Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

57
Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Donald E. Low, MD Canada Canada

Transcript of Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

Page 1: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

Dose Adjustments and Fighting the Emergence of Resistance in

Pneumococci

Dose Adjustments and Fighting the Emergence of Resistance in

Pneumococci

Donald E. Low, MDDonald E. Low, MDCanadaCanada

Page 2: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

Optimize antimicrobial useOptimize antimicrobial useOptimize antimicrobial useOptimize antimicrobial use

1. Prevent resistance from emerging

2. Prevent colonization/infection with pre-existing resistant strains

1. Prevent resistance from emerging

2. Prevent colonization/infection with pre-existing resistant strains

Page 3: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

AntimicrobialsAntimicrobialsAntimicrobialsAntimicrobials β-Lactams Fluoroquinolones

β-Lactams Fluoroquinolones

Page 4: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

Emergence of resistance in pneumococciEmergence of resistance in pneumococciEmergence of resistance in pneumococciEmergence of resistance in pneumococci

ß-lactam– Acquisition of DNA which encodes resistance

element Fluoroquinolones

– Spontaneous point mutations

ß-lactam– Acquisition of DNA which encodes resistance

element Fluoroquinolones

– Spontaneous point mutations

Page 5: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

β-Lactamsβ-Lactams

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Page 7: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

Mechanism of actionMechanism of actionMechanism of actionMechanism of action

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Mechanism of action: Mechanism of action: -Lactams bind to PBP-Lactams bind to PBPMechanism of action: Mechanism of action: -Lactams bind to PBP-Lactams bind to PBP

PeptidoglycanLayer

CytoplasmicMembrane

Penicillin-Binding Proteins

Cross-link

Cell wall

Slide of M. Jacobs

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Mechanisms of resistance: Mechanisms of resistance: alterations in target alterations in target binding sitebinding siteMechanisms of resistance: Mechanisms of resistance: alterations in target alterations in target binding sitebinding site

PeptidoglycanLayer

CytoplasmicMembrane

Penicillin-Binding Proteins

Cross-link

Cell wall

Slide of M. Jacobs

Page 10: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

Mechanism of resistanceMechanism of resistanceMechanism of resistanceMechanism of resistance PBPs with reduced binding affinities which

are the products of mosaic genes that have arisen via inter-species transformation and recombination events

resistance develops in a step-wise manner with the level of resistance in a particular strain reflecting the number of PBPs affected by the mosaicism

PBPs with reduced binding affinities which are the products of mosaic genes that have arisen via inter-species transformation and recombination events

resistance develops in a step-wise manner with the level of resistance in a particular strain reflecting the number of PBPs affected by the mosaicism

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-Lactam Resistance due to Alterations in the Penicillin -Lactam Resistance due to Alterations in the Penicillin Binding Protein (PBP) Target Binding SitesBinding Protein (PBP) Target Binding Sites-Lactam Resistance due to Alterations in the Penicillin -Lactam Resistance due to Alterations in the Penicillin Binding Protein (PBP) Target Binding SitesBinding Protein (PBP) Target Binding Sites

Gene

pbp1a

pbp1b

pbp2a

pbp2b

pbp2x

PenicillinSusceptible

PenicillinResistant

PenicillinIntermediate

Slide of M. Jacobs

Page 12: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

Antimicrobial susceptibilities and analysis of genes Antimicrobial susceptibilities and analysis of genes related to penicillin or macrolide resistance in related to penicillin or macrolide resistance in S. pneumoniaeS. pneumoniae

Antimicrobial susceptibilities and analysis of genes Antimicrobial susceptibilities and analysis of genes related to penicillin or macrolide resistance in related to penicillin or macrolide resistance in S. pneumoniaeS. pneumoniae

0

10

20

30

40

50

60

70

No

. o

f str

ain

s

Penicillin MIC (ug/ml)

1a+2x+2b

2x + 2b

1a + 2x

1a, 2x, or2bnone

0

10

20

30

40

50

60

70

No

. o

f str

ain

s

Penicillin MIC (ug/ml)

