New Directions in AdvancedNew Directions in AdvancedFluoroquinoloneFluoroquinoloneTherapyTherapyJohn C.John C.RotschaferRotschafer, , PharmPharmD, FCCPD, FCCPProfessorProfessorCollege of PharmacyCollege of PharmacyUniversity of MinnesotaUniversity of MinnesotaFluoroquinolonesFluoroquinolonesGenericGenericTrade NameTrade NameNorfloxacinNorfloxacinNoroxinNoroxin®®CiprofloxacinCiprofloxacinCiproCipro®®OfloxacinOfloxacinFloxinFloxin®®FleroxacinFleroxacinTemafloxacinTemafloxacinOmnifloxOmniflox®®EnoxacinEnoxacinPenetrexPenetrex®®LomefloxacinLomefloxacinMaxaquinMaxaquin®®LevofloxacinLevofloxacin**LevaquinLevaquin®®SparfloxacinSparfloxacin**ZagamZagam®®GrepafloxacinGrepafloxacin**RaxarRaxar®®TrovafloxacinTrovafloxacin**TrovanTrovan®®*Advanced Generation Product*Advanced Generation ProductNew Advanced Generation New Advanced Generation FluoroquinolonesFluoroquinolones❖Moxifloxacin (Bayer)•Avelox ®❖Gatifloxacin (BMS/Schering)•Tequin®☯☯DesDes--fluoroquinolonefluoroquinolone44SpectrumSpectrum−−Staphylococci & PCNStaphylococci & PCN--S/R S. S/R S. pneumoniaepneumoniae−−EnterococcusEnterococcus−−BacteroidesBacteroides& & PeptostreptococcusPeptostreptococcus−−EnterobacteriaceaeEnterobacteriaceae44PharmacokineticsPharmacokinetics−−Usual dose 400mg QDUsual dose 400mg QD−−AUC (Total/Free) 75/18.8 mg hr/LAUC (Total/Free) 75/18.8 mg hr/LS. S. pneumoniaepneumoniaeAUC/MIC Ratio = 75/0.06 = 1250 (313 Free)AUC/MIC Ratio = 75/0.06 = 1250 (313 Free)−−HalfHalf--life 14life 14--18 hrs18 hrs−−Protein binding ~75%Protein binding ~75%BMS 284756 BMS 284756 --DesquinDesquinFluoroquinoloneFluoroquinoloneMechanism of ActionMechanism of Action■■Thought to form a complex with DNAThought to form a complex with DNA--gyrasegyrase✦✦TopoisomeraseTopoisomeraseIIII--((gyrAgyrA& B)& B)❖❖Thought to be the Thought to be the prefered prefered target especially for target especially for gram negativesgram negatives✦✦TopoisomeraseTopoisomeraseIVIV--((parCparC& E)& E)❖❖May in fact be May in fact be prefered prefered target for gram positivestarget for gram positivesand gram negativesand gram negatives■■TopoisomeraseTopoisomerasemutations(mutations(gyrgyrA & A & parCparC) ) result inresult influoroquinolonefluoroquinoloneresistanceresistanceFluoroquinolonesFluoroquinolones■■ConcentrationConcentration--dependent killersdependent killers✦✦True for Gram negatives but True for Gram negatives but questionable for other bacteriaquestionable for other bacteria■■Good intracellular penetrationGood intracellular penetration✦✦Atypical pathogens of URTI & Atypical pathogens of URTI & LRTI’sLRTI’s■■Prolonged post antibiotic effectProlonged post antibiotic effect■■Well suited for Well suited for parenteralparenteralto oral switch to oral switch ++price considerationsprice considerationsNew New FluoroquinolonesFluoroquinolonesDrugDrugRoute DoseRoute Dose--mgmgIntervalIntervalCiproCipro®®POPO250/500/750250/500/750Q12HQ12HCiproCipro®®IVIV400400Q12HQ12HLevaquinLevaquinPO/IVPO/IV500/750500/750Q24HQ24HAveloxAvelox®®PO/IVPO/IV400400Q24HQ24HTequinTequin®®PO/IVPO/IV400400Q24HQ24HFactiveFactive®®POPO320320Q24HQ24HGram