care unit, fitness remained significant (adjusted OR 1.63, 95% CI 1.03-2.59). CRAB fitness had a similar effect on 14-day mortailty, although the association was not statistically significant (OR 1.56, 95% CI 0.95-2.57). It became significant after adjusting for age, Charlson score, SOFA score and recent surgery (adjusted OR 1.88, 95% CI 1.09-3.25)., Conclusions: In vivo CRAB fitness was associated with clinical failure in patients with CRAB infection., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

A total of 54 unique clinical Acinetobacter baumannii strains isolated from cerebrospinal fluid (CSF) together with 21 bloodstream isolates collected from five tertiary hospitals in East China between April 2013 and November 2016 were studied for antimicrobial susceptibility patterns and the prevalence of antimicrobial resistance genes. Molecular epidemiological characteristics of CSF isolates and the phylogenetic relationship of isolates from different sources were assessed using multilocus sequence typing (MLST) and core genome MLST (cgMLST). Of the 54 CSF isolates, 51 (94.4%) were bla OXA-23 -carrying carbapenem-resistant A. baumannii. Their average resistance rate to different classes of antibiotics was extremely high (>90%), except for tigecycline and colistin. According to the Oxford MLST scheme, all CSF isolates fell into 10 defined sequence types (STs) and 4 novel STs. ST195 and ST208 were the leading STs in isolates from either source. A total of 50 CSF isolates and 20 bloodstream isolates were assigned to clonal complex 92 (CC92), revealing a wild distribution of CC92 in the hospitals of East China. In combination with epidemiological data linked in time and space, cgMLST results elucidated intrahospital and interhospital polyclonal dissemination of A. baumannii causing meningitis. Based on cgMLST, there was no correlation between phylogeny and the source of isolation of A. baumannii. These results emphasise that the genetic potential of this pathogen is vast enough to infect multiple human body sites., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Tigecycline is an alternative antibiotic for managing carbapenem-resistant Gram-negative bacterial infections. However, disk diffusion and automated testing often show false-intermediate or false-resistant results in tigecycline susceptibility, misleading clinical antimicrobial therapy. Broth microdilution (BMD) is the reference method for testing tigecycline susceptibility, but it is labor intensive and time consuming to perform in clinical laboratories. Therefore, a simple and accurate method is urgently needed. We evaluated the performance of VITEK 2, E-test, Kirby-Bauer disk diffusion (KB), and modified KB disk diffusion (mKB) versus BMD in testing tigecycline susceptibility of 372 strains of carbapenem-resistant Klebsiella pneumoniae (CRKP) and 346 strains of carbapenem-resistant Acinetobacter baumannii (CRAB). BMD confirmed that 96.8% of CRKP and 91% of CRAB strains were susceptible to tigecycline. E-test, VITEK 2, KB, and mKB yielded categorical agreement of 96.7/59.3%, 69.9/54.3%, 78.5/87.3%, and 96.5%/91% for CRKP/CRAB, respectively. No very major error was found for either CRKP or CRAB by any method. No major error was found for CRKP or CRAB by the mKB method. The mKB method enhanced by R-buffer is simple, accurate, and inexpensive for clinical laboratories to test the susceptibility of CRKP and CRAB isolates to tigecycline.

This study aimed to investigate the efficacy of colistin both alone and in combination with either meropenem or levofloxacin against CRAB clinical isolates. The OXA carbapenemase genes and multilocus sequence typing were detected after 35 CRAB isolates biochemical identification. Then, the minimum inhibitory concentrations, minimum bactericidal concentrations, antibiotic interactions of the test antibiotics, and synergistic effects were determined by the checkerboard method and time-kill assays. The chromosomal gene bla OXA-51-like was detected in all isolates, and bla OXA-23-like and bla OXA-24-like were present in 91.4% and 25.7% of the isolates, respectively. The combination of colistin and meropenem displayed the highest rate of synergy (51.4%) against the 35 isolates, while the colistin-levofloxacin combination showed a higher rate of indifference interaction (22.9%) than that of the colistin-meropenem (8.6%) combination. The synergistic effect of colistin against the CRAB isolates was confirmed. The combination of colistin with meropenem is recommended against CRAB isolates.

