Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.

Michael R. Jacobs, MD, PhDProfessor of Pathology and Medicine

Case Western Reserve University

Director of Clinical Microbiology

University Hospitals of Cleveland

Cleveland, OH

Application of Pharmacokinetic and

Pharmacodynamic Principles to Otitis Media and other

Respiratory Tract Infections

Limitations of outpatient clinical studies in respiratory tract infections

• High-rate spontaneous resolution makes it difficult to show differences between agents

• Bacteriologic outcome studies are not often performed due to necessity for invasive procedure (ear, sinus or lung tap) to obtain specimen

• Most studies are therefore designed to show equivalent clinical outcome between established and new agents

• Inadequacies of agents studied are therefore often not apparent

Jacobs. Clin Microbiol Infect 2001;7:589–96

1977 FDA Guidance on AOM

“In the absence of culture of

middle ear fluid, no specific

claim can be made regarding the

effectiveness of any anti-

infective drug”

Objectives

• Define pharmacokinetics and pharmacodynamics

• Correlate serum pharmacokinetic parameters for various drug classes with outcome of infection in outpatient respiratory tract infections

• Show examples of these correlations in animal models and in humans

• Apply these principles to treatment of otitis media and other respiratory tract infections

Impact of limited clinical data and increasing pathogen resistance on choice of

antibacterial therapy

• There is a need for:– accurate prediction of efficacy

– newer dosage regimens

– newer antibacterials

– revised susceptibility breakpoints

– statistically valid clinical studies


Evaluating antibacterial efficacy using pharmacokinetics and pharmacodynamics

• Pharmacokinetics (PK)– serum concentration profile

– penetration to site of infection

• Pharmacodynamics (PD)– susceptibility – MIC (potency)

– concentration- vs. time-dependent killing

– persistent (post-antibiotic) effects (PAE)


GI Absorption

Blood

Renalexcretion

Pharmacokinetics

Extracellular compartment

of tissues

Oral ingestion

Drug Pharmacokinetics in bloodS

eru

m A

nti

bio

tic

Co

nce

ntr

atio

n

0

2

4

6

8

10

0 1 2 3 4 5 6 7 8

Time (hours)

(mcg

/mL

)

9 10 11 12

Dose Dose

Pharmacokinetic ParametersS

eru

m A

nti

bio

tic

Co

nce

ntr

atio

n

0

2

4

6

8

10

0 1 2 3 4 5 6 7 8

Time (hours)

(mcg

/mL

)

9 10 11 12

Dose Dose

Concentration present for 50% of dosing interval (6 h if given q12h)

Area under curvePeak

serum conc.

Patterns of antibacterial activity

Pattern Pharmacodynamiccorrelate

Time-dependent killing Time above MIC and minimal to moderate (T>MIC)persistent effects

Time-dependent killing AUC/MIC ratioand prolonged persistent effects Concentration-dependent AUC/MIC ratiokilling and prolonged orpersistent effects Peak/MIC ratio


Time Above MIC: -Lactams

T>MIC (% of dosing interval) required for the static dose against most organisms in neutropenic mice vary from 25-35% for penicillins and from 30-45% for cephalosporins

The presence of neutrophils reduces the T>MIC required for efficacy by 5-10%

Free drug levels of penicillins and cephalosporins need to exceed the MIC for 35-50% of the dosing interval to produce maximum survival

0 20 40 60 80 100

0

20

40

60

80

100

Time above MIC (%)

Penicillins

Cephalosporins

Mo

rtal

ity

afte

r 4

day

s o

f th

erap

y (%

)

Craig. Diagn Microbiol Infect Dis 1996; 25:213–217

Relationship between Time above MIC and efficacy in animal infection models

infected with S. pneumoniae

An

tib

ioti

c co

nce

ntr

atio

n

MIC

Time

24-hr AUC/MIC is correlated with outcome of infection, the magnitude required for success and MIC at which this occurs becomes the PD breakpoint

24-hr AUC/MIC and Peak/MIC RatiosCorrelation of serum pharmacokinetics with MIC (susceptibility) of an organism

Area under the curve to MIC ratio

Peak to MIC ratio

Relationship between 24 Hr AUC/MIC and mortality for fluoroquinolones against S. pneumoniae in

immunocompetent animalsM

ort

alit

y (%

)

24-hr AUC/MIC

1 25 10 5 2.5

0

20

40

60

80

100

100 50

At dosing comparable to dosing in humans:

• Azithromycin and clarithromycin were able to reduce inoculum by 3 log10 cfu/lung for macrolide susceptible S. pneumoniae

• Azithromycin and clarithromycin were NOT able to reduce inoculum by 3 log10 cfu/lung for H influenzae or for macrolide non-susceptible S. pneumoniae (erm and mef mechanisms)

S. pneumoniae and H. influenzae pneumonia in rats:ED50 based on 3 log10 reduction in cfu/lung

Mitten M. et al. Antimicrob Agents Chemother 2001; 45: 2585–2593.

