Appropriate Use of Quinolones Quinolones in the in the Appropriate - - PowerPoint PPT Presentation

Appropriate Use of Appropriate Use of Quinolones Quinolones in the in the Hospital: Is Microbiology Telling You All? Hospital: Is Microbiology Telling You All?

David C. Hooper, M.D. David C. Hooper, M.D. Division of Infectious Diseases Division of Infectious Diseases Infection Control Unit Infection Control Unit Massachusetts General Hospital Massachusetts General Hospital Harvard Medical School Harvard Medical School Boston, Massachusetts Boston, Massachusetts GSK Chair of Infectious Diseases Lesson to Students – Leuven, March 27th, 2007

Sites of Action of Antimicrobial Sites of Action of Antimicrobial Agents in Clinical Use Agents in Clinical Use

Neu HC. Science 1992; 257:1064-73

Topoisomerase IV Linezolid (Oxazolidinone) Daptomycin (Lipopeptide) Telithromycin (Ketolide) Glycylcyclines

Fluoroquinolones Fluoroquinolones Mechanisms of Action Mechanisms of Action

• Inhibit DNA synthesis

Inhibit DNA synthesis

• Stabilize DNA strand breaks created by

Stabilize DNA strand breaks created by actions of DNA actions of DNA gyrase gyrase and and topoisomerase topoisomerase IV by binding enzyme IV by binding enzyme-

• DNA complexes

DNA complexes

• Bactericidal

Bactericidal -

• requires additional events

requires additional events after initial interaction with enzyme after initial interaction with enzyme-

• DNA

DNA complexes complexes

Fluoroquinolones Fluoroquinolones Available Available in the United States in the United States

• Norfloxacin

Norfloxacin ( (Noroxin Noroxin) ) 1986 (PO) 1986 (PO)

• Ciprofloxacin (

Ciprofloxacin (Cipro Cipro) ) 1987 (PO), 1990 (IV) 1987 (PO), 1990 (IV)

• Ofloxacin

Ofloxacin ( (Floxin Floxin) ) 1990 (PO), 1992 (IV) 1990 (PO), 1992 (IV)

• Levofloxacin

Levofloxacin ( (Levaquin Levaquin) ) 1996 (IV & PO) 1996 (IV & PO)

• Gatifloxacin

Gatifloxacin ( (Tequin Tequin) ) 1999 (IV & PO) 1999 (IV & PO)

• Moxifloxacin

Moxifloxacin ( (Avelox Avelox) ) 1999 (PO), 2001 (IV) 1999 (PO), 2001 (IV)

• Gemifloxacin

Gemifloxacin ( (Factive Factive) ) 2003 (PO) 2003 (PO)

Fluoroquinolone Structures

Gemifloxacin

Properties of Newer Quinolones Properties of Newer Quinolones

• Broad spectrum activity

– Gram-negative bacteria – Improved against Gram-positive bacteria – Improved against Anaerobes

• Once or twice daily dosing
• Some with apparent reduced risk of

selection of resistance

• Broad spectrum activity

– Gram-negative bacteria – Improved against Gram-positive bacteria – Improved against Anaerobes

• Once or twice daily dosing
• Some with apparent reduced risk of

selection of resistance

Fluoroquinolones Fluoroquinolones Spectrum of Activity Spectrum of Activity

• Enterobacteriaceae

Enterobacteriaceae

• Haemophilus

Haemophilus spp spp. . Neisseria Neisseria spp spp. .

• Legionella

Legionella, , Mycoplasma Mycoplasma, Chlamydia , Chlamydia [ [Levofloxacin Levofloxacin, , Gatifloxacin Gatifloxacin, , Moxifloxacin Moxifloxacin] ]

• Pseudomonas

Pseudomonas aeruginosa aeruginosa [Ciprofloxacin, [Ciprofloxacin, Levofloxacin Levofloxacin] ]

Fluoroquinolones Fluoroquinolones Spectrum of Activity Spectrum of Activity

• Staphylococci (MSSA, MSSE) [

Staphylococci (MSSA, MSSE) [Levofloxacin Levofloxacin, , Gatifloxacin Gatifloxacin, , Moxifloxacin Moxifloxacin, , Gemifloxacin Gemifloxacin] ]

• Streptococci (+/

Streptococci (+/-

• enterococci

enterococci) [ ) [Levofloxacin Levofloxacin, , Gatifloxacin Gatifloxacin, , Moxifloxacin Moxifloxacin, , Gemifloxacin Gemifloxacin] ]

• Anaerobes [

Anaerobes [Gatifloxacin Gatifloxacin, , Moxifloxacin Moxifloxacin] ]

• Mycobacteria

Mycobacteria ( (M. tuberculosis, M.

