Significant impairment of high-dose methotrexate clearance following vancomycin administration in the absence of overt renal impairment

R. Blum,+, J. F. Seymour and G. Toner

Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Melbourne 8006, Australia

Received 22 February 2001; revised 9 May 2001; accepted 23 May 2001.


    Abstract
 Top
 Abstract
 Introduction
 Case 1
 Case 2
 Discussion
 References
 
Background

Methotrexate is an antimetabolite cytotoxic drug which is predominantly renally excreted. Vancomycin, a glycopeptide antibiotic that is used in the febrile neutropaenic patient, can be nephrotoxic. There are no previous reports of any interactions between these two drugs.

Patients and methods

We describe two patients with osteosarcoma treated with high-dose methotrexate-containing chemotherapy who had significantly delayed methotrexate clearance several weeks following exposure to vancomycin.

Results

These patients were treated with alternating chemotherapy consisting of 12 g/m2 methotrexate, 60 mg/m2 cisplatin, 75 mg/m2 adriamycin and 15 g/m2 ifosfamide. In both patients, serum methotrexate levels fell to below 0.2 µmol/l within 48–96 h during initial treatment cycles. However, following recent exposure to therapeutic vancomycin in the preceding 10 days and in the absence of overt renal impairment, both patients manifested markedly prolonged methotrexate clearance, requiring 170–231 h to reach serum levels of less than 0.2 µM. Subclinical renal impairment was documented by impaired glomerular filtration rates in both cases by technetium 99 m diethylene triamine penta-acetic acid scanning. Subsequent methotrexate cycles using an unmodified schedule were cleared within 72 h. Both cases had their glomerular filtration rate re-assessed, which showed marked improvement.

Conclusions

Recent exposure to vancomycin, even in the absence of overt renal impairment, may adversely affect methotrexate excretion, which can subsequently lead to increased toxicity of the antimetabolite. The glomerular filtration rate should be measured in such cases so that appropriate dose modification of methotrexate can be made.

Key words: delayed excretion, methotrexate, nephrotoxicity, vancomycin


    Introduction
 Top
 Abstract
 Introduction
 Case 1
 Case 2
 Discussion
 References
 
Methotrexate is an important drug used in the management of malignancy and connective tissue disorders, such as rheumatoid arthritis. In neoplastic disease, it can be used both in standard doses of 30–40 mg/m2 for the treatment of breast or bladder cancer, or high doses of 1–12 g/m2 for lymphoma, leukaemia and osteosarcoma. These higher doses have the potential to cause fatal toxicities and, therefore, methotrexate dose excretion needs to be monitored carefully.

Methotrexate is an inhibitor of dihydrofolate reductase, a critical enzyme in maintaining the intracellular folate pool in its reduced form as tetrahydrofolate, which is important for the synthesis of purine nucleotides and some amino acids [1]. The volume of distribution approaches that of total body water and ~60% is bound to albumin. Methotrexate generally follows a triphasic elimination pattern. The three phases consist of a distribution phase of ~45 min and two elimination phases. Following standard (~40 mg/m2) or high-dose (500 mg/m2) methotrexate, the mean elimination half-lives are 2 and 8 h, respectively [2]. The latter two phases are prolonged in patients with renal impairment.

A small proportion of administered methotrexate undergoes hepatic metabolism and is subsequently eliminated by the kidneys. In high doses, 90% of the total methotrexate is renally excreted unchanged. Renal clearance involves glomerular filtration, tubular secretion and tubular resorption. As a result, methotrexate clearance is critically dependent upon renal function [3, 4].

High-dose methotrexate with leucovorin rescue is used in the treatment of osteosarcoma, lymphoma and leukaemia. This treatment is usually given as a prolonged infusion, the duration of which can range from 4 to 48 h. High-dose methotrexate is usually well tolerated provided that patients are adequately hydrated and the urinary pH is kept above 7. Alkalization of the urine increases methotrexate excretion and reduces the risk of precipitation within the renal tubules, which can lead to acute renal failure [5].

