- Email: [email protected]
Theophylline toxicity secondary to ciprofloxacin administration
CASE REPORT ciprofioxacin, interaction with theophylline; theophylline, interaction with ciprofloxacin
Theophylline Toxicity Secondary to Ciprofloxacin Administration We report the case of a 79-year-old woman who presented from a skilled nursing facility to the emergency department with signs and symptoms of theophylline toxicity and a serum theophylline concentration of 53.7 rag~ L. The patient had been on a regular regimen of aminophylline for two months, with the addition of ciprofloxacin three days before arrival as the only identifiable potential cause of theophylline intoxication. She was monitored and treated conservatively with serial doses of activated charcoal, which resulted in a reduction of her serum theophylline level to a therapeutic cpncentration in i5 hours without adverse sequelae. The number of cases of theophylline intoxication secondary to concurrent ciprofloxacin administration is likely to increase, especially in nursing home populations, and it should be suspected when these patients present to the ED with the appropriate signs and symptoms. Management of theophylline intoxication should be based on clinical presentation as well as concentrations of the drug. [Spivey JM, Laughlin PH, Goss TF, Nix DE: Theophylline toxicity secondary to ciprofloxacin administration. Ann Emerg Med October 1991;20:113Ll134.]
INTRODUCTION Ciprofloxacin, a fluoroquinolone antibiotic, is active against a broad spectrum of Gram-negative and Gram-positive organisms. Because of the ease of oral administration and the increased activity against Gram-negative bacterial pathogens, ciprofloxacin is becoming an attractive antibiotic to use for urinary tract, soft tissue, and bone infections in the nursing home patient. Recently, results from two clinical trials have suggested that ciprofloxacin is a cost-effective alternative to cefamandole and ceftazidime in the treatment of lower respiratory tract infections in nursing h o m e patients. 1,z Nursing home residents may be at increased risk for significant drug interactions with ciprofloxacin because of the number of medications they receive. Also, when administered the same dose given to younger patients, elderly patients reach and maintain higher serum ciprofloxacin concentrations than their younger counterparts. Ciprofloxacin administered concomitantly with theophylline in volunteers and patients has demonstrated the potential to reduce theophylline clearance significantly. 3-s Patients with chronic obstructive pulmonary disease (COPD) experience more frequent lower respiratory tract infections, which are also more often caused by organisms appropriate for ciprofloxacin treatment. Furthermore, these patients are often managed with chronic theophylline therapy. We report a case of theophylline toxicity believed to be secondary to ciprofloxacin administration in a nursing home patient with COPD.
J Michael Spivey, PharmD* Paul H Laughlin, MD, FACEPt Thomas F Goss, PharmD*¢ David E Nix, PharmD** Buffalo, New York From The Clinical Pharmacokinetics Laboratory* and Department of Emergency Medicine,t Millard Fillmore Hospital; and the School of Pharmacy, State University of New York at Buffalo,* Buffalo, New York. Received for publication February 11, 1991. Accepted for publication March 22, 1991. Address for reprints: David E Nix, PharmD, The Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, 3 Gates Circle, Buffalo, New York 14209.
CASE REPORT A 79-year-old nursing home patient was transported to the emergency department after she was found unresponsive, tachycardic, and in acute respiratory distress. On admission, examination revealed an agitated, confused w o m a n moderately short of breath with a productive cough and complaints of chest pain. Vital signs included a temperature of 36.1 C; pulse, 132 and irregular; respirations, 28; and blood pressure, 126/68 m m Hg. ECG monitoring revealed sinus tachycardia with multiple premature
20:10 October 1991
Annals of Emergency Medicine
1131/119
THEOPHYLLINE TOXICITY Spivey et al
ventricular and atrial contractions. The remainder of the physical examination was unremarkable. Her medical history was significant for long-standing COPD, coronary artery disease, and an anterior myocardial infarction three months prior to admission. Eight days before admission, she developed an elevated temperature and productive cough and was treated with 250 mg cephalexin every six hours. During the next throee days, there was no improvement in her lower respiratory tract infection. Her temperature increased to 38.7 C, and her WBC c o u n t was 10,100/mm 3 with 82% p o l y m o r p h o n u c l e a r cells and no bands. She was begun on 500 mg ciprofloxacin twice daily three days before admission, and a sputum culture was obtained. The culture later revealed s-hemolytic streptococci (not S t r e p t o c o c c u s p ~ e u m o n i a e ) and Neisseria c o n s i s t e n t with n o r m a l flora. Within 24 hours after starting ciprofloxacin, she became increasingly anxious. Medication on admission included 400 mg aminophylline four times