All of the drugs in this group contain
a β-lactam ring in their structure
• features of
• mechanism of
• pharmacologic and
Same Mechanism of Action : Inhibit cell wall
Bactericidal (except against
Enterococcussp.); time-dependent killers
Short elimination half-life
Primarily renally eliminated
Cross-allergenicity - except aztreonam
All penicillin derivatives produce their
bacteriocidal effects by inhibition of
bacterial cell wall synthesis. Specifically,
the cross linking of peptides on the
mucopolysaccharide chains is
prevented. If cell walls are improperly
made cell walls allow water to flow into
the cell causing it to burst.
It is the last step in peptidoglycan synthesis
that is inhibited by the beta-lactam antibiotics.
Penicillin binds at the active site of the
transpeptidase enzyme that cross-links the
It does this by mimicking the D-alanyl-D-
alanine residues that would normally bind to
Penicillin irreversibly inhibits the enzyme
transpeptidase by reacting with a serine residue
in the transpeptidase.
Binding to PBPs results in:
› Inhibition of transpeptidase: transpeptidase
catalyzes the cross-linking of the
pentaglycine bridge with the fourth residue
(D-Ala) of the pentapeptide. The fifth reside
(also D-Ala) is released during this reaction.
Spheroblasts are formed.
› Structural irregularities: binding to PBPs may
result in abnormal elongation, abnormal
shape, cell wall defects.
Figure 45-2. The transpeptidase reaction in Staphylococcus aureus that is
inhibited by penicillins and cephalosporins.
Production of β-lactamase
Modification of target PBPs
Impaired penetration of drug to
The shortage of antolytic enzyme
The presence of an efflux pump.
Natural Penicillins: extracted from the
cultural solution of penicillia.
› Prototype is penicillin G
› Is pH sensitive. Therefore not given orally.
› Effective against Gram-positive cells
› Susceptible to penicillinase
Have broader spectrum. Are effective against
Gram-negative cells, too.
Are not resistant to penicillinases
pen-susc S. aureus Neisseria sp.
pen-susc S. pneumoniae
Group streptococci Anaerobes
viridans streptococci Above the
Enterococcus Clostridium sp.
Treponema pallidum (syphilis)
It is relatively unstable in acid, thus the
bioavailability is low.
There is poor penetration into the
cerebrospinal (CSF), unless inflammation
Active renal tubular secretion results in a
Oral Administration of Penicillin G.
About one-third of an orally administered
dose of penicillin G is absorbed from the
intestinal tract under favorable
Gastric juice at pH 2 rapidly destroys the
antibiotic. The decrease in gastric acid
production with aging accounts for
better absorption of penicillin G from the
gastrointestinal tract of older individuals
After intramuscular injection, peak
concentrations in plasma are reached within
15 to 30 minutes. This value declines rapidly,
since the half-life of penicillin G is 30 minutes.
Repository preparations of penicillin G are
employed. The two such compounds
currently favored are
penicillin G procaine
penicillin G benzathine.
Such agents release penicillin G slowly from
the area in which they are injected and
produce relatively low but persistent
concentrations of antibiotic in the blood.17
Long acting (every 12 h ) .
Used to prevent subacute bacterial
endocarditis due to dental extraction or
tonsillectomy in patients with congenital
or acquired valve disease .
Long acting (every 3-4 weeks )
Treatment of β-hemolytic streptococcal
Used as prophylaxis against reinfection with
β- hemolytic streptococci so prevent
rheumatic fever .
Once a week for 1-3 weeks for treatment of
syphilis (2.4 million units I.M.)
It is the drug of first choice for treating the
infections of the above mentioned
The simultaneous administration of the
relevant antitoxin is often necessary for the
treatment of diphtheria and tetanus.
The combination of an aminoglycoside is
also necessary for bactericidal effects in
Available PO, IM, IV (dosed in units)
Drug of Choice (DoC) [2-4 MU IV q4h]
› T. pallidum, N. meningitidis, Group A Strep, and
› Procaine PenG (12 hrs)
› Benzathine Pen (5 days) [2.4 MU IM for syphilis]
Adverse Reactions – other than skin rash
› Penicillin “serum sickness”/drug fever
› Jarisch-Herxheimer reaction (1° and 2° syphilis)
› Hemolytic anemia, pancytopenia, neutropenia
The oral form of Penicillins,
Indicated only in minor infections
because of their relatively poor
bioavailability, weaker antimicrobial
activity, the need for dosing many times
Narrow antimicrobial spectrum.
