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Background: In clinical practice, the incidence of hypofibrinogenemia (HF) after tigecycline (TGC) treatment significantly exceeds the probability claimed by drug manufacturers. Objective: We aimed to identify the risk factors for TGC-associated HF and develop prediction and survival models for TGC-associated HF and the timing of TGC-associated HF. Methods: This single-center retrospective cohort study included 222 patients who were prescribed TGC. First, we used binary logistic regression to screen the independent factors influencing TGC-associated HF, which were used as predictors to train the extreme gradient boosting (XGBoost) model. Receiver operating characteristic curve (ROC), calibration curve, decision curve analysis (DCA), and clinical impact curve analysis (CICA) were used to evaluate the performance of the model in the verification cohort. Subsequently, we conducted survival analysis using the random survival forest (RSF) algorithm. A consistency index (C-index) was used to evaluate the accuracy of the RSF model in the verification cohort. Results: Binary logistic regression identified nine independent factors influencing TGC-associated HF, and the XGBoost model was constructed using these nine predictors. The ROC and calibration curves showed that the model had good discrimination (areas under the ROC curves (AUC) = 0.792 [95% confidence interval (CI), 0.668–0.915]) and calibration ability. In addition, DCA and CICA demonstrated good clinical practicability of this model. Notably, the RSF model showed good accuracy (C-index = 0.746 [95%CI, 0.652–0.820]) in the verification cohort. Stratifying patients treated with TGC based on the RSF model revealed a statistically significant difference in the mean survival time between the low- and high-risk groups. Conclusions: The XGBoost model effectively predicts the risk of TGC-associated HF, whereas the RSF model has advantages in risk stratification. These two models have significant clinical practical value, with the potential to reduce the risk of TGC therapy. [ABSTRACT FROM AUTHOR]

Background: Klebsiella pneumoniae is the most commonly encountered pathogen in clinical practice. Widespread use of broad-spectrum antibiotics has led to the current global dissemination of carbapenem-resistant K. pneumoniae, which poses a significant threat to antibacterial treatment efficacy and public health. Outer membrane vesicles (OMVs) have been identified as carriers capable of facilitating the transfer of virulence and resistance genes. However, the role of OMVs in carbapenem-resistant K. pneumoniae under external pressures such as antibiotic and phage treatments remains unclear. Methods: To isolate and purify OMVs under the pressure of phages and tigecycline, we subjected K. pneumoniae 0692 harboring plasmid-mediated blaNDM-1 and blaKPC-2 genes to density gradient separation. The double-layer plate method was used to isolate MJ1, which efficiently lysed K. pneumoniae 0692 cells. Transmission electron microscopy (TEM) was used to characterize the isolated phages and extract OMV groups for relevant morphological identification. Determination of protein content of each OMV group was conducted through bicinchoninic acid assay (BCA) and proteomic analysis. Results: K. pneumoniae 0692 released OMVs in response to different environmental stimuli, which were characterized through TEM as having the typical structure and particle size of OMVs. Phage or tigecycline treatment alone resulted in a slight increase in the mean protein concentration of OMVs secreted by K. pneumoniae 0692 compared to that in the untreated group. However, when phage treatment was combined with tigecycline, there was a significant reduction in the average protein concentration of OMVs compared to tigecycline treatment alone. Proteomics showed that OMVs encapsulated numerous functional proteins and that under different external stresses of phages and tigecycline, the proteins carried by K. pneumoniae 0692-derived OMVs were significantly upregulated or downregulated compared with those in the untreated group. Conclusions: This study confirmed the ability of OMVs to carry abundant proteins and highlighted the important role of OMV-associated proteins in bacterial responses to phages and tigecycline, representing an important advancement in microbial resistance research. [ABSTRACT FROM AUTHOR]

Background: A novel plasmid-mediated resistance–nodulation–division (RND) efflux pump gene cluster tmexCD1-toprJ1 in Klebsiella pneumoniae tremendously threatens the use of convenient therapeutic options in the post-antibiotic era, including the "last-resort" antibiotic tigecycline. Results: In this work, the natural alkaloid harmaline was found to potentiate tigecycline efficacy (4- to 32-fold) against tmexCD1-toprJ1-positive K. pneumoniae, which also thwarted the evolution of tigecycline resistance. Galleria mellonella and mouse infection models in vivo further revealed that harmaline is a promising candidate to reverse tigecycline resistance. Inspiringly, harmaline works synergistically with tigecycline by undermining tmexCD1-toprJ1-mediated multidrug resistance efflux pump function via interactions with TMexCD1-TOprJ1 active residues and dissipation of the proton motive force (PMF), and triggers a vicious cycle of disrupting cell membrane integrity and metabolic homeostasis imbalance. Conclusion: These results reveal the potential of harmaline as a novel tigecycline adjuvant to combat hypervirulent K. pneumoniae infections. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance poses a global threat to human health. Analyzing monitoring data on antimicrobial resistance can assist clinicians in making strategic decisions and promptly identifying outbreaks of antimicrobial-resistant organisms. The China Antimicrobial Surveillance Network (CHINET) was established in 2004 to monitor the trends in bacterial epidemiology and antimicrobial resistance. In this study, we analyzed the distribution and changing antimicrobial resistance profiles of Enterobacter spp. isolated from 53 hospitals across China between 2015 and 2021 using the CHINET data. Over the seven-year period, a total of 37,966 clinical isolates of Enterobacter spp. were obtained, accounted for 2.5% of all isolates and 5.7% of Enterobacteriaceae isolates. Among those isolates, Enterobacter cloacae was the most prevalent, comprising 93.7% (35,571/37,966). The majority of strains were isolated from respiratory tract samples (44.6%), followed by secretion, pus (16.4%), and urine samples (16.0%). As for patient composition, 37,966 Enterobacter spp. strains were predominantly isolated from inpatients (92.9%), whereas 7.1% were isolated from outpatients and emergency patients. Among inpatients, isolates from patients in surgical ward accounted for the highest percentage (24.4%). E. cloacae exhibited the lowest rates of resistance to amikacin, tigecycline, polymyxin B, imipenem, and meropenem (resistance rates < 8%). However, the percentage of carbapenem-resistant Enterobacter spp. was 10.0%, presenting a rising tendency over the 7-year study period. Antimicrobial resistance profiles of Enterobacter spp. isolates varied according to the department of isolation and patient age (adult or child), with the intensive care unit having the highest proportion of carbapenem-resistant Enterobacter spp. isolates. [ABSTRACT FROM AUTHOR]

Multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) is a formidable pathogen responsible for severe intracranial infections post-craniotomy, exhibiting a mortality rate as high as 71%. Tigecycline (TGC), a broad-spectrum antibiotic, emerged as a potential therapeutic agent for MDR A. baumannii infections. Nonetheless, its clinical application was hindered by a short in vivo half-life and limited permeability through the blood–brain barrier (BBB). In this study, we prepared a novel core–shell nanoparticle encapsulating water-soluble tigecycline using a blend of mPEG-PLGA and PLGA materials. This nanoparticle, modified with a dual-targeting peptide Aβ11 and Tween 80 (Aβ11/T80@CSs), was specifically designed to enhance the delivery of tigecycline to the brain for treating A. baumannii-induced intracranial infections. Our findings demonstrated that Aβ11/T80@CSs nanocarriers successfully traversed the BBB and effectively delivered TGC into the cerebrospinal fluid (CSF), leading to a significant therapeutic response in a model of MDR A. baumannii intracranial infection. This study offers initial evidence and a platform for the application of brain-targeted nanocarrier delivery systems, showcasing their potential in administering water-soluble anti-infection drugs for intracranial infection treatments, and suggesting promising avenues for clinical translation. [ABSTRACT FROM AUTHOR]

Background Klebsiella variicola is considered a newly emerging human pathogen. Clinical isolates of carbapenemase and broad-spectrum β-lactamase-producing K. variicola remain relatively uncommon. A strain of K. variicola 4253 was isolated from a clinical sample, and was identified to carry the blaIMP−4 and blaSFO−1 genes. This study aims to discern its antibiotic resistance phenotype and genomic characteristics. Methods Species identification was conducted using MALDI-TOF/MS. PCR identification confirmed the presence of the blaIMP−4 and blaSFO−1 genes. Antibiotic resistance phenotype and genomic characteristics were detected by antimicrobial susceptibility testing and whole-genome sequencing. Plasmid characterization was carried out through S1-PFGE, conjugation experiments, Southern blot, and comparative genomic analysis. Results K. variicola 4253 belonged to ST347, and demonstrated resistance to broad-spectrum β-lactamase drugs and tigecycline while being insensitive to imipenem and meropenem. The blaIMP−4 and blaSFO−1 genes harbored on the plasmid p4253-imp. The replicon type of p4253-imp was identified as IncHI5B, representing a multidrug-resistant plasmid capable of horizontal transfer and mediating the dissemination of drug resistance. The blaIMP−4 gene was located on the In809-like integrative element (Intl1-blaIMP−4-aacA4-catB3), which circulates in Acinetobacter and Enterobacteriaceae. Conclusions This study reports the presence of a strain of K. variicola, which is insensitive to tigecycline, carrying a plasmid harboring blaIMP−4 and blaSFO−1. It is highly likely that the strain acquired this plasmid through horizontal transfer. The blaIMP−4 array (Intl1-blaIMP−4-aacA4-catB3) is also mobile in Acinetobacter and Enterobacteriaceae. So it is essential to enhance clinical awareness and conduct epidemiological surveillance on multidrug-resistant K. variicola, conjugative plasmids carrying blaIMP−4, and the In809 integrative element. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to characterise the whole-genome structure of two clinical Klebsiella pneumoniae strains co-harbouring mcr-8.1 and tmexCD1-toprJ1, both resistant to colistin and tigecycline. Methods: K. pneumoniae strains TGC-02 (ST656) and TGC-05 (ST273) were isolated from urine samples of different patients hospitalised at separate times in 2021. Characterisation involved antimicrobial susceptibility testing (AST), conjugation assays, whole-genome sequencing (WGS), and bioinformatics analysis. Comparative genomic analysis was conducted on mcr-8.1-carrying and tmexCD1-toprJ1-carrying plasmids. Results: Both K. pneumoniae isolates displayed a multidrug-resistant phenotype, exhibiting resistance or reduced susceptibility to ampicillin, ampicillin/sulbactam, cefazolin, aztreonam, amikacin, gentamicin, tobramycin, ciprofloxacin, levofloxacin, nitrofurantoin, trimethoprim/sulfamethoxazole, apramycin, tigecycline and colistin. WGS analysis revealed that clinical strain TGC-02 carried the TmexCD1-toprJ1 gene on a 200-Kb IncFII/IncFIB-type plasmid, while mcr-8 was situated on a 146-Kb IncFII-type plasmid. In clinical strain TGC-05, TmexCD1-toprJ1 was found on a 300-Kb IncFIB/IncHI1B/IncR-type plasmid, and mcr-8 was identified on a 137-Kb IncFII/IncFIA-type plasmid. Conjugation experiments assessed the transferability of these plasmids. While transconjugants were not obtained for TGC-05 despite multiple screening with tigecycline or colistin, pTGC-02-tmex and pTGC-02-mcr8 from clinical K. pneumoniae TGC-02 demonstrated self-transferability through conjugation. Notably, the rearrangement of pTGC-02-tmex and pTGC-02-mcr8 via IS26-based homologous recombination was observed. Moreover, the conjugative and fusion plasmids of the transconjugant co-harboured the tmexCD1-toprJ1 gene cluster and mcr-8.1, potentially resulting from IS26-based homologous recombination. Conclusion: The emergence of colistin- and tigecycline-resistant K. pneumoniae strains is concerning, and effective surveillance measures should be implemented to prevent further dissemination. [ABSTRACT FROM AUTHOR]

