Electrolyte abnormalities associated with antibacterial agents

August 2004

The antibacterial agents are frequently cited as causes of drug intolerance or allergic reactions. However, all medications are associated with unintended effects, which range in severity from minor irritations to life-threatening reactions. Adverse drug reactions may be associated with either the entire class of agents, such as ß-lactam–induced drug fever, or more commonly with an individual product, such as trovafloxacin (Trovan, Pfizer)-associated hepatic injury.

Common adverse effects associated with antibacterial agents include hypersensitivity reactions, gastrointestinal effects and nephrotoxicity. This article will focus on the less-recognized adverse reaction of electrolyte imbalance associated with antibacterial therapy. It should be noted that diarrhea and nephrotoxicity can have a significant impact on an individual’s electrolyte balance, but those issues will not be covered at this time.

Potassium imbalances

Electrolyte abnormalities associated with antimicrobial therapy frequently affect potassium and magnesium, and less frequently, sodium and calcium. The electrolyte that antibacterial agents affect most is potassium; the agents may cause either hypo- or hyperkalemia. In most cases, the electrolyte abnormality is associated with an individual agent and should not be considered a class effect.

IV penicillin G has been associated with both hypo- and hyperkalemia, although hyperkalemia is more frequent. Penicillin G is formulated as a potassium salt and contains 1.75 mEq of potassium per million units of penicillin. A sodium salt formulation is also available and contains 2 mEq of sodium per million units of penicillin. However, the potassium formulation is more frequently used in clinical practice. The usual adult dose of penicillin G ranges from 12 to 30 million units per day depending on the indication for use. This will also deliver approximately 24 to 60 mEq of potassium per day. In most patients, the kidneys are able to adequately excrete the additional potassium load, but accumulation may occur. Patients receiving high daily doses or who have decreased renal function are at particular risk for developing significant hyperkalemia. Therefore, serum potassium should be monitored regularly.

If a patient does develop clinically significant hyperkalemia, immediate treatment would include an anion exchange resin or other standard treatment modalities. To continue the IV penicillin G therapy, several interventions can be made to lessen or prevent hyperkalemia from occurring again. The patient could be given regularly scheduled doses of an anion exchange resin, but this may not be very palatable for the patient. One could also request that the sodium formulation of penicillin G be used instead of the potassium-containing product.

Rarely, penicillin G has been associated with hypokalemia. In these cases, it is thought that penicillin may be acting as a nonresorbable anion, which promotes the excretion of potassium.

The extended-spectrum penicillin ticarcillin has been associated with significant hypokalemia. Although ticarcillin is no longer available in the United States, the ß-lactam/ß-lactamase inhibitor combination of ticarcillin-clavulanic acid (Timentin, GlaxoSmithKline) is also associated with hypokalemia. Ticarcillin-clavulanic acid contains approximately 4.75 mEq of sodium per gram of drug. Therefore, an individual may receive between 58 and 88 mEq of sodium each day while receiving ticarcillin-clavulanic acid. This sodium loading is the cause of hypokalemia. As the sodium load is introduced to the kidneys, they will perceive the body’s need for the extra sodium, causing the kidneys to retain it. This results in a compensatory spilling of potassium, causing hypokalemia. Patients should have frequent monitoring of potassium and may require potassium replacement.

Hypokalemia is infrequently associated with piperacillin or piperacillin-tazobactam (Zosyn, Wyeth), as the sodium load is much smaller when compared with ticarcillin-clavulanic acid. The sodium content of piperacillin is approximately 1.85 mEq of sodium per gram of drug.

Therapy with trimethoprim-sulfamethoxazole has been associated with hyperkalemia. This reaction is related to the trimethoprim component and not the sulfa component. Trimethoprim is an organic cation and acts similar to amiloride, a potassium-sparing diuretic (Ann Intern Med. 1993;119:296-301). Trimethoprim blocks apical membrane sodium channels in the distal nephron, resulting in decreased urine potassium excretion and increased serum potassium.

Hyperkalemia has been found to occur with all doses of trimethoprim. It has also been reported with both oral and IV formulations. However, when using standard doses, such as those used for treating urinary tract infections, hyperkalemia is usually not significant, with only small rises in the serum potassium (Am J Nephrol. 1999;19:389-394). Clinically significant hyperkalemia is more likely to occur when high-dose trimethoprim-sulfamethoxazole is used, such as in the treatment of Pneumocystis carinii pneumonia or Nocardia. Patients should have serum potassium monitored, especially if they have impaired renal function or are receiving high-dose therapy.

Hyponatremia

There are a few case reports of hyponatremia associated with the use of quinupristin-dalfopristin (Synercid, Monarch), with serum sodium levels falling to critical levels. In one case report, the serum sodium dropped to below 120 mmol/L after seven days of therapy (Ann Intern Med. 2000;133:485 [Letter]). The decrease in serum sodium was accompanied by a decrease in serum osmolarity and an increase in urine osmolarity. The serum sodium and serum osmolarity returned to normal when quinupristin-dalfopristin was discontinued. These are similar findings to what is seen with inappropriate secretion of antidiuretic hormone, and this is the proposed mechanism by which quinupristin-dalfopristin induces this syndrome.

Electrolyte imbalance can be due to numerous reasons in patients with serious illnesses. The possibility that an antibacterial agent could be the cause of the electrolyte abnormality is often overlooked. Antibacterial agents primarily cause imbalance in potassium homeostasis, but can also affect other electrolytes as well.

For more information:

• Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal mechanism of trimethoprim-induced hyperkalemia. Ann Intern Med. 1993;119:296-301.
• Alappan R, Buller GK, Perazella MA. Trimethoprim-sulfamethoxazole therapy in outpatients: is hyperkalemia a significant problem? Am J Nephrol. 1999;19:389-394.
• Cole RP, Roberts WD, Cheng MD. Hyponatremia associated with quinupristin-dalfopristin. Ann Intern Med. 2000;133:485 (Letter).

• Marianne Billeter, PharmD, BCPS, is Clinical Pharmacology Specialist, Infectious Diseases, at Ochsner Clinic Foundation, New Orleans.