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


Dosing

regimen

Concentrations in

serum

Concentrations at


effect


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


Dosing

regimen

Concentrations in

serum

Concentrations at


effect


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

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


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


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


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.

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