Antibioterapie Model Poole

7/27/2019 Antibioterapie Model Poole

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Michael D. Poole, MD, PhD


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Study design: What to payattention to

Pharmacodynamic/pharmacokinetic properties

Bacterial elimination studies (requires a culture

during or at end of therapy). Clinical studies can be (and commonly are)

manipulated to suggest bacteriologic efficacy whenit may not be there.


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What about all the papers

and studies that suggestsomething different thanguideline recommendations?

There are different ways to performsinusitis trials

Clinical diagnosis, clinical endpointBacteriologic diagnosis, clinical endpoint

Bacteriologic diagnosis, bacteriologic endpoint


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Sample Sizes in SinusitisComparing Antibiotic A with 90% killing rate with

Antibiotic B with a killing rate of

:*

Clinical Diagnosis

Clinical endpointBacteriologic

diagnosis,

Clinical endpoint

Bacteriologicdiagnosis,

Bacteriologic

endpoint50% 1,900 543 14660% 3,256 912 22970% 7,039 1925 43880% 26,958 7142 1403

Poole, MD, et al.

Abstr Amer Acad OtolaryngolAnn Meeting, 2002

*Based on an alpha = 0.05; beta 0.1; Non-bacterial,

non-resolving = 10%, non-bacterial, resolving (viral) = 40%,Spontaneous resolution of all bacterial cases = 50%


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Minimum Inhibitory Concentration

(MIC)

64 32 16 8 4 2 1 0.5 0.25 Control(no antibiotic)

MIC


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Penicillin-resistant S. pneumoniaeDefined

NCCLS document M100-S12. 2002.

penicillin-susceptible = MIC 2 g/mL

Penicillin-resistant S. pneumoniaeisdefined as penicillin MIC of >2 g/mL


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20% R1219.9% R>1

11.9% R1% R

15.7%

15.1%

17.7%

12.6%9.6%

19.1%

18.5%

22.8% 22.5%

Regional S. pneumoniae Penicillin Resistance:TRUST 7 (2002-2003) Respiratory Season

Penicillin resistance defined as an MIC of 2 mg/ml

Data on file, Ortho-McNeil Pharmaceutical, Inc. In vitro activity does not necessarily correlate with clinical results.

National PenicillinResistance Rate = 17.3%


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25.6%

25.2%

15.2%

32.5%

40.6% 31.7%

25.2%17.6%

31.9%

20% R1219.9% R>1

11.9% R1% R

Regional S. pneumoniae Azithromycin Resistance:TRUST 7 (2002-2003) Respiratory Season

Azithromycin resistance defined as an MIC of 2 mg/ml

Data on file, Ortho-McNeil Pharmaceutical, Inc. In vitro activity does not necessarily correlate with clinical results.

National AzithromycinResistance Rate = 27.5%


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S. pneum on iaeAntibiogram: Sinus IsolatesTRUST 6 & 7 (2002-2003), N = 390

MIC90 MIC90Antimicrobial (mg/mL) Interp Cata % S % I % RLevofloxacin 1 S 99.2 0.0 0.8

Amox/clav 8 R 86.2 3.3 10.5

Cefuroxime 8 R 59.2 4.6 36.2

Erythromycin 16 R 58.7 0.0 41.3

Azithromycin >32 R 58.7 0.3 41.0

TMP-SMX >4 R 55.9 9.5 34.6

Penicillin 4 R 51.5 18.2 30.3

a: Interpretive category result of S, I, R based on MIC90 value (mg/ml).

Sahm et al. ICAAC2003, abstr C2-924. Data on file, Ortho-McNeil Pharmaceutical,

Inc.

In vitro activity does not necessarily correlate with clinical results.


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3.1 2.9 2.7 2.1 2.8

169.7

8.2 7.4

12.7 15.3 14 12.2 10.7

1

0.8

3.2 6.82.5

6.37.3

14.5 19.7

12.34.8

1.64.1

9.9

10.1

11.3

7.7

10.4

11.2

0

5

10

15

20

2530

35

40

45

50

1985

1986

1987

1988-1989

1990-1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

Intermediate (MICs 0.12 to 1.0 g/mL)

Resistant (MICs 4.0 g/mL)Resistant (MICs = 2.0 g/mL)

Doern GV.Am J Med. 1995;99(suppl 6B):S3S7.

Jacobs MR, et al.Antimicrob Agents Chemother. 1999;43:19011908.

