Nephrotoxicity Associated with Low-dose Methotrexate and Outpatient Parenteral Microbial Therapy: A Case Report, Review of the Literature and Pathophysiologic Insights

Benjamin Ramalanjaona¹, Gil Hevroni¹, Samantha Cham², Cameron Page¹, Moro O. Salifu¹ and Samy I. McFarlane^1,

¹Department of Internal Medicine, SUNY-Downstate Health Science University, Brooklyn, New York, United States-11203

²Department of Pharmacy, SUNY-Downstate Health Science University, Brooklyn, New York, United States-11203

Cite this paper

Benjamin Ramalanjaona, Gil Hevroni, Samantha Cham, Cameron Page, Moro O. Salifu and Samy I. McFarlane. Nephrotoxicity Associated with Low-dose Methotrexate and Outpatient Parenteral Microbial Therapy: A Case Report, Review of the Literature and Pathophysiologic Insights. American Journal of Medical Case Reports. 2020; 8(11):400-404. doi: 10.12691/AJMCR-8-11-6

Abstract

Methotrexate (MTX) toxicity can affect multiple organ systems, manifesting as nephrotoxicity, myelosuppression, hepatotoxicity, mucositis, and gastrointestinal upset. Serious adverse events are rare in patients prescribed low-dose methotrexate. We present a case of an 86-year-old female on a weekly dose of oral MTX 12.5 mg for rheumatoid arthritis presenting with painful gingiva and oral bleeding during outpatient antimicrobial therapy (OPAT) for osteomyelitis with vancomycin and piperacillin-tazobactam. She had acute kidney injury (AKI), elevated serum MTX levels, thrombocytopenia, neutropenia, and a vancomycin level three times therapeutic concentration. MTX toxicity was suspected to have been triggered by vancomycin and piperacillin-tazobactam causing AKI and impaired renal clearance of MTX which itself is nephrotoxic. The patient was managed with leucovorin, alkalinized intravenous fluids, and filgrastim injections over a 2-week period. Her renal function continued to be reduced at 5-week outpatient follow-up, far after other markers of toxicity normalized. This case demonstrates the importance of considering potential drug-drug interactions and the need for robust monitoring for OPAT in select groups.

Keywords

outpatient parenteral antimicrobial therapy, anti-folate, methotrexate, nephrotoxicity, monitoring, surveillance

