1. The document discusses different classes of beta-lactam antibiotics including penicillins, cephalosporins, carbapenems, and monobactams. 2. All beta-lactams work by inhibiting bacterial cell wall synthesis through binding to penicillin-binding proteins. This prevents cross-linking of peptide chains in the cell wall causing the cell to burst. 3. Specific types of penicillins are discussed including natural penicillins, aminopenicillins, anti-staph penicillins, and anti-pseudomonal penicillins. Their spectrums of activity and uses are described.

1. 1

2. 2

3. 3
Monobactams
All of the drugs in this group contain
a β-lactam ring in their structure
Penicillins
N
O
S
Carbapenems
N
O
N
O
N
O
S
Cephalosporins
share similar
• features of
chemistry,
• mechanism of
action,
• pharmacologic and
clinical effects.

4.  Same Mechanism of Action : Inhibit cell wall
synthesis
 Bactericidal (except against
Enterococcussp.); time-dependent killers
 Short elimination half-life
 Primarily renally eliminated
 Cross-allergenicity - except aztreonam
4

5.  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.
5

6. 6
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
peptidoglycan strands.
It does this by mimicking the D-alanyl-D-
alanine residues that would normally bind to
this site.
Penicillin irreversibly inhibits the enzyme
transpeptidase by reacting with a serine residue
in the transpeptidase.

7. 7
 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.

8. 8
Figure 45-2. The transpeptidase reaction in Staphylococcus aureus that is
inhibited by penicillins and cephalosporins.

9. 9

10.  Production of β-lactamase
enzymes
 Trapping mechanism
 Modification of target PBPs
 Impaired penetration of drug to
target PBPs
 The shortage of antolytic enzyme
 The presence of an efflux pump.
10

11.  Penicillins
› Natural penicillins
 PenG, PenVK, Benzathine Pen, Procaine Pen
› Aminopenicillins
 Ampicillin, Amoxicillin
› Anti-Staph penicillins
 Oxacillin, Dicloxacillin
› Anti-Pseudomonal
 [Carboxy] Ticarcillin
 [Ureido] Piperacillin
11

12.  Natural Penicillins
 Penicillin G
 Penicillin VK
 Semisynthetic penicillins:
 Acid-stable penicillins
(Penicillin V);
 Penicillinase-Resistant Penicillins
(Nafcillin, Oxacillin, Methicillin)
 Extended-spectrum penicillins
(Ampicillin and Amoxycillin);
 Antipseudomonal
(Carbenicillin, Ticarcillin)
12

13.  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
 Semisynthetic Penicillins:
 Have broader spectrum. Are effective against
Gram-negative cells, too.
 Are not resistant to penicillinases
13

14. Gram-positive Gram-negative
pen-susc S. aureus Neisseria sp.
pen-susc S. pneumoniae
Group streptococci Anaerobes
viridans streptococci Above the
diaphragm
Enterococcus Clostridium sp.
Other :
Treponema pallidum (syphilis)
14

15. Pharmacokinetics
 It is relatively unstable in acid, thus the
bioavailability is low.
 There is poor penetration into the
cerebrospinal (CSF), unless inflammation
is present.
 Active renal tubular secretion results in a
short half-life.
15

16.  Oral Administration of Penicillin G.
About one-third of an orally administered
dose of penicillin G is absorbed from the
intestinal tract under favorable
conditions.
 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
16

17.  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

18.  Long acting (every 12 h ) .
 Acid unstable
 Penicillinase sensitive
 Used to prevent subacute bacterial
endocarditis due to dental extraction or
tonsillectomy in patients with congenital
or acquired valve disease .
18

19.  Long acting (every 3-4 weeks )
 Acid unstable
 Penicillinase sensitive
 Treatment of β-hemolytic streptococcal
pharyngitis.
 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.)
19

20. Therapeutic uses
 It is the drug of first choice for treating the
infections of the above mentioned
pathogens.
 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
enterococcal endocarditis.
20

