Quinupristin--dalfopristin-induced reticulocytopenic anemia.

To The Editor: Quinupristin-dalfopristin was approved by the FDA in 1999 for bacteremia and life-threatening infections with vancomycin-resistant Enterococcus faecium. (1) Other indications include complicated skin and soft-tissue infections with methicillin-susceptible Staphylococcus aureus and Streptococcus pyogenes. (2) Quinupristin-dalfopristin has also been used for methicillin-resistant S aureus, coagulase-negative staphylococcus, and Streptococcus pneumoniae. (3) Adverse drug events (ADEs) associated with quinupristin-dalfopristin include infusion-site reactions (42%), infusion-site pain (40%), edema (17%), arthralgias (47%), myalgias (6%), gastrointestinal effects (3 to 5%), rash (2.5%), headache (1.6%), pruritus (1.5%), and hyperbilirubinemia (25%). (1,2) Reticulocytopenic anemia is a rare ADE from prolonged quinupristin-dalfopristin use. This report describes the third case of severe but reversible reticulocytopenic anemia due to quinupristin-dalfopristin.

A 52-year-old woman was transferred from a rehabilitation facility for symptomatic anemia. Over the preceding month, she experienced lightheadedness, generalized malaise, and easy fatigability. She denied hemoptysis, hematemesis, melena, and hematochezia. Medical history included hypertension, depression, gout, and right knee osteomyelitis. Bone cultures grew E faecium (sensitive to vancomycin, tetracycline, ampicillin), coagulase-negative staphylococcus (sensitive to vancomycin, tetracycline), and Enterobacter cloacae (sensitive to imipenem, amikacin). She had undergone multiple debridements and was receiving quinupristin-dalfopristin (750 mg IV every 8 hours) and imipenem (250 mg IV every 6 hours). These antibiotics had begun 4 weeks earlier. Other medications were amlodipine, escitalopram, colchicine, and docusate. She took no nonsteroidal-anti-inflammatory drugs or cyclo-oxygenase-2-inhibitors.

Her allergies included rash with sulfonamides, penicillin, and vancomycin. Since initiation of antibiotics, she had mild nausea, vomiting, arthralgias, and myalgias, but denied any fevers, chills, sweats, or rash. Physical examination revealed pallor, a healing surgical scar on her right knee, and a right subclavian Hickman catheter. The hemoglobin was 6.8 g/dL with normal red blood cell (RBC) indices. The absolute reticulocyte count was 2.4 K/mcL (normal 28.4 to 150 K/mcL). Peripheral smear showed numerous microcytes and ovalocytes. Leukocyte and platelet counts, iron studies, renal and hepatic function, electrolytes, coagulation studies, folate, vitamin [B.sub.12], and thyroid stimulating hormone levels were normal. Parvovirus B 19 serologies were negative.

Before antibiotic therapy, the hemoglobin level was 13 g/dL. No prior reticulocyte counts had been performed. During antibiotic therapy, progressive anemia developed. Review of the medical literature identified two similar cases of severe but reversible reticulocytopenic anemia due to quinupristin-dalfopristin. (4) None of the other medications appeared to be contributing to this phenomenon. Because of its possible contribution to her anemia and reticulocytopenia, quinupristin-dalfopristin was discontinued. Linezolid was avoided due to the risk of additional myelosuppression. Doxycycline (100 mg orally every 12 hours) was added and the imipenem dosage was increased (500 mg IV every 6 hours). Four days later, the absolute reticulocyte count was 146 K/mcL. She completed her course of doxycycline and imipenem without additional complications.

This is the third reported case of severe but reversible reticulocytopenic anemia due to quinupristin-dalfopristin. (4) The proposed mechanism, direct toxicity to RBC precursors, is suggested by the abnormal RBC morphology seen on peripheral smear. In this patient, as with previous cases, the hypothesis of ADE is supported by complete reversal of anemia and reticulocytopenia after discontinuation of quinupristin-dalfopristin. Based on the Naranjo probability scale, the likelihood that quinupristin dalfopristin caused the anemia and reticulocytopenia is probable. (6) Clinical vigilance and close monitoring of hemoglobin levels are essential during extended courses of quinupristin-dalfopristin.

Kirk M. Chan-Tack, MD

Institute of Human Virology 

University of Maryland School of Medicine

Baltimore, MD

Sanjay Mehta, MD

Division of Infectious Diseases

University of Maryland School of Medicine

Baltimore, MD

References

1. Moellering RC, Linden PK, Reinhardt I, et al. The efficacy and safety of quinupristin-dalfopristinfor the treatment of infections caused by vancomycin-resistant Enterococcusjaecium. J Antimicrob Chemother 1999;44:251-261.

2. Nichols RL, Graham DR, Barriere SL, et al. Treatment of hospitalized patients with complicated gram':positive skin and soft tissue infections: two randomized, multi centre studies of quinupristin-dalfopristin versus cefazolin, oxacillin or vancomycin. Antimicrob Chemother 1999;44:263-273.

3. Jones RN, Ballow CH, Biedenbach DL, et al. Antimicrobial activity of quinupristin-dalfopristin tested against over 28,000 recent clinical isolates from 200 medical centers in the United States and Canada. Diagn Microbiol Infect Dis 1998;31:437-451.

4. Launay O, Chemlal K, Andrieu V, et al. Severe reversible reticulocytopenic anemia associated with quinupristin-dalfopristin therapy. Clin Infect Dis 1997;25:156.

5. Evans PC, Almas JP, Criddle FJ. Anemia and reversible reticulocytopenia associated with extended quinupristin/dalfopristin. Ann Pharmacother 2004;38:720-721.

6. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-245.