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penicillin and Cephalosporins
Citation preview
8/5/2012
1
© 2010 Delmar, Cengage Learning1
By- Jitendra Bhangale
Assistant Professor & Head,
Department of Pharmacology,
Smt N. M. Padalia Pharmacy College,
Ahmedabad
© 2010 Delmar, Cengage Learning2
These are antibiotics having a B-lactam ring.
The two major groups are penicillins and cephalosporins.
Monobactams and carbapenems are relatively newer additions.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
8/5/2012
2
© 2010 Delmar, Cengage Learning3
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning4
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
It was originally obtained from the fungus Penicillium notatum, but thepresent source is a high yielding mutant of P. chrysogenum.
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© 2010 Delmar, Cengage Learning5
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
In gram-positive microorganisms, the cell wall is 50 to 100 moleculesthick, but it is only 1 or 2 molecules thick in gram-negative bacteria.
The peptidoglycan is composed of glycan chains, which are linear strandsof two alternating amino sugars (N-acetylglucosamine and N-acetylmuramic acid) that are cross-linked by peptide chains.
© 2010 Delmar, Cengage Learning6
The cell walls of bacteria are
essential for their
normal growth and
development.
Peptidoglycan provides rigid
mechanical stability by
virtue of its highly cross-
linked latticework
structure.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
8/5/2012
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© 2010 Delmar, Cengage Learning7
The final stage involves completion of the cross-link.
This is accomplished by a transpeptidation reaction that occurs
outside the cell membrane.
The transpeptidase itself is membrane-bound.
The terminal glycine residue of the pentaglycine bridge is linked to
the fourth residue of the pentapeptide (D-alanine), releasing
the fifth residue (also D-alanine).
It is this last step in peptidoglycan synthesis that is inhibited by
the b-lactam antibiotics.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning8
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
There are additional, related targets for the actions of penicillins
and cephalosporins; these are collectively termed penicillin-
binding proteins (PBPs). All bacteria have several such entities
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© 2010 Delmar, Cengage Learning9
Penicillin G
Acid resistance to Penicillin G (Semisynthetic)
Penicillin V
Penicillinase-resistant penicillins
Methicillin, Nafcillin, Oxacillin, Cloxacillin & Dicloxacillin
Extended spectrum penicillins
Aminopenicillins: Ampicillin, Bacampicillin, Amoxicillin
Carboxypenicillins: Carbenicillin, Ticarcillin
Ureidopenicillins: Piperacillin, Mezlocillin, Azlocillin
B-lactamase inhibitors: Clavulanic acid, Sulbactam, TazobactamBy Jitendra Bhangale
Asst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning10
Cocci:
Streptococci
Pneumococci,
Staphylococcus aureus
Gram negative cocci-
Nelsseria gonorrhoeae
N. meningitidis
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Bacilli: Gram-positive bacilli-
B. anthracis,
Corynebacterium diphtheriae
Clostridia
Listeria
spirochetes
But Bacteroides fragilis is largely
resistant.
Antibacterial spectrum
PnG is a narrow spectrum antibiotic primarily to gram-positive
bacteria
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© 2010 Delmar, Cengage Learning11
Pharmacokinetics
Absorption
Penicillin G is acid labile-destroyed by gastric acid.
Absorption of sod. PnC from i.m. site is rapid and complete.
Distribution
It is distributed mainly extracellularly; reaches most body fluids,
but penetration in serous cavities and CSF is poor.
Excretion
Very rapid renal excretion
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning12
Adverse reaction
ThrombophlebitisMental confusionMuscular twitchingsConvulsionsComaHypersensitivity rashItchingUrticariaFeverWheezingAngioneuroticEdemaSerum sicknessExfoliative dermatitis
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Immediate type of
hypersensitivity-
Angioedema
Bronchospasm
serum sickness
Contact dermatitis
Jarisch-Herxheimer reaction
(shivering, fever, myalgia,
exacerbation of lesions, even
vascular collapse)
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© 2010 Delmar, Cengage Learning13
Therapeutic uses
Streptococcal infections
Pneumococcal infections
Meningococcal infections
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Gonorrhoea
Syphilis
Diphtheria
Tetanus and gas gangrene
© 2010 Delmar, Cengage Learning14
Acid-resistant alternative to Penicillin-G.
