Nephrotoxic Interaction between Cyclosporine and Ciprofloxacin
Daisy Chung, PharmD
Jawaid Akhtar, MD
Toxicology Treatment Program
Department of Emergency Medicine
Address for Correspondence:
Toxicology Treatment Program
Int J Med Toxicol 2000; 3(2): 9
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Cyclosporine and ciprofloxacin have been used in the transplant setting. Cyclosporine, an immunosuppressive agent, is used to prevent organ rejection in kidney, liver, and heart transplant patients. It inhibits both interleukin-2 production and interleukin-2 induced T-lymphocyte proliferation. Ciprofloxacin, a broad-spectrum fluoroquinolone antibiotic, may be used to treat various post-transplant infections. However, there have been reports in the literature of enhanced nephrotoxicity associated with the concommitant use of ciprofloxacin with cyclosporine. This toxicity may be the result of a pharmacokinetic or pharmacodynamic interaction. This article will focus on the possible association between increased nephrotoxicity and the cyclosporine-ciprofloxacin combination.
A 58-year-old heart transplant recipient was started on immunosuppression therapy with prednisone and cyclosporine. The patient’s cyclosporine maintenance dose was 4.0 - 4.7 mg/kg/day. Thirty-four months post-transplant, the patient underwent hip surgery and subsequently developed wound cellulitis and bacteremia. He was treated with a 17-day course of imipenem-cilastatin and was discharged on ciprofloxacin 750 mg orally every 8 hours. Four days after ciprofloxacin initiation, the patient’s serum creatinine rose from 1.4 to 2.2 mg/dl. Other findings included a normal urinalysis and normal renal ultrasound. Ciprofloxacin was discontinued, and the patient remained on prednisone therapy. Creatinine levels returned to baseline over two weeks without dialysis.
A major side effect of cyclosporine is nephrotoxicity, which has been reported in 25-38 % of kidney, liver, and heart transplant cases. Clinical presentation may include prolonged acute tubular necrosis and gradual rise in serum creatinine (< 0.15 mg/dl/day). The exact mechanism of nephrotoxicity is unknown. However, ischemia and decreased renal blood flow may play a role.
The monitoring of blood and plasma cyclosporine levels is useful in dosage adjustments. The therapeutic range is not absolutely defined, as it is both method and specimen-dependent. It is recommended that the same analytical method be used consistently. Cyclosporine level monitoring is also useful in differentiating between nephrotoxicity and graft rejection. High cyclosporine concentrations increase the risk of nephrotoxicity, while low concentrations increase the risk of graft rejection.
Cyclosporine undergoes extensive hepatic metabolism by cytochrome P450 III-A enzymes. Therefore, monitoring of cyclosporine levels is important with the concomitant administration of drugs that affect hepatic enzymes, including phenytoin and fluconazole. Caution should also be exercised if nephrotoxic drugs are concomitantly administered with cyclosporine.3
Nephrotoxicity associated with ciprofloxacin is rare. There are few case reports of interstitial nephritis, nonspecific nephritis, and acute renal failure associated with ciprofloxacin.1
Ciprofloxacin is not as extensively metabolized in the liver as cyclosporine. Approximately 30-50% of the drug undergoes renal excretion, while 20-40 % undergoes biliary excretion. Since most of the drug is excreted renally, it is necessary to adjust the dose of ciprofloxacin in patients with renal insufficiency. Ciprofloxacin is an inhibitor of cytochrome P450 I-A2 hepatic enzymes, which may lead to interactions with drugs that are metabolized through this pathway. 3
There is conflicting information in the literature about the possible interaction between ciprofloxacin and cyclosporine. Most of the case reports suggest a synergistic nephrotoxicity.4 However, pharmacokinetic studies suggest a lack of interaction.
Nasir et al. describe two case reports of increased cyclosporine levels with ciprofloxacin.5 The first case is about a heart-lung transplant recipient who was started on ciprofloxacin for infection eight months post-transplant. Ciprofloxacin was dosed at 500 mg orally three times daily. Twenty-eight hours after ciprofloxacin initiation, cyclosporine levels rose from 538 to 1613 ng/ml. Serum creatinine also increased from 1.6 to 2.2 mg/dl. The second case is about a renal transplant recipient who was started on the same ciprofloxacin regimen for an infected foot ulcer. Four weeks after ciprofloxacin initiation, cyclosporine levels increased from 497 to 1032 ng/ml. Information on the patient’s serum creatinine was not given.
