IDS A GUIDELINE S

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

Michael J. Rybak,1,2,3 Ben M. Lomaestro,4 John C. Rotschafer,5 Robert C. Moellering, Jr.,6,7,8 Willam A. Craig,9 Marianne Billeter,10 Joseph R. Dalovisio,11 and Donald P. Levine3

1Anti-Infective Research Laboratory, Department of Pharmacy Practice, College of Pharmacy & Health Sciences, and 2Department of Medicine, School of Medicine, Wayne State University, and 3Detroit Receiving Hospital & University Health Center, Detroit, Michigan; 4Albany Medical Center, Albany, New York; 5Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis; 6Shields Warren-Mallinckrodt Medical Research, 7Harvard Medical School, and 8Department of Medicine, Beth Israel Deaconess Medical Center,

Boston, Massachusetts; 9University of Wisconsin School of Medicine and Public Health, Madison; and 10Oshsner Medical Centers and 11Department of Infectious Diseases, Oschsner Health System, New Orleans, Louisiana

Practice guidelines for therapeutic monitoring of vancomycin treatment for Staphylococcus aureus infection in adult patients were reviewed by an expert panel of the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. A literature review of existing evidence regarding vancomycin dosing and monitoring of serum concentrations, in addition to patient outcomes combined with expert opinion regarding the drug’s pharmacokinetic, pharmacodynamic, and safety record, resulted in new recommendations for targeting and adjustment of vancomycin therapy.

EXECUTIVE SUMMARY

Adjustment and targeting of specific serum concentra- tions of vancomycin in patients have been the subject of debate for many years. The primary premise for monitoring and adjustment of serum vancomycin con- centrations is based on the perceived need to achieve serum concentrations at some multiple above the min- imum inhibitory concentration (MIC) for the offend- ing organisms and the avoidance of potential adverse effects, such as ototoxicity or nephrotoxicity. The lack

Received 9 April 2009; accepted 10 April 2009; electronically published 1 July

2009.

These guidelines were developed and issued on behalf of the Infectious Diseases Society of America.

Reprints or correspondence: Michael J. Rybak, Anti-Infective Research Laboratory, Wayne State University, 259 Mack Ave., Detroit, MI 48201 ([email protected]).

Clinical Infectious Diseases 2009; 49:325–7

© 2009 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2009/4903-0001$15.00

DOI: 10.1086/600877

of well-designed randomized clinical evaluations or data to support a clear relationship between specific serum concentrations and patient outcome has been the overriding contributor to this controversy. Unfor- tunately, the controversy has resulted in variable clinical practice methods. In some cases, monitoring is infre- quent or avoided. In other cases, monitoring and dos- age adjustment is overly aggressive.

The relationship between serum concentrations and treatment success or failure in serious Staphylococcus aureus infections has recently been established. Failure rates exceeding 60% for S. aureus displaying a vanco- mycin MIC value of 4 mg/L prompted recommenda- tions in 2006 from the Clinical and Laboratory Stan- dards Institute to lower the breakpoint for susceptibil- ity from 4 to 2 mg/L and in 2008 from the US Food and Drug Administration. Recently, a number of stud- ies have established a relationship between vancomy- cin treatment failures and infections in patients with methicillin-resistant S. aureus displaying an MIC of

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Vancomycin Therapeutic Guidelines • CID 2009:49 (1 August) • 325

2 mg/L. Vancomycin displays concentration-independent ac- tivity against S. aureus, with the area under the concentration curve (AUC) divided by the MIC as the primary predictive pharmacodynamic parameter for efficacy. On the basis of in vitro, animal, and limited human data, an AUC/MIC value of 400 has been established as the pharmacokinetic-pharmaco- dynamic target. To achieve this target, larger vancomycin doses and high trough serum concentrations are required. Although vancomycin administration is associated with some adverse ef- fects, the committee felt that the potential benefit of increased drug dosage was worth the risk of mostly reversible adverse events.

LITERATURE REVIEW, ANALYSIS, AND CONSENSUS

The expert panel reviewed the literature on pharmacokinetics, pharmacodynamics, efficacy, resistance, and toxicity of van- comycin.[1] A computerized literature search of PubMed for all relevant data published in the English language from 1958 through 2008 was conducted and forms the basis of these rec- ommendations. The quality of the studies was rated, and con- sensus recommendations were graded using the classification scheme of the Canadian Medical Association (table 1). It should be noted that the majority of the published vancomycin-mon- itoring studies were not randomized but consisted of obser- vational data. In addition, data from pediatric studies were not included; therefore, the recommendations are only for adult patients. The committee members were assigned specific topic areas and met via several teleconferences and in person to re- view the draft guidelines. The draft monitoring guidelines were circulated among committee members and were reviewed by each participating professional society for comments and re-

visions. The final guidelines were reviewed and approved by the 3 supporting organizations.

SUMMARY OF RECOMMENDATIONS

Therapeutic Vancomycin Dose Adjustment and Drug Monitoring Dosage. Initial vancomycin dosages should be calculated on the basis of actual body weight, including for obese patients. Subsequent dosage adjustments should be based on actual se- rum concentrations, to achieve targeted therapeutic concentra- tions. Continuous infusion regimens are unlikely to substantially improve patient outcome, compared with intermittent dosing. (Level of evidence, II; grade of recommendation, A.)

Peak versus trough concentrations. Trough serum van- comycin concentrations are the most accurate and practical method of monitoring the effectiveness of vancomycin. Trough serum concentrations should be obtained just before the fourth dose, at steady-state conditions. (Note that steady-state achieve- ment is variable but occurs approximately just before the fourth dose.) (Level of evidence, II; grade of recommendation, B.)

Avoidance of development of resistance. On the basis of the evidence suggesting that S. aureus exposure to trough serum concentrations of !10 mg/L can produce strains with vanco- mycin–intermediately susceptible S. aureus (VISA)–like char- acteristics, it is recommended that trough serum vancomycin concentrations always be maintained at 110 mg/L to avoid the development of resistance. (Level of evidence, III; grade of rec- ommendation, B.)

Recommended trough serum concentrations and dosage adjustments. On the basis of the potential to improve pen- etration, to increase the probability of optimal target serum concentrations, and to improve clinical outcomes of compli- cated infections, such as bacteremia, endocarditis, osteomyelitis,

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Table 1. Definition of quality of evidence and strength of recommendation.

Assessment Type of evidence

Quality of evidence

Level I Evidence from at least 1 properly designed randomized, controlled trial

Level II

Evidence from at least 1 well-designed clinical trial, with- out randomization; from cohort or case-controlled ana- lytic studies (preferably from 11 center); from multiple time series; or from dramatic results of uncontrolled experiments

Level III Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

Strength of recommendation

Grade A Good evidence to support a recommendation for use

Grade B Moderate evidence to support a recommendation for use

Grade C Poor evidence to support a recommendation

NOTE. Adapted from the Canadian Task Force on the Periodic Health Examination [2].

326 • CID 2009:49 (1 August) • Rybak et al

meningitis, and hospital-acquired pneumonia caused by S. au- reus, trough serum vancomycin concentrations of 15–20 mg/ L are recommended. Trough serum vancomycin concentrations in that range should achieve an AUC/MIC of 1400 for most patients if the MIC is !1 mg/L. (Level of evidence, III; grade of recommendation, B.) To achieve rapid attainment of this target concentration for seriously ill patients, a loading dose of 25–30 mg/kg (based on actual body weight) can be considered. (Level of evidence, III; grade of recommendation, B.) A targeted AUC/MIC of 1400 is not achievable with conventional dosing methods if the vancomycin MIC is “2 mg/L for a patient with normal renal function (i.e., creatinine clearance, 70–100 mL/ min). Therefore, alternative therapies should be considered. Vancomycin dosages of 15–20 mg/kg (based on actual body weight) given every 8–12 h are required for most patients with normal renal function to achieve the suggested trough serum concentrations when the MIC is !1 mg/L. It should be noted that currently available nomograms were not developed to achieve these targeted end points. Individual pharmacokinetic adjustments and verification of achievement of target serum concentrations are recommended. When individual doses ex- ceed 1 g (e.g., 1.5 and 2 g), the infusion period should be extended to 1.5–2 h. (Level of evidence, III; grade of recom- mendation, B.)

Vancomycin toxicity. There are limited data suggesting a

direct causal relationship between toxicity and specific serum vancomycin concentrations. There are also conflicting data characterized by confounding nephrotoxic agents, inconsistent and highly variable definitions of toxicity, and the inability to examine the time sequence of events surrounding changes in renal function secondary to vancomycin exposure. A patient should be considered to have vancomycin-induced nephrotox- icity if multiple (at least 2 or 3 consecutive) high serum cre- atinine concentrations (increase of 0.5 mg/dL or 150% increase from baseline, whichever is greater) are documented after sev- eral days of vancomycin therapy in the absence of an alterna- tive explanation. (Level of evidence, II; grade of recommen- dation, B.)

Monitoring of serum concentrations to reduce toxicity.

Available evidence does not support monitoring of peak serum vancomycin concentrations to decrease the frequency of ne- phrotoxicity. (Level of evidence, I; grade of recommendation, A.) Monitoring of trough serum vancomycin concentrations to reduce nephrotoxicity is best suited for patients receiving aggressive dose targeting to produce sustained trough serum concentrations of 15–20 mg/L or who are at risk of toxicity, such as patients receiving concurrent treatment with nephro- toxins. (Level of evidence, III; grade of recommendation, B.) Monitoring is also recommended for patients with unstable renal function (either deteriorating or significantly improving

function) and for patients receiving prolonged courses of ther- apy (13–5 days). (Level of evidence, II; grade of recommen- dation, B.) All patients receiving prolonged courses of vanco- mycin treatment should have at least 1 steady-state trough serum concentration measured just before the fourth dose. Fre- quent monitoring (11 measurement of trough concentration before the fourth dose) for short-course therapy (!5 days) or for lower-intensity dosing (targeted to attain trough serum van- comycin concentrations of !15 mg/L) is not recommended. (Level of evidence, II; grade of recommendation, B.) There are limited data to support the safety of sustained trough serum vancomycin concentrations of 15–20 mg/L. When this target range is desired, once-weekly measurements of trough concen- trations for hemodynamically stable patients is recommended. Frequent (in some instances, daily) monitoring of trough con- centrations is advisable to prevent toxicity in hemodynamically unstable patients. The exact frequency of monitoring is often a matter of clinical judgment. (Level of evidence, III; grade of recommendation, B.) Data on comparative vancomycin toxicity for continuous versus intermittent administration are conflict- ing, and no recommendation can be made. Monitoring of se- rum vancomycin concentrations to prevent ototoxicity is not recommended, because this toxicity is rarely associated with monotherapy and does not correlate with serum vancomycin concentrations. Monitoring may be more important when other ototoxic agents, such as aminoglycosides, are adminis- tered. (Level of evidence, III; grade of recommendation, B.)

