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Red Man Syndrome: Incidence, Etiology, and Prophylaxis Mark R. Wallace, John R. Mascola,* and Edward C. Oldfield III

Departments of Internal Medicine (Infectious Disease Division) and Clinical Investigation. Naval Hospital. San Diego. California

Vancomycin is an antibiotic experiencing a resurgence during the past 10 years. Increasing clinical problems with methicillin-resistant staphylococcal infections and growing concerns about enterococcal disease have sparked a dramatic upswing in the use of this glycoprotein compound. Initially called "Mississippi mud" due to impurities, vancomycin was labeled toxic and fell from favor as a first-line antibiotic. A new purified preparation of vancomycin has been available for several years and is much better tolerated [I]. Despite the availability of the new, less toxic vancomycin formulation, side effects still occur; ototoxicity, neutropenia, fixed drug eruptions, fever, and phlebitis are reported. The most common adverse reaction has been an infusion-related histamine-like reaction characterized by flushing of the upper body, pruritus, and occasionally hypotension [2-4]. Chest pain and muscle spasm may also occur, with or without the other manifestations of this syndrome, dubbed the "red man syndrome" (RMS) [5, 6]. While generally only a nuisance manifested by flushing, mild pruritus, or both, vancomycin-induced cardiovascular toxicity can be severe, resulting in profound hypotension [7, 8] and even cardiac

arrest [9, 10]. These severe reactions have been less common since the relationship between rapid «30 min) infusion of vancomycin and hypotension was recognized. However, RMS [11, 12] and hypotensive reactions [13] continue to occur even with "slow" (~l h) infusions. Reduction of dosage from I g to 500 mg is associated with fewer reactions in normal adult volunteers [14], but the pharmacokinetics and expense factors favor dosing at 1 g every 12 h versus 500 mg every 6 h [I, 14]. The incidence and etiology of red man reactions are unknown. Studies have reported rates of 0-35% in patients [1520], but work done in normal volunteers has demonstrated rates of 70%-90% [4, 21]. It has been suggested that histamine release plays a role in the etiology of RMS. This conclusion is based on histamine levels obtained from two patients [22] as well as data from normal volunteers [4] and from in vitro work [22]. Data from patients prospectively studied are not yet available. Studies in animals [23] and human volunteers [24] suggest that antihistamines may ameliorate or block this response.

Patients and Methods Received 7 December 1991; revised 8 July 1991. Presented in part: 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, Houston, September 1989 (abstract 648). Informed consent was obtained from patients as approved by the Committee for the Protection of Human Subjects, Naval Hospital, San Diego. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Departments of the Navy or Defense nor the US government. Sponsor: Chief, Navy Bureau of Medicine and Surgery, Washington, DC, Clinical Investigation Program (88-16-2385-00). Reprints or correspondence: Cdr. M. R. Wallace. Clinical Investigation Department. Naval Hospital, San Diego. CA 92134-5000. * Present address: Internal Medicine Department. National Naval Medical Center. Bethesda. Maryland. The Journal of Infectious Diseases This article is in the public domain.

1991;164:1180-5

Study objectives. This prospective, double-blind, placebocontrolled study was conducted in hospitalized patients receiving their first and second l-g doses of intravenous vancomycin. A primary objective was to establish the incidence of RMS in carefully observed inpatients. Other goals of the study were to establish whether pretreatment with diphenhydramine could prevent RMS and to evaluate the possible role of histamine release in the pathogenesis of RMS. RMS definition. We define RMS as the occurrence of any of the following during a vancomycin infusion: flushing, pruritus, chest pain, muscle spasm, or hypotension (defined as a drop of ~ 10 mm Hg in the systolic blood pressure). Patients were prospectively enrolled into a study designed to assess the frequency, etiology, and possible prophylaxis of RMS.

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The red man syndrome (RMS) is the most common toxicity of vancomycin therapy. A prospective trial to investigate the frequency, causation, and possible prophylaxis of this syndrome was conducted. Thirty-three patients were observed during their first two doses (l g/60 min) of vancomycin. Before dose 1, they were randomized to double-blinded pretreatment with either diphenhydramine (50 mg) or placebo. Patients were examined frequently, and histamine levels were obtained at 0, 30, and 60 min during dose 1. Those with first-dose reactions were rerandomized for pretreatment and had histamine levels drawn during a second infusion. Of 17 patients with placebo pretreatment, 8 (47%) had RMS. None of the 16 pretreated with diphenhydramine had a first-dose reaction (P = .003). Three of the eight first-dose reactors had a second-dose RMS reaction; in one of these three, it was more severe than the dose 1 RMS despite diphenhydramine pretreatment. RMS events were associated with elevated plasma histamine; this was especially true of severe reactions.

110 1991; 164 (December)

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Red Man Syndrome

Table 1.

Baseline patient characteristics in red man syndrome. Pretreatment

Patient characteristics Age, years ± SE Weight, kg ± SE Creatinine, p.mol/l ± SE Vancomycin peak, p.g/ml Dose, mg/kg Sex, M/F Race, no. White Black Pacific Islands History of penicillin allergy, no.

Diphenhydramine (n = 16)

Placebo = 17)

(n

48.7 ± 4.55 79.1 ± 4.25 76.9 ± 4.42 39.3 13.3 12/4

47.3 ± 4.25 72.2 ± 3.10 94.6 ± 8.84 43.7 14.3 14/3

10 3 3

16 0 1

8

7

P

.82 .20 .10 .37 .5

Diagnostics, Dallas, TX). Serum creatinine levels were done in the clinical laboratory by standard techniques. RMS evaluation. The reactions observed were graded by an a priori scoring system. Pruritus, muscle pain, and chest tightness were graded mild, moderate, or severe by each patient as noted above. One point was awarded for each mild symptom, 2 points for each moderate symptom, and 3 points for each severe symptom. Flushing was graded by the investigator (>80% of all infusions were done by one of us, M.R.W.); facial flush only was awarded 1 point; facial plus upper body, 2 points; and wholebody involvement, 3 points. Because hypotension is a more serious concern with RMS, 2 points were awarded for a systolic blood pressure drop of 10-14 mm Hg, 3 points for a drop of 15-20 mm Hg, and 4 points for a drop of>20 mm Hg. A total score of ~ 5 was defined as severe RMS. Statistical analysis. Fisher's exact test was used to compare differences in proportion between groups. Student's t test was used to compare continuous valued variables.

Results Patient characteristics. During the 7-month study period, 115 patients at this institution were given vancomycin, and 1 12 patients were evaluated for possible entry into this study. The following patients were excluded: 32 who were on systemic steroids or antihistamines, 29 who received their first dose in the operating room, 14 who were unable or unwilling to give informed consent, and 4 whose attending physician preferred the 500-mg to the I-g dose of vancomycin. Thirtythree patients were enrolled and completed the two-dose protocol. One patient refused the serial blood draws but was included for clinical evaluation; she did not have a reaction. Entry characteristics are given in table 1. The patients were diverse in their indications for vancomycin therapy: 5 had soft-tissue infections, 7 had febrile neutropenia, 6 had orthopedic infections, and 11 had miscellaneous infections (pelvic inflammatory disease, endocarditis, meningitis, sinus ab-

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Subject eligibility. All adult inpatients given vancomycin between 10 October 1988 and 10 May 1989 were contacted. Patients were eligible if they were scheduled to receive at least two doses of 1 g of vancomycin and had not received any vancomycin in the 2 weeks before study entry. Patients who had received antihistamines or steroids within 48 h of the initiation of vancomycin therapy were excluded. Patients receiving their first dose of vancomycin in the operating room were excluded, as multiple factors other than the vancomycin infusion might affect their evaluation. Study design. Enrolled patients about to receive their first I-g dose of vancomycin were randomized in a double-blind fashion to receive either 50 mg of oral diphenhydramine or identical placebo tablets 45-60 min before the start of the vancomycin infusion (four patients were unable to take medication by mouth and received their diphenhydramine or identical saline placebo intravenously 15-30 min before infusion). Vancomycin hydrochloride (1 g, Vancocin; Eli Lilly, Indianapolis) was administered over 60 min in 250 ml of 5%dextrose solution by infusion pump. Immediately before the first vancomycin infusion, a baseline plasma sample for histamine assay was drawn into an evacuated glass tube containing EDTA and placed on ice. Subsequent plasma samples for histamine determination were obtained at 30 min into the infusion and immediately after completion. A peak vancomycin level was also obtained at the conclusion of the infusion. During the infusion, all patients were monitored continuously by one of the investigators. Patients had vital signs (pulse, blood pressure, and respiratory rate) recorded every 15 min, and their skin was examined at the same intervals. Skin flushing was described as facial only, upper torso and face, or whole body. Auscultation of the lungs was also done every 15 min. Patients were questioned regarding pruritus, muscle spasm, and chest pain every 15 min and were free to volunteer other complaints at any time. Symptoms were graded as mild, moderate, or severe by the patient. A mild symptom was defined as barely noticeable, while severe reactions were incapacitating. A second I-g infusion of vancomycin was received by all patients; two patients received their second doses 24 h after the first (due to mild renal insufficiency). All other second doses followed the first by 12 h. Clinical monitoring of the second dose was identical to the first infusion. Patients who did not have a first-dose reaction received their second dose over 60 min without pretreatment and had no additional histamine or vancomycin levels drawn. Patients suffering a first-dose RMS reaction had dose 2 infused over 90 min with clinical monitoring every 15 min; samples for histamine were done at 0, 45, and 90 min. Patients with first-dose reactions were independently randomized to pretreatment with diphenhydramine or placebo before their second dose. Assay methodology. Iced blood samples were transported to a refrigerated centrifuge. Sera and plasma were separated at 7900 g for 10 min and then stored at -70°C. Histamine concentrations in plasma were determined in duplicate by RIA (Histamine; AMAC, Westbrook, ME). Elevated histamine levels in this assay are> 1 ng/ml. All assays were done before the breaking of the double-blind code. Vancomycin concentrations in serum were determined by a fluorescence polarization immunoassay technique (Abbott

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Table 2.

Patient no.

110 1991; 164 (December)

Clinical data in red man syndrome (RMS).

Dose I

1* 5 18 18 20 22 24 30 30* 33

2 I I

2 I I I I

RMS pruritis*

2 8 4 7 4 5 4 3 7

I

I

2 2 2 2 3 0 2 2

2 2 2 2 2 0

2

I

I

2

Flushingt

I I

I

2 0 I

Drop in systolic blood pressure (mm Hg)

Baseline

Maximum

0 22 0 20 0 0 0 0 12 0 0

0.27 0.30 0.34 0.90 0.11 0.16 0.34 0.39 0.31 0.80 0.01

0.32 4.91 0.19 3.34 0.45 1.17 5.72 0.32 0.24 0.23 0.04

Histamine (ng/rnt)'

* RMS pruritis. muscle spasm. and chest tightness were graded mild (I). moderate (2). or severe (3) by patient. Patient 22 experienced grade 2 muscle spasm and chest tightness. t Flushing was graded as facial only (I). facial and upper body (2), or whole body (3). t Normal range to 1.0 ng/m\. f Premedicated with diphenhydramine.

scess, abdominal wound infection, and fevers of unknown origin). Four penicillin-allergic patients received vancomycin as preoperative prophylaxis. Of the 33 patients enrolled, I 5 reported a history of penicillin allergy. RMS reactions. Of 17 patients receiving placebo treatment before dose 1,8 (47%, 95% confidence interval, 23%72%) suffered RMS; of the 16 patients pretreated with diphenhydramine, 0 suffered a reaction (P = .003). There were no subsequent signs or symptoms of RMS in any of the 25 patients who did not have a reaction to dose I. Three (37%) of the 8 first-dose reactors had RMS with dose 2; in one case it was more severe. Two of the three second-dose reactors had received diphenhydramine pretreatment; the other had received placebo (P = NS). The RMS events varied widely in severity; these reactions and the associated histamine levels are shown in table 2. All but one were characterized by pruritus, flushing, or both. A single patient had chest pain and muscle spasm as his only manifestation of "RMS." He was included in our collection of positives because he met our prestudy definition of RMS, and his histamine levels suggest his reaction was similar in mechanism to the others. Reactions typically began 15-45 min into the infusion and persisted throughout the infusion. No infusions were stopped prematurely, and no reactions were associated with bronchospasm. In all II RMS episodes, the signs and symptoms ofRMS had resolved entirely within 30 min; in many cases, the reaction was waning even as the infusion was nearing completion. Three patients had a significant drop in blood pressure (> 10 mm Hg); all were female. Two of the eight patients who reacted to dose I (subjects 18 and 30) had moderate pruritis and erythema as well as a drop in pressure; these two patients had mild second-dose events without hypotension and were able to tolerate third and subsequent doses without problems. Patient I is of special inter-

est; she had a mild reaction to an initial 60-min infusion (placebo pretreatment), then suffered severe RMS with a drop in systolic blood pressure from 110 to 88 mm Hg with her second dose (diphenhydramine pretreatment) despite an infusion time of90 min. A third dose was not attempted. Her first-dose reaction was not associated with any increase in histamine levels, while the second-dose severe reaction correlated with a 16-fold increase in histamine level. Her medical history was notable for severe adverse reactions to many oral antibiotics and other drugs, but she had not previously received vancomycin. The first-dose RMS patients in the placebo group (8/ I 7, 47%) tended to be smaller (mean weight, 66.0 vs. 77.8 kg, P = .06) and to have higher immediate postinfusion vancomycin levels (49.5 vs. 37.1 J,Lg/ml, P = .09) than their nonreacting counterparts. There was no correlation between a penicillin allergy history and RMS. Four of 15 patients with a history of penicillin allergy had first-dose RMS, and 4 of 18 without such history had a reaction (27% vs. 22%, P = 1.00). Elevated plasma histamine levels (> I ng/ml) occurred with six infusions; maximal histamine levels occurred at midinfusion in three and at the end of the infusion in three others. When the analysis is restricted to first-dose RMS occurrences, 3 (38%) of8 RMS patients and I (4%) of24 nonRMS subjects (I non-RMS patient refused phlebotomy) had an elevated level (P = .04). Severe RMS events (global score ~5) were often associated with elevated histamine levels. Three (75%) of four severe RMS patients had high histamine levels compared with one (14%) of seven mild reactions (P = .09). One patient (subject 22) had severe chest and back pain associated with a high (5.71 ng/rnl) plasma histamine during dose I; during his second infusion, he had no symptoms, but his histamine level again rose to 5.26 ng/rnl. This patient received placebo before both doses. The other ele-

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I

Total score

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Red Man Syndrome

vated histamine in a nonreactor was patient 23. Her histamine level rose to 1.31 ng/ml from a baseline of0.48, but she suffered no symptoms. She was also pretreated with placebo. The baseline and maximal histamine levels of all RMS reactions are provided in table 2.

Discussion

was believed unwise, and she was not subsequently rechallenged. This case illustrates the need for careful monitoring of all first-dose vancomycin infusions and of subsequent doses in patients with signs or symptoms of adverse reaction to a first infusion. Subsequent doses in persons without a first-dose reaction appear to be safe, as we noted no reactions in the 25 patients who did not have RMS with dose 1. Elevated histamine levels were associated with RMS in our study, occurring in 3 (38%) of 8 first-dose reactors but only 1 (4%) of24 nonreactors (P = .04). Patients with severe RMS were more likely to have elevated plasma histamine (3/4, 75%) than were those with mild RMS (1/7, 14%, P = .09). RMS has many features in common with the symptoms observed in normal volunteers receiving histamine infusions. Flushing, headache, and hypotension were often observed in the study of histamine toxicity in normal subjects by Kaliner et al. [26]. Histamine levels drawn in two clinical RMS reactions [22] and in volunteers receiving vancomycin infusions [4, 24] also suggest that histamine plays at least a partial role in RMS. Our data would support the concept of histamine as a factor in severe RMS, but only one of our seven patients with mild RMS had an elevated level. While it is possible that our 30-min blood sampling missed small histamine peaks in these patients, we believe this is unlikely. Previous work on RMS in volunteers has shown that histamine levels tend to increase progressively throughout the infusion in RMS reactions [4, 27], making it improbably that our mid-infusion and immediate end-infusion draws both missed any major histamine elevations. Reactions to vancomycin not related to histamine-mediated infusion have been documented [27], and it seems reasonable to speculate that some RMS reactions may be mediated by factors other than histamine. The frequent occurrence of pruritus in RMS also suggests the involvement of other factors, as pruritus has not been noted in humans given histamine infusions [26]. The opposite is true of headache, which occurs frequently in experimental histamine infusions but not in clinical RMS [4, 26]. Perhaps other mediators, such as bradykinin, serotonin, or the slowly reacting substance of anaphylaxis, are also involved [24]. It is also possible that vancomycin itself is responsible for some ofthe manifestations of RMS. Direct cardiac depression has been observed in dog studies with vancomycin infusions, although that study did not measure histamine or any other vasoactive substance, suggesting that direct cardiotoxicity may be responsible for some of the hypotensive effects of infusion [28]. Studies in animals [23] and normal volunteers [24] have demonstrated the efficacy of antihistamine pretreatment in prevention ofRMS. While data from studies using histamine infusion in volunteers [26], as well as morphine anesthesiainduced histamine release in surgical patients [29], have indicated that a combination of H I and Hz blockers is most effective in preventing histamine-mediated cardiovascular