• M. tuberculosis, M. kansasii

kansasii, , M.

• M. fortuitum

fortuitum) [Ciprofloxacin, ) [Ciprofloxacin, Levofloxacin Levofloxacin, , Gatifloxacin Gatifloxacin, , Moxifloxacin Moxifloxacin] ]

Activity of Quinolones Against 75 Ciprofloxacin-Resistant Isolates of Streptococcus pneumoniae

Quinolone Quinolone Cumulative % Isolates at MIC ( Cumulative % Isolates at MIC (μ μg/ml) g/ml) ≤ ≤0.06 0.12 0.06 0.12-

• 0.25 0.5

0.25 0.5-

• 1 2

1 2-

• 4 8

4 8-

• 16 32

16 32-

• 64

64 Levofloxacin Levofloxacin 16 67 95 100 16 67 95 100 Gatifloxacin Gatifloxacin 4 64 93 100 4 64 93 100 Moxifloxacin Moxifloxacin 56 71 97 100 56 71 97 100 Gemifloxacin Gemifloxacin 61 92 100 61 92 100

Chen DK et al. 1999. N Engl J Med. 341:233-9

Pharmacokinetic Properties of Pharmacokinetic Properties of Oral Oral Fluoroquinolones Fluoroquinolones

Drug Dose Drug Dose C Cmax

max

t t½

½

Renal Renal

(mg (mg -

• (

(μ μg/ml) (h) g/ml) (h) Clearance

Clearance

frequency) frequency) (% of total) (% of total) Ciprofloxacin 500 BID 2.2 3.3 50 Ciprofloxacin 500 BID 2.2 3.3 50 Levofloxacin Levofloxacin 500 QD 5.7 6 500 QD 5.7 6-

• 8 65

8 65 750 QD 750 QD 8.6 8.6 Gatifloxacin Gatifloxacin 400 QD 4.1 7 400 QD 4.1 7-

• 8 80

8 80 Moxifloxacin Moxifloxacin 400 QD 4.5 13 22 400 QD 4.5 13 22 Gemifloxacin Gemifloxacin 320 QD 320 QD 1.8 1.8 7 30

Pharmacokinetic Properties of Pharmacokinetic Properties of IV IV Fluoroquinolones Fluoroquinolones

Drug Dose Drug Dose C Cmax

max

t t½

½

Renal Renal

(mg (mg -

• (

(μ μg/ml) (h) g/ml) (h)

Clearance Clearance

frequency) frequency) (% of total) (% of total) Ciprofloxacin 400 BID 4.3 3.3 50 Ciprofloxacin 400 BID 4.3 3.3 50 Levofloxacin Levofloxacin 500 QD 6.4 6 500 QD 6.4 6-

• 8 65

8 65 750 QD 750 QD 12.1 12.1 Gatifloxacin Gatifloxacin 400 QD 4.6 7 400 QD 4.6 7-

• 8 80

8 80 Moxifloxacin Moxifloxacin 400 QD 4.2 13 22 400 QD 4.2 13 22

Specific Uses of Specific Uses of Fluoroquinolones Fluoroquinolones

• Typhoid and enteric fever

Typhoid and enteric fever

• Prostatitis

Prostatitis ( (vs vs trimethoprim trimethoprim-

• sulfa)

sulfa)

• Complicated urinary tract infections

Complicated urinary tract infections

• Community

Community-

• acquired pneumonia

acquired pneumonia

– – hospitalized patients ( hospitalized patients (vs vs ceftriaxone ceftriaxone + + macrolide macrolide) )

• Prosthetic joint infection

Prosthetic joint infection

– – for salvage when prosthesis cannot be removed for salvage when prosthesis cannot be removed – – with with rifampin rifampin

