Abstract
Purpose
Ciprofloxacin can inhibit the cytochrome P450-mediated metabolism of theophylline, but the clinical relevance of this drug interaction is uncertain. We studied the risk of theophylline toxicity associated with the co-prescription of ciprofloxacin and theophylline.
Methods
This was a population-based, nested case–control study of a cohort of Ontario residents aged 66 years of age or older treated with theophylline between April 1, 1992 and March 31, 2009. Within this group, case patients were those hospitalized with theophylline toxicity. For each case, 50 age- and sex-matched control patients were identified from the same cohort. The odds ratio (OR) for the association between hospitalization for theophylline toxicity and receipt of ciprofloxacin in the 14 days preceding hospitalization was determined.
Results
Among the 77,251 elderly patients receiving therapy with theophylline, 180 eligible case patients hospitalized for theophylline toxicity and 9000 matched controls were identified. Following multivariable adjustment, a nearly twofold increase in the risk of theophylline toxicity following the receipt of ciprofloxacin was observed [adjusted OR 1.86, 95% confidence interval (CI) 1.18–2.93]. In contrast, there was no increased risk of theophylline toxicity within a group of patients receiving neutral comparator antibiotics (levofloxacin, trimethoprim-sulfamethoxazole or cefuroxime) (adjusted OR 0.78; 95% CI 0.38–1.62).
Conclusion
Treatment with ciprofloxacin is associated with a significant increase in the risk of theophylline toxicity. When clinically appropriate, alternate antibiotics should be considered for elderly patients receiving theophylline.
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References
Barnes PJ (2005) Theophylline in chronic obstructive pulmonary disease: new horizons. Proc Am Thorac Soc 2:334–339
Zhou Y, Wang X, Zeng X et al (2006) Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology 11:603–610
Ram FS, Jardin JR, Atallah A et al (2005) Efficacy of theophylline in people with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. Respir Med 99:135–144
Yasui K, Agematsu K, Shinozaki K et al (2000) Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism. J Leukoc Biol 67:529–535
Ito K, Lim S, Caramori G et al (2002) A molecular mechanism of action of theophylline: induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci USA 99:8921–8926
Barnes PJ, Adcock IM, Ito K (2005) Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J 25:552–563
Ford PA, Durham AL, Russell RE, Gordon F, Adcock IM, Barnes PJ (2010) Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest 137:1338–1344
Cosio BG, Soriano JB (2009) Theophylline again? Reasons for believing. Eur Respir J 34:5–6
Wang Y, Wang CZ, Lin KX, Qian GS, Zhuo WL, Li SP (2005) Comparison of inhaled corticosteroid combined with theophylline and double-dose inhaled corticosteroid in moderate to severe asthma. Respirology 10:189–195
Dadashzadeh S, Tajerzaden H (2001) Dose dependent pharmacokinetics of theophylline: Michaelis–Menten parameters for its major metabolic pathways. Eur J Drug Metab Pharmacokinet 26:77–83
Dahlqvist R, Billing B, Miners JO, Birkett DJ (1984) Nonlinear metabolic disposition of theophylline. Ther Drug Monit 6:290–297
Self TH, Chafin CC, Soberman JE (2000) Effect of disease states on theophylline serum concentrations: are we still vigilant? Am J Med Sci 319:177–182
Sessler CN (1990) Theophylline toxicity: clinical features of 116 consecutive cases. Am J Med 88:567–576
Mountain RD, Neff TA (1984) Oral theophylline intoxication. a serious error of patient and physician understanding. Arch Intern Med 144:724–727
Pashko S, Simons WR, Sena MM, Stoddard ML (1994) Rate of exposure to theophylline-drug interactions. Clin Ther 16:1068–1077
Zhang ZY, Kaminsky LS (1995) Characterization of human cytochromes P450 involved in theophylline 8-hydroxylation. Biochem Pharmacol 50:205–211
Ha HR, Chen J, Freiburghaus AU, Follath F (1995) Metabolism of theophylline by cDNA-expressed human cytochromes P-450. Br J Clin Pharmacol 39:321–326
Mahr G, Sörgel F, Granneman GR et al (1992) Effects of temafloxacin and ciprofloxacin on the pharmacokinetics of caffeine. Clin Pharmacokinet 22[Suppl 1]:90–97
Fuhr U, Anders EM, Mahr G, Sörgel F, Staib AH (1992) Inhibitory potency of quinolone antibacterial agents against cytochrome P450IA2 activity in vivo and in vitro. Antimicrob Agents Chemother 36:942–948
Iyer Parameswaran G, Murphy TF (2009) Chronic obstructive pulmonary disease: role of bacteria and updated guide to antibacterial selection in the older patient. Drugs Aging 26(12):985–995
Albertson TE, Chan AL (2009) Antibiotic therapy in elderly patients with acute exacerbation of chronic bronchitis. Expert Rev Respir Med 3:539–548
Batty KT, Davis TM, Ilett KF, Dusci LJ, Langton SR (1995) The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects. Br J Clin Pharmacol 39:305–311
Davis RL, Quenzer RW, Kelly HW, Powell JR (1992) Effect of the addition of ciprofloxacin on theophylline pharmacokinetics in subjects inhibited by cimetidine. Ann Pharmacother 26:11–13