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We found a 47% rate of first-dose RMS despite careful adherence to the manufacturer's recommendations regarding dilution and infusion time. Only one prospective study in patients [15] has found a similar rate (35%), although research results using volunteers [4, 21] consistently found rates of 70%-90%. Five other studies in patients [16-20] have found rates of 0-9%; in one prospective study, the 2% rate of RMS in the vancomycin-containing antibiotic regimen was identical to that of the nonvancomycin regimen [19]. Several reasons might account for these vast differences. First, like the volunteer RMS studies, our protocol was designed specifically to evaluate RMS. Close monitoring of the patient's skin examination, blood pressure, and symptoms uncovered several mild reactions that would have gone unnoticed in the typical hospital setting. Several of our patients volunteered that they were aware ofan "antibiotic reaction," but they would not have "bothered anyone" if an investigator had not been immediately available. Another factor that may lead to underestimation ofRMS in patients is the widespread use of antihistamines and systemic steroids. Of 112 patients screened for study entry, 32 (29%) were receiving an HI-blocker, systemic steroids, or both. As this and other studies have demonstrated, antihistamines are effective in preventing RMS. A third factor is the frequency of vancomycin first doses being given in the operating room. Of 112 patients started on vancomycin, 29 (26%) received their initial dose in the operating room and were excluded from our study. It is likely that only the most severe RMS would be noticed in the surgical suite. On the basis of these considerations, we suspect that the true rate of RMS in hospitalized patients not receiving serendipitous antihistamine prophylaxis is much higher than previously appreciated. RMS has been considered a mild reaction, occurring primarily on the first dose with subsequent reactions, if present, oflesser severity [4, 25]. In general, our results agreed with this hypothesis. Of 17 first-dose infusions, 8 (47%)were associated with RMS, and 3 (37%) of those 8 had second-dose RMS. Two of the three second-dose reactions were mild in comparison with the first-dose events, and both received a third dose without any problems. However, one patient (subject 1) did not fit these commonly accepted notions. After mild first-dose RMS, she suffered a severe reaction to dose 2, with clinically significant hypotension, tachycardia, and severe pruritus. This dose was both slowly infused (90 min) and preceded by diphenhydramine. The RMS resolved within minutes after completion of the infusion; a third dose