General Clinical Uses of Fluoroquinolones

• Urinary Tract Infections

Urinary Tract Infections

• Prostatitis

Prostatitis

• Sexually Transmitted Diseases

Sexually Transmitted Diseases

• Gastroenteritis

Gastroenteritis

• Intraabdominal

Intraabdominal Infections Infections

• Respiratory Tract Infections

Respiratory Tract Infections

• Bone & Joint Infections

Bone & Joint Infections

• Skin & Soft Tissue Infections

Skin & Soft Tissue Infections

• Other Broad Uses in Hospitalized Patients

Other Broad Uses in Hospitalized Patients

General Clinical Uses of Fluoroquinolones

• Urinary Tract Infections

Urinary Tract Infections

• Prostatitis

Prostatitis

• Sexually Transmitted Diseases

Sexually Transmitted Diseases

• Gastroenteritis

Gastroenteritis

• Intraabdominal

Intraabdominal Infections Infections

• Respiratory Tract Infections

Respiratory Tract Infections

• Bone & Joint Infections

Bone & Joint Infections

• Skin & Soft Tissue Infections

Skin & Soft Tissue Infections

• Other Broad Uses in Hospitalized Patients

Other Broad Uses in Hospitalized Patients

Fluoroquinolone Drug Interactions

• Antacids,

Antacids, sucralfate sucralfate, multivalent , multivalent cations cations impair oral absorption impair oral absorption

• Increase

Increase theophylline theophylline and caffeine and caffeine ( (Enoxacin Enoxacin > Ciprofloxacin) > Ciprofloxacin)

• NSAIDs

NSAIDs possibly possibly potentiate potentiate neurotoxicity neurotoxicity ( (Enoxacin Enoxacin) )

• Potentiation

Potentiation of

• f warfarin

warfarin effect is effect is sporadic sporadicA

A

• High doses may increase

High doses may increase cyclosporin cyclosporin levels levels (Ciprofloxacin) (Ciprofloxacin)

ASeen in some elderly patients on multiple drugs

Adverse Effects of Adverse Effects of Fluoroquinolones Fluoroquinolones

• Gastrointestinal

Gastrointestinal

– – Nausea, vomiting, diarrhea Nausea, vomiting, diarrhea

• Hepatic

Hepatic

– – Idiosyncratic hepatitis ( Idiosyncratic hepatitis (trovafloxacin trovafloxacin) )

• Central Nervous System

Central Nervous System

– – Dizziness ( Dizziness (trovafloxacin trovafloxacin), insomnia, ), insomnia, seizures seizures

• Cardiovascular

Cardiovascular

– – QT QTC

C prolongation, arrhythmias

prolongation, arrhythmias ( (sparfloxacin sparfloxacin, , grepafloxacin grepafloxacin) )

Effects of Drugs on Cardiac Conduction

Drug Drug QT QTC

C Prolongation

Prolongation I Ikr

kr a a

hERG hERG IC IC30

30 b b

( (msec msec) ) ( (μ μM) M) ( (μ μM) M) Sparfloxacin Sparfloxacin 13 13-

• 15 0.23 10

15 0.23 10 Grepafloxacin Grepafloxacin 10 10 27.2 39 27.2 39 Moxifloxacin Moxifloxacin 7 7 --

• 92

92 Gatifloxacin Gatifloxacin 5 5-

• 6

6 26.5 104 26.5 104 Levofloxacin Levofloxacin 5 5 Erythromycin Erythromycin 8 8-

• 15

15 Clarithromycin Clarithromycin 2 2-

• 6

6

aAnderson et al. 3rd ECC bChen et al. ICAAC 2000 abstr 765

Adverse Effects of Adverse Effects of Fluoroquinolones Fluoroquinolones

• Metabolic

Metabolic

– – Hypoglycemia and Hypoglycemia and potentiation potentiation of hypoglycemic

• f hypoglycemic

agents ( agents (clinafloxacin clinafloxacin, , gatifloxacin gatifloxacin) )

• Skin

Skin

– – Photosensitivity Photosensitivity – – UVA (320 UVA (320-

• 420) (

420) (sparfloxacin sparfloxacin, , lomefloxacin lomefloxacin) ) – – Rash ( Rash (gemifloxacin gemifloxacin – – young women, Rx for >10 young women, Rx for >10 days) days)

• Musculoskeletal

Musculoskeletal

– – Cartilage erosion in Cartilage erosion in weightbearing weightbearing joints joints (animals, ?children) (animals, ?children) – – Tendinopathy Tendinopathy, tendon rupture , tendon rupture