Acknowledgments

Potential conflicts of interest. M.J.R. received research grants from Astellas, Cubist, Forest, and Pfizer; consulted for Astellas, Cubist, Forest, Ortho-McNeil, and Targanta; and has served on speakers’ bureaus for Cubist, Wyeth, Pfizer, and Targanta. J.C.R. has received research grants from Ortho-McNeil and Astra-Zeneca; has been a consultant for Ortho- McNeil, Schering, Cubist, Wyeth, Pfizer, Theravance, Optimer, and Bayer; and has served on speakers’ bureaus for Ortho-McNeil, Schering, Pfizer, Wyeth, and Cubist. R.C.M. was a former consultant for Eli Lilly. W.A.C. has received research funding from Johnson & Johnson and Astra-Zeneca and has been a consultant for Bristol-Myers Squibb and Forest Pharma- ceuticals. M.B. has received research funding from Cubist and has served on speakers’ bureaus for Sanofi-Pasteur, Pfizer, and Ortho-McNeil. J.R.D. has received a consulting fee to testify on Capitol Hill regarding the clinical impact of the methicillin-resistant S. aureus outbreak in the United States; no product-specific data were discussed. B.M.L. and D.P.L.: no conflicts.

References

1. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009; 66:82–98. Available at: http://www.ashp.org/ DocLibrary/BestPractices/BPVancoAJHP.aspx. Accessed 25 June 2009.
2. Canadian Task Force on the Periodic Health Examination. The periodic health examination. Can Med Assoc J 1979; 121:1193–254.

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Vancomycin Therapeutic Guidelines • CID 2009:49 (1 August) • 327

Official reprint from UpToDate® www.uptodate.com

©2023 UpToDate®

Vancomycin hypersensitivity

Author: Peter F Weller, MD, MACP

Section Editor: N Franklin Adkinson, Jr, MD

Deputy Editor: Anna M Feldweg, MD Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2023. | This topic last updated: Apr 28, 2023.

INTRODUCTION

Vancomycin causes several different types of hypersensitivity reactions, ranging from localized skin reactions to generalized cardiovascular collapse. The most common adverse reaction is vancomycin infusion reaction (VIR). VIR is a rate-dependent infusion reaction, not a true allergic reaction.

Vancomycin hypersensitivity will be reviewed here. Other antibiotics that commonly cause hypersensitivity reactions include the beta-lactam antibiotics and sulfonamides, and hypersensitivity reaction to these drugs are discussed separately. (See “Penicillin allergy: Immediate reactions” and “Sulfonamide allergy in HIV-uninfected patients”.)

TERMINOLOGY

The terms “red man syndrome” or “red neck syndrome” have commonly been used to describe vancomycin infusion reaction (VIR). Another term that is variably used is vancomycin flushing syndrome or reactions. This terminology originated from the dramatic erythema that develops in some patients in response to infusion of vancomycin, but the terms could be misconstrued as insulting to specific groups of people in the United States, and the emphasis on flushing, which is a prominent feature but not the only one, may lead to the reaction being missed in patients with darker skin [1,2]. Thus, the term “vancomycin infusion reaction” is preferred.

VANCOMYCIN INFUSION REACTION

The most common adverse reaction to vancomycin is “vancomycin infusion reaction (VIR),” previously known as “red man syndrome,” although we will avoid further use of this term for the reasons outlined previously. (See ‘Terminology’ above.)

Route of administration — VIR occurs principally with parenteral administration of vancomycin. Rarely, VIR has been caused by topical administration of vancomycin powder [3]. In contrast, oral administration of vancomycin in subjects with Clostridioides difficile infections does not usually result in systemic absorption [4]. However, for some patients, especially those with impaired kidney function or other abnormalities, oral administration can lead to detectable serum levels of the medication, and VIR to oral vancomycin may be possible [5].

Signs and symptoms — VIR may develop with the first administration of vancomycin. It is characterized by flushing, erythema, and pruritus, usually affecting the upper body, neck, and face more than the lower body. Pains and muscle spasms in the back and chest, dyspnea, and hypotension may also occur [6,7]. Otherwise unexplained hypotension has been reported [8,9]. In a retrospective review of multiinstitutional electronic medical records, amongst 3165 recipients of vancomycin, 491 experienced adverse drug reactions, of which 134 were immediate hypersensitivity reactions [10].

VIR is rarely life threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [8,11]. Immunoglobulin E (IgE) mediated anaphylaxis can present with symptoms similar or identical to those of severe VIR, and clinicians should be mindful of this alternative diagnosis. Unlike VIR, an IgE-mediated reaction to vancomycin does not occur with initial administration but instead requires sensitization to develop from a previous course of vancomycin. (See ‘IgE-mediated anaphylaxis’ below.)

Mechanism — VIR is an idiopathic reaction, which is not thought to involve drug-specific antibodies. VIR is a form of pseudoallergic drug reaction, which is an adverse drug reaction with signs and symptoms that mimic immunologic drug allergies but in which IgE- mediated immunologic mechanisms have not been demonstrated.

Studies in animals indicate that vancomycin directly activates mast cells, resulting in release of vasoactive mediators, such as histamine [12,13]. A mast cell specific G-protein

coupled receptor in mice and its human orthologue, MRGPRX2, have been identified as mediating pseudoallergic mast cell activation, as elicited by candidate agents, including ciprofloxacin [14]. In this study, vancomycin was not evaluated, although vancomycin was shown to activate human mast cells through MRGPRX2 in an in vitro study [15]. (See “Mast cells: Surface receptors and signal transduction”, section on ‘MRGPRX2’.)

In several human studies, the degree of elevation in serum histamine was related to the clinical severity of VIR [16-18]. However, in other studies, increased serum histamine concentrations did not predict VIR, and VIR occurred without detectable elevations in plasma histamine [19], suggesting either that other mediators may be involved or that plasma histamine is not a sufficiently sensitive marker for mast cell activation localized to the skin.

Relationship to infusion rate — VIR is usually a rate-related infusion reaction, as illustrated by the following observations [16,20-22]:

• In one study, 10 healthy presurgical patients received rapid infusions of 1 gram of vancomycin over 10 minutes [20]. All developed VIR, seven had severe cutaneous reactions, and five had a reduction in blood pressure of 20 percent or more, necessitating discontinuation of the infusion.
• In a report of 10 adult male volunteers, the incidence and severity of VIR following the infusion of 1 gram of vancomycin over either one or two hours was compared [16]. Eight subjects developed VIR (two severe, three moderate, and three mild) with the one-hour infusion compared with three (all mild) with the two-hour infusion. However, two studies with a total of 62 hospitalized patients with serious infections found a much lower risk of VIR (less than 10 percent) following 1 gram infused over one hour [17,19].

Predisposing medications — Mast cells are more easily activated when vancomycin is given in combination with certain other medications. The combination of vancomycin and opioids (eg, morphine, meperidine, codeine) enhances dose- or rate-related mast cell degranulation [23]. Adverse reactions can occur following administration of vancomycin in patients being treated with an opioid or following the administration of opioids in patients being treated with vancomycin [24].

Similar interactions can occur between vancomycin and radiocontrast dye, some muscle

relaxants used in general anesthesia, and any other agents that potentiate mast cell degranulation ( table 1). Thus, when possible, these agents should not be administered simultaneously or in close approximation with vancomycin.

Prevention of initial reactions — Prevention of VIR involves the use of slower infusion rates and, in some situations, premedication.

Slower infusion rates — To avoid VIR, vancomycin should be infused at a rate no higher than 10 mg/minute or, for a 1 gram dose, over a minimum of 100 minutes (whichever results in a slower infusion) [22]. We advise even slower rates of infusion for patients who are also receiving opioids or other medications that predispose to mast cell activation

( table 1). (See ‘Predisposing medications’ above.)

Premedication — Empiric premedication to prevent VIR is not usually necessary for patients who are receiving vancomycin for the first time at rates of infusion ≤10 mg/min. We generally do not administer premedication for doses ≤500 mg given over one hour or doses of 500 mg to 1 gram given over two hours.

In contrast, empiric premedication with antihistamines is commonly employed if more rapid infusions of vancomycin are required in emergency or presurgical settings. We administer premedication for patients receiving vancomycin at high rates of infusion (more than 10 mg/minute or 1 gram over one hour). Oral antihistamines are preferred when possible. Although H1 antihistamines may be sufficient for mildly increased infusion rates, we suggest administration of both an H1 and H2 antihistamine to minimize the likelihood of a reaction if significantly faster rates are used (eg, 1 gram over 10 minutes).

The efficacy of pretreatment with antihistamines in reducing the incidence and severity of VIR was evaluated in the following studies:

• A randomized trial of 33 patients found that pretreatment with diphenhydramine (50 mg orally) completely prevented VIR in a group of patients receiving 1 gram of vancomycin over 60 minutes [17]. Reactions occurred in 47 percent of the placebo group compared with none in the diphenhydramine group.
• In a randomized trial of very rapid infusions (1 gram over 10 minutes) in 30 presurgical patients, oral premedication with both H1 and H2 antihistamines was given [20]. Subjects received oral diphenhydramine (≤1 mg per kg) plus oral

cimetidine (≤4 mg per kg) one hour before infusion. The incidence and severity of VIR were significantly lower in the antihistamine-treated group, although one antihistamine-treated patient had intolerable itching and could not complete the infusion. Hypotension did not occur in the antihistamine group but developed in 50 percent of patients in the placebo group.

• The same investigators performed another randomized trial in 40 patients using the same medications, doses, and setting as in the previous trial (ie, 1 gram over 10 minutes), although the antihistamine premedications (diphenhydramine and cimetidine) were administered intravenously [25]. Patients treated with an antihistamine had significantly lower rates of hypotension (11 versus 63 percent) and cutaneous findings (63 versus 100 percent). Itching was severe enough in two antihistamine-treated patients to necessitate discontinuation of the infusion.

Based upon these limited data, premedication with H1 alone may be sufficient to prevent VIR following mildly increased rates of infusion, although even the combination of H1 and H2 antihistamines did not completely prevent VIR following very rapid infusions (1 gram over 10 minutes) of vancomycin. Oral and intravenous antihistamine premedications appear to be similarly efficacious.

Management — The optimal management of VIR has not been evaluated in randomized trials. The approach outlined herein is based upon the author’s clinical experience.

• For mild reactions (eg, flushing that is not bothersome to the patient), symptoms typically resolve in minutes, and antihistamines are usually not necessary. We usually restart the infusion at one-half of the previous rate.
• For moderate reactions (eg, the patient is uncomfortable due to flushing or pruritus but hemodynamically stable and not experiencing chest pain or muscle spasm), we typically interrupt the infusion and treat with diphenhydramine (50 mg orally or intravenously) and famotidine (20 mg intravenously). Symptoms usually subside promptly. The infusion can then be restarted at one-half the original rate or 10 mg/minute, whichever is slower.
• For severe reactions (eg, involving muscle spasm, chest pain, or hypotension), we stop the infusion and treat with diphenhydramine (50 mg intravenously) as well as famotidine (20 mg intravenously) and, if hypotension is present, intravenous fluids.

Once symptoms have resolved, the infusion can be restarted and given over four or more hours. For administration of future doses, we suggest repeat premedication with antihistamines before each dose and infusion over four hours, as well as continuous hemodynamic monitoring during infusions.

• It may be difficult or impossible to distinguish severe VIR from anaphylaxis. Flushing and hypotension are features of both reactions. Hives, laryngeal edema, and wheezing are suggestive of anaphylaxis, and patients with these signs and symptoms should be treated with intramuscular epinephrine, in addition to the measures above. Overviews of the treatment of anaphylaxis in adults and in children (with specific medication doses) are provided in the tables ( table 2 and table 3). Infusions must not be restarted if anaphylaxis is suspected, because slowing the rate and administering premedications will not prevent IgE-mediated anaphylaxis. (See ‘IgE- mediated anaphylaxis’ below.)

