In vitro evaluation of double-carbapenem combinations against OXA-48-producing Klebsiella pneumoniae isolates using time–kill studies

Galani, Irene; Nafplioti, Konstantina; Chatzikonstantinou, Marianthi; Souli, María

doi:10.1099/jmm.0.000725

Cited by 14 publications

(18 citation statements)

References 24 publications

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“…Administration of a double carbapenem (with or without colistin) seems a promising salvage treatment in infections caused by PDR isolates harboring serine-carbapenemases. In vitro data showed synergistic activity of DCC against OXA-48 producing MDR and XDR K. pneumoniae (134). Finally, two kidney transplant recipients were reportedly cured with DCC plus oral fosfomycin from urinary tract infections caused by NDM-harboring Enterobacteriaceae (135).…”

Section: Old and Established Antibioticsmentioning

confidence: 99%

The “Old” and the “New” Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How

Karaiskos

Lagou

Pontikis

et al. 2019

Front. Public Health

226

166

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The recent expansion of multidrug resistant and pan-drug-resistant pathogens poses significant challenges in the treatment of healthcare associated infections. An important advancement, is a handful of recently launched new antibiotics targeting some of the current most problematic Gram-negative pathogens, namely carbapenem-producing Enterobacteriaceae (CRE) and carbapenem-resistant P. aeruginosa (CRPA). Less options are available against carbapenem-resistant Acinetobacter baumannii (CRAB) and strains producing metallo-beta lactamases (MBL). Ceftazidime-avibactam signaled a turning point in the treatment of KPC and partly OXA- type carbapenemases, whereas meropenem-vaborbactam was added as a potent combination against KPC-producers. Ceftolozane-tazobactam could be seen as an ideal beta-lactam backbone for the treatment of CRPA. Plazomicin, an aminoglycoside with better pharmacokinetics and less toxicity compared to other class members, will cover important proportions of multi-drug resistant pathogens. Eravacycline holds promise in the treatment of infections by CRAB, with a broad spectrum of activity similar to tigecycline, and improved pharmacokinetics. Novel drugs and combinations are not to be considered “panacea” for the ongoing crisis in the therapy of XDR Gram-negative bacteria and colistin will continue to be considered as a fundamental companion drug for the treatment of carbapenem-resistant Enterobacteriaceae (particularly in areas where MBL predominate), for the treatment of CRPA (in many cases being the only in vitro active drug) as well as CRAB. Aminoglycosides are still important companion antibiotics. Finally, fosfomycin as part of combination treatment for CRE infections and P. aeruginosa , deserves a greater attention. Optimal conditions for monotherapy and the “when and how” of combination treatments integrating the novel agents will be discussed.

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Section: Old and Established Antibioticsmentioning

confidence: 99%

The “Old” and the “New” Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How

Karaiskos

Lagou

Pontikis

et al. 2019

Front. Public Health

226

166

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“…There have been a number of case reports and series describing treatment failures with carbapenem-containing regimens in the treatment of OXA-48-producing bacterial infections (4,(27)(28)(29). Dual carbapenem combinations, particularly those with imipenem, have shown synergy in vitro against both OXA-48 and KPC producers (30,31). Although, only some study isolates (K. pneumoniae but not recombinant E. coli) showed this result and produced values close to the cutoff value for defining synergy (30).…”

mentioning

confidence: 99%

Treatment of Infections by OXA-48-Producing Enterobacteriaceae

Stewart

Harris

Henderson

et al. 2018

Antimicrob Agents Chemother

118

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Carbapenemase-producing (CPE) contribute significantly to the global public health threat of antimicrobial resistance. OXA-48 and its variants are unique carbapenemases with low-level hydrolytic activity toward carbapenems but no intrinsic activity against expanded-spectrum cephalosporins. is typically located on a plasmid but may also be integrated chromosomally, and this gene has progressively disseminated throughout Europe and the Middle East. Despite the inability of OXA-48-like carbapenemases to hydrolyze expanded-spectrum cephalosporins, pooled isolates demonstrate high variable resistance to ceftazidime and cefepime, likely representing high rates of extended-spectrum beta-lactamase (ESBL) coproduction. data from pooled studies suggest that avibactam is the most potent beta-lactamase inhibitor when combined with ceftazidime, cefepime, aztreonam, meropenem, or imipenem. Resistance to novel avibactam combinations such as imipenem-avibactam or aztreonam-avibactam has not yet been reported in OXA-48 producers, although only a few clinical isolates have been tested. Although combination therapy is thought to improve the chances of clinical cure and survival in CPE infection, successful outcomes were seen in ∼70% of patients with infections caused by OXA-48-producing treated with ceftazidime-avibactam monotherapy. A carbapenem in combination with either amikacin or colistin has achieved treatment success in a few case reports. Uncertainty remains regarding the best treatment options and strategies for managing these infections. Newly available antibiotics such as ceftazidime-avibactam show promise; however, recent reports of resistance are concerning. Newer choices of antimicrobial agents will likely be required to combat this problem.

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“…However, an in vitro study [59] has indicated that in DCT, the imipenem-containing combinations show the most efficacy in the treatment for carbapenemase-producing K. pneumoniae infection, while ertapenem may not be the best option to inactivate carbapenemases. This may be related to particularly enhanced in vitro activity of imipenem-containing combinations, even imipenem at sub-inhibitory concentrations [65]. However, in vivo data on imipenem-containing DCT are limited, which may be attributed to the central nervous system toxicity of imipenem and short stability of intravenous preparation [56,66].…”

Section: Discussionmentioning

confidence: 99%

Double-carbapenem therapy in the treatment of multidrug resistant Gram-negative bacterial infections: a systematic review and meta-analysis

Wang

et al. 2020

BMC Infect Dis

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Background: To compare the efficacy and safety of double-carbapenem therapy (DCT) with other antibiotics for the treatment of multidrug resistant (MDR) Gram-negative bacterial infections. Methods: Cochrane Library, PubMed, Embase and Web of Science as well as Chinese databases were searched from database establishment to February 2019. All types of studies were included if they had evaluated efficacy and safety of DCT regimens in patients with MDR Gram-negative bacterial infections. Clinical response, microbiological response, adverse events and mortality were the main outcomes. The protocol was registered with PROSPERO No. CRD42019129979. Results: Three cohort or case-control studies consisting of 235 patients and 18 case series or case reports consisting of 90 patients were included. The clinical and microbiological responses were similar between DCT and other regimens in patients with carbapenem-resistant Enterobacteriaceae (CRE) infection. DCT achieved a lower mortality than comparators in patients with CRE infection (OR = 0.44, 95% CI = 0.24-0.82, P = 0.009). Ertapenem was the most reported antibiotic in DCT regimens in case series or case reports. Moreover, clinical and microbiological improvements were found in 59 (65.6%) and 63 (70%) in total 90 cases, respectively. Conclusions: DCT was as effective as other antibiotics in treating MDR Gram-negative bacterial infections, with similar efficacy response and lower mortality. DCT could be an alternative therapeutic option in the treatment of MDR Gram-negative bacterial infections. High-quality randomized controlled trials were required to confirm the beneficial effects of DCT.

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In vitro evaluation of double-carbapenem combinations against OXA-48-producing Klebsiella pneumoniae isolates using time–kill studies

Abstract: Dual combinations of carbapenems, including those containing sub-inhibitory concentrations of antibiotics, were synergistic against multidrug-resistant (MDR) and extensively drug-resistant (XDR) K. pneumoniae isolates harbouring blaOXA-48.

Cited by 14 publications

References 24 publications

The “Old” and the “New” Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How

The “Old” and the “New” Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How

Treatment of Infections by OXA-48-Producing Enterobacteriaceae

Double-carbapenem therapy in the treatment of multidrug resistant Gram-negative bacterial infections: a systematic review and meta-analysis

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