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Enterobacterales (especially carbapenem-resistant) are considered an urgent threat to public health. The available antibiotic therapy is limited due to the increase of multidrug-resistant (MDR) strains. Tigecycline, a minocycline derivative, has emerged as a potential key agent in the treatment ofMDR isolates. The aim of the study was to evaluate the synergistic effect of tigecycline in combination with nine antimicrobial agents--ceftazidime/avibactam, colistin, ertapenem, gentamicin, imipenem, levofloxacin, meropenem/vaborbactam, polymyxin B, and rifampicin. Eighty clinical Enterobacter cloacae strains were obtained frompatients of two University Hospitals in Bialystok, Poland. The E-test method was used to determine synergistic interactions. Among all combinations, synergy was reported in 61% of cases, addition in 32%, and indifference in 7%. The highest synergy rates were observed in tigecycline combinations with: ceftazidime/avibactam(60/80; 75%), imipenem(60/80; 75%), polymyxin B (55/80; 68.75%) and rifampicin (55/80; 68.75%), while the lowest synergy rate was noted in tigecycline-levofloxacin (26/80; 32.5%). The tigecycline-gentamicin showed the highest rate of indifference; antagonism, was not observed in any combination. In conclusion, tigecycline appears more suitable for use in combination therapy rather than as monotherapy and can be effectively paired with various antimicrobial agents against MDR E. cloacae. Further research will be necessary to confirm these results. [ABSTRACT FROM AUTHOR]

Tigecycline (TGC) is currently used to treat carbapenem-resistant Acinetobacter baumannii (CRAB) infections, while eravacycline (ERV), a new-generation tetracycline, holds promise as a novel therapeutic option for these infections. However, differences in resistance mechanism between ERV and TGC against A. baumannii remain unclear. This study sought to compare the characteristics and mechanisms of ERV and TGC resistance among clinical A. baumannii isolates. A total of 492 isolates, including 253 CRAB and 239 carbapenemsensitive A. baumannii (CSAB) isolates, were collected from hospitalized patients in China. The MICs of ERV and TGC against A. baumannii were determined by broth microdilution. Genetic mutations and expressions of adeB, adeG, adeJ, adeS, adeL, and adeN in resistant strains were examined by PCR and qPCR, respectively. The in vitro recombination experiments were used to verify the resistance mechanism of ERV and TGC in A. baumannii. The MIC90 of ERV in CRAB and CSAB isolates were lower than those of TGC. A total of 24 strains resistant to ERV and/or TGC were categorized into three groups: only ERVresistant (n = 2), both ERV- and TGC-resistant (n = 7), and only TGC-resistant (n = 15). ST208 (75%, n = 18) was a major clone that has disseminated in all three groups. The ISAba1 insertion in adeS was identified in 66.7% (6/9) of strains in the only ERV-resistant and both ERV- and TGC-resistant groups, while the ISAba1 insertion in adeN was found in 53.3% (8/15) of strains in the only TGC-resistant group. The adeABC and adeRS expressions were significantly increased in the only ERV-resistant and both ERV- and TGC-resistant groups, while the adeABC and adeIJK expressions were significantly increased and adeN was significantly decreased in the only TGC-resistant group. Expression of adeS with the ISAba1 insertion in ERV- and TGC-sensitive strains significantly increased the ERV and TGC MICs and upregulated adeABC and adeRS expressions. Complementation of the wildtype adeN in TGC-resistant strains with the ISAba1 insertion in adeN restored TGC sensitivity and significantly downregulated adeIJK expression. In conclusion, our data illustrates that ERV is more effective against A. baumannii clinical isolates than TGC. ERV resistance is correlated with the ISAba1 insertion in adeS, while TGC resistance is associated with the ISAba1 insertion in adeN or adeS in A. baumannii. [ABSTRACT FROM AUTHOR]

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/Objectives: As a primary source of mortality and disability, bacterial infections continue to develop a severe threat to humanity. Nuclear medicine imaging (NMI) is known for its promising potential to diagnose deep-seated bacterial infections. This work aims to develop a new technetium-99m (99mTc) labeled tigecycline radiopharmaceutical as an infection imaging agent. Methods: Reduced 99mTc was used to make a coordinate complex with tigecycline at pH 7.7–7.9 at room temperature. Instantaneous thin-layer chromatography impregnated with silica gel (ITLC-SG) and ray detector equipped high-performance liquid chromatography (ray-HPLC) was performed to access the radiolabeling yield and radiochemical purity (RCP). Results: More than 91% labeling efficiency was achieved after 25 min of mild shaking of the reaction mixture. The radiolabeled complex was found intact up to 4 h in saline. Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) infection-induced rats were used to record the biodistribution of the radiopharmaceutical and its target specificity; 2 h' post-injection biodistribution revealed a 2.39 ± 0.29 target/non-target (T/NT) ratio in the E. coli infection-induced animal model, while a 2.9 ± 0.31 T/NT value was recorded in the S. aureus bacterial infection-induced animal model. [99mTc]Tc-tigecycline scintigraphy was performed in healthy rabbits using a single photon emission computed tomography (SPECT) camera. Scintigrams showed normal kidney perfusion and excretion into the bladder. Conclusion: In conclusion, the newly developed [99mTc]Tc-tigecycline radiopharmaceutical could be considered to diagnose broad-spectrum bacterial infections. [ABSTRACT FROM AUTHOR]

The emergence of inactivation enzyme-encoding genes tet(X), blaEBR, and estT challenges the effectiveness of tetracyclines, β-lactams, and macrolides. This study aims to explore the concurrence and polymorphism of their variants in Empedobacter sp. strains from food-producing animals and surrounding environments. A total of eight tet(X) variants, seven blaEBR variants, and seven estT variants were detected in tet(X)-positive Empedobacter sp. strains (6.7%) from chickens, sewage, and soil, including 31 Empedobacter stercoris and 6 novel species of Taxon 1. All of them were resistant to tigecycline, tetracycline, colistin, and ciprofloxacin, and 16.2% were resistant to meropenem, florfenicol, and cefotaxime. The MIC90 of tylosin, tilmicosin, and tildipirosin was 128 mg/L, 16 mg/L, and 8 mg/L, respectively. Cloning expression confirmed that tet(X6) and the novel variants tet(X23), tet(X24), tet(X25), tet(X26), and tet(X26.2) conferred high-level tigecycline resistance, while all of the others exhibited relatively low-level activities or were inactivated. The bacterial relationship was diverse, but the genetic environments of tet(X) and blaEBR were more conserved than estT. An ISCR2-mediated tet(X6) transposition structure, homologous to those of Acinetobacter sp., Proteus sp., and Providencia sp., was also identified in Taxon 1. Therefore, the tet(X)-positive Empedobacter sp. strains may be ignored and pose a serious threat to food safety and public health. [ABSTRACT FROM AUTHOR]

Tigecycline is a last-resort drug used to treat serious infections caused by multidrug-resistant bacteria. tet(X4) is a recently discovered plasmid-mediated tigecycline resistance gene that confers high-level resistance to tigecycline and other tetracyclines. Since the first discovery of tet(X4) in 2019, it has spread rapidly worldwide, and as a consequence, tigecycline has become increasingly ineffective in the clinical treatment of multidrug-resistant infections. In this study, we identified and analyzed tet(X4)-positive Escherichia coli isolates from duck farms in Hunan Province, China. In total, 976 samples were collected from nine duck farms. Antimicrobial susceptibility testing and whole-genome sequencing (WGS) were performed to establish the phenotypes and genotypes of tet(X4)- positive isolates. In addition, the genomic characteristics and transferability of tet (X4) were determined based on bioinformatics analysis and conjugation. We accordingly detected an E. coli strain harboring tet(X4) and seven other resistance genes in duck feces. Multi-locus sequence typing analysis revealed that this isolate belonged to a new clone, and subsequent genetic analysis indicated that tet(X4) was carried in a 4608-bp circular intermediate, flanked by ISVsa3-ORF2-abh elements. Moreover, it exhibited transferability to E. coli C600 with a frequency of 10-5. The detection of tet(X4)-harboring E, coli strains on duck farms enhances our understanding of tigecycline resistance dynamics. The transferable nature of the circular intermediate of tet(X4) contributing to the spread of tigecycline resistance genes poses a substantial threat to healthcare. Consequently, vigilant monitoring and proactive measures are necessary to prevent their spread. [ABSTRACT FROM AUTHOR]

