Impact of Prophylactic Trimethoprim-Sulfamethoxazole on Clearance of High-Dose Methotrexate in Adult Patients

Abstract

PURPOSE

High-dose methotrexate (HDMTX) is an antineoplastic dosing strategy used to treat various cancers including primary central nervous system lymphoma. Trimethoprim-sulfamethoxazole (TMP/SMX) is commonly used for antibiotic prophylaxis against Pneumocystis pneumonia infections in this patient population. Significant drug-drug interactions between TMP/SMX and methotrexate (MTX) leading to adverse outcomes have been documented, primarily in adult patients taking MTX for rheumatologic conditions.

METHODS

This study is a single-center, retrospective, cohort study comparing outcomes in patients where TMP/SMX was held during HDMTX and patients who received concurrent prophylactic TMP/SMX during treatment. The primary end point was mean MTX level at 24, 48, and 72 hours. Secondary end points included rate of nonhematologic toxicity, rate of hematologic toxicity, median days to MTX clearance, and frequency of glucarpidase utilization.

RESULTS

In total, 248 cycles of HDMTX were analyzed from 221 individual patients. One hundred ninety-one cycles were administered without prophylactic TMP/SMX, and 57 were administered with TMP/SMX. The median MTX level at 24, 48, and 72 hours in those without versus with prophylactic TMP/SMX was 4.30 versus 4.30, 0.29 versus 0.30, and 0.14 versus 0.15, respectively. Similarly, rates of hematologic and nonhematologic toxicities did not differ significantly between groups with the exception of neutropenia; however, there was no corresponding increased rate of neutropenic fever. Only one patient received glucarpidase and had not received TMP/SMX.

CONCLUSION

Prophylactic TMP/SMX had minimal interaction with HDMTX and does not lead to increased time to clearance or clinically relevant toxicities. Prophylactic TMP/SMX can be safely administered with HDMTX in adult patients.

BACKGROUND

High-dose methotrexate (HDMTX; >500 mg/m²) is a dosing strategy used to treat various cancers, including primary central nervous system lymphoma.¹ When given as a bolus (defined as infusion <6 hours), methotrexate (MTX) levels are obtained 24 hours after the start of the infusion and then every 24 hours thereafter to assess for drug clearance and guide leucovorin dosing.² This practice was devised in the 1970s from data indicating that MTX levels are predictive for toxicities.³

Trimethoprim-sulfamethoxazole (TMP/SMX) is an antibiotic commonly used for prophylaxis against Pneumocystis pneumonia infections in the hematologic malignancy patient population. Drug-drug interactions between TMP/SMX and MTX have been documented in the literature, primarily in patients taking MTX for rheumatologic conditions.^4–7 Specifically, Hamid et al⁸ reported a patient taking MTX 10 mg weekly who was prescribed a full treatment dose of TMP/SMX for cellulitis and experienced mucositis 2 weeks later. By contrast, a retrospective study of patients taking MTX 10 mg every seven days with prophylactic dose TMP/SMX found that this combination was tolerated in 94 of 100 (94%) patients. The remaining six patients discontinued TMP/SMX because of transaminitis (four), memory loss (one), and leukopenia (one). The authors concluded that it was safe to administer prophylactic dosed TMP/SMX concomitantly with MTX 10 mg every seven days in patients without underlying liver or hematologic abnormalities.⁹

Watts et al¹⁰ reviewed this interaction in pediatric patients receiving HDMTX concurrent with prophylactic TMP/SMX. They ultimately found that the medication combination did not prolong the time to MTX clearance or lead to increased rates of myelosuppression. While these data demonstrated safety in the pediatric population, questions still remain regarding the applicability to adult patients. First, MTX is renally cleared, so it would be anticipated that adolescent and young adult patients would have better renal function and thus better clearance when compared with adult patients. Second, this trial assessed prophylactic TMP/SMX dosed at 75 mg/m² TMP every 12 hours three times weekly, which varies from the standard prophylactic doses used in adults (80 mg TMP once daily or 160 mg TMP three times weekly). Finally, the authors only evaluated MTX levels and the presence of myelosuppression, not including other toxicities such as mucositis, nephrotoxicity, or dermatologic toxicity. This project aimed to assess the impact of concurrent TMP/SMX on HDMTX clearance and toxicities in adult patients.

