Carbapenems resistance is threatning

CARBAPENEMS are a class of beta-lactum, broad spectrum antibiotics which act by inhibiting the cell wall synthesis and are known to be most effective against gram negative infections.

Carbapenems, often in combination with other agents, remain a mainstay of therapy in patients with serious hospital-acquired infection. 

Carbapenems can be grouped as (2),

Group 1 includes broad-spectrum Carbapenems, with limited activity against non-fermentative Gram-negative bacilli, particularly suitable for community acquired infections (e.g. ertapenem).

Group 2 includes broad-spectrum Carbapenems, with activity against non-fermentative Gram-negative bacilli that are particularly suitable for nosocomial infections (e.g. imipenem and meropenem).

Group 3 includes Carbapenems with clinical activity methicillin-resistant Staphylococcus aureus

Amongst these the most widely used Carbapenems include:

• Meropenum
• Imipenum +Cilastin

Mechanism of resistance

• The stability of the carbapenems against gram-negative pathogens, which are resistant to other beta-lactams, comes from the protection against AmpC beta-lactamases and the extended-spectrum beta-lactamases (ESBLs). These enzymes can be produced by a variety of gram negative organisms (ie E. coli, Klebsiella pneumoniae, Enterobacter spp. and Serratia marcescens).
• When comparing wild-type and ESBL producing strains of E coli or Klebsiella, they found no increase or a one dilution doubling in MIC₉₀. Ertapenem MIC₉₀ increased by two to three doubling dilutions for ESBL producing isolates and a four doubling-dilutions for AmpC beta-lactamase isolates. By the Clinical and Laboratory Standards Institute (CLSI) breakpoints, ertapenem still maintained susceptibility to these organisms. another scientist conducted a similar study observing AmpC beta-lactamase producing strains of Enterobacter spp. and Serratia marcescens. Similar results were found for imipenem/cilastatin, meropenem and doripenem as the previous study. This in vitro data suggest that ertapenem is less stable than the other carbapenems to the beta-lactamase enzymes and may confer resistance more rapidly in vivo.
• P. aeruginosa has become resistant to many of the beta-lactam antibiotics. It remains fairly sensitive to the carbapenems, excluding ertapenem. Ertapenem lacks pseudomonal activity and is a niche of this agent. P. aeruginosa is associated with increasing MICs of the imipenem, meropenem and doripenem but needs an AmpC beta-lactamase to become resistant. The mechanisms for the increase of MICs is associated with loss of the porin Opr D, combined with activity of chromosomal beta lactamase (Amp C); in addition, overexpression of multi-drug efflux pumps is considered to confer meropenem and doripenem resistance. Meropenem and doripenem are thought to maintain more antipseudomonal activity than imipenem/cilastatin because of the multiple mechanisms of resistance required to cause resistance to P. aeruginosa. Another consideration is the enzymes referred to as “carbapenemases.” These enzymes hydrolyse all penicillins and cephalosporins, but may also lead to rapid hydrolysis of carbapenems.
• Although the carbapenems spectrum of activity is broad, some gram positive organisms exhibit intrinsic resistance. Methicillin-resistant S. aureus (MRSA) and Enterococcus faecium have intrinsic resistance to the carbapenems. All the carbapenems have poor binding affinity for PBP 2a (found on MRSA) and PBP 5 (found on E. faecium). Imipenem/cilastatin and doripenem have more potent activity against gram positive aerobic bacteria. Imipenem/cilastatin also demonstrates lower MICs for E. faecalis compared with the other carbapenems.
• In clinical practice, it is relevant to consider the in vitro mechanisms of action and each agent’s mechanism of resistance. If treating a P. aeurginosa, which has demonstrated some resistance to other beta-lactam antibiotics, it is critical to monitor isolates for MIC “creeps” and be aware that some isolates may mount resistance to the carbapenems. Pathogens such as Stenotrophomonas maltophilia and Aeromonas spp., may also produce carbapenem resistant strains (ie due to production of metallo-beta-lactamases production). When treating polymicrobial infections, it is essential to remember the intrinsic resistance to MRSA and E. faecium to the carbapenems and choose other first-line gram positive antibiotics for these organisms.
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