A Power point presentation on Betalactam antibiotics suitable for undergraduate medical students. This Ppt is already presented in theory class lectures to the students of NEIGRIHMS, Shillong, Meghalaya

1. Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

2. What are they ?
• Have Beta-lactam rings
• Important groups are (PCcM)
• Penicillin – the first antibiotic
 Cephalosporins
 Carbapenems
 Monobactams

3. Penicillins
 First ever antibiotic - 1941 – Flemming, Florey and Chain
 Sources – Fungus Penicillium notatum and P. crysogenum
 Penicillin G (PnG) – benzyl side chain (original Penicillin)
 Sod. PnG is highly water soluble, thermolabile and acid
labile
Amide linkage
- Split off by
amidase
to produce 6-
aminopenicillanic
Salt formation
with Na+ or K+
Broken by ß-
lactamase

4. Penicillin - MOA

5. MOA – Penicillin Image
Essential of Medical Phamracology by KD Tripathi; Jaypee Brothers; 7th edition 2013

6. Mechanism of action
 The principal bacteriocidal mechanism is inhibition of cell
wall synthesis
 The bacterial cell wall is a structure of highly cross-linked
mucopeptide complex, in which peptidoglycan is a main
component
 Bacteria synthesize UDP–N-acetylmuramic acid pentapeptide
(Park neucleotide) and UDP–N-acetyl glucosamine
 They are linked together forming long strands and UDP splits
off
 The final step is cleavage of the terminal D-alanine
 The energy released is utilized in cross-linking with adjacent
peptide chains – by 5 glycine (Gly5)

7. Penicillin - MOA
 Pencillin binding proteins (PBP) – enzymes and proteins –
several PBPs and also different among species
 ß-lactum antibiotics inhibit transpeptidase – cross linking
prevented – defective cell wall
 Results in Cell wall deficient (CWD) forms – hyperosmotic
inside swells up and bursts
 Also may be bizarre shaped and filamentous forms
 Globular giant forms or protoplasts
 Rapidly multiplying organisms – more victims
 Gm+ve bacteria entirely peptidoglycan and gm-ve
alternating with lipoprotein
 Peptidoglycan cell wall unique in bacteria

8. MOA Penicillin - Video

9. Bacteria Vs Vertebrate

10. PnG – antibacterial spectrum
 Narrow spectrum – mainly gm+ve and few gm-ve
 Cocci: Streptococci, pneumococi, Staph. aureus
 Gm-ve cocci – Neisseria gonorrhoeae, N. meningitidis,
Gonococci
 Bacilli: gm+ve bacilli – B. anthracis, C. diphtheriae,
all Clostridia, Listeria, Spirochaetes (T. pallidum,
Leptospira) – Fragilis
 Gm-ve bacilli: Mycobacterium tuberculosis,
rickettsiae, chlamydiae, protozoa, fungi, viruses – Not
sensitive

11. Mechanism of Resistance
1. Inherently insensitive – PBP deeper
2. Penicillinase: Narrow spectrum ß-lactamase inactivates
PnG – opens the ß-lactam ring
• Gm+ve Staphylococci and gonococci, E. Coli, H. influenzae
etc. – elaborate large amounts – diffuses to surroundings
• Gm-ve bacteria in small quantity
• Staphylococcal penicillinase – inducible by methicillin
3. Penicillin tolerant bacteria – low affinity for penicillin –
altered PBP (pneumococci)
• Methicillin resistant Staph. aureus (MRSA) – altered PBP
4. Less permeability to penicillin – low level penicillinase
resistant gonococci and also H. influenzae – plasmid
5. Porins channels – gm-ve bacteria

12. PnG - Kinetics
 Absorption: Acid labile – 1/3rd a dose absorbed orally
 IM administration – good, rapid and complete absorption –
peak 30 min.
 Distribution: extracellularly and reaches most body fluids
– serous cavities and CNS poor
 In presence of inflammation – good penetration (meningitis,
sinovitis)
 Metabolism: Little metabolized – rapid excretion
 Excretion: 10% glomerular filtration – tubular secretion –
30 min plasma half life
 Longer tubular secretion in neonates – shorter during
childhood – long for elderly and renal failure
 Probenecid

13. Preparations and doses
 Unitage: 1 U of CPPnG = 0.6µg of standard preparation; 1
g = 1.6 million unit
 Sodium penicillin G (crystalline penicillin): dry
powder in vial – also repository PnG injections
 Repository penicillin G injections: deep IM
 Procaine penicillin G injections: aqueous suspension –
sustained effects 12 – 24 hours
 Fortified procaine penicillin: 3 L U procaine penicillin + 1 L U
Na+ penicillin
 Benzathine penicilline G: 0.6 to 2.4 MU IM every 2 -4
weeks