“After administration of azithromycin at 30 mg/kg as single daily doses in our chinchilla model of EOM due to NTHI, we were able to achieve levels in serum and AUCs approximately twice those observed in children treated with 10 mg/kg or with 10, 5, 5, 5, and 5 mg/kg as single daily doses and concentrations in MEF comparable to those reported for children with AOM. Our observations provide evidence that current doses of azithromycin administered to children are likely to have a modest antibacterial effect on AOM due to NTHI, characterized by a reduction in density of infection. Maximizing the dosing of azithromycin in children has the potential to improve the microbiologic outcome.”

Franz E. Babl, Stephen I. Pelton, and Zhong Li. Experimental Acute Otitis Media Due to Nontypeable Haemophilus influenzae: Comparison of High and Low Azithromycin Doses with Placebo. Antimicrobial Agents and Chemotherapy, 2002, 46:2194-2199

Microbiologic outcome of middle ear fluid in experimental acute otitis media in chinchillas due to non-typeable

Haemophilus influenzae (NTHI)

Relationship between Time above MIC and bacterial eradication with -lactams in otitis media

20

40

60

80

100

Time above MIC (% of dosing interval)

0 20 40 60 80 100

Bac

teri

al e

rad

i ca t

i on

(%

)

0

PSSP

PISP-PRSP

H. influenzae

Craig & Andes, Pediatr Infect Dis J, 1996

Dagan et al studies

Relationship between Time above MIC and bacterial eradication with -lactams in maxillary sinusitis

Craig & Andes, Pediatr Infect Dis J, 1996

Gwaltney & Scheld studies

20

40

60

80

100

Time above MIC (% of dosing interval)

0 20 40 60 80 100

Bac

teri

al e

rad

i ca t

i on

(%

)

0

PSSP

H. influenzae

Clinicalfailure rate 43% 11.5% 1%

Levofloxacin PK/PD correlations134 hospitalized patients with respiratory tract, skin or complicated urinary

tract infections treated with 500 mg qd for 5–14 days

Jacobs. Clin Microbiol Infect 2001;7:589–96 [Adapted from Preston et al. JAMA 1998;279:125–9]

4 3

23

3

100

10

10

20

30

40

50

60

70

80

90

100N

o.

of

pat

ien

ts

AUC:MIC <25 Peak:MIC <3

AUC:MIC 25–100Peak:MIC 3–12

AUC:MIC >100 Peak:MIC >12

Success

Failure

Clinical outcome

PK/PD breakpointALL ORGANISMS

Amoxicillin 2

Amox/clav 2

Cefuroxime axetil 1

Cefprozil 1

Cefixime 0.5

Cefaclor 0.5

Loracarbef 0.5

Azithromycin 0.12

Clarithromycin 0.25

Pharmacodynamic breakpoints (µg/ml) for oral agents used for RTIs

NCCLS PK/PDS. pneumoniae H. influenzae ALL

ORGANISMS

Amoxicillin 2 4 2

Amox/clav 2 4 2

Cefuroxime axetil 1 4 1

Cefprozil 2 8 1

Cefixime – 1 0.5

Cefaclor 1 8 0.5

Loracarbef 2 8 0.5

Azithromycin 0.5 4 0.12

Clarithromycin 0.25 8 0.25

Pharmacodynamic vs. NCCLS breakpoints (values in µg/ml)

Based on M100-S11, National Committee for Clinical Laboratory Standards, 2001; Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32.

Susceptibility of US Isolates at PK/PD breakpointsPercentage of strains susceptible

Agent S. pneumoniae H. influenzae M. catarrhalisAmox/clav 90 97 100

Amoxicillin 90 61 14

Cefaclor 27 2 5

Cefixime 57 99 100

Cefpodoxime 63 99 64

Cefprozil 64 18 6

Cefuroxime 64 79 37

Cefdinir‡ 61 97 100

Azithromycin 67 0 100

Clindamycin* 89 NA NA

Doxycycline 76 20 96

Levofloxacin 99.8 100 99

TMP/SMX* 57 75 9Based on M100-S11, National Committee for Clinical Laboratory Standards, 2001; Sinus and Allergy Health

Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32. ‡Jacobs M. (unpublished)

