Fever, Rash, and Pancytopenia following Vancomycin Rechallenge in the Presence of Ceftazidime

TO THE EDITOR: Vancomycin is known to adversely affect the hematopoietic system. The typical reaction is reversible neutropenia, affecting 2–18% of those receiving the drug.1 6 Other reactions, such as thrombocytopenia, have been reported.7 Our literature search revealed two reports of pancytopenia attributed to vancomycin’s adverse reaction.8 , 9 I n the majority of cases, systemic manifestations of idiosyncratic drug reaction were present with the decline in blood cell counts. We report a case in which reversible pancytopenia followed a rechallenge of intravenous v a n c o m y c i n . Case Report. A 43-year-old Israeli woman underwent open reduction for a comminuted right calcaneal fracture. She was not known to be allergic to any medications. The patient experienced persistent pain and there was discharge from her surgical wound, presumably due to infection. She received several antibiotics without apparent success. Subsequently, in view of the high likelihood of methicillin-resistant S t a p h y l o c o c c u s, empiric therapy with vancomycin was begun. At the time vancomycin was initiated, the patient was receiving the following medications: trimethoprim/sulfamethoxazole (TMP/SMX) 160/800 mg bid, acetaminophen/propoxyphene 500/40 mg tid, ferrous sulfate 160 mg qd, vitamin B1 2 1 0 0 0 μg im weekly, and dipyrone 1 g prn; all had been started one month or more before initiation of vancomycin. On the first day of vancomycin administration, the patient experienced flushing and had an episode of presyncope, during which her BP was 85/53 mm Hg. Assuming this to be Red Man syndrome, a slower rate of infusion was instituted. Vancomycin was continued for an additional 10 days with improved control of the wound discharge. On day 10 of vancomycin administration, the patient developed fever (39.7 ̊C), chills, and disseminated, lacy macular rash; the drug was discontinued. Complete blood cell count (CBC) was not obtained. Following 48 hours off the drug, the local symptoms worsened and vancomycin was resumed with premedication with hydrocortisone and diphenhydramine. The first rechallenge dose of vancomycin was followed by pruritus, but no other adverse effects occurred. Twenty-four hours following vancomycin reinstitution, the patient developed hectic fever, chills, and a confluent, erythematous rash. She was presumed to be septic, and ceftazidime was added to her treatment regimen. CBC revealed thrombocytopenia (118 0 0 0 / m m3) and a relative decline in hemoglobin (from 13.8 to 12.2g/dL) and white blood cell count (WBC) (from 7600 to 3500/mm3) compared with an earlier analysis obtained two days into vancomycin therapy. The following day, the patient remained febrile and the rash progressed to diffuse cutaneous erythema. A repeat count revealed a hemoglobin of 10 g/dL, WBC of 2600/mm3 with 62% neutrophils and 5% eosinophils (high–normal range), and platelets 118 0 0 0 / m m3. At this point, both drugs were discontinued. The following day, the rash disappeared and the temperature returned to normal. A repeat CBC four days later revealed complete recovery of all lineages (hemoglobin 14.1 g/dL, WBC 9700/mm3 , and platelets 304 0 0 0 / m m3). D i s c u s s i o n . We present a case in which rash and a systemic febrile reaction followed the reinstitution of vancomycin in a patient who was seemingly allergic to the drug. Adverse reaction occurred three times during the hospital course. The first reaction, following the second vancomycin dose is consistent with Red Man syndrome, which is known to produce rash, flushing, and hypotension.1 0 1 2 It is not clear whether vancomycin was rapidly infused, but the syndrome was shown to also occur with slow vancomycin infusion.1 2 The second reaction occurred later in the course of therapy and seemed to be an idiosyncratic reaction. The third reaction, which occurred after vancomycin rechallenge, was more dramatic, manifesting as fever and generalized erythema, and was accompanied by reversible mild pancytopenia. All three reactions resolved on change (slower infusion rate) or discontinuation of vancomycin. What was the offending drug or drug combination? At first glance, several drugs could be responsible. Dipyrone is an established cause of agranulocytosis13 and TMP/SMX is known to affect the hemopoietic s y s t e m ,1 4 as does ceftazidime, a rare cause of cytopenias.1 5 , 1 6 N e v e r t h eless, several clinical points make vancomycin the likely causative drug. First, both TMP/SMX and dipyrone had been started more than one month before vancomycin institution, without an apparent adverse reaction. Second, fever was shown to appear in this patient while on vancomycin, and to resolve on its discontinuation, and was later present with the decline in blood cell counts. Third, all symptoms were fully reversible on vancomycin discontinuation, which is typical for vancomycin-induced neutropenia.1 , 3 Finally, the time from vancomycin institution to pancytopenia and the cumulative dose of vancomycin were 14 d and 28 g, respectively; both were consistent with vancomycin-induced cytopenia. Clayman and Capaldo1 7 described fever, sometimes extreme, as part of vancomycin adverse reaction. Although vancomycin-induced neutropenia is not a rare occurrence, several points are unique to the case. Pancytopenia is rarely described with relation to vancomycin.8 , 9 Its possible etiologies are diverse and include marrow suppression, sequestration, and peripheral destruction. In the case described above, there was no clinical basis to suggest sequestration (e.g., splenomegaly, portal hypertension) nor was there evidence of peripheral destruction, such as icterus, or microangiopathy. Therefore, we presume, as did earlier researchers, that marrow suppression is the mechanism of cytopenia. The occurrence of pancytopenia in accordance with the typical pattern of vancomycin-related neutropenia suggests a similar, possibly immunologic, mechanism, affecting precursors common to all three lineages, rather than exclusive granulocyte precursors. The occurrence of a more severe adverse reaction on rechallenge with the drug was formerly described.1 7 In the above case, there seemed to be an escalation of the response with each cycle, culminating in hectic fever and pancytopenia. Clayman and Capaldo1 7 report extreme fever on vancomycin administration in an allergic patient, a step-up from a previous lower-grade fever. Using the Naranjo probability scale,1 8 we computed a “probable” score of 7 for vancomycin. Although the presence of drug-fever is not a universal feature of vancomycin-induced cytopenias, some cases do mention its presence.9 I n others, drug-fever may have been present, but ascribed to the underlying infection. The only prospective report of vancomycin-induced neutropenia does not address the presence of fever with neutropenia.3 The concurrent use of ceftazidime may have contributed to the adverse reaction, although ceftazidime is not likely to have independently caused it, since the drug was added to vancomycin after the onset of fever. We described a systemic reaction to vancomycin that occurred on rechallenge of the drug in a previously allergic patient. The reaction consisted of high fever, dermal erythema, and mild pancytopenia. Concomitant administration of glucocorticoids and antihistamines did not prevent its occurrence. The nature of the reaction and its underlying mechanisms are not clear. We conclude that, in a patients suspected of having an idiosyncratic reaction to vancomycin, the drug should be resumed only if essential. We support the recommendation that blood cell counts be monitored while the patient is taking vancomycin,3 especially in patients receiving longer courses of therapy (exceeding 1 wk), and in those who have adversely reacted to the drug.