The addition of sulbactam restores the complete range of cefoperazone activity against bacteria and extends its spectrum of action to include the Acinetobacter species. The effectiveness of cefoperazone/sulbactam against multiresistant Acinetobacter baumannii has not been investigated. The purpose of the current meta-analysis was to compare the efficacy of cefoperazone/sulbactam-based therapeutic regimens and non-cefoperazone/sulbactam-based therapeutic regimens in the treatment of multiresistant Acinetobacter baumannii infections. The current meta-analysis of 10 retrospective studies provides evidence that cefoperazone/sulbactam-based therapeutic regimens are superior to non-cefoperazone/sulbactam-based therapeutic regimens in terms of 30-day mortality and clinical improvement in patients with multiresistant Acinetobacter baumannii infections. The risk of mortality was reduced by 38% among multiresistant Acinetobacter baumannii infections in patients who received cefoperazone/sulbactam-based therapeutic regimens. The cefoperazone/sulbactam-based combination therapy was superior to the cefoperazone/sulbactam monotherapy in terms of 30-day mortality when both therapeutic regimens were compared to the tigecycline monotherapy in patients with multiresistant Acinetobacter baumannii infections. [ABSTRACT FROM AUTHOR]

The optimal use of antibiotics represents a cornerstone in controlling antibiotic resistance. Strategies such as antibiotic stewardship programs (ASPs) have been developed to influence the rational use of antibiotics. This study evaluated the appropriateness of the empirical use of antibiotics based on antibiotic susceptibility results with the aim of participating effectively in improving local ASPs. In a cross-sectional study conducted at a tertiary hospital in Saudi Arabia, 500 inpatients received empirical antibiotics, and their culture and sensitivity results were included. The appropriateness of the empirical use of antibiotics was determined based on their alignment with the culture and sensitivity results. More than half of the participants (56.4%) were men, and nearly half (43%) were over 61 years old. The empirical uses of antibiotics were appropriately prescribed in 58% of the patients. Ciprofloxacin and ceftriaxone were the most prescribed antibiotics, while vancomycin, piperacillin–tazobactam, and tigecycline were the most appropriately prescribed antibiotics. E. coli was the main microorganism isolated in the susceptibility results and was appropriately prescribed in 59% of the patients. The highest microbial sensitivity was observed for linezolid, vancomycin, and tigecycline. Antibiotics were appropriately prescribed empirically in more than half of the participants. Activating interventional ASP is crucial to fill the gap in prescribing antimicrobials. Considering the expected type of organisms and the local susceptibility pattern is likely to yield a more appropriate empirical use of antibiotics. [ABSTRACT FROM AUTHOR]

Tigecycline-resistant Acinetobacter baumannii (TRAB) is increasing in Thailand, complicating antibiotic treatment due to limited antibiotic options. The specific resistance mechanism behind tigecycline resistance is still unclear, necessitating further investigation. We investigated the presence of OXA-type carbapenemases, the antimicrobial susceptibility profile, the inhibitory effect of carbonyl cyanide m-chlorophenylhydrazone (CCCP) on tigecycline susceptibility, the expression levels of RND-type efflux pumps and amino acid substitutions within a two-component regulatory system on 30 Thai clinical isolates. Our investigation revealed that most of (73.3%) TRAB isolates expressed at least one member of the Ade efflux pumps. The ade B was most frequently expressed (63.3%), followed by ade R (50%), ade S (43.3%), ade J (30%) and ade G (10%). Overexpression of the AdeABC was associated with increased tigecycline minimum inhibitory concentrations (MICs) and amino acid substitutions within the AdeRS. Notably, isolates harbouring simultaneous mutations in these genes exhibited an increase in the transcription level of the ade B. Our findings highlight the significant role of the AdeABC system in tigecycline resistance among Thai clinical TRAB isolates. This is supported by point mutations within the AdeRS and upregulated expression of the ade B. These results provide valuable insights for understanding resistance mechanisms and developing novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Xiaotong Tian,1,2 Jing Lin,1,2 Menglan Zhou,3,4 Ying Ge,1 Taisheng Li,1 Li Zhang,1 Zhengyin Liu1 1Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China; 2Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China; 4Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, People’s Republic of ChinaCorrespondence: Zhengyin Liu; Li Zhang, Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China, Email liuzhy@pumch.cn; zhangli36@pumch.cnPurpose: To evaluate the clinical outcomes and safety of tigecycline (TGC) plus cefoperazone/sulbactam (CPS) or TGC monotherapy in patients with hospital-acquired pneumonia (HAP) caused by Carbapenem-Resistant Acinetobacter baumannii (CRAB).Methods: This was a retrospective analysis of multicenter data from 62 Chinese hospitals with CRAB HAP. Risk factors for receiving TGC with CPS therapy and predictors of mortality were assessed using multivariate logistic and Cox regression analyses, respectively. Propensity score matching (PSM) evaluated the efficacy and safety of antimicrobial regimens.Results: A total of the 180 patients were included, with 95 receiving TGC monotherapy and 85 receiving combination therapy. Multivariate logistic regression analysis revealed that older age (P = 0.011), and intensive care unit (ICU) admission (P = 0.007) were significant risk factors for combination therapy. Multivariate Cox regression demonstrated that combination therapy was associated with a significantly higher risk of 90-day mortality (P = 0.031). Patients in the standard-dose TGC (SDT) plus CPS subgroup had significantly higher rates of SOFA scores ≥ 7 (P = 0.009) and MV used (P = 0.028), as well as higher 30-/90-day mortality compared to high-dose TGC (HDT) plus CPS group. TGC plus CPS significantly reduced CRP levels (P = 0.009), while the variations in ALT, TBIL, Cr, Hb, and PLT levels did not differ between different antimicrobial regimens after PSM.Conclusion: HDT and CPS combination therapy was more effective in patients with advanced age and more severe condition. Safety profiles of different antimicrobial regimens were similar with liver, kidneys, and coagulation functions.Keywords: carbapenem-resistant Acinetobacter baumannii, hospital acquired pneumonia, tigecycline, cefoperazone/sulbactam, risk factors

Abstract 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.

Shuping Song,1,* Jieqiong Liu,2,3,* Wei Su,1 Haitao Yu,4 Binbin Feng,1 Yinshan Wu,1 Feng Guo,1 Zhenwei Yu2 1Intensive Care Unit, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3Department of Pharmacy, The 903rd Hospital of PLA Joint Logistic Support Force, Hangzhou, People’s Republic of China; 4Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Feng Guo; Zhenwei Yu, Email 3408003@zju.edu.cn; yzw_srrsh@zju.edu.cnBackground: Tigecycline is considered one of the last resorts for treating infections caused by multidrug-resistant bacteria. Continuous renal replacement therapy (CRRT) is widely used in critically ill patients, especially those with acute kidney injury or severe infections. However, pharmacokinetic data for tigecycline in patients receiving CRRT are limited.Methods: This was a single-center prospective clinical study with intensive sampling that included critically ill patients who received tigecycline and CRRT. A population pharmacokinetic (PPK) model was developed and evaluated by goodness-of-fit plots, bootstrap analysis, visual predictive checks, and numerical predictive checks. Pharmacokinetic/pharmacodynamic target attainment and cumulative fraction of response analyses were performed to explore the potential need for dose adjustments of tigecycline in CRRT.Results: In total, 21 patients with 167 concentrations were included. A two-compartment model adequately described the tigecycline concentration–time points, but no covariates were found to adequately explain the viability in the pharmacokinetic parameters of tigecycline. The typical values of CL, Q, V1 and V2 were 4.42 L/h, 34.8 L/h, 30.9 L and 98.7 L, respectively. For most infections, the standard regimen of 50 mg/12 h was deemed appropriate, expect for skin and soft skin tissue infections and community-acquired pneumonia caused by Acinetobacter baumannii and Klebsiella pneumoniae, which required a dosage regimen of 100 mg/12 h or higher.Conclusion: A tigecycline PPK model describing critically ill patients undergoing CRRT was successfully developed. The optimized dosage regimens for various infections are recommended.Keywords: tigecycline, population pharmacokinetics, critically ill, continuous renal replacement therapy

Objective To investigate the effect of different antibacterial agents combined with tigecycline in patients with multidrug-resistant Acinetobacter baumannii (MDRAB)-related ventilator-associated pneumonia (VAP), and to provide options for better treatment of the disease in clinical practice. Methods A retrospective analysis was performed for the clinical data of the patients with MDRAB-related VAP who were admitted from January 2016 to August 2023 in Qingdao municipal Hospital, and according to the treatment regimen, they were divided into tigecycline group (group A) with 56 patients, cefoperazone-sulbactam combination therapy group (B group) with 42 patients, and carbapenem combination therapy group (group C) with 24 patients. The three groups were compared in terms of infection and related outcome measures. Results There were no significant diffe-rences in the type of pathogene infected and infection sites between the three groups (P>0.05). Groups B and C had a significantly higher bacterial clearance rate than group A (χ2=5.38,4.48,P0.05). Conclusion Tigecycline combined with cefoperazone-sulbactam or carbapenem achieves a higher bacterial clearance rate than tigecycline alone in MDRAB-related VAP, and combined medication is a relatively good treatment option.

Objectives: To investigate the tet(X) gene, a determinant of tigecycline resistance, in the emerging pathogen Elizabethkingia meningoseptica and its association with an integrative and conjugative element (ICE). Methods: All E. meningoseptica genomes from the National Center for Biotechnology Information (n = 87) were retrieved and annotated for resistome searches using the CARD database. A phylogenic analysis was performed based on the E. meningoseptica core genome. The ICE was identified through comparative genomics with other ICEs occurring in Elizabethkingia spp. Results: Phylogenetic analysis revealed E. meningoseptica genomes from six countries distributed across different lineages, some of which persisted for years. The common resistome of these genomes included blaBlaB, blaCME, blaGOB, ranA/B, aadS, and catB (genes associated with resistance to β-lactams, aminoglycosides, and chloramphenicol). Some genomes also presented additional resistance genes (dfrA, ereD, blaVEB, aadS, and tet(X)). Interestingly, tet(X) and aadS were located in an ICE of 49 769 bp (ICEEmSQ101), which was fully obtained from the E. meningoseptica SQ101 genome. We also showed evidence that the other 27 genomes harboured this ICE. The distribution of ICEEmSQ101, carrying tet(X), was restricted to a single Chinese lineage. Conclusions: The tet(X) gene is not prevalent in the species E. meningoseptica, as previously stated for the genus Elizabethkingia, since it is present only in a single Chinese lineage. We identified that several E. meningoseptica genomes harboured an ICE that mobilized the Elizabethkingia tet(X) gene and exhibited characteristics similar to the ICEs of other Flavobacteria, which would favour their transmission in this bacterial family.

Objectives: Clostridioides difficile ranks among the primary sources of healthcare-related infections and diarrhoea in numerous nations. We evaluated the drug susceptibility and resistance mechanisms of C. difficile isolates from a hospital in Chongqing, China, and identified resistance rates and resistance mechanisms that differed from previous findings. Methods: The toxin genes and drug resistance genes of clinical strains were detected using Polymerase Chain Reaction (PCR), and these strains were subjected to Multilocus Sequence Typing (MLST). The agar dilution technique was employed for assessing susceptibility of antibiotics. Clinical data collection was completed through a review of electronic medical records. Results: A total of 67 strains of toxin-producing C. difficile were detected. All C. difficile isolates demonstrated susceptibility to both metronidazole and vancomycin. However, resistance was observed in 8.95%, 16.42%, 56.72%, 56.72%, 31.34% and 5.97% of the isolates for tigecycline, tetracycline, clindamycin, erythromycin, moxifloxacin and rifampin, respectively. Among the strains with toxin genotypes A + B + CDT - and belonging to the ST3, six strains exhibited reduced susceptibility to tigecycline (MIC=0.5mg/L) and tetracycline (MIC=8mg/L). The tetA(P) and tetB(P) genes were present in these six strains, but were absent in tetracycline-resistant strains. Resistance genes (ermB, tetM, tetA(P) and tetB(P)) and mutations (in gyrA, gyrB, and rpoB) were identified in resistant strains. Conclusions: In contrast to prior studies, we found higher proportions of ST3 isolates with decreased tigecycline sensitivity, sharing similar resistance patterns and resistance genes. In the resistance process of tigecycline and tetracycline, the tetA(P) and tetB(P) genes may play a weak role.

Objectives: To investigate the genomic differences between two extensively drug resistant, ST16 strains of Klebsiella pneumoniae recovered from patients in the same ICU, one of which was colistin resistant. Methods: Antimicrobial susceptibilities of the isolates were determined using VITEK-2. Hybrid assemblies for both strains were generated using Oxford Nanopore and Illumina technologies. The sequence type, capsule type, O-locus type, antimicrobial resistance determinants and plasmids carried by the isolates were inferred from the genome sequence. The phylogenetic placement, antimicrobial resistance, and virulence determinants of the isolates relative to a collection (n = 871) of ST16 isolates were assessed. Results: Both BC16, a colistin-resistant blood stream isolate and U23, a colistin-sensitive urinary isolate displayed near-identical antimicrobial resistance profiles and genome sequences with varying plasmid profiles. The BC16 genome only had 21 SNPs relative to U23 and belonged to the same capsule, O-antigen locus and multi-locus sequence types. The mgrB locus in BC16 was disrupted by an IS5 element. Phylogenetically, U23 and BC16 were placed on a clade with 4 strains belonging to K-type K48 and O-type O2a as opposed to majority (n = 807) of the strains (K-type K51 and O-type O3b). Conclusions: BC16 was a colistin resistant derivative of U23, which evolved colistin resistance by an IS5-mediated disruption of the mgrB locus, likely during treatment of the index patient with colistin in the ICU. The strains belong to a rare subtype of ST16 with unique capsular and O-antigen types underscoring the utility of genomic surveillance networks and open-access genomic surveillance data in tracking problem clones.

Abstract 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 bla NDM-1 and bla KPC-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.

