Continuing Education Activity

Vancomycin infusion reaction, formerly known as red man syndrome, is a rate-dependent hypersensitivity reaction that occurs when vancomycin, a glycopeptide antibiotic, is infused too rapidly. Unlike an allergic reaction, vancomycin infusion reaction is an anaphylactoid response caused by the direct release of histamine from mast cells and basophils, independent of the immune system. The severity of the reaction typically correlates with the dosage and infusion rate, although cases have been reported even with slower infusion rates. Clinically, VIR presents as a pruritic, erythematous rash that primarily affects the face, neck, and upper torso, with occasional involvement of the extremities. Additional symptoms may include angioedema, weakness, and chest or back pain. Given the widespread use of vancomycin, healthcare providers need to recognize, prevent, and manage vancomycin infusion reactions effectively.

This activity provides an in-depth review of vancomycin infusion reactions, focusing on its evaluation, diagnosis, and management, highlighting key strategies for prevention, including appropriate infusion rates and premedication when necessary. In addition, it emphasizes the importance of interprofessional collaboration in optimizing patient care, ensuring timely recognition, and implementing appropriate interventions to improve outcomes for affected patients.

Objectives:

• Identify the etiology of vancomycin infusion reaction.

• Differentiate vancomycin infusion reaction from other diagnoses with a similar presentation.

• Implement treatment and management options for vancomycin infusion reaction.

• Communicate with the interprofessional team to optimize care coordination and enhance the treatment of vancomycin infusion reaction, improving patient outcomes.

Introduction

Vancomycin infusion reaction, formerly known as red man syndrome, is one of two types of hypersensitivity reactions that can occur with vancomycin administration— the other being anaphylaxis.[1] Anaphylaxis is an allergic immunoglobulin E (IgE) immune-mediated reaction, whereas vancomycin infusion reaction is an anaphylactoid hypersensitivity response triggered by the rapid infusion of vancomycin, a glycopeptide antibiotic.[2][3] 

Vancomycin infusion reaction occurs due to the release of histamine from the degranulation of mast cells and basophils, a nonimmune-mediated process. The amount of histamine released is typically related to the dose of vancomycin and the infusion rate. Although vancomycin infusion reaction is typically associated with rapid infusion rates (for example, <1 h), it has been reported with slower rates, even several days after vancomycin administration.[2][4][5]

Vancomycin infusion reaction has rarely been reported with topical application and oral administration, typically when treating Clostridiodes difficile.[6][7] The condition manifests as a pruritic, erythematous rash on the face, neck, and upper torso, which may involve the extremities to a lesser degree and angioedema.

Symptoms of vancomycin infusion reaction may include weakness, chest and back pain, hypotension, shock, and even cardiac arrest.[8] Differentiation must be made from vancomycin-induced anaphylaxis, an IgE-mediated response that requires prior exposure to vancomycin. Treatment typically involves stopping the infusion and re-administering vancomycin at a slower rate.

Etiology

Vancomycin is a glycopeptide antibiotic used to treat infections caused by most gram-positive bacteria, including methicillin- and oxacillin-resistant Staphylococcus aureus, S epidermidis, penicillin-resistant Streptococcus pneumoniae, certain Enterococci, and Listeria monocytogenes. This antibiotic is also prescribed for patients with β-lactam allergies or infections involving drug-resistant organisms.[4][9]

Clinical indications for vancomycin treatment include skin and soft tissue infections, bacteremia, endocarditis, pneumonia, bone and joint infections, infections related to surgically implanted devices, central line-associated bloodstream infections, and central nervous system infections.[4][9][10][11] Vancomycin is also commonly used as empiric therapy for serious infections when methicillin-resistant S aureus or other resistant gram-positive pathogens are suspected.

In addition to vancomycin, other antibiotics such as rifampin, cefepime, teicoplanin, ciprofloxacin, and amphotericin B can cause infusion-related reactions due to their ability to directly induce mast cell and basophil degranulation.[1][5][12][13] These reactions can present with symptoms similar to vancomycin infusion reactions.

Vancomycin infusion reactions most commonly occur with parenteral administration of vancomycin but may rarely occur from oral, topical, or intraperitoneal use.[6][7][14][15] The occurrence of vancomycin infusion reaction is typically linked to infusion rates of 1 g in less than 1 hour. Symptoms typically appear within 4 to 10 minutes after starting the first intravenous dose, although they can also develop later during the infusion or shortly after its completion. In some cases, vancomycin infusion reaction has been reported with subsequent doses up to 7 days later.[1][4] 

Guidelines from infectious disease societies provide recommendations on vancomycin dosing, administration routes, and infusion rates.[9][11] The guidelines also emphasize monitoring vancomycin serum trough levels to ensure therapeutic efficacy while minimizing toxicity and the risk of antibiotic resistance.[11] For most patients with normal renal function, a dosing regimen of 15 to 20 mg/kg, based on actual body weight, is recommended every 8 to 12 hours to achieve the desired serum trough. Current treatment guidelines advise infusing vancomycin at a rate no faster than 1 g/h or 10 mg/min, whichever is longer.[1]