Trends in Inpatient Antibiotic Use

5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999

Year Defined Daily Doses

Third generation cephalosporins Aminoglycosides Fluoroquinolones

Increasing Increasing Quinolone Quinolone Resistance Resistance Associated with Increasing Use Associated with Increasing Use

a few minutes ago

Neuhauser MM et al. JAMA 2003; 289:885-8

Ciprofloxacin Resistance in Gram Ciprofloxacin Resistance in Gram-

• Negative Bacilli in ICUs in the

Negative Bacilli in ICUs in the United States United States -

• 1994

1994-

• 2000

2000

Species Resistant Species Resistant Change ChangeA

A

Cross Resistance to: Cross Resistance to:

(%) (%) (%) (%)

Gent Gent Ceftaz Ceftaz Imip Imip

(%, (%, CipR/CipS CipR/CipS) ) P.

• P. aeruginosa

aeruginosa 24 24 +13 +13 66/21 40/14 38/11 66/21 40/14 38/11 Enterobacter Enterobacter sp. 10

• sp. 10

+6 +6 49/4 82/32 4/1 49/4 82/32 4/1 K.

• K. pneumoniae

pneumoniae 12 12 +7 +7 67/7 65/6 3/0.5 67/7 65/6 3/0.5

• E. coli
• E. coli

3 +2 3 +2 All All isolates isolatesB

B

19 +10 19 +10 Neuhauser MM et al. JAMA 2003; 289:885-888

AChange relative to 1990-1993 Bn=35,790

Factors Associated with Factors Associated with Fluoroquinolone Fluoroquinolone Resistance Resistance

Resistant Pathogen Risk Factors Resistant Pathogen Risk Factors

Staphylococci (MRSA, MRCNS) Staphylococci (MRSA, MRCNS) Quinolone Quinolone Use, Use, Co Co-

• selection,

selection, Nosocomial Nosocomial Spread Spread Pseudomonas Pseudomonas aeruginosa aeruginosa Quinolone Quinolone Use, Use, Nosocomial Nosocomial Spread Spread Klebsiella Klebsiella pneumoniae pneumoniae Quinolone Quinolone Use, Use, Nosocomial Nosocomial Spread Spread Campylobacter Campylobacter jejuni jejuni Quinolone Quinolone Use, Use, Forei Foreign Travel gn Travel Escherichia coli Escherichia coli Quinolone Quinolone Use, Use, ?Anim ?Animal Use al Use

Pharmacodynamics Pharmacodynamics of

• f Quinolone

Quinolone-

• Resistant Mutant Selection

Resistant Mutant Selection

Drlica K and Zhao X. Clin Infect Dis. 2007; 44:681

Mechanisms of Resistance Mechanisms of Resistance to to Fluoroquinolones Fluoroquinolones

• Chromosomal mutations

Chromosomal mutations

– – Alterations in DNA Alterations in DNA gyrase gyrase and/or and/or topoisomerase topoisomerase IV IV – – Active drug efflux (MDR pumps) +/ Active drug efflux (MDR pumps) +/-

• reduced

reduced porin porin diffusion channels diffusion channels

• Plasmid

Plasmid-

• mediated resistance

mediated resistance

– – Enteric gram Enteric gram-

• negative bacteria; target

negative bacteria; target protection mechanism by protection mechanism by Qnr Qnr proteins proteins – – Drug modification Drug modification

Bacterial Type II Bacterial Type II Topoisomerases Topoisomerases Quinolone Quinolone Target Enzymes Target Enzymes

Enzyme Enzyme Subunits Subunits Activities Activities DNA DNA Gyrase Gyrase

( (Topoisomerase Topoisomerase II) II)

2 2 GyrA GyrA 2 2 GyrB GyrB DNA DNA Supercoiling Supercoiling (DNA Relaxation) (DNA Relaxation) (DNA (DNA Decatenation Decatenation) ) Topoisomerase Topoisomerase IV IV 2 2 ParC ParC ( (GrlA GrlA) ) 2 2 ParE ParE ( (GrlB GrlB) ) DNA DNA Decatenation Decatenation (DNA Relaxation) (DNA Relaxation)

Stepwise Increases in Stepwise Increases in Quinolone Quinolone Resistance: Role of Differing Resistance: Role of Differing Sensitivities of Enzyme Targets Sensitivities of Enzyme Targets

5 10 15 20 25 30 35 Wildtype parC parC gyrA

Topoisomerase IV DNA gyrase Relative MIC

Stepwise Increases in Stepwise Increases in Quinolone Quinolone Resistance: Role of Differing Resistance: Role of Differing Sensitivities of Enzyme Targets Sensitivities of Enzyme Targets

5 10 15 20 25 30 35 Wildtype parC parC gyrA

Topoisomerase IV DNA gyrase Relative MIC

Activity of Activity of Gemifloxacin Gemifloxacin and and Ciprofloxacin Against Ciprofloxacin Against Topoisomerase Topoisomerase IV and IV and Gyrase Gyrase

Enzyme Enzyme IC IC50

50 (

(μ μg/ml) g/ml) Gemifloxacin Gemifloxacin Ciprofloxacin Ciprofloxacin Topoisomerase Topoisomerase IV IV Wildtype Wildtype 0.25 0.25 2.5 2.5-

• 5.0

5.0 ParC ParC (Ser80Phe) 50 (Ser80Phe) 50 250 250 Gyrase Gyrase Wildtype Wildtype 0.31 0.31 10 10

Ince D et al. Antimicrob Agents Chemother. 2003; 47:274-82

200x 200x 100x 100x ~1x ~1x 2 2-

• 4x

4x

Drug Target Differences and Drug Target Differences and Frequency of Mutant Selection Frequency of Mutant Selection

Ince D et al. Antimicrob Agents Chemother. 2003; 47:274-82

Mechanisms of Resistance Mechanisms of Resistance to to Fluoroquinolones Fluoroquinolones

• Chromosomal mutations

Chromosomal mutations

– – Alterations in DNA Alterations in DNA gyrase gyrase and/or and/or topoisomerase topoisomerase IV IV – – Active drug efflux (MDR pumps) +/ Active drug efflux (MDR pumps) +/-

• reduced

reduced porin porin diffusion channels diffusion channels

• Plasmid

Plasmid-

• mediated resistance

mediated resistance

– – Enteric gram Enteric gram-

• negative bacteria; target

negative bacteria; target protection mechanism by protection mechanism by Qnr Qnr proteins proteins – – Drug modification Drug modification

In37 in transconjugant 12-4

intI1 dfr16 aadA2 qacE Δ1 sul1

• rf513

qnr ampR qacE Δ1 sul1

• rf6

IS6100 EcoRII catB3 aar-3 qacE Δ1 sul1

• rf513

qnr ampR qacE Δ1 sul1

• rf5 orf6

IS6100 EcoRII EcoRII cytosine methylase

aac(6’)

• Ib

Gene cassettes 5’-CS 3’-CS1 Common region 3’-CS2

In36 in transconjugant 4-59

intI1 aadA2 qacE Δ1 sul1

• rf513

blaCTX-M-9

• rf3-like

qacE Δ1 sul1

In60

EcoRII cytosine methylase IS3000 intI1 aadA2 qacE Δ1 sul1

• rf513

ampC ampR qacE Δ1 sul1

• rf5

pSAL-1

intI1 aadB sul1

• rf513
• rf5

In7

qacE Δ1 intI1 aacA4 aadA2 sul1

• rf513

catA2 qacE Δ1 sul1

• rf5

In6

qacE Δ1

Unique region

In35 (InS21)

intI1 blaOXA-2 orfD qacE Δ1 sul1

• rf513

blaCTX-M-2

• rf3

qacE Δ1

• rf5

qacE Δ1 sul1 dfrA10 sul1 dfr16 aac(6’)

• Ib

intI1 blaOXA-30

Wang M et al. Antimicrob Agents Chemother. 2003; 47:2242-8

Occurrence of Occurrence of Integron Integron-

• Carrying

Carrying Enteric Bacteria in ICUs Enteric Bacteria in ICUs

Variable Variable

• No. (%) of ICU Patients
• No. (%) of ICU Patients

Medical Neurosurgical Medical Neurosurgical

(n = 277) (n = 277) (n = 180) (n = 180) Total colonized Total colonized 19 (7) 19 (7) 12 (7) 12 (7) Acquired colonization Acquired colonization 14 (5) 14 (5) 9 (5) 9 (5) Time to acquisition (d) Time to acquisition (d) 10 10 ± ± 10 10 12 12 ± ± 10 10 Acquisition rate Acquisition rate (per 1000 patient (per 1000 patient-

• days) 10

days) 10 8 8

Nijssen S et al. Clin Infect Dis. 2005; 41:1-9.

Resistance Profiles of Resistance Profiles of Integron Integron-

• Carrying Enteric Bacteria

Carrying Enteric Bacteria

Antimicrobial Antimicrobial Percent Resistant Percent Resistant Integron Integron ( (-

• )

) Integron Integron (+) (+)

(n = 120) (n = 120) (n = 54) (n = 54) Piperacillin Piperacillin 24 24 94* 94* Ceftazidime Ceftazidime 26 26 33 33 Cefotaxime Cefotaxime 29 29 44* 44* Meropenem Meropenem Gentamicin Gentamicin 2 2 94* 94* Ciprofloxacin Ciprofloxacin 3 3 33* 33* Nijssen S et al. Clin Infect Dis. 2005; 41:1-9.

Effect of qnrA on Quinolones

Wang M et al. Antimicrob Agents Chemother. 2004; 48:1400-1

QnrA QnrA Promotes Selection of Promotes Selection of Higher Higher-

• Level

Level Quinolone Quinolone Resistance Resistance

Martínez-Martínez L et al. Lancet 1998; 351:797-9

The Newest Mechanism of Plasmid The Newest Mechanism of Plasmid-

• Mediated

Mediated Quinolone Quinolone Resistance Resistance

• Specific modification of some

Specific modification of some quinolones quinolones (ciprofloxacin, (ciprofloxacin, norfloxacin norfloxacin) )

• Mutant of a common

Mutant of a common aminoglycoside aminoglycoside acetyltransferase acetyltransferase enzyme, Aac(6 enzyme, Aac(6’ ’)Ib, which causes resistance to )Ib, which causes resistance to kanamycin kanamycin, , tobramycin tobramycin, and , and amikacin amikacin

– – Mutations Trp102Arg and Asp179Tyr = Aac(6 Mutations Trp102Arg and Asp179Tyr = Aac(6’ ’)Ib )Ib-

• cr

cr – – Acetylates ciprofloxacin at Acetylates ciprofloxacin at piperazinyl piperazinyl N N – – Slight decrease in Slight decrease in kanamycin kanamycin acetylation acetylation

• Low

Low-

• level resistance (4

level resistance (4-

• fold)

fold)

• Promotes selection of high

Promotes selection of high-

• level resistance with

level resistance with quinolone quinolone exposure exposure

• aac(6

aac(6’ ’) )-

• Ib

Ib-

• cr located on plasmids with and without

cr located on plasmids with and without qnr qnr genes genes Robicsek A et al. Nature Medicine 2006; 12;83-88

Limiting Bacterial Resistance Limiting Bacterial Resistance to to Fluoroquinolones Fluoroquinolones

• Monitor Resistance

Monitor Resistance

• Good Infection Control to Limit Spread

Good Infection Control to Limit Spread

• Focused and Balanced Use to Limit

Focused and Balanced Use to Limit Selective Pressures Selective Pressures

• Adequate Dosing to Limit Mutant

Adequate Dosing to Limit Mutant Selection Selection

Pharmacodynamic Pharmacodynamic Factors Factors Affecting Risk of Selection of Affecting Risk of Selection of Quinolone Quinolone Resistance Resistance

• Selecting Drug Concentration

Selecting Drug Concentration in Vitro in Vitro

• C

Cmax

max/MIC

/MIC -

• Animal Models

Animal Models

• AUC/MIC

AUC/MIC -

• Human Use

Human Use

Limiting Bacterial Resistance Limiting Bacterial Resistance to to Fluoroquinolones Fluoroquinolones

• Possible Use of Combination Regimens:

Possible Use of Combination Regimens:

– – With Other Antibiotics With Other Antibiotics – – Specific Inhibitors of Resistance Mechanisms Specific Inhibitors of Resistance Mechanisms

• Development of New

Development of New Quinolones Quinolones

– – Similar Activity Against Both Enzyme Targets Similar Activity Against Both Enzyme Targets – – Improved Therapeutic Index Improved Therapeutic Index