Amoxicillin-clavulanate

0

10

20

30

40

50

60

% o

f st

rain

s

0.0

2

0.0

3

0.0

6

0.1

2

0.2

5

0.5 1 2 4 8

16

>1

6

H. influenzae

S. pneumoniae

M. catarrhalis

MIC in ug/mL

Alexander Project USA 2000

PK/PD breakpoint based

on current approved

dosing regimens

Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL

ORGANISMS

Amoxicillin 2 4 2

Amox/clav 2 4 2

Cefaclor

05

10152025

303540

% o

f str

ain

s

0.5 1 2 4 8 16 32 64 >64

H. influenzae

S. pneumoniae

M. catarrhalis

MIC in ug/mL



on current approved

dosing regimens


ORGANISMS

Cefaclor 1 8 0.5

Cefuroxime axetil

05

1015202530354045

% o

f st

rain

s

0.0

2

0.0

3

0.0

6

0.1

2

0.2

5

0.5 1 2 4 8

16

>1

6

H. influenzae

S. pneumoniae

M. catarrhalis

MIC in ug/mL



on current approved

dosing regimens


ORGANISMS

Cefuroxime axetil 1 4 1

Cefprozil

0

10

20

30

40

50

% o

f st

rain

s

0.12 0.25 0.5 1 2 4 8 16 >16

H. influenzae

S. pneumoniae

M. catarrhalis

MIC in ug/mLAlexander Project USA 2000


on current approved

dosing regimens


ORGANISMS

Cefprozil 2 8 1

Cefixime

0

10

20

30

40

50

60

70

% o

f st

rain

s

0.0

2

0.0

3

0.0

6

0.1

2

0.2

5

0.5 1 2 4 8

16

>1

6

H. influenzae

S. pneumoniae

M. catarrhalis

MIC in ug/mL



on current approved

dosing regimens


ORGANISMS

Cefixime – 1 0.5

Azithromycin

0

20

40

60

80

100

% o

f st

rain

s

0.0

3

0.0

6

0.1

2

0.2

5

0.5 1 2 4 8

16

32

>3

2

H. influenzae

S. pneumoniae

M. catarrhalis

MIC in ug/mL



on current approved

dosing regimens


ORGANISMS

Azithromycin 0.5 4 0.12

Clarithromycin

0

10

20

30

40

50

60

70

% o

f st

rain

s

0.0

3

0.0

6

0.1

2

0.2

5

0.5 1 2 4 8

16

32

>3

2

H. influenzae

S. pneumoniae

M. catarrhalis

MIC in ug/mL



on current approved

dosing regimens


ORGANISMS

Clarithromycin 0.25 8 0.25

Clindamycin

0

20

40

60

80

100

% o

f str

ain

s

0.03 0.06 0.12 0.25 0.5 1 >1

H. influenzae

S. pneumoniae

M. catarrhalis

MIC in ug/mL



on current approved

dosing regimens Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL

ORGANISMS

Clindamycin 0.25 NA 0.25

Telithromycin

01020304050607080

% o

f st

rain

s

0

0.0

1

0.0

2

0.0

3

0.0

6

0.1

2

0.2

5

0.5 1 2 4

>4

H. influenzae

S. pneumoniae

M. catarrhalis

MIC in ug/mL

Nagai AAC 2002, 46:371-7; Pankuch AAC 1998, 42:3032-34

PK/PD breakpoint based on

current investigational

dosing regimens


ORGANISMS

Telithromycin ? ? 0.5

Doxycycline

0

10

20

30

40

50

60

70

% o

f st

rain

s

0.03 0.06 0.12 0.25 0.5 1 2 4 8 >8

H. influenzae

S. pneumoniae

M. catarrhalis

MIC in ug/mL



on current approved

dosing regimens


ORGANISMS

Doxycycline ? ? 0.25

Ciprofloxacin

01020304050607080

% o

f st

rain

s

0.0

1

0.0

2

0.0

3

0.0

6

0.1

2

0.2

5

0.5 1 2 4 8

>8

H. influenzae

S. pneumoniae

M. catarrhalis

MIC in ug/mL



on current approved

dosing regimens


ORGANISMS

Clarithromycin NA 1 1

Levofloxacin

0102030405060708090

% o

f st

rain

s

0.0

08

0.0

15

0.0

3

0.0

6

0.1

2

0.2

5

0.5 1 2

>2

H. influenzae

S. pneumoniae

M. catarrhalis

MIC in ug/mLAlexander Project USA 2000


on current approved

dosing regimens


ORGANISMS

Levofloxacin 2 2 2

Trimethoprim-sulfamethoxazole

05

1015202530354045

% o

f st

rain

s

0.02 0.03 0.06 0.12 0.25 0.5 1 2 4 >4

H. influenzae

S. pneumoniae

M. catarrhalis

MIC in ug/mL



on current approved

dosing regimens


ORGANISMS

Trimeth-sulfa 0.5 0.5 0.5

Conclusions: antibacterial choice for empiric use in RTI

• Most clinical studies do not show clinical differences between agents

• PK/PD parameters correlate with bacteriological and clinical outcome in animal models and in humans

• PK/PD parameters can be used to select agents with maximum potential for bacterial eradication

• Currently available agents vary significantly in achieving PK/PD parameters necessary for bacterial eradication

1977 FDA Guidance on AOM

“In the absence of culture of

middle ear fluid, no specific

claim can be made regarding the

effectiveness of any anti-

infective drug”

New FDA Guidance on AOM

•Do we admit there is a problem?

•What does it take to fix the problem?

•Will we fix the problem?

•When will this be achieved?

Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.

Documents

dose slide

timedependent killing

drug pharmacokinetics

anti infective drug

clin microbiol

valid clinical studies

time hours mcgml

dose concentration present