ID Exam I IPCS 2

what is pharmacokinetics?

• What the body does to the drug (ADME)

• Used to develop a model for designing individualized drug regimens

• Goal is to increase effectiveness of treatment and/or decrease the side effects

what is pharmacodynamics?

• What the drug does to the body

• The antimicrobial affect on the pathogen

what are antimicrobial agents that have concentration-dependent activity? what is the goal?

• rate/extent of bactericidal activity increases with increasing antimicrobial concentrations

• the goal is to optimize Peak:MIC or AUC:MIC

what are antimicrobial agents that have non-concentration dependent activity? what is the goal?

• rate/extent of killing does not increase with increasing antibiotic concentrations, instead it is increased by length of exposure

• the goal is to optimize time concentrations remain above MIC (t>MIC)

what is the timeline of antimicrobial therapy?

1. clinical illness

2. empiric antibiotics

3. culture processing

4. ID

5. targeted antibiotics

what is the blood culture pathway?

1. Collection

- samples incubated

- usually 2 aerobic and 2 anaerobic

2. Alert

- machine alerts for positive culture (spin for 5-10 min, grow for 5 days)

3. Gram stain

- tech performs STAT gram stain

4. Incubation

what is the timeframe for the gram stain?

24-48 hours

what is the timeframe for the blood culture?

additional 24-48 hours

what is the time frame for susceptibility?

additional 24 hours

what is rapid diagnostic technology used for? what are examples?

- helps us speed up timeframe

- ex: MALI-TOF, ePlex, BioFire FilmArray/Torch

what is MIC vs MBC?

MIC

- minimum inhibitory concentration

- lowest antimicrobial concentration that inhibits visible bacterial growth

MBC

- minimum bactericidal concentration

- lowest antimicrobial concentration that results in microbial death

what is the time-dependent killing for β-lactams?

what is the goal for β-lactams?

when is the maximal killing achieved for β-lactams?

• time>MIC

• keep serum concentrations above MIC for at least 40-70% of dosing interval

• max. killing achieved at 4-5x MIC

β-lactams toxicity is common/rare

rare

--> assays for therapeutic drug monitoring aren't widely available

what are the PK parameters for β-lactams?

• lower volume of distribution (0.15-0.3 L/kg)

• short half-loves (1-2 hrs)

• low protein binding (~25%)

• excreted via glomerular filtration + tubular secretion

β-lactams in ICU patients

100% fT > 4-6 MIC

what is the definition of pharmacy to dose (PTD)?

Formal pharmacy consult for pharmacist-managed dosing and policy-directed management

what is the definition of therapeutic drug monitoring (TDM)?

Assay procedures to determine drug concentrations in plasma, further interpreted and applied to develop safe + effective regimens

what are the goal AUC values?

Target: 500 mcg*h/mL

Range: 400-600 mcg*h/mL

500-600 range more applicable to severe infections (MRSA< endocarditis, meningitis)

when are MICs available after initiating therapy?

72-96 hours

what is the surrogate marker for AUC?

trough levels 15-20 mcg/mL

MIC ≤ 1 mcg/mL

100% chance of achieving goal AUC/MIC ≥ 400

MIC ≥ 2 mcg/mL

goal not achievable in patient with normal renal function

how do higher troughs ≥ 15 mcg/mL of vancomycin impact nephrotoxicity?

• > 2.5-fold increase risk in nephrotoxicity

• 3-fold increased risk when initial trough ≥ 15 mcg/mL

• greatest risk when troughs > 20 mcg/mL

how many patients can achieve AUC/MIC ≥ 400 with troughs < 15 mcg/mL?

60%

what is a very poor surrogate marker for AUC?

Cmin

why does AUC have high variability?

- depends on dose + renal function

- trough concentration explains 40% of the inter-individual variability in the AUC

is a vancomycin MIC of 2mcg/mL an indication to switch therapy?

no

--> for all pts who don't improve on vancomycin, an alternative is recommended regardless of MIC

What are the general AUC/MIC targets for general dosing?

