CHAPTER 43: Beta – Lactam & Other Cell Wall- & Membrane-Active Antibiotics
Beta Lactam Compounds
Penicillins
- share features of chemistry, MOA,
pharmacology, and immunologic
characteristics with Cephalosphorins,
Monobactams, carbapenems, and
Beta-lactamase inhibitors
- All are B-lactam cpds, because of their
four-membered lactam ring
 Chemistry
- Thiazolidine ring attached to a beta
lactam ring which carries a secondary
amino group ( where other substituents
attached)
- 6-aminopenicillanic acid nucleus:
essential for biologic activity
- Penicilloic acid: hydrolysis form,
inactive, lacks of antibacterial activity
due to beta-lactamases
A. Classification
- 6-aminopenicillanic acid applies
antibacterial effect
- Stable to gastric acid and for oral use:
Penicillin V, dicloxacillin, amoxicillin,
etc.
1. Penicillins (ex. Penicillin G)
- Greater activity against gram (+)
organismns, gram (-) cocci and non-
Beta-lactamase producing anaerobes
- Little activity against gram (-) rods
- Susceptible to hydrolysis by B-
lactamases
2. Antistaphylococcal penicillins (ex.
Nafcillin)
- Resistant to staphyloccal beta
lactamases
- Active against staphylococci and
streptococci
- Not against enterococci. Anaerobic
bacteria, gram (-) cocci and rods
3. Extended-spectrum penicillins (amino
penicillins and antipseudomonal
penicillins)
- Activity against gram (-) rods
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- Susceptible to hydrolysis by beta-
lactamases
B. Penicillin Units and Formulations
- Pen G – activity is defined in units
- Crystalline sodium pen G = approx. 1600
units/mg (1 unit=0.6mcg; 1 million
units/penicillin = 0.6)
- Semisynthetic penicillin is measured by
weight
- Minimum inhibitory concentration
(MIC) – is in mcg/mL
- Most penicillin is formulated as sodium
and potassium salt of the free acid
- Potassium Pen G – 1.7 mEq of K/million
units of penicillin (2.8 mEq/g)
- Nafcillin- Na, 2.8 mEq/g
- Procaine salts and benzathine salts of
Pen G (for repository forms for IM
injections)
- Dry crystalline form, penicillin salts are
stable for years for 4c
- Solutions lose their activity rapidly
within 24hrs at 20c (must be prepared
fresh for administration)
 Mechanism of Action
- Inhibit bacterial growth by interfering
with the transpeptidase reaction of
bacterial cell wall synthesis
Function of cell wall
 Maintains cell integrity,
prevents lysis from high
osmotic pressure
 Composed of complex, cross-
linked polymer of
polysaccharide and peptides
known as peptidoglycan
 Polysaccharide – alternating
amino sugars, N-
acetylglucosamine and N-
acetylmuramic acid
 acetylmuramic acid –
presence of linked of five-
amino-acid peptide; this peptde
terminates in D-alanyl-D
alanine
CHAPTER 43: Beta – Lactam & Other Cell Wall- & Membrane-Active Antibiotics
Penicillin-binding protein (PBP)
 an enzyme; which removes the
terminal alanine in the process
of forming a cross-link with
nearby peptide
 beta-lactam antibiotics,
structured analogs of the
natural D-ala-D-ala substrate,
covalently bind to the active
site of PBPs
 the binding inhibit
transpeptidation reaction and
stop peptidoglycan synthesis
- beta lactam antibiotics kill bacterial cells
only when they are actively growing and
synthesizing cell wall
 Resistance
General Mechanisms:
1. Inactivation of antibiotic by Beta-
lactamase – most common, produced
by Staphylococcus aureus,
Haemophilus influenza, E. coli. Others,
AmpC by P. auruginosa and
Enterobacter sp. and extended
spectrum B-lactamases (ESBLs)
Enterobacteriacea for both penicillin
and cephalosporins
2. Modification of target PBP’s
– basis of methicillin resistance in
staphylococci and penicillin resistance
in pneumococci and most resistant
enterococci
–Produce PBPs that have low affinity
for binding B-lactam antibiotics
3. Impaired penetration of drug to target
PBP’s
– occurs on gram negative only due to
impermeable outer membrane of their
cell wall
– beta lactam antibiotics enters the
cell through porins (outer-membrane
protein channels)
4. Antibiotic efflux – gram (-) produce
efflux pump w/c consist of
cytoplasmic and periplasmic protein
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components, transport drugs acroos
the cell wall outer membrane
Carbapenems – resistance to
penicillinase and cephalosporinase but
susceptible by metallo-Beta- lactamases
 Pharmacokinetics
- Absorption of orally administered drug
differs greatly for individual penicillins;
depends on acid stability and protein
