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Empiric Treatment of Upper
Respiratory Infections
Michael E. Pichichero, MD
Professor o f Microbio logy and Immunolog y,
Professor o f Pediatr ics and Professor o f Medicine
University of Rochester Medical Center
Elmwood Pediatric Group
Rochester, NY
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Factors That Influence Clinical Outcome
Proper Diagnosis
PK/PD Properties
Treatment
Choice
Clinical Outcome/Effectiveness
Otitis Media Sinusitis Tonsillopharyngitis
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Normal Tympanic Membrane in Childre
• Translucent/transparent
• Gray or pink color
• Neutral position
• Fully mobile with pneumatic otoscope
• No effusion
Pichichero ME. Am Fam Phys ic ian. 2000;61:2051-2056
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Acute Otitis Media in Children
•Tympanic membrane characteristics
– Opaque
– Red, yellow, or white color
– Bulging or full position
– Reduced mobility but may respond to
positive pressure on pneumatic otoscopy
– Effusion present
Pichichero ME. Am Fam Phys ic ian. 2000;61:2051-2056
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Otitis Media With Effusionin Children
•Tympanic membrane characteristics – Translucent or opaque
– Gray or pink color
– Neutral or retracted position
– Reduced mobility, responds to negative
pressure on pneumatic otoscopy
– Effusion present
Pichichero ME. Am Fam Phys ic ian. 2000;61:2051-2056
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% Correct Diagnosis of Video Presented Tympanic
Membrane and Middle Ear Findings Among PediatricianCorrect Diagnosis Italian Greek S. African US
n=66 n=115 n=36 n=219
OME 94 52 88 46
OME 18 23 22 48
Retracted, otherwise normal 89 43 71 54
AOM 72 56 66 72
OME 29 39 35 54
OME 36 29 46 29
Retracted, otherwise normal 36 28 48 48
OME 42 28 35 49Retracted, otherwise normal 66 26 68 58
Overall Mean 54 36 53 51Pichichero ME. Eur J Clin Micro Inf Dis 2003
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Potential Reasons for Misdiagnosis of
Acute Otitis Media
• Reliance on inaccurate history
• Failure to remove cerumen
• Screaming (crying) can make tympanic membranes
red• Poor light from otoscope (bulb and/or battery)
• Failure to evaluate tympanic membrane mobility and
position (pneumatic otoscopy)
• Inappropriately sized speculum
Outcomes Management Educational Workshops, Inc. 2001
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Pediatric Acute Bacterial Sinusitis and URIComparison of Clinical Course for Diagnosis
Fever Purulent Nasal Discharge
Severity
Days 1 2 3 4 5 6 7 8 9
UncomplicatedURI
1 2 3 4 5 6 7 8 9
Acute Sinusitis(Severe)
1 2 3 4 5 6 7 8 9
Acute Sinusitis(Persistent)
AAP Guidelines 2002
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8234 (98.2%) RAD tests negative,
11,427
RAD GAS tests performed between
January 1996 and June 1999 (3 years, 5 months)
8385 (73.4%) RAD tests negative 3042 (26.6%) RAD tests positivand treated
also cultured
200 (2.4%) RAD tests negative,culture positive
Mayes T, Pichichero ME. Clin Pediatr (Phila). 2001;40:191-195
Diagnosing GAS Pharyngitis
Is a Follow-up Throat Culture Necessary?
