1

Selection of antibiotics for acute otitis media: Application

of pharmakokinetic and pharmacodynamic principles

Selection of antibiotics for acute otitis media: Application

of pharmakokinetic and pharmacodynamic principles

Michael R. Jacobs, MD, PhDProfessor of Pathology

Case Western Reserve University

Director of Clinical Microbiology

University Hospitals of Cleveland

Cleveland, OH

Slide 2

S. pneumoniae Penicillin Susceptibility United States 1979–20001–4

34

1316

29

11

25

33

173.823456

25

7 813

10

15

8

14

3

0

10

20

30

40

50

60

1979

1980

1981

1982

1983

1984

1985

1986

1987

1988

–89

1990

–91

1992

–93

1994

–95

1997

1998

1999

2000

Year

% P

enic

illin

resi

stan

t Resistant MIC > 2.0 g/mlIntermediate MIC = 0.12–1.0 g/ml

1. Doern GV. Am J Med 1995; 99(suppl 6B):3S–7S.2. Jacobs MR et al. Antimicrob Agents Chemother 1999; 43:1901–1908.

3. Jacobs MR et al. ICAAC 1999, poster C-61.4. Jacobs MR. USA Alexander Project data 2000

Slide 3

Temporal Trends in Macrolide Resistance Among Invasive Streptococcus pneumoniae Isolates and Macrolide Use USA 1993-1999

Hyde, TB, et al. JAMA 2001; 286: 1857-1862

Slide 4

S. pneumoniae: susceptibility of middle ear fluid isolates in two time periods*S. pneumoniae: susceptibility of middle ear fluid isolates in two time periods*

Agent MIC90 (ug/ml) % Susceptible*1973-85 1995-98 1973-85

Amoxicillin

Amox-clav

Cefuroxime

Cefprozil

Clarithromycin

Azithromycin

.03

.03

.5

.5

.03

.12

2

2

>4

16

>2

>4

100

100

100

100

98

98

91

92

54

55

63

63

1995-98

*Based on PK/PD breakpointsJacobs M PIDJ 2000;19:S 47

1973-85: N=50; 1995-98: N=440

Slide 5

H. influenzae: susceptibility of middle ear fluid isolates in two time periods*H. influenzae: susceptibility of middle ear fluid isolates in two time periods*

Agent MIC90 (ug/ml) % Susceptible*1973-85 1995-98 1973-85

Amoxicillin

Amox-clav

Cefuroxime

Cefprozil

Clarithomycin

Azithromycin

>8

.5

1

8

16

2

>8

1

2

16

16

2

84

100

94

6

2

2

54

97

76

14

0

0

1995-98

*Based on PK/PD breakpointsJacobs M PIDJ 2000;19:S 47

1973-85: N=50; 1995-98: N=271

Slide 6

Acute otitis media studies in children

Slide 7 Dagan R. Personal communication

The role of antibacterials The role of antibacterials is to eradicate is to eradicate

the causative organismsthe causative organismsfrom the site of from the site of

infectioninfection

Slide 8

Outpatient clinical studies in respiratory tract infections

• High rate of spontaneous resolution makes it difficult to show clinical 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

Marchant C. et al. J Pediatr 1992; 120:72–77.

Slide 9

Sample sizes required to detect differences between antibacterial drugs for acute otitis mediaComparison of bacteriologic vs clinical outcomes in trials of two drugs (half the patients would be in each arm of a study)

0

500

1000

1500

2000

30 vs90

40 vs90

50 vs90

60 vs90

70 vs90

80 vs90

Bacteriologic efficacy of drug A compared with drug B

Num

ber o

f pat

ient

s re

quire

d

Bacteriologicdiagnosis andoutcome

Bacteriologicdiagnosis/clinical outcome

Clinicaldiagnosis andoutcome

Marchant C. et al. J Pediatr 1992; 120:72–77.

Slide 10

Azithromycin in AOM: clinical outcome at end of therapy studies• Four studies using a common comparator were compared1-4

• Study designs differed – two were clinical diagnosis and outcome1,3

– one was bacteriologic diagnosis, clinical outcome2

– one was bacteriologic diagnosis and outcome4

• Patient ages in these studies differed: the first three were 0.5–15 years old (mean 4–6 years), while the fourth was 0.5-4 years (mean 1.3 years)

• Sample sized required for studies to be powered to show differences between agents were determined based on calculations published by Marchant et al.5

1McLinn S. et al. Pediatr Infect Dis J 1996; 15, supp1: S3–92Aronovitz G. et al. Pediatr Infect Dis J 1996; 15, supp1: S15–19

3Khurana C.et al. Pediatr Infect Dis J 1996; 15, supp1: S24–294Dagan R. et al. Pediatr Infect Dis J 2000; 19:95–104

