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Application of Pharmacokinetic and Pharmacodynamic Principles to Otitis Media and other Respiratory Tract Infections. Michael R. Jacobs, MD, PhD Professor of Pathology and Medicine Case Western Reserve University Director of Clinical Microbiology University Hospitals of Cleveland

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slide1

Application of Pharmacokinetic and Pharmacodynamic Principles to Otitis Media and other Respiratory Tract Infections

Michael R. Jacobs, MD, PhD

Professor of Pathology and Medicine

Case Western Reserve University

Director of Clinical Microbiology

University Hospitals of Cleveland

Cleveland, OH

limitations of outpatient clinical studies in respiratory tract infections
Limitations of outpatient clinical studies in respiratory tract infections
  • High-rate spontaneous resolution makes it difficult to show differences between agents
  • Bacteriologic outcome studies are not often performed due to necessity for invasive procedure (ear, sinus or lung tap) to obtain specimen
  • Most studies are therefore designed to show equivalent clinical outcome between established and new agents
  • Inadequacies of agents studied are therefore often not apparent

Jacobs. Clin Microbiol Infect 2001;7:589–96

1977 fda guidance on aom
1977 FDA Guidance on AOM

“In the absence of culture of middle ear fluid, no specific claim can be made regarding the effectiveness of any anti-infective drug”

objectives
Objectives
  • Define pharmacokinetics and pharmacodynamics
  • Correlate serum pharmacokinetic parameters for various drug classes with outcome of infection in outpatient respiratory tract infections
  • Show examples of these correlations in animal models and in humans
  • Apply these principles to treatment of otitis media and other respiratory tract infections
slide5
Impact of limited clinical data and increasing pathogen resistance on choice of antibacterial therapy
  • There is a need for:
    • accurate prediction of efficacy
    • newer dosage regimens
    • newer antibacterials
    • revised susceptibility breakpoints
    • statistically valid clinical studies

Jacobs. Clin Microbiol Infect 2001;7:589–96

evaluating antibacterial efficacy using pharmacokinetics and pharmacodynamics
Evaluating antibacterial efficacy using pharmacokinetics and pharmacodynamics
  • Pharmacokinetics (PK)
    • serum concentration profile
    • penetration to site of infection
  • Pharmacodynamics (PD)
    • susceptibility – MIC (potency)
    • concentration- vs. time-dependent killing
    • persistent (post-antibiotic) effects (PAE)

Jacobs. Clin Microbiol Infect 2001;7:589–96

slide7

Pharmacokinetics

Oral ingestion

Extracellular

compartment

of tissues

Blood

Renal

excretion

GI Absorption

drug pharmacokinetics in blood

10

8

Serum Antibiotic Concentration

6

(mcg/mL)

4

2

0

9

11

0

1

2

3

4

5

6

7

8

12

10

Dose

Dose

Time (hours)

Drug Pharmacokinetics in blood
pharmacokinetic parameters

Concentration present for 50% of dosing interval (6 h if given q12h)

10

Area under curve

8

Serum Antibiotic Concentration

6

(mcg/mL)

4

2

0

9

11

0

1

2

3

4

5

6

7

8

12

10

Dose

Dose

Peak serum conc.

Time (hours)

Pharmacokinetic Parameters
patterns of antibacterial activity
Patterns of antibacterial activity

Pattern Pharmacodynamic correlate

Time-dependent killing Time above MIC

and minimal to moderate (T>MIC)

persistent effects

Time-dependent killing AUC/MIC ratio

and prolonged persistent

effects

Concentration-dependent AUC/MIC ratio

killing and prolonged or

persistent effects Peak/MIC ratio

Jacobs. Clin Microbiol Infect 2001;7:589–96

time above mic lactams
Time Above MIC: -Lactams
  • T>MIC (% of dosing interval) required for the static dose against most organisms in neutropenic mice vary from 25-35% for penicillins and from 30-45% for cephalosporins
  • The presence of neutrophils reduces the T>MIC required for efficacy by 5-10%
  • Free drug levels of penicillins and cephalosporins need to exceed the MIC for 35-50% of the dosing interval to produce maximum survival
slide12
Relationship between Time above MIC and efficacy in animal infection models infected with S. pneumoniae

100

Penicillins

Cephalosporins

80

60

Mortality after 4 days of therapy (%)

40

20

0

0

20

40

60

80

100

Time above MIC (%)

Craig. Diagn Microbiol Infect Dis 1996; 25:213–217

slide13

Area under the curve to MIC ratio

Peak to MIC ratio

24-hr AUC/MIC and Peak/MIC RatiosCorrelation of serum pharmacokinetics with MIC (susceptibility) of an organism

