Post on 02-Apr-2018
7/27/2019 Poole_Antibiotics and Resistance in Otology
1/18
Michael D. Poo le, M.D., Ph.D.
7/27/2019 Poole_Antibiotics and Resistance in Otology
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
7/27/2019 Poole_Antibiotics and Resistance in Otology
3/18
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
7/27/2019 Poole_Antibiotics and Resistance in Otology
4/18
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
7/27/2019 Poole_Antibiotics and Resistance in Otology
5/18
How can we evaluate and estimate
relative antibiotic efficacy?
Clinical Trials?
Guidelines?
Modeling?
http://localhost/var/www/apps/conversion/Poole%20Therapeutic%20Outcome%20Model_Blank.xls7/27/2019 Poole_Antibiotics and Resistance in Otology
6/18
Issues in Resistance
7/27/2019 Poole_Antibiotics and Resistance in Otology
7/18
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
7/27/2019 Poole_Antibiotics and Resistance in Otology
8/18
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
7/27/2019 Poole_Antibiotics and Resistance in Otology
9/18
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?
7/27/2019 Poole_Antibiotics and Resistance in Otology
10/18
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.
7/27/2019 Poole_Antibiotics and Resistance in Otology
11/18
Cipro/Quinolone Resistance of Concern
Pseudomonas aeruginosa (4 50%)
E. coli(10 60%)
Staphylococci (5 75%)
Streptococcus pneumoniae (1 5%)
Hemophilus influenzae (1 5%)
7/27/2019 Poole_Antibiotics and Resistance in Otology
12/18
Resistance to Topical Cipro
(Breakpoint of 256mg/ml)
Pseudomonas aeruginosa (0%)
E. coli(1%)
Staphylococci (0%)
Streptococcus pneumoniae (0%)
Hemophilus influenzae (0%)
7/27/2019 Poole_Antibiotics and Resistance in Otology
13/18
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
7/27/2019 Poole_Antibiotics and Resistance in Otology
14/18
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.
7/27/2019 Poole_Antibiotics and Resistance in Otology
15/18
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)
7/27/2019 Poole_Antibiotics and Resistance in Otology
16/18
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)
7/27/2019 Poole_Antibiotics and Resistance in Otology
17/18
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)
7/27/2019 Poole_Antibiotics and Resistance in Otology
18/18
Slides are available at:
www. vlscience.com/Academy.htm
Therapeutic model at:
www.therapeuticmodel.com