Lesson #5: Vancomycin Monitoring
Great work! That was probably the hardest part of your journey. We are glad you made it this far. Now that you have gotten some practice using the equations, it is time to collect some data by evaluating trough levels.
Measurements of vancomycin serum concentrations are recommended if the therapy is expected to continue for 72 hours or longer. Vancomycin is believed to display time-dependent bacterial killing; therefore, monitoring of peak concentrations is not routinely recommended. Instead, serum trough concentrations should be obtained before the next steady-state dose (~4-5 half-lives).
Therapeutic Plasma concentrations:
- Peak = 30-40 mcg/mL
- Trough = 10-20 mcg/mL
Indication | Recommended trough range |
Severe infections: | 15-20 mcg/mL |
Uncomplicated infections: | 10-15 mcg/mL |
*2020 Guideline Update Alert*
ASHP released new consensus guidelines recommending changes in vancomycin monitoring that emphasized a AUC/MIC ratio of 400-600 (assuming a MIC of 1 mg/L) over targeting a goal trough of 10-20 mcg/mL. Bayesian software programs, compared to traditional PK calculations, are recommended to evaluate daily AUC values and trough-only monitoring is not recommended. If Bayesian software is not available, AUC can also be manually calculated using first-order PK equations using two levels (peak and a trough). This change in practice will require further education to pharmacists and nurses to ensure success.
Ordering Troughs
Trough levels are drawn when the drug is expected to reach steady-state concentrations (~ 4 to 5 half-lives). This may vary between institutions, but the general rule is listed below.
Dosing interval | Trough should be drawn: |
Q8hr, Q12hr | 30 minutes prior to the 4th dose |
Q24hr | 30 minutes prior to the 3rd dose |
Pulse dosing or Hemodialysis | 24 hours after the loading dose then every 24-48 hours or when level is expected to be <20 mcg/mL |
In patients with Q24hr dosing intervals, serum trough concentrations are drawn before the 3rd dose for earlier evaluation of drug concentrations with the understanding that the trough level is not completely at steady-state and will be higher as doses accumulate. (ex: if the level comes back 13 mcg/mL before the 3rd dose, you would not need to change the regimen as the level will be higher once serum concentrations reach steady-state)
If a loading dose is administered, it can be counted as the first dose when timing a trough level.
BACK TO DR. VANKO: Blood cultures have returned growing methicillin-resistant staphylococcus aureus (MRSA) sensitive to vancomycin. We want to continue vancomycin for at least 5 days until the first negative blood culture so we need to order a trough level.
TEST MY KNOWLEDGE
Checking Levels Earlier
Vancomycin trough levels are usually drawn at steady-state concentrations. However, there may be situations where you can check a trough earlier:
- Worsening renal function
- Clinical condition is deteriorating (e.g. fevers, leukocytosis, hypotension)
- Concerns for toxicity (e.g. acute kidney injury)
Acute kidney injury is defined as:
- Scr increase of 0.3 mg/dL over <48 hours OR
- Increase in Scr >1.5 times baseline OR
- Urine output < 0.5 ml/kg/hr for 6 hours
Evaluating Trough Levels
You have done the hard work calculating what dosing regimen to give, and now have successfully ordered and received a trough level back. Before you pat yourself on the back for a job well done or lose your cool because the trough level came back >25 mcg/mL, I want you to repeat the following:
“Was this trough drawn at the appropriate time?”
Half of all vancomycin levels are drawn either too early or too late. These incorrect levels can lead to misinterpretation and inappropriate dose adjustments.
In addition to evaluating the time the trough was drawn, it is helpful to review the previous doses to determine if administration times were appropriate (e.g., given 8 hours apart if the regimen was q8hr) as this can affect the interpretation of your trough value.
In the event that the trough was not drawn at the appropriate time, the following equation can be used to calculate an extrapolated trough.
Extrapolated trough = Ctrough x e-Ket
For example: Patient is on 1000 mg every 12 hours and the trough returned = 21 mcg/mL (drawn 2 hours early). What would the extrapolated trough be if the level was drawn on time, considering ke = 0.0084 and t is the time in hours it was drawn inappropriately (ex: 2 hours early)?
Extrapolated trough = 21 x e ^(-0.084 x 2) =18 mcg/mL (so keep cool and carry on)
If the trough was drawn 2 hours LATE instead of early, the extrapolated trough would be:
Extrapolated trough = 21 x e^(-0.084 x -2) = 25 mcg/mL
Adjusting the Regimen
There are generally two accepted methods for adjusting your dosing regimen. Method #1 utilizes patient-specific kinetics to determine a new dose and interval that will get the patient to therapeutic goals. Since vancomycin follows linear kinetics, Method #2 can also be used to determine a new dosing regimen. Let’s take a look at both.
Method #1:
Ke = (-) ln {(Ctrough x Vd / dose) / [ 1 + Ctrough x Vd / dose)}
Dosing interval (T)
Before, we were using an estimated population kinetics to determine a dose for the patient. Now that we have a measured trough level, we can calculate the patient’s specific elimination constant (Ke) to determine the new dosing regimen.
Once you have obtained the patient’s specific elimination constant, you plug it into the same vancomycin equations previously discussed to determine a new maintenance dose and interval.
Method #2:
Since vancomycin follows linear kinetics, ratio and proportions can be used to determine the new dose or X.
Dose = New dose (X)
Trough obtained Goal trough
Since vancomycin follows linear kinetics, ratio and proportions can be used to determine the new dose or X.
Example: Dose is 1250 mg every 12 hours and measured trough 10 mcg/mL drawn at the appropriate time.