This is nothing but Phenoxymethyl penicillin.
It is acid stable therefore oral absorption is better.
The antibacterial spectrum of penicillin V is identical to PnG,
gram negative bacteria and anaerobes.
It is used only for streptococcal pharyngitis,
sinusitis,
otitis media,
prophylaxis of rheumatic fever
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
8/5/2012
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© 2010 Delmar, Cengage Learning15
Side chains of this class of penicillin protect the B-lactam ring from
attack by staphylococcal penicillinase.
Examples:
Methicillin
Nafcillin
Oxacillin
Cloxacillin
Dicloxacillin
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning16
It is highly penicillinase resistant but not acid resistant-must be
injected.
MRSA have emerged in many areas.
The drug of choice for these organisms is vancomycin/linezolid,
but ciprofloxacin can also be used.
Adverse effect:
Haematuria
Albuminuria
Reversible interstitial nephritis
It has been replaced by cloxacillin.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
8/5/2012
9
© 2010 Delmar, Cengage Learning17
It has an isoxazolyl side chain and is highly penicillinase as well
as acid resistant.
Oxacillin, Dicloxacillin, Flucloxacillin are other isoxazolyl
penicillins, similar to cloxacillin, but not marketed in India.
Nafcillin is another parenteral penicillinase resistant penicillin.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning18
Examples:
Aminopenicillins:
Ampicillin
Bacampicillin
Amoxicillin
Carboxypenicillins:
Carbenicillin
Ticarcillin
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Ureidopenicillins:
Piperacillin
Mezlocillin
Azlocillin
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© 2010 Delmar, Cengage Learning19
Ampicillin is not degraded by
gastric acid.
Oral absorption is incomplete.
Food interferes with
absorption.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Uses
Urinary tract infections:
Respiratory tract infections:
Meningitis:
Gonorrhoea
Typhoid fever:
Cholecystitis
Antibacterial spectrumIt is active against all organisrn sensitive to PnG; in addition many
gram-negative bacilli, e.g. H. Influenzae, E-Coli, Proteus andShigella
© 2010 Delmar, Cengage Learning20
It is an ester prodrug of ampicillin which is nearly completely
absorbed from the g.i.t.
Talampicillin,
Pivampicillin,
Hetacillin are other prodrugs of ampicillin
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
8/5/2012
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© 2010 Delmar, Cengage Learning21
Oral absorption is better
Food does not interfere with absorption
Incidence of diarrhoea is lower.
Uses:
Bronchitis, urinary infection and gonorrhoea.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning22
Carboxypenicillins
The special feature of this penicillin congener is its activity against
pseudomonas aeruginosa and indole positive proteus which
are not inhibited by PnG or aminopenicillins.
It is inactive orally and is excreted rapidly in urine
High doses have also caused bleeding by interferring with platelet
function
Ticarcillin
It is more potent than carbenicillin against Pseudomonas.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
8/5/2012
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© 2010 Delmar, Cengage Learning23
Piperacillin
This antipseudomonal penicillin is about 8 times more active than
carbenicillin.
It has good activity against Klebsiella and is used mainly in
neutropenic/immunocompromised patients having serious
gram-negative infections, and in burns.
Mezlocillin
It has activity similar to ticarcillin aqainst Pseudomonns and
inhibits Klebsiella as well.
It is given parenterally primarily for infections caused bv enteric
bacilli.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning24
B-lactamases are a family of enzymes produced by many gram-
positive and gram-negative bacteria that inactivate B-lactam
antibiotics by opening the B-lactam ring.
