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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 1
CHSPSC, LLC Antimicrobial Stewardship Education Series
March 8, 2017Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1
Featured Speaker:
Larry Danziger, Pharm.D.Professor of Pharmacy and MedicineUniversity of Illinois at Chicago
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Submission of an online post‐test and evaluation is the only way to obtain CE credit for this webinar
Go to www.ProCE.com/CHSRx Webinar attendees will also receive an email with a direct link to the
web page Print your CE statement of completion online
– Credit for live or enduring (not both)
Deadline: April 7, 2017 CPE Monitor (applicable to pharmacists)
– CE credit automatically uploaded to NABP/CPE Monitor upon completion of post‐test and evaluation (user must complete the “claim credit” step)
Online Evaluation, Self-Assessmentand CE Credit
Attendance Code
Code will be provided at the end of today’s activity
Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 2
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 3
2016 Pharmacy Education Series
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It is the policy of ProCE, Inc. to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Dr. Danziger has disclosed the following financial/commercial relationships: Speaker for Allergan, MedCo, and Merck.
Please note: The opinions expressed in this activity should not be construed as those of the CME/CE provider. The information and views are those of the faculty through clinical practice and knowledge of the professional literature. Portions of this activity may include unlabeled indications. Use of drugs and devices outside of labeling should be considered experimental and participants are advised to consult prescribing information and professional literature.
March 8, 2017Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1
Featured Speaker:
Larry Danziger, Pharm.D.Professor of Pharmacy and MedicineUniversity of Illinois at Chicago
CE Activity Information & Accreditation
ProCE, Inc. (Pharmacist CE)
– 1.0 contact hour
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Funding:This activity is self‐funded through CHSPSC.
Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 4
Antimicrobial Pharmacokinetics / Pharmacodynamics: Optimizing Therapeutic Outcomes
March 8, 2017
Larry H. Danziger, Pharm.DProfessor of Pharmacy and MedicineUniversity of Illinois at Chicago
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ObjectivesUpon completion of this presentation, the participant should be able to:
• Describe the pharmacodynamic (PD) properties of antimicrobials
• Identify strategies to maximize the PD properties in selecting and dosing antimicrobials
• Describe the factors to consider to safely prescribe Gentamicin and Vancomycin, to be able to monitor levels logically and interpret them
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 5
DeSear: Previous Discussion
• Selecting an antimicrobial agent and dosing scheme is based on a complex set of considerations
– What is the best pharmacodynamic (PD) predictor of efficacy for the drug chosen?
• AUC/MIC
• T>MIC
• Cmax: MIC
– How does the MIC impact PD?
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Background
• The rational use of antibacterial drugs should be based upon two principles
• First, the specific identity of the infecting organism must be determined
• Second, a test must be devised which will provide an accurate estimate that the antibiotic will be effective in vivo
Petersdorf and Plorde Annu. Rev. Med. 14:41-56; 1963
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Background
Science has made tremendous progress over the last 30 years:
– Established critical values for outcome parameters that predict clinical & microbiologic success
– Identified PK parameters linked to a biologic measure of action, the MIC
– Devised tests to determine antibiotic performance characterized as concentration dependent or independent
– Established pharmacodynamic outcome parameters
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Background
• Minimum inhibitory concentration (MIC)
– The lowest concentration of drug that prevents visible bacterial growth after 24 hours of incubation in a specified growth medium
– Organism and antimicrobial specific
– Interpretation• Pharmacokinetics/Pharmacodynamics of the drug in humans
• Drug’s activity versus the organism
• Site of infection
• Drug resistance mechanisms
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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HOST
BUG
DRUG
Factors Influencing Clinical Outcome
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Site of infection
Infecting pathogen
Resistance of infecting pathogen
Host - Protein binding
Host - Immune system
Drug class
Dosing regimen (dose & duration)
Treatment endpoint
Factors Influencing Clinical Outcome
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Bug: How Do We Predict Antimicrobial Effect?
Parameter Definition Limitations
MIC(Minimum inhibitory
concentration)
Concentration at which a standard inoculum of 105
organisms are inhibited after 24-48 hours
• In vitro conditions differ from those at infection site
• Only reflects a specific time point
• In vitro drug concentrations remain constant
• Measured against standard inoculum
• Lacks information on:
- Rate of bactericidal activity
- Persistent effects
• In vitro tests may not adequately predict outcome
MBC(Minimum bactericidal
concentration)
Concentration at which a 99.9% reduction in the standard inoculum occurs
Levison ME. Infect Dis Clin North Am 2000;14:281-291. Craig WA. Clin Infect Dis 1998;26:1-12.
