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Carbaphenems

Carbapenems are a class of beta-lactam antibiotics with a broad spectrum of antibacterial activity, and have a structure which renders them highly resistant to beta-lactamases. Carbapenem antibiotics were originally developed from thienamycin, a naturally-derived product of Streptomyces cattleya.

Structure:

Carbapenems Structure

The carbapenems are structurally very similar to the penicillins, but the sulfur atom in position 1 of the structure has been replaced with a carbon atom, and hence the name of the group, the carbapenems.

Examples:

The following drugs belong to the carbapenem class:

ptr Imipenem (often given as part of Imipenem/cilastatin)
ptr Imipenem can be hydrolysed in the mammalian kidney by a dehydropeptidase enzyme, and so is given with a dehydropeptidase inhibitor, cilastatin.
ptr Meropenem
ptr Ertapenem
ptr Doripenem
ptr Panipenem/betamipron
ptr Biapenem
ptr PZ-601
ptr PZ-601 is a carbapenem antibiotic currently being tested as having a broad spectrum of activity including strains resistant to other carbapenems. Faropenem is closely related, but it is a penem, not a carbapenem.

Carbapenem Biosynthesis:

The biosynthesis of carbapenem-5-carboxylate provides a model to understand the biosynthesis of the clinically useful carbapenem Thienamycin, an antibiotic more potent than most penicillin. In contrast to clavulanic acid biosynthesis, that of the simplest carbapenem requires only three steps - all of which we are presently investigating. The first enzyme CarB is an unusual member of the crotonase superfamily, the second CarA is a synthetase that in effect catalyses a reverse β-lactamase reaction, and the third CarC catalyses an unprecedented epimerisastion reaction.

 
Carbapenem Biosynthesis

Development of Resistance with Carbapenem Use:

Currently, three carbapenem antimicrobials are available for use. Imipenem was first marketed in 1985, followed 10 years later by meropenem, and then by ertapenem in 2001. Similar to the penicillins, the carbapenems exert their antimicrobial effect through binding to penicillin-binding proteins (PBPs), interfering with bacterial cell wall synthesis. These agents differ in their binding affinity to the various PBPs-PBP1a and 1b, PBP2, and PBP3. There are also differences in the pharmacokinetic properties of the carbapenems.

Table 1. Properties of the carbapenems.

Carbapenem

Indications

Elimination half-life

Percent protein binding

Dosing interval

Penicillin binding protein affinity

Imipenem (with cilastatin)

  • Lower respiratory tract infections.
  • Urinary tract infections
  • Intra-abdominal infections
  • Gynecologic infections
  • Bacterial septicemia
  • Bone and joint infections
  • Skin and skin structure infections
  • Endocarditis
  • Polymicrobic infections.

1 h

20%

3 to 4 times daily

PBP2 > PBP1a/b > PBP3 (weak)

Meropenem

  • Skin and skin structure
  • Intraabdominal
  • Bacterial meningitis

1 h

2%

3 to 4 times daily

PBP2 > PBP3 > PBP 1/a/b (strong)

Ertapenem

  • Complicated intra-abdominal
  • Complicated skin and skin structure infections
  • Community acquired pneumonia
  • Complicated urinary tract infections
  • Acute pelvic infections
  • Prophylaxis for elective colorectal surgery

3.8 h

92-95%

Once daily

PBP2 > PBP3 > PBP 1/a/b (strong)

Bacterial Resistance and The Carbapenems:

Resistance to beta-lactams, which include the carbapenems, can occur by a number of mechanisms-PBP alterations, diminished expression of outer membrane proteins, and production of beta-lactamases. Beta-lactamase are enzymes produced by bacteria which can hydrolyze the beta-lactam ring of beta-lactams and carbapenems, resulting in inactivation of the antimicrobial. The actions of beta-lactamases can be overcome in 2 ways, either by use of an inhibitors (such as sulbactam and tazobactam) or by producing beta-lactam structures that fully or partially resist hydrolysis.

Bacterial Resistance
 

Several different beta-lactamases have been identified. Extended-spectrum beta-lactamases, or ESBLs, were recognized shortly after the use of ceftazidime and cefotaxime began. ESBLs are produced by Enterobacteriaceae and can induce resistance to penicillins, first-, second-, and third-generation cephalosporins. Risk factors that have been associated with infection or colonization with ESBL producing organisms include prolonged hospitalization, use of invasive devices (e.g., urinary catheters, central venous lines, and endotracheal tubes), and antibiotic use (e.g., third-generation cephalosporins, fluoroquinolones, and aminoglycosides).

Treatment of infections with ESBL-producing organisms is difficult due to increasing resistance to non beta-lactam antimicrobials as well as beta-lactam/beta-lactamase inhibitor combinations. Carbapenems have been recommended, based on in vitro as well as clinical data. However, recent publications have reported cases of resistance of ESBL-producing organisms to the carbapenems, primarily ertapenem

Due to their expanded spectra, the desire to avoid generation of resistance and the fact that they have generally poor oral bioavailability.