Antifolates, Antifolates, DNA gyrase DNA gyrase

inhibitors, Novel inhibitors, Novel lipopeptideslipopeptides

Pawitra PulbutrM.Sc. In Pharm (Pharmacology)

วั�ตถุ�ประสงค์�เชิ�งพฤต�กรรม

• เข้�าใจและอธิ�บายถุ�งกลไกการออกฤทธิ�" , กลไกการดื้%&อยา , เภส�ชิจลนศาสตร� , อาการไม*พ�งประสงค์�ท+,เก�ดื้จากการใชิ�ยา , การน-าไปใชิ�ประโยชิน�ทางค์ล�น�ก รวัมท�&งข้�อดื้+และข้�อเส+ยข้องยาต�านแบค์ท+เร+ยในกล�*ม Antifolatesไดื้�แก* Sulfonamides และ Trimethopr

im, ยากล�*ม DNA gyrase inhibitor และยากล�*ม Lipopeptides

Antifolate drugsAntifolate drugs

• Interfere folate synthesis and Interfere folate synthesis and folate usage folate usage

• Sulfonamides• Trimethoprim• Other antimalarial/ antiprotozoal Other antimalarial/ antiprotozoal

….…. Pyrimethamine• Other cancer chemotherapy ….Other cancer chemotherapy ….

Methotrexate

Simple folate Simple folate synthesis and synthesis and

usage pathwayusage pathway

Tetrahydrofolate = Cofactor in Purine and Thymidylate

synthesis

Adenine, Guanine, Cytosine, Thymidine

PABAPABA

SpectrumSpectrum of sulfonamides of sulfonamides

• Broad spectrumBroad spectrum• Gram positiveGram positive• Gram negativeGram negative• ChlamydiaChlamydia• Protozoa … Plasmodium, Protozoa … Plasmodium,

EntamoebaEntamoeba• Not effective to RickettsiaeNot effective to Rickettsiae

Mechanism of resistanceMechanism of resistance

• No folate synthesis bacteria … Use exogenous folateUse exogenous folate

• Overexpression of PABA• Low affinity of Dihydropteroate Low affinity of Dihydropteroate

synthasesynthase to Sulfonamides… plasmid encoded

• Decrease Sulfonamides uptake

•

Type of sulfonamidesType of sulfonamides

• Oral absorbable – short acting … Sulfisoxazole, Sulfisoxazole,

SulfamethizoleSulfamethizole– intermediate acting … Sulfadiazine, Sulfadiazine,

SulfamethoxazoleSulfamethoxazole– long acting … SulfadoxineSulfadoxine

• Oral non-absorbable … SulfasalazineSulfasalazine

• Topical … Sulfacetamide, Sulfacetamide, SulfadiazineSulfadiazine

Clinical usesClinical uses

• Oral absorbable • Most … Combination with Combination with

Dihydrofolate reductase inhibitorsDihydrofolate reductase inhibitors … SynergismSynergism

• Dihydrofolate reductase inhibitors = Trimethoprim or PyrimethamineTrimethoprim or Pyrimethamine

• Cotrimoxazole (Bactrim®) = Sulfamethoxazole + Trimethoprim– Pneumocystic cariniiPneumocystic carinii pneumonia in AIDS pneumonia in AIDS– Urinary tract infection (UTI)Urinary tract infection (UTI)– Some respiratory tract infection (RTI)Some respiratory tract infection (RTI)– DiarrheaDiarrhea

ADRsADRs• 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

ADRsADRs

• Urinary tract disturbance esp. neutral or acid urine– Crystalluria, hematuria, obstructionCrystalluria, hematuria, obstruction– Drink a lot of water , NaHCO3Drink a lot of water , NaHCO3

• Hematopoietic disturbance– Hemolytic anemia in Hemolytic anemia in G6PD G6PD

deficiencydeficiency patients patients

• Use in pregnancy– Kernicterus … increase free bilirubinKernicterus … increase free bilirubin

FluoroquinolonesFluoroquinolones• synthetic fluoronated analog of

nalidixic acid• Mechanism of actionMechanism of action

– Inhibit DNA gyrase enzyme Inhibit DNA gyrase enzyme (topoisomerase II) (topoisomerase II)

