"Adverse Drug Event "

Probable Vancomycin induced Red Man Syndrome

Case report:
An eight year old female child, a known case of congenital cyanotic heart disease (single atrium, single ventricle with hypoplasia of pulmonary artery) was admitted to Pediatric ward of the institute with complaints of headache, fever, convulsions and recurrent respiratory tract infections. Her CT scan revealed an abscess in the right cerebral hemisphere. She was started on Vancomycin (15mg/kg) in 20cc of Normal Saline over 1 hr qds. Concurrent medications used were Inj. Cefotaxime (200 mg/kg/d), Phenytoin (5 mg/kg/d) and Metronidazole (10 mg/kg/d).On 12th day of medication she developed red, itchy, maculopapular lesions. The rash started on the buttocks and extended towards trunk and face. This was attributed as an adverse effect to Vancomycin [Red man syndrome(RMS)] or Hypersensitivity reaction to Phenytoin. Vancomycin was discontinued immediately while Phenytoin was substituted by Carbamazepine. Patient could not be followed up as she left the institute against medical advice.
In this patient however, a cause effect relationship of the rash to vancomycin is difficult to attribute as phenytoin was a confounder and also known to produce rash. If patient is on several medicines, it is difficult to attribute causality to a single drug. However, several criteria and algorithms are available to help establish causality. The discussion of this paper focuses on red man syndrome.

Discussion
Vancomycin is the drug of choice for the treatment of infections due to methicillin-resistant staphylococci (MRSA), Corynebacterium jeikeium, and resistant strains of Streptococcus pneumoniae. Vancomycin can cause two types of hypersensitivity reactions, the RMS and anaphylaxis [1]. RMS is an infusion related reaction peculiar to vancomycin [2]. It typically consists of pruritus, an erythematous rash that involves the face, neck, and upper torso. In severe cases, patients complain of chest pain and dyspnea. Signs of RMS usually appear about 4-10 min after an infusion is started or may begin soon after its completion. It is often associated with rapid (<1 hour) infusion of the first dose of vancomycin. The reaction may not be of the same severity with successive exposures, but it can occur for the first time after several doses or with a slow infusion [3]. Delayed reactions at or near the end of a 90 or 120 min infusion have been seen in patients who had been on vancomycin therapy over 7 days without prior incident. RMS was in the past attributed to impurities found in vancomycin preparations, earning the drug the nickname 'Mississippi mud'. But reports of the syndrome persisted even after improvements in the compound's purity [4]. The hypersensitivity reactions that can arise are due to vancomycin stimulating the mast cells to release histamine. The extent of histamine release is related partly to the amount of drug infused and rate of the vancomycin infusion. Studies of vancomycin also show that the most severe reactions occur in patients younger than 40. Children seem to be particularly susceptible [5]. Antibiotics such as Ciprofloxacin, AmphotericinB, Rifampcin and Teicoplanin [6] can also cause RMS. The effects of RMS can be relieved by antihistamines. Pretreatment with hydroxyzine can significantly reduce erythema and pruritus associated with RMS [7]. Administration of diphenhydramine to patients before starting vancomycin infusion can help prevent the occurrence of RMS even with the first dose of vancomycin [8]. If RMS appears, vancomycin infusion should be discontinued immediately. Administration of diphenhydramine hydrochloride (5mg/kg/d in 3-4 divided doses) intravenously or orally can abort most of the reactions. Once the rash and itching dissipate, the infusion can be resumed at a slower rate and/or at a lesser dosage. The drug should not be withheld rather the dose should be adjusted.

In summary, Administration of vancomycin over 2 h reduces the frequency and severity of RMS and the amount of histamine released compared with those after a 1-h infusion in healthy volunteers. Each intravenous dose of vancomycin should be administered over at least a 60 min interval to minimize the infusion-related adverse effects [9].

References
1. Lori, WaznyD.; Behnam, D. Desensitization protocols for vancomycin hypersensitivity. Ann Pharmacother. 2001;35:1458-1464.
2. Davis RL, Smith AL, Koup JR. The 'red man's syndrome' and slow infusion of vancomycin [letter]. Ann Intern Med. 1986;104:285-286.
3. Wilson APR. Comparative safety of teicoplanin and vancomycin. Int J Antimicrobial Agents. 1998;10:143-152.
4. Renz CL, Thurn JD, Finn HA, Lynch JP, Moss J. Clinical investigations: antihistamine prophylaxis permits rapid vancomycin infusion. Crit Care Med. 1999;27:1732-1737.
5. Korman T, Turnidge J, Grayson M. Risk factors for cutaneous reactions associated with intravenous vancomycin. J Antimicrob Chemother. 1997;39:371-381.
6. Wilson APR. Comparative safety of teicoplanin and vancomycin. Int J Antimicrobial Agents. 1998;10:143-152.
7. Sahai J, Healy DP, Garris R, Berry A, Polk RE. Influence of antihistamine pre-treatment on vancomycin induced red-man syndrome. J Infect Dis. 1989;160:876-881.
8. Wallace MR, Mascola JR, Oldfield EC. Red man syndrome: incidence, aetiology and prophylaxis. J Infect Dis. 1991;164:1180-1185.
9. Wilhelm MP, Estes LPD. Symposium on Antimicrobial Agents - Part XII. Vancomycin. Mayo Clin Proc. 1999;74:928-935