INTRODUCTION. The pathogenesis of antibiotic-associated drug-induced liver injury (DILI) in children has not been fully elucidated to date. Certain genotypes in patients increase the probability of developing DILI. Therefore, the identification of pharmacogenetic markers associated with DILI in children is essential.АIM. This study aimed to identify pharmacogenetic biomarkers of new-onset DILI associated with tigecycline and meropenem in children.MATERIALS AND METHODS. This prospective observational study was conducted in the Morozov Children’s City Clinical Hospital from 1 February 2020 to 1 September 2021. The study analysed the incidence and types of antibiotic-associated adverse drug reactions (ADRs) in 100 critically ill children aged 0 to 17 years (44 boys and 56 girls). Pharmacogenetic testing was performed in children with ADRs (n=30) to identify potential mechanisms involved in the development of their ADRs. The authors isolated and tested DNA from buccal epithelium swabs using the Agena Bioscience iPLEX® PGx Pro-based VeriDose® Core Panel covering 68 single nucleotide polymorphisms (SNPs) or short insertions and deletions (INDELs) and 5 copy number variants (CNVs).RESULTS. The odds of developing DILI associated with meropenem and tigecycline were higher in carriers of the homozygous cytochrome genotype CYP3A5*3/*3 (OR: 12.6; 95% CI: 1.9–79.4, r=6.54, p=0.011) than in patients with the heterozygous genotype CYP3A5*1A/*3. The odds were even higher in patients not carrying the CYP3A5*1A/*3 genotype (OR: 17.14; 95% CI: 1.79–16.3, r=6.24, p=0.013). The detection of the CYP3A5*3/*3 ge­notype had a prognostic accuracy of 76.7%, a sensitivity of 82%, and a specificity of 74% in predicting the risk of DILI associated with meropenem and tigecycline. Moreover, children with DILI carried the heterozygous ge­notype SLCO1B1*1/*5 (rs4149056 polymorphism) more often than children with other adverse reactions ­associated with meropenem and tigecycline (r=9.8, p=0.002).CONCLUSION. The results of this study prove the prognostic significance of the homozygous cytochrome genotype CYP3A*3/*3 as an indicator of a potential risk for developing DILI associated with meropenem and tigecycline in children in critical conditions.The study was registered at ClinicalTrials.gov under No. NCT04141657 on 24 October 2019.

Clostridioides difficile infection (CDI) is the leading cause of nosocomial diarrhea in the United States. Tigecycline has been proposed as a potential treatment for CDI, though limited clinical data exist to support this practice. The objective of this study was to determine if the provision of tigecycline provides a clinically meaningful benefit to inpatients with CDI. This study was a retrospective chart review enrolling inpatients receiving treatment for CDI. Patients were divided into cohorts depending on whether they received a standard antibiotic therapy regimen for CDI or an antibiotic treatment regimen that included tigecycline. The primary outcome was clinical recovery at the time of hospital discharge. A total of 39 and 22 patients were included in the standard antibiotic therapy and tigecycline groups, respectively. ATLAS (Age, Treatment, Leukocyte, Albumin, Serum creatinine) scores at the time of CDI diagnosis were similar between the two groups, though patients in the tigecycline groups were more likely to represent a recurrent episode of CDI. There was no difference in the rate of clinical recovery at the time of hospital discharge between the standard antibiotic therapy and tigecycline groups (38.5% vs. 36.4%, p = 0.8710). These data do not support the routine use of tigecycline for the treatment of CDI, though interpretation is limited due to baseline differences between groups and the retrospective, observational nature of this study.

Objectives: Eravacycline, a new tetracycline derivative, exhibits broad-spectrum antimicrobial susceptibility. This study aimed to comprehensively investigate in vitro activities of eravacycline, tigecycline, and ertapenem against various Gram-positive, Gram-negative, and anaerobic bacteria. Methods: Minimum inhibitory concentrations (MICs) were determined using the broth microdilution method. The following bacterial species were collected: vancomycin-sensitive (VS) Enterococci species, vancomycin-resistant Enterococci species (VRE), Staphylococcus aureus, Streptococcus anginosus, Bacteroides species, Clostridioides difficile, Clostridium innocuum, Clostridium perfringens, Parabacteroides distasonis, and Stenotrophomonas maltophilia. Results: We found that eravacycline exhibited superior in vitro activity compared to tigecycline and ertapenem. Notably, it exhibited the lowest MIC90 for several bacterial species, including VS E. faecalis (0.12 µg/mL), VS E. faecium (0.12 µg/mL), and others. Besides, VRE was susceptible to eravacycline (MIC90:0.12 µg/mL) and tigecycline (MIC90:0.12 µg/mL), but was all resistant to ertapenem (MIC90 > 64 µg/mL). S. aureus was also susceptible to eravacycline (MIC90:0.5 µg/mL) as well as tigecycline (MIC90:1.0 µg/mL). Furthermore, S. anginosus showed higher susceptibility to eravacycline (MIC90:2.0 µg/mL) and tigecycline (MIC90:4.0 µg/mL), but lower to ertapenem (MIC90:32.0 µg/mL). Eravacycline and tigecycline also demonstrated good susceptibility to anaerobes, including Bacteroides species (susceptibility rate: 100%), P. distasonis (100%), C. difficile (94.1‒100%), C. innocuum (94.1‒96.1%), and C. perfringens (88.9‒96.3%). For S. maltophilia, both tigecycline and eravacycline showed an MIC90 of 2 µg/mL. A moderate-to-strong correlation (rho = 0.608–0.804, P < 0.001) was noted between the MIC values of eravacycline and tigecycline against various bacterial species. Conclusions: Our study highlights the potential of eravacycline as an effective treatment option for multidrug-resistant bacterial infections.

Abstract Blood flow infections (BSIs) is common occurrences in intensive care units (ICUs) and are associated with poor prognosis. The study aims to identify risk factors and assess mortality among BSI patients admitted to the ICU at Shanghai Ruijin hospital north from January 2022 to June 2023. Additionally, it seeks to present the latest microbiological isolates and their antimicrobial susceptibility. Independent risk factors for BSI and mortality were determined using the multivariable logistic regression model. The study found that the latest incidence rate of BSI was 10.11%, the mortality rate was 35.21% and the mean age of patients with BSI was 74 years old. Klebsiella pneumoniae was the predominant bacterial isolate. Logistic multiple regression revealed that tracheotomy, tigecycline, gastrointestinal bleeding, shock, length of hospital stay, age and laboratory indicators (such as procalcitonine and hemoglobin) were independent risk factors for BSI. Given the elevated risk associated with use of tracheotomy and tigecycline, it underscores the importance of the importance of cautious application of tracheostomy and empirical antibiotic management strategies. Meanwhile, the independent risk factors of mortality included cardiovascular disease, length of hospital stay, mean platelet volume (MPV), uric acid levels and ventilator. BSI patients exhibited a significant decrease in platelet count, and MPV emerged as an independent factor of mortality among them. Therefore, continuous monitoring of platelet-related parameters may aid in promptly identifying high-risk patients and assessing prognosis. Moreover, monitoring changes in uric acid levels may serve as an additional tool for prognostic evaluation in BSI patients.