Positive MICGram Positive MIC--90 (mg/L)90 (mg/L)BlondeauBlondeauJ: JAC 43(J: JAC 43(SupplSupplB):1B):1--11, 199911, 1999TrovTrovCiproCiproGatiGatiLevoLevoMoxMoxMSSAMSSA0.060.060.50.5--110.120.120.250.250.120.12MRSAMRSA223232--12812844161622E. E. faecalisfaecalis0.50.522--64640.50.5-->4>40.50.5--220.50.5--88E. E. faeciumfaecium2244-->128>12844-->64>6422--323222S. S. pneumoniaepneumoniae::PCNPCN--SS.12.12--.25.2511--220.50.511--22.06.06--.25.25PCNPCN--NSNS.12.12--.25.2511--220.50.511--22.12.12--.25.25PCNPCN--RR.12.12--.25.2511--220.50.511--22.12.12--.25.25GrGrA A StreptStrept0.250.2511--220.50.5110.250.25Fluoroquinolone S. pneumoniaeMIC-90Fluoroquinolone MIC-90(mg/L)Levofloxacin 1-2Gatifloxacin 0.25-0.5Moxifloxacin 0.12-0.25Sitafloxacin 0.06-0.12Gemifloxacin 0.015Assorted Abstracts ICAAC 2000Assorted Abstracts ICAAC 2000PCNPCN--R R S. S. pneumoniaepneumoniaeFeikenFeikenDR. DR. Am J Public HealthAm J Public Health. 90:223. 90:223--229, 2000229, 2000■■Retrospective 1995Retrospective 1995--1997 study of US 5,837 1997 study of US 5,837 adults adults pneumococcalpneumococcalpneumonia or pneumonia or bacteremia bacteremia ✦✦3,452 Pen3,452 Pen--S, 377 PenS, 377 Pen--NS, and 364 PenNS, and 364 Pen--RR■■PenPen--R (MIC R (MIC ≥≥≥≥≥≥≥≥4)4)5.5 x RR death after day 2, 5.5 x RR death after day 2, 7.1 x RR death after day 4.7.1 x RR death after day 4.■■CefotaximeCefotaxime--R (MIC R (MIC ≥≥≥≥≥≥≥≥2) 4.3 2) 4.3 x RR death x RR death after after day 2, 5.9 day 2, 5.9 x RR deathx RR deathafter day 4.after day 4.Increased Efficacy for Advanced Generation Fluoroquinolones in CAPMetge et al ICAAC 2000•Inpatient: FQ vs. Ceftriaxone and Macrolide–5 additional clinical successes/100 pts Tx with FQ’s–Reduced cost with FQ’s•Outpatient: FQ vs. New Generation Macrolide–3 additional clinical successes/100 pts Tx with FQ’s–Reduced cost with FQ’sFQFQ--R S. R S. pneumoniae pneumoniae ––Hong KongHong KongHo, P.L. et al JAC48:659Ho, P.L. et al JAC48:659--665, 2001665, 2001■■Hong Kong Hong Kong ✦✦4 month period January to April 2000 use E4 month period January to April 2000 use E--testtest✦✦6 hospital laboratories 30 consecutive isolates/hospital6 hospital laboratories 30 consecutive isolates/hospital■■PCNPCN--R = 60.6% (R = 60.6% (ClonalClonal))■■FQFQ--R S. R S. pneumoniae pneumoniae (almost all PCN(almost all PCN--R)R)✦✦Ciprofloxacin Ciprofloxacin 17.8%17.8%✦✦Levofloxacin Levofloxacin 13.3%13.3%❖❖100 mg tablet of 100 mg tablet of ofloxacin ofloxacin and and levofloxacinlevofloxacin❖❖200200--600 mg/ day as TID, BID, or QD600 mg/ day as TID, BID, or QD✦✦Gatifloxacin Gatifloxacin 12.2%12.2%✦✦Moxifloxacin Moxifloxacin 8.9%8.9%Gram Negative MICGram Negative MIC--90 (mg/L)90 (mg/L)BlondeauBlondeauJ: JAC 43(J: JAC 43(SupplSupplB):1B):1--11, 199911, 1999TrovTrovCiproCiproGatiGatiLevoLevoMoxMoxH. H. influenzae influenzae 0.0150.015.015.015--.03.03<0.03<0.03.03.03--.47.47.03.03--.06.06M. M. catarrhalis catarrhalis 0.030.03.015.015--.06.06<0.03 <0.03 .06.06--.09.09.012.012--.06.06P. P. aeruginosa aeruginosa .25.25--88.25.25--44>4>4.5.5-->4>488E. E.