- Email: [email protected]
Severe methotrexate toxicity due to a concomitant administration of ciprofloxacin
Lettres à la rédaction / Médecine et maladies infectieuses 43 (2013) 35–41
39
Severe methotrexate toxicity due to a concomitant administration of ciprofloxacin
Déclaration d’intérêts Les auteurs déclarent ne pas avoir de conflits d’intérêts en relation avec cet article.
Toxicité grave au méthotrexate chez une patiente recevant de la ciprofloxacine
Références 1. Introduction [1] Bottone EJ. Yersinia enterocolitica: overview and epidemiologic correlates. Microbes Infect 1999;1:323–33. [2] Nicolas X, Le Berre R, Ansart S, Tandé D, Lerch C, Garre M. Bactériémie et pneumopathie à Yersinia enterocolitica sérotype 0:3 chez un immunocompétent. Med Mal Infect 2005;35:370–3. [3] Girszyn N, Kerleau JM, Robaday S, Lefebvre, Marie I, Levesque H. Pneumopathie avec bactériémie à Yersinia enterocolitica chez un diabétique porteur de l’antigène HLA-B27. Rev Med Interne 2007;28:882– 4. [4] Mofredj A, Guérin JM, Leibinger F, Masmoudi R. Spontaneous pleural empyema due to Yersinia enterocolitica. South Med J 2003;96:525– 7. [5] Clarridge J, Roberts C, Peters J, Musher D. Sepsis and empyema caused by Yersinia enterocolitica. J Clin Microbiol 1983;17:936–8. [6] Piroth L, Meyer P, Bielefeld P, Besancenot JF. Bactériémie à Yersinia et surcharge en fer. Rev Med Interne 1997;18:932–8. [7] Rano A, Agusti C, Jimenez P, Angrill J, Benito N, Danes C, et al. Pulmonary infiltrates in non-HIV immunocompromised patients: a diagnostic approach using non-invasive and bronchoscopic procedures. Thorax 2001;56:379– 87.
P.-A. Jarrot a R. Mahmoudi a,∗,b J.-L. Novella a,b P. Manckoundia c,d a Service de médecine interne et gérontologie clinique, hôpital Maison-Blanche, centre hospitalier universitaire de Reims, 45, avenue Cognacq-Jay, 51092 Reims cedex, France b Faculté de médecine, EA 3797, université de Reims Champagne-Ardenne, 51092 Reims, France c Service de médecine interne gériatrie, hôpital de Jour, hôpital de Champmaillot, CHU, BP 87909, 2, rue Jules-Violle, 21079 Dijon cedex, France d Inserm/U887, motricité-plasticité : performance, dysfonctionnement, vieillissement et technologies d’optimisation, faculté des sciences du sport, université de Bourgogne, 21078 Dijon, France ∗ Auteur
correspondant. Adresse e-mail : [email protected] (R. Mahmoudi) Rec¸u le 23 aoˆut 2012 Rec¸u sous la forme révisée le 9 octobre 2012 Accepté le 11 octobre 2012 Disponible sur Internet le 10 décembre 2012 http://dx.doi.org/10.1016/j.medmal.2012.10.004
Methotrexate is an antifolate agent used at high dose (i.e., > 1 g/m2 intravenously) in the treatment of some tumors (acute lymphoblastic leukemia, non-Hodgkin lymphomas, osteosarcomas). Antibacterial agents, proton pump inhibitors, and non-steroidal anti-inflammatory agents are known to affect methotrexate elimination [1]. We report a case of unexpected and life-threatening toxicity following administration of high-dose methotrexate in a patient receiving ciprofloxacin. 2. Case report A 28-year-old female patient was hospitalized for a primary mediastinal B-cell non-Hodgkin’s lymphoma. Cure was not achieved after four cycles of R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesin, bleomycin, and prednisone), and the regimen was changed to IVAM (ifosfamide, etoposide, cytarabine, and high-dose methotrexate 3 g/m2 ). High dose methotrexate was infused according to our standard protocol to reduce its toxicity: alkaline load with sodium bicarbonate before initiating the infusion, alkaline hydration, additional 70 mmol of sodium bicarbonate over 15 minutes if urinary pH was lower than 7.5, and intravenous calcium folinate rescue. Urine output and pH were monitored, and methotrexate plasma levels were measured daily using the enzyme-multiplied immunoassay technique (EMIT® ). The first cycle of IVAM was well tolerated with an appropriate elimination of methotrexate within 48 hours. Three weeks later, the patient was hospitalized for the second cycle of IVAM. White blood cells and serum creatinine level (46 mol/L, normal range: 32–85 mol/L) were normal. Hydration, alkalization, and folic acid were given as in cycle 1. The patient presented with fever and chills without any microbiological documentation, and a marked increase in C-reactive protein (138 mg/L) one day before the methotrexate infusion. Intravenous cefotaxime was initiated (1 g three times a day). No source of infection was identified, nevertheless ciprofloxacin, 500 mg twice a day, was given as oral second-line antibiotherapy, 20 hours after methotrexate administration. The other concomitant drug was valacyclovir 500 mg twice a day, for the prevention of Herpes simplex virus and varicella-zoster virus infections. Plasma concentrations of methotrexate were in the expected range 24 and 48 hours after initiating the infusion (3.9 mol/L
40
Lettres à la rédaction / Médecine et maladies infectieuses 43 (2013) 35–41
and 0.8 mol/L, respectively). However, the concentration was slightly higher than expected at 72 hours (observed value of 0.28 mol/L for an expected value below 0.20 mol/L). Four hours after initiating ciprofloxacin, serum creatinine value increased by 41% (65 mol/L). The values were similar on the next day. The patient was nevertheless discharged, with a recommendation to continue ciprofloxacin for three additional days. On day 7, the patient was hospitalized for a febrile pancytopenia (hemoglobin: 9.6 g/dL, white blood cells: 200/L, differential count not performed, platelets: 38,000/L), mucositis, diarrhea, and necrotic skin lesions. The renal function was normal (serum creatinine: 54 mol/L). Blood and urine cultures were sterile. Broad-spectrum antibiotics (piperacillin/ tazobactam, vancomycin, and metronidazole) were initiated in combination with lenograstim, intravenous acyclovir, analgesics, and parenteral nutrition. Hematological toxicity could have been due to other cytotoxic drugs, but the associated symptoms (especially skin lesions) led to the determination of plasma methotrexate level. On day 11, the concentration was 0.10 mol/L (limit of quantification: 0.04 mol/L). In most patients, MTX is not detectable in plasma on day 4. Hyper hydration and folinic acid were started again on the same day. The methotrexate level decreased to 0.06 mol/L on day 13 and was less than 0.04 mol/L on day 16. On day 14, the fever persisted and empirical caspofungin therapy was added to the antibiotics. On day 19, Trichosporon asahii grew in multiple blood cultures and caspofungin was replaced by intravenous voriconazole. Autologous stem cell transplantation was performed because of the severe clinical status and persistent aplasia. Blood cultures became negative 2 days after the initiating voriconazole, and neutrophil count was normal 11 days after transplantation. The patient was discharged 38 days after admission, with an oral voriconazole therapy because of a chronic disseminated Trichosporon infection. 3. Discussion Methotrexate is primarily eliminated by the kidneys and in a lesser part by the liver. Thus, methotrexate clearance is critically dependent on renal function. Delayed methotrexate elimination associated with severe adverse effects may be caused by renal impairment related to insufficient alkaline hydration, acid beverages, or drug-drug interactions [1,2]. The first cycle was well tolerated by our patient and methotrexate was eliminated as expected. The second cycle was characterized by a delayed elimination of methotrexate, despite administrating the same hydration and alkalization procedures, and normal baseline renal function. We suspect that the concomitant administration of ciprofloxacin delayed methotrexate renal elimination and in turn led to severe toxicity. Another explanation for the delayed methotrexate elimination could be renal impairment caused by sepsis. Nevertheless, an author had already reported two cases of delayed methotrexate elimination in children receiving ciprofloxacin concomitantly. But the authors did not suggest any convincing explanation for the interaction mechanism [3]. Various interactions involving methotrexate with antibacterial