daily, 500 mg ciprofloxacin twice daily, 2.5 mg terbutaline three times daily, 5 mg prednisone twice daily, 20 mg isosorbide d i n i t r a t e three times daily, 200 mg meprobamate four times daily, 40 mg furosemide twice daily, 10 mg hydroxyzine three times daily as needed for anxiety, and 50 mg diphenhydramine at bedtime. Of these medications, only ciprofloxacin was recently added to her treatment regimen. Forty days before admission, a morning, predose serum theophylline concentration of 17.1 mg/L had been obtained while she was on 400 mg aminophylline four t i m e s daily (7:00 AM, 11:00 AM, 4:00 PM, and 10:00 PM). Laboratory data on admission included an arterial blood gas with pH 7.44; Pco2, 42 m m Hg; Poz, 61 m m Hg; and HGO3, 28 mmol/L. The serum chemistry profile was remarkable for glucose of 194 mg/dL; sodium, 130 m m o l / L ; chloride, 81 mmol/L; and SGOT, 55 IU/L. Serial creatine phosphokinase isoenzymes showed no acute elevations in the MB-band. The serum theophylline concentration determined by fluorescence polarization immunoassay was reported as 107 mg/L approximately one hour after her morning aminophylline dose. 120/1132
FIGURE. Serum theophylline concentrations versus time after admission. Treatment included a 25-g aqueous slurry of activated charcoal followed by 100 mL magnesium citrate every two hours for a total of six doses. The patient was transferred to the intermediate cardiac care unit for telemetry monitoring. She remained in sinus tachycardia during the next 24 hours with occasional premature v e n t r i c u l a r c o n t r a c t i o n s . Subsequently, her heart rate and rhythm normalized, and she recovered uneventfully. The p a t i e n t was discharged back to the nursing home on 300 mg t h e o p h y l l i n e (Theodur ®) twice daily. A subsequent steadystate theophylline serum concentration was 14.8 mg/L. Serum theophylline concentrations are shown (Figure). Because of the unexpected drop in serum theophylline concentrations from 107 mg/L on admission to 38.6 mg/L eight hours after admission, we reassayed the admission serum sample both at our laboratory and at the hospital laboratory. The repeated serum theophylline concentrations were 55.5 and 52.0 mg/L, respectively, which suggested that a possible dilution error was made when the initial sample was first assayed. The serum theophylline concentrations declined to within the therapeutic range (10 to 20 rag/L) within 15 hours of admission (Figure). Her theophylline half-life based on the last four concentration time points was 6.1 hours while receiving activated charcoal.
DISCUSSION Many factors have been shown to inhibit theophylline metabolism, resulting in increased serum concentrations. Both congestive heart failure and the development of pneumonia have been noted to significantly reduce theophylline clearance.9,10 Our patient had no history or evidence of acute congestive heart failure. At the time of her acute myocardial infarction, a two-dimensional echocardiogram showed some left ventricular hypertrophy but a normal ejection fraction. F u r t h e r m o r e , no recent changes in cardiac medications were made. Her moderate tachycardia did not appear to diminish ventricular function. A n n a l s of E m e r g e n c y
Medicine
O0
10
r rl
0
5
l
lI
Jl
10 15 20 25 30 35 Time (hr)
Although pneumonia may cause a reduction in theophylline clearance, it did not appear to be a likely source of the elevated serum theophylline concentrations. The lower respiratory tract infection was first noted eight days before admission, and no symptoms of theophylline intoxication were noted for the first six days. O n l y after s t a r t i n g ciprofloxacin were the symptoms of intoxication noted. Her lower respiratory tract infection was either self-limiting or mild because she did not require further antimicrobial treatment during this admission. In healthy volunteers, ciprofloxacin has been shown to significantly decrease the m e a n t h e o p h y l l i n e clearance by 18% to 31% .3-6 In addition, Raoof et al reported a mean 10.5-mg/L increase in serum theophylline concentrations in 61% of hospitalized patients on t h e o p h y l l i n e when administered ciprofloxacin.Z Three cases of patients hospitalized because of theophylline toxicity secondary to ciprofloxacin administration have been reported in the literature. 11-1g Richardson reported a similar case in which a nursing home patient was hospitalized with a theophylline concentration of 53 mg/L after three days of ciprofloxacin administration. H Theophylline toxicity occurred within three to five days in the other two cases, one of which was fatal J2,13 In addition, other quinolone antibiotics similar in structure to ciprofloxacin also have been shown to impair t h e o p h y l l i n e clearance to 20:10 October 1991
THEOPHYLLINE TOXICITY Spivey et al
