for students

1. Beta – Lactam Antibiotics

2. • Penicillins
• Cephalosporins
• Monobactams
• Carbapenems

3. Cell Wall Acting Biosynthetic Antibiotics
Penicillins
Cephalosporins
Carbapenems
Monobactams
Glycopeptides

4. Penicillins
discovered in London in 1928 by Alexander Fleming
(Scottish scientist)
produced by the fungi penicillium
 Penicillium notatum,
 The first man to be treated with penicillin was a policeman.

5.  by Alexander Fleming (1881-1955),
 Howard Florey ( 1898-1968) and
 Ernst Chain (1906-1979), penicillin was first produced on a large
scale for human use in 1943.
 many lives were saved during World War II because this
medication was available.
E. Chain H. Florey
A. Fleming

6. Penicillins
Produced by Penicillium chrysogenum
Modifications:
decrease acid lability;
increase absorption;
resistant to penicillinase;
broader spectrum (e.g., Ampicillin).

7. Chemistry and properties
C
R - C - NH - CH
O
CH3
CH3
C
S
N
CH
COOH
=
O
2 1
2 - Beta lactam ring
1 - Thiazolidine ring
Penicillin – F, G, X, K.

8. C
R - C - NH - CH
O
CH3
CH3
C
S
N
CH
COOH
Amidase
Different semisynthetic Penicillins
6-Amino
penicillanic
acid
Na, K
=
O
CH
Unitage
1U of crystalline sod. Benzyl penicillin = 0.6 μg of std ppn.
1g = 1.6 million units or 1 MU = 0.6 g

9. Penicillin acts on which component of cell wall

10. Gram-negative cell Gram-positive cell
Outer membrane
Peptidoglycan
Peptidoglyca
Penicillin
Binding proteins
(PBPs)
Inner (cytoplasmic) membrane

11. Transpeptidase
D-Alanine
Penicillins
Cephaosporins
Glycine
L-Lysine
D-Glutamate
L-Alanine
D-Alanine
D-Alanine
PENICILLINS & CEPHALOSPORINS

12. MECHANISM OF ACTION
They act by inhibition of bacterial cell wall synthesis
1. The β-lactam binds to Penicillin Binding Protein (PBP)
2. PBP is unable to crosslink peptidoglycan chains
Thus exposing the osmotically less stable membrane
This cause lysis of bacterial cell wall
BACTERICIDAL

13. Mechanism of Action
 Penicillin binding proteins
 Enzymes involved in forming cross linkages between
peptidoglycan chains inactivated by penicillin
 Inhibition of transpeptidase
Hinders last step in formation of cross links needed for cell wall
integrity
Active against multiplying and not resting bacteria
Inactive against mycobacteria, protozoa, fungi and viruses

14. Antibacterial Spectrum
 Penicillins are active against Gram positive bacteria
but susceptible to Beta-lactamase.
Gram- positive aerobic cocci – Staph, S.pneumoniae (gpA),
S.pyogenes.
Gram-negative cocci -N.meningitidis & gonorrhea.

15. Gram- positive bacilli : Bacillus anthracis, Clostridium sp.
Corynebacterium diphtheriae
Listeria : Highly sensitive.
Spirochetes : T. pallidum, Leptospira,
Actinomycetes israelii – mod. Sensitive.
but inactive against B.fragilis, Anaerobes
Gram negative bacteria, Myco. Tuberculosis,
Rickettsiae,Clamydiae, protozoa,
fungai and viruses - Insensitive
Antibacterial Spectrum

16. Bacterial Resistance
1. b-lactamase activity
• Hydrolyzes cyclic amide bond of b-lactam ring
• Usually acquired by transfer of plasmids
2. Decreased permeability to drug
3. Altered penicillin binding proteins, Porin channels
antibiotic unable to penetrate
4. Efflux

17. Absorption,distribution & metabolism
 Administration -- Oral, IV, IM
Penicillin G – acid labile
Oral absorption of most penicillins is poor
( except penicillin v, Amoxicillin)
Distribution
Widely distributed (extracellular)
Tissue Penetration --- excellent ( body fluids)
have poor penetration into BBB
Inflammation ( eg. Meningitis ) permits entrance into CSF

18. Half life --- 30min.
Metabolism ---- Minimal, except in renal failure
Excretion - Kidney - Glomerular filteration, tubular secretion.
Adjust dose in renal compromise
Probenecid inhibits penicillin secretion

19. Preparations and dose
Sod. penicillin G (crystalline penicillin) injection 0.5-5 MU i.m./i.v.
6-12 hourly.
It is available as dry powder in vials to be dissolved in sterile water
at the time of injection.
Repository penicillins
Developed to prolong duration of penicillin G in the blood
1. Procaine penicillin G . Duration 12- 24 hr
It is given i.m and not i.v ( risk of procaine toxicity)
aqueous suspension.