binding
Nafcillin – GIT absorption is erratic; not oral
administration, higly protein bound; achieve
lower free-drug concentration in serum
Dicloxacillin, Ampicillin, and amoxicillin
- Acid stable, relatively well absorbed
- Absorption of most oral penicillin is
impaired by food except for Amoxcillin
- Drugs must be administered atleast 1-2
hrs before or after a meal
Pen G – Intravenous administration, IM can cause
local irritation and local pain
Pen G and Ampicillin – less protein bound,
increase serum levels
- Penicillins are polar molecules so
intracellular concentrations are below
than those found in extracellular fluids
Benzathine and Procaine penicillins
- Delay absorption, prolong blood and
tissue concentration
- Singe IM injection of 1.2 million units
Penicillin concentrations in most tissues are equal
to those in serum
 Excretion
- Sputum, breastmilk (3-15%) of those in
the serum
- Poor penetration in the eye, prostate and
CNS
- 1-5mcg/mL of penicillin for bacterial
meningitis, kill also pneumococci and
meningocci
- Rapidly excreted in kidneys
Tubular secretion – 90% of renal excretion and
remaining is glomerular excretion
T1/2 of Pen G = 30 mins, but on present of renal
failure 10hrs
Ampicillin & Extended-spectrum penicillins
CHAPTER 43: Beta – Lactam & Other Cell Wall- & Membrane-Active Antibiotics
- Excreted more slowly than Pen G and - IM for tx of syphilis
T1/2 = 1 hr Procaine Pen
Nafcillin – primarily cleared by biliary excretion - Pneumococcal pneumonia and
Oxacillin, dicloxacillin, and cloxacillin gonorrhea
- Eliminated by both kidney and biliary B. Penicillin Resistant to Staphylococcal Beta-
excretion Lactamase (Methicillin, Nafcillin, and
- No dosage adjustments is required in pt Isoxazolyl Penecillin)
with renal failures - Semisynthetic penicillin
Clearance of penicillin is less efficient in the - For infection cause by B-lactamase-
newborn, dose adjustment for weight alone result producing staphylococci
in higher conc. for longer periods than in adult. - Penicillin susceptible streptococci and
pneumococci
 Clinical Uses - Listeria monocytogenes, enterococci,
- Should be given 1-2 hrs before or after a methicillin-resistant strains of
meal for oral administration except for staphylococci are resistant
amoxicillin - Drug of choice for Methicillin-
- Should not be given with food to susceptible and penicillin-resistant
minimize binding to food proteins and strains staphylococci
acid inactivation Isoxazolyl Penecillin & Dicloxacillin
- Blood levels of penicillins can be raised - Tx for mild and moderate localized
by administration of probenecid; staphylococcal infections
impairs renal tubular secretion of weak - Relatively acid-stable
acids Methicillin – 1st antistaphylococcal penicillin
- Never use to viral infections developed but no longer used due to its high
A. Penicillin Adverse drug effects
Penicillin G Oxacillin and Nafcillin
– drug of choice for infections caused by - Intermittent IV infusion,
streptococci, meningococci, some enterococci, - Drug of choice for serious
penicillin-susceptible pneumococci, staphylococcal infections such as
staphylococci non beta lactamases producing endocarditis
– syphilis; Treponema pallidum and other C. Extended-Spectrum Penicillins
spirochetes (Aminopenicillins, Carboxypenicillins, and
– Clostiridium species, Actinomyces, gram (+) Ureidopenicillin)
rods, non beta lactamases producing gram (-) - Greater activity that penicillin against
anaerobic organisms gram (-) bacteria
– high dose, given as continuous IV infusion - Enhanced ability to penetrate the gram-
negative outer membrane
Penicillin V - Inactivated by beta-lactamases
– oral form, for minor infections Amoxicillin
– poor bioavailability - better absorbed orally
– need for dosing four times daily - bacterial sinusitis,otitis, lower
– narrow antibacterial spectrum respiratory tract infections
Benzathine penicillin and Procaine Pen G Ampicillin & Amoxicillin
- Intramuscular injection yield low but - most active oral B-lactam antibiotics
prolonged drug levels against pneumococci
- Effective for beta-hemolytic Ampicillin
streptococcal pharyngitis - shigellosis, IV for anaerobes enterococci,
Benzathine penicillin G (2.4 million) L. monocytogenes and B-lactamase-

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CHAPTER 43: Beta – Lactam & Other Cell Wall- & Membrane-Active Antibiotics
negative strains of gram (-) cocci and
bacilli (E.coli, Salmonella sp. and H.