New dose is: 2500/10 = x /15 x = 3750 mg so the new dosing regimen will be 1250 mg q8hrs (3750 mg/3)
The general rule of thumb is if your trough level is way off from your goal, like the example above, adjust your interval. However, if your trough level is closer to your goal, then adjust the maintenance dose.
Trough levels | Recommendation |
Very low (e.g. <10 mcg/mL) | A new loading dose may be given and the interval will need to be shortened |
High 20-25 mcg/mL | Decrease the dose or interval |
Very high >26 mcg/mL | Hold the dose of vancomycin and draw a random level in 24 hours. If level returns <20 mcg/mL, consider re-initiating vancomycin at a lower dose or longer interval |
TEST MY KNOWLEDGE
You’re mighty impressive! Now it’s time to complete the FINAL quiz and help Dr. Vanko escape the lab. Hurry before it is too late!
Lesson #5: Vancomycin Monitoring Read More »
Lesson #4: Vancomycin Dosing
After reviewing the important terminology, background, and equations, it is finally time to grab your calculator.
You will be going through step by step on considerations when dosing vancomycin and will get the opportunity to practice and test your comprehension of the equations.
So, if you are ready, let’s get started!
Step 1: Assess the Patient
Before you start on your calculations, it is important to assess whether it is appropriate to give vancomycin by checking the following:
- Allergies
- Indication for therapy
- Current antibiotic therapy
- Microbiology results if available
- Serum creatinine (Scr)
Allergies
Determine if the patient has had anaphylactic reactions to vancomycin in the past. Oftentimes, vancomycin-infusion reactions (previously known as red man syndrome) are listed as an allergy though it is not a true allergic reaction but a rate-dependent infusion reaction that can be avoided by extending the infusion time.
Indication for therapy
Evaluate whether vancomycin is appropriate to give. This can be difficult as vancomycin is oftentimes ordered empirically while awaiting cultures to result. The CDC has established guidelines on situations where vancomycin is appropriate to give:
- Serious infections caused by beta-lactam-resistant gram-positive organisms
- Infections caused by gram-positive organisms in patients with serious allergies to beta-lactam antimicrobials
- Antibiotic-associated colitis
- Prophylaxis for endocarditis
- Prophylaxis for major surgical procedures at institutions with high rates of MRSA or MRSE
Current antibiotic therapy
Review the patient’s antibiotic regimen and assess if it is appropriate.
- If we are starting vancomycin, is the patient currently on another antibiotic that covers the exact same organisms? If so, is double coverage needed?
- Is vancomycin an appropriate antibiotic to give based on the infectious disease we are treating? (e.g. we would not want to give IV vancomycin if we are treating Clostridioides difficile, we would switch it to oral vancomycin which does not require us to calculate a dosing regimen)
- Will vancomycin cover the suspected organisms for the infectious disease we are treating? (e.g. vancomycin does not cover pseudomonas so we would want to pick another antibiotic)
Microbiology results if available
Review the patient’s cultures (e.g. blood cultures, urine cultures, sputum cultures) and assess for opportunities to narrow therapy or change therapy based on antibiotic resistance.
Serum creatinine (Scr)
Assess the patient’s renal function by collecting important laboratory values such as serum creatinine.
Back to Dr. Vanko
During this time, Dr. Vanko developed fevers and a high white count. Blood cultures were drawn, and preliminary results show staphylococcus in the blood. No sensitivities have returned yet.
In the meantime, it was decided that he should be put on broad-spectrum antibiotics, vancomycin and cefepime. I like to call this very popular combination, vancopime. 
Dr. Vanko
Age: 65 years old
Height: 176 cm
Actual body weight: 72 kg
Allergies: atorvastatin, peanuts
Temp: 100.4° F
WBC: 24
Scr: 1.2
TEST MY KNOWLEDGE
Step 2: Calculate the Creatinine Clearance
The next step is to calculate an estimated creatinine clearance (CrCl) using the Cockcroft-Gault formula
CrCl (female) = CrCl (male) x 0.85
Clinical Note
This step may seem deceptively easy, but a lot of people tend to over or underestimate a patient’s CrCl by inputting incorrect weights and Scr into the equation. The CrCl is the backbone for all further pharmacokinetic equations, so it is important to estimate it correctly! Let us take a moment and discuss it through.
- Ideal body weight (IBW) (men) = 50 kg + 2.3 kg for each inch over 5 feet
- Ideal body weight (IBW) (women) = 45.5 kg + 2.3 kg x for each inch over 5 feet
Weight
When determining the weight used for the CrCl equation, ideal body weight is recommended unless:
Scenario | Recommended weight to use: |
Actual body weight <IBW | Actual body weight |
Actual Body Weight >30% over IBW | Adjusted body weight |
Dr. Vanko, 65 year old Male
Height: 5’9” (69.3 inches)
Actual body weight: 72 kg
Allergies: atorvastatin, peanuts
Temp: 100.4° F
WBC: 24
Scr: 1.2
TEST MY KNOWLEDGE
Serum Creatinine
Clinical judgment is needed when deciding what Scr to use. Why can’t we use the patient’s Scr that we obtained from their lab work, you ask? Well, it turns out that Scr is not the best marker for renal status in patients who have low muscle mass (e.g., bed-bound, elderly). Because of this, we will have to ‘tweak’ our Scr value in certain circumstances. Mastering this will require some experience and practice on your end, but be sure to refer to your institution’s policy.