Jacobs MR, et al.ICAAC1999. Abstract C-61.Alexander Project 1999-2000. GlaxoSmithKline, data on file.

No

nsusceptibleis

olates(%)

Penicillin-nonsusceptibleS. pneumoniae:

U.S. Surveillance1985-2000


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0

5

10

15

20

1992 1993 1994 1995 1996 1997 1998 1999 2000

MIC 2 g/mL

MIC 4 g/mL

MIC 8 g/mL

MIC 16 g/mL

Distribution of Penicillin MICs inS. pneumoniaeIs Changing:

U.S. 1992-2000

Data on file. Alexander Project. GlaxoSmithKline.

Year

P

ercentageofstrains


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Amoxicillin in Middle Ear Fluid

Current NCCLS

amoxicillinbreakpoint for

S. pneumoniae

Adapted from Seikel K, et al.Pediatr Infect Dis J. 1997;16:710

711;Adapted from Harrison CJ, et al.Pediatr Infect Dis J. 1998;17:657658.

Time (h)

C

oncentration(g/m

L)

8

7

6

5

4

3

21

0

35 mg/kg (Seikel)45 mg/kg (Seikel)

0 1 2 3

30 mg/kg (Harrison)13 mg/kg (Harrison)


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0

10

20

30

40

50

60

MIC (g/mL)0.0

15

0.0

3

0.0

6

0.1

2

0.2

50.5 1 2 4 8 1

6

>16

%o

fstrains

Amoxicillin/Clavulanate

Data on file. Alexander Project 2000..

M. catarrhalis

S. pneumoniae

H. infl uenzae

Shaded floor represents PK/PD breakpoint


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There is no rational reason to use low/regular

doses of amoxicillin (or amox-clavulanate):Pediatrics 80-100 mg/kg, Adults 3-4 g/daily,divided BID

Higher doses (of either) will markedly reduce H.influenzaefailures) (15-25%) and some S.pneumoniaefailures (~5%). Hemophilusfailuresare related to the less than optimal intrinsic activity

of amoxicillin against beta-lactamase negative H.influenzae.

Hemophilus influenzaeis the most common failure

cause for amoxicillin-clavulanate.


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Data from A lexander Proj ect 1999-2000, analyzed by Mic hael Jacob s

100 10094

98 100

77 83

Amox

(HD)

Ceftria

x

cefdinir

(QD)

Cefdinir

(BID)

Cefprozil

Cefuroxime

cefa

clor

Pen -Sn = 4,254

Proportion of Susceptible Pnc Isolates that areSusceptible to High Dose Amox, Ceftriaxone and Oral

Cephalosporins, (by Pk/Pd Breakpoints)

100 99

25

59

73

77

22

Amox

(HD)

Ceftria

x

cefdinir

(QD)

Cefdinir

(BID)

Cefprozil

Cefuroxime

cefa

clor

Pen -In = 905

87

78

0 0 0 0 0

Amox

(HD)

Ceftria

x

cefdinir

(QD)

Cefdinir

(BID)

Cefprozil

Cefuroxime

cefa

clor

Pen -Rn = 1,250

n = 6,409


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There is no defensible role for cefprozil, loracarbef, and

cefaclor in ear and sinus infection.

NO oral cephalosporin has clinical activity against penicillinresistant S. pneumoniae.

Cefpodoxime (Vantin) is the most active of the oralcephalosporins, especially for amoxicillin or amox-clavulanate failures.

Cefdinir (Omnicef) is the best choice for 1st line therapy ofchildren, but is likely less effective than high-doseamoxicillin.

Ceftriaxone (Rocephin), given at usual IV/doses for 3-7days, is highly effective for the usual pathogens, includingmost ceftriaxone and penicillin resistantS. pneumoniae.


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0

10

20

30

40

50

60

70

80

90

100

Pen-S Pen-I Pen-R

Erythromycin-resistant Clindamycin-resistant TMP/SMX-resistant

Penicillin-nonsusceptibleS. pneumoniaeis Frequently Cross-

resistant to Other Classes of Antibiotic*

Resistantisolate

s(%)

(n=2,756) (n=848) (n=589)

Hoban DJ, et al. Clin Inf Dis. 2000:32(suppl 2):S81-S93.