agents have been reported in relation with additional antifolate effect (trimethoprim), or delayed elimination (amoxicillin, piperacillin, oxacillin, pristinamycin). The molecular mechanism underlying the interaction with penicillins is probably related to the blockade of the proximal renal organic anion transporters OAT1 and OAT3 by antibacterial agents. Ciprofloxacin is a weak OAT3 inhibitor but has no impact on methotrexate uptake in human kidney cells. The interaction with other transporters located in the kidney is another hypothesis; but such an interaction has never been reported yet [4]. An alternative mechanism for the interaction could be due to the chemical properties of ciprofloxacin and its low solubility at a pH greater than 6.8 [5]. Thorsteinsson et al. reported that the co-administration of ciprofloxacin and bicarbonate resulted in crystalluria in five out of six healthy volunteers, when the urinary pH was greater than 7.3 [6]. Crystalluria may induce calculus formation or oliguria, resulting in acute renal failure [5,7]. The patient had a urinary pH of 8 or more at onset of ciprofloxacin therapy and during the following 2 days, due to standard alkalization given during high-dose methotrexate therapy. 4. Conclusion We suspect that the interaction between methotrexate and ciprofloxacin resulted from a crystallization of ciprofloxacin due to high urinary pH induced by a bicarbonate infusion. We do not recommend administering ciprofloxacin along with high dose methotrexate, because of possible severe adverse effects. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Levêque D, Santucci R, Gourieux B, Herbrecht R. Pharmacokinetic drugdrug interactions with methotrexate in oncology. Expert Rev Clin Pharmacol 2011;4:743–50. [2] Santucci R, Levêque D, Herbrecht R. Cola beverage and delayed elimination of methotrexate. Br J Clin Pharmacol 2010;70:762–4. [3] Dalle J-H, Auvrignon A, Vassal G, Leverger G. Interaction between methotrexate and ciprofloxacin. J Pediatr Hematol/Oncol 2002;24: 321–2. [4] Levêque D, Jehl F. Molecular determinants of fluoroquinolone antibacterial agents pharmacokinetics. Curr Clin Pharmacol 2009;4: 191–7. [5] Sedlacek M, Suriawinata A, Schoolwerth A, et al. Ciprofloxacin crystal nephropathy – a new cause of acute renal failure. Nephrol Dial Transplant 2006;21:2339. [6] Thorsteinsson SB, Bergan T, Oddsdottir S, et al. Crystalluria and ciprofloxacin, influence of urinary pH and hydration. Chemotherapy 1986;32:408–17. [7] Yarlagadda SG, Perazella MA. Drug-induced crystal nephropathy: an update. Exp Opin Drug Saf 2008;7:147–58.
A. Jarfaut a R. Santucci a,∗ D. Levêque a R. Herbrecht b
Lettres à la rédaction / Médecine et maladies infectieuses 43 (2013) 35–41 a
Pharmacy, hôpital de Hautepierre, hôpitaux universitaires de Strasbourg, 67098 Strasbourg, France b Oncology and Hematology Department, hôpital de Hautepierre, hôpitaux universitaires de Strasbourg, 67098 Strasbourg, France ∗ Corresponding
author. E-mail addresses: [email protected] (A. Jarfaut), [email protected] (R. Santucci)
41
Received 6 July 2012 Received in revised form 30 October 2012 Accepted 27 November 2012 Available online 14 January 2013 http://dx.doi.org/10.1016/j.medmal.2012.11.006
39
Severe methotrexate toxicity due to a concomitant administration of ciprofloxacin
Déclaration d’intérêts Les auteurs déclarent ne pas avoir de conflits d’intérêts en relation avec cet article.
Toxicité grave au méthotrexate chez une patiente recevant de la ciprofloxacine
Références 1. Introduction [1] Bottone EJ. Yersinia enterocolitica: overview and epidemiologic correlates. Microbes Infect 1999;1:323–33. [2] Nicolas X, Le Berre R, Ansart S, Tandé D, Lerch C, Garre M. Bactériémie et pneumopathie à Yersinia enterocolitica sérotype 0:3 chez un immunocompétent. Med Mal Infect 2005;35:370–3. [3] Girszyn N, Kerleau JM, Robaday S, Lefebvre, Marie I, Levesque H. Pneumopathie avec bactériémie à Yersinia enterocolitica chez un diabétique porteur de l’antigène HLA-B27. Rev Med Interne 2007;28:882– 4. [4] Mofredj A, Guérin JM, Leibinger F, Masmoudi R. Spontaneous pleural empyema due to Yersinia enterocolitica. South Med J 2003;96:525– 7. [5] Clarridge J, Roberts C, Peters J, Musher D. Sepsis and empyema caused by Yersinia enterocolitica. J Clin Microbiol 1983;17:936–8. [6] Piroth L, Meyer P, Bielefeld P, Besancenot JF. Bactériémie à Yersinia et surcharge en fer. Rev Med Interne 1997;18:932–8. [7] Rano A, Agusti C, Jimenez P, Angrill J, Benito N, Danes C, et al. Pulmonary infiltrates in non-HIV immunocompromised patients: a diagnostic approach using non-invasive and bronchoscopic procedures. Thorax 2001;56:379– 87.
