Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Pharmacol. Mar 9, 2015; 4(1): 75-95
Published online Mar 9, 2015. doi: 10.5497/wjp.v4.i1.75
Carbapenemases: A worldwide threat to antimicrobial therapy
José Miguel Sahuquillo-Arce, Alicia Hernández-Cabezas, Fernanda Yarad-Auad, Elisa Ibáñez-Martínez, Patricia Falomir-Salcedo, Alba Ruiz-Gaitán
José Miguel Sahuquillo-Arce, Grupo de investigación de infecciones respiratorias, Instituto de Investigación Sanitaria - Fundación para la Investigación Hospital La Fe., Torre A, 46026 Valencia, Spain
Alicia Hernández-Cabezas, Fernanda Yarad-Auad, Elisa Ibáñez-Martínez, Patricia Falomir-Salcedo, Alba Ruiz-Gaitán, Servicio de Microbiología, Hospital Universitari i Politécnic La Fe, 46009 Valencia, Spain
Author contributions: All authors contributed equally to this manuscript.
Conflict-of-interest: The authors declare they have no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: José Miguel Sahuquillo-Arce, MD, Grupo de investigación de infecciones respiratorias, Instituto de Investigación Sanitaria - Fundación para la Investigación Hospital La Fe., Bulevar Sur, s/n, Hospital U. y P. La Fe, Torre A, Planta 6ª, 46026 Valencia, Spain.
Telephone: +34-96-3862764
Received: July 29, 2014
Peer-review started: July 29, 2014
First decision: October 16, 2014
Revised: November 14, 2014
Accepted: November 27, 2014
Article in press: December 1, 2014
Published online: March 9, 2015

Carbapenems are potent β-lactams with activity against extended-spectrum cephalosporinases and β-lactamases. These antibiotics, derived from thienamycn, a carbapenem produced by the environmental bacterium Streptomyces cattleya, were initially used as last-resort treatments for severe Gram-negative bacterial infections presenting resistance to most β-lactams but have become an empirical option in countries with high prevalence of Extended Spectrum β-lactamase-producing bacterial infections. Imipenem, the first commercially available carbapenem, was approved for clinical use in 1985. Since then, a wide variety of carbapenem-resistant bacteria has appeared, primarily Enterobacteriaceae such as Escherichia coli or Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa and Acinetobacter baumannii, presenting different resistance mechanisms. The most relevant mechanism is the production of carbapenem-hydrolyzing β-lactamases, also known as carbapenemases. These enzymes also inactivate all known β-lactams, and some of these enzymes can be acquired through horizontal gene transfer. Moreover, plasmids, transposons and integrons harboring these genes typically carry other resistance determinants, rendering the recipient bacteria resistant to almost all currently used antimicrobials, as is the case for K. pneumoniae carbapenemase - or New Delhi metallo-β-lactamases-type enzymes. The recent advent of these enzymes in the health landscape presents a serious challenge. First, the emergence of carbapenemases limits the currently available treatment options; second, these enzymes pose a risk to patients, as some studies have demonstrated high mortality associated with carbapenemase-producing bacterial infections; and third, these circumstances require an extra cost to sanitary systems, which are particularly cumbersome in developing countries. Therefore, emphasis should be placed on the early detection of these enzymes, the prevention of the spread of carbapenemase-producing bacteria and the development of new drugs resistant to carbapenemase hydrolysis.

Keywords: Carbapenemases, Origin, Epidemiology, Evolution, Multi-Drug-resistant bacteria

Core tip: Carbapenemase-producing bacteria were a rare curiosity 15 years ago, as these bacteria were primarily detected in hospital settings. However, now carbapenemase-producing bacteria are observed in farms, companion or wild animals and even in distant glaciers, becoming an epidemic. The relevance this subject has acquired can be easily demonstrated through a search in any medical database; more than 1500 articles have been published depicting the exponential isolation of these bacteria since 1990, with an alarming acceleration in the last seven years.