Examples:
Clavulanic acid
Sulbactam and.
Tazobactam
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
8/5/2012
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© 2010 Delmar, Cengage Learning25
Clavulanic acid is obtained from Streptomyces clavuligerus, it has
a b-lactam ring but no antibacterial activity of its own.
It inhibits a wide variety (class II to class V) of B-lactamases.
Clavulanic acid is a progressive inhibitor.
It is also called a 'suicide’ inhibitor, it gets inactivated after
binding to the enzyme.
It permeates the outer layers of the cell wall of gram negative
bacteria and inhibits the periplasmically located B-
lactamase.
Sulbactam and Tazobatam are semisynthetic B lactamase
inhibitor.By Jitendra Bhangale
Asst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning26
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
8/5/2012
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© 2010 Delmar, Cengage Learning27
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
It was originally obtained from the fungus Cephalosporium acremonium.
© 2010 Delmar, Cengage Learning28
First Generation CephalosporinsParenteral
CephalothinCefazolin
OralCefadroxilCephalexinCephradine
Second generation cephalosporinsParenteral
CefuroximeCefoxitin
OralCefuroxime axetilCefaclor
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Third Generation CephalosporinsParenteral
CefotaximeCeftizoximeCeftriaxoneCeftazidimeCefoperazone
OralCefpodoxime proxetilCefdinirCeftibutenCeftamet pivoxilCefixime
Forth generation cephalosporinsParenteral
CefepimeCefpirome
8/5/2012
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© 2010 Delmar, Cengage Learning29
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Parenteral
Cephalothin
Cefazolin
Oral
Cefadroxil
Cephalexin
Cephradine
© 2010 Delmar, Cengage Learning30
Streptococci
Gonococci
Meningococci
C. diphtheriae
H. influenzae
Clostridia
Actinomyces
Klebsiella
E. coli
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Antibacterial spectrum for Ist generation cephalosporins
It is a narrow spectrum antibiotic primarily to gram-positive bacteria
8/5/2012
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© 2010 Delmar, Cengage Learning31
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Parenteral
Cefuroxime
Cefoxitin
Oral
Cefuroxime axetil
Cefaclor
© 2010 Delmar, Cengage Learning32
E coli
H. influenzae
Pr. mirabills
C. diphtheriae
H. Influenzae
None inhibits P. aeruginosa
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Antibacterial spectrum for II generation cephalosporins
It is a narrow spectrum antibiotic primarily to gram-negative
bacteria
8/5/2012
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© 2010 Delmar, Cengage Learning33
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
ParenteralCefotaximeCeftizoximeCeftriaxoneCeftazidimeCefoperazone
OralCefpodoxime proxetilCefdinirCeftibutenCeftamet pivoxilCefixime
© 2010 Delmar, Cengage Learning34
E coli
Pseudomonas
H. Influenzae
Not active on anaerobes
(particularly Bact. fragilis), Staph. aureus and Ps. aeruginosa
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Antibacterial spectrum for III generation cephalosporins
It is primarily active against gram-negative bacteria.
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© 2010 Delmar, Cengage Learning35
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Parenteral
Cefepime
Cefpirome
Oral
Not invented yet
© 2010 Delmar, Cengage Learning36
Highly resistance to B lactamase
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Antibacterial spectrum for IV generation cephalosporins
Similar to III generation cephalosporins.
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© 2010 Delmar, Cengage Learning37
Pain
Diarrhoea
Hypersensitivity reactions
Nephrotoxicity
Bleeding
Neutropenia and thrombocytopenia
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning38
Respiratory, urinary and soft tissue infections
Penicillinase producing staphylococcal infections
Septicaemias
Surgical prophylaxis
Meningitis
Gonorrhoea
Typhoid
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
8/5/2012
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© 2010 Delmar, Cengage Learning39
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad