Flashcards in 17 Antimicrobial PK/PD Beringer Deck (77):
What is the definition of Pharmacokinetics (PK)?
Characterization of absorption, distribution, metabolism, elimination. Quantification of the amount and time course of a compound within the body
What is the definition of Pharmacodynamics (PD)?
Examines relationship between drug concentration vs. time and the rate and extent of antimicrobial effect at the site of infection
How is antimicrobial activity measured for individual antibiotic activity?
MIC/MBC. Bactericidal rate vs. drug concentration. Persistent effects (e.g. PAE)
How is antimicrobial activity measured for combination therapy?
Specialty lab tests. Serum bactericidal titer (SBT). Synergy testing (checkerboard)
What is the MIC/MBC ratio?
Antibiotic concentration at which growth of the majority of a standard population of bacteria is inhibited (MIC) or killed (MBC). Inoculum size used: 1x10^6 (might not relate accurately in vivo). Laboratory conditions for growth (pH, aerobic environement, exponential phase) may not translate in vivo. Continuous exposure to fixed drug concentration in lab might not translate well in vivo d/t fluctuating levels in vivo
What is MIC/MBC best used for?
Acute infections, not chronic
For concentration vs. bactericidal rate, what is Time-Dependent Killing?
Bactericidal activity saturable at concentrations of 4-5 times the MIC (i.e. B-lactams). Multiple doses/day to keep stead level
For concentration vs. bactericidal rate, what is Concentration-Dependent Bactericidal Activity?
Killing increases linearly with increasing antibiotic concentrations (i.e. Aminoglycosides). High dose used QD
Which drug class doesn't benefit from a high peak concentration?
No advantage in B-lactams, just causes more ADRs
What do In-Vitro persistent effects depend on?
Type of organisms. Type of antimicrobial agents. Concentration of antimicrobial. Duration of exposure
What are some In-Vivo measures of persistent effects?
Postantibiotic Leukocyte Enhancement (PA-LE). Postantibiotic Sub-MIC Effect (PA-SME)
What is the In-Vitro measure of persistent effects?
Postantibiotic Effect (PAE): persistent suppression of bacterial growth after short exposure to antibiotics
How do PAEs compare in-vivo and in-vitro?
In-vivo PAE are 3-4x longer than reported in-vitro. Persistent effects exposure dependent (PAE for aminoglycosides increases proportionally with AUC)
What is Type I Pattern of Activity for Antimicrobials?
Concentration-dependent killing and moderate-prolonged persistent effects
What are the goals of therapy for Type I Pattern of Activity?
What are the PK/PD parameters for Type I Pattern of Activity?
Dependent on 24h-AUC/MIC. Peak/MIC
What is Type II Pattern of Activity for Antimicrobials?
Time-dependent killing and minimal persistent effects
What are the goals of therapy for Type II Pattern of Activity?
Maximize duration of exposure
What are the PK/PD parameters for Type II Pattern of Activity?
T > MIC (time above MIC)
What is Type III Pattern of Activity for Antimicrobials?
Time-dependent killing and moderate-prolonged persistent effects
What are the goals of therapy for Type III Pattern of Activity?
Maximize amount of drug
What are the PK/PD parameters for Type III Pattern of Activity?
What antibiotics have Type I Pattern of Activity?
Aminoglycosides! FQs. Metronidazole. Daptomycin. Ketolides. Amphotericin B
What antibiotics have Type II Pattern of Activity?
B-lactams. Macrolides. Oxazolidinones. Flucytosine
What antibiotics have Type III Pattern of Activity?
Vancomycin. Azithromycin. Clindamycin. Streptogramins. Tetracyclines
What are the PK/PD goals for Aminoglycosides?
Peak/MIC > 10, AUC24 70-100
What are the PK/PD goals for Quinolones?
AUC24/MIC > 125 (P. aeruginosa), > 30-50 (S. penumoniae)
What are the PK/PD goals for Vancomycin?
Maximize T>MIC, AUC24/MIC > 400 (?)
What are the PK/PD goals for B-Lactams?
T>MIC > 40-50%, > 100% for some severe infections
What type of dosing do you want to use for Aminoglycosides?
Extended interval dosing
What type of dosing do you want to use for Vancomycin?
Trough vs. AUC24/MIC
What type of dosing do you want to use for B-Lactams?
Continuous infusion (need LD). If doing prolonged infusion, no LD needed
What type of dosing do you want to use for Quinolones?
