dose adjustments and fighting the emergence of resistance in pneumococci donald e. low, md canada
TRANSCRIPT
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
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
AntimicrobialsAntimicrobialsAntimicrobialsAntimicrobials β-Lactams Fluoroquinolones
β-Lactams Fluoroquinolones
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
β-Lactamsβ-Lactams
Mechanism of actionMechanism of actionMechanism of actionMechanism of action
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
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
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
-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
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
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
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
Dagan & Leibovitz. Lancet Infect Dis 2002; 2:593–604
What’s the evidence this actually happens?
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
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
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
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
Toltzis et al. PIDJ 2005
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
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
Infection
Inappropriatetreatment
Failed bacterial eradication
Spread
Selectionof resistant
bacteria
Increasingresistance
Appropriatetreatment
Maximize clinical cure
Bacterialeradication
Minimize potential for resistance
Breaking the ‘vicious cycle’
FluoroquinolonesFluoroquinolones
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)
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
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
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
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
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
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
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
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
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
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
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
41
Wild type
1st step
1st and 2nd
42
43
44
45
46
47
Pneumococcal pneumonia with first-step Pneumococcal pneumonia with first-step mutantmutant
48
Wild type
1st step
1st and 2nd
49
50
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)
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)
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
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
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
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
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