Protected: Vancomycin Renal Dosing Lesson #1: Important Terminology
Protected: Vancomycin Renal Dosing Lesson #1: Important Terminology Read More Ā»
Lithium
Lithium is a common āmood stabilizerā used to treat the manic episodes of bipolar disorder, a mood disorder that is characterized by episodes of mania, hypomania, and depression. ā ā
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The exact cause of bipolar disorder is unknown but is highly linked to family history, genetics, and abnormalities in neurotransmitters. This makes it tricky to pinpoint exactly how lithium works to treat bipolar but there are many proposed mechanisms of action. ā ā
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Whenever you see the medication lithium, always think SALT as lithium (Li+) is located close to sodium (Na+) on the periodic table and they share similar structures. Because of this, lithium levels are often affected by salt and water balance as well as renal function (excreted mainly through kidneys). ā ā
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Dehydration can cause lithium levels to increase while increasing sodium intake can cause lithium levels to decrease. Medications that affect water and salt balance (ex: diuretics, NSAIDs, ACEI) can also alter lithium concentrations. ā ā
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The starting dose of lithium is 300 mg two or three times a day (The brand name is Lithobid to help you remember that it can be given BID or twice daily)ā ā
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Lithium is considered teratogenic due to the potential for fetal cardiac defects. The risks and benefits should be discussed with a healthcare provider before starting it in women of childbearing age.ā ā
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Lithium is a popular drug that often shows up on tests due to its narrow therapeutic index and many side effects. ā ā
ACE-inhibitors ā
Ā Letās talk about ACE-inhibitors ā ā
ā ā
š Angiotensin-converting enzyme (ACE) inhibitors are a class of drugs mainly used in the treatment of hypertension and heart failure with reduced ejection fraction (HFrEF). They are one of the top 200 drugs prescribed and because of that, they are an important class to know. ā ā
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ā Drugs in this class end in the suffix ā-prilā such as: ā ā
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-LisinoPRILā ā
-FosinoPRILā ā
-EnalaPRILā ā
-RamiPRILā ā
-QuinaPRILā ā
-BenazePRILā ā
ā ā
āDo not use this medication in patients who: ā ā
ā ā
-Have a hypersensitivity to ACE inhibitors or any of their componentsā ā
-Pregnant or breastfeeding: box warning for patients who are or may become pregnant as it can cause fetal toxicityā ā
-History of angioedema, bilateral renal stenosis, and concurrent use with aliskiren in patients with diabetesā ā
ā ā
ACE-inhibitors ā Read More Ā»
Chronic Kidney Disease
Ā Renal adjustments in CKD and AKIĀ
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š Acute kidney injury is not very cute ā
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š§ Most drugs, particularly water-soluble drugs and their metabolites, are eliminated largely by the kidneys in urine. ā
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āļø It is important to know which drugs require dose adjustments to prevent accumulation and toxicity in patients with chronic kidney disease (CKD) as well as those with acute kidney injury. ā
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š¤ Things to keep in mind when renally adjusting medications: ā
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šš» Use estimated GFR or CrCl to determine drug dosingā
šš» If the patient is on hemodialysis, the type of HD will also determine drug dosingā
šš» CrCl should be monitored periodically in patients with AKI to determine if doses need to be adjusted when CrCl improvesā
šš» Some medications require individualized therapy (ex: serum drug level monitoring, vital signs, adverse effects) when dose adjustingā
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Chronic Kidney Disease Read More Ā»
Antidepressants
Ā Major depressive disorder (MDD) is a mood disorder characterized by persistent feelings of sadness and loss of interest that interferes with normal daily functioning.ā
ā Ā The exact chemical basis for depression is poorly understood but is thought to be linked to decreased levels of the neurotransmitters, serotonin, dopamine, and norepinephrine. This cause is also known as the monoamine hypothesis.ā
ā 
Ā Because of this, the drugs developed to treat MDD selectively target the reuptake of serotonin and norepinephrine, increasing levels of these neurotransmitters in the synapse and enhancing NT signaling.ā
ā Ā SSRIs are generally first-line due to their improved tolerability compared to the others (TCAs and MOAIs) and relative safety in cases of overdose.ā
ā Ā Studies have shown equivalent efficacy among antidepressants, therefore the initial choice is made empirically based on patient factors and the nuances of each drug.ā
5-HT3 Inhibitors
š 5-HT3 Inhibitors (ex: ondansetron) ā
ā
š¤¢š¤® Nausea and vomiting are two of the most common presenting complaints ā
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5-HT3 inhibitors (such as ondansetron) are one of the top 200 drugs prescribed and are used for the prevention of:ā
šĀ chemotherapy-induced nausea and vomitingā
šĀ radiation-induced nausea and vomitingā
šĀ postoperative nausea and vomitingā
šĀ off-label for nausea and vomiting associated with pregnancy
Vancomycin ā
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 name glycopeptides! ā
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MOA: binds to D-alanyl-D-alanine on the outer surface of cell membranes preventing cross-linking. This interferes with cell wall synthesis and results in bacterial cell death. ā
ā Another way to think of it: cell walls are like LEGO pieces linking together. The more that are linked, the stronger the structure is. Vancomycin prevents this cross-linking leading to an unstable structure. ā
ā Vancomycin = think mainly gram-positive coverage including MRSA! (gram-negatives do NOT have a thick cell wall and lack the D-ala-D-ala sequence, making vancomycin useless against them)ā
NOTE: Recently, the term āred man syndrome (RMS)ā has been replaced and is now recognized as āvancomycin flushing syndromeā or “vancomycin infusion reaction”.
