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European Journal of Clinical... Jul 2022Tigecycline is unique glycylcycline class of semisynthetic antimicrobial agents developed for the treatment of polymicrobial infections caused by multidrug-resistant... (Review)
Review
Tigecycline is unique glycylcycline class of semisynthetic antimicrobial agents developed for the treatment of polymicrobial infections caused by multidrug-resistant Gram-positive and Gram-negative pathogens. Tigecycline evades the main tetracycline resistance genetic mechanisms, such as tetracycline-specific efflux pump acquisition and ribosomal protection, via the addition of a glycyclamide moiety to the 9-position of minocycline. The use of the parenteral form of tigecycline is approved for complicated skin and skin structure infections (excluding diabetes foot infection), complicated intra-abdominal infections, and community-acquired bacterial pneumonia in adults. New evidence also suggests the effectiveness of tigecycline for the treatment of severe Clostridioides difficile infections. Tigecycline showed in vitro susceptibility to Coxiella spp., Rickettsia spp., and multidrug-resistant Neisseria gonnorrhoeae strains which indicate the possible use of tigecycline in the treatment of infections caused by these pathogens. Except for intrinsic, or often reported resistance in some Gram-negatives, tigecycline is effective against a wide range of multidrug-resistant nosocomial pathogens. Herein, we summarize the currently available data on tigecycline pharmacokinetics and pharmacodynamics, its mechanism of action, the epidemiology of tigecycline resistance, and its clinical effectiveness.
Topics: Anti-Bacterial Agents; Community-Acquired Infections; Humans; Microbial Sensitivity Tests; Minocycline; Tigecycline; Treatment Outcome
PubMed: 33403565
DOI: 10.1007/s10096-020-04121-1 -
Journal of the Pediatric Infectious... Feb 2020Infections due to carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent in children and are associated with poor clinical outcomes. Optimal treatment... (Review)
Review
Infections due to carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent in children and are associated with poor clinical outcomes. Optimal treatment strategies for CRE infections continue to evolve. A lack of pediatric-specific comparative effectiveness data, uncertain pediatric dosing regimens for several agents, and a relative lack of new antibiotics with pediatric indications approved by the US Food and Drug Administration (FDA) collectively present unique challenges for children. In this review, we provide a framework for antibiotic treatment of CRE infections in children, highlighting relevant microbiologic considerations and summarizing available data related to the evaluation of FDA-approved antibiotics (as of September 2019) with CRE activity, including carbapenems, ceftazidime-avibactam, meropenem-vaborbactam, imipenem/cilastatin-relebactam, polymyxins, tigecycline, eravacycline, and plazomicin.
Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Child; Drug Therapy, Combination; Enterobacteriaceae Infections; Humans; Polymyxins; Sisomicin; Tetracyclines; Tigecycline; beta-Lactamase Inhibitors
PubMed: 31872226
DOI: 10.1093/jpids/piz085 -
Annals of Medicine Dec 2022The progressive increase in antibiotic resistance in recent decades calls for urgent development of new antibiotics and antibiotic stewardship programs to help select... (Review)
Review
The progressive increase in antibiotic resistance in recent decades calls for urgent development of new antibiotics and antibiotic stewardship programs to help select appropriate treatments with the goal of minimising further emergence of resistance and to optimise clinical outcomes. Three new tetracycline-class antibiotics, eravacycline, omadacycline, and tigecycline, have been approved within the past 15 years, and represent a new era in the use of tetracyclines. These drugs overcome the two main mechanisms of acquired tetracycline-class resistance and exhibit a broad spectrum of activity against gram-positive, gram-negative, anaerobic, and atypical pathogens, including many drug-resistant strains. We provide an overview of the three generations of tetracycline-class drugs, focussing on the efficacy, safety, and clinical utility of these three new third-generation tetracycline-class drugs. We also consider various scenarios of unmet clinical needs where patients might benefit from re-engagement with tetracycline-class antibiotics including outpatient treatment options, patients with known β-lactam antibiotic allergy, reducing the risk of infection, and their potential as monotherapy in polymicrobial infections while minimising the risk of any potential drug-drug interaction. KEY MESSAGESThe long-standing safety profile and broad spectrum of activity of tetracycline-class antibiotics made them a popular choice for treatment of various bacterial infections; unfortunately, antimicrobial resistance has limited the utility of the early-generation tetracycline agents.The latest generation of tetracycline-class antibiotics, including eravacycline, tigecycline, and omadacycline, overcomes the most common acquired tetracycline resistance mechanisms.Based on characteristics and clinical data, these newer tetracycline agents provide an effective antibiotic option in the treatment of approved indications in patients with unmet clinical needs - including patients with severe penicillin allergy, with renal or hepatic insufficiency, recent infection, or polymicrobial infections, and those at risk of drug-drug interactions.
