Red Man Syndrome: Causes, Symptoms, and Prevention

Red Man Syndrome is a condition that occurs due to the body’s reaction to the antibiotic drug vancomycin. It presents with a red, itchy rash that typically appears on the face, neck, and upper body. The condition is now more commonly referred to as Vancomycin Flushing Syndrome (VFS) instead of Red Man Syndrome, to move away from racially insensitive terminology. This reaction is not a true allergy but rather a pseudoallergic response caused by the rapid release of histamine in the body. It has been reported in around 5 to 50% of patients receiving intravenous (IV) vancomycin.¹Martel, T., Jamil, R., & Afzal, M. (2025). Vancomycin Infusion Reaction. StatPearls. Another study reported its occurrence in about 3.7 to 47% of patients receiving the drug for infections.²dos Reis Damasceno, M. P., Júlio, I. G., Rainer, J. B., & da Costa, A. F. (2023). Vancomycin infusion reaction: case report. Rev Med (São Paulo), 102(1), 199049.

Vancomycin is frequently prescribed to treat serious bacterial infections. Treating stubborn bacterial strains like methicillin-resistant Staphylococcus aureus (MRSA) requires strong antibiotics such as vancomycin. The signs and symptoms of this reaction usually appear within a few minutes of starting the infusion. In most cases, doctors manage it by pausing or slowing the IV infusion. Medications such as antihistamines and sometimes corticosteroids are used to help relieve the symptoms. to alleviate symptoms.

Vancomycin Flushing Syndrome: An Allergic Reaction

Red Man Syndrome is not a true allergic or anaphylactic reaction but rather a reaction caused by the direct release of the chemical histamine in the body. Anaphylaxis is a life-threatening reaction in which the body releases histamine in large quantities, which leads to a cascade of negative events. This release is mediated by IgE antibodies present in the body. Latex allergy is an example of an IgE-mediated allergic reaction. However, in VFS, the release of histamine is not mediated by IgE antibodies. Therefore, clinicians believe it isn’t a “true allergic reaction”. This flushing reaction mostly occurs during intravenous infusion of vancomycin. It’s extremely rare to experience it after oral intake, since vancomycin is poorly absorbed when taken by mouth.³Sowmya, B., Venkatachala, S. N., & Kumar, R. (2018). A rare case of red man syndrome with oral vancomycin. The American Journal of Gastroenterology, 113(Supplement), S1488. https://journals.lww.com/ajg/fulltext/2018/10001/a_rare_case_of_red_man_syndrome_with_oral.1488.aspx

Red Man Syndrome (RMS) Symptoms

Red Rash:

As the name indicates, an intense red-colored rash develops on different body parts. The most commonly involved regions include the face/neck and upper body regions. However, it may also develop on the extremities and lead to angioedema (sudden swelling of the lower layer of skin/mucosa, mostly commonly seen in the hands/feet and lips region). Clinical analysts describe the rash to be maculopapular, having pinpoint lesions.

VFS is the most common adverse reaction to the vancomycin antibiotic (accounting for 16% of all reactions). The rash usually develops within a few minutes of IV vancomycin infusion. Most patients notice a red rash within 4-10 minutes of vancomycin administration. Sometimes, other symptoms like flushing, itching, and hives may also accompany the rash.⁴Alvarez-Arango, S., Ogunwole, S. M., Sequist, T. D., Burk, C. M., & Blumenthal, K. G. (2021). Vancomycin infusion reaction—moving beyond “red man syndrome”. The New England journal of medicine, 384(14), 1283. Burning and itching are frequently seen in most patients.

Some healthcare workers notice skin pallor in severe allergic (anaphylactic) responses to drugs like vancomycin. The pallor or skin cyanosis is most noticeable in the hands and feet. It usually accompanies serious presentations, like breathing difficulties and fainting.

Note: You should immediately report to your doctor if experiencing these symptoms!

Hypotension:

The fall in blood pressure (hypotension) is a serious consequence of the syndrome and is usually seen in severe cases of VFS. The development of hypotension is attributed to the release of histamines in an allergic response.⁵Gorski, L. (2023). Vancomycin, A Common Home Infusion Antibiotic. Home Healthcare Now, 41(5), 289-290.

Severe, uncontrolled reactions can even induce shock and cardiac arrest.⁶Martel, T., Jamil, R., & Afzal, M. (2025). Vancomycin Infusion Reaction. StatPearls. In rare encounters, vancomycin flushing syndrome has proven to be life-threatening by inducing cardiac arrest. Therefore, experts advise healthcare professionals to carefully observe patients with suspected red man syndrome⁷.Khakurel, S., & Rawal, S. (2021). Vancomycin-induced cardiac arrest: a case report. Journal of Medical Case Reports, 15, 1-3.

