Emerging Resistance to Carbapenems: A Potential Threat to The Management of Infectious Disease

Carbapenems are well known for their broadest spectrum of clinical activity and utmost potency among the different β-lactam antibiotics. Unfortunately, the recent emergence of multidrug-resistant pathogens seriously threatens this class of lifesaving drugs. Recently, alarm has been raised over the spread of drug resistance to carbapenem antibiotics among these coliforms, commonly due to production of various β-lactamase. Carbepenem resistant strains are increasingly being detected in every corner of the world. The spread carbapenem resistant strains seem to be a potential nightmare situation. This is a new threat for the humanity. Carbapenem resistance genes are moving across the globe. The carbepenem resistant bacteria appear suddenly and spread rapidly before the public health care systems and laboratories can detect it. Currently we have few options left among new antibiotics to combat against the carbapenem resistant bacterial strains, none of them are safe. Antimicrobial resistance (AMR) is unresponsiveness of a microorganism to an antimicrobial agent to which it was previously sensitive. Resistant organisms (they include bacteria, fungi, viruses and some parasites) are able to withstand attack by antimicrobial medicines, such as antibiotics, antifungals, antivirals, and antimalarials, so that standard treatments become ineffective and infection persist increasing risk of spread to others. The development of resistance is a natural and ancient phenomenon that occurs when microorganisms are exposed to antimicrobial drugs, and resistant traits can be exchanged between certain types of bacteria (WHO, 2013). The development of antibiotic resistance started right from beginning of use of antibiotics. Alexander Fleming, who discovered the first antibiotic, warned about the possibility of antibiotic resistance. The phenomenon of antibiotic resistance was detected just after the discovery of antibiotic (McKenna, 2013). The irrational use of antimicrobial medicines accelerates this natural phenomenon. Poor infection control practices encourage the spread of resistant strains (WHO, 2013). Rising level of antimicrobial resistance is major crisis of this era, and emerging resistance to carbepenems is not less than a nightmare. Carbapenems is an important element of our antibiotic resources. Among the various β-lactams currently available, carbapenems has a unique status as it have broader spectrum and are relatively resistant to hydrolysis by most β-lactamases. In addition carbapenems diffuse easily in bacteria and hence it is more efficient. Carbapenems are resistant to beta-lactamase as it circumvent β-lactamase enzyme by binding it with high affinity and acylating the enzyme, rendering it inactive (Drawz & Bonomo, 2010). Among different β-lactams, carbapenems possess the broadest spectrum of activity and great potency. Carbapenems are active against both some gram-positive, good number of Gram-negative bacteria, and anaerobes. But they are not active against intracellular bacteria, such as the Chlamydiae. Carbapenems are unique in its class of β-lactams capable of inhibiting l,dtranspeptidases (Mainardi et al., 2008). As a result, they are considered as “last-line agents” or “antibiotics of last resort” to deal with serious infections and multi drug resistant strains (Angela et al., 2011). Thienamycin is the parent compound of all carbapenem. A carbapenem has common structure having the 4:5 fused ring lactam of penicillins with a double bond between C-2 and C-3 but with the substitution of carbon for sulfur at C-1. The hydroxyethyl side chain of thienamycin is a radical departure from the structure of conventional penicillins and cephalosporins, all of which have an acylamino substituent on the β-lactam ring. This hydroxyethyl side chain is a key attribute of carbapenems and is important for activity. Although thienamycin is a natural product and its purification process is not efficient. With the course of time, the semisynthetic product like Imipenem, Meropenem, Ertapenem, Doripenem,, Panipenem, Biapenem gained more importance (Krisztina et al., 2011). Mechanisms of resistance to carbapenems occurs through production of β-lactamases, efflux pumps, and mutations that alter the expression or function of porins and PBPs. Combinations of these mechanisms can result in high levels of resistance to carbapenems in certain bacterial species, especially in Klebsilla neumoniae, P. aeruginosa, and A. baumannii (Mena et al., 2006; Krisztina et al., 2011). Carbapenem resistance in Gram-positive cocci occurs as a result of substitutions in amino acid sequences of PBPs or production of a new carbapenem-resistant PBP (Koga, et al 2009). While among Gram-negative bacteria carbapenem resistance is due to expression of β-lactamases and efflux pumps, as well as porin loss and alterations in PBP (Pearson, Van Delden & Iglewski, 1999). Carbapenemases belongs to specific β-lactamases family. Expression of this enzyme seems to be the most common cause of carbapenem resistance. Some important classes of carbepenamases are class A carbapenemases (e.g., KPC and GES enzymes), class B metallo-β-lactamases (e.g., VIM, IMP, and NDM β-lactamases), and class D carbapenemases have recently reported. Although, class C β-lactamases, such as CMY-10 and PDC β-lactamases are not much affective, but it can lead to carbapenem resistance, particularly when it is expressed in combination with other resistance mechanisms (Krisztina., et al 2011; Elizabeth et al., 2012). It is frightening that bacterial strain producing ESBL and carbapenemase are also being found in the food animals, various food animal species and food products (Lee, 2013). A carbapenemresistant isolate of Escherichia coli, which lacked OmpF and OmpC porins, carried a marR mutation and expressed a functional yedS, a normally nontranslated gene. MarR and YedS render these strains resistant to carbapenems. The production of YedS was regulated by the small RNA MicF in a MarAdependent way (Stuart et al., 2013). The bacterial strain producing the New Delhi metallo-betalactamase (NDM-1) was first detected in India. It had frightened the developed nation also. These isolates carrying NMD-1 commonly belongs Escherichia coli, Klebsiella pneu-