Advances in Fluoroquinolones Therapy

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1 Advances in Fluoroquinolones Therapy Fluoroquinolones Synthetic antimicrobial agents with the characteristic 4- quinolone ring structure containing a fluorine moiety at the 6-position. Some members also have a -piperazinyl group at the 7-position. Ayman M. Noreddin PhD, R.Ph. Associate Professor of Pharmacy Practice College of Pharmacy, Duluth University of Minnesota Fluoroquinolone agents have greater intrinsic antibacterial activity and a broader antibacterial spectrum than the quinolone agents (their precursors) Fluoroquinolones in the US Mechanism of Action of Fluoroquinolones (Fluoroquinolones bind to two nuclear enzymes,inhibiting DNA replication) Ciprofloxacin (IV/PO) Levofloxacin (IV/PO) Grepafloxacin Trovafloxacin floxacin (IV/PO) Gatifloxacin (IV/PO) Clinafloxacin Sparfloxacin Gemifloxacin (PO)? Sitafloxacin Garenoxacin ABT 49 New Fluoroquinolones Fluoroquinolone Topoisomerase IV (parc and pare) DNA gyrase (gyra and gyrb)

2 Activity of Fluoroquinolones vs. Typical Respiratory Pathogens Activity of Fluoroquinolones vs. Atypical Respiratory Pathogens Pathogens Cipro MIC 90 (µg/ml) Gati Levo Gemi MIC 90 (µg/ml) S. pneumoniae (PenS) S. pneumoniae (PenR) Pathogens C. pneumoniae L. pneumoniae Cipro 0.06 Gati Levo Gemi H. influenzae <0.03 <0.03 < M. pneumoniae M. catarrhalis <0.03 <0.03 < Felmingham et al. ICC Zhanel GG, et al. Drugs. 00;6:3-59. Zhanel GG, et al. Drugs. 00;6:3-59. In vitro Activity of New Fluoroquinolones vs. Gram-Negative Bacilli Fluoroquinolone Indications DISEASE LEVO GATI MOI GEM Pathogens Cipro Gati Gemi MIC90 (µg/ml) Levo RTI ABECB Sinusitis CAP /HAP E. coli GU Cystitis K. pneumoniae Complicated UTI Acute pyelonephritis Ps. aeruginosa STD B. fragilis 6 8 SSSI Uncomplicated Zhanel GG, et al. Drugs. 00;6:3-59. Complicated

3 Advantages of New Fluoroquinolones:. Activity vs. common respiratory pathogens, including atypicals. Activity vs. resistant organisms (S.pneumoniae) 3. Good respiratory tissue uptake 4. OD dosing 5. IV/PO formulation 6. Safety Fluoroquinolones Liabilities Safety: Hepatic Cardiac Glucose homeostasis CNS toxicity GI Upset Rash Photosensitivity Drug Interactions metabolized drugs Antacid Interactions Low doses and resistance development Unresolved Questions With New Fluoroquinolones potency of individual agents against S.pneumoniae resistance development safety clinical data on: nursing home pneumonia pneumonias in high risk patients fluoroquinolones vs macrolides treating inpatient pneumonia orally what to do with gatifloxacin and moxifloxacin what role will gemifloxacin have How do we compare activity of individual fluoroquinolones? 3

4 How do we compare activity? * The drugs are very similar in spectrum. Clinically it comes down to activity vs the following two organisms where differences are seen: S. pneumonia P. aeruginosa * Use of Pharmacodynamic principles to differentiate between the different fluoroquinolones Fluoroquinolone Pharmacodynamics Concentration dependent bacterial killers prolonged persistent effects bacteriological eradication: AUC/MIC (AUIC) Cpmax/MIC Give large doses less frequently (eg. OD) Turnidge. Drugs 999. Pickerill et al. Pharmacother 000. Zhanel et al. Drugs 00. Pharmacodynamic Targets for Fluoroquinolones in Respiratory Infections Nosocomial pneumonia: AUC/MIC 5 Target for bacterial eradication Community acquired pneumonia: AUC/MIC 30 AUC/MIC 00 Target for bacterial eradication Target for preventing resistance Andes and Craig. ICAAC 000. Preston et al. JAMA 998. Forrest et al. AAC 993. Thomas et al. AAC