5Marchant C. et al. J Pediatr 1992; 120:72–77

Slide 11

88 88

100

8890 92 86

70

0

20

40

60

80

100

Pe

rce

nt

su

cc

es

s

McLinn Aronovitz Khurana Dagan

Comparator

Azithro

Mean age (range) years ? (1-15) 4.0 (2-15) 5.7 (0.5-12) 1.3 (0.5-4)

N evaluable at EOT 553 (82%) 92 (54%) 444 (84%) 143 (60%)

P value for clin. outcome 0.64 0.10 0.42 0.023

No. of patients needed to show: 60% vs 90% bact. efficacy 2000 800 2000 800 clin/100 bact 30% vs 90% bact. efficacy 542 234 542 100 clin/30 bact

Azithromycin in AOM: clinical outcome at end of treatment

Slide 12

Using pharmacokinetics and pharmacodynamics to predict bacterial efficacy

Slide 13

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)

Slide 14

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 or

persistent effects Peak/MIC ratio

Slide 15

Time serum conc. is above MIC (%)

Mor

talit

y a f

ter 4

day

s of

ther

a py

(%)

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

0 20 40 60 80 100

0

20

40

60

80

100Penicillins

Cephalosporins

Relationship between time above MIC and efficacy in animal infection models infected with S. pneumoniae

Slide 16

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

Time serum conc. is above MIC (% of dosing interval)

Bac

ter ia

l era

d ic a

t ion

day

4- 6

of t

hera

py (%

)

20

40

60

80

100

0 20 40 60 80 1000

PSSPPISP-PRSPH. influenzae

Craig W., Andes D. Pediatr Infect Dis J 1996; 15:255–259.Dagan R. et al. studies

*Howie, V. Clin Pediatr 1972, 11:205-214].

Spontaneous resolution of H. influenzae*

Spontaneous resolution of

S. pneumoniae*

Slide 17

Microbiologic outcome of middle ear fluid in experimental acute otitis media in chinchillas due to non-typeable Hemophilus influenzaeF E Babl, S I Pelton, Z Li. Experimental Acute Otitis Media Due to Non-typable Haemophilus Influenzae: Comparison of High and Low Dose Azithromycin with Placebo. Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Canada, August 2000 and submitted for publication

100 100

63

92 93

36

96

53

23

0

20

40

60

80

100

0 5 10/11Day of Study

% c

ultu

re p

ositi

ve

No therapy 30 mg/kg/day x 5 120 mg/kg/day x 5

34/34 35/38 76/79 30/30 28/30 40/75†‡ 19/30 10/28† 17/75†

* Number of ears; denominator changes due to in # of animals

† p<0.05 Rx vs. placebo

‡ p<0.05 30 vs. 120 mg/kg

Azithromycin therapy

†

† ‡

†

Slide 18

012345678

0 3 5 9 11Day

Log

10 C

FU

/ml

Placebo 30 mg/kg 120 mg/kg

Azithromycin therapy

† p<0.05 Rx vs. placebo

‡ p<0.05 30 vs. 120 mg/kg

†‡

†

†

†

Median CFU by treatment group in middle ear fluid in experimental acute otitis media in chinchillas due to non-typeable Hemophilus influenzaeF E Babl, S I Pelton, Z Li. Experimental Acute Otitis Media Due to Non-typable Haemophilus Influenzae: Comparison of High and Low Dose Azithromycin with Placebo. Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Canada, August 2000 and submitted for publication

Slide 19

Azithromycin concentrations in plasma and lung after single and multiple 50 mg/kg oral dosing in rats. These levels are about twice those achieved in humans

0 4 8 12 16 20 24

Hours after dose

0.001

0.01

0.1

1

10

100

Con

cent

ratio

n (

g/m

L or

g/

g)

Plasma: 50 mg/kg Single doseLung: 50 mg/kg Single dosePlasma: 50 mg/kg Multiple doseLung: 50 mg/kg Multiple dose

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

H. Influenzae MIC90 2 g/mL

Slide 20

Clarithromycin concentrations in plasma and lung after single and multiple 50 mg/kg oral dosing in rats. These levels are about twice those achieved in humans

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

0 4 8 12 16 20 240.001

0.01

0.1

100

Plasma: 50 mg/kg Single doseLung: 50 mg/kg Single dosePlasma: 50 mg/kg bid Multiple doseLung: 50 mg/kg bid Multiple dose

Hours after dose

Con

cent

ratio

n (

g/m

L or

g/

g)

1

10 H. Influenzae MIC90 16 g/mL

Slide 21

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

1

10

1000.

