02. penicillins and other beta lactam antibiotics.ppt

Detailed pharmacology of penicillin and beta lactam antibiotics

1. CELL WALL SYNTHESIS INHIBITORS
Lecture by: Dr.Saiqua lashari
Pharm-D
SHAH ABDUL LATIF UNIVERSITY
KHAIRPUR MIRS

2. BETA LACTAM ANTIBIOTICS AND OTHER
INHIBITORS OF CELL WALL SYNTHESIS
Penicillins
Cephalosporins
Monobactams
Carbapenems
Vancomycin

3. P e n icillin G
P e nic illin V
M e th icillin
O xa cillin
N afcillin
C lo xa cillin
D iclo xa cillin
A m p icillin
P ip e rac illin
T ica rcillin
C arb e n icillin
A m o xy cillin
M e zlo c illin
A zlo c illin
Penicillins
C efa zo lin
C e fa d ro x il
C ep h a le x in
C ep h a lo th in
C ep h ra din e
C ep h a pir in
1st generation
C e fa c lor
C e fa m a n d o le
C e fo n ic id
C e fa m e ta z o le
C e fo te tan
C e fo x itin
C e fu ro xim e
2nd generation
C efdin ir
C e fix im e
C efo p e ra zo n e
C e fo ta xim e
C efta z id im e
M o xa la c ta m
C e ftria xo n e
C e ftib u te n
C e ftiz o xim e
3rd generation
C e fe p im e
4th generation
Cephalosporins
Im ip e n a m s /C ila s ta tin
Carbepenams
A ztre o na m
M onobactams
B eta lactam an tib io tcs
V a ncom ycin
B acitracin
O th er antib io tics
INHIBITORS OF CELL WALL SYNTHESIS

4. A
 
beta-lactam 
(
β-lactam)
 
ring 
is a four-membered 
lactam. A
 
lactam 
is a cyclic
amide, and
 
beta-lactams 
are named so because the nitrogen atom is attached to
the
 
β-carbon atom relative to the carbonyl. The simplest
 
β-lactam 
possible is 2-
azetidinone.
 
β-lactams 
are significant structural units of medicines.

5. Penicillins
•First antibiotic to be used clinically.
•Alexander Fleming – 1929.
•First penicillins from cultures of Penicillium
notatum( fungus ) in 1941-Chain & Florey.
•Presently from cultures of Penicillium
chrysogenum.
HISTORY OF
PENICILLINS?
https://www.medicalnewstoday.com/articles/216798#history

6. •The Scottish physician Alexander Fleming
was the first to suggest that a Penicillium
mould( funji) must secrete an antibacterial
substance, and the first to concentrate the
active substance involved, which he
named
 
penicillin, the first modern antibiotic,
in 1928.
Fast facts on penicillin
•Penicillins were the first
 
antibiotic 
that doctors used.
•There are several antibiotics in the penicillin class.
•Experts credit Alexander Fleming with discovering penicillins.
•Penicillin works by interfering with bacteria cell walls.
•Less than 1 percent of people are dangerously allergic to
penicillin.

7. •Basic structure of Penicillin
consists of a
Thiazolidine ring (A) fused to a
Beta lactam ring (B) to which
side chains (R) are attached
through an amide linkage.

9. •In Natural penicillin, Pn G, R- side chain is a
benzyl side chain
•But in semisynthetic penicillins R is anything
other than benzyl moiety.

10. 10
.Moieties A and B together constitute the 6-aminopennicillanic acid
nucleus.
•The penicillin nucleus is the chief structural requirement for
antibacterial activity.
•Side chain determines many of the antibacterial and pharmacological
characteristics of a particular type of penicillin.
•Several types of natural penicillins
– F, G , X , & K.
– PnG (benzyl penicillin)
•Greatest antimicrobial activity
•Only natural penicillin used clinically.
•Na & K salts more stable.
•Na salt of PnG
•K salt of PnG