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FDA-Approved Drugs for theTreatment of Acute Otitis Media
Aminopenicillins
Amoxicillin
Amoxicillin/clavulanate (Augmentin®)
Cephalosporins
2nd generation
Cefprozil (Cefzil®)Cefaclor (Ceclor ®)
Loracarbef (Lorabid®)
Cefuroxime (Ceftin®)
3rd generation
Cefdinir (Omnicef ®)Cefpodoxime (Vantin®)
Ceftibuten (Cedax®)
Cefixime (Suprax®)
Combination
TMP-SMX (Bactrim® or Septra®
Erythromycin-sulfisoxazole
(pediazole®)
Macrolides
Azithromycin (Zithromax®
)Clarithromycin (Biaxin®)
Parenteral
Ceftriaxone (Rocephin®)
Th R l ti hi B t
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The Relationship BetweenPharmacokinetics/Pharmacodynamics and
Clinical Outcome
Pharmacokinetics
(PK)
Effect in Humans Serum concentration profile
Penetration to site of infection
Pharmacodynamic
(PD)
Effect in Bacteria Potency (MICs)
Mechanism of killing
Clinical Effectiveness
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Comparative (In Vitro) Activity of Antibiotics
Against Susceptible Streptococcus Pneumon iae
NOTE: Drugslisted alphabetically
in each group
*Double dose: 80-100 mg/kg/d
CeftriaxoneAmoxicillin*
Amoxicillin/clavulanate*
Cefdinir
Cefpodoxime proxetil
Cefprozil
Cefuroxime axetilClindamycin
Azithromycin
Cefaclor
Clarithromycin
Loracarbef Trimethoprim/sulfamethoxazole
Cefixime
Ceftibuten
Highest
Lowest Outcomes Management Educational Workshops, Inc. 20
Activity
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CefiximeCeftibuten
Ceftriaxone
Amoxicillin-clavulanate
Cefdinir
Cefpodoxime proxetil
Cefuroxime axetil
Cefprozil
Cefaclor
Loracarbef
Trimethoprim-sulfamethoxazole
AzithromycinClarithromycin
Amoxicillin
Erythromycin
Comparative (In Vitro) Activity of Antibiotics Against
Haemoph i lus Inf luenzae Beta-Lactamase (+)
Highest
Lowest
NOTE: Drugslisted alphabetically
in each group
Outcomes Management Educational Workshops, Inc
Activity
A t Otiti M di
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Acute Otitis MediaDouble Tympanocentesis
Rate of eradication at day 3 to 15
- H. inf luenzae Azithromycin 39% Amox/clav 87%
- S. pneumo Azithromycin 68% Amox/clav 90%
Rate of eradication at day end of therapy (day 12 to 14)
- H inf luenzae Azithromycin 58% Amox/clav 91%
- S. pneumo Azithromycin 80% Amox/clav 86%
Overall Azithromycin 70% (N=73)
Amox/clav 86% (N=70)(P=.02
Amoxicillin/clavulanate (45:6.4 mg/kg/d administered at 12 hour intervals for 1
days) versus azithromycin (10 mg/kg single dose on day 1 followed by 5mg/kg/d every 24 hours on days 2 to 5)
Antibiotic Treatment Choices for Resistant
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Antibiotic Treatment Choices for Resistant
Streptococcus pneumoniae AOM Italy Greece
Pre-course Post-course Pre-course Post-cours
Amox/Clav ES 51% 52% 18% 24%
Higher activity 38% 48% 59% 76%
cephalosporin
Lower activity 3% 0% 3% 0%
cephalosporin
Azithromycin 8% 0% 5% 0%
TMP/SMZ 0% 0% 5% 0%Pichichero ME. Eur J Clin Micro Inf Dis 2003
Antibiotic Treatment Choices for Beta-lactamase
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Antibiotic Treatment Choices for Beta-lactamase
+ H. in fluenzae
Italy Greece
Pre-course Post-course Pre-course Post-course
Amox/Clav ES 58% 65% 40% 53%
Higher activity 32% 37% 30% 47%
cephalosporin
Lower activity 5% 0% 10% 0%
cephalosporin
Azithromycin 5% 0% 10% 0%
TMP/SMZ 0% 0% 10% 0%
Pichichero ME. Eur J Clin Micro Inf Dis 2003
Cephs vs Pen Bacterial Cure in GABHS Tonsillopharyngitis
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Cephs vs Pen Bacterial Cure in GABHS Tonsillopharyngitis
Favors Pen Favors Cephs N OR (95% CI)
1.77(0.57,5.562.62(0.76,9.051.46(0.61,3.49
2.75(1.14,6.655.91(0.30,117.61.00(0.06,17.6
Years 1970-1979 676 2.06(1.27,3.34
5.63(1.18,27.0
2.61(0.48,14.16.51(1.41,30.02.24(1.40,3.58
4.19(1.09,16.03.03(0.60,15.40.78(0.22,2.762.73(1.04,7.13
10.00(2.01,49.83.67(0.27,49.28.28(1.02,67.3
Years 1980-1989 1710 2.84(1.97,4.09Casey JR and Pichichero ME, ICAAC 2003
Cephs vs Pen Bacterial Cure in GABHS Tonsillopharyngitis
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Cephs vs Pen Bacterial Cure in GABHS Tonsillopharyngitis
Favors Pen Favors Cephs N OR (95% CI)