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]

Introduction: The dissemination of strains producing tetracyclines monooxygenase Tet(X) from breeding farms to the natural environment poses a potential threat to public health. Methods: Antimicrobial susceptibility testing and WGS were performed to identify resistance phenotypes and genotypes. Cloning experiments, sequence alignment, and homology modeling were used to characterize the function and formation mechanisms of the recombinant variant. The mobilization potential of Tet(X) was assessed by collinearity analysis, conjugation experiments, and phylogenetic analysis. Results: Three tet(X)-producing Elizabethkingia meningoseptica strains were isolated from bullfrog breeding ponds, the sewage outlet, and downstream river in Zhejiang Province, China. These strains carry a novel Tet(X) variant, differing from Tet(X6) by seven residues, and possess the ability to degrade tetracyclines. Interestingly, the novel Tet(X) is a recombinant variant formed by homologous recombination of Tet(X6) and the C-terminal of Tet(X2). Further analysis revealed that Tet(X6) formed several Tet(X) variants, including Tet(X5), through homologous recombination. The novel tet(X) gene is located on a circularizable integrative and conjugative element (ICEEmeChn3), with ISwz1 participating in the recombination of its multi-drug resistance region, potentially facilitating the mobilization and recombination of tet(X) in early hosts. These three strains were clonally transmitted and shared a close genetic relationship (SNP < 62) with a clinically-sourced strain isolated from the same province. Discussion: To our knowledge, this is the first report of homologous recombination between Tet(X) variants with differing activities. These clonal strains provide evidence of the transmission of tet(X)-positive strains from aquaculture sewage to the natural environment, highlighting the need to strengthen the monitoring and management of this emerging farming model. [ABSTRACT FROM AUTHOR]

The emergence and widespread of tigecycline resistance undoubtedly poses a serious threat to public health globally. The exploration of combination therapies has become preferred antibacterial strategies to alleviate this global burden. In this study, tigecycline-resistant tet(X4)-positive Escherichia coli were selected for adjuvant screening. Interestingly, 9-aminominocycline (9-AMC), one of the tigecycline metabolites, exhibits synergistic antibacterial activity with tigecycline using checkerboard assay. The efficacy in vitro and in vivo was evaluated, and the synergistic mechanism was further explored. The results suggested that 9-AMC combined with tigecycline could inhibit the growth of antibiotic resistant bacteria, efficiently retard the evolution of tet(X4) gene and narrow the drug mutant selection window. In addition, the combination of tigecycline and 9-AMC could destroy the normal membrane structure of bacteria, inhibit the formation of biofilm, remarkably reduce the level of intracellular ATP level, and accelerate the oxidative damage of bacteria. Furthermore, 9-AMC is more stable in the bind of Tet(X4) inactivating enzyme. The transcriptomics analysis revealed that the genes related to the 9-AMC and tigecycline were mainly enriched in ABC transporters. Collectively, the results reveal the potentiation effects on tigecycline and the probability of 9-AMC as a novel tigecycline adjuvant against tet(X4)-positive Escherichia coli, which provides new insights for adjuvant screening. [ABSTRACT FROM AUTHOR]

Tigecycline serves as a last-resort antimicrobial agent against severe infections caused by multidrug-resistant bacteria. Tet(X) and its numerous variants encoding flavin-dependent monooxygenase can confer resistance to tigecycline, with tet(X4) being the most prevalent variant. This study aims to investigate the prevalence and characterize tigecycline resistance gene tet(X) in E. coli isolates from various origins in Yangzhou, China, to provide insights into tet (X) dissemination in this region. In 2022, we tested the presence of tet(X) in 618 E. coli isolates collected from diverse sources, including patients, pig-related samples, chicken-related samples, and vegetables in Yangzhou, China. The antimicrobial susceptibility of tet(X)-positive E. coli isolates was conducted using the agar dilution method or the broth microdilution method. Whole genome sequencing was performed on tet(X)-positive strains using Illumina and Oxford Nanopore platforms. Four isolates from pig or pork samples carried tet(X4) and exhibited resistance to multiple antimicrobial agents, including tigecycline. They were classified as ST542, ST10, ST761, and ST48, respectively. The tet(X4) gene was located on IncFIA8-IncHI1/ST17 (n=2), IncFIA18-IncFIB(K)-IncX1 (n=1), and IncX1 (n=1) plasmids, respectively. These tet(X4)-carrying plasmids exhibited high similarity to other tet(X4)-bearing plasmids with the same incompatible types found in diverse sources in China. They shared related genetic environments of tet(X4) associated with ISCR2, as observed in the first identified tet(X4)-bearing plasmid p47EC. In conclusion, although a low prevalence (0.65%) of tet(X) in E. coli strains was observed in this study, the horizontal transfer of tet(X4) among E. coli isolates mediated by pandemic plasmids and the mobile element ISCR2 raises great concerns. Thus, heightened surveillance and immediate action are imperative to curb this clinically significant resistance gene and preserve the efficacy of tigecycline. [ABSTRACT FROM AUTHOR]

Introduction: The rapid spread of plasmid-mediated tet(X4) conferring high tigecycline resistance poses a significant threat to public health. Escherichia coli as the most common pathogen which carries tet(X4) has been widely disseminated in China. Thus, comprehensive investigations are required to understand the mechanism of transmission of tet(X4)-positive E. coli. Methods: In this study, a total of 775 nonduplicate samples were collected in Guangdong, China from 2019 to 2020. We screened for tet(X4)-positive E. coli by PCR amplification and species identification. Furthermore, we analyzed the phylogenetics and genetic context of tet(X4)-positive E. coli through wholegenome sequencing and long-reads sequencing. Results: Overall, 146 (18.84%) tet(X4)-positive E. coli were isolated, comprising 2 isolates from humans and 144 isolates from pigs. The majority of tet(X4)-positive E. coli exhibited resistance to multiple antibiotics but all of them were susceptible to amikacin and colistin. Phylogenetic analysis showed that ST877, ST871, and ST195 emerged as the predominant sequence types in tet(X4)-positive E. coli. Further analysis revealed various genetic environments associated with the horizontal transfer of tet(X4). Notably, a 100-kbp large fragment insertion was discovered downstream of tet(X4), containing a replicon and a 40-kbp gene cluster for the bacterial type IV secretion system. Discussion: The high colonization rate of tet(X4)-positive E. coli in animals suggests that colonization as a key factor in its dissemination to humans. Diverse genetic context may contribute to the transfer of tet(X4). Our findings underline the urgent need for controlling the spread of plasmid-mediated tigecycline resistance. [ABSTRACT FROM AUTHOR]

Objective: Pakistan bears most of the burden of drug-resistant typhoid, challenging its healthcare systems with substantial cost. This study’s purpose is to investigate resistance in community-acquired salmonella typhi to guide its evidence-based empiric treatment. Material & Methods: This study used retrospective data from the microbiology laboratory, Khyber Teaching Hospital, Peshawar (September 2022-March 2023). Data of routine diagnostic samples for typhoid was retrieved from the database. Kirby– Bauer disk diffusion method was employed to determine the sensitivity of S. Typhi against a panel of 21 selected antibiotic discs (not exclusively for each isolate). Results: Among 1742 suspected patients, 239 (13.92%) were positive for S. Typhi with 212/238 (89.1%), 227/233 (97.4%), and 196/239 (82.0%) isolates resistant to chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole, respectively. High resistance (88.0% to ciprofloxacin) was detected against fluoroquinolones. Third-generation cephalosporins also showed poor activity with 144/158 (91.1%) and 120/136 (88.2%) resistance towards ceftriaxone and cefixime, respectively, except for cefoperazone/sulbactam (2/123, 1.6%). Among 157 tested isolates, 3 (1.9%), 9 (5.7%), and 123 (78.3%) were labeled as non-resistant, MDR, and XDR strains, respectively. XDRs were less resistant to azithromycin (1/114), piperacillin/tazobactam (1/123), carbapenems (0/123), and tigecycline (0/123). Conclusion: XDR S. Typhi was observed as the dominant strain in Peshawar regions for which azithromycin is still the drug of choice. With emerging resistance, azithromycin safety should be ensured through antibiotic stewardship principles. An interesting finding was the enhanced activity of cefoperazone/sulbactam, suggesting future studies. Alternative options are expensive antibiotics which can be used as a last resort. [ABSTRACT FROM AUTHOR]