P.-A. Jarrot a R. Mahmoudi a,∗,b J.-L. Novella a,b P. Manckoundia c,d a Service de médecine interne et gérontologie clinique, hôpital Maison-Blanche, centre hospitalier universitaire de Reims, 45, avenue Cognacq-Jay, 51092 Reims cedex, France b Faculté de médecine, EA 3797, université de Reims Champagne-Ardenne, 51092 Reims, France c Service de médecine interne gériatrie, hôpital de Jour, hôpital de Champmaillot, CHU, BP 87909, 2, rue Jules-Violle, 21079 Dijon cedex, France d Inserm/U887, motricité-plasticité : performance, dysfonctionnement, vieillissement et technologies d’optimisation, faculté des sciences du sport, université de Bourgogne, 21078 Dijon, France ∗ Auteur
correspondant. Adresse e-mail : [email protected] (R. Mahmoudi) Rec¸u le 23 aoˆut 2012 Rec¸u sous la forme révisée le 9 octobre 2012 Accepté le 11 octobre 2012 Disponible sur Internet le 10 décembre 2012 http://dx.doi.org/10.1016/j.medmal.2012.10.004
Methotrexate is an antifolate agent used at high dose (i.e., > 1 g/m2 intravenously) in the treatment of some tumors (acute lymphoblastic leukemia, non-Hodgkin lymphomas, osteosarcomas). Antibacterial agents, proton pump inhibitors, and non-steroidal anti-inflammatory agents are known to affect methotrexate elimination [1]. We report a case of unexpected and life-threatening toxicity following administration of high-dose methotrexate in a patient receiving ciprofloxacin. 2. Case report A 28-year-old female patient was hospitalized for a primary mediastinal B-cell non-Hodgkin’s lymphoma. Cure was not achieved after four cycles of R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesin, bleomycin, and prednisone), and the regimen was changed to IVAM (ifosfamide, etoposide, cytarabine, and high-dose methotrexate 3 g/m2 ). High dose methotrexate was infused according to our standard protocol to reduce its toxicity: alkaline load with sodium bicarbonate before initiating the infusion, alkaline hydration, additional 70 mmol of sodium bicarbonate over 15 minutes if urinary pH was lower than 7.5, and intravenous calcium folinate rescue. Urine output and pH were monitored, and methotrexate plasma levels were measured daily using the enzyme-multiplied immunoassay technique (EMIT® ). The first cycle of IVAM was well tolerated with an appropriate elimination of methotrexate within 48 hours. Three weeks later, the patient was hospitalized for the second cycle of IVAM. White blood cells and serum creatinine level (46 mol/L, normal range: 32–85 mol/L) were normal. Hydration, alkalization, and folic acid were given as in cycle 1. The patient presented with fever and chills without any microbiological documentation, and a marked increase in C-reactive protein (138 mg/L) one day before the methotrexate infusion. Intravenous cefotaxime was initiated (1 g three times a day). No source of infection was identified, nevertheless ciprofloxacin, 500 mg twice a day, was given as oral second-line antibiotherapy, 20 hours after methotrexate administration. The other concomitant drug was valacyclovir 500 mg twice a day, for the prevention of Herpes simplex virus and varicella-zoster virus infections. Plasma concentrations of methotrexate were in the expected range 24 and 48 hours after initiating the infusion (3.9 mol/L
40
Lettres à la rédaction / Médecine et maladies infectieuses 43 (2013) 35–41
and 0.8 mol/L, respectively). However, the concentration was slightly higher than expected at 72 hours (observed value of 0.28 mol/L for an expected value below 0.20 mol/L). Four hours after initiating ciprofloxacin, serum creatinine value increased by 41% (65 mol/L). The values were similar on the next day. The patient was nevertheless discharged, with a recommendation to continue ciprofloxacin for three additional days. On day 7, the patient was hospitalized for a febrile pancytopenia (hemoglobin: 9.6 g/dL, white blood cells: 200/L, differential count not performed, platelets: 38,000/L), mucositis, diarrhea, and necrotic skin lesions. The renal function was normal (serum creatinine: 54 mol/L). Blood and urine cultures were sterile. Broad-spectrum antibiotics (piperacillin/ tazobactam, vancomycin, and metronidazole) were initiated in combination with lenograstim, intravenous acyclovir, analgesics, and parenteral nutrition. Hematological toxicity could have been due to other cytotoxic drugs, but the associated symptoms (especially skin lesions) led to the determination of plasma methotrexate level. On day 11, the concentration was 0.10 mol/L (limit of quantification: 0.04 mol/L). In most patients, MTX is not detectable in plasma on day 4. Hyper hydration and folinic acid were started again on the same day. The methotrexate level decreased to 0.06 mol/L on day 13 and was less than 0.04 mol/L on day 16. On day 14, the fever persisted and empirical caspofungin therapy was added to the antibiotics. On day 19, Trichosporon asahii grew in multiple blood cultures and caspofungin was replaced by intravenous voriconazole. Autologous stem cell transplantation was performed because of the severe clinical status and persistent aplasia. Blood cultures became negative 2 days after the initiating voriconazole, and neutrophil count was normal 11 days after transplantation. The patient was discharged 38 days after admission, with an oral voriconazole therapy because of a chronic disseminated Trichosporon infection. 