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Slide 1
S. pneumoniae Penicillin SusceptibilityUnited States 1979–20001–4
34
1316
29
11
25
33
173.8234562 5 7 8
13
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
enici
llin re
sista
nt
Resistant MIC > 2.0 µg/mlIntermediate MIC = 0.12–1.0 µg/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
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Slide 2
Temporal Trends in Macrolide Resistance Among Invasive Streptococcus pneumoniaeIsolates and Macrolide Use USA 1993-1999
Hyde, TB, et al. JAMA 2001; 286: 1857-1862
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Slide 3
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
22
>416>2>4
1001001001009898
919254556363
1995-98
*Based on PK/PD breakpointsJacobs M PIDJ 2000;19:S 47
1973-85: N=50; 1995-98: N=440
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Slide 4
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
>8.518
162
>812
1616
2
8410094
622
54977614
00
1995-98
*Based on PK/PD breakpointsJacobs M PIDJ 2000;19:S 47
1973-85: N=50; 1995-98: N=271
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Slide 5 Dagan R. Personal communication
The role of antibacterials is to eradicate
the causative organismsfrom the site of
infection
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Slide 6
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.
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Slide 7
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 andoutcomeBacteriologicdiagnosis/clinical outcomeClinicaldiagnosis andoutcome
Marchant C. et al. J Pediatr 1992; 120:72–77.
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Slide 8
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
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Slide 9
88 88
100
8890 92 86
70
0
20
40
60
80
100
Perc
ent s
ucce
ss
McLinn Aronovitz Khurana Dagan
ComparatorAzithro
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 0.023No. of patients needed to show:60% vs 90% bact. efficacy 2000 800 2000 800 clin/100 bact30% vs 90% bact. efficacy 542 234 542 100 clin/30 bact
Azithromycin in AOM: clinical outcome at end of treatment
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Slide 10
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)
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Slide 11
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
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Slide 12
Time serum conc. is above MIC (%)
Craig W. Diagn Microbiol Infect Dis 1996; 25:213–217.
0 20 40 60 80 100
0
20
40
60
80
100PenicillinsCephalosporins
Relationship between time above MIC and efficacy in animal infection models infected with S. pneumoniae
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Slide 13
Relationship between time above MIC and bacterial eradication with β-lactams in otitis media
Time serum conc. is above MIC (% of dosing interval)
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*
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Slide 14
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
ult
ure
po
siti
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
†
† ‡
†
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Slide 15
012345678
0 3 5 9 11Day
Lo
g10
CF
U/m
l
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
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Slide 16
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 24Hours after dose
0.001
0.01
0.1
1
10
100
Conc
entra
tion
(µg/
mL
or µ
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 µg/mL
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Slide 17
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
Conc
entra
tion
(µg/
mL
or µ
g/g)
1
10 H. Influenzae MIC90 16 µg/mL
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Slide 18
S. pneumoniae and H. influenzae pneumonia in rats:ED50 based on ≥3 log10 reduction in cfu/lung
1
10
1000.0
01
0.002
0.004
0.008
0.015
0.030
0.060
0.120
0.250
0.500
1.000
2.000
4.000
8.000
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 (µg/ml)
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Slide 19
S. pneumoniae and H. influenzae pneumonia in rats:ED50 based on ≥3 log10 reduction in cfu/lung
1
10
1000.0
01
0.002
0.004
0.008
0.015
0.030
0.060
0.120
0.250
0.500
1.000
2.000
4.000
8.000
ED50
(mg/
kg/d
)
AZI SP
CLARI SP
AZI HI
CLARI HI
MIC (µg/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
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Slide 20
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.
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Slide 21
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 µg/mL; AUC:MIC ratio < 0.1
Haemophilus: MIC90 = 1 µg/mL; AUC:MIC ratio = 3
PK/PD bkpt. 0.12 µg/mL
M. cat: MIC90 = 0.12 µg/mLMacrolide S: MIC90 = 0.06 µg/mL; AUC:MIC ratio = 50
Macrolide R (mefE): MIC90 = 8 µg/mL; AUC:MIC ratio 0.4
Seru
m co
nc.(µg
/mL)
24 hr12 hr0
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Slide 22
NCCLS* PK/PD +S. pneumoniae H. influenzae ALL
ORGANISMSAmoxicillin 2 – 2Amox/clav 2 4 2Cefuroxime axetil 1 4 1Cefdinir 0.5 1 0.5Cefprozil 2 8 1Cefixime – 1 0.5Cefaclor 1 8 0.5Loracarbef 2 8 0.5Azithromycin 0.5 4 0.12Clarithromycin 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.
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Slide 23
Susceptibility of Isolates at PK/PD and NCCLS breakpoints
Percentage of strains susceptibleAgent S. pneumoniae H. influenzae M. catarrhalisAmox/clav 90 97 100Amoxicillin 90 61 14Cefaclor 27 2 5Cefixime 57 99 100Cefpodoxime 63 99 64Cefprozil 64 18 6Cefuroxime 64 79 37Cefdinir‡ 61 97 100Azithromycin 67 0 100Clindamycin* 89 NA NADoxycycline 76 20 96Levofloxacin 99.8 100 99TMP/SMX* 57 75 9
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)
90 100 NA90 63 NA46 82 NA55 100 NA63 100 NA67 86 NA65 98 NA61 99 NA68 97 NA89 NA NA76 NA NA
99.8 100 NA57 75 NA
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Slide 24
NCCLS* PK/PD+
Bkpt %S Bkpt %SAmoxicillin 2 90 2 90Amoxicillin/clav 2 90 2 90Clindamycin 0.25 89 NA NA
S. pneumoniae: oral agents approved or recommended for AOM with ≥90% of recent US strains susceptible atNCCLS 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.
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Slide 25
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).
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Slide 26
0.03
0.06
0.12
0.25 0.5 1 2 4 8
16 32 64
S. pneumo
H. infl0
10
20
30
40
50
% o
f iso
late
s
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)
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Slide 27
Azithromycin MICs (S. pneumoniae and H. influenzae)
0.03
0.06
0.12
0.25 0.5 1 2 4 8
16 32 64
S. pneumo
H. infl0
10
20
30
40
50
% o
f iso
late
s
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
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Slide 28
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