pharmacology of antimicrobial agents

1. BETA LACTAM
ANTIBIOTICS
PREPARED BY:-
VINEET SRIVASTAVA
M.PHARM (PHARMACOLOGY)
UNITED INSTITUTE OF PHARMACY
PRAYAGRAJ

2. INTRODUCTION
 ANTIBIOTICS:-substances produced by microorganisms, which selectively
suppress the growth of or kill other microorganism at low concentration.
Beta-lactam antibiotics:-These are antibiotic having Beta lactam ring.
 Two major groups are:-
a) Penicillins
b) Cephalosporins
 Others:-
a) Monobactams
b) Carbapenems

3. HISTORY
 Penicillin, the world’s first antibiotic, was discovered by British scientist Alexander
Fleming in 1928 on accident.
 Penicillin was the first antibiotic to be used clinically in 1941.
 Originally obtained from fungus Penicillium notatum.
 Present source is high yielding mutant of P. chrysogenum.
Fleming, Florey and Chain received a Nobel prize in
1945 for medicine for their work on penicillin.

4. CHEMICAL STRUCTURE
 (1) Thiazolidine ring;
 (2) β-lactam ring;
 (X) Bond which is broken by penicillinase
 Consists of fused thiazolidine and β-lactam
 rings to which side chains are attached
through an amide linkage.
 Penicillin G ,having a benzyl side chain
at R (benzyl penicillin), is original penicillin
used clinically.
 Stable in dry state, but solution deteriorates rapidly
at room temp, though it remains stable at 4°C for 3 days.

5. MOA OF PENICILLIN
 Penicillin is a group of antibiotics that are commonly used to treat different
types of gram positive and gram negative bacteria infections.

6. MOA PENICILLIN
 Interfere with the synthesis of bacterial cell wall.
 Cell wall composed of peptidoglycan, glycon consists of two amino sugars:-
1) N-acetylmuramic acid
2) N-acetylglucosamine
 Peptidoglycan residues are linked together forming long stands and UDP is
split off.
 Final step is cleavage of D-alanine of the peptide by transpeptidase.
 This cross bridging provide strength to bacterial cell wall.
 Beta lactam antibiotics inhibit the trans peptidase so that cross linking does not
take place.

7. PENICILLIN
BIND (PBP) ON THE CELL WALL OF SUSCEBTIBLE BACTERIA
INHIBITS TRANSPEPTIDATION
PREVENTS PEPTIDOGLYCAN SYNTHESIS
CELL WALL DEFICIENT FORMS SPHEROPLASTS AND
FILAMANTOUS FORMS
AUTOLYSIS
CELL DEATH (BACTERIALACTION)

8. CLASSIFICATION
 Natural Penicillins-Penicillin G
 Semisynthetic Penicillin-
Acid Resistant:-Penicillin V
Penicillinase resistant:-Methicillin, Cloxacillin
 Extended Spectrum-
Amino Penicillin:-Ampicillin, Amoxycillin, Bacampicillin
Carboxy Penicillin:-Carbenicillin, Ticarcillin
Ureido Penicillin:-Pipetacillin, Mezlocillin

9. Penicillin G
 Narrow spectrum
antibiotic
 Primarily to gram
positive cocci, bacilli
and few gram negative
 Obtained from fermentations
of the mold Penicillin chrysogenum.

10. PHARMACOKINETIC
 Penicillin G is acid labile and destroyed by
gastric juice.
 Food interfere with its absorption, hence given
2 hr after meal.
 Do not cross BBB, but inflamed menninges.
 Probenecid blocks the renal tubular secretion of
penicillin, prolong its duration of action.
 Plasma t1/2 is 30 min.
 Neonates have slower tubular secretion.
 10 percent excreted from glomerular filtration
and rest by tubular secretion

11. CLINICAL USE
 Drug of choice for infection caused by
 Streptococci
 Maningococci
 some Enterococci
 Actinimyces
 non β lactamase producing gram negative
 anaerobic organism
 Clostridium species other gram positive rods
 etc.

12. SIDE EFFECTS
 Penicillin G is one of most non-toxic antibiotics.
 20MU can be injected in a day without any organ
toxicity.
 Local irritancy
 Hypersensitivity.
 Manifestation of penicillin allergy are:-
 Superinfections
 Jarisch-Herxheimer reaction.

13. ACID RESISTANT PENICILLINS
PENICILLIN V (Phenoxymethyl Penicillin)
 Orally active
 Acid labile
 Blood level is reached in 1 hr
 T1/2 is 30-60 min
 Antibacterial spectrum is identical to Penicillin G, but about 1/5 is active
against Neisseria, other gram negative bacteria and anaerobes.
 Used in streptococcal pharyngitis, sinusitis, otitis media etc.
 DOSE:-
250-500 mg-given 6 hourly.
infants:- 60 mg

14. PENICILLANASE-RESISTANT PENICILLIN
 Antistaphylococcal penicillin
 These penicillin are resistant to staphylococcal β-lactamases.
 They are active against staphylococci and streptococci
but not against enterococci, anaerobic bacteria and gram negative
cocci and rods.
 These congeners have side chains that protect the beta lactam ring
from attack by staphylococci penicillinase.
 Indicated in infections caused by penicillinase producing staphylococci
(drug of choice, except in MRSA).
 Non-penicillinase producing organisms are less sensitive to these
drugs to PnG.

15. METHICILLIN
 Acid labile
 Not used clinically, except to identify resistant strains.
 MRSA is succeptible to vencomycin/linezolid and rarely ciprofloxacin.
 It is highly penicillinase resistant but not acid resistant-must be injected.
 Adverse reaction-haematuria, albuminuria, reversible interistitial
nephritis.
 It is no longer used.

16. CLOXACILLIN/DICLOXACILLIN
 Isoxazolyl side chain
 Highly acidic and penicillinase resistant
 More active than metyhicillin
 Less active against PnG sunsitive organism.
 Should not be used as substitute of PnG
 Given in staphylococcus infection
 >90% protein bound, eliminate primarily by kindey and liver.
 Plasma t1/2 is about 1 hr.

17. EXTENDED SPECTRUM PENICILLIN
 These drug retain the antibacterial spectrum of penicillin and
have improved activity against gram-negative organisms.
 Like penicillin, however, they are relatively succeptible
to hydrolysis by β-lactamase.
EXAMPLE:-
 Aminopenicillin:-Ampicillin, Amoxycillin, Bacampicillin
Carboxypenicillin:-Carbenicillin, Ticarcillin
Ureidopenicillin:-Pipetacillin, Mezlocillin

18. AMPICILLIN
 Active against all organism sensitive to PnG.
 In addition, many gram negative organism bacilli eg H. influenza, E. coli,
Helicobactor pylori etc.
 More activethan PnG for Strep. viridians, enterococci and Listeria etc.
PHARMACOKINETICS:-
 Acid resistant
 Oral absorption is incomplete but adequate
 Primary excreation is kidney, partly enterohepatic circulation occurs.
 Plasma half life is 1 hr.

19. AMPICILLIN
USES:-
 UTI, RTI, Meningitis, Gonorrhoea, typhoid fever, bacillary dysentry
Cholecystitis, Acute necrotizing ulcerative gingivitis and Septicemias etc.
ADVERSE EFFECT:-
 Diarrhoea (it is incompletely absorbed- the unabsorbed drug irritates the lower
intestine as well as caused marked alteration of bacterial flora).
 Rashes
 hypersensitivity

20. AMPICILLIN
INTERACTIONS:-
 Hydrocortisone- inactivates ampicillin if mixed in the I.V solution.
 Oral contraceptive- failure of oral contraception.
 Probenecid- retards renal excretion.
DOSE:-
 Adult 250-500 mg every 6 hr
 Child 50-100 mg/kg given in equally divided doses every 6 hr
 Maximum 2-4 g/day.

21. CARBENICILLIN
 Penicillin congener
 Special feature- it is active against Pseudomonas aeriginosa and
indole positive Proteus.
 It is neither penicillinase resistant nor acid resistant.
 It has gram negative coverage which includes Pseudomonas aeriginosa but
limited coverage in gram positive bacteria.
 Less active against salmonella, E. coli, Enterobacter.
 Klebisella and gram postive cocci are remain unaffected.

22. CARBENICILLIN
USES:-
 Burns
 Septicemia
 Urinary tract infection
 Uncomplicated gonorrhoea
PHARMACOKINETICS:-
 orally inactive
 Rapidly excreted in Urine
 Plasma half life 1 hr
 Dose 1-2 g i.m or 1-5 g i.v.

23. UREIDOPENICILLINS
PIPERACILLIN
 These are called antipseudomonal penicillins
 Piperacillin is 8 times more potent then carbenicillin
 It has good activity against Klebsiella, many enterobacteriacae
and some Bacteroids.
 It is used mainly in neutropenia/ immunocompromised
or burn patients and serious gram negative infections.
 Concurrent use of gentamicin or tobramycin
is advised.
 Elimination t½ is 1 hr.

24. BETA LACTAMASE INHIBITORS
INTRODUCTION
 Three inhibitors of this enzyme clavulanic acid,
sulbactam and tazobactam.
 They contain Beta lactam rind but themselves,
do not have significant anti bacterial activity.
 Inactivate bacterial β-lactamases and are used to enhance
the anti bacterial actions of β-lactam antibiotics.
 These are clinically use in combination with specific
penicillin or cephalosporins.

25. CLAVULANIC ACID
 Obtained from Streptomyces clavuligerus
 it has a β-lactam ring but no antibacterial activity of its own.
 It inhibits a wide variety (class II to class V) of β-lactamases
(but not class I cephalosporinase).
 It is a ‘progressive’ inhibitor: binding with β-lactamase is reversible
initially, but becomes covalent later—inhibition increasing
with time.
 Called a ‘suicide’ inhibitor, it gets inactivated after binding to
the enzyme.

