Antifolates, DNA gyrase inhibitors, Novel lipopeptides

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Antifolates, DNA gyrase inhibitors, Novel
lipopeptides

• Pawitra Pulbutr
• M.Sc. In Pharm (Pharmacology)

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  Antifolates ?????? Sulfonamides ??? Trimethoprim,
  ??????? DNA gyrase inhibitor ??????????
  Lipopeptides

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Antifolate drugs

• Interfere folate synthesis and folate usage
• Sulfonamides
• Trimethoprim
• Other antimalarial/ antiprotozoal .
  Pyrimethamine
• Other cancer chemotherapy . Methotrexate

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PABA
Simple folate synthesis and usage pathway
Tetrahydrofolate Cofactor in Purine and
Thymidylate synthesis
Adenine, Guanine, Cytosine, Thymidine
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Spectrum of sulfonamides

• Broad spectrum
• Gram positive
• Gram negative
• Chlamydia
• Protozoa Plasmodium, Entamoeba
• Not effective to Rickettsiae

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Mechanism of resistance

• No folate synthesis bacteria Use exogenous
  folate
• Overexpression of PABA
• Low affinity of Dihydropteroate synthase to
  Sulfonamides plasmid encoded
• Decrease Sulfonamides uptake

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Type of sulfonamides

• Oral absorbable
• short acting Sulfisoxazole, Sulfamethizole
• intermediate acting Sulfadiazine,
  Sulfamethoxazole
• long acting Sulfadoxine
• Oral non-absorbable Sulfasalazine
• Topical Sulfacetamide, Sulfadiazine

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Clinical uses

• Oral absorbable
• Most Combination with Dihydrofolate reductase
  inhibitors Synergism
• Dihydrofolate reductase inhibitors Trimethoprim
  or Pyrimethamine
• Cotrimoxazole (Bactrim) Sulfamethoxazole
  Trimethoprim
• Pneumocystic carinii pneumonia in AIDS
• Urinary tract infection (UTI)
• Some respiratory tract infection (RTI)
• Diarrhea

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ADRs

• Hypersensitivity
• Cross hypersentivity also with other sulfonamide
  containing agents sulfonylureas, thiazide
  diuretics, furosemides
• fever, skin rash, exfoliative dermatitis,
  photosensitivity, n/v, diarrhea
• Steven-Johnson syndrome severe skin mucous
  membrane eruption can be lethal

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ADRs

• Urinary tract disturbance esp. neutral or acid
  urine
• Crystalluria, hematuria, obstruction
• Drink a lot of water , NaHCO3
• Hematopoietic disturbance
• Hemolytic anemia in G6PD deficiency patients
• Use in pregnancy
• Kernicterus increase free bilirubin

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Fluoroquinolones

• synthetic fluoronated analog of nalidixic acid
• Mechanism of action
• Inhibit DNA gyrase enzyme (topoisomerase II)
• Inhibit topoisomerase IV
• DNA gyrase essential for DNA relaxation of
  supercoiled DNA
• Topoisomerase IV essential for chromosomal
  separation to daughter cells

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Quinolones

• Old quinolones nalidixic acid, oxolinic acid,
  cinoxacin
• No systemic antibacterial level
• Fluoroquinolones
• Systemic antibacterial level
• Classified into 4 groups
• Gram negative
• Gram positive gtgtgt Newer agents

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Clinical uses

• UTI
• norfloxacin 400 mg bid, ciprofloxacin 250-500 mg
  bid, ofloxacin 200-400 mg bid, levofloxacin 250
  mg OD, lomefloxacin 400 mg OD, gatifloxacin 400
  mg single dose
• Bacterial diarrhea
• norfloxacin 400 mg bid, ciprofloxacin 500 mg bid
• Gonococcal infection
• norfloxacin 800 mg single dose, ofloxacin 300 mg
  bid, ciprofloxacin 500 mg single dose,
  lomefloxacin 400 mg single dose, gatifloxacin
  400 mg single dose

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Clinical uses

• Chlamydial urethritis, cervicitis
• ofloxacin 300 mg bid
• Legionellosis
• ciprofloxacin as second line drug
• MAC, Atypical mycobacterial infection
• levofloxacin, gatifloxacin, moxifloxacin as
  alternative

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Clinical uses

• Meningococci carrier eradication
• Ciprofloxacin, ofloxacin
• Skin skin structure infection
• ofloxacin 400 mg bid, levofloxacin 500 - 750 mg
  bid, ciprofloxacin 500-750 mg bid, trovafloxacin
  200 mg OD, moxifloxacin 400 mg OD
• Infection of bone joint
• ciprofloxacin 500- 750 mg bid
• Intraabdominal infection
• trovafloxacin

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Clinical uses

• Respiratory tract infection
• Acute exacerbation of chronic bronchitis
• Levofloxacin 500 mg OD, Ciprofloxacin 500 mg bid,
  Lomefloxacin 400 mg OD, Gatifloxacin 400 mg OD,
  Moxifloxacin 400 mg OD, Sparfloxacin 400 mg on
  day 1 200 mg OD for 10 days
• Community acquired pneumonia (CAP)
• Levofloxacin 500 mg OD, Trovafloxacin 200 mg OD,
  Gatifloxacin 400 mg OD, Moxifloxacin 400 mg OD,
  Sparfloxacin 400 mg on day 1 200 mg OD for 10
  days
• Nosocomial pneumonia
• Trovafloxacin IV 300 mg followed by 200 mg OD
• Sinusitis
• Levofloxacin 500 mg OD , Ciprofloxacin 500 mg
  bid, Gatifloxacin 400 mg OD, Moxifloxacin 400 mg
  OD

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Novel Antibacterial Lipopeptides

• Daptomycin (Cubicin)
• 13-member aminoacid cyclic lipopeptide
• Cell membrane disturbance
• Channel forming gtgtgt Ca dependent
• Acyl tail binding
• Depolarization efflux of intracellular content
• Inhibit macromolecule synthesis
• Cell death gtgtgt bactericidal
• Active on gram positive only
• Concentration dependent

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Daptomycins mechanism of action
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Daptomycin

• Spectrum
• Gram positive
• MRSA gt linezolid, quinupristin/ dalfopristin
• VRSA gt linezolid, quinupristin/ dalfopristin
• VRE gt linezolid, quinupristin/ dalfopristin
• GISA gt linezolid, quinupristin/ dalfopristin
• PRSP gt linezolid, quinupristin/ dalfopristin
• Table 2
• Also active to some anaerobes gtgtgt Clostridium,
  Propionibacterium

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Antibacterial agents

• Cell wall synthesis inhibitors
• Beta-lactam ABO
• Penicillins
• Cephalosporins
• Monobactam
• Carbapenem
• Beta-lactamase inhibitors
• Vancomycin
• Bacitracin
• Cycloserine

• Protein synthesis inhibitors
• Chloramphenicol
• Tetracyclines
• Macrolides
• Ketolides
• Clindamycin
• Streptogramins
• Oxazolidinones
• Aminoglycosides

• Antifolates
• Sulfonamides
• Trimethoprim / Pyrimethamine

• DNA gyrase inhibitors
• Fluoroquinolones

• Novel lipopeptides Daptomycin

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• THE END