Unveiling carbapenem resistance: mechanism and therapeutic strategies
DOI:
https://doi.org/10.18203/2320-6012.ijrms20251676Keywords:
Centers for accelerating phage, Carbapenem-resistant A. baumannii, Carbapenem-resistant Enterobacterales, Antimicrobial resistance, Extended-spectrum beta-lactamase, Multidrug resistance, New Delhi metallo-beta-lactamase, Carbapenem-resistant K. pneumoniae, Ventilator-associated pneumonia, Bloodstream infectionsAbstract
This review provides an overview of the carbapenem resistance, its underlying causing microbes, its mechanism of transmission, risk factors, and its treatment options and challenges. Carbapenem resistance in Gram-negative organisms such as E. coli and K. pneumoniae, S. pneumoniae, S. aureus, P. aeruginosa, and A. baumannii are major causing microbes. Here we discuss the importance of infection control measures to mitigate the spread of resistance and urgent need for novel therapeutic strategy to defeat this resistance. Furthermore, we explore innovative approaches including the development of new antibiotics, combination therapies and the repurposing of existing drugs to combat carbapenem-resistance strains. Understanding the molecular basis of carbapenem resistance is crucial for developing effective treatment strategies and controlling the spread of antibiotic-resistant bacteria.
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Codjoe FS, Donkor ES. Carbapenem Resistance: A Review. Med Sci. 2017;6(1):1. DOI: https://doi.org/10.3390/medsci6010001
Ko W, Tseng S, Chou C, Li T, Li R, Zhang Y, et al. Molecular epidemiology and comparative genomics of carbapenemase-producing Escherichia coli isolates from 19 tertiary hospitals in China from 2019 to 2020. Front Microbiol. Front Microbiol. 2023;14:1056399. DOI: https://doi.org/10.3389/fmicb.2023.1224271
Yehouenou CL, Soleimani R, Kpangon AA, Simon A, Dossou FM, Dalleur O. Carbapenem-Resistant Organisms Isolated in Surgical Site Infections in Benin: A Public Health Problem. Trop Med Infect Dis. 2022;7(8):200. DOI: https://doi.org/10.3390/tropicalmed7080200
Ruekit S, Srijan A, Serichantalergs O, Margulieux KR, Mc Gann P, Mills EG, et al. Molecular characterization of multidrug-resistant ESKAPEE pathogens from clinical samples in Chonburi, Thailand (2017-2018). BMC Infect Dis. 2022;22(1):695. DOI: https://doi.org/10.1186/s12879-022-07678-8
Kumari P, Kaul G, Kumar TA, Akhir A, Shukla M, Sharma S, et al. Heterocyclic Diaryliodonium-Based Inhibitors of Carbapenem-Resistant Acinetobacter baumannii. Microbiol Spectr. 2023;11(2):e0477322. DOI: https://doi.org/10.1128/spectrum.04773-22
Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA. Carbapenems: Past, present, and future. Antimicrob Agents Chemot. 2011;55:4943-60. DOI: https://doi.org/10.1128/AAC.00296-11
Caliskan-Aydogan O, Alocilja EC. A Review of Carbapenem Resistance in Enterobacterales and Its Detection Techniques. Microorganisms. 2023;11(6):1491. DOI: https://doi.org/10.3390/microorganisms11061491
Bonardi S, Pitino R. Carbapenemase-producing bacteria in food-producing animals, wildlife and environment: A challenge for human health. Ital J Food Saf. 2019;8(2):7956. DOI: https://doi.org/10.4081/ijfs.2019.7956
Liu YC, Lu CY, Yen TY, Chang LY, Chen JM, Lee PI, et al. Clinical characteristics and outcomes of carbapenem-resistant Enterobacterales bacteremia in pediatric patients. J Microbiol Immunol Infect. 2023;56(1):84-92. DOI: https://doi.org/10.1016/j.jmii.2022.09.010
Dankittipong N, Fischer EAJ, Swanenburg M, Wagenaar JA, Stegeman AJ, de Vos CJ. Quantitative Risk Assessment for the Introduction of Carbapenem-Resistant Enterobacteriaceae (CPE) into Dutch Livestock Farms. Antibiotics. 2022;11(2):281. DOI: https://doi.org/10.3390/antibiotics11020281
Taggar G, Rheman MA, Boerlin P, Diarra MS. Molecular epidemiology of carbapenemases in enterobacteriales from humans, animals, food and the environment. Antibiotics. MDPI AG. 2020;9(10):693. DOI: https://doi.org/10.3390/antibiotics9100693
