MIC KEY

M-O-U-S-E? No.

The minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial that will inhibit growth of a certain microbe.  In the United States, the Clinical and Laboratory Standards Institute (CLSI) provides standardization of MIC determinations and publish guidelines regularly (the European organization is EUCAST).  Each antimicrobial listed in a culture report will be assigned one of three breakpoints determined by CLSI: “susceptible,” “intermediate,” or “resistant.” 

Many factors, including laboratory and clinical information, determine the interpretation of reported MIC breakpoints.  The term “breakpoint” can be thought of three different, yet interrelated, ways. A microbiologic breakpoint is determined by a multitude of in vitro tests evaluating the physical interaction of the drug with the microbe.  A clinical breakpoint factors in whether there is a good chance of infection resolution, mainly based off of clinical studies.  Similar to a clinical breakpoint, pharmacokinetic/pharmcodynamic breakpoints factor for such things as location of infection and ability to obtain proper drug levels in that area of the body.

Let us use the drug daptomycin for a VRE pneumonia as an example.  The drug may have excellent bacteriocidal activity against the specific cultured organism in vitro, but when factoring in clinical and PK/PD data, we know lung surfactant inactivates daptomycin.  We would not be able to successfully treat the infection with this antimicrobial agent.  The MIC report might state “susceptible” in vitro, but clinically it may as well be regarded as resistant. 

Sooo…can’t I just pick the drug with the lowest number next to it that says “susceptible?”

Apples and oranges, my friend.  It is not useful to compare the MIC concentration value of one drug to another.  The MIC expressed in “mg/L” is unique to each drug based off of PK/PD data done with fancy modeling and simulations.  The determination of what concentrations to use when setting up dilutions to test MICs incorporate things like protein binding, tissue distribution, and even the type of bug that was cultured.  Let’s look at an example:

Source: Urine	E. coli >100,000/mL	Status: Final
Results:
Ampicillin	>/= 16	Resistant
Cefazolin	4	Susceptible
Ciprofloxacin	</= 0.5	Susceptible
Gentamicin	</= 2	Susceptible
Nitrofurantoin	</= 32	Susceptible
Piperacillin/Tazobactam	</= 8	Susceptible

Just strictly looking at numbers, it appears ciprofloxacin would be better than the rest since its MIC is </= 0.5 mg/L.  Nitrofurantoin, even though the report says susceptible, has a larger MIC concentration of </= 32 mg/L.  Both would eradicate this microbe with similar efficacy.  Cefazolin has a value of 4 mg/L.  Notice that it does not have the “</=” designation.  This means the MIC for cefazolin is right at the breakpoint of susceptible and intermediate – an MIC of 8 mg/L may read as intermediate.  The number would still be less than 32 such as for nitrofurantoin but would possibly have less chance of clearing the infection.  Also note that resistance is reported for an MIC of 16 for ampicillin.  Even though it is less than 32, the likelihood of ampicillin clearing the infection would be low.

The key to correctly interpreting this data is to also incorporate antimicrobial stewardship.  If this is an otherwise healthy young female with an uncomplicated cystitis, nitrofurantoin should be the drug of choice.  Although other antibiotics are listed as “susceptible,” it’s like using a shotgun when a Nerf gun would do the job.  Nitrofurantoin is only used for this indication and should be considered first.  Ciprofloxacin would cure the infection and isn’t wrong to use in this situation, but we should preserve our use of it for silly things like anthrax and pseudomonas.

Bottom Line:

• Interpreting culture results appropriately requires an appreciation for the microbe species and location of infection
• Comparing MIC concentrations between different drugs is like comparing apples and oranges
• Utilizing an antibiotic with the “</=” designation may be your best bet
• Exercise antimicrobial stewardship and choose the lowest-spectrum antimicrobial that will get the job done
• Consult your friendly pharmacist for assistance

Bugs 'n' Drugs: Vancomycin Dosing

"Hey, Daddy-O.  Are you hip to that newfangled antibiotic, vancomycin?  That stuff is Fat City for beta-lactamase-producing bacteria," said every 1950s physician everywhere.

Ah, a simpler time.  One could just give a patient 1 gram every 12 hours and they'd be riding on easy street.  Today we have some scary bugs and not enough antibiotics to cover them.  To further complicate things, we are struggling with the phenomenon of the vancomycin MIC creep - it means our vancomycin susceptibilities are worsening.  The worst thing our 1950s counterparts had to worry about was not letting "Rock 'n' Roll" poison America's youth.  It's too late for that, but it's not too late to optimize our vanco dosing strategies to help decrease resistance!  Hooray!

Vancomycin is a weird drug.  The pharmacokinetics and dynamics are a bit more complex than other medications.  For instance, it is neither fully a time-dependent antibiotic (beta-lactams), nor a fully concentration-dependent antibiotic (aminoglycosides).  Many different kinetic models have been proposed, but the general consensus is that it involves the ratio of the area under the drug concentration-versus-time curve and the MIC.  We call it the AUC/MIC ratio.

This simply means the trough level we obtain is a marker for an appropriate AUC/MIC ratio.  We know that we need to target a trough of 10 mg/L for a bug with an MIC <1.  The trough required for an MIC = 1 is around 15 mg/L.  As the MIC approaches 2 or more, we can no longer use vanco as a treatment option.  We are seeing MICs of 1 and 1.5 far more than we previously have.  Two ways of combating the vancomycin MIC creep is to do the standard antimicrobial stewardship (no more vanco x1 dose and d/c on oral antibiotics), and appropriately dose the drug.  

Due to the complex kinetics involved, there are a multitude of dosing strategies.  Each institution may do things differently based on practicality and accuracy of the pharmacy kinetic team.  However, each strategy is based off of two things: body weight and renal function.

Standard Method:

• Most common dosing technique
• Load 20-25 mg/kg (max. 2000 mg)
• 15 mg/kg at various intervals (every 8, 12, 24, etc. hours) based on renal function

Our pharmacy uses the Rodvold Method with a couple twists.  This is based of off years of kinetic data and how our pharmacy team has done in regards to obtaining a target trough.  I won't bore you with the details, but just know we rarely do a loading dose and rarely dose at 8-hour intervals.

I'll cut to the chase.  1,000 mg of vanco is not a one-size fits all dose.  We have to be sure we are setting up these patients for success during their hospital course.  Here is my recommendation for when your friendly ER pharmacists are not around: 

• To the right of the vanco order in our system, click on the grey box with the ellipsis in it.  Select "Vanco Rx to Dose."  The RN will then call down to the main pharmacy where our team will conjure up a dose using our vanco voodoo.

• Dose it yourself. It's super fun! I recommend a 15-20 mg/kg one-time dose using actual body weight, rounded to the nearest 250mg.  We will take care of the dosing interval when it gets continued in-house.  

Bottom line:

• Vanco dosing is patient-specific
• 15-20 mg/kg one-time dose with a max of 2 grams, or
• Utilize "pharmacy to dose" function
• Under-dosing vanco will increase the time required to get to a therapeutic trough
• One gram q12h for everyone is not recommended