PENICILLINS AND BETALAKTAMASE
INHIBITOR
BY
Ruhsyahadati
Classification
Penicillin G and penicillin highly active against sensitive strains of gram-positive cocci, but they are readily hydrolyzed by penicillinase.
V Thus they are ineffective against most strains of S. aureus.
The penicillinase-resistant have less potent antimicrobial activity against microorganisms that are sensitive to penicillin G, but they are
penicillins, nafcillin, the agents of first choice for treatment of penicillinase-producing S. aureus and S. epidermidis that are not
oxacillin, cloxacillin and methicillin resistant.
dicloxacillin
Aminopenicillin antimicrobial activity is extended to include such gram-negative microorganisms as Haemophilus influenzae,
(Ampicillin and E. coli, and Proteus mirabilis. Frequently these drugs are administered with a β-lactamase inhibitor such as
amoxicillin) clavulanate or sulbactam to prevent hydrolysis by class A β-lactamases.
Carbenicillin and antimicrobial activity is extended to include Pseudomonas, Enterobacter, and Proteus spp. These agents are
ureidopenicillin inferior to ampicillin against gram positive cocci and Listeria monocytogenes and are less active than
piperacillin against Pseudomonas.
Mezlocillin, azlocillin and have excellent antimicrobial activity against many isolates of Pseudomonas, Klebsiella, and certain other
piperacillin gram-negative microorganisms. However, the emergence of broad-spectrum beta-lactamases is threatening
the utility of these agents . Piperacillin retains the activity of ampicillin against gram-positive cocci and L.
monocytogenes.
Absorption
• Oral penicillin G should be administered at least 30 minutes before a
meal or 2 hours after. Gastric juice at pH 2 rapidly destroys the
antibiotic.
• Parenteral penicillin G After intramuscular injection, peak
concentrations in plasma are reached within 15-30 minutes.
• Penicillin V is more stable in an acidic medium
• Ampicillin is stable in acid and is well absorbed after oral
administration. Intake of food prior to ingestion of ampicillin
diminishes absorption.
• Isoxazolyl Penicillins are (oxacillin, dicloxacillin, and Cloxacillin) more
efficient when they are taken on an empty stomach.
• Carbenicillin and ticarcillin are not absorbed from the gastrointestinal
tract and must be administered either i.m. or i.v.
Distribution
• Penicillin G
– is distributed widely throughout the body, but the concentrations in various fluids and tissues differ
widely.
– Volume of distribution is ~0.35 L/kg
– Approximately 60% of the penicillin G in plasma is reversibly bound to albumin.
– Significant amounts appear in liver, bile, kidney, semen, joint fluid, lymph, and intestine.
– Penicillin does not readily enter the CSF when the meninges are normal.
• Isoxazolyl Penicillins are bound to plasma albumin to a great extent (~90-95%); none is
removed from the circulation to a significant degree by hemodialysis.
• Nafcillin
– ~90% bound to plasma protein.
– Peak concentrations of nafcillin in bile are well above those found in plasma.
– Concentrations of the drug in CSF appear to be adequate for therapy of staphylococcal meningitis.
• About 20% of amoxicillin is protein bound in plasma, a value similar to that for
ampicillin.
• Carbenicillin is about 50% and ticarcillin 45% bound to serum proteins
Metabolism
• Penicillin G
– metabolized to penicilloic acid.
– When renal function is impaired, 7-10% of the antibiotic may be inactivated each hour by
the liver.
• There are no active Ampicillin metabolites formed in the body before
excretion. Unexcreted AMP is inactivated chiefly in the liver.
• Amoxicillin is excreted in the urine in an unchanged active form during the first
6 hours.
• Carbenicillin and Ticarcillin
– Approximately 80% of ticarcillin can be recovered from the urine as the active drug
during the first 6 hours after administration, while carbenicillin is 95%.
– A small amount of carbenicillin is inactivated in the liver, but this is slower than with
other penicillins. Some ticarcillin is metabolized in the liver to produce antibacterially
inactive penicilloic acid.
Elimination
• Under normal conditions, penicillin G is eliminated rapidly from the
body mainly by the kidney but in small part in the bile and by other
routes.
• Approximately 60-90% of an intramuscular dose of penicillin G in
aqueous solution is eliminated in the urine, largely within the first hour
after injection.
• The t1/2 for elimination of penicillin G is ~30 minutes in normal adults.
• Approximately 10% of the drug is eliminated by glomerular filtration
and 90% by tubular secretion.