Eichenberger EM, Thaden JT. Epidemiology and mechanisms of resistance of extensively drug resistant gram-negative bacteria. Antibiotics. 2019;8(6):37. DOI: https://doi.org/10.3390/antibiotics8020037
Karakonstantis S, Kritsotakis EI, Gikas A. 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. Infection. 2020;48:835-51. DOI: https://doi.org/10.1007/s15010-020-01520-6
Prestinaci F, Pezzotti P, Pantosti A. Antimicrobial resistance: A global multifaceted phenomenon. Pathogens Global Health. 2015;109:309-18. DOI: https://doi.org/10.1179/2047773215Y.0000000030
Munita JM, Arias CA. Mechanisms of Antibiotic Resistance. Microbiol Spectr. 2016;4(2):10.1128/microbiolspec.VMBF-0016-2015. DOI: https://doi.org/10.1128/microbiolspec.VMBF-0016-2015
Lee CS, Doi Y. Therapy of infections due to carbapenem-resistant gram-negative pathogens. Infect Chemother. 2014;46(3):149-64. DOI: https://doi.org/10.3947/ic.2014.46.3.149
Ayukekbong JA, Ntemgwa M, Atabe AN. The threat of antimicrobial resistance in developing countries: Causes and control strategies. Antimicrobial Resistance and Infection Control. 2017;6:47. DOI: https://doi.org/10.1186/s13756-017-0208-x
Beshah D, Desta AF, Woldemichael GB, Belachew EB, Derese SG, Zelelie TZ, et al. High burden of ESBL and carbapenemase-producing gram-negative bacteria in bloodstream infection patients at a tertiary care hospital in Addis Ababa, Ethiopia. PLoS One. 2023;18(6):e0287453. DOI: https://doi.org/10.1371/journal.pone.0287453
Jiang Y, Ding Y, Wei Y, Jian C, Liu J, Zeng Z. Carbapenem-resistant Acinetobacter baumannii: A challenge in the intensive care unit. Front Microbiol. 2022;13:1045206. DOI: https://doi.org/10.3389/fmicb.2022.1045206
Cogliati Dezza F, Covino S, Petrucci F, Sacco F, Viscido A, Gavaruzzi F, et al. Risk factors for carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infections and related mortality in critically ill patients with CRAB colonization. JAC Antimicrob Resist. 2023;5(4):dlad096. DOI: https://doi.org/10.1093/jacamr/dlad096
Bartal C, Rolston KVI, Nesher L. Carbapenem-resistant Acinetobacter baumannii: Colonization, Infection and Current Treatment Options. Infect Dis Therapy. 2022;11:683-94. DOI: https://doi.org/10.1007/s40121-022-00597-w
Aldali HJ, Khan A, Alshehri AA, Aldali JA, Meo SA, Hindi A, et al. Hospital-Acquired Infections Caused by Carbapenem-Resistant Enterobacteriaceae: An Observational Study. Microorganisms. 2023;11(6):1595. DOI: https://doi.org/10.3390/microorganisms11061595
Castanheira M, Huband MD, Mendes RE, Flamm RK. Meropenem-vaborbactam tested against contemporary Gram-negative isolates collected worldwide during 2014, including Carbapenem-resistant, KPC-producing, multidrug-resistant, and extensively drug-resistant enterobacteriaceae. Antimicrob Agents Chemother. 2017;61(9):e00567-17. DOI: https://doi.org/10.1128/AAC.00567-17
Karampatakis T, Tsergouli K, Behzadi P. Carbapenem-Resistant Klebsiella pneumoniae: Virulence Factors, Molecular Epidemiology and Latest Updates in Treatment Options. Antibiotics. 2023;12(2):234. DOI: https://doi.org/10.3390/antibiotics12020234
He W, Wu C, Chen G, Zhang G, Zhao Z, Wen S, et al. Comparative Genomic Analysis of Hypervirulence Carbapenem-Resistant Klebsiella pneumoniae from Inpatients with Infection and Gut Colonization, China. Infect Drug Resist. 2023;16:5251-61. DOI: https://doi.org/10.2147/IDR.S416770
Ljubović AD, Granov Ð, Husić E, Gačanović D, Halković J, Lab Ing AČ, et al. Prevalence of extended-spectrum β-lactamase and carbapenem-resistant Klebsiella pneumoniae in clinical samples. Saudi Med J. 2023;44(8):801-7. DOI: https://doi.org/10.15537/smj.2023.44.8.20230237
Aldali JA. Acinetobacter baumannii: A multidrug-resistant pathogen, has emerged in Saudi Arabia. Saudi Med J. 2023;44:732-44. DOI: https://doi.org/10.15537/smj.2023.44.8.20230194