– Inhibit topoisomerase IVInhibit topoisomerase IV– DNA gyrase = essential for DNA DNA gyrase = essential for DNA

relaxation of supercoiled DNArelaxation of supercoiled DNA– Topoisomerase IV = essential for Topoisomerase IV = essential for

chromosomal separation to daughter chromosomal separation to daughter cellscells

QuinolonesQuinolones

• Old quinolones … nalidixic acid, oxolinic acid, cinoxacin – No systemic antibacterial level

• Fluoroquinolones– Systemic antibacterial levelSystemic antibacterial level– Classified into 4 groupsClassified into 4 groups– Gram negativeGram negative– Gram positive >>> Newer agentsGram positive >>> Newer agents

Clinical usesClinical uses• UTIUTI

– 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 diarrheaBacterial diarrhea– norfloxacin 400 mg bid, ciprofloxacin 500

mg bid • Gonococcal infectionGonococcal 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 usesClinical uses• Chlamydial urethritis, cervicitis

– ofloxacin 300 mg bid • Legionellosis

– ciprofloxacin as second line drug

• MAC, Atypical mycobacterial infection– levofloxacin, gatifloxacin,

moxifloxacin as alternative

Clinical usesClinical 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 trovafloxacin 200 mg OD, moxifloxacin 400 mg ODmg OD, moxifloxacin 400 mg OD

• Infection of bone & joint– ciprofloxacin 500- 750 mg bid

• Intraabdominal infection– trovafloxacintrovafloxacin

Clinical usesClinical uses• Respiratory tract infectionRespiratory tract infection• Acute exacerbation of chronic bronchitis

– Levofloxacin 500 mg OD, Ciprofloxacin 500 mg bid, Lomefloxacin 400 mg OD, Gatifloxacin 400 Gatifloxacin 400 mg OD, Moxifloxacinmg OD, Moxifloxacin 400 mg OD, Sparfloxacin 400 mg OD, Sparfloxacin 400 mg on day 1; 200 mg OD for 10 days400 mg on day 1; 200 mg OD for 10 days

• Community acquired pneumonia (CAP)– Levofloxacin 500 mg OD, Trovafloxacin 200 mg Trovafloxacin 200 mg

OD, Gatifloxacin 400 mg OD, Moxifloxacin 400 OD, Gatifloxacin 400 mg OD, Moxifloxacin 400 mg OD, Sparfloxacin 400 mg on day 1; 200 mg mg OD, Sparfloxacin 400 mg on day 1; 200 mg OD for 10 daysOD for 10 days

• Nosocomial pneumonia– Trovafloxacin IV 300 mg followed by 200 mg Trovafloxacin IV 300 mg followed by 200 mg

ODOD • Sinusitis

– Levofloxacin 500 mg OD , Ciprofloxacin 500 mg bid, Gatifloxacin 400 mg OD, Moxifloxacin Gatifloxacin 400 mg OD, Moxifloxacin 400 mg OD400 mg OD

Novel Antibacterial: Novel Antibacterial: LipopeptidesLipopeptides• Daptomycin (Cubicin®)• 13-member aminoacid cyclic lipopeptide• Cell membrane disturbance• Channel forming >>> CaChannel forming >>> Ca++++ dependent dependent• Acyl tail binding• Depolarization & efflux of intracellular Depolarization & efflux of intracellular

contentcontent• Inhibit macromolecule synthesis• Cell death >>> bactericidal• Active on gram positive only**Active on gram positive only**• Concentration dependentConcentration dependent

Daptomycin’s Daptomycin’s mechanism of mechanism of

actionaction

DaptomycinDaptomycin• Spectrum• Gram positive**Gram positive**• MRSAMRSA … > linezolid, quinupristin/ dalfopristin • VRSAVRSA… > linezolid, quinupristin/ dalfopristin • VREVRE … > linezolid, quinupristin/ dalfopristin • GISAGISA… > linezolid, quinupristin/ dalfopristin • PRSP… > linezolid, quinupristin/ dalfopristin • Table 2• Also active to some anaerobes >>>

Clostridium, PropionibacteriumClostridium, Propionibacterium

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