ID Basics: Antibiotic Susceptibility Testing/Reporting ... · Antibiotic Susceptibility...

ID Basics:

Antibiotic Susceptibility Testing/Reporting

Antibiotic Pharmacodynamics

Pharmacy Morning Report

September 2016

Dimple Patel, Pharm.D., BCPS-AQ ID

Clinical Pharmacist – Infectious Diseases

Microbiology: Basics

Organism Identification

• Growth characteristics on selective media

o Shape, size, color, smell

• Gram stain – initial step in identification

o Gram-positive

» Thick peptidoglycan layer of cell

wall retains crystal violet stain

o Gram-negative

» Thin peptidoglycan layer of cell wall

does not retain stain –

counterstained with safranin to

characterize morphology

Gram-Positive Organisms

GPC in

pairs &

chains

Gram-Negative Organisms

Acinetobacter

StenotrophomonasMay look like cocco-bacilli

Antimicrobial Susceptibility Testing

Minimum Inhibitory Concentration (MIC)

• Lowest concentration of antimicrobial that inhibits visible growth of

organism

Broth Microdilution E-Test

MIC

Clinical Microbiology Labs

Automated Susceptibility Testing devices

• Perform organism identification and antibiotic susceptibility testing

for many antibiotics in 1 step

MALDI-TOF

Matrix-assisted laser desorption ionization – time of flight mass

spectrometry

7Patel R. Clin Infect Dis 2013;57:564-72.

MALDI-TOF

Spots are shot with UV laser

to desorb and ionize organism

from matrix

Ions travel up analyzer and

collide with ion detector

generating a mass spectrum

Molecular weight is calculated

and matched to organism MW

in MALDI library

Organism identification TAT:

30 minutes

Still requires Microscan for

susceptibility testing

8Patel R. Clin Infect Dis 2013;57:564-72.

How do we know if the MIC is “good enough”?

Breakpoints for susceptibility

• Developed for each bug-drug combination

• Based on achievable blood levels of the drug when

administered at normal doses

Factors considered in breakpoint determination

• PK-PD

• Typical dosing

• Wild-type organism distribution

• Penetration into various body sites (for site-specific

breakpoints)

CLSI M100-S

True/False:

When selecting definitive antibiotic therapy, it is

appropriate to choose the agent with the lowest

reported MIC

Can’t compare MIC’s of 2 different drugs!

• Example – Pseudomonas aeruginosa

• Recall: Susceptibility breakpoint based on achievable blood levels of the drug when administered at normal therapeutic doses▫ Typical dosing:

Piperacillin/tazobactam is dosed 4,500 MG q6h

Ciprofloxacin is dosed 400 MG q8h

▫ Also consider differences in pharmacodynamics Pip/tazo works best if level is above MIC for >50% of dosing interval (time-dependent

killing)

Cipro works best if AUC:MIC ratio > ~100 (exposure-dependent killing)

Susceptible Intermediate Resistant

Piperacillin/tazobactam

≤ 16 32-64 ≥ 128

Ciprofloxacin ≤ 1 2 ≥ 4

> 10-fold difference

Which antibiotic to choose for definitive therapy?

Which antibiotic to choose for definitive therapy?

Consider drug factors: Clinical studies

Tissue penetration

Resistance potential

Collateral damage • narrow-spectrum

therapy is ideal

Cost

Consider patient factors: Allergies

Drug interactions

Renal/hepatic function

Severity of illness

Etc.

Reporting of MIC Values

ESBL Reporting

16

ESBL Treatment

B-lactam/B-lactamase inhibitor (BLBLI) comboso B-lactamase inhibitors inhibit ESBL

o Activity limited by organism burden

Severe systemic infectionso Carbapenems are drugs of choice

o Worse outcomes with B-lactam/B-lactamase inhibitor (BLBLI) combos despite in vitro susceptibility

o Results of BLBLI are suppressed for non-urine ESBL’s

Urinary tract infections• Recent study of ESBL E. coli bacteremia

o Majority were urinary or biliary source

o Tx with BLBLI was not associated with increased mortality or LOS

• BLI levels in urine are likely enough to overcome ESBL

• Results of BLBLI are reported for urine ESBL’s – may consider using in UTI if “S”o But don’t forget aminoglycosides, nitrofurantoin, TMP/SMX,

fluoroquinolones, or fosfomycin for ESBL UTI’s

17

Rodriguez-Bano J, et al. Clin Infect Dis 2012;54:167-74.Retamar P, et al. Antimicrob Agents Chemother 2013;57:3402-4.

