1.

Define the terms:-

I. Antibiotic
II. Bacteriostatic
III. Bactericidal

2. List 5 targets for antimicrobial agents

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Beta-Lactam Antibiotics & Other
Inhibitors of Cell Wall
Synthesis
Tony Liwa, MD
Department of Clinical Pharmacology
May 2023
Penicillins
Penicillins are classified as β-lactam drugs
because of their unique four-membered lactam
ring.
They share features of chemistry, mechanism of
action, pharmacologic and clinical effects, and
immunologic characteristics with cephalosporins,
monobactams, carbapenems, and β-lactamase
inhibitors, which also are β-lactam compounds.
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Chemistry
 All Penicillins have the basic structure.
 A thiazolidine ring (A) is attached to a β-lactam ring (B)
that carries a secondary amino group (RNH–)
 Structural integrity of the 6-aminopenicillanic acid
nucleus is essential for the biologic activity of these
compounds.
 If the β-lactam ring is enzymatically cleaved by
bacterial β-lactamases, the resulting product,
penicilloic acid, lacks antibacterial activity. 6
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Classification
 Penicillin can be assigned to one of three groups.
 Within each of these groups are compounds that are
relatively stable to gastric acid and suitable for oral
administration, e.g, penicillin V, dicloxacillin, and
amoxicillin.

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Penicillin G
These have the greatest activity against gram-
positive organisms, gram-negative cocci, and
non- β-lactamase-producing anaerobes.
However, they have little activity against gram-
negative rods.
They are acid labile and susceptible to hydrolysis
by lactamases.
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Antistaphylococcal Penicillins (nafcillin)
These penicillins are resistant to staphylococcal
lactamases.
They are active against staphylococci and
streptococci but inactive against enterococci,
anaerobic bacteria, and gram-negative cocci and
rods.

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Extended-Spectrum Penicillins- Ampicillin
These drugs retain the antibacterial spectrum of
penicillin and have improved activity against gram
negative organisms,
but they are destroyed by lactamases.

Amoxicillin: Similar to Ampicillin but better

absorbed.
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Oxacillins
Cloxacillin, Flucloxacillin
Beta lactamases resistant
Can be taken orally
Highly protein bound

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Penicillin Units
 The activity of penicillin G was originally defined in
units.
 Crystalline sodium penicillin G contains approximately
1600 units/mg (1 unit = 0.6 μg; 1 million units of
penicillin = 0.6 g).
 Semisynthetic penicillins are prescribed by weight
rather than units.
 The MIC of any penicillin (or other antimicrobial) is
usually given in g/mL. 14
Mechanism of Action
 Like all β-lactam antibiotics, inhibit bacterial growth by
interfering with a specific step in bacterial cell wall
synthesis.
 The cell wall is a rigid outer layer that is not found in
animal cells.
 It completely surrounds the cytoplasmic membrane,
maintaining the shape of the cell and preventing cell
lysis from high osmotic pressure.
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Cell wall
 The cell wall is composed of a complex cross-linked
polymer, peptidoglycan (murein, mucopeptide),
consisting of polysaccharides and polypeptides.
 The polysaccharide contains alternating amino sugars,
N-acetylglucosamine and Nacetylmuramic acid.
 A five-amino-acid peptide is linked to the N-
acetylmuramic acid sugar. This peptide terminates in D-
alanyl-D-alanine.
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Mechanism of Action
 Penicillin-binding proteins (PBPs) catalyze the transpeptidase
reaction that removes the terminal alanine to form a crosslink
with a nearby peptide, which gives cell wall its structural
rigidity.
 β-Lactam antibiotics are structural analogs of the natural D-
Ala-D-Ala substrate and they are covalently bound by PBPs
at the active site.
 After a β-lactam antibiotic has attached to the PBP, the
transpeptidation reaction is inhibited peptidoglycan synthesis
is blocked, and the cell dies.
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Penicillins and cephalosporins are bactericidal
only if cells are actively growing and synthesizing
cell wall.

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Clinical uses
 Bacterial meningitis (strept pneumoniae) - Benzyl
penicillin IV.
 Bone and joint infections (Staphs aureus) -
Flucloxacillin
 Skin and soft tissues (Staphs pyogenes or aureus) -
Benzyl, flucloxacillin.
 Pharyngitis (S.pyogenes) - Phenoxymethlpenicillin
 Otitis media - amoxycillin)
 Pneumonia - amoxycillin)
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Unwanted effects
Relatively free from direct toxic effects
Hypersensitivity reaction (skin rashes and fever,
anaphylactic shock)
Broad spectrum - alter the bacterial flora- git
disturbances and super-infections.

