The Risks of Using Trimethoprim/Sulfamethoxazole in Patients with Renal and Cardiac Compromise

Abstract

The purpose of this article is to familiarize physicians with the risks of prescribing trimethoprim/sulfamethoxazole (TMP/SMX) for patients who have kidney or cardiac pathology, have hyperkalemia, or take other interacting medications. Although TMP/SMX is a drug that is frequently used to treat skin and soft-tissue infections of the leg and foot, particularly if methicillin-resistant Staphylococcus aureus is identified, it is not an innocuous antibiotic. Literature documenting the many adverse effects of TMP/SMX is reviewed. A case history is presented illustrating the association of TMP/SMX with the development of a life-threatening situation. Ways of avoiding these adverse events are discussed, and the use of safer antibiotics is recommended.

Trimethoprim/sulfamethoxazole (TMP/SMX) (Bactrim; AR Scientific, Philadelphia, Pennsylvania) was approved by the Food and Drug Administration in 1973 and was first sold in the United States in 1974 to treat a variety of bacterial infections [1]. Since then, it has been listed as one of the recommended treatments for soft-tissue and skin infections [2,3] caused by gram-positive and gram-negative bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) [4–6].

Although approved for this type of treatment, TMP/SMX is not benign; it can cause acute kidney injury and symptomatic hyperkalemia. The risk of prescribing TMP/SMX is further increased if it is prescribed when the patient has a preexisting high serum creatinine level, low glomerular filtration rate, or hyperkalemia. These serious effects are more likely to occur if the patient has a compromised renal or cardiac system [7–27]. The risks of prescribing TMP/SMX are further increased if the patient is taking one or more of the following cardiac or kidney medications: amiloride, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, spironolactone, and potassium supplements [10,13]. In addition, patients who take nonsteroidal anti-inflammatory drugs are also more likely to develop hyperkalemia [10].

The following studies more specifically document that TMP/SMX can potentiate cardiac and renal pathology. Kalowski et al [7] found that TMP/SMX should not be prescribed for patients with a serum creatinine level greater than 2 mg/dL or creatinine clearance less than 40 mL/min because it causes deterioration of renal function. Retrospective studies by Gentry and Nguyen [10] and Rajput et al [11] showed that patients taking TMP/SMX developed acute kidney injury and hyperkalemia more frequently than those treated with other antibiotics. Parham et al [28] showed how hyperkalemia could, by itself, induce deadly cardiac arrhythmias in patients with renal dysfunction. These changes were especially noted when elevated creatinine levels or cardiac pathology were reported before taking TMP/SMX [10,13].

Case Report

The following case report illustrates the life-threatening pathology that can develop when TMP/SMX is prescribed for patients with preexisting renal and cardiac pathology.

An interview of the patient by one of us (A.F.H.) revealed the following history. The patient noted a painful red “bump” on the dorsum of his foot that became larger and more painful and evolved to become “a hole in his foot” (Fig. 1). He then sought podiatric medical care. He indicated that the treating podiatric physician did not inquire about his medical history, did not take any cultures of the wound, and did not debride the wound. He was given prescriptions for a 7-day course of TMP/SMX twice daily and for Tylenol with Codeine #3 (Teva Pharmaceuticals USA, Parsippany, New Jersey). Eight days later he contacted his podiatric physician because he was in more pain and the wound seemed to be worse. The podiatric physician prescribed a 10-day course of TMP/SMX. After taking TMP/SMX for 3 days, the patient indicated that he “felt weird” and noted that his legs had “swelled up” and that he could not breathe. He thought he was having a heart attack and called 911. He was taken to the emergency department at a local hospital.

Figure 1. View of foot ulceration.

Figure 1. View of foot ulceration.

The following medical history was obtained from the patient‘s cardiologist. The patient was a 76-year-old man who, several months before his 911 call, was documented as having adult-onset diabetes, hypertension, severe coronary artery disease, a recent myocardial infarction complicated by congestive heart failure, abnormal electrocardiograms, and renal functional impairment, with a serum creatinine level of 1.67 mg/dL (reference range, 0.5–1.30 mg/dL) and a potassium level of 5.1 mEq/L (reference range, 3.6–5.2 mEq/L). His medications included metformin, pregabalin (Lyrica; Viatris Inc, Canonsburg, Pennsylvania), irbesartan (Avapro; sanofi‐aventis US, Bridgewater, New Jersey), carvedilol, minoxidil, and spironolactone. Laboratory tests taken on admission at the emergency department laboratory showed an elevated potassium level of 6.1 mEq/L (reference range, 3.6–5.2 mEq/L) and an elevated creatinine level of 5.73 mg/dL (reference range, 0.5–1.30 mEq/L). Cultures showed the presence of MRSA. A photograph of the lesion is shown in Fig. 1.

