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![Page 1: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/1.jpg)
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
![Page 2: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/2.jpg)
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
![Page 3: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/3.jpg)
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”
![Page 4: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/4.jpg)
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
![Page 5: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/5.jpg)
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
Jacobs. Clin Microbiol Infect 2001;7:589–96
![Page 6: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/6.jpg)
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)
Jacobs. Clin Microbiol Infect 2001;7:589–96
![Page 7: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/7.jpg)
GI Absorption
Blood
Renalexcretion
Pharmacokinetics
Extracellular compartment
of tissues
Oral ingestion
![Page 8: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/8.jpg)
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
![Page 9: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/9.jpg)
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.
![Page 10: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/10.jpg)
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
Jacobs. Clin Microbiol Infect 2001;7:589–96
![Page 11: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/11.jpg)
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
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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
![Page 13: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/13.jpg)
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
![Page 14: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/14.jpg)
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
![Page 15: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/15.jpg)
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.
![Page 16: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/16.jpg)
“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)
![Page 17: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/17.jpg)
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
![Page 18: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/18.jpg)
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
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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
![Page 20: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/20.jpg)
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
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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.
![Page 22: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/22.jpg)
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)
![Page 23: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/23.jpg)
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
![Page 24: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/24.jpg)
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
Alexander Project USA 2000
PK/PD breakpoint based
on current approved
dosing regimens
Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL
ORGANISMS
Cefaclor 1 8 0.5
![Page 25: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/25.jpg)
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
Alexander Project USA 2000
PK/PD breakpoint based
on current approved
dosing regimens
Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL
ORGANISMS
Cefuroxime axetil 1 4 1
![Page 26: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/26.jpg)
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
PK/PD breakpoint based
on current approved
dosing regimens
Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL
ORGANISMS
Cefprozil 2 8 1
![Page 27: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/27.jpg)
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
Alexander Project USA 2000
PK/PD breakpoint based
on current approved
dosing regimens
Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL
ORGANISMS
Cefixime – 1 0.5
![Page 28: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/28.jpg)
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
Alexander Project USA 2000
PK/PD breakpoint based
on current approved
dosing regimens
Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL
ORGANISMS
Azithromycin 0.5 4 0.12
![Page 29: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/29.jpg)
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
Alexander Project USA 2000
PK/PD breakpoint based
on current approved
dosing regimens
Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL
ORGANISMS
Clarithromycin 0.25 8 0.25
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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
Alexander Project USA 2000
PK/PD breakpoint based
on current approved
dosing regimens Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL
ORGANISMS
Clindamycin 0.25 NA 0.25
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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
Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL
ORGANISMS
Telithromycin ? ? 0.5
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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
Alexander Project USA 2000
PK/PD breakpoint based
on current approved
dosing regimens
Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL
ORGANISMS
Doxycycline ? ? 0.25
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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
Alexander Project USA 2000
PK/PD breakpoint based
on current approved
dosing regimens
Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL
ORGANISMS
Clarithromycin NA 1 1
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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
PK/PD breakpoint based
on current approved
dosing regimens
Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL
ORGANISMS
Levofloxacin 2 2 2
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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
Alexander Project USA 2000
PK/PD breakpoint based
on current approved
dosing regimens
Susceptible breakpoint NCCLS PK/PDS. pneumoniae H. influenzae ALL
ORGANISMS
Trimeth-sulfa 0.5 0.5 0.5
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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
![Page 37: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/37.jpg)
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”
![Page 38: Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649d9d5503460f94a86e04/html5/thumbnails/38.jpg)
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?