Carbapenem-Sparing Strategies for ESBL Producers: When and How

Karaiskos, Ilias; Giamarellou, Helen

doi:10.3390/antibiotics9020061

Cited by 104 publications

(101 citation statements)

References 106 publications

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“…In extended spectrum b-lactamase infections, use of conventional (i.e. piperacillin/tazobactam) or novel b-lactam/b-lactamase inhibitor combinations may be appropriate, with fosfomycin, aminoglycosides and temocillin reasonable options in patients with complicated urinary tract infection [16]. Overall, further research is required to identify optimal treatment regimens [17].…”

Section: Discussionmentioning

confidence: 99%

Risk factors for carbapenem-resistant Gram-negative bacterial infections: a systematic review

Palacios‐Baena

Giannella

Manissero³

et al. 2021

Clinical Microbiology and Infection

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Background: Rapid and widespread increases in carbapenem resistance (CR) necessitate identification of risk factors to guide appropriate interventions. Objectives: We aimed to identify risk factors for CR Gram-negative infection through a systematic literature review. Data sources: We searched MEDLINE (via OvidSP and PubMed) and Embase (via OvidSP) databases and the Cochrane Central Register of Controlled Trials. Study eligibility criteria: Prospective or retrospective cohort and caseecontrol studies reporting quantitative data on risk factors associated with infections due to CR Gram-negative pathogens in hospitalized patients were eligible. Participants: Studies included hospitalized patients with CR infection caused by Gram-negative bacterial pathogens (Enterobacterales and non-fermenters). Methods: Searches were conducted in January 2018/December 2019 to identify studies published since 2007. Risk factor data were extracted and grouped by factor. The primary metric was proportion of studies reporting a significant association with CR infection for each factor. Results: In total, 92 studies were identified. Risk factors most frequently reported as significantly associated with CR infection (>10 studies) were previous antibiotic use (91.1%; 72/79 studies); previous carbapenem use (82.6%; 57/69); previous colonization (72.7%; 8/11); mechanical ventilation (66.7%; 36/54); previous intensive care unit stay (64.4%; 38/59); dialysis (61.1%; 11/18); catheter (58.0%; 40/69); length of stay in hospital (54.5%; 30/55); comorbidities (52.7%; 39/74); APACHE II (51.7%; 15/29); and intubation (51.4%; 18/35). Risk factors were mostly consistent across different species and sites of infection. Conclusions: Several variables, particularly previous antibiotic use, are strong risk factors for CR infection. Interventions to mitigate against CR infection should target these factors.

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Section: Discussionmentioning

confidence: 99%

Risk factors for carbapenem-resistant Gram-negative bacterial infections: a systematic review

Palacios‐Baena

Giannella

Manissero³

et al. 2021

Clinical Microbiology and Infection

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“…Members of the Enterobacterales order are common causes of both community-acquired and nosocomial infections, including bloodstream-infections, lower respiratory tract infections and urinary tract infections [35]. Carbapenems have become essential components of therapy in infections caused by extended-spectrum cephalosporin resistant strains, especially for vulnerable patient groups, such as children, pregnant women and the elderly [1][2][3][4]36]. Although intrinsic resistance to carbapenems has been previously described in Stenotrophomonas maltophilia (conferred by the metallo-b-lactamase L1), acquired carbapenem-resistance (through mutational events or via horizontal gene transfer) has emerged as a significant clinical problem in the last 15-20 years [37,38].…”

Section: Discussionmentioning

confidence: 99%

Detection of VIM, NDM and OXA-48 producing carbapenem resistant Enterobacterales among clinical isolates in Southern Hungary