Pen-S, MIC 0.06 g/mL; Pen-I, MIC 0.12-1 g/mL; Pen-R, MIC 2 g/mL

* NCCLS breakpoints used


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Distribution of macrolide MICs amongH. in fluenzae(Alexander study 1997-2000)

97% baseline

1% hyper-

susceptible

2% hyper-

resistant

Macrolide Susceptibility ofH. influenzae


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Resistance Mechanisms

Strains Efflux RibosomalMutation

Hypersusceptible (-) (-)Baseline (+) (-)High level resistant (+) (+)

Conclusion: Macrolide and KetolideResistance in H. influenzae

Peric, Applebaum, et al. 2003


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Telithromycin

0

10

20

30

40

50

6070

80

%o

fstrains

MIC (g/mL)

0

0.008

0.015

0.0 3

0.0 6

0.1 2

0.2 5

0.5 1 2 4 >

4

M. catarrhal is

S. pneumoniae

H. influenzae

Adapted from:Nagai K, et al.Antimicrob Agents Chemother. 2002;46:371377.Pankuch GA, et al.Antimicrob Agents Chemother. 1998;42:30323034.

Shaded floor represents PK/PD breakpointGreen represents susceptible range


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Telithromycin (Ketek)

Technically, a ketolide, derived from clarithromycin

Has an additional binding ribosomal binding site onthe molecule, so it appears to be active against

most of the macrolide-resistant pneumococci.

Similar to the macrolides, the MICs to Hemophilusare high enough that the efficacy is poor to fair.

Some concerns about drug-drug interactions.

If all of the above are true, it is somewhat lesseffective than amoxicillin.


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Macrolides and Ketolides have activity against H.influenzaethat is equal to or near that of placebo(ear and sinus disease) Macrolide resistant S.pneumoniaeare common.

They are significantly less effective than high doseamoxicillin for previously untreated patients;markedly less effective than quinolones and amox-

clavulanate for second line therapy. Telithromycin (Ketek) has somewhat better activity

than macrolides against S. pneumoniae.


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R i l L fl i


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1.0%

1.0%

0.9%

0.9%

0.9% 0.7%

0.9%1.7%

0.7%

20% R1219.9% R>111.9% R1% R

Regional S. pneumon iaeLevofloxacinResistance:

TRUST 7 (2002-2003) Respiratory Season

Levofloxacin resistance defined as an MIC of 8 mg/mLData on file, Ortho-McNeil Pharmaceutical, Inc. In vitro activity does not necessarily correlate with clinical results.

National LevofloxacinResistance Rate = 0.96%


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Similar Susceptibilities of Newer FluoroquinolonesAgainst S. pneumon iae

Antimicrobial %S %I %R

Canadian Bact Surv Netwk, Low, et al AAC 2002;46:1295-1301

Levofloxacin 99.0 0.1 0.9

Gatifloxacin 99.1 0.1 0.8Moxifloxacin 99.1 0.5 0.4

TRUST 7, USA (2002-2003), Data on file, Ortho-McNeil Pharmaceutical, Inc.

Levofloxacin 99.0 0.0 1.0

Gatifloxacin 99.1 0.1 0.8

Moxifloxacin 99.1 0.5 0.4

Low et al (2000 data): N= 2,245; TRUST 7 (2002-2003): N = 4, 377


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Levafloxacin (Levaquin), 750 mg

Significantly improves an already very good PK/PDprofile.

Has been tested in the setting of a 5 day course inpneumonia and sinusitis.

Will likely supplant 500 mg qd dosing.


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Implications of AntimicrobialPotency on Resistanced

Bigger is better!

Dead bugs

dont

become

RESISTANT!


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Levofloxacin (Levaquin), gatifloxacin (Tequin), and

moxifloxacin (Avelox) are very active agents forrespiratory tract infections.

They are roughly equal (within 1-2%) in clinical

efficacy. There are some differences in adverse effects and

safety profiles.

Safety and resistance issues make them, ingeneral, appropriate for second line therapy.

We will see more short course trials of sinusitiswith good microbiologic outcome.

