Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis—the TOPIC study: a randomised controlled trial

• Published in: The Lancet (British edition) Vol. 365; no. 9459; pp. 573 - 578
• Main Authors: Smyth, Alan, Tan, Kelvin H-V, Hyman-Taylor, Pauline, Mulheran, Michael, Lewis, Sarah, Stableforth, David, Knox, Alan
• Format: Journal Article
• Language: English
• Published: London Elsevier Ltd 12.02.2005; Lancet; Elsevier Limited
• Subjects: Acetylglucosaminidase - urine; Adolescent; Adult; Adults; Age; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - adverse effects; Antibiotics; Biological and medical sciences; Ceftazidime; Ceftazidime - administration & dosage; Child; Child, Preschool; Children; Chronic Disease; Chronic infection; Clinical trials; Creatine; Creatinine; Creatinine - blood; Cystic fibrosis; Cystic Fibrosis - microbiology; Cystic Fibrosis - physiopathology; Double-Blind Method; Drug Administration Schedule; Drug dosages; Drug Therapy, Combination - administration & dosage; Evidence-based medicine; Female; Forced Expiratory Volume; Gastroenterology. Liver. Pancreas. Abdomen; General aspects; Hearing loss; Humans; Infusions, Intravenous; Intravenous administration; Laboratories; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lung diseases; Male; Medical sciences; Medical treatment; Middle Aged; Other diseases. Semiology; Patients; Pharmacokinetics; Pneumology; Pseudomonas aeruginosa; Pseudomonas Infections - complications; Pseudomonas Infections - drug therapy; Randomization; Respiratory function; Respiratory system : syndromes and miscellaneous diseases; Tobramycin; Tobramycin - administration & dosage; Tobramycin - adverse effects; United Kingdom > UK; United States > US; Respiratory disease; Metabolic diseases; Cystic fibrosis; Genetic disease; Medicine; Antibiotic; Pulmonary fibrosis; Treatment; Aminoglycoside; Digestive diseases; Clinical trial; Tobramycin; Antibacterial agent; Comparative study; Pancreatic disease
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(05)17906-9

Intravenous tobramycin (three-times daily) is widely used for pulmonary exacerbations in patients with cystic fibrosis who have chronic Pseudomonas aeruginosa infection. We undertook a double-blind, randomised controlled trial to assess the safety and efficacy of once versus three-times daily tobramycin in these patients. 244 patients from 21 cystic-fibrosis centres in the UK were randomly assigned to once or three-times daily tobramycin (with ceftazidime) for 14 days. Treatment was given as 30-min infusions of tobramycin in 0·9% saline. Primary outcome measure was change in forced expiratory volume in 1 s (FEV1), over the 14 days of treatment, expressed as a percentage of the predicted normal value for age, sex, and height. We also measured the change in FEV1 expressed as a percentage of baseline. Secondary outcomes included change in serum creatinine. The study was powered for equivalence, and primary analysis was per protocol. 219 patients (107 once daily, 112 three-times daily) completed the study per protocol. None was lost to follow-up, although 20 discontinued intervention. Of 122 patients assigned to once daily treatment, three did not receive the study regimen. The mean change in FEV1 (% predicted) over 14 days was similar on the two regimens (10·4% [once daily] vs 10·0% [three-times daily]; adjusted mean difference 0·4% [95% CI –3·3 to 4·1]). Mean % change in FEV1 from baseline was also similar in both treatments (21·9%vs 22·1%; –0·1% [–8·0 to 7·9]). There was no significant difference in % change in creatinine from baseline (–1·5% [once daily] vs 1·7% [three-times daily]). However, in children, once daily treatment was significantly less nephrotoxic than was thrice daily (mean % change in creatine –4·5% [once daily] vs 3·7% [thrice daily]; adjusted mean difference –8·0%, 95% CI –15·7 to –0·4). No patients developed hearing loss during the study, although two reported acute dizziness and were withdrawn from the study. Intravenous tobramycin has equal efficacy if given once or three-times daily (with ceftazidime) for pulmonary exacerbations of cystic fibrosis. The once daily regimen might be less nephrotoxic in children.