What is the rate of hyperkalemia with Bactrim DS daily three times a week when given concurrently with ACEi/ARB?

Comment by InpharmD Researcher

Data describing the risk for hyperkalemia associated with concomitant administration of Bactrim® (trimethoprim-sulfamethoxazole) with ACE inhibitors or ARBs primarily stems from spontaneous reporting and retrospective data but is not specific to use of Bactrim DS daily three times weekly. One study revealed a hyperkalemia incidence of 8.96% when patients received concomitant administration of higher doses of Bactrim (defined as receiving more than 5 mg/kg/day of Bactrim) with ACE inhibitors. Additionally, the concomitant administration of ACE inhibitors with Bactrim (not dose specific) was associated with a 3.27 times higher odds of developing hyperkalemia. Another retrospective study demonstrated a numerically increased risk of hyperkalemia with concomitant administration of ACE inhibitors and high-dose Bactrim (4 or more double-strength tablets per day) compared with the standard dose (10.34% vs. 1.78%). The risk of hyperkalemia associated with concomitant administration of Bactrim and ARBs is not entirely clear as available studies pooled ARBs with other hyperkalemic-inducing drugs. Risk of hyperkalemia may be higher in older adult patients, potentially leading to increased risk of sudden death.

Background

A 2022 review article discusses the clinically significant drug interactions of renin-angiotensin-aldosterone-system (RAAS) blockers. Trimethoprim can increase serum potassium levels by inhibiting potassium excretion through the blockade of epithelial sodium channels in the distal nephron. There are reports that the administration of trimethoprim-sulfamethoxazole to treat infections in older adults receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) was associated with an increased risk of sudden death. The unrecognized severe hyperkalemia might induce the incident as many older adults may have physiological changes that affect pharmacokinetics by decreasing excretion. Another population study reviewed the death of 39,879 older adults taking either ACE inhibitors or ARBs who died from sudden cardiac death. The study found approximately three sudden cardiac deaths per 1,000 patients who had been co-prescribed trimethoprim-sulfamethoxazole within 14 days. Again, it was speculated that unrecognized severe hyperkalemia might underlie this finding. No further information on dosing and frequency of trimethoprim-sulfamethoxazole administration was provided. When it comes to choosing an antibiotic for treating an underlying infection for patients on RAAS blockers, prescribers are encouraged to choose an alternative antibiotic regimen, and if that’s not possible, serum potassium should be closely monitored in this population. [1], [2], [3]

Another population-based, nested case-control, 14-year study of a cohort of elderly patients 66 years or older was conducted to characterize the risk of hyperkalemia-associated hospitalization in elderly patients treated with trimethoprim-sulfamethoxazole along with either an ACE inhibitor or ARB. A total of 4,148 admissions involving hyperkalemia were identified during the study period. Among these, 371 cases took place within 14 days of antibiotic exposure. It was reported that patients taking an ACE inhibitor or ARB also prescribed trimethoprim-sulfamethoxazole were seven times more likely to be hospitalized for hyperkalemia than patients with similar RASS inhibition therapy who had been prescribed amoxicillin (adjusted odds ratio 6.7; 95% confidence interval 4.5 to 10.0). The findings suggest that among older patients treated with ACE inhibitors or ARBs, administration of trimethoprim-sulfamethoxazole is associated with an increased risk of hyperkalemia-associated hospitalization relative to other antibiotics, and alternate antibiotic therapy should be considered in these patients when clinically appropriate. This study did not provide further evaluation of the dose and frequency of trimethoprim-sulfamethoxazole administration. [4]

References:

[1] Mohamed Pakkir Maideen N, Balasubramanian R, Muthusamy S, Nallasamy V. An Overview of Clinically Imperative and Pharmacodynamically Significant Drug Interactions of Renin-Angiotensin-Aldosterone System (RAAS) Blockers. Curr Cardiol Rev. 2022;18(6):e110522204611. doi:10.2174/1573403X18666220511152330
[2] ​​Webb MG. Life-threatening interaction between renin-angiotensin-aldosterone system inhibitors and trimethoprim-sulfamethoxazole in older adults. The Journal for Nurse Practitioners. 2016;12(3):e115-e118.
[3] Fralick M, Macdonald EM, Gomes T, et al. Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. BMJ. 2014;349:g6196. Published 2014 Oct 30. doi:10.1136/bmj.g6196
[4] Antoniou T, Gomes T, Juurlink DN, Loutfy MR, Glazier RH, Mamdani MM. Trimethoprim-sulfamethoxazole-induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system: a population-based study. Arch Intern Med. 2010;170(12):1045-1049. doi:10.1001/archinternmed.2010.142
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the rate of hyperkalemia with Bactrim DS daily three times a week when given concurrently with ACEi/ARB?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

 

An Evaluation of Hyperkalemia and Serum Creatinine Elevation Associated With Different Dosage Levels of Outpatient Trimethoprim-Sulfamethoxazole With and Without Concomitant Medications

Design

Retrospective study

N= 6,162

Objective

To examine the incidence of hyperkalemia and serum creatinine elevation in patients receiving high-dose and standard-dose trimethoprim-sulfamethoxazole (TMP-SMX) and examine the association between certain concomitant medications

Study Groups

High-dose (n= 1,306)

Standard-dose (n= 4,856)

Inclusion Criteria

Received TMP-SMX at a Veterans Affairs Medical Center (VMAC) in Oklahoma

Exclusion Criteria

 Received a course of TMP-SMX for more than 30 days, had no weight documented, found to be an inpatient or discharged from an inpatient stay at the time of the TMP-SMX prescription

Methods

Data were collected from the administrative database of electronic medical records of outpatient visits from the VMAC to identify each episode of an outpatient receiving TMP-SMX. Serum potassium and creatinine concentrations were obtained from the nearest date prior to or on the day of the TMP-SMX prescription through 30 days after the prescription date. Only the first course of TMP-SMX for a patient within the study period was included for analysis. High-dose was defined as receiving more than 5 mg/kg/day of TMP-SMX, while standard-dose was defined as receiving <5 mg/kg/day. Adverse drug events (ADE) related to serum potassium were graded as followed:

Serum potassium (mEq/L):

Grade 1: 5.6-6.0

Grade 2: 6.1-6.5

Grade 3: 6.6-7.0

Grade 4: >7.0

 

Duration

Received TMP-SMX: January 2007 to December 2011

Outcome Measures

Development of hyperkalemia, variables associated with hyperkalemia

Baseline Characteristics

  

High-dose (n= 1,306)

Standard-dose (n= 4,856)

 p-value

Age, years

 57.6 59.1 0.002

Male

 90% 90.4%  

Prescribed duration, days

 10.5 9.78 < 0.001

Evidence of elevated serum creatinine

 1.15% 0.51% 0.018

Concomitant medications

NSAID

NSAID at regular dose

ACE inhibitor

ARB

Spironolactone

Potassium supplement


16.7%

7.89%

15.4%

2.22%

0.84%

5.59%


15.6%

7.72%

15.8%

2.84%

1.01%

5.77%

  

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; NSAID, non-steroidal anti-inflammatory drug

Results

Endpoint

High-dose (n= 1,306)

Standard dose (n= 4,856)

p-Value

Development of any grade hyperkalemia

Grade 1 or 2

Grade 3 or 4

3.06%

2.60%

0.46%

1.05%

0.97%

0.08%

< 0.0001

< 0.0001

0.0085

Univariate variables associated with development of hyperkalemia

 Hyperkalemia present (n= 91) Hyperkalemia absent (n= 6,071) p-value

Age, years

 

 67.7 ± 10.3 58.7 ± 14.1 < 0.0001

Male gender

 90 (98.9%) 5,476 (90.2%) 0.0019

Dose

TMP-SMX dose, mg/kg/day

TMP-SMX dose ≥ 5 mg/kg/day


5.40 ± 2.64

40 (44%)


4.18 ± 1.77

1,266 (20.8%)


< 0.0001

< 0.0001

Concomitant receipt of

NSAID

NSAID at regular dose

ACE inhibitor

ARB

Spironolactone

Potassium supplement


25 (27.5%)

7 (7.69%)

41 (45%)

5 (5.49%)

4 (4.40%)

9 (9.89%)


948 (15.6%)

471 (7.76%)

927 (15.3%)

162 (2.67%)

56 (0.92%)

344 (5.67%)


0.0044

0.98

< 0.0001

0.1

0.012

0.12

Baseline evidence of elevated serum creatinine

 19 (20.9%) 21 (0.35%) < 0.0001

The incidences of hyperkalemia occurring in patients receiving high-dose TMP-SMX and an individual concomitant hyperkalemia-inducing drug ranged from 5.48% (potassium supplement) to 8.96% (ACE inhibitor), with an incidence for any hyperkalemia-inducing drug of 7.93%.

Multivariate analysis also found concomitant receipt of an ACE inhibitor (odds ratio [OR] 3.27; 95% confidence interval [CI] 2.06 to 5.14; p < 0.0001) and high-dose TMP-SMX prescribed (OR 2.92; 95% CI 1.85 to 4.60; p < 0.0001) to be independently associated with the development of hyperkalemia.