Aim: We sought to investigate the genetic epidemiological relatedness of carbapenem-resistant Acinetobacter baumannii (CRAB) strains of a suspected outbreak in a Lebanese tertiary care hospital to implement necessary infection prevention and control measures. Methods: Twenty-eight nonduplicate CRAB isolates detected among hospitalized patients between January 2016 and July 2017 were studied by real-time polymerase chain reaction (PCR), pulsed-field gel electrophoresis and multilocus sequence typing analyses. Results: Twenty-seven isolates harbored bla OXA-23 , of which one also carried bla NDM-1 . The isolates distributed temporally in two presumably episodes were stratified by pulsed-field gel electrophoresis into many clusters. Although several clones have become endemic in the hospital, we have rapidly implemented appropriate infection prevention and control measures, achieving full eradication from August 2017 to November 2019. Conclusion: We have successfully investigated and controlled a polyclonal outbreak of OXA-23 producing ST2 CRAB.

The aim of this study was to investigate the in vitro interactions of ambroxol hydrochloride (ABH) or amlodipine (AML) with commonly used antibacterial agents, including meropenem, imipenem-cilastatin sodium, biapenem, cefoperazone-sulbactam, polymyxin B, and tigecycline, against six carbapenem-resistant Acinetobacter baumannii (CRAB) clinical isolates. Drug interactions were interpreted using two models, that is, the fractional inhibitory concentration index (FICI) model and the percentage of growth difference (ΔE) model. The results show that a majority of the combination groups exhibited partial synergy and additive interactions, such as the combinations of carbapenems and cefoperazone-sulbactam (SCF) with ABH or AML. While the combination of PB/AML exhibited synergistic interactions against all tested isolates, and PB/ABH exhibited synergistic interactions against two isolates. The FICI and ΔE model correlated very well for the combinations of PBABH and PB/AML against AB2. The combinations of TGC with ABH or AML mainly exhibited additive and indifferent interactions. There were no antagonistic interactions observed in any of the combinations. In conclusion, this study revealed that the non-antibacterial agents ABH or AML can work synergistically or partial synergistically with antibacterial agents against CRAB. This finding is crucial for overcoming the carbapenem resistance of A. baumannii. SIGNIFICANCE AND IMPACT OF THE STUDY: Drug combination is an effective approach for the treatment of resistant bacterial infection. The significance of using drug combination is that it can reduce drug dosage requirements, reduce the toxic effects of agents and prevent or delay the emergence of drug resistance. This study measured the in vitro interactions between non-antimicrobial agents and antibacterial agents against carbapenem-resistant Acinetobacter baumannii and the results of this study provide new insight to find strategies to overcome the carbapenem resistance in A. baumannii., (© 2019 The Society for Applied Microbiology.)

Background: Infection with carbapenem-resistant Acinetobacter baumannii (CRAB) is an increasing problem for critically ill patients. The srains are frequently resistant to all antibiotics and disinfectants are often used to block the spread of these bacteria, playing an important role in infection control., Objectives: The aim of this study was to investigate the antibiotic susceptibility, the clonal relationship, disinfectant resistance gene, β-lactamase genes and the disinfectant sensitivity of 82 A. baumannii isolates collected at a large hospital in Wuhan, China., Design: A retrospective basic study., Methods: Here we investigated 82 A. baumannii isolates from intensive care unit patients in a major teaching hospital in China for the distribution of resistance-associated genes and susceptibility to chlorine disinfectant (CLR), benzalkonium bromide (BB) and Chlorhexidine gluconate(CHG). Multi-locus sequence typing (MLST) was applied to explore their genetic evolution relationships., Results: qacE (30.48%, 25/82) and qac△E1 (76.82%, 63/82) genes were detected in our study, while none were positive for qacA/B, qacC/D or qacG. The MIC values of CLR were 250mg/L; The MIC values ranged from 32 to 128μg/mL for BB; The MIC values ranged from 0.0019% to 0.0078% for CHG. The presence or absence of qacE gene has a significant impact(p＜0.05) on MICs of BB or CHG. All isolates harboured bla OXA-51/23 genes, and 98.78% of isolates contained the ISaba1 insertion sequence. All isolates were classified into 8 sequence types(STs) within clonal complex 92(CC92)., Conclusions: The predominant CRAB strains in our intensive care unit are bla OXA-23 -containing A. baumannii of CC92. The high prevalence of qac genes and reduced susceptibility to disinfectants confirm the need for continued vigilance against nosocomial infections., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