Respiratory Symptoms:

The onset of most allergic reactions is characterized by shortness of breath and chest pain. The release of histamines in an allergic response to the antibiotic causes multiple events that lead to shortness of breath. Several patients experience narrowing of the airways (due to inflammation) and bronchospasm, and excessive production of mucus. These steps lead to shortness of breath, which may be accompanied by chest pain. Reports suggest that shortness of breath, fever, chills, and chest pain are less common symptoms of the syndrome.⁸Martindale, A., Mitchell, J., & Hassoun, A. (2021). A Rare Case of Red Man Syndrome from Intraperitoneal Vancomycin. Other less prevalent symptoms of red man syndrome include:

• Fever
• Chillls
• Nausea and vomiting
• Muscle weakness and spasms (of trunk muscles)
• Headache
• Dizziness

Some patients also report to the ER with back pain and rapid heart rate after taking vancomycin.

Red Man Syndrome Causes

Experts believe that the overstimulation of certain immune cells, specifically mast cells, by vancomycin is the main reason behind the development of Red Man Syndrome. Unlike classic allergic responses like allergic asthma, which are IgE-mediated, this reaction is non-IgE-mediated and results from a direct activation of mast cells.

Earlier, health experts suspected that the reaction was caused by impure vancomycin formulations, and the syndrome was nicknamed “Mississippi mud” due to the drug’s muddy appearance in early preparations. However, even after the purity of vancomycin significantly improved, cases of Vancomycin Flushing Syndrome continued to occur. This helped confirm that the reaction had nothing to do with the drug’s purity, and the term was eventually abandoned.

As mentioned, mast cells play a vital role in red man syndrome. Researchers have found that administration of vancomycin leads to the activation of the MRGPRX2 gene in mast cells. This gene activation causes the release of histamine, leading to the development of rash and other symptoms.⁹Azimi, E., Reddy, V. B., & Lerner, E. A. (2017). MRGPRX2, atopic dermatitis, and red man syndrome. Itch, 2(1), e5.

Other Antibiotics:

Clinical literature shows that various drugs can cause red man syndrome. Most common medications include:¹⁰M Shaju, A., Panicker, N., Chandni, V., Lakshmi Prasanna, V. M., Nair, G., & Subeesh, V. (2022). Drugs‐associated with red man syndrome: An integrative approach using disproportionality analysis and Pharmip. Journal of Clinical Pharmacy and Therapeutics, 47(10), 1650-1658.

• Ciprofloxacin
• Amphotericin B
• Infliximab
• Rifampin
• Cefepime
• Teicoplanin

Risk Factors:

Clinicians have noted certain risk factors associated with VFS. Healthcare workers and paramedical staff can avoid vancomycin flushing syndrome by taking care of these factors.

• Infusing too quickly: In several cases, RMS is seen after a rapid infusion of vancomycin.¹¹M Shaju, A., Panicker, N., Chandni, V., Lakshmi Prasanna, V. M., Nair, G., & Subeesh, V. (2022). Drugs‐associated with red man syndrome: An integrative approach using disproportionality analysis and Pharmip. Journal of Clinical Pharmacy and Therapeutics, 47(10), 1650-1658. Therefore, healthcare providers should administer vancomycin slowly (over 2 hours).
• Young patients: It has been seen that VFS is more prevalent in individuals younger than 40 years of age. Therefore, the adverse reaction is mostly encountered in pediatric patients.
• Patients with a history of Red Man Syndrome: You are highly likely to develop vancomycin flushing syndrome if you have a history of the allergic response. However, the severity of symptoms varies from the first experience to repeated incurrence.

Red Man Syndrome Diagnosis

Doctors diagnose the disease with clinical evaluation of the rash (and other symptoms) and history of the drugs. As there is no specific laboratory test for red man syndrome. The major symptoms your doctor will be looking for include a pinpoint rash on the upper body with flushing and hypotension following vancomycin administration (oral or intravenous).

Differential Diagnosis:

Red Man Syndrome Vs Stevens-Johnson Syndrome

Both reactions are adverse drug reactions, but have slight differences. While vancomycin flushing syndrome is a non-life-threatening issue arising due to rapid infusion of the antibiotic, Stevens-Johnson syndrome is a potentially fatal consequence that can be triggered by certain medications (or infections). Red man syndrome is characterized by erythema, flushing, and can be managed by slowing down the infusion rate and antihistamine medications. However, Stenvens-Johnson syndrome leads to severe skin blistering and may require hospitalization.
Moreover, hydromopromphone allergy can also have presentations similar to red man, but the former is a true allergic response involving IgE antibodies.

Red Man Syndrome Treatment

In the vast majority of cases, no treatment is needed because the symptoms subside within a few minutes. Medical workers have noted that the rash usually develops shortly after the start of infusion and goes away within 20 minutes. However, in some cases, the red rash may persist for several hours. Thus, treatment is necessary in such cases. The first step is to cease administration of the antibiotic causing the problem, i.e., amphotericin, ciprofloxacin, or vancomycin.

