For MBBS/BDS as part of Antimicrobial agents

1. β-Lactam Antibiotics

2. • BETA-LACTAM ANTIBIOTICS (inhibitors of cell wall synthesis)
• Drugs includes- Penicillin, cephalosporin, Monobactam & Carbapenem
• All of them have β -lactam ring in their chemical structure
• Penicillin:-
• First antibiotic developed &
used clinically
Discovered accidentally by
Alexander Fleming(1928)
High-yielding source→ Penicillium chrysogenum
Low- yielding source→ Penicillium notatum
• The side chain of natural penicillin can be split off by an amidase to
produce 6-aminopenicillanic acid
β-Lactam ring
Thiazolidine
ring

3. • β-Lactam ring is broken by – Penicillinase (β-Lactamase), and by gastric acid.
• Resultant Product is Penicilloic acid with
• No anti-bacterial activity but
• Acts as antigenic determinant (Major determinant)
• Bacterial Cell wall is composed of Peptidoglycans
Cross linked by peptide chains.
• NAM – NAG-(Aminosugar)
• ( N-acetyl muramic acid and N- acetyl
glucosamine)
• Cross linked by a Pentaglycine cross bridge
• Cross bridging is transpeptidation reaction.
• Transpeptidase and related proteins (Penicillin Binding Proteins) are used for
making cross linkage.
• Cross linking provides stability, strength

5. • MOA:- All β-lactams antibiotics
↓↓
Bind to specific receptor called PBP(Penicillin binding protein) located on outer cell
membrane of bacteria
↓↓
Inhibit cell wall synthesis of bacteria by inhibiting transpeptidation
↓↓
(Bactericidal Action)
Result:-
Damage of cross linking
Weakening of cell wall
Bacterial membrane bursts
Bacterial lysis

6. Mechanism of bacterial resistance to penicillins:-
1. by producing β-lactamases, which destroy the β-lactam ring, e.g. S. aureus, E.
coli, gonococci, H. influenzae, etc.
2. due to altered PBPs, which have less affinity for β-lactams, e.g. S. pneumoniae
3. due to decreased ability of the drug to penetrate to its site of action
Pharmacokinetics:-
Most of the orally administered penicillin G is destroyed by gastric acid (acid
labile); hence penicillin-G is usually given by i.v. route.
It can also be administered by i.m. route but is painful
Distribution- throughout body tissues, but poorly crosses the BBB (except-
meningitis)
Metabolism- less bcoz of rapid excretion
Excretion:-urine mainly by active tubular secretion
Slow excretion in neonate & infants→renal function is not completely developed

7. The action of penicillins can be augmented and prolonged by giving
probenecid simultaneously. Mechanism includes
1.Probenecid block the Tubular secretion of Penicillin –G
2.Probenecid also ↓ the Volume of distribution of penicillin
Classification of Penicillin:- Penicillin
Natural penicillins
Penicillin-G Procaine penicillin G Benzathine penicillin G
Semisynthetic penicillins
Acid-resistant penicillin Penicillinase-resistant
penicillins
Extended-spectrum
penicillins
Phenoxymethyl
penicillin
(Penicillin V)
Methicillin
Oxacillin
Cloxacillin
Dicloxacillin
Aminopenicillins
Carboxypenicill
ins
Ureidopenicillin
s

8. Extended-spectrum penicillins
Aminopenicillins
Ureidopenicillins
Carboxypenicillins
Ampicillin
Amoxicillin
Carbenicillin
Carbenicillin indanyl
Ticarcillin
Mezlocillin
Piperacillin
Depot penicillins:-
Penicillin-G + poorly water-soluble compounds such as procaine, benzathine
Result- Aqueous suspension
Penicillin-G Procaine penicillin G Benzathine penicillin G Fortified procaine penicillin G
Duration-4–6 h 12–24 h 3–4 weeks 12–24 h
Rapid onset of action Moderate plasma
concentration
Slow onset but has longest duration
of action
Rapid onset with high plasma
concentration and
longer duration of action
severe infections—
meningitis, endocarditis,
pneumonia, etc
used in mild to-
moderate infections
Used in syphilis, rheumatic
fever prophylaxis, etc
used in mild-to-moderate
infections by sensitive organisms