11. 11
Mechanism of action
All β lactam antibiotics interfere with the synthesis of
bacterial Cell wall
•Bacteria are surrounded by a thick cell wall that
confers stability & rigidity to their cell structure
•Cell wall is composed of peptide chains &
glycan chains
•Extensively cross linked
•Peptidoglycan layer envelops the cell & does
not allow bacteria to swell & prevent death due
to lysis

12. 12
Bacterial Cell Wall Synthesis
Glycan chains consist of two aminosugars
–N acetyl muramic acid (NAM) &
–N acetyly glucosamine (NAG)
•Pentapeptide side chain is linked to NAM sugar
•Forms the peptidoglycan molecule
•Peptidoglycan residues are linked together and UDP is split off
•Final step is cleavage of terminal D alanine of the peptide chains by
transpeptidases
•Catalyzed by PBPs, transmembrane surface enzymes present in bacteria
•Energy is released which is utilized for establishing cross linkages
between peptide chains of the neighbouring strands.
•This cross linking Provides stability and rigidity to the cell wall

13. 13
Mechanism of action
•Penicillins inhibit bacterial cell wall synthesis
•Inhibit the PBPs catalysed process of transpeptidation
–cross linking (maintains close knit structure of bacterial cell
wall) does not occur
•Last step in peptidoglycan synthesis
•When susceptible bacteria divide in the presence of β lactam
antibiotic cell wall deficient forms are produced.
•Interior of bacterium is hyperosmotic
•Osmotic drive occurs
•BACTERIA swell and bursts
•Lysis of bacteria- BACTERICIDAL

14. •Rapid cell wall synthesis occur when organisms are actively
multiplying.
Beta lactam antibiotics are more lethal in this phase.
Peptidoglycan cell wall is unique to bacteria.
No such substance is synthesized by higher animals.
Penicillins are practically non toxic to man.

15. •G +ve bacteria
Cell wall is entirely made of
peptidoglycan.
Cell wall is 50-100 layers thick
Extensively cross linked
May be considered as a single
giant peptide molecule,
The peptidoglycan layer is
easily accessible to β - lactam
antibiotics
Inhibition of transpeptidation
reaction becomes easier
•G -ve bacteria
Have two membranes
Outer membrane
Inner membrane
Peptidoglycan sandwiched
b/w the two
Outer membrane consists
of lipopolysaccharides with
narrow porin channels ;
•barrier to β-lactam
antibiotics
•Hence weaker activity
Reason for higher
susceptibility(capable of
being affected) of g +ve
bacteria to Pn G

16. 16
Gram-positive Bacterial Membrane
Structure
The lipid bi-
layer cell
membrane of
most of the
Gram-positive
bacteria is
covered by a
porous
peptidoglycan
layer
Peptidoglyc
an cell wall
Cytoplasmic
Membrane



17. 17
Gram-negative Bacterial Membrane
Structure
•Gram-negative
bacteria are
surrounded by two
membranes.
•The outer
membrane
functions as an
efficient
permeability
barrier containing
lipopolysaccharide
s (LPS) and porins.
Outer
membrane
Peptidoglycan
cell wall
Cytoplasmic
membrane




18. •Penicillins with hydrophillic character , Ampicillin & amoxycillin can diffuse through
these porin channels ;
•show activity against some gram-negative bacteria also
•but not against psuedomonas aeruginosa because these bacteria lack in such
classical permeable porin channels.

20. PENICILLINASE

21. Efflux
pump in
some G -ve
Bacteria

22. 22
PBP’s :
Penicillin
Binding
Proteins
Gram –ve bacteria Gram +ve bacteria

23. 23
Penicillin G
•Natural Penicillin
•Narrow spectrum
•Primarily active against G +ve
bacteria
–Few gram negative & anaerobes

24. Antibacterial spectrum :
•G +ve Cocci : streptococci are highly sensitive
•So are pneumococci
•S. aureus- >90% have acquired resistance.
•Gram +ve Bacilli : B. anthrasis, C. diphtheria, all
Clostridia, Listeria are highly sensitive.
•Gram -ve cocci:
•N. gonorrhoe (Highly resistant),
•N. meningitides are susceptible to Pn G.
•G –ve bacilli , Myco TB rickettsia, chlamydia,
protozoa, fungi & viruses are totally
unresponsive.