1a+2x+2b

2x + 2b

1a + 2x

1a, 2x, or2bnone

Hiramatsu K et a. Intern J Antimicrob Agents 2004

PBP changes

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Resistance due to selectionResistance due to selectionResistance due to selectionResistance due to selection

acquisition of piece of DNA

via inter-species

transformation and

recombinationSanders CC et al. J Infect Dis 1986;154:792-800

Treatment with marginally active drug

Resistant bugs are selected for by

drug treatment as susceptible strains

die off

Resistant clone

multiplies

Resistance spreads

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Maximizing T>MICMaximizing T>MIC

Increased dosing frequency

Higher dose

Improved pharmacodynamic profile within class

Increased duration of infusion

Increased dosing frequency

Higher dose

Improved pharmacodynamic profile within class

Increased duration of infusion

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Dagan & Leibovitz. Lancet Infect Dis 2002; 2:593–604

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What’s the evidence this actually happens?

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Adapted from Guillemot & Carbon JAMA 1998; 279:365–370

25

50

75

100 Oral cephalosporinAmoxicillin

Penicillin susceptibility (MIC) in µg/ml

‘High dose’

Median

‘Low dose’Perc

entil

e of

dai

ly d

ose

0

0.0160.032

0.0640.125

0.250.50

12

Sub-optimal dosage leads to increased resistance

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Effect of Short-Course, High-Dose Amoxicillin Therapy on Resistant Pneumococcal Carriage

• Children were randomly assigned to receive 1 of 2 twice-daily regimens of amoxicillin: 90 mg/kg per day for 5 days (n = 398) or 40 mg/kg per day for 10 days (n = 397)

• At the day 28 visit, risk of penicillin-nonsusceptible pneumococcal carriage was significantly lower in the short-course, high-dose group (24%) compared with the standard-course group (32%); relative risk (RR), 0.77; 95% confidence interval (CI), 0.60-0.97; P = .03; risk of trimethoprim-sulfamethoxazole nonsusceptibility was also lower in the short-course, high-dose group (RR, 0.77; 95% CI, 0.58-1.03; P = .08).

Schrag et al. JAMA 2001; 286:49–56

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Impact of Amoxicillin on Pneumococcal Colonization Compared With Other Therapies for Acute Otitis Media

• Children presenting with acute otitis media were randomized to receive amoxicillin, cefprozil, ceftriaxone or azithromycin.

• Nasopharyngeal specimens were collected on days 0, 3–5, 10–14 and 28–30 and assessed for the presence of S. pneumoniae

Toltzis et al. PIDJ 2005

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Impact of Amoxicillin on Pneumococcal Colonization Compared With Other Therapies for Acute Otitis Media

• Colonization by nonsusceptible pneumococci was unaltered during the observation period in all treatment groups, with no detectable differences among groups at each visit

• By contrast, there was a substantial reduction in the prevalence of colonization by penicillin-susceptible organisms, most notably in subjects treated with amoxicillin

• This resulted in a proportional shift toward resistant organism colonization in all groups, with this shift being significantly more pronounced among amoxicillin recipients than in the other groups at 10–12 days (P < 0.02 for each comparison with amoxicillin)

Toltzis et al. PIDJ 2005

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Toltzis et al. PIDJ 2005

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Bacteriological eradication maximizes clinical success: evidence in AOM

Bacteriological success

97% clinical success

faster resolution of signs and symptoms

Bacteriological failure

63% clinical success

slower resolution ofsigns and symptoms

Dagan et al. Pediatr Infect Dis J 1998; 17:776–782

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Failure of bacteriological eradication results in clinical failure in AECB

Pechère. Infect Med 1998; 15(Suppl. E):46–54

Eradication failure rate (%)

Clin

ical

failu

re ra

te (%

)

Meta-analysis: 12 studies, 16 antibioticsSlope = 0.59, correlation = 0.83

0 10 20 30 40 50 60 70 80

60

50

40

30

20

0

10

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Infection

Inappropriatetreatment

Failed bacterial eradication

Spread

Selectionof resistant

bacteria

Increasingresistance

Appropriatetreatment

Maximize clinical cure

Bacterialeradication

Minimize potential for resistance

Breaking the ‘vicious cycle’

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FluoroquinolonesFluoroquinolones

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Topoisomerases:Topoisomerases:Critical Enzymes in DNA ReplicationCritical Enzymes in DNA ReplicationTopoisomerases:Topoisomerases:Critical Enzymes in DNA ReplicationCritical Enzymes in DNA Replication