Tetracyclines constitute a unique class of antibiotic agents, widely prescribed for both community and hospital infections due to their broad spectrum of activity. Acting by disrupting protein synthesis through tight binding to the 30S ribosomal subunit, their interference is typically reversible, rendering them bacteriostatic in action. Resistance to tetracyclines has primarily been associated with changes in pump efflux or ribosomal protection mechanisms. To address this challenge, tetracycline molecules have been chemically modified, resulting in the development of third-generation tetracyclines. These novel tetracyclines offer significant advantages in treating infections, whether used alone or in combination therapies, especially in hospital settings. Beyond their conventional antimicrobial properties, research has highlighted their potential non-antibiotic properties, including their impact on immunomodulation and malignancy. This review will focus on third-generation tetracyclines, namely tigecycline, eravacycline, and omadacycline. We will delve into their mechanisms of action and resistance, while also evaluating their pros and cons over time. Additionally, we will explore their therapeutic potential, analyzing their primary indications of prescription, potential future uses, and non-antibiotic features. This review aims to provide valuable insights into the clinical applications of third-generation tetracyclines, thereby enhancing understanding and guiding optimal clinical use. [ABSTRACT FROM AUTHOR]

Introduction: Tigecycline has a broad spectrum of activity, including activity against drug-resistant Gram-positive and -negative microorganisms. Its side effects are significant, but hypoglycemia is a rare finding during treatment. We aim to present an event of severe hypoglycemia in a patient with type 2 diabetes mellitus with replacement renal therapy, and hemodialysis after initiating tigecycline. Case presentation: A 54-year-old female diagnosed with type 2 diabetes mellitus was under treatment with basal-bolus insulin therapy and oral antihypertensive drugs. She started hemodialysis 24 months ago. She complained of recurrent fever for the last seven months and was treated with several antibiotics. In two separate blood cultures, she tested positive for methicillin-resistant Staphylococcus epidermidis (MRSE). Based on the antibiogram, we started treatment with tigecycline 100 mg/day. After 6-8 hours from the first dose, the patient is complicated with events of hypoglycemia and then continues with severe hypoglycemia (40-47 mg/dL). The patient continued to have hypoglycemia for about 16-18 hours after the last dose. We didn't find any reasons to explain the cause of episodes of hypoglycemia. She did not have high blood insulin levels (insulin 4.11 mIU/L [range 2.6-24.9]). We followed her for six months and the patient did not experience episodes of hypoglycemia. Conclusions: The association of severe hypoglycemia with tigecycline treatment is a very rare event and published papers on this topic are limited. Clinicians should be aware of this rare event when administering tigecycline and should routinely check blood glucose level during the treatment. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii is a challenging multidrug-resistant pathogen in healthcare. Phage vB_AbaSi_W9 (GenBank: PP146379.1), identified in our previous study, shows lytic activity against 26 (89.66%) of 29 carbapenem-resistant Acinetobacter baumannii (CRAB) strains with various sequence types (STs). It is a promising candidate for CRAB treatment; however, its lytic efficiency is insufficient for complete bacterial lysis. Therefore, this study aimed to investigate the clinical utility of the phage vB_AbaSi_W9 by identifying antimicrobial agents that show synergistic effects when combined with it. The A. baumannii ATCC17978 strain was used as the host for the phage vB_AbaSi_W9. Adsorption and one-step growth assays of the phage vB_AbaSi_W9 were performed at MOIs of 0.001 and 0.01, respectively. Four clinical strains of CRAB belonging to different sequence types, KBN10P04948 (ST191), LIS2013230 (ST208), KBN10P05982 (ST369), and KBN10P05231 (ST451), were used to investigate phage–antibiotic synergy. Five antibiotics were tested at the following concentration: meropenem (0.25–512 µg/mL); colistin, tigecycline, and rifampicin (0.25–256 µg/mL); and ampicillin/sulbactam (0.25/0.125–512/256 µg/mL). The in vitro synergistic effect of the phage and rifampicin was verified through an in vivo mouse infection model. Phage vB_AbaSi_W9 demonstrated 90% adsorption to host cells in 1 min, a 20 min latent period, and a burst size of 114 PFU/cell. Experiments combining phage vB_AbaSi_W9 with antibiotics demonstrated a pronounced synergistic effect against clinical strains when used with tigecycline and rifampicin. In a mouse model infected with CRAB KBN10P04948 (ST191), the group treated with rifampicin (100 μg/mL) and phage vB_AbaSi_W9 (MOI 1) achieved a 100% survival rate—a significant improvement over the phage-only treatment (8.3% survival rate) or antibiotic-only treatment (25% survival rate) groups. The bacteriophage vB_AbaSi_W9 demonstrated excellent synergy against CRAB strains when combined with tigecycline and rifampicin, suggesting potential candidates for phage–antibiotic combination therapy in treating CRAB infections. [ABSTRACT FROM AUTHOR]

Tigecycline is widely used for treating complicated bacterial infections for which there are no effective drugs. It inhibits bacterial protein translation by blocking the ribosomal A-site. However, even though it is also cytotoxic for human cells, the molecular mechanism of its inhibition remains unclear. Here, we present cryo-EM structures of tigecycline-bound human mitochondrial 55S, 39S, cytoplasmic 80S and yeast cytoplasmic 80S ribosomes. We find that at clinically relevant concentrations, tigecycline effectively targets human 55S mitoribosomes, potentially, by hindering A-site tRNA accommodation and by blocking the peptidyl transfer center. In contrast, tigecycline does not bind to human 80S ribosomes under physiological concentrations. However, at high tigecycline concentrations, in addition to blocking the A-site, both human and yeast 80S ribosomes bind tigecycline at another conserved binding site restricting the movement of the L1 stalk. In conclusion, the observed distinct binding properties of tigecycline may guide new pathways for drug design and therapy. Tigecycline is widely used to treat complex bacterial infections. Here, authors present cryo-EM structures of tigecycline-bound eukaryotic ribosomes, revealing how it also targets the human mitoribosome with distinct binding properties. [ABSTRACT FROM AUTHOR]

Blood flow infections (BSIs) is common occurrences in intensive care units (ICUs) and are associated with poor prognosis. The study aims to identify risk factors and assess mortality among BSI patients admitted to the ICU at Shanghai Ruijin hospital north from January 2022 to June 2023. Additionally, it seeks to present the latest microbiological isolates and their antimicrobial susceptibility. Independent risk factors for BSI and mortality were determined using the multivariable logistic regression model. The study found that the latest incidence rate of BSI was 10.11%, the mortality rate was 35.21% and the mean age of patients with BSI was 74 years old. Klebsiella pneumoniae was the predominant bacterial isolate. Logistic multiple regression revealed that tracheotomy, tigecycline, gastrointestinal bleeding, shock, length of hospital stay, age and laboratory indicators (such as procalcitonine and hemoglobin) were independent risk factors for BSI. Given the elevated risk associated with use of tracheotomy and tigecycline, it underscores the importance of the importance of cautious application of tracheostomy and empirical antibiotic management strategies. Meanwhile, the independent risk factors of mortality included cardiovascular disease, length of hospital stay, mean platelet volume (MPV), uric acid levels and ventilator. BSI patients exhibited a significant decrease in platelet count, and MPV emerged as an independent factor of mortality among them. Therefore, continuous monitoring of platelet-related parameters may aid in promptly identifying high-risk patients and assessing prognosis. Moreover, monitoring changes in uric acid levels may serve as an additional tool for prognostic evaluation in BSI patients. [ABSTRACT FROM AUTHOR]