Gajdács

Ábrók

Lázár

et al. 2020

AMicr

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Infections caused by carbapenem-resistant Enterobacterales (CRE) present an important therapeutic problem, as there are limited number of effective therapeutic alternatives available. In this study, phenotypic and genotypic methods were used to characterize carbapenemase-production and other resistance-determinants (AmpC and ESBL-production, efflux pump-overexpression) in 50 isolates (Klebsiella spp. n = 35, Escherichia coli n = 12 and Enterobacter cloacae complex n = 3) collected at the Albert Szent-Györgyi Clinical Center (University of Szeged) between 2014 and 2017. Minimum inhibitory concentrations of meropenem, sulfamethoxazole/trimethoprim, tigecycline, amikacin, moxifloxacin, colistin and fosfomycin were also determined. 24% of isolates were AmpC-producers, while 30% carried blaCTX-M ESBL-genes. Carbapenemase-genes were detected in 18 (36%) of the tested isolates: in 2 isolates blaNDM, in 6 isolates blaOXA-48-like and in 12 isolates, blaVIM was detected by PCR. The species-distribution for isolates positive for carbapenemase-genes was the following: Klebsiella pneumoniae n = 11, Klebsiella oxytoca n = 1, E. coli n = 5, E. cloacae complex n = 1. Efflux pump-overexpression based on the PAβN-screening agar was shown in n = 3 of the tested strains. In nine isolates (18%), carbapenemase and ESBL-genes were detected simultaneously. Highest levels of resistance were noted for fosfomycin (74%) and moxifloxacin (70%), while all isolates were susceptible to colistin. Among applied phenotypic tests in this study the modified carbapenem inactivation method (mCIM) proved to be the most accurate one compared to that of PCR results.

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“…The loss of this class, because of inappropriate and excessive use, will be nothing short of catastrophic for the provision of modern health care. Hence, new options for the treatment of infections caused by ESBL-producing pathogens that can spare the use of carbapenems are urgently required (9).…”

mentioning

confidence: 99%

Pharmacodynamics of Cefepime Combined with the Novel Extended-Spectrum-β-Lactamase (ESBL) Inhibitor Enmetazobactam for Murine Pneumonia Caused by ESBL-Producing Klebsiella pneumoniae

Johnson

McEntee

Farrington

et al. 2020

Antimicrob Agents Chemother

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Klebsiella pneumoniae strains that produce extended-spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options, and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being developed for the treatment of serious infections caused by ESBL-producing organisms. The pharmacokinetics-pharmacodynamics (PK-PD) of cefepime-enmetazobactam against ESBL-producing K. pneumoniae was studied in a neutropenic murine pneumonia model. Dose-ranging studies were performed. Dose fractionation studies were performed to define the relevant PD index for the inhibitor. The partitioning of cefepime and enmetazobactam into the lung was determined by comparing the area under the concentration-time curve (AUC) in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains. Cefepime, given as 100 mg/kg of body weight every 8 h intravenously (q8h i.v.), had minimal antimicrobial effect. When this background regimen of cefepime was combined with enmetazobactam, a half-maximal effect was induced with enmetazobactam at 4.71 mg/kg q8h i.v. The dose fractionation study suggested both fT > threshold and fAUC:MIC are relevant PD indices. The AUCELF:AUCplasma ratio for cefepime and enmetazobactam was 73.4% and 61.5%, respectively. A ≥2-log kill in the lung was achieved with a plasma and ELF cefepime fT > MIC of ≥20% and enmetazobactam fT > 2 mg/liter of ≥20% of the dosing interval. These data and analyses provide the underpinning evidence for the combined use of cefepime and enmetazobactam for nosocomial pneumonia.

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Carbapenem-Sparing Strategies for ESBL Producers: When and How

Cited by 104 publications

References 106 publications

Risk factors for carbapenem-resistant Gram-negative bacterial infections: a systematic review

Risk factors for carbapenem-resistant Gram-negative bacterial infections: a systematic review

Detection of VIM, NDM and OXA-48 producing carbapenem resistant Enterobacterales among clinical isolates in Southern Hungary

Pharmacodynamics of Cefepime Combined with the Novel Extended-Spectrum-β-Lactamase (ESBL) Inhibitor Enmetazobactam for Murine Pneumonia Caused by ESBL-Producing Klebsiella pneumoniae

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