9. Precautions for using Penicillin-G therapy:-
1. Before giving penicillin, history of previous administration and allergic
manifestations, if any, must be noted.
2. In patients with history of asthma, allergic rhinitis, hay fever, etc. there is an
increased risk of penicillin allergy; hence it should be avoided in such cases.
3. Sensitivity test should be performed by an intradermal test on the ventral aspect
of forearm. Itching, erythema and wheal formation are watched for. A negative skin
test does not ensure absolute safety.
4. Inj. adrenaline and
hydrocortisone should be kept
ready before injecting penicillin
to treat the anaphylactic reaction

10. Adverse reactions of penicillin G:-
1. Hypersensitivity reactions(type-I), such as skin rashes, urticaria, fever,
dermatitis, bronchospasm, angioedema, joint pain, serum sickness or anaphylactic
reaction.
• It is not a dose-related adverse drug reaction and can occur with any dosage form
of penicillin.
• Rx of Anaphylactic shock-
• 1. Inj. adrenaline 0.3–0.5 mL of 1:1000 solution intramuscularly.
• 2. Inj. hydrocortisone 200 mg intravenously.
• 3. Inj. diphenhydramine 50–100 mg intramuscularly or intravenously
• Jarisch–Herxheimer reaction:-It is an acute exacerbation of signs and symptoms
of syphilis during penicillin therapy due to release of endotoxins from the dead
organisms.
• The manifestations are fever, chills, myalgia, hypotension, circulatory collapse,
etc.
• Rx-with aspirin and corticosteroids.

11. Therapeutic uses of penicillin G:-
In dentistry:- necrotizing gingivitis, periodontal infections, etc. either alone or
with metronidazole
Pneumococcal infections: In pneumonia, meningitis or other serious infections,
3rd -generation cephalosporins (DOC). However, i.v. penicillin G can be used as
an alternative if the organism is sensitive
Streptococcal infections:- streptococcal pharyngitis, otitis media, rheumatic
fever(Procaine penicillin G or benzathine penicillin G ), etc
Meningococcal meningitis- I.V. penicillin G but DOC- 3rd generation
cephalosporine
Syphilis:- Penicillin G DOC. The alternative drugs-ceftriaxone and azithromycin
and doxycycline
Diphtheria: It is an acute infection of upper respiratory tract caused by C.
diphtheriae. Pt. allergic to penicillin- erythromycin preferred

12. • Clostridial infections (tetanus and gas gangrene):- The main treatment is the
neutralisation of the toxin by using human tetanus immunoglobulin. For gas
gangrene, penicillin G is used as an adjunct to antitoxin.
• Other infections: Anthrax, listeria infections, leptospirosis, actinomycosis, rat-
bite fever, etc. are effectively treated with penicillin G.
• Anaerobic infections: Penicillin G is effective for the treatment of anaerobic
infections (periodontal)
• Prophylactic uses of penicillins:-
1. Rheumatic fever: The causative organism β-haemolytic streptococcus.
prophylaxis, inj. benzathine penicillin G(i.m. once a month)
• Pt. allergic to penicillin →erythromycin or sulphadiazine.
2. Bacterial endocarditis: Patients with valvular lesions are at high risk of
developing infective endocarditis hence they should receive chemoprophylactic
agents before dental or surgical procedures to prevent bacteraemia.

13. • Penicillin-G & V are natural penicillin both are β-lactamase sensitive
• But Penicillin-V→ acid stable (can be given orally)
• Procaine Penicillin-G & benzathine Penicillin-G→ longest half life due to delayed
intramuscular absorption
• Cloxacillin & dicloxacillin→ Acid stable (good absorption so can be given orally)
• Methicillin→ high Nephrotoxic (withdrawn from market)
• Limitations/drawbacks of penicillin G:-
1. Acid labile – orally not very effective.
2. Short duration of action (to overcome this, repository penicillins have been developed).
3. Narrow spectrum of antibacterial activity (mainly against gram-positive organisms).
4. Destroyed by penicillinase enzyme.
5. Possibility of anaphylaxis.
To overcome Limitation of Penicillin-G →semisynthetic penicillins have been
developed