5 Free AUIC S. pneumoniae Free AUIC P. aeruginosa Cipro Levo Gati Total 0 ±.4 48 ± ±.9 30 ± 3.3 AUC 0-4 (mg hr/l) Free AUIC ±. 35 ± 3. 4 ±.0 5 ±. AUIC MIC (mg/l) Cipro Levo Gati Total 0 ±.4 50 ± ±.9 30 ± 3.3 AUC 0-4 (mg hr/l) Free AUIC ±. 35 ± <7.5 4 ±.0 <4 5 ±. AUIC <4-56 <9-70 <6 < MIC (mg/l) 4 - >4 > 4 8 CLSI (NCCLS) Breakpoints: Cipro none, levo, gati, moxi NCSL (NCCLS) Breakpoints: Cipro 4, levo 8, gati 8 (urinary tract only), moxi none NCSL (NCCLS) 00, Blondeau JM JAC ; suppl B, -. Levofloxacin serum concentration 6 0 C max (peak) AUIC=48 AUIC=96 Time, hours Levofloxacin 500 mg daily Peak = 5.7 AUC4=48 AUIC=4 MIC

6 MONTE CARLO SIMULATION Applied to PK-PD Monte Carlo Simulation Analysis 0,000 Trials.035 Forecast: Elderly Patients Certainty is 95.70% for AUC/MIC= 30 Dudley MN, Ambrose PG. Pharmacodynamics in the study of drug resistance and establishing in vitro susceptibility breakpoints: ready for prime-time. Current Opinion in Microbiology 000;3:55-5 Curtsey of Dr. Noreddin Target attainment potential of levofloxacin administered once daily to various patient populations Target attainment potential of gatifloxacin 400mg administered once daily to various patient populations Target Free-Drug AUC0-4/MIC Target Free-Drug AUC0-4/MIC Elderly 500mg 750mg 95.9% 98.5% 88.8% 97% 8.% 56.6% Elderly patients 97.7% 96.% 59.5% Immunocompromised 500mg 8.% 65.% 0.7% Immunocompromised patients 95.3% 90.% 30.% 750mg 96.4% 89.7% 8.6% Healthy Volunteers 500mg 78.9% 3.6% 0.00% Healthy Volunteers 93.3% 9.7% 3.3% 750mg 93.3% 9.% 3.% Curtsey of Dr. Noreddin Curtsey of Dr. Noreddin 6

7 Ecological Issues With New Fluoroquinolones (Respiratory Infections) Collateral Damage Question: In treating CAP are there any potential negative consequences in using anaerobic fluoroquinolones that also kill anaerobic colonic flora (B. fragilis)? Antibiotic Delivery Antibiotic Skin Resp GU Infected Site GI Curtsy of Dr. Rotschafer Exposure of Colonic Flora to Non-Anaerobic Agents (Ciprofloxacin 500 mg BID or Levofloxacin 500 mg QD) CFU/mL.0E+0.0E+09.0E+08.0E+07.0E+06.0E+05.0E+04.0E+03.0E+0.0E+0.0E+00 LOD TIME (hours) B. fragilis 797 C. albicans 767 VRE (facium) 47 K. pneumoniae P555 C. difficile Zhanel GG, et al. Presented at the 0nd General Meeting of the American Society for Microbiology, May 9-3, 00, Salt Lake City, Utah. Exposure of Colonic Flora to Anaerobic Agents (Gatifloxacin 400 mg QD or floxacin 400 mg QD) CFU/mL.0E+0.0E+09.0E+08.0E+07.0E+06.0E+05.0E+04.0E+03.0E+0.0E+0.0E+00 LOD TIME (hours) B. fragilis 797 C. albicans 767 VRE (facium) 47 K. pneumoniae P555 C. difficile Zhanel GG, et al. Presented at the 0nd General Meeting of the American Society for Microbiology, May 9-3, 00, Salt Lake City, Utah. 7

8 Effect of Antibiotic Therapy on the Density of VRE in Stool of Colonized Patients Examples of Patients Mean. log/g Mean 0.6 log/g Change in No. of VRE (log/g) Donskey CJ, et al. N Engl J Med. 000;343: Anti-anaerobic Agents Clindamycin (oral) Meropenem Vancomycin Trovafloxacin Cefoxitin Minimal Anti-anaerobic Activity Dicloxacillin Ciprofloxacin Levofloxacin TMP/SM Resistance Development Fluoroquinolone (Ciprofloxacin) Use and Ciprofloxacin Resistant S. pneumoniae (Canada, ) Clinical failure of levofloxacin reported in patients with quinolone-resistant S. pneumoniae Percent FRSP 5 <5 years 5-64 years 4 65 years Quinolone use Chen DK, et al. N Engl J Med. 999;34: Prescriptions per 00 persons Fatal meningitis due to levofloxacin-r S. pneumoniae respiratory tract infection (RTI) (Wortmann & Bennett. Clin Infect Dis 999; 9: ) 58-year-old male HIV +; splenectomy, sinus congestion plus fever Levofloxacin 500 mg/qd. Meningitis on day 4. Died Levofloxacin disc = 0 Levofloxacin treatment failure in pneumococcal pneumonia (Kuehnert et al. Ann Intern Med 999; 3:3 33) 63-year-old male with community-acquired pneumonia (CAP) Levofloxacin 500 mg/qd. Persistent disease S. pneumoniae (sputum) levofloxacin MIC >3 µg/ml. Cured with ceftriaxone Patient exposed to levofloxacin days earlier for bronchitis Three levofloxacin treatment failures of pneumococcal RTI (Fishman et al. 39th ICAAC, San Francisco, Abstract 85) Three cases of S. pneumoniae infection (CAP, sinusitis, hospital-acquired pneumonia) Two patients were levofloxacin-r (MICs >4 to >3 µg/ml) Two patients had significant history of prior fluoroquinolone use 8

9 Clinical Case of Fluoroquinolone Failure (NEJM Toronto 00 CAP With Empyema) 66-year-old woman COPD on 8 days of Ciprofloxacin 500 mg BID for?aecb admitted for CAP with pleural effusion Rx: Levofloxacin 500 mg daily Admission blood culture grew S. pneumoniae Pleural fluid tapped 4 days later grew S. pneumoniae The isolate was resistant to levo/gati/moxi Mechanisms of Resistance to Fluoroquinolones Efflux pump is a less potent and less common cause of resistance Efflux pump Cell wall Mutation of bacterial genes for binding sites causes resistance DO NOT USE ANY FLUOROQUINOLONE IF ON FQ IN LAST 3 MONTHS! DNA Zhanel G. Can J Infect Dis 999;0:07 Possible Mechanisms of Fluoroquinolone Resistance (S. pneumoniae) Point mutations in target sites QRDRs GyrA ParC GyrB ParE Efflux Decreased permeability Mutations outside the QRDR (?) MIC changes vs mutations Mutation MIC levo MIC moxi None.0 0. par C 4.0 gyr A/par C efflux Smith HJ, et al. J Antimicrob Chemother. 00;49:

10 Fluoroquinolone Killing FQ-Susceptible S.pneumoniae Fluoroquinolone Killing of FQ-Resistant S.pneumoniae (Strain 680) ( Strain460 : ParC Ser79-Phe).00E+09.00E+08.00E+07.00E+06.00E+05.00E+04.00E+03.00E+0.00E+0.00E GC Cip Levo Gati Gare.E+09.E+08.E+07.E+06.E+05.E+04.E+03.E+0.E+0.E GC Cip Levo Gati Gare Fluoroquinolone Killing of FQ-Resistant S. pneumoniae Preventing the Emergence of Resistance (Strain 670: ParC Ser79-Tyr and GyrA Ser 8-Phe).0E+09 control.0e+08.0e+07.0e+06.0e+05.0e+04 LOD.0E+03.0E+0.0E+0.0E Levo 500 mg QD (8) Gati 400 mg QD (4) 400 mg QD () CT g QD (0.06) - There is one mutant in every 0 7 to 0 8 bacteria - Mutant subpopulations are present at the start of therapy - Drug concentrations must exceed MIC of original isolate and first-step mutants Zhanel GG, et al. N Engl J Med

11 Selection of S. pneumoniae resistance to fluoroquinolones Consequences of Low Overall FQ activity vs S.pneumoniae Not a significant problem at the moment, but it has the potential to grow and/or spread. Early fluoroquinolone resistance may be linked to low AUIC Quinolones in the community...? Organism sub-populations are selected rather than eradicated Very slow decline in the numbers of organisms (i.e. bacteriostatic actions) Host defense must be intact to resolve the infection Residual colonization even in cured patients PK/PD vs FQ resistance Low doses in relation to MIC (Low AUIC) are a potential problem in the development of S. pneumoniae resistance to the Weaker Quinolones Resistance to one, will cross over to all It is better to use the most active FQ from the begin Rapid Bacterial Eradication Ordinarily an advantage for an antibiotic Quick eradication leads to shorter courses of therapy, and lessens the risks of emergence of selected resistant organisms Fewer bacteria present will produce a more rapid clinical response Shorter treatment courses are advantageous, if we assure rapid bacterial killing Beta Lactams and macrolides do not do this Fluoroquinolones do, some more than others.

12 Treatment of CAP: Symptom Resolution at 3 Days (Levofloxacin 750mg OD x 5days vs 500mg OD x 0days) What s the Future of Fluoroquinolones n/n (%) of Patients Fever (patient reported) Purulent sputum Shortness of breath 750 mg x 5days 6/39 (67.4) 97/39 (40.6) 84/39 (35.) 500 mg x 0days 30/38 (54.6) 73/38 (30.7) 66/38 (7.7) P Value* Using the safest agent High dose/short course Dunbar et al. CID 003. How do you make your decision? Cost Indications Safety Hepatic Cardiac Glucose homeostasis Activity S. pneumoniae vs P. aeruginosa Resistance development Hit it hard, hit it quick, and be focused