Methotrexate with Dicloxacillin Interaction Details

Brand Names Associated with Methotrexate

Brand Names Associated with Dicloxacillin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 17, 2023

Interaction Effect

Increased methotrexate exposure, an increased risk of methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy

Interaction Summary

Methotrexate toxicity has been reported in several patients taking a variety of penicillins. Methotrexate is renally eliminated through both tubular secretion and glomerular filtration  and penicillins interfere with the renal tubular secretion of methotrexate . Therefore, use caution when coadministering methotrexate and dicloxacillin as this may increase methotrexate plasma concentrations, prolong methotrexate exposure, and increase the risk of hematologic and gastrointestinal toxicities . In some cases, the coadministration of methotrexate with oral penicillin antibiotics like dicloxacillin may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate . If concurrent use is required, carefully monitor patients  for methotrexate adverse reactions .

Severity

Major

Onset

Delayed

Evidence

Probable

How To Manage Interaction

The concurrent use of methotrexate and penicillins, including dicloxacillin, may increase methotrexate plasma concentrations, prolong methotrexate exposure, and increase the risk of hematologic and gastrointestinal toxicities and should be undertaken with caution. In some cases, the coadministration of methotrexate with oral penicillin antibiotics like dicloxacillin may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate . If concomitant use is required, carefully monitor patients  for methotrexate adverse reactions .

Mechanism Of Interaction

Decreased methotrexate renal clearance due to competition for tubular secretion

Literature Reports

A) An 18-year-old man experienced neurotoxicity and renal failure following coadministration of high-doses of methotrexate and piperacillin/tazobactam. He received 5 doses of piperacillin/tazobactam 4.5 g for a urinary tract infection in conjunction with methotrexate for osteosarcoma. Adjuvant treatment with methotrexate 4 weeks after surgery during course 1 was uneventful, however during the second course of methotrexate, the 24-hour post-infusion concentration rose to 75 mcmol/L, which was 10 times the expected level for leucovorin rescue. He experienced double vision and non-oliguric renal failure. Neurologic symptoms and renal function improved with intensified leucovorin rescue and hyperhydration. Piperacillin/tazobactam was discontinued and the patient successfully tolerated 2 more cycles of high-dose methotrexate without sequelae .

B) In one study, four of five low-dose methotrexate patients received penicillins prior to or shortly after admission to the hospital. Methotrexate clearances were probably reduced sufficiently by concomitant therapy with the penicillins, resulting in neutropenia. Three of the reported patients died, while the other two experienced lengthy recovery periods. Penicillins that were administered to these five patients included amoxicillin, amoxicillin with clavulanic acid, piperacillin, piperacillin in combination with flucloxacillin, and flucloxacillin in combination with benzylpenicillin. It was proposed that the penicillins, which are weak organic acids, competitively inhibited active tubular secretion of methotrexate, resulting in toxic methotrexate serum concentrations .

C) A 15-year-old female with osteogenic sarcoma received two courses of high-dose methotrexate (12 g/m(2)) 14 days apart. Leucovorin rescue at 15 mg/m(2) was administered during both methotrexate courses. During the first course, the patient also received empiric therapy with mezlocillin (330 mg/kg daily) and gentamicin (7.5 mg/kg daily). The patient experienced significantly more gastrointestinal toxicity, despite antiemetic therapy, during the first course of methotrexate. Methotrexate serum concentrations were monitored, and showed that terminal methotrexate elimination was 27.2 hours during the first course of treatment, when mezlocillin was also being administered, and only 10.1 hours during the second course. The authors suggested that if methotrexate elimination is indeed reduced by mezlocillin, then the concurrent use of these two drugs would require extensive monitoring of methotrexate concentrations and leucovorin doses may need to be increased and administered for longer periods of time .

D) A 47-year-old man experienced methotrexate toxicity within 1 week of adding furosemide and penicillin to weekly methotrexate in the management of dermatomyositis. He was receiving IV methotrexate 50 mg weekly, with a white blood cell (WBC) count stabilized in the 4000/mm(3)-range, when furosemide 40 mg every other day and oral penicillin 250 mg every other day were added for mild fluid retention and mild cellulitis, respectively. Within 1 week, the patient experienced skin ulcerations, mouth ulcers, fatigue, cough, fever, and rigors. His WBC count fell to 700/mm(3) and he developed staphylococcal sepsis. The authors postulated that the renal clearance of methotrexate was reduced by the presence of furosemide and penicillin competing for tubular secretion .

E) A 16-year-old boy with osteogenic sarcoma received 10 cycles of high-dose methotrexate [8 g/m(2)]. During cycle 10, amoxicillin 1 g every 6 hours was started 6 hours after the initiation of the methotrexate infusion and was discontinued after 6 doses. When compared to the first 9 cycles, significant differences for total plasma clearance, mean residence time, and distribution half-life of methotrexate were noted during the tenth cycle. High methotrexate plasma levels persisted for at least 8 days, probably as a result of reduced renal excretion as a consequence of methotrexate-induced acute renal failure .

F) A 15-year-old girl with osteogenic sarcoma received 2 courses of high-dose methotrexate [12 g/m(2)], with leucovorin rescue [15 mg/m(2)], 14 days apart. During the first course, she also received empiric mezlocillin (330 mg/kg daily) and gentamicin (7.5 mg/kg daily). The patient experienced significantly more gastrointestinal toxicity during the first course, despite antiemetic therapy. Methotrexate serum concentrations were monitored; the methotrexate t(1/2) was 27.2 hours during the first course of treatment, when mezlocillin was also being administered, and only 10.1 hours during the second course. The authors suggested the concurrent use of mezlocillin and methotrexate would require extensive monitoring of methotrexate concentrations and leucovorin doses may need to be increased and administered for longer periods of time .

G) Four of 5 low-dose methotrexate patients reported received penicillins prior to or shortly after admission to the hospital. Methotrexate clearances were probably reduced sufficiently by concomitant therapy with the penicillins, resulting in neutropenia. Three of the reported patients died, while the other 2 experienced lengthy recovery periods. Penicillins that were administered to these 5 patients included amoxicillin, amoxicillin/clavulanic acid, piperacillin, piperacillin/flucloxacillin, and flucloxacillin/benzylpenicillin. It was proposed that the penicillins, which are weak organic acids, competitively inhibited active tubular secretion of methotrexate, resulting in toxic methotrexate serum concentrations .

Methotrexate Overview

• Methotrexate is used to treat severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body) that cannot be controlled by other treatments. Methotrexate is also used along with rest, physical therapy, and sometimes other medications to treat severe active rheumatoid arthritis (RA; a condition in which the body attacks its own joints, causing pain, swelling, and loss of function) that cannot be controlled by certain other medications. Methotrexate is also used to treat certain types of cancer including cancers that begin in the tissues that form around a fertilized egg in the uterus, breast cancer, lung cancer, certain cancers of the head and neck, certain types of lymphoma, and leukemia (cancer that begins in the white blood cells). Methotrexate is in a class of medications called antimetabolites. Methotrexate treats cancer by slowing the growth of cancer cells. Methotrexate treats psoriasis by slowing the growth of skin cells to stop scales from forming. Methotrexate may treat rheumatoid arthritis by decreasing the activity of the immune system.

Dicloxacillin Overview

• Dicloxacillin is used to treat infections caused by certain types of bacteria. Dicloxacillin is in a class of medications called penicillins. It works by killing bacteria.

• Antibiotics such as dicloxacillin will not work for colds, flu, or other viral infections. Using antibiotics when they are not needed increases your risk of getting an infection later that resists antibiotic treatment.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.