1. Antibiotics
F.A. Fehintola

2. Introduction Selective toxicity: Basic principle of chemotherapy
Seeks to exploit certain characteristics peculiar to organisms or cell groups towards its elimination with a view to improving the health status of the host.

3. Introduction Antibiotics
Are products of various species of micro-organisms including bacteria and fungi that suppress growth of other micro-organisms
The term is sometimes used interchangeably with antibacterial, thus including such synthetic agents as:
Sulphonamides
Quinolones

4. Mechanism of action Inhibition of cell wall synthesis
Membrane dysfunction
Ribosome dysfunction
DNA dysfunction
Others:
Anti-metabolites
Nucleic acid analogue

5. Mechanism of action Inhibition of cell wall: Penicillins
Cephalosporins
Cycloserine
Vancomycin
Bacitracin

6. Mechanism of action Cell membrane dysfunction: Polymixin
Ribosome dysfunction:
Tetracyclines
Aminoglycosides
Chloramphenicol
Clindamycin
Macrolides

7. Mechanism of action DNA dysfunction: DNA gyrase inhibitor
DNA dependent RNA polymerase inhibitor
Rifamycins
DNA gyrase inhibitor
quinolones

8. Mechanism of action Anti-metabolites: Sulphonamides Trimethoprim
Nucleic acid analogue
antiviral agents

9. Drug resistance
The organism survives and/or multiplies in the presence of a given antibiotic
This may be:
Chromosomal: mutation
Extra-chromosomal: plasmid
Propagation may be vertical or horizontal

10. Drug resistance Mutation is followed by vertical transmission AND
Horizontal acquisition involves:
Transformation
Transduction
Conjugation

11. Drug resistance: Mutation
Organism previously sensitive
Random process
Alteration of drug target or production of inactivating enzyme
Ribosomal mutation
Aminoglycosides
Tetracyclines
DNA gyrase mutation
quinolones
RNA polymerase gene mutation
Rifampicin

12. Drug resistance: transduction, transformation, conjugation
Involves bacteriophage
Plasmid transfer of resistance trait
Commonly occurs in Staph. aureus for the production of penicillinase
Transformation:
Direct ‘capture’ of genetic materials from the environment
Alteration of target e.g. PBP

13. Drug resistance: transduction, transformation, conjugation
Direct contact between the donor and recipient
Genetic material traverses the sex pilus
Common among Gram –ve bacteria
May occur between pathogenic and non-pathogenic bacteria

14. Drug resistance Biochemical expression Destructive enzymes
Aminoglycosides
penicillins
chloramphenicol
Altered target
Antifolates
Rifamycins
quinolones
Reduced penetration
tetracyclines

15. Guides to successful antibiotic use
Sound clinical judgement
Bacteriological back-up
Individualisation of therapy
Immune status, age, genetics, co-morbidity
Except in special circumstances antibiotics should be used only after ‘definitive’ diagnosis
Severe infection, chemoprophylaxis
Pharmacology of the antibiotics esp. when used in combination

16. The Beta Lactam antibiotics
Penicillins
Cephalosporins
Monobactam
Carbapenem

17. Penicillins Mechanism of action involves:
Inhibition of cross-linkage between units of peptidoglycan
Peptidoglycan consists of
Polysaccharide
N-acetyl muramic
N-acetyl glucosamine
Pentapeptide
Bacterial transpeptidase enzyme also binds the penicillin since it is similar to its original substrate (D-alanyl- D-alanine)

18. Penicillins Classes: Penicillins Aminopenicillins Antistaphylococcal
Benzyl penicillin
Aminopenicillins
Ampicillin
amoxicyllin
Antistaphylococcal
Methicilin
Nafcillin
oxacillin
Antipseudomonal
Carbenicillin
ticarcillin
Beta lactamase inhibitors: sulbactam, clavulanic acid, tazobactam

19. Penicillin G Spectrum of activity Gram +ve organisms mainly
Gram –ve cocci
Some anaerobes (non lactamase producing)
Effective dose 4-24 m units per day in divided doses
Penicillin V is oral formulation
Benzathine penicillin and procaine penicillin belong to this class
Half or quarter dose in renal failure depending Cr. clearance

20. aminopenicillin Also known as extended spectrum
Ampicillin & amoxycillin are examples
Enhanced activity against G-ve organisms
Susceptible to lactamases
Amoxycillin enjoys better absorption
Effective in anaerobes, entorococci, E. coli, Shigella, salmonella spp.
Lack activity against klebsiella, pseudomonas proteus etc

21. antipseudomonal Carbenicillin, ticarcillin are examples
Pseudomonas infections are usually treated with penicillins in combination with aminoglycosides
Antipseudomonal drugs may be combined with lactamase inhibitor to further extend their activities

22. Adverse effects Hypersensitivity Haemolytic anaemia
Anaphylaxis
Serum sickness
angioedema
urticaria
Haemolytic anaemia
Interstitial nephritis
Methicillin
Pseudomembranous colitis
ampicillin

23. Cephalosporins

24. Cephalosporins Cephalosporium fungus
Ring structure derived from 7- amino cephalosporanic acid
B lactam antibiotics
In general, G-ve activity increases as the G+ve activity decreases
Freq of dosing also decreases with newer generation
Relatively stable in acid and aqueous media

25. Classification 1st generation: cephalexin cephradine cefadroxil
2nd generation: cefuroxime cefoxitin cefaclor ceproxil
3rd generation: cefotaxime ceftriaxone
Antipseudomanas: ceftazidime cefoperazone
4th generation: cefepime

26. Mechanism of action
Inhibition of cell wall synthesis* thus disrupting functional stability of the bacteria
Resistance
Plasmid mediated synthesis of B- lactamase enzyme – major
Minor ones incl: reduced cell penetration and altered target site (PBP)
* Blockade of transpeptidation, the final process of peptidoglycan synthesis

27. Absorption Distribution Elimination
Oral, and parenteral routes employed
Widely distributed throughout the body (penetrates well into CNS aqueous humour, synovial fluid and crosses placenta)
Some – ceftriazone, cefuroxime, cefotaxime cross blood-brain barrier readily
Extn; tubular secretion in the kidney*
* Probenecid interferes with this
NB: Notable exceptions 40-50% of ceftriazone and 75% of cefoperazone are excreted in bile

28. Clinical applications
Pre-op to prevent wound infection
Klebsiella, Serratia, Enterobacter, Proteus, Haemophilus infections
Gonorrhoea
Meningitis – cefotaxime, ceftriaxone, ceftazidime*
Treatment of anaerobes- used in combination with other antibiotics to clear aerobes
* in case of Pseudomonas meningitis

29. Clinical applications
Community acquired pneumonias
cefuroxime
ceftriaxone
cefotaxime
Typhoid – ceftriaxone, cefoperazone
Lyme Dx – ceftriaxone, cefotaxime
Neutropenic patients
usually combined with aminoglycosides

30. Cephalexin An e.g of 1st generation Orally administered
Spectrum: Strept & Staph
NOT effective in enterococcal infection
Not metabolized: parent drug eliminated in the urine
Usual dose mg per Kg per day (determined by severity of infection)

31. Cephalexin ADR: Pseudomembranous colitis,
GI upset, Anaphylaxis, fever,
Arthalgia, erythema multiforme, cholestatic jaundice,
Blood disorders, interstial nephritis,
Hypertonia, sleep disturbances, confusion.

32. Cefuroxime Both oral and parenteral routes employed
Spectrum: klebsiella, E. coli, Proteus, Haemophilus
Activity against G+ve less than 1st generation
T1/2 about 2 hours and given 8-12 hrly
CNS 10% conc in plasma
The cefuroxime axetil, given orally; is 30-50% absorbed
ADR: As for 1st generation

33. Ceftriaxone Relatively long half-life Administered once or 2ce daily
Spectrum: Enterobacteriaceae, Pseudomonas, Serratia, Neisseria, Staph and Strep
50-60% recovered from urine and rest secreted in bile
ADRs:
As above; may displace bilirubin in plasma and should be avoided in <6/52 olds
Also caution in hepatic disease

34. Classification First Cefazolin, cephalexin Staph, strept Second
inactive against G+ve organism
Cefuroxime, cefaclor
E. coli, Haemophilus, Proteus
Third activity against G+ve org similar to 1st
Ceftriazone, cefotaxime
Enterobacteriaceae, Staph, Serratia, strept
Fourth more β lactam resistant than 3rd generation
cefepime
= 3rd generation

35. Vancomycin Cell wall active antibiotic
Binds to the D-alanyl D alanine terminus of cell wall precursor
Affects only the Gram +ve organism
Resistance follows alteration of the target
Cross resistance may occur with*:
Teicoplanin
Daptomycin
* Other glycopeptides

36. Vancomycin Poorly absorbed if taken orally
Usual adult dose is 1 g I.V infusion (may be given orally to treat pseudomembranous colitis 250 mg 6hrly)
Elimination half is 6 hours
About 55% plasma protein binding
CSF conc. ~ 7-30% in inflammation
~90% excreted by kidney, so accumulates in CRF
Synergism with aminoglycosides (and ADRs too!)

37. Vancomycin Recommended for only serious infections like MRSA
Also useful in penicillin-sensitive staph. Infections
ADRs: hypersensitivity reactions including anaphylaxis
Phlebitis, pain, fever
Red man syndrome (intense flushing, tachycardia and hypotension)
Nephrotoxicity
Ototoxicity