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• Site of Infection
• Site defines the most likely organisms
– Especially helpful in empiric antimicrobial selection
• Site also determines the dose and route of administration of antimicrobial
– Efficacy determined by adequate concentrations of antimicrobial at site of infection
– Serum concentrations vs tissue concentrations and relationship to MIC
Host and Drug Factors
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Optimizing Antimicrobial Therapy
[C] @Infection
Site
PathogenMIC
DRUGPharmacokinetics
Pharmacodynamic
Profile
BacteriaKilled
Host
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Basic Pharmacokinetic Model
Drug at Absorption
Site
Drug in Body
Excreted Drug
Metabolite in Body
Eliminated Metabolite
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Basic Pharmacodynamics Model
Dosage regimen
Concentration vs. time in serum
Concentration vs. time at site of
infection
Concentration vs. time in tissue and other body fluids
Pharmacologic or toxic effect
Antimicrobial effect versus time
Pharmacokinetics Pharmacodynamics
Craig WA. Clin Infect Dis 1998;26:1-12.
Absorption
Distribution
Elimination
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C Min = Trough
AUC
C Max = Peak
Time
Concentration
Pharmacokinetic Definitions
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 11
PK / PD DefinitionsAUC = area under the serum concentration curve, measurement of drug absorbed and persistence
AUC24/MIC ratio = AUC over 24 hours divided by the MIC, predicts efficacy of concentration-dependent antibiotics
Cmax = peak plasma level, highest concentration of drug in the blood
Cmax/MIC ratio = Peak/MIC ratio, predicts efficacy of concentration-dependent antibiotics
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PK / PD Definitions
Cmin = trough level
T>MIC = time above MIC, percentage of time over 24 hours that drug concentration exceeds the MIC
PAE = Post Antibiotic Effect, delayed regrowth of bacteria following exposure to an antibiotic
Varies according to drug-bug combination
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Efficacy and PK /PD Relationships
• 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
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Antimicrobial Pharmacodynamics
• Correlates the drug concentration and the clinical effect (ie, bacteria killed)
• Often use surrogate marker such as minimum inhibitory concentration (MIC)
• Index serum concentration (pharmacokinetic profile) to MIC
• The pharmacodynamic relationship is different for different antimicrobial classes
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
ProCE, Inc.www.ProCE.com 13
PK / PD RelationshipsMicrobiology
•Susceptibility Testing
•MIC
•Bactericidal Rate
Pharmacokinetics
•Peak/Trough concentration
•AUC
•Half-life
Pharmacodynamics
•AUC / MIC
•Peak / MIC
•Time > MIC
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Important PD Parameters• Concentration dependent
– Cmax/MIC: Optimize dose to produce higher unbound drug concentrations
– AUC/MIC: Optimize the dose and exposure to unbound drug concentrations
– Concentration Dependent agents bacterial killing as the drug concentrations exceed the MIC
• Peak/MIC (AUC/MIC) ratio important
• Quinolones, aminoglycosides
Craig WA. Clin Infect Dis 2001;33(Suppl 3):S233-37.
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Concentration Dependent
Concentration
Time
Cmax = peak
MIC
Cmin = trough
Cmax/ MIC
AUC/ MIC
Aminoglycosides
Fluoroquinolones
Metronidazole
Daptomycin
Glycopeptides
Adapted from: Roberts JA, et al. Crit Care Med.2009;37:840-85127
Bacterial KillingTime-Kill Curves of P. aeruginosa
Conc.-Dependent
Lo
g1
0CF
U/
mL
Time (hours)
9
8
7
6
5
4
3
2
0 2 4 6 0 2 4 6 8
Control¼ MIC1 MIC
4 MIC
16 MIC64 MIC
Time-Dependent
Craig WA, et al. Scand J Infect Dis, 1991;Suppl (74)
Tobramycin Ticarcillin
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Relationship between AUC/MIC ratio for the nonprotein bound fraction of levofloxacin and ciprofloxacin
Scaglione F, et al. Antimicrob Agents Chemother. 2003 Sep;47(9):2749-55.