What are the PK properties of Aminoglycosides?
F < 5%. Distributes freely in the vascular space and interstitial spaces of most tissues. Urine concentration exceed peak plasma levels 25-100x within 1 hr of drug admin, remain above therapeutic levels for days after multiple-dose regimen, with a terminal T1/2 of 48-200hrs. Renal clearance ~ CrCl (GFR). T1/2 = 2hrs
Where is the highest tissue/fluid penetration for Aminoglycosides?
Renal cortex. Inner ear (lymph)
What is the Extended Interval Dosing for Aminoglycosides?
Gentamicin, Tobramycin: 5-7 mg/kg QD. Amikacin: 15mg/kd QD
What are the target serum concentrations for Gentamicin, Tobramycin using Extended-Interval?
Peak: 20 mg/L. Trough: < 0.5 mg/L
What is the target serum concentration for Amikacin using Extended-Interval?
Peak: 60 mg/L. Trough: < 2.5 mg/L
What are the reasons for Extended Interval Aminoglycoside dosing?
PK + PDN --> single larger doses at longer intervals to achieve greater efficacy and reduced toxicity. 1) Maximize early concentration that would achieve greater killing activity (peak to MIC ratio) without concern for subsequent period of sub-MIC levels. 2) Decrease renal cortical and inner ear tissue uptake of AG since the process is SATURABLE, thereby reducing nephrotoxicity and ototoxicity
What concentrations generally have better survival for aminoglycosides in patients with serious infections?
Peak > 5mg/L. Peak/MIC > 10
When is Extended Interval dosing NOT indicated for aminoglycosides?
Meningitis, endocarditis, enterococcal and staphylococcal infections, documented infections in neutropenic hosts. Hyperkinetic patients: burns, spinal cord injury, pregnancy. Renally impaired pts: CrCl < 20 ml/min, dialysis
On the ODA dosing charge, how should aminoglycosides be dosed for CrCl > 60?
On the ODA dosing charge, how should aminoglycosides be dosed for CrCl 40-60?
On the ODA dosing charge, how should aminoglycosides be dosed for CrCl 20-40?
On the ODA dosing charge, how should aminoglycosides be dosed for CrCl < 20?
7mg/kg, then follow levels to determine time of next dose (level < 1mcg/ml)
What are the limitations of Nomogram (ODA monitoring)?
No indication of achievement of PD goals (i.e. peak/MIC, AUC). Restricted to monitoring of 7mg/kg dose, and random levels between 6-14 hours after dose. Individualized dosing requires measurement of Peak and random concentration
What are the general characteristics of Peak & AUC24 dosing of Aminoglycosides?
Once daily dosing individualized to achieve a target AUC24 of 72-100 mg x h/L. A mean dose of 6.7mg/kg required to achieve AUC of 93
What are the sampling times like for Extended-Interval Dosing of Aminoglycosides?
2 levels following initial dose: 1st level 1hr after end of infusion, 2nd level 2-4x t1/2s after. Based on target AUC24 (70-100)
What are the sampling times like for Traditional Dosing of Aminoglycosides?
Peak: 0.5h after 0.5h infusion. Trough: < 0.5h prior to next scheduled dose
For once-daily monitoring of Aminoglycosides, what are the therapeutic levels to look for?
Peaks: 20-30mg/L (breakpoint MIC 2): obtain 1-2 hours after infusion (prolonged distribution phase). Troughs: < 0.5mg/L (not useful for monitoring). Random: timing - 2-3 t1/2s from peak concentration. Adjust dose to achieve Peak/MIC > 10 and AUC24 ~70-100
What are the general characteristics of B-lactams?
PK + PD --> smaller more frequent doses to maximize efficacy, minimize toxicity, and minimize cost. 1) Maximize time concentrations exceed MIC. 2) Reduced daily dosage necessary to achieve goals may minimize costs and potential dose related ADRs
What is Continuous Infusion (CI) like for B-Lactams?
May be most beneficial for treatment of serious infections + short half-life drug. GOAL is to achieve a constant unbound concentration ~4-5 times MIC. LD necessary to rapidly achieve therapeutic concentrations
How is the loading dose for B-Lactams calculated?
Desired concentration x Vd: 5(MIC)(Vd)
How is the maintenance dose for B-Lactams calculated?
When should B-Lactam doses be adjusted?
Doses should be adjusted for protein binding (divide dose by fraction unbound). Caution with doses exceeding manufacturer recommended dosing
What are the limitations to routine clinical application for B-Lactam CI dosing?