3. Discussion Methotrexate is primarily eliminated by the kidneys and in a lesser part by the liver. Thus, methotrexate clearance is critically dependent on renal function. Delayed methotrexate elimination associated with severe adverse effects may be caused by renal impairment related to insufficient alkaline hydration, acid beverages, or drug-drug interactions [1,2]. The first cycle was well tolerated by our patient and methotrexate was eliminated as expected. The second cycle was characterized by a delayed elimination of methotrexate, despite administrating the same hydration and alkalization procedures, and normal baseline renal function. We suspect that the concomitant administration of ciprofloxacin delayed methotrexate renal elimination and in turn led to severe toxicity. Another explanation for the delayed methotrexate elimination could be renal impairment caused by sepsis. Nevertheless, an author had already reported two cases of delayed methotrexate elimination in children receiving ciprofloxacin concomitantly. But the authors did not suggest any convincing explanation for the interaction mechanism [3]. Various interactions involving methotrexate with antibacterial
agents have been reported in relation with additional antifolate effect (trimethoprim), or delayed elimination (amoxicillin, piperacillin, oxacillin, pristinamycin). The molecular mechanism underlying the interaction with penicillins is probably related to the blockade of the proximal renal organic anion transporters OAT1 and OAT3 by antibacterial agents. Ciprofloxacin is a weak OAT3 inhibitor but has no impact on methotrexate uptake in human kidney cells. The interaction with other transporters located in the kidney is another hypothesis; but such an interaction has never been reported yet [4]. An alternative mechanism for the interaction could be due to the chemical properties of ciprofloxacin and its low solubility at a pH greater than 6.8 [5]. Thorsteinsson et al. reported that the co-administration of ciprofloxacin and bicarbonate resulted in crystalluria in five out of six healthy volunteers, when the urinary pH was greater than 7.3 [6]. Crystalluria may induce calculus formation or oliguria, resulting in acute renal failure [5,7]. The patient had a urinary pH of 8 or more at onset of ciprofloxacin therapy and during the following 2 days, due to standard alkalization given during high-dose methotrexate therapy. 4. Conclusion We suspect that the interaction between methotrexate and ciprofloxacin resulted from a crystallization of ciprofloxacin due to high urinary pH induced by a bicarbonate infusion. We do not recommend administering ciprofloxacin along with high dose methotrexate, because of possible severe adverse effects. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Levêque D, Santucci R, Gourieux B, Herbrecht R. Pharmacokinetic drugdrug interactions with methotrexate in oncology. Expert Rev Clin Pharmacol 2011;4:743–50. [2] Santucci R, Levêque D, Herbrecht R. Cola beverage and delayed elimination of methotrexate. Br J Clin Pharmacol 2010;70:762–4. [3] Dalle J-H, Auvrignon A, Vassal G, Leverger G. Interaction between methotrexate and ciprofloxacin. J Pediatr Hematol/Oncol 2002;24: 321–2. [4] Levêque D, Jehl F. Molecular determinants of fluoroquinolone antibacterial agents pharmacokinetics. Curr Clin Pharmacol 2009;4: 191–7. [5] Sedlacek M, Suriawinata A, Schoolwerth A, et al. Ciprofloxacin crystal nephropathy – a new cause of acute renal failure. Nephrol Dial Transplant 2006;21:2339. [6] Thorsteinsson SB, Bergan T, Oddsdottir S, et al. Crystalluria and ciprofloxacin, influence of urinary pH and hydration. Chemotherapy 1986;32:408–17. [7] Yarlagadda SG, Perazella MA. Drug-induced crystal nephropathy: an update. Exp Opin Drug Saf 2008;7:147–58.
A. Jarfaut a R. Santucci a,∗ D. Levêque a R. Herbrecht b
Lettres à la rédaction / Médecine et maladies infectieuses 43 (2013) 35–41 a
Pharmacy, hôpital de Hautepierre, hôpitaux universitaires de Strasbourg, 67098 Strasbourg, France b Oncology and Hematology Department, hôpital de Hautepierre, hôpitaux universitaires de Strasbourg, 67098 Strasbourg, France ∗ Corresponding
author. E-mail addresses: [email protected] (A. Jarfaut), [email protected] (R. Santucci)
41
Received 6 July 2012 Received in revised form 30 October 2012 Accepted 27 November 2012 Available online 14 January 2013 http://dx.doi.org/10.1016/j.medmal.2012.11.006