7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 1/29

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 

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 2/29

Factors That Influence Clinical Outcome

Proper Diagnosis

PK/PD Properties

Treatment

Choice

Clinical Outcome/Effectiveness

Otitis Media Sinusitis Tonsillopharyngitis

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 3/29

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 

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 4/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 5/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 6/29

% 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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 7/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 8/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 9/29

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?

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 10/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 11/29

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 

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 12/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 13/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 14/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 15/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 16/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 17/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 18/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 19/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 20/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 21/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 22/29

Shortened Course Antibiotics

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 23/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 24/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 25/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 26/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 27/29

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

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 28/29

What do the patientsdo with leftover 

antibiotic?

Conclusion: A Pragmatic Question

7/27/2019 Otite Si Sin

http://slidepdf.com/reader/full/otite-si-sin 29/29

HOST

BUG

DRUG

Factors Influencing Clinical Outcome