A i i bi l f Rhi i i i


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Antimicrobials for Rhinosinusitis

Respiratory Quinolones (92%)

HD Amoxicillin/clavulanate (91%)

Amoxicillin/clavulanate (87%)

HD Amoxicillin (83%)

Cefpodoxime proxetil (81%)Cefixime (80%)

Cefuroxime axetil (80%)

Cefdinir (78%)

TMP/SMX (77%)

Cefprozil (70%)

Macrolides (68%)

Placebo (60%)

More effective,

More antibiotic use

Less effective,

Less antibiotic use

Sinus and Allergy Health Partnership.Otolaryng ol Head Neck Surg) 2004

/ d d


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2004 AAP/AAFP RecommendedAntibacterial Agents for Initial

Treatment for AOM

Antibacterial

agents in past

month if age < 2

years or daycare

At diagnosis Clinically defined treatment failure at

48-72 hours after treatment

Recommended Recommended

No High-dose

amoxicillin

High-dose

amoxicillin/

clavulanate

or cefdinir;

or cefpodoxime;

or cefuroxime;

or ceftriaxone

Yes High-dose

amoxicillin or

amoxicillin/

clavulanate

High-dose

amoxicillin/

clavulanate

or cefdinir;

or cefpodoxime;

or cefuroxime;

or ceftriaxone

Ob ti O ti A tibi ti


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Observation Option vs. AntibioticTherapy

Age Certain Diagnosis Uncertain Diagnosis

< 6 months Antibacterial therapy Antibacterial therapy

6 months-2 yrs Antibacterial therapy Antibacterial therapyif severe illness

Observe if non-severe

2 years Antibacterial therapyif severe illness

Observe if non-severe

Observe

Proportion of AOM Episodes Culture Positive for


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Kilpi T. Pediatr Infect Dis J. 2001;20:654-662.

0

5

10

15

20

25

30

35

40

1 2 3 4 5 >5

H. influenzae

S. pneumoniae

Culturepo

sitive(%)

Episodes of AOM

Proportion of AOM Episodes Culture-Positive forH. influenzaeor S. pneumoniae

(Finland, 1994-1997)

N = 203 144 98 71 34 35


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AOM is currently the best bacterial respiratory

infection to study.

Conjugated pneumococcal vaccines have changedAOM somewhat.

Only a few drugs are very efficacious for AOM:high dose Amox-clav, ceftriaxone

H. influenzaeis now our most important AOM

pathogenespecially for ENT patients.Most antibiotic failures are not failures.

We have been mis-informed about antibiotic

effectiveness in AOM.


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S-Pnc

Non-S-Pnc

Hi

Hi BL+placebo

*For amoxicillin only

84%

52%

%p

ersistence *

Bacter io logic

Failure Rates on

Day 4-6 inAOM: Double Tap

Studies

Dagan,personal communication


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Reasons why primary careclinicians think antibiotics fail

when they do not.

Misinterpret intercurrent infections as

failuresOME after AOM is characterized as a failure

Cases of OME are diagnosed as AOM and arecalled failures.

Cli i l R f AOM Withi


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Leibovitz E, et al. Pediatr Infect Dis J. 2003;22:209-216.

Relapses vs. new infections determined forS. pneumon iaeby

PFGE and serotyping, and forHaemop hi lus inf luenzaeby PFGE

and -lactamase production

0

20

40

6080

100

C

linicalrelapse

(%)

n= 39 n = 38 n = 21 n = 10

Bacteriologic relapsesNew infections

Days 1-7 Days 8-14 Days 15-21 Days 22-28

Clinical Recurrences of AOM Within28 d After EOT

EOT = end of therapy.


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when they do not.





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when they do not.





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Pediatric Chronic Sinusitis

2.5 year old boy with an 18 month history ofchronic sinusitis. Major symptoms includecongestion, rhinorrhea, poor sleeping, relapsingcough. No history of systemic or lower respiratoryinfections. 4-5 bouts of AOM, resolving onantibiotics.

On antibiotics almost monthly. Has had culturesthat grew DRSP and H. influenzae at various times.

Tested neg. for CF. Attends a small (7-10 kids)daycare.


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Pediatric Chronic Sinusitis, cont

Family sought allergy referral: Had skin testing:negative. Had PneumoVax and antibody responsetest that showed varying levels to differentserotypes.

Has had two prior CTs, one last month. Oneshowed pan-sinusitis (taken while sick), othershowed scattered ethmoid and maxillary mucosal

thickening. Exam: Normal general exam. TMs retracted

without fluid. Nose: moderate mocupurulentsecretions. No polyps. Oropharynx normal.

2004


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2004For Problematic Pediatric Sinusitis or AOM

Augmentin ES600 (90 mg/kg/d, BID)

For Augmentin failures. Cefpodoxime (Vantin).Then culture.

Clindamycin + ceftibuten (Cedax) or TMP-SMX orcefixime (Suprax)

High dose Amoxicillin + ceftibuten (Cedax) or TMP-SMX

Ceftriaxone + .(observation, high dose amoxicillin,more ceftriaxone)

For allergic/intolerant : macrolides (mild cases).Consider rifampin (20 mg/kg/d) plus clindamycin orTMP-SMX for severe AOM.


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The Psycho-neuroses ofChronic Pediatric Sinusitis

The child is usually no different than many otherchildren who have same clinical/radiographicfindings without the level of anxiety.

The family has generally been misinformed andmisled about a number of issues.

Re-education is time consuming.

Areas of Dis-informaton


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Areas of Dis informaton

He/she has the same infection back again.

Wrong. Symptoms and presentation may be the same

The sinuses are blocked up.

A simplistic pro-surgical explanation that is generally

wrong.Nothing works for him/her.

Wrong

The CT abnormalities prove how serious it is.Wrong

It is all due to his/her allergies.

Wrong

Managing the child (and family) with


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Managing the child (and family) withchronic sinusitis

Manage each episode individually (Do not use thesame shotgun poly-pharmacy for every episode.)

Prospectively, the number of infections in going tobe exaggerated over historical counts.

Have someone in the office with the time andpatience to talk the family down when the childbecomes ill not over-reacting.

Dont lower your antibiotic prescribing thresholdbecause of the past history.

Obtain cultures when therapy may not be working...

Patience


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Causes & Treatment Strategies for


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Causes & Treatment Strategies forChronic Rhinosinusitis

Adapted from Benninger, et al. Otolaryngol Head Neck Surg , 2003;129:S1-32.

CRS

Bacteria

Super-antigenOsteitis Allergy

Fungi

TreatEtiology-Antibiotics-Antifungals-MechanicaldebridementAttenuateInflammation-Steroids-Anti-IL-5-IL-4R-Anti-IgE-Immunotherapy-Anti-leukotrienes-Macrolides

IL-5, IL-4IL-8, IF-gGM-CSF

Bio-films

P i O i i


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Post-operative OpportunisticBacterial Maxillary Sinusitis

What causes it?

What sinuses are involved?

Why is this something different than whatthey originally had?

Treatment?


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Rising Incidence of CA-MRSA


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Rising Incidence of CA-MRSA(Community Acquired Methicillin Resistant

Staph aureus)

Rapid increase in community acquired strains MOREVirulent. More transmissable.

Can be resistant to macrolides, clindamycin, quinolones,

sulfasalmost everything but vanco and rifampinWarningIf the strain tests resistant to erythromycin

(even if tested Suscept to clinda), resistance to clindamay be inducibleemerges during therapy

Most can be treated with drainage,TMP-SMX + rifampin,

Many are susceptible to clindamycin.

All are susceptible to Vancomycin


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Although the risk is small, aminoglycosides should

not be used with non-intact TMs or used withappropriate consent.

From a microbiologic standpoint, there is no

significant clinical difference between ciprofloxacinand ofloxacin.

The presence of a potent steroid (dexamethasone)appears to have significant positive impact of

treatment of infections. Effect in surgery patientsis unknown.

A neutral pH drop (ofloxacin otic) may predispose

to yeast overgrowth.

Draining Ears: Resistant bugs


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Draining Ears: Resistant bugs,Pseudomonas,

MRSA or Enterococcus

May have failed IVvancomycin!

Rx: Topical agents

Otic quinolones

Aminoglycosides

Forget susceptibilitytest results

Sudden Cardiac Death and Erythromycin


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Sudden Cardiac Death and Erythromycin Looked at a cohort of Tennessee Medicaid patients:

1.2 million patient years, and 1476 cases of sudden

cardiac death

Patients on erythromycin had a 2 x rate of death.

Patients on erthromycin PLUS an strong inhibitor of

cytochrome P-450 had a 5.35 increase in rate. Nitro-imidazole antifungal agents, diltiazem, verapamil,

and troleandomycin

Presumptive mechanism of increased risk inprolongation of Q-T interval and subsequentarrythmias.

No increase with amoxicillin or prior erythromycin

Ray, WA et al. NEJM. 2004; 351 1089


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Probable Implications

Large drug usage database analysis, whencombined with outcome data is a very potent new

tool.

This is probably the tip of the iceberg concerningcombinations of drugs that alter Q-T interval or arecompetitively metabolized.

With regard to antimicrobials, will likely increaseconcerns about erythromycin, clarithromycin, ?telithromycin, and the flouroquinolones (esp.moxifloxacin)

Antibioterapie Model Poole

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