Epidemiology

Vancomycin causes 2 types of hypersensitivity reactions—anaphylaxis and vancomycin infusion reaction, with the latter being more common.[1] Anaphylaxis is an allergic IgE immune-mediated reaction, whereas a vancomycin infusion reaction is an anaphylactoid hypersensitivity reaction caused by the rapid infusion of vancomycin.[2][3] 

The exact incidence of vancomycin infusion reaction is not well established. Published studies estimate that vancomycin infusion reaction occurs in 5% to 50% of hospitalized patients receiving intravenous vancomycin.[16] Several risk factors have been identified, including age between 2 and 40 years, Caucasian ethnicity, previous history of vancomycin infusion reaction, vancomycin treatment exceeding 7 days, premedication with antihistamines, and higher vancomycin doses.[16][17] 

Severe cases of vancomycin infusion reaction can involve angioedema, hypotension, tachycardia, weakness, muscle spasms, chest or back pain, and the characteristic rash of the face, neck, and upper torso. However, most cases of vancomycin infusion reactions are mild and easily managed. Life-threatening reactions are infrequent.[1] 

Pathophysiology

Vancomycin was discovered in 1952 from soil samples collected in the jungles of Borneo. Early antibiotic preparations were impure and had a brownish color, leading to the nickname Mississippi mud. Initially, clinicians believed vancomycin infusion reaction and other potential complications, such as ototoxicity and nephrotoxicity, were due to these impurities.[18] However, the reaction persisted even after vancomycin was purified.

Studies in animals and humans have shown that vancomycin activates mast cell and basophil degranulation, leading to increased histamine release.[18][19][20] The amount of histamine released has been linked to the dose and infusion rate. However, not all studies have found a direct correlation between elevated histamine levels and the severity of vancomycin infusion reaction. Some research suggests that delayed histamine metabolism may also contribute to the reaction due to its inhibition of histamine N-methyltransferase and diamine oxidase enzymes.[1][10]

History and Physical

Obtaining a detailed history and performing a thorough clinical examination are crucial for all patients seeking medical care. Identifying a complete list of medications and exposures is essential, including any history of similar reactions. As most cases of vancomycin infusion reaction occur in hospitalized patients, it is often easier to link the response to the infusion. However, if a patient is taking multiple medications or has undergone recent procedures with overlapping adverse events, such as hypotension from anesthesia, establishing a definitive association with vancomycin may be more challenging. Nevertheless, a classic clinical presentation occurring concurrently with vancomycin administration strongly suggests a vancomycin infusion reaction. Differentiating this reaction from anaphylaxis is critical to ensuring appropriate management.

The clinical presentation of vancomycin infusion reaction varies widely, ranging from mild symptoms to severe, life-threatening complications, including angioedema, respiratory distress, chest pain, hypotension, shock, and cardiac arrest.[1][8] Symptoms may appear as early as 4 minutes after initiating the first dose or as late as 7 days after completing treatment.[1] Patients receiving intravenous vancomycin for infections are at risk of developing vancomycin infusion reactions.

The signs and symptoms of vancomycin infusion reaction can include: [1][4]

• Erythematous rash on the face, neck, and upper torso
• Nausea and vomiting
• Pruritis
• Hypotension
• Fever and chills
• Weakness and dizziness
• Respiratory distress
• Chest or back pain and trunk muscle spasms
• Cardiac arrest
• Angioedema
• Tachycardia

A rash on the extremities may occur but is typically less severe compared to the rash on the face, neck, and upper torso.[1][4] In some cases, the rash on the extremities may be more localized or faint, and its appearance can be delayed compared to the more prominent rash on the upper body.

Evaluation

The diagnosis of vancomycin infusion reaction is primarily clinical based on thorough patient examination. Signs and symptoms such as pruritus, erythema (mainly on the face and upper body), headache, chills, paresthesia, and dizziness may appear. Shortness of breath and chest pain may be present in more severe cases. Hypotension is also commonly observed. Although laboratory tests are not typically helpful in diagnosing vancomycin infusion reactions, they may help rule out other potential causes. Severe cases should be differentiated from IgE-mediated anaphylactic reactions.[4]

Treatment / Management

When a patient develops vancomycin infusion reaction, the intravenous vancomycin infusion should be stopped immediately, and supportive care should be initiated. To manage the reaction, H1- and H2-receptor antagonists, such as diphenhydramine and cimetidine, respectively, should be administered to block histamine receptors. In most cases, future doses of vancomycin may be safely given at reduced infusion rates, and the risk of vancomycin infusion reaction can be minimized by pretreating with antihistamines.[1][21]

Mild cases, including flushing and pruritus, can be managed with antihistamines such as diphenhydramine (50 mg orally or intravenously) and an H2 antagonist, such as cimetidine, administered intravenously. Most episodes of vancomycin infusion reaction resolve within approximately 20 minutes, after which vancomycin can be restarted at 50% of the original infusion rate. Future doses should be administered at a slower rate, typically over 2 hours.[16]

Moderate-to-severe cases presenting with symptoms of severe rash, hypotension, tachycardia, chest pain, back pain, muscle spasms, weakness, and angioedema should be managed according to severity. Patients with severe symptoms should be evaluated for anaphylaxis or other serious conditions before diagnosing a vancomycin infusion reaction. If signs of anaphylaxis are present—such as hypotension, stridor, difficulty breathing, wheezing, and hives—emergent treatment for anaphylaxis should be initiated, including the administration of epinephrine.[22][23] 

Pretreatment with diphenhydramine and cimetidine may help reduce the risk of vancomycin infusion reaction for patients requiring a rapid infusion of vancomycin. However, the most effective preventive measure is maintaining infusion rates below 10 mg/min, as slower administration significantly decreases the likelihood of a reaction.[19][24]

After symptoms resolve, vancomycin can be restarted and infused over 4 hours. If alternative antibiotics are available, they should be considered. However, if vancomycin must be continued, patients should be premedicated with H1- and H2-receptor antagonists administered intravenously 1 hour before each dose, and vancomycin should be infused over 4 hours under close monitoring.[21][22][23] If necessary, rapid or slow desensitization can be performed to allow for the continued administration of vancomycin.[25]

Differential Diagnosis

Vancomycin infusion reaction should be differentiated from an anaphylactic reaction, as both can present with pruritis, an erythematous rash, and tachycardia. However, anaphylaxis is characterized by additional symptoms such as stridor, angioedema, hives, and wheezing due to bronchospasm.

Anaphylactic reactions are IgE-mediated and require prior exposure to the allergen. Vancomycin infusion reaction is a rate-dependent anaphylactoid adverse reaction that most commonly occurs during a patient's first exposure to intravenous vancomycin.[22][23]

Prognosis

The prognosis for patients with vancomycin infusion reaction is excellent, particularly in nonsevere cases with appropriate management. Proper precautions and treatment guidelines should be followed to minimize the risk of recurrence. Hypotension should be managed with normal intravenous saline and other supportive care measures.[1]

Vancomycin may be re-administered after an episode of vancomycin infusion reaction if the medical team deems it appropriate. The infusion should be given at least 60 minutes to reduce the risk of recurrence, with longer durations recommended for doses increasing 1 g.[1] In cases where patients have a history of vancomycin infusion reaction or when extending the infusion duration is impractical due to time constraints, pretreatment with antihistamines and an H2 receptor blocker can help prevent future episodes.[21] Desensitization should be considered in appropriate clinical scenarios when continued vancomycin therapy is necessary.[25]

Complications

Vancomycin infusion reaction occurs due to the direct degranulation of basophils and mast cells triggered by the rapid infusion of vancomycin. In most cases, symptoms are manageable and primarily related to histamine release. However, severe symptoms, such as hypotension, angioedema, chest pain, and cardiac arrest, can be life-threatening and require immediate medical intervention.

Consultations

If a vancomycin infusion reaction occurs, the primary medical team should be notified immediately, and the pharmacy team should be involved in decision-making. Together, they should assess the diagnosis, determine the appropriate management strategy, and decide whether to continue vancomycin with precautionary measures or select an alternative antibiotic to prevent recurrence.

Deterrence and Patient Education

To improve patient outcomes, healthcare providers should be well-informed about the clinical presentation and management of vancomycin infusion reactions. If a vancomycin infusion reaction occurs, patients should receive evidence-based care and be educated about the response, its causes, and preventive measures for future treatments.

Pearls and Other Issues

Key facts to keep in mind about vancomycin infusion reaction:

• Vancomycin infusion reaction is a non–IgE-mediated hypersensitive reaction.
• Caused by direct mast cell and basophil degranulation, leading to histamine release.
• Associated with rapid infusion of vancomycin.
• Symptoms typically occur within minutes of infusion but can also appear later.
• Management should include stopping the infusion immediately if symptoms occur, administering antihistamines, and restarting the infusion at a slower rate.
• For prevention, infuse vancomycin over ≥60 minutes and pretreat with antihistamines in high-risk patients.
• Symptoms include flushing, pruritis, and erythema of the upper body and can occur within minutes of infusion. 

Enhancing Healthcare Team Outcomes

To maximize patient care and safety, the healthcare team should evaluate patient history by reviewing patient records or obtaining patient testimonies to determine any history of hypersensitivity reactions to vancomycin. Identifying prior reactions helps decide whether pretreatment is necessary before administering a vancomycin infusion. All patients should be explicitly asked about past vancomycin-related hypersensitivity reactions.

In addition, all patients receiving vancomycin infusions should be closely monitored, and any concerns should be communicated to the medical team. Clear communication between staff, particularly during shift changes, is crucial to minimize errors and promptly address any adverse reactions. 

The primary medical team should be notified immediately if a vancomycin infusion reaction develops. The medical and pharmacy teams should collaborate to confirm the diagnosis, determine appropriate management, and decide whether to continue vancomycin with precautions or whether an alternative antibiotic is necessary. 

Finally, all healthcare professionals must be familiar with their facility's vancomycin infusion protocols and know where to access them to ensure proper administration and minimize the risk of a vancomycin infusion reaction. Ongoing education and training on infusion protocols and adverse reaction management can improve patient safety and outcomes.