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Objective To evaluate the effectiveness and safety of using tigecycline as a salvage therapy in critically ill children who did not respond to other antibiotics. Methods We conducted a retrospective cohort analysis that included children who received tigecycline for at least 48 hours and four doses during their pediatric intensive care unit admission. Demographic and clinical features of the subjects were evaluated through a comprehensive review of medical records. The effectiveness of tigecycline was assessed by thoroughly evaluating clinical and microbiological outcomes. Results During the study period, 72 pediatric patients with 88 episodes of infection received tigecycline according to antimicrobial susceptibility in 62.5% of cases and empirically in 37.5%. The median duration of tigecycline therapy was 10 days (range, 2–33 days). Klebsiella pneumoniae (n = 17, 30.9%) was the most frequently isolated pathogen, followed by Acinetobacter baumannii (n = 10, 18.1%). Ventilator-associated pneumonia was the most common infection (n = 29). Of the 55 isolated pathogens, 43 were multidrug-resistant (MDR), and 2 were extensively drug-resistant (XDR) gram-negative bacteria. Clinical response and microbiological clearance were achieved in 42 and 50.9% of episodes, respectively. The overall mortality was 40.9%, with an attributable mortality rate of 29.5%. Conclusion Tigecycline could be used as a salvage therapy for critically ill pediatric patients infected with MDR or XDR pathogens in the lack of alternative treatment options. [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]

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]

Tigecycline-non-susceptible Klebsiella pneumoniae (TNSKP) is increasing and has emerged as a global public health issue. However, the mechanism of tigecycline resistance remains unclear. The objective of this study was to investigate the potential role of efflux pump system in tigecycline resistance. 29 tigecycline-non-susceptible Klebsiella pneumoniae (TNSKP) strains were collected and their minimum inhibitory concentrations (MIC) were determined by the broth microdilution method. The ramR, acrR, rpsJ, tet(A), and tet(X) were amplified by polymerase chain reaction (PCR). The mRNA expression of different efflux pump genes and regulator genes were analyzed by real-time PCR. Additionally, KP14 was selected for genome sequencing. KP14 genes without acrB, oqxB, and TetA were modified using suicide plasmids and MIC of tigecycline of KP14 with target genes knocked out was investigated. It was found that MIC of tigecycline of 20 out of the 29 TNSKP strains decreased by over four folds once combined with phenyl-arginine-β-naphthylamide dihydrochloride (PaβN). Most strains exhibited upregulation of AcrAB and oqxAB efflux pumps. The strains with acrB, oqxB, and tetA genes knocked out were constructed, wherein the MIC of tigecycline of KP14∆acrB and KP14∆tetA was observed to be 2 µg/mL (decreased by 16 folds), the MIC of tigecycline of KP14ΔacrBΔTetA was 0.25 µg/mL (decreased by 128 folds), but the MIC of tigecycline of KP14∆oqxB remained unchanged at 32 µg/mL. The majority of TNSKP strains demonstrated increased expression of AcrAB-TolC and oqxAB, while certain strains showed mutations in other genes associated with tigecycline resistance. In KP14, both overexpression of AcrAB-TolC and tet(A) gene mutation contributed to the mechanism of tigecycline resistance. [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]

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]

Backgroud: Although not fully investigated, studies show that Legionella pneumophila can develop antibiotic resistance. As there is limited data available for Portugal, we determined the antibiotic susceptibility profile of Portuguese L. pneumophila serogroup 1 (LpnSg1) isolates against antibiotics used in the clinical practice in Portugal. Methods: Minimum inhibitory concentrations (MICs) were determined for LpnSg1 clinical (n = 100) and related environmental (n = 7) isolates, collected between 2006–2022 in the context of the National Legionnaire´s Disease Surveillance Programme, against azithromycin, clarithromycin, erythromycin, levofloxacin, ciprofloxacin, moxifloxacin, rifampicin, doxycycline, tigecycline, and amoxicillin/clavulanic acid, using three different assays. Isolates were also PCR-screened for the presence of the lpeAB gene. Results: Twelve isolates had azithromycin MICs above the EUCAST tentative highest WT MIC, 9 of which were lpeAB negative; for erythromycin and clarithromycin, all isolates tested within the susceptible range. The number of isolates with MICs above the tentative highest WT MIC for the remaining antibiotics was: ciprofloxacin: 7; levofloxacin: 17; moxifloxacin: 8; rifampicin: 11; doxycycline: 82; tigecycline: 4. EUCAST breakpoints are not available for amoxicillin/clavulanic acid. We estimated the ECOFFs and one isolate had a MIC eightfold higher than the E-test ECOFF. Additionally, a clinical isolate generated three colonies growing on the E-test inhibition zone that resulted in MICs fourfold higher than for the parental isolate. Conclusions: We report, for the first time, elevated MICs against first-line and other antibiotics (including azithromycin, fluoroquinolones and amoxicillin/clavulanic acid commonly used to treat pneumonia patients in Portugal) in Portuguese L. pneumophila strains. Results point towards decreased susceptibility in circulating strains, justifying further investigation. [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]

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.