8.84(0.44,1.77.66.50(2.10,20.121.61(0.42,6.142.15(1.29,3.581.55(0.24,9.941.33(0.57,3.08
4.58(1.19,17.683.13(1.66,5.883.07(1.51,6.232.88(0.99,8.38
4.25(1.75,10.323.57(1.61,7.91
5.19(2.68,10.072.53(1.40,4.55
6.38(0.28,143.54.80(2.44,9.45
7.06(4.34,11.49
1.24(0.50,3.06
Years 1990-1999 4739 3.25(2.49,4.23
Overall 7125 3.02(2.49,3.67
Casey JR and Pichichero ME, ICAAC 2003
C h P Cli i l C i GABHS T ill h iti
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Cephs vs Pen Clinical Cure in GABHS Tonsillopharyngitis
Favors Pen Favors Cephs N OR (95% CI)
2.30(0.57,9.62)
1.46(0.61,3.49)
3.61(1.45,8.99)
1.00(0.06,17.62
Years 1970-1979 464 2.19(1.25,3.85)
3.82(0.77,19.03
0.98(0.13,7.24)3.00(0.59,15.33
2.24(1.40,3.58)
2.69(0.87,8.29)
11.23(0.61,205.9
18.46(0.96,354.3
1.02(0.34,3.07)
Not Estimable
5.23(1.12,24.38
Years 1980-1989 1690 2.36(1.65,3.37)Casey JR and Pichichero ME, ICAAC 2003
Cephs vs Pen Clinical Cure in GABHS Tonsillopharyngitis
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Cephs vs Pen Clinical Cure in GABHS Tonsillopharyngitis
Favors Pen Favors Cephs N OR (95% CI
4.40(0.89,21.8
0.63(0.21,1.9
2.78(1.21,6.3
Not Estimabl0.36(0.12,1.0
9.64(1.16,80.4
1.81(0.93,3.5
2.67(1.42,5.0
2.77(1.17,6.5
3.00(1.21,7.42.36(0.81,6.9
3.02(1.56,5.8
4.06(1.73,9.5
2.43(0.20,29.6
1.31(0.68,2.5
4.98(2.59,9.5Years 1990-1999 4294 2.30(1.62,3.2
Overall 6448 2.34(1.84,2.9
Casey JR and Pichichero ME, ICAAC 2003
Sensitivity Analysis of Bacterial Cure Rate
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Sensitivity Analysis of Bacterial Cure Rate
No. of No. of Odds Ratio
Trials Participants (95% CI)
All trials 35 7125 3.02 (2.49-3.6Double blinded studies 6 1432 2.31 (1.39-3.8
Quality score > 2 11 2673 2.50 (1.85-3.3
Clinical status defined 9 2080 2.12 (1.54-2.9
Compliance monitoring 26 4906 2.85 (2.33-3.4detailed
GABHS typing performed 24 5395 3.10 (2.42-3.9
Carriers eliminated 7 1716 2.51 (1.55-4.0
Follow up test of cure 9 2398 3.53 (2.75-4.53 - 14 days after therapy
Casey JR and Pichichero ME, ICAAC, 2003
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Shortened Course Antibiotics
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Shortened Course Antibiotics
in Acute Otitis Media
Summary
Pichichero ME, Cohen R. Pediatr Infect Dis J 1997;16:680-695
27 clinical trials
• 6932 patients; 3766 shortened
therapy
• No difference in outcome, EXCEPT
recurrent, persistent AOM, maybe
Private Practice Study of 2172 Patients
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0
20
40
60
80
100
All Ages <= 2 years > 2 years
% C u r e d + I m
p r o v e d
5-Day 7-Day 10-Day
Private Practice Study of 2172 Patients
5-, 7- and 10-Day Treatment of AOM
According to Age
Pichichero et al.Otolaryngol Head Neck Surgery 2001:124:381-387
Private Practice Study of 2172 Patients
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0
25
50
75
100
No episodes within 1month of enrollment
1 or more episodeswithin 1 month of
enrollment
% C u r e d +
I m p r o v e d
5-Day 7-Day 10-Day
According to Prior Episodes
Pichichero et al.Otolaryngol Head Neck Surgery 2001:124:381-387
Private Practice Study of 2172 Patients
5-, 7- and 10-Day Treatment of AOM
P<0.001
5 day Cefprozil Versus 10 day Penicillin V Treatment fo
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5-day Cefprozil Versus 10-day Penicillin V Treatment fo
Pediatric Group A Streptococcal Tonsillopharyngitis
Clinical Bacterial Efficacy
Regimen V2 V3 V2 V3
Cefprozil 99/106 (93%) 91/100 (91%) 87/106 (82%) 72/90 (80%)
Penicillin V 105/114 (92%) 89/102 (87%) 85/112 (76%) 73/102 (72%)
G. A. Syrogiannopoulos, et al. ICAAC 2003
Failure to Eradicate Group A Beta-hemolytic
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p y
Streptococcus from the Pharynx of Patients
Suffering from Tonsillitis/pharyngitis
Kafetzis et al. IJAA 2003
Antibiotic No. of Failed to Relapsed Total
Patients Eradicate
Pen-V X10 d 91 13% 13% 26%
Clarithromycin X10 d 86 15% 12% 27%
Cefprozil X 5 d 88 2% 6% 8%
C l i A P ti Q ti
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What do the patientsdo with leftover
antibiotic?
Conclusion: A Pragmatic Question
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HOST
BUG
DRUG
Factors Influencing Clinical Outcome