Antibiotic concentration

MIC

Time

24-hr AUC/MIC is correlated with outcome of infection, the magnitude required for success and MIC at which this occurs becomes the PD breakpoint

slide14
Relationship between 24 Hr AUC/MIC and mortality for fluoroquinolones against S. pneumoniae in immunocompetent animals

100

80

60

Mortality (%)

40

20

0

100

1

2.5

5

10

25

50

24-hr AUC/MIC

s pneumoniae and h influenzae pneumonia in rats ed 50 based on 3 log 10 reduction in cfu lung
S. pneumoniae and H.influenzae pneumonia in rats:ED50 based on  3 log10 reduction in cfu/lung

At dosing comparable to dosing in humans:

  • Azithromycin and clarithromycin were able to reduce inoculum by  3 log10 cfu/lung for macrolide susceptible S. pneumoniae
  • Azithromycin and clarithromycin were NOT able to reduce inoculum by  3 log10 cfu/lung for H influenzae or for macrolide non-susceptible S. pneumoniae (erm and mef mechanisms)

Mitten M. et al. Antimicrob Agents Chemother 2001; 45: 2585–2593.

slide16

Microbiologic outcome of middle ear fluid in experimental acute otitis media in chinchillas due to non-typeable Haemophilus influenzae (NTHI)

“After administration of azithromycin at 30 mg/kg as single dailydoses in our chinchilla model of EOM due to NTHI, we were ableto achieve levels in serum and AUCs approximately twice thoseobserved in children treated with 10 mg/kg or with 10, 5, 5,5, and 5 mg/kg as single daily doses and concentrationsin MEF comparable to those reported for children with AOM. Ourobservations provide evidence that current doses of azithromycinadministered to children are likely to have a modest antibacterialeffect on AOM due to NTHI, characterized by a reduction in densityof infection. Maximizing the dosing of azithromycin in childrenhas the potential to improve the microbiologic outcome.”

Franz E. Babl, Stephen I. Pelton, and Zhong Li. Experimental Acute Otitis Media Due to Nontypeable Haemophilus influenzae: Comparison of High and Low Azithromycin Doses with Placebo. Antimicrobial Agents and Chemotherapy, 2002, 46:2194-2199

relationship between time above mic and bacterial eradication with lactams in otitis media

100

80

60

Bacterial eradication (%)

40

PSSP

PISP-PRSP

20

H. influenzae

0

0

20

40

60

80

100

Time above MIC (% of dosing interval)

Relationship between Time above MIC and bacterial eradication with -lactams in otitis media

Craig & Andes, Pediatr Infect Dis J, 1996

Dagan et al studies

relationship between time above mic and bacterial eradication with lactams in maxillary sinusitis

100

80

60

Bacterial eradication (%)

40

PSSP

20

H. influenzae

0

0

20

40

60

80

100

Time above MIC (% of dosing interval)

Relationship between Time above MIC and bacterial eradication with -lactams in maxillary sinusitis

Craig & Andes, Pediatr Infect Dis J, 1996

Gwaltney & Scheld studies

slide19

Levofloxacin PK/PD correlations134 hospitalized patients with respiratory tract, skin or complicated urinary tract infections treated with 500 mg qd for 5–14 days

100

100

Clinical outcome

90

80

Success

70

60

Failure

50

No. of patients

40

23

30

20

4

3

3

1

10

0

AUC:MIC <25

AUC:MIC 25–100

AUC:MIC >100

Peak:MIC <3

Peak:MIC 3–12

Peak:MIC >12

Clinical

failure rate 43% 11.5% 1%

Jacobs. Clin Microbiol Infect 2001;7:589–96

[Adapted from Preston et al. JAMA 1998;279:125–9]

pharmacodynamic breakpoints g ml for oral agents used for rtis
PK/PD breakpoint

ALL ORGANISMS

Amoxicillin 2

Amox/clav 2

Cefuroxime axetil 1

Cefprozil 1

Cefixime 0.5

Cefaclor 0.5

Loracarbef 0.5

Azithromycin 0.12

Clarithromycin 0.25

Pharmacodynamic breakpoints (µg/ml) for oral agents used for RTIs
pharmacodynamic vs nccls breakpoints values in g ml
NCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Amoxicillin 2 4 2

Amox/clav 2 4 2

Cefuroxime axetil 1 4 1

Cefprozil 2 8 1

Cefixime – 1 0.5

Cefaclor 1 8 0.5

Loracarbef 2 8 0.5

Azithromycin 0.5 4 0.12

Clarithromycin 0.25 8 0.25

Pharmacodynamic vs. NCCLS breakpoints (values in µg/ml)