The emergence and worldwide dissemination of mobile tigecycline resistance genes tet(X3)/tet(X4) posed an enormous threat to the public health. Urgently, feasible strategies must be implemented to restore the clinical efficacy of tetracyclines and prolong the lifespan of existing drugs to address the emerging global antimicrobial resistance threat. Herein, versatile structural scaffolds of quinones for antibiotic adjuvants discovery enlightened a promising and underappreciated reservoir to circumvent the antibiotic resistance. 2-methoxy-1,4-naphthoquinone (MNQ) exhibited the potent potentiation (4 to 32-fold) with tetracyclines, along with effective inhibition on biofilm formation. Mechanistic studies revealed that MNQ synergistically operates with tetracyclines by inhibiting the enzymatic activity of Tet(X3)/Tet(X4) proteins through interaction with their active residues. Furthermore, exposure to MNQ significantly dissipate the proton motive force, leading to a cascade of membrane structural damage and metabolic homeostasis imbalance. Encouragingly, the MNQ-tetracyclines combination showcased substantial therapeutic benefits in two in vivo infection models, as evidenced by the reduced bacterial burden and mitigated pathological injury. Our findings propose a potential therapeutic option and a novel tetracyclines' adjuvant against drug-resistant pathogens carrying Tet(X3)/Tet(X4). [ABSTRACT FROM AUTHOR]

Background: Despite recent advances in locoregional, systemic, and novel checkpoint inhibitor treatment, hepatocellular carcinoma (HCC) is still associated with poor prognosis. The feasibility of potentially curative liver resection (LR) and transplantation (LT) is limited by the underlying liver disease and a shortage of organ donors. Especially after LR, high recurrence rates present a problem and circulating tumor cells are a major cause of extrahepatic recurrence. Tigecycline, a commonly used glycylcycline antibiotic, has been shown to have antitumorigenic effects and could be used as a perioperative and adjuvant therapeutic strategy to target circulating tumor cells. We aimed to investigate the effect of tigecycline on HCC cell lines and its mechanisms of action. Methods: Huh7, HepG2, Hep3B, and immortalized hepatocytes underwent incubation with clinically relevant tigecycline concentrations, and the influence on proliferation, migration, and invasion was assessed in two- and three-dimensional in vitro assays, respectively. Bioinformatic analysis was used to identify specific targets of tigecycline. The expression of RAC1 was detected using western blot, RT-PCR and RNA sequencing. ELISA and flow cytometry were utilized to measure reactive oxygen species (ROS) generation upon tigecycline treatment and flow cytometry to detect alterations in cell cycle. Changes in mitochondrial function were detected via seahorse analysis. RNA sequencing was performed to examine involved pathways. Results: Tigecycline treatment resulted in a significant reduction of mitochondrial function with concomitantly preserved mitochondrial size, which preceded the observed decrease in HCC cell viability. The sensitivity of HCC cells to tigecycline treatment was higher than that of immortalized non-cancerous THLE-2 hepatocytes. Tigecycline inhibited both migratory and invasive properties. Tigecycline application led to an increase of detected ROS and an S-phase cell cycle arrest. Bioinformatic analysis identified RAC1 as a likely target for tigecycline and the expression of this molecule was increased in HCC cells as a result of tigecycline treatment. Conclusion: Our study provides evidence for the antiproliferative effect of tigecycline in HCC. We show for the first time that this effect, likely to be mediated by reduced mitochondrial function, is associated with increased expression of RAC1. The reported effects of tigecycline with clinically relevant and achievable doses on HCC cells lay the groundwork for a conceivable use of this agent in cancer treatment. [ABSTRACT FROM AUTHOR]

Background: We investigated the associations between the different doses of tigecycline, its efficacy and safety, and the role of tigecycline therapeutic drug monitoring for patients in the intensive care unit. Methods: This study was a single-center cohort including patients infected with multidrug-resistant Acinetobacter baumannii (MDR-AB) and multidrug-resistant Klebsiella pneumoniae (MDR-KP) causing pulmonary infections. The steady-state plasma concentration after tigecycline administration was determined by High-Performance Liquid Chromatography (HPLC) in patients admitted to the ICU between October 2020 and December 2021. Multivariate analyses of tigecycline's clinical efficacy and safety were performed to control confounding factors. Results: For this study, we included 45 patients and 45 blood samples to determine steady-state trough concentrations of tigecycline. All patients were divided into the High Dose (HD) and Standard Dose (SD) groups. The median trough concentration of tigecycline was 0.56 μg/mL in the HD group, which was higher than in the SD group (0,21 μg/mL), p = 0.000. There was no significant difference between the two groups of patients in terms of bacterial eradication rate, mortality rate, and clinical efficacy. Multiple regression analysis showed that the ICU days were correlated with mortality OR 1.030(1.005–1.056), p = 0.017. APACHE II was significantly associated with clinical efficacy OR 0.870(0.755–1.002), p = 0.045. The level of fibrinogen decline in the HD group was significantly higher than in the SD group (-3.05 ± 1.67 vs -1.75 ± 1.90), p = 0.038. We identified that age and tigecycline treatment duration influenced fibrinogen decline. Conclusions: Tigecycline plasma concentrations are significantly increased when using a high dose. However, the plasma concentration of tigecycline is not correlated with clinical efficacy and adverse reactions. Fibrinogen decline appears to be related to the patient's age and days of tigecycline. Large sample data are still needed to confirm the clinical guidance significance of tigecycline TDM. [ABSTRACT FROM AUTHOR]

The emergence and prevalence of plasmid-encoded RND-type efflux pump TMexCD-TOprJ severely compromise tigecycline treatment, which is recognized as the last resort for multidrug-resistant (MDR) Gram-negative bacterial infections. There is an urgent need for rapid antibiotic susceptibility testing (AST) that can simultaneously identify the genotype and phenotype of tmexCD-toprJ-positive bacteria. Through characterizing transcriptional profiling responses of tmexCD-toprJ-positive and -negative strains after exposure to 2 μg/mL tigecycline, here we identified 12 differentially RNA biomarkers and developed an RNA-based AST (RBAST) to distinguish tmexCD-toprJ-positive and -negative K. pneumoniae. These mRNA biomarkers were successfully validated in tigecycline exposure time variations, concentration shifts, and other tmexCD-toprJ variants. In addition, a group of clinical isolated strains was effectively distinguished using RBAST, with an accuracy of over 94% during 3 h test period. Our work highlights the potential of RNA transcripts as biomarkers for rapid AST, which will contribute to deploying effective antibiotic regimens in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Infection with extensive-drug-resistant (XDR) carbapenem-resistant (CR) Gram-negative bacteria (GNB) are viewed as a serious threat to human health because of the limited therapeutic options. This imposes the urgent need to find agents that could be used as adjuvants or combined with carbapenems to enhance or restore the susceptibility of XDR CR- GNB. Therefore, this study aimed to examine the effect of propranolol (PR) in combination with Meropenem (MEM) on the susceptibility profile of XDR CR-GNB recovered from severely infected patients as well as to evaluate combining MEM with either tigecycline (TGC) or amikacin (AK). Methods: A total of 59 non-duplicate CR- GNB were investigated for carbapenemase production by the major phenotypic methods. Molecular identification of five major carbapenemase-coding genes was carried out using polymerase chain reactions (PCR). Antimicrobial susceptibility tests were carried out using standard methods. Phenotypic and genotypic relatedness was carried out using the heatmap and ERIC PCR analysis. PR, 0.5 -1 mg/mL against the resulting non-clonal XDR CR-GNB pathogens were evaluated by calculating the MIC decrease factor (MDF). A combination of MEM with either AK or TGC was performed using the checkerboard assay. Results: A total of 21 (35.6%) and 38 (64.4%) CR-GNB isolates were identified as enterobacterial isolates (including 16 (27.1%) Klebsiella Pneumoniae and 5 (8.5%) Escherichia coli) and non-fermentative bacilli (including, 23 (39%), Acinetobacter baumannii, and 15 (25.4%) Pseudomonas aeruginosa). The heatmap and ERIC PCR analysis resulted in non-clonal 28 XDR CR isolates. PR, at a concentration of 0.5 mg /ml, decreased MICs values of the tested XDR CR isolates (28; 100%) and restored susceptibility of only 4 (14.3%) isolates. However, PR (1 mg/mL) when combined with MEM has completely (28; 100%) restored the susceptibility of the tested XDR CR- GNB to MEM. The MEM + AK and MEM + TGC combination showed mostly additive effects (92.8% and 71.4%, respectively). Conclusion: PR at a concentration of 1 mg/mL restored the susceptibility of XDR CR- GNB to MEM which is considered a promising result that should be clinically investigated to reveal its suitability for clinical use in patients suffering from these life-threatening pathogens. [ABSTRACT FROM AUTHOR]

