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Venice,Venice, MayMay 2929 --3131

FluoroquinolonesFluoroquinolones:: statestate ofof thethe artart andand futurefuture needsneeds

HartmutHartmut MM LodeLode RCMSRCMS -- affil.affil. InstituteInstitute forfor clinicalclinical PharmacologyPharmacology CharitCharitéé -- UniversitUniversitäätsmedizintsmedizin BerlinBerlin

-- BerlinBerlin --

FQI and Gram – pos. Pathogens Agenda

• Fluoroquinolones

• Pathogens - S. pneumoniae - S. aureus - Enterococci

- Selection of MRSA - Conclusions Quinolones - Timeline

• 1962

• 1986

• 1987

• 1991

• 1992 ,*§ ,

• 1997 ,§ §

• 1998 ,†§ ‡§

• 1999(+) ,§ §

• 2000(+) ‡§, gemifloxacin§

*withdrawn 1992, †restricted (Food and Drug Administration) 1999, ‡ § withdrawn 1999, enhanced activity against

Classification of Quinolones (I) (PEG 1998)

Group I • Norfloxacin

FQ with limited • indications (e.g. UTI)

Group II • Ciprofloxacin • Enoxacin “Classical” FQ with broad

indications; no suff. • pneumococcal activity • Ofloxacin

Classification of Quinolones (II) (PEG 1998)

Group III • Levofloxacin FQ with enhanced activity against gram- • Sparfloxacin positive and atypical pathogens

Group IV • Moxifloxacin

FQ with high activity • Gatifloxacin against gram-positive and atypical pathogens • Gemifloxacin and anaerobes ComparativeComparative inin--vitrovitro activitiesactivities ofof fluoroqinolonesfluoroqinolones againstagainst GramGram--positivepositive bacteriabacteria

Bacterium Cip Gati Grepa Levo Moxi

E. faecalis 2-64 0.5->4 0.37-4 0.5-2 0.5-8 E. faecium 4->128 4->64 4-12.5 2-32 2 S. aureus MSSA 0.5-1 0.12 0.25 0.25 0.12 MRSA 32-128 4 4 16 2 S. epidermidis 8 2 0.25 0.5-1 2 S. pneumoniae Pen S 1-2 0.5 0.25-0.5 1-2 0.06-0.25 Pen I 1-2 0.5 0.25-0.5 1-2 0.12-0.25 Pen R 1-2 0.5 0.25-0.5 1-2 0.12-0.25 S. pyogenes 1-2 0.5 0.25 1 0.25

Blondeau JM JAC 1999;43:Suppl. B. 1-11

In vitro activity of gemifloxacin and ciprofloxacin against Gram-positive bacteria from the US I

Lowe NL et al. Drugs 2000;59:1137-1147 In vitro activity of gemifloxacin and ciprofloxacin against Gram-positive bacteria from the UK II

Lowe NL et al. Drugs 2000;59:1137-1147 In vitro activity of new fluoroquinolones against S. pneumoniae isolates, including multidrug-resistance strains collected throughout the USA

MIC Agents MDR strains Total n Range 90 %S %I %R (mg/l)

Gemifloxacin MDR 361 <0.004-4 0-0.3 96.4 1.4 2.2

Non-MDR 1,118 <0.004-0.5 0.03 99.5 0.2 0.3

Levofloxacin MDR 361 0.25->32 1.0 96.4 0 3.6

Non-MDR 1,118 <0.12-32 1.0 99.5 0 0.5

Moxifloxacin MDR 361 <0.03-16 0.12 97.0 1.4 1.7

Non-MDR 1,118 <0.03-4.0 0.12 99.5 0.3 0.2

Adapted from Draghi DC et al. Int J Antimicrob Agents 2006;28:525

Different in vitro activity against S. pneumoniae

MIC90 (mg/L) Pen S Pen I Pen R Moxifloxacin 0.06–0.25 0.12–0.25 0.12–0.25 Levofloxacin 1–2 1–2 1–2 Amoxicillin/clavulani 0.03 1 4 c acid 0.06–0.25 2–4 8–16 Clarithromycin 0.03–0.25 4–64 32–>256 Azithromycin 0.06–0.12 4–8 >64 Pen S, penicillin susceptible; Pen I, intermediate susceptibility to penicillin; Pen R, penicillin resistant

Blondeau. J Antimicrob Chemother 1999; 43(Suppl B): 1–11 PharmacodynamicPharmacodynamic parametersparameters forfor quinolonesquinolones usedused toto treattreat S.S. pneumoniaepneumoniae infectioninfection

MIC90 AUC0-24 Free drug Free AUC Free AUC:MIC (mg/l) (mg/h/l) (%) (%) (mg/h/l)

Ciprofloxacin, 750mg b.i.d. 1.0 40 70 28 28

Levofloxacin, 500mg q.d. 1.0 48 70 34 34

Levofloxacin, 750mg q.d. 1.0 101 70 70 70

Gatifloxacin, 400mg q.d. 0.25 33 80 26 104

Moxifloxacin, 400mg q.d. 0.25 48 50 24 96

MIC = minimal inhibitory concentration

AUC24 = 24-h area under the plasma concentration curve b.i.d. = twice a day q.d. = once a day

Adapted from Wispelwey B CID 2005;41:127

PharmacodynamicPharmacodynamic activityactivity ofof fluoroqinolonesfluoroqinolones againstagainst S.S. pneumoniaepneumoniae

MIC MPC AUC:MIC 90 T>MPC, h (mg/l) (mg/l) (mg/h/l)

Gemifloxacin 0.03 1 4 140-280

Moxifloxacin 0.25 2 18 190

Gatifloxacin 0.5 4 1-2 103

Levofloxacin 1 8 0 48

MIC = minimal inhibitory concentration MPC = mutant prevention concentration AUC = area under the plasma concentration curve T>MPC = time that the drug concentration is above the MPC

Adapted from Wispelwey B CID 2005;41:127

AUC/MICAUC/MIC ratiosratios forfor S.S. pneumoniaepneumoniae

300 (148–240) 250

Free 200 AUC/MIC (80–133) 150 (55–88) 100 100 Resistance Prevention (25–42) ~AUC/MIC=100 50 (20–35) 35 Efficacy ~AUC/MIC=35 0 Cipro Levo Levo Gati Moxi 750 mg q12h 500 mg qd 750 mg qd 400 mg qd 400 mg qd

Adapted from Doern GV. CID 2001: 33 (Supp 3): S187–92 and Ball P. The Quinolones Third Edition. Ed: Academic Press. 2000. pp1–31.

ResistanceResistance MechanismsMechanisms inin FluoroquinolonesFluoroquinolones (I)(I)

ChromosomallyChromosomally--encodedencoded:: • Impaired drug targets (DNA gyrase and topoisomerase IV)

• Decreased outer-membrane permeability (Porin defects)

• Over-expression of naturally occuring efflux systems

Poirel L et al. CMI 2008;14:295-297

ResistanceResistance MechanismsMechanisms inin FluoroquinolonesFluoroquinolones (II)(II)

PlasmidPlasmid--mediatedmediated quinolonequinolone resistanceresistance (PMQR):(PMQR):

• Qnr A/B/S – binding directly to both DNA gyrase and topoisomerase IV

• AAC (6´)-Ib-cr-aminoglycoside and ciprofloxacin acetyltransferase

• Qep A – quinolones efflux pump

Poirel L et al. CMI 2008;14:295-297

WorldwideWorldwide ratesrates ofof S.S. pneumoniaepneumoniae nonnon--susceptiblesusceptible toto fluoroquinolonesfluoroquinolones

Croatia Italy Northern Ireland Ciprofloxacin 3.6% Levofloxacin 5.6% Canada Ciprofloxacin 15% Levofloxacin 3.4% Levofloxacin 1.6% Japan Levofloxacin 1.3%

Spain Ciprofloxacin 7% Hong Kong Ciprofloxacin 17.8% United States Levofloxacin 13.3% Ciprofloxacin 2.3% Saudi Arabia Levofloxacin 0.0%

South Africa Singapore Levofloxacin 0.0% Levofloxacin 1.6%

Desphande et al. DMID 2006; Doern et al. Clin Infect Dis 2005; Ho et al. J Antimicrob Chemother 2000; Nagai et al. Antimicrob Agents Chemother 2002; Thornsberry et al. Clin Infect Dis 2002; Goldsmith et al. J Antimicrob Chemother 1998; Pankuch et al. Antimicrob Agents Chemother 2002; Perez-Trallero et al. Antimicrob Agents Chemother 2001; Powis et al. Antimicrob Agents Chemother 2004

S. pneumoniae resistance to fluoroquinolones remains low • Alexander Project1 • Ofloxacin resistance low in 2001 in: • France: 1.2% • Germany: 0.7% • Spain: 0.9% • USA: 0.7% • TARGETed Surveillance Study2 • Low resistance rates across USA, South Africa, Mexico, Italy, France, Spain and Germany:

• 0–0.6% for moxifloxacin • 0–3.0% for levofloxacin • EARSS (2003) 3 • Low resistance in the UK: 0.8% for moxifloxacin • FAST4 • Resistance to fluoroquinolones in the USA • Non-multi-drug resistant strains: 0.3–0.5% • Multi-drug resistant strains: 1.7–3.6% 1) Felmingham et al. J Antimicrob Chemother 2005; 56(Suppl S2): ii3–21 2) Morrissey et al. Int J Antimicrob Agents 2007; 30: 345–51 3) Johnson et al. Int J Antimicrob Agents 2005; 25: 539–41 4) Draghi et al. Int J Antimicrob Agents 2006; 28: 525–31

Fluoroquinolone resistant S. pneumoniae are rare in patients without identified risk factors (1) • Of 3654/3979 isolates tested the following resistance rates were recorded: • 0.79% (n=29) to moxifloxacin • 3% (n=109) to ciprofloxacin • 2.2% (n=80) to levofloxacin • Resistance was highest in respiratory isolates, isolates from cases acquired in institutions and cases with recent exposure to fluoroquinolones • Fluoroquinolone resistance was rare in patients with community-acquired pneumococcal infections without prior exposure to fluoroquinolones • <0.2% for moxifloxacin; <1% for levofloxacin

McGeer et al. ICAAC 2006, Abstract A2603

E E par(E) C C TopoisomeraseTopoisomerase IVIV C •• CiprofloxacinCiprofloxacin par(C) •• LevofloxacinLevofloxacin •• GatifloxacinGatifloxacin B B gyr(B) •• MoxifloxacinMoxifloxacin A A

DNADNA gyrasegyrase gyr(A)

Adapted from Doern GV. CID 2001: 33 (Supp 3): S187–92

Range of inhibitory concentrations of 5-fluoroquinolones for DNA gyrase and topoisomerase IV isolated from different bacterial species

Van Bambeke F et al. CMJ 2005;11:256

Fluoroquinolone use and pneumococcal resistance rates, Canada

% levo R Total fluoroquinolone use Levo use Moxi use 4 6

3,5

3 4 2,5

2

1,5 2 % of isolates 1

0,5 Rx per 10,000 population

0 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Fluoroquinolone-resistant pneumococci: Canadian Bacterial Surveillance Network

4 Moxifloxacin

3,5 Levofloxacin 3

2,5

2

1,5 % resistant

1

0,5

0 1997 1998 1999 2000 20012002 2003 2004 2005 2006 2007

Canadian Bacterial Surveillance Network, updated Feb 2008 Annual prevalence of single gyrA mutations, Canada, 1993–2007

3,5 [Approx 3000 samples]

3

2,5

2

1,5

1

0,5

0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Canadian Bacterial Surveillance Network, updated Feb 2008 S. aureus Bacteremia

Quinolones?:

ƒ Ciprofloxacin + Rifampcin for right-sided S. aureus endocarditis Am J Med 1996; 101: 68 ƒ Ciprofloxacin + for orthopedic implant-associated infection [no bacteremias] JAMA 1998; 279: 1537 ƒ Fleroxacin + Rifampicin (1x600 mg p.o.) for staphylococcal infection [80% bacteremic] is comparable to standard therapy (iv Flucloxacillin [4x2 g] or Vancomycin) Clin Infect Dis 2004; 39: 1285 In vitro activity of moxifloxacin and other antimicrobial agents against MRSA, MSSA and VISA strains I

Antibiotic (susceptible MIC (µg ml-1) Susceptible -1 breakpoint, µg ml ) % Range MIC50 MIC90

CA-MRSA (33 isolates) Moxifloxacin (≤0.5) ≤0.03-32 1 8 15.2 Doxycycline (≤4) 0.125-4 0.125 0.25 100 (≤8) 0.5-4 2 2 100 SXT (≤2/38) 0.06-0.25 0.06 0.125 100 Clindamycin (≤0.5) 0.125->128 0.125 >128 93.9 Erythromycin (≤0.5) 0.5->128 128 >128 9.1 Rifampicin (≤1) 0.008-0.015 0.008 0.008 100 Vancomycin (≤2) 0.5-1 1 1 100 Levofloxacin (≤1) ≤0.5->16 4 >16 15.1

Goldstein E J et al. J Med Microbiol 2008;57:452 In vitro activity of moxifloxacin and other antimicrobial agents against MRSA, MSSA and VISA strains II

Antibiotic (susceptible MIC (µg ml-1) Susceptible -1 breakpoint, µg ml ) % Range MIC50 MIC90

HA-MRSA (24 isolates) Moxifloxacin (≤0.5) 1-32 4 32 0 Doxycycline (≤4) 0.06-2 0.125 0.25 100 Trimethoprim (≤8) 0.5-4 2 4 100 SXT (≤2/38) 0.06-0.25 0.125 0.125 100 Clindamycin (≤0.5) ≤0.06->128 0.125 >128 62,5 Erythromycin (≤0.5) 0.5->128 >128 >128 0 Rifampicin (≤1) 0.008-0.03 0.008 0.015 100 Vancomycin (≤2) 0.5-1 1 1 100 Levofloxacin (≤1) 4->16 >16 >16 0

Goldstein E J et al. J Med Microbiol 2008;57:452 Antibiograms of inpatient and outpatient MSSA and MRSA

Agent % Resistant Outpatient Inpatient Outpatient Inpatient MSSA MSSA MRSA MRSA (n=546) (n=692) (n=512) (n=946) Linezolid 0.0 0.0 0.0 0.0 Vancomycin 0.0 0.0 0.0 0.0 Rifampin 0.0 0.1 1.4 3.4 Levofloxacin 5.7 8.7 39.6 68.0 Clindamycin 8.6 7.1 32.4 57.7 Erythromycin 35.0 38.3 90.0 94.0

Draghi DC et al. Diagn Microbiol Infect Dis 2006;55:129

Time-kill responses of orally available antimicrobials alone and in combination against MRSA

Van Bambeke F et al. CMJ 2005;11:256

Time-kill curves of quinolone-exposed S. aureus 944 and S. aureus 916 at comparable AUC/MIC ratios (466h)

Firsov AA et al. AAC 2005;49:2642-2647

Changes in the susceptibility of S. aureus 201 during and after 3-day

treatments with four fluoroquinolones at different AUC24/MIC ratios

Firsov AA et al. AAC 2003;47:1604-1613

SusceptibilitySusceptibility andand resistanceresistance genesgenes toto fluoroquinolonesfluoroquinolones inin MRSAMRSA isolatedisolated inin 20022002

METHODS: Analysis of 100 MRSA (Tokyo) with mutation in the QRDR

RESULTS: • 97% mutation in grlA and gyrA

• Only double mutation resulted in high-level resistance to LXF/MOF • 15% mutations in norA (efflux pump) – all had also double mutations

Noguchi N et al. IJAA 2005;25:374-379 Risk factors associated with nosocomial methicillin-resistant (MRSA) infection including previous use of antimicrobials

METHODS: Case control study of 121 pat. Infected with MRSA versus 123 pat. Infected with MSSA in Albany Medical Center

RESULTS: Risk factors for MRSA • previous exposure to levofloxacin (OR 8.01) • previous exposure to (OR 4.06) • previous hospitalization (OR 1.95) • enteral feedings (OR 2.55) • surgery (OR 2.24)

Graffunder EM Venezia RA JAC 2002;49:999-1005

MRSAMRSA inin GermanGerman ICUICU duringduring 20002000--2003:2003: DataData fromfrom ProjectProject SARSSARS

METHODS: Prospective, ICU-based surveillance study 38 German ICUs – 2000-2003

RESULTS: • 500.000 patients – day 9552 S. aureus – 2.249 MRSA

• Mean cumulative MRSA: 23.6%

• Positive correlation of MRSA incidence with ciprofloxacin and imipenem usage

Meyer E et al. Infection Control and Hospital Epidemiology 2006;27:146 Conclusions

• Modern FQI are active against MDR S.pneumoniae

• FQI are not usefull in MRSA- , MRSE- and Enterococcal Infections

- FQI overusage may select for MRSA

- New FQI with activity against resistant Gram-pos. pathogens are urgently needed but at ECCMID/Barcelona only one new FQI (zabofloxacin) was presented

THANK YOU

Enjoy the meeting ! Distribution of agr group and function among SCCmec II HAMRSA (50 strains) and SCCmec IV CAMRSA (200 strains)

100 - 90 - 85 86 80 - CAMRSA 70 - 100 - 70 - HAMRSA agr functional 60 - 80 - % 50 - agr dysfunctional 60 - 40 - % 30 - 40 - 48 % 20 - 12 12 9.5 20 - 3,5% 10 - 4.5 0.5 0 - 0 - I II III HAMRSA CAMRSA agr group MRSA classification

Tsuji BT et al. Diagnostic Microbiol Infect Dis 2007;58:41-47 AUC/MIC-dependent antistaphylococcal effects of seven quinolones

Firsov AA et al. AAC 2005;49:2642-2647

In vitro activity of gemifloxacin and ciprofloxacin against Gram-positive bacteria from the US and UK

Lowe NL et al. Drugs 2000;59:1137-1147 Index of quinolone therapeutic potentials expressed as

the clinically achievable ratio of AUCther /MIC50 related to the predicted AUC/MIC BPs

Firsov AA et al. AAC 2005;49:2642-2647

Current estimates of resistance to ciprofloxacin

Jacoby JA et al. CID 2005;41:S120 InIn vitrovitro activityactivity ofof moxifloxacinmoxifloxacin (MXF)(MXF) andand otherother fluoroquinolonesfluoroquinolones againstagainst GramGram--positivepositive pathogenspathogens

Organism Range of MIC90 values (µg/ml) [%S] [total no. Of clinical isolates] MXF CIP GAT GEM LVX

Gram-positive bacteria

Streptococcus pneumoniae 0.12-0.5 1-4 0.25-0.5 0.03-0.06 1 [98.2-100] (untyped) [14559] [98.2-100]

S. pneumoniae (PS) [5711] 0.12-0.25 2 0.25-0.5 0.03 1 [93.9-99.5]

S. pneumoniae (PI) [1607] 0.12-0.25 1 0.25 0.03 1 [98.8-99.8]

S. pneumoniae (PR) [1152] 0.12-0.25 1 0.25-0.5 0.03 1 [99.4-100]

S. pyogenes [3792] 0.12-0.25 0.25 0.5-1 [100]

Staphylococcus aureus 0.06-0.12 0.5-1 0.03 0.25 (MS) [92]

S. aureus (MR) [131] 2-4 >16-32 4 8 4-8

Keating G M et al. Drugs 2004;20:2347-2377

Fluoroquinolone resistance decreased since 2003, despite increased fluoroquinolone use • Antimicrobial surveillance in the Maritime region of Canada between 1998 and 2006 found that: •levofloxacin use selects for fluoroquinolone resistance in S. pneumoniae at a higher frequency than moxifloxacin or gatifloxacin •increased prevalence of S. pneumoniae first- step parC mutations coincided with increased use of levofloxacin •switch to moxifloxacin and gatifloxacin resulted in reduced levofloxacin resistance and decreased number of first-step parC mutations Davidson & Campbell. ICAAC 2006, Poster C2-434