Topics: Anti-Bacterial Agents; Coinfection; Drug Resistance, Multiple, Bacterial; Humans; Hypersensitivity; Microbial Sensitivity Tests; Tetracycline; Tetracyclines; Tigecycline
PubMed: 35723082
DOI: 10.1080/07853890.2022.2085881 -
Microbiology Spectrum Oct 2021Tigecycline is regarded as a last-resort treatment for multidrug-resistant Acinetobacter baumannii. However, tigecycline resistance in A. baumannii has increased...
Tigecycline is regarded as a last-resort treatment for multidrug-resistant Acinetobacter baumannii. However, tigecycline resistance in A. baumannii has increased worldwide. In this study, we investigated tigecycline heteroresistance in A. baumannii isolates from South Korea. Antibiotic susceptibility testing was performed on 323 nonduplicated A. baumannii isolates. Among 260 and 37 tigecycline-susceptible and -intermediate-resistant A. baumannii isolates, 146 (56.2%) and 22 (59.5%) isolates were identified as heteroresistant to tigecycline through a disk diffusion assay and population analysis profiling. For selected isolates, an time-kill assay was performed, and survival rates were measured after preincubation with diverse concentrations of tigecycline. Heteroresistant isolates showed regrowth after 12 h of 2× MIC of tigecycline treatment, and resistant subpopulations were selected by preexposure to tigecycline. Furthermore, genetic alterations in , and were assessed, and the relative mRNA expression levels of and were compared. The tigecycline resistance in subpopulations might be due to the insertion of IS in , leading to the overexpression of the AdeABC efflux pump. However, the tigecycline resistance of subpopulations was not stable during serial passages in antibiotic-free medium. The reversion of tigecycline susceptibility by antibiotic-free passages might occur by additional insertions of IS in and nucleotide alterations in in some mutants. Tigecycline heteroresistance is prevalent in A. baumannii isolates, which results in treatment failure. Tigecycline resistance is mainly due to the overexpression of the AdeABC efflux pump, which is associated with genetic mutations, but this resistance could be reversed into susceptibility by additional mutations in antibiotic-free environments. The evidence that antibiotic heteroresistance is responsible for treatment failure in clinical settings is increasing. Thus, detection and characterization of heteroresistance would be important for appropriate therapeutic guidance to treat bacterial infections. However, data on tigecycline heteroresistance in Gram-negative bacteria is currently limited, although tigecycline is regarded as a last-line antibiotic against infections caused by antibiotic-resistant pathogens. In this study, we investigated the tigecycline heteroresistance in Acinetobacter baumannii, which has been listed by the WHO as a priority for research and development of new antibiotics. We found very high prevalence of tigecycline-heteroresistant A. baumannii clinical isolates, which may result in treatment failure due to the selection of resistant subpopulations. We also identified the main resistance mechanism in tigecycline-resistant subpopulations, that is, upregulation of AdeABC efflux pumps due to IS insertion in
Topics: Acinetobacter Infections; Acinetobacter baumannii; Anti-Bacterial Agents; Bacterial Proteins; Disk Diffusion Antimicrobial Tests; Drug Resistance, Multiple, Bacterial; Humans; Membrane Transport Proteins; RNA, Messenger; Ribosomal Proteins; Tigecycline
PubMed: 34523993
DOI: 10.1128/Spectrum.01010-21 -
Drug Resistance Updates : Reviews and... Sep 2018Vancomycin-resistant enterococci (VRE) are important nosocomial pathogens. Invasive VRE infections are difficult to treat since common therapeutic options including... (Review)
Review