• AUC 500 mg*hr/L

• Cmax 35 mg/L

• Cmin 12.5 mg/L

What are the general AUC/MIC targets for severe infections?

• AUC 600 mg*hr/L

• Cmax 35 mg/L

• Cmin 17.5 mg/L

What are the overall ranges for the general AUC/MIC targets?

• AUC 400-600 mg*hr/L

• Cmax 30-35 mg/L

• Cmin 10-20 mg/L

what are the severe infections that may be accounted for in AUC/MIC targets?

endocarditis, meningitis, S. aureus bacteremia, or pneumonia

what loading dose should be considered in patients with severe infections?

20-25 mg/kg TBW

doses of ____ daily are generally not recommended without prior history of tolerance

<4

when should vancomycin doses be drawn if therapy is expected to continue for more than 72 hours?

around the 4th or 5th dose

when should peak level be drawn?

1-2 hours after the end of infusion

when should trough levels be drawn?

• 30 min to 1 hr prior to next dose

• must be at least 6 hours (or 1 half life) after the peak level

what drugs are considered as natural aminoglycosides due to their synthesis from organisms?

gentamicin and tobramycin

what was the first semi-synthetic aminoglycoside?

Amikacin (chemically modified version of kanamycin)

what is the structure of aminoglycosides?

amino sugars joined by glycosidic bonds to an aminocyclitol nucleus

How do aminoglycosides inhibit protein synthesis?

• by binding to the 16S ribosomal rRNA of the 30S ribosome- strong, irreversible bond leads to "post-antibiotic" effect

• further leads to mistranslation + incorrect formation of polypeptides that cause cell damage

how may aminoglycosides display bactericidal activity?

when used in high-doses for gram-negative organisms... due to uptake in affected cells via integration into lipopolysaccharide layer which leads to rapid uptake

what happens with aminoglycosides are used with cell-wall active antibiotics (B-lactams)?

synergy... theorized to increase aminoglycoside uptake, despite small doses

conflicting evidence in vitro and in vivo based on specific organisms

what are aminoglycosides active against?

Gram negative bacteria including:

• Proteus spp

• Klebsiella spp

• Escherichia coli

what aminoglycosides are effective against Pseudomonas aeruginosa?

ONLY Tobramycin and Amikacin

what are aminoglycosides effective against when used in synergy?

gram-positive infections (MRSA, Enterococcus spp) – generally gentamicin only

What do aminoglycosides have NO activity against?

anaerobes

what aminoglycosides can be used to treat TB?

Streptomycin and amikacin

what aminoglycosides have no activity against TB?

Gentamicin and tobramycin

what is amikacin resistant to?

enzyme inactivation

--> amikacin generally remains stable against organisms resistant to gentamicin and tobramycin

what aminoglycoside has superior efficacy in Pseudomonas aeruginosa infections?

• Tobramycin

• Generally used in combination with another active agent, especially in critically-ill patients

describe the pharmacokinetics of aminoglycosides:

One compartment model

• Higher peak:MIC = bactericidal effect

Absorption

• Highly polar molecules – not well absorbed from GI tract, only given IV generally

Distribution

• Volume of distribution (Vd) ~ 0.3 L/kg (can range from 0.2 to 0.5 L/kg)

• Patients with ascites/edema (⬇️ output) – increased Vd

• Distributes well into urine, ascitic fluid, pleural fluid, synovium

• Poor distribution into CNS, bile, adipose tissue

Metabolism - N/A

Elimination

• 95% unchanged in urine, t1/2 ~1-4 hours

• Assume ~50% of drug is removed by each hemodialysis session

what should be remembered when working with aminoglycoside drugs?

aminoglycosides are concentration-dependent drugs --> higher peak = better bactericidal effects

a peak aminoglycoside concentration/MIC of __:__ should be achieved to maximize the drug effect

10:1

extended vs traditional dosing regimens for aminoglycosides:

• Traditional dosing regimens generally elicit smaller doses (1-3 mg/kg) given more frequently (q8-12h)

•Extended interval dosing regimens generally elicit higher doses (~5-7 mg/kg) given less frequently (q24-72h)

what are the advantages of extended interval dosing regimens over traditional dosing regimens?