1) Check STABILITY of compounds to ensure 24h activity (i.e. carbapenems not stable). 2) Check COMPATABILITY with other drugs administered (or start another IV line)
When are prolonged infusions most important for B-lactams?
When MIC is bordering the "Susceptibility" range for that particular organism
How does the Apache II score relate to B-lactams?
A high Apache II score is usually correlated with poor outcomes (score of 17+)
What are the Pharmacokinetics of Vancomycin?
F < 5%; may reach therapeutic serum concentration in presence of inflammatory bowel disease and renal failure. CSF penetration variable, meningitis requires intrathecal administration (5mg). Elimination by glomerular filtration almost exclusively. T1/2 normal = 6-8hrs; anuric ~7.5 days
What is the therapeutic monitoring for Vancomycin?
Target trough: 5-10 (usually 15-20); sampling time < 1hr prior to next scheduled dose, ensure therapeutic levels above MICs, risk of nephrotoxicity with concurrent aminoglycoside therapy, trough > 10. "Peak" monitoring: unnecessary from therapeutic standpoint, may provide additional PK information (Vd)
What is the PD of Vancomycin?
Time-dependent killing, moderate persistent effects. Maximal bactericidal activity at 4-5x MIC (i.e. MIC 1.0 --> trough target 10mg/L accounting for 50% ppb). Higher concentrations for deep tissue infections (endocarditis, meningitis, osteomyelties)
What is the Goal PD of Vancomycin?
Maintain levels above MIC throughout dosing interval, AUC/MIC > 400 (?)
What are the Vancomycin Persistent Effects?
Post-antibiotic MIC effect = 3.6 hours. In-vivo PAE for vancomycin = moderate, less than aminoglycosides (10 hrs)
What AUC/MIC for Vancomycin has the best outcomes with S. aureus?
What is Nephrotoxicity like with Vancomycin?
Nephrotoxicity associated with: Trough concentration > 10, length of therapy > 3 weeks, concurrent aminoglycosides. A 50% increase in CrCl from baseline after 3 days is a sign of acute kidney damage
What are the dosing outlines for Vancomycin?
Nomogram useful for defining initial dose. Does NOT provide assessment of achievement of PD target (T > MIC) or AUC24/MIC. PK methods with estimation of trough concentration and T>MIC and/or AUC24/MIC most precise
What is monitoring like for Vancomycin?
Most clinical outcome data based on maintaining concentrations above MIC (T>MIC) --> trough concentration monitoring. Emerging data on efficacy based on AUC/MIC ratios
What are the general characteristics of Fluoroquinolones?
PK + PD --> doses individualized to achieve specific AUC/MIC ratios. Larger doses necessary for treatment of nosocomial infections (pneumonia, bacteremias) with Gram (-) organisms (i.e. P. aeruginosa) for AUC/MIC = 125: Cipro: 400mg IV Q8h, Levo: 750mg PO/IV QD. Community acquired respiratory infections (S. pneumonia) require only AUC/MIC 30-50
For FQs, what is the AUC/MIC requirement for P. aeruginosa?
125 (usually w/ Lower Respiratory Tract Infection w/ P aeruginosa)
For FQs, what is the AUC/MIC requirement for S. pneumonia?
30-50 (usually w/ Community Acquired Pneumonia w/ S. pneumoniae)
What did the study of ciprofloxacin AUC/MIC show for outcomes?
Both clinical and microbiological outcomes significantly associated with AUC/MIC. Greatest improvement with AUC/MIC > 125
When measuring combination antibiotic activity, what are SBTs?
Serum bactericidal titers. Utilized to determine whether concentrations of the antibiotic(s) in a patients serum are capable of killing the infecting microorganism
When measuring combination antibiotic activity, what is Synergy Testing (checkerboard)?
Tests the activity of different antibiotic combinations, arranged in checkerboards of serial two-fold dilutions in clinically achievable combinations
What are SBTs and Synergy Testing most useful?
1) Infection caused by multi-drug resistant organism. 2) Patient not responding to current therapy
What is the relationship of SBTs and Clinical Outcomes?
SBTs > 1:2 had better outcomes than SBTs < 1:2
How are synergy studies interpreted?
By calculating the fractional inhibitory concentration (FIC) which compares the activity of an agent in combination (Agent A + Agent B) with the activity of the antibiotic alone (Agent A or Agent B)