AUC/MIC and Survival Relationship for Quinolones
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Important PD Parameters• Concentration independent
– T > MIC: Optimize duration of unbound drug concentration at or above the MIC
– Concentration Independent (Time-Dependent) agents kill bacteria when the drug concentrations exceed the MIC
• Time>MIC important
• Penicillins, cephalosporins, vancomycin
Craig WA. Clin Infect Dis 2001;33(Suppl 3):S233-37.
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Concentration Independent
Concentration
Time
Cmax = peak
MIC
Cmin = troughT > MIC
Beta-lactams
Clindamycin
Macrolides
Linezolid
Vancomycin
Adapted from: Roberts JA, et al. Crit Care Med.2009;37:840-85131
3 10 30 100 300 1000 3000
24 h AUC/MIC ratio
5
6
7
8
9
10
0 20 40 60 80 100
Time above MIC (%)
5
6
7
8
9
10R² = 94%
Peak MIC ratio
01 1 10 100 1000 10000
Log 1
0C
FU p
er lu
ng a
t 24
h
5
6
7
8
9
10
Craig. Diagn Microbiol Infect Dis 1996; 25:213–217
Relationship between Time above MIC and efficacyin animal infection models
Cefotaxime in K. pneumoniae
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0 20 40 60 80 100
0
20
40
60
80
100
Time above MIC (%)
Penicillins
Cephalosporins
Craig. Diagn Microbiol Infect Dis 1996; 25:213–217
Relationship between Time above MIC and efficacyin animal infection models
S. pneumoniae
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PD of Specific Antimicrobials
PD Parameter
Cmax/MIC AUC/MIC T > MIC
• Aminoglycosides
• Fluoroquinolones• Metronidazole
• Aminoglycosides
• Azithromycin
• Daptomycin
• Glycopeptides
• Ketolides
• Quinupristin/dalfopristin
• Beta-lactams
• Aztreonam
• Erythromycin
• Clarithromycin
• Linezolid
• Clindamycin
•Vancomycin
Rodvold KA. Pharmacotherapy 2001;21:319S-330S. Nicolau DP. J Infect Chemother 2003;9:292-296.
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Pharmacodynamic Parameters for Prediction of Successful Outcomes
0
1
2
3
4
5
6
7
0 4 8 12 16 20 24
Time (h)
Co
nce
ntr
atio
n (
mg
/L) Peak/MIC 10x ( Gm - ) Aminoglycosides / Fluoroquinolones
AUC/MIC >125 ( Gm - ) or >30 ( Gm + ) Fluoroquinolones
Time > MIC>50% Cephalosporins / Macrolides
MIC
AUC/MIC >100 Daptomycin or >50 Colistin
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Post Antibiotic Effect (PAE)
Concentration
Time
Cmax = peak
MICPAE
Cmin = trough
Persistent suppression of bacterial regrowth following brief exposure to an antimicrobial
Adapted from: Roberts JA, et al. Crit Care Med.2009;37:840-85136
Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Post Antibiotic Effect (PAE)• Gram-positive organisms
– Most antibiotics (beta-lactams) exhibit PAE ~1-2 hours
– Aminoglycosides exhibit PAE < 1 hour
– Prolonged for Fluoroquinolones
• Gram-negative organisms
– Most beta-lactams (except imipenem) have a negligible PAE
– Aminoglycosides and quinolones have PAE > 2-3 hours
– Prolonged for Fluoroquinolones
• Clinical significance unknown
– Helps choose appropriate dosing interval
Craig w, et al. The Post Antibiotic Effect. Ann Inter Med1987;106(6):900-902.
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Clinical Applications
Using PK and PD
to predict
patient outcome
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Relationship Between Cmax:MIC Ratio and Clinical Response
Aminoglycosides
55
6570
8389 92
0
10
20
30
40
50
60
70
80
90
100
2 4 6 8 10 12+
Cmax:MIC
Clinical response
(%)
Moore RD et al. J Infect Dis. 1987;155:93-99.