TP-6076 is a synthetic fluorocycline antibiotic that inhibits bacterial protein synthesis. In this study, carbapenem-resistant Acinetobacter baumannii clinical isolates from 13 Greek hospitals were tested for susceptibility to TP-6076 and comparator antibiotics. Broth microdilution plates were used to determine minimum inhibitory concentrations (MICs). A total of 121 non-duplicate A. baumannii isolates were tested. The MIC 50 and MIC 90 values of TP-6076 were 0.03 mg/L and 0.06 mg/L, respectively. Tigecycline was the second most active antibiotic (MIC 90 , 2 mg/L), followed by minocycline (MIC 90 , 8 mg/L). TP-6076 exhibited MIC 90 values that were one dilution lower against tigecycline- and minocycline-susceptible isolates than against resistant isolates. There was no difference in the MIC 90 value for colistin-susceptible or -resistant isolates. In conclusion, TP-6076 exhibited greater antimicrobial activity in vitro against carbapenem-resistant A. baumannii than comparator antibiotics., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: This study aimed to investigate antibiotic prescribing patterns and effectiveness of different anti-carbapenem-resistant Acinetobacter baumannii (CRAB) strategies for CRAB pneumonia., Methods: We conducted a multicentre, retrospective study in three hospitals. During 2010-2015, adult ICU patients with CRAB pneumonia treated with at least one antimicrobial agent covering the CRAB isolate in vitro for more than 2 days were included. We used multivariate logistic regression to analyse the associations of anti-CRAB strategies with ICU mortality and other clinical outcomes., Results: Among 238 patients with CRAB pneumonia, tigecycline monotherapy (84, 35.3%) was the most common antibiotic strategy, followed by tigecycline with colistin (43, 18.1%), colistin monotherapy (34, 14.3%), colistin combination without tigecycline (33, 13.9%), tigecycline combination without colistin (32, 13.4%), and sulbactam-based therapy without tigecycline and colistin (12, 5.0%). In multivariate analysis, tigecycline-based therapy was associated with higher ICU mortality than non-tigecycline therapy (adjusted OR 2.30, 95% CI 1.19-4.46). There was no difference between colistin-based therapy and non-colistin therapy. Compared with tigecycline monotherapy, colistin monotherapy was associated with lower ICU mortality (aOR 0.30, 95% CI 0.10-0.88). Treatment failure analyses showed similar trends. Tigecycline-based therapy was associated with higher treatment failure rate than non-tigecycline therapy (aOR 2.51, 95% CI 1.39-4.54), whereas colistin-based therapy was associated with lower treatment failure rate than non-colistin-based therapy (aOR 0.48, 95% CI 0.27-0.86)., Conclusions: Tigecycline was commonly prescribed for CRAB pneumonia. However, tigecycline-based therapy was associated with higher ICU mortality and treatment failure. Our study suggests that colistin monotherapy may be a better antibiotic strategy for CRAB pneumonia., (Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: In May 2015, we noticed an increase in carbapenem-resistant Acinetobacter baumannii (CRAB) infections in the Medical Intensive Care Unit (MICU). To investigate this, we studied the extent of environmental contamination and subsequent onward clonal transmission of CRAB., Methods: We conducted a one-day point prevalence screening (PPS) of the patients and environment in the MICU. We screened patients using endotracheal tube aspirates and swabs from nares, axillae, groin, rectum, wounds, and exit sites of drains. We collected environmental samples from patients' rooms and environment outside the patients' rooms. CRAB isolates from the PPS and clinical samples over the subsequent one month were studied for genetic relatedness by whole genome sequencing (WGS)., Results: We collected 34 samples from seven patients and 244 samples from the environment. On the day of PPS, we identified 8 CRAB carriers: 3 who