METHODS

After The Johns Hopkins Institutional Review Board approval, we performed a single-center retrospective chart review of patients admitted to The Johns Hopkins Hospital for HDMTX administration between January 2016 and June 2022. Inclusion criteria were patients age >18 years with hematologic malignancies who received MTX infusion at doses >500 mg/m² over 4 hours once per cycle. Cohorts were separated on the basis of receipt of prophylactic TMP/SMX starting on or before the day of MTX infusion versus no TMP/SMX exposure during MTX infusion until documented MTX clearance. Doses of 80 mg trimethoprim once daily or 160 mg trimethoprim three times weekly were considered prophylactic. Only the first HDMTX cycle was collected and analyzed unless patients without TMP/SMX received concomitant TMP/SMX in later cycles. The first HDMTX cycle with concomitant TMP/SMX was also collected for those patients. Patients were excluded if they received HDMTX over 24 hours or for investigational use. All patients underwent urine alkalinization with sodium bicarbonate infusion to achieve a urine pH of >7.5, and the urine output was >100 mL/h for two consecutive hours. Similarly, all patients received leucovorin on the basis of an institutional standard dosing protocol starting 24 hours after HDMTX infusion. Patients were eligible for discharge with MTX level <0.2 μmol/L and discharged with leucovorin 5 mg PO once every 6 hours for 72 hours.

The primary end point of this study was median MTX level at 24, 48, and 72 hours in patients who received versus did not receive concurrent prophylactic TMP/SMX. Secondary end points were rates of hematologic toxicity, nonhematologic toxicity, median length of stay, and glucarpidase utilization. The Common Terminology Criteria for Adverse Events v. 5.0 was used to define toxicity end points with toxicities grade 3 or greater considered significant toxicities. Institutional guidelines for glucarpidase utilization required MTX level >50 μmol/L at 24 hours or >5 μmol/L at 48–60 hours with evidence of renal impairment defined by serum creatinine ≥23 baseline or urine output <0.5 mL/kg/h for >12 hours.

Descriptive statistics were used to describe the primary end point which was then analyzed by the two-sample Wilcoxon rank-sum (Mann-Whitney) test. Odds ratios were used to describe the relationship between a secondary end point occurring in patients with versus without prophylactic TMP/SMX. All data analyses were conducted using the statistical program Stata (version 17, StataCorp LLC, College Station, TX).

RESULTS

A total 221 patients were included, with 248 HDMTX cycles. Concurrent TMP/SMX was administered in 57 cycles compared with 191 cycles without concurrent TMP/SMX. Descriptive statistics are shown in Table 1. Median age was similar between those with and without TMP/SMX, with about half of patients in each group receiving HDMTX for primary CNS lymphoma. The median MTX dose was slightly higher in the group with TMP/SMX than without (6.24 g/m² v 5.06 g/m²). Concurrent chemotherapy was given with HDMTX in 35% of patients with TMP/SMX and 36% of those without TMP/SMX, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone being the most common regimen.

TABLE 1.

Patient Characteristics (n = 248)

Description	Without TMP/SMX (n = 191)	With TMP/SMX (n = 57)
Age, years, median (range)	63 (23–86)	62 (25–86)
Sex, No. (%)
Male	110 (58)	39 (68)
Female	81 (42)	18 (32)
Race, No. (%)
White	139 (73)	37 (65)
Black	23 (12)	11 (19)
Asian	16 (8)	4 (7)
Other	13 (7)	5 (9)
Diagnosis, No. (%)
PCNSL	94 (49)	29 (51)
DLBCL	64 (34)	19 (33)
Burkitťs lymphoma	9 (5)	4 (7)
Other	20 (13)	5 (9)
MTX dose, g/m2, median	5.06	6.24
Concurrent chemotherapy, No. (%)	69 (36)	20 (35)

Abbreviations: DLBCL, diffuse large B-cell lymphoma; MTX, methotrexate; PCNSL, primary central nervous system lymphoma; SMX, sulfamethoxazole; TMP, trimethoprim.

MTX levels at 24 hours were 4.3 μmol/L versus 4.3 μmol/L (P = .87), those at 48 hours were 0.3 μmol/L versus 0.29 μmol/L (P = .59), and those at 72 hours were 0.15 μmol/L versus 0.14 μmol/L (P = .91) in those who received versus did not receive concurrent TMP/SMX, respectively (Fig 1). There were no differences in nonhematologic toxicities between either group including changes in serum creatinine, AST, ALT, total bilirubin, or development of mucositis (Table 2). Patients were statistically more likely to experience neutropenia when given prophylactic TMP/SMX concurrent with HDMTX (odds ratio, 3.59 [95% CI, 1.55 to 8.29]). Importantly, this finding was not accompanied by a significant increase in leukopenia or febrile neutropenia with odds ratios of 1.51 (95% CI, 0.82 to 2.80) and 0.88 (95% CI, 0.18 to 4.30), respectively. There was also no difference in the rates of anemia or thrombocytopenia between each group. Only one patient received glucarpidase, and they did not receive TMP/SMX during HDMTX. The median length of stay for both groups was 4 days.

FIG 1.

MTX levels at 24, 48, and 72 hours. MTX, methotrexate; SMX, sulfamethoxazole; TMP, trimethoprim.

TABLE 2.

