Monday, October 22, 2018

Sulfamethoxazole/trimethoprim and increase in serum creatinine: When to be concerned

A 65 year old male is being treated for an infection on his forearm that developed purulent drainage within the last few days.  He denies experiencing any penetrating trauma to his arm and denies any other complaints at this time.  He weighs 70 kg, His WBC count is 14.7 x 109/L, serum creatinine is 1.3 mg/dL, and his vital signs are within normal limits.  His past medical history includes hypertension and an MRSA infection last year.  He is currently taking valsartan 160 mg daily and chlorthalidone
12.5 mg daily for his hypertension.  The decision is made to incise and drain the wound and begin treatment with sulfamethoxazole/trimethoprim (SMX/TMP) 2 double-strength tablets twice daily for at least 5 days.  On day 3, his WBC count is now normal but his serum creatinine increased to 1.6 mg/dL.  What are the effects of SMX/TMP on the serum creatinine and what should we do in this situation?

The problem in this case is that SMX/TMP is on a short list of medications that are known to increase the serum creatinine in a way that doesn't necessarily reflect a decrease in underlying kidney function.  The mechanism for this increase relates to how creatinine is eliminated from the body.  Creatinine is eliminated both through (1) glomerular filtration and (2) active tubular secretion into more distal parts of the kidney by various transporters.  If those transporters are inhibited by a drug (ie. TMP) it doesn't have any direct effect on glomerular filtration but the serum concentration will rise to a higher value and return to baseline when the drug is discontinued.  

The clinical difficulty is that SMX/TMP is also associated with actual kidney impairment, is eliminated by the kidney, and can accumulate causing other adverse effects.  The study that best examined the effects of SMX/TMP on developing AKI was a retrospective review of more than 6000 patients that compared those who received low dose (<5mg/kg/day TMP) with high dose (>5 mg/kg/day TMP)1.  These authors defined AKI using the NIH definitions and thoughtfully excluded the expected mild increase of serum creatinine by TMP (ie. they excluded mild increases to the 1.4.-1.9 mg/dL range and there had to be an absolute increase of 0.5 mg/dL if moving from one AKI severity grade to the next).  They found there was a higher rate of AKI in the high-dose group compared to the low-dose group (1.99% vs. 0.7%, p=0.0001).  Variables associated with the development of AKI were advanced age, taking an ACEI (OR = 2.36) or potassium supplement (OR = 4.1), and a higher baseline serum creatinine.

How much of an increase is normal

It would be helpful to know how much we should expect SMX/TMP to increase the creatinine and still consider the underlying GFR unchanged.  Several studies were done as early as the 1970s that tested how TMP affected the serum creatinine and the glomerular filtration rate (GFR).  These small studies were mostly done by administering an agent that is eliminated solely by glomerular filtration but not tubular secretion (ie. iothalamate, inulin).  Then, they added TMP and monitored to see if that truly affected the GFR or just increased serum creatinine.

Here is the summary of these types of studies and how much they changed the serum creatinine2.  Of note, only 4 patients in these studies also experienced a decrease in GFR but that was thought to be due to sepsis, pyelonephritis, or being given an inappropriately high dose of SMX/TMP.  The GFR in the rest of the patients was confirmed to be unchanged from baseline, despite the rise in serum creatinine.

Change in SCr
Berglund, et al – 1975
21 infected
Trollfors, et al – 1980
25 infected
Kainer & Rosenberg – 1981
10 healthy
Kastrup, et al – 1985
15 healthy
Berg, et al – 1989
16 stable renal transplant

Back to the patient case

SMX/TMP was a correct treatment choice because of the purulent drainage and his history of MRSA infection. Two DS twice daily was the correct dose (usually ~10 mg/kg/day of TMP and each DS contains 160 mg of TMP).  We can see that the serum creatinine increased from 1.3 to 1.6 mg/dL, an increase of 23%.  Here are some possible paths this case could take us down:
  1. Continue the treatment course (and risk further impairing the kidneys if it is actual AKI), 
  2. Continue SMX/TMP but reduce the dose (and risk undertreating the patient if the AKI is false), or
  3. Change our treatment to a different antibiotic.  The trouble with this option is that vancomycin, linezolid, clindamycin, daptomycin, ceftaroline, and the tetracyclines all have their drawbacks.
Looking at the above studies, we can see that it is not unexpected to see increases of serum creatinine of up to around 20-25% while the GFR remains unchanged.  So in conclusion, the SMX/TMP could probably be continued unchanged (choice #1) but if the rise continues to around 1.8 mg/dL (increase of 38%), it might be wise to consider another antibiotic.  

Take home points

  • TMP is known to increase serum creatinine up to percentages in the 20s and it's not reflective of a decrease in GFR
  • Actual AKI can occur with SMX/TMP
    • Risks include high-dose, ACEI, potassium supplements, high baseline serum creatinine
  • Absolute risk is still low (single digit percent)
  • Other examples of drugs that increase serum creatinine but do not affect GFR include:
    • Cimetidine
    • Dronedarone (about 10%)
    • Cobicistat (up to 0.4 mg/dL)
    • Dolutegravir (about 0.15 mg/dL)

1. Gentry CA, Nguyen AT. An evaluation of hyperkalemia and serum creatinine elevation association with different dosage levels of outpatient trimethoprim-sulfamethoxazole with and without concomitant medications.  Ann Pharmacother 2013;47(12):1618-26.
2. Delanaye P, Mariat C, Cavalier E, et al.  Trimethoprim, creatinine, and creatinine-based equations.  Nephron Clin Prac 2011;119:187-94.

image from MilitaryHealth


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