18

What does an interpretation of “IB” mean?!

AmpC-Harboring Organisms

Extended spectrum cephalosporinase

AmpC gene harbored chromosomally

o Usually repressed/turned off in wild-type organisms

Primarily CAPES (or SPACE) organisms

o Citrobacter (freundii)

o Acinetobacter

o Pseudomonas, Providencia

o Enterobacter

o Serratia

o (Morganella)

19Jacoby GA. Clin Micro Rev 2009;22:161-82.Macdougall C. J Pediatr Pharmaco Ther 2011;16:23-30.

AmpC: Stable Derepression & Emergence of

Resistance During Therapy

AmpC production is usually repressed

Spontaneous mutants within the population permanently

hyperproduce AmpC these mutants are stably derepressed

• Mutants occur at frequency of 10-5 to 10-8

Selection of stably derepressed mutants can occur during therapy

with ampC-labile β-lactams (usually 3rd generation cephalosporins)

Most commonly a problem with Enterobacter and Pseudomonas


Treatment with 3rd Gen Ceph

AmpC Repressed

AmpC Derepressed

AmpC Substrates (in vitro)

Hydrolyzed by ampC (good substrates)

o Ceftazidime

o Ceftriaxone

o Cefotaxime

o Piperacillin

o Ticarcillin

o Aztreonam

Stable to ampC (poor substrates)

o Carbapanems

o Cefepime


Risk of Emergence of Resistance During Therapy

22Macdougall C. J Pediatr Pharmaco Ther 2011;16:23-30.

CLSI M100-S - Enterobacteriaceae

25

26

“IB” = Inducible B-lactamase

This isolate is currently susceptibleto ceftriaxone – “IB” warns that the isolate may become resistant during therapy via selection of stably derepressed mutants

Tagged as “IB” based on species, not on additional lab testing

27

This isolate is already resistant to ceftriaxone

AmpC is likely already stably derepressed in this population

• CAPES organism• Not a KPC

28

Note: Cefepime retains susceptibility in both isolates

29

Tamma PD, et al. Clin Infect Dis 2013;57:781-8.Siedner MJ, et al. Clin Infect Dis. 2014;58:1554-1563

Study Findings:

• No significant differences in mortality or LOS in patients treated with

cefepime vs. carbapenems for AmpC producing organisms

• Cefepime may be a therapeutic option for invasive infections caused

by AmpC

Conclusions

Cefepime appears to be a good option for treatment of infections

due to organisms that harbor ampCo Carbapenem-sparing

o Appropriate dosing is a must

– CrCl >60: 2 g IV q8-12h

– CrCl 30-60: 2 g IV q12-24h

– CrCl 11-29: 1-2g IV q24h

– HD: 0.5-1 g IV q24h (or 1-2 g after each HD)

Reasonable to use cefepime to treat these infections, especially in

non-critically ill patients

AmpC hyperproduction may be less of an issue for Citrobacter,

Serratia, Providencia, and Morganella

30

Antibiograms

Antibiotic susceptibility “report card”

Cumulative report of local susceptibility patterns to help guide empiric

therapy

o Use patient-specific susceptibility data once available

Updated annually

Minimum of 30 isolates per organism needed for statistical validity of

% susceptible estimate

May run separate antibiogram for:

o Particular units (inpatient vs. ED vs. ICU)

o Specimen sources (urine vs. systemic)

o Special populations (pediatrics, cystic fibrosis)

Example: Hospital Acquired Pneumonia

ATS/IDSA guidelines (2016)

• Choice of anti-pseudomonal B-lactam for regimen

o A look at our antibiogram for Pseudomonas aeruginosa:

» Aztreonam: 77%

» Cefepime: 85%

» Carbapenems: 90%

» Piperacillin/tazobactam: 93% most reliable for empiric

coverage of P. aeruginosa

at MMC

ATS/IDSA. Am J Resp Crit Care Med 2005; 171:388-416.