Clostridioides difficile infection (CDI) is the leading cause of nosocomial diarrhea in the United States. Tigecycline has been proposed as a potential treatment for CDI, though limited clinical data exist to support this practice. The objective of this study was to determine if the provision of tigecycline provides a clinically meaningful benefit to inpatients with CDI. This study was a retrospective chart review enrolling inpatients receiving treatment for CDI. Patients were divided into cohorts depending on whether they received a standard antibiotic therapy regimen for CDI or an antibiotic treatment regimen that included tigecycline. The primary outcome was clinical recovery at the time of hospital discharge. A total of 39 and 22 patients were included in the standard antibiotic therapy and tigecycline groups, respectively. ATLAS (Age, Treatment, Leukocyte, Albumin, Serum creatinine) scores at the time of CDI diagnosis were similar between the two groups, though patients in the tigecycline groups were more likely to represent a recurrent episode of CDI. There was no difference in the rate of clinical recovery at the time of hospital discharge between the standard antibiotic therapy and tigecycline groups (38.5% vs. 36.4%, p = 0.8710). These data do not support the routine use of tigecycline for the treatment of CDI, though interpretation is limited due to baseline differences between groups and the retrospective, observational nature of this study. [ABSTRACT FROM AUTHOR]

Stenotrophomonas maltophilia is an opportunistic, multidrug-resistant non-fermentative Gram-negative bacillus, posing a significant challenge in clinical treatment due to its numerous intrinsic and acquired resistance mechanisms. This study aimed to evaluate the adequacy of antibiotics used for the treatment of S. maltophilia infections in critically ill patients using a pharmacokinetic/pharmacodynamic (PK/PD) approach. The antibiotics studied included cotrimoxazole, levofloxacin, minocycline, tigecycline, cefiderocol, and the new combination aztreonam/avibactam, which is not yet approved. By Monte Carlo simulations, the probability of target attainment (PTA), the PK/PD breakpoints, and the cumulative fraction of response (CFR) were estimated. PK parameters and MIC distributions were sourced from the literature, the European Committee on Antimicrobial Susceptibility Testing (EUCAST), and the SENTRY Antimicrobial Surveillance Program collection. Cefiderocol 2 g q8h, minocycline 200 mg q12h, tigecycline 100 mg q12h, and aztreonam/avibactam 1500/500 mg q6h were the best options to treat empirically infections due to S. maltophilia. Cotrimoxazole provided a higher probability of treatment success for the U.S. isolates than for European isolates. For all antibiotics, discrepancies between the PK/PD breakpoints and the clinical breakpoints defined by EUCAST (or the ECOFF) and CLSI were detected. [ABSTRACT FROM AUTHOR]

Plasmid-mediated tigecycline resistance genes, notably the tet(X) and tmexCD-toprJ genes, have garnered considerable attention due to their transferability. This study aims to investigate the prevalence and resistance mechanisms associated with tet(X) and tmexCD-toprJ in flies, which are important reservoirs of antimicrobial resistance genes. A total of 52 tigecycline resistant bacterial isolates were collected, among which 40 (76.9 %) and 12 (23.1 %) were positive for tet(X) and tmexCD-toprJ, respectively. Tigecycline resistant bacteria were isolated from diverse geographical locations in China, with tet(X4)-positive Escherichia coli and tmexCD1-toprJ1-positive Klebsiella pneumoniae dominant among the isolates. The prevalence of tet(X) in rural area was significantly higher than that in urban area (2.7 % vs. 0.3 %; P 0.05). Most tet(X)-positive strains (n = 40, 100.0 %), and 11(91.7 %) of the tmexCD1-toprJ1-positive strains exhibited multi-drug resistance. The IncFIB(Mar)/IncHI1B hybrid plasmid carrying tmexCD1-toprJ1 was identified by whole-genome sequencing analysis, which dominated the transmission of tmexCD1-toprJ1 in K. pneumoniae. Genetic context analysis showed that tmexCD1-toprJ1 was related locally to IS26, and IS26 may exacerbate the spread of tmexCD1-toprJ1 in different bacteria. In addition, the genetic structure of tmexCD1-toprJ1 also contains several antimicrobial resistance genes, including aph(3′)-Ic, sul1, blaDHA-1, blaCTX-M−5, etc., conferring resistance to aminoglycosides, sulfonamides, and carbapenems. This study provides insights into the epidemiology and transmission dynamics of tigecycline resistance genes, informing targeted intervention strategies to mitigate antimicrobial resistance dissemination.

ABSTRACT Tetracyclines and glycylcycline are among the important antibiotics used to combat infections caused by multidrug-resistant Gram-negative pathogens. Despite the clinical importance of these antibiotics, their mechanisms of resistance remain unclear. In this study, we elucidated a novel mechanism of resistance to tetracycline and glycylcycline antibiotics via lipopolysaccharide (LPS) modification. Disruption of the Escherichia coli PhoPQ two-component system, which regulates the transcription of various genes involved in magnesium transport and LPS modification, leads to increased susceptibility to tetracycline, minocycline, doxycycline, and tigecycline. These phenotypes are caused by enhanced expression of phosphoethanolamine transferase EptB, which catalyzes the modification of the inner core sugar of LPS. PhoPQ-mediated regulation of EptB expression appears to affect the intracellular transportation of doxycycline. Disruption of EptB increases resistance to tetracycline and glycylcycline antibiotics, whereas the other two phosphoethanolamine transferases, EptA and EptC, that participate in the modification of other LPS residues, are not associated with resistance to tetracyclines and glycylcycline. Overall, our results demonstrated that PhoPQ-mediated modification of a specific residue of LPS by phosphoethanolamine transferase EptB governs intrinsic resistance to tetracycline and glycylcycline antibiotics.IMPORTANCEElucidating the resistance mechanisms of clinically important antibiotics helps in maintaining the clinical efficacy of antibiotics and in the prescription of adequate antibiotic therapy. Although tetracycline and glycylcycline antibiotics are clinically important in combating multidrug-resistant Gram-negative bacterial infections, their mechanisms of resistance are not fully understood. Our research demonstrates that the E. coli PhoPQ two-component system affects resistance to tetracycline and glycylcycline antibiotics by controlling the expression of phosphoethanolamine transferase EptB, which catalyzes the modification of the inner core residue of lipopolysaccharide (LPS). Therefore, our findings highlight a novel resistance mechanism to tetracycline and glycylcycline antibiotics and the physiological significance of LPS core modification in E. coli.

Enterobacterales (especially carbapenem-resistant) are considered an urgent threat to public health. The available antibiotic therapy is limited due to the increase of multidrug-resistant (MDR) strains. Tigecycline, a minocycline derivative, has emerged as a potential key agent in the treatment of MDR isolates. The aim of the study was to evaluate the synergistic effect of tigecycline in combination with nine antimicrobial agents—ceftazidime/avibactam, colistin, ertapenem, gentamicin, imipenem, levofloxacin, meropenem/vaborbactam, polymyxin B, and rifampicin. Eighty clinical Enterobacter cloacae strains were obtained from patients of two University Hospitals in Bialystok, Poland. The E-test method was used to determine synergistic interactions. Among all combinations, synergy was reported in 61% of cases, addition in 32%, and indifference in 7%. The highest synergy rates were observed in tigecycline combinations with: ceftazidime/avibactam (60/80; 75%), imipenem (60/80; 75%), polymyxin B (55/80; 68.75%) and rifampicin (55/80; 68.75%), while the lowest synergy rate was noted in tigecycline-levofloxacin (26/80; 32.5%). The tigecycline-gentamicin showed the highest rate of indifference; antagonism, was not observed in any combination. In conclusion, tigecycline appears more suitable for use in combination therapy rather than as monotherapy and can be effectively paired with various antimicrobial agents against MDR E. cloacae. Further research will be necessary to confirm these results.

Abstract 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.

