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Vancomycin Side Effects

Vancomycin Side Effects
8 Aug 2020 Blog

Vancomycin (brand name: Vancocin®) is an antibiotic that can be used for multiple severe bacterial infections. When first approved by the FDA in the 1950’s, vancomycin was less pure than it is today1, resulting in a higher risk of side effects.

Even though the medication was effective against drug resistant bacteria, the side effects of vancomycin and the availability of other FDA approved drugs made its use much less common.

Over time, the methods used to purify vancomycin improved and the risk of drug-resistant bacteria grew substantially

By the 1980s, vancomycin became a mainstay in clinical practice.1

To this day, multiple treatment guidelines recommend vancomycin as one of the first antibiotics that should be started in patients with severe infections before the infecting bacteria has been identified.2

Even with a decreased risk of side effects due to improved manufacturing, clinicians must make sure that the patient is receiving just the right amount of vancomycin.

The balance of treating the patient’s serious infection while making sure they do not receive too much medication is delicate, as side effects of too much vancomycin can be dangerous.

Vancomycin side effects include the following3:

  • Kidney damage (nephrotoxicity)
  • Hearing loss (ototoxicity)
  • “Red man” or “red person” syndrome
  • Other less common side effects such as:
    • allergic reactions: hives, difficulty breathing or wheezing
    • Low white blood cells (neutropenia) or high eosinophil counts (eosinophilia)
    • Blood vessel inflammation (vasculitis or phlebitis) 
    • Stomach pain, muscle pain, abdominal pain, or back pain 

An important caveat when reviewing these side effects is that they are not all allergic reactions, but instead a normal occurrence in patients receiving too much vancomycin, or an infusion given too rapidly.         

Kidney Damage

vancomycin dosing in hemodialysis patients

Vancomycin is cleared primarily in the kidneys.

In large amounts, vancomycin can cause kidney problems such as acute kidney injury (AKI).

To calculate kidney function, clinicians collect a serum creatinine value. Creatinine is produced when muscles are broken down.

When this muscle byproduct reaches the kidney, it flows freely into the urine at a specific rate called the creatinine clearance.4

The creatinine clearance is then used to estimate how frequently vancomycin and other medications that are cleared by the kidney should be given to the patient.

Since this calculation relies on muscle breakdown, patients with a very high muscle mass can give the illusion that they have poor kidney function, as they have more circulating creatinine.

Likewise, patients with a low muscle mass can appear to have much more efficient kidneys.

This difference in clearance from patient to patient highlights the need for an accurate representation of the patient’s vancomycin level to prevent acute kidney injury.

There are multiple definitions of AKI that exist.

In the 2020 vancomycin consensus guidelines,5 AKI is defined as the following:

  • An increase in serum creatinine of > 0.5 mg/dL or
  • A 50% increase from baseline in two consecutive daily readings, or
  • A decrease in calculated creatinine clearance of 50% from baseline on two consecutive days in the absence of an alternative explanation.

Another definition of AKI used in the literature comes from the international acute kidney injury guidelines published by the Kidney Disease Improving Global Outcomes (KDIGO) organization.6

The KDIGO guidelines define AKI as a 0.3 mg/dL or greater increase in the patient’s serum creatinine within 48 hours of a previous serum creatinine lab draw.

Some researchers will use the same definition as the 2020 vancomycin consensus guidelines to detect AKI, and others will use the KDIGO definitions.

There are also some studies that will include patients who have other reasons for having kidney damage, such as other medications or chronic medical conditions.

The different ways acute kidney injury from vancomycin is studied is the most likely reason for such a range in AKI reports.

Prescription drugs, medical conditions, and patient characteristics that increase the risk of AKI when combined with vancomycin include but are not limited to the following7-11:

Medications 

  • Acyclovir
  • Amikacin
  • Amphotericin B
  • Gentamicin
  • Loop diuretics (i.e., furosemide, torsemide)
  • Piperacillin-tazobactam
  • Tobramycin

Medical conditions

  • AIDS
  • Cancer
  • Chronic kidney disease
  • Diabetes
  • Heart diseases
  • Muscle wasting diseases such as cerebral palsy or amyotrophic lateral sclerosis (ALS)
  • Severely high or low blood pressure

Patient characteristics

  • Advanced age  
  • Amputation of one or more limbs
  • Very high or low body weight

The way that vancomycin causes acute kidney injury is not well understood.

