poole_antibiotics and resistance in otology

7/27/2019 Poole_Antibiotics and Resistance in Otology

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Michael D. Poo le, M.D., Ph.D.


2/18

Antimicrobial Effects: Whats involved?

Pharmacokinetics

(PK)

Effect in Humans:

Serum concentration profile

Penetration to site of infection

Pharmacodynamics

(PD)

Effect in Bacteria:Potency (MICs)

Mechanism of killing

Clinical Effectiveness


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MIC

Quinolones

Aminoglycosides

Macrolides

Time >MIC(time-dependent activity)

MIC

AUC24/MIC(concentration-dependent activity)

Predictors of Bacterial Eradication:

Pharmacokinetic/Pharmacodynamic

Profiles

Craig WA. Clin Infect Dis. 1998;26:1-12.

25-125

Optimal profile:AUC/MIC ratio at least:

25-30 (Strep., other gram-positive)

125 (gram-negative bacilli)

40-50%

Optimal profile:Antibiotic level exceeds MIC for

at least 40-50% of dosing interval

Penicillins

Cephalosporins


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Susceptibility of Isolates at PK/PD Breakpoints

Percentage of Strains susceptible

Agent S. pn eumon iae H. infl uenzae M. catarrhalis

Amox/clav 95 97 100Amoxicillin 95 61 14

Cefaclor 27 2 5

Cefixime 57 99 100

Cefpodoxime 63 99 64Cefprozil 64 18 6

Cefuroxime 64 79 37

Macrolides 67 0 100

Clindamycin* 89 NA NA

Doxycycline 76 20 96

Resp. Quinolones 99.8 100 99

TMP/SMX* 57 75 9

*based on NCCLS breakpoints

Sinus and Allergy Health Partnership. Antimicrobial Treatment Guidelines for AcuteBacterial Rhinosinusitis Otolaryngol Head Neck Surg2000;123(supp 1 part 2):S1S32


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How can we evaluate and estimate

relative antibiotic efficacy?

Clinical Trials?

Guidelines?

Modeling?
http://localhost/var/www/apps/conversion/Poole%20Therapeutic%20Outcome%20Model_Blank.xls


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Issues in Resistance


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Mechanism of Action of FQ

Fluoroquinolonesbind with enzymesessential to DNAreplication

Examples include: Ciprofloxacin

Gatifloxacin

Levofloxacin

Moxifloxacin

Ofloxacin

Sparfloxacin

Trovafloxacin

Gemifloxacin

DNA

Ribosomes

Adapted fromNeu HC. Science. 1992;257:1064-1072.

DNA gyrase/topoisomeraseinhibitors


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40

50

60

70

80

90

100

1997 1998 1999 2000 2001 2002 2003

year

Percentsuscep

tible

Levofloxacin

Augmentin

Augmentin2

Clindamycin

Azithromycin

Trimeth/sulfa

Cleveland Study: S. pneumoniae 1997-2003

N=688

Jacobs, M. personal communication


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How is resistance spread?

Spontaneous mutations Spread and Selection of resistant clones by

antibiotic use

Need to eradicate the carrier state ofsusceptible strains

Issues

Where is the carrier state?

How often is it carried?

How much antibiotics are given?

How efficient is the transmission of strains?


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Nasopharyngeal Carriage: Gatifloxacin effects

0

1020

30

40

5060

70

80

90

100

Percentage

Pre-Tx Post-Tx Eradication

S. pneumoniaeH. influenzae

M. catarrhalis

S. pyogenes

Arguedas A, et al. Pediatr Infec t Dis J. 2003;22:949.


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Cipro/Quinolone Resistance of Concern

Pseudomonas aeruginosa (4 50%)

E. coli(10 60%)

Staphylococci (5 75%)

Streptococcus pneumoniae (1 5%)

Hemophilus influenzae (1 5%)


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Resistance to Topical Cipro

(Breakpoint of 256mg/ml)

Pseudomonas aeruginosa (0%)

E. coli(1%)

Staphylococci (0%)

Streptococcus pneumoniae (0%)

Hemophilus influenzae (0%)


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Draining Ears : Regu lar bugs ,

Pseudomonas,

MRSA orEnterococcus

May have failed IV

vancomycin! Rx: Topical agents

Otic quinolones

Aminoglycosides

Combinations

(with Polymyxin)

Ignore

susceptibility tests


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Some points need to be made

over and over

Laboratory definitions of antibiotic

susceptibility patterns are not pertinent to

topical therapy with most antibiotics. Topical quinolones remain uniformly active

against bacterial targets in AOMT, OE, and

CSOM.


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Ciprofloxacin + Dexamethasone vsOfloxacin in AOMT*: Microbiologic

Eradication

* AOMT = acute otitis media with tympanostomy tubes. P = .0012.Data on file; Alcon Laboratories, Inc.

0

20

40

60

80

100

Ciprofloxacin 0.3% +

Dexamethasone 0.1%

Ofloxacin 0.3%

80.3%

66.4%

%ofPatients

WithMicrobiologic

Eradication

(n=208)(n=217)


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Ciprofloxacin + Dexamethasone vsCiprofloxacin in AOMT*: Shorter Time

to Cessation of Otorrhea

* AOMT = acute otitis media with tympanostomy tubes. P .004.Data on file; Alcon Laboratories, Inc.

Median No. of Days to Cessation of Otorrhea

0

1

2

3

4

5

6

Ciprofloxacin 0.3% +

Dexamethasone 0.1%

Ciprofloxacin 0.3%

Days

4

5

(n=87)(n=80)


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Ciprofloxacin + Dexamethasone vsOfloxacin in AOMT*:

Faster Clinical Response

* AOMT = acute otitis media with tympanostomy tubes . P < .05.

Data on file; Alcon Laboratories, Inc.

0

20

40

60

80

100

Day 1 Day 11 Day 18

30.9

% of

Patients

Cured

84.1 84.6

18.0

63.171.0

Ciprofloxacin 0.3% + Dexamethasone 0.1% (n=208)

Ofloxacin 0.3% (n=217)


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Slides are available at:

www. vlscience.com/Academy.htm

Therapeutic model at:

www.therapeuticmodel.com

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