• Maximizes PK/PD parameters

• Post-antibiotic effect

• Decreased nephrotoxicity/ototoxicity due to decreased accumulation

How may many institutions perform aminoglycoside dosing?

Either the Hartford (7mg/kg) or Urban-Craig nomograms (5 mg/kg)

• Usually higher dosing (Hartford nomogram) is used for more severe infections

• Only a single random level drawn 8 to 12 hours after the start of the infusion of the first or second dose (ideally first)

antimicrobial resistance is a _________________

public health threat

what are common examples of antimicrobial resistance?

• Methicillin-resistant Staphylococcus aureus (MRSA)

• Carbapenem-resistant Enterobacterales (CRE)

• Vancomycin-resistant Enterococcus (VRE)

• Extended-spectrum b-lactamases (ESBLs)

what are the ways antimicrobial resistance occurs?

Efflux Pumps:

• Antimicrobial actively pumped out of cell

Entry Inhibition:

• Antimicrobial actively blocked from entering cell

Inactivation:

• Breakdown of active drug

Target site modification

• Active drug unable to elicit effect

what may gram-negative pathogens commonly cause?

intra-abdominal infections (IAIs), urinary tract infections (UTIs), ventilator-associated pneumonia (VAP), bacteremia

What is the mechanism of resistance for B-Lactamases?

B-lactamases cleave the B-lactam ring of antimicrobial agents that lead to antibiotic inactivation - therefore, the antimicrobial agent cannot elicit its effect

what is typing of B-lactamases dependent on?

which agent(s) they inactivate/hydrolyze

how are extended spectrum b-lactamases (ESBL) encoded? what does this mean?

frequently plasmid-encoded - meaning they usually have genes that encode resistance to other classes of antibiotics

what is horizontal transfer of resistance?

• Transfer of resistance genes from one organism to another

- Transduction (bacteriophages/integrons)

- Conjugation (plasmid)

- Transformation (incorporation of chromosomal DNA/plasmids)

what do plasmids contain that play a role in protein recognition to remove elements from host DNA?

insertion sequences

what may ESBLs have the framework to do?

hydrolyze/inactive all agents with an ester/amide bond (e.g., penicillins, cephalosporins, monobactams, carbapenems) but this will not always be the case

how do efflux pumps interact with antibiotics?

• They can export antibiotics from the intracellular matrix

• Outer membrane porins may also decrease entry of the antibiotic into the cell

what is modified in fluoroquinolone resistance?

target site protection/modification to alter agent binding

what is modified to reach the target site in aminoglycoside resistance?

Alteration of ribosomal proteins that lead to high level resistance

what may gram-positive pathogens commonly cause?

Skin and skin structure infections, bacteremia, hospital/community-acquired pneumonia

what are examples of gram-positive pathogens?

• methicillin-resistant Staphylococcus aureus

• B-lactam resistant Pneumococcus spp

• vancomycin-resistant Enterococcus spp

what is the clinical pearl regarding the staphylococci resistance mechanism of inactivation?

Plasmid-encoded B-lactamase - nafcillin/cefazolin generally stable

(penicillin affected)

what is the clinical pearl regarding the staphylococci resistance mechanism of target replacement?

PBP2a has a low affinity for b-lactams - this would show as MRSA

(B-lactams affected)

what is the clinical pearl regarding the staphylococci resistance mechanism of target modification?

Leads to linezolid resistance often with other concomitant mutations

(linezolid affected)

what is the clinical pearl regarding the staphylococci resistance mechanism of drug entry?

Repulsion of antibiotic due to increase in cell envelope charge

(daptomycin affected)

what is the clinical pearl regarding the enterococci resistance mechanism of inactivation?

