Carbapenemase producing Klebsiella pneumoniae: implication on future therapeutic strategies
35
Citation
117
Reference
10
Related Paper
Citation Trend
Abstract:
Introduction The emergence of carbapenemase resistant Gram-negative is designated as an ‘urgent’ priority of public health. Carbapenemase producing Klebsiella pneumoniae (CPKP) is linked with significant mortality. Conventionally used antibiotics (polymyxins, tigecycline, aminoglycosides, etc.) are associated with poor efficacy and toxicity profiles are quite worrisome.Areas covered This article reviews mechanism of resistance and evidence regarding novel treatments of infections caused by CPKP, focusing mainly on currently approved new therapies and implications on future therapeutic strategies. A review of novel β-lactam/β-lactamase inhibitors (BLI) recently approved and in clinical development as well as cefiderocol, eravacycline and apramycin are discussed.Expert opinion Newly approved and forthcoming antimicrobial agents are promising to combat infections caused by CPKP. Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam are novel agents with favorable outcome and associated with improved mortality in KPC-producing K. pneumoniae infections. However, are inactive against metallo-β-lactamases (MBL). Novel BLI in later stage of development, i.e. aztreonam-avibactam, cefepime-zidebactam, cefepime-taniborbactam, and meropenem-nacubactam as well as cefiderocol are active in vitro against both KPC and MBL. Potential expectations of future therapeutic strategies are improved potency against CPKP, more tolerable safety profile, and capability of overcoming current resistance mechanism of multidrug-resistant K. pneumoniae.Keywords:
Tigecycline
Colistin
Ceftazidime/avibactam
Aztreonam
Cefepime
Avibactam
We show that a previously described Klebsiella pneumoniae variant that is resistant to ceftazidime-avibactam plus meropenem-vaborbactam, has a ramR plus ompK36 mutation, and produces the V239G variant KPC-3 (V240G per the standard numbering system) exhibits resistance to ceftazidime-avibactam plus aztreonam and imipenem-relebactam but not cefepime-taniborbactam. The V239G variant does not generate collateral β-lactam susceptibility like many KPC-3 variants associated with ceftazidime-avibactam resistance.
Aztreonam
Cefepime
Ceftazidime/avibactam
Cite
Citations (17)
Background: It is often challenging to select appropriate combination therapies to treat infections caused by carbapenem-resistant Enterobacterales (CRE) with high-level resistance to carbapenem. Methods: We investigated the in vitro synergistic activity of ceftazidime-avibactam-, polymyxin- or tigecycline-, and meropenem-based combinations using checkerboard assays against 16 CRE including Klebsiella pneumoniae carrying bla KPC-2 (CR1- bla KPC-2 ) and Enterobacter cloacae carrying bla NDM-1 (CR2- bla NDM-1 ) with meropenem MICs ≥ 128 mg/L. Time-kill assays were used to observe synergistic bactericidal activity. Results: Meropenem in combination with ertapenem, amikacin, tigecycline or polymyxin B, and tigecycline plus ceftazidime-avibactam showed weak synergistic activities against CR1- bla KPC-2 and CR2- bla NDM-1 . Polymyxin B combined with tigecycline or ceftazidime-avibactam, and ceftazidime-avibactam plus amikacin showed synergistic effects against two tigecycline-non-susceptible KPC-producers or three ceftazidime-avibactam-resistant NDM-producer, and 50% (5/10) of strains with amikacin MICs ≥ 4096 mg/L, respectively. Synergistic interactions of ceftazidime-avibactam plus aztreonam or meropenem in checkerboard assays were measured for 100% (16/16) and 93.8% (15/16) of strains, respectively. The time-kill assay further verified that the ceftazidime-avibactam combination had the potential to restore aztreonam susceptibility and reduced meropenem MICs to 8 mg/L. Conclusion: Ceftazidime-avibactam plus aztreonam or meropenem could be an effective strategy for treating CRE infections, particularly those with high-level resistance to carbapenems and/or ceftazidime-avibactam. Keywords: ceftazidime-avibactam, checkerboard assays, time-kill assays, synergistic effect, meropenem, aztreonam
Aztreonam
Ceftazidime/avibactam
Tigecycline
Avibactam
Amikacin
Polymyxin B
Ertapenem
Carbapenem
Cite
Citations (8)
Introduction The emergence of carbapenemase resistant Gram-negative is designated as an ‘urgent’ priority of public health. Carbapenemase producing Klebsiella pneumoniae (CPKP) is linked with significant mortality. Conventionally used antibiotics (polymyxins, tigecycline, aminoglycosides, etc.) are associated with poor efficacy and toxicity profiles are quite worrisome.Areas covered This article reviews mechanism of resistance and evidence regarding novel treatments of infections caused by CPKP, focusing mainly on currently approved new therapies and implications on future therapeutic strategies. A review of novel β-lactam/β-lactamase inhibitors (BLI) recently approved and in clinical development as well as cefiderocol, eravacycline and apramycin are discussed.Expert opinion Newly approved and forthcoming antimicrobial agents are promising to combat infections caused by CPKP. Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam are novel agents with favorable outcome and associated with improved mortality in KPC-producing K. pneumoniae infections. However, are inactive against metallo-β-lactamases (MBL). Novel BLI in later stage of development, i.e. aztreonam-avibactam, cefepime-zidebactam, cefepime-taniborbactam, and meropenem-nacubactam as well as cefiderocol are active in vitro against both KPC and MBL. Potential expectations of future therapeutic strategies are improved potency against CPKP, more tolerable safety profile, and capability of overcoming current resistance mechanism of multidrug-resistant K. pneumoniae.
Tigecycline
Colistin
Ceftazidime/avibactam
Aztreonam
Cefepime
Avibactam
Cite
Citations (35)
The increased frequency and dissemination of enterobacteria resistant to various antimicrobials is currently worldwide concern. In January 2010, a 94-year-old patient with chronic lymphocytic leukemia was admitted to the University Hospital. This patient died 21 days after hospitalization due to the clinical worsening. Klebsiella pneumoniae producing of extended-spectrum β-lactamases (ESBLs) was isolated of urine culture. This bacterium demonstrated resistance to ceftazidime, ciprofloxacin, levofloxacin, ertapenem and imipenem. Susceptibility to cefoxitin, cefepime, meropenem, colistin and tigecycline. This study reports the first case of infection by Klebsiella pneumoniae carrying the bla kpc gene in the State of Mato Grosso do Sul, Brazil.
Ertapenem
Tigecycline
Colistin
Cefepime
Cite
Citations (14)
Background: Avibactam, relebactam and vaborbactam are β-lactamase inhibitors that proved their efficiency against KPC-producing Enterobacterales. Regarding their inhibitor activity towards Ambler’s class A extended spectrum β-lactamases (ESBL) and Ambler’s class C cephalosporinase (AmpC), they should be active on most of the carbapenem-resistant non-carbapenemase-producing Enterobacterales (CR non-CPE). Objectives: Determine the in vitro activity of ceftazidime-avibactam, imipenem-relebactam and meropenem-vaborbactam and comparators against CR non-CPE. Methods: MICs to ceftazidime/avibactam, imipenem/relebactam, meropenem/vaborbactam, but also temocillin, ceftolozane/tazobactam, ertapenem, colistin, eravacycline and tigecycline were determined by broth microdilution (ThermoFisher) on a collection of 284 CR non-CPE (inhibition zone diameter < 22 mm to meropenem). Whole genome sequencing was performed on 90 isolates to assess the genetic diversity as well as resistome. Results: According to EUCAST breakpoints, susceptibility rates of ceftazidime, imipenem, meropenem and ertapenem used at standard dose were 0.7%, 45.1%, 14.8% and 2.5%, respectively. Increased exposure of ceftazidime, imipenem and meropenem led to reach 3.5%, 68.3% and 67.7% susceptibility, respectively. Using the EUCAST clinical breakpoints, susceptibility rates of ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam were 88.4%, 81.0% and 80.6%, respectively. Susceptibility rates of temocillin, ceftolozane/tazobactam, tigecycline, eravacycline, and colistin were 0%, 4.6%, 27.8%, 54.9% and 90.1%. MICs distributions with and without the presence of the inhibitor demonstrated a better ability of avibactam and relebactam compared to vaborbactam to restore susceptibility to the associated β-lactam. Conclusions: This study demonstrated the in vitro efficacy of ceftazidime/avibactam, imipenem/relebactam and to a lesser extent meropenem/vaborbactam against CR non-CPE. Moreover, to test all β-lactams/β-lactamases inhibitors combinations without a priori for CRE, non-CPE is crucial since resistance to one of the β-lactam/β-lactamase inhibitor combinations does not predict resistance to another molecule, depending on the resistance mechanisms involved.