Topoisomerase IV (parC, parE)

DNA gyrase (gyrA, gyrB)

Topoisomerase IV (parC, parE)

DNA gyrase (gyrA, gyrB)

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Development of ResistanceDevelopment of ResistanceDevelopment of ResistanceDevelopment of Resistance De novo

– Spontaneous mutations in primary target – The frequency of a spontaneous mutation is 1/107

to 108

De novo– Spontaneous mutations in primary target – The frequency of a spontaneous mutation is 1/107

to 108

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stepwise occurrence “First-step”

– enzyme for which the quinolone has the greatest affinity

– MIC increases “Second-step”

– result in a further increase in MIC

stepwise occurrence “First-step”

– enzyme for which the quinolone has the greatest affinity

– MIC increases “Second-step”

– result in a further increase in MIC

Spontaneous MutationSpontaneous MutationSpontaneous MutationSpontaneous Mutation

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Fluoroquinolone Use and Pneumococcal Fluoroquinolone Use and Pneumococcal Resistance: Canada, 1988–1998Resistance: Canada, 1988–1998Fluoroquinolone Use and Pneumococcal Fluoroquinolone Use and Pneumococcal Resistance: Canada, 1988–1998Resistance: Canada, 1988–1998

Year

0

1

2

3

4

5

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998

% c

ipro

-R p

neu

mo

cocc

i

0

1

2

3

4

5

6

Prescrip

tion

s per 100

Perso

ns

<15 years

15-64 years

65 years

Quinolone use

Chen et al. 1999 NEJM

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0

0.2

0.4

0.6

0.8

1

1.2

1993 1994 1995 1996 1997 1998

Year

Per

cen

t re

du

ced

su

scep

tib

ilit

y to

cip

rofl

oxac

in

MIC=4MIC=8-16MIC>16

From 1994 to 1998, there was a statistically significant increase in the

proportion of isolates with a MIC for ciprofloxacin of 32 g/ml (P=0.04)

Chen et al. 1999 NEJM

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Relationship between increased Relationship between increased levofloxacin use and decreased levofloxacin use and decreased susceptibility of susceptibility of S. pneumoniaeS. pneumoniae in the US in the US

Relationship between increased Relationship between increased levofloxacin use and decreased levofloxacin use and decreased susceptibility of susceptibility of S. pneumoniaeS. pneumoniae in the US in the US All data for S. pneumoniae blood isolates collected

from US hospitals participating in the SENTRY Antimicrobial Surveillance Program (1997–2002) were included

Annual regional quinolone use data for the same period were obtained from IMS and matched using designated “Metropolitan Statistical Areas” to the geographical region surrounding each SENTRY Program hospital

The primary outcome variable was the in vitro activity of levofloxacin against S. pneumoniae

All data for S. pneumoniae blood isolates collected from US hospitals participating in the SENTRY Antimicrobial Surveillance Program (1997–2002) were included

Annual regional quinolone use data for the same period were obtained from IMS and matched using designated “Metropolitan Statistical Areas” to the geographical region surrounding each SENTRY Program hospital

The primary outcome variable was the in vitro activity of levofloxacin against S. pneumoniae

Bhavnani et al Diagn Microbiol Infect Dis 2005

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PD therapeutic goals for fluoroquinolones: Peak:MIC or AUC:MIC ratio 35–40

Time

AUC:MIC ratio, or Peak:MIC ratio

Peak

Area under curve (AUC)

Ant

ibio

tic c

once

ntra

tion

(g/

ml)

Wright et al. J Antimicrob Chemother 2000; 46:669–683

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Page 36: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

Fluoroquinolone pharmacodynamics for Fluoroquinolone pharmacodynamics for S. S. pneumoniaepneumoniae: relationship between AUC and bacterial : relationship between AUC and bacterial

eradicationeradication

Fluoroquinolone pharmacodynamics for Fluoroquinolone pharmacodynamics for S. S. pneumoniaepneumoniae: relationship between AUC and bacterial : relationship between AUC and bacterial

eradicationeradication

In vitro model– Lacy et al. Antimicrob Agents Chemother 1999;43:672–677– Lister & Sanders. J Antimicrob Chemother 1999;43:79–86