The primary toxicities of high-dose methotrexate infusions are myelosuppression and gastrointestinal mucositis. When mucositis occurs, its onset is usually 3–7 days post-treatment and precedes myelosuppression. Myelosuppresssion and mucositis have usually resolved by about day 14. Other toxicities include acute and chronic hepatitis, self-limiting pneumonitis and central nervous system disturbances [1]. The risk of potentially fatal toxicity is significantly increased with high-dose methotrexate in the setting of renal impairment and is related to prolonged periods of exposure due to elevated serum levels. At 24 and 48 h, toxicity is greater if the serum levels are above 20 and 2 µmol/l, respectively [6].

Vancomycin is a glycopeptide antibiotic which inhibits cell wall synthesis. It is active against Gram-positive bacteria, including methicillin-resistant staphylococci. It is widely distributed in total body water and has a plasma half-life of 6 h. Elimination is virtually entirely by glomerular filtration. Side effects include infusional reactions, which may be anaphylactoid or the ‘redman syndrome’, and auditory and vestibular problems including impaired hearing, tinnitus and, occasionally, vestibular dysfunction [7]. Other side effects include renal impairment manifested by increasing urea and creatinine, especially in patients exposed to high trough serum vancomycin concentrations [8]. This is more likely to occur when patients are concomitantly exposed to aminoglycosides or in the presence of pre-existing renal impairment [9]. This drug-related azotaemia usually resolves within days of drug cessation.

We report two patients with osteosarcoma treated with a chemotherapy regime containing repeated high-dose methotrexate in whom, initially, there was normal clearance of methotrexate and no toxicity. However, when exposed to vancomycin within the preceding 10 days, they had prolonged methotrexate excretion and subsequent toxicity.


    Case 1
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 Abstract
 Introduction
 Case 1
 Case 2
 Discussion
 References
 
A 29-year-old man was referred to our institute for management of distal femoral osteosarcoma. He received pre- operative chemotherapy consisting of repeated cycles of 12 g/m2 methotrexate, 60 mg/m2 cisplatin, 75 mg/m2 adriamycin and 15 g/m2 ifosfamide [2, 9]. The patient had no significant past medical history predisposing him to renal impairment and took no regular medications. The initial physical examination, which included blood pressure and urine analysis, was normal. Initial serum levels of creatinine and urea were 0.1 mmol/l (normal range: 0.06–0.13 mmol/l) and 7 mmol/l (2.5–7.7 mmol/l), respectively. During day 1 of treatment he received 23 g methotrexate (12 g/m2) intravenously (i.v.) over 4 h. Twenty hours post completion of methotrexate treatment, he commenced folinic acid i.v. every 6 h, receiving a total of 18 doses. Urine pH was kept above 7.0 during methotrexate elimination. The serum methotrexate level fell to a safe level of 0.2 µmol/l within 72 h (Figure 1). There were no major toxicities from this or subsequent chemotherapy courses. During day 49 he received a second identical course of 23 g methotrexate (12 g/m2) without complication.



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Figure 1. Fall of serum methotrexate concentration over time, case 1.

 
He was admitted during day 130 with a non-neutropaenic febrile illness, following recently administered cisplatin. Serum levels of creatinine and urea were 0.07 mmol/l and 3.7 mmol/l, respectively. Vancomycin (1 g) twice daily, 1 g cefepime three times daily and 240 mg gentamicin daily were commenced on the first day of admission. A vancomycin trough level on day 131, following the third dose, was 5 mmol/l (<10 mmol/l) but was found to be 59 mmol/l after the sixth dose. Subsequent vancomycin doses were withheld. Gentamicin levels were closely monitored and always fell within the therapeutic range. Acinetobacter calcoaceticus and Strenotrophomonas maltophilia were isolated, the peripheral access was removed and oral bacterium was given for 1 week. During the entire admission the patient’s renal function remained normal.

