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Telithromycin-induced acute interstitial nephritis: A first case report
CASE REPORT
Telithromycin-Induced Acute Interstitial Nephritis: A First Case Report Michel Tintillier, MD, Lotti Kirch, MD, Carole Almpanis, MD, Jean-Pierre Cosyns, PhD, Jean-Michel Pochet, MD, and Charles Cuvelier, MD ● Telithromycin, a ketolide antibiotic used for the treatment of community-acquired respiratory infections, is widely prescribed in primary care practice. Treatment-related adverse events are mainly of gastrointestinal origin and generally mild in intensity. The authors report the first case of telithromycin-induced severe acute interstitial nephritis. Practitioners should be aware of the possibility that telithromycin therapy could result in this form of drug-induced acute renal failure. Am J Kidney Dis 44:E25-E27. © 2004 by the National Kidney Foundation, Inc. INDEX WORDS: Telithromycin; acute interstitial nephritis (AIN).
T
ELITHROMYCIN is the first ketolide antibiotic to undergo clinical development. It has been specifically designed to treat community-acquired respiratory tract infections.1 Its oral absolute bioavailability is 57%.2 The absorbed telithromycin is eliminated via various pathways with 7% excreted unchanged in feces, 13% excreted in urine, and 37% metabolized by the liver.3 Adverse events were generally mild and mainly of gastrointestinal origin.4 We report the first case of telithromycin-induced acute interstitial nephritis (AIN). CASE REPORT An 18-year-old man was admitted to our hospital with a 3-week history of fever, headache, diffuse myalgia, general weakness, dry cough, and nausea. A week before admission, he received telithromycin (Ketek/R), 800 mg once daily for 5 days, with little improvement of his symptoms. Three days after antibiotic initiation, serum creatinine level was noted to be 1.58 mg/dL (140 mol/L), and he was referred to our hospital. He had also taken Paracetamol (acetaminophen) but no nonsteroidal antiinflammatory drugs. No ocular symptoms, arthralgia, or rash were reported. Physical examination was unremarkable: blood pressure was 100/60 mm Hg, pulse rate was 80 beats per minute, and body temperature was 36.3°C. There was no rash or adenopathy. Results of laboratory tests were as follows: leukocyte count, 12,900/L (neutrophils 74.6%, eosinophils 2.1%); C-reactive protein, 5.2 mg/dL; and serum creatinine, 2.3 mg/dL (203 mol/L). Urinalysis showed aseptic leukocyturia (6 to 10 per field), proteinuria ⫹⫹ (93 mg/dL), and glycosuria ⫹⫹. Angiotensine-convertase, C3, C4, and cryoglobulins were within normal limits. All viral, bacterial, and autoimmune serologies (including hepatitis B virus and hepatitis C virus, cytomegalovirus, Epstein Barr virus, Hantaan virus, Parvovirus B19 IgM, Borrelia, Chlamydia pneumoniae IgM, antineutrophils cytoplasmic antibodies, and antinuclear antibodies) were either negative or noncontributive. Renal
ultrasound scan was normal. One week later, serum creatinine level rose to 4.6 mg/dL (407 mol/L). A percutaneous renal biopsy was performed and found severe interstitial edema, a marked diffuse infiltration with lymphocytes and some eosinophils (Fig 1). The glomeruli were normal. There was no viral inclusion. No immune deposits were seen by immunofluorescent microscopy. The patient was treated with pulse methylprednisolone, 500 mg daily for 3 days, followed by oral methylprednisolone, 32 mg daily. Two weeks after starting corticosteroid treatment, serum creatinine level declined to 0.9 mg/dL (80 mol/L).
DISCUSSION
Telithromycin-induced renal toxicity has not been reported previously. However, 1 case of AIN has been described in a patient who received clarithromycin therapy.5 It is well known that telithromycin toxicity and adverse effects are similar to those of clarithromycin.6 This similarity is not surprising, because the ketolides are new semisynthetic erythromycin-A derivatives structurally similar to clarithromycin.6 AIN has been associated with a variety of infections and drug therapies or it may develop without an identified cause. Extrarenal manifes-
From the Department of Nephrology, Clinique et Maternite´ Sainte Elisabeth, Namur, and Department of Pathology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium. Received February 23, 2004; accepted in revised form April 12, 2004. Address reprint requests to M. Tintillier, Department of Nephrology, Clinique et Maternite´ Sainte Elisabeth, Place Godin, 15, 5000 Namur, Belgium. E-mail: m.tintillier@ ibelgique.com © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4402-0026$30.00/0 doi:10.1053/j.ajkd.2004.04.045
American Journal of Kidney Diseases, Vol 44, No 2 (August), 2004: E25-E27
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TINTILLIER ET AL
Fig 1. High-power view shows severe and diffuse interstitial edema and mononuclear and eosinophilic infiltration (arrows), compatible with immunoallergic AIN (original magnification ⴛ250).
tations of hypersensibility are strongly suggestive but are not pathognomonic of drug-induced AIN. Anaphylaxis is rare.7,8 Low-grade fever, maculopapular rash, mild arthralgias, and eosinophilia are present in less than 50% of cases, with the exception of AIN induced by nonsteroidal antiinflammatory drugs in which fever, rash, and eosinophilia are absent.9 In other reports, rash, fever, and eosinophilia were present in a minority of cases of drug-related AIN with incidence rates of 14.8%, 27.3%, and 23.3%, respectively. The classic triad of fever, arthralgia, and rash was only present in 10% to 30% of cases of drug-induced AIN.8,10 In our patient, eosinophilia was present, whereas fever, rash, and eosinophils in the urine were absent. In drug-induced AIN, eosinophils are identified as a component of the interstitial cellular infiltrate on renal biopsy as we observed in our patient. Eosinophilic infiltration was not massive because of delay or time lag between the renal biopsy and telithromycin drug exposure. In our patient, we pointed to telithromycin as the etiologic agent of tubulointerstitial damage for the following reasons. First, the occurrence of AIN was temporally related to telithromycin therapy. The development of renal failure followed the initiation of telithromycin treatment. The only other medication received by the pa-
tient was Paracetamol. Despite its very large utilization, only a single anecdotic case has been reported.11 Second, microscopic examination disclosed some eosinophils as a component of the interstitial cellular infiltrate, suggesting an immunoallergic etiopathogeny.7 Third, viral inclusions were not seen in the biopsy, and viral serology results were either negative or noncontributive. Fourth, systemic corticotherapy led to a more rapid and more complete recovery of renal function in drug-induced AIN.7,8 In our patient, renal function showed complete recovery only 2 weeks after the beginning of corticosteroid therapy. We report the first case of telithromycininduced severe AIN. Practitioners should be aware of the possibility that telithromycin therapy could result in this form of drug-induced acute renal failure. REFERENCES 1. Xiong YQ, Le TP: Telithromycin (HMR 3347): The first ketolide antibiotic. Drugs Today (Barc) 37:617-628, 2001 2. Perret C, Wessels DH: Oral bioavailability of the ketolides telithromycin (HMR 3647) is similar in both elderly and young subjects [abstract n°MoP250]. Clin Microbiol Infect 6:203-204, 2000 (suppl 1) 3. Aventis Pharma. Data on file. Ketek (telithromycin). Briefing document for the FDA Anti-infective Drug Products Advisory Committee Meeting. Aventis Pharma, Bridgewater, New Jersey, US; Executive Summary, 2001 March
TELITHROMYCIN-INDUCED INTERSTITIAL NEPHRITIS
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4. Quinn J, Ruoff GE, Ziter PS: Efficacy and tolerability of 5-day, once-daily telithromycin compared with 10-day, twice-daily clarithromycin for the treatment of group A beta-hemolytic streptococcal tonsillitis/pharyngitis: A multicenter, randomised, double-blind parallel-group study. Clin Ther 25:422-443, 2003 5. Baylor P, Williams K: Interstitial nephritis, thrombocytopenia, hepatitis, and elevated serum amylase levels in a patient receiving clarithromycin therapy. Clin Infect Dis 29:1350-1351, 1999 6. Bryskier A, Agouridas C, Chantot JF: Acid stability of new macrolides. J Chemother 5:S158-159, 1993 (suppl 1)
7. Ten RM, Torres VE, Milliner DS, Schwab TR, Holley KE, Gleich GJ: Acute interstitial nephritis: Immunologic and clinical aspects. Mayo Clin Proc 63:921-930, 1988 8. Baker RJ, Pusey CD: The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant 19:8-11, 2004 9. Rossert J: Drugs-induced acute interstitial nephritis. Kidney Int 60:804-817, 2001 10. Michel DM, Kelly CJ: Acute interstitial nephritis [review article]. J Am Soc Nephrol 9:506-515, 1998 11. Spz6e B, Trinn C, Toth T, Brasch H, Nagy J: Paracetamol-induced tubulointerstitial nephritis in a chronic alcoholic patient. Orv Hetil 139:2385-2387, 1998
Telithromycin-Induced Acute Interstitial Nephritis: A First Case Report Michel Tintillier, MD, Lotti Kirch, MD, Carole Almpanis, MD, Jean-Pierre Cosyns, PhD, Jean-Michel Pochet, MD, and Charles Cuvelier, MD ● Telithromycin, a ketolide antibiotic used for the treatment of community-acquired respiratory infections, is widely prescribed in primary care practice. Treatment-related adverse events are mainly of gastrointestinal origin and generally mild in intensity. The authors report the first case of telithromycin-induced severe acute interstitial nephritis. Practitioners should be aware of the possibility that telithromycin therapy could result in this form of drug-induced acute renal failure. Am J Kidney Dis 44:E25-E27. © 2004 by the National Kidney Foundation, Inc. INDEX WORDS: Telithromycin; acute interstitial nephritis (AIN).