Background: We investigated the presence of heteroresistance against both tigecycline and colistin in Acinetobacter baumannii and then evaluated the effectiveness of combined antibiotic treatment given the existence of discrete tigecycline- and colistin-resistant subpopulations. Methods: We performed population analysis profiling (PAP) to evaluate the degree of composite heteroresistance in A. baumannii isolates, with the extent of this resistance quantified using subsequent antibiotic susceptibility testing. We then evaluated the amino acid sequence of PmrBAC and the relative mRNA expression levels of pmrB. Finally, we investigated the combined antibiotic efficacy of tigecycline and colistin in multiple-heteroresistant isolates using dual PAP and in vitro time-killing assays. Results: All tigecycline-heteroresistant A. baumannii isolates, with the exception of one colistin-resistant isolate, were also heteroresistant to colistin. Evaluations of the colistin-resistant subpopulations revealed amino acid alterations in PmrA and PmrB and increased expression of pmrB. All tigecycline-resistant subpopulations were susceptible to colistin, and all colistin-resistant subpopulations were susceptible to tigecycline. Dual PAP analysis using tigecycline and colistin showed no heteroresistance, and in vitro time-killing assays revealed that a combination of these two antibiotics effectively eliminated the bacterial cells. Conclusion: Our results suggest that multiple heteroresistance to tigecycline and colistin is highly prevalent among A. baumannii clinical isolates and that these resistant subpopulations exist independently in single multiple heteroresistant isolates. Therefore, our findings may explain the success of combined antibiotic therapies in these infections. [ABSTRACT FROM AUTHOR]

Background: The development of tigecycline resistance in hypervirulent Klebsiella pneumoniae strains has resulted in decreased virulence that is associated with reduced production of capsular polysaccharides (CPS). In this study, we investigated the mechanisms that link tigecycline susceptibility to decreased virulence. Methods: We compared transcriptomes from tigecycline-susceptible wild-type strains and tigecycline-resistant mutants using mRNA sequencing. ompR-overexpressed and ompR-deleted mutants were constructed from wild-type strains and tigecycline-resistant mutants, respectively. Antibiotic susceptibility tests were performed, and string tests and precipitation assays were conducted to identify phenotypic changes related to tigecycline susceptibility and ompR expression. Bacterial virulence was assessed by serum resistance and Galleria mellonella infection assays. Results: Transcriptomic analyses demonstrated a significant decrease in the expression of ompK35 in the tigecycline-resistant mutants. We observed that tigecycline-resistant mutants overexpressed ompR, and that the expression of ompK35 was regulated negatively by ompR. While tigecycline-resistant mutants and ompR-overexpressed mutants exhibited reduced hypermucoviscosity and virulence, deletion of ompR from tigecycline-resistant mutants restored their hypermucoviscosity and virulence. Conclusions: In hypervirulent K. pneumoniae strains, ompR expression, which is regulated by exposure to tigecycline, may affect the production of CPS, leading to bacterial virulence. [ABSTRACT FROM AUTHOR]

Background: The emergence of carbapenem-resistant Enterobacterales (CRE) continues to threaten public health due to limited therapeutic options. In the current study the incidence of carbapenem resistance among the 104 clinical isolates of Escherichia coli and the genomic features of carbapenem resistant isolates were investigated. Methods: The susceptibility to imipenem, tigecycline and colistin was tested by broth dilution method. Susceptibility to other classes of antimicrobials was examined by disk diffusion test. The presence of blaOXA-48, blaKPC, blaNDM, and blaVIM carbapenemase genes was examined by PCR. Molecular characteristics of carbapenem resistant isolates were further investigated by whole-genome sequencing (WGS) using Illumina and Nanopore platforms. Results: Four isolates (3.8%) revealed imipenem MIC of ≥32 mg/L and positive results for modified carbapenem inactivation method and categorized as carbapenem resistant E. coli (CREC). Colistin, nitrofurantoin, fosfomycin, and tigecycline were the most active agents against all isolates (total susceptibility rate of 99, 99, 96 and 95.2% respectively) with the last three compounds being found as the most active antimicrobials for carbapenem resistant isolates (susceptibility rate of 100%). According to Multilocus Sequence Type (MLST) analysis the 4 CREC isolates belonged to ST167 (n = 2), ST361 (n = 1) and ST648 (n = 1). NDM was detected in all CREC isolates (NDM-1 (n = 1) and NMD-5 (n = 3)) among which one isolate co-harbored NDM-5 and OXA-181 carbapenemases. WGS further detected blaCTX-M-15, blaCMY-145, blaCMY-42 and blaTEM-1 (with different frequencies) among CREC isolates. Co-occurrence of NDM-type carbapenemase and 16S rRNA methyltransferase RmtB and RmtC was found in two isolates belonging to ST167 and ST648. A colistin-carbapenem resistant isolate which was mcr-negative, revealed various amino acid substitutions in PmrB, PmrD and PhoPQ proteins. Conclusion: About 1.9% of E. coli isolates studied here were resistant to imipenem, colistin and/or amikacin which raises the concern about the outbreaks of difficult-to-treat infection by these emerging superbugs in the future. [ABSTRACT FROM AUTHOR]

Background: Tigecycline has in vitro bacteriostatic activity against a broad spectrum of bacteria, including carbapenem-resistant Gram-negative bacteria (CR-GNB). However, the role of tigecycline in treatment of nosocomial pneumonia caused by CR-GNB remains controversial and clinical evidences are limited. We aimed to investigate the clinical benefits of tigecycline as part of the combination treatment of nosocomial CR-GNB pneumonia in intensive care unit (ICU). Methods: This multi-centre cohort study retrospectively enrolled ICU-admitted patients with nosocomial pneumonia caused by CR-GNB. Patients were categorized based on whether add-on tigecycline was used in combination with at least one anti-CR-GNB antibiotic. Clinical outcomes and all-cause mortality between patients with and without tigecycline were compared in the original and propensity score (PS)-matched cohorts. A subgroup analysis was also performed to explore the differences of clinical efficacies of add-on tigecycline treatment when combined with various anti-CR-GNB agents. Results: We analysed 395 patients with CR-GNB nosocomial pneumonia, of whom 148 received tigecycline and 247 did not. More than 80% of the enrolled patients were infected by CR-Acinetobacter baumannii (CRAB). A trend of lower all-cause mortality on day 28 was noted in tigecycline group in the original cohort (27.7% vs. 36.0%, p = 0.088). In PS-matched cohort (102 patient pairs), patients with tigecycline had significantly lower clinical failure (46.1% vs. 62.7%, p = 0.017) and mortality rates (28.4% vs. 52.9%, p < 0.001) on day 28. In multivariate analysis, tigecycline treatment was a protective factor against clinical failure (PS-matched cohort: aOR 0.52, 95% CI 0.28–0.95) and all-cause mortality (original cohort: aHR 0.69, 95% CI 0.47–0.99; PS-matched cohort: aHR 0.47, 95% CI 0.30–0.74) at 28 days. Kaplan–Meier survival analysis in subgroups of patients suggested significant clinical benefits of tigecycline when added to a colistin-included (log rank p value 0.005) and carbapenem-included (log rank p value 0.007) combination regimen. Conclusions: In this retrospective observational study that included ICU-admitted patients with nosocomial pneumonia caused by tigecycline-susceptible CR-GNB, mostly CRAB, tigecycline as part of a combination treatment regimen was associated with lower clinical failure and all-cause mortality rates. [ABSTRACT FROM AUTHOR]

Background: There have been no reports of tigecycline-associated drug-related liver injury (DILI) identified by histopathological assistance and causal assessment method. We reported the histopathological manifestations for the first time and described tigecycline-associated liver injury's pattern, severity, duration, and outcome.Case Presentation: A 68-year-old male with post-liver transplantation was given high-dose tigecycline intravenously (loading dose 200 mg, followed by 100 mg every 12 h) combined with polymyxin B (50,000 units by aerosol inhalation every 12 h) for hospital-acquired pneumonia caused by carbapenem-resistant Klebsiella pneumoniae. At the same time, tacrolimus was discontinued. Liver function was initially normal but started to decline on day 4 of tigecycline. Reducing the dose of tigecycline and resuming tacrolimus could not reverse the deterioration. Therefore, a liver puncture biopsy was performed for further diagnosis, with histopathological findings being cytotoxic injury. The updated RUCAM scale was used to evaluate the causal relationship between tigecycline and liver injury, with the result of 7 points indicating a "probable" causality grading. Methylprednisolone was initiated to treat DILI that was determined to be Grade 1 cholestatic injury. Total bilirubin and transaminase levels returned to normal on day 4 and 11 after tigecycline withdrawal, respectively. Monthly outpatient follow-up showed that the patient's liver function stayed normal.Conclusions: This case possessed a significant reference value for differential diagnosis and treatment prognosis of tigecycline-associated DILI. With early diagnosis and timely management, the tigecycline-associated DILI of this patient was successfully reversed. [ABSTRACT FROM AUTHOR]