He was re-admitted on day 168 with a febrile neutropaenic episode post high-dose ifosfamide. Again he was commenced on 1 g vancomycin twice daily and 1 g cefepime i.v. three times daily. A vancomycin trough level after three doses was 5 mmol/l. Vancomycin was ceased after five doses. No source of infection was identified. His renal function remained normal throughout the admission with creatinine and urea levels in the range of 0.08–0.09 mmol/l and 5.9–6.9 mmol/l, respectively. A lower total dose of 20.2 g (12 g/m2) methotrexate was administered on day 176 because of a reduced body surface area (BSA). At the time, the serum creatinine was 0.08 mmol/l and the urea was 6.9 mmol/l. Folinic rescue was administered in an identical manner to previous cycles. Methotrexate levels remained above 0.2 µmol/l for 231 h (Figure 1). During that time urine was well alkalinized with the pH maintained above 7. No other renally toxic agents were administered during the admission. Serum creatinine ranged from 0.08 to 0.16 mmol/l over this time. The patient developed grade III mucositis. This had not been a feature of previous high-dose methotrexate cycles. On day 183 a quantitative glomerular filtration rate (GFR) scan using technetium 99 m diethylene triamine penta-acetic acid (DTPA) was performed measuring a value of 64 ml/min. The subsequent methotrexate dose was administered on day 251 and the serum level fell to less than 0.2 µM within 96 h. A further renal scan was performed during day 260 revealing a GFR of 100 ml/min, and the final scheduled methotrexate dose of 20.2 g (12 g/m2) was cleared within 3 days (Figure 1).


    Case 2
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 Abstract
 Introduction
 Case 1
 Case 2
 Discussion
 References
 
A 29-year-old woman was admitted for chemotherapy for distal left femur osteosarcoma prior to and following limb-sparing surgery according to the previously mentioned protocol. She had no significant past medical history predisposing her to renal impairment. The only regular medication prior to commencement of treatment was the oral contraceptive pill. During her first admission for chemotherapy, her clinical examination, which included blood pressure and urine analysis, was normal. Her renal function was normal with creatinine and urea levels of 0.08 mmol/l and 3.8 mmol/l, respectively. On day 1 the dose of methotrexate given was 20 g (12 g/m2) followed by folinic rescue as previously described. Methotrexate fell to a safe level below 0.2 µmol/l within 72 h (Figure 2). Subsequent chemotherapy was given without major complications, including the day 49 methotrexate dose of 20 g (12 g/m2). On day 224 the patient was admitted with methicillin-resistant staphylococcus epidermidis septicaemia complicating pancytopaenia following recently administered ifosfamide. On admission her creatinine and urea were 0.07 and 3.7 mmol/l, respectively. Cefepime (1 g) i.v. three times daily was immediately commenced and 1 g vancomycin twice daily was added on day 2 due to persisting fevers. A vancomycin trough level taken after the third dose was 4 mg/l. A repeat trough level after the sixth dose was 12.5 mg/l, following which the vancomycin dose was reduced to 750 mg i.v. twice daily. It was ceased after a total of 10 doses. Her serum creatinine and urea remained within the normal range: 0.07–0.09 and 3.2–3.5 mmol/l, respectively. On day 233 she received a methotrexate dose of 20 g (12 g/m2) with a schedule identical to the previous doses. Her serum creatinine and urea were 0.09 mmol/l and 3.5 mmol/l, respectively. Folinic rescue was given in an identical manner to previous cycles. The patient was well hydrated and urine pH did not drop below 7. It took 170 h for the serum methotrexate level to fall below 0.2 µmol/l (Figure 2). The patient suffered grade 2 mucositis, which she had not had with previous methotrexate treatments. No concomitant nephrotoxic agents were administered. A renal scan performed on day 241 revealed bilaterally impaired renal function with a GFR value of 87 ml/min. Repeat GRF prior performed on day 317 estimated the GFR to be 100 ml/min. Her last methotrexate dose was administered on day 328. She was given a lower methotrexate dose of 19 g (12 g/m2) because of a reduced BSA. Her renal function according to serum creatinine and urea were normal. She again cleared the drug under 72 h (Figure 2).