varying degrees.S,14, is Enoxacin increased the urinary excretion of unchanged theophylline and inhibited the elimination of theophylline urinary metabolites, thereby suggesting that the mechanism involved is inhibition of the cytochrome P4so isoenzymes responsible for theophylline metabolism. 14 The time course of this interaction was studied by Rogge and associates, who showed that the changes in theophylline concentrations were generally complete by three days after the addition or discontinuation of enoxacin. 15 This case emphasizes the difficulty in using isolated case reports to evaluate drug interactions. Before ciprofloxacin administration, the patient was stabilized on 400 mg aminophylline (320 mg theophylline) before meals and at bedtime with a reported serum concentration of 17.1 mg/L. She then was started on ciprofloxacin and exhibited both clinical and laboratory evidence of theophylline intoxication. Review of medication administratio n and pharmacy records indicated appropriate compliance. Subsequently, ciprofloxacin was stopped, and she was discharged on 300 mg theophylline (sustainedrelease) every 12 hours. A repeat theophylline c o n c e n t r a t i o n was 14.8 mg/L, despite a m u c h lower total daily theophylline dose than taken before admission. The preadmission theophylline concentration of 17.1 mg/L represented a trough concentration taken before her morning dose. Nine hours elapsed between her bedtime dose at 10:00 PM and her morning dose at 7:00 AM, allowing her theophylline c o n c e n t r a t i o n to decline to within the therapeutic range. To further probe the question of the discrepancy in the preadmission and postadmission theophylline concentrations, a computer simulation was used to estimate the patient's theophylline concentrations on her preadmission a m i n o p h y l l i n e regimen. From her discharge theophylline level, an estimated theophylline clearance of 1.69 L/hr was calculated. This clearance and the measured half-life from her admission were used in the simulation to estimate her theophylline concentrations before admission. A morning trough theophylline concentration of 17 mg/ L was estimated, which agreed with the preadmission theophylline concentration of 17.8 mg/L. In addition, 20:10 October 1991
an estimated theophylline concentration of 28 mg/L was simulated at the time the patient's initial admission sample of 55.5 mg/L was drawn. The simulation suggests that ciprofloxacin administration led to an approximately 46% to 49% increase in the patient's serum theophylline concentrations. It is plausible that the patient tolerated her chronic a m i n o p h y l l i n e regimen with estimated theophylline concentrations in the range of 17 to 38 mg/L with few clinical symptoms of intoxication. Once ciprofloxacin was begun, her theophylline concentrations were further elevated, and she became s y m p t o m a t i c . Within two doses of ciprofloxacin, she exhibited increased anxiety. Also, she received only a total of five doses of ciprofloxacin before admission. In addition, the patient was not tachycardiac before the day of admission. Her pulse ranged from 72 to 88 the three days before admission, which supports an acute rise in serum theophylline concentrations. Although the total magnitude of the interaction is difficult to assess, computer simulations and clinical data supported an acute elevation in theophylline concentrations. The decision to manage this case with multiple-dose activated charcoal was made in part because charcoal hemoperfusion is not readily available at our hospital. One criterion for prophylactic charcoal hemoperfusion for chronic theophylline toxicity is a serum concentration of more than 60 mg/L. 16 A leading toxicology text calls for charcoal hemoperfusion for patients more than 60 years with theophylline concentrations of more than 40 mg/L. 17 Charcoal hemoperfusion was discussed for this patient because of the serum theophylline c o n c e n t r a t i o n of 107 mg/L originally reported and the likelihood that the serum concentration would remain above 20 mg/L for a significant period. At high serum theophylline concentrations, metabolic enzyme saturation can occur, thereby reducing metabolic clearance. In fact, we observed saturation above 40 mg/L in this case. The proportionally slower theophylline e l i m i n a t i o n between the first and second time points probably represented metabolic saturation (Figure). If charcoal h e m o p e r f u s i o n had Annals of Emergency Medicine
been available, we may have subjected this patient to an invasive procedure that would not have been warranted because of an incorrectly reported serum theophylline concentration. Reanalysis of the admission serum sample by two laboratories showed the actual theophylline concentration to be 52.0 to 55.5 mg/L. Although the patient was still at risk for neurologic and cardiac complications at this theophylline concentration, reduction in her theophylline concentration by metabolic clearance andactivated charcoal treatment was sufficient. We must caution against the use of a single serum theophylline concentration to constitute a basis for initiating an invasive procedure such as charcoal hemoperfusion. Any value out of the assay limits should be p r o m p t l y r e p e a t e d to v e r i f y the value. Laboratories should have a procedure for verifying serious theophylline intoxications, and sample dilution schemes and results should be checked by a supervisor.