Mangioni D, Fox V, Chatenoud L, Bolis M, Bottino N, Cariani L, et al. Genomic Characterization of Carbapenem-Resistant Acinetobacter baumannii (CRAB) in Mechanically Ventilated COVID-19 Patients and Impact of Infection Control Measures on Reducing CRAB Circulation during the Second Wave of the SARS-CoV-2 Pandemic in Milan, Italy. Microbiol Spectr. 2023;11(2):e0020923. DOI: https://doi.org/10.1128/spectrum.00209-23
Mączyńska B, Jama-Kmiecik A, Sarowska J, Woronowicz K, Choroszy-Król I, Piątek D, et al. Changes in Antibiotic Resistance of Acinetobacter baumannii and Pseudomonas aeruginosa Clinical Isolates in a Multi-Profile Hospital in Years 2017-2022 in Wroclaw, Poland. J Clin Med. 2023;12(15):5020. DOI: https://doi.org/10.3390/jcm12155020
Doi Y. Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections. Clin Infect Dis. 2019;69:S565-75. DOI: https://doi.org/10.1093/cid/ciz830
Sheu CC, Chang YT, Lin SY, Chen YH, Hsueh PR. Infections caused by carbapenem-resistant Enterobacteriaceae: An update on therapeutic options. Front Microbiol. 2019;10:80. DOI: https://doi.org/10.3389/fmicb.2019.00080
Logan LK, Weinstein RA. The epidemiology of Carbapenem-resistant enterobacteriaceae: The impact and evolution of a global menace. J Infect Dis. 2017;215:S28-36. DOI: https://doi.org/10.1093/infdis/jiw282
De Pascale G, Martucci G, Montini L, Panarello G, Cutuli SL, Di Carlo D, et al. Double carbapenem as a rescue strategy for the treatment of severe carbapenemase-producing Klebsiella pneumoniae infections: A two-center, matched case-control study. Crit Care. 2017;21(1):173. DOI: https://doi.org/10.1186/s13054-017-1769-z
Soontaros S, Leelakanok N, Mepradis Y, Auamnoy T. Factors influencing decision making and antibiotic prescribing patterns for the treatment of carbapenemresistant Enterobacteriaceae (CRE) among non-infectious physicians in Thailand: a qualitative study. Transl Clin Pharmacol. 2022;30(4):187-200. DOI: https://doi.org/10.12793/tcp.2022.30.e18
Grégoire N, Mimoz O, Mégarbane B, Comets E, Chatelier D, Lasocki S, et al. New colistin population pharmacokinetic data in critically ILL patients suggesting an alternative loading dose rationale. Antimicrob Agents Chemother. 2014;58(12):7324-30. DOI: https://doi.org/10.1128/AAC.03508-14
Katip W, Uitrakul S, Oberdorfer P. Clinical Efficacy and Nephrotoxicity of the Loading Dose Colistin for the Treatment of Carbapenem-Resistant Acinetobacter baumannii in Critically Ill Patients. Pharmaceutics. 2021;14(1):31. DOI: https://doi.org/10.3390/pharmaceutics14010031
Piperaki ET, Tzouvelekis LS, Miriagou V, Daikos GL. Carbapenem-resistant Acinetobacter baumannii: in pursuit of an effective treatment. Clin Microbiol Infect. 2019;25:951-7. DOI: https://doi.org/10.1016/j.cmi.2019.03.014
Karaiskos I, Giamarellou H. Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: Current and emerging therapeutic approaches. Expert Opinion Pharmacotherapy. Informa Healthcare. 2014;15:1351-70. DOI: https://doi.org/10.1517/14656566.2014.914172
Agyeman AA, Bergen PJ, Rao GG, Nation RL, Landersdorfer CB. A systematic review and meta-analysis of treatment outcomes following antibiotic therapy among patients with carbapenem-resistant Klebsiella pneumoniae infections. Int J Antimicrobial Agents. 2020;55(1):105833. DOI: https://doi.org/10.1016/j.ijantimicag.2019.10.014
Geng TT, Xu X, Huang M. High-dose tigecycline for the treatment of nosocomial carbapenem-resistant Klebsiella pneumoniae bloodstream infections. Medicine (United States). 2018;97(8):e9961. DOI: https://doi.org/10.1097/MD.0000000000009961
Silver LL. Fosfomycin: Mechanism and resistance. Cold Spring Harb Perspect Med. 2017;7(2):a025262. DOI: https://doi.org/10.1101/cshperspect.a025262
Abdallah M, Olafisoye O, Cortes C, Urban C, Landman D, Quale J. Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including multidrug-resistant isolates, from New York City. Antimicrob Agents Chemother. 2015;59(3):1802-5. DOI: https://doi.org/10.1128/AAC.04809-14
