Cell Wall Inhibitors

Cephalosporins
Carbapenems
Monobactams
β-Lactamase Inhibitors

Lec. 3

Assistant. Prof. Dr. Inssaf IH. Al-Shemmary

 2. Cephalosporins
They are β-lactam antibiotics that are closely related both
structurally and functionally to the penicillins. Most
cephalosporins are produced semi-synthetic. Cephalosporins
have the same mode of action as penicillins, and they are
affected by the same resistance mechanisms.

Antibacterial spectrum
Cephalosporins have been classified as first, second, third and
fourth generation, based largely on their bacterial susceptibility
and resistance to β-lactamases.
1. First generation: (cephalexin, cefazolin, cephalothin and
cefadroxil).
. These drugs are very active against gram +ve cocci,
including Staphylococci, Steptococci. They are resistant to the
staphylococcal penicillinase and also have activity against gram –ve
rods mainly Proteus E. coli, and Klebsiella pneumonia. Cefazolin
finds application as a single prophylaxis dose prior to surgery because
of its 1.8 hr half-life and its activity against penicillinase producing
Staphylococc. Cefazolin is effective for most surgical procedures
including orthopedic surgery because of its ability to penetrate bone.
2. Second generation: (cefaclor, cefoxitin, cefuroxime,
cefamandole, cefotetan). The 2nd generation cephalosporins have
greater activity against the additional gram-negative organisms: H.
influenzae, Enterobacter, whereas activity against gram positive
organisms is weaker.
3. Third generation: (cefotaxime, ceftriaxone, ceftazidime
cefoperazone, ceftizoxime, cefixime). The major features of these
drugs are their gram –ve coverage and the ability of some to cross
the blood brain barrier. Although inferior to first-generation
cephalosporins in regard to their activity against gram-positive cocci,
the third-generation cephalosporins have enhanced activity against
gram-negative bacilli.
Ceftriaxone or cefotaxime are drugs of choice in the treatment
of meningitis. Ceftriaxone has the largest half-life of any
cephalosporin (6 -8 hr), which permits once a day dosing.

4. Fourth generation: Cefepime is classified as a fourth-

generation cephalosporin and must be administered parenterally,
active against streptococci and staphylococci (but only those
that are methicillin-susceptible). Cefepime is also effective
against aerobic gram-negative organisms such as E. coli
Pharmacokinetics
1. Administration: Many of the cephalosporins must be
administered IV or IM because of their poor oral absorption.
Others such as cephalexin are administered orally.

2. Distribution: All cephalosporins distribute very well into

body fluids as CSF. All cephalosporins cross the placenta.

3. Fate: Elimination of cephalosporins occurs through tubular

secretion and/or glomerular filtration. Ceftriaxone is excreted
through the bile into the feces.
Adverse effects
1. Allergic Manifestations: The cephalosporins should be avoided or
used with caution in individuals who are allergic to penicillins
(5-15% show cross-sensitivity). In contrast, the incidence of allergic
reactions to cephalosporins is 1 – 2% in patients without a history of
allergy to penicillins.
2. disulfiran-like effect: When cefamandole, cefotetan or
cefoperazone is ingested with alcohol, a disulfiran-like effect is seen.
This occurs because they block the second step in alcohol oxidation ,
results in the accumulation of acetaldehyde. The toxicity is due to the
presence of the methyl thio tetrazol (MTT) group.
3. Bleeding: bleeding also associated with agents that contain the
MTT group because of anti-vitamin K effects.
 3. Carbapenems
Carbapenems (Imipenem, meropenem, ertapenem) are synthetic
β-lactam antibiotics. .Imipenem is compounded with cilastatin to
protect it from metabolism by renal dehydropeptidase.

Antibacterial spectrum: Imipenem/cilastatin and meropenem are

the broadest-spectrum β-lactam antibiotic. It is active against
penicillinase-producing gram-positive and gram-negative
organisms. Meropenem has antibacterial activity similar to that of
imipenem.
Pharmacokinetics: Imipenem and meropenem are
administered IV and penetrate well into body tissues and fluids,
including the CSF when the meninges are inflamed. They are
excreted by glomerular filtration.
Imipenem undergoes cleavage by a dehydropeptidase found in the
brush border of the proximal renal tubule. This enzyme forms an
inactive metabolite that is potentially nephrotoxic. Compounding
the imipenem with cilastatin protects the parent drug and, thus,
prevents the formation of the toxic metabolite. This allows the drug
to be used in the treatment of urinary tract infections.
Adverse effects: Imipenem/cilastatin can cause nausea,
vomiting, and diarrhea. Eosinophilia and neutropenia are less
common.
 4. Monobactams
Aztreonam which is the only commercially available
monobactam. Aztreonam is resistant to the action of β-
lactamases. Aztreonam is active against the enterobacteriaceae,
but it also acts against aerobic gram-negative rods,. It lacks
activity against gram-positive organisms and anaerobes.This
narrow antimicrobial spectrum. It is administered either IV or
IM and is excreted in the urine. It can accumulate in patients
with renal failure. Aztreonam is relatively nontoxic, but it may
cause phlebitis, skin rash.This drug may offer a safe alternative
for treating patients who are allergic to penicillins and/or
cephalosporins.
 5. β-Lactamase Inhibitors
β-Lactamase inhibitors such as clavulanic acid, sulbactam
and tazobactam contain a β-lactam ring but, by themselves,
do not have significant antibacterial activity. They bind to and
inactivate β-lactamases, thus protecting the antibiotics that are
normally substrates for these enzymes.

They are potent inhibitors of many but not all bacterial β-

lactamases. β-Lactamase inhibitors are most active against β-
lactamases produced by Staph., H. influenza, E. coli but they
are not good inhibitors to β-lactamases produced by
Pseudomonas.