screened positive and 5 previously known clinical infections. We detected environmental contamination in nearly two-thirds of the rooms housing patients with CRAB. WGS demonstrated genetic clustering of isolates within rooms but not across rooms. We analysed 4 CRAB isolates from clinical samples following the PPS. One genetically-related CRAB was identified in the respiratory sample of a patient with nosocomial pneumonia, who was admitted to the MICU five days after the PPS., Conclusion: The extensive environmental colonization of CRAB by patients highlights the importance of environmental hygiene. The transmission dynamics of CRAB needs further investigation., Competing Interests: This study was approved by the National Health Group of Singapore Domain Specific Review Board (NHG DSRB: 2014/00046).The authors report no conflict of interest relevant to this article.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is an important clinical threat. Combination therapy that exerts a synergistic effect has become a potential solution to combat CRAB. However, choosing an optimal combination regimen is challenging. A dynamic in vitro pharmacokinetic/pharmacodynamic (PK/PD) model that can simulate the pharmacokinetic profiles of antibiotics provides a powerful tool to compare antibacterial responses to different clinical dosage regimens. In this study, the synergistic effect of the combination of meropenem and colistin was tested in 12 clinical CRAB isolates from Chinese patients using the chequerboard technique. The antibacterial effect was investigated in an in vitro PK/PD diffusion model by simulating different dosage regimens: meropenem monotherapy (0.5 g with 0.5-h infusion or 1 g with 3-h infusion); colistin monotherapy (fixed unbound concentration maintained at 0.25, 0.5 or 1 mg/L); and combination of meropenem and colistin. The chequerboard method showed that the combination of meropenem and colistin had synergistic effects against all 12 isolates, with fractional inhibitory concentration indices (FICIs) of ≤0.5. Moreover, the dynamic in vitro PK/PD model demonstrated that for clinical CRAB isolates with a meropenem MIC of 128 mg/L, the combination (meropenem 1 g with 3-h infusion combined with colistin maintained at 1 mg/L) could achieve 3.8 log 10 killing after 24 h, whereas monotherapy was unable to provide such an antibacterial effect. Taken together, these results suggest that the combination of meropenem and colistin might be a promising therapy against CRAB., (Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Background: The emergence of carbapenem-resistant Acinetobacter baumannii (CRAB) complex has posed a great challenge to clinicians worldwide. Sitafloxacin has been shown to have in vitro activity against pathogens resistant to other fluoroquinolones. However, data comparing the anti-CRAB activity of sitafloxacin with that of other antimicrobial agents are limited., Methods: Genospecies were identified by 16S-23S ribosomal RNA intergenic spacer sequencing. Minimum inhibitory concentrations (MICs) were determined by an agar dilution method. Isolates with sitafloxacin MICs ≤ 2 mg/L were provisionally considered as susceptible to sitafloxacin. The MIC breakpoint for tigecycline susceptibility was 2 mg/L., Results: A total of 167 CRAB complex blood isolates (146 A. baumannii, 7 Acinetobacter pittii, and 14 Acinetobacter nosocomialis) were collected from January 2009 to December 2011. Around 90% of the A. baumannii isolates were resistant to amikacin, cefepime, ceftazidime, piperacillin/tazobactam, ampicillin/sulbactam, ciprofloxacin, and levofloxacin. By contrast, the rate of resistance to colistin, sitafloxacin, and tigecycline was relatively low (0%, 41.1%, and 65.1%, respectively). The MIC50 and MIC90 of ciprofloxacin, levofloxacin, and sitafloxacin were 128 mg/L and >128 mg/L; 16 mg/L and 64 mg/L; 2 mg/L and 8 mg/L, respectively. Compared with ciprofloxacin and levofloxacin, sitafloxacin had a significantly lower MIC (p < 0.001), and the rate of resistance to sitafloxacin was significantly lower than that to ciprofloxacin (97.9% vs. 41.1%, p < 0.001), levofloxacin (97.3% vs. 41.1%, p < 0.001), and tigecycline (p < 0.001)., Conclusion: Sitafloxacin has acceptable in vitro activity against CRAB, even against isolates resistant to other fluoroquinolones. Sitafloxacin may be considered an alternative drug of choice in treating CRAB related infections., (Copyright © 2014. Published by Elsevier B.V.)