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.

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.

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.

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]

OBJECTIVE: To explore the effects of tigecycline on coagulation function and liver function. METHODS: Clinical data of 55 patients receiving anti-infective treatment with tigacycline in Beijing Friendship Hospital, Capital Medical University from Jan. 2019 to Jun. 2022 were collected. Levels of coagulation function indicators including peripheral blood fibrinogen ( FIB), activated partial thrombin time ( APTT), international normalized ratio ( INR), D-dimer and platelet count ( PLT) were recordedbefore medication ( T0 ), 7 d after medication ( T7 ) and at the end of medication ( Tf ). The levels of liver function indicators in T0, T7 and Tf were recorded, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and albumin (ALB). The coagulation function and liver function indicators were statistically analyzed. RESULTS: After treatment with tigecycline, the FIB level of patients showed a decreasing trend, and the FIB level of T7 and Tf was lower than that of T0, with statistically significant difference (P<0. 05); the APTT of T7 and Tf was longer than that of T0, the difference was statistically significant ( P < 0. 05); the D-dimer level showed a decreasing trend, and the D-dimer level of Tf was lower than that of T0, with statistically significant difference ( P < 0. 05), suggesting that tigecycline had some effects on coagulation function. After treatment with tigecycline, ALT levels of T7 and Tf were lower than those of T0, the difference was statistically significant (P<0. 05), showing a decreasing trend; the levels of ALP, AST, TBIL and ALB in T7 and Tf were not significantly different from those in T0, without statistically significant differences (P>0. 05), suggesting that tigecycline had no effect on liver function. CONCLUSIONS: Tigecycline may cause a decrease in FIB levels, prolongation of APTT, and a decrease in D-dimer levels, and patients’ coagulation needs to be closely monitored during administration to prevent bleeding. [ABSTRACT FROM AUTHOR]

Objectives To elucidate the mechanism of tigecycline resistance in Escherichia coli that is mediated by the tet (A) variant gene. Methods E. coli strain 573 carried a plasmid-borne tet (A) variant gene, tentatively designated tet (A)TIG, that conferred decreased tigecycline susceptibility (MIC 0.5 mg/L). When exposed to increasing concentrations of tigecycline (0.25–8 mg/L), mutants growing at 2, 4 and 8 mg/L were obtained and sequenced. Copies of plasmid and tet (A)TIG relative to the chromosomal DNA in the mutants were determined by WGS and quantitative PCR (qPCR). Expression of tet (A)TIG in the mutants was evaluated by RT–qPCR. The tet (A)TIG-carrying plasmids were visualized by S1-PFGE and Southern blot hybridization. PCR served for the detection of a tet (A)TIG-carrying unconventional circularizable structure (UCS). Results Tigecycline resistance with maximum MICs of 16 mg/L was seen in E. coli mutants selected in the presence of tigecycline. Compared with the parental strain, the relative copy number and transcription level of tet (A)TIG in the mutants increased significantly in the presence of 2, 4 and 8 mg/L tigecycline, respectively. With increasing tigecycline selection pressure, the tet (A)TIG-carrying plasmids in the mutants increased in size, correlating with the number of tandem amplificates of a ΔTn As1 -flanked UCS harbouring tet (A)TIG. These tandem amplificates were not stable in the absence of tigecycline. Conclusions Tigecycline resistance is due to the tandem amplification of a ΔTn As1 -flanked tet (A)TIG-carrying plasmid-borne segment in E. coli. The gain/loss of the tandem amplificates in the presence/absence of tigecycline represents an economic way for the bacteria to survive in the presence of tigecycline. [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]

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

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]

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]

Background Antimicrobial stewardship programs can optimize antimicrobial use and have been federally mandated in all hospitals. However, best stewardship practices in immunocompromised patients with cancer are not well established. Methods An antimicrobial time out, in the form of an email, was sent to physicians caring for hospitalized patients reaching 5 days of therapy for targeted antimicrobials (daptomycin, linezolid, tigecycline, vancomycin, imipenem/cilastatin, meropenem) in a comprehensive cancer center. Physicians were to discontinue the antimicrobial if unnecessary or document a rationale for continuation. This is a quasi-experimental, interrupted time series analysis assessing antimicrobial use during the following times: period 1 (before time-out: January 2007-June 2010) and period 2 (after time-out: July 2010-March/2015). The primary antimicrobial consumption metric was mean duration of therapy. Days of therapy per 1000 patient-days were also assessed. Results Implementation of the time-out was associated with a significant decrease in mean duration of therapy for the following antimicrobials; daptomycin: −0.89 days (95% confidence interval [CI], −1.38 to −.41); linezolid: −0.89 days (95% CI, −1.27 to −.52); meropenem: −0.97 days (95% CI, −1.39 to −.56); tigecycline: −1.41 days (95% CI, −2.19 to −.63); P <.001 for each comparison. Days of therapy/1000 patient-days decreased significantly for meropenem (−43.49; 95% CI, −58.61 to −28.37; P <.001), tigecycline (−35.47; 95% CI, −44.94 to −26.00; P <.001), and daptomycin (−9.47; 95% CI, −15.25 to −3.68; P =.002). Discussion A passive day 5 time-out was associated with reduction in targeted antibiotic use in a cancer center and could potentially be successfully adopted to several settings and electronic health records. [ABSTRACT FROM AUTHOR]

Multiple myeloma is an incurable plasma cell malignancy. Most patients end up relapsing and developing resistance to antineoplastic drugs, like bortezomib. Antibiotic tigecycline has activity against myeloma. This study analyzed tigecycline and bortezomib combination on cell lines and plasma cells from myeloma patients. Apoptosis, autophagic vesicles, mitochondrial mass, mitochondrial superoxide, cell cycle, and hydrogen peroxide were studied by flow cytometry. In addition, mitochondrial antioxidants and electron transport chain complexes were quantified by reverse transcription real-time PCR (RT-qPCR) or western blot. Cell metabolism and mitochondrial activity were characterized by Seahorse and RT-qPCR. We found that the addition of tigecycline to bortezomib reduces apoptosis in proportion to tigecycline concentration. Supporting this, the combination of both drugs counteracts bortezomib in vitro individual effects on the cell cycle, reduces autophagy and mitophagy markers, and reverts bortezomib-induced increase in mitochondrial superoxide. Changes in mitochondrial homeostasis and MYC upregulation may account for some of these findings. These data not only advise to avoid considering tigecycline and bortezomib combination for treating myeloma, but caution on the potential adverse impact of treating infections with this antibiotic in myeloma patients under bortezomib treatment. [ABSTRACT FROM AUTHOR]

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

Objective Ventriculitis is an example of the increasing global trend in difficult-to-treat infections in neonates caused by pathogens resistant to conventional therapies. This article describes the first use of intravenous and intraventricular tigecycline to treat ventriculitis caused by vancomycin-resistant enterococci in a preterm neonate and systematically review the literature on challenges posed by the definitions, diagnosis, and treatment of neonatal ventriculitis Methods The authors searched PubMed and Internet search engines for "ventriculitis" in the period from 2003 to 2023 restricting the research to "Newborn," "Human," "English language," and "full-text availability." Results Thirty-seven publications (20 case reports, 6 case series, and 11 research articles) were extracted upon research. Preterm birth, posthemorrhagic ventricular dilatation requiring placement of ventricular access devices, and sepsis preceded neonatal ventriculitis. Infections caused by rare microorganisms, in particular gram-negative bacteria resistant to conventional therapies, predominated in the publications describing the need for a combination of intravenous (IV) and intraventricular (IVT) therapies. Survivors of neonatal ventriculitis developed neurodevelopmental impairments such as hydrocephalus, seizures, motor function, hearing, and vision impairment. Conclusion Clinical suspicion of ventriculitis indicated by subtle signs is key for prompt diagnosis. Effective IV and IVT antibiotics are essential to prevent serious sequelae and mortality. The drug delivery method should be changed if there is no clinical response. This study emphasizes the urgent need for pediatric trials of antibiotics against organisms resistant to other drugs. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the potential of tamoxifen and N-desmethyltamoxifen metabolites as therapeutic agents against multidrug-resistant Escherichia coli and Acinetobacter baumannii, using a repurposing approach to shorten the time required to obtain a new effective treatment against multidrug-resistant bacterial infections. Characterisation and virulence studies were conducted on E. coli (colistin-susceptible C1-7-LE and colistin-resistant MCR-1+) and A. baumannii (tigecycline-susceptible Ab#9 and tigecycline-resistant Ab#186) strains. The efficacy of the metabolite mix (33.3% each) and N-desmethyltamoxifen in combination with colistimethate sodium (CMS) or tigecycline was evaluated in experimental models in mice. In the pneumonia model, N-desmethyltamoxifen exhibited significant efficacy against Ab#9 and both E. coli strains, especially E. coli MCR-1+ (−2.86 log10 CFU/g lungs, −5.88 log10 CFU/mL blood, and −50% mortality), and against the Ab#186 strain when combined with CMS (−2.27 log10 CFU/g lungs, −2.73 log10 CFU/mL blood, and −40% mortality) or tigecycline (−3.27 log10 CFU/g lungs, −4.95 log10 CFU/mL blood, and −50% mortality). Moreover, the metabolite mix in combination with both antibiotics decreased the bacterial concentrations in the lungs and blood for both A. baumannii strains. In the sepsis model, the significant efficacy of the metabolite mix was restricted to the colistin-susceptible E. coli C1-7-LE strain (−3.32 log10 CFU/g lung, −6.06 log10 CFU/mL blood, and −79% mortality). N-desmethyltamoxifen could be a new therapeutic option in combination with CMS or tigecycline for combating multidrug-resistant GNB, specifically A. baumannii. [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]