Hypersensitivity – 5 to 20 %
skin rashes, fever, eosinophilia, angioedema,
serum sickness, and anaphylactic shock.
Cross-reactivity exists among all penicillins
and even other β-lactams
The most serious hypersensitivity reaction is
anaphylactic shock. (very rare, the ratio is
about 0.5 to 1 of 10000 patients )
As soon as anaphylactic shock occurs,
instantly inject adrenaline to deliver trachea
edema and spasm.
Ask allergic history carefully .
Must make skin test .
The injection of these drugs is made up
before it is injected.
As a number of these drugs are
replaced, the skin test must be done
After every injection, all of patients must
be observed, and the drugs for an
emergency treatment are prepared at
any time 26
How to prevent the occurrence
of anaphylactic shock?
Other adverse effects:
Gastrointestinal upset, ( orally
Nephrotoxicity, is very rare.
results from alterations in intestinal flora. A
higher incidence occurs with broad-
Penicillins : Adverse effects
Developed to overcome the penicillinase
enzyme of S. aureus which inactivated natural
methicillin-susceptible S. aureus
a. Methicillin and isoxazolyl penicillins (e.g.
oxacillin, cloxacillin and dicloxacillin)
b. They are the drugs of first choice for
treating infections of the penicillase-
productive aurococcus. But penicillin-
susceptible strains of streptococci and
pneumococci are also susceptible
c. Enterococci and methicillin-resistant strains
of staphylococci are resistant to these
DoC – MSSA, MSSE [2g IV q4h]
› Actually less active against Pen susceptible
isolates than Pen
› More active than Vanc vs. MSSA
Significant hepatic metabolism
› No need to dose adjust for renal impairment
› Hepatotoxicity (cholestatic hepatitis)
› Kernicterus in neonates
NOT equivalent to IV Ox (therapeutically)
› Poor oral absorption
› ~50% (better on empty stomach)
Dose: 250-500mg po QID
Developed to increase activity against gram-
Gram-positive Gram-negative pen-
susc S. aureus Proteus mirabilis
Group streptococci Salmonella, Shigella
viridans streptococci some E. coli
Enterococcus sp. βL- H. influenzae
Ampicillin and amoxicillin
a. They are similar to penicillin G in the
activity against gram-positive organisms
but are weaker than the latter.
b. They are more satisfactory for the
treatment of enterococci and
c. They are similar to chloramphenicol in the
activity against gram-negative organisms.
d. They are acid-resistant but are not
e. Pseudomonas aeruginosa are fail to
respond to these drugs.
f. Amox better tolerated PO and better
absorbed (Amp must be taken on empty
Developed to further increase activity
against resistant gram-negative aerobes
marginal Proteus mirabilis
some E. coli
βL- H. influenzae
a. Extend the ampicillin spectrum of
activity to P.aeruginosa and
enterobacter species. But their activity
cocci is less than that of ampicillin.
b. They are not acid-resistant and
c. Ticarcillin is more active than
carbenicillin against P.aeruginosa and
d. Chiefly used to treat serious infections
caused by G-
P.aeruginosa, indole-positive proteus
e. Generally used in combination with an
aminoglycoside for pseudomonal
Developed to further increase activity against resistant
viridans strep Proteus mirabilis
Group strep Salmonella, Shigella
some Enterococcus E. coli
βL- H. influenzae
Anaerobes Enterobacter sp.
Fairly good activity Pseudomonas aeruginosa
some Klebsiella sp.
Spectrum: most Enterobacteriaceae (E.
coli, Proteus, Klebsiella, Enterbacter,
Serratia, Citrobacter, Salmonella and
Most active penicillin vs. Pseudomonas
Often used in combination with
Aminoglycoside or Cipro/Levofloxacin
› Bleeding (platelet dysfunction)
clavulanic acid, sulbactam, tazobactam
a. Inactivate bacterial beta-lactamases
and are used to enhance the
antibacterial actions of beta-lactam
b. Only have weak antibacterial action.
c. Inhibitors of many but not all bacterial
beta-lactamases and can protect
hydrolyzable penicillins from inactivation
by the enzymes.
d. Available only in fixed combinations
with specific penicillins.
The companion penicillin, not the beta-
lactamase inhibitor, determines the
antibacterial spectrum of the combination.
Augmentin (Amox/Clav) PO
Spectrum: MSSA and upper respiratory
infections (S. pneumo, H.Inf, M. catarrhalis)
and most anaerobes
Clav is responsible for most of the GI side-
effects seen with Amox/Clav
Variable ratios of Amox/Clav in