Vancomycin-resistant enterococci (VRE) are important nosocomial pathogens. Invasive VRE infections are difficult to treat since common therapeutic options including ampicillin and glycopeptides often fail. In vitro, most VRE remain susceptible to last-resort antibiotics such as linezolid, tigecycline and daptomycin. However, neither tigecycline nor linezolid act in a bactericidal manner, and daptomycin has proven activity only at high dosages licensed for treating enterococcal endocarditis. Despite these pharmacological and therapeutic limitations, reports on resistance to these last-resort drugs in VRE, and enterococci in general, have increased in recent years. In this review, we briefly recapitulate the current knowledge on the mode of action as well as the known and novel mechanisms of resistance and describe surveillance data on resistance to linezolid, tigecycline and daptomycin in enterococci. In addition, we also suggest a common nomenclature for designating enterococci and VRE with resistances to these important last-resort antibiotics.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Carbon-Oxygen Ligases; Daptomycin; Genotype; Gram-Positive Bacterial Infections; Humans; Linezolid; Microbial Sensitivity Tests; Mutation; Tigecycline; Vancomycin Resistance; Vancomycin-Resistant Enterococci
PubMed: 30447411
DOI: 10.1016/j.drup.2018.10.002 -
Emerging Microbes & Infections Dec 2021Hypervirulent carbapenem-resistant (hv-CRKP) has recently aroused increasing attention, especially ST11, the predominant CRKP clone in China. Here, we report a case of...
Hypervirulent carbapenem-resistant (hv-CRKP) has recently aroused increasing attention, especially ST11, the predominant CRKP clone in China. Here, we report a case of hv-CRKP-associated infection and reveal the in-host evolution of its mechanism of resistance to tigecycline and polymyxin under clinical therapy. A total of 11 carbapenemase (KPC)-producing CRKP strains were consecutively isolated from a male patient who suffered from continuous and multisite infections. String and antimicrobial susceptibility tests identified seven hypermucoviscous strains and three tigecycline-resistant and four colistin-resistant strains. larvae infection model confirmed the hypervirulence. Pulsed-field gel electrophoresis (PFGE) separated three PFGE clusters among all strains, and further Southern blotting detected that was located on the same-sized plasmid. Whole-genome sequencing showed that all strains belonged to the hv-CRKP ST11-KL64 clone. Diverse hypervirulence factors and resistance genes were identified. Further sequencing with the Nanopore platform was performed on the CRKP-Urine1 strain, which contained one virulence plasmid (pVi-CRKP-Urine1) and two resistance plasmids (pKPC-CRKP-Urine1 and pqnrS1-CRKP-Urine1). The gene mutations responsible for tigecycline or colistin resistance were then amplified with PCR followed by sequencing, which indicated that mutations of and were the potential loci for tigecycline resistance and that the , and genes for colistin resistance. A novel frameshift mutation of was identified in the high-level tigecycline-resistant strain (MIC, 128 mg/L). The results indicate that the hypervirulent ST11-KL64 clone is a potential threat to antiinfection treatment and is capable of rapid and diverse evolution of resistance during tigecycline and polymyxin treatment.
Topics: Aged; Carbapenems; Drug Resistance, Bacterial; Evolution, Molecular; Frameshift Mutation; High-Throughput Nucleotide Sequencing; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Polymyxins; Tigecycline; Whole Genome Sequencing
PubMed: 34074225
DOI: 10.1080/22221751.2021.1937327 -
Infection Dec 2020The management of carbapenem-resistant infections is often based on polymyxins, tigecycline, aminoglycosides and their combinations. However, in a recent systematic... (Review)
Review
Treatment options for K. pneumoniae, P. aeruginosa and A. baumannii co-resistant to carbapenems, aminoglycosides, polymyxins and tigecycline: an approach based on the mechanisms of resistance to carbapenems.