Sutcliffe JA, O’Brien W, Fyfe C, Grossman TH. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob Agents Chemother. 2013;57(11):5548-58. DOI: https://doi.org/10.1128/AAC.01288-13
Armin S, Fallah F, Karimi A, Karbasiyan F, Alebouyeh M, Rafiei Tabatabaei S, et al. Antibiotic Susceptibility Patterns for Carbapenem-Resistant Enterobacteriaceae. Int J Microbiol. 2023;2023. DOI: https://doi.org/10.1155/2023/8920977
Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, et al. Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(1):1-12. DOI: https://doi.org/10.1086/595011
Wise MG, Karlowsky JA, Mohamed N, Kamat S, Sahm DF. In vitro activity of aztreonam–avibactam against Enterobacterales isolates collected in Latin America, Africa/Middle East, Asia, and Eurasia for the ATLAS Global Surveillance Program in 2019-2021. Eur J Clin Microbiol Infect Dis. 2023;42(9):1135-43. DOI: https://doi.org/10.1007/s10096-023-04645-2
Rabaan AA, Eljaaly K, Alhumaid S, Albayat H, Al-Adsani W, Sabour AA, et al. An Overview on Phenotypic and Genotypic Characterisation of Carbapenem-Resistant Enterobacterales. Medicina. 2022;58(11):1675. DOI: https://doi.org/10.3390/medicina58111675
Rodríguez-Baño J, Gutiérrez-Gutiérrez B, Machuca I, Pascual A. Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae. Clin Microbiol Rev. 2018;31(2):e00079-17. DOI: https://doi.org/10.1128/CMR.00079-17
Oliva A, D’Abramo A, D’Agostino C, Iannetta M, Mascellino MT, Gallinelli C, et al. Synergistic activity and effectiveness of a double-carbapenem regimen in pandrug-resistant Klebsiella pneumoniae bloodstream infections. J Antimicrobial Chemotherapy. 2014;69:1718-20. DOI: https://doi.org/10.1093/jac/dku027
Mantzana P, Protonotariou E, Kassomenaki A, Meletis G, Tychala A, Keskilidou E, et al. In Vitro Synergistic Activity of Antimicrobial Combinations against Carbapenem- and Colistin-Resistant Acinetobacter baumannii and Klebsiella pneumoniae. Antibiotics. 2023;12(1):93. DOI: https://doi.org/10.3390/antibiotics12010093
Scudeller L, Righi E, Chiamenti M, Bragantini D, Menchinelli G, Cattaneo P, et al. Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli. Int J Antimicrobial Agents. 2021;57(5):106344. DOI: https://doi.org/10.1016/j.ijantimicag.2021.106344
Falcone M, Daikos GL, Tiseo G, Bassoulis D, Giordano C, Galfo V, et al. Efficacy of Ceftazidime-avibactam plus Aztreonam in Patients with Bloodstream Infections Caused by Metallo-β-lactamase-Producing Enterobacterales. Clin Infect Dis. 2021;72(11):1871-8. DOI: https://doi.org/10.1093/cid/ciaa586
Falagas ME, Lourida P, Poulikakos P, Rafailidis PI, Tansarli GS. Antibiotic treatment of infections due to carbapenem-resistant enterobacteriaceae: Systematic evaluation of the available evidence. Antimicrob Agents Chemother. 2014;58(2):654-63. DOI: https://doi.org/10.1128/AAC.01222-13
Trecarichi EM, Tumbarello M. Therapeutic options for carbapenem-resistant Enterobacteriaceae infections. Virulence. Taylor and Francis Inc.; 2017;8:470-84. DOI: https://doi.org/10.1080/21505594.2017.1292196
Alosaimy S, Morrisette T, Lagnf AM, Rojas LM, King MA, Pullinger BM, et al. Clinical Outcomes of Eravacycline in Patients Treated Predominately for Carbapenem-Resistant Acinetobacter baumannii. Microbiol Spectr. 2022;10(5):e0047922. DOI: https://doi.org/10.1128/spectrum.00479-22
Abdul-Mutakabbir JC, Griffith NC, Shields RK, Tverdek FP, Escobar ZK. Contemporary Perspective on the Treatment of Acinetobacter baumannii Infections: Insights from the Society of Infectious Diseases Pharmacists. Infect Dis Therapy. 2021;10:2177-202. DOI: https://doi.org/10.1007/s40121-021-00541-4
Kollef M, Dupont H, Greenberg DE, Viale P, Echols R, Yamano Y, et al. Prospective role of cefiderocol in the management of carbapenem-resistant Acinetobacter baumannii infections: Review of the evidence. Int J Antimicrobial Agents. 2023;62(2):106882. DOI: https://doi.org/10.1016/j.ijantimicag.2023.106882
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