25. •Most anaerobic microorganisms including
clostridium species are highly sensitive.
•So are spirochaetes (T. pallidum,
Leptospira and others)

26. Pharmacokinetics:
Injectable penicillin
•Acid labile -destroyed by gastric acid.
•Absorption from IM site is rapid, reaches
most body fluids
•Plasma half life is 30 minutes.

27. excreted by rapid renal excretion.
10 % by GF; 90 % TS.
TS is blocked by Probenecid, higher
and long lasting plasma concentrations
are achieved.
Rarely used for this purpose
Repository preparations are used
»Pencillin G procaine
»Pencillin G benzathine

28. •Release penicillin slowly from the
area in which they are injected &
produce relatively low but
persistent concentrations of
antibiotics in the blood.

29. Preparations:
•Penicillin G(Sodium penicillin G (crystalline)/
benzyl penicillin).
•Procaine penicillin G.
•Bezathaine penicillin G

30. Therapeutic Uses :
•Streptococcal infections.
DOC (Drug of choice ) for sensitive strains
•Pneumococcal.
Used for senstive strains
Replaced by third generation cephalosporins.
•Meningococcal.
•Gonorrhoea- not reliable,
•Syphylis- drug of choice,
•Diphtheria- for carrier state.
•Tetanus and gas gangrene.

31. Infections with Anaerobes
•Periodontal infections usually respond well to
penicillin G.
Mild-to-moderate infections at these sites may be
treated with oral medication
(either penicillin G or penicillin V 400,000
units four times daily).
More severe infections should be treated with 12 million
to 20 million units of penicillin G intravenously..
•Necrotising gingivitis
•Vincents angina

32. Prophylactic use :
•Rheumatic fever
1.2 million units , im, once a month, lifelong in
high risk people.
•Bacterial endocarditis - caused by dental
extractions, endoscopies, catheterization,
etc. cause bacteremia which in patients
with valvular defects can cause
endocarditis.

33. INFECTIVE ENDOCARDITIS
•Some cases of endocarditis occur after
dental procedures.
•Prophylactic antibiotics are given to
patients with predisposing congenital
or valvular anomalies.

34. ENDOCARDITIS PROPHYLAXIS
ROUTE DOC DOSE
ORAL


Penicillin
allergy
AMOXICILLIN
2 g; 1 hr before procedure
CLINDAMYCIN, OR
CEPHALEXIN OR
AZITHROMYCIN /
CLARITHROMYCIN
600 mg; 1 hr before procedure
2 g; 1 hr before procedure
500 mg; 1 hr before procedure
PAREN
TERAL
Penicillin
allergy
AMPICILLIN
2 g IM or IV; 30 minutes before
procedure
600 mg IV; 1 hr before
procedure
1 g IM or IV; 30 minute before
procedure
CLINDAMYCIN
OR
CEFAZOLIN

36. •Acid resistant alternative to Pn G:
•Phenoxymethyl penicillin (Penicillin V VERTRAULICH )
•Penicillinase resistant penicillin:
•Cloxacillin
•Methicillin
•Extended spectrum penicillins:
•Aminopenicillins
–Ampicillin
–Bacampicillin
–Amoxycillin
•Carboxypenicillins
–Carbenicillin,
–Ticarcillin.
•Ureidopenicillins
–Mezlocillin,
–Piperacillin,Azlocillin

37. Phenoxymethyl penicillins: (Pn V)
•It differs from Pn G only in that it is acid stable
•Oral absorption is better
•Antibacterial spectrum is identical to penicillin G. Less
active against Neisseria & other gram -ve bacteria &
anaerobes.
•Not dependable in serious conditions.
•Primarily for streptococcal infections like pharyngitis,
sinusitis, otitis media, prophylaxis of rheumatic fever.
Dose: 250-500 mg 6 hrly. 250 mg= 4 lac unit.