In animal studies, vancomycin has been associated with an increase in free radicals causing inflammation in the kidneys.

In most patients, kidney damage caused by vancomycin is reversible and the kidneys recover on their own after the medication is stopped.

In severe cases of kidney injury where vancomycin therapy is not adjusted, patients may need dialysis.

Human studies evaluating how the kidneys are damaged from vancomycin use are limited as most cases resolve without requiring kidney biopsy.

Without a strong understanding of how vancomycin causes kidney injury, predicting which patients may experience this side effect can be challenging.

Rates of acute kidney injury in patients who receive vancomycin range from 5-7% all the way up to over 40%.7

Without the addition of medications that cause drug interactions or medical conditions that increase the risk of kidney damage, AKI from vancomycin is much less likely.

It is also easier to predict who might experience AKI by testing the amount of vancomycin in the patient’s blood.

Testing vancomycin levels was recommended in the 2009 vancomycin consensus guidelines.12

In 2009, the most accurate way to predict if the patient had safe and effective levels of vancomycin in their blood was by using collected levels to calculate the vancomycin area-under-the-curve (AUC).

The AUC measures the exposure of the drug in the body to the infecting bacteria. Calculating the AUC was considered to be time-consuming in 2009 when the guidelines were written.

Instead, the 2009 vancomycin consensus guidelines recommended that the trough level could be used in place of the AUC.

Trough levels are collected when the drug concentration is at its lowest in the blood, which is right before the next scheduled dose.

By assuring that the trough stayed above a minimum level, it was assumed that the AUC was also within range.

Unfortunately, this practice led to AUC levels that were often above or below the range needed to treat the patient’s infection safely and effectively.

Between 2009 and 2020, software programs that could easily estimate the AUC became commercially available.

Through direct AUC estimation, it was found that the rate of AKI could be decreased by roughly 50% compared to using trough levels.13

In 2020, the vancomycin consensus guidelines recommended AUC monitoring instead of trough-only monitoring and specifically highlighted the capabilities of software programs to perform these calculations.

Hearing Loss

When vancomycin was first brought to market, impurities in the drug were believed to increase the patient’s risk of hearing problems.

This occurrence was more common if vancomycin drug levels in the patient were maintained over twice as high than is currently recommended for therapeutic use.10

Most of the evidence that vancomycin may cause hearing loss is from studies conducted decades prior.

To this extent, vancomycin induced hearing loss remains very rare and controversial.

Animal models have not identified this side effect with today’s version of vancomycin, supporting that the impurities previously present in the drug may have been to blame.

When combined with other medications that are known to cause hearing loss in high doses, there is a theoretical risk that vancomycin may contribute to this side effect.

Interestingly, some of the same medications that increase the risk of kidney damage have also been found to contribute to hearing loss.

Specifically, the aminoglycosides such as tobramycin, gentamicin, and amikacin were highlighted in the 2009 vancomycin consensus guidelines as medications that may potentially increase this risk.

Without the combination of one or more added drugs that can cause hearing loss, the 2009 vancomycin guidelines did not recommend monitoring for this side effect.

Thus, monitoring for hearing loss is not common practice.

In the 2020 vancomycin consensus guidelines, routine evaluation of the patient’s hearing before, during, and after vancomycin therapy is not recommended.

Red Man Syndrome

Vancomycin Dosing Guidelines: A Clinical Summary

Red man syndrome is a hypersensitivity reaction.

It is also known as red person syndrome, and it is the most common hypersensitivity reaction associated with vancomycin. 

Red man syndrome should not be confused with a drug allergy. In some patients, administration of vancomycin too quickly can cause itching and a rash.

The rash seen in red man syndrome is commonly on the face, neck, chest, and upper arms.