Anti-Histamine Medicines:

If your symptoms do not vanish on their own, your doctor will give you an oral dose of antihistamines. These drugs halt the release of histamines and help alleviate symptoms. A dose of 50mg diphenhydramine hydrochloride (oral or intravenous) can successfully abort most of the allergic reactions caused by infusion.
Most healthcare providers adopt the following strategy to manage patients with a confirmed diagnosis of red man syndrome:¹²Shrivastava, S., & Shrivastava, S. (2024). Vancomycin Flushing Syndrome: A Case Report. Cureus, 16(4).

• Discontinue vancomycin administration
• Give an antihistamine (via mouth or vein) and wait for about 20 minutes for symptoms to resolve
• Give corticosteroids if serious symptoms (like breathing difficulty) are present

Corticosteroids:

IV corticosteroids are given in severe cases. These drugs help bring down inflammation quickly, which is required in cases of bronchospasm. Sometimes, doctors administer IV fluids along with corticosteroids to manage serious patients.
Most of the time, doctors wait and adjust the dosage of the antibiotic to rid you of the symptoms.

Red Man Syndrome Prevention

The first and foremost requirement to prevent red man syndrome is to slowly infuse the antibiotic, i.e., over 60 minutes (or more). Healthcare providers should pretreat high-risk patients with antihistamines.

Wrapping Up

Red man syndrome, or presently known as vancomycin flushing syndrome, is a type of pseudoallergic reaction of the body to antibiotic administration. Generally, rapid infusion of vancomycin (and sometimes other antibiotics like ciprofloxacin, rifampin, etc.) leads to overactivation of mast cells, which leads to the release of histamine. It presents with an itchy, red rash on the face, neck, and upper body. Other symptoms, like hypotension and breathing difficulties, accompany the erythematous rash. Headache, fever, and chills are less common symptoms. In most cases, the symptoms subside within 20 minutes. However, when persistent, doctors stop antibiotic administration, give antihistamines and corticosteroids to alleviate symptoms. To prevent RMS, doctors advise slow infusion of antibiotics (≥ 60 minutes) and pretreatment of high-risk patients with antihistamine drugs.

Refrences

• 1
  Martel, T., Jamil, R., & Afzal, M. (2025). Vancomycin Infusion Reaction. StatPearls.
• 2
  dos Reis Damasceno, M. P., Júlio, I. G., Rainer, J. B., & da Costa, A. F. (2023). Vancomycin infusion reaction: case report. Rev Med (São Paulo), 102(1), 199049.
• 3
  Sowmya, B., Venkatachala, S. N., & Kumar, R. (2018). A rare case of red man syndrome with oral vancomycin. The American Journal of Gastroenterology, 113(Supplement), S1488. https://journals.lww.com/ajg/fulltext/2018/10001/a_rare_case_of_red_man_syndrome_with_oral.1488.aspx
• 4
  Alvarez-Arango, S., Ogunwole, S. M., Sequist, T. D., Burk, C. M., & Blumenthal, K. G. (2021). Vancomycin infusion reaction—moving beyond “red man syndrome”. The New England journal of medicine, 384(14), 1283.
• 5
  Gorski, L. (2023). Vancomycin, A Common Home Infusion Antibiotic. Home Healthcare Now, 41(5), 289-290.
• 6
  Martel, T., Jamil, R., & Afzal, M. (2025). Vancomycin Infusion Reaction. StatPearls.
• 7
  .Khakurel, S., & Rawal, S. (2021). Vancomycin-induced cardiac arrest: a case report. Journal of Medical Case Reports, 15, 1-3.
• 8
  Martindale, A., Mitchell, J., & Hassoun, A. (2021). A Rare Case of Red Man Syndrome from Intraperitoneal Vancomycin.
• 9
  Azimi, E., Reddy, V. B., & Lerner, E. A. (2017). MRGPRX2, atopic dermatitis, and red man syndrome. Itch, 2(1), e5.
• 10
  M Shaju, A., Panicker, N., Chandni, V., Lakshmi Prasanna, V. M., Nair, G., & Subeesh, V. (2022). Drugs‐associated with red man syndrome: An integrative approach using disproportionality analysis and Pharmip. Journal of Clinical Pharmacy and Therapeutics, 47(10), 1650-1658.
• 11
  M Shaju, A., Panicker, N., Chandni, V., Lakshmi Prasanna, V. M., Nair, G., & Subeesh, V. (2022). Drugs‐associated with red man syndrome: An integrative approach using disproportionality analysis and Pharmip. Journal of Clinical Pharmacy and Therapeutics, 47(10), 1650-1658.
• 12
  Shrivastava, S., & Shrivastava, S. (2024). Vancomycin Flushing Syndrome: A Case Report. Cureus, 16(4).