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Detabase » Lactabase » Beta Lactamase » Beta Lactam Antibiotics » Carbaphenems
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Carbaphenems
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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.
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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:
Imipenem (often given as part of Imipenem/cilastatin)
Imipenem can be hydrolysed in the mammalian kidney by a dehydropeptidase enzyme,
and so is given with a dehydropeptidase inhibitor, cilastatin.
Meropenem
Ertapenem
Doripenem
Panipenem/betamipron
Biapenem
PZ-601
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.
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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.
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Table 1. Properties of the carbapenems.
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Carbapenem
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Indications
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Elimination half-life
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Percent protein binding
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Dosing interval
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Penicillin binding protein affinity
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Imipenem (with cilastatin)
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- 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.
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1 h
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20%
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3 to 4 times daily
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PBP2 > PBP1a/b > PBP3 (weak)
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Meropenem
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- Skin and skin structure
- Intraabdominal
- Bacterial meningitis
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1 h
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2%
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3 to 4 times daily
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PBP2 > PBP3 > PBP 1/a/b (strong)
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Ertapenem
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- Complicated intra-abdominal
- Complicated skin and skin structure infections
- Community acquired pneumonia
- Complicated urinary tract infections
- Acute pelvic infections
- Prophylaxis for elective colorectal surgery
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3.8 h
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92-95%
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Once daily
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PBP2 > PBP3 > PBP 1/a/b (strong)
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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. |
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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.
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