**1. Antibiotic resistance as a global threat**

The global burden of antibiotic resistance is mounting continuously; preferably it piles up the pressure on veterinary medicine and on human. The WHO made a landmark by promoting and declaring AMR as a global health concern. The agenda of global health concerns are at the developmental stages, for example, a book named as *The Evolving Threat of Antimicrobial Resistance: Options for Action* is a precious addition to the archive [1]. Currently, the world is experiencing dramatic pre-antibiotic era, and many of the untreated infection emerge on a large-scale; clinicians often encounter many patients with such infections that normally reported as PDR or MDR bacteria by many laboratories and not responding to already available therapeutics. It has been estimated that yearly about two million people acquire vulnerable infections just because of these antibiotic-resistant pathogens, and as a result of this, about 23,000 people die according to Centers for Disease Control and Prevention (CDC) [2].

In a historical perspective, antibiotic resistance is a mounting and compelling concern. New types of antibiotic-resistant bacteria are taking control of ancient drugs. We may be entering the post-antibiotic era, because of increased persistence, spread, and the emergence of superbugs. It has been reported that annually, in the USA, about 99,000 deaths are caused by antibiotic-resistant pathogen-related hospital-acquired infections [3]. While in America, the annual death rate is about 50,000 caused by two usual HAIs, known as sepsis and pneumonia, which cost around \$8 billion to the economy of the USA. The patients infected with bacterial strains that are resistant to antibiotics must stay in the hospital minimum for 13 days, which adds to 8 million days annually. An annual report of the cost of economy loss with regard to a productivity loss of around \$35 billion has been demonstrated within healthcare settings [3].

### **2. Causes of antibiotic resistance**

Currently, the multifarious causes of resistance constitute many factors including improper use and regulations, lack of awareness, aberrant antibiotic usage, the use of antibiotics as a growth promoter in livestock as well as in poultry for infection control, and online marketing [4]. Fundamentally, the reason behind the resistance evolution is the improper and excessive use of antimicrobials. The powerful drivers of antibiotic resistance include infection control standards, sanitation system, drug quality, water hygiene systems, diagnostics and therapeutics, and migration or travel quarantine. Genetic mutations and exchange of genetic material between organisms play a key role in the distribution of antibiotic resistance [5]. MDR organisms in hospital wastes are associated with public health illnesses because they are ultimately disseminated to humans. In this regard, recently a study has been conducted in Pakistan to find the occurrence of ESBL producing *K. pneumoniae* in hospital wastes including hospital sludge and wastewater, operation theater waste. They found the significant percentage of extended-spectrum β-lactamases (ESBL) producing MDR *K. pneumoniae* in these wastes [6]. Similarly another study conducted by [7] reported the patterns of antibiotic-resistant *K. pneumoniae* in clinical isolates with special reference to fluoroquinolones, depicting an alarming threat of antibiotic resistance among *K. pneumoniae*-related nosocomial infections.

#### **3. Carbapenems**

Carbapenems are effective β-lactam antimicrobials and have very potent efficacy against many ESBL-producing bacteria and are also administered intravenously.

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**Table 1.**

*Carbapenem Resistance: Mechanisms and Drivers of Global Menace*

In order to treat bacterial infections, carbapenems are considered as the most reliable and the last resort class of antimicrobials. Carbapenem agent has a very unique structure, usually defined by carbapenem coupled to B-lactam ring, which provide protection against the majority of b-lactamases as well as metallo-b-lactamases, and thus possess extended antibacterial activity [8]. Carbapenems work by penetrating the cell wall of bacteria, binding with penicillin-binding proteins (PBPs), and result in inactivation of intracellular autolytic inhibitor enzymes, ultimately killing the

In addition, carbapenems mainly target "transpeptidase inhibition enzyme" during bacterial cell wall synthesis, preventing peptide cross-linking activity, leading to enhanced autolytic activity, and thus resulting in cell death. Therefore, carbapenems are considered as effective antimicrobials to treat life-threatening and invasive infections due to their "concentration-independent killing effect" on

Carbapenemases are versatile b-lactamases, having the capability to hydrolyze carbapenems, cephalosporins, penicillins, and monobactams. Carbapenemases typically belong to two molecular families, namely, "metallo-carbapenemases" in which activity is inhibited by EDTA, used zinc molecule at their active sites, and "serine-based carbapenemases" in which activity is not inhibited by EDTA rather used serine residues at their active sites and inactivated through β-lactamase inhibi-

β-Lactamases are classified based on two properties: functional and molecular ones. Functional classification was proposed by a scientist "Bush" in 1988, who classified β-lactamases into four functional groups namely, groups 1–4. Carbapenems fall under subgroup the 2f and group 3 [12]. Later on another scientist, Rasmussen, suggested that group 3 can be further divided into three functional subgroups on

The molecular classification was proposed by scientist "Frere" and colleagues, who classified carbapenemases into class A, class B, and class D car-

Class A carbapenemases require a serine active site at position number 70 in Ambler numbering system, fall under the group 2f, and have the ability to hydro-

Class A SME, NMC, KPC, IMI, GES All *Enterobacteriaceae*, rarely *P. aeruginosa* Class B VIM, SPM, GIM, IMP *Acinetobacter* species*, P. aeruginosa*,

*Enterobacteriaceae*

lyze carbapenems, penicillins, aztreonam, and cephalosporins [14].

**Classification Enzymes Common bacteria**

Class D OXA *Acinetobacter* species

*DOI: http://dx.doi.org/10.5772/intechopen.90100*

bacterial cell.

infecting bacteria [9, 10].

**4. Carbapenemases**

tors like tazobactam and clavulanic acid [11].

the basis of substrate specificity [13].

Subclass B1 VIM-2, IMP-1, SPM-1, CcrA and BcII

Subclass B3 Gob-1, FEZ-1, CAU-1 & L1

*Molecular classification scheme of carbapenemases [16].*

Subclass B2 Sfh-1, CphA

bapenemases (**Table 1**).

#### *Carbapenem Resistance: Mechanisms and Drivers of Global Menace DOI: http://dx.doi.org/10.5772/intechopen.90100*

In order to treat bacterial infections, carbapenems are considered as the most reliable and the last resort class of antimicrobials. Carbapenem agent has a very unique structure, usually defined by carbapenem coupled to B-lactam ring, which provide protection against the majority of b-lactamases as well as metallo-b-lactamases, and thus possess extended antibacterial activity [8]. Carbapenems work by penetrating the cell wall of bacteria, binding with penicillin-binding proteins (PBPs), and result in inactivation of intracellular autolytic inhibitor enzymes, ultimately killing the bacterial cell.

In addition, carbapenems mainly target "transpeptidase inhibition enzyme" during bacterial cell wall synthesis, preventing peptide cross-linking activity, leading to enhanced autolytic activity, and thus resulting in cell death. Therefore, carbapenems are considered as effective antimicrobials to treat life-threatening and invasive infections due to their "concentration-independent killing effect" on infecting bacteria [9, 10].
