antimicrobial agents , Thienamycin, Imipenem , Meropenem, Doripenem, Ertapenem,adverse effects, absolute stereochemistry of carbapenems,

1. Carbapenems
Dr. Shilpa Sudhakar Harak
Asst. Prof., Pharm. Chem.,
GES Sir Dr. M. S. Gosavi College of Pharmaceutical Education
and Research, Nashik

2. Carbapenems
Structural modifications
 The sulfur atom is not part of the 5-membered ring but, rather, has been replaced by a
methylene moiety at that position.
 Carbon is roughly half the molecular size of sulfur.
 Consequently, the carbapenem ring system is highly strained and very susceptible to
reactions cleaving the β-lactam bond.
 The sulfur atom is now attached to C-3 as par t of a functionalized side chain
 At C-6, there is a 2-hydroxyethyl group attached with α-stereochemistry.
 Thus, the absolute stereochemistry of the molecule is 5R,6S,8S.
 The endocyclic olefinic linkage also enhances the reactivity of the β-lactam ring.
Effects on Activity
 Has extremely intense and broad-spectrum antimicrobial activity as well as
 Inactivates β-lactamases
 Hence molecule has the functional features of the best of the β-lactam antibiotics as
well as the β-lactamase inhibitors.
 Consequently, the carbapenem ring system is highly strained and very susceptible to
reactions cleaving the β-lactam bond.

3. Thienamycin
 first of the carbapenems,
 Isolated from Streptomyces cattleya.
 The terminal amino group in the side chain attached to C-3 is
nucleophilic and attacks the β-lactam bond of a nearby molecule
through an intermolecular react ion destroying activity
 Ultimately, this problem was overcome by changing the amino group
to a less nucleophilic N-formiminoyl moiety by a semisynthetic
process to produce imipenem.
 With these striking differences from the penicillins and
cephalosporins, it is not surprising that thienamycin analogues bind
differently to the penicillin biding proteins (especially strongly to PBP-
2), but i t is gratifying that the result is very potent broad-spectrum
activity.

4. Imipenem
 Penetrates very well through porins and is very stable,
 Imipenem is very stable to most –lactamases however Inhibitory to many
β-lactamases.
 Imipenem is not orally active.
 Renal dehydropeptidase-l hydrolyzes imipenem through hydrolysis of the
β-lactam & deactivates.
 An inhibitor for this enzyme, cilastatin, is coadministered with imipenem
to protect it.
 Inhibition of human dehydropeptidase does not have deleterious
consequences hence combination is highly efficacious. On injection, it
penetrates well into most tissues, but not cerebrospinal fluid, and it is
subsequently excreted in the urine. This very potent combination is
especially useful for treatment of serious infections by aerobic gram-
negative bacilli, anaerobes, and Staphylococcus aureus.
 It is used clinically for a number of significant infections.

5. Imipenem
 The more common adverse effects are irritation at the infusion site, nausea,
vomiting, diarrhea, and pruritus.
 Of greater concern is the ability of imipenem to induce seizures.
 The risk factors for seizure development include impaired renal function,
preexisting CNS disease or infection, and use of large doses.
 Imipenem is indicated for the treatment of a wide variety of bacterial infections of
the skin and tissues, lower respiratory tract, bones and joints, and genitourinary
tract, as well as of septicemia and endocarditis caused by -lactamase–producing
strains of susceptible bacteria.

6. Meropenem
 II generation, orally inactive - most extensive clinical evaluation.
 Approved as Merrem for treatment of multiply-resistant bacteria and for empirical
therapy for serious infections, such as bacterial meningitis, septicemia, pneumonia,
and peritonitis.
 It exhibits greater potency against Gram-negative and anaerobic bacteria than
does imipenem, but it is slightly less active against most Gram-positive species.
 It is not effective against MRSA.
 Meropenem is not hydrolyzed by DHP-I and is resistant to most -lactamases,
including a few carbapenemases that hydrolyze carbapenem.
 Mewtabolism : Approx unchanged 70% to 80% - excreted in the urine (IV/IM).
 The remainder is the inactive metabolite formed by hydrolytic cleavage of the beta–
lactam ring.
 The lower incidence of nephrotoxicity of meropenem (compared with imipenem)
has been correlated with its greater stability to DHP-I and the absence of the DHP-I
inhibitor cilastatin in the preparation.
 Meropenem appears to be less epileptogenic than imipenem when the two agents
 are used in the treatment of bacterial meningitis.

7. Doripenem
 Doripenem is the newest of the approved
carbapenems.
 It also contains the 4-β-methyl group, which confers
stability toward dehydropeptidase-1, so it is given as
a single agent.
 It is similar in spectrum to imipenem and meropenem
but is considered more potent against Pseudomonas
species (63).

8. Ertapenem
 Ertapenem is another synthetic carbapenem with a rather
complex side chain at C-3.
 As with meropenem and doripenem, the 4-β-methyl
group confers stability toward dehydropeptidase-1.
 It is not active against Pseudomonas or Acinetobacter
and thus should not be substituted for other
carbapenems for these organisms (63).
 This class of antimicrobial agents is under intensive
investigation, and several analogs are currently in various
phases of preclinical investigation, including tebipenem,
an oral prodrug carbapenem (64).