The management of carbapenem-resistant infections is often based on polymyxins, tigecycline, aminoglycosides and their combinations. However, in a recent systematic review, we found that Gram-negative bacteria (GNB) co-resistant to carbapanems, aminoglycosides, polymyxins and tigecycline (CAPT-resistant) are increasingly being reported worldwide. Clinical data to guide the treatment of CAPT-resistant GNB are scarce and based exclusively on few case reports and small case series, but seem to indicate that appropriate (in vitro active) antimicrobial regimens, including newer antibiotics and synergistic combinations, may be associated with lower mortality. In this review, we consolidate the available literature to inform clinicians dealing with CAPT-resistant GNB about treatment options by considering the mechanisms of resistance to carbapenems. In combination with rapid diagnostic methods that allow fast detection of carbapenemase production, the approach proposed in this review may guide a timely and targeted treatment of patients with infections by CAPT-resistant GNB. Specifically, we focus on the three most problematic species, namely Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Several treatment options are currently available for CAPT-resistant K. pneumonia. Newer β-lactam-β-lactamase combinations, including the combination of ceftazidime/avibactam with aztreonam against metallo-β-lactamase-producing isolates, appear to be more effective compared to combinations of older agents. Options for P. aeruginosa (especially metallo-β-lactamase-producing strains) and A. baumannii remain limited. Synergistic combination of older agents (e.g., polymyxin- or fosfomycin-based synergistic combinations) may represent a last resort option, but their use against CAPT-resistant GNB requires further study.
Topics: Acinetobacter Infections; Acinetobacter baumannii; Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Klebsiella Infections; Klebsiella pneumoniae; Polymyxins; Pseudomonas Infections; Pseudomonas aeruginosa; Tigecycline
PubMed: 32875545
DOI: 10.1007/s15010-020-01520-6 -
Advances in Therapy Mar 2020Studies assessing the effect of high dose tigecycline on severe infections are limited and remain controversial. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Studies assessing the effect of high dose tigecycline on severe infections are limited and remain controversial.
OBJECTIVES
To assess systematically the effectiveness and safety of high dose tigecycline in the treatment of severe infections.
METHODS
Pubmed, Web of Science, Embase, MEDLINE, Cochrane Library and ClinicalTrials were searched up to February 20, 2019 for studies that compared the effectiveness and safety of high dose tigecycline with standard dose tigecycline or other non-tigecycline-containing regimens in the treatment of severe infections. Rates for all-cause mortality, clinical cure, microbiological eradication and adverse events were analysed.
RESULTS
Ten studies with 593 patients were included. The results indicated that using high dose tigecycline resulted in better outcomes compared with controls with lower all-cause mortality (OR 0.44, 95% CI 0.30-0.66, p < 0.0001), higher clinical cure (OR 3.43, 95% CI 2.09-5.63, p < 0.00001), higher microbiological eradication (OR 2.25, 95% CI 1.44-3.50, p = 0.0003), and without increasing adverse events rates. Subgroup analysis showed that high dose tigecycline reduced all-cause mortality in nosocomial acquired pneumonia (OR 0.39, 95% CI 0.22-0.70, p = 0.002), bloodstream infections (OR 0.19, 95% CI 0.06-0.58, p = 0.004) and mixed infections (OR 0.20, 95% CI 0.07-0.59, p = 0.003), with no statistical differences in complicated intra-abdominal infections (OR 2.04, 95% CI 0.80-5.23, p = 0.14). In carbapenem-resistant pathogens, the microbiological eradication rate in those given high dose tigecycline did not differ from controls (OR 1.07, 95% CI 0.44-2.60, p = 0.87), although mortality was reduced (OR 0.20, 95% CI 0.09-0.45, p = 0.0001). The main limitation of the review is that most of the included studies are observational studies with small sample sizes and high risks of bias.
CONCLUSIONS
High dose tigecycline treatment is effective and safe for severe infections owing to its lower all-cause mortality, higher clinical cure, microbiological eradication and comparable adverse events. However, as a result of the high risks of bias of the included studies, well-designed randomised clinical trials are warranted to establish the effectiveness and safety of high dose tigecycline compared with standard dose tigecycline and other commonly used antibiotics.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Humans; Infections; Observational Studies as Topic; Severity of Illness Index; Tigecycline
PubMed: 32006240
DOI: 10.1007/s12325-020-01235-y -
Clinical Microbiology and Infection :... Mar 2023Heteroresistance refers to subpopulation-mediated differential antimicrobial susceptibility within a clonal bacterial population. Usually, it designates a resistant... (Review)
Review
BACKGROUND
Heteroresistance refers to subpopulation-mediated differential antimicrobial susceptibility within a clonal bacterial population. Usually, it designates a resistant subpopulation identified within an isolate considered susceptible by classical antimicrobial susceptibility testing. Heteroresistance lacks a uniform microbiological definition for diagnostic laboratories, and its clinical impact remains unclear for most bacterial species.
