Effect of ceftriaxone and cefepime on high-dose methotrexate clearance

Design

Case presentation

A 24-year-old male weighing 51 kg with osteosarcoma of the jaw was currently receiving high-dose methotrexate, doxorubicin, and cisplatin (MAP) chemotherapy. Methotrexate 19 g intravenously (IV) over 4 hours was infused on weeks 4, 5, 10, and 11, with 18 g IV given on weeks 16 and 17. Serum methotrexate levels were drawn every 24 hours after completion of methotrexate infusion or until levels were less than 0.1 micromol/L. Leucovorin 25 mg by mouth every 6 hours was initiated 24 hours after the start of methotrexate infusion. The patient was also receiving amlodipine, magnesium oxide, methadone, morphine, nortriptyline, promethazine as needed, ondansetron as needed, rivaroxaban, and zolpidem as needed.

After 3 weeks, the patient was hospitalized for a peripherally inserted catheter-induced venous thrombosis along with oxacillin susceptible Staphylococcus aureus bacteremia. He was treated with ceftriaxone for six weeks, which was completed during week 8. The patient was hospitalized due to neutropenic fever when scheduled to receive his week 9 high-dose methotrexate, and the methotrexate was delayed to week 10. On week 16, he was admitted for methotrexate therapy and was diagnosed with Pseudomonas aeruginosa pneumonia and was started on cefepime therapy. He received his week 17 high-dose methotrexate concurrently with cefepime and was later discharged to continue cefepime therapy at home. After 17 weeks of MAP, the patient underwent successful surgical operation on his neck mass without recurrence at three months.

Overall, there were determined to be no observable differences in the clearance of methotrexate, methotrexate serum concentrations, or serum creatinine between the weeks the patient had no antibiotic (weeks 10, 11, and 16), ceftriaxone (weeks 4 and 5), and cefepime (week 17).

Study Author Conclusions

In the observation of this patient, the clearance of methotrexate does not seem to be clinically affected by concomitant ceftriaxone or cefepime. Methotrexate is mainly secreted by organic anion transporter 3 (OAT3), and the ceftriaxone should not interfere significantly with OAT3 based on its lack of interaction with probenecid. The extent of interaction of other cephalosporins with methotrexate will theoretically depend on the extent of each drug’s affinity for OAT3 and future animal studies or case reports are needed to determine the extent of this interaction.

Two cases of severe neutropenia in patients on low-dose methotrexate and ceftriaxone

Design

Case presentation 1

A 69-year-old, 116-kg man with psoriatic arthritis presented with new swelling and pain in his right knee. His medical history also included hyperlipidemia, gastroesophageal reflux disease, and degenerative joint disease. Additionally, he had undergone right total knee arthroplasty due to complications from prosthetic joint infection (PJI) five years prior. Despite recurrent infections necessitating multiple arthroplasty revisions and treatment with various antimicrobials such as vancomycin, ceftriaxone, ampicillin, nafcillin, ciprofloxacin, and levofloxacin, his condition persisted. Methotrexate 10 mg, which he took on Wednesdays and Saturdays, was intermittently paused during treatment. However, he eventually achieved suppression of Escherichia coli infection with levofloxacin 500 mg orally daily.

Post-surgery, he was started on vancomycin 15 mg/kg intravenously (IV) Q12H and ertapenem 1 g IV Q24H. However, on postoperative day (POD) 1, he developed shaking chills and fever, prompting a change in his antibiotic regimen to piperacillin-tazobactam 3.375 g intravenously Q6H due to the possibility of aspiration pneumonia. By POD 4, he was afebrile and stable. He opted to hold his usual methotrexate dose that day and was switched to ceftriaxone 2 g every 24 hours for 6 weeks and metronidazole 500 mg orally TID for 7 days. Aside from this, no other changes were made to his medications at discharge. 

On POD 8, outpatient laboratory tests showed normal results, allowing the patient to resume oral methotrexate. However, by POD 14, after receiving 12 doses of ceftriaxone and 3 doses of oral methotrexate, the patient's absolute neutrophil count (ANC) dropped significantly from 1,800 × 10⁶/L to 300 × 10⁶/L. Consequently, ceftriaxone and methotrexate were discontinued, and the patient was switched to daptomycin. Despite this change, the patient remained profoundly neutropenic with an ANC of 0, necessitating two doses of granulocyte colony-stimulating factor (G-CSF) for recovery. Throughout this period, the patient's serum creatinine concentration decreased from 1.2 mg/dL to 0.93 mg/dL by POD 19, while serum alanine transaminase concentration ranged from 13–30 IU/L. After 14 days of treatment with daptomycin and two doses of G-CSF, the patient's ANC recovered, allowing for the restart of methotrexate therapy at a dose of 10 mg orally twice weekly. Although an expected fluctuation in ANC occurred upon resumption of methotrexate, the patient did not experience neutropenia again.