Antibiotic

Pharmacodynamics

(“what the drug does to the body/bug”)


Minimum Inhibitory Concentration (MIC)

o Antimicrobial concentration that inhibits visible microbial

growth in vitro after an incubation period

o Measure most often used historically to characterize

antimicrobial activity

Lodise TP, Lomaestro BM and Drusano GL. Pharmacotherapy 2006;26(9):1320-32


Limitations of MIC for characterizing antimicrobial activity:o Doesn’t account for changes in drug concentration throughout

dosing interval

o Does not account for interpatient pharmacokinetic (PK)

variability

o Does not provide info on rate of kill (static vs. cidal)

Combining MIC with PK parameters overcomes many of

these limitationso Provides more useful info for predicting outcomes

Lodise TP, Lomaestro BM and Drusano GL. Pharmacotherapy 2006;26(9):1320-32

Antimicrobial PD Overview

Roberts JA, Kruger P, Paterson DL, et al. Crit Care Med 2008;36:2433-2440.

Reproduced for educational purposes

vancomycin

Antibiotic Pharmacodynamic Parameters

Peak: MIC(Concentration-Dependent)

AUC : MIC(Exposure-Dependent)

% Time > MIC(Time-Dependent)

Craig W. Clin Infect Dis 1998;26:1-12.

Goal of therapy: To optimize ß-lactam exposure (time above

MIC) for optimal bactericidal activity

Required unbound % T>MIC for cidal kill:

o 60-70% of dosing interval - cephalosporins

o 50% of dosing interval - penicillins

o 40% of dosing interval - carbapenems

ß-lactam Pharmacodynamics

Drusano GL. Clin Infect Dis 2003;36(Suppl1):S42-50.

Strategies to Optimize Time Above MIC

Using higher doseo Doubling dose only buys you ~1 additional half-life

above MIC (1-2 hours for most ß-lactams)

Increasing dosing frequencyo Using more total drug – safety concerns?

Extending duration of infusiono Lower peaks – ok for ß-lactams

o Longer time above MIC

Piperacillin/Tazobactam Dosing

Kim A, Sutherland CA, Kuti JL, et al. Pharmacotherapy 2007;27(11):1490-7.

New Breakpoint Old Breakpoint

What is the most widely ordered antibiotic at MMC?

a. Cefepime

b. Vancomycin

c. Metronidazole

d. Piperacillin/tazobactam

e. MMCacillin

Vancomycin Background

Spectrum of activity – Gram + only Staphylococcus aureus (MSSA & MRSA)

Coagulase-(-) Staphylococci

Streptococcus spp.

Enterococcus spp. (not VRE)

Corynebacterium jeikeium

Listeria monocytogenes

Gram-positive anaerobes (Actinomyces spp.,

Peptostreptococcus spp., Clostridium difficile, etc.)

Intrinsically Vancomycin Resistant Gram-Positives:

Leuconostoc spp.

Pediococcus spp.

Erysipelothrix rhusiopathiae

Lactobacillus spp. (except acidophilus)

Nocardia spp.

Vancomycin Pharmacokinetics

Absorption:

o Negligible oral absorption

o Severe colitis po vanco for severe C. difficile may result in significant

absorption

Distribution:

o Penetration into most tissues increases with inflammation (i.e. CNS, lung, etc)

o Penetration into skin tissue is significantly lower in diabetics vs. non-diabetics

o Distributes well into adipose tissue – dose based on actual body weight

o Protein biding: ~50%

Metabolism:

o Negligible

Elimination:

o Unchanged via kidneys by glomerular filtration when given IV

o Elimination half life (t1/2) ~4-6 hours in normal renal function

o Oral doses are eliminated in the feces

Vancomycin Pharmacodynamics

Roberts JA, Kruger P, Paterson DL, et al. Crit Care Med 2008;36:2433-2440.

Reproduced for educational purposes only.

vancomycin

Recommendations for Dosing and

Monitoring of Vancomycin

Guidelines can be accessed here: http://www.ajhp.org/content/66/1/82.full

Why so much focus on vancomycin dosing?

Very few antimicrobials in development

Continued emergence of resistance • Vancomycin-intermediate S. aureus (VISA,

hVISA)

• Can be minimized with optimal dosing

Focus has shifted from relying on newer

agents to preserving current agents

Boucher HW, Talbot GH, Bradley JS, et al. Clin Infect Dis 2009;48(1):1-12

Arias CA and Murray BE. N Engl J Med 2009;360(5):439-443

AUC/MIC ≥ 400 - target for clinical effectiveness for MRSA– Correlates to trough 15-20 mcg/mL when MIC ≤ 1

Vancomycin penetration is limited into various body tissues. For patients with serious, deep-seated infections, a trough of 15-20 mcg/mL should be targeted:

– Pneumonia– Osteomyelitis– Meningitis– Endocarditis– Bacteremia

Trough target of 10-15 mcg/mL is appropriate in less severe infections where vancomycin penetration is adequate

– Cellulitis– Urinary tract infection

Rationale for Monitoring Vancomycin Levels: Efficacy

Rybak M, Lomaestro B, Rotschafer JC, et al. Am J Health-Syst Pharm. 2009;66:82-98.