In both cases, a correlation between the metabolism of cyclosporine and ciprofloxacin was not shown. Cyclosporine is metabolized through a pathway different from the one that ciprofloxacin inhibits. Therefore, the two drugs should not pharmacokinetically interact. In addition, pharmacokinetic studies have shown that the two drugs are metabolized by different cytochrome 450 enzymes.6
Elston and Taylor reported the case of a cardiac transplant recipient with pyelonephritis who took ciprofloxacin 500 mg orally twice daily.7 After 14 days of ciprofloxacin, the patient’s serum creatinine increased from 123.8 to 176.8 m mol/L. However, cyclosporine levels did not increase.
In this case, a clear association between ciprofloxacin-cyclosporine and nephrotoxicity was not shown. Other factors, rather than ciprofloxacin, may have contributed to the elevation in serum creatinine. Perhaps the patient was also taking nephrotoxic drugs. However, information about the patient’s other medications was not given.
Although these case reports suggest an interaction between cyclosporine and ciprofloxacin, multiple pharmacokinetic studies have refuted these findings. Lang et al. studied ten kidney transplant patients who received ciprofloxacin 750 mg orally twice daily for 7 days.8 Cyclosporine levels were maintained between 100 to 200 ng/ml. Ciprofloxacin did not appear to have an effect on cyclosporine and serum creatinine levels. Also, it did not appear to increase the risk of nephrotoxicity.
Van Buren et al. studied 15 renal transplant patients receiving ciprofloxacin 500 mg orally twice daily for 7 days.9 No significant changes were seen in serum creatinine and cyclosporine pharmacokinetic parameters before and after ciprofloxacin therapy. Cyclosporine-induced nephrotoxicity was not seen, despite the addition of ciprofloxacin.
Unlike previous studies, Tan et al. conducted a study on ten healthy male volunteers.10 This was a randomized two-period crossover study with a six-day washout period. Ciprofloxacin was dosed at 500 mg orally twice a day, and cyclosporine was dosed at 5 mg/kg/d. Mean cyclosporine concentrations did not change with or without ciprofloxacin.
Pharmacokinetic studies have suggested a lack of interaction between ciprofloxacin and cyclosporine. This matches the fact that cyclosporine is affected by a different metabolic pathway than ciprofloxacin. Confounding factors, such as other medications and comorbidities, may have resulted in the nephrotoxicity described in case reports. However, it would be prudent to monitor cyclosporine levels and exercise caution with the coadministration of ciprofloxacin and cyclosporine.
- Hoey LL, Lake KD. Does ciprofloxacin interact with cyclosporine? Ann Pharmacother 1994;28:93-6.
- Avent CK, Krinsky D, Kirklin JK, et al. Synergistic nephrotoxicity due to ciprofloxacin and cyclosporine. Am J Med 1988;85:452-3.
- Threlkeld DS, et al. Drug Facts and Comparisons. 1999 ed. St. Louis: Facts and Comparisons, 1999: 738c.
- Burckart GJ, Venkataramanan R, Ptachcinski RJ. Overview of transplantation. In: Pharmacotherapy: a pathophysiologic approach. 3rd ed. Stamford: Appleton & Lange, 1997: 129-147.
- Nasir M, Rotellar C, Hand M, et al. Interaction between cyclosporin and ciprofloxacin. Nephron 1991;57:245-6.
- Elston RA, Taylor J. Possible interaction of ciprofloxacin with cyclosporin A. J Antimicrob Chemother 1988;21(5):679-80.
- Lang J, de Villaine JF, Garraffo R, et al. Cyclosporine (cyclosporin A) pharmacokinetics in renal transplant patients receiving ciprofloxacin. Am J Med 1989;87(5A):82S-85S.
- Van Buren DH, Koestner J, Adedoyin A, et al. Effect of ciprofloxacin on cyclosporine pharmcokinetics. Transplantation 1990;50(5):888-9.
- Tan KKC, Trull AK, Shawket S. Co-administration of ciprofloxacin and cyclosporin: lack of evidence for a pharmacokinetic interaction. Br J Clin Pharmacol 1989;28:185-7.
Int J Med Toxicol 2000; 3(2): 9
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