26. PHARMACOKINETICS
 Rapid oral absorption.
 Bioavailibility- 60%
 t½ is 1 hr.
 Pharmacokinetics matches amoxicillin with which it is used.
 it is eliminated mainly by glomerular filtration and its excretion
is not affected by probenecid.
 Addition of clavulanic acid re-establishes the activity of amoxicillin against β-
lactamase producing resistant Staph. aureus, H.influenzae, N. gonorrhoeae,
E. coli, Proteus, Klebsiella, Salmonella Shigella and Bact. fragilis

27. USES:-
 Odontogenic infection.
 Skin and soft tissue infection.
 Respiratory tract infection.
 Intra abdominal and gynaecological infection.
SIDE EFFECTS:-
 G.I tolerance is poor
 Candida stomatitis
 Rashes
 Hepatic injury in some cases have been reported.

28. CEPHALOSPORINS
BY THE ADDITION OF DIFFERENT SIDE CHAINS
 At position 7 antibacterial spectrum against specific organism can be altered.
 At position 3 pharmacokinetics can be altered.

29.  Cephalosporins is a group of semisynthetic antibiotics
 First isolated from fungus Cephalosporium.
 All cephalosporins are bactericidal and have same
mechanism of action as penicillin.
MOA:-
 Inhibition of bacterial cell wall synthesis
 Transpeptidases enzyme is inhibited leading to
failure of cross linkage of peptide chain of strands
no stability to cell wall.
 Bactericidal action is exhibited by lysis of cell wall
deficient.

30. CLASSIFICATION

31. CEFAZOLINE
 These were developed in 1960s.
 Have high activity against gram positive bacteria but weaker
against gram negative bacteria.
 It is prototype drug active against streptococci, gonococci, H, influenza etc.
 Quit susceptible to staphylococcal β lactamase.
 Can be given I.M or I.V
 Has longer t1/2 due to slower tubular screation.
 Half life is 2hr.

32. ADVERSE EFFECT:-
 Pain after I.M injection.
 Diarrhoea
 Hypersensitivity reaction
 Neutropenia
 Thrombocytopenia
 Nephrotoxicity
 Asthma
 Urticaria

33. USES:-
 Commonly used antibiotics
 Alternative to penicillin in ENT, upper tract infection
 RTI, UTI and soft tissue infection
 Skin infection
 Septicaemia
 Surgical prophylaxis
 Meningitis
 Typhoid
 Gonorrhoea

34. MONOBACTAM
AZTREONAM
 Monocyclic β lactam ring.
 Β lactam ring is not fused with another.
 Narrow spectrum antibiotic.
 Structurally similar to ceftazidime.
 Inhibit gram-negative enteric bacilli and
H. influenza.
 Does not inhibit gram-positive bacteria.
 MOA is to binds to PBP-3 which break
the bacterial cell.

35. PHARMACOKINETIC
 Poor oral absorption
 Route of administration is I.V or I.M.
 Eliminated unchanged in Urine
 Plasma half life is 1.8 hr.
ADVERSE EFFECT
 Nausea
 Skin rashes
 Elevation of serum aminotransferase
 Occasionally abnormal liver function

36. CLINICAL USES
 Use in patient allergic to peniciilin and cephalosporin
 Pneumonia
 Hospital acquired pneumonia
 Meningitis
 Sepsis
 Urinary tract infections
 Osteomylitis

37. CARBAPENEMS
 Carbapenems are β lactams that contain fused
β lactam ring system- different from penicillins.
 It is unsaturated & contains a carbon atom
instead of the sulfur atom.
 MOA is same as other β lactamase.
Example
 Imipenam
 Meropenem
 Faropenem
 Doripenem
 Ertapenem

38. IMIPENEM
 Derivative of thienamycin
 Potent and broad spectrum antibiotic
 Inhibit gram postive cocci, Enterobacteriacae and listeria
as well as anarobes bacteria fragilis.
 Rapidly hydrolysis by the enzyme dehydropeptidase I.
 Given with cilastatin which block its breakdown in kidney.
DOSE
 Imipenem-cilastatin 0.5 g i.v. 6 hourly
 4g/day is effective dose in wide reange.

39. CLINICAL USES:-
 Hospital-acquired respiratory.
 Urinary tract infections
 Abdominal and pelvic infections
 Skin infection
 Neutropenia
 Cancer and AIDS patient
 Ps. aeruginosa infection should be combined with gentamycin.

40. PHARMACOKINETIC
 Not absorbed orally.
 All carbapenems are eliminated from kidney
 Dose reduction is needed in renal failure.
 Plasma half life.
ADVERSE EFFECT
 At high dose induce seizures
 Diarrhoea
 Vomiting
 Skin rashes and hypersensitivity.