OBJECTIVES
This narrative review aims to provide a practical overview on the latest developments in the field of heteroresistance for both clinical microbiologists and physicians, with a particular focus on ESKAPE pathogens.
SOURCES
A literature search was performed on Pubmed and Google with the key words heteroresistance (heterogeneity OR heterogeneous) AND antibiotic resistance. Among the 836 publications selected based on their abstracts, the most relevant for the detection, epidemiology and clinical impact of heteroresistance in ESKAPE pathogens are discussed here.
CONTENT
Heteroresistance is only clearly defined for heterogeneous vancomycin intermediate Staphylococcus aureus. We compiled a larger microbiological definition to be applicable to other bacterial species and antibiotics in the clinical context. We highlighted the key technical points of population analysis profile, which is the reference standard for detecting heteroresistance. Heteroresistance to polymyxins, β-lactams (carbapenems, cefiderocol), fosfomycin, tigecycline and aminoglycosides is frequently reported in multidrug-resistant gram-negative pathogens. Treatment failure due to heteroresistance has been described in case reports or retrospective studies, so far confirmed by meta-analyses in the case of heterogeneous vancomycin intermediate S. aureus only. Finally, to treat pandrug-resistant bacterial infections, the option of targeting susceptible subpopulations of resistant isolates using tailored antibiotic combinations is also discussed.
IMPLICATIONS
Systematic heteroresistance screening by clinical laboratories is not currently recommended. Nevertheless, we should be aware of this phenomenon, and in specific cases, such as treatment failure, heteroresistance should be tested by reference laboratories. Additional studies using standardized methods are needed to improve our understanding of heteroresistance and further assess its clinical impact.
Topics: Humans; Anti-Bacterial Agents; Retrospective Studies; Staphylococcus aureus; Tigecycline; Carbapenems; Bacteria; Microbial Sensitivity Tests
PubMed: 36270588
DOI: 10.1016/j.cmi.2022.10.018 -
Nature Microbiology Sep 2019Tigecycline is one of the last-resort antibiotics to treat complicated infections caused by both multidrug-resistant Gram-negative and Gram-positive bacteria....
Tigecycline is one of the last-resort antibiotics to treat complicated infections caused by both multidrug-resistant Gram-negative and Gram-positive bacteria. Tigecycline resistance has sporadically occurred in recent years, primarily due to chromosome-encoding mechanisms, such as overexpression of efflux pumps and ribosome protection. Here, we report the emergence of the plasmid-mediated mobile tigecycline resistance mechanism Tet(X4) in Escherichia coli isolates from China, which is capable of degrading all tetracyclines, including tigecycline and the US FDA newly approved eravacycline. The tet(X4)-harbouring IncQ1 plasmid is highly transferable, and can be successfully mobilized and stabilized in recipient clinical and laboratory strains of Enterobacteriaceae bacteria. It is noteworthy that tet(X4)-positive E. coli strains, including isolates co-harbouring mcr-1, have been widely detected in pigs, chickens, soil and dust samples in China. In vivo murine models demonstrated that the presence of Tet(X4) led to tigecycline treatment failure. Consequently, the emergence of plasmid-mediated Tet(X4) challenges the clinical efficacy of the entire family of tetracycline antibiotics. Importantly, our study raises concern that the plasmid-mediated tigecycline resistance may further spread into various ecological niches and into clinical high-risk pathogens. Collective efforts are in urgent need to preserve the potency of these essential antibiotics.
Topics: Animals; Chickens; China; Drug Resistance, Bacterial; Environmental Microbiology; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Genes, Bacterial; Humans; Mice; Microbial Sensitivity Tests; Plasmids; Swine; Tetracyclines; Tigecycline
PubMed: 31235960
DOI: 10.1038/s41564-019-0496-4