Colistimethate sodium (CMS) is increasingly used to treat multidrug-resistant Gram-negative bacilli infections. However, the incidence of CMS-associated nephrotoxicity has not been evaluated in patients with carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia. This retrospective study included 120 patients with CRAB pneumonia treated with intravenous CMS for ≥72 h. The objective of the study was to determine risk factors for CMS-induced nephrotoxicity and 30-day mortality in patients with CRAB pneumonia. Of the 120 patients with CRAB pneumonia, 61 (51%) developed nephrotoxicity. Multivariate analysis showed that dose per ideal body weight (IBW) [odds ratio (OR)=1.28, 95% confidence interval (CI) 1.01-1.62; P=0.04], Charlson co-morbidity index (OR=1.31, 95% CI 1.06-1.60; P=0.01) and septic shock (OR=3.16, 95% CI 1.32-7.60; P=0.01) were associated with CMS-associated nephrotoxicity. Thirty-day mortality was 33% (39/120). Multivariate analysis showed that higher daily doses of CMS per IBW [hazard ratio (HR)=0.81, 95% CI 0.67-0.98; P=0.03] and longer duration of CMS therapy (HR=0.86, 95% CI 0.79-0.95; P=0.002) were associated with increased survival. Septic shock (HR=3.91, 95% CI 1.95-7.83; P<0.001) and corticosteroid use (HR=3.49, 95% CI 1.67-7.28; P=0.001) were associated with decreased survival in patients with CRAB pneumonia. Higher daily doses of CMS per IBW, Charlson comorbidity index and septic shock were significant risk factors for CMS-associated nephrotoxicity. However, CMS-associated nephrotoxicity does not appear to have an impact on mortality., (Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Carbapenem-resistant Acinetobacter baumannii (CRAB) is an increasingly common nosocomial pathogen. We sought to identify clinical and microbiological predictors of 14-day mortality among patients with CRAB bacteraemia. This case-control study included all adult patients in one Israeli hospital with CRAB on blood culture between July 2008 and June 2011. Cases were defined as patients who died within 14 days of bacteraemia onset and controls as patients who survived over 14 days. Sequence-typing of the blaOXA-51-like gene and REP-PCR identified CRAB clone groups. Logistic regression was performed to analyze predictors of 14-day all-cause mortality. To correct for differences in treatment onset, Cox regression was used to examine the effect of receiving an active antibiotic. Eighty-three cases and 89 controls were included. Six major CRAB clone groups were identified, with 14-day mortality ranging from 17 to 66%. Independent predictors of 14-day mortality were severity of illness (OR = 1.38 for each 1-point increase in Sequential Organ Failure Assessment (SOFA) score; 95% CI, 1.21, 1.56), independence in activities of daily living (ADL) on admission (OR = 3.40; 95% CI, 1.20, 9.67, for fully dependent vs. independent), surgery before bacteraemia (OR = 0.25; 95% CI, 0.11, 0.59) and clone group (OR = 7.76; 95% CI, 2.52, 23.85, for the most virulent group vs. the reference group). In the multivariate Cox model using a propensity score to adjust for SOFA, clone, ADL and surgery, active antibiotic treatment was protective (HR = 0.30; 95% CI, 0.15, 0.60). Differences in virulence between CRAB clones may partly explain heterogeneous results in previous studies of mortality following CRAB infection., (© 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.)

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAb) is 1 of the most problematic antimicrobial-resistant bacteria. We sought to elucidate the international epidemiology and clinical impact of CRAb. METHODS: In a prospective observational cohort study, 842 hospitalized patients with a clinical CRAb culture were enrolled at 46 hospitals in five global regions between 2017 and 2019. The primary outcome was all-cause mortality at 30 days from the index culture. The strains underwent whole-genome analysis. RESULTS: Of 842 cases, 536 (64%) represented infection. By 30 days, 128 (24%) of the infected patients died, ranging from 1 (6%) of 18 in Australia-Singapore to 54 (25%) of 216 in the United States and 24 (49%) of 49 in South-Central America, whereas 42 (14%) of non-infected patients died. Bacteremia was associated with a higher risk of death compared with other types of infection (40 [42%] of 96 vs 88 [20%] of 440). In a multivariable logistic regression analysis, bloodstream infection and higher age-adjusted Charlson comorbidity index were independently associated with 30-day mortality. Clonal group 2 (CG2) strains predominated except in South-Central America, ranging from 216 (59%) of 369 in the United States to 282 (97%) of 291 in China. Acquired carbapenemase genes were carried by 769 (91%) of the 842 isolates. CG2 strains were significantly associated with higher levels of meropenem resistance, yet non-CG2 cases were over-represented among the deaths compared with CG2 cases. CONCLUSIONS: CRAb infection types and clinical outcomes differed significantly across regions. Although CG2 strains remained predominant, non-CG2 strains were associated with higher mortality. Clinical Trials Registration. NCT03646227.