carbapenam and monobactam - Home
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Carbapenems
Carbapenems are:
- β-lactams that contain a fused β-lactam ring and a
5-membered ring system that differs from the penicillins
in being unsaturated (double bond between C-2 and C-3)
and containing a carbon atom instead of the sulfar atom.
OH H
H
H
S
HC
H3C
R
N
N
COOH
Carbapenem
H
S
R
O
H
N
O
CH3
CH3
COOH
Penicillin
Thienamycin
Thienamycin isolated from fermentation of cultures of
Streptomyces cattleya.
OH H
H
S
H3C
NH3+
O
N
Thienamycin
O-
O
An unfortunate property of thienamycin is its chemical
instability (unstable) in solution.
Another shortcoming is its susceptibility to hydrolytic
inactivation by renal dehydropeptidase-I (DHP-I).
Imipenem
Imipenem is N-formimidoylthienamycin, the most stable
derivatives of thienamycin.
HN
OH
H
H
NH
S
H3C
N
O
O
Imipenem
OH
Mechanism of action
Imipenem like other β-lactam antibiotics binds to penicillinbinding proteins, disrupts bacterial cell wall synthesis and
cause death of susceptible micro-organisms.
Structure activity relationship
OH H
H
4
H3C
1
O
S
3
NH3+
2
N
Thienamycin
O-
O
HN
OH
H3C
H
H
4
1
N
O
3
NH
S
2
O
Imipenem
OH
Uses:
- Aerobic Gm +ve organisms such as S. aureus, Enterococci
and Streptococci
- Aerobic Gm –ve bacteria such as E. coli, Klebsiella and
Enterobacter spp. and P. aeruginosa.
- Anaerobes such as B. fragilis and Clostridium.
Poor distribution in CSF (not used in meningitis)
Pharmacokinetics
Adverse reactions
Investigational carbapenems
The extended spectrum of antibacterial activity associated with
the carbapenems together with their resistance to inactivation
by most β-lactamase make this class of β-lactamas an attractive
target for drug development.
In the design new carbapenems, structural variations are being
investigated with the objective of developing analogues with
advantages over imipenem.
Improvements that are particularly desired include:
- Stability to hydrolysis catalysed by DHP-I.
- Increased potency against Ps. aeruginosa.
- Enhanced pharmacokinetic properties, such as oral
bioavailability and a longer duration of action.
Modification by:
- Incorporation of a β-methyl group at the 4-position confers
stability of the carbapenems to hydrolysis by renal DHP-I.
- Substituents at the 3-position appear to affect primarily the
spectrum of antibacterial activity of the carbapenems by
influencing their penetration into bacteria.
Meropenem
OH
H
H 4
H3C
O
CH3
3
S
O
2
N1
HO
Meropenem
O
N
H
N
CH3
H3C
Meropenem is a second generation carbapenem.
Meropenem is not hydrolyzed by DHP-I and is resistant to most
β-lactamases, including a few carbapenemases that hydrolyze
carbapenem.
The lower incidence of nephrotoxicity of meropenem (compared
with imipenem) has been correlated with its greater stability to
DHP-I.
Biapenem
OH H
H
CH3
+
N
S
H3C
N
N
N
O
-O
O
Biapenem
Biapenem is a second generation carbapenem with chemical
and microbiological properties similar to those of meropenem.
Biapenem is stable to DHP-I and is resistant to most
β-lactamases.
Monobactam
Monobactams have a monocyclic β-lactam ring
and are resistant to β-lactamases.
R
O
H
C
N
H
H
CH3
N
O
Monobactam
SO3H
Aztreonam
S
H2N
N
C
O
H
C
N
N
N
Aztreonam
CH3
CH3
O
O
C
COOH
SO3H
CH3
Aztreonam was isolated from Chromobacterium violaceum .
Aztreonam is the first clinically useful monobactam.
The antimicrobial activity of Aztreonam differs from those of
other β-lactam antibiotics and more closely resembles that of
an aminoglycosides in activity without the nephrotoxicity of
aminoglycosides.
Mechanism of action
Uses:
Aztreonam is unique among the β-lactam antibiotics b/c it is
active only against Gm–ve aerobes and inactive against
Gm +ve and anaerobes.
The combination of Aztreonam and piperacillin is synergistic
against some strains of P. aeruginosa and Enterobacter spp.
Pharmacokinetics:
1- Absorption
2- Excretion
3- Penetration/distribution
Toxicity
It is a safe agent with side effect similar to those of other
β-lactams.
Adverse effects
Tigemonam
S
H2N
O
N
C
C
H
N
Aztreonam
CH3
H2N
N
N
O
C
O
COOH
S
CH3
N
SO3H
C
O
H
C
N
CH3
CH3
N
N
Tigemonam
CH3
O
O
SO3H
CH2COOH
It is an investigational monobactam that is orally active.
It is highly resistant to β-lactamases.
The antibacterial spectrum of activity of tigemonam resembles
that of aztreonam.
It is very active against the Enterobacteriaceae, including:
E. coli, Klebsiella, Proteus, Enterobacter species.