Medicines Q&As
Q&A 386.1
What is the clinical significance of the interaction between
methotrexate and penicillins?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Date Written: 12th October 2011
Background
Methotrexate (MTX) is an immunomodulatory drug used for a number of conditions including
rheumatoid arthritis, cancer, and psoriasis. Its use may be associated with a number of serious side
effects, including blood dyscrasias, liver cirrhosis and pulmonary toxicity1.
Penicillins are a widely used group of broad spectrum antibiotics which may interact with
methotrexate1. The interaction does not, however, appear on the Summary of Product Characteristics
for MTX2. Many patients who are taking MTX will also require antibacterial therapy with penicillins at
some point in their lives3.
Answer
Mechanism
MTX is cleared by the kidney, through tubular secretions and glomerular filtration4 . Penicillins are
weak acids which are capable of competing with methotrexate within the tubules of the kidney,
leading to reduced tubular secretion and therefore retention of MTX. Increased MTX levels can in turn
predispose to toxicity4. Evidence for this mechanism is mostly limited to animal studies and human
case reports5,6,7 and its existence has also been disputed3,8. Penicillins do not appear to interfere with
the glomerular filtration aspect of MTX clearance.
Onset of methotrexate toxicity following initiation of a penicillin may be delayed4.
Evidence
Amoxicillin
One case report describes a 16 year old given high dose methotrexate IV for osteogenic sarcoma.
Co-administration of amoxicillin resulted in a 56% reduction in excretion of methotrexate, leading to a
prolonged increase in methotrexate levels. The patient suffered from MTX toxicity consisting of
nausea, vomiting, renal failure, myelosuppression, fever, and dermatologic abnormalities 8,9.
A case series reported by Lim et al looked at patients who had suffered from MTX-induced
pancytopenia. One of the patients included (who was taking a dose of 10mg weekly MTX) had
initiated a course of amoxicillin on the day of admission to hospital with symptoms of sepsis, malaena,
and mucositis. The patient died due to a colonic haemorrhage. The authors of the paper do not
attribute the development of pancytopenia to an interaction, but a follow-up letter to the authors
suggests this may be a cause6,10,11.
Oral amoxicillin for 7 days was given to a patient taking a 7.5mg weekly dose of MTX. The patient
developed neutropenia and thrombocytopenia, which was thought to be due to reduced MTX
clearance. The patient died despite folinic acid rescue therapy. The patient was also given IV
flucloxacillin, and IV benzylpenicillin8,12.
Neutropenia and thrombocytopenia were also observed in a patient who was prescribed co-amoxiclav
(amoxicillin and clavulanic acid) for psoriasis8,12.
Flucloxacillin
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Medicines Q&As
A patient receiving MTX 5mg weekly for rheumatoid arthritis suffered suspected MTX-induced
pneumonitis following a course of flucloxacillin. This prompted the authors to conduct a study in 10
patients with RA who were given flucloxacillin, which suggested no clinically significant
pharmacokinetic effect on MTX levels. This small study is limited by the fact that it looks only at
pharmacokinetic factors, and the limited number of patients recruited to the study, who were all being
treated for rheumatoid arthritis3.
A patient administered both flucloxacillin and piperacillin IV died as a result of neutropenia and
thrombocytopenia thought to be due to MTX toxicity. The MTX dose of 2.5mg three times a week was
being given for psoriasis12.
Phenoxymethylpenicillin
A patient receiving 50mg IV MTX weekly for dermatomyositis experienced MTX toxicity (including
leukopenia, thrombocytopenia, deranged LFTs, and skin ulcerations) within a week of initiation of
starting phenoxymethylpenicillin. The patient was treated with folinic acid and fluid replacement. This
patient had also been coprescribed furosemide. Attribution of the cause of toxicity is postulated to be
due to the interaction between both penicillin and furosemide, although it is acknowledged that the
patient had also received his dose of MTX two days earlier than scheduled, which could have been a
contributory factor8,13.
Antipseudomonal penicillins
A 50 year old female being treated with an intrathecal high dose MTX- containing regime for Burkitt’s
lymphoma experienced a prolonged increase in MTX levels which resolved only on discontinuation of
piperacillin/tazobactam. During a later cycle of the MTX- containing chemotherapy,
Piperacillin/tazobactam was not administered, and MTX levels reduced14.
A 67% reduction in methotrexate clearance was observed in a patient receiving a high dose IV course
of MTX for chronic myeloid leukaemia. The patient required prolonged folinic acid rescue8.
Rick Factors:
Not all patients who use penicillins concurrently with MTX are affected by this interaction. So far, there
is no way of predicting who it may occur in, as current available evidence does not suggest any strong
risk factors for developing the interaction. Reports of symptomatic interactions are not limited to high
dose methotrexate therapy8. Theoretically, patients with a degree of existing renal impairment may be
more susceptible to the interaction10.
Management
Patients who require a penicillin antibiotic whilst taking methotrexate therapy should be closely
monitored for the duration of the treatment. One resource suggests measuring platelets and white cell
counts twice weekly for two weeks. If methotrexate toxicity is suspected, methotrexate levels should
be performed, and folinic acid rescue should be available where required8. Another resource suggests
considering a dose reduction and monitoring serum methotrexate levels4.
Patients should be counselled to look out for adverse effects of methotrexate such as sore throat,
infection, leukopenia, thrombocytopenia, and skin ulcerations1,4.
Summary
The evidence for an interaction between methotrexate and penicillins is limited to case reports and
animal studies. So far, there is no conclusive evidence that any particular patient group is more at risk
of an interaction occurring, and it does not appear to be dose related.
