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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.