8 - Antimicrobials Flashcards
Pharmacokinetics is drug ______
Movement
Pharmacodynamics is drug _____
Activity
What is the triad of antimicrobials?
- Infection
- Pharmacokinetics
- Pharmacodynamics
What determines infection?
Severity plus
- Age
- Co-morbidities
- Immune function
- Pathogen(s)
- Site of infection
What determines pharmacokinetics?
Antimicrobial plus
- Age
- Body weight
- Fluid status
- Plasma proteins (albumin)
- Organ function (dialysis)
- Co-morbidities
- Drug interactions
What determines pharmacodynamics?
Antmicrobial:
- MOA
- Potency (MIC)
- Static or cidal activity
- Resistance
- Synergy/ antagonism
Define MIC
Lowest concentration of a specific agent needed to inhibit visible growth of an organism
Lower MIC = more _____ drug
Potent
Most common method of determining MIC
Disk diffusion (Kirby-Bauer method)
Limitations of MIC testing?
- Lack of automation
- Not studied in fastidious or slow-growing bacteria (ex: HACEK group)
- Sometimes need quantitative instead of qualitative
What are MIC breakpoints?
- Used to classify MICs into susceptible, intermediate, or resistant categories
- Maximum MIC for the particular category (ex: anything at or below is reported as susceptible)
Define susceptible
Implies the infection should be effectively treated w/ the agent or recommended doses for the type of infection and infecting species, unless otherwise CI’d
Define intermediate
- Indicates strains w/ MICs that may be at or above blood/tissue concs achieved w/ recommended doses
- Response rates may be lower than for susceptible infections
- Also implies potential clinical effectiveness if agent is physiologically concentrated at infection site or if higher doses can be used
Define resistant
Indicates stains w/ MICs that may not be inhibited by systemic concs usually achieved w/ recommended doses, and/or may fall w/in ranges where specific resistance mechanisms are likely (ex: beta-lactamases) or indicates that clinical studies have not demonstrated reliable efficacy
Why may MIC breakpoints differ for antimicrobials against the same organism?
- MIC dependent on kinetics profile (protein-binding, free fraction)
- Drugs w/ higher systemic availability will have higher breakpoints
Why may MIC breakpoints differ for infection site for the same antimicrobial against the same organism?
- MIC based on drug’s ability to get to the infection site
- Ex: meningitis MIC for penicillin will be lower than for bloodstream b/c not as much penicillin can get in CSF
Why do some MIC breakpoints differ for antimicrobial route of administration?
Bioavailability
What are the goals of using PK-PD based antimicrobial dosing in px?
- Increase likelihood of success
- Minimize emergence of resistance
What is mutant selection window (MSW)?
- Range of antibiotic concentration in which drug-resistant bacteria mutants can be selectively enriched and amplified
- Concentration zone is between MIC of susceptible pathogens and that of the least susceptible mutants (MIC -> MPC)
What is mutant prevention concentration (MPC)?
Antibiotic concentration that corresponds to MIC of the least susceptible mutants in a colony
What are the limitations in using MPC and MSW to dose patients?
- Doses needed to achieve MPC are higher than those for curing and exceed those registered for the drug
- Sometimes MPC is unattainable
- Increased risk of adverse effect
- MSW hasn’t been studied in many infective pathologies or at the site of infection
Which antimicrobials are concentration dependent?
- Aminoglycosides
- [Fluoroquinolones]
Which antimicrobials are time dependent?
- Penicillin
- Cephalosporins
- Carbapenems
Which antimicrobials are both concentration and time dependent?
- FQs
- Vancomycin
- Linezolid
- Daptomycin
- [AGs, macrolides, tetracyclines]
Do px w/ cystic fibrosis have very high or very low drug clearance? Why is this?
- Very high; can be 50% higher than px w/o CF
- Don’t exactly know why; may be due to total body water and how drugs are handled in the lungs
Which px are most likely to benefit from individualized antimicrobial dosing?
- Serious infections w/ high rates of complications, tx failure, or mortality
- Infections associated w/ relatively resistant pathogens
- Px who are immunocompromised due to malignancy, neutropenia, diabetes, renal disease, HIV/AIDS, critical illness, immunosuppressant therapy
- Pt populations w/ altered or variable PK due to age, obesity, organ dysfunction, dialysis, critical illness
- Px who are predisposed to dose-related adverse effects or toxicity
Do we adjust doses for a critically ill px w/ a low serum creatinine due to hyper glomerular filtration?
No
Gentamicin is more active against _____, while tobramycin is more active against _____
- E. coli
- Pseudomonas
PD target for aminoglycosides
- fCmax/MIC > 8-10x**
- AUC24 / MIC (> 80)
Dettli equation
ke = 0.0024 * Clcr + 0.01
What is Dettli equation used for?
Aminoglycosides ONLY
PD target for vancomycin
AUC/MIC > 400 & < 700
What is the importance of trough serum concentrations for vancomycin?
- Used as a surrogate for AUC
- Assuming that troughs of 15-20 will correlate to AUC/MIC 400-700
- New guidelines will say to measure AUC b/c doses are being changed based on troughs when AUC is within the range
How was Clcr calculated in the Wesner nomogram for vancomycin?
Using IBW / DW
How was Clcr calculated in the Thalakada nomogram for vancomycin?
Wasn’t calculated; only use sCr and age
How was Clcr calculated in the Kullar nomogram for vancomycin?
ABW
How do you calculate %T>MIC?
(ln Cmax - ln MIC) / ke
- Written as a % of the dosing interval, where in most cases t’ can be included in the time above MIC
PD target for beta-lactams
%fT>MIC
> 40% (static)
> 70% (cidal)
> 75-100% (serious infection)
PD target for fluoroquinolones
f AUC/MIC > 90 (gram neg and pseudomonas)
> 30 (Strep pneumoniae)
What is the adjustment factor (AF) for antimicrobials?
- 30% for beta-lactams, daptomycin, and linezolid
- 40% for AGs, FQs, and vanco
How do you calculate DW?
IBW + AF (ABW-IBW)
What is ideal body weight?
- Males = 50 kg + 2.3 kg for every inch above 5 feet
- Females = 45.5 kg + 2.3 kg for every inch above 5 feet
Aminoglycosides are used w/ beta-lactams for synergy in tx of _____ infections
Streptococcal and enterococcal
Vd of AGs
0.2-0.3 L/kg
AG protein binding
< 10%
AG t1/2 in normal renal function
2-3 h
Desired peak and trough levels for AGs (normal dosing)
- Peaks 6-10 mg/L; 8-10 mg for LRTIs and other serious infections; 4-6 mg/L for uncomplicated TI
- Troughs 0.5-1.5 mg/L
Loading dose for AGs (normal dosing)
2 mg/kg based on ABW or DW in obesity > 130% of IBW (round to nearest 10 mg)
Maintenance dose for AGs (normal dosing)
- Use nomogram
- % of loading dose based on Clcr
How often should AG peaks and troughs be measured?
- Around the 3rd dose
- Repeat every 3-4 days
- Draw troughs prior to dose, and peaks 30 mins after end of infusion
Desired peak and trough levels for AGs used for synergy (normal dosing)
- Peak 3-5 mg/L
- Trough 0.5-1 mg/L
How should you monitor AGs for nephrotoxicity?
- Follow sCr, blood urea nitrogen, and urine output 2-3 times/week
Risk factors for nephrotoxicity w/ AGs
- High trough concs
- Duration of therapy
- Advanced age
- Diabetes
- Dehydration
- Concurrent nephrotoxins
How should you monitor AGs for ototoxicity?
- Assess for signs of vertigo, tinnitus, double-vision, pressure/ fullness/ pain in ears and new onset hearing loss especially if duration > 5 days
- Doesn’t correlate w/ peak or trough levels
Risk factors for auditory and vestibular toxicity w/ AGs
- Auditory = age, genetic predisposition, and pre-existing hearing deficit
- Vestibular = duration of therapy and cumulative exposure
Benefits of extended-interval AG dosing
- May provide better PD target attainment against pathogens w/ elevated MICs (ex: pseudomonas)
- Higher concs may limit emergence of adaptive-resistance mechanisms
- May reduce or delay nephrotoxicity
When is extended-interval AG dosing not recommended?
- CNS infections
- Osteomyelitis
- Enterococcal endocarditis
- Significant renal dysfunction (Clcr < 40 mL/min)
Maintenance dose for AGs (EID)
5-7 mg/kg based on ABW or DW in obesity > 130% of IBW (round to nearest 10 mg)
How often are AGs administered w/ EID?
- q24h
- q36-48h in those w/ Clcr of 40-60 mL/min as long as accompanied by diligent monitoring
When should peak and troughs levels be measured w/ EID?
Around 2nd dose and repeat every 3-4 days
Target peak and trough for AG (EID)
- Peak 16-24 mg/L
- Trough < 1 mg/L
What should be done if troughs are 1-2 mg/L or > 2 mg/L w/ EID?
- 1-2 mg/L reduce dose, extend interval, or change to traditional dosing
- > 2 mg/L change to traditional dosing
What is VISA?
Vancomycin-intermediate susceptible staph aureus)
Vd and protein binding of vancomycin
- Vd = 0.7 L/kg (0.9 L/kg for critically ill)
- Protein binding = 50% (estimate)
t1/2 of vancomycin in normal renal function
6-8 h
Loading dose for vancomycin
25-30 mg/kg based on ABW or DW (round to nearest 250 mg increment)
Maintenance dose for vancomycin
10-20 mg/kg (round to nearest 250 mg increment) every 8-12 h
Matzke regression correlation
ke = 0.00083 * Clcr + 0.0044
When is Matzke regression correlation used?
Vancomycin
When should vanco peaks and troughs be measured?
- Around 3rd or 4th dose and repeated weekly
- Draw troughs prior to dose, and collect peaks 1-2 h after infusion
Target peak and trough for vancomycin
- Peak < 40 mg/L
- Trough 10-20 mg/L (15-20 mg/L for complicated infections like bacteremia, endocarditis, osteomyelitis, meningitis, hospital-acquired pneumonia)
What does Red man syndrome look like?
Rash/erythema of face, neck, and upper torso (sometimes hypotension)
What are the suggested infusion times for vanco?
- 1 h for 1 g or less
- 1.5 h for 1.25-1.75 g
- 2 h for 2 g or more
What is a normal BUN (blood urea nitrogen)?
2.5 - 7.1 mmol/L