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Relationship Between AUC / MIC and Clinical Response
Ciprofloxacin in Seriously Ill Patients
16Clinical100% -
50% -
75% -
25% -
% o
f Pat
ient
s C
ured
9
0 - 62.5 62.5 - 125 125 - 250
10
250 - 500
7
> 500
22Microbiologic
Forrest A., et al. Antimicrob Agents Chemother 1993;37:1073.40
Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Clinical Failure Rate 43% 11.5% 1%
Relationship Between AUC / MIC and Clinical Response
Levofloxacin
Jacobs. Clin Microbiol Infect 2001;7:589–96 ; [Adapted from Preston et al. JAMA 1998;279:125–9]
4 3
23
3
100
10
102030405060708090
100
No
. o
f p
atie
nts
AUC:MIC <25 Peak:MIC <3
AUC:MIC 25–100Peak:MIC 3–12
AUC:MIC >100 Peak:MIC >12
SuccessFailure
134 hospitalized patients with respiratory tract, skin or complicated urinary tract infections treated with 500 mg qd for 5–14 days
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Limitation of Pharmacodynamics
Bacterial sample should be in the fluid where the bacteria is obtained: difficult if not impossible to obtain
Technology for measuring MIC’s has 100% variability (1-2 fold dilutions)
Antibiotic PD parameters, f-AUC/MIC & f-Peak/MIC incorporate MIC in the denominator
One tube dilution can double or half the value of your PD outcome predictor or change the amount of time where f-antibiotic concentration > MIC
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Limitation of Pharmacodynamics
All methods of determining MIC are not equal
PD outcome parameter should specify MIC method
Remember: Bacteria differ in their susceptibility to antibiotics, even among same species
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Limitations of Pharmacokinetics
Young healthy volunteers: worst case
Most PK studies done in males
Actual patients: clinically appropriate, usually not available
May or may not account for protein-binding
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Other Considerations
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Will the antibiotic get to the site of Infection?
Blood and tissue concentrations
• Ampicillin/piperacillin concentrations in bile
• Fluoroquinolones concentrations in bone
• Quinolones, TMP/SMX, cephalosporins, amoxicillin concentrations in prostate
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Will the antibiotic get to the site of Infection?
Ability to cross blood-brain barrier
• Dependent on inflammation, lipophilicity, low mw, low protein binding, low degree of ionization
• 3rd or 4th generation cephalosporins, chloramphenicol, ampicillin, PCN, oxacillin
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Other Problems
Local infection problems
• Aminoglycosides inactivated by low pH and low oxygen tension
• Beta-lactams inoculum effect
–More vulnerable to hydrolysis of beta-lactamases
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Timing of Antibiotics
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Early treatment of infection
Compliance with the 6-hour sepsis bundle and hospital mortality (n = 101). NNT, number needed to treat; RR, relative risk
Gao F, et al. Critical Care. 2005; 9:R76450
Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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Requirements For Short Course Antibiotic Therapy
Fully susceptible pathogen; no risk of selection of resistance
Bactericidal antibiotics (or combination) with optimum dose/dosing regimen
Rapid onset of antibiotic action
Good penetration of antibiotic into the infection site
Antibiotic active against non-dividing bacteria
Antibiotic action not affected by adverse infection conditions
No foreign body present
No abscess formation
No signs of immunodeficiency
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Disease Longer Treatment (days) Equally Effective Shorter Treatment (days)
Abdominal infection 10 4
Bronchitis in people with Chronic Obstructive Pulmonary Disease (COPD)
7 or more 5 or fewer
Bacterial sinus infection 10 5
Cellulitis (skin infection) 10 5 to 6
Chronic bone infection 84 42
Kidney infection 10 to 14 5 to 7
Pneumonia acquired in the hospital
10 to 15 8 or fewer
Pneumonia acquired outside the hospital
10 to 14 3 to 5
Short Course Antimicrobial Therapy
Adapted from: Spellberg B, The New Antibiotic Mantra: "Shorter is Better," JAMA Internal Medicine, July 25, 2016.
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1CHS Pharmacy Education Series
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What Factors Promote Antimicrobial Resistance?
• Exposure to sub-optimal levels of antimicrobial
• Exposure to microbes carrying resistance genes
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Selective pressure for antibiotic concentration lower than the MIC
MIC
Time
Traditional hypothesis on emergence of AMR
Plasm
a concentrations
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The selection window hypothesis
Mutant prevention concentration (MPC)(to inhibit growth of the least susceptible, single step mutant)
MICSelective concentration (SC)to block wild-type bacteria
Plasm
a concentrations
All bacteria inhibited
Growth of only the most resistant subpopulation
Growth of all bacteria
Mutant Selection window
Adapted from: Canton R, et al. Enferm Infecc Microbiol Clin 2013;31 Supl 4:3-1155
Summary Antimicrobial PK/PD
Through the integration of microbiologic data, pharmacodynamics data and pharmacokinetic
parameters, determination of optimal antimicrobial therapy is possible
DRUG
BUG HOST
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