Time dependent antibiotics: How do targets differ for different agents? - Cephalosporins - PCN - Carbapenems

Target can differ for different agents - Cephalosporins 60% - PCN 50% - Carbapenems 35-40%

Pogue: Pharmacokinetics Flashcards by Andrew Kumar

Pharmacokinetics

Pharmacodynamics

Pharmacokinetics:
“What the body does to the drug”

Absorption
Distribution
Metabolism
Excretion

Pharmacodynamics
“What the drug does to the body”

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Bioavailability

If give an antibiotic by any route other than
intravenous the fraction of the drug available for
use

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Drugs with complete or near complete bioavailability (7):

Fluoroquinolones
TMP-SMX
clindamycin
linezolid
tetracyclines
metronidazole
fluconazole

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Volume of Distribution
Definition:

Aminoglycosides vs Tigecycline

Measure of a drugs lipophilicity or hydrophilicity
• Can impact what antibiotics are ideal for
different sources of infection

– Aminoglycosides: Low Vd; hydrophilic
– Tigecycline: High Vd; lipophilic

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Clearance:

What happens with renal insufficiency?

Clearance is a measure of the removal of drug
from the body

– Key concept: many antimicrobials are renally cleared therefore dose adjustments needed in renal insufficiency

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Half-life:

Amount of time it takes remove 50% of the drug from
the body
– Helps determine the dosing interval for a drug
– Important determinant of total drug removal and
“steady state”

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How many half-lifes does it take to reach steady state?

4-5

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When is loading dose given?

When drugs have long half-lives

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When should bactericidal drugs be used?

With immunosuppressed or patients with serious infection

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Antimicrobial susceptibility

Susceptible

– PK/PD targets are achievable and you would expect common doses of the antimicrobial to lead to clinical success

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Antimicrobial susceptibility

Intermediate

Intermediate
– MICs are elevated for the organism toward the
antimicrobial in question
– One MIGHT see clinical success with dose-optimization
strategies

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Antimicrobial susceptibility

Resistant

Resistant
– PK/PD targets not obtainable- would not expect clinical
success with the agent

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PK/PD targets associated with efficacy

T>MIC

T>MIC
– B-‐lactams
– Macrolides
– Oxazolidinones

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PK/PD targets associated with efficacy

AUC/MIC

AUC/MIC
– Vancomycin
– Fluoroquinolones
– Tetracyclines
– Polymyxins
– Daptomycin

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PK/PD targets associated with efficacy

Cmax/MIC

Cmax (peak)/MIC

– Aminoglycosides

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Time dependent antibiotics:

Concentration independent or dependent?

What is the PK/PD parameter associated with efficacy?

What is the representative class?

Concentration independent: at a fixed value above the MIC (usually regarded as 4-5x MIC) there will be no added effect

T>MIC is the PK/PD parameter associated with efficacy
- Optimize the amount of time the conc. of the agent is above the MIC

B-lactams are the representative class
-penicillins, ephalosporins, carbapenems, aztreonam

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Time dependent antibiotics:

How do targets differ for different agents?

Cephalosporins
PCN
Carbapenems

Target can differ for different agents

Cephalosporins 60%
PCN 50%
Carbapenems 35-40%

What parameters will help determine serum concentrations?

Half life

Time dependent antibiotics

Preferential dosing regimens

Smaller, more frequent dosing

Peak concentration =

For aminoglycosides
For vancomycin:

Peak concentration – timing of blood draw is immediately after completion of the distribution phase

30 minutes post end of infusion for aminoglycosides
60 minutes post end of infusion for vancomycin

Trough concentration:

Random concentration:

Extrapolated Cmax:

Trough concentration – drawn within 0-30 minutes before the next dose is given

Random concentration – drawn at any time between the peak and trough times

Extrapolated Cmax – mathematically calculated maximum drug concentration

MIC:

MBC:

Traditional tests evaluating antibiotic activity against bacteria

MIC (minimum inhibitory concentration) lowest drug concentration that inhibits bacterial growth

MBC (minimum bactericidal concentration) lowest drug concentration that kills bacteria

MBCs are not routinely tested in the clinical setting

Why is there no loading dose with B-lactam?

Small half life

What are Monte Carlo simulations used for?

To extrapolate PK parameters/levels seen in small number of patients to large numbers

What is PTA? | What is considered "good coverage?"

Probability of target attainment PTA> 90%

What are the simulations drivers of?

More recent breakpoint changes for cephalosporins, carbapenems in G- bacilli

Concentration-dependent antibiotics What 2 different PD parameters are associated with kill? What are higher doses associated with?

Cmax/MIC AUC/MIC Bacterial killing

Aminoglycosides Target Cmax/MIC ratio is?