Case presentation 2

A 54-year-old, 88-kg man with unspecified inflammatory arthritis for 10 years presented with shoulder pain. The patient had been on chronic immunosuppression with methotrexate 25 mg orally weekly, prednisone 2.5 mg orally daily, and hydroxychloroquine 200 mg orally twice daily, achieving good symptomatic control. His other home medications included diazepam as needed for anxiety, folic acid 1 mg BID, ibuprofen and hydrocodone-acetaminophen as needed for pain relief, omeprazole 20 mg daily, sulindac 200 mg BID, acetaminophen as needed for pain, and venlafaxine daily. Upon presentation, he was diagnosed with adhesive capsulitis and had undergone arthroscopic capsular release approximately 7 months prior. However, he subsequently developed a periarticular fluid collection, which tested positive for methicillin-sensitive Staphylococcus aureus, raising concerns for septic arthritis. Consequently, his methotrexate was discontinued, and he commenced outpatient vancomycin 1,750 mg IV Q12H and ceftriaxone 2 g IV Q24H as per instructions from his home care providers.

The patient was admitted to the institution for further treatment, with methotrexate being on hold for 3 weeks at that time. Suspecting subacute osteomyelitis of the humeral head, he underwent resection of the native joint with implantation of an antibiotic-impregnated spacer. Perioperative prophylaxis included cefazolin 2 g IV Q8H, transitioning to ceftriaxone 2 g IV Q24H for 6 weeks postoperatively due to prior growth of methicillin-sensitive Staphylococcus aureus and intraoperative cultures showing growth of Cutibacterium (Propionibacterium) acnes. There were no other major changes to his medications. On POD 1, his baseline serum creatinine concentration was 0.7 mg/dL, and it remained stable, not exceeding 0.73 mg/dL throughout the next month of weekly laboratory tests. His laboratory test results remained stable during the first 2 weeks of ceftriaxone therapy, prompting the decision to restart his home dosage of methotrexate. However, five days after initiating methotrexate, his ANC dropped from 1,510 × 10⁶ /L to 430 × 10⁶/L, and his white blood cell count (WBC) decreased from 4.17 × 10⁹/L to 3.33 × 10⁹/L. A methotrexate concentration test performed 8 days after the last dose showed detectable levels at 0.04 micromol/L. Consequently, methotrexate, prednisone, and ceftriaxone were stopped, and the patient was initiated on daptomycin 500 mg IV daily.

Two days later, his ANC increased to 1,380 × 10⁶/L, and his WBC returned to 4.18 × 10⁹/L. Following ANC recovery, he transitioned from daptomycin to ertapenem 1 g IV Q24H and completed 6 weeks of IV antibiotics. Methotrexate was restarted without adverse effects on ANC or WBC count. The patient continued on methotrexate, hydrochloroquine, and prednisone. After an observation period without antibiotics, he successfully underwent primary total shoulder arthroplasty.

Study Author Conclusions

Two patients receiving ceftriaxone therapy in the setting of a joint infection developed profound neutropenia after resuming oral methotrexate therapy for inflammatory arthritis.

Critique 

The authors suggest a potential mechanism of interaction between methotrexate and ceftriaxone, which could involve competition between the two drugs at the OAT3 transporter in the kidneys or protein displacement of methotrexate by ceftriaxone. However, whether this specific mechanism is responsible for the observed effects in the two patients' cases remains unknown.

Methotrexate-induced acute kidney injury in patients with hematological malignancies: three case reports with literature review

Design

Case presentation

One patient within the case series of reported methotrexate-induced acute kidney injuries, a 72-year-old female, was diagnosed with primary central nervous system lymphoma 1 month prior to receiving chemotherapy. Induction chemotherapy, which included methotrexate 2 g/m², was initiated 2 weeks prior to the occurrence of high-dose methotrexate toxicity and led to a decrease in tumor size. Prior to the second course of therapy, the patient developed a urinary tract infection, which was treated with ceftriaxone 1 g once daily.

