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