Based on M100-S11, National Committee for Clinical Laboratory Standards, 2001; Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32.

susceptibility of us isolates at pk pd breakpoints
Susceptibility of US Isolates at PK/PD breakpoints

Percentage of strains susceptible

Agent S. pneumoniae H. influenzae M. catarrhalis

Amox/clav 9097 100

Amoxicillin 90 61 14

Cefaclor 27 2 5

Cefixime 57 99 100

Cefpodoxime 63 99 64

Cefprozil 64 18 6

Cefuroxime 64 79 37

Cefdinir‡ 61 97 100

Azithromycin 67 0 100

Clindamycin* 89 NA NA

Doxycycline 76 20 96

Levofloxacin 99.8100 99

TMP/SMX* 57 75 9

Based on M100-S11, National Committee for Clinical Laboratory Standards, 2001; Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32. ‡Jacobs M. (unpublished)

amoxicillin clavulanate

PK/PD breakpoint based on current approved dosing regimens

Amoxicillin-clavulanate

Susceptible breakpointNCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Amoxicillin 2 4 2

Amox/clav 2 4 2

Alexander Project USA 2000

cefaclor

PK/PD breakpoint based on current approved dosing regimens

Cefaclor

Susceptible breakpointNCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Cefaclor 1 8 0.5

Alexander Project USA 2000

cefuroxime axetil

PK/PD breakpoint based on current approved dosing regimens

Cefuroxime axetil

Susceptible breakpointNCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Cefuroxime axetil 1 4 1

Alexander Project USA 2000

cefprozil

PK/PD breakpoint based on current approved dosing regimens

Cefprozil

Susceptible breakpointNCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Cefprozil 2 8 1

Alexander Project USA 2000

cefixime

PK/PD breakpoint based on current approved dosing regimens

Cefixime

Susceptible breakpointNCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Cefixime – 1 0.5

Alexander Project USA 2000

azithromycin

PK/PD breakpoint based on current approved dosing regimens

Azithromycin

Susceptible breakpointNCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Azithromycin 0.5 4 0.12

Alexander Project USA 2000

clarithromycin

PK/PD breakpoint based on current approved dosing regimens

Clarithromycin

Susceptible breakpointNCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Clarithromycin 0.25 8 0.25

Alexander Project USA 2000

clindamycin

PK/PD breakpoint based on current approved dosing regimens

Clindamycin

Susceptible breakpointNCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Clindamycin 0.25 NA 0.25

Alexander Project USA 2000

telithromycin

PK/PD breakpoint based on current investigational dosing regimens

Telithromycin

Susceptible breakpointNCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Telithromycin ? ? 0.5

Nagai AAC 2002, 46:371-7; Pankuch AAC 1998, 42:3032-34

doxycycline

PK/PD breakpoint based on current approved dosing regimens

Doxycycline

Susceptible breakpointNCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Doxycycline ? ? 0.25

Alexander Project USA 2000

ciprofloxacin

PK/PD breakpoint based on current approved dosing regimens

Ciprofloxacin

Susceptible breakpointNCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Clarithromycin NA 1 1

Alexander Project USA 2000

levofloxacin

PK/PD breakpoint based on current approved dosing regimens

Levofloxacin

Susceptible breakpointNCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Levofloxacin 2 2 2

Alexander Project USA 2000

trimethoprim sulfamethoxazole

PK/PD breakpoint based on current approved dosing regimens

Trimethoprim-sulfamethoxazole

Susceptible breakpointNCCLS PK/PD

S. pneumoniae H. influenzaeALL ORGANISMS

Trimeth-sulfa 0.5 0.5 0.5

Alexander Project USA 2000

conclusions antibacterial choice for empiric use in rti
Conclusions: antibacterial choice for empiric use in RTI
  • Most clinical studies do not show clinical differences between agents
  • PK/PD parameters correlate with bacteriological and clinical outcome in animal models and in humans
  • PK/PD parameters can be used to select agents with maximum potential for bacterial eradication
  • Currently available agents vary significantly in achieving PK/PD parameters necessary for bacterial eradication
1977 fda guidance on aom37
1977 FDA Guidance on AOM

“In the absence of culture of middle ear fluid, no specific claim can be made regarding the effectiveness of any anti-infective drug”

new fda guidance on aom
New FDA Guidance on AOM
  • Do we admit there is a problem?
  • What does it take to fix the problem?
  • Will we fix the problem?
  • When will this be achieved?