SUMMARY We report a case of theophylline toxicity that m o s t likely resulted from the administration of ciprofloxacin. Acute signs of intoxication, computer simulations, and well-documented interaction studies support this conclusion. When a patient is admitted with theophylline toxicity resulting from chronic theophylline administration, concurrent medications such as ciprofloxacin should be considered as a potential cause of the elevated t h e o p h y l l i n e c o n c e n t r a tions. With increased use of ciprofloxacin in nursing home patients, similar cases of ciprofloxacin-induced theophylline toxicity can be expected. To maintain stable theophylline concentrations, theophylline should be prescribed with constant dosing intervals {eg, every six hoursJ rather than four times a day with meals and at bedtiome. We advise caution in using a single serum theophylline concentration to determine the management of theophylline toxicity and suggest reanalyzing any sample out of the assay sensitivity limits before charcoal hemoperfusion is begun, except where the clinical situation dictates its use.
REFERENCES 1. Peterson PK, Stein D, Guay DR, et ah Prospective
1133/121
THEOPHYLLINE TOXICITY Spivey et al
study of lower respiratory tract infections in an extended-care nursing home program: Potential role of oral ciprofloxacin. A m J Med 1988;85:i64-171. 2. Tranholme GM, Schmitt BA, Spear J, et al: Randomized study of intravenous/oral ciprofloxacin versus ceftazidime in the treatment of hospital and nursing home patients with lower respiratory tract infections. A m J Med 1989~87(suppl 5A):1165-118S. 3. Nix DE, DeVito JM, Whitbread MA, et al: Effect of multiple dose oral ciprofloxacin on the pharmacokinetics of theophylline and indocyanine green. J Antimicrob Chemother 1987;I9:263-269. 4. Schwartz J, Jauregui L, Lettieri J, et ah Impact of ciproffoxacin on theophylline clearance and steady-state concentrations in serum. Antimicrob Agents Chemother 1988;32:75-77. 5. Wijnands WJA, Vree TB, Van Herwaarden CLA: The influence of quinolone derivatives on theophylline clearance. Br J Clin Pharmacol 1986;22:677-683. 6. Prince RA, Casabar E, Adair CG, et al: Effect of quire
122/1134
olone antimicrobials on theophylline pharmacokinetics. ] Clin Pharmacol 1989~29:650-654. 7. Raoof S, Wollschlager C, Khan IZA: Ciprofloxacin increases s e r u m levels of t h e o p h y l l i n e . A m ] M e d 1987;82(suppl 4A):118-118. 8. Rybak MJ, Bowles SK, Chandrasekar PH, et al: Increased theophylline concentrations secondary to ciprofloxacin. Drug Intell Clin Pharmacol 1987~2i:879-88i. 9. Jnsko WJ, Gardner MJ, Maugione A, et al: Factors affecting theophylline clearance: Age, tobacco, marijuana, cirrhosis, c o n g e s t i v e heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and ethanol. J Pharm Sci 1979;68:1358-1366. I0. Powell JR, Vozeh S, Hopeweli P, et al: Theophylline disposition in acutely ill hospitalized patients: The effect of smoking, heart failure, severe airway obstruction, and pneumonia. A m Rev Respir Dis 1978;118: 229-238. i1. Richardson JP: Theophylline toxicity associated with the administration of ciprofloxacin in a nursing
Annals of Emergency Medicine
home patient. J A m Geriatr Soc 1990;38:236-238. 12. Duraski RM: Ciprofloxacin-induced theophylline toxicity. S Med ] 1988;81:1206. 13. Holden R: Probable fatal interaction between cip ~ rofloxacin and theophylline. Br Med J 1988;297:1339. 14. Beckmann J, Elsaber W, Gundert-Remy U, et al: Enoxacin-A potent inhibitor of theophylline metabolism. Eur J Clin Pharrnacol 1987;33:227-230. 15. Rogge NIC, Solomon WR, Sedman AJ, et ah The theophylline-enoxacin interaction: II. Changes in the disposition of theophylline and its metaboiites during intermittent administration of enoxacin. Clin Pharmacol Ther 1989;46:420-428. 16. Goldberg MJ~ Park GD, Berlinger WG: Treatment of t h e o p h y l l i n e i n t o x i c a t i o n . J Aller Clin lrnmuno] 1986;78:811-817. 17. Haddad LM, Winchester JF: Clinical Management of Poisoning and Drug Overdose, ed 2. Philadelphia, WB Saunders, 1990, p 1415.
20:10 October 1991
Theophylline Toxicity Secondary to Ciprofloxacin Administration We report the case of a 79-year-old woman who presented from a skilled nursing facility to the emergency department with signs and symptoms of theophylline toxicity and a serum theophylline concentration of 53.7 rag~ L. The patient had been on a regular regimen of aminophylline for two months, with the addition of ciprofloxacin three days before arrival as the only identifiable potential cause of theophylline intoxication. She was monitored and treated conservatively with serial doses of activated charcoal, which resulted in a reduction of her serum theophylline level to a therapeutic cpncentration in i5 hours without adverse sequelae. The number of cases of theophylline intoxication secondary to concurrent ciprofloxacin administration is likely to increase, especially in nursing home populations, and it should be suspected when these patients present to the ED with the appropriate signs and symptoms. Management of theophylline intoxication should be based on clinical presentation as well as concentrations of the drug. [Spivey JM, Laughlin PH, Goss TF, Nix DE: Theophylline toxicity secondary to ciprofloxacin administration. Ann Emerg Med October 1991;20:113Ll134.]
INTRODUCTION Ciprofloxacin, a fluoroquinolone antibiotic, is active against a broad spectrum of Gram-negative and Gram-positive organisms. Because of the ease of oral administration and the increased activity against Gram-negative bacterial pathogens, ciprofloxacin is becoming an attractive antibiotic to use for urinary tract, soft tissue, and bone infections in the nursing home patient. Recently, results from two clinical trials have suggested that ciprofloxacin is a cost-effective alternative to cefamandole and ceftazidime in the treatment of lower respiratory tract infections in nursing h o m e patients. 1,z Nursing home residents may be at increased risk for significant drug interactions with ciprofloxacin because of the number of medications they receive. Also, when administered the same dose given to younger patients, elderly patients reach and maintain higher serum ciprofloxacin concentrations than their younger counterparts. Ciprofloxacin administered concomitantly with theophylline in volunteers and patients has demonstrated the potential to reduce theophylline clearance significantly. 3-s Patients with chronic obstructive pulmonary disease (COPD) experience more frequent lower respiratory tract infections, which are also more often caused by organisms appropriate for ciprofloxacin treatment. Furthermore, these patients are often managed with chronic theophylline therapy. We report a case of theophylline toxicity believed to be secondary to ciprofloxacin administration in a nursing home patient with COPD.
J Michael Spivey, PharmD* Paul H Laughlin, MD, FACEPt Thomas F Goss, PharmD*¢ David E Nix, PharmD** Buffalo, New York From The Clinical Pharmacokinetics Laboratory* and Department of Emergency Medicine,t Millard Fillmore Hospital; and the School of Pharmacy, State University of New York at Buffalo,* Buffalo, New York. Received for publication February 11, 1991. Accepted for publication March 22, 1991. Address for reprints: David E Nix, PharmD, The Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, 3 Gates Circle, Buffalo, New York 14209.
CASE REPORT A 79-year-old nursing home patient was transported to the emergency department after she was found unresponsive, tachycardic, and in acute respiratory distress. On admission, examination revealed an agitated, confused w o m a n moderately short of breath with a productive cough and complaints of chest pain. Vital signs included a temperature of 36.1 C; pulse, 132 and irregular; respirations, 28; and blood pressure, 126/68 m m Hg. ECG monitoring revealed sinus tachycardia with multiple premature
20:10 October 1991
Annals of Emergency Medicine
1131/119
THEOPHYLLINE TOXICITY Spivey et al
ventricular and atrial contractions. The remainder of the physical examination was unremarkable. Her medical history was significant for long-standing COPD, coronary artery disease, and an anterior myocardial infarction three months prior to admission. Eight days before admission, she developed an elevated temperature and productive cough and was treated with 250 mg cephalexin every six hours. During the next throee days, there was no improvement in her lower respiratory tract infection. Her temperature increased to 38.7 C, and her WBC c o u n t was 10,100/mm 3 with 82% p o l y m o r p h o n u c l e a r cells and no bands. She was begun on 500 mg ciprofloxacin twice daily three days before admission, and a sputum culture was obtained. The culture later revealed s-hemolytic streptococci (not S t r e p t o c o c c u s p ~ e u m o n i a e ) and Neisseria c o n s i s t e n t with n o r m a l flora. Within 24 hours after starting ciprofloxacin, she became increasingly anxious. Medication on admission included 400 mg aminophylline four times daily, 500 mg ciprofloxacin twice daily, 2.5 mg terbutaline three times daily, 5 mg prednisone twice daily, 20 mg isosorbide d i n i t r a t e three times daily, 200 mg meprobamate four times daily, 40 mg furosemide twice daily, 10 mg hydroxyzine three times daily as needed for anxiety, and 50 mg diphenhydramine at bedtime. Of these medications, only ciprofloxacin was recently added to her treatment regimen. Forty days before admission, a morning, predose serum theophylline concentration of 17.1 mg/L had been obtained while she was on 400 mg aminophylline four t i m e s daily (7:00 AM, 11:00 AM, 4:00 PM, and 10:00 PM). Laboratory data on admission included an arterial blood gas with pH 7.44; Pco2, 42 m m Hg; Poz, 61 m m Hg; and HGO3, 28 mmol/L. The serum chemistry profile was remarkable for glucose of 194 mg/dL; sodium, 130 m m o l / L ; chloride, 81 mmol/L; and SGOT, 55 IU/L. Serial creatine phosphokinase isoenzymes showed no acute elevations in the MB-band. The serum theophylline concentration determined by fluorescence polarization immunoassay was reported as 107 mg/L approximately one hour after her morning aminophylline dose. 120/1132
FIGURE. Serum theophylline concentrations versus time after admission. Treatment included a 25-g aqueous slurry of activated charcoal followed by 100 mL magnesium citrate every two hours for a total of six doses. The patient was transferred to the intermediate cardiac care unit for telemetry monitoring. She remained in sinus tachycardia during the next 24 hours with occasional premature v e n t r i c u l a r c o n t r a c t i o n s . Subsequently, her heart rate and rhythm normalized, and she recovered uneventfully. The p a t i e n t was discharged back to the nursing home on 300 mg t h e o p h y l l i n e (Theodur ®) twice daily. A subsequent steadystate theophylline serum concentration was 14.8 mg/L. Serum theophylline concentrations are shown (Figure). Because of the unexpected drop in serum theophylline concentrations from 107 mg/L on admission to 38.6 mg/L eight hours after admission, we reassayed the admission serum sample both at our laboratory and at the hospital laboratory. The repeated serum theophylline concentrations were 55.5 and 52.0 mg/L, respectively, which suggested that a possible dilution error was made when the initial sample was first assayed. The serum theophylline concentrations declined to within the therapeutic range (10 to 20 rag/L) within 15 hours of admission (Figure). Her theophylline half-life based on the last four concentration time points was 6.1 hours while receiving activated charcoal.
DISCUSSION Many factors have been shown to inhibit theophylline metabolism, resulting in increased serum concentrations. Both congestive heart failure and the development of pneumonia have been noted to significantly reduce theophylline clearance.9,10 Our patient had no history or evidence of acute congestive heart failure. At the time of her acute myocardial infarction, a two-dimensional echocardiogram showed some left ventricular hypertrophy but a normal ejection fraction. F u r t h e r m o r e , no recent changes in cardiac medications were made. Her moderate tachycardia did not appear to diminish ventricular function. A n n a l s of E m e r g e n c y
Medicine
O0
10
r rl
0
5
l
lI
Jl
10 15 20 25 30 35 Time (hr)
Although pneumonia may cause a reduction in theophylline clearance, it did not appear to be a likely source of the elevated serum theophylline concentrations. The lower respiratory tract infection was first noted eight days before admission, and no symptoms of theophylline intoxication were noted for the first six days. O n l y after s t a r t i n g ciprofloxacin were the symptoms of intoxication noted. Her lower respiratory tract infection was either self-limiting or mild because she did not require further antimicrobial treatment during this admission. In healthy volunteers, ciprofloxacin has been shown to significantly decrease the m e a n t h e o p h y l l i n e clearance by 18% to 31% .3-6 In addition, Raoof et al reported a mean 10.5-mg/L increase in serum theophylline concentrations in 61% of hospitalized patients on t h e o p h y l l i n e when administered ciprofloxacin.Z Three cases of patients hospitalized because of theophylline toxicity secondary to ciprofloxacin administration have been reported in the literature. 11-1g Richardson reported a similar case in which a nursing home patient was hospitalized with a theophylline concentration of 53 mg/L after three days of ciprofloxacin administration. H Theophylline toxicity occurred within three to five days in the other two cases, one of which was fatal J2,13 In addition, other quinolone antibiotics similar in structure to ciprofloxacin also have been shown to impair t h e o p h y l l i n e clearance to 20:10 October 1991
THEOPHYLLINE TOXICITY Spivey et al