20. Fortified procaine penicillin G inj:
3 lac U procaine penicillin and 1 lac U sod. penicillin G
rapid & sustained blood levels.
FORTIFIED P.P. INJ 3+1 lac U vial.
2. Benzathine penicillin G: 0.6-2.4 MU i.m. every 2-4 weeks
aqueous suspension.
It releases penicillin extremely slowly-plasma concentrations
effective for prophylactic purposes for up to 4 weeks:
 PENIDURE-LA
Repository penicillins ( cont.)

21. Adverse effects of penicillins
1.Hypersensitivity reactions ( occur in 1-10% of pts;
fatality occur in 0.002%)
( immediate, accelerated & late allergic reactions)
Urticarial rash, Fever, Bronchospasm
Serum sickness, Exfoliative dermatitis
Stevens- Johnson syndrome
Penicilloic acid- hapten for immune reaction
b-lactam ---- cross reactivity
Procaine penicillin

22. • Acute (< 30 min)
• Urticaria, angioedema, bronchoconstriction, GI, shock
• Accelerated (30 min- 48 hrs)
• Urticaria, pruritis, wheezing, mild laryngeal edema, local inflammatory
reactions
• Delayed (> 2 days)
• Skin rash
• Oral glossitis, flurred tongue, black and brown tongue, cheilosis, severe
stomatitis with loss buccal mucosa
Skin tests: benzylpenicilloyl-polylysine

23. 2. Local irritancy and direct toxicity
3. Super infections -- Diarrhoea
4. Jarisch-Herxheimer reaction
syphilitic patient (particularly secondary syphilis)
shivering, fever, myalgia, exacerbation of lesions, vascular collapse
sudden release of spirochetal lytic products
( lasts for 12-72 hours)

24. Uses of penicillin G
1. STREPTOCOCCAL INFECTIONS
Pharyngitis
Otitis media
Scarlet fever
Rheumatic fever
7-10 days
Subacute bacterial endocarditis
Penicillin G 10-20 MU i.v.
daily
⁺
Streptomycin 0.5 g i.m BD
or
Gentamicin - 2-6 wks

25. 2. Pneumococcal infections
Not recommended for empirical therapy
Pneumococcal (lobar) pneumonia
Meningitis
PnG 3-6 MU i.v. 6hry
Penicillin sensitive

26. 3. Meningococcal infections
meningitis high dose i.v.
4.Gonorrhoea
ophthalmia neonatorum
saline irrigation
+
sod. PnG 10,000-20,000 U/ml 1
drop in each eye every 1-3
hours
severe cases- 50,000 U i.m. BD for 1 week in
addition

27. 5. Syphilis - T. pallidum
drug of choice
1. Early and latent syphilis
Inj. procaine penicillin 1.2 MU daily for 10 days or
Inj .benzathine penicillin 2.4 MU 1-3 weekly
2. Late syphilis
Benzathine penicillin 2.4 MU weekly for 4 weeks
3. Cardiovascular and neurosyphilis
sod. PnG. 5 MU i.m. 6 hourly for 2 weeks followed by the above
regimen
4. Leptospirosis
PnG 1.5 MU i.v. 6 hourly for 7 days - curative.

28. 6. Diphtheria
Antitoxin therapy – primary treatment
Procaine penicillin 1-2 MU daily for 10 days - prevents carrier
state
7. Tetanus and gas gangrene
Antitoxin – primary treatment
PnG 6-12 . MU / day- kill the causative organism

29. 8. Rare infections
1. Anthrax
2. Actinomycosis
3. Trench mouth
4. Rat bite fever
5. Listeria monocytogenes
6. Pasteurella multocida
Drug of choice

30. 9. Prophylactic uses
(a) Rheumatic fever:
Benzathine penicillin - 1.2 MU X 4 weeks till 18 yrs
or 5 years after an attack
(b) Bacterial endocarditis:
PnG – protection
amoxicillin
(c) Agranulocytosis patients:
Penicillin alone
Penicillin ⁺ aminoglycoside

