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Fluoroquinolones in 2007: the Angels, the in 2007: the Angels, the Fluoroquinolones Devils, and What Should the Clinician Do? Devils, and What Should the Clinician Do? David C. Hooper, M.D. David C. Hooper, M.D. Division of Infectious

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SLIDE 1

Fluoroquinolones Fluoroquinolones in 2007: the Angels, the in 2007: the Angels, the Devils, and What Should the Clinician Do? Devils, and What Should the Clinician Do?

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 – Mont-Godinne, March 29th, 2007

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SLIDE 2

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

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SLIDE 3

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)

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SLIDE 4

Fluoroquinolone Structures

Gemifloxacin

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SLIDE 5

Fluoroquinolone Fluoroquinolone Use in Patients with Use in Patients with Respiratory Tract Infections Respiratory Tract Infections in the United States in the United States

Ciprofloxacin Levofloxacin Ofloxacin

Doern GV Clin Infect Dis. 2001;23(suppl 3):S187-92

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SLIDE 6

Outpatient Systemic Antibacterial Outpatient Systemic Antibacterial Use Use – – Europe vs. United States Europe vs. United States

Goossens H et al. Clin Infect Dis. 2007; 44:1091

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SLIDE 7

Quinolone Use – Europe vs. US

Goossens H et al. Clin Infect Dis. 2007; 44:1091

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SLIDE 8

Goossens H et al. Clin Infect Dis. 2007; 44:1091

Quinolone Use – Europe vs. US

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SLIDE 9

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] ]

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SLIDE 10

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] ]

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SLIDE 11

General 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

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SLIDE 12

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

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SLIDE 13

Cross Resistance Among Penicillin Cross Resistance Among Penicillin-

  • Resistant

Resistant Strains of Strains of Streptococcus Streptococcus pneumoniae pneumoniae

Antimicrobial % Resistant to Other Antimicrobial Antimicrobial % Resistant to Other Antimicrobial Penicillin Penicillin Penicillin Penicillin Penicillin Penicillin Susceptible Intermediate Resistant Susceptible Intermediate Resistant

(n=2636) (n=356, (n=2636) (n=356, 10% 10%) (n=483, ) (n=483, 14% 14%) ) Amoxicillin Amoxicillin 0.0 0.0 1.8 1.8 82.2 82.2 Cefuroxime Cefuroxime 0.1 0.1 34.8 34.8 100 100 Cefotaxime Cefotaxime 0.0 0.0 2.8 2.8 42.4 42.4 Meropenem Meropenem 0.0 0.8 0.0 0.8 52.0 52.0 Erythromycin 3.2 Erythromycin 3.2 35.1 35.1 61.3 61.3 TMP TMP-

  • SMX

SMX 6.6 6.6 49.4 49.4 92.3 92.3 Tetracycline 1.3 Tetracycline 1.3 19.1 25.5 19.1 25.5 Whitney CG et al. N. Engl. J. Med. 2000;343:1917-24

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SLIDE 14

Cross Resistance Among Penicillin Cross Resistance Among Penicillin-

  • Resistant

Resistant Strains of Strains of Streptococcus Streptococcus pneumoniae pneumoniae

Antimicrobial % Resistant to Other Antimicrobial Antimicrobial % Resistant to Other Antimicrobial Penicillin Penicillin Penicillin Penicillin Penicillin Penicillin Susceptible Intermediate Resistant Susceptible Intermediate Resistant

(n=2636) (n=356) (n=483) (n=2636) (n=356) (n=483)

Chloramphenicol Chloramphenicol 0.4 0.4 6.7 6.7 14.7 14.7 Clindamycin Clindamycin 0.5 0.5 10.7 10.7 12.2 12.2 Rifampin Rifampin 0.2 0.2 0.0 0.0 0.2 0.2 Levofloxacin Levofloxacin 0.1 0.3 0.1 0.3 0.7 0.7 Quinupristin Quinupristin-

  • dalfopristin

dalfopristin 0.0 0.6 0.0 0.6 0.2 0.2

Whitney CG et al. N. Engl. J. Med. 2000;343:1917-24

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SLIDE 15

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

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SLIDE 16

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

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SLIDE 17

Randomized Comparison of Randomized Comparison of Levofloxacin Levofloxacin with with Ceftriaxone/Cefuroxime Ceftriaxone/Cefuroxime for Treatment for Treatment

  • f Community
  • f Community-
  • Acquired Pneumonia

Acquired Pneumonia

Pathogen No. (%) of Patients Responding to: Pathogen No. (%) of Patients Responding to: Levofloxacin Levofloxacin Ceftriaxone/Cefuroxime Ceftriaxone/Cefuroxime

Cured Improved Failed Cured Improved Failed Cured Improved Failed Cured Improved Failed S.

  • S. pneumoniae

pneumoniae 23(77) 7(23) 0 24(73) 7(21) 2(6) 23(77) 7(23) 0 24(73) 7(21) 2(6) [ [bacteremic bacteremic] 7(78) 2(22) 0 4(50) 4(50) ] 7(78) 2(22) 0 4(50) 4(50) 0 H.

  • H. influenzae

influenzae 24(80) 6(20) 0 17(71) 2(8) 5 24(80) 6(20) 0 17(71) 2(8) 5(21) (21) C.

  • C. pneumoniae

pneumoniae 34(72) 12(26) 1(2) 34(63) 16(30) 4(7) 34(72) 12(26) 1(2) 34(63) 16(30) 4(7) M.

  • M. pneumoniae

pneumoniae 15(79) 4(21) 0 17(77) 5(22) 0 15(79) 4(21) 0 17(77) 5(22) 0 L.

  • L. pneumophila

pneumophila 4(80) 1(20) 0 2(66) 0 1 4(80) 1(20) 0 2(66) 0 1(33) (33)

File TM et al. Antimicrob Agents Chemother. 41:1965 (1997)

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SLIDE 18

Comparison of High Comparison of High-

  • Dose Short

Dose Short-

  • Course with

Course with Conventional Conventional-

  • Course

Course Levofloxacin Levofloxacin for for Community Community-

  • Acquired Pneumonia

Acquired Pneumonia

Dunbar LM et al. Clin Infect Dis 2003; 37: 752 Clinical Responses by Severity Clinical Responses by Severity

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SLIDE 19

Dunbar LM et al. Clin Infect Dis 2003; 37: 752

Comparison of High Comparison of High-

  • Dose Short

Dose Short-

  • Course with

Course with Conventional Conventional-

  • Course

Course Levofloxacin Levofloxacin for for Community Community-

  • Acquired Pneumonia

Acquired Pneumonia

Clinical Responses by Pathogen Clinical Responses by Pathogen

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SLIDE 20

Moxifloxacin Moxifloxacin vs vs Amoxicillin Amoxicillin-

  • Clavulanate

Clavulanate in Community in Community-

  • Acquired Pneumonia

Acquired Pneumonia

Moxifloxacin 400 mg QD IV → PO Amox-clav 1.2g TID IV → 625 mg TID-QID PO (± clarithromycin) Finch R et al. Antimicrob Agents Chemother. 2002; 46:1746-54

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SLIDE 21

Moxifloxacin Moxifloxacin vs vs Amoxicillin Amoxicillin-

  • Clavulanate

Clavulanate in Community in Community-

  • Acquired Pneumonia

Acquired Pneumonia

Eradication Eradication Moxifloxacin Moxifloxacin Amox Amox-

  • Clav

Clav

% (n/N) % (n/N) % (n/N) % (n/N) Total Total 94 (60/64) 94 (60/64) 82 (58/71) 82 (58/71) S.

  • S. pneumoniae

pneumoniae Sputum Sputum 100 (18/18) 100 (18/18) 77 (17/22) 77 (17/22) Blood Blood 100 (11/11) 100 (11/11) 90 (9/10) 90 (9/10) H.

  • H. influenzae

influenzae 100 (12/12) 100 (12/12) 90 (9/10) 90 (9/10) M.

  • M. pneumoniae

pneumoniae 100 (13/13) 100 (13/13) 95 (16/17) 95 (16/17)

Finch R et al. Antimicrob Agents Chemother. 2002; 46:1746-54

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SLIDE 22

IDSA Guidelines for Initial Empiric IDSA Guidelines for Initial Empiric Treatment of Patients with Treatment of Patients with Community Community-

  • Acquired Pneumonia

Acquired Pneumonia

Outpatients Outpatients

  • Previously healthy without use of antimicrobials

Previously healthy without use of antimicrobials within 3 months within 3 months (except in areas with >25%

(except in areas with >25% macrolide macrolide resistance) resistance) – – a a macrolide macrolide or

  • r doxycycline

doxycycline

  • Patients with co

Patients with co-

  • morbid illness or prior antimicrobials

morbid illness or prior antimicrobials (c (chronic heart, lung, or liver disease, diabetes, malignancy,

hronic heart, lung, or liver disease, diabetes, malignancy, immunosuppression immunosuppression or antimicrobials within last 3 mo)

  • r antimicrobials within last 3 mo)

– – Respiratory Respiratory fluoroquinolone fluoroquinoloneA

A OR

OR – – β β-

  • Lactam

Lactam plus a plus a macrolide macrolide

Mandell LA et al. Clin Infect Dis 2007; 44:S27

A A[levofloxacin

[levofloxacin (750 mg), (750 mg), moxifloxacin moxifloxacin (400 mg), or (400 mg), or gemifloxacin gemifloxacin (320mg)] (320mg)]

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SLIDE 23

IDSA Guidelines for Initial Empiric IDSA Guidelines for Initial Empiric Treatment of Patients with Treatment of Patients with Community Community-

