Overview of pharmacological principles for prescribing...
Transcript of Overview of pharmacological principles for prescribing...
Overview of pharmacological principles for prescribing
antimicrobials to treat RTIs
Donald E. Low, MD, FRCPC
Toronto, Ontario
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
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
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
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
Pharmacology of Antibacterial therapy
Dosing
regimen
Concentrations in
serum
Concentrations at
site of infectionAntibacterial
effect
Pharmacokinetics Pharmacodynamics
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?
Serum concentration
Concentration at the site of infection
Effect
Serum concentration
Concentration at the site of infection
Effect
• Protein binding
• Tissue distribution
• Concentrations in tissue fluids
• Extracellular vs. intracellular infections
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
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?
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
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
Patterns of antibacterial activity
• Time-dependent killing
Time above MIC (T > MIC)
– β-lactams
• Concentration-dependent killing
AUC:MIC or Peak:MIC ratio
– Fluoroquinolones
Time>MIC
Peak/MIC
AUC/MIC
PharmacodynamicsPharmacokineticsfree serum levels
Maximize
bacterial
eradicatiion
Utilizing PK/PD principles to optimize
therapy
• Maximize clinical outcomes
• Minimize the emergence of resistance
Utilizing PK/PD principles to optimize
therapy
• Maximize clinical outcomes
• Minimize the emergence of resistance
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.
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
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
)
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]
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
Utilizing PK/PD principles to optimize
therapy
• Maximize clinical outcomes
• Minimize the emergence of resistance
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
Opatowski L et al. AAC 2010
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
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
Keypad Question: What AUC/MIC ratio
best predicts fluoroquinolone efficacy?
1. 25
2. >35
3. 75
4. >100
The Canadian Experience:
Validating the value of
optimal PK/PD parameters
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
E E
C C
B B
A A
par(C)
gyr(A)
DNA gyrase
Topoisomerase IV
• Ciprofloxacin
• Levofloxacin
Preferential Target Sites
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
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
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
Drusano G, Nature Reviews Microbiology 2004
Wild type
1st step mutant
1st and 2nd mutants
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
E E
C C
B B
A A
par(C)
gyr(A)
DNA gyrase
Topoisomerase IV
• Ciprofloxacin
• Levofloxacin
• Moxifloxacin
Preferential Target Sites
(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
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
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
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?
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.