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Figure 2. Fall of serum methotrexate concentration over time, case 2.

 

    Discussion
 Top
 Abstract
 Introduction
 Case 1
 Case 2
 Discussion
 References
 
We describe two patients with osteosarcomas, treated with chemotherapy containing high-dose methotrexate, who manifest impaired methotrexate excretion soon after exposure to vancomycin. Both patients had previously received several cycles of high-dose methotrexate with prompt excretion of the drug. Although the chemotherapy regime contained several potentially nephrotoxic agents, including methotrexate, ifosfamide and cisplatin, it was only after recent exposure to vancomycin that methotrexate excretion was significantly delayed. While it is possible that the concomitant administration of other medications may have altered the extent of protein binding of methotrexate, one would predict that this would primarily affect the peak plasma concentration rather than drug clearance [10]. Not only did both patients have higher peak serum levels following recent exposure to vancomycin, but the excretion was markedly delayed, which could not be explained by displacement from protein binding alone. Our proposed hypothesis is that vancomycin can cause sub-clinical nephrotoxicity, which may interfere with the excretion of methotrexate.

The mechanism of vancomycin-induced nephrotoxicity is not well understood. In animal studies, vancomycin can cause dilation of the lumina of the renal tubules, dilation of the Bowman’s capsule, destruction of renal epithelial cells and formation of hyaline casts [7]. Electron microscopic examination revealed an increase in the number of vacuoles and lysosymes, swollen mitochondria and deformed nuclei of the tubular epithelia [11]. This would suggest that the major site of damage is the renal tubules. Such damage would be predicted to interfere with methotrexate excretion, as renal handling of the drug is predominantly dependent on tubular function. In both cases, there was documented impaired glomerular filtration measured by a quantitative GRF scan using technetium 99 m DTPA. This test measures GFR and not tubular function. However, if there is sufficient tubular damage resulting in desquamated epithelia blocking the tubules, impaired drainage of the nephron could result in an impaired GFR measurement. One problem is that the GFRs were not measured before the prolonged methotrexate exposure. Therefore, it is difficult to be certain whether the specific degree of renal impairment measured was wholly attributable to previous vancomycin exposure. Some of the subsequent impairment of GRF may have been due to the prolonged elevated methotrexate serum levels. However, the nephrotoxic effects of methotrexate are also predominantly tubular.

Because methotrexate is predominantly renally excreted, any nephrotoxicity resulting from recent exposure to vancomycin would potentiate the side effect profile of the antimetabolite. This is particularly important in the case of high-dose methotrexate, where the toxicities are potentially fatal. Renal impairment may occur in the face of normal serum creatinine and urea (noted at the time of methotrexate administration in both cases) and non-toxic trough levels of vancomycin (illustrated by the second case only). Such subclinical nephrotoxicity can be assessed by measuring GFR with a DTPA renal scan. In this way, dose modification of methotrexate can be made according to the GFR measured, to minimize any significant complications of treatment.

In conclusion, the administration of vancomycin, an antibiotic commonly used in cancer patients who have treatment-induced febrile neutropaenia, can result in renal impairment. This nephrotoxicity may not be detected by the measurement of serum urea and creatinine concentrations. When methotrexate has been administered in the proceeding 7–10 days, excretion of the drug can be impaired, resulting in a prolonged systemic exposure to the cytotoxic drug. This results in potentially significant toxicity, particularly in the case of high doses, where the outcome may be fatal. To minimize such complications, we believe it would be prudent to assess GFR in this situation, to allow dose modification of methotrexate if necessary.


    Footnotes
 
+ Correspondence to: Tel: +61-3-9656-1111; Fax: +61-3-9656-1408; E-mail: rblum@alphalink.com.au Back


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 Case 2
 Discussion
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