If concurrent use of MTX and a penicillin is required, patients should be carefully monitored during
treatment. Monitoring may include measuring platelets and blood counts twice weekly for two weeks,
with methotrexate levels being taken if the patient becomes symptomatic.
From the National Electronic Library for Medicines. www.nelm.nhs.uk
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Medicines Q&As
Limitations
There have been no large, controlled studies in humans to determine the mechanism or clinical effect
of this potential interaction, so information is mainly limited to animal studies and case reports. This
makes it difficult to estimate incidence and likelihood of the interaction. Only evidence relating to UK
licensed penicillin antibiotics have been included in this Q&A.
Disclaimer
 Medicines Q&As are intended for healthcare professionals and reflect UK practice.
 Each Q&A relates only to the clinical scenario described.
 Q&As are believed to accurately reflect the medical literature at the time of writing.
 The authors of Medicines Q&As are not responsible for the content of external websites and
links are made available solely to indicate their potential usefulness to users of NeLM. You
must use your judgement to determine the accuracy and relevance of the information they
contain.
 See NeLM for full disclaimer.
Quality Assurance
Prepared by
Hayley Johnson, Regional Drug and Therapeutics Centre
Date Prepared
12th October 2011
Checked by
Vincent Cassidy, Regional Drug and Therapeutics Centre
Date of check
23rd November 2011
Search strategy
Embase
METHOTREXATE/it [it=Drug Interaction]; AND [*AMOXICILLIN/ OR *AMOXICILLIN PLUS
CLAVULANIC ACID/ OR *AMPICILLIN/ OR *BENZATHINE PENICILLIN/ OR *BENZATHINE
PENICILLIN V/ OR *FLUCLOXACILLIN/ OR *PENICILLIN G/ OR *PENICILLIN V/ OR
*PIPERACILLIN/ OR *TICARCILLIN/]
Medline (“cut and paste” whole search strategy)
*METHOTREXATE/ AND [*PENICILLIN G/ OR *PENICILLIN V/ OR *FLOXACILLIN/ OR
TEMOCILLIN.af; OR *AMOXICILLIN/ OR *AMPICILLIN/ OR *AMOXICILLIN-POTASSIUM
CLAVULANATE COMBINATION/ OR CO-FLUAMPICIL.af OR *PIPERACILLIN/ OR *TICARCILLIN/
OR PIVMECILLINAM.af;]
.
In-house database/ resources
eBNF 63
Micromedex
Medicines Complete
References
1
Joint Formulary Committee. British National Formulary 62 ed. London : British Medical Association
and Royal Pharmaceutical Society of Great Britain; 2011 Accessed online via Medicines Complete
http://www.medicinescomplete.com/mc/bnf/current/index.htm on 12.10.2011
From the National Electronic Library for Medicines. www.nelm.nhs.uk
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Medicines Q&As
Summary of Product Characteristics – Maxtrex (methotrexate). Pharmacia Ltd. Accessed via
http://www.medicines.org.uk/EMC/medicine/6003/SPC/Maxtrex+Tablets+2.5+mg/ on 12/10/2011
[date of revision of the text Aug 2008, last updated on the eMC: 24/09/2008]
3 Herrick AL, Greenan DM, Griffen K et al. Lack of Interaction between flucloxacillin and methotrexate
in patients with rheumatoid arthritis. Br J Clin Pharmacol 1996; 41: 223-227
4 DRUGDEX®System: Methotrexate. In: Klasco RK (Ed): DRUGDEX® System (electronic version).
Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com/.
Accessed on 12/10/2011
5 Williams WM, Chen TS and Huang KC. Effect of penicillin on the renal tubular secretion of
methotrexate in the monkey. Cancer Res 1984; 44: 1913-1917
6 Sathi N, Ackah J, and Dawson J. Methotrexate induced neutropenia associated with coprescription
of penicillins: serious and under-reported? Rheumatology 2006; 45: 362-363
7 Takeda M, Khamdang S, Narikawa S et al. Characterizastion of methotrexate transport and its drug
interactions with human organic anion transporters. Journal of Pharmacology and Experimental
Therapeutics 2002; 302(2) 666-671.
8 Baxter K (ed), Stockley’s Drug Interactions. [online] London: Pharmaceutical Press. Accessed via
www.medcinescomplete.com on 12/10/2011
9 Ronchera CL, Hernandez T, Peris JE et al. Pharmacokinetic interaction between high dose
methotrexate and amoxicillin. Ther Drug Monit. 1993 Oct;15(5):375-9.
10 Lim AYN, Gaffney K, and Scott DGI. Methotrexate-induced pancytopenia: serious and underreported? Our experience of 25 cases in 5 years. Rheumatology 2005; 44: 1051-1055.
11 Lim, AYN, Gaffney K, Scott DGI. Methotrexate-induced pancytopenia: serious and under reported?
Our experience of 25 cases in 5 years: reply. Rheumatology 2006; 45: 363-364
12 Mayall B, Poggi G, and Parkin JD. Neutropenia due to low-dose methotrexate therapy for psoriasis
and rheumatoid arthritis may be fatal. Med J Aust. 1991 Oct 7;155(7):480-4.
13 Nierenberg DW and Mamelok RD. Toxic reaction to methotrexate in a patient receiving penicillin
and furoseide: A possible interaction. Arch Dermatol 1983; 119: 449-450
14 Zarychanski R, Wlodarczyk K, Ariano R et al. Pharmacokinetic interaction between methotrexate
and piperacillin/tazobactam resulting in prolonged toxic concentrations of methotrexate. Journal of
Antimicrobial Chemotherapy 2006. 58 (1): 228-230.
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From the National Electronic Library for Medicines. www.nelm.nhs.uk
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