Antimicrobial PK/PD and Resistance

what is pharmacokinetics (PK)

ADME: absorption, distribution, metabolism, excretion

what is pharmacodynamics (PD)

the antimicrobial's effect on the pathogen

what do we want to optimize with concentration dependent activity

peak:MIC or AUC:MIC

what do we want to optimize with non-concentration dependent activity

time > MIC

timeline of antimicrobial therapy

clinical illness -> empiric antibiotics -> culture processing -> ID -> targeted antibiotics

time to gram stain

24-48 hours

time to organism ID after gram stain

additional 24-48 hours

time to susceptibilities after ID

additional 24 hours

MALDI-TOF

rapid ID in minutes, must be from direct-colony smear

ePlex

rapid ID in ~1.5 hours, organism + resistance genes, direct from blood culture bottle

BioFire

rapid ID in ~1 hour, organism + resistance genes, direct from blood culture bottle

MIC

lowest antimicrobial concentration that inhibits visible bacterial growth

MBC

lowest antimicrobial concentration that results in microbial death

E-test

exponential gradient strip used to find the MIC

drugs that are peak:MIC

aminoglycosides

drugs that are AUC:MIC

fluoroquinolones, macrolides, glycopeptides (vancomycin)

drugs that are time > MIC

β-lactams (also tetracyclines and oxazolidinones on the Rybak graph)

β-lactam T>MIC goal

at least 40-70% of dosing interval

maximal killing for β-lactams

4-5x MIC

β-lactam PK

low Vd, short half-life (1-2 h), low protein binding, renally eliminated

ICU factors that change PK

changes in Vd, fluid resuscitation, vasopressors, hypoalbuminemia, augmented renal clearance

when do we draw vancomycin levels

around 4th or 5th dose if therapy > 72 hours

when do we draw peak concentration

1-2 hours after end of infusion

when do we draw trough concentration

30 min-1 hour before next dose (at least 6 hours after peak)

AUC target for vancomycin

500 (range 400-600 mg hr/L)

AUC target for severe infections

500-600 (Cmin 15-17.5)

severe infections for vancomycin

endocarditis, meningitis, S. aureus bacteremia, pneumonia

Cmax target for vancomycin

30-35 mg/L

Cmin target for vancomycin

10-20 mg/L

vancomycin loading dose

20-25 mg/kg TBW for severe infections

vancomycin max daily dose

4 g/day not recommended without prior tolerance

risk of vancomycin troughs ≥ 15

nephrotoxicity (greatest risk > 20)

vancomycin MIC of 2

NOT an indication to switch therapy

aminoglycoside mechanism of action

binds 16S rRNA of 30S ribosome -> mistranslation

aminoglycosides mainly cover

gram-negative bacilli (no anaerobes)

aminoglycosides that cover pseudomonas

tobramycin and amikacin only

aminoglycoside used for gram-positive synergy

gentamicin

aminoglycosides that treat TB

streptomycin and amikacin

aminoglycoside resistant to enzyme inactivation

amikacin

aminoglycoside Vd

~0.3 L/kg (increased with ascites/edema)

aminoglycoside poor distribution

CNS, bile, adipose tissue

aminoglycoside elimination

95% unchanged in urine, half-life 1-4 hours

aminoglycoside removal by hemodialysis

~50% per session

aminoglycoside peak:MIC goal

10:1

traditional aminoglycoside dosing

1-3 mg/kg q8-12h

extended interval aminoglycoside dosing

5-7 mg/kg q24-72h

Hartford vs Urban-Craig nomogram

Hartford = 7 mg/kg, Urban-Craig = 5 mg/kg

when to draw level for extended interval dosing

random level 8-12 hours after start of infusion (ideally 1st dose)

amikacin level on nomogram

divide by 2 or 3 before plotting

advantages of extended interval dosing

maximizes PK/PD, post-antibiotic effect, less nephro/ototoxicity

4 mechanisms of resistance

efflux pumps, entry inhibition, inactivation, target site modification

how do efflux pumps work

proteins in membrane that pump antibiotics out of the cell

how does permeability work

outer membrane porins decrease entry of antibiotics into cell

how do β-lactamases work

cleave β-lactam ring leading to inactivation

example of penicillinases (class A)

CTX-M, TEM, SHV, KPC

example of metallo-β-lactamases (class B)

IMP, VIM, NDM

example of cephalosporinases (class C)

AmpC

example of oxacillinases (class D)

OXA

why ESBLs are a big deal

often plasmid-encoded, can carry resistance to other antibiotic classes

3 types of horizontal transfer

transduction (bacteriophages), conjugation (plasmid), transformation (DNA uptake)

staphylococci resistance for penicillin

inactivation (blaZ)

staphylococci resistance for β-lactams

target replacement (mecA -> PBP2a = MRSA)

staphylococci resistance for linezolid

target modification (23S rRNA)

staph and enterococci resistance for daptomycin

drug entry (cell envelope charge repels drug)

enterococci resistance for vancomycin

target replacement (van genes)

enterococci resistance for β-lactams

target modification (pbp5) -> why cephalosporins don't cover enterococcus

streptococci resistance for β-lactams

target modification (PBPs)

fluoroquinolone resistance

target site modification

aminoglycoside resistance

altered ribosomal proteins

novel agent that covers MBL

cefiderocol

meropenem-vaborbactam does NOT cover

OXA-48, MBL

ceftolozane-tazobactam does NOT cover

KPC, MBL

MRSA on BioFire

mecA/C and MREJ

VRE gene on BioFire

vanA/B

how to read MICs

compare to each drug's breakpoint (S/I/R), not other drugs' MIC numbers