influenzae)
Carboxypenicillins (Ticarcillin)
- carbenicillin
- broad spectrum for gram negative
pathogens incl. P. aeruginosa
- co-formulation of beta lactamase
inhibitor Tazobactam
Ureidopenicillin ( Piperacillin)
- gram negative bacilli such as Kleibsiella
pneumoniae and P. aeruginosa
Due to resistance of P. aeruginosa,
antipseudomonal B-lactam is sometimes used in
combination with and aminoglycoside or
fluoroquinolones in UTI
Clavulanic acid, sulbactam or tazabactam
- B-lactamase inhibitor
- Combined with ampicillin, amoxicillin,
piperacillin
- Extends for B-lactamase producing
strains of S. aureus and gram negative
producing beta-lactamases
 Adverse Reactions
-well tolerated
-hypersensitivity, potential anaphylaxis
- serum sickness type; urticaria, fever, joint
swelling, angioedema, pruritus, and
respiratory compromise, rashes
- oral lesions, nephritis, eosinophilia,
hemolytic anemia, vasculitis
- seizures in renal railure
o Nafcillin – neutropenia, interstitial
nephritis
o Oxacillin – hepatitis
Methicilin – interstitial nephritis
Large doses- nausea, vomiting and diarrhea
o Ampicillin – pseudomembranous
colitis, vaginal candidiasis
Piperacillin-tazobactam when combined with
vancomycin has been associated with greater
incidence of acute kidney injury compared to
alternate B-lactam agents.
Cephalosporins & Cephamycins
- More stable than penicillins
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- Broader spectrum of activity
- E. coli and Klebsiella sp can hydrolyze it
- Not active against L. monocytogenes
- Ceftaroline (only drug which has an
activity against enterococci)
 Chemistry
- 7-aminocephalosporanic acid -
Nucleus, similar to the 6-
aminopenicillanic acid
- Intrinsic antimicrobial activity of
cephalosporin is low
FIRST GENERATION CEPHALOSPORINS
- Cefazolin, cefadroxil, cephalexin,
cephalothin, cephapirin, cephradine
- Very active against gram positive cocci
such as streptococci and staphylococci
- Not active against MRSA
- E.coli, K. pneumoniae, Proteus mirabilis
are sensitive
 Pharmacokinetics & Dosage
A. Oral
Cephalexin
-1st oral, excretion is mainly by glomerular
filtration and tubular secretion into the
urine
- probenecid can increase serum
concentration, dosage is adjust in the
presence of renal failure
B. Parenteral
Cefazolin
- Only first gen parenteral , both IV and IM
- Excretion via kidney and adjustments
must be done for impaired renal
function
 Clinica Use
Oral – UTI, Staphylococcal or streptococcal
infection, inc. cellulitis/ soft tissue abscess
Cefazolin
- penetrates well in the tissue
- drug of choice for surgical prophylaxis
and for many streptococcal and
staphylococcal infections
- E.coli and K. pneumoniae
- Does not penetrate CNS
- For serious staphylococcal infections ex.
Bacteremia
CHAPTER 43: Beta – Lactam & Other Cell Wall- & Membrane-Active Antibiotics
- Used in pt with mild penicillin allergy

SECOND-GENERATION CEPHALOSPORINS
- Cefaclor, cefamandole, cefonicid,
cefuroxime, cefprozil, loracarbef,
ceforanide, cefoxitin and cefotetan
- Same with first gen but have extended
gram-negative coverage

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