Scenario | Recommended Scr to round to: |
Scr <0.8 mg/dL | 0.8 mg/dL |
Age >65 years or quadriplegic/bed bound | 1 mg/dL |
Dr. Vanko, 65 year old Male
Height: 5’9” (69.3 inches)
Actual body weight: 72 kg
Allergies: atorvastatin, peanuts
Temp: 100.4° F
WBC: 24
Scr: 1.2
TEST MY KNOWLEDGE
Step 3: Determine Your Dosing Strategy
Now that you have calculated the patient’s CrCl, the next step is to determine your approach to dosing based on the patient’s renal function.
In a patient with good renal function, you want to continue with scheduled vancomycin dosing calculating a maintenance dose and interval.
In a patient with unstable renal function (AKI) or poor renal function (CKD), you would want to dose by levels or start hemodialysis dosing.
Vancomycin renal dosing strategies are discussed in another course.
TEST MY KNOWLEDGE
Step 4: Loading Dose
Loading doses are strongly recommended in severe infections (e.g., sepsis, bacteremia), obesity, or any time steady-state concentrations are difficult to achieve. Compared to the equation for maintenance dose, the loading dose equation is not dependent on renal status; therefore, administration of a loading dose can be considered without regard to the patient’s creatinine clearance.
There are two methods for calculating a loading dose.
Method #1: Use the weight based equation
LD = 20-25 mg/kg x actual body weight
Method #2: Use the pharmacokinetic equation
LD = desired peak x Vd.
For desired peak, use estimated peaks of 30-40 mcg/mL.
*2020 Guideline Update Alert*
ASHP released new recommendations in critically ill patients with suspected or documented serious MRSA infections, a loading dose of 20-35 mg/kg (max dose of 3,000 mg). The magnitude of the loading dose should be driven by the severity of the infection and the need to get to therapeutic concentrations rapidly.
TEST MY KNOWLEDGE
Step 5: Calculate the Dosing Interval
Now that you have the patient’s creatinine clearance, you can calculate the estimated elimination constant (Ke). We will need this to calculate an interval for the patient.
Ke = (0.00083 x CrCl + 00.0044)
TEST MY KNOWLEDGE
In practice, there are two methods for calculating the dosing interval
Method #1: Use the dosing interval equation
Estimated Dosing Interval = [ln (desired peak/desired trough) / Ke] + t’
This method allows you to estimate a more precise interval that correlates to your patient’s estimated creatinine clearance.
Dosing intervals should be rounded to clinically acceptable intervals of 8 hours, 12 hours, 18 hours, 24 hours, etc.
Method #2: Determine an interval off of estimated population creatinine clearance tables
Creatinine Clearance (mL/min) | Recommended Interval |
>90 | Q8hr |
50-90 | Q12hr |
15-49 | Q24hr |
<15 | Pulse dosing |
Reference: Lexicomp Inc.
TEST MY KNOWLEDGE
Step 6: Calculate the Maintenance Dose
In practice, there are two methods for calculating the maintenance dose
Method #1: weight-based calculation using the actual body weight
MD = 15 mg/kg x Actual Body Weight
Method #1 is often the most popular method
Method #2: using the maintenance dose pharmacokinetic equation
MD = LD x 1-e-KeT
Method #2 can be calculated by hand or using an institution-approved dosing calculator
Regardless of the method chosen, remember to round the dose to the nearest 250 mg increments.
TEST MY KNOWLEDGE
Step 7: Calculate the Estimated Peak and Trough
To determine the estimated peak and trough from the dose and interval you have chosen, the following equations are used:
Cpeak = (Dose/t’)(1-e-Ke(t’)) / Vd(Ke)(1-e-Ke(T))
Cmin = Cpeak (e-Ke(T-t’))
In practice, institution-specific calculators are used to assist with calculating a peak and trough.
TEST MY KNOWLEDGE
As you can see from this example, 750 mg every 12 hours will get us closer to the desired goal trough and peak.
Whohoo! You made it through the TOUGHEST section. Those calculations were just a warmup. If you’re looking to get additional practice. Check out this worksheet for additional vancomycin dosing problems!
Let’s review what you have learned about vancomycin dosing in this quick 5-minute quiz.
Lesson #4: Vancomycin Dosing Read More »
Lesson #3: Equations Explained
Now on to the fun part! Let’s take a look at some of the fundamental equations and break them down. Our goal is to understand the rationale behind the equations, increasing our confidence in applying them to save Dr. Vanko. But keep in mind, a miscalculation could lead to grave outcomes. (no pressure 
)
Loading Dose (LD) | 20-25 mg/kg x Actual body weight |
Volume of Distribution (Vd) | 0.7 L/kg x Actual body weight |
Elimination Constant (Ke) | 0.00083 (CrCl) + 0.0044 |
Interval (T) | In(desired peak/desired trough)/Ke + t’ |
Maintenance dose (MD) | LD x 1-e-KeT |
Peak (Cpeak) | (Dose/t’)(1-e-Ke(t’)) / Vd(Ke)(1-e-Ke(T)) |
Trough (Cmin) | Cpeak (e-Ke(T-t’)) |
Vd = volume of distribution, Ke = elimination constant, T= interval, t’ = infusion time
Loading Dose
LD = 20-25 mg/kg OR LD = desired peak x Vd
Loading doses are used to get the patient to therapeutic drug concentrations quicker. The thought behind the practice is to ‘fill the tank‘ since we are starting from nothing. Loading doses are recommended in severe infections (e.g. sepsis, bacteremia, meningitis) where rapid attainment of therapeutic drug concentrations are desired to prevent adverse outcomes.
In general, we want to use the lower loading dose range (20 mg/kg dose) in indications with a lower trough goal (10-15 mcg/mL) and the higher range (25 mg/kg) in indications with a higher trough goal (15-20 mcg/mL).
