Transcript Sulfonamides,Trimethoprim and Quinolones

Antifolates,
DNA gyrase inhibitors,
Novel lipopeptides
Pawitra Pulbutr
M.Sc. In Pharm
(Pharmacology)
วัตถุประสงค์เชิงพฤติกรรม
• เข้าใจและอธิบายถึงกลไกการออกฤทธิ์, กลไกการดื้อยา, เภสัชจลนศาสตร์,
อาการไม่พงึ ประสงค์ท่เี กิดจากการใช้ยา, การนาไปใช้ประโยชน์ทางคลินิก
รวมทัง้ ข้อดีและข้อเสียของยาต้านแบคทีเรียในกลุม่ Antifolates ได้แก่
Sulfonamides และ Trimethoprim, ยากลุม่ DNA gyrase inhibitor และ
ยากลุม่ Lipopeptides
Antifolate drugs
• Interfere folate synthesis and folate
usage
• Sulfonamides
• Trimethoprim
• Other antimalarial/ antiprotozoal ….
Pyrimethamine
• Other cancer chemotherapy ….
Methotrexate
PABA
Simple folate
synthesis and
usage pathway
Tetrahydrofolate = Cofactor in
Purine and Thymidylate synthesis
Adenine, Guanine, Cytosine, Thymidine
Spectrum of sulfonamides
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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
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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
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UTI
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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
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norfloxacin 400 mg bid, ciprofloxacin 500 mg
bid
Gonococcal infection
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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
– 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
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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
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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
• Cell wall synthesis inhibitors
• Beta-lactam ABO
• Penicillins
• Cephalosporins
• Monobactam
• Carbapenem
• Beta-lactamase inhibitors
• Vancomycin
Protein synthesis inhibitors
• Chloramphenicol
• Tetracyclines
• Macrolides
• Ketolides
• Clindamycin
• Streptogramins
• Oxazolidinones
• Bacitracin
• Aminoglycosides
• Cycloserine
Antifolates
• Sulfonamides
• Trimethoprim / Pyrimethamine
DNA gyrase inhibitors
• Fluoroquinolones
• Novel lipopeptides: Daptomycin