001

0.00

2

0.00

4

0.00

8

0.01

5

0.03

0

0.06

0

0.12

0

0.25

0

0.50

0

1.00

0

2.00

0

4.00

0

8.00

0

ED50

(mg/

kg/d

)

AZI SP

CLARI SP

AZI HI

CLARI HI

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

AZI, CLARI approved human dosing provides PK similar to approx. 25 mg/kg/d in this model

MIC (g/ml)

Slide 22

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

1

10

1000.

001

0.00

2

0.00

4

0.00

8

0.01

5

0.03

0

0.06

0

0.12

0

0.25

0

0.50

0

1.00

0

2.00

0

4.00

0

8.00

0

ED50

(mg/

kg/d

)

AZI SP

CLARI SP

AZI HI

CLARI HI

MIC (g/ml)

Macrolide susceptible S.

pneumoniae

Macrolide

resistant S.

pneumoniae

(efflux)

ED50 of macrolide resistant (ribosomal methylase) S.

pneumoniae: >100 mg/kg/d

H. influenzae

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

Slide 23

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.

Slide 24

Azithromycin 10 mg/kg day 1; 5 mg/kg d 2–5

Adapted from Drusano G. et al. J Chemother 1997; 9(suppl 3):38–44.

AUC = 3 mg.h/L

32

16

8

4

2

1

0.5

0.25

0.12

0.06

Macrolide R (ermB): MIC90 ≥ 32 g/mL; AUC:MIC ratio < 0.1

Haemophilus: MIC90 = 1 g/mL; AUC:MIC ratio = 3

PK/PD bkpt. 0.12 g/mL

M. cat: MIC90 = 0.12 g/mL

Macrolide S: MIC90 = 0.06 g/mL; AUC:MIC ratio = 50

Macrolide R (mefE): MIC90 = 8 g/mL; AUC:MIC ratio 0.4

Seru

m c

onc.

(g/

mL)

24 hr12 hr0

Slide 25

NCCLS* PK/PD +

S. pneumoniae H. influenzae ALL ORGANISMS

Amoxicillin 2 – 2

Amox/clav 2 4 2

Cefuroxime axetil 1 4 1

Cefdinir 0.5 1 0.5

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 (µg/mL)

*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.

Slide 26

Susceptibility of Isolates at PK/PD and NCCLS breakpoints

Percentage 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)

90 100 NA

90 63 NA

46 82 NA

55 100 NA

63 100 NA

67 86 NA

65 98 NA

61 99 NA

68 97 NA

89 NA NA

76 NA NA

99.8 100 NA

57 75 NA

Slide 27

NCCLS* PK/PD+

Bkpt %S Bkpt %S

Amoxicillin 2 90 2 90

Amoxicillin/clav 2 90 2 90

Clindamycin 0.25 89 NA NA

S. pneumoniae: oral agents approved or recommended for AOM with 90% of recent US strains susceptible at NCCLS or PK/PD breakpoints (µg/mL)

*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.

Slide 28

NCCLS* PK/PD+

Bkpt %S Bkpt %SAmoxicillin/clav 4 100 2 97Cefdinir‡ 1 99 0.5 97Cefixime 1 100 0.5 100Cefpodoxime 2 100 0.5 99

Cefuroxime axetil 4 98 1 80Cefprozil 8 86 1 18Loracarbef 8 90 0.5 10Azithromycin 4 97 0.12 0

H. influenzae: oral agents approved or recommended for AOM with 90% of recent US strains susceptible at NCCLS or PK/PD breakpoints (µg/mL)

*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.

‡ Data from Jacobs M. (unpublished).

Slide 29

0.0

3

0.0

6

0.1

2

0.2

5

0.5 1 2 4 8

16

32

64

S. pneumo

H. infl0

10

20

30

40

50

% o

f is

ola

tes

MIC (ug/ml)

Jacobs et al. ICAAC 1999 poster C-61.

MIC that includes

90% of H. influenzae

MIC that includes

90% of S. pneumoniae

Azithromycin MICs (S. pneumoniae and H. influenzae)

Slide 30

Azithromycin MICs (S. pneumoniae and H. influenzae)

0.0

3

0.0

6

0.1

2

0.2

5

0.5 1 2 4 8

16

32

64

S. pneumo

H. infl0

10

20

30

40

50

% o

f is

ola

tes

MIC (ug/ml)

Jacobs et al. ICAAC 1999 poster C-61.

Efficacy animal models equivalent to current dosing

Efficacy in animal models

equivalent to 4X current dosing

PK/PD breakpoint

based on current

approved dosing

Slide 31

Conclusions: Antibacterial choice for empiric use in acute otitis media

• Most clinical studies are too small to show clinical differences between agents

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

• Few oral agents approved for pediatric use are active against 90% of current US strains of the key otitis media pathogens at approved dosing regimens

• Bacteriologic outcome studies in children and animal studies have repeatedly validated these conclusions