14. PnG - ADRs
 Upto 20 MU
 Local irritancy and direct toxicity – Pain, nausea and thrombophlebitis; CNS
toxicities – muscular twitching, convulsion, coma; also bleeding, arachnoiditis
 Hypersensitivity (1-10%) – PnG – rash, itching, urticaria, fever; also wheezing,
angioneurotic edema, serum sickness and exfoliative dermatitis – Anaphylaxis 1
– 4/10,000 – all penicillins may cause
 Most common in parenteral administration – procaine
 Also cross sensitivity
 Scratch test (2 – 10 MU) intradermal
 Negative intradermal test
 Topical application – highly sensitizing - banned except freshly prepared
solution
 Superinfection – rare
 Jarisch-Herxheimer reaction – fever, shivering, myalgia and exagerbation of
lesions – vascular collapse

15. PnG - Uses Streptococcal infections – Pharyngitis, otitis media,, scarlet fever,
rheumatic fever … SABE by Str. Viridans and fecalis – high dose 10 – 20
MU daily with gentamicin
 Pneumococcal infections – lobar pneumonia, meningitis - rarely used
now
 Menigococcal infections: Mostly responsive - IV
 Gonorrhoea – unreliable – Ophthalmia neonatorum – irrigation with
saline and PnG
 Syphilis: 1. 2 MU daily X 10 days Procaine penicillin, or 2.4 MU weekly;
Late syphilis – Benzathine penicillin 2.4 MU weekly X 4 weeks
 Diphtheria (carrier state), Tetanus and gas gangrene (adjuvant)
 DOC in anthrax, actinomycetes, rat bite fever - PnG
 Prophylactic: Rheumatic fever – Benzathine penicillin – 4 weekly
upto 18 years; Bacterial endocarditis and aggranulocytosis

16. Semisynthetic penicillins
 Produced chemically by altering side chain or
incorporating precursors
1. Acid resistant Penicillin: Phenoxymethyl penicillin
(Penicillin V) – 1 hour – 1/5th lower grade infections
2. Penicillinase resistant penicillin: Methicillin
(MRSA) – penicillinase resistant but not acid
resistant
 Cloxacillin and dicloxacillin (acid resistant) – weaker
than PnG but stronger than methicillin

17. Other penicillins
1. Extended spectrum:
a) Aminopenicillins: Ampicillin, Becampicillin,
Amoxicillin
b) Carboxypenicillins: Carbanecillin
c) Ureidopenicillins: Piperacillin, Mezlocillin
2. ß-lactamase inhibitors: Clavulanic acid, sulbactam
and tazobactam

18. Ampicillin Active against organisms sensitive to PnG with additional H.
influenzae, E. coli, Proteus, Salmonella, Shigella
 More effective than PnG in Strep. Viridans, enterococci and
gonococci
 Not resistant to penicillinase and developed resistance
 Not usefull against gm-ve - pseudomonas, Klebsiella, indole
positive Proteus
 Kinetics: acid stable, food interferes absorption, enterohepatic
circulation
 Uses: UTI, RTI (bronchitis, sinusitis, otitis media), Meningitis
(1st line before), Gonorrhoea (1st line for non-penicillinase
producing gonococci), Typhoid fever, Bacillary dysentery,
Cholecystitis, SABE, H. pylori, Septicaemias
 ADRs: Diarrhoea, alteration of gut flora, high incidence of rash
– in AIDS patients … history of hypersensitivity
 Becampicillin and Amoxicillin – similar drugs

19. Amoxcillin
 Close congener of Ampicillin
 Faster oral absorption, no food interference, lesser
diarrhoea, more sustained effect and higher plasma
conc.
 Less effective against H. influenzae and Shigella
 Effective against Penicillin resistant Strep. Pneumoniae
 Uses: Bronchitis, UTI, SABE and gonorrhoea, H. pylori

20. Carboxypenicillins - carbenicillin Active against Ps. aeruginosa and indole positive Proteus
 Less effective against Salmonella, E. coli, Enterobacter,
Klebsiella and gm+ cocci
 Resistance strains of Ps. Aeruginosa developed
 Not acid resistant, not penicillinase resistant – given IM or
IV – available as Na+ salt – CHF and renal failure, bleeding
 Uses: seriuos infection caused by Pseudomonas e.g. burns,
UTI, septicaemia - combined with gentamicin (1 -2 mg
IM/IV 4 – 6 hrly)
 Ureidopenicilins (Piperacillin): 8 times more active
than carbenicillin, good against Klebsiella and many
enterobacteriaceae. Used for treating seriuous gm-ve
infectionsin immunocompromised and neutropenic
patients

21. Beta-lactamase inhibitors
 Enzymes produced by gm+ve and gm-ve bacteria –
inactivate ß-lactum antibiotics by opening ß-lactum ring –
Clavulanic acid, Sulbactum and Tazobactum
 Clavulanic acid: Streptomyces clavuligerus; has a beta
lactum ring but no antibacterial actuvity – inhibits a wide
variety of lactamases (+ and -)
 MOA: Progressive inhibitor; binds to ß-lactamases
reversibly initially followed by covalent later – sucide
inhibitor
 Permeates the outer layer of gm-ve cell wall an inhibits
periplasmically located ß-lactamases
 Kinetics: Orally absorbed and can also be given
parenterally; elimination half-life 1 hr – matches
Amoxicillin - Coamoxiclav