Copyright

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References

[1]	Laupland KB, Valiquette L. Outpatient parenteral antimicrobial therapy. Canadian Journal of Infectious Diseases and Medical Microbiology. 2013; 24(1): 9-11.
[2]	Rucker RW, Harrison GM. Outpatient intravenous medications in the management of cystic fibrosis. Pediatrics. 1974 Sep 1; 54(3): 358-60.
[3]	Norris AH, Shrestha NK, Allison GM, Keller SC, Bhavan KP, Zurlo JJ, Hersh AL, Gorski LA, Bosso JA, Rathore MH, Arrieta A. 2018 Infectious Diseases Society of America clinical practice guideline for the management of outpatient parenteral antimicrobial therapy. Clinical Infectious Diseases. 2018 Nov 13; 68(1): e1-35.
[4]	Anglen LJV, Mandel RM, Nathan RV, Krinsky AH, Luu Q, Bacon AE, et al. Safety and Effectiveness of Outpatient Parenteral Antimicrobial Therapy (OPAT) in the Aged Population. Open Forum Infectious Diseases. 2017; 4(suppl_1).
[5]	Buehrle DJ, Shields RK, Shah N, Shoff C, Sheridan K. Risk factors associated with outpatient parenteral antibiotic therapy program failure among intravenous drug users. InOpen forum infectious diseases 2017 Jul 1 (Vol. 4, No. 3). Oxford University Press.
[6]	Rutter WC, Burgess DR, Talbert JC, Burgess DS. Acute kidney injury in patients treated with vancomycin and piperacillin-tazobactam: a retrospective cohort analysis. Journal of hospital medicine. 2017 Feb; 12(2): 77.
[7]	Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD. Preventing and managing toxicities of high-dose methotrexate. The oncologist. 2016 Dec; 21(12): 1471.
[8]	Malaviya AN, Sharma A, Agarwal D, Kapoor S, Garg S, Sawhney S. Low-dose and high-dose methotrexate are two different drugs in practical terms. International journal of rheumatic diseases. 2010 Oct; 13(4): 288-93.
[9]	van Ede AE, Laan RF, Blom HJ, De Abreu RA, van de Putte LB. Methotrexate in rheumatoid arthritis: An update with focus on mechanisms involved in toxicity. InSeminars in arthritis and rheumatism 1998 Apr 1 (Vol. 27, No. 5, pp. 277-292). WB Saunders.
[10]	Liu L, Liu S, Wang C, Guan W, Zhang Y, Hu W, Zhang L, He Y, Lu J, Li T, Liu X. Folate supplementation for methotrexate therapy in patients with rheumatoid arthritis: a systematic review. JCR: Journal of Clinical Rheumatology. 2019 Aug 1; 25(5): 197-202
[11]	Shaikh N, Sardar M, Raj R, Jariwala P. A rapidly fatal case of low-dose methotrexate toxicity. Case reports in medicine. 2018; 2018.
[12]	Jariwala P, Kumar V, Kothari K, Thakkar S, Umrigar DD. Acute methotrexate toxicity: a fatal condition in two cases of psoriasis. Case reports in dermatological medicine. 2014;2014.
[13]	Affleck A, Goudie A, Smith R. Fatal, incidental, idiopathic pulmonary fibrosis in a patient receiving long-term low-dose methotrexate for psoriasis. Clinical and experimental dermatology. 2019 Jul; 44(5): 591-2.
[14]	Mameli A, Barcellona D, Marongiu F. Fatal cytopenia induced by low-dose methotrexate in elderly with rheumatoid arthritis. identification of risk factors. American journal of therapeutics. 2017 Jan 1; 24(1): e106-7.
[15]	Mori S, Hidaka M, Kawakita T, Hidaka T, Tsuda H, Yoshitama T, Migita K, Ueki Y. Factors associated with myelosuppression related to low-dose methotrexate therapy for inflammatory rheumatic diseases. PLoS One. 2016 Apr 29; 11(4): e0154744.
[16]	Maher RL, Hanlon J, Hajjar ER. Clinical consequences of polypharmacy in elderly. Expert opinion on drug safety. 2014 Jan 1; 13(1): 57-65.
[17]	Felson DT. The effect of age and renal function of the efficacy and toxicity of methotrexate in rheumatoid arthritis, rheumatoid arthritis clinical trial archive group. J Rheumatol. 1995; 22: 218-23.
[18]	Gomes DM, Smotherman C, Birch A, Dupree L, Della Vecchia BJ, Kraemer DF, Jankowski CA. Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin-tazobactam or cefepime. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2014 Jul; 34(7): 662-9.
[19]	Baldwin DS, Levine BB, McCluskey RT, Gallo GR. Renal failure and interstitial nephritis due to penicillin and methicillin. New England Journal of Medicine. 1968 Dec 5; 279(23): 1245-52.
[20]	Liu P, Tepperman BS, Logan AG. Acute renal failure induced by semi-synthetic penicillins. Canadian Family Physician. 1981 Mar; 27: 507.
[21]	Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. The oncologist. 2006 Jun 1; 11(6): 694-703.
[22]	Jaspal S, Dimattia M, Bruno C, Lee DH. Factors Associated With Failure of Outpatient Parenteral Antibiotic Therapy (OPAT). InOpen Forum Infectious Diseases 2015 Dec 1 (Vol. 2, No. suppl_1). Oxford University Press.
[23]	Yan M, Elligsen M, Simor AE, Daneman N. Patient characteristics and outcomes of outpatient parenteral antimicrobial therapy: a retrospective study. Canadian Journal of Infectious Diseases and Medical Microbiology. 2016; 2016.
[24]	Keller SC, Williams D, Gavgani M, Hirsch D, Adamovich J, Hohl D, Gurses AP, Cosgrove SE. Rates of and risk factors for adverse drug events in outpatient parenteral antimicrobial therapy. Clinical Infectious Diseases. 2018 Jan 1; 66(1): 11-9.