Background: Tigecycline has broad-spectrum anti-bacterial activity and often used for critically ill patients with complicated infections. Only a few clinical studies have reported the coagulation disorder induced by tigecycline. The aim of this study was to investigate the association between tigecycline and coagulation dysfunction using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Method: Data from January 2005 to December 2020 in FAERS were retrieved. We investigated the clinical characteristics of the coagulation dysfunction events and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare tigecycline with the full database and other antibiotics. Results: The total number of reports of coagulation dysfunction related to tigecycline as the primary suspect drug was 223. The median time to event of the coagulation dysfunction events was 10 (interquartile range [IQR] 6.75–13) days. 80.72% coagulation-related adverse events appeared within the first 14 days since the initiation of tigecycline administration. The overall ROR (95% CI) for coagulation-related adverse events was 3.55 (3.08, 4.09). The RORs (95% CI) for thrombocytopenia, hypofibrinogenaemia, coagulopathy, activated partial thromboplastin time prolonged, international normalized ratio increased, prothrombin time prolonged were 8.21 (6.34, 10.62), 705.41 (526.81, 944.54), 30.67 (21.92, 42.92), 42.98 (24.85, 74.31), 4.67 (2.51, 8.71), and 27.99 (15.01, 52.19), respectively. In analyses stratified on comparing tigecycline to vancomycin and daptomycin, significant coagulation dysfunction signals were found with the RORs (95% CI) 2.74 (2.34, 3.22) and 3.08 (2.57, 3.70). Conclusions: We found a strong signal of high frequency of reporting coagulation dysfunction in tigecycline. Health professionals should be aware of the potential coagulation disorders risk and monitor coagulation parameters during anti-bacterial therapy with tigecycline, particularly the need to monitor fibrinogen levels. [ABSTRACT FROM AUTHOR]

Background: Prevalence of extended-spectrum beta-lactamase-producing-Enterobacteriaceae (ESBL-E) has risen in patients with urinary tract infections. The objective of this study was to determine explore the risk factors of ESBL-E infection in hospitalized patients and establish a predictive model.Methods: This retrospective study included all patients with an Enterobacteriaceae-positive urine sample at the first affiliated hospital of Jinan university from January 2018 to December 2019. Antimicrobial susceptibility patterns of ESBL-E were analyzed, and multivariate analysis of related factors was performed. From these, a nomogram was established to predict the possibility of ESBL-E infection. Simultaneously, susceptibility testing of a broad array of carbapenem antibiotics was performed on ESBL-E cultures to explore possible alternative treatment options.Results: Of the total 874 patients with urinary tract infections (UTIs), 272 (31.1%) were ESBL-E positive. In the predictive analysis, five variables were identified as independent risk factors for ESBL-E infection: male gender (OR = 1.607, 95% CI 1.066-2.416), older age (OR = 4.100, 95% CI 1.678-12.343), a hospital stay in preceding 3 months (OR = 1.872, 95% CI 1.141-3.067), invasive urological procedure (OR = 1.810, 95% CI 1.197-2.729), and antibiotic use within the previous 3 months (OR = 1.833, 95% CI 1.055-3.188). In multivariate analysis, the data set was divided into a training set of 611 patients and a validation set of 263 patients The model developed to predict ESBL-E infection was effective, with the AuROC of 0.650 (95% CI 0.577-0.725). Among the antibiotics tested, several showed very high effectiveness against ESBL-E: amikacin (85.7%), carbapenems (83.8%), tigecycline (97.1%) and polymyxin (98.2%).Conclusions: The nomogram is useful for estimating a UTI patient's likelihood of infection with ESBL-E. It could improve clinical decision making and enable more efficient empirical treatment. Empirical treatment may be informed by the results of the antibiotic susceptibility testing. [ABSTRACT FROM AUTHOR]

Background: Tigecycline is a tetracycline derivative that constitutes one of the last-resort antibiotics used clinically to treat infections caused by both multiple drug-resistant (MDR) Gram-negative and Gram-positive bacteria. Resistance to this drug is often caused by chromosome-encoding mechanisms including over-expression of efflux pumps and ribosome protection. However, a number of variants of the flavin adenine dinucleotide (FAD)-dependent monooxygenase TetX, such as Tet(X4), emerged in recent years as conferring resistance to tigecycline in strains of Enterobacteriaceae, Acinetobacter sp., Pseudomonas sp., and Empedobacter sp. To date, mechanistic details underlying the improvement of catalytic activities of new TetX enzymes are not available. Results: In this study, we found that Tet(X4) exhibited higher affinity and catalytic efficiency toward tigecycline when compared to Tet(X2), resulting in the expression of phenotypic tigecycline resistance in E. coli strains bearing the tet(X4) gene. Comparison between the structures of Tet(X4) and Tet(X4)-tigecycline complex and those of Tet(X2) showed that they shared an identical FAD-binding site and that the FAD and tigecycline adopted similar conformation in the catalytic pocket. Although the amino acid changes in Tet(X4) are not pivotal residues for FAD binding and substrate recognition, such substitutions caused the refolding of several alpha helixes and beta sheets in the secondary structure of the substrate-binding domain of Tet(X4), resulting in the formation of a larger number of loops in the structure. These changes in turn render the substrate-binding domain of Tet(X4) more flexible and efficient in capturing substrate molecules, thereby improving catalytic efficiency. Conclusions: Our works provide a better understanding of the molecular recognition of tigecycline by the TetX enzymes; these findings can help guide the rational design of the next-generation tetracycline antibiotics that can resist inactivation of the TetX variants. [ABSTRACT FROM AUTHOR]

Background: The current emergence of multi-drug resistance among nosocomial pathogens has led to increased use of last-resort agents including Tigecycline (TGC). Availability of reliable methods for testing TGC susceptibility is crucial to accurately predict clinical outcomes. We evaluated the influence of different methodologies and type of media on TGC susceptibility of different gram-negative bacteria of clinical origin.Methods: The TGC susceptibility of 84 clinical isolates of Klebsiella pneumoniae (n = 29), Escherichia coli (n = 30), and Acinetobacter baumannii (n = 25) was tested by broth microdilution (BMD), Etest, agar dilution (AD) and disk diffusion (DD) methods using Mueller Hinton agar from Difco and Mueller Hinton broth (MHB) from two different manufacturers (Difco and Condalab). FDA TGC susceptibility breakpoints issued for Enterobacteriaceae were used for interpretation of the results.Results: MICs determined by BMD using MHB from two suppliers showed a good correlation with overall essential agreement (EA) and categorical agreement (CA) being 100% and 95% respectively. However, a twofold rise in BMD-Condalab MICs which was detected in 50% of the isolates, resulted in changes in susceptibility categories of few isolates with MICs close to susceptibility breakpoints leading to an overall minor error (MI) rate of 4.7%. Among the tested methods, Etest showed the best correlation with BMD, being characterized with the lowest error rates (only 1% MI) and highest overall EA (100%) and CA (98.8%) for all subsets of isolates. AD yielded the lowest overall agreement (EA 77%, CA 81%) with BMD in a species dependent manner, with the highest apparent discordance being found among the A. baumannii isolates. While the performance of DD for determination of TGC susceptibility among Enterobacteriaceae was excellent, (CA:100% with no errors), the CA was lower (84%) when it was used for A. baumannii where an unacceptably high minor-error rate was noted (16%). No major error or very major error was detected for any of the tested methods.Conclusions: Etest can be reliably used for TGC susceptibility testing in the three groups of studied bacteria. For the isolates with close-to-breakpoint MICs, testing susceptibility using the reference method is recommended. [ABSTRACT FROM AUTHOR]

Background: This antimicrobial surveillance study reports in vitro antimicrobial activity and susceptibility data for a panel of agents against respiratory isolates of Enterobacterales and Pseudomonas aeruginosa.Methods: Isolates from respiratory specimens were collected in Africa/Middle East, Asia/South Pacific, Europe and Latin America between 2016 and 2018, as part of the Antimicrobial Testing Leadership and Surveillance (ATLAS) program. Broth microdilution methodology was used to quantify minimum inhibitory concentrations, from which rates of susceptibility were determined using EUCAST breakpoints (version 10). Rates of subsets with genes encoding β-lactamases (extended-spectrum β-lactamases [ESBLs], serine carbapenemases and metallo-β-lactamases [MBLs]) were also determined, as well as rates of multidrug-resistant (MDR) P. aeruginosa.Results: Among all respiratory Enterobacterales isolates, susceptibility to ceftazidime-avibactam, meropenem, colistin and amikacin was ≥94.4% in each region. For Enterobacterales isolates that were ESBL-positive or carbapenemase-positive/MBL-negative, ceftazidime-avibactam susceptibility was 93.6 and 98.9%, respectively. Fewer than 42.7% of MBL-positive Enterobacterales isolates were susceptible to any agents, except colistin (89.0% susceptible). Tigecycline susceptibility was ≥90.0% among Citrobacter koseri and Escherichia coli isolates, including all β-lactamase-positive subsets. ESBL-positive Enterobacterales were more commonly identified in each region than isolates that were ESBL/carbapenemase-positive; carbapenemase-positive/MBL-negative; or MBL-positive. Among all respiratory P. aeruginosa isolates, the combined susceptibility rates (susceptible at standard dosing regimen plus susceptible at increased exposure) were highest to ceftazidime-avibactam, colistin and amikacin (≥82.4% in each region). Susceptibility to colistin was ≥98.1% for all β-lactamase-positive subsets of P. aeruginosa. The lowest rates of antimicrobial susceptibility were observed among MBL-positive isolates of P. aeruginosa (≤56.6%), with the exception of colistin (100% susceptible). MDR P. aeruginosa were most frequently identified in each region (18.7-28.7%), compared with the subsets of ESBL-positive; carbapenemase-positive/MBL-negative; or MBL-positive isolates.Conclusions: Rates of susceptibility among the collections of respiratory Enterobacterales and P. aeruginosa isolates were highest to ceftazidime-avibactam, colistin and amikacin in each region. Tigecycline was active against all subsets of C. koseri and E. coli, and colistin was active against all subsets of P. aeruginosa. The findings of this study indicate the need for continued antimicrobial surveillance among respiratory Gram-negative pathogens, in particular those with genes encoding MBLs. [ABSTRACT FROM AUTHOR]

Background: Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function.Results: The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75-91%).Conclusions: The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp. [ABSTRACT FROM AUTHOR]

Background: Bloodstream infection (BSI) caused by multidrug-resistant Acinetobacter baumannii (MDR-AB) has been increasingly observed among hospitalized patients. The following study analyzed the epidemiology and microbiological characteristics of MDR-AB, as well as the clinical features, antimicrobial treatments, and outcomes in patients over a six years period in China. Methods: This retrospective study was conducted in a large tertiary hospital in China between January 2013 and December 2018. The clinical and microbiological data of all consecutive hospitalized patients with MDR-AB induced bloodstream infection were included and analyzed. Results: A total of 108 BSI episodes were analyzed. All MDR isolates belonged to ST2, a sequence type that has spread all over the world. Overall, ST2 strains showed strong biofilm formation ability, high serum resistance, and high pathogenicity. As for the clinical characteristics of the patient, 30-day mortality was 69.4% (75/108). The three main risk factors included mechanical ventilation, intensive care unit (ICU) stay, and thrombocytopenia; three protective factors included a change of antimicrobial regimen within 48 h after positive blood culture, use of the antibacterial agent combination, and more inpatient days. The most effective antibacterial regimen was the combination of cefoperazone/sulbactam and tigecycline. Conclusions: BSI caused by ST2 A.baumannii represents a difficult challenge for physicians, considering the high mortality associated with this infection. The combination of cefoperazone/sulbactam and tigecycline may be an effective treatment option. [ABSTRACT FROM AUTHOR]

Background: The recent emergence and dissemination of high-level mobile tigecycline resistance Tet(X) challenge the clinical effectiveness of tigecycline, one of the last-resort therapeutic options for complicated infections caused by multidrug-resistant Gram-negative and Gram-positive pathogens. Although tet(X) has been found in various bacterial species, less is known about phylogeographic distribution and phenotypic variance of different genetic variants. Methods: Herein, we conducted a multiregional whole-genome sequencing study of tet(X)-positive Acinetobacter isolates from human, animal, and their surrounding environmental sources in China. The molecular and enzymatic features of tet(X) variants were characterized by clonal expression, microbial degradation, reverse transcription, and gene transfer experiments, while the tet(X) genetic diversity and molecular evolution were explored by comparative genomic and Bayesian evolutionary analyses. Results: We identified 193 tet(X)-positive isolates from 3846 samples, with the prevalence ranging from 2.3 to 25.3% in nine provinces in China. The tet(X) was broadly distributed in 12 Acinetobacter species, including six novel species firstly described here. Besides tet(X3) (n = 188) and tet(X4) (n = 5), two tet(X5) variants, tet(X5.2) (n = 36) and tet(X5.3) (n = 4), were also found together with tet(X3) or tet(X4) but without additive effects on tetracyclines. These tet(X)-positive Acinetobacter spp. isolates exhibited 100% resistance rates to tigecycline and tetracycline, as well as high minimum inhibitory concentrations to eravacycline (2–8 μg/mL) and omadacycline (8–16 μg/mL). Genetic analysis revealed that different tet(X) variants shared an analogous ISCR2-mediated transposon structure. The molecular evolutionary analysis indicated that Tet(X) variants likely shared the same common ancestor with the chromosomal monooxygenases that are found in environmental Flavobacteriaceae bacteria, but sequence divergence suggested separation ~ 9900 years ago (7887 BC), presumably associated with the mobilization of tet(X)-like genes through horizontal transfer. Conclusions: Four tet(X) variants were identified in this study, and they were widely distributed in multiple Acinetobacter spp. strains from various ecological niches across China. Our research also highlighted the crucial role of ISCR2 in mobilizing tet(X)-like genes between different Acinetobacter species and explored the evolutionary history of Tet(X)-like monooxygenases. Further studies are needed to evaluate the clinical impact of these mobile tigecycline resistance genes. [ABSTRACT FROM AUTHOR]

Background: Multidrug-resistant infections due to Mycobacterium abscessus often require complex and prolonged regimens for treatment. Here, we report the evaluation of a new ex vivo antimicrobial susceptibility testing model using organotypic cultures of murine precision-cut lung slices, an experimental model in which metabolic activity, and all the usual cell types of the organ are found while the tissue architecture and the interactions between the different cells are maintained. Methods: Precision cut lung slices (PCLS) were prepared from the lungs of wild type BALB/c mice using the Krumdieck® tissue slicer. Lung tissue slices were ex vivo infected with the virulent M. abscessus strain L948. Then, we tested the antimicrobial activity of two drugs: imipenem (4, 16 and 64 μg/mL) and tigecycline (0.25, 1 and 4 μg/mL), at 12, 24 and 48 h. Afterwards, CFUs were determined plating on blood agar to measure the surviving intracellular bacteria. The viability of PCLS was assessed by Alamar Blue assay and corroborated using histopathological analysis. Results: PCLS were successfully infected with a virulent strain of M. abscessus as demonstrated by CFUs and detailed histopathological analysis. The time-course infection, including tissue damage, parallels in vivo findings reported in genetically modified murine models for M. abscessus infection. Tigecycline showed a bactericidal effect at 48 h that achieved a reduction of > 4log10 CFU/mL against the intracellular mycobacteria, while imipenem showed a bacteriostatic effect. Conclusions: The use of this new organotypic ex vivo model provides the opportunity to test new drugs against M. abscessus, decreasing the use of costly and tedious animal models. [ABSTRACT FROM AUTHOR]

Background: A drug-oriented antibiotic stewardship intervention targeting tigecycline utilization was launched at Makassed General Hospital, Beirut, Lebanon, in 2016 as a part of a comprehensive Antibiotic Stewardship Program (ASP). In this study, we evaluated the effect of this intervention on changing tigecycline prescription behavior in different types of infections, patient outcome and mortality, along with tigecycline drug use density, when compared to an earlier period before the initiation of ASP. Methods: This is a retrospective chart review of all adult inpatients who received tigecycline for more than 72 h between Jan-2012 and Dec-2013 [period (P) 1 before ASP] and between Oct-2016 and Dec-2018 [period (P) 2 during ASP]. Results: Tigecycline was administered to 153 patients during P1 and 116 patients during P2. The proportion of patients suffering from cancer, those requiring mechanical ventilation, and those with hemodynamic failure was significantly reduced between P1 and P2. The proportion of patients who received tigecycline for FDA-approved indications increased from 19% during P1 to 78% during P2 (P < 0.001). On the other hand, its use in off-label indications was restricted, including ventilator-associated pneumonia (26.1% in P1, 3.4% in P2, P < 0.001), hospital-acquired pneumonia (19.6% in P1, 5.2% in P2, P = 0.001), sepsis (9.2% in P1, 3% in P2, P = 0.028), and febrile neutropenia (15.7% in P1, 0.9% in P2, P < 0.001). The clinical success rate of tigecycline therapy showed an overall significant increase from 48.4% during P1 to 65.5% during P2 (P = 0.005) in the entire patient population. All-cause mortality in the tigecycline-treated patients decreased from 45.1% during P1 to 20.7% during P2 (P < 0.0001). In general, mean tigecycline consumption decreased by 55% between P1 and P2 (P < 0.0001). Conclusion: The drug-oriented ASP intervention targeting tigecycline prescriptions improved its use and patient outcomes, where it helped curb the over-optimistic use of this drug in off-label indications where it is not a suitable treatment option. [ABSTRACT FROM AUTHOR]

Background: Tigecycline is a last-resort antibiotic used to treat severe infections caused by extensively drug-resistant bacteria. Recently, novel tigecycline resistance genes tet(X3) and tet(X4) have been reported, which pose a great challenge to human health and food security. The current study aimed to establish a TaqMan-based real-time PCR assay for the rapid detection of the tigecycline-resistant genes tet(X3) and tet(X4). Results: No false-positive result was found, and the results of the TaqMan-based real-time PCR assay showed 100% concordance with the results of the sequencing analyses. This proposed method can detect the two genes at the level of 1 × 102 copies/μL, and the whole process is completed within an hour, allowing rapid screening of tet(X3) and tet(X4) genes in cultured bacteria, faeces, and soil samples. Conclusion: Taken together, the TaqMan-based real-time PCR method established in this study is rapid, sensitive, specific, and is capable of detecting the two genes not only in bacteria, but also in environmental samples. [ABSTRACT FROM AUTHOR]

Objective: Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative Staphylococcus (MRCoNS) are among the main causes of nosocomial infections, which have caused major problems in recent years due to continuously increasing spread of various antibiotic resistance features. Apparently, vancomycin is still an effective antibiotic for treatment of infections caused by these bacteria but in recent years, additional resistance phenotypes have led to the accelerated introduction of newer agents such as linezolid, tigecycline, daptomycin, and quinupristin/dalfopristin (Q/D). Due to limited data availability on the global rate of resistance to these antibiotics, in the present study, the resistance rates of S. aureus, Methicillin-resistant S. aureus (MRSA), and CoNS to these antibiotics were collected. Method: Several databases including web of science, EMBASE, and Medline (via PubMed), were searched (September 2018) to identify those studies that address MRSA, and CONS resistance to linezolid, tigecycline, daptomycin, and Q/D around the world. Result: Most studies that reported resistant staphylococci were from the United States, Canada, and the European continent, while African and Asian countries reported the least resistance to these antibiotics. Our results showed that linezolid had the best inhibitory effect on S. aureus. Although resistances to this antibiotic have been reported from different countries, however, due to the high volume of the samples and the low number of resistance, in terms of statistical analyzes, the resistance to this antibiotic is zero. Moreover, linezolid, daptomycin and tigecycline effectively (99.9%) inhibit MRSA. Studies have shown that CoNS with 0.3% show the lowest resistance to linezolid and daptomycin, while analyzes introduced tigecycline with 1.6% resistance as the least effective antibiotic for these bacteria. Finally, MRSA and CoNS had a greater resistance to Q/D with 0.7 and 0.6%, respectively and due to its significant side effects and drug-drug interactions; it appears that its use is subject to limitations. Conclusion: The present study shows that resistance to new agents is low in staphylococci and these antibiotics can still be used for treatment of staphylococcal infections in the world. [ABSTRACT FROM AUTHOR]

Background: The management of Klebsiella pneumoniae carbapenemase producing (KPC) infections represents a major challenge. Several safety and efficacy concerns are shared by available antibiotics used in KPC infections, leading to the occurrence of serious adverse drug reactions (ADRs), with ceftazidime-avibactam possibly showing a more favourable risk-benefit profile. We investigated the potential impact of resistance on ADR reports in countries with different prevalence of KPC isolates (Italy vs. United Kingdom [UK]), and described safety profile of newer and older antibiotics used in KPC infections. Methods: Three spontaneous reporting systems (SRSs) with different features (Italy, UK and worldwide FAERS) were used to describe safety profiles of colistin, meropenem, tigecycline, gentamicin and ceftazidime-avibactam in terms of System Organ Class and Preferred Term level. ADRs were plotted with prevalence of KPC isolates in Italy and UK. A comparison between before-after the KPC outbreak period (1999–2008 vs. 2009–2018) of overall and serious ADRs for selected antibiotics in each SRS was performed. Relationship between total and serious number of ADR reports per year and KPC isolates per year after KPC outbreak (2009–2017) was investigated for both Italy and UK. Results: A total of 16,329 ADR reports were collected in the three SRSs, with meropenem (42.6%) and gentamicin (36.9%) having the highest number of reports. Significant increase in total and serious ADR reports after the KPC outbreak compared to previous 10 years was found for colistin, meropenem and gentamicin (p < 0.01). No significant increase in tigecycline ADRs was reported in FAERS and UK database. Unexpected safety signals involving selected antibiotics were not detected. Significant positive relationship between overall and serious ADR reports and KPC isolates per year for both Italy (p < 0.01; p = 0.005) and UK (p = 0.032; p = 0.013) was found. Conclusion: KPC outbreak led to significant increase in ADRs to selected antibiotics, and a close relationship with antimicrobial resistance was found, both in countries with high and low resistance rate. New safety signals were not detected for selected agents. Active surveillance should be maintained to promptly identify unexpected safety issues. [ABSTRACT FROM AUTHOR]

The emergence of tigecycline-resistant tet(X2/X3/X4/X5) genes poses a new threat to the efficacy of anti-infective therapy and the safety of our food and environment. To control the transfer of such genes, a sensitive and rapid molecular method is warranted to detect tet(X2/X3/X4/X5) genes in clinical isolates. Herein, we established a loop-mediated isothermal amplification (LAMP) assay to rapidly detect tet(X2/X3/X4/X5) genes, and the results were assessed by chromogenic visualization. The specificity and sensitivity of the primers during the LAMP assay for the simultaneous detection of tet(X2/X3/X4/X5) genes were determined in this study. All 48 clinical strains without tet(X2/X3/X4/X5) genes yielded negative results during the LAMP assay, substantiating the high specificity of the LAMP primers. The detection thresholds of this assay were 1.5 × 10 2 CFU/ml and 0.2 fg/uL corresponding to a 10 to 100-fold and 100-fold increase in sensitivity compared to polymerase chain reaction (PCR) assays. Out of 52 bacterial strains tested, using PCR as a reference, our research revealed that the LAMP assay demonstrated a sensitivity and specificity of 100%. To sum up, our novel approach has huge prospects for application in the simultaneous detection of tet(X2/X3/X4/X5) genes and can be applied to detect other drug-resistance genes., (© 2023. The Author(s).)

Background: Clostridioides difficile is a bacterium that causes antibiotic-associated infectious diarrhea and pseudomembranous enterocolitis. The impact of C. difficile infection (CDI) in China has gained significant attention in recent years. However, little epidemiological data are available from Chongqing, a city located in Southwest China. This study aimed to investigate the epidemiological pattern of CDI and explore the drug resistance of C. difficile isolates in Chongqing., Methods: A case-control study was conducted to investigate the clinical infection characteristics and susceptibility factors of C. difficile. The features of the C. difficile isolates were evaluated by testing for toxin genes and using multi-locus sequence typing (MLST). The susceptibility of strains to nine antibiotics was determined using agar dilution technique., Results: Out of 2084 diarrhea patients, 90 were tested positive for the isolation of toxigenic C. difficile strains, resulting in a CDI prevalence rate of 4.32%. Tetracycline, cephalosporins, hepatobiliary disease, and gastrointestinal disorders were identified as independent risk factors for CDI incidence. The 90 strains were classified into 21 sequence types (ST), with ST3 being the most frequent (n = 25, 27.78%), followed by ST2 (n = 10, 11.11%) and ST37 (n = 9, 10%). Three different toxin types were identified: 69 (76.67%) were A + B + CDT - , 12 (13.33%) were A - B + CDT - , and 9 (10%) were A + B + CDT + . Although substantial resistance to erythromycin (73.33%), moxifloxacin (62.22%), and clindamycin (82.22%), none of the isolates exhibited resistance to vancomycin, tigecycline, or metronidazole. Furthermore, different toxin types displayed varying anti-microbial characteristics., Conclusions: The strains identified in Chongqing, Southwest China, exhibited high genetic diversity. Enhance full awareness of high-risk patients with HA-CDI infection, particularly those with gastrointestinal and hepatocellular diseases, and emphasize caution in the use of tetracycline and capecitabine. These findings suggest that a potential epidemic of CDI may occur in the future, emphasizing the need for timely monitoring., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Acinetobacter baumannii nosocomial ventriculitis/meningitis, especially those due to drug-resistant strains, has substantially increased over recent years. However, limited therapeutic options exist for the Acinetobacter baumannii ventriculitis/meningitis because of the poor penetration rate of most antibiotics through the blood-brain barrier. Case presentation: A 57-year-old male patient developed ventriculitis from an extensively drug-resistant strain of Acinetobacter baumannii after the decompressive craniectomy for severe traumatic brain injury. The patient was successfully treated with intraventricular and intravenous polymyxin B together with intravenous tigecycline. Conclusions: The case illustrates intraventricular polymyxin B can be a therapeutic option against extensively drug-resistant Acinetobacter baumannii ventriculitis. [ABSTRACT FROM AUTHOR]

Background: The in vitro activity of tigecycline and comparator agents was evaluated against Gram-positive and Gram-negative isolates collected in Latin American centers between 2004 and 2015 as part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) global surveillance study. Methods: Minimum inhibitory concentrations (MICs) were determined using the broth microdilution methodology according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Antimicrobial susceptibility was determined using CLSI breakpoints, except for tigecycline for which the US Food and Drugs Administration breakpoints were used. Results: A total of 48.3% (2202/4563) of Staphylococcus aureus isolates were methicillin-resistant S. aureus (MRSA). All MRSA isolates were susceptible to linezolid and vancomycin, and 99.9% (2199/2202) were susceptible to tigecycline. Among Streptococcus pneumoniae isolates, 13.8% (198/1436) were penicillin-resistant; all were susceptible to linezolid and vancomycin, and 98.0% (194/198) were susceptible to tigecycline. Susceptibility was >99.0% for linezolid and tigecycline against Enterococcus faecium and Enterococcus faecalis isolates. A total of 40.8% (235/576) E. faecium and 1.6% (33/2004) E. faecalis isolates were vancomycin-resistant. Among the Enterobacteriaceae, 36.3% (1465/4032) of Klebsiella pneumoniae isolates, 16.4% (67/409) of Klebsiella oxytoca isolates and 25.4% (1246/4912) of Escherichia coli isolates were extended-spectrum β-lactamase (ESBL) producers. Of the ESBL-producing K. pneumoniae and E. coli isolates, susceptibility was highest to tigecycline [93.4% (1369/1465) and 99.8% (1244/1246), respectively] and meropenem [86.9% (1103/1270) and 97.0% (1070/1103), respectively]. A total of 26.7% (966/3613) of Pseudomonas aeruginosa isolates were multidrug-resistant (MDR). Among all P. aeruginosa isolates, susceptibility was highest to amikacin [72.8% (2632/3613)]. A total of 70.3% (1654/2354) of Acinetobacter baumannii isolates were MDR, and susceptibility was highest to minocycline [88.3% (2079/2354) for all isolates, 86.2% (1426/1654) for MDR isolates]. Tigecycline had the lowest MIC90 (2 mg/L) among A. baumannii isolates, including MDR isolates. Conclusions: This study of isolates from Latin America shows that linezolid, vancomycin and tigecycline continue to be active in vitro against important Gram-positive organisms such as MRSA, and that susceptibility rates to meropenem and tigecycline against members of the Enterobacteriaceae, including ESBL-producers, were high. However, we report that Latin America has high rates of MRSA, MDR A. baumannii and ESBL-producing Enterobacteriaceae which require continued monitoring. [ABSTRACT FROM AUTHOR]

