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Overview of pharmacological principles for prescribing
antimicrobials to treat RTIs
Donald E. Low, MD, FRCPC
Toronto, Ontario
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Differences between in vitro and in vivo
antimicrobial activity
In vitro:
• Drug concentration
constant
• No host defenses
present
• No effect of disease
severity
• No effect of
comorbid factors
In vivo:
• Drug concentration
variable
• Host defenses
present
• Effect of disease
severity
• Effect of comorbid
factors
Craig, W.A. Infect Dis Clin North Am 2003: 17 (3), 479-501
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Determinants of clinical outcome
Bacterial
eradication
Clinicalsuccess
Antibiotics
PK/PDprofile
Hostdefenses
Bacteria
Craig, WA. Infect Dis Clin North Am 2003. Jacobs, MR. Drug Discovery Today 2004
Bacterial
survival
Clinicalfailure
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What are pharmacodynamic properties
of fluoroquinolones?
1. Time dependent:
optimal activity when concentration of
antibiotic above the MIC for 40% of dosing
interval
2. Concentration dependent:
optimal activity when has peak concentration
10 X the MIC
3. Bacteriostatic
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Pharmacodynamic parameters(in vivo potency)
0
AUC:MIC
T>MIC
Cmax:MIC
Concentration
Time (hours)
MIC
AUC = Area under the concentration–time curve
Cmax = Maximum plasma concentration
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Pharmacology of Antibacterial therapy
Dosing
regimen
Concentrations in
serum
Concentrations at
site of infectionAntibacterial
effect
Pharmacokinetics Pharmacodynamics
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Pharmacology of Antibacterial therapy
Dosing
regimen
Concentrations in
serum
Concentrations at
site of infectionAntibacterial
effect
Pharmacokinetics Pharmacodynamics
Where is the drug? How does it work?
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Serum concentration
Concentration at the site of infection
Effect
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Serum concentration
Concentration at the site of infection
Effect
• Protein binding
• Tissue distribution
• Concentrations in tissue fluids
• Extracellular vs. intracellular infections
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Bacteria, such as S. pneumoniae,
form in the interstitial space
Macrolide antibiotics accumulate
largely inside cells
-Lactam antibiotics are located largely
in the interstitial space
Cars Diagn Microbiol Infect Dis 1997; 27::29–34
Extracellular concentrations importantfor key respiratory tract pathogens
Fluoroquinolones accumulate
in interstitial space and inside cells
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Pharmacology of Antibacterial therapy
Dosing
regimen
Concentrations in
serum
Concentrations at
site of infectionAntibacterial
effect
Pharmacokinetics Pharmacodynamics
Where is the drug? How does it work?
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Types of time kill activity in vitro
0
1
2
3
4
5
6
7
8
9
10
0 3 5
Minimal concentrationdependent killing
e.g. β-lactams
Control
1 x MIC
4 x MIC
8 x MIC
16 x MIC
Hours
Log C
FU
/mL
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Types of time kill activity in vitro
0
1
2
3
4
5
6
7
8
9
10
0 3 5
Minimal concentrationdependent killing
e.g. Fluoroquinolones
Control
1 x MIC
4 x MIC
8 x MIC
16 x MIC
Hours
Log C
FU
/mL
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Patterns of antibacterial activity
• Time-dependent killing
Time above MIC (T > MIC)
– β-lactams
• Concentration-dependent killing
AUC:MIC or Peak:MIC ratio
– Fluoroquinolones
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Time>MIC
Peak/MIC
AUC/MIC
PharmacodynamicsPharmacokineticsfree serum levels
Maximize
bacterial
eradicatiion
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Utilizing PK/PD principles to optimize
therapy
• Maximize clinical outcomes
• Minimize the emergence of resistance
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Utilizing PK/PD principles to optimize
therapy
• Maximize clinical outcomes
• Minimize the emergence of resistance
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Time>MIC
2
Drug A: 50% of interval
Drug B: 30% of interval4
6
8
0
PD therapeutic goals:-lactams – ‘Time above MIC’
MIC
Time
Co
nce
ntr
atio
n (
µg
/mL
)
Target
A time above MIC of > 40% appears to correlate with clinical and bacteriological outcome. Drug B does not achieve this pharmacodynamic target.
