Introduction

Carbapenem resistance is a major and an on-going public health problem

globally. It occurs mainly among Gram-negative pathogens such as Klebsiella

pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii, and may

be intrinsic or mediated by transferable carbapenemase-encoding genes.

(https://www.researchgate.net/publication/321986022_Carbapenem_Resistance_A_Review) .

Carbapenems are one of the antibiotics of last resort for many bacterial

infections, such as Escherichia coli and Klebsiella Pneumoniae .Recenty, Alarm

has been raised over the spread of drug resistance to Carbapenem antibiotics

among this coliforms, Due to production of New Delhi Metallo-B-

Lactamase,NDM-1.

Carbapenems possess broad spectrum antibacterial activity and have a

unique structure that is defined by a carbapenem coupled to a β-lactam ring

which confers protection against most β lactamases such as metallo-β-lactamase

(MBL) as well as extended spectrum β-lactamases . Consequently, carbapenems

are considered one of the most reliable drugs for treating bacterial infections

and the emergence and spread of resistance to these antibiotics constitute a

major public health concern.

(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872158/)
Enterobacteriaceaethat are resistant to carbapenems, known as carbapenem-

resistant Enterobacteriaceae(CRE), have gradually emerged and thus strictly

limiting options for treatment . This is considered a serious threat because CRE

are significantly associated with higher mortality rates. Production of various

carbapenemases is a key mechanism mediating the emergence of

CRE.Klebsiella pneumoniae carbapenemase (KPC), encoded by blaKPC gene,

is a particularly important enzyme related to treatment failure in serious

infections and is produced by various species of Enterobacteriaceae. Resistance

to carbapenems among Enterobacteriaceae could also be mediated by other

families of carbapenemases including NDM, IMP, VIM and OXA-48, in which

outbreaks of K.pneumoniae producing these enzymes have been described .

Other non-enzymatic mechanisms were also related to carbapenem resistance.

For example, a decrease in expression of outer membrane proteins (OMPs)

(ttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139116)

In the recent past, carbapenems were potent against all multiple drug resistant

(MDR) Gram negative bacteria and in combination with their negligible

toxicity to the host, carbapenems became the preferred last resort antibiotics for

the treatment of MDR Gram negative bacterial infections. Development of

carbapenem resistance (CR) in Enterobacteriaceae is of great concern because

there is no obvious next line of antibiotics to use against carbapenemase

producing (CP) Enterobacteriaceae. MDR has left less efficient antibiotics to

take care of these expensive hard to treat life threatening infections

(https://bmcresnotes.biomedcentral.com/articles/10.1186/s13104-018-3738-

2)
 Review of
Literatrue

Over seventy years the antimicrobial era has been marked by successive

discoveries of a wide range of antibiotics and the subsequent emergence of

antibiotic resistance. Bacterial resistance continues to increase, and drug

researchers and manufacturing industries are not producing new drugs to

replace the existing antimicrobials against which resistance has developed. The

effects on current infection rates cannot be simply estimated . The economic

impact related to antimicrobial resistance was expected to cost over $105 billion
annually worldwide and the largest relative economic impact was projected to

be suffered by Africa with a drop in GDP of US $2895 billion in 2050,

representing 20% of the region’s total economic output .

In recent times, development of antimicrobial resistance is rapidly changing,

and the impending public health challenges these may cause in many health

sectors need worldwide coordinated interventions. Many deaths have occurred

as a result of this in Europe, and the European Centre for Disease Prevention

and Control (ECDC) had estimated that 25,000 people may die each year from

infections related to antimicrobial resistance . Global reports documenting the

infection burden of common and diverse bacterial pathogens that have

developed resistance to available antimicrobial agents is alarming. Spellberg et

al. reported the annual costs of combating resistant bacterial infections to be

between $21 billion and $34 billion in the USA alone.

(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872158/)

Carbapenems are derivatives of thienamycin (from Streptomyces cattleya) and

differ from penicillins by the replacement of the sulfur by a methylene group in

the five-membered ring of the β-lactams. Currently, four carbapenems are

available for parenteral use in the United States:imipenem, meropenem,

ertapenem, and doripenem. Imipenem is combined with cilastatin to reduce

the hydrolysis of imipenem by renal dehydropeptidase.

Carbapenems have a very wide antibacterial spectrum, have a high

specificity for PBP2 of gram-positive and gram-negative microorganisms

(resulting in ovoid organisms), and are not hydrolyzed by most β-lactamases.

Microbial resistance to carbapenems is via the loss of an outer membrane

protein, resulting in retarding cell wall penetration of the drugs, altered PBPs in

Enterococcus faecium and MRSA, and hydrolysis by metallo β-lactamases and

other β-lactamases.

(https://www.sciencedirect.com/topics/neuroscience/carbapenem)

Carbapenems are classified as FDA pregnancy category B or C drugs, are cross-

allergenic with other β-lactams, may increase the level of serum liver

transaminases, may induce PMC, and are associated with a 3% to 4% incidence

of skin rash. Imipenem, meropenem, and ertapenem are associated with

increased central nervous system (CNS) toxicity and seizures. Doripenem has a

lower risk of CNS toxicity.