The global emergence of antimicrobial resistance to multiple antibiotics has recently become a significant concern. Gram-negative bacteria, known for their ability to acquire mobile genetic elements such as plasmids, represent one of the most hazardous microorganisms. This phenomenon poses a serious threat to public health. Notably, the significance of tigecycline, a member of the antibiotic group glycylcyclines and derivative of tetracyclines has increased. Tigecycline is one of the last-resort antimicrobial drugs used to treat complicated infections caused by multidrug-resistant (MDR) bacteria, extensively drug-resistant (XDR) bacteria or even pan-drug-resistant (PDR) bacteria. The primary mechanisms of tigecycline resistance include efflux pumps' overexpression, tet genes and outer membrane porins. Efflux pumps are crucial in conferring multi-drug resistance by expelling antibiotics (such as tigecycline by direct expelling) and decreasing their concentration to sub-toxic levels. This review discusses the problem of tigecycline resistance, and provides important information for understanding the existing molecular mechanisms of tigecycline resistance in Enterobacterales. The emergence and spread of pathogens resistant to last-resort therapeutic options stands as a major global healthcare concern, especially when microorganisms are already resistant to carbapenems and/or colistin. [ABSTRACT FROM AUTHOR]

Background: Due to the growing resistance to routinely used antibiotics, the search for new antibiotics or their combinations with effective inhibitors against multidrug-resistant microorganisms is ongoing. In our study, we assessed the in vitro drug susceptibility of Klebsiella pneumoniae strains producing New Delhi metallo-ß-lactamases (NDM) to antibiotics included in the Infectious Diseases Society of America (IDSA) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommendations. Methods: A total of 60 strains of NDM-producing K. pneumoniae were obtained from different patients hospitalized at the 4th Military Hospital in Wroclaw between 2019 and 2022 and subjected to drug susceptibility to selected antibiotics, including the effects of drug combinations. Results: Among the tested antibiotics, the highest sensitivity (100%) was observed for cefiderocol, eravacycline (interpreted according to the European Committee on Antimicrobial Susceptibility Testing [EUCAST]), and tigecycline. Sensitivity to intravenous fosfomycin varied depending on the method used. Using the "strip stacking" method, determining cumulative sensitivity to ceftazidime/avibactam and aztreonam demonstrated 100% in vitro sensitivity to this combination among the tested strains. Conclusion: The in vitro susceptibility assessment demonstrated that, the best therapeutic option for treating infections caused by carbapenemase-producing strains seems to be a combination of ceftazidime/avibactam with aztreonam. Due to the safety of using both drugs, cost effectiveness, and the broadest indications for use among the tested antibiotics, this therapy should be the first-line treatment for carbapenemase-producing Enterobacterales infections. Nevertheless, a comprehensive evaluation of the efficacy of treating infections caused by NDM-producing K. pneumoniae strains should include not only in vitro susceptibility assessment but also an analysis of clinical cases. [ABSTRACT FROM AUTHOR]

