New Research Sheds Light on Optimal Management of Vancomycin Infusion Reactions

Before deciding on a single treatment strategy to manage vancomycin-infusion reactions (VIR), oncology providers should consider therapeutic implications, according to a report published in the Journal of Hematology and Oncology Pharmacy.¹

Gram-positive bacterial infections represent a major mortality risk for patients with cancer. Vancomycin is an antibiotic that is administered intravenously (IV) to treat bacterial infections, making appropriate use a key factor in supporting this patient population.²

VIR is a well-documented hypersensitivity reaction that is common across diverse patient populations. Key signs that a patient is experiencing VIR include flushing, pruritus, chest pain, muscle spasm, and hypotension. The typical onset time of reactions is 15 to 40 minutes into the infusion; they may continue for the duration of the infusion. The typical resolution time is 30 minutes after treatment.

Severity of VIR is typically classified into 3 different thresholds. A mild reaction is when a patient can tolerate flushing and other symptoms. A moderate reaction means a patient may be uncomfortable because of flushing or pruritis but is hemodynamically stable and is not experiencing muscle spasms and chest pain. A severe reaction, on the other hand, means a patient is experiencing muscle spasms, chest pains, and hypotension.

VIR, though common, is usually mild and easily treatable. However, it has the potential to cause severe reactions in some individuals. Severe VIR is more common in patients older than 40 years.

According to study authors, best management strategies may include premedication, infusion-rate adjustment, and, in some cases, alternative antibiotic therapy.

Premedication

Multiple studies have assessed the efficacy of antihistamine pretreatment to prophylaxis against VIR severity. Rapid vancomycin administration, when the infusion rate is less than or equal to 10 mg/minute, is often required in an emergency or presurgical setting, but comes with inherent risk of VIR. Both oral and IV histamine type 1 antagonists, such as hydroxyzine or diphenhydramine below 1 mg/kg, and type 2 antagonists, such as cimetidine below 4 mg/kg have demonstrated promising efficacy in reducing the effects of rapid vancomycin administration, yet patients will still require careful monitoring for subsequent doses.3-6 These H1 and H2 antagonists have also showed promising efficacy in reducing the severity of VIR symptoms in patients who have already developed moderate or severe reactions. ^3-6

Concurrent Medication and Infusion-Rate Adjustments

For patients who develop moderate or severe VIR and need to hold medication, the introduction of 50-mg diphenhydramine (oral or IV) and 20-mg IV famotidine may be appropriate, according to clinical guidelines.5 Alternatively, the use of IV fluids may be successful in achieving hemodynamic stabilization in a hypotensive patient. Once a patient has returned to their precreation clinical status, vancomycin may be reintroduced. However, a reduced infusion rate is advised.

When restarting vancomycin infusion, either a 50% reduction in rate speed or a decrease to below 1000 mg/hour, with a target of 10 mg/minute, is advised. The slower the better. One possible strategy proposed by Healy et al extends the duration time from 1 hour to 2 hours, as trough concentrations and areas under the curve are similar for both these infusion times.¹ Moreover, more frequent, lower doses of vancomycin may also be an effective strategy. For example, 500 mg every 6 hours instead of 1 g every 12 hours may be preferable. However, this method may pose some relevant pharmacokinetic, workflow, and financial implications.

Alternate Antibiotics?

If vancomycin is the only effective antibiotic available for a patient who experienced VIR with the first dose, they should be pretreated with a histamine type 1 antagonist and the infusion rate should be extended so that it lasts over 2 hours.

However, for patients with a history of VIR, antibiotics with similar activity and efficacy to vancomycin may be considered. It is important to note that patients receiving these treatments will still require routine monitoring and nuanced dosing and infusion rates.

Daptomycin, a cyclic lipopeptide antibiotic, or telavancin, dalbavancin, and oritavancin, all semisynthetic lipoglycopeptide antibiotics (and vancomycin analogs), are recommended alternative treatments for patients requiring antibiotic infusion.

For skin and skin-structure infections, the recommended daptomycin dose is 4 to 6 mg/kg once daily. For bloodstream infections, the standard dose increased to 8 to 10 mg/kg once daily. The standard duration with daptomycin is 5 to 14 days.

Alternatively, telavancin is typically prescribed at 10 mg/kg once daily for at least 14 days for blood stream infections. Oritavancin and dalbavancin represent long-acting antibiotic; for skin and soft-tissue infections, their recommended doses are 1.2 g and 1.5 g, respectively.

The adverse events associated with these alternative treatments are limited and less frequent than with vancomycin. Pseudoallergic VIR symptoms may occur and are best managed with slower infusion rates.

Teicoplanin is a drug with an antibacterial spectrum like vancomycin; however, this agent is currently only used outside the United States. Its profile suggests it may be a safer alternative for patients who cannot tolerate a vancomycin-induced release of histamine. The recommended loading dose for teicoplanin is 6 mg/kg twice daily for 48 hours for complicated infection, followed by a maintenance dose of 6 mg/kg once daily. Because this treatment is not widely available, it is recommended to consider the alternatives first.

“The percentage of patients who require an alternative therapy for VIR is generally low, but considerable variability exists in this area, because rarer forms of vancomycin hypersensitivity, which can manifest as IgE-mediated [immunologic] anaphylaxis, drug-induced hypersensitivity syndrome, or linear IgA bullous dermatosis, may still necessitate such treatment,” study authors noted.

“Appropriate precautions may also be taken before the use of an alternative antibiotic therapy is considered, including slowing the infusion rate and completing relevant premedication or coadministration of H1 and H2 antagonists. For patients with a history of anaphylaxis to vancomycin, alternative therapy with nonglycopeptide antibiotic is recommended whenever possible,” they concluded.

Reference

1. Haque S, Cubbison C, Pucik K, Bubalo J. Vancomycin infusion reaction: a clinical and therapeutic overview. J Hematol Oncol Pharm. 2022;13(12):146-150.
2. Alqahtani S, Almatrafi A, Bin Aydan N, et al. Optimization of vancomycin dosing regimen in cancer patients using pharmacokinetic/pharmacodynamic modeling. Pharmacotherapy. 2020;40(12):1192-1200. doi:10.1002/phar.2475
3. Wallace MR, Mascola JR, Oldfield EC III. Red man syndrome: incidence, etiology, and prophylaxis. J Infect Dis. 1991;164:1180-1185.
4. Weller PF. Vancomycin hypersensitivity. UpToDate. Wolters Kluwer; 2021. AccessedAugust 25, 2022. https://bit.ly/3clJZna
5. Renz CL, Thurn JD, Finn HA, et al. Oral antihistamines reduce the side effects from rapid vancomycin infusion. Anesth Analg. 1998;87:681-685.
6. Sahai J, Healy DP, Shelton MJ, et al. Comparison of vancomycin- and teicoplanin-induced histamine release and “red man syndrome.” Antimicrob Agents Chemother. 1990;34:765-769.