Selective Toxicity and Anti-Bacterial Chemotherapy

Concept of Selective Toxicity

• Selective toxicity targets the parasite or unwanted cell while leaving the host relatively unharmed
• Selective toxicity is the foundation of chemotherapy

Selective Toxicity Feasibility

• Achieved by exploiting the biochemical differences between the parasite and the host cell
• Selective toxicity is more difficult to achieve when the unwanted cell or parasite closely resembles the host

Parasitic Cells

• Bacteria
• Protozoa
• Fungi
• Helminths
• Viruses
• Cancerous or neoplastic cells

Anti-Bacterial Chemotherapy Classes

• Includes:
  • Sulphonamides
  • Penicillins
  • Cephalosporins
  • Aminoglycosides
  • Macrolides
  • Quinolones

Sulphonamides

• These are synthetic structural analogues of p-aminobenzoic acid
• Trimethoprim is in this class
• Example drugs are:
  • Sulphadiazine
  • Sulphamethoxazole

Sulphonamides Mechanism of Action

• Target folate's role as an essential co-factor in purine and DNA synthesis
• Bacteria must synthesize folate from PABA
• These drugs inhibit dihydropteroate synthase, a microbial enzyme for incorporating para-aminobenzoic acid into dihydropteroic acid, a folic acid precursor
• The synthetic pathway gets inhibited at two points
• Sulphonamides are bacteriostatic

Sulphonamides Spectrum of Activity and Clinical Uses

• Useful for:
  • Acute UTIs
  • Chronic bronchitis
  • Genital infections (acute gonococci urethritis, bacterial prostatitis)
  • Opthalmic preps for bacterial conjunctivitis
• concentrates in prostate and vaginal fluids, suitable for infections at these sites

Sulphonamides Pharmacokinetics

• Well-distributed and penetrates CS fluid, placental barrier, and appears in breast milk, bound to serum albumin
• Metabolized by liver enzymes
• Excreted by glomerular filtration (GF)

Sulphonamides Adverse Effects

• Nausea and vomiting
• Hypersensitivity reactions (rashes, fever)
• Crystalluria (nephrotoxicity)
• Hemolytic anemia in G-6PD patients
• Fulminant hepatic necrosis
• Agranulocytosis
• Jaundice in newborns

Penicillins

• Discovered in 1928 by Sir Alexander Fleming
• Penicillin's can be classified as:
  • Beta-lactamase sensitive
  • Beta-lactamase resistant
  • Broad spectrum

Penicillins Types

• Beta-lactamase sensitive eg. Penicillin G
• Beta-lactamase resistant eg. Flucloxacillin and methicillin
• Broad spectrum eg. Amoxicillin

Penicillins Mechanism of Action

• Penicillins are bactericidal
• They bind to penicillin-binding proteins on susceptible microorganisms
• They inhibit the enzyme that inserts the cross-links to the peptide chains (transpeptidation or cross-linkage) required for peptidoglycan synthesis
• Peptide chains are required to attach to the backbone of the peptidoglycan
• Process weakens the cell wall and causes cell rupture or autolysis

Penicillins Clinical Uses

• Considered first-choice drugs for many infections, including:
  • Bacterial meningitis
  • Bone infections
  • Joint infections
  • Skin infections
  • Soft tissue infections
  • Throat infections
  • Bronchi infections
  • Urinary tract infections
  • Gonorrhoea
  • Syphilis

Penicillins Side Effects

• Hypersensitivity
• Diarrhoea
• Possible C difficile infection
• Jarisch-Herxheimer reaction
• Nephritis
• Neurotoxicity
• Platelet dysfunction

Cephalosporins

• First discovered in 1945 by Guiseppe Brotzu
• Cephalosporins are classified by generation

Cephalosporins Generations

• 1st generation eg. cephalexin, cephadroxil (oral), cephradine (parenteral)
• 2nd generation eg. cefuroxime(oral), cefamandole(parenteral)
• 3rd generation eg. Cefdinir(oral), cefixime(oral), cefotaxime (parenteral), ceftriaxone
• 4th generation eg. Cefepime, Cefluprenam, Cefozopran, Cefpirome, Cefquinome
• The anti-staphylococci action increases from generations 1-3, when spectrum against aerobic Gram -ve bacilli is considered

Cephalosporins Mechanism of Action

• Has similar action to the penicillins
• Bactericidal, beta-lactam
• Has a degree of beta-lactamase resistance

Cephalosporins Spectrum of Activity

• Useful for skin and soft tissue infections against:
  • Streptococci
  • Staph
  • E. coli
  • P. mirabilis
  • Pneumoniae
• Active against H. influenzae such as cefaclor, cefamandole
• Can treat respiratory infections due to S. pneumoniae (sinusitis, otitis media, pneumonia)
• Treats infections like septicaemia, meningitis, pneumonia, biliary tract and UTI

Cephalosporins Adverse Effects

• Hypersensitivity reactions mirror those of penicillin, including the potential for cross-reactivity
• Can produce diarrhoea, nausea, and vomiting

Aminoglycosides

• These are antibacterial agents that interfere with protein synthesis
• Act on ribosomes:
  • Gentamicin
  • Streptomycin
  • Neomycin
  • Amikacin
• Composed of two or more amino sugars linked by glycosidic bonds to an aminocyclitol ring
• Route of administration is parenteral, due to poor absorption

Aminoglycosides Mechanism of Action

• Irreversibly binds to the bacterial ribosome's 30S subunit
• Inhibits the translation of mRNA to protein
• Active against streptococci and pneumococci
• Streptomycin use to act against Mycobacterium tuberculosis
• Gentamycin is used for enterobacteriaceae and enterococci infections

Aminoglycosides Adverse Effects

• Dose-dependent ototoxicity and nephrotoxicity
• Should be reserved for serious infections
• Can produce neuromuscular paralysis
• May lead to allergic contact dermatitis

Macrolides

• These are inhibitors of the larger 50S subunit
• Composed of:
  • Erythromycin
  • Clarithromycin
  • Azithromycin
• These may be bacteriostatic or bactericidal
• Binds reversibly to a site on the 50S subunit of the bacterial ribosome, preventing ribosome translocation along mRNA

Macrolides Spectrum of Activity and Uses

• Erythromycin exhibits a similar spectrum to penicillin G
• Active against most Gram +ve bacteria and spirochaetes and infections caused by staphylococci, pneumococci and clostridia
• Clarithromycin is also effective against H. influenzae and Helicobacter pylori
• Azithromycin more effective against respiratory infections due to H. influenzae

Quinolones and Fluoroquinolones

• These are inhibitors of nucleic acid synthesis
• They are bactericidal
• The examples are:
  • Nalidixicacid
  • Norfloxacin
  • Ciprofloxacin
  • Balofloxacin
  • Moxifloxacin

Quinolones and Fluoroquinolones Mechanism of Action

• Inhibits topoisomerase II (DNA gyrase), the enzyme that packages DNA into supercoils which is essential for DNA transcription, replication and repair

Quinolones and Fluoroquinolones Spectrum of Activity and Clinical Uses

• Useful for:
  • Complicated UTI
  • Gonorrhoea
  • Cervicitis
  • Prostitis
• Also for:
  • Typhoid fever
  • Septicaemia
  • Respiratory infections (not due to pneumococci)

Quinolones and Fluoroquinolones Adverse Effects

• Gl disturbances
• CNS effects (nausea, headache, light-headedness)
• Nephrotoxicity-possible crystalluria
• Tendonitis, tendon rapture
• Phototoxicity

Selecting Antibiotic Therapy

• Antibiotics can be used prophylactically or therapeutically
• Selection factors:
  • Bacterial
  • Host
  • Drug
• Antibacterial therapy should be initiated for bacterial infections only

Bacterial Factors

• Involves identifying the causative organism
• Can make reasonable guess based on statistical probabilities, eg. UTI in sexually active premenopausal women is due to E.coliin (85% cases)
• Cellulitis of arm or leg often due to Strept pyogenes or Staph aureus

Host Factors

• Site of infection
• Allergies
• Renal & hepatic function
• Concomitant medications
• Age
• Route of administration

Drug Factors

• Activity against the parasite
• Available routes of administration
• Adverse effects profile
• Dosing frequency
• Compliance factors
• Cost of treatment