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Cephalosporins
 Cephalosporins and cephamycins are similar to
penicillin chemically, in mechanism of action, and in
toxicity.
 Are more stable than penicillin to many bacterial β-
lactamases and therefore usually have a broader
spectrum of activity.
 Are not active against enterococci and Listeria
monocytogenes.
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Chemistry
 They are soluble in water and relatively stable to pH
and temperature changes.
 Cephalosporins can be classified into four major groups
or generations, depending mainly on the spectrum of
antimicrobial activity.
 First-generation compounds have better activity against
gram ve+ organisms and the later compounds exhibit
improved activity against gram -ve aerobic organisms.
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Narrow Spectrum (First-Generation)
Cephalosporins
Cefadroxil
Cefazolin
Cephalexin
Cephalothin
Cephapirin
Cephradine
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Intermediate Spectrum (Second-Generation)
Cephalosporins
 Cefaclor
 Cefamandole
 Cefmetazole
 Cefonicid
 Cefotetan
 Cefoxitin
 Cefuroxime
 Loracarbef 26
Broad-Spectrum (Third- & Fourth-Generation)
Cephalosporins
 Cefdinir
 Cefditoren
 Cefepime
 Cefixime
 Cefoperazone
 Cefotaxime
 Cefpodoxime proxetil
 Ceftibuten (Cedax)
 Ceftizoxime (Cefizox)
 Ceftriaxone (Rocephin)
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Clinical uses
Septicemia
Pneumonia
Meningitis
Biliary tract infections
UTI
Sinusitis

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Unwanted effects
Hypersensitivity reactions similar to that occur in
Penicillins.
Some cross-reaction occurs in about10%.
Nephrotoxicity have been reported.
Diarrhoea.
Alcohol intolerance and
Bleeding (Vit K antagonism).
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Monobactams
These are drugs with a monocyclic -lactam ring.
 They are relatively resistant to lactamases and
active against gram-negative rods (including
pseudomonas and serratia).
They have no activity against gram-positive
bacteria or anaerobes.

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Aztreonam
The half-life is 1-2 hrs and is greatly prolonged in
renal failure.
Penicillin-allergic patients tolerate aztreonam
without reaction.
Occasional skin rashes and elevations of serum
aminotransferases occur during administration of
aztreonam, major toxicity has not yet been
reported. 31
Beta-Lactamase Inhibitors (Clavulanic
Acid, Sulbactam & Tazobactam)
These substances resemble β-lactam molecules
but themselves have very weak antibacterial
action.
They are potent inhibitors of many but not all
bacterial lactamases and can protect hydrolyzable
penicillins from inactivation by these enzymes.
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Structures of β-lactamase inhibitors

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Beta lactamase inhibitors
β-Lactamase inhibitors are most active against
Ambler class A β-lactamases such as those
produced by staphylococci, H influenzae, N
gonorrhoeae, salmonella, shigella, E coli

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Beta lactamase inhibitors
They are not good inhibitors of class C β-
lactamases, which typically are chromosomally
encoded and inducible, produced by
enterobacter, citrobacter, serratia, and
pseudomonas, but they do inhibit chromosomal
lactamases of legionella, bacteroides, and
branhamella.

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Beta lactamase inhibitors
 The three inhibitors differ slightly with respect to
pharmacology, stability, potency, and activity, but these
differences are of little therapeutic significance.
 Are available only in fixed combinations with specific
penicillins.
 The antibacterial spectrum of the combination is
determined by the companion penicillin, not the β-
lactamase inhibitor.
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Beta lactamase inhibitors
 An inhibitor will extend the spectrum of a penicillin
provided that the inactivity of the penicillin is due to
destruction by β-lactamase and that the inhibitor is
active against the lactamase that is produced.
 Thus, ampicillin-sulbactam is active against β-
lactamase-producing S aureus and H influenzae but
not serratia, which produces a lactamase that is not
inhibited by sulbactam.
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Beta lactamase inhibitors
The indications for penicillin-β-lactamase inhibitor
combinations are empirical therapy for infections
caused by a wide range of potential pathogens in
both immunocompromised and immunocompetent
patients and treatment of mixed aerobic and
anaerobic infections, such as intra-abdominal
infections.

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Beta lactamase inhibitors
Doses are the same as those used for the single
agents.
Adjustments for renal insufficiency are made
based on the penicillin component.

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Carbapenems
The carbapenems are structurally related to β-
lactam antibiotics.
Ertapenem, imipenem, and meropenem are
licensed for use.
Imipenem has a wide spectrum with good activity
against many gram-negative rods, including
Pseudomonas aeruginosa, gram-positive
organisms, and anaerobes.
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Imipenem
Imipenem is inactivated by dehydropeptidases in
renal tubules, resulting in low urinary
concentrations.
Consequently, it is administered together with an
inhibitor of renal dehydropeptidase, cilastatin, for
clinical use.

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Carbapenems
 Meropenem is similar to imipenem but has slightly
greater activity against gram-negative aerobes and
slightly less activity against gram-positives.
 It is not significantly degraded by renal
dehydropeptidase and does not require an inhibitor.
 Ertapenem is less active than meropenem or imipenem
against Pseudomonas aeruginosa and acinetobacter
species.
 It is not degraded by renal dehydropeptidase. 42
Carbapenems
Carbapenems penetrate body tissues and fluids
well, including the cerebrospinal fluid.
All are cleared renally, and the dose must be
reduced in patients with renal insufficiency.

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Carbapenems
Ertapenem has the longest half-life (4 hours) and
is administered as a once-daily dose of 1g i.v or
i.m.
I.M ertapenem is irritating, and for that reason the
drug is formulated with 1% lidocaine for
administration by this route.

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Indications
 A carbapenem is indicated for infections caused by
susceptible organisms that are resistant to other
available drugs and for Rx of mixed aerobic and
anaerobic infections.
 Carbapenems are active against many highly penicillin-
resistant strains of pneumococci.
 A carbapenem is antibiotic of choice for Rx of
enterobacter infections, since it is resistant to destruction
by the lactamases produced by these organisms. 45
Indications
Strains of P. aeruginosa may rapidly develop
resistance to imipenem or meropenem, so
simultaneous use of an aminoglycoside is
recommended for infections caused by those
organisms.
Ertapenem is insufficiently active against P.
aeruginosa and should not be used to treat
infections caused by that organism.
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Adverse effects
 The most common adverse effects of carbapenems-which tend
to be more common with imipenem - are nausea, vomiting,
diarrhea, skin rashes, and reactions at the infusion sites.
 Excessive levels of imipenem in patients with renal failure may
lead to seizures.
 Meropenem and ertapenem are less likely to cause seizures
than imipenem.
 Patients allergic to penicillins may be allergic to carbapenems
as well.
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Vancomycin
 Vancomycin is an antibiotic produced by Streptococcus
orientalis.
 With the single exception of flavobacterium, it is active
only against gram-positive bacteria, particularly
staphylococci.
 Vancomycin is a glycopeptide of molecular weight
1500.
 It is water-soluble and quite stable.
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Mechanisms of Action
 Vancomycin inhibits cell wall synthesis by binding firmly
to the D-Ala-D-Ala terminus of peptidoglycan
pentapeptide.
 This inhibits the transglycosylase, preventing further
elongation of peptidoglycan and cross-linking.
 The peptidoglycan is thus weakened and the cell
becomes susceptible to lysis.
 The cell membrane is also damaged, which contributes
to the antibacterial effect. 49
Basis of Resistance
Resistance to vancomycin in enterococci is due to
modification of the D-Ala-D-Ala binding site of the
peptidoglycan building block in which the terminal
D-Ala is replaced by D-lactate.
This results in the loss of a critical hydrogen bond
that facilitates high-affinity binding of vancomycin
to its target and loss of activity.

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Antibacterial activity
 Vancomycin is bactericidal for gram-positive bacteria in
concentrations of 0.5-10 μg/mL.
 Most pathogenic staphylococci, including those
producing lactamase and those resistant to nafcillin and
methicillin, are killed by 4 μg/mL or less.
 Vancomycin kills staphylococci relatively slowly and
only if cells are actively dividing; the rate is less than
that of the penicillins both in vitro and in vivo.
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Vancomycin is synergistic with gentamicin and
streptomycin against E faecium and E faecalis
strains that do not exhibit high levels of
aminoglycoside resistance.

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Pharmacokinetics
Vancomycin is poorly absorbed from the
intestinal tract and is administered orally only for
the treatment of antibiotic-associated
enterocolitis caused by Clostridium difficile.
Parenteral doses must be administered
intravenously.

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Pharmacokinetics
The drug is widely distributed in the body.
CSF levels 7–30% of simultaneous serum
concentrations are achieved if there is meningeal
inflammation.
90% of the drug is excreted by glomerular
filtration.
In the presence of renal insufficiency, striking
accumulation may occur. 54
Clinical uses
 Parenteral vancomycin: sepsis or endocarditis caused
by methicillin resistant staphylococci.
 However, vancomycin is not as effective as an
antistaphylococcal penicillin for Rx of serious infections
such as endocarditis caused by methicillin-susceptible
strains.
 Vancomycin in combination with gentamicin is an
alternative regimen for treatment of enterococcal
endocarditis in a patient with serious penicillin allergy.
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Clinical uses
Vancomycin (in combination with cefotaxime,
ceftriaxone, or rifampin) is also recommended for
treatment of meningitis suspected or known to be
caused by a highly penicillin-resistant strain of
pneumococcus (i.e, MIC > 1 μg/mL).

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Clinical uses
 Oral vancomycin, is used to treat antibiotic-associated
enterocolitis caused by Clostridium difficile.
 However, because of the emergence of vancomycin-
resistant enterococci and the strong selective pressure
of oral vancomycin for these resistant organisms,
metronidazole is strongly preferred as initial therapy
and vancomycin should be reserved for treatment of
refractory cases.
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Adverse reactions
 Are encountered in about 10% of cases.
 Vancomycin is irritating to tissue, resulting in phlebitis at the site
of injection.
 Chills and fever may occur.
 Ototoxicity is rare and nephrotoxicity uncommon with current
preparations.
 However, administration with another ototoxic or nephrotoxic
drug, such as an aminoglycosides, increases the risk of these
toxicities.
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Adverse effects
 Ototoxicity can be minimized by maintaining peak
serum concentrations below 60 μg/mL.
 Among the more common reactions is the so-called
"red man" or "red neck“ syndrome.
 This infusion-related flushing is caused by release of
histamine.
 It can be largely prevented by prolonging the infusion
period to 1-2 hrs or increasing the dosing interval.
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Teicoplanin
 Teicoplanin is a glycopeptide antibiotic that is very
similar to vancomycin in mechanism of action and
antibacterial spectrum.
 Unlike vancomycin, it can be given intramuscularly as
well as intravenously.
 Teicoplanin has a long half-life (45–70 hours),
permitting once-daily dosing.

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Fosfomycin
 Fosfomycin trometamol, a stable salt of fosfomycin
(phosphonomycin), inhibits a very early stage of
bacterial cell wall synthesis.
 An analog of phosphoenolpyruvate, it is structurally
unrelated to any other antimicrobial agent.
 It inhibits the cytoplasmic enzyme enolpyruvate
transferase by covalently binding to the cysteine
residue of the active site and blocking the addition of
phosphoenolpyruvate to UDP-N-acetylglucosamine.
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Fosfomycin
This reaction is the first step in the formation of
UDP-N-acetylmuramic acid, the precursor of N-
acetylmuramic acid, which is found only in
bacterial cell walls.

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Fosfomycin
 Fosfomycin is active against both gram-positive and gram-
negative organisms.
 In vitro synergism occurs when fosfomycin is combined with β-
lactam antibiotics, aminoglycosides, or fluoroquinolones.
 Fosfomycin trometamol is available in both oral and parenteral
formulations.
 The active drug is excreted by the kidney, with urinary
concentrations exceeding MICs for most urinary tract
pathogens.
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Clinical use
Fosfomycin is approved for use as a single 3g
dose for treatment of uncomplicated lower urinary
tract infections.
The drug appears to be safe for use in
pregnancy.

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Bacitracin
It is active against gram-positive microorganisms.
Bacitracin inhibits cell wall formation by interfering
with dephosphorylation in cycling of the lipid
carrier that transfers peptidoglycan subunits to the
growing cell wall.
There is no cross-resistance between bacitracin
and other antimicrobial drugs.
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Bacitracin
 Is markedly nephrotoxic if administered systemically.
 Hypersensitivity reactions (e.g., skin rashes) are rare.
Because of its marked toxicity when used systemically, it is
limited to topical use.
 Bacitracin is poorly absorbed.
 Topical application results in local antibacterial activity without
significant systemic toxicity.
 The small amounts of bacitracin that are absorbed are
excreted by glomerular filtration.
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Bacitracin
 Bacitracin, 500 units/g in an ointment base (often
combined with polymyxin or neomycin), is useful for
the suppression of mixed bacterial flora in surface
lesions of the skin, in wounds, or on mucous
membranes.
 Solutions of bacitracin containing 100–200 units/mL in
saline can be employed for irrigation of joints, wounds,
or the pleural cavity.

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Cycloserine
Cycloserine is an antibiotic produced by
Streptomyces orchidaceus.
It is water-soluble and very unstable at acid pH.
Cycloserine inhibits many gram-positive and
gram-negative organisms, but it is used almost
exclusively to treat tuberculosis caused by strains
of M tuberculosis resistant to first line agents.
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Cycloserine
Cycloserine is a structural analog of D-alanine
and inhibits the incorporation of D-alanine into
peptidoglycan pentapeptide by inhibiting alanine
racemase, which converts L-alanine to D-alanine,
and D-alanyl-D-alanine ligase.

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Cycloserine
After ingestion of 0.25 g of cycloserine blood
levels reach 20-30 g/mL-sufficient to inhibit many
strains of mycobacteria and gram -ve bacteria.
The drug is widely distributed in tissues.
Most of the drug is excreted in active form into
the urine.

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Adverse effects
Cycloserine causes serious dose-related central
nervous system toxicity with headaches, tremors,
acute psychosis, and convulsions.
If oral dosages are maintained below 0.75 g/d,
such effects can usually be avoided.

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