Background: The incidence of infectious spondylodiscitis has been increasing over the last few years. This reflects the expanding elderly and immunocompromised populations and the rising implementation of invasive spinal procedures. Infection may be inoculated into the disc space directly during invasive spinal procedures. Osteomyelitis caused by Acinetobacter species is rare and mainly caused by multidrug-resistant strains.Case Presentation: We present the case of a 72-year-old Greek woman with postoperative spondylodiscitis caused by a multidrug-resistant Acinetobacter baumannii strain that was successfully treated, after she declined surgical treatment, with prolonged and high dosage of tigecycline. She received intravenously administered tigecycline 200 mg per day for 60 days and then 100 mg per day for a total of 102 days and was infection-free.Conclusions: We reviewed the literature on the role of Acinetobacter baumannii as a cause of osteomyelitis, emphasizing the difficulty of treatment and the potential role of tigecycline in conservative treatment of the infection. We believe that 102 days in total is the longest time that any patient has received tigecycline in the literature, thus our patient is a unique case of successful treatment of spondylodiscitis. [ABSTRACT FROM AUTHOR]

Background: Drug resistance and disease progression are still the major obstacles in the treatment of chronic myeloid leukemia (CML). Increasing researches have demonstrated that autophagy becomes activated when cancer cells are subjected to chemotherapy, which is involved in the development of drug resistance. Therefore, combining chemotherapy with inhibition of autophagy serves as a new strategy in cancer treatment. Tigecycline is an antibiotic that has received attention as an anti-cancer agent due to its inhibitory effect on mitochondrial translation. However, whether combination of tigecycline with inhibition of autophagy could overcome drug resistance in CML remains unclear. Methods: We analyzed the biological and metabolic effect of tigecycline on CML primary cells and cell lines to investigate whether tigecycline could regulate autophagy in CML cells and whether coupling autophagy inhibition with treatment using tigecycline could affect the viabilities of drug-sensitive and drug-resistant CML cells. Results: Tigecycline inhibited the viabilities of CML primary cells and cell lines, including those that were drugresistant. This occurred via the inhibition of mitochondrial biogenesis and the perturbation of cell metabolism, which resulted in apoptosis. Moreover, tigecycline induced autophagy by downregulating the PI3K-AKT-mTOR pathway. Additionally, combining tigecycline use with autophagy inhibition further promoted the anti-leukemic activity of tigecycline. We also observed that the anti-leukemic effect of tigecycline is selective. This is because the drug targeted leukemic cells but not normal cells, which is because of the differences in the mitochondrial biogenesis and metabolic characterization between the two cell types. Conclusions: Combining tigecycline use with autophagy inhibition is a promising approach for overcoming drug resistance in CML treatment. [ABSTRACT FROM AUTHOR]

Background: Difficult-to-treat infections caused by rapidly growing mycobacteria (RGM) are increasingly observed in clinical settings. However, studies on antimicrobial susceptibilities and effective treatments against RGM in Japan are limited.Methods: We conducted susceptibility testing of potential antimicrobial agents, including tigecycline and tebipenem, against RGM. Clinical RGM isolates were collected from a university hospital in Japan between December 2010 and August 2013. They were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and the sequencing of 16S rRNA, rpoB, and hsp65 genes. The samples were utilized for susceptibility testing using 16 antimicrobials, with frozen broth microdilution panels.Results: Forty-two isolates were obtained: 13, Mycobacterium abscessus complex; 12, Mycobacterium chelonae; 9, Mycobacterium fortuitum; and 8, M. fortuitum group species other than M. fortuitum. Different antimicrobial susceptibility patterns were observed between RGM species. Clarithromycin-susceptible strain rates were determined to be 0, 62, and 100% for M. fortuitum, M. abscessus complex, and M. chelonae, respectively. M. abscessus complex (100%) and >80% M. chelonae isolates were non-susceptible, while 100% M. fortuitum group isolates were susceptible to moxifloxacin. Linezolid showed good activity against 77% M. abscessus complex, 89% M. fortuitum, and 100% M. chelonae isolates. Regardless of species, all tested isolates were inhibited by tigecycline at very low minimal inhibitory concentrations (MICs) of ≤0.5 μg/mL. MICs of tebipenem, an oral carbapenem, were ≤4 μg/mL against all M. fortuitum group isolates.Conclusions: Our study demonstrates the importance of correct identification and antimicrobial susceptibility testing, including the testing of potential new agents, in the management of RGM infections. [ABSTRACT FROM AUTHOR]

Background: This study provided a theoretical basis for the clinical diagnosis and treatment of bacterial infection after liver transplantation through analyzing the pathogenic distribution, drug sensitivity and risk factors of bacterial infection after liver transplantation., Methods: We collected clinical data from 207 recipients undergoing liver transplantation of graft from donation after citizens' death donors in the Third Xiangya Hospital of Central South University from January 2019 to December 2021 and analyzed the composition and distribution of bacterial pathogens, drug resistance and risk factors of infection., Results: A total of 90 bacterial infections occurred in 55 recipients within two months after liver transplantation, and the incidence of bacterial infection was 26.6% (55/207). The gram-negative bacteria (46/90, 51.1%) were more prevalent than gram-positive bacteria (44/90, 48.9%). Common sites of infection were the abdominal/biliary tract (26/90, 28.9%), lung (22/90, 22.4%) and urinary tract (22/90, 22.4%). Fourteen cases (6.8%) died after liver transplantation. Klebsiella pneumoniae (17/90, 18.9%) was the most frequent gram-negative bacteria causing infection in liver transplant recipients and 58.7%, 50%, 80.4% and 89.1% of gram-negative bacteria were sensitive to amikacin, minocycline, tigecycline and polymyxin B, respectively. The most common gram-positive bacteria was Enterococcus faecium (30/90, 33.3%) and 97.7%, 100%, 86.4%, 100% and 100% of gram-positive bacteria were sensitive to vancomycin, teicoplanin, daptomycin, tigecycline and linezolid, respectively. Univariate analysis revealed that bacterial infection was associated with female, age (≥ 50 years old), preoperative albumin (≤ 30 g/L), operation duration (≥ 400 min), intraoperative blood loss (≥ 3000 ml) and postoperative ventilator support. Binary Logistic regression analysis showed that female (OR = 3.149, 95% CI: 1.418-6.993, P = 0.005), operation duration (≥ 400 min) (OR = 2.393, 95% CI: 1.202-4.765, P = 0.013) and intraoperative blood loss (≥ 3000 ml) (OR = 2.052, 95% CI: 1.007-4.183, P = 0.048) were independent risk factors for bacterial infection after liver transplantation., Conclusion: The incidence of early bacterial infection after liver transplantation was high, and the infection sites were mainly abdominal/biliary tract, respiratory tract and urinary tract. The most common pathogenic bacterium was gram-negative bacterium. Our study also identified several independent risk factors for bacterial infection after liver transplantation, including female gender, operation duration of 400 min or more, and intraoperative blood loss of 3000 ml or more. By addressing these risk factors, such as implementing strategies to optimize surgical procedures and minimize blood loss, healthcare professionals can work towards reducing the incidence of bacterial infections following liver transplantation., (© 2023. The Author(s).)

Background: Thuricin CD is a two-component antimicrobial, belonging to the recently designated sactibiotic subclass of bacteriocins. The aim of this study was to investigate the effects of thuricin CD, as well as the antibiotics, tigecycline, vancomycin, teicoplanin, rifampicin and nitazoxanide when used independently and when combined at low concentrations on the viability of Clostridium difficile 20291 R027, TL178 R002, Liv022 R106, DPC6350 and VPI10463 biofilms and planktonic cells. Results: On the basis of XTT (2,3-bis[2-methyloxy-4-nitro-5-sulphophenyl] -2H-tetrazolium-5-carboxanilide)-menadi-one biofilm viability assays, we found that thuricin CD was effective against biofilms of R027, Liv022 R106 and DPC6350 when used independently while nitazoxanide and rifampicin were also potent against biofilms of R027 and DPC6350, when applied on their own. Tigecycline was found to be effective against R027 and DPC6350 biofilms, whereas teico-planin and vancomycin when used independently were only effective against DPC6350 biofilms. The efficacies of the antibiotics rifampicin, tigecycline, vancomycin and teicoplanin against C. difficile 20291 R027 biofilms were significantly potentiated when combined with thuricin CD, indicating effective antimicrobial combinations with this sactibiotic against R027 biofilms. However, the potency of nitazoxanide against R027 biofilms was significantly diminished when combined with thuricin CD, indicating an ineffective combination with this sactibiotic against R027 biofilms. Paired combinations of thuricin CD along with these five antibiotics were effective at diminishing the viability of DPC6350 biofilms. However, such combinations were largely ineffective against biofilms of TL178 R002, Liv022 R106 and VPI10463. Conclusions: To the best of our knowledge, this is the first study to highlight the activity of a sactibiotic bacteriocin against biofilms and the first to reveal the potency of the antibiotics tigecycline, teicoplanin and nitazoxanide against C. difficile biofilms. On the basis of this study, it is apparent that different strains of C. difficile possess varying abilities to form biofilms and that the sensitivities of these biofilms to different antimicrobials and antimicrobial combinations are strain-dependent. Since the formation of relatively strong biofilms by certain C. difficile strains may contribute to increased cases of antibiotic resistance and recurrence and relapse of C. difficile infection, the findings presented in this study could provide alternative strategies to target this pathogen. [ABSTRACT FROM AUTHOR]