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Craig Respir Med 2001; 95(Suppl. A):S12–S19
20
40
60
80
100
Time>MIC (%)
0 20 40 60 80 100
0
PSSP
PISP-PRSP
H. influenzae
Otitis media (Circles)
Sinusitis (Squares)
‘Time above MIC’ and bacteriologic efficacy: AOM and sinusitis
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Time
Area under curve (AUC) to
MIC ratio, or Peak (Cmax)
to MIC ratio
24 hr AUC/MIC and Peak/MIC ratios correlate with outcomethe magnitude of these ratios required for success = the PD breakpoint
PD therapeutic goals: fluoroquinolones –24 hr AUC:MIC or Peak:MIC
Correlation of serum pharmacokinetics and MIC C
on
ce
ntr
ati
on
(µg
/mL
)
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Levofloxacin PK/PD correlations134 hospitalized patients with respiratory tract, skin or complicated
urinary tract infections treated with 500 mg qd for 5–14 days
4 3
23
3
100
10
10
20
30
40
50
60
70
80
90
100
AUC/MIC <25
Peak/MIC <3
AUC/MIC 25–100
Peak/MIC 3–12AUC/MIC >100
Peak/MIC >12
Clinical failure rate 43% 11.5% 1%
Clinical outcomeSuccess
Failure
Jacobs. Clin Microbiol Infect 2001; 7:589–96 [Adapted from Preston et al. JAMA 1998; 279:125–9]
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Forrest A et al. Antimicrob Agents Chemother. 1993;37:1073-1081.
Fluoroquinolone Therapy for Nosocomial Pneumonia: Correlation Between Drug
Exposure and Clinical Outcome
4440
88
7177
22
30
8186
82
0
20
40
60
80
100
0-62.5 62.5-125 125-250 250-500 >500
Microbiological
Clinical
Patients
cured
(%)
AUC:MIC
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Utilizing PK/PD principles to optimize
therapy
• Maximize clinical outcomes
• Minimize the emergence of resistance
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Antibiotic Dose Impact on Resistance Selection
in the Community: A Mathematical Model of
β-Lactams and S. pneumoniae Dynamics
Lowest doses resulted in high prevalence of
nonsusceptible strains (≥70%) with still low MICs (1mg/L)
Whereas high doses resulted in lower prevalence of
nonsusceptible strains (<40%) and higher MICs (2mg/L)
Therefore: limiting β-lactam use while increasing doses
could help in reducing prevalence
Opatowski L et al. AAC 2010
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Opatowski L et al. AAC 2010
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Drug PSSP PISP PRSP
Cefaclor 60 0 0
Cefuroxime axetil 75 35 0
Placebo
S. pneumoniae
Bac
teri
olo
gic
al p
ersi
sten
ce(%
)
PSSP PISP/PRSP
9 1021
62
84
2/22 4/414/19 18/29
Cefuroxime axetil (30 mg/kg/day bid x 10 days)
Cefaclor (40 mg/kg/day tid x 10 days)
Time > MIC (% of dosing interval)
The predicted T > MIC and bacteriological eradication rates
Dagan & Leibovitz Lancet Infect Dis 2002; 2:593–604
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Summary: Use of PK/PD
• PK/PD allows the rational comparison of
the efficacy of different antibacterials
based on their ability to eradicate bacterial
pathogens
• Determine the optimal dosage regimens
for new antibacterial agents
–Maximize clinical treatment
–Minimize the emergence of resistance
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Keypad Question: What AUC/MIC ratio
best predicts fluoroquinolone efficacy?
1. 25
2. >35
3. 75
4. >100
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The Canadian Experience:
Validating the value of
optimal PK/PD parameters
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Mechanisms of Action/Resistance
• FQs bind preferentially to
two target sites:
– Topoisomerase IV(ParC)
– DNA gyrase (GyrA)
• Resistance emerges
as a result of
spontaneous mutations
in these target sites
E E
C C
B B
A A
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E E
C C
B B
A A
par(C)
gyr(A)
DNA gyrase
Topoisomerase IV
• Ciprofloxacin
• Levofloxacin
Preferential Target Sites
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6/26/2010
SAM-2 The Science Behind
32
Fre
e A
UC
/ M
IC
Ciprofloxacin
750 mg q12
Levofloxacin
500 mg q24
(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
Resistance Prevention ~AUC/MIC≥100
Efficacy ~AUC/MIC≥35
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6/26/2010
SAM-2 The Science Behind
Chen DK, et al. N Engl J Med. 1999;341:233-239.
