Yazdan Mirzanejad slides

S. pneumoniae Penicillin Susceptibility United States 1979–20001–4 60

Resistant MIC > 2.0 µg/ml Intermediate MIC = 0.12–1.0 µg/ml

40

33

13

2

1980

1979

0

Year

Slide 1

17

16

13

11 2000

15

1994–95

3

25

1999

3.8 14

1992–93

4

1987

5

1986

6

1985

8

1984

7

1983

2

5

1982

10

34

1998

10

29

1997

8

20

1990–91

3

1988–89

30

1981

% Penicillin resistant

50

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

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

Slide 2

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

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

MIC90 (ug/ml) 1973-85 1995-98 .03 2

% Susceptible* 1973-85 1995-98 100 91

Amox-clav

.03

2

100

92

Cefuroxime

.5

>4

100

54

Cefprozil

.5

16

100

55

Clarithromycin

.03

>2

98

63

Azithromycin

.12

>4

98

63

Slide 3

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

*Based

on PK/PD breakpoints Jacobs M PIDJ 2000;19:S 47

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

MIC90 (ug/ml) 1973-85 1995-98 >8 >8

% Susceptible* 1973-85 1995-98 84 54

Amox-clav

.5

1

100

97

Cefuroxime

1

2

94

76

Cefprozil

8

16

6

14

16

16

2

0

2

2

2

0

Clarithomycin Azithromycin Slide 4

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

*Based

on PK/PD breakpoints Jacobs M PIDJ 2000;19:S 47

The role of antibacterials is to eradicate the causative organisms from the site of infection Slide 5

Dagan R. Personal communication

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

Slide 6

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

Sample sizes required to detect differences between antibacterial drugs for acute otitis media

Number of patients required

Comparison of bacteriologic vs clinical outcomes in trials of two drugs (half the patients would be in each arm of a study) 2000 Bacteriologic diagnosis and outcome

1500 1000

Bacteriologic diagnosis/clinic al outcome

500 0

30 vs 90

40 vs 90

50 vs 90

60 vs 90

70 vs 90

80 vs 90

Clinical diagnosis and outcome

Bacteriologic efficacy of drug A compared with drug B Slide 7

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

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 S. et al. Pediatr Infect Dis J 1996; 15, supp1: S3–9 G. et al. Pediatr Infect Dis J 1996; 15, supp1: S15–19 3Khurana C.et al. Pediatr Infect Dis J 1996; 15, supp1: S24–29 4Dagan R. et al. Pediatr Infect Dis J 2000; 19:95–104 5Marchant C. et al. J Pediatr 1992; 120:72–77 1McLinn

2Aronovitz

Slide 8

Azithromycin in AOM: clinical outcome at end of treatment 100

Comparator Azithro

Percent success

100 80

88

88

88

90

92

86 70

60 40 20 0 McLinn

Mean age (range) years

Aronovitz

Khurana

Dagan

? (1-15)

4.0 (2-15)

5.7 (0.5-12)

1.3 (0.5-4)

553 (82%)

92 (54%)

444 (84%)

143 (60%)

0.64

0.10

0.42

0.023

No. of patients needed to show: 60% vs 90% bact. efficacy 2000 30% vs 90% bact. efficacy 542

800 234

2000 542

N evaluable at EOT P value for clin. outcome

Slide 9

800 clin/100 bact 100 clin/30 bact

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 10

Patterns of antibacterial activity

Slide 11

Pattern

Pharmacodynamic correlate

Time-dependent killing and minimal to moderate persistent effects

Time above MIC (T > MIC)

Time-dependent killing and prolonged persistent effects

AUC/MIC ratio

Concentration-dependent killing and prolonged persistent effects ratio

AUC/MIC ratio or Peak/MIC

Relationship between time above MIC and efficacy in animal infection models infected with S. pneumoniae 100

Penicillins Cephalosporins

80 60 40 20 0 0

20

40

60

80

100

Time serum conc. is above MIC (%)

Slide 12

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

Relationship between time above MIC and bacterial eradication with β-lactams in otitis media 100 80 60

Spontaneous resolution of H. influenzae* Spontaneous resolution of S. pneumoniae*

40

PSSP PISP-PRSP H. influenzae

20 0

0

20

40

60

80

100

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

Slide 13

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].

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

% culture positive

F 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

92

96

93

80 53

60

†‡

63 36

40 20

34/34 35/38 76/79

30/30 28/30 40/75†‡

†

23

†

19/30 10/28† 17/75†

0 0 No therapy

Slide 14

100

Azithromycin therapy

5

Day of Study

30 mg/kg/day x 5

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

10/11

120 mg/kg/day x 5 † 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 nontypeable Hemophilus influenzae

Log10 CFU/ml

F 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

8 7 6 5 4 3 2 1 0

† p<0.05 Rx vs. placebo ‡ p<0.05 30 vs. 120 mg/kg †

0

3

5 Day Placebo

Slide 15

†

†‡

30 mg/kg

9

†

11

120 mg/kg

Azithromycin therapy

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 Concentration (µg/mL or µg/g)

100

10

1

0.1

Plasma: Lung: Plasma: Lung:

0.01

0.001

Slide 16

H. Influenzae MIC90 2 µg/mL

0

4

8

12

50 mg/kg 50 mg/kg 50 mg/kg 50 mg/kg 16

Single dose Single dose Multiple dose Multiple dose 20

24

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

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 Concentration (µg/mL or µg/g)

100

10

1

0.1

Plasma: Lung: Plasma: Lung:

0.01

0.001

Slide 17

H. Influenzae MIC90 16 µg/mL

0

4

8

12

50 mg/kg 50 mg/kg 50 mg/kg bid 50 mg/kg bid 16

Single dose Single dose Multiple dose Multiple dose 20

24

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

S. pneumoniae and H. influenzae pneumonia in rats: ED50 based on ≥3 log10 reduction in cfu/lung 100 AZI SP

ED50 (mg/kg/d)

CLARI SP

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

AZI HI CLARI HI

10

Slide 18

8.000

4.000

2.000

1.000

0.500

0.250

0.120

0.060

0.030

0.015

0.008

0.004

0.002

0.001

1

MIC (µg/ml) Adapted from Mitten et al. Antimicrob Agents Chemother 2001; 45: 2585–2593

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

100

Macrolide resistant S. pneumoniae (efflux)

AZI SP

ED50 (mg/kg/d)

CLARI SP AZI HI CLARI HI

10

Macrolide susceptible S. pneumoniae

ED50 of macrolide resistant (ribosomal methylase) S. pneumoniae: >100 mg/kg/d

Slide 19

8.000

4.000

2.000

1.000

0.500

0.250

0.120

0.060

0.030

0.015

0.008

0.004

0.002

0.001

1

MIC (µg/ml) Adapted from Mitten et al. Antimicrob Agents Chemother 2001; 45: 2585–2593

S. pneumoniae and H. influenzae pneumonia in rats: ED50 based on ≥ 3 log10 reduction in cfu/lung 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) Slide 20

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

Azithromycin 32

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

16 Serum conc. (µg/mL)

10 mg/kg day 1; 5 mg/kg d 2–5

8

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

4 2 1

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

0.5 0.25

PK/PD bkpt. 0.12 µg/mL

0.12

M. cat: MIC90 = 0.12 µg/mL

0.06 0

Slide 21

AUC = 3 mg.h/L

Macrolide S: MIC90 = 0.06 µg/mL; AUC:MIC ratio = 50 12 hr

24 hr

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

Pharmacodynamic vs NCCLS breakpoints (µg/mL) PK/PD +

NCCLS* 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

Slide 22

+Sinus

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

Susceptibility of Isolates at PK/PD and NCCLS breakpoints Percentage of strains susceptible

Agent Amox/clav Amoxicillin Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime Cefdinir‡ Azithromycin Clindamycin* Doxycycline Levofloxacin TMP/SMX* Slide 23

S. pneumoniae

H. influenzae

M. catarrhalis

90 90 27 57 63 64 64 61 67 89 76 99.8 57

97 61 2 99 99 18 79 97 0 NA 20 100 75

100 14 5 100 64 6 37 100 100 NA 96 99 9

90 90 46 55 63 67 65 61 68 89 76 99.8 57

100 63 82 100 100 86 98 99 97 NA NA 100 75

NA NA NA NA NA NA NA NA NA NA NA NA NA

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. ‡Jacobs M. (unpublished)

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

PK/PD+

Bkpt

%S

Bkpt

%S

Amoxicillin

2

90

2

90

Amoxicillin/clav

2

90

2

90

0.25

89

NA

NA

Clindamycin

Slide 24

+Sinus

*M100-S11, National Committee for Clinical Laboratory Standards, 2001.

and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32.

H. influenzae: oral agents approved or recommended for AOM with ≥90% of recent US strains susceptible at NCCLS or PK/PD breakpoints (µg/mL) NCCLS* Amoxicillin/clav Cefdinir‡ Cefixime Cefpodoxime Cefuroxime axetil Cefprozil Loracarbef Azithromycin Slide 25

+Sinus

PK/PD+

Bkpt 4 1 1 2

%S 100 99 100 100

Bkpt 2 0.5 0.5 0.5

%S 97 97 100 99

4 8 8 4

98 86 90 97

1 1 0.5 0.12

80 18 10 0

*M100-S11, National Committee for Clinical Laboratory Standards, 2001.

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

Azithromycin MICs (S. pneumoniae and H. influenzae) MIC that includes ≥90% of H. influenzae

50

MIC that includes ≥90% of S. pneumoniae

30 20 10

H. infl

32

16

8

4

2

0.5

0.25

0.12

1

MIC (ug/ml)

S. pneumo 64

Slide 26

0.06

0

0.03

% of isolates

40

Jacobs et al. ICAAC 1999 poster C-61.

Azithromycin MICs (S. pneumoniae and H. influenzae) Efficacy animal models equivalent to current dosing Efficacy in animal models equivalent to 4X current dosing

50

20 10

H. infl

32

16

8

4

2

0.5

0.25

0.12

1

MIC (ug/ml)

S. pneumo 64

Slide 27

0.06

0

0.03

% of isolates

PK/PD breakpoint 40 based on current 30 dosing approved

Jacobs et al. ICAAC 1999 poster C-61.

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 Slide 28