varying degrees.S,14, is Enoxacin increased the urinary excretion of unchanged theophylline and inhibited the elimination of theophylline urinary metabolites, thereby suggesting that the mechanism involved is inhibition of the cytochrome P4so isoenzymes responsible for theophylline metabolism. 14 The time course of this interaction was studied by Rogge and associates, who showed that the changes in theophylline concentrations were generally complete by three days after the addition or discontinuation of enoxacin. 15 This case emphasizes the difficulty in using isolated case reports to evaluate drug interactions. Before ciprofloxacin administration, the patient was stabilized on 400 mg aminophylline (320 mg theophylline) before meals and at bedtime with a reported serum concentration of 17.1 mg/L. She then was started on ciprofloxacin and exhibited both clinical and laboratory evidence of theophylline intoxication. Review of medication administratio n and pharmacy records indicated appropriate compliance. Subsequently, ciprofloxacin was stopped, and she was discharged on 300 mg theophylline (sustainedrelease) every 12 hours. A repeat theophylline c o n c e n t r a t i o n was 14.8 mg/L, despite a m u c h lower total daily theophylline dose than taken before admission. The preadmission theophylline concentration of 17.1 mg/L represented a trough concentration taken before her morning dose. Nine hours elapsed between her bedtime dose at 10:00 PM and her morning dose at 7:00 AM, allowing her theophylline c o n c e n t r a t i o n to decline to within the therapeutic range. To further probe the question of the discrepancy in the preadmission and postadmission theophylline concentrations, a computer simulation was used to estimate the patient's theophylline concentrations on her preadmission a m i n o p h y l l i n e regimen. From her discharge theophylline level, an estimated theophylline clearance of 1.69 L/hr was calculated. This clearance and the measured half-life from her admission were used in the simulation to estimate her theophylline concentrations before admission. A morning trough theophylline concentration of 17 mg/ L was estimated, which agreed with the preadmission theophylline concentration of 17.8 mg/L. In addition, 20:10 October 1991
an estimated theophylline concentration of 28 mg/L was simulated at the time the patient's initial admission sample of 55.5 mg/L was drawn. The simulation suggests that ciprofloxacin administration led to an approximately 46% to 49% increase in the patient's serum theophylline concentrations. It is plausible that the patient tolerated her chronic a m i n o p h y l l i n e regimen with estimated theophylline concentrations in the range of 17 to 38 mg/L with few clinical symptoms of intoxication. Once ciprofloxacin was begun, her theophylline concentrations were further elevated, and she became s y m p t o m a t i c . Within two doses of ciprofloxacin, she exhibited increased anxiety. Also, she received only a total of five doses of ciprofloxacin before admission. In addition, the patient was not tachycardiac before the day of admission. Her pulse ranged from 72 to 88 the three days before admission, which supports an acute rise in serum theophylline concentrations. Although the total magnitude of the interaction is difficult to assess, computer simulations and clinical data supported an acute elevation in theophylline concentrations. The decision to manage this case with multiple-dose activated charcoal was made in part because charcoal hemoperfusion is not readily available at our hospital. One criterion for prophylactic charcoal hemoperfusion for chronic theophylline toxicity is a serum concentration of more than 60 mg/L. 16 A leading toxicology text calls for charcoal hemoperfusion for patients more than 60 years with theophylline concentrations of more than 40 mg/L. 17 Charcoal hemoperfusion was discussed for this patient because of the serum theophylline c o n c e n t r a t i o n of 107 mg/L originally reported and the likelihood that the serum concentration would remain above 20 mg/L for a significant period. At high serum theophylline concentrations, metabolic enzyme saturation can occur, thereby reducing metabolic clearance. In fact, we observed saturation above 40 mg/L in this case. The proportionally slower theophylline e l i m i n a t i o n between the first and second time points probably represented metabolic saturation (Figure). If charcoal h e m o p e r f u s i o n had Annals of Emergency Medicine
been available, we may have subjected this patient to an invasive procedure that would not have been warranted because of an incorrectly reported serum theophylline concentration. Reanalysis of the admission serum sample by two laboratories showed the actual theophylline concentration to be 52.0 to 55.5 mg/L. Although the patient was still at risk for neurologic and cardiac complications at this theophylline concentration, reduction in her theophylline concentration by metabolic clearance andactivated charcoal treatment was sufficient. We must caution against the use of a single serum theophylline concentration to constitute a basis for initiating an invasive procedure such as charcoal hemoperfusion. Any value out of the assay limits should be p r o m p t l y r e p e a t e d to v e r i f y the value. Laboratories should have a procedure for verifying serious theophylline intoxications, and sample dilution schemes and results should be checked by a supervisor.
