Quinolones in the Hospital in the Hospital Quinolones Pros and - - PowerPoint PPT Presentation

Quinolones Quinolones in the Hospital in the Hospital Pros and Cons Pros and Cons

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 Clinical Seminar – 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 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] ]

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

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) )

Risk Factors for Prolonged QT Risk Factors for Prolonged QT-

• Associated

Associated Arrhthymias Arrhthymias

• ↓

↓ K K+

+,

, ↓ ↓ Mg Mg++

++

• Cardiomyopathy

Cardiomyopathy

• Bradycardia

Bradycardia

• Congenital prolonged QT syndromes

Congenital prolonged QT syndromes

• Use of other

Use of other antiarrhythmics antiarrhythmics: :

Class III Class III (block K (block K+

+ channel)

channel)

Amiodarone Amiodarone Sotalol Sotalol Ibutilide Ibutilide Bretylium Bretylium

Class Class Ia Ia (block Na (block Na+

+ & K

& K+

+ channels)

channels)

Quinidine Quinidine Disopyramide Disopyramide Procainamide Procainamide

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

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

Shorr AF et al. Clin Infect Dis 2005; 40:S115

Quinolone Quinolone Treatment of Treatment of Hospital Hospital-

• Acquired Pneumonia

Acquired Pneumonia

Quinolone Quinolone Treatment of Treatment of Hospital Hospital-

• Acquired Pneumonia

Acquired Pneumonia

Shorr AF et al. Clin Infect Dis 2005; 40:S115

Outcomes of Outcomes of Quinolone Quinolone Treatment of Hospital Treatment of Hospital-

• Acquired

Acquired Pneumonia Pneumonia

Clinical Outcomes Clinical Outcomes Microbiological Outcomes Microbiological Outcomes

Shorr AF et al. Clin Infect Dis 2005; 40:S115

Development of Development of Quinolone Quinolone Resistance Related to Therapy in Resistance Related to Therapy in Hospital Hospital-

• Acquired Pneumonia

Acquired Pneumonia

Shorr AF et al. Clin Infect Dis 2005; 40:S115

Moxifloxacin Moxifloxacin vs.

• vs. Piperacillin

Piperacillin-

• Tazobactam/Amoxicillin

Tazobactam/Amoxicillin-

• Clavulanate

Clavulanate for for Complicated Intra Complicated Intra-

• abdominal Infections

abdominal Infections

Malagoni MA et al. Ann Surg 2006; 244:204

Malagoni MA et al. Ann Surg 2006; 244:204

Moxifloxacin Moxifloxacin vs.

• vs. Piperacillin

Piperacillin-

• Tazobactam/Amoxicillin

Tazobactam/Amoxicillin-

• Clavulanate

Clavulanate for for Complicated Intra Complicated Intra-

• abdominal Infections

abdominal Infections

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

Prevalence of Bacterial Resistance Prevalence of Bacterial Resistance to to Fluoroquinolones Fluoroquinolones

Staphylococci (MRSA, MRSE) Staphylococci (MRSA, MRSE) Pseudomonas Pseudomonas aeruginosa aeruginosa 60 60-

• 95%

95% 24 24-

• 44%

44% Campylobacter Campylobacter jejuni jejuni Escherichia coli Escherichia coli 3 3-

• 70%

70% Klebsiella Klebsiella pneumoniae pneumoniae 12 12-

• 20%

20% 3 3-

• 50%

50% Enterobacter Enterobacter spp spp. . 10 10-

• 12%

12%

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

Risk Factors and Clinical Effects of Ciprofloxacin Resistance in an ICU

Levin PD et al. Infect Control Hosp Epidemiol 2007; 28:331

Epidemiology of Ciprofloxacin Epidemiology of Ciprofloxacin Resistance in Resistance in Klebsiella Klebsiella pneumoniae pneumoniae

• 455

455 Bacteremias Bacteremias (440 patients) in 12 (440 patients) in 12 hospitals in 7 countries hospitals in 7 countries

• 25 (5.5%) with MIC of ciprofloxacin

25 (5.5%) with MIC of ciprofloxacin ≥ ≥ 4 4 μ μg/ml g/ml

– – 15/25 (60%) also ESBL 15/25 (60%) also ESBL-

• producing

producing

• 83 (18%) ESBL

83 (18%) ESBL-

• producing

producing

– – 15/83 (18%) also ciprofloxacin 15/83 (18%) also ciprofloxacin-

• resistant

resistant

Paterson DL et al. Clin Infect Dis 30:473-8 (2000)

Epidemiology of Ciprofloxacin Epidemiology of Ciprofloxacin Resistance in Resistance in Klebsiella Klebsiella pneumoniae pneumoniae

• Risk factors for resistance (multivariate)

Risk factors for resistance (multivariate)

– – Prior receipt of Prior receipt of quinolone quinolone (p=0.0065) (p=0.0065) – – ESBL ESBL-

• producing strain (p=0.012)

producing strain (p=0.012) – – Hospitalization in Turkish center (p=0.011) Hospitalization in Turkish center (p=0.011) – – Not prior receipt of 3rd Not prior receipt of 3rd-

• gen cephalosporin

gen cephalosporin (p=0.17) (p=0.17) – – Not indwelling urinary catheter (p=0.24) Not indwelling urinary catheter (p=0.24)

Paterson DL et al. Clin Infect Dis 30:473-8 (2000)

Epidemiology of Ciprofloxacin Epidemiology of Ciprofloxacin Resistance in Resistance in Klebsiella Klebsiella pneumoniae pneumoniae

• Nosocomial

Nosocomial acquisition acquisition

– – 72% of ciprofloxacin 72% of ciprofloxacin-

• resistant cases

resistant cases – – 54% of ciprofloxacin 54% of ciprofloxacin-

• susceptible cases (p=0.08)

susceptible cases (p=0.08)

• Clustering based on PFGE genotype

Clustering based on PFGE genotype

– – 4 clusters of 2 4 clusters of 2-

• 4 cases each in 3 hospitals

4 cases each in 3 hospitals – – In 2 clusters exposure to In 2 clusters exposure to quinolone quinolone occurred in 1st

• ccurred in 1st

case case

• Mortality (14 days)

Mortality (14 days)

– – 4/25 (16%) 4/25 (16%) Cip Cip-

• R vs. 120/427 (28%)

R vs. 120/427 (28%) Cip Cip-

• S (p=0.19)

S (p=0.19)

Paterson DL et al. Clin Infect Dis 30:473-8 (2000)

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

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.

Plasmid Plasmid-

• Encoded

Encoded Quinolone Quinolone Resistance: Resistance: Qnr Qnr Genes Genes

Robicsek A et al. Lancet Infect Dis 2006; 6:629-40

Worldwide Distribution of Worldwide Distribution of Qnr Qnr Quinolone Quinolone Resistance Genes Resistance Genes

Robicsek A et al. Lancet Infect Dis 2006; 6:629-40

Characteristics of Characteristics of qnr qnr-

• positive and

positive and qnr qnr-

• negative Isolates

negative Isolates

Robicsek A et al. Antimicrob Agents Chemother 2006; 50:2872

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

Pharmacodynamics Pharmacodynamics of

• f Quinolone

Quinolone-

• Resistant Mutant Selection

Resistant Mutant Selection

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

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