14. Extended spectrum Penicillins
• Aminopenicillin:-
All are β-lactamase sensitive but acid stable
All are semisynthetic derivatives of penicillin
Antimicrobial spectrum:-
Strept. pneumoniae & Pyogenes
Additional action-(gram-ve) E.coli,salmonella,shilgella,H influenza,
H.pylori,proteus mirabilis,listeria
Not effective against-MRSA & pseudomonas
Drugs includes- Amoxycillin & Ampicillin

15. Ampicillin Amoxycillin
Food ↓Absorption of ampicillin(incomplete
absorption from gut)
No effect of Food
Effective in meningitis Not effective in meningitis
More damage to intestinal flora so more chance
of superinfection
Less damage to intestinal flora so less chances
of superinfection
Effective against Shigella and Haemophilus
influenzae
Less effective against Shigella and H.
influenzae
Ampicillin reduces the effectiveness of oral
contraceptives
Does not reduce the effectiveness of oral
Contraceptives
Preferred by i.m. or i.v. route except GIT
infection
Preferred by oral route
Duration is shorter Duration is longer
Concentrated in bile(suitable for cholecystitis) Concentrated in respiratory secretion & sputum
Dose:- Ampicillin 250–500 mg QID Dose:- Amoxicillin 250–500 mg TID

16. • Therapeutic uses:-
• In dentistry:- (most commonly use Antibiotics)
• Acute necrotizing ulcerative gingivitis,
• dentoalveolar abscess,
• Osteomyelitis of mandible, etc.
• Ludwig’s angina in immunocompetent individuals- Ampicillin–sulbactam
• URTI(upper respiratory tract infection)- Ampicillin and amoxicillin
• pharyngitis, sinusitis, otitis media, bronchitis, etc. caused by S. pyogenes, S.
pneumoniae and H. influenzae
• Cholecystitis –Ampicillin but less effective then FQS
• H.Pylori-both effective but Amoxicillin preferred
• UTI-due to E.coli (safe in pregnancy)
• Gonorrhoea- Ampicillin/Amoxicillin + probenecid
• Typhoid-Ampicillin-12gm per day (DOC-fluoroquinolone or ceftriaxone)
Amoxicillin is used alone or with
metronidazole

17. • Meningitis:-listeria meningitis DOC-Ampicillin
• Bacillary dysentery-(shigella)-Ampicillin
• Bacterial endocarditis- Ampicillin + gentamicin & Prophylaxis-Amoxicillin
• Side effect:- Skin rash(more with ampicillin), Nausea, vomiting, diarrhoea
• Antipseudomonal penicillins:-
• They are carbenicillin, carbenicillin indanyl, ticarcillin, mezlocillin and
piperacillin.
• Uses:-
• Serious infections—bacteremias, pneumonias, UTIs, burns, etc. by P.
aeruginosa and Proteus→ piperacillin than carbenicillin.
• UTI caused by P. aeruginosa and Proteus spp-Carbenicillin indanyl(orally)
• Mixed nosocomial infection- Ticarcillin + β-lactamase inhibitor
+aminoglycoside

18. β-Lactamase Inhibitors
• Contains β-lactams ring but negligible Antibiotic effect
• Drugs includes-clavulanic acid, sulbactam and tazobactam.
• They structurally resemble β-lactam molecules.
• Beta-lactamase inhibitors bind to lactamases and inactivate them.
• Coadministration:-(β-lactams+ β-lactamase inhibitors)→ ↑ the activity of β-
lactams by preventing them from enzymatic destruction(↑spectrum)
• Clavulanic acid:-
• Derived from streptomyces clavigerus
• MOA:- It competitively and irreversibly inhibits -lactamases produced by a wide
range of gram-positive and gram-negative bacteria.
• After binding to the enzyme, clavulanic acid itself gets inactivated hence it is
called a ‘suicide’ inhibitor
• Combination therapy required dose reduction in renal insufficiency