21.  Penicillin G, Penicillin V
21

22.  Pneumococcal Infections
› Pneumococcal Meningitis
› Pneumococcal Pneumonia
 Streptococcal Infections
› Streptococcal Pharyngitis (including Scarlet Fever)
› Streptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis
 Staphylococcal Infections
 Meningococcal Infections
 Gonococcal Infections
 Syphilis
 Actinomycosis
 Diphtheria
 Anthrax
 Clostridial Infections
 Fusospirochetal Infections
 Rat-Bite Fever
 Listeria Infections
 Lyme Disease
 Erysipeloid
 Surgical Procedures in Patients with Valvular Heart Disease
22

23.  Available PO, IM, IV (dosed in units)
 Drug of Choice (DoC) [2-4 MU IV q4h]
› T. pallidum, N. meningitidis, Group A Strep, and
Actinomycosis
 Long-acting forms
› 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
23

24.  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.
24

25.  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.
25

26. 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
again.
 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?

27.  Other adverse effects:
 Gastrointestinal upset, ( orally
administered preparations)
 Nephrotoxicity, is very rare.
 Superinfections.
results from alterations in intestinal flora. A
higher incidence occurs with broad-
spectrum penicillins.
27
Penicillins : Adverse effects

28. Developed to overcome the penicillinase
enzyme of S. aureus which inactivated natural
penicillins
Gram-positive
methicillin-susceptible S. aureus
Group streptococci
viridans streptococci
28

29.  Methicillin
 Nafcillin
 Oxacillin
 Dicloxacillin
29

30. 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
penicillins
30

31. 31
 IV
 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
 ADRs
› Hepatotoxicity (cholestatic hepatitis)
› Neutropenia
› Kernicterus in neonates

32. 32
 Oral
 NOT equivalent to IV Ox (therapeutically)
› Poor oral absorption
› ~50% (better on empty stomach)
 Dose: 250-500mg po QID

33. Developed to increase activity against gram-
negative aerobes
Gram-positive Gram-negative pen-
susc S. aureus Proteus mirabilis
Group streptococci Salmonella, Shigella
viridans streptococci some E. coli
Enterococcus sp. βL- H. influenzae
Listeria monocytogenes
33

34. 34

35. 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
streptococcus viridians.
35

36. c. They are similar to chloramphenicol in the
activity against gram-negative organisms.
d. They are acid-resistant but are not
penicillase-resistant.
e. Pseudomonas aeruginosa are fail to
respond to these drugs.
f. Amox better tolerated PO and better
absorbed (Amp must be taken on empty
stomach)
36

37. Developed to further increase activity
against resistant gram-negative aerobes
Gram-positive Gram-negative
marginal Proteus mirabilis
Salmonella, Shigella
some E. coli
βL- H. influenzae
Enterobacter sp.
Pseudomonas aeruginosa
37

38. 38

39. carbenicillin, ticarcillin
a. Extend the ampicillin spectrum of
activity to P.aeruginosa and
enterobacter species. But their activity
to G+
cocci is less than that of ampicillin.
b. They are not acid-resistant and
penicillase-resistant.
c. Ticarcillin is more active than
carbenicillin against P.aeruginosa and
enterobacter species.
39

40. d. Chiefly used to treat serious infections
caused by G-
microorganisms, particular
P.aeruginosa, indole-positive proteus
and enterobacter.
e. Generally used in combination with an
aminoglycoside for pseudomonal
infections.
40

41. Developed to further increase activity against resistant
gram-negative aerobes
Gram-positive Gram-negative
viridans strep Proteus mirabilis
Group strep Salmonella, Shigella
some Enterococcus E. coli
βL- H. influenzae
Anaerobes Enterobacter sp.
Fairly good activity Pseudomonas aeruginosa
Serratia marcescens
some Klebsiella sp.
41

42.  IV
 DoC: Pseudomonas
 Spectrum: most Enterobacteriaceae (E.
coli, Proteus, Klebsiella, Enterbacter,
Serratia, Citrobacter, Salmonella and
Shigella)
 Most active penicillin vs. Pseudomonas
 Often used in combination with
Aminoglycoside or Cipro/Levofloxacin
 ADRs
› Bleeding (platelet dysfunction)
› Neutropenia/Thrombocytopenia
42

43. clavulanic acid, sulbactam, tazobactam
a. Inactivate bacterial beta-lactamases
and are used to enhance the
antibacterial actions of beta-lactam
antibiotics.
b. Only have weak antibacterial action.
43

44. 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.
44

45.  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
liquids/tabs/chew tabs
45