DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20203635

An overview of carbapenem, its resistance and therapeutic options for infections caused by carbapenem resistant bacteria

Hari P. Nepal, Rama Paudel

Abstract


Carbapenems are beta-lactam drugs that have broadest spectrum of activity. They are commonly used as the drugs of last resort to treat complicated bacterial infections. They bind to penicillin binding proteins (PBPs) and inhibit cell wall synthesis in bacteria. Important members that are in clinical use include doripenem, ertapenem, imipenem, and meropenem. Unlike other members, imipenem is hydrolyzed significantly by renal dehydropeptidase; therefore, it is administered together with an inhibitor of renal dehydropeptidase, cilastatin. Carbapenems are usually administered intravenously due to their low oral bioavailability. Most common side effects of these drugs include nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites. Increasing resistance to these antibiotics is being reported throughout the world and is posing a threat to public health.  Primary mechanisms of carbapenem resistance include expulsion of drug and inactivation of the drug by production of carbapenemases which may not only hydrolyze carbapenem, but also cephalosporin, penicillin, and aztreonam. Resistance especially among Gram negative bacteria is of much concern since there are only limited therapeutic options available for infections caused by carbapenem resistant Gram-negative bacterial pathogens. Commonly used drugs to treat such infections include polymyxins, fosfomycin and tigecycline.


Keywords


Carbapenems, Drugs of last resort, Resistance, Therapeutic options

Full Text:

PDF

References


Wallace PKM, Endimiani A, Taracila MA, Bonomo Ra. Carbapenems: past, present, and future. Antimicrob Agents Chemother. 2011;55:4943-60.

Bradley JS, Garau J, Lode H, Rolston KV, Wilson SE, Quinn JP. Carbapenems in clinical practice: a guide to their use in serious infection. Int J Antimicrob Agents. 1999;11:93-100.

World Health Organization (WHO). Guidelines for the prevention and control of carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa in health care facilities. WHO, November 2017. Available at: https://www.who.int/infection-prevention/ publications/guidelines-cre/en. Accessed 20 June 2020.

Meletis G. Carbapenem resistance: overview of the problem and future perspectives. Ther Adv Infect Dis. 2016;3(1):15-21.

Deck DH, Winston LG. Chapter 43: Beta-lactam and other cell wall membrane-active antibiotics. In: Katzung BG, editor. Basic and Clinical Pharmacology, 14e. New York, NY: McGraw-Hill; 2018. Available at: http://accessmedicine.mhmedical. com/content.aspx?bookid=2249&sectionid=175215158. Accessed on 10 May 2020.

Bassetti M, Nicolini L, Esposito S, Righi E, Viscoli C. Current status of newer carbapenems. Curr Med Chem. 2009;16:564-75.

Gaibani P, Ambretti S, Berlingeri A, Gelsomino F, Bielli A, Landini MP, et al. Rapid increase of carbapenemase-producing Klebsiella pneumoniae strains in a large Italian hospital: surveillance period 1 March 30 September 2010. Euro Surveill. 2011;16(8):19800.

Nicasio AM, Kuti JL, Nicolau DP. The current state of multidrug-resistant Gram-negative bacilli in North America. Pharmacotherapy. 2008;28:235-49.

Patel G, Bonomo RA. Status report on carbapenemases: challenges and prospects. Expert Rev Anti Infect Ther. 2011;9:555-70.

Sanchez M. Antibiotic resistance in the opportunistic pathogen Stenotrophomonas maltophilia. Front Microbiol. 2015;6:658.

Halat DM. Moubareck CA. The current burden of carbapenemases: Review of significant properties and dissemination among Gram-negative bacteria. Antibiotics. 2020;9:186.

Centers for Disease Control and Prevention (CDC). Health care associated infections: carbapenem-resistant Enterobacteriaceae (CRE). Available at: https://www.cdc.gov/hai/organisms/cre/cre-patients.html. Accessed on 20 June 2020.

Brink AJ. Epidemiology of carbapenem-resistant Gram-negative infections globally. Curr Opin Infect Dis. 2019;32:609-16.

World Health Organization (WHO). Prioritization of pathogens to guide discovery, research and development of new antibiotics for drug resistant bacterial infections, including tuberculosis. WHO, Sep 2017. Available at: https://www.who.int/ medicines/areas/rational_use/prioritization-of-pathogens/en. Accessed on 20 June 2020.

Shortridge D, Gales AC, Streit JM, Huband M, Tsakris A, Jones RN. Geographic and temporal patterns of antimicrobial resistance in Pseudomonas aeruginosa over 20 years from the SENTRY antimicrobial surveillance program. Open Forum Infect Dis. 2019;6(S1):63-8.

European Centre for Disease Prevention and Control. Surveillance of antimicrobial resistance in Europe. Annual report of the European Antimicrobial Resistance Surveillance Network (EARS Net) 2017. Available at: https://www.ecdc.europa.eu/sites/ default/files/documents/EARS-Net-report-2017-update-jan-2019.pdf. Accessed on 20 June 2020.

Ruppe E, Woerther PL, Barbier F. Mechanisms of antimicrobial resistance in Gram-negative bacilli. Ann Intensive Care. 2015;5:21.

Eichenberger EM, Thaden JT. Epidemiology and mechanisms of resistance of extensively drug resistant Gram-negative bacteria. Antibiotics. 2019;8:37.

Weiner LM, Webb AK, Limbago B, Dedeck MA, Patel J, Kallen AJ, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention. Infect Control Hosp Epidemiol. 2016;37:1288-301.

Grundmann H, Glasner C, Albiger B, Aanensen DM, Tomlinson CT, Andrasevic, et al. Occurrence of carbapenemase producing Klebsiella pneumoniae and Escherichia coli in the European Survey of Carbapenemase-Producing Enterobacteriaceae (Eu SCAPE): a prospective, multinational study. Lancet Infect Dis. 2017;17:153-63.

Livorsi DJ, Chorazy ML, Schweizer ML, Balkenende EC, Blevins AE, Nair R, et al. A systematic review of the epidemiology of carbapenem-resistant Enterobacteriaceae in the United States. Antimicrob Resist Infect Control. 2018;7:55.

McCann E, Srinivasan A, Ryke DA, Ye G, Pestel DD, Murray J, et al. Carbapenem-non susceptible Gram-negative pathogens in ICU and non-ICU settings in US hospitals in 2017: a multicenter study. Open Forum Infect Dis. 2018;5:1-7.

Kelly AM, Mathema B, Larson EL. Carbapenem-resistant Enterobacteriaceae in the community: a scoping review. Int J Antimicrob Agents. 2017;50:127-34.

Tzouvelekis L, Markogiannakis A, Piperaki E, Souli M, Daikos GL. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect. 2014;20:862-72.

Gales AC, Jones RN, Sader HS. Contemporary activity of colistin and polymyxin B against a worldwide collection of Gram-negative pathogens: results from the SENTRY Antimicrobial Surveillance Program (2006-09). J Antimicrob Chemother. 2011;66(9):2070-4.

Tran TB, Velkov T, Nation RL, Forrest A, Tsuji B, Bergen PJ, et al. Pharmacokinetics/ pharmacodynamics of colistin and polymyxin B: are we there yet? Int J Antimicrob Agents. 2016;48:592-7.

Perez F, Chakhtoura ENG, Wallace PK, Wilson BM, Bonomo RA. Treatment options for infections caused by carbapenem-resistant Enterobacteriaceae; can we apply “precision medicine” to antimicrobial chemotherapy? Expert Opin Pharmacother. 2016;17(6):761-81.

Zavascki AP, Bulitta JB, Landersdorfer CB. Combination therapy for carbapenem-resistant Gram-negative bacteria. Expert Rev Anti Infect Ther. 2013;11(12):1333-53.

Levin AS, Barone AA, Penco J, Santos MV, Marinho S, Arruda EA, et al. Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Clin Infect Dis. 1999;28(5):1008-11.

Pike M, Saltiel E. Colistin and polymyxin-induced nephrotoxicity: focus on literature utilizing the RIFLE classification scheme of acute kidney injury. J Pharmacy Practice. 2014;27(6):554-61.

Mammina C, Bonura C, Bernardo DF, Aleo A, Fasciana T, Sodano C, et al. Ongoing spread of colistin-resistant Klebsiella pneumoniae in different wards of an acute general hospital, Italy, June to December 2011. Euro Surveill. 2012;17(33):20248.

Marchaim D, Chopra T, Pogue JM, Perez F, Hujer AM, Rudin S, et al. Outbreak of colistin-resistant, carbapenem-resistant Klebsiella pneumoniae in metropolitan Detroit, Michigan. Antimicrob Agents Chemother. 2011;55(2):593-9.

Kontopoulou K, Protonotariou E, Vasilakos K, Kriti M, Koteli A, Antoniadou E, et al. Hospital outbreak caused by Klebsiella pneumoniae producing KPC-2 beta-lactamase resistant to colistin. J Hosp Infect. 2010;76(1):70-3.

Gobernado M. Fosfomycin. Rev Esp Quimioter. 2003;16(1):15-40.

Kaase M, Szabados F, Anders A, Gatermann SG. Fosfomycin susceptibility in carbapenem resistant Enterobacteriaceae from Germany. J Clin Microbiol. 2014;52(6):1893-7.

Endimiani A, Patel G, Hujer KM, Swaminathan M, Perez F, Rice LB, et al. In vitro activity of fosfomycin against Bla KPC-containing Klebsiella pneumoniae isolates, including those non susceptible to tigecycline and/or colistin. Antimicrob Agents Chemother. 2010;54(1):526-9.

Falagas ME, Giannopoulou KP, Kokolakis GN, Rafailidis PI. Fosfomycin: use beyond urinary tract and gastrointestinal infections. Clin Infect Dis. 2008;46(7):1069-77.

Fritzenwanker M, Imirzalioglu C, Herold S, Wagenlehner FM, Zimmer KP, Chakraborty T. Treatment options for carbapenem resistant Gram-negative infections. Dtsch Arztebl Int. 2018;115:345-52.

Kasbekar N. Tigecycline: a new glycylcycline antimicrobial agent. Am J Health Syst Pharm. 2006;63:1235-43.

Doi Y. Treatment options for carbapenem-resistant Gram-negative bacterial infections. Clin Infect Dis. 2019;69(7):565-75.

Stein GE, Babinchak T. Tigecycline: an update. Diagn Microbiol Infect Dis. 2013;75:331-6.

Beauduy CE, Winston LG. Chapter 44: Tetracyclines, macrolides, clindamycin, chloramphenicol, streptogramins, and oxazolidinones. In: Katzung BG, editor. Basic and Clinical Pharmacology, 14e. New York, NY: McGraw-Hill; 2018. Available at: http://access medicine.mhmedical.com/content.aspx?bookid=2249&sectionid=175215158. Accessed on 20 June 2020.

Bassetti M, Eckmann C, Bodmann KF, Dupont H, Heizmann WR, Montravers P, et al. Prescription behaviours for tigecycline in real-life clinical practice from five European observational studies. J Antimicrob Chemother. 2013;68(2):5-14.

Brust K, Evans A, Plemmons R. Tigecycline in treatment of multidrug-resistant Gram-negative bacillus urinary tract infections: a systematic review. J Antimicrob Chemother. 2014;69(10):2606-10.

Trecarichi EM, Tumbarello M. Therapeutic options for carbapenem-resistant Enterobacteriaceae infections. Virulence. 2017;8(4):470-84.

Falcone M, Paterson D. Spotlight on ceftazidime/avibactam: a new option for MDR Gram-negative infections. J Antimicrob Chemother. 2016;71(10):2713-22.