Following VIR of any severity, the patient’s medication list should be reviewed to determine if other predisposing medications (eg, opioids) ( table 1) can be identified and discontinued before restarting the infusion.

Recurrent reactions — Some individuals experience recurrent and persistent symptoms despite premedication and slower infusion rates [17,24,26]. These individuals may have mast cells and/or basophils that are easily activated. Patients with mast cell disorders are particularly prone to VIR with vancomycin. (See “Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis”, section on ‘Triggers for mediator release’ and “Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis”.)

Desensitization can be attempted if there is no equally effective alternative antibiotic and vancomycin is absolutely required. (See ‘Desensitization’ below.)

IgE-MEDIATED ANAPHYLAXIS

Anaphylaxis is an immunologically mediated reaction involving drug-specific IgE antibodies. Anaphylaxis in response to vancomycin administration is believed to be rare, although reactions involving angioedema, respiratory distress, and bronchospasm with demonstrable drug-specific IgE have been described [26-28]. (See “Anaphylaxis: Emergency

treatment”.)

Patients with anaphylactic reactions to vancomycin often have a history of multiple prior exposures. Anaphylaxis does not occur on the first administration of the medication, because prior exposure to the drug is necessary to form drug-specific IgE antibodies.

Clinical manifestations — The symptoms of anaphylaxis include (but are not limited to) urticaria, angioedema, generalized pruritus, tachycardia, hypotension, nausea and vomiting, lightheadedness, and hypotension ( table 4).

Although severe vancomycin infusion reactions (VIR) and anaphylaxis can present with similar signs and symptoms, wheezing and respiratory distress are more common in anaphylaxis, whereas VIR more often involves chest pains causing a sensation of chest tightness. Angioedema is usually seen in anaphylaxis only. However, it may not be possible to distinguish anaphylaxis from severe VIR based upon clinical presentation. The patient should be assumed to have anaphylaxis in such cases and managed accordingly.

Acute management — If anaphylaxis is suspected, the vancomycin infusion should be stopped immediately, and the patient should be treated with intramuscular epinephrine. Overviews of the treatment of anaphylaxis in adults and in children (with specific medication doses) are provided in the tables ( table 2 and table 3). A more detailed discussion of the treatment of anaphylaxis is presented separately. (See “Anaphylaxis: Emergency treatment”.)

Diagnosis — Differentiating between anaphylaxis and severe VIR is usually based upon clinical signs and symptoms. Unfortunately, serum and skin tests cannot reliably discriminate between these two reactions. In addition, vancomycin skin testing has not been validated, and the positive and negative predictive values are unknown.

Serum tests — Serum tryptase levels have been studied in severe reactions to vancomycin [29-35]. Tryptase is stored preformed within mast cell granules and released during mast cell degranulation. Elevations in these mast cell-derived mediators are variably found in IgE-mediated anaphylaxis, although normal levels do not exclude anaphylaxis. (See “Laboratory tests to support the clinical diagnosis of anaphylaxis”, section on ‘Tryptase’.)

Skin testing — Skin testing with vancomycin has not been validated, and the positive and

negative predictive value of the results are not known. However, isolated case reports described reactions that were highly suggestive of IgE-mediated drug allergy in which skin test results were positive [36]. As an example, one patient developed generalized urticaria and respiratory distress after several doses of vancomycin [27]. Intradermal skin tests were positive at 0.1 mcg/mL, whereas control subjects had positive results only at much higher concentrations (>10 mcg/mL). The patient was desensitized over 13 days, after which repeat skin testing was negative, which is a clinical marker of successful desensitization in IgE-mediated reactions. Another case report also documented positive skin tests results that converted to negative following desensitization [37]. (See ‘Desensitization’ below.)

These reports suggest that skin testing with appropriate vancomycin concentrations may reflect clinical reactivity and provide supportive evidence for the clinical diagnosis of anaphylaxis. A positive skin test at concentrations of 1 mcg/mL or lower is strongly suggestive of drug allergy in a patient with a reaction that had features of allergy.

Use of alternate medications — Other antimicrobial agents should be considered for patients who have experienced very severe symptoms in response to vancomycin. Some patients receive vancomycin because of a reported history of allergy to penicillins, yet penicillin may be a superior antibiotic for certain infections, such as native valve endocarditis due to methicillin-sensitive Staphylococcus aureus. (See “Antimicrobial therapy of left-sided native valve endocarditis”.)

Patients are sometimes labeled as penicillin allergic based on a vague past history or may have lost the allergy over time. Presurgical evaluation by an allergy specialist to confirm or exclude penicillin allergy should be arranged whenever possible. Several studies have demonstrated the value of avoiding vancomycin for surgical prophylaxis in patients with a self-reported history of penicillin allergy [38-40]. (See “Penicillin allergy: Immediate reactions”, section on ‘Impact of penicillin allergy on care’.)

There are limited antibiotic options for certain infections, however, such as methicillin- resistant S. aureus, coagulase-negative staphylococci, and ampicillin-resistant enterococci. Daptomycin has been used successfully in a patient intolerant to vancomycin [41].

Alternative agents are discussed in detail in specific topic reviews. (See “Methicillin- resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia” and “Infection due to coagulase-negative staphylococci: Treatment” and “Treatment of enterococcal infections”.)

Glycopeptide antibiotics structurally similar to vancomycin include telavancin, dalbavancin, and oritavancin [42]. (See ‘Use of related drugs’ below.)