Schwartz J, Jauregui L, Lettieri J, Bachmann K (1988) Impact of ciprofloxacin on theophylline clearance and steady-state concentrations in serum. Antimicrob Agents Chemother 32:75–77
Loi CM, Parker BM, Cusack BJ, Vestal R (1993) Individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism in male nonsmokers. Br J Clin Pharmacol 36:195–200
Robson RA, Begg EJ, Atkinson HC, Saunders DA, Frampton CM (1990) Comparative effects of ciprofloxacin and lomefloxacin on the oxidative metabolism of theophylline. Br J Clin Pharmacol 29:491–493
Prince RA, Casabar E, Adair CG, Wexler DB, Lettieri J, Kasik JE (1989) Effect of quinolone antimicrobials on theophylline pharmacokinetics. J Clin Pharmacol 29:650–654
Wijnands WJ, Vree TB, van Herwaarden CL (1986) The influence of quinolone derivatives on theophylline clearance. Br J Clin Pharmacol 22:677–683
Spivey JM, Laughlin PH, Goss TF, Nix DE (1991) Theophylline toxicity secondary to ciprofloxacin administration. Ann Emerg Med 20:1131–1134
Semel JD, Allen N (1991) Seizures in patients simultaneously receiving theophylline and imipenem or ciprofloxacin or metronidazole. South Med J 84:465–468
Karki SD, Bentley DW, Raghavan M (1990) Seizure with ciprofloxacin and theophylline combined therapy. DICP 24:595–596
Richardson JP (1990) Theophylline toxicity associated with the administration of ciprofloxacin in a nursing home patient. J Am Geriatr Soc 38:236–238
Thomson AH, Thomson GD, Hepburn M, Whiting B (1987) A clinically significant interaction between ciprofloxacin and theophylline. Eur J Clin Pharmacol 33:435–436
Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA (2003) Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 289:1652–1658
Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA (2004) Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 351:543–551
Park-Wyllie LY, Juurlink DN, Kopp A et al (2006) Outpatient gatifloxacin therapy and dysglycemia in older adults. N Engl J Med 354:1352–1361
Lipscombe LL, Gomes T, Lévesque LE, Hux JE, Juurlink DN, Alter DA (2007) Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA 298:2634–2643
Lubin JH, Gail MH (1984) Biased selection of controls for case-control analyses of cohort studies. Biometrics 40:63–75
Austin PC, Grootendorst P, Anderson GM (2007) A comparison of the ability of different propensity score models to balance measured variables between treated and untreated subjects: a Monte Carlo study. Stat Med 26:734–753
Schneeweiss S, Seeger JD, Maclure M, Wang PS, Avorn J, Glynn RJ (2001) Performance of comorbidity scores to control for confounding in epidemiologic studies using claims data. Am J Epidemiol 154:854–864
Acknowledgments
We thank Brogan Inc., Ottawa for use of their Drug Product and Therapeutic Class Database.
Conflicts of interest and financial disclosure
Tony Antoniou has received an unrestricted research grant from Glaxo-Smith-Kline Inc, Merck and Pfizer for a number of different studies. Ms. Gomes has no conflicts of interest to disclose. Dr. Mamdani has no conflicts of interest to disclose. Dr. Juurlink has no conflicts of interest to disclose.
Funding/support
Tony Antoniou is supported by a scholarship from the Canadian Observational Cohort (CANOC) Collaboration. This project was supported by research funds from the Ontario Drug Policy Research Network, the Canadian Institutes of Health Research and the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The sponsors had no role in the design and conduct of the study, in the collection, analysis and interpretation of the data or in the preparation, review or approval of the manuscript. The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred.
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Appendix 1: Medications included in multivariable model
Appendix 1: Medications included in multivariable model
Medication use in 90 days preceding index date:
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CYP1A2 inhibitors: Allopurinol, Cimetidine, Disulfiram, Duloxetine, Ethinyl estradiol, Fluvoxamine, Isoniazid, Mefenamic acid, Mexiletine, Norfloxacin, Propafenone, Propranolol, Propylthiouracil, Riluzole, Rofecoxib, Ticlopidine
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CYP3A4 inhibitors: Amiodarone, Amprenavir, Aprepitant, Atazanavir, Clarithromycin, Darunavir, Delavirdine, Diltiazem, Erythromycin, Fluconazole, Fosamprenavir, Imatinib, Indinavir, Itraconazole, Lopinavir/ritonavir, Nefazodone, Nelfinavir, Ritonavir, Saquinavir, Telithromycin, Verapamil, Voriconazole
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CYP1A2/3A4 inducers: Amobarbital, Carbamazepine, Dexamethasone, Efavirenz, Etravirine, Nevirapine, Phenobarbital, Phenytoin, Pioglitazone, Primidone, Rifampin, Secobarbital
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Antoniou, T., Gomes, T., Mamdani, M.M. et al. Ciprofloxacin-induced theophylline toxicity: a population-based study. Eur J Clin Pharmacol 67, 521–526 (2011). https://doi.org/10.1007/s00228-010-0985-0
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DOI: https://doi.org/10.1007/s00228-010-0985-0