22. Clavulanic acid
 Uses: Clavulanic acid re-establishes activity of
amoxicillin against resistant Staph. Aureus (but not
MRSA), Influenzae, Gonorrhoea, E. coli, Proteus,
Klebsiella, Salmonella and Shigella
 Skin and soft tissue infections, intraabdominal and
gynaecological sepsis, UTI, RTI and biliary infections
 Gonorrhoea including PPNG – single dose Amoxicillin
3 gm – Clavulanic acid 0.5 gm and Probenecid 1 gm
 ADRs: Same as amoxicillin but poorer GI tolerance,
candida stomatitis/vaginitis and rashes

23. Sulbactum
 Semisynthetic and related to Clavulanic acid
 Progressive inhibitor of ß-lactamases
 2-3 times less potent than clavulanic acid
 Does not produce chromosomal ß-lactamases
 Given parenterally – erratic oral absorption
 Combined with ampicillin – Sultamicillin
 Uses: PPNG, mixed aerobic and anaerobic infections,
intra-abdominal, gynaecological, surgical and skin-
soft tissue infections – hospital acquired

24. Tazobactum
 ß-lactamases inhibitor – similar to sulbactum
 Combined with Piperacillin
 Used in Peritonitis, Pelvic/urinary/ respiratory
infections caused by beta lactamase producing bacilli
 Not useful against inducible chromosomal ß-
lactamases produced by enterobacteriaceae and
piracillin resistant pseudomonas

25. Cephalosporins
 Obtained from Cephalosporium acremonium
 The nucleus consist of a lactam ring + Dihydrothiazine
ring
 7-aminocephalosporanic acid
 Same MOA as Penicillin
 R1 and R2 – spectrum and pharmacokinetic activity
respectively

26. Common features
Excreted primarily by the kidney
Exceptions Cefoperazone, Ceftriaxone ( Bile less in urine)
Probenecid slows the tubular secretion
CSF concentration good
Cross the placenta
High concentrations in synovial & pericardial fluids and
aqueous humor

27. Resistance
 Altering the PBPs reducing affinity
 Impermeability to the antibiotic or its efflux
 Elaboration of beta-lactamases
 Individual cephalosporins differ
 Antibacterial spectrum and potency
 Susceptibility to beta-lactamases
 Pharmacokinetic properties

28. First generation
Parenteral: Cefazolin and Cephalothin
Oral: Cephalexin, Cephradine, Cefadroxil
Good activity against gram +ve bacteria
Relatively modest activity against gram-ve bacteria
Not effective against Enterococci, MRSA, S.
epidermidis and B. fragilis
Cefazolin: Surgical prophylaxis (2 hours half life)
Cefadroxil has good tissue penetration

29. Second generation
Parenteral: Cefuroxime, Cefotetan, Cefoxitin
Oral: Cefuroxime axetil, Cefaclor
Increased activity against gram -ve microorganisms
Enterobacter spp., indole-positive Proteus spp., and
Klebsiella spp.
Cefuroxime & Cefoxitin: resistant to gram –ve β-lactamases
Cefoxitin, Cefotetan also active against anaerobes (B.
fragilis)

30. Third generation
Parenteral: Cefotaxime, Ceftizoxime, Ceftriaxone,
Ceftazidime, Cefoperazone
Oral: Cefixime, Cefpodoxime proxetil, Ceftibuten,
Cefditoren pivoxil
Much more active against the Enterobacteriaceae
Highly resistant to β-lactamases
Antipseudomonal: Ceftazidime and Cefoperazone

31. Uses - Cefotaxime
1.Gram –ve meningitis
2.Hospital Acquired Infections
3.Septicemia in immunocompromised patients
4.Single dose therapy of Gonorrhoea
(1 g Cefotaxime im + 1g Probenecid oral)
Ceftizoxime inhibit B. fragilis

32. Ceftriaxone
1. Meningitis
2.Multiresistant typhoid fever
3.Complicated UTI
4.Abdominal Sepsis & Septicemia
5.Gonorrhoea & Chancroid

33. Third generation – contd.
Ceftazidime
Antipseudomonal
Cause Neutropenia, thrombocytopenia, ↑ transaminase
& ↑ blood urea
Cefoperazone
Antipseudomonal
Cause Hypoprothrombinemia & Disulfiram like reaction

34. Fourth generation
Parenteral: Cefepime, Cefpirome
Extended spectrum of activity compared with the third
generation
Increased stability from hydrolysis by plasmid and
chromosomally mediated β-lactamases
Empirical treatment of serious infections in hospitalized
patients when gram +ve microorganisms,
Enterobacteriaceae, and Pseudomonas all are potential
etiologies

35. Adverse effects - cephalosporins
 Pain after IM and thrombophlebitis
 Diarrhoea
 Hypersensitivity reaction – like penicillin -10%
 Nephrotoxicity
 Bleeding – hypoprothombinaemia – cefoperazone,
ceftriaxone
 Neutropenia
 Disulfiram like reaction - cefoperazone

36. Semisynthetic Penicillins are still usefull
in various serious infections if used
judiciously