In vivo model– Andes & Craig. 39th ICAAC 1999 [Abstr. P-0191]– Mattoes et al. Antimicrob Agents Chemother 2001:45;2092–2097

In vivo human– Ambrose et al. Antimicrob Agents Chemother 2001;45:2793–2797

– Free-drug 24-hour AUC:MIC >33.7 resulted in 100% microbiological eradication; probability of response was 64% at AUC:MIC <33.7

In vitro model– Lacy et al. Antimicrob Agents Chemother 1999;43:672–677– Lister & Sanders. J Antimicrob Chemother 1999;43:79–86

In vivo model– Andes & Craig. 39th ICAAC 1999 [Abstr. P-0191]– Mattoes et al. Antimicrob Agents Chemother 2001:45;2092–2097

In vivo human– Ambrose et al. Antimicrob Agents Chemother 2001;45:2793–2797

– Free-drug 24-hour AUC:MIC >33.7 resulted in 100% microbiological eradication; probability of response was 64% at AUC:MIC <33.7

AUC/MIC of 40 optimizes antibacterial killing against S. pneumoniae

Page 37: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

Fre

e A

UC

/ MIC

Ciprofloxacin

750 mg q12

Levofloxacin

500 mg q24

Gatifloxacin

400 mg q24

Moxifloxacin

400 mg q24

(94-188)

(52-170)

(16-103)

(11-22)

0

50

100

150

200

250

300

Grant E., Nicolau DP. Antibiotic for Clinicians 1999;3(Suppl 1):21-28.

Comparison of Quinolone In Vivo Potency for Streptococcus pneumoniae

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Emergence of First Step ParC Mutation in Streptococcus pneumoniae

Emergence of First Step ParC Mutation in Streptococcus pneumoniae

TRUST surveillance program, 1999-2000 found that 6.6% and 71% of the S. pneumoniae isolates having an MIC of 1.0 g/ml and 2.0 g/ml, respectively, contain a first step parC mutation. Davies TA, et al. AAC 2002;46:119-124

164 unique patient isolates of S. pneumoniae, 29.9% of the isolates harbored a mutation in either the parC or the gyrA gene, with the majority of isolates (67.3%) having a mutation in the parC locus only. Brueggemann AB, et al. AAC 2002;46(3):680-688

TRUST surveillance program, 1999-2000 found that 6.6% and 71% of the S. pneumoniae isolates having an MIC of 1.0 g/ml and 2.0 g/ml, respectively, contain a first step parC mutation. Davies TA, et al. AAC 2002;46:119-124

164 unique patient isolates of S. pneumoniae, 29.9% of the isolates harbored a mutation in either the parC or the gyrA gene, with the majority of isolates (67.3%) having a mutation in the parC locus only. Brueggemann AB, et al. AAC 2002;46(3):680-688

Page 39: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

Emergence of First Step ParC Mutation in Streptococcus pneumoniae

Emergence of First Step ParC Mutation in Streptococcus pneumoniae

examined 115 S. pneumoniae isolates with a levofloxacin MIC of >2 mg/mL for first-step parC mutations. A total of 48 (59%) of 82 isolates with a levofloxacin MIC of 2 mg/mL, a level considered susceptible by NCCLS criteria, had a first-step mutation in parC. Lim et al. EID 2003

examined 115 S. pneumoniae isolates with a levofloxacin MIC of >2 mg/mL for first-step parC mutations. A total of 48 (59%) of 82 isolates with a levofloxacin MIC of 2 mg/mL, a level considered susceptible by NCCLS criteria, had a first-step mutation in parC. Lim et al. EID 2003

Page 40: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

Targets for the FluoroquinolonesTargets for the FluoroquinolonesTargets for the FluoroquinolonesTargets for the Fluoroquinolones First-step

– Topoisomerase IV (parC, parE)

– DNA gyrase (gyrA, gyrB)

First-step

– Topoisomerase IV (parC, parE)

– DNA gyrase (gyrA, gyrB)

or

Page 41: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

41

Wild type

1st step

1st and 2nd

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42

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43

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44

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46

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47

Pneumococcal pneumonia with first-step Pneumococcal pneumonia with first-step mutantmutant

