Clinafloxacin-Theophylline Drug Interaction

Objective: To report an apparent pharmacokinetic interaction between clinafloxacin and theophylline in a patient with chronic obstructive pulmonary disease (COPD). Case Summary: A patient with a history of COPD was admitted for a fracture of the right femoral neck. Admission medications included extended-release theophylline 400 mg bid. The initial serum theophylline concentration was 81.03 µmol/L (normal 55—110). A subsequent concentration was subtherapeutic (46.62 µmol/L) and the theophylline dosage was increased to 300 mg tid. Therapeutic steady-state concentrations were achieved. The patient later developed pneumonia and was enrolled in a study of nosocomial acquired pneumonia involving clinafloxacin versus ceftazidime. He was randomized to receive clinafloxacin 200 mg iv ql2h. After clinafloxacin therapy was initiated, the serum theophylline concentration increased into the toxic range (155.96 µmol/L). Theophylline administration was held for 2 doses and the dosage then reduced to 200 mg tid. Serum concentrations decreased to within the therapeutic range. Discussion: The fluoroquinolones have been shown to interact with the hepatic metabolism of theophylline and increase serum theophylline concentrations. The quinolone metabolite, 4-oxo-quinolone, inhibits the N-demethylation of theophylline, leading to a decrease in the clearance of theophylline. The resultant rise in theophylline concentrations corresponds with the decrease in clearance and possible toxicity. In our patient, careful monitoring of theophylline concentrations and dosage adjustments resulted in the restoration of therapeutic serum concentrations. Conclusions: The observation of this drug interaction between clinafloxacin and theophylline suggests a need for prudent monitoring of theophylline concentrations. Dosage adjustments may be warranted when this combination of medications is used. Such action may prevent significant toxicities and prolonged hospitalization. Further controlled clinical trials in healthy volunteers are needed to substantiate the interaction between clinafloxacin and theophylline.

Metabolic Correlates of Theophylline Therapy: A Concentration-Related Phenomenon

OBJECTIVE: To determine the relationship of serum theophylline concentration with electrolyte and glucose abnormalities across a broad range of theophylline concentrations. DESIGN: Retrospective review of a computerized laboratory database between June 1, 1984 and June 1, 1986. SETTING: A midwestern university medical center. PATIENTS: Eight hundred sixty-nine patients with serum theophylline concentrations of >5.5 μmol/L and a random unmatched sample (control group) of 350 in- and outpatient adults and children with no history of reactive airways disease or theophylline exposure. RESULTS: Patients with measurable theophylline had a higher risk of hypokalemia, hyponatremia, hyperglycemia, hypophosphatemia, and hypomagnesemia compared with the unexposed control group. Unadjusted odds ratios (OR) were: (1) hypokalemia OR=4.2 (95 percent CI 2.2 to 7.9); (2) hyponatremia OR=5.4 (95 percent CI 2.0 to 12.9); (3) hypomagnesemia OR=1.6 (95 percent CI 1.0 to 2.5); (4) hyperglycemia OR=2.3 (95 percent CI 1.7 to 3.0); and (5) hypophosphatemia OR=2.7 (95 percent CI 1.2 to 5.3). A linear concentration—response relationship was documented between serum theophylline concentration and all metabolic disturbances. conclusions: Measurable theophylline was associated with increased risk for glucose and electrolyte abnormalities in a concentration-related fashion across a broad range of theophylline concentrations from 5.5 to ≥110 μmol/L.

Management of Theophylline Overdose Patients in the Intensive Care Unit

In a retrospective survey of all adults admitted to the Intensive Care Unit with acute theophylline poisoning over the last five years, we identified 38 patients (6.8% of all admissions for poisoning), two of whom died. Thirty-five (92%) had taken a sustained-release preparation. Eight patients had grand mal seizures and six developed arrhythmias (ventricular fibrillation, 3; atrial fibrillation, 2; supraventricular tachycardia, 1). Severe vomiting was present in 34 (89%) and proved to be a serious obstacle to the administration of enteral charcoal. The vomiting was controlled by intravenous metoclopramide in seventeen patients (50%), but the remaining seventeen required mechanical ventilation with sedation and muscle relaxation for the effective delivery of nasogastric charcoal. Importantly, in nine (24%), the serum theophylline concentration continued to rise despite enteral charcoal. Charcoal haemoperfusion was used in seven (18%). We present an algorithm for the management of severe, acute theophylline poisoning.