Goal Peak | Goal Trough | Loading dose |
30 mcg/mL | 10-15 mcg/mL | LD = 20 mg/kg x total body weight* |
35 mcg/mL | 15-20 mcg/mL | LD = 25 mg/kg x total body weight* |
*Total body weight = actual body weight
Another method of calculating the loading dose is with the equation LD = desired peak x Vd. Taking a closer look at this equation, you will find that it is familiar. It is the same equation as the volume of distribution equation we previously reviewed, just rearranged to find the dose.
or Dose (mg) = Concentration (mg/mL) x Volume of distribution
In this example, knowing the population estimated volume of distribution and the desired concentration (or peak), you are trying to find the dose (or amount of sugar dissolved in the container as discussed in lesson #1) to achieve that.
This equation allows you to target a goal peak. Common goal peaks range from 30-40 mcg/mL.
It is important to follow your institution’s policy as each institution will have specific indications for loading as well as the maximum dose allowed.
Volume of Distribution
Vd = 0.7 L/kg
As discussed previously, the equation for determining the volume of distribution is:
Why then is the equation for the volume of distribution of vancomycin 0.7 L/kg?
This equation was derived from population kinetic studies, in which a large sample of patients was administered vancomycin and then plasma concentrations were drawn and compared to the doses given. The average volume of distribution per weight of the patients in this study resulted in the commonly used Vd equation 0.7 L/kg.
The volume of distribution can vary significantly between patients with ranges reported in the literature from 0.5-1 L/kg, making determinations of an exact dose rather tricky. That is why population kinetics is an estimation all around! 😎
Elimination Constant
Population Ke = 0.00083 (CrCl) + 0.0044
Ke is the elimination constant or the fraction of vancomycin that is eliminated from the body per unit of time. Because vancomycin is primarily eliminated via the kidneys, the elimination constant is directly related to Creatinine Clearance.
This equation is derived similarly to the volume of distribution equation. Population kinetic studies were conducted in a random group of people with Ke plotted against Creatinine Clearance resulting in a line of best fit (y = mx + b) shown below.
Half-Life
Estimated half-life (t1/2) = 0.693/Ke
Half-life is defined as the time it takes for the concentration of the drug to decrease by 50% in the body as shown in the graph below. After 4-5 half-lives, drug concentrations reach negligible levels in the body.
If you have taken chemistry, you may remember learning how to calculate the half-life of a radioactive substance (ex: uranium) as it decays or using half-life to determine the age of a piece of coal. The half-life equation for vancomycin is essentially the same.
The numerator is the natural log of 2. Knowing what the patient’s elimination constant is, you are calculating how long it will take the serum concentration of drug to decrease by half. A simplified way to think of it is shown below.
Goal peak = 30 mcg/mL —> after 1 half-life concentrations will decrease by 50% —> 15 mcg/mL
Redose the patient after each half-life to keep drug concentrations within the goal trough of 15 mcg/mL
The half-life can be used to determine the dosing interval.
General rule: you do not want to use an interval that is LESS than your calculated half-life as this can lead to overaccumulation and high drug concentrations (example: using a dosing interval of every 12 hours when your t1/2 was 16 hours). However, if you make the clinical judgment to use an interval that is less than your calculated half-life, decrease your maintenance dose to 10-12 mg/kg to ensure trough levels stay within the goal. If you’re unsure, you can input your calculated maintenance dose and interval into the estimated peak and trough equations to get a better idea.
Interval
Estimated interval = In (desired peak/desired trough)/ (Ke + t’)
Where t’ = infusion time is usually 1 hour
To calculate the interval, the equation requires you to input the desired peak (Cpeak) of 30-40 mcg/L.
Since the half-life and interval equations are both dependent on clearance (Ke) to determine how much of the drug will be eliminated from the body, they produce similar results. For the most part, if you memorize the half-life equation (t1/2 = 0.693/Ke), it should be around the same as your interval equation. You just have to add in your infusion time. Let’s test it out for fun! 
It is important to round your calculations to their nearest standard intervals (e.g. every 8 hours, 12 hours, or 24 hours).
Maintenance Dose
MD = LD x 1-e-KeT
The maintenance dose equation calculates the amount of drug lost from the loading dose at the end of the interval previously determined. This amount becomes your maintenance dose.
For example:
- You administer a loading dose of 2,000 mg.
- Based on your calculations, the patient’s elimination constant and interval come out to be Ke = 0.073 and T = 12 hours. Remember that the elimination constant and interval equations have already taken into account your desired peak (30 mcg/mL) and trough (15 mcg/mL).
- Approximately 12 hours after you have given your 2,000 mg loading dose, the amount of drug eliminated will be 1,167 mg, where the drug concentration is expected to be around 15 mcg/mL.
- Your maintenance dose would be 1,250 mg rounded to the nearest 250 mg increments.
Peak
Peak (Cpeak) = Dose/t’)(1-e-Ke(t’)) / Vd(Ke)(1-e-Ke(T))
After calculating your maintenance dose and interval rounded to the nearest increments, you want to determine what your Cpeak will be. This requires you to utilize the Cpeak equation above. It’s a pretty busy equation so it’s okay if you’re eyes are spinning out of your head now. 
Simply put, the equation is a component of the time it takes for the drug to infuse into the blood circulation over the elimination of the drug from the body. When these two components reach equilibrium you have to achieve maximum blood concentration in the body. The amount goes in = the amount eliminated 🧘.
Trough
Trough (Ctrough) = Cpeak (e-Ke(T-t’))
After calculating the estimated peak (Cpeak), you can calculate what the trough level will be at the end of your dosing interval.
This gives you the estimated trough at steady state.