Adverse Events

N/A

Study Author Conclusions

This large study demonstrated that the risks for adverse events associated with TMP-SMX—namely, hyperkalemia and acute renal injury—are much more likely to be associated with patients receiving high-dose regimens, having any baseline serum creatinine concentration elevation, and receiving certain concomitant medications (particularly ACE inhibitors). Future prospective studies would be useful to further validate the differences in the rates of ADEs between high-dose and standard-dose TMP-SMX and to confirm variables affecting these rates. The results suggest that additional warnings should be communicated to clinicians about the need for laboratory monitoring of serum creatinine and potassium concentrations at baseline and during therapy in patients receiving high-dose TMP-SMX in the outpatient setting.

InpharmD Researcher Critique

Due to this being a retrospective study that could not control for confounding factors, there are likely other factors that could have contributed to patients developing hyperkalemia.



References:

Gentry CA, Nguyen AT. An evaluation of hyperkalemia and serum creatinine elevation associated with different dosage levels of outpatient trimethoprim-sulfamethoxazole with and without concomitant medications. Ann Pharmacother. 2013;47(12):1618-1626. doi:10.1177/1060028013509973

 

A Comparison of Adverse Drug Reactions Between High- and Standard-Dose Trimethoprim-Sulfamethoxazole in the Ambulatory Setting

Design

Retrospective cohort study

N= 982

Objective

To characterize the adverse reactions associated with short-term high-dose trimethoprim-sulfamethoxazole (TMP-SMX) therapy compared to short-term standard-dose TMP-SMX for traditional indications

Study Groups

High-dose (n= 491)

Standard-dose (n= 491)

Inclusion Criteria

Received TMP-SMX at a Veterans Affairs Medical Center (VAMC)

Exclusion Criteria

Received TMP-SMX for more than 21 days, prescribed TMP-SMX for a prophylaxis indication, infected with human immunodeficiency virus

Methods

Information was collected through a medical chart review from a VAMC in Oklahoma. Each episode (case) of a patient receiving high-dose TMP-SMX (4 or more double-strength tablets per day) in the medical record review was matched by the next closest prescription number with a patient (control) receiving standard-dose TMP-SMX (< 4 double-strength tablets per day). Each course of a high-dose TMP-SMX patient was included as a separate episode.

Duration

Received TMP-SMX: July 2010 to December 2011

Outcome Measures

Hyperkalemia incidence, hyperkalemia while receiving specific medications, variables associated with hyperkalemia

Baseline Characteristics

  

High-dose (n= 491)

Standard-dose (n= 491)

  

Age, years*

56

59

  

Males*

94.2%

92.5%

  

Indication

Cellulitis

Abscess

Urinary tract infection

Sinusitis

Wound infection

Other


47.6%

22.9%

3.06%

3.06%

5.71%

17.7%


30.8%

8.55%

22.0%

8.55%

3.46%

26.6%

  

Serum creatinine, mg/dL

1.16

1.41

  

*Data were provided for patients that had data available regarding concomitant medications (n= 241 in both groups). Of these patients, 15 had the presence of hyperkalemia, and 467 did not.

Results

Endpoint

High-dose (n= 491)

Standard-dose (n= 491)

p-value

Hyperkalemia

 17 (3.46%) 4 (0.81%) 0.0066

Hyperkalemia while receiving ACE inhibitor

 6/58 1/56 Not provided

Hyperkalemia while receiving hyperkalemic-inducing drug*

 7/88 1/80 Not provided

Variables associated with hyperkalemia

 Hyperkalemia present (n= 15) Hyperkalemia absent (n= 467) p-value

Mean age

 67.5 ± 12.0 57.1 ± 14.3 0.002

High-dose TMP-SMX

 13 (86.7%) 2 (13.3%) 0.007

Concomitant ACE inhibitor

 7 (46.7%) 107 (22.9%) 0.048

ACE, angiotensin-converting enzyme

*Hyperkalemic-inducing drug was considered to be an ACE inhibitor, ARB, potassium supplement, or potassium-sparing diuretic.

Adverse Events

N/A

Study Author Conclusions

ADRs such as hyperkalemia are more likely to be associated with the use of high-dose TMP-SMX in the ambulatory setting. Clinicians should use caution when initiating high-dose TMP-SMX and consider laboratory monitoring in patients of advanced age or those receiving concomitant ACE inhibitor therapy.

InpharmD Researcher Critique

Due to the retrospective nature of this study, additional factors were not accounted for that could have confounded the risk of hyperkalemia. Analyses comparing the incidence of hyperkalemia, specifically in patients receiving ACEs or ARBs concomitantly with high-dose or standard-dose TMP-SMX, were largely descriptive.



References:

Nguyen AT, Gentry CA, Furrh RZ. A comparison of adverse drug reactions between high- and standard-dose trimethoprim-sulfamethoxazole in the ambulatory setting. Curr Drug Saf. 2013;8(2):114-119. doi:10.2174/1574886311308020004