Secondary End Points

Toxicity End Point	Without TMP/SMX (n = 191)			With TMP/SMX (n = 57)			ORa
	Any Grade		Grade 3/4	Any Grade		Grade 3/4
Nonhematologic, No. (%)
Serum creatinine	36 (19)		5 (3)	8 (14)		1 (2)	0.70 (0.31–1.62)
AST	115 (60)		24 (13)	34 (60)		3 (5)	1.07 (0.58–1.98)
ALT	128 (67)		35 (18)	39 (68)		12 (21)	1.01 (0.55–1.85)
Total bilirubin	47 (25)		3 (2)	8 (14)		0 (0)	0.50 (0.22–1.14)
Mucositis		32 (17)			8 (14)		0.77 (0.38–1.59)
Hematologic, No. (%)
Leukopenia	59 (31)		21 (11)	23 (40)		12 (21)	1.51 (0.82–2.80)
Anemia	80 (42)		18 (9)	20 (35)		5 (9)	0.82 (0.55–1.22)
Thrombocytopenia	60 (31)		12 (6)	16 (28)		3 (5)	0.85 (0.44–1.64)
Neutropeniab	16 (10)		12 (7)	13 (27)		7 (14)	3.59 (1.55–8.29)
Febrile neutropeniab		8 (5)			2 (4)		0.88 (0.18–4.30)
Glucarpidase use, No. (%)		1 (0.5)			0 (0)		-
Length of stay, days, medianc		4			4		-

Abbreviations: OR, odds ratio; SMX, sulfamethoxazole; TMP, trimethoprim.

^aORs are comparing patients who had any grade toxicity in each group.

^bn = 175 for without TMP/SMX and n = 49 for with TMP/SMX because of unavailable data.

^cExcludes patients admitted for >14 days as these admissions were prolonged because of nonmethotrexate toxicities.

DISCUSSION

In this study, we aimed to investigate the potential drug interactions between prophylactic TMP/SMX and HDMTX. Our findings indicate that there was no statistically significant difference in MTX levels at 24, 48, and 72 hours between patients who received prophylactic TMP/SMX and those who did not. In addition, most secondary outcomes showed no statistically significant differences between the two groups, with the exception of neutropenia.

The mechanism of the drug-drug interaction remains unclear. It has been hypothesized that TMP/SMX can increase unbound MTX in blood and decrease its excretion.¹² However, the lack of a significant difference in MTX levels suggests that prophylactic TMP/SMX does not appear to affect the pharmacokinetics of MTX. Similar concomitant TMP/SMX and MTX use examined by Beach et al¹³ found no alteration of serum pharmacokinetics although low doses might have been insufficient for effect. Another hypothesis for this interaction is that both MTX and TMP/SMX can result in folate deficiency and subsequently produce bone marrow suppression. A systematic literature review found that all case reports of reported drug-drug interactions were in patients receiving concomitant treatment dose TMP/SMX and MTX.¹⁴ Thus, it is possible that lower prophylactic doses of TMP/SMX do not deplete folate levels to a degree that yields a clinically meaningful interaction or that aggressive folate supplementation with leucovorin can negate this mechanism.

The absence of significant differences in most secondary outcomes between the two groups further supports the lack of a substantial drug interaction between prophylactic TMP/SMX and MTX. However, the group that received prophylactic TMP/SMX had a statistically significant increase in neutropenia. However, TMP/SMX has been associated with neutropenia when used in the absence of MTX in some studies and our findings are consistent with a mild effect.¹⁵ It is noteworthy that the absolute number of patients who developed neutropenia was relatively small and the absence of concomitant increases in febrile neutropenia suggests that the impact is likely not clinically important in most instances, but that in the presence of neutropenia, TMP/SMX should be avoided or discontinued when possible.

One of the limitations of this study is its retrospective nature, which introduces inherent biases and limitations in data collection. The reliance on medical records for data extraction might have resulted in incomplete or inaccurate information, particularly the presence of mucositis. In addition, the inclusion of only the first treatment cycle, unless patients received TMP/SMX in subsequent cycles, might have limited capturing the full extent of any potential drug interactions.

In conclusion, prophylactic TMP/SMX had minimal interaction with HDMTX and did not lead to decreased MTX clearance or clinically relevant toxicities. Neutropenia was the only statistically significant adverse event that was worse for patients who received TMP/SMX; however, it is possible that this is simply an artifact of the small number of patients who experienced this toxicity. Further research is needed to elucidate the potential impact of prophylactic TMP/SMX on neutropenia.

CONTEXT.

Key Objective

The objective of this study was to assess the impact of prophylactic TMP/SMX on HDMTX clearance and toxicities in adult patients.

Knowledge Generated

Our findings indicate that there was no statistically significant difference in methotrexate levels at 24, 48, and 72 hours between patients who received prophylactic TMP/SMX and those who did not. Additionally, there were no differences in toxicities that are normally associated with methotrexate with the exception of neutropenia.

Relevance

These findings show that prophylactic TMP/SMX can be continued through each HDMTX cycle. This allows for adequate prevention of pneumocystis pneumonia during treatment and potentially prevents medication-related errors upon hospital discharge.