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Mind the Gap- HAGMA
āļø High anion gap metabolic acidosis (HAGMA) occurs when the body produces too much acid, or when the kidneys are not removing enough acid from the body.ā
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š Several drugs and toxins have been implicated as direct or indirect causes of HAGMA. The three most common ones to consider are methanol, ethylene glycol and salicylates.ā
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š¬ļø Symptoms are generally non-specific, with dyspnea being common secondary to stimulation of the central respiratory center. Screening for toxic ingestions, including over-ingestion of aspirin and acetaminophen, is important. ā
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š Additionally, screening for features suggestive of diabetes (e.g., polyuria, polydipsia, polyphagia) or renal failure (e.g., nocturia, pruritus, anorexia) is essential.ā
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š Primary treatment of high anion gap metabolic acidosis requires correction of the underlying cause
Mind the Gap- HAGMA Read More Ā»
Antiretrovirals
ā This is a great way to remember the names of antiretrovirals ā Antiretroviral medications are used to treat HIV by blocking different stages of the virus’s life cycle (e.g., blocking entry into the host’s CD4 lymphocyte, inhibiting viral DNA from replicating, etc.)ā ā š However, learning the names of antiretroviral medications is horribly difficult. There are lots of drugs, with a dizzying array of names, abbreviations, and combination tablets.ā Hopefully, this will help you not to completely BLANK on which drug belongs to which type of antiretroviral! š¤
ā
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.Ā
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
[qsm quiz=16]
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:
āWas this trough drawn at the appropriate time?ā
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. Letās take a look at both.
Method #1:
Ke = (-) ln {(Ctrough x Vd / dose) / [ 1 + Ctrough x Vd / dose)}
Ā Ā Ā Ā 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 patientās specific elimination constant (Ke) to determine the new dosing regimen.
Once you have obtained the patientās 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.
Ā Ā Ā Ā DoseĀ Ā Ā Ā Ā Ā Ā Ā =Ā Ā Ā Ā Ā New dose (X)
Trough obtainedĀ Ā Ā Ā Ā Ā 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:Ā Ā Ā Ā Ā Ā 2500/10 = x /15Ā Ā Ā Ā 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
[qsm quiz=18]
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 Ā»
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: 100.4Ā° F
WBC: 24
Scr: 1.2
TEST MY KNOWLEDGE
[qsm quiz=6]
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 patientās 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: 100.4Ā° F
WBC: 24
Scr: 1.2
TEST MY KNOWLEDGE
[qsm quiz=7]
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 <0.8Ā 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: 100.4Ā° F
WBC: 24
Scr: 1.2
TEST MY KNOWLEDGE
[qsm quiz=8]
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 patientās 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
[qsm quiz=9]
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
[qsm quiz=10]
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
[qsm quiz=11]
In practice, there are two methods for calculating the dosing interval
Method #1: Use the dosing interval equation
Estimated Dosing Interval =Ā [ln (desired peak/desired trough) / Ke]Ā + t’
This method allows you to estimate a more precise interval that correlates to your patientās 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
[qsm quiz=12]
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
[qsm quiz=13]
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/tā)(1-e-Ke(tā)) / Vd(Ke)(1-e-Ke(T))
CminĀ = Cpeak (e-Ke(T-tā))
In practice, institution-specific calculators are used to assist with calculating a peak and trough.
TEST MY KNOWLEDGE
[qsm quiz=14]
As you can see from this example, 750 mg every 12 hours will get us closer to the desired goal trough and peak.Ā
Whohoo! You made it through the TOUGHEST section. Those calculations were just a warmup. If you’re looking to get additional practice. Check out thisĀ worksheetĀ for additional vancomycin dosing problems!
Let’s review what you have learned about vancomycin dosing in this quick 5-minute quiz.Ā
Lesson #4: Vancomycin Dosing Read More Ā»
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 weightĀ |
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(tā)) / Vd(Ke)(1-e-Ke(T)) |
Trough (Cmin) | Cpeak (e-Ke(T-tā)) |
Vd = volume of distribution, Ke = elimination constant, T= interval, t’ = infusion time
Loading Dose
LD = 20-25 mg/kgĀ ORĀ 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 institutionās 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! š
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,Ā 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 tā = 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.Ā
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(tā)) / 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 š§.
Trough
Trough (Ctrough) = Cpeak (e-Ke(T-tā))
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 Ā»
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!
Vancomycinās stem ā-mycinā is derived fromĀ 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 inĀ –vancinĀ as in similar toĀ 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:
BactericidalĀ drugs cause bacteria to be suicidalĀ and die while
bacteriostaticĀ drugs cause bacteria to beĀ staticĀ 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 aĀ 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 š)
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 institutionās 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. (š§ 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.
Thatās 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. Ā
Lesson #2: Vancomycin Background Read More Ā»
IV Fluids Review
š¦ ā IV fluids – What the tonic?
āļøThe human body is composed of 60% water š¦ ā
-Two-thirds of it is available INTRAcellularly (space INside cells)ā
-One-third of it is stored EXTRAcellularly (EXTERNAL space in blood vessels and around cells)ā
ā
ā There are different types of fluids with varying chemical compositions of salt and electrolytes that are designed to bring fluid into cells or keep fluid within the bloodstream.ā
ā
š Key Tips:ā
-Water flows where sodium (or particles) goes!ā
-Solutions want to have the same ratio or balance of solvents (water) to solute (particles such as salt)ā
-Water will flow from an area of low particles to an area of high particlesā
-Semi-permeable membranes allow water to pass through but not particlesā
ā
ā First, think of the starting point as the space within blood vessels (or intravascular space) since IV fluids are infused directly into the bloodstream š©øā
ā
ā ISOtonic fluids: āISOlated in the vasculatureāā
-Equal amounts of water and particles so there is no movement between the compartmentsā
-Water from IV fluids stay ISOlated in the vasculature ā used in situations where there is fluid loss and replacement is needed (ex: hemorrhage, diarrhea, vomiting)ā
-Examples include: 0.9% sodium chloride (normal saline), dextrose 5% in water (D5W), lactated ringer (LR)ā
ā
ā HypOtonic fluids: āOut of the vasculatureāā
-Low amounts of particles compared to waterā
-Water flows OUT of the vascular into the cellsā
-Used in situations where we have intracellular dehydration (ex: DKA, HHS)ā
-Examples include: 0.45% sodium chloride (1/2 normal saline), 2.5% dextrose in water ā
ā
ā HypErtonic fluids: āEnter the vasculatureāā
-High amounts of particles compared to water ā
-Water ENTERS the highly concentrated vasculature from cellsā
-Used in situations where there are swollen cells (ex: cerebral edema) or hyponatremiaā
-Examples include: 3% sodium chloride (hypertonic saline), dextrose 10% in water (D10W) ā
Vasopressors and Inotropesā
Vasopressors and Inotropesā
Vasopressors and Inotropesā
ā
Vasopressors and inotropes OH NO! šš»āāļø These medications are commonly used in the critical care setting in patients with shock (or those with extremely low blood pressure) leading to end-organ damage (acute kidney injury, increased LFTs, etc.). ā
ā
šš» Vasopressors are drugs that cause vasoconstriction, therefore increasing mean arterial pressure (MAP). Vaso refers to blood vessels and pressor means to put pressure on or constrict making up the word ā VASO-pressor. š©øā
ā
Examples of vasopressors include:ā
ā
ā Norepinephrineā
ā Epinephrineā
ā Vasopressinā
ā Phenylephrineā
ā
šš» Inotropes are drugs that affect cardiac contractility (or the force of muscular contractions). They can also be used as chronotropes (drugs that increase heart rate). THINK: Ino = strength; Chrono = time. Some vasopressors may also have effects on contractility and are called inopressors. ā
ā
Examples of positive inotropic agents include: ā
ā
ā Milrinoneā
ā Dobutamineā
ā Dopamineā
ā Isoproterenoneā
ā
š§ With the many different types of vasopressors and inotropes, it is important to understand how they work to use them effectively. Choosing the wrong agent or using it inappropriately, can harm the patient. ā
Vasopressors and Inotropesā Read More Ā»