Efficacy of once-daily tobramycin monotherapy for acute pulmonary exacerbations of cystic fibrosis: A preliminary study

Abstract

Our objective was to compare the efficacy, safety, and microbiology of once-daily intravenous (IV) tobramycin with conventional 8-hourly tobramycin/ceftazidime IV therapy for acute Pseudomonas aeruginosa (PA) pulmonary exacerbations in cystic fibrosis (CF). CF patients with PA-induced pulmonary exacerbations were allocated to receive either once-daily tobramycin (Mono) or conventional therapy with tobramycin/ceftazidime given 8-hourly (Conv). The two longitudinal groups received therapy in a double-blind, randomized manner over a period of 2 years. Tobramycin doses were adjusted to achieve a daily area under the time-concentration curve of 100 mg x hr/L in both groups. Results were assessed for both short-term changes (efficacy and safety after 10 days of IV antibiotics during acute exacerbations) and long-term changes (efficacy, safety, and sputum microbiology between study entry and exit). Pulmonary function tests (PFTs) on admission were similar in both groups. After 10 days of IV antibiotics, absolute mean improvements in percent of predicted PFTs were 12.8, 12.1, and 13.7 for forced expiratory volume in 1 sec (FEV(1)), forced vital capacity (FVC), and forced expired flow between 25--75% of FVC (FEF(25--75%)) in the Conv group (n = 51 admissions) compared to 10.6, 9.9, and 10.6 in the Mono group (n = 47)(P<0.05 for all). Sixteen percent in the Conv group and 15% of patients in the Mono group did not respond to therapy by day 10. Long-term PFT patterns were similar for the Conv and Mono groups. The time between admissions did not differ. The Mono group showed a significant increase in tobramycin minimum inhibitory concentrations (MICs) against PA from study entry to study exit (P = 0.02, n = 27 strains); this failed to reach significance in the Conv group (P = 0.08, n = 25). There was no significant increase in the number of isolates, with MIