Current and Future Perspectives in the Treatment of Multidrug-resistant Gram-negative Infections

Overview

Journal J Antimicrob Chemother

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2021 Dec 1

PMID 34849997

Citations 38

Authors

Matteo Bassetti

Javier Garau

Affiliations

Soon will be listed here.

Abstract

Microbial resistance is a serious threat to human health worldwide. Among the World Health Organisation's list of priority resistant bacteria, three are listed as critical-the highest level of concern-and all three are Gram-negative. Gram-negative resistance has spread worldwide via a variety of mechanisms, the most problematic being via AmpC enzymes, extended-spectrum β-lactamases, and carbapenemases. A combination of older drugs, many with high levels of toxicity, and newer agents are being used to combat multidrug resistance, with varying degrees of success. This review discusses the current treatments for multidrug-resistant Gram-negative bacteria, including new agents, older compounds, and new combinations of both, and some new treatment targets that are currently under investigation.

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References

Karaiskos I, Galani I, Souli M, Giamarellou H . Novel β-lactam-β-lactamase inhibitor combinations: expectations for the treatment of carbapenem-resistant Gram-negative pathogens. Expert Opin Drug Metab Toxicol. 2019; 15(2):133-149. DOI: 10.1080/17425255.2019.1563071. View

Munoz-Price L, Poirel L, Bonomo R, Schwaber M, Daikos G, Cormican M . Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis. 2013; 13(9):785-96. PMC: 4673667. DOI: 10.1016/S1473-3099(13)70190-7. View

Eichenberger E, Thaden J . Epidemiology and Mechanisms of Resistance of Extensively Drug Resistant Gram-Negative Bacteria. Antibiotics (Basel). 2019; 8(2). PMC: 6628318. DOI: 10.3390/antibiotics8020037. View

Frohlich C, Sorum V, Thomassen A, Johnsen P, Leiros H, Samuelsen O . OXA-48-Mediated Ceftazidime-Avibactam Resistance Is Associated with Evolutionary Trade-Offs. mSphere. 2019; 4(2). PMC: 6437269. DOI: 10.1128/mSphere.00024-19. View

Kalil A, Metersky M, Klompas M, Muscedere J, Sweeney D, Palmer L . Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016; 63(5):e61-e111. PMC: 4981759. DOI: 10.1093/cid/ciw353. View

Torres A, Zhong N, Pachl J, Timsit J, Kollef M, Chen Z . Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis. 2017; 18(3):285-295. DOI: 10.1016/S1473-3099(17)30747-8. View

Chatterjee A, Modarai M, Naylor N, Boyd S, Atun R, Barlow J . Quantifying drivers of antibiotic resistance in humans: a systematic review. Lancet Infect Dis. 2018; 18(12):e368-e378. DOI: 10.1016/S1473-3099(18)30296-2. View

Hackel M, Lomovskaya O, Dudley M, Karlowsky J, Sahm D . Activity of Meropenem-Vaborbactam against Clinical Isolates of KPC-Positive Enterobacteriaceae. Antimicrob Agents Chemother. 2017; 62(1). PMC: 5740317. DOI: 10.1128/AAC.01904-17. View

Vickers R, Bassetti M, Clancy C, Garey K, Greenberg D, Nguyen M . Combating resistance while maintaining innovation: the future of antimicrobial stewardship. Future Microbiol. 2019; 14:1331-1341. DOI: 10.2217/fmb-2019-0227. View

10.

Pantel L, Florin T, Dobosz-Bartoszek M, Racine E, Sarciaux M, Serri M . Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site. Mol Cell. 2018; 70(1):83-94.e7. DOI: 10.1016/j.molcel.2018.03.001. View

11.

Satlin M, Lewis J, Weinstein M, Patel J, Humphries R, Kahlmeter G . Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing Position Statements on Polymyxin B and Colistin Clinical Breakpoints. Clin Infect Dis. 2020; 71(9):e523-e529. DOI: 10.1093/cid/ciaa121. View

12.

Yaghoubi S, Zekiy A, Krutova M, Gholami M, Kouhsari E, Sholeh M . Tigecycline antibacterial activity, clinical effectiveness, and mechanisms and epidemiology of resistance: narrative review. Eur J Clin Microbiol Infect Dis. 2021; 41(7):1003-1022. PMC: 7785128. DOI: 10.1007/s10096-020-04121-1. View

13.

Stone G, Newell P, Bradford P . Activity of Ceftazidime-Avibactam against Isolates from Patients in a Phase 3 Clinical Trial for Treatment of Complicated Intra-abdominal Infections. Antimicrob Agents Chemother. 2018; 62(7). PMC: 6021638. DOI: 10.1128/AAC.02584-17. View

14.

Shah P, Ryzner K . Evaluating the appropriate use of piperacillin/tazobactam in a community health system: a retrospective chart review. P T. 2013; 38(8):462-83. PMC: 3814439. View

15.

Chastain D, White B, Cretella D, Bland C . Is It Time to Rethink the Notion of Carbapenem-Sparing Therapy Against Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae Bloodstream Infections? A Critical Review. Ann Pharmacother. 2017; 52(5):484-492. DOI: 10.1177/1060028017748943. View

16.

Lepape A, Jean A, De Waele J, Friggeri A, Savey A, Vanhems P . European intensive care physicians' experience of infections due to antibiotic-resistant bacteria. Antimicrob Resist Infect Control. 2020; 9(1):1. PMC: 6941296. DOI: 10.1186/s13756-019-0662-8. View

17.

Pogue J, Bonomo R, Kaye K . Ceftazidime/Avibactam, Meropenem/Vaborbactam, or Both? Clinical and Formulary Considerations. Clin Infect Dis. 2018; 68(3):519-524. DOI: 10.1093/cid/ciy576. View

18.

Strich J, Ricotta E, Warner S, Lai Y, Demirkale C, Hohmann S . Pharmacoepidemiology of Ceftazidime-Avibactam Use: A Retrospective Cohort Analysis of 210 US Hospitals. Clin Infect Dis. 2020; 72(4):611-621. PMC: 7884805. DOI: 10.1093/cid/ciaa061. View

19.

Yam E, Hsu L, Yap E, Yeo T, Lee V, Schlundt J . Antimicrobial Resistance in the Asia Pacific region: a meeting report. Antimicrob Resist Infect Control. 2020; 8:202. PMC: 6921568. DOI: 10.1186/s13756-019-0654-8. View

20.

Averbuch D, Tridello G, Hoek J, Mikulska M, Akan H, Yanez San Segundo L . Antimicrobial Resistance in Gram-Negative Rods Causing Bacteremia in Hematopoietic Stem Cell Transplant Recipients: Intercontinental Prospective Study of the Infectious Diseases Working Party of the European Bone Marrow Transplantation Group. Clin Infect Dis. 2017; 65(11):1819-1828. DOI: 10.1093/cid/cix646. View