During the second course of therapy, the patient's serum creatinine (Cr) increased to 2.4 mg/dL, and serum methotrexate concentration was 7.8 nmol/mL, however, her creatinine was 0.51 mg/dL on day 0 and urinary volume on day 1 was 4,050 mL, with no urinary abnormalities noted. Blood tests revealed serum creatine phosphokinase of 20 IU/L, blood urea nitrogen (BUN) of 22 mg/dL (BUN/Cr ratio of 10.8), and uric acid of 6.3 mg/dL on day 2. Plasma exchange with fresh frozen plasma was performed four times and with 5% albumin three times; hemodialysis was performed four times.

The patient experienced other complications induced by high-dose methotrexate, including pancytopenia, and developed a fever during blood purification therapy. The patient was subsequently treated with antibiotics again, and her serum methotrexate concentrations could not be easily decreased below 0.5 nmol/L, thus, plasma exchange was performed repeatedly. Despite intensive therapy, the patient's condition continued to worsen owing to aggravation of lymphoma. The patient was eventually transferred to hospice.

Study Author Conclusions

Here, we report three cases of high-dose-methotrexate-induced renal failure in patients with hematological malignancies. Because prolonged elevation of serum methotrexate concentrations will damage cells, methotrexate should be eliminated and prompt recognition and effective treatment are essential in patients undergoing therapy who experience numerous complications. Although the efficacy of methotrexate elimination provided by the various modalities remains unknown, the use of combined methods, such as hemodialysis and plasma exchange, appears superior and desirable.

Critique

While acute kidney injury developed in this patient who concomitantly received ceftriaxone while on methotrexate therapy, a potential interaction was not addressed. The primary focus of this report was to describe the development of AKI while on methotrexate therapy, which developed prior to the initiation of ceftriaxone therapy.

Acute kidney injury following methotrexate treatment

Design

Case presentation

A 54-year-old female with a history of primary lymphoma of the central nervous system and cancer-related pulmonary embolus developed non-oliguric acute kidney injury (AKI) during admission for cycle 12 of high-dose methotrexate and rituximab therapy. The patient's serum creatinine peaked at 1.6 and 1.7 mg/dL after administration of methotrexate 4.2 and 4.88 g/m², respectively. The AKI was treated with hydration and supportive management in both cases with improvement in creatinine levels after treatment for each episode. The patient's home medications included levetiracetam and apixaban.

On day 2 of admission, her serum methotrexate level was 9.30 mcmol/L, and she began oral leucovorin. Methotrexate levels decreased to 0.76 mcmol/L on day 3. Serum creatinine subsequently rose to 1.4 mg/dL on day 4, peaking at 3.3 mg/dL on day 9. Urinalysis and culture on admission were indicative of a urinary tract infection despite the patient denying symptoms. On day 8, the patient was initiated on a 3-day course of intravenous ceftriaxone, given her AKI. She was also treated with continuous bicarbonate-containing intravenous fluids and underwent kidney biopsy on day 9 due to persistent AKI. 

After kidney biopsy, which was largely unremarkable, serum creatinine decreased to 2.8 mg/dL at discharge on day 11. Slow methotrexate clearance was observed, with a level of 0.04 mcmol/L at discharge. Oral leucovorin was continued for an additional 3 days as an outpatient, and oral prednisone was started for treatment of acute interstitial nephritis observed on her kidney biopsy. Serum creatinine ultimately returned to baseline levels 2 months post-discharge.

Study Author Conclusions

Given the development of AKI after each course of methotrexate, and improvement with proper treatment, a straightforward diagnosis of methotrexate toxicity could have been assumed. Indeed, kidney biopsy is often deferred in similar cases with this presumed diagnosis. However, this case highlights the potential value of kidney biopsy in revealing other treatable and concomitant causes for the functional decline. By correlating pathologic fndings with clinical information, appropriate therapy for both methotrexate toxicity and interstitial nephritis was achieved for this patient, underscoring that biopsy should still be strongly considered in suspected methotrexate nephrotoxicity.

Critique

While acute kidney injury developed in this patient who concomitantly received ceftriaxone while on methotrexate therapy, a potential interaction was not addressed. The primary focus of this report was to describe the development of AKI while on methotrexate therapy, which developed prior to the initiation of ceftriaxone therapy.