• Most common adverse effects are unrelated to drug

levels:o Infusion-related reactions: fever, chills, phlebitis

o “Red man syndrome”: histamine-mediated flushing of face, neck,

upper torso due to rapid infusion

» Minimized by infusing 1 gram/hour

» May administer antihistamine prior to infusion

» NOT considered an allergy!!!

Rationale for Monitoring Vancomycin Levels: Toxicity


• Initially dubbed “Mississippi Mud” (1950’s and 60’s)

• Many reports of nephrotoxicity and ototoxicity with original formulation

• Product purified over the next 2 decades reports of adverse events dropped off

• serum levels have been implicated in reports of toxicity, and it was assumed that monitoring levels and adjusting doses accordingly would lead to less toxicity

– Cause-and-effect is difficult to study

– Recent studies confounded by concomitant use of known nephrotoxins (aminoglycosides)

» On it’s own, it is not thought to be as nephrotoxic as was once believed

» Reversible upon discontinuation



Vancomycin-Induced Nephrotoxicity Definitiono At least 2-3 consecutive high SCr levels (increase of 0.5 mg/dL or ≥

50% increase from baseline) after several days of vancomycin therapy with no alternative explanation

Limited / conflicting data suggest a direct causal relationship between toxicity and specific levels:

o Evidence does not support monitoring peaks

o Monitor troughs to reduce nephrotoxicity if:

– Aggressive dosing (targeting troughs of 15-20 mcg/mL)

– High risk of nephrotoxicity (concomitant nephrotoxins)

– Unstable renal function

– Receiving vancomycin for > 3 days



Ototoxicity

• Majority of cases were from early reports and were attributed to

impurities in formulation or concomitant ototoxins

• RARE incidence of ototoxicity has not consistently correlated

with serum vancomycin concentrations

• Monitoring of vancomycin levels to prevent ototoxicity is not

recommended



Prevention of Resistance

• Constant exposure of S. aureus to subtherapeutic levels of

vanco development of VISA or hVISA

• Trough vancomycin levels should always be maintained above

10 mcg/mL to avoid the development of resistance

Rationale for Monitoring Vancomycin Levels: Resistance


Question 1

Vancomycin ________ levels are monitored to _____________.

a) Trough; ensure efficacy

b) Trough; prevent ototoxicity

c) Peak; ensure efficacy

d) Peak; prevent nephrotoxicity

55

56

Rationale for Monitoring Vancomycin Levels

TROUGH PEAK

Efficacy

Toxicity

Nephrotoxicity

Ototoxicity

Prevention of Resistance

Question 2

What are the ideal vancomycin trough levels that maximize

efficacy when treating serious infections due to MRSA?

a) 5-10 mcg/mL

b) 5-15 mcg/mL

c) 10-15 mcg/mL

d) 15-20 mcg/mL

57

Recommendations for Vancomycin Dosing

and Monitoring

Initial Vancomycin Dosing: Why isn’t there a standard?

Several dosing nomograms exist for patients with varied

weight/renal function

• Most are old

• Most were validated with targets of 5-10 or 5-15 mcg/mL

• Most were studied using homogenous patient populations

(few critically ill, very old, or obese patients)

No well-validated dosing nomogram has been established to

target troughs of 15-20 mcg/mL

If any one nomogram worked for most patients, we probably

wouldn’t need to monitor levels – lots of interpatient variability!

All vancomycin dosing guidelines provide a first guess and are

often based on population PK estimates

Different Approaches to Initial Dosing….