Desensitization — Desensitization is a procedure that alters the immune activation by the drug and results in temporary tolerance, allowing the patient with a drug hypersensitivity reaction to receive an uninterrupted course of the medication safely. (See “Rapid drug desensitization for immediate hypersensitivity reactions”.)

Indications — Readministration of vancomycin to a patient with a past severe VIR or possible anaphylaxis may need to be considered when no other antimicrobial of equivalent efficacy is available. Vancomycin desensitization is appropriate for both suspected IgE-mediated reactions (preferably confirmed by skin testing) and may be clinically useful for severe VIR that was refractory to the measures outlined above [24,27,37,43,44]. (See ‘Management’ above.)

Precautions — Desensitization, or any form of reexposure, is contraindicated in patients with the following types of past reactions:

• Exfoliative skin reactions – Reactions involving blistering, peeling, or sloughing of the skin, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (see “Stevens-

Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae”)

• Drug reaction with eosinophilia and systemic symptoms (DRESS), also called the drug- induced hypersensitivity syndrome [45,46] (see “Drug hypersensitivity: Classification and clinical features”)

Desensitization is generally not performed in patients with past drug fever, hematologic or renal hypersensitivity reactions, phlebitis, or linear immunoglobulin A (IgA) bullous dermatosis. (See ‘Other forms of hypersensitivity’ below.)

Referral — Consultation with an allergy specialist experienced in adverse drug reactions is recommended if desensitization is under consideration. Precautions regarding desensitization include the following:

• Desensitization is performed immediately before required treatment because maintaining tolerance requires continual exposure to the drug.
• Other concurrent health issues should be as well controlled as possible, particularly cardiopulmonary conditions (eg, heart failure, asthma).
• Patients should optimally not be taking medications that may increase the likelihood of anaphylaxis or interfere with treatment of anaphylaxis, such as angiotensin- converting enzyme inhibitors or beta blockers.
• Desensitizations should be performed in an appropriate medical setting, with proper monitoring and immediate availability of rescue medications and equipment. Desensitizations for IgE-mediated sensitivities to intravenous medications are usually performed in an intensive care unit.
• Documentation of informed consent, including a thorough discussion of risks and benefits of the procedure, is essential.

The safety of desensitization as a general technique is reviewed separately. (See “Rapid drug desensitization for immediate hypersensitivity reactions”, section on ‘Safety’.)

Protocols — A variety of intravenous protocols have been published. Most can be completed over several hours, which is important for patients who are infected and acutely in need of treatment [24,43,47-49]. Other protocols involve intermittent doses that increase incrementally over periods ranging from 2 to 13 days [27,37]. Studies comparing the success rates of different protocols have not been performed.

A protocol that can be completed in several hours is provided ( table 5) [47].

Symptoms during desensitization — Symptoms during desensitization have been noted in as many as 30 percent of cases and are usually mild (eg, flushing, pruritus, limited urticaria). Most symptoms can be managed without discontinuation of the desensitization protocol. Mild symptoms are managed by halting the infusion and treating the symptoms that do not subside spontaneously. Once symptoms have subsided, the last tolerated step is repeated. This “stepping back” may be performed again if needed, or an intermediate step can be inserted after the last tolerated step and before the problematic step by reducing the infusion rate of the problematic step.

If moderate or severe symptoms develop, the infusion should be halted and the symptoms treated. The decision to proceed with desensitization depends upon the patient’s status and need for vancomycin.

There is one report of a patient who failed a rapid protocol and was subsequently successfully desensitized using a 13-day procedure [37].

Duration of effect — Desensitization induces a temporary state of tolerance, allowing the drug to be administered safely as long as the patient remains continually exposed to it.

Once the initial desensitization is complete, the patient can receive subsequent doses normally, and no symptoms are anticipated. However, serum levels of vancomycin must be monitored carefully to ensure that the concentration in the blood does not drop below detectable levels [28,50]. It is not known what threshold level of drug is required to maintain the tolerized state. However, the drug levels should be kept within the therapeutic range if possible, both to maintain tolerance and treat the infection. This may require continuous, rather than intermittent, dose infusions.

If the drug level becomes undetectable, then desensitization should be repeated in order to reintroduce the medication safely. Once the course of treatment is completed, it must be clearly explained to patients that they still have an allergy to vancomycin and would have to be desensitized again if it were required in the future.

OTHER FORMS OF HYPERSENSITIVITY

The most common hypersensitivity reaction to vancomycin is skin rash. Other reactions, not all of which are immune mediated, include hematologic and kidney disorders, drug fever, and phlebitis [51,52].

DRESS — Vancomycin has elicited drug reaction with eosinophilia and systemic symptoms (DRESS), which is also called drug-induced hypersensitivity syndrome [45,53-55]. This drug reaction involves rash, atypical lymphocytosis, frequent but not uniform eosinophilia, and, often, lymphadenopathy. There may be hepatic, kidney, and/or pulmonary involvement.

Treatment involves discontinuing the causative drug and, conventionally, administration of glucocorticoids [46,54]. Amongst an extensive review of electronic medical records of patients developing DRESS, antibiotics accounted for 74 percent, with vancomycin the most common antibiotic (39 percent) overall [56]. (See “Drug reaction with eosinophilia and systemic symptoms (DRESS)”.)

Expression of the HLA-A*32:01 allele was found in 83 percent of 23 cases of vancomycin- elicited DRESS versus 0 percent in vancomycin-tolerant control subjects [57]. The authors

suggest that, while administration of vancomycin often needs to be initiated rapidly, since DRESS will not develop usually until after two weeks of drug administration, testing for the HLA-A*32:01 allele be performed soon after initiation of the drug to assess genetic risks for DRESS development. Any drug culprit in DRESS should be avoided in the future as rechallenge can precipitate severe and fatal reactions.