Ceftazidime/avibactam
Carbapenem
Avibactam
Enterobacteriaceae Infections
Carbapenem-resistant enterobacteriaceae
Cite
Citations (14)
Fosfomycin
Tigecycline
Colistin
Carbapenem
Cite
Citations (54)
Tigecycline
Colistin
Carbapenem-resistant enterobacteriaceae
Cite
Citations (155)
Carbapenem-resistant Klebsiella pneumoniae has globally emerged as an urgent threat leading to the limitation for treatment. K. pneumoniae carrying blaOXA-48, which plays a broad magnitude of carbapenem susceptibility, is widely concerned. This study aimed to characterize related carbapenem resistance mechanisms and forage for new antibiotic combinations to combat blaOXA-48-carrying K. pneumoniae. Among nine isolates, there were two major clones and a singleton identified by ERIC-PCR. Most isolates were resistant to ertapenem (MIC range: 2–>256 mg/L), but two isolates were susceptible to imipenem and meropenem (MIC range: 0.5–1 mg/L). All blaOXA-48-carrying plasmids conferred carbapenem resistance in Escherichia coli transformants. Two ertapenem-susceptible isolates carried both outer membrane proteins (OMPs), OmpK35 and OmpK36. Lack of at least an OMP was present in imipenem-resistant isolates. We evaluated the in vitro activity of an overlooked antibiotic, azithromycin, in combination with other antibiotics. Remarkably, azithromycin exhibited synergism with colistin and fosfomycin by 88.89% and 77.78%, respectively. Bacterial regrowth occurred after exposure to colistin or azithromycin alone. Interestingly, most isolates were killed, reaching synergism by this combination. In conclusion, the combination of azithromycin and colistin may be an alternative strategy in dealing with blaOXA-48-carrying K. pneumoniae infection during a recent shortage of newly effective antibiotic development.
Ertapenem
Colistin
Aztreonam
Fosfomycin
Carbapenem
Tigecycline
Cite
Citations (7)
Purpose: A case of a patient with sepsis from a urinary source due to carbapenemase-producing Klebsiella pneumoniae treated with a novel combination of aztreonam, ceftazidime/avibactam, and colistin is described. Summary: An 80-year-old South Asian male presented to the hospital with sepsis from a urinary source. Blood and urine cultures were positive for a carbapenemase-producing K pneumoniae sensitive only to colistin and tigecycline. Novel beta-lactamase inhibitor combinations ceftazidime/avibactam and meropenem/vaborbactam were resistant. Patient was initially on ceftazidime/avibactam and colistin combination followed by tigecycline and colistin with lack of improvement. Metallo-beta-lactamase (MBL)-producing K pneumoniae was suspected based on the sensitivity pattern and history of medical treatment in India. Patient was then initiated on novel combination of ceftazidime/avibactam, aztreonam, and colistin. Patient’s white blood cell (WBC) count and fever curve normalized. Unfortunately, the patient failed to recover completely likely because of his multiple comorbidities and declining functional status, resulting in the family’s decision to pursue hospice. Conclusion: The combination of ceftazidime/avibactam and aztreonam should be considered as a viable treatment option for patients with infections caused by MBL-producing Enterobacteriaceae.
Colistin
Ceftazidime/avibactam
Tigecycline
Aztreonam
Avibactam
Bacteremia
Cite
Citations (14)
This study assessed the in vitro antimicrobial activity of ceftazidime-avibactam (CAZ-AVI) and a panel of comparator agents, including aztreonam, cefepime, ceftazidime, meropenem, imipenem, colistin, piperacillin-tazobactam, and tigecycline against isolates of fluoroquinolone-resistant (FQ-R) Klebsiella pneumoniae collected in 2018 and 2019 from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program. Susceptibility and minimum inhibitory concentration were determined using broth microdilution for all antimicrobial agents by a central reference laboratory according to the Clinical and Laboratory Standards Institute guidelines and European Committee on Antimicrobial Susceptibility Testing guidelines. Of all the K. pneumoniae isolates (n = 10,906), 44.1% (4,814/10,906) were FQ-R. Of these, 71.3% (3,432/4,814) were extended-spectrum β-lactamase (ESBL)-positive, and 10.4% (499/4,814) were CAZ-AVI-resistant. CAZ-AVI showed high susceptibility (>87%) against all the FQ-R K. pneumoniae isolates. However, metallo- β-lactamase-positive isolates showed low susceptibility (3.8%; 18/470) to CAZ-AVI. Among the different geographical regions, CAZ-AVI showed the highest activity against isolates collected from North America (98.2%, 216/220) and lowest against those collected from Asia Pacific (APAC) (81.7%; 882/1,079). Among comparator agents, carbapenems showed a relatively lower susceptibility (<71.5%), while only tigecycline and colistin were active (>85%) across all isolates. In conclusion, CAZ-AVI may be a potential treatment option for FQ-R K. pneumoniae isolates. However, increasing CAZ-AVI resistance among ESBL-positive and metallo-β-lactamase-positive isolates and in isolates from APAC warrants continuous surveillance.
Tigecycline
Broth microdilution
Colistin
Ceftazidime/avibactam
Cefepime
Aztreonam
Cite
Citations (1)