19. Preparation
(Brand Name)
Route(s) of
Administration
Uses
Clavulanic acid +
amoxicillin
(Augmentin)
Oral, i.m., i.v. Skin, soft tissue, otitis media, respiratory and urinary
tract infections caused by -lactamase-producing strains
of S. aureus, E. coli, H. inuenzae and gonococci
Clavulanic acid +
ticarcillin
i.m., i.v. Mixed nosocomial infections due to aerobic gram-
negative bacilli,S. aureus and Bacteroides spp
Sulbactam + ampicillin Oral, i.m., i.v. Intra-abdominal and pelvic infections (mixed aerobic
and anaerobic infections) due to -lactamase-producing
strains of S. aureus, gram negative aerobes and
anaerobes
Tazobactam +
piperacillin
i.v. Severe infections caused by -lactamase-producing
strains of
gram-negative bacilli

20. Question paper discussion
1.Write short note on: -Amoxycillin
2. Discuss the pharmacological basis for the use of :
A. Amoxycillin with clavulanic acid
B.Probenecid with Penicillin
3. Classification of β-lactam antibiotics. Discuss mechanism of action uses and
adverse effect of amoxycillin
4. Classify Penicillins. Discuss their mechanism of action, uses, drug interactions
& adverse effects
5.Discuss mechanism of action, side effects and therapeutic uses of Penicillin.
6. Enumerate penicillin antimicrobials. Discuss the Antibacterial spectrum, uses
precaution & adverse effects of extended spectrum penicillin

21. CEPHALOSPORINS
• The first cephalosporins were obtained from a fungus, Cephalosporium
acremonium.
• Later, semisynthetic cephalosporins were developed.
• Cephalosporins are β-lactam antibiotics.
• MOA:- Similar to penicillin (Bactericidal action)but they bind with different
binding protein.
• All resistant to β-lactamases (Except-1st Generation)
• Classification:- Based on Spectrum of activity (Divided into 4-generations)
1St generation 2nd Generation 3rd Generation 4th Generation
Cephalexin (O)
Cefadroxil (O)
Cefazolin (P)
Cephradine(i.m./O)
Cephalothin(i.m.)
Cefaclor
Cefuroxime
Cefoxitin
Cefotetan
Cefixime (O)
Ceftriaxone (i.m., i.v.)
Cefotaxime (i.m., i.v.)
Cefoperazone (i.m., i.v.)
Ceftazidime (i.m., i.v.)
Ceftizoxime(i.v.,i.m.)
Cefepime (i.v.)
Cefpirome(i.v./i.m.)

22. 1St generation 2nd Generation 3rd Generation 4th Generation
AMS:-
 Effective-Mainly
gram(+ve) cocci
 Not effective against-
MRSA, Pseudomonas,
Salmonella
AMS:-
Effective- activity ↑ against
(Gm-Ve) & Anaerobes
Not effective against-
Pseudomonas, Salmonella
AMS:-
Effective-
Active against
(Gm-Ve) & Anaerobes,
Pseudomonas, Salmonella
less effective against-(Gm +
ve)
AMS:-
Effective- active against
(Gm-Ve) & Anaerobes,
Pseudomonas
Sensitive to β-lactamase Cefoxitin, cefuroxime-
resistant to β-lactamases
All are resistant to β-
lactamases
All are resistant to β-
lactamases
Cross BBB
Excretion-kidney
Cefuroxime-cross BBB
Excretion-Kidney
Cross BBB, reach
high concentration in
CSF
Excretion-kidney, bile
Cross BBB
Uses:-
In dentistry:-
 Odontogenic infections-
Cephalexin and cefadroxil
 Prophylaxis of bacterial
endocarditis before dental
procedures
Uses:-
In dentistry:-
 Orodental
Infections-Cefaclor or
Cefuroxime axetil
Uses:-
In dentistry:-
 Cefixime & cefotaxime-
dentoalveolar infection
Limited use