Patients may also experience flu-like symptoms.

In most cases, this adverse reaction is mild in nature and resolves when the infusion is stopped or slowed.

The appearance and symptoms of red man syndrome can be summarized as follows:

  • Itchy, red skin rash on the face, neck, chest, and upper arms
  • Dizziness
  • Agitation
  • Chills
  • Fever
  • In severe cases, chest pain, swelling of the lips and face, and shortness of breath

Red man syndrome is caused by a histamine response to the active ingredient.

This means that antihistamines such as diphenhydramine can be used to decrease the effects of red man syndrome.

This reaction is more common when vancomycin is administered more quickly.

Knowing this risk, vancomycin is commonly given at a rate of 60 minutes per gram of drug or longer.

In patients with known or suspected red man syndrome, infusion rates are cut in half (i.e., 120 minutes per gram of vancomycin) and patients are sometimes pre-treated with antihistamines.

Some patients seem to be more likely than others to experience this side effect.

Currently, there is no reliable method of identifying which patients may experience red man syndrome prior to receiving vancomycin.

The odds of having this infusion reaction also ranges considerably from as low as 3.7% to as high as 47% of patients who receive the drug.

On occasion, red man syndrome can be delayed and present near the end of a vancomycin infusion in patients who have received the drug for at least 7 days.

Summary

Vancomycin Side Effects

As with any medication, vancomycin has side effects that require consideration of the risks and benefits of using the drug. Some of these side effects include:

  • Kidney damage, which requires very close monitoring of drug levels and changes in risk based on the patient’s characteristics, disease states, and other medications
  • Hearing loss, which is very rare with today’s version of the drug, but may still be possible when combined with other medications that can cause hearing damage
  • “Red man” or “red person” syndrome, which is related to the rate of the infusion of the drug and is easily reversible by decreasing the rate and pre-treatment with antihistamines

In practice, close monitoring of vancomycin can prevent or decrease the severity of these side effects.

With the help of precision dosing software such as provided by DoseMeRx, clinicians can make sure that their patients have just the right amount of vancomycin to treat their infection while decreasing their risk of some of these adverse effects.

About the author

Dr. Brandon Reynolds

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References

  1. Levine, DP. Vancomycin: A History. Clin Infect Dis. 2006;42:S5-S12.
  2. Liu C, Bayer A, Cosgrove S et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011; 52(3):e18-e55
  3. Patel S, Preuss CV, Bernice F. Vancomycin. StatPearls [Internet]. Last update Feb 2020.
  4. Shahbaz H, Gupta M. Creatinine clearance. StatPearls [Internet]. Last update July 2019.
  5. Rybak MJ, Le J, Lodise T, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases PharmacistsAm J Health-Syst Pharm. 2020; 77(11):835-864.
  6. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney inter., Suppl. 2012; 2:1–138.
  7. Bamgbola O. Review of vancomycin-induced renal toxicity: an update. Ther Adv Endocrinol Metab. 2016; 7(3):136-147
  8. Sivagnanam S, Deleu D. Red man syndrome. Crit Care. 2003; 7(2):119-120
  9. Cappelletty D, Jablonski A, Jung R. Risk factors for acute kidney injury in adult patients receiving vancomycin. Clin Drug Investig. 2014; 34(3):189-193
  10. Brummett RE, Fox KE. Vancomycin- and erythromycin-induced hearing loss in humans. Antimicrob Agents Chemother. 1989; 33(6):791-796
  11. Farooqi S, Dickhout J. Major comorbid disease processes associated with the incidence of acute kidney injury. World J Nephrol. 2016; 5(2):139-146
  12. Rybak MJ, Lomaestro BM, Rotscahfer JC, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists.Clin Infect Dis. 2009; 49(3):325-327
  13. Finch N, Zasowski E, Murray K, et al. A quasi-experiment to study the impact of vancomycin area-under-the-concentration-time curve-guided dosing on vancomycin-associated nephrotoxicity. Antimicrob Agents Chemother. 2017; 61(12):e01293-17

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