Dermatologic — The most common form of vancomycin hypersensitivity reaction is skin rash. Other dermatologic reactions include linear IgA bullous dermatosis (LABD) and various other rare disorders.

Maculopapular and urticarial eruptions — Maculopapular skin eruptions are the most frequent dermatologic manifestations of vancomycin hypersensitivity [58-62]. In a systematic review of patients receiving teicoplanin or vancomycin, skin rashes occurred in 57 of 889 (6 percent), while vancomycin infusion reaction (VIR) occurred in 18 of 414 (4 percent) [62]. Urticarial eruptions are also reported [60].

Vancomycin-related linear IgA bullous dermatosis — LABD is an autoantibody- mediated skin reaction to vancomycin ( picture 1) [63-69]. In a review of immune- mediated reactions to vancomycin, LABD was the most commonly identified immune- mediated adverse reaction [36]. This entity may be confused with toxic epidermal necrolysis, although LABD does not usually involve mucosal membranes [70-72]. In addition, a nonbullous, morbilliform variant of vancomycin-induced LABD has been reported [73]. LABD can appear from one day to one month from the time of initial vancomycin administration. The reaction appears to be idiosyncratic and unrelated to peak or trough serum vancomycin levels. LABD is discussed in more detail separately. (See “Linear IgA bullous dermatosis”.)

Rare severe cutaneous reactions — Stevens-Johnson syndrome [74,75], exfoliative dermatitis [76], toxic epidermal necrolysis [77], extensive fixed drug eruption [78], and leukocytoclastic vasculitis [79] have all been described in association with vancomycin use in case reports. Early recognition and discontinuation of the drug are critical.

Desensitization has no efficacy in these reactions and should not be performed for the purposes of circumventing recurrence, as reexposure to the drug could result in a more severe or fatal recurrence of the reaction. (See “Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis”.)

Hematologic — Hematologic manifestations of vancomycin-related reactions include

leukocytosis, eosinophilia, neutropenia, and immune thrombocytopenia [59,80-85]. Neutropenia tends to occur with longer courses of therapy, and weekly monitoring of the white blood cell count and differential leukocyte counts during prolonged administration is indicated [86]. A case of agranulocytosis in a patient with kidney insufficiency was also reported [18]. Vancomycin should be discontinued if these conditions develop.

Drug-induced fever — Uncommonly, vancomycin has been implicated as a cause of drug- induced fever [51,52,87]. In some instances, fever has occurred concomitant with vancomycin-elicited neutropenia [58,81].

Kidney — Vancomycin may cause nephrotoxicity, especially in patients receiving confounding nephrotoxins or who have kidney insufficiency or altered hemodynamics [88- 90]. (See “Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults”.)

On occasion, vancomycin can also elicit immunologically mediated kidney damage due to acute interstitial nephritis [91-93]. Vancomycin should be discontinued if it is a likely cause of acute interstitial nephritis. (See “Clinical manifestations and diagnosis of acute interstitial nephritis”.)

USE OF RELATED DRUGS

Glycopeptide antibiotic analogs — The agents that share structural similarities with vancomycin include teicoplanin, dalbavancin, oritavancin, and telavancin [42]. Teicoplanin has been in use longer than the other agents, so there is more experience with the adverse reactions it can cause.

Teicoplanin — Teicoplanin, which is not available in the United States, is a glycopeptide antimicrobial with structural similarity to vancomycin, equivalent efficacy in treating invasive beta-lactam-resistant, gram-positive infections, but with apparently lower rates of adverse events, particularly nephrotoxicity and vancomycin infusion reaction (VIR) [62,94- 96].

• Teicoplanin can cause flushing and pruritus, but clinically significant infusion reactions are rare with teicoplanin [94,97,98].
• Teicoplanin has been implicated in perioperative anaphylaxis [99-101].

There is only limited information about the safety of teicoplanin in patients with a previous hypersensitivity reaction to vancomycin:

• Recurrence of vasculitic rash was described in two patients treated with teicoplanin who had previously reacted to vancomycin [102].
• A retrospective series evaluated 117 patients who had drug-induced fever (24 patients), rash (77 patients), both (8 patients), or neutropenia (8 patients) while receiving vancomycin and were switched to teicoplanin [58]. Clinical information and the development of drug-induced fever, rash, or neutropenia with teicoplanin were determined by medical record review. Ten percent of patients developed fever, rash, or neutropenia in response to teicoplanin; there were no fatalities due to drug adverse reactions to teicoplanin. Of note, 50 percent of patients with neutropenia in response to vancomycin also developed neutropenia in response to teicoplanin. Thus, the majority of patients in the series tolerated teicoplanin, with the exception of those with neutropenia, in whom one-half had recurrence.
• Teicoplanin can induce drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome, like vancomycin [45,53]. Cross- sensitivity to both drugs is possible, as described in at least one case report [45].

Dalbavancin, oritavancin, and telavancin — These analogs of vancomycin are approved for use in the United States, including for skin and skin structure infections [42]. Telavancin is administered daily, while oritavancin and dalbavancin are long lived and are usually given as a single dose. While the long-lasting antimicrobial effects of these agents are beneficial, adverse reactions to these agents may produce persistent symptoms that extend well beyond discontinuation of the drug.

Reports of adverse effects from these agents are limited but appear to be less common than with vancomycin [103].

• VIR-like reactions have been reported with both dalbavancin and oritavancin and can be managed with slower infusion rates [104].
• Anaphylaxis has also been reported with both agents, but details that might distinguish IgE-mediated anaphylaxis from nonimmune-mediated pseudoallergic reactions are not available [104].