T
ELITHROMYCIN is the first ketolide antibiotic to undergo clinical development. It has been specifically designed to treat community-acquired respiratory tract infections.1 Its oral absolute bioavailability is 57%.2 The absorbed telithromycin is eliminated via various pathways with 7% excreted unchanged in feces, 13% excreted in urine, and 37% metabolized by the liver.3 Adverse events were generally mild and mainly of gastrointestinal origin.4 We report the first case of telithromycin-induced acute interstitial nephritis (AIN). CASE REPORT An 18-year-old man was admitted to our hospital with a 3-week history of fever, headache, diffuse myalgia, general weakness, dry cough, and nausea. A week before admission, he received telithromycin (Ketek/R), 800 mg once daily for 5 days, with little improvement of his symptoms. Three days after antibiotic initiation, serum creatinine level was noted to be 1.58 mg/dL (140 mol/L), and he was referred to our hospital. He had also taken Paracetamol (acetaminophen) but no nonsteroidal antiinflammatory drugs. No ocular symptoms, arthralgia, or rash were reported. Physical examination was unremarkable: blood pressure was 100/60 mm Hg, pulse rate was 80 beats per minute, and body temperature was 36.3°C. There was no rash or adenopathy. Results of laboratory tests were as follows: leukocyte count, 12,900/L (neutrophils 74.6%, eosinophils 2.1%); C-reactive protein, 5.2 mg/dL; and serum creatinine, 2.3 mg/dL (203 mol/L). Urinalysis showed aseptic leukocyturia (6 to 10 per field), proteinuria ⫹⫹ (93 mg/dL), and glycosuria ⫹⫹. Angiotensine-convertase, C3, C4, and cryoglobulins were within normal limits. All viral, bacterial, and autoimmune serologies (including hepatitis B virus and hepatitis C virus, cytomegalovirus, Epstein Barr virus, Hantaan virus, Parvovirus B19 IgM, Borrelia, Chlamydia pneumoniae IgM, antineutrophils cytoplasmic antibodies, and antinuclear antibodies) were either negative or noncontributive. Renal
ultrasound scan was normal. One week later, serum creatinine level rose to 4.6 mg/dL (407 mol/L). A percutaneous renal biopsy was performed and found severe interstitial edema, a marked diffuse infiltration with lymphocytes and some eosinophils (Fig 1). The glomeruli were normal. There was no viral inclusion. No immune deposits were seen by immunofluorescent microscopy. The patient was treated with pulse methylprednisolone, 500 mg daily for 3 days, followed by oral methylprednisolone, 32 mg daily. Two weeks after starting corticosteroid treatment, serum creatinine level declined to 0.9 mg/dL (80 mol/L).
DISCUSSION
Telithromycin-induced renal toxicity has not been reported previously. However, 1 case of AIN has been described in a patient who received clarithromycin therapy.5 It is well known that telithromycin toxicity and adverse effects are similar to those of clarithromycin.6 This similarity is not surprising, because the ketolides are new semisynthetic erythromycin-A derivatives structurally similar to clarithromycin.6 AIN has been associated with a variety of infections and drug therapies or it may develop without an identified cause. Extrarenal manifes-
From the Department of Nephrology, Clinique et Maternite´ Sainte Elisabeth, Namur, and Department of Pathology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium. Received February 23, 2004; accepted in revised form April 12, 2004. Address reprint requests to M. Tintillier, Department of Nephrology, Clinique et Maternite´ Sainte Elisabeth, Place Godin, 15, 5000 Namur, Belgium. E-mail: m.tintillier@ ibelgique.com © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4402-0026$30.00/0 doi:10.1053/j.ajkd.2004.04.045
American Journal of Kidney Diseases, Vol 44, No 2 (August), 2004: E25-E27
e25
e26
TINTILLIER ET AL
Fig 1. High-power view shows severe and diffuse interstitial edema and mononuclear and eosinophilic infiltration (arrows), compatible with immunoallergic AIN (original magnification ⴛ250).
tations of hypersensibility are strongly suggestive but are not pathognomonic of drug-induced AIN. Anaphylaxis is rare.7,8 Low-grade fever, maculopapular rash, mild arthralgias, and eosinophilia are present in less than 50% of cases, with the exception of AIN induced by nonsteroidal antiinflammatory drugs in which fever, rash, and eosinophilia are absent.9 In other reports, rash, fever, and eosinophilia were present in a minority of cases of drug-related AIN with incidence rates of 14.8%, 27.3%, and 23.3%, respectively. The classic triad of fever, arthralgia, and rash was only present in 10% to 30% of cases of drug-induced AIN.8,10 In our patient, eosinophilia was present, whereas fever, rash, and eosinophils in the urine were absent. In drug-induced AIN, eosinophils are identified as a component of the interstitial cellular infiltrate on renal biopsy as we observed in our patient. Eosinophilic infiltration was not massive because of delay or time lag between the renal biopsy and telithromycin drug exposure. In our patient, we pointed to telithromycin as the etiologic agent of tubulointerstitial damage for the following reasons. First, the occurrence of AIN was temporally related to telithromycin therapy. The development of renal failure followed the initiation of telithromycin treatment. The only other medication received by the pa-
tient was Paracetamol. Despite its very large utilization, only a single anecdotic case has been reported.11 Second, microscopic examination disclosed some eosinophils as a component of the interstitial cellular infiltrate, suggesting an immunoallergic etiopathogeny.7 Third, viral inclusions were not seen in the biopsy, and viral serology results were either negative or noncontributive. Fourth, systemic corticotherapy led to a more rapid and more complete recovery of renal function in drug-induced AIN.7,8 In our patient, renal function showed complete recovery only 2 weeks after the beginning of corticosteroid therapy. We report the first case of telithromycininduced severe AIN. Practitioners should be aware of the possibility that telithromycin therapy could result in this form of drug-induced acute renal failure. REFERENCES 1. Xiong YQ, Le TP: Telithromycin (HMR 3347): The first ketolide antibiotic. Drugs Today (Barc) 37:617-628, 2001 2. Perret C, Wessels DH: Oral bioavailability of the ketolides telithromycin (HMR 3647) is similar in both elderly and young subjects [abstract n°MoP250]. Clin Microbiol Infect 6:203-204, 2000 (suppl 1) 3. Aventis Pharma. Data on file. Ketek (telithromycin). Briefing document for the FDA Anti-infective Drug Products Advisory Committee Meeting. Aventis Pharma, Bridgewater, New Jersey, US; Executive Summary, 2001 March
TELITHROMYCIN-INDUCED INTERSTITIAL NEPHRITIS
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4. Quinn J, Ruoff GE, Ziter PS: Efficacy and tolerability of 5-day, once-daily telithromycin compared with 10-day, twice-daily clarithromycin for the treatment of group A beta-hemolytic streptococcal tonsillitis/pharyngitis: A multicenter, randomised, double-blind parallel-group study. Clin Ther 25:422-443, 2003 5. Baylor P, Williams K: Interstitial nephritis, thrombocytopenia, hepatitis, and elevated serum amylase levels in a patient receiving clarithromycin therapy. Clin Infect Dis 29:1350-1351, 1999 6. Bryskier A, Agouridas C, Chantot JF: Acid stability of new macrolides. J Chemother 5:S158-159, 1993 (suppl 1)
7. Ten RM, Torres VE, Milliner DS, Schwab TR, Holley KE, Gleich GJ: Acute interstitial nephritis: Immunologic and clinical aspects. Mayo Clin Proc 63:921-930, 1988 8. Baker RJ, Pusey CD: The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant 19:8-11, 2004 9. Rossert J: Drugs-induced acute interstitial nephritis. Kidney Int 60:804-817, 2001 10. Michel DM, Kelly CJ: Acute interstitial nephritis [review article]. J Am Soc Nephrol 9:506-515, 1998 11. Spz6e B, Trinn C, Toth T, Brasch H, Nagy J: Paracetamol-induced tubulointerstitial nephritis in a chronic alcoholic patient. Orv Hetil 139:2385-2387, 1998