Tigecycline-associated hypofibrinogenemia has been reported as an important adverse effect in recent years, but controlled studies minimizing confounding factors are needed. The objective of our study was to assess changes in fibrinogen levels in patients for hospitalization, comparing two antibiotic episodes (tigecycline and other) within the same patients. The retrospective, self-controlled case series study was conducted at our University Hospitals. The study compared the change in fibrinogen levels during the patient's hospitalization for tigecycline (TigePer) and another antibiotic period (OtherPer). In addition, bleeding events, bleeding risk (determined by the IMPROVE bleeding risk score), as well as 15- and 30-day mortality rates between TigePer and OtherPer were compared. The study enrolled 50 patients with 100 episodes of antibiotic treatment. The median age (interquartile range) of the patients was 68.5 (21.5) years, and 38 % were female. As compared to OtherPer, TigePer had a statistically significant reduction in fibrinogen levels (p < 0.001), with a hypofibrinogenemia rate of 40 % in TigePer as compared to 2 % in OtherPer (p < 0.001). TigePer demonstrated a significantly higher 15-day mortality rate (p = 0.006). No significant differences were observed between the two periods in terms of bleeding risk, rate of bleeding events, and 30-day mortality rate (p > 0.05). Hypofibrinogenemia and other coagulopathies, without associated bleeding events, are more frequently observed in patients receiving tigecycline. Therefore, it is crucial for clinicians to monitor fibrinogen levels during tigecycline use. • Patients undergoing tigecycline treatment are prone to low fibrinogen levels. • High incidence of hypofibrinogenemia is associated with the use of tigecycline. • Tigecycline can elevate INR levels without causing bleeding events or risk. • The 30-day mortality rate did not differ between the groups. [ABSTRACT FROM AUTHOR]

Objective: In recent years, the number of Gram-negative bacteria (GNB) resistant to ceftazidime-avibactam (CZA) isolated from clinic has been increasing. We aimed to evaluate the clinical efficacy in patients with CZA-resistant GNB infections, and analyze the risk factors for clinical treatment failure and death. Methods: Clinical data of patients with CZA-resistant GNB infections were collected retrospectively, and the influencing factors were analyzed by binary logistic regression. Results: A total of 75 patients with CZA-resistant GNB infections were enrolled in the study, and the clinical effective rate was 56% (42/75). Multivariate analysis showed that continuous renal replacement therapy (CRRT) during anti-infection treatment was an independent risk factor for clinical treatment failure (OR 0.177, 95% CI 0.05-0.63, p < 0.008). The 28-day mortality rate in 75 patients was 18.7% (14/75). Multivariate analysis showed that the regimen of colistin E 750,000 U q12h (OR 0.020, 95% CI 0.00-0.56, p < 0.021), co-administration of tigecycline (OR 8.851, 95% CI 2.38-1316.87, p < 0.012) and CRRT during anti-infection treatment (OR 79.610, 95% CI 4.87-1300.26, p < 0.002) were independent affecting factors for 28-day mortality in patients with CZAresistant GNB infections. Conclusions: Patients with CZA-resistant GNB infections had a higher possibility of clinical treatment failure and death. The results of the study based on small sample size from a single center showed that clinical treatment failure and death were more likely to happen in patients on CRRT, and the regimen of colistin E 750,000 U q12h or co-administration of tigecycline may reduce or increase mortality, respectively. Further validation in rigorously designed multicenter clinical studies with larger sample sizes is needed. [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.

Introduction: Mediastinitis remains one of the most serious complications of cardiac surgery. The reported incidence is 1-4%, while the related mortality varies from 10-47%. Case Presentation: A patient with triple vessel disease (TVD) was hospitalized at our clinic for coronary artery bypass graft (CABG) surgery. The preoperative examination results were normal. We performed standard CABG under extracorporeal circulation. The patient had a favorable postoperative course. On the fifth postoperative day, the wound showed seropurulent drainage. The treatment of the patient's wound continued with open dressing, negative wound pressure device, debridement, minimal muscle plasticity, and total bilateral muscle pectoral flap plasticity. The infecting microorganism was identified as multidrug-resistant Acinetobacter baumani, and systemic antibiotic therapy was initiated. The patient had "per secundum closure" of the wound after all these efforts. The wound healed completely 2 months after discharge, and the patient was in good health. Conclusions: Mediastinitis is associated with high mortality and high financial and human costs. The occurrence of this high-risk complication can be prevented through constant vigilance at every step from admission to discharge. [ABSTRACT FROM AUTHOR]

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.