31.  Procaine penicillin and benzathine penicillin are
salts of PnG and not semisynthetic penicillins.
 The aim of producing semisynthetic penicillins
has been to overcome the shortcomings of PnG.
SEMISYNTHETIC PENICILLINS
31

32. 1. Poor oral efficacy.
2. Susceptibility to penicillinase.
3. Narrow spectrum of activity.
4. Hypersensitivity reactions (this has not been
overcome in any preparation).
Drawbacks of Penicillin G
32

33. CLASSIFICATION
1. Acid-resistant alternative to penicillin G
Phenoxymethyl penicillin (Penicillin V).
2. Penicillinase-resistant penicillins Methicillin, Cloxacillin.
3. Extended spectrum penicillins
(a) Aminopenicillins: Ampicillin, Bacampicillin, Amoxicillin.
(b) Carboxypenicillins: Carbenicillin, Ticarcillin.
(c) Ureidopenicillins: Piperacillin, Mezlocillin.
β-Iactamase inhibitors:
Clavulanic acid, Sulbactam, Tazobactam
SEMISYNTHETIC PENICILLINS
33

34. Acid resistant Penicillins
Phenoxy methyl penicillin (penicillin v)
Acid stable
spectrum of activity is similar to penicillin G
Oral absorption ---- better
plasma t 1/2 --- 30-60 min.
Neisseria
gram negative bacteria and
anaerobes Less active

35. Uses
streptococcal pharyngitis, sinusitis, otitis media,
prophylaxis of rheumatic fever
less serious pneumococcal infections
trench mouth.
Dose: 250-500 mg,
children 125-250 mg given 6 hourly,
(250 mg = 4 lac U)

36. C NH CH CH C
O
O C N CH
CH3
CH3
COOH
S
Site of penicillinase action
Breakage of the lactam ring
PENICIlLINASE RESISTANT PENICIlLINS
side chains that protect the β lactam ring from attack by
staphylococcus

37. Penicillinase-resistant penicillins
Methicillin Oxacillin
Cloxacillin Dicloxacillin
Floxacillin Nafcillin
Lower activity against G+ compared to Penicllin G
For infections caused by penicillinase producing S. aureus.
However, MRSA has emerged.
Not effective against G- aerobes( E.coli, klebsiella,N.gonorrhea or
pseudomonas spp.) & anaerobes.
High protein and food binders

38. PENICIlLINASE-RESISTANT PENICIlLINS
non penicillinase producing penicillin - less sensitive
 For beta-lactamase-producing staphylococci,
 penicillin-susceptible strains of streptococci and pneumococci are
also susceptible.
Group A Streptococcal pharyngitis
Prophlaxis against group A streptococci
 In pts with history of rheumatic heart disease. 250–500 mg orally
every 4 to 6 h
(25 mg/kg/d for children), is suitable for treatment
 mild to moderate localized staphylococcal infections

39. Methicillin
Penicillinase resistant & not acid resistant.
PK - similar to Penicillin G.
Methicillin Resistant staphylococci Aureus (MRSA) – common
Side effects
Hematuria , albuminuria, nephritis

40. MRSA Resistance to Beta-Lactams
Beta-Lactam
Modified from David Spach, MD
Cell Wall
Cell Membrane
Alternative Penicillin Binding
Protein PBP2a
DNA

41. Cloxacillin
Aromatic ring attachment - resistant to acid hydrolysis ,
protect the lactam ring from degradation
non penicillinase producing organisms - less sensitive
Penicillinase producing staphylococci Aureus -- More
active than methicillin
T ½ - 1hour.
250–500 mg orally every 4 to 6 h

42. 


 












L









 L
L
L
L
L
L
L 
L
-lactamase
production

43. Extended Spectrum Penicillins
AMPICILLIN
 Amino group - confers more activity to pass through cell wall
barriers
 Ampicillin penetrate both Gm-positive and Gm-negative bacteria
 Activity against H.influenza, proteus , E. coli, and salmonella &
shigella.
 Resistance due to plasmid mediated penicillinase
 Oral absorption – Incomplete. Enterohepatic circulation
 T ½ - 1hr.
 Dose 0.5 – 2g oral/ IM/ IV. Every 6h.
Ampicillin + sulbactam

44. Adverse effects
Gastric upset – Diarrhoea
bacterial flora alteration
Ampicillin Rash
 develops if patient has AIDS, EB virus or lymphoma
Interactions
Hydrocortisone inactivates ampicillin
Oral contraceptive failure
Probenacid - retards ampicillin excretion