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48

Wild type

1st step

1st and 2nd

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49

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50

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Fluoroquinolone treatment failuresFluoroquinolone treatment failuresFluoroquinolone treatment failuresFluoroquinolone treatment failures

19 treatment failures that met our case definition: – LRTI due to a fluoroquinolone resistant

pneumococci that – failed clinically or bacteriologically after ≥ 48

hours of fluoroquinolone therapy, such that additional antimicrobial therapy was required

19 treatment failures that met our case definition: – LRTI due to a fluoroquinolone resistant

pneumococci that – failed clinically or bacteriologically after ≥ 48

hours of fluoroquinolone therapy, such that additional antimicrobial therapy was required

(Fuller and Low, CID, In Press)

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Fluoroquinolone treatment failuresFluoroquinolone treatment failuresFluoroquinolone treatment failuresFluoroquinolone treatment failures 7 had a history of prior fluoroquinolone use

QRDR characterization available for 15 isolates– 12 had mutations in both parC and qyrA– 3 had mutation in parC only

7 had a history of prior fluoroquinolone use QRDR characterization available for 15 isolates– 12 had mutations in both parC and qyrA– 3 had mutation in parC only

(Fuller and Low, CID, In Press)

Page 53: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

Levofloxacin Resistance in Levofloxacin Resistance in S. pneumoniaeS. pneumoniae::Results from a Cross-Canada Surveillance StudyResults from a Cross-Canada Surveillance StudyLevofloxacin Resistance in Levofloxacin Resistance in S. pneumoniaeS. pneumoniae::Results from a Cross-Canada Surveillance StudyResults from a Cross-Canada Surveillance Study

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

1997 1998 1999 2000 2001 2002 2003 2004

Perc

en

t o

f re

sis

tan

t is

ola

tes

0

1

2

3

4

5

6

7

8

9

10

Pre

scri

pti

on

s p

er

100 p

op

'n

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

1997 1998 1999 2000 2001 2002 2003 2004

Perc

en

t o

f re

sis

tan

t is

ola

tes

0

1

2

3

4

5

6

7

8

9

10

Pre

scri

pti

on

s p

er

100 p

op

'n

Canadian Bacterial Surveillance Network, Feb. 2005

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Prescriptions for Fluroquinolones used for RTIsPrescriptions for Fluroquinolones used for RTIsPrescriptions for Fluroquinolones used for RTIsPrescriptions for Fluroquinolones used for RTIs

0

100,000

200,000

300,000

400,000

500,000

600,000

700,000

800,000

900,000

1,000,000

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Total FQs Cipro BID Avelox Gati Levo

0

100,000

200,000

300,000

400,000

500,000

600,000

700,000

800,000

900,000

1,000,000

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Total FQs Cipro BID Avelox Gati Levo

Source: IMS Canada

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Relative risk of infection with FQ resistant pneumococci, by Relative risk of infection with FQ resistant pneumococci, by prior antibiotic useprior antibiotic useRelative risk of infection with FQ resistant pneumococci, by Relative risk of infection with FQ resistant pneumococci, by prior antibiotic useprior antibiotic use

02468

101214161820

No prior AB Prior AB - not FQ Prior FQ

Perc

en

t cip

rofl

oxacin

resis

tan

t

02468

101214161820

No prior AB Prior AB - not FQ Prior FQ

Perc

en

t cip

rofl

oxacin

resis

tan

t

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Risk factors for levofloxacin resistance: Risk factors for levofloxacin resistance: Multivariable analysisMultivariable analysisRisk factors for levofloxacin resistance: Risk factors for levofloxacin resistance: Multivariable analysisMultivariable analysis

9.9 (2.2, 45)Nosocomial

12.9 (3.9, 43)Nursing home acquired

12.1 (4.1, 35)Prior FQ use

Odds Ratio (95% CL)Characteristic

Page 57: Dose Adjustments and Fighting the Emergence of Resistance in Pneumococci Donald E. Low, MD Canada.

ConclusionsConclusionsConclusionsConclusions That the best way to fight the emergence of

antimicrobial resistance is to minimize the use of these agents

When needed, the strategy of best dosage may depend on the class of agents or agent within the class

That the best way to fight the emergence of antimicrobial resistance is to minimize the use of these agents

When needed, the strategy of best dosage may depend on the class of agents or agent within the class