In the several hours after admission to the hospital, the patient became oliguric and hypertensive. The serum potassium level rose to 6.5 mE/L, the creatinine level rose to 6.79 mg/dL, and the troponin I level rose to 1.52 (from a normal level of 0.04 ng/mL on admission). At this point, he was diagnosed as having acute coronary syndrome with myocardial necrosis/heart attack. The rising serum potassium and creatinine levels along with his falling urine output levels resulted in him being placed on hemodialysis. Due to the abnormal blood chemistries, the patient exhibited confusion, agitation, and respiratory failure. He was intubated and placed on a ventilator. Shortly thereafter, he developed atrial fibrillation with a rapid ventricular rate and rising troponin I levels. This indicated a worsening myocardial ischemia/infarction. After the next 2 days of dialysis, the fibrillation terminated and normal heart rate resumed. The respiratory status improved and he was extubated. The troponin I levels reached a peak 15.00, indicating a moderately large amount of myocardial necrosis. With continuing dialysis, the serum creatinine levels lowered but remained greater than 2.0 mg/dL. After several days in the hospital, the patient’s urine output increased. He was discharged from the hospital after 3 weeks and continued on dialysis for an additional month. His cardiologist discontinued his taking spironolactone and continued him on furosemide. Three months after his release from the hospital, his creatinine level was 1.65 mg/dL and his potassium level ranged from 2.8 to 4.1 mEq/L (reference range, 3.6–5.2 mEq/L). His cardiac status improved to pre-event levels, and he was advised never to take TMP/SMX in the future.

Discussion

Trimethoprim/sulfamethoxazole has been described as being “randomly” and “freely” prescribed by clinicians who were not aware of its potential deleterious actions [29]. It is not the purpose of this article to prove that TMP/SMX was the cause of this patient’s heart attack, renal failure, and atrial fibrillation. Instead, it is to prevent the use of TMP/SMX when cardiac or renal pathology is present and to emphasize the importance of obtaining a thorough medical history, a review of symptoms, and a complete list of medications before prescribing TMP/SMX.

The need to use alternative antibiotics to TMP/SMX was emphasized by Antoniou and colleagues [30], who, over a 14-year study, identified 4,148 hospital admissions for hyperkalemia and found that “compared with amoxicillin, the use of TMP/SMX was associated with nearly a 7-fold increased risk of hyperkalemia hospitalizations. No such risk was found with comparator antibiotics.” If patients, such as the one described in this case history, require an antibiotic to treat MRSA, other acceptable antibiotics are doxycycline and minocycline [6]. Clindamycin has also been recommended [2]. However, its use is associated with the onset of Clostridium difficile–induced colitis [31]. If required, linezolid can be considered [6].

Because many patients with cardiac and renal pathology are taking multiple medications, there is increased risk of adverse drug interactions. These adverse drug interactions can easily be avoided by using one of the free digital drug interaction checkers that can be found online, including PDR, Epocrates, Avicenna, and Medline/Medscape. When the combination of TMP/SMX (Bactrim) and spironolactone is listed, several drug interaction checkers identify “moderate” or “serious” risks (depending on the app). With so many medications presently being used, the drug interaction checker is a most needed tool. If a drug interaction checker is not available, hospital pharmacies can be contacted to determine potential drug interactions.

Conclusions

Trimethoprim/sulfamethoxazole should not be prescribed for patients who have inadequate cardiac or renal function or who take the following medications: amiloride, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, spironolactone, and potassium supplements. In addition, those taking nonsteroidal anti-inflammatory drugs are more likely to develop hyperkalemia, which increases the probability of TMP/SMX having adverse effects. Also, TMP/SMX can cause life-threatening conditions such as acute kidney injury, congestive heart failure, hyperkalemia, and increased cardiac pathology. If the patient’s status is not known, alternative antibiotics should be prescribed.