23. Uses:-
• Surgical prophylaxis & septic arthritis-1st generation (DOC-cefazolin)
• Safe in pregnancy (UTI, respiratory tract infection)-cephalexin, cefadroxil
• Respiratory tract infections:- otitis media and sinusitis, oral cefuroxime axetil
can be used
• Intra-abdominal and pelvic infections:- 2nd generation (Cefoxitin & cefotetan)
• Community-acquired pneumonia : Ceftriaxone, cefotaxime (3rd gen)
• Gonorrhoea:- Ceftriaxone (DOC) (3rd gen)
• Typhoid fever: Ceftriaxone & cefoperazone (3rd gen)
• Meningitis- caused by Haemophilus influenzae: Inj. Cefotaxime & ceftriaxone
• Mixed aerobic and anaerobic infections-3rd gen
• Septicaemia:- caused by gram-negative infections-3rd gen
• Nosocomial infection- 3rd gen

24. • Pharmacokinetics:-
• Administered either orally or parenterally
• Excretion- mainly via kidney either by glomerular filtration or by tubular
secretion.(Except-Cefoperazone-bile)
• Active tubular secretion- of cephalosporins is blocked by probenecid, resulting in
higher blood levels and longer duration of action.
• Metabolism:-the body before their excretion.
• Cefotaxime is deacetylated in the body before its excretion.
• Side effects:-
• Hypersensitivity:-They are skin rashes, urticaria and rarely anaphylaxis.
• GI disturbances—mainly diarrhoea, vomiting and anorexia
• Pain at the site of i.m. injection (cephalothin)
• Thrombophlebitis- I.V. cephalosporins
• Nephrotoxicity may occur. Co-administration of cephalothin and gentamicin
increases the nephrotoxicity.

25. • Disulfiram-like reaction:-has been reported with cefotetan and cefoperazone
• Severe bleeding:- can occur either due to hypoprothrombinaemia (which
responds to vitamin K therapy) or thrombocytopaenia and/or platelet dysfunction
• Semisynthetic β-lactam antibiotic
• Containg Carbon atom in place of sulfur atom so called “Carbapenams”
• Drugs includes-Imipenem, meropenem, doripenem, faropenem
• Considered as “ Drugs of last resort”
• MOA:- similar like penicillin i.e. inhibit cell wall systhesis after binding with
penicillin binding protein(PBP) exert Bactericidal action
• Broader spectrum than other β-lactam antibiotic(Post antibiotic effect) &
resistant to β-lactamase
CARBAPENEMS

26. • Spectrum of activity:-
• Gm +ve organisms like streptococci, staphylococci, enterococci, Listeria and C.
difficile (anaerobe)
• Gm -ve organisms like P. aeruginosa, enterobacteriaceae and B. fragilis
(anaerobes)
• I.M. is painful so I.V. route is preferred
• Only imipenem hydrolysed by →renal dehydropeptidase present in renal brush
border(↓urinary conc)
• Cilastatin-Inhibitors of renal dehydropeptidase (should be combined)
USES:-
Mixed bacterial infections:- urinary, respiratory, intra-abdominal, gynaecologic,
skin, soft tissue, bone and joint infections
(Imipenem+ cilastatin) ↑Conc. Imipenem in urine leading to ↑spectrum
SE:- Nausea, vomiting and skin rashes & rare side effect-Seizures

27. • Meropenem:- (I.V.)
• Resistant to →dehydropeptidase (combination not required)
• Seizures less likely & effective against imipenem resistant P. aeruginosa.
• Faropenem:- (orally) Used for respiratory and genitourinary infections.
• MONOBACTAMS:- (i.v./i.m.)
• Drugs:-Aztreonam
• β-lactam antibiotic with only one ring(β-lactam) in its structure (absence of sulfur
containing thiazolidine ring)→so called “Monobactam”
• Resistant → β-lactamase
• Effective against →only gm-ve bacteria
• Lack of cross sensitivity with other β-lactam antibiotics (due to Lack of ‘S’ ring)
(except ceftazidime) hence use in pt. allergic to penicillin or cephalosporine
• USES:- Genitourinary, intra-abdominal infection (hospital aquired Gm-ve
infection)

28. Thank You