38. Penicillinase resistant penicillins:
•Have side chains that protect the beta lactam ring
from attack by staphylococcal penicillinase.
•Their only indication is infection caused by
penicillinase producing staphylococci infection for
which they are drug of choice.

39. Cloxacillin:
Highly penicillinase & Acid resistant.
Can be given orally.
Effective against penicillinase producing
bacteria.
Dose: 250-500 mg 6 hrly.
Oxacillin
dicloxacillin
flucloxacillin are similar

40. Methicillin:
Highly penicillinase but not Acid resistant.
Must be injected i.v
MRSA have emerged in many areas
These are insensitive to penicillinase resistant penicillins / other B lactams
& erythromycin/ aminoglycosides/ tetracyclines etc.
Have altered PBPs ; do not bind penicillins
DOC= Vancomycin
linezolid/ ciprofloxacin can also be used.
Nephrotoxicity

41. Extended spectrum penicillins:
•Active against wide variety of gram –ve
bacteria as well. Psuedomonas, kleibseilla,
proteus (lack porin channels)
Aminopenicillins :
•Amino substitution in the side chain
Ampicillin
•Active against all organisms as penicillin G + many gram
–ve bacteria(Hydrophillic; penetrate porin chanels).
H.influenzae, E.coli, Proteus, Salmonella,
and Shigella.
Many have developed resistance.

42. •Pharmacokinetics:
Oral absorption-incomplete but
adequate.
Food interferes with absorption, I
hour before meals.(amoxycillin)
Elimination: Primary channel
kidney.
•Dose: 0.5-2G oral/IM/IV 6 hrly.

43. Adverse effects :
Diarrhoea
•Unabsorbed drug irritates the lower
intestines.
•Alteration of normal bacterial flora.
Rashes

44. Bacampicillin
•Prodrug of ampicillin
•Completely absorbed.
Does not disturb intestinal ecology.
Incidence of diarrhoea is less
•Higher plasma levels are obtained.
•Better tissue penetration
Talampicillin
Pivampicillin
Hetacillin
•Are other prodrugs of ampicillin.

45. Amoxycillin :
Congener of ampicillin
Similar in all respects except:
»Oral absorption is better.
»Food does not interfere.
»Higher & more sustained blood levels.
»Incidence of diarrhoea is less.
»Less active against shigella & H.influenzae.
•Dose : 0.25-1 G oral/IM.

46. Aminopenicillins
Therapeutic Uses:
•In dentistry: Ampicillin/ Amoxicillin is used alone or with
metronidazole in
acute necrotising ulcerative gingivitis
or peridontitis
pulpitis,
dentoalveolar abcess,
osteomyelitis of mandible etc
•UTI/RTI/Meningitis/Gonorrhoea/Typhoid fever/Bacillary dysentry/
•Cholecystitis/Septicemia & mixed infections.

47. Carboxypenicillins:
•Carbenicillin
•Ticarcillin

48. Carbenicillin
Comparable activity against many gram
positive & -ve organisms.
Special feature of this penicillin congener is its
activity against Pseudomonas auerginosa and
indole positive Proteus which are not inhibited by Pn
G or aminopenicillins.
Neither penicillinase nor acid resistant
Inactive orally ; P/E administration.

49. Used as : 1-5 G IV 4-6 hrly.
and excreted in urine.
C/I : in renal patients is affected
Indications:
Serious infections caused by Pseudomonas or
Proteus eg.
Burns,
UTI,
Septicemia.
Piperacillin is now preferred.

50. Ticarcillin
•More potent than carbenicillin.
•Other properties are similar to carbenicillin.

51. Ureidopenicillins :
Piperacillin
•This Antipseudomonal penicillin is 8 times
more active than carbenicillin.
•Good activity against Klebsiella.
•Dose: 3-4 G 6-8 hrly.
•It is available in combination with Tazobactam.