The rapid spread of mobile tigecycline resistance presents a significant public health threat, particularly with the increasing prevalence of tet(X4)-positive Enterobacterales across various species. This study aimed to investigate the epidemic features and transmission dynamics of tet(X4)-positive Klebsiella pneumoniae (K. pneumoniae) through the analysis of 206 raw meats, including pork (n = 182), beef (n = 16), duck (n = 5), and chicken (n = 3). These samples were collected from schools, markets, and restaurants in Chengdu City, China. A total of 25 isolates were obtained from 13 administrative regions. All isolates exhibited resistance to tetracycline, tigecycline, ampicillin, chloramphenicol, and florfenicol. Over half of the isolates also demonstrated resistance to streptomycin (80 %), sulfamethoxazole/trimethoprim (72 %), ciprofloxacin (64 %), and ampicillin/sulbactam (56 %). Among these strains, 14 distinct sequence types (STs) were identified, revealing evidence of inter-regional clonal spread, notably among 9 K. pneumoniae ST3393. Phylogenetic analysis revealed the presence of two K. pneumoniae ST5 closely resembling hypervirulent K. pneumoniae from Jiangsu. Importantly, 12 isolates were capable of transferring tigecycline resistance to Escherichia coli J53. Further plasmid analysis showed that the tet(X4)-harboring plasmids in K. pneumoniae could be classified into four types, primarily belonging to the IncFIA(HI1)/HI1A/HI1B hybrid plasmid (n = 16) and IncFII plasmid (n = 7), which significantly contributed to the cross-species dissemination of tet(X4). In summary, this study highlights the prevalence of MDR tet(X4)-positive K. pneumoniae in Chengdu, driven predominantly by clonal expansion and plasmid-mediated horizontal gene transfer. These findings emphasize the importance of continuous surveillance of tet(X4)-positive K. pneumoniae in raw meat and the implementation of effective measures to control their spread.

Abstract 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. Graphical abstract

Abstract 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 bla IMP−4 and bla SFO−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 bla IMP−4 and bla SFO−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 bla IMP−4 and bla SFO−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 bla IMP−4 gene was located on the In809-like integrative element (Intl1-bla IMP−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 bla IMP−4 and bla SFO−1. It is highly likely that the strain acquired this plasmid through horizontal transfer. The bla IMP−4 array (Intl1-bla IMP−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 bla IMP−4 , and the In809 integrative element.

ABSTRACT: Objectives: To evaluate the susceptibility of globally pneumonia-causing meropenem-resistant (MEM-R) Acinetobacter baumannii isolates against important antibiotics and estimate appropriate dosages of indicated antibiotics. Methods: We extracted the 2014–2021 Antimicrobial Testing of Leadership Surveillance database regarding the susceptibility of MEM-R A. baumannii isolates causing pneumonia against important antibiotics. The susceptibility and carbapenemase-encoding gene (CPEG) data of pneumonia-causing MEM-R A. baumannii isolates from patients hospitalized in intensive care units of five major regions were analyzed. The susceptibility breakpoints (SBP) recommended by the Clinical and Laboratory Standards Institute (CLSI) in 2022, other necessary criteria [SBP of MIC for colistin, 2 mg/L, in the CLSI 2018; and cefoperazone-sulbactam (CFP-SUL), 16 mg/L], and the pharmacokinetic and pharmacodynamic data of indicated antibiotics were employed. Results: Applying the aforementioned criteria, we observed the susceptible rates of colistin, minocycline, and CFP-SUL against the pneumonia-causing MEM-R A. baumannii isolates globally (n = 2905) were 93.2%, 69.1%, and 26.3%, respectively. Minocycline was significantly more active in vitro (MIC ≤4 mg/L) against the pneumonia-causing MEM-R A. baumannii isolates collected from North and South America compared to those from other regions (>90% vs. 58–72%). Additionally, blaOXA-23 and blaOXA-72 were the predominant CPEG in pneumonia-causing MEM-R A. baumannii isolates. Conclusions: After deliberative estimations, dosages of 200 mg minocycline intravenously every 12 h (SBP, 8 mg/L), 100 mg tigecycline intravenously every 12 h (SBP, 1 mg/L), and 160 mg nebulized colistin methanesulphonate every 8 h (SBP, 2 mg/L) are needed for the effective treatment of pneumonia-causing MEM-R A. baumannii isolates.

Background Tigecycline, a glycylcycline antibiotic is a promising option for the treatment of single or multidrug resistant pathogens. The aim of the study was to evaluate the in-vitro Tigecycline susceptibility of various pathogens from clinical samples received at the tertiary care hospitals in South India. Methods The analysis of specimens from patients admitted were carried out in this prospective cross sectional study. The identification and antimicrobial susceptibility testing was performed by semi-automated Vitek 2 systems and Kirby Bauer method. Pattern of data analysis was done by descriptive statistics. Results Among 2574 isolates, 812 isolates were Gram positive pathogens and 1762 isolates were Gram negative pathogens. Resistance to Tigecycline was more common among Gram negative pathogens (18.62%) in comparison to the Gram positive pathogens (0.49%). Among 740 Extended Spectrum Beta Lactamases (ESBL) producers such as Klebsiella species & E coli, 629 isolates were susceptible, and 93 isolates were resistant to the tigecycline. All the methicillin resistant Staphylococcus aureus (MRSA) isolates were susceptible to tigecycline. Conclusion Multidrug resistant (MDR) pathogens like Acinetobacter species, and Klebsiella species were found to be highly effective in vitro to tigecycline for elimination of infections caused by both Gram positive and Gram negative pathogens. The use of combination therapy becomes crucial to prevent the development of Pan Drug resistance.

Purpose Infection by carbapenem-resistant Klebsiella pneumoniae (CRKP) has high mortality. There is no clear optimal therapeutic choice for pneumonia caused by CRKP. The aim of this study was to compare the clinical outcomes and safety of the standard doses of polymyxin B-based regimens vs tigecycline-based regimens and to identify risk factors for mortality.Methods This retrospective cohort study included patients with pneumonia caused by CRKP between January 1, 2020 and December 31, 2022. The primary outcomes were 7-day bacterial eradication rate and 14- and 28-day all-cause mortality. The secondary outcome was incidence of acute kidney injury.Results Seventy-three patients were included in this study, 29 in the polymyxin B-based combination therapy group and 44 in tigecycline-based combination therapy group. There were no significant differences between the two groups in terms of the 7-day bacterial eradication rate (31.03% vs 20.45%, p = 0.409), the 14-day all-cause mortality (37.93% vs 22.73%, p = 0.160), and the incidence of acute kidney injury (14.29% vs 6.82%, p = 0.526). The 28-day all-cause mortality in the polymyxin B-based therapy group was higher than in the tigecycline-based group (75.86% vs 45.45%, p = 0.010). Binary logistic regression analysis revealed that male and previous use of carbapenems were independent factors associated with 28-day all-cause mortality for patients treated with polymyxin B (p

ABSTRACTThe emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) poses grave threats to human health. These strains increased dramatically in clinical settings in China in the past few years but not in other parts of the world. Four isogenic K. pneumoniae strains, including classical K. pneumoniae, carbapenem-resistant K. pneumoniae (CRKP), hypervirulent K. pneumoniae (hvKP) and CR-hvKP, were created and subjected to phenotypic characterization, competition assays, mouse sepsis model and rat colonization tests to investigate the mechanisms underlying the widespread nature of CR-hvKP in China. Acquisition of virulence plasmid led to reduced fitness and abolishment of colonization in the gastrointestinal tract, which may explain why hvKP is not clinically prevalent after its emergence for a long time. However, tigecycline treatment facilitated the colonization of hvKP and CR-hvKP and reduced the population of Lactobacillus spp. in animal gut microbiome. Feeding with Lactobacillus spp. could significantly reduce the colonization of hvKP and CR-hvKP in the animal gastrointestinal tract. Our data implied that the clinical use of tigecycline to treat carbapenem-resistant K. pneumoniae infections facilitated the high spread of CR-hvKP in clinical settings in China and demonstrated that Lactobacillus spp. was a potential candidate for anticolonization strategy against CR-hvKP.

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]