8-12:1

Aminoglycosides | Why aren't higher peaks associated with increased toxicity?

Higher peaks are not associated with increased toxicity as long as you can target low troughs for an “aminoglycoside free interval” – Nephrotoxicity, ototoxicityAminoglycosides

What is the post-antibiotic effect? What is it for aminoglycosides?

Post antibiotic effect – Describes a persistent suppression of microbial growth after a prior antimicrobial exposure – Continued suppression of growth for a certain period of time despite drug concentrations that fall below the MIC – With the aminoglycosides it is 4-6 hours

Application of Cmax/MIC Aminoglycoside Dosing Traditional dosing vs. extended interval dosing

Traditional dosing – 1-2 mg/kg q8h – Targeting peaks of ~8-10; troughs of <1 Extended interval dosing – 5-7 mg/kg q24h – Allows us to shoot for higher troughs (~14-22) and thus target higher MIC organisms (i.e. P.aeruginosa) - Also get lower troughs – Take advantage of post-antibiotic effect – Undetectable trough reduces or delays nephrotoxicity

Application of AUC/MIC: Vancomycin What is Vanco primarily used for? What is the PK/PD goal AUC/MIC ratio? What is used for a “surrogate” for reaching AUC/MIC targets? Historically, what were target troughs?

Application of AUC/MIC: Vancomycin Vancomycin primarily used for MRSA coverage – PK/PD goal is an AUC/MIC ratio of ≥ 400 for invasive MRSA infections – AUC’s not obtained in patients

Application of AUC/MIC: Vancomycin What is used for a “surrogate” for reaching AUC/MIC targets? Historically, what were target troughs?

– A trough of 15-20 mcg/mL is used for a “surrogate” for reaching AUC/MIC targets • Historically target troughs were 5-20 mcg/mL – Will hit AUC/MIC targets if the vancomycin MIC ≤ 1 mcg/mL - The reason we switch to alternative agents for invasive MRSA infections when the MIC >1

AUC/MIC Applications: FQs What is AUC/MIC? G+ vs G-

AUC/MIC is PK/PD parameter of interest Different between G+ and G- Levels not routinely obtained

AUC/MIC Applications: FQs Two main applications of FQs

S.pneumoniae target is AUC/MIC >30 (Free drug only) G-, including P. aeruginosa - AUC/MIC >125 (free drug 60-90)

PK/PD application: CAP What don't respiratory FQs include? Levofloxacin and CAP: Moxifloxacin: excellent agent for?

Respiratory FQ do not include ciprofloxacin -Even at lower MIC (1.0) - unlikely to obtain goal AUC/MIC targets (even with high-dose cipro) Levofloxacin and CAP - High dose (750 mg daily) likely necessary to ensure adequate coverage Moxifloxacin - Due to low MICs, excellent agent for CAP

FQ and Pseudomonas ``` Do FQs have good activity? What is MIC90? Moxifloxacin? Cipro? Levofloxacin vs Cipro: ```

No MIC90 is 32 mcg/mL for all agents For all intents and purposes moxifloxacin lacks anti-pseudomonal activity Ciprofloxacin tends to be one dilution more potent Levofloxacin (high dose) can get about twice as high of an AUC as ciprofloxacin (high dose) - Making cipro and levofloxacin roughly equivalent anti-pseudomonal agents

What is essential for optimizing AUC/MIC for pseudomonas?

High dose Cipro 750 mg PO BID or 400 mg IV q8h Levofloxacin 750 mg daily

Synergistic Combinations: Against Gram (-) bacilli: Against Eneterococci:

Against Gram (-) bacilli: AMG + beta-lactam Against Eneterococci: gentamicin/streptomycin + ampicillin/vancomycin o Note: although ampicillin and vancomycin are cidal drugs, require this synergistic effect with the AMG to be cidal against enterococci

What is aminoglycoside toxicity associated with?

Toxicity: nephortoxicity and ototoxicity associated with AUC or elevated trough concentrations, NOT PEAK CONCENTRATIONS!!

Post Antibiotic Effect:

Definition: refers to the time period after removal of an antibiotic (or sub MIC concentrations) during which there is no bacterial growth

Post antibiotic effect Most classes of antibiotics have PAE against: What have a longer PAE than cell wall active drugs? What have PAE against Gram (-) bacilli for ~2-4 hours?

Most classes of antibiotics have PAE against aerobic Gram (+) cocci (except enterococcus) Agents inhibiting RNA or protein synthesis often have a longer PAE than cell wall active drugs AMGs, imipenem, and FQs have PAE against Gram (-) bacilli for ~2-4 hours (focus on AMG) - 2-4 hours without immune system help - Possibly up to 9 hours with help from the immune system