52. Piperacillin in combination with beta lactamase
inhibitor (zosyn)
•has the broadest antibacterial spectrum amongst
the penicillins.
•High billiary concentrations are achieved.
•Important agent for the treatment of patients with
serious infections caused by psuedomonas,
proteus & klebseilla
Bacteremias
pneummonias
and infections following burns and UTIs
Pseudomonas infection in neutropenic/
immunocompromised patients .

53. Adverse reactions to penicillins
•Pain & sterile inflammatory reactions at the
sites of i.m injection.
•Phlebitis & thrombophlebitis on i.v injection.
•Nausea with / without vomiting.
•Mild to severe diarrhoea.
•mental confusion, muscular twitchings,
convulsions, coma.
•Procaine penicillin: hallucinations,
convulsions.

54. •Hypersensitivity reactions:
incidence 1-10%., rash, itching,
urticaria & fever acute
anaphylactic reactions.
History
Senstivity test
Inj adrenaline & hydrocortisone
handy
•Jarisch Herxheimer Reaction.

55. β - Lactamase inhibitors

56. β lactamases
•Family of enzymes produced by g-ve
& g+ve organisms
•Inactivate β lactam antibiotics by
opening the β lactam ring

57. β -lactamase inhibitors
•Potent inhibitors of β -lactamases
•Resemble β -lactam antibiotic
•Do not possess antimicrobial action

58. •Bind irreversibly to the catalytic site of
susceptible β -lactamases particularly
penicillinase to prevent hydrolysis of
penicillins
•Suicide inhibitors

59. Clavulanic acid Sulbactam Tazobactam
Beta lactamase Inhibitors
Currently 3 ß-lactamase
inhibitors are available
Clavulanic acid, ORAL/PARENTRAL derived S. clavuligerus
Sulbactam I.M/I.V semisynthetic,
and tazobactam I.M/I.V str. analogue of sulbactam

60. •These agents are given together with
hydrolyzable penicillins to protect them from
inactivation.
•Extends the use of penicillin against β - lactamase
producing bacteria.
•ACCORDING TO THEIR COMMON pK features
Clavulanic acid + amoxacillin
Sulbactam + ampicillin
Tazobactam + piperacillin & are available as fixed dose
combinations

61. Clavulanic acid 125 mg +
amoxacillin 250mg= augmentin
Sulbactam 0.5g + ampicillin 1g
Tazobactam 0.25g +piperacillin 2g
available as fixed dose
combinations

62. Most effective against β-lactamases produced
by:
•Staphylococci
•H. influenzae
•N. gonorrhoeae
•Salmonella
•Shigella
•E. coli
•K. pneumoniae

63. •The β -lactamase inhibitors are effective
against ß-lactamase producing organisms.
e.g. ampicillin in combination with sulbactam is
effective against ß-lactamase producing S.
aureus and H. influenzae.
•Non β - lactamase producing micro-
organisms : no advantage
•Ineffective against Methicilin resistant
staph aureus.= vancomycin

64. THERAPEUTIC USES
•Sulbactam is used in Odontogenic infections
caused by β-lactamase producing strains of
Staph. Aureus, H. influenzae E. coli, N.
gonorrhoeae, Salmonella, Shigella.
•Mixed nosocomial infections.
•Skin & Soft tissue infection,
•Urinary, biliary and respiratory tract infection,
•Mixed intra-abdominal and pelvic infections,
•Hospital acquired infection= nosocomial infections

65. UNITAGE OF PENICILLIN
•Activity of natural penicillins (Pn G) is
described in units
–Crystalline sod Pn G contains 1600 units /mg.
–1 unit of PnG =o.6 Ug
–Or, 600 mg of Pn G = 1 million units
•Semi synthetic penicillins are prescribed by weight
–Amox 500 mg 8 hrly orally

66. •1 mg = 1600 units
•1600 units = 1 mg
•1 unit = 0.6 Ug
•0.6 Ug = 1 unit
•6 Ug = 10 unit
•6000 Ug = 10,000 units
•6 mg = 10,000 units
•600 mg = 10,000,00 units