Antifolates, DNA gyrase inhibitors, Novel lipopeptides Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)

วัตถุประสงค์เชิงพฤติกรรม เข้าใจและอธิบายถึงกลไกการออกฤทธิ์, กลไกการดื้อยา, เภสัชจลนศาสตร์, อาการไม่พึงประสงค์ที่เกิดจากการใช้ยา, การนำไปใช้ประโยชน์ทางคลินิก รวมทั้งข้อดีและข้อเสียของยาต้านแบคทีเรียในกลุ่ม Antifolates ได้แก่ Sulfonamides และ Trimethoprim, ยากลุ่ม DNA gyrase inhibitor และยากลุ่ม Lipopeptides

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

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

Spectrum of sulfonamides Broad spectrum Gram positive Gram negative Chlamydia Protozoa … Plasmodium, Entamoeba Not effective to Rickettsiae

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

Type of sulfonamides Oral absorbable short acting … Sulfisoxazole, Sulfamethizole intermediate acting … Sulfadiazine, Sulfamethoxazole long acting … Sulfadoxine Oral non-absorbable … Sulfasalazine Topical … Sulfacetamide, Sulfadiazine

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

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

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

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

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

Clinical uses UTI Bacterial diarrhea Gonococcal infection 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

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

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

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

Novel Antibacterial: Lipopeptides Daptomycin (Cubicin®) 13-member aminoacid cyclic lipopeptide Cell membrane disturbance Channel forming >>> Ca++ dependent Acyl tail binding Depolarization & efflux of intracellular content Inhibit macromolecule synthesis Cell death >>> bactericidal Active on gram positive only** Concentration dependent

Daptomycin’s mechanism of action

Daptomycin Spectrum Gram positive** MRSA … > linezolid, quinupristin/ dalfopristin VRSA… > linezolid, quinupristin/ dalfopristin VRE … > linezolid, quinupristin/ dalfopristin GISA… > linezolid, quinupristin/ dalfopristin PRSP… > linezolid, quinupristin/ dalfopristin Table 2 Also active to some anaerobes >>> Clostridium, Propionibacterium

Antibacterial agents Novel lipopeptides: Daptomycin 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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