CASE REPORT Linezolid-Associated Acute Interstitial Nephritis and ...

CASE REPORT Linezolid-Associated Acute Interstitial Nephritis and Drug Rash With Eosinophilia and Systemic Symptoms (DRESS) Syndrome Sébastien Savard, MD, MSc,1 Simon Desmeules, MD,1 Julie Riopel, MD,2 and Mohsen Agharazii, MD1 Linezolid is a recent addition to the antibiotic armamentarium against Gram-positive bacteria, including multiresistant staphylococci and enterococci. Linezolid is relatively well tolerated and is not believed to be nephrotoxic. However, we report the case of an 88-year-old woman who was treated for prosthetic joint infection and methicillin-resistant Staphylococcus aureus bacteremia with vancomycin followed by linezolid therapy. On day 7 of linezolid treatment, the patient developed severe pruritus, macular rash, facial edema, eosinophilia, marked increase in serum creatinine level, and mild hepatitis. Renal biopsy showed acute interstitial nephritis with eosinophilic cells. Discontinuation of linezolid and a short course of prednisone led to rapid improvement of renal function. This case of linezolid-associated acute interstitial nephritis within the context of a drug rash with eosinophilia and systemic symptoms (DRESS) syndrome in a patient treated with linezolid raises concerns about the presumed renal safety of this drug. Clinicians should be aware of this potential life-threatening adverse reaction and monitor kidney function while patients are using linezolid. Am J Kidney Dis 54:e17-e20. © 2009 by the National Kidney Foundation, Inc. INDEX WORDS: Linezolid; acute kidney injury; acute interstitial nephritis; drug rash with eosinophilia and systemic symptoms (DRESS) syndrome; eosinophilia; hepatitis; fever.

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inezolid, the first member of the oxazolidinone antibiotic class, inhibits the initiation phase of bacterial protein synthesis by binding to the 50S ribosomal subunit.1 Its excellent bioavailability and its activity against most methicillin-sensitive and -resistant Grampositive bacteria make it an attractive treatment option that is proved to be as effective as vancomycin and yet without reported nephrotoxicity.2 Despite gastrointestinal side effects and thrombocytopenia, linezolid generally is well tolerated.3 However, more recently, 2 cases of linezolid-associated acute interstitial nephritis (AIN) have raised concerns about the renal safety of this drug.4,5 More than a decade ago, the term DRESS syndrome (drug rash with eosinophilia and systemic symptoms) was introduced to describe drug hypersensitivity syndrome with fever, erythroderma or exfoliative dermatitis, lymph node enlargement, hematologic abnormalities (eosinophilia and atypical lymphocytes), and internal organ involvement (hepatitis, carditis, nephritis, and pneumonitis) that occurs 2-6 weeks after the initiation of various drugs.6-8 In the present report, we describe a case of linezolid-associated AIN and DRESS syndrome in an octogenarian woman with a previously normal creatinine level.

CASE REPORT On June 27, 2008, an 88-year-old woman was admitted to the Hôtel-Dieu de Quebec Hospital (Quebec City, Canada) for low-grade hyperthermia, severe lumbar pain, and suspicion of arthritis of her left prosthetic knee. Medical history included hypertension, chronic carriage of methicillinresistant Staphylococcus aureus, and total left knee and right hip replacements in 2002. At presentation, medications included bisoprolol, perindopril, hydrochlorothiazide, and pantoprazole. Initial investigation showed erythrocyte sedimentation rate of 80 mm/h, C-reactive protein level of 142 mg/L, and white blood cell count of 11.9 ⫻ 103/␮L (11.9 ⫻ 109/L) with normal eosinophil count. Thirty-six hours after admission, both blood culture and prosthetic joint aspiration results were positive for methicillin-resistant Staphylococcus aureus. Magnetic resonance imaging revealed L5-S1 spondylodiscitis with a small epidural abscess. Transoesophageal

From the Divisions of 1Nephrology and 2Pathology, Centre Hospitalier Universitaire de Québec, L’Hôtel-Dieu de Québec Hospital, and Faculty of Medicine, Laval University, Quebec, Canada. Received May 28, 2009. Accepted in revised form July 27, 2009. Originally published online as doi: 10.1053/j.ajkd. 2009.07.013 on September 7, 2009. Address correspondence to Mohsen Agharazii, MD, Centre de Recherche de l’Hôtel Dieu de Québec, CHUQ-HôtelDieu de Québec, 11 Cote du Palais, Quebec City, QC, Canada, G1R 2J6. E-mail: mohsen.agharazii@crhdq. ulaval.ca © 2009 by the National Kidney Foundation, Inc. 0272-6386/09/5406-0033$36.00/0 doi:10.1053/j.ajkd.2009.07.013

American Journal of Kidney Diseases, Vol 54, No 6 (December), 2009: e17-e20

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e18 echocardiography did not show valvular abnormalities. At this time, serum creatinine level was 0.77 mg/dL (68 ␮mol/ L), corresponding to an estimated creatinine clearance of 55 mL/min according to the Cockcroft-Gault formula. Intravenous therapy with vancomycin was initiated on day 2 of hospitalization, with gentamicin for 4 days. The patient also received a single dose of linezolid on day 5. Surgical debridement and irrigation were performed. On day 11, despite 10 days of therapeutic dosages of vancomycin, the patient was still febrile. After exclusion of other potential sources of infections, rifampin therapy was introduced, but had to be stopped on day 19 of hospitalization because of gastrointestinal intolerance. On day 25 of hospitalization, vancomycin therapy was discontinued and replaced the day after by linezolid, 600 mg, twice daily because of persistent hyperthermia. On day 32, seven days after the introduction of linezolid, the patient reported severe pruritus, followed by a maculopapular rash on the face and trunk with facial edema, leading to linezolid therapy discontinuation. The skin rash was associated with a marked increase in serum eosinophil levels, mild increase in hepatic enzyme levels, and oliguric acute decrease in kidney function (Fig 1). No nonsteroidal anti-inflammatory drugs were administered during hospitalization. Renal ultrasound and complement levels were normal. Urinalysis showed slight proteinuria (protein excretion, 15-30 mg/dL), and urinary sediment showed 0-1 erythrocyte with 2-5 leukocytes per high power field and rare granular casts. On day 34, AIN was suspected; prednisone, 50 mg/d, was introduced for the first week, and 25 mg/d was introduced for the second week. Renal biopsy, performed 7 days after the onset of symptoms, showed moderate to severe tubulointerstitial nephritis with occasional eosinophils (Fig 2). Mild signs of acute tubular injury were present. Small areas of birefringent calcium oxalate crystals were found in 13 tubular lumens on 2 specimens of 0.1 ⫻ 1.2 and 0.1 ⫻ 1.1 cm. There was mild tubular atrophy and interstitial fibrosis with mild to moderate arteriosclerosis. Immunofluorescence and electron microscopy showed no specific findings. Treatment was completed with daptomycin and fusidic acid. The patient did not

Savard et al require dialysis and was discharged 13 days after the onset of her rash with a serum creatinine level of 1.1 mg/dL (97 ␮mol/L) and normal eosinophil count.

DISCUSSION Linezolid is a potent antibiotic of the oxazolidinone class with favorable pharmacokinetics and excellent oral and intravenous bioavailability. Its activity against multidrug-resistant Gram-positive bacteria combined with good tolerability makes this drug very attractive. However, an increasing number of serious potential adverse reactions, including neurologic,9,10 hematologic,11 and metabolic abnormalities,12 have been reported and cause concerns about its prolonged use. In the present report, we decribe a case of AIN within the context of DRESS syndrome associated with fever, maculopapular rash, facial edema, eosinophilia, and mild hepatitis that occurred after 7 days of linezolid exposure. Discontinuation of linezolid therapy and a short course of corticosteroid therapy led to recovery of kidney function within a week. The kidney biopsy specimen showed AIN with slight deposition of oxalate calcium crystals in some tubular lumens. There was no history of contrast media injection and no causes of secondary hyperoxaluria. Acute tubular injury therefore is believed to be the most likely cause of the oxalate crystal deposition. Previously, Esposito et al4 reported a case of AIN attributed to linezolid therapy in a transplant recipient with mild eosinophilia, but no rash or fever. Creatinine level increased 8 days after

Figure 1. Biochemical and treatment timeline. The graph shows serum creatinine level, eosinophil count, and aspartate aminotransferase (AST) and ␥ glutamyltransferase (GGT) activity. Vancomycin was introduced on day 2, and the last dose was received on day 25. Linezolid was given once on day 5, then from days 26-32 inclusively. Prednisone therapy was started on day 34 for 14 days. Conversion factor for serum creatinine in mg/dL to ␮mol/L, ⫻88.4.

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Figure 2. Renal biopsy specimen shows tubulitis, signs of acute tubular injury, and an interstitial infiltrate of lymphocytes, plasmocytes, and occasional eosinophils. (Hematoxylin and eosin stain; original magnification, ⫻400.)

linezolid introduction and remained increased on day 23 of therapy. The kidney biopsy showed mild interstitial inflammation of 10% with mild focal tubulitis. Of note, only partial recovery was achieved with an increased dose of prednisolone for 2 weeks. It is uncertain whether the systemic response was downplayed by the immunosuppressive drugs used by the patient (cyclosporine, mycophenolate mofetil, and prednisolone, 2.5 mg/d) or whether the creatinine level increase was secondary to mild acute rejection. More recently, Hammer et al5 reported a second case of AIN in a patient using linezolid that occurred after 7 days of treatment. The patient had a diffuse maculopapular rash, arthralgia, fever, poor urine output, and a peak serum creatinine level of 16 mg/dL (1,414 ␮mol/L). Despite early withdrawal of linezolid and corticosteroid therapy, the patient required dialysis therapy for 6 weeks, and creatinine level slowly returned to baseline after 8 months. The evolution of this patient is unusual because the rate of creatinine level increase suggests an abrupt decrease in glomerular filtration rate during the first day of linezolid therapy. In addition, in drug-induced cases of AIN, withdrawal of the drug and corticosteroid therapy usually result in rapid improvement in renal function. Therefore, there may have been factors other than linezolid that could have contributed to the abrupt decrease in glomer-

ular filtration rate and the very slow recovery of renal function in the case described by Hammer et al.5 DRESS syndrome, a severe form of druginduced hypersensitivity syndrome, is distinguished from other more common cutaneous drug reactions by the presence of visceral involvement.13 The complete syndrome usually includes fever (78%-100%); skin lesion (84%-100%); hematologic abnormalities, such as eosinophilia (⬎50%) or atypical lymphocytes; lymph node enlargement (⬍30%); and visceral dysfunction8 with liver abnormalities (60%-100%)8,13 or nephritis (10%).13,14 Aromatic anticonvulsants, allopurinol, minocycline, and sulfonamides are the most frequently reported triggering medications.13,15 However, various classes of drugs also have been reported.7,8,13-17 Although DRESS manifestations typically appear 2 or more weeks after initiation of a drug therapy, heterogeneity in delay to onset of symptoms was observed by Peyrière et al8 depending on the drugs involved. Furthermore, delays as short as 2-7 days have been reported,8 especially when the patient was previously sensitized. The relatively short interval between the introduction of linezolid and clinical manifestation of DRESS syndrome in our report potentially could be explained by earlier exposure to a single dose of linezolid on day 5 of hospitalization.

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However, there are some potential confounding elements in the present case. First, vancomycin-induced DRESS syndrome has been described recently.14,16 In our patient, vancomycin therapy was stopped 7 days before the onset of clinical symptoms; therefore, vancomycin-induced DRESS syndrome is highly unlikely. Second, the patient also was using pantoprazole, which also has been described to potentially induce AIN.18 However, reintroduction of pantoprazole was well tolerated in this case. Suspicion of linezolid-associated DRESS syndrome therefore is based on the clear temporal relationship between the introduction of linezolid and gradual increase in eosinophil count, acute renal failure, and hepatitis. Therefore, this appears to be a likely and non–dose-related linezolid adverse drug reaction.19 A rechallenge with the suspect drug would have been the ultimate test to ascertain causality, but obviously would have been unethical. In summary, we report a case of linezolidassociated AIN in a context of DRESS syndrome. Close monitoring of kidney function is recommended for timely recognition and treatment of this potential adverse reaction.

ACKNOWLEDGEMENTS Support: None. Financial Disclosure: None.

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