Reports of adverse reactions to dalbavancin and oritavancin in patients with previous serious adverse reactions to vancomycin are also limited, and we would advise exploring other options before using related glycopeptide agents. Specifically, alternative antibiotics should be utilized when possible. If the concern is about a VIR-like infusion-related event, appropriate precautions should be taken (slower infusion rate, consideration of relevant coadministered medications) ( table 1).

Graded challenge has be performed in a controlled setting to ascertain if a patient with a previous immediate hypersensitivity reaction to vancomycin could tolerate one of the newer glycopeptide agents. One case report described a graded challenge of dalbavancin in a patient with a past severe hypersensitivity reaction to vancomycin [105]. However, the patient was also receiving opioids and had other conditions that could have potentiated the reaction to vancomycin, so the safety of this approach in other patients with severe hypersensitivity is unclear.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See “Society guideline links: Drug allergy and hypersensitivity”.)

SUMMARY AND RECOMMENDATIONS

• Terminology and clinical manifestations – Vancomycin infusion reaction (VIR; also known as “red man syndrome,” though we avoid the use of this term going forward) is a common adverse reaction to vancomycin. VIR is characterized by flushing, erythema, and pruritus, usually of the upper body. Chest or back pains and hypotension may also occur. It is a rate-related infusion reaction caused by direct activation of mast cells by the drug. Other agents that activate mast cells, such as opioids, muscle relaxants, and radiocontrast media, can predispose patients to developing VIR with vancomycin infusion. (See ‘Vancomycin infusion reaction’ above.)
• Slower infusion rates can prevent VIR – VIR can usually be prevented by administering the drug at rates ≤10 mg/minute (or 1 gram over more than 100 minutes). We do not empirically premedicate patients who have no history of

previous VIR or have never received vancomycin before if the drug is to be administered at these rates. (See ‘Prevention of initial reactions’ above.)

• Premedication for patients who require faster infusions – In patients who require more rapid infusions of vancomycin (ie, at rates exceeding 10 mg/minute or 1 gram over one hour), we recommend antihistamine premedication with at least an H1 antihistamine (Grade 1B). We suggest a combination of H1 and H2 antihistamines (Grade 2C). We administer the combination of diphenhydramine (50 mg orally) and famotidine (20 mg orally) one hour before infusion, although the optimal regimen has not been determined. (See ‘Prevention of initial reactions’ above.)
• Treatment of VIR – VIR is treated by stopping the infusion. Further treatment depends upon the severity of the reaction. The patient’s medication list should be reviewed carefully to determine if other predisposing medications can be identified and discontinued ( table 1). (See ‘Management’ above.)
  • For mild reactions (eg, flushing that is not bothersome to the patient), symptoms typically resolve in minutes, and antihistamines are usually not necessary. We usually restart the infusion at one-half of the previous rate.
  • For moderate reactions (eg, the patient is uncomfortable due to flushing or pruritus but is hemodynamically stable and not experiencing chest pain or muscle spasm), we suggest treating with an H1 antihistamine (Grade 2C). We administer diphenhydramine (50 mg orally or intravenously). We usually restart the infusion at one-half of the previous rate.
  • For severe reactions (eg, muscle spasms, chest pain, or hypotension), in addition to stopping the infusion, we suggest treatment with both H1 and H2 antihistamines (Grade 2C). We administer diphenhydramine (50 mg intravenously) and famotidine (20 mg intravenously). Intravenous fluids may be needed for hypotension. We suggest infusing any subsequent doses of vancomycin over four hours with continuous hemodynamic monitoring during infusions.
• Prevention of repeat reactions – For patients with a previous history of VIR who require vancomycin again, we recommend antihistamine premedication with at least an H1 antihistamine (Grade 1B). We suggest a combination of H1 and H2 antihistamines (Grade 2C). We administer the combination of diphenhydramine (50

mg orally) and famotidine (20 mg orally) one hour before infusion and infuse each vancomycin dose over four hours.

• Indications for desensitization – For patients with recurrent VIR despite premedication and slow infusion rates who absolutely require vancomycin in the future, we suggest desensitization (Grade 2C). Desensitization involves gradually reintroducing the culprit drug in serially increasing doses to induce a state of temporary clinical tolerance. There are several published protocols. We prefer a rapid protocol that allows the patient to receive a full dose of vancomycin within several hours ( table 5). (See ‘Desensitization’ above.)
• Rare anaphylaxis – Anaphylaxis in response to vancomycin administration is rare. Symptoms of anaphylaxis overlap with those of severe VIR, although wheezing, significant dyspnea, and angioedema are more suggestive of anaphylaxis ( table 4). Multiple prior vancomycin courses should raise concern about the potential for immunoglobulin E (IgE) mediated anaphylaxis. (See ‘Clinical manifestations’ above.)
  • Treatment – For patients with anaphylaxis of any severity:
    • The infusion should be stopped immediately and not restarted.
    • Epinephrine should be administered promptly, at the doses specified for adults ( table 2) or children ( table 3). (See ‘Acute management’ above and “Anaphylaxis: Emergency treatment”, section on ‘Immediate management’.)
  • Future management options – For patients with past anaphylaxis to vancomycin, an alternative drug should be used whenever possible. For patients with serious infections that cannot be adequately treated with alternate antibiotics, we suggest vancomycin desensitization (Grade 2C). (See ‘Desensitization’ above.)
• Other rare types of reactions – Other rare forms of vancomycin hypersensitivity include drug reaction with eosinophilia and systemic symptoms (DRESS)/drug- induced hypersensitivity syndrome, linear immunoglobulin A (IgA) bullous dermatosis (LABD) ( picture 1), and immune-mediated hematologic and kidney disorders. The drug must be discontinued if these occur. Desensitization in patients with these reactions is not effective and may be dangerous. (See ‘Other forms of hypersensitivity’ above.)

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