Carbapenem

Introduction

Carbapenem are a family of β-lactams antibiotics chemically based on the bicyclic system of carbapenem. They are of great importance amongst the other β-lactams because of their broad-spectrum and their potency. Carbapenem are often used as last-line agents, used especially in hospitalized patients suspected to be infected by MDR (multi-drug-resistant) bacteria.

The first carbapenem to be discovered was Thienamycin, isolated from species of Streptomyces Cattleya, and the parent also of the subsequently synthtetized analogues.

Mechanism of action (pharmacodynamics)

Carbapenems are not easily diffusible through the cell wall. They enter Gram-negative bacteria through the porins. Once in the periplasmic space, they finally find their target, PBPs (penicillin binding proteins), enzymes (i.e. transglycolases, transpeptidases) who lead the building of peptidoglycan, main constituent of the bacterial cell wall. Since they acylate them, they arrest the synthesis of peptidoglycan.

They are particularly effective even because they are able to bind a great variety of PBPs.

The substituent 6α - hydroxyethyl group, with this specific stereochemistry (completely new in carbapenems in respect to the other β-lactams) plays an important role in hindering the β-lactamic bond and preventing the hydrolysis by β-lactamases (ESBL also).

Chemical structure: the carbapenem nucleus

 

The carbapenem backbone consists of a Δ2 - pyrroline ring fused to a  β-lactam nucleus.

Differently to the penam nucleus of penicillins it has a methylene group that replace a sulfur atom.

 

The presence of this particular nucleus determines remarkable differences in reactivity of carbapenems among the other β-lactams. Above all, carbapenems are more reactive (when they find their target) and not stable in acidic solutions.

This is due to two factors:

  • The Δ2 - pyrroline ring makes the nucleus way more strained than penam (penicillins) and cefam (cephalosporins). Indeed C-C bonds are shorter than C-S bonds. Considering that the ring is already five-membered (in cefam we have a six-membered dihydro thiazine) this makes carbapenems the most reactive β-lactams.
  • The double bond (C=C bond) has an electrowithdrawing effect that makes the carbonyl of the β-lactam more electrophilic.

This has two obvious consequences:

  • The great potency of carbapenems
  • Carbapenems can't be administered by mouth (via OS) because they couldn't stand the acidic pH of the stomach.

Thienamycin: properties and pharmacokinetics 

  •  chemical-physical properties and structure

  •   (1R) -1- hydroxyethyl group at C6 with inverted stereochemistry compared to the other β-lactams, key attribute for the activity and resistance to hydrolysis by β-lactamases
  •    2-aminoethylthio at C2
  • At physiological pH (7,4) thienamycin is a zwitterion (it has both a carboxy and an amino group), and it is therefore extremely hydrophilic (logP = -3,8)

 The presence of an amino group and a β-lactam in the same structure has another important consequence. Concentrated solutions of thienamycin are indeed unstable because they tend to dimerize giving this product (chemically is an addition-elimination reaction):

That's why thienamycin has no clinical use.

  • Pharmacokinetics

Thienaycin has an half-life of approximately 10 hours because it suffers active secretion in the urines, hydrolysis by the renal enzyme DHP-1 and oxydation of the side chain 2-aminoethylthio.

 

Thienamycin derivatives: Imipenem 

Imipenem and Meropenem are two semisynthetic derivatives ot the parent Thienamycin both available in clinical practice.

  • Differently from Thienamycin, the amino group has been substituted with an amidine group, remarkably more basic (higher pKb) than the amine. This means at the same pH value it is more protonated. When the nitrogen is protonated it can't act as a nucleophile and imipenem is therefore stable in concentrated solutions (thienamycin wasn't because of dimerization).
  • The other important problem concerning thienamycin pharmacokinetics, was the hydrolysis by DHP -1, a renal enzyme , that produces toxyc metabolites and shorten the half- life. For this reason Imipenem is administered with cilastatine, a DHP - 1 inibitor. When administered together the approximate half - life of Imipinem grows to 1 hour.
  • Clinical use

Imipenem can be administered intravenously or intramuscularly, and is active against a great variety of Gram + and Gram - bacteria, even non-responsive infections to cephalosporins or β-lactams in general. Not active on Pseudomonas Aeruginosa.

Thienamycin derivatives: meropenem and ertapenem

Meropenem is produced via total synthesis. Differently from imipenem It has a methyl group (β) at C1 and a different substitution at C2 that accounts for the higher stability to DHP - 1 and oxydative enzymes.

Notice that the R group at C2 has a remarkably higher steric hindrance than what we saw for imipenem.

 

  • Clinical use

It has an half-life of about 1 hour (no cilastatine needed) and it is administered intravenously. It is more active than imipenem towards Gram negative bacteria (passes more efficiently through the porins) and is also active on Pseudomonas Aeruginosa, contrarily to the imipenem.

Ertapenem is the most recent carbapenem approved for clinical use (2002)

It is slightly different structurally speaking from meropenem; it has a β methyl group at C1 too and a pretty similar substituent at the sulfur. Instead of an N,N dimethyl it has a larger meta carboxy phenil group.

This additional carboxylate changes the acid-base properties of the molecule increasing the percentage of the monoanionic form.

This determines an increased binding to plasma proteins.

  • Clinical use 

The improved binding to plasma proteins determines an half-life of more than 4 hours. This allows a single somminstration (intravenously) per day. Is not active on MRSA, ampicillin resistent enterococci , Pseudomonaus Aeruginosa and Acinetobacter Baumanii.

 The problem of bacterial resistance

  • Carbapenem resistance in enterobacteriaceae

Enterobacteriaceae is a family constituted by Gram negative bacteria whose natural habitat is the animal intestine (human also). They are responsible for a long list of infections, systemic (i.e typhus), intestinal and urinary. One of the family main representative is Klebsiella pneumoniae.

We are recently experiencing a loss of efficacy in the treatment of certain infections provoked by Enterobacteriaceae. The main mechanism of resistance is due to the production of beta lactamase enzymes. Notwithstanding carbapenems are still usefull in the treatment of infections caused by enterobacteriaceae expressing ESBL (extended spectrum beta lactamase), on whom third generation cephalosporins are not effective, the growing number of isolates containing bacteria producing carbapenemase (carbapenems-resistant enterobacteriaceae or CRE) has lead to the use of antibiotics such as colistin precedently considered non attractive because of their toxicity.

  •  Carbapenem resistance in Pseudomonas Aeruginosa and Acinetobacter Baumanii

The mechanism of resistance in this species is the sum of different actions: poor membrane permeability (porins), active efflux and deactivating enzymes, beta lactamases also such as metallo beta lactamases (such as New Dehli metallo beta lactamase).

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