Background: The Tigecycline Evaluation and Surveillance Trial (T.E.S.T) is a global antimicrobial surveillance study of both gram-positive and gram-negative organisms. This report presents data on antimicrobial susceptibility among organisms collected in Mexico between 2005 and 2012 as part of T.E.S.T., and compares rates between 2005-2007 and 2008-2012. Method: Each center in Mexico submitted at least 200 isolates per collection year; including 65 gram-positive isolates and 135 gram-negative isolates. Minimum inhibitory concentrations (MICs) were determined using Clinical Laboratory Standards Institute (CLSI) broth microdilution methodology and antimicrobial susceptibility was established using the 2013 CLSI-approved breakpoints. For tigecycline US Food and Drug Administration (FDA) breakpoints were applied. Isolates of E. coli and K. pneumoniae with a MIC for ceftriaxone of >1 mg/L were screened for ESBL production using the phenotypic confirmatory disk test according to CLSI guidelines. Results: The rates of some key resistant phenotypes changed during this study: vancomycin resistance among Enterococcus faecium decreased from 28.6 % in 2005-2007 to 19.1 % in 2008-2012, while β-lactamase production among Haemophilus influenzae decreased from 37.6 to 18.9 %. Conversely, methicillin-resistant Staphylococcus aureus increased from 38.1 to 47.9 %, meropenem-resistant Acinetobacter spp. increased from 17.7 to 33.0 % and multidrug-resistant Acinetobacter spp. increased from 25.6 to 49.7 %. The prevalence of other resistant pathogens was stable over the study period, including extended-spectrum β-lactamase-positive Escherichia coli (39.0 %) and Klebsiella pneumoniae (25.0 %). The activity of tigecycline was maintained across the study years with MIC90s of ≤2 mg/L against Enterococcus spp., S. aureus, Streptococcus agalactiae, Streptococcus pneumoniae, Enterobacter spp., E. coli, K. pneumoniae, Klebsiella oxytoca, Serratia marcescens, H. influenzae, and Acinetobacter spp. All gram-positive organisms were susceptible to tigecycline and susceptibility among gram-negatives ranged from 95.0 % for K. pneumoniae to 99.7 % for E. coli. Conclusion: Antimicrobial resistance continues to be high in Mexico. Tigecycline was active against gram-positive and gram-negative organisms, including resistant phenotypes, collected during the study. [ABSTRACT FROM AUTHOR]

Background: Empiric therapy for healthcare-associated infections remains challenging, especially with the continued development of Gram-negative organisms producing extended-spectrum β-lactamases (ESBLs) and the threat of multi-drug-resistant organisms. Current treatment options for resistant Gram-negative infections include carbapenems, tigecycline, piperacillin-tazobactam, cefepime, ceftazidime, and two recently approved therapies, ceftolozane-tazobactam and ceftazidime-avibactam. Methods: This systematic literature review surveys the published clinical trial evidence available since 2000 in support of both current and emerging treatment options in the settings of complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI). When available, clinical cure rates for patients with infections from ESBL-producing strains are provided, as is information about efficacy against Pseudomonas aeruginosa. Results: Clinical trial evidence to guide selection of empiric antibiotic therapy in patients with complicated, hospital-acquired, Gram-negative IAIs and UTIs is limited. Though most of the clinical trials explored in this overview enrolled patients with complicated infections, often patients with severe infections and multiple comorbidities were excluded. Conclusions: Practitioners in the clinical setting who are treating patients with complicated, hospital-acquired, Gram-negative IAIs and UTIs need to consider the possibility of polymicrobial infections, antibiotic-resistant organisms, and/or severely ill patients with multiple comorbidities. There is a severe shortage of evidence-based research to guide the selection of empiric antibiotic therapy for many patients in this setting. New therapies recently approved or in late-stage development promise to expand the number of options available for empiric therapy of these hospital-acquired, Gram-negative infections. [ABSTRACT FROM AUTHOR]

Background: The Tigecycline Evaluation and Surveillance Trial (TEST) is a global antimicrobial susceptibility surveillance study which has been ongoing since 2004. This report examines the in vitro activity of tigecycline and comparators against clinically important pathogens collected globally between 2004 and 2013. Methods: Antimicrobial susceptibility was determined using guidelines published by the Clinical and Laboratory Standards Institute. The Cochran Armitage Trend Test was used to identify statistically significant changes in susceptibility between 2004 and 2013. Results: Among the Enterobacteriaceae susceptibility was highest to the carbapenems [imipenem 97.1% (24,655/25,381), meropenem 97.0% (90,714/93,518)], tigecycline (97.0%, 115,361/118,899) and amikacin (96.9%, 115,200/118,899). Against Acinetobacter baumannii the highest rates of susceptibility were for minocycline (84.5%, 14,178/16,778) and imipenem (80.0%, 3,037/3,795). The MIC90 for tigecycline was 2 mg/L. 40% (6,743/16,778) of A. baumannii isolates were multidrug-resistant. Enterococci were highly susceptible to tigecycline and linezolid (>99%); vancomycin resistance was observed among 2% of Enterococcus faecalis (325/14,615) and 35% of Enterococcus faecium (2,136/6,167) globally. 40% (14,647/36,448) of Staphylococcus aureus were methicillin-resistant while 15% (2,152/14,562) of Streptococcus pneumoniae were penicillin-resistant. Against S. aureus and S. pneumoniae susceptibility to linezolid, vancomycin, and tigecycline was ≥99.9%. Globally, 81% (331/410) of statistically significant susceptibility changes during the study period were decreases in susceptibility. Conclusions: Amikacin, the carbapenems, and tigecycline were active against most gram-negative pathogens while linezolid, tigecycline, and vancomycin retained activity against most gram-positive pathogens collected in TEST during 2004-2013. [ABSTRACT FROM AUTHOR]

Background We report here on 14438 Streptococcus pneumoniae and 14770 Haemophilus influenzae isolates collected from 560 centres globally between 2004 and 2012 as a part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.). Methods MIC testing was performed using broth microdilution methods as described by the Clinical and Laboratory Standards Institute (CLSI) using CLSI-approved breakpoints; US Food and Drug Administration breakpoints were used for tigecycline as CLSI breakpoints are not available. Results At least 99% of S. pneumoniae isolates globally were susceptible to levofloxacin, linezolid, tigecycline or vancomycin. Penicillin resistance was observed among 14.8% of S. pneumoniae and was highest in Asia/Pacific Rim (30.1%) and Africa (27.6%); 23.4% of S. pneumoniae isolates were penicillin-intermediate, which were most common in Africa (37.6%). Minocycline susceptibility among S. pneumoniae decreased by 20% between 2004-2008 and 2009-2012. High (>98.5%) susceptibility was reported among H. influenzae to all antimicrobial agents on the T.E.S.T. panel excluding ampicillin, to which only 78.3% were susceptible. β-lactamase production was observed among 20.2% of H. influenzae isolates; 1.5% of isolates were β-lactamase negative, ampicillin-resistant. Conclusions S. pneumoniae remained highly susceptible to levofloxacin, linezolid, tigecycline and vancomycin while H. influenzae was susceptible to most antimicrobial agents in the testing panel (excluding ampicillin). [ABSTRACT FROM AUTHOR]

Background: Several antibiotics have shown promising anti-malarial effects and have been useful for malarial chemotherapy, particularly in combination with standard anti-malarial drugs. Tigecycline, a semi-synthetic derivative of minocycline with a unique and novel mechanism of action, is the first clinically available drug in a new class of glycylcycline antibiotics. Methods: Tigecycline was tested in vitro against chloroquine (CQ)-sensitive (D6) and resistant strains (W2) of Plasmodium falciparum alone and in combination with CQ. Tigecycline was also tested in vivo in combination with CQ in Plasmodium berghei-mouse malaria model for parasitaemia suppression, survival and cure of the malaria infection. Results: Tigecycline was significantly more active against CQ-resistant (W2) than CQ-susceptible (D6) strain of P. falciparum. Tigecycline potentiated the anti-malarial action of CQ against the CQ-resistant strain of P. falciparum by more than seven-fold. Further, treatment of mice infected with P. berghei with tigecycline (ip) produced significant suppression in parasitaemia development and also prolonged the mean survival time. Treatment with as low as 3.7 mg/kg dose of tigecycline, once daily for four days, produced 77-91% suppression in parasitaemia. In vivo treatment with tigecycline in combination with subcurative doses of CQ produced complete cure in P. berghei-infected mice. Conclusion: Results indicate prominent anti-malarial action of tigecycline in vitro and in vivo in combination with CQ and support further evaluation of tigecycline as a potential combination candidate for treatment of drug-resistant cases of malaria. [ABSTRACT FROM AUTHOR]

Background Tigecycline resistance in Acinetobacter baumannii is primarily acquired through overexpression of the AdeABC efflux pump. Besides AdeRS, other two-component regulatory systems (TCSs) involving the regulation of this transporter have not been clarified. Results In this study, we found that the TCS genes baeR and baeS are co-transcribed and function as stress responders under high osmotic conditions. The baeSR and adeAB genes showed increased transcription in both the laboratory-induced and clinical tigecycline-resistant strains compared with the wild-type strain. The deletion of baeR in the ATCC 17978 strain led to 67–73% and 68% reduction in adeA and adeB expression, respectively, with a resultant 2- fold decrease in the tigecycline minimal inhibition concentration (MIC). In contrast, the overexpression of baeR resulted in a doubled tigecycline MIC, with a more than 2-fold increase in adeA and adeB expression. The influence of baeR knockout on adeAB gene expression can also be observed in the laboratory-induced tigecycline-resistant strain. A timekill assay showed that the baeR deletion mutant showed an approximate 1-log10 reduction in colony forming units (CFUs) relative to the wild-type strain when the tigecycline concentration was 0.25 μg/mL throughout the assay period. The wild-type phenotype could be restored by trans-complementation with pWH1266-kanr-baeR. Increasing the tigecycline concentration to 0.5 μg/mL produced an even more marked 4.7-log10 reduction in CFUs of the baeR deletion mutant at 8 h, while only a 2.1-log10 reduction was observed for the wildtype strain. Conclusions Taken together, these data show for the first time that the BaeSR TCS influences the tigecycline susceptibility of A. baumannii through the positive regulation of the resistancenodulation- division efflux pump genes adeA and adeB. [ABSTRACT FROM AUTHOR]