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Acknowledgments

We thank John B. Stone for help in doing the histamine assays, Robert Thompson for help in preparing the study drug, and Robert Gray for statistical assistance. References I. Kirby WMM. Vancomycin therapy of severe staphylococcal infections. J Antimicrob Chemother 1984; 14(suppl 0):73-8. 2. McHenry MC, Gavan TL. Vancomycin. Pediatr Clin North Am 1983;30:31-47. 3. Red men should go: vancomycin and histamine release. Lancet 1990;335: 1006-7. 4. Polk RE, Healy DP, Schwartz LB, Rock DT, Garson ML, Roller K. Vancomycin and the red-man syndrome: pharmacodynamics of histamine release. J Infect Dis 1988; 157:502-7. 5. Southorn PA, Plevak OJ, Wright AJ, Wilson WR. Adverse effects of vancomycin administered in the perioperative period. Mayo Clin Proc 1986;61: 721-4. 6. Gatterer G. Spasmodic low back pain in a patient receiving intravenous vancomycin during continuous ambulatory peritoneal dialysis. Clin Pharmacol 1984;3:87-9. 7. Symons NLP, Hobbes AFT. Leaver HK. Anaphylactoid reactions to vancomycin during anaesthesia: two clinical reports. Can Anaesth Soc J 1985;32: 178-81. 8. Newfield P. Roizen MF. Hazards of rapid administration of vancomycin. Ann Intern Med 1979;91: 581. 9. Mayhew JF. Deutsch S. Cardiac arrest following administration of vancomycin. Can Anaesth Soc J 1985;32:65-6. 10. Glicklich 0, Figura I. Vancomycin and cardiac arrest. Ann Intern Med 1984; 10 I:880-1. II. Davis RL. Smith AL. Koup JR. The "red man's syndrome" and slow infusion of vancomycin. Ann Intern Med 1986; 104:285-6. 12. Pau AK, Khakoo R. Red-neck syndrome: with slow infusion of van comycin. N Engl J Med 1985;313:756-7. 13. Waters BG. Rosenberg M. Vancomycin-induced hypotension. Oral Surg Oral Med Oral Pathol 1981;52:239-40. 14. Healy DP. Garson ML. Rock DT. Polk RE. Comstock TJ. Comparison of steady-state pharmacokinetics of two dosage regimens of vancomycin in normal volunteers. Antimicrob Agents Chemother 1987;31 :393-7. 15. Odio C, Mohs E. Sklar FH. Nelson JD. McCracken GH. Adverse reactions to vancomycin used as prophylaxis for CSF shunt procedures. Am J Dis Child 1984; 138: 17-9. 16. Smith SR. Cheesbrough J. Spearing R. Davies JM. Randomized prospective study comparing vancomycin with teicoplanin in the treatment of infections associated with Hickman catheters. Antimicrob Agents Chemother 1989;33:1193-7. 17. Schifter S. Aagaard MT, Jensen LJ. Adverse reactions to vancomycin. Lancet 1985;2:499. 18. Downs NJ, Neihart RE. Dolezal JM, Hedges GR. Mild nephrotoxicity associated with vancomycin use. Arch Intern Med 1989; 149: 177781. 19. Shenep JL. Hughes WT. Roberson PK. et al. Vancomycin. ticarcillin, and amikacin compared with ticarcillin-clavulanate and amikacin in the empirical treatment of febrile, neutropenic children with cancer. N Engl J Med 1988;319:1053-7. 20. Rubin M. Hathorn JW. Marshall 0, Gress J, Steinberg SM. Pizzo PA. Gram-positive infections and the use of vancomycin in 550 episodes of fever and neutropenia. Ann Intern Med 1988;108:30-5. 21. Boeckh M. Lode H. Borner K. Hoflken G, Wagner J. Koeppe P. Pharmacokinetics and serum bactericidal activity of vancomycin alone

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effects, studies in RMS reactions have not shown benefit from the addition of the H 2 blocker to HI blockers [24]. We found diphenhydramine, an H I blocker, to be highly effective in preventing first-dose RMS. As no patient without a first-dose reaction had a problem with subsequent doses, an HI blocker before dose 1 would seem to represent excellent RMS prophylaxis. One caveat, however, is the inexplicable failure of diphenhydramine pretreatment to prevent two second-dose reactions. Patient 18 had severe first-dose RMS (placebo pretreatment) and a mild second-dose reaction (antihistamine pretreatment), suggesting a possible amelioration ofthe RMS by the HI blocker. Patient 1, however, had a mild first-dose reaction and a severe, hypotensive seconddose reaction despite diphenhydramine prophylaxis. Thus, while HI prophylaxis shows merit in preventing RMS, it is not perfect, and patients with first-dose reactions must be carefully observed during subsequent doses whether or not they are pretreated with an antihistamine. The clinician who wishes to prevent vancomycin-induced RMS has several options. Antihistamine prophylaxis before the first dose appears safe and effective, but it involves the administration of a second drug. Using a lower vancomycin dose in a more frequent schedule (500 mg every 6 h vs. 1 g every 12 h) causes less RMS in volunteers [14], but it is less satisfactory from a pharmacokinetic and cost perspective [1, 14]. Infusions over 2 h have recently been shown to reduce the frequency and severity ofRMS when compared with l-h infusions [30]. While the patient is tethered to the infusion device longer, this method is inexpensive and does not significantly alter the pharmacokinetics. An obvious way to prevent RMS is to avoid using vancomycin. Teicoplanin is an investigational glycopeptide antibiotic that is similar to vancomycin in antibacterial spectrum. Two recent crossover studies in volunteers have shown a high rate of RMS with vancomycin (70%-90%) but none with teicoplanin [31, 32]. Case reports show that results in patients with vancomycin reactions subsequently given teicoplanin have been contradictory, with cross-reactivity in one report [33] but not in another [34]. The final verdict on RMS and teicoplanin is not yet in, but it does appear that teicoplanin causes fewer infusion-related events. When patients suffer first-dose RMS, what should be done about subsequent infusions? Few data exist to answer this difficult question. Seven of our eight patients with first-dose reactions had little or no problem with a second dose infused over 90 min, and none had any RMS symptoms with any later dose. If vancomycin is the best (or only) antibiotic option for a patient with first-dose RMS, we recommend giving the second dose over ~2 h after pretreatment with an HI blocker. Close observation is mandatory, and the infusion should be stopped if there is a clinically significant drop in blood pressure or the onset of chest or muscle pain.

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22.

23. 24.

25.

26.

28.

and in combination with ceftazidime in healthy volunteers. Antimicrob Agents Chemother 1988;32:92-5. Levy JH, Kettlekamp N, Goertz P, Hermens J, Hirshman CA. Histamine release by vancomycin: a mechanism for hypotension in man. Anesthesiology 1987;67: 122-5. Wold JS, Turnipseed SA. Toxicology of vancomycin in laboratory animals. Rev Infect Dis 1981;3:5224-9. Sahai J, Healy DP, Garris R, Berry A, Polk RE. Influence of antihistamine pretreatment on vancomycin-induced red-man syndrome. J Infect Dis 1989; 160:876-81. Best CJ, Ewart M, Sumner E. Perioperative complications following the use of vancomycin in children: a report of two cases. Br J Anaesth 1989;62:576-7. Kaliner M, Shelhamer JH, Ottesen EA. Effects of infused histamine: correlation of plasma histamine levels and symptoms. J Allergy Clin ImmunoI1982;69:283-9. Sahai J, Polk RE, Schwartz LB, Healy DP, Westin EH. Severe reaction to vancomycin not mediated by histamine release and documented by rechallenge. J Infect Dis 1988; 158: 1413-4. Cohen LS, Wechsler AS, Mitchell JH, Glick G. Depression of cardiac

29.

30.

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33. 34.

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function by streptomycin and other antimicrobial agents. Am J Cardiol 1970;26:505-11. Philbin DM, Moss J, Akins CW, et al. The use of H I and H2 histamine antagonists with morphine anesthesia: a double-blind study. Anesthesiology 1981;55:292-6. Healy DP, Sahai JV, Fuller SH, Polk RE. Vancomycin-induced histamine release and "red man syndrome": comparison of 1- and 2-hour infusions. Antimicrob Agents Chemother 1990;34:550-4. Sahai J, Healy DP, Shelton MJ, Miller JS, Ruberg SJ, Polk R. Comparison of vancomycin- and teicoplanin-induced histamine release and "red man syndrome." Antimicrob Agents Chemother 1990;34:7659. Lagast H, Dodion P, Klastersky J. Comparison of pharmacokinetics and bactericidal activity of teicoplanin and vancomycin. J Antimicrob Chemother 1986;18:513-20. McElrath MJ, Goldberg D, Neu He. Allergic cross-reactivity ofteicoplanin and vancomycin. Lancet 1986; I :47. Schlemmer B, Falkman H, Boudjadja A, Jacob L, LeGall Jr. Teicoplanin for patients allergic to vancomycin. N Engl J Med 1988;318: 1127-8.

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27.

Red Man Syndrome

Red man syndrome: incidence, etiology, and prophylaxis.

The red man syndrome (RMS) is the most common toxicity of vancomycin therapy. A prospective trial to investigate the frequency, causation, and possibl...
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