• The maximal tubular secretory capacity for penicillin in the normal
adult male is ~3 million units (1.8 g) per hour.
• Excreted rapidly by the kidney.
• Normally, ~50% of a dose of these drugs is excreted in the
urine in the first 6 hours after oral administration.
• There also is significant hepatic elimination of these
agents in the bile.
• The half-lives for all are between 30 and 60 minutes.
• The t1/2 of Ampicillin is ~80 minutes.
• Severe renal impairment markedly prolongs the
persistence of ampicillin in the plasma (hemodialysis
removes ~40% of the body store in ~7 hours).
• T1/2 of amoxicillin is similar to that for ampicillin,
but effective concentrations of orally
administered amoxicillin are detectable in the
plasma for twice as long as with ampicillin,
because of the more complete absorption.
• Most of a dose of the antibiotic is excreted in an
active form in the urine.
• Probenecid delays excretion of the drug.
• Serum levels after both i.m. and i.v.
administration of ticarcillin are similar to those of
carbenicillin, and its serum half-life (70 minutes)
is only slightly longer than that of carbenicillin (60
minutes)
• Carbenicillin and ticarcillin are excreted in urine
by glomerular filtration and tubular secretion.
Mechanism of Action
B. Schematic of Penicillin Binding Protein 2(PBP2) from S. aureus. PBP2 has two
enzymatic activities that are crucial to synthesis of the peptidoglycan layers of
bacterial cell walls: a transpeptidase that crosslinks amino acid side chains, and a
glycosyltransferase that links subunits of the glycopeptide polymer. The
transpeptidase and glycosyltransferase domains are separated by a linker region.
The glycosyltransferase is thought to be partially embedded in the membrane.
Mechanism of Resistance
• Altered PBP
– the most highly penicillin-resistant Streptococcus pneumoniae isolates have
decreased affinity for β-lactam antibiotics as a result of interspecies
homologous recombination events
• Enzymatic degradation
– β-Lactamases are capable of inactivating certain of these antibiotics
• Inability of the agent to penetrate to its site of action
– In gram-negative bacteria, the surface structure is more complex, and their
inner membrane, which is analogous to the cytoplasmic membrane of gram-
positive bacteria, is covered by the outer membrane, lipopolysaccharide, and
capsule. The outer membrane functions as an impenetrable barrier for some
antibiotics.
• Active efflux pumps serve as another mechanism of resistance,
removing the antibiotic from its site of action before it can act
Introduction
• Certain molecules can inactivate β-lactamases, thereby
preventing the destruction of β-lactam antibiotics that
are substrates for these enzymes.
• β-Lactamase inhibitors are most active against plasmid-
encoded β-lactamases (including the enzymes that
hydrolyze ceftazidime and cefotaxime), but they are
inactive at clinically achievable concentrations against the
type I chromosomal β-lactamases induced in gram-
negative bacilli (such as Enterobacter, Acinetobacter, and
Citrobacter) by treatment with second- and
thirdgeneration cephalosporins.
Clavulanic Acid
• Clavulanic acid is produced by Streptomyces clavuligerus
• has poor intrinsic antimicrobial activity, but it is a “suicide” inhibitor
that irreversibly binds β-lactamases produced by a wide range of gram-
positive and gram-negative microorganisms.
• Clavulanic acid is well absorbed by mouth and also can be given
parenterally.
• Combined with amoxicillin and ticarcillin
– Amoxicillin plus clavulanate is effective in vitro and in vivo for β-lactamase-
producing strains of staphylococci, H. influenzae, gonococci, and E. coli.
– Ticarcillin plus clavulanate is effective for aerobic gram-negative bacilli, S.
aureus, and Bacteroides spp.
• should be adjusted for patients with renal insufficiency.
Sulbactam
• Another β-lactamase inhibitor similar in structure to
clavulanic acid.
• must be adjusted for patients with impaired renal
function
• It is available for intravenous or intramuscular use
combined with ampicillin
• has good activity against gram-positive cocci, including β-
lactamase-producing strains of S. aureus, gram-negative
aerobes (but not resistant strains of E. coli or
Pseudomonas), and anaerobes
Tazobactam
• Tazobactam is a penicillanic acid sulfone β-
lactamase inhibitor.
• In comparison with the other available inhibitors,
it has poor activity against the inducible
chromosomal β-lactamases of Enterobacteriaceae
but has good activity against many of the plasmid
β-lactamases, including some of the extended-
spectrum class.
