This document discusses beta-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam, which inhibit beta-lactamase enzymes produced by bacteria and restore the effectiveness of beta-lactam antibiotics. Clavulanic acid inhibits a wide range of beta-lactamases. Sulbactam and tazobactam are similar to clavulanic acid but less potent. These inhibitors are often combined with antibiotics like amoxicillin and piperacillin to treat infections caused by beta-lactamase producing bacteria. Carbapenems and monobactams were also developed to be resistant to beta-l

1. Chapter Content
-History & Classification
-SAR & Synthesis
-Use & Adverse Effects
According to PCI Syllabus
Especially For
OU,JNTU,UPTU Students

2. β-lactamase Inhibitors
β-lactamases are a family of enzymes produced by many
gram-positive and gram-negative bacteria that inactivate
β-lactam antibiotics by opening the β-lactam ring.
Different β-lactamases differ in their substrate affinities.
Three inhibitors of this enzyme:
Clavulanic Acid Acid
Sulbactam
Tazobactam

3. Beta Lactam Ring
Beta Lactam Ring Ring Open
Loss of Activity

4. Clavulanic Acid
-Obtained from Streptomyces clavuligerus, it has a β-lactam ring but
no antibacterial activity of its own.
-It inhibits a wide variety (class II to class V) of β-lactamases (but not
class I cephalosporinase) produced by both gram-positive and gram-
negative bacteria.
-Clavulanic acid is a ‘progressive’ inhibitor :binding with β-lactamase
is reversible initially, but becomes covalent later—inhibition
increasing with time.
-Called a ‘suicide’ inhibitor, it gets inactivated after binding to the
enzyme.
-It permeates the outer layers of the cell wall of gram negative
bacteria and inhibits the periplasmically located β-lactamase.

5. Addition of clavulanic acid re-establishes the activity of amoxicillin
against β-lactamase producing resistant Staph. Aureus , H.
influenzae, N. gonorrhoeae, E. coli, Proteus, Klebsiella, Salmonella
and Shigella. Bact. fragilis are not responsive to amoxicillin alone,
but are inhibited by the combination.
Amoxicillin sensitive strains are not affected by the addition of
clavulanic acid.

6. Coamoxiclav is indicated for:
Skin and soft tissue infections, intra-abdominal and
gynecological sepsis, urinary, biliary and respiratory tract
infections: especially when empiric antibiotic.
therapy is to be given for hospital acquired infections.
Gonorrhea (including PPNG) single dose amoxicillin 3 g +
clavulanic acid 0.5 g +probenecid 1 g is highly curative.
Adverse effects of Clavulanic acid :
• They are the same as for amoxicillin alone; g.i. tolerance is
poorer—especially in children.
• Candida stomatitis/ vaginitis
• Rashes
• Hepatic injury in some case with the combination.

7. Sulbactam
It is a semisynthetic β-lactamase inhibitor, related chemically
as well as in activity to clavulanic acid.
It is also a progressive inhibitor, highly active against class
II to V but poorly active against class I β-lactamase.
On weight basis, it is 2–3 times less potent than clavulanic acid
for most types of the enzyme, but the same level of inhibition
can be obtained at the higher concentrations achieved clinically.
Oral absorption of sulbactam is inconsistent. Therefore, it is
preferably given parenterally.

8. It has been combined with ampicillin for use against β-
lactamase producing resistant strains.
Absorption of its complex salt with ampicillin—sultamicillin
tosylate is better, which is given orally.
Main Adverse Effects :
Pain At Site Of Injection
Thrombophlebitis Of Injected Vein
Rash
Diarrhoea

9. Tazobactam similar to sulbactam.
Its pharmacokinetics matches with piperacillin with which it has been
combined for use in severe infections like peritonitis,
pelvic/urinary/respiratory infections caused by β-lactamase
producing bacilli.
However, the combination is not active against piperacillin-resistant
Pseudomonas, because tazobactam (like clavulanic acid and
sulbactam) does not inhibit inducible chromosomal β-lactamase
produced by Enterobacteriaceae.
It is also of no help against Pseudomonas that develop resistance by
losing permeability to piperacillin.
Dose: 0.5 combined with piperacillin 4 g injected i.v. over 30 min 8

10. Other β-Lactam antibiotics
Carbapenems and monobactams were developed to deal with β-lactamase-
producing Gram-negative organisms resistant to penicillin’s.
Carbapenems Monobactams
Imipenem Aztreonam

11. Carbapenems
Imipenem :
• Acts in the same way as the other β-lactams.
• It has a very broad spectrum of antimicrobial activity, being
active against many aerobic and anaerobic Gram-positive
and Gram-negative organisms.
• However, many of the ‘methicillin-resistant’ staphylococci are
less susceptible, and resistant strains of P.aeruginosa have
emerged during therapy.
• Resistance to imipenem was low, but is increasing as some
organisms now have chromosomal genes that code for
imipenem-hydrolysing β-lactamases.
• It is sometimes given together with cilastatin, which inhibits its
inactivation by renal enzymes.

12. -Meropenem is similar but is not metabolized by the
kidney.
-Ertapenem has a broad spectrum of antibacterial
actions but is licensed only for a limited range of
indications.
Most carbapenems are not orally active, and are used
only in special situations.
Unwanted effects :
Similar to other β-lactams
Nausea and vomiting being the most frequently
seen.

13. The main monobactam is aztreonam, which is resistant
to most β-lactamases.
It is given by injection .
Plasma half-life 2 h.
Aztreonam has an unusual spectrum of activity and is
effective only against Gram-negative aerobic bacilli
such as pseudomonas species, Neisseria meningitidis and
Haemophilus influenzae.
It has no action against Gram-positive organisms or
anaerobes.

14. Adverse effects :
Similar to those of other β-lactam antibiotics
but this agent does not necessarily cross-react
immunologically with penicillin and its products,
and so does not usually cause allergic
reactions in penicillin sensitive individuals.