Rheumatology Advance Access originally published online on December 6, 2005
Rheumatology 2006 45(3):361-362; doi:10.1093/rheumatology/kei200
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LETTER TO THE EDITOR |
Methotrexate induced neutropenia associated with coprescription of penicillins: serious and under-reported?
Department of Rheumatology, St Helens Hospital, Marshalls Cross Road, St Helens, Merseyside, UK, WA9 3DA
Correspondence to: N. Sathi. Email: Nsathi{at}doctors.org.uk
SIR, We read Lim et al.'s concise report on methotrexate-induced pancytopenia with great interest. Among the predisposing factors they listed were old age, poor nutrition, hypoalbuminaemia, stomatitis and renal impairment [1]. No mention was made of the risks associated with penicillin usage.
Penicillin has been shown to compete with the renal tubular secretion of methotrexate and hence its clearance. This was shown by Williams et al. [2] in vivo and in vitro in rhesus and cynomolgus monkeys. It works by inhibiting the cellular uptake of methotrexate and hence stimulating its efflux. The findings were backed up in Bloom et al.'s work [3] in four patients who received high-dose methotrexate. Reduced renal excretion of methotrexate was demonstrated when penicillins were coprescribed. A total of five cases of methotrexate-induced neutropenia in association with penicillin coprescription have been reported [4, 5]. In four of the cases, who had been treated with low-dose methotrexate, renal impairment was felt to be an associated risk factor. Three of these patients were elderly. Two of the four cases reported by Mayall et al. [5] had methotrexate levels measured, which in both cases were found to be in the toxic range. The other case was in a 16-yr-old patient on high-dose methotrexate.
Of the cases described by Lim et al., we note that five had renal impairment (Patients 1, 13, 19, 20 and 23). Twenty-three out of 25 of the patients reported were over the age of 65. This included Patient 23, who was also on amoxicillin. Interestingly, nine of the patients (Patients 1, 4, 6, 8, 13, 18, 19, 23 and 24) presented with sepsis. Is there any information as to whether they had been treated with penicillin antibiotics before admission to hospital or during the aplastic episode? Mayall et al. [5] felt that patients who were renally impaired were more likely to have prolonged clearance of methotrexate when a penicillin was coprescribed. This, he noted, contributed to the deaths of three of the patients reported in his series. Herrick et al. [6], on the other hand, reported no significant evidence of methotrexate toxicity in 10 patients who were coprescribed flucloxacillin. However, they did not include elderly or renally impaired patients and concentrated on measuring methotrexate levels. It seems further work on a larger scale including renally impaired elderly patients is needed in order to elucidate whether we should all avoid the coprescribing of penicillins and methotrexate.
The authors have declared no conflicts of interest.
References
- Lim AYN, Gaffney K, Scott DGI. Methotrexate-induced pancytopenia: serious and under reported? Our experience of 25 cases in 5 years. Rheumatology 2005;44:1051–5.
[Abstract/Free Full Text] - Williams WM, Chen TS, Huang KC. Effect of penicillin on the renal tubular secretion of methotrexate in the monkey. Cancer Res 1984;44:1913–7.
[Abstract/Free Full Text] - Bloom EJ, Ignoffo RJ, Reis CA, Cadman E. Delayed clearance of methotrexate associated with antibiotics and anti inflammatory agents. Clin Res 1986;34;560A.
- Ronchera CL, Hernandez T, Peris JE et al. Pharmacokinetic interaction between high dose methotrexate and amoxycillin. Ther Drug Monit 1993;15:375–9.[Web of Science][Medline]
- Mayall B, Poggi G, Parkin JD. Neutropenia due to low dose methotrexate therapy for psoriasis and rheumatoid arthritis may be fatal. Med J Aust 1991;155:480–4.[Web of Science][Medline]
- Herrick AL, Grennan DM, Griffen K, Aarons L, Gifford LA. Lack of interaction between flucloxacillin and methotrexate in patients with rheumatoid arthritis. Br J Clin Pharmacol 1996;41:223–7.[Medline]
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