Fluoroquinolone Use and Pneumococcal Resistance: Canada, 1988–1998
Year
0
1
2
3
4
5
1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998
%cip
ro-R
pn
eu
mo
co
cci
0
1
2
3
4
5
6
Pre
scrip
tion
s p
er 1
00
Pers
on
s
<15 years
15-64 years
65 years
Quinolone use
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6/26/2010
SAM-2 The Science Behind
Fluoroquinolone-Resistant Pneumococci in Respiratory Isolates from Older Adults:Canadian Bacterial Surveillance Network, 1988-2002
0
1
2
3
4
5
6
7
8
1988 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Year
% R
esi
sta
nt
iso
late
s
Cipro
Lev
Canadian Bacterial Surveillance Network, Feb 2003
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Drusano G, Nature Reviews Microbiology 2004
Wild type
1st step mutant
1st and 2nd mutants
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Pérez-Trallero et al. (Emerg Infect Dis) S.pneumoniae serotype 3 became resistant to fluoroquinolones,
macrolides, lincosamides, quinupristin-dalfopristin, and
telithromycin
Anderson et al. (Clin Infect Dis) 15 episodes of CAP; 6 cases of reinfection or relapse
Ross et al. (N Eng J Med) 1 case of treatment failure
Kays et al. (Pharmacotherapy) 1 case of treatment failure
Davidson et al. (N Eng J Med ) 4 cases of treatment failure
Piper et al. (41st ICAAC) Levofloxacin-resistant S.pneumoniae in 6 hospitalized patients.
Empey et al. (Ann Pharmacotherapy) 1 case of treatment failure
Urban et al. (J Infect Dis) 2 cases of levofloxacin treatment failures
Weiss et al. (Clin Infect Dis) 16 hospitalized patients (13 AECB, 3 pneumonia)
5 patients with ciprofloxacin-resistant S.pneumoniae
Ho et al. (Clin Infec Dis) Levofloxacin-resistant S.pneumoniae in 27 hospitalized patients
Kuehnert et al. (Ann Int Med) 1 case of treatment failure
Fishman et al. (39th ICAAC) 3 cases of treatment failure
Davies and Maesen (J Antimicrob Chem) 3 cases of treatment failure; 7 cases of reinfection or recurrence
Year Author/Journal Summary
Quinolone Resistance/Treatment Failures in Pneumococci
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E E
C C
B B
A A
par(C)
gyr(A)
DNA gyrase
Topoisomerase IV
• Ciprofloxacin
• Levofloxacin
• Moxifloxacin
Preferential Target Sites
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(94-188)
6/26/2010
SAM-2 The Science Behind
38
Fre
e A
UC
/ M
IC
Ciprofloxacin
750 mg q12
Levofloxacin
500 mg q24
(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
Resistance Prevention ~AUC/MIC≥100
Efficacy ~AUC/MIC≥35
Moxifloxacin
400 mg q24
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Fluoroquinolone-Resistant Pneumococci in
Respiratory Isolates from Adults >64 years:
1988-2009
0
1
2
3
4
5
6
7
1993199
4199
5199
6199
7199
8199
9200
0200
1200
2200
3200
4200
5200
6200
7200
8200
9
0
2
4
6
8
10
12
14
16
18
20
Levo R Moxi R Levo Use Moxi
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0
1
2
3
4
5
6
7
1993199
4199
5199
6199
7199
8199
9200
0200
1200
2200
3200
4200
5200
6200
7200
8200
9
0
2
4
6
8
10
12
14
16
18
20
Levo R Moxi R Levo Use Moxi
Fluoroquinolone-Resistant Pneumococci in
Respiratory Isolates from Adults >64 years:
1988-2009
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Changing Paradigm in Initial Antimicrobial Therapy
• Is the incidence of resistant pathogen(s) cause for concern?
– Decreasing clinical effectiveness
– Failure to eradicate
potential to exacerbate spread of resistant clones
– Increasing cost of management
• If so, perhaps the most potent antibiotics should be utilized as initial therapy?
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Consensus Principle Strategies to Optimize Outcomes and Minimize Resistance
• Antibiotic choices should be based on local susceptibility patterns Get it right early in compromised host
• Pharmacodynamics (determination of in vivo potency) can assist appropriate choices of agents and dosage
• Maximize the reduction in bacterial load with the aim of bacterial eradication PLUS shorter courses of therapy Prevent resistance
Ball P et al. J Antimicrob Chemother. 2002;49:31-40.