Antibiotics

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Antibiotics

• F.A. Fehintola

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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.

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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

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Mechanism of action

• Inhibition of cell wall synthesis
• Membrane dysfunction
• Ribosome dysfunction
• DNA dysfunction
• Others
• Anti-metabolites
• Nucleic acid analogue

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Mechanism of action

• Inhibition of cell wall
• Penicillins
• Cephalosporins
• Cycloserine
• Vancomycin
• Bacitracin

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Mechanism of action

• Cell membrane dysfunction
• Polymixin
• Ribosome dysfunction
• Tetracyclines
• Aminoglycosides
• Chloramphenicol
• Clindamycin
• Macrolides

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Mechanism of action

• DNA dysfunction
• DNA dependent RNA polymerase inhibitor
• Rifamycins
• DNA gyrase inhibitor
• quinolones

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Mechanism of action

• Anti-metabolites
• Sulphonamides
• Trimethoprim
• Nucleic acid analogue
• antiviral agents

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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

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Drug resistance

• Mutation is followed by vertical transmission
  AND
• Horizontal acquisition involves
• Transformation
• Transduction
• Conjugation

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Drug resistanceMutation

• 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

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Drug resistance transduction, transformation,
conjugation

• Transduction
• 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

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Drug resistance transduction, transformation,
conjugation

• 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

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Drug resistance

• Biochemical expression
• Destructive enzymes
• Aminoglycosides
• penicillins
• chloramphenicol
• Altered target
• Antifolates
• Rifamycins
• quinolones
• Reduced penetration
• Aminoglycosides
• tetracyclines

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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

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The Beta Lactam antibiotics

• Penicillins
• Cephalosporins
• Monobactam
• Carbapenem

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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)

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Penicillins

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

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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

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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

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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

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Adverse effects

• Hypersensitivity
• Anaphylaxis
• Serum sickness
• angioedema
• urticaria
• Haemolytic anaemia
• Interstitial nephritis
• Methicillin
• Pseudomembranous colitis
• ampicillin

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• Cephalosporins

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Cephalosporins

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

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Classification

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

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• 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

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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

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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

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Clinical applications

• Community acquired pneumonias
• cefuroxime
• ceftriaxone
• cefotaxime
• Typhoid ceftriaxone, cefoperazone
• Lyme Dx ceftriaxone, cefotaxime
• Neutropenic patients
• usually combined with aminoglycosides

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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 25-100 mg per Kg per day (determined
  by severity of infection)

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Cephalexin

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

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Cefuroxime

• Both oral and parenteral routes employed
• Spectrum klebsiella, E. coli, Proteus,
  Haemophilus
• Activity against Gve 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

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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 lt6/52 olds
• Also caution in hepatic disease

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

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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!)

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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