  • Acquired Pneumonia

Acquired Pneumonia

Hospitalized patients Hospitalized patients (non (non-

  • ICU)

ICU)

  • Respiratory

Respiratory fluoroquinolone fluoroquinoloneA

A OR

OR

  • β

β-

  • Lactam

Lactam plus a plus a macrolide macrolide Hospitalized patients Hospitalized patients (ICU) (ICU)

  • (

(Cefotaxime Cefotaxime, , ceftriaxone ceftriaxone, or , or ampicillin ampicillin-

  • sulbactam

sulbactam) plus ( ) plus (azithromycin azithromycin or respiratory

  • r respiratory

fluoroquinolone fluoroquinolone) )

Mandell LA et al. Clin Infect Dis 2007; 44:S27

A A[levofloxacin

[levofloxacin (750 mg), (750 mg), moxifloxacin moxifloxacin (400 mg), or (400 mg), or gemifloxacin gemifloxacin (320mg)] (320mg)]

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SLIDE 24

IDSA Guidelines for Initial Empiric IDSA Guidelines for Initial Empiric Treatment of Patients with Treatment of Patients with Community Community-

  • Acquired Pneumonia

Acquired Pneumonia

Special considerations Special considerations

  • If

If Pseudomonas Pseudomonas aeruginosa aeruginosa

– – ( (Piperacillin Piperacillin-

  • tazobactam

tazobactam, , cefepime cefepime, , imipenem imipenem, or , or meropenem meropenem) ) plus [ciprofloxacin or plus [ciprofloxacin or levofloxacin levofloxacin (750 mg)] OR (750 mg)] OR – – ( (Piperacillin Piperacillin-

  • tazobactam

tazobactam, , cefepime cefepime, , imipenem imipenem, or , or meropenem meropenem) ) plus plus aminoglycoside aminoglycoside plus ( plus (azithromycin azithromycin or respiratory

  • r respiratory

fluoroquinolone fluoroquinoloneA

A)

)

  • If community

If community-

  • acquired MRSA

acquired MRSA

– – Add Add vancomycin vancomycin or

  • r linezolid

linezolid

A A[levofloxacin

[levofloxacin (750 mg), (750 mg), moxifloxacin moxifloxacin (400 mg), or (400 mg), or gemifloxacin gemifloxacin (320mg)] (320mg)]

Mandell LA et al. Clin Infect Dis 2007; 44:S27

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SLIDE 25

General 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

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SLIDE 26

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

Quinolone Quinolone Treatment of Treatment of Hospital Hospital-

  • Acquired Pneumonia

Acquired Pneumonia

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SLIDE 27

Quinolone Quinolone Treatment of Treatment of Hospital Hospital-

  • Acquired Pneumonia

Acquired Pneumonia

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

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SLIDE 28

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

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SLIDE 29

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

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SLIDE 30

Fluoroquinolones Fluoroquinolones Adverse Effects Adverse Effects

  • Nausea, vomiting, diarrhea, taste perversion

Nausea, vomiting, diarrhea, taste perversion

  • Insomnia, HA, dizziness (

Insomnia, HA, dizziness (trovafloxacin trovafloxacin), ), psychiatric, seizures [inhibit GABA binding to psychiatric, seizures [inhibit GABA binding to receptors] receptors]

  • Rash, photosensitivity (

Rash, photosensitivity (lomefloxacin lomefloxacin, , sparfloxacin sparfloxacin, , gemifloxacin gemifloxacin) )

  • Hepatotoxicity

Hepatotoxicity ( (trovafloxacin trovafloxacin) )

  • Dysglycemia

Dysglycemia ( (gatifloxacin gatifloxacin) )

  • QT prolongation (

QT prolongation (sparfloxacin sparfloxacin > > moxifloxacin moxifloxacin) )

  • Cartilage erosions in juvenile animals

Cartilage erosions in juvenile animals

  • Tendinitis

Tendinitis

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SLIDE 31

Temporal Trends in Temporal Trends in Quinolone Quinolone Resistance in Resistance in S.

  • S. pneumoniae

pneumoniae

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

1997 1998

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SLIDE 32

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

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SLIDE 33

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

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SLIDE 34

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%

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SLIDE 35

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)

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SLIDE 36

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)

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SLIDE 37

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)

slide-38
SLIDE 38

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

slide-39
SLIDE 39

Plasmid Plasmid-

  • Encoded

Encoded Quinolone Quinolone Resistance: Resistance: qnr qnr Genes Genes

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

slide-40
SLIDE 40

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.

slide-41
SLIDE 41

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.

slide-42
SLIDE 42

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

slide-43
SLIDE 43

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

slide-44
SLIDE 44

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

slide-45
SLIDE 45

Pharmacodynamics Pharmacodynamics of

  • f Quinolone

Quinolone-

  • Resistant Mutant Selection

Resistant Mutant Selection

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

slide-46
SLIDE 46

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