Rare – usually found in E. Faecalis

(penicillin affected)

what is the clinical pearl regarding the enterococci resistance mechanism of target replacement?

Usually acquired resistance – may differ depending on Enterococcus spp

(vancomycin affected)

what is the clinical pearl regarding the enterococci resistance mechanism of target modification?

Reason why cephalosporins do not cover Enterococcus spp

(B-lactams affected)

what is the clinical pearl regarding the enterococci resistance mechanism of drug entry?

Repulsion of antibiotic due to increase in cell envelope charge

(daptomycin affected)

how may daptomycin exhibit resistence?

• antibiotic is "diverted" from the septum

• the positively charged daptomyacin-calcium complex is "repelled" from the cell surface

what is the clinical pearl regarding the streptococci resistance mechanism of target modification?

Type of PBP will determine which B-lactam resistance pattern you will see

(B-lactams affected)

What are the different things to consider when making policy changes?

• Practice change starts with small steps

• Always identify key stakeholders

• Important to implement education AND process changes

• Practice change takes time – be patient and diligent

what are the PK parameters of penicillins?

• MOA: Inhibition of bacterial cell wall synthesis by binding to penicillin binding proteins (PBPs)

• Prevention of cross-linking = bactericidal activity

• Half life: Variable - generally ~ 1 hour

• Oral absorption: Variable

• Distributed to most tissues (lung, liver, kidney, muscle, bone)

• CSF penetration is enhanced in setting of inflammation

time-dependent killing for penicillins =

time > MIC

what is the goal serum concentration for penicillins?

Keep serum concentrations above MIC for at least 50-60% of dosing interval

when is the maximal killing achieved for penicillins?

at 4-5x MIC

Up to ____% of the US population reports penicillin allergy

20

What is penicillin allergy history is important to determine?

IgE-mediated (immediate) versus T-cell mediated (delayed) versus potential intolerance

what may all penicillins may cause?

neutropenia, neurotoxicity (rare but usually with higher doses), or renal injury (AIN - nafcillin/oxacillin)

what are the PK parameters for cephalosporins?

• MOA: Inhibition of bacterial cell wall synthesis by binding to penicillin binding proteins (PBPs)

• Prevention of cross-linking = bactericidal activity

• Bind to different PBPs than narrow spectrum penicillins

• Half life: Variable - generally 1-2 hours

• Oral absorption: Variable, agent and "generation" dependent

• Distributed to most tissues (lung, liver, kidney, muscle, bone/joint)

• CSF penetration is enhanced in setting of inflammation

time-dependent killing for cephalosporins =

Time > MIC

what is the goal serum concentration for cephalosporins?

Keep serum concentrations above MIC for at least 60-70% of dosing interval

when is maximum killing achieved for cephalosporins?

4-5x MIC

what are adverse effects of cephalosporins?

• GI adverse effects common (up to 20%)

• Variable association with CDI - highest risk appears to be ceftriaxone/cefepime

• May cause neutropenia, neurotoxicity (rare but usually with higher doses), or renal injury

• Local reactions (phlebitis/pain at IV site) can be common

what are the PK parameters for carbapenems?

• MOA: Inhibition of bacterial cell wall synthesis by binding to penicillin binding proteins (PBPs)

• Prevention of cross-linking = bactericidal activity

• Half life: Variable - generally 1-2 hours, ertapenem = 4 hours

• Distributed to most tissues (lung, liver, kidney, muscle, bone/joint)

• CSF penetration is enhanced in setting of inflammation

what is time-dependent killing of carbapenems =

Time > MIC

what is the goal serum concentrations for carbapenems?

above MIC for at least 40-50% of dosing interval

when is maximum killing for carbapenems achieved?

at 4-5x MIC

carbapenems allergy:

• Low incidence

• Less frequently reported than penicillins; minimal cross reactivity with penicillin and cephalosporin allergy

ADRs of carbapenems are similar to...

the ADRs of penicillins and cephalosporins