SUMMARY We report a case of theophylline toxicity that m o s t likely resulted from the administration of ciprofloxacin. Acute signs of intoxication, computer simulations, and well-documented interaction studies support this conclusion. When a patient is admitted with theophylline toxicity resulting from chronic theophylline administration, concurrent medications such as ciprofloxacin should be considered as a potential cause of the elevated t h e o p h y l l i n e c o n c e n t r a tions. With increased use of ciprofloxacin in nursing home patients, similar cases of ciprofloxacin-induced theophylline toxicity can be expected. To maintain stable theophylline concentrations, theophylline should be prescribed with constant dosing intervals {eg, every six hoursJ rather than four times a day with meals and at bedtiome. We advise caution in using a single serum theophylline concentration to determine the management of theophylline toxicity and suggest reanalyzing any sample out of the assay sensitivity limits before charcoal hemoperfusion is begun, except where the clinical situation dictates its use.
REFERENCES 1. Peterson PK, Stein D, Guay DR, et ah Prospective
1133/121
THEOPHYLLINE TOXICITY Spivey et al
study of lower respiratory tract infections in an extended-care nursing home program: Potential role of oral ciprofloxacin. A m J Med 1988;85:i64-171. 2. Tranholme GM, Schmitt BA, Spear J, et al: Randomized study of intravenous/oral ciprofloxacin versus ceftazidime in the treatment of hospital and nursing home patients with lower respiratory tract infections. A m J Med 1989~87(suppl 5A):1165-118S. 3. Nix DE, DeVito JM, Whitbread MA, et al: Effect of multiple dose oral ciprofloxacin on the pharmacokinetics of theophylline and indocyanine green. J Antimicrob Chemother 1987;I9:263-269. 4. Schwartz J, Jauregui L, Lettieri J, et ah Impact of ciproffoxacin on theophylline clearance and steady-state concentrations in serum. Antimicrob Agents Chemother 1988;32:75-77. 5. Wijnands WJA, Vree TB, Van Herwaarden CLA: The influence of quinolone derivatives on theophylline clearance. Br J Clin Pharmacol 1986;22:677-683. 6. Prince RA, Casabar E, Adair CG, et al: Effect of quire
122/1134
olone antimicrobials on theophylline pharmacokinetics. ] Clin Pharmacol 1989~29:650-654. 7. Raoof S, Wollschlager C, Khan IZA: Ciprofloxacin increases s e r u m levels of t h e o p h y l l i n e . A m ] M e d 1987;82(suppl 4A):118-118. 8. Rybak MJ, Bowles SK, Chandrasekar PH, et al: Increased theophylline concentrations secondary to ciprofloxacin. Drug Intell Clin Pharmacol 1987~2i:879-88i. 9. Jnsko WJ, Gardner MJ, Maugione A, et al: Factors affecting theophylline clearance: Age, tobacco, marijuana, cirrhosis, c o n g e s t i v e heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and ethanol. J Pharm Sci 1979;68:1358-1366. I0. Powell JR, Vozeh S, Hopeweli P, et al: Theophylline disposition in acutely ill hospitalized patients: The effect of smoking, heart failure, severe airway obstruction, and pneumonia. A m Rev Respir Dis 1978;118: 229-238. i1. Richardson JP: Theophylline toxicity associated with the administration of ciprofloxacin in a nursing
Annals of Emergency Medicine
home patient. J A m Geriatr Soc 1990;38:236-238. 12. Duraski RM: Ciprofloxacin-induced theophylline toxicity. S Med ] 1988;81:1206. 13. Holden R: Probable fatal interaction between cip ~ rofloxacin and theophylline. Br Med J 1988;297:1339. 14. Beckmann J, Elsaber W, Gundert-Remy U, et al: Enoxacin-A potent inhibitor of theophylline metabolism. Eur J Clin Pharrnacol 1987;33:227-230. 15. Rogge NIC, Solomon WR, Sedman AJ, et ah The theophylline-enoxacin interaction: II. Changes in the disposition of theophylline and its metaboiites during intermittent administration of enoxacin. Clin Pharmacol Ther 1989;46:420-428. 16. Goldberg MJ~ Park GD, Berlinger WG: Treatment of t h e o p h y l l i n e i n t o x i c a t i o n . J Aller Clin lrnmuno] 1986;78:811-817. 17. Haddad LM, Winchester JF: Clinical Management of Poisoning and Drug Overdose, ed 2. Philadelphia, WB Saunders, 1990, p 1415.
20:10 October 1991