45. AMPICILLIN
Uses
1. Respiratory tract infection (H. Influenza) -- otitis media, sinusitis,
chronic bronchitis, pneumonia.
2. Bacterial meningitis
3. Urinary & biliary infections - E. Coli
4. Typhoid fever - Samonella infections
5. Gonorrhea
6. Bacillary dysentry - Shigella
7. Prophlaxis of infective endocarditis

46. Amoxicillin
Simillar to Ampicillin
Oral absorption is good
Diarrhoea – Less.
Less active against H.influenza, and shigella.
Amoxicillin- clavulanic acid (augmentin)
For -- chronic bronchitis, Urinary infections, SABE, gonorrhea.
DOSE - 0.25–1g orally every 4 to 6 h.

47. •Carboxypenicillins
- Carbenicillin, Ticarcillin
•Ureidopenicillins
- Mezlocillin, Piperacillin
Antipseudomonal penicillins
These drugs retain activity against streptococci
additional effects against Gram-negative organisms
Enterobacteriaceae and Pseudomonas.

48. Carbenicillin
First antipseudomonal carboxypenicillin
Also indole positive Proteus which are not inhibited by PnG or
aminopenicillins
E. coli, salmonella, enterobacter & gm positive cocci. –
less active
Oral absorption -- No
DOSE - 1- 2g IM every 4 to 6 h.
Indications
Serious infections caused by Pseudomonas or Proteus (e.g. burns,
urinary tract infection, septicaemia)
more active, better tolerated alternative --- Ticarcillin

49. Ureidopenicillins
piperacillin, mezlocillin
8 timesmore potent than Carbencillin
selected Gram-negative bacilli such as K. pneumoniae.
antipseudomonal penicillin is frequently used in combination with
an aminoglycoside or fluoroquinolones.
Neutropenic/ immunocompromised patients
Disadvantages
Ticarcillin and piperacillin are readily destroyed by S.penicillinase

50. b-lactamase Inhibitors
b-lactamases are a family of enzymes produced by many
gram-positive and gram-negative bacteria.

51. C NH CH CH C
O
O C N CH
CH3
CH3
COOH
S
Site of penicillinase action
Breakage of the lactam ring
BETA-LACTAMASE INHIBITORS
•Clavulanic acid
•Sulbactam
•Tazobactam

52. Clavulanic acid
Streptomyces clavuligerus .
It has b lactam ring
No antibacterial activity of its own.
It inhibits a wide variety (class II to class V) of b lactamases
( not class I cephalosporinase) ---- both gram-positive and gram-
negative bacteria.
'progressive' inhibitor : reversible & covalent inhibition
'suicide' inhibitor --- inactivated after binding to the enzyme.

53. Pharmacokinetics
oral absorption -- rapid
bioavailability --- 60%.
Its elimination t1/2 of 1 hr.
Tissue distribution matches amoxicillin (coamoxiclav).
Elimination --- glomerular filtration and its excretion is not
affected by probenecid.
Amoxicillin --- excreted unchanged by tubular secretion.

54. Coamoxiclav
 Skin and soft tissue infections
 intra-abdominal (empirical therapy)
 gynaecological sepsis hospital acquired infections
 urinary, biliary and respiratory tract infections
 Gonorrhoea - amoxicillin 3 g + clavulanic acid 0.5 g + probenecid 1 g
single dose
AUGMENTIN: Amoxicillin 250 mg + clavulanic acid 125 mg
500 mg + 125 mg tab; 1-2 tab TDS.
AUGMENTIN: Amoxicillin 1 g + clavulanic acid 0.2 g vial
0.5 g + 0.1 g vial i.m. or i.v. 6--8 hourly

55. semisynthetic b lactamase inhibitor
It is also a progressive inhibitor
highly active against class II to V but poorly active against class I
b lactamase.
Oral absorption --- inconsistent, given parenterally.
It has been combined with ampicillin for use against
b lactamase producing resistant strains.
Ampicillin 1 g + sulbactam 0.5 g per vial inj
1-2 vial deep i.m. or i.v. injection 6-8 hourly.
Sulbactam

56. Tazobactam
Similar to sulbactam.
Its pharmacokinetics matches with piperacillin
Severe infections --- peritonitis, pelvic / urinary / respiratory
infections ( β lactamase producing bacilli).
not active against piperacillin-resistant Pseudomonas,
(does not inhibit inducible chromosomal β lactamase
produced by Enterobacteriaceae).
Dose: 0.5g with piperacillin 4 g injected iv. over 30 min
8 hourly.