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

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

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

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

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

6. 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

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

8. 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

9. 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

10. 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

11. 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

12. 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

13. Clinical uses UTI Bacterial diarrhea Gonococcal infection
norfloxacin 400 mg bid, ciprofloxacin mg bid, ofloxacin 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

14. 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

15. Clinical uses Meningococci carrier eradication
Ciprofloxacin, ofloxacin
Skin & skin structure infection
ofloxacin 400 mg bid, levofloxacin mg bid, ciprofloxacin mg bid, trovafloxacin 200 mg OD, moxifloxacin 400 mg OD
Infection of bone & joint
ciprofloxacin mg bid
Intraabdominal infection
trovafloxacin

16. 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

17. 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

18. Daptomycin’s mechanism of action

19. 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

20. 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

21. THE END