ASHP/IDSA/SIDP Guidelines:

• Consider 25 mg/kg loading dose in severely ill patients

• 15-20 mg/kg IV q8-12h in patients with normal renal function

• No guidance on initial doses in patients with renal dysfunction

Adjusting weight-based dose AND interval based on renal function

Adjusting only interval based on renal function (example):

• CrCl >80: 15-20 mg/kg IV q8-12h

• CrCl 60-80: 15-20 mg/kg IV q12-24h

• CrCl 20-60: 15-20 mg/kg IV q24-48h

• CrCl <20: 15-20 mg/kg x1, then redose per level


Vancomycin Monitoring

Monitor trough levels at steady state

(3-5 half-lives)

o Typically within 30 minutes prior

to the 4th dose

o Ensure the level is a “true”

trough!

Do not order levels if therapy is not

expected to continue beyond 3 days

Nuances to Interpreting Vancomycin Trough Levels

Must always assess appropriateness of timing of level relative

to the time of the dose:

• If level drawn too soon after dose (not a true “trough”)

will result in a high level but dose adjustment based on this

level may not be appropriate

o Example: Patient receiving 1250 mg IV q12h

Date/Time of Dose Level and Date/Time of Level

Dose 1: 12/10 2200

“Trough” results as 27.4 mcg/mL; Drawn 12/12 0443 (~5 hours too early; Do not hold or adjust dose based on this level; draw trough within 30 minutes prior to next dose)

Dose 2: 12/11 1000

Dose 3: 12/11 2200

Dose 4: 12/12 1000

Vancomycin Trough Level Errors

Specifying the date and time the trough level should be drawn

should minimize most errors related to inappropriately timed levels

63

Nuances to Interpreting Vancomycin Trough Levels

Must always assess appropriateness of timing of level relative

to the time of the dose:

• If level drawn prior to reaching steady state will result

in level lower than “steady state” trough, cannot make

assessments about dosing based on this level

o Example: Patient receiving 1250 mg IV q12h

Date/Time of Dose Level and Date/Time of Level

Dose 1: 12/10 2200“Trough” results as 8.7 mcg/mL; Drawn 12/11 0912 (prior to second dose; Should not make dose adjustments based on this level; draw another trough prior to 4th dose)

Dose 2: 12/11 1000

Dose 3: 12/11 2200

Dose 4: 12/12 1000

Random Levels

• Should only be ordered in patients without standing vancomycin

orders being “dosed per level”

– Typically used in patients with CrCl <20 mL/min

– Typically ordered ~24-48 hours after dose

• May be ordered in patients whose initial standing vancomycin

dose resulted in a supra-therapeutic level

– Subsequent dose held

– Random level monitored to determine when standing vancomycin

should be restarted

• Hemodialysis patients

– Random levels should be ordered on the day of dialysis prior to the

dialysis session

» This is essentially a “trough”

» Inaccurate level if drawn during or after HD due to ~6 hour vancomycin

redistribution phase post HD

Vancomycin Dose Adjustment Guidelines

First assess whether level is accurate and drawn correctly

In general, vancomycin displays fairly linear pharmacokinetics (double the total dose, double the trough)

• One approach to adjusting dose:o Set up a proportion and solve for New Daily Dose:

Observed Trough = Current Daily DoseTarget Trough New Daily Dose

o Divide this new daily dose q8h, q12h, q24h, etc.

o Note – changing the dosing interval tends to have more of an impact on the trough vs. changing the dose

• There will always be exceptions to this – must use judgment when deciding whether to be more aggressive or conservative with dose adjustments

Re-check trough at steady state on the new regimen

Vancomycin Dose Adjustment Guidelines

Hemodialysis Patients

• High-flux hemodialysis (HD) removes ~30% of vancomycin in

body

• Post-HD dose of 7.5 mg/kg (500 mg in most patients) will

replace what was removed during dialysis

• Subsequent post-HD doses may be adjusted using the

proportion method based on pre-HD level

Pearls for Vancomycin Dosing

Initial Dosing

• One dose does not fit all o Must take patient weight and renal function into account

• All weight-based doses are based on Actual Body Weight

• Doses should be rounded to the nearest 250 mg in adults

Monitoring Levels

• Must always assess timing of level relative to dose

• Trough Targets o 15-20 mcg/mL for serious infections

o 10-15 mcg/mL for mild-moderate infections (cellulitis, UTI)

Dose Adjustments

• The proportion method is a good starting point for guiding dose

adjustments

• Changes to the interval impacts the trough more than changes to

the dose

• Should re-check trough at steady state after each dose adjustment

MMC Adult Antimicrobial Guidelines

Thank you!

Contact info:

• Ext. 4313

• Cell: 732-423-6198

• Email: [email protected]

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