Great job finishing Lesson #3: Vancomycin Equations! You are over halfway done with your mission. Now on to the next quiz to see how well you know these equations. If you obtain 80% on the quiz, you will unlock a special token (vancomycin equation cheat sheet) to help you with the rest of your journey. Good luck!
Lesson #3: Equations Explained Read More »
Lesson #2: Vancomycin Background
Vancomycin belongs to a class of antibiotics called glycopeptides. Drugs in this class are composed of a cyclic peptide bound by two sugar molecules (glycogen), hence the class name glycopeptide!
Vancomycin’s stem “-mycin” is derived from Streptomyces bacteria, reminding us that vancomycin mainly covers gram-positive organisms.
Additional antibiotics in the glycopeptide class include:
- Dalbavancin
- Telavancin
- Oritavancin
The newer antibiotics in this class all end in –vancin as in similar to vancomycin.
Mechanism of Action
Gram-positive bacterial cell walls are made of a peptidoglycan matrix that gives them structure and rigidity. This is done via transpeptidase-mediated cross-linking as shown in the figure below.
Side Note – transpeptidase is a type of bacterial enzyme or molecule that cross-links peptidoglycan chains making the cell wall stable and rigid.
Vancomycin binds to D-alanyl-D-alanine (also known as D-ala-D-ala) terminus portion of the peptide precursor on the outer surface of cell membranes preventing transpeptidase-mediated cross-linking. Preventing peptidoglycan cross-linking interferes with cell wall synthesis resulting in weak bacterial cell walls and ultimately cell death.
Another way to look at it!
The cell walls are like LEGO pieces linking together. The more that are linked, the stronger the structure or cell wall becomes. Vancomycin prevents cross-linking by attaching to the nubs of the LEGO pieces (D-ala-D-ala), therefore preventing cross-linking. Check out the beautiful illustration below to get a better understanding.
Ultimately, this leads to an unstable structure and the LEGO pieces break apart leading to bacteria death. This is how vancomycin exhibits bactericidal killing versus bacteriostatic.
- Bactericidal: killing the bacteria
- Bacteriostatic: prevents the bacteria from replicating
MNEMONIC:
Bactericidal drugs cause bacteria to be suicidal and die while
bacteriostatic drugs cause bacteria to be static and unmoving
Vancomycin Coverage
Mainly gram-positive cocci
- Staphylococcus aureus (including MSSA and MRSA)
- Staphylococcus epidermidis (including MSSE and MRSE)
- Streptococcus spp.
- Enterococcus spp.
- Clostridioides difficile
Interesting fact
Gram-negatives do NOT have a thick cell wall and lack the D-ala-D-ala sequence, making vancomycin useless against them
Vancomycin Side Effects
Like most drugs administered intravenously, vancomycin can cause infusion-related reactions causing hypotension, redness, and itching. Other common side-effects of vancomycin include:
- Nephrotoxicity
- Ototoxicity
- Thrombophlebitis
- Vancomycin infusion reaction (VIR) – previously known as “red man syndrome”
A mnemonic to remember these side-effects would be that vancomycin can cause a TON of Vancomycin infusion reactions
Thrombophlebitis
Ototoxicity (rare)
Nephrotoxicity
Vancomycin infusion reactions
Vancomycin Pharmacokinetics
ABSORPTION:
Oral vancomycin has a bioavailability of <10% and is therefore poorly absorbed from the gastrointestinal tract. It should only be given intravenously when treating systemic infections.
EXCEPTION: Vancomycin is given orally in Clostridium difficile-associated colitis as high concentrations are achieved in the colon. Trough levels are not needed as it is not absorbed from the GI tract into the bloodstream.
METABOLISM:
Vancomycin is mainly given via injection directly into the bloodstream. Therefore, vancomycin undergoes no metabolism and is excreted unchanged in the urine.
DISTRIBUTION:
Vancomycin has a large volume of distribution, Vd = 0.7 L/kg, distributing well into tissues and intracellular fluids. The only exception is cerebrospinal fluid (CSF), where vancomycin has poor penetration. This changes when the meninges are inflamed, leading to better penetration of vancomycin during meningitis. (How convenient 😎)
Since vancomycin distributes well into most tissues, total/actual body weight is recommended for calculations versus ideal or adjusted body weight. At some institutions, morbidly obese patients are dosed based on adjusted body weight while others dose on total body weight and cap their dose at 2,500 mg. It is important to follow your institution’s policy as it relates to morbidly obese patients.
*2020 Guideline Update*
ASHP updated their recommendations in obesity, encouraging the use of actual body weight for vancomycin dosing and capping the dose at 3,000 mg for loading doses and 4,500 mg/day for empiric maintenance doses.
ELIMINATION:
- IV vancomycin is primarily eliminated by the kidneys
- Oral vancomycin is primarily eliminated in the feces
Vancomycin exhibits first-order elimination where a constant proportion or percentage of the drug is eliminated over a period of time versus a constant amount. (🧠 Remember the mnemonic from our last lesson: you have to FIRST cut the pie into PORTIONS)
Vancomycin Therapeutic Goals
Vancomycin requires routine drug monitoring to ensure effectiveness and prevent adverse effects. Trough levels are drawn to measure therapeutic outcomes because vancomycin follows time-dependent killing. These levels are drawn 30 minutes prior to the administration of the next dose to ensure that drug concentrations are maintained above the minimum inhibitory concentration (MIC).
Trough goals based on indication (KNOW THIS):
- 10-15 mcg/mL: urinary tract infections (UTI), cellulitis
- 15-20 mcg/mL: bacteremia, pneumonia
Interesting fact
Back in the days, goal troughs used to be lower (5-10 mcg/mL) for serious infections. However, since resistance rates have increased, higher goal troughs are needed to adequately treat the infection
*2020 Guideline Update Alert*
ASHP released new consensus guidelines recommending changes in vancomycin monitoring that emphasized a AUC/MIC ratio of 400-600 (assuming a MIC of 1 mg/L) over targeting a goal trough of 10-20 mcg/mL. Bayesian software programs, compared to traditional PK calculations, are recommended to evaluate daily AUC values and trough-only monitoring is not recommended. If Bayesian software is not available, AUC can also be manually calculated using first-order PK equations using two levels (peak and a trough). This change in practice will require further education to pharmacists and nurses to ensure success.
That’s it! You have finished the second lesson. Do you think you have mastered the understanding of vancomycin? We will just have to put your knowledge to the test.
You will be asked a series of questions. If you pass, you will gain access to unlock the next lesson and be one step closer to escaping the lab.
Lesson #2: Vancomycin Background Read More »
Lesson #1: Important Terminology
Welcome to the first part of your journey!
I know you probably have your calculators out and are ready to do some practice problems, but first, we need to review some essential key terms to ensure your success in this course. Take a look at the words below. Do they ring any bells? If it does, it is because you have probably come across many of these words in various pharmacokinetic lessons. Let’s take a moment and review them!
NOTE: If you feel comfortable with these terms, feel free to scroll down to the end and complete the quiz to move on to the next lesson.
| Peak | Highest serum concentration of a drug achieved in the bloodstream collected 1-2 hours after the completion of infusion |
| Trough | Lowest serum concentration of a drug in the bloodstream collected prior to the administration of the next dose |
| Half-life (t ½) | The time required for serum concentrations of the drug to decrease by 50% |
| Steady State | When serum drug concentrations in the body remain constant. For most drugs this is around 4-5 half-lives. |
| Volume of distribution | Value of the physiologic volume of blood and tissues that the drug binds or distributes into (e.g. higher Vd, the more the drug distributes into tissues and the lower the Vd the more the drug stays in the blood) |
| Creatinine Clearance | Value that determines how well the blood plasma is cleared of creatinine per unit of time by the kidneys. It is a measurement of renal function and correlates with how well drugs will be eliminated from the kidneys. |
Topic: Absorption
Definition:
Absorption is the amount of drug that is absorbed at the site of administration (e.g., gut, lungs, intramuscular, rectal, topical,etc.) and enters the blood circulation. Intravenous drugs are not absorbed since they are injected directly into the bloodstream and, therefore, are considered 100% bioavailable.
How drugs cross membranes:
Unless administered intravenously, all drugs have to cross a membrane to be absorbed and reach the site of action. There are two main ways most drugs achieve this, passive or active diffusion.
Passive diffusion
Passive diffusion is the passage of drugs across the cell membrane (e.g., from gut to the bloodstream) from a higher concentration gradient to a lower concentration gradient. The vast majority of drugs utilize this type of absorption.
Certain characteristics allow drugs to diffuse easier across membranes:
- Smaller in size
- Uncharged or unionized
- Lipid soluble
- Weak acids and bases
‘Essentially, the smaller, weaker, uninteresting, and slippery (lipids) a drug is, the easier it passes through membranes and gets absorbed into the circulation!’
Active transportation
Active transportation is the passage of drugs across the cell membrane using energy in the form of ATP, hence the name active. This type of absorption is usually limited to drugs that are structurally similar to other substances in the body (e.g., ions, vitamins, proteins, amino acids).
Why is absorption important?
How well a drug is absorbed is linked to the drug’s bioavailability. The higher the amount of drug that is absorbed, the higher blood concentrations will be leading to increased bioavailability. If a drug’s oral dose is the same as it’s IV dose (such as levofloxacin), then it has a bioavailability of 100%, or 1. A drug’s bioavailability is particularly important when deciding which medication to give in serious infections (e.g., bacteremia) where higher drug concentrations are desired.
Topic: Distribution
Once a drug is absorbed, it distributes throughout the body via the bloodstream. The bloodstream acts as an internal highway transporting drug molecules to target organs where it intends to work as well as other tissues, where unwanted side effects or adverse reactions can occur. This process is described as distribution, by which drug molecules move from the bloodstream to various tissues and organs of the body.
How widespread a drug distributes in the body depends on the drug molecule’s characteristics.
• Lipophilic drugs tend to distribute into fat tissues
• Highly protein-bound drugs can accumulate in certain organs
• Small, lipophilic drugs can cross the blood-brain barrier into the central nervous system
Do these characteristics sound familiar to you? If so, good. They are the same characteristics that make a drug molecule more easily absorbed from its site of administration. Our body is made of the same cellular membranes, so having the same features can help facilitate distribution.
To relate distribution to the pharmacokinetics of drugs, we use the term volume of distribution (Vd). The volume of distribution estimates the apparent volume that the drug dissolves in. This volume is a representation of the different fluid and tissue compartments in our bodies.
For example:
Suppose you dissolve 100 mg of sugar in a container of unknown size. You take a sample of the dissolved mixture and find that the concentration is 1 mg/mL (don’t ask me how you were able to find this concentration – maybe you have a special lab in your basement). Utilizing the simple equation below, you can figure out what volume of liquid the container holds.
Let’s try our example now in the human body.
You give your friend 500 mg of a drug to test your experiment. They were kind enough to provide you with a sample of blood, and utilizing the special lab you have in your basement, you obtain a plasma concentration of 0.01 mg/mL. You then perform the fancy equation you learned and find the following result.
Volume of distribution = 500 mg drug/0.01 mg/mL = 50,000 mL or 50 L
To put it into perspective, 50 L is the amount of water the standard-size tub can hold. Aside from assuming your friend is a giant water balloon, it is crucial to understand that this is a hypothetical volume. The concentration in the blood measured low (0.01 mg/mL), but you are sure you saw your friend swallow the whole pill. Where could the rest of the drug have gone? This example illustrates that the drug is widely distributed in the body elsewhere besides the bloodstream, such as the tissues, fat, bound to protein, etc.
From the example above, you can see that the volume of distribution is not an actual volume. It just gives you an IDEA of how well the drug has distributed into all the different fluid compartments, tissues, and organs of the body. The higher the volume of distribution, the more extensive drugs distribute throughout the body into tissues and organs. The lower the volume of distribution, the higher concentration of drug remains in the bloodstream.
Topic: Metabolism
Metabolism is a process by which your body converts food into energy, eliminates waste, and transforms drug molecules for easier facilitation of excretion. Drugs administered orally will need to pass through the liver to be metabolized before entering the blood circulation. This process is called the first-pass metabolism.
IMPORTANT TO NOTE:
First-pass metabolism only applies to drugs administered orally. Alternative routes of administration such as intravenous, sublingual, intramuscular, etc. all BYPASS first-pass metabolism since they are absorbed directly into the systemic circulation.
Metabolism of drugs in the liver turns it into a new molecule (often called metabolites) that is easier for the kidneys to excrete. Some drug formulations depend on liver metabolism to activate the drug (called prodrugs).
The liver is the body’s metabolic factory, hosting a series of enzymes called cytochrome P-450. These enzymes can be inhibited or induced by drugs. If a drug inhibits one of these enzymes, it can prevent another drug that is dependent on the same metabolic pathway from being broken down, increasing drug concentrations, and leading to toxicity. On the flip side, if a drug induces (ramps up) these enzymes, it will increase the rate of metabolism, reducing the effectiveness of some medicines.
Let’s take a look at an example.
Drug A inhibits CYP3A4
Drug B is metabolized by CYP3A4
The inhibition of CYP3A4 will lead to higher plasma concentrations of Drug B.
Importance:
Metabolism plays a direct role in how much drug reaches blood circulation, affecting therapeutic outcomes and toxicity levels. This subject is of particular importance with medications known to inhibit or induce metabolism leading to drug interactions.
Topic: Elimination
After the drug has been absorbed, metabolized, and delivered to the site of action, the final step is elimination. There are many pathways for drug elimination that may include the removal of drugs into urine, bile, sweat, saliva, milk, and other body fluids. Total body clearance is the sum of these individual clearance processes.
Clearance is the rate at which drugs get removed from the body. It is a measurement of the volume of plasma containing the amount of drug to be eliminated over a given time.
In an example earlier, we dissolved 100 mg of sugar in an unknown container. Imagine there is a filter pump now connected to the container filtering out sugar and returning the clean water. The filter continues to do this in terms of volume of mL per minute. Each time clean water is pumped back into the container, the concentration of sugar gets diluted further. Because of this, it is challenging to determine clearance by mg/minute as the mg amount will change over time with each dilution. A more consistent method would be to use the volume of fluid per unit of time.
The filter pump’s rate in mL per minute is the clearance of the container. The higher the amount of volume containing the drug removed per unit of time, the better the system (body) is at eliminating the drug (or in this example, the sugar).
Clearance = rate of removal of drug (mg/min)
Plasma concentration of drug (mg/mL)
Current laboratory techniques are not able to detect all drugs in the body, making it difficult to measure clearance based on drug plasma concentrations. An easier and less costly alternative is to use creatinine clearance.
This method determines the kidneys’ clearance of a waste product, creatinine, from the body. Creatinine clearance is also measured in mL/min and is a value that determines how well the kidneys clear the blood plasma of creatinine per unit of time. It is a measurement of renal function and correlates with how well the kidneys eliminate drugs.
Most medications follow two types of elimination models – first order elimination or zero order elimination.
- First-order elimination is the constant decrease in the PROPORTION (e.g. percentage %) of drug eliminated over time
- Zero-order elimination is the constant AMOUNT (e.g. mg) of drug eliminated over time
See an example of the two models below:
MNEMONIC
“When you FIRST cut a pie into PORTIONS, you have to ZERO in on the AMOUNT of calories per slice”
First-order = PORTIONS (%)
Zero-order = AMOUNT (mg)
Topic: Trough
The trough is the lowest serum concentration of a drug in the bloodstream collected prior to the administration of the next dose. Trough levels are used to determine the therapeutic effectiveness and toxicity of a medication. Most medications have standard laboratory trough ranges. If a medication requires monitoring and is continued for an extended period, it is essential to measure trough concentrations to determine the drug’s effectiveness and prevent toxicity.
Trough levels must be ordered and drawn correctly to allow for accurate interpretation. If the trough level is drawn too early while the drug is still infusing, it can lead to falsely high readings and vice versa.
Topic: Peak
The peak is the highest level of a drug in a patient’s bloodstream and is usually measured 30 minutes to 1 hour after the drug has finished infusing. Peak levels help determine the effectiveness of medications that are concentration-dependent. High peak levels can also lead to toxicity in certain medications.
Peak levels must be ordered and drawn appropriately to allow for accurate interpretation. If the peak level is obtained too early while the drug is still infusing, it can result in falsely high levels and vice versa.
Topic: Half-Life
Half-life (t ½) is the time required for serum concentration of the drug to decrease by 50%. In other words, after one half-life, the concentration of the drug should be half of the starting dose. After each subsequent half-life, more of the drug gets eliminated until it reaches negligible levels around 4-5 half-lives.
Half-life helps us determine when the next dose should be administered or the dosing interval.
Congratulations on finishing Lesson #1 Important Terminology. Check your understanding by completing the quiz below and see if you can unlock the code that leads to Lesson #2.
Good luck!
Lesson #1: Important Terminology Read More »
Drugs that cause Constipation
Drugs that cause Constipation Read More »
Top Antibiotic Coverage Mnemonics
It is common for learners to struggle with memorizing antibiotic coverage when they are first introduced to the subject. With so many unfamiliar bacteria and antibiotics to know, it can be more than enough to get your head spinning.
In school, you probably learned the spectrum of activity for antibiotics by grouping bacteria into 3 common classifications:
Gram-positive bacteria (e.g., Streptococcus, Staphylococcus, Enterococcus)
Gram-negative bacteria (e.g., E. coli, Klebsiella, Salmonella, Shigella, Pseudomonas)
Atypicals (e.g., Chlamydophilia, Legionella, Mycoplasma)
Additionally, you learned that they are then further subclassified into aerobes, anaerobes, lactose-fermenting, and non-lactose-fermenting. But wait, don’t get cross-eyed just yet! Memorizing the spectrum of activity of antibiotics does not have to be that difficult. In this article, I’ll share some memorization tips on remembering the common bugs and what drugs cover them.
BUGS AND DRUGS
A great tip for remembering antibiotic coverage starts with memorizing the antibiotics that cover the major categories of bacteria including anaerobes and atypicals as well as resistant pathogens such as methicillin-resistant staphylococcus aureus (MRSA) and pseudomonas. From there, you can build upon your knowledge of other less commonly seen bacteria or infections through the application of the material during class, rotations, and clinical practice.
Needless to say, these are a MUST for you to know for exams. Review the mnemonics below and quiz yourself to see how much you remember.
NOTE: Clindamycin, doxycycline, and Bactrim (generic: sulfamethoxazole/trimethoprim) cover community-acquired MRSA infections while vancomycin, ceftaroline, and daptomycin cover hospital-acquired MRSA infections. Other antibiotics not listed include: linezolid, telavancin, dalbavancin, oritavancin, tigecycline (this mnemonic story can get pretty long!)
NOTE: Atypical bacteria do not color with Gram staining (because they lack a cell wall) and remain colorless. They are neither gram-positive nor gram-negative; they are ATYPICAL! 🙂
NOTE: These are the main antibiotics that empirically cover anaerobes. There are other antibiotics that do have some anaerobic coverage but since anaerobes are hard to culture and identify, empiric therapy is often used in practice.
NOTE: Other antibiotics not listed include: cefiderocol, colistin, ceftolozane/tazobactam
TIPS FOR SUCCESS
- Keep in mind, memorizing these antibiotic spectra of activity can come in handy for exams but it doesn’t always apply to clinical practice (ex: you wouldn’t recommend daptomycin for MRSA pneumonia since daptomycin gets deactivated by the lung surfactants. You also wouldn’t recommend doxycycline as the first-line option for hospital-associated pneumonia.)
- Other things to keep in mind when recommending an antibiotic to the team: potential toxicities, renal and hepatic function, CPK monitoring (esp. with daptomycin), which type of infection the drugs can or cannot be used for (moxifloxacin should not be used for UTIs as it doesn’t concentrate well in the urine making it ineffective), contraindications, drug interactions, and routine antibiotic doses (pneumonia dosing vs. bacteremia dosing)
- At the end of the day, the best way to become comfortable with bugs and drugs is to practice, practice, practice. It takes time and effort but eventually, you’ll start to see a pattern with which antibiotic should be used based on patient-specific factors, cultures and sensitivity, and the type of infectious disease.
QUIZ YOURSELF
A) Which of the following antibiotics can be used for a patient with MRSA+ pneumonia?
- Daptomycin
- Vancomycin
- Gentamicin
- Azithromycin
B) All of the following antibiotics cover pseudomonas EXCEPT for?
- Meropenem
- Cefepime
- Ertapenem
- Piperacillin/tazobactam
C) A patient is in need of anaerobic coverage for a diabetic foot infection, which of the following antibiotics would provide adequate anaerobe coverage?
- Levofloxacin
- Cefepime
- Clindamycin
- Tobramycin
D) Which antibiotic would provide coverage for atypical pathogens and streptococcus pneumoniae in a healthy patient diagnosed with community-acquired pneumonia (assuming local resistance is low)?
- Metronidazole
- Clindamycin
- Azithromycin
- Amoxicillin
ANSWERS: A. 2, B. 3., C. 3., D. 3.
Hope these were helpful! If you have any additional memorization tips of your own, feel free to share them in the comments below.
If you are interested in learning more, check out our Antibiotics Pharmacology Coloring Book or Top 200 Drugs Made Easy Coloring Book for additional memorization tips!
Top Antibiotic Coverage Mnemonics Read More »
Uterine Relaxant Drugs
👶🏻 Preterm labor occurs when labor begins too early. If this happens before the 37th week of gestation, the fetal organs, especially the lungs, might not be fully developed.
💊 In these cases, labor can be suppressed with uterine relaxants that relax the uterine muscle and slow down contractions for up to 48 hours. It gives the fetus a few more days in the uterus as a corticosteroid is given to speed up the development of a preterm infant’s lungs. Steroids help the lungs mature and may promote the production of surfactant, a substance that prevents the collapse of alveoli (small sacs in the lungs where the air is exchanged).
💊 Uterine relaxants are also called tocolytics (toco = childbirth, lytic = terminate) and include several different types of drugs.
Uterine Relaxant Drugs Read More »
Antibiotic Renal Dosing
Antibiotic Renal Dosing Read More »
Diuretic Classes
Ketamine Properties
Ketamine Properties Read More »