Michael D. Poole, M.D., Ph.D.

Antimicrobial Effects: Whats involved?

Effect in Humans:
Serum concentration profile Penetration to site of infection

Effect in Bacteria:
Potency (MICs) Mechanism of killing

Pharmacokinetics (PK)

Pharmacodynamics (PD)

Clinical Effectiveness

Predictors of Bacterial Eradication: Pharmacokinetic/Pharmacodynamic Profiles

Time >MIC
(time-dependent activity)
MIC

AUC24 /MIC

(concentration-dependent activity)
MIC

40-50%

25-125

Penicillins Cephalosporins

Quinolones Aminoglycosides Macrolides

Optimal profile: Antibiotic level exceeds MIC for at least 40-50% of dosing interval

Optimal profile: AUC/MIC ratio at least: 25-30 (Strep., other gram-positive) 125 (gram-negative bacilli) Craig WA. Clin Infect Dis. 1998;26:1-12.

Susceptibility of Isolates at PK/PD Breakpoints

Agent

Percentage of Strains susceptible S. pneumoniae H. influenzae M. catarrhalis

95 95 27 57 63 64 64 67 89 76 99.8 57 97 61 2 99 99 18 79 0 NA 20 100 75 100 14 5 100 64 6 37 100 NA 96 99 9

Amox/clav Amoxicillin Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime Macrolides Clindamycin* Doxycycline Resp. Quinolones TMP/SMX*

*based on NCCLS breakpoints

Sinus and Allergy Health Partnership. Antimicrobial Treatment Guidelines for Acute Bacterial Rhinosinusitis Otolaryngol Head Neck Surg 2000;123(supp 1 part 2):S1S32

How can we evaluate and estimate relative antibiotic efficacy?

Clinical Trials? Guidelines? Modeling?

Issues in Resistance

Mechanism of Action of FQ

Fluoroquinolones bind with enzymes essential to DNA replication

DNA gyrase/ topoisomerase inhibitors

Examples include:

DNA

Ciprofloxacin Ribosomes Gatifloxacin Levofloxacin Moxifloxacin Ofloxacin Sparfloxacin Trovafloxacin Gemifloxacin Adapted from Neu HC. Science. 1992;257:1064-1072.

Cleveland Study: S. pneumoniae 1997-2003 N=688

100

90

Percent susceptible

80

70 Levofloxacin 60 Augmentin Augmentin2 50 Clindamycin Azithromycin 40 1997 1998 1999 2000 year 2001 2002 2003 Trimeth/sulfa

Jacobs, M. personal communication

How is resistance spread?

Spontaneous mutations Spread and Selection of resistant clones by antibiotic use Need to eradicate the carrier state of susceptible strains Issues
Where is the carrier state? How often is it carried? How much antibiotics are given? How efficient is the transmission of strains?

Nasopharyngeal Carriage: Gatifloxacin effects

100 90 80 70 60 50 40 30 20 10 0
Pre-Tx Post-Tx Eradication

Percentage

S. pneumoniae H. influenzae M. catarrhalis S. pyogenes

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

Cipro/Quinolone Resistance of Concern

Pseudomonas aeruginosa (4 50%) E. coli (10 60%) Staphylococci (5 75%) Streptococcus pneumoniae (1 5%) Hemophilus influenzae (1 5%)

Resistance to Topical Cipro (Breakpoint of 256 mg/ml)

Pseudomonas aeruginosa (0%) E. coli (1%) Staphylococci (0%) Streptococcus pneumoniae (0%) Hemophilus influenzae (0%)

Draining Ears: Regular bugs, Pseudomonas, MRSA or Enterococcus

May have failed IV vancomycin! Rx: Topical agents

Otic quinolones Aminoglycosides Combinations (with Polymyxin)

Ignore susceptibility tests

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.

Ciprofloxacin + Dexamethasone vs Ofloxacin in AOMT*: Microbiologic Eradication

100

% of Patients With Microbiologic Eradication

80.3%

80 60 40 20 0

66.4%

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

Ofloxacin 0.3% (n=217)

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

Ciprofloxacin + Dexamethasone vs Ciprofloxacin in AOMT*: Shorter Time to Cessation of Otorrhea

Median No. of Days to Cessation of Otorrhea
6 5 4

5
4

Days

3 2 1 0

Ciprofloxacin 0.3% + Dexamethasone 0.1% (n=87)

Ciprofloxacin 0.3% (n=80)

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

Ciprofloxacin + Dexamethasone vs Ofloxacin in AOMT*: Faster Clinical Response

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

100 80
% of Patients Cured

Ofloxacin 0.3% (n=217)

84.1 63.1 84.6 71.0

60 40 20 0 Day 1 Day 11 Day 18

30.9 18.0

* AOMT = acute otitis media with tympanostomy tubes . P < .05. Data on file; Alcon Laboratories, Inc.

Slides are available at:

www. vlscience.com/Academy.htm Therapeutic model at: www.therapeuticmodel.com