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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



Factors That Influence Clinical Outcome

Proper Diagnosis

PK/PD Properties

Treatment

Choice

Clinical Outcome/Effectiveness

Otitis Media Sinusitis Tonsillopharyngitis



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



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




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




% 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



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



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



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?



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



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



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



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



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



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



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




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






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



Cephs vs Pen Clinical Cure in GABHS Tonsillopharyngitis


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





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



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



Shortened Course Antibiotics



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



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


5-, 7- and 10-Day Treatment of AOM

According to Age

Pichichero et al.Otolaryngol Head Neck Surgery 2001:124:381-387




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


5-, 7- and 10-Day Treatment of AOM

P<0.001

5 day Cefprozil Versus 10 day Penicillin V Treatment fo



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



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



What do the patientsdo with leftover

antibiotic?

Conclusion: A Pragmatic Question



HOST

BUG

DRUG

Factors Influencing Clinical Outcome

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