Methotrexate and trimethoprim: why this antibiotic combination is avoided

Methotrexate is an immunosuppressant given once weekly, according to SPS. Low doses, below 25mg a week, are used for conditions including rheumatoid arthritis and psoriasis, and higher doses are used for cancer. The NHS says it treats rheumatoid arthritis, psoriasis, Crohn's disease and other autoimmune conditions. SPS notes that methotrexate use can be associated with serious side effects, including blood disorders, liver cirrhosis and lung toxicity, which is why it involves regular monitoring and is prescribed by specialists, for example rheumatologists.

Trimethoprim is an antibiotic. The NHS describes it as used to treat bacterial infections including urinary tract infections such as cystitis. Co-trimoxazole is a combination antibiotic containing trimethoprim and sulfamethoxazole, as SPS explains. Because urinary and chest infections are common, a person on methotrexate can easily be offered one of these antibiotics by a prescriber who does not know about the methotrexate, for example in an out-of-hours or walk-in setting.

SPS says taking methotrexate with trimethoprim or co-trimoxazole can increase the risk of bone marrow suppression. The mechanism is not fully understood but may be due to additive antifolate effects, meaning both medicines interfere with folate-dependent processes in cells that divide quickly, such as blood cells. The sulfamethoxazole in co-trimoxazole can also increase the amount of free methotrexate in the blood, either by competing for protein binding or by reducing clearance through the kidneys.

The Scottish guidance adds that the combination increases the risk of haematological toxicity, bone marrow depression and kidney damage, and describes the severity as severe, with some cases fatal even after short courses. It stresses that effects can appear late: SPS says the interaction may be delayed, and the Scottish guidance says that adverse reactions may persist for weeks, even over 2 months, after the antibiotic course has finished.

Bone marrow suppression means the bone marrow makes too few blood cells. A shortage of white cells causes infections and fever, a shortage of platelets causes bruising and bleeding, and a shortage of red cells causes tiredness and breathlessness.

SPS says people should be counselled to report signs of myelosuppression, such as sore throat, mouth ulcers, fever or chills, unexplained bruising or bleeding, and shortness of breath. The NHS side effects page for methotrexate similarly says to tell your doctor or call 111 immediately for a high temperature or feeling hot, cold or shivery, muscle aches or sore throat, which may be signs of infection, and for bleeding gums, blood in pee, vomiting blood or unexplained bruising, which may be signs of a blood disorder.

• Sore throat, mouth ulcers or a high temperature.

• Chills or feeling hot, cold or shivery.

• Unexplained bruising, bleeding gums or blood in pee.

• New breathlessness, or a persistent cough or chest pain.

• Swollen ankles or passing much less urine than usual.

The NHS says there are many medicines that affect the way methotrexate works, and that you should always show your patient card to healthcare professionals who may not know about your methotrexate treatment, to alert them to your once-weekly dose. It lists co-trimoxazole, trimethoprim and other antibiotics among medicines to tell your doctor about, along with NSAIDs, diuretics, epilepsy medicines, theophylline and medicines for indigestion such as omeprazole.

Practically, tell every prescriber, including GPs, out-of-hours clinicians, dentists and pharmacists, that you take methotrexate before accepting an antibiotic, and ask them to check. SPS says that prescribers should consult a local microbiologist to consider alternative antibiotics. The NHS trimethoprim page also lists methotrexate among medicines to check with a pharmacist or doctor about before taking trimethoprim.

Do not stop or change your methotrexate yourself. The NHS says to follow your doctor's instructions. SPS notes that in the presence of a severe infection some people on stable methotrexate can miss doses while taking an antibiotic and restart once they feel better, but this is a decision for the specialist team.

Sometimes there is no suitable alternative. SPS says that if concurrent use cannot be avoided, the person should be counselled to report signs of myelosuppression, the full blood count should be monitored frequently, and consideration given to additional monitoring above routine for at least 2 months, noting that this period is based on a case report of bone marrow hypoplasia occurring more than 2 months after a 10-day course of co-trimoxazole.

The Scottish guidance adds that kidney function should be considered and regular folate supplementation continued or started, and that the advice does not apply to co-trimoxazole used as prophylaxis against Pneumocystis pneumonia, where specialist advice should be sought. It also notes that if the combination has already occurred, methotrexate should be restarted only once the person is clinically stable and blood tests have returned to baseline.

Trimethoprim is not the only concern. SPS covers NSAIDs, which can increase the risk of renal toxicity and methotrexate toxicity, proton pump inhibitors, penicillins such as amoxicillin, antiseizure medicines, fluconazole, statins and others, and says each should be reviewed case by case. For penicillins it suggests that a short course may be used with caution and monitoring for signs of toxicity such as sore throat, bruising and bleeding.

The NHS also says that if you take methotrexate you should not take folic acid or vitamin products containing folic acid in addition to any prescribed by your doctor, and that there is not enough information to say whether other herbal remedies or supplements are safe with it.

If you are on methotrexate and have just been prescribed trimethoprim or co-trimoxazole, ask a pharmacist or call NHS 111 for advice before taking it, particularly out of hours. If you have already taken it and have a fever, sore throat, mouth ulcers, bruising or bleeding, call NHS 111 or your specialist team straight away. If you are very breathless, confused or unwell, call 999 or go to A&E.

The NHS also says to contact 111 for advice now if you have taken more than your prescribed dose of methotrexate or have taken it daily instead of weekly, because taking too much can cause serious side effects and in some cases can be fatal.

The same advice applies wherever you are treated. Private clinics, pharmacies and online prescribing services may not have access to your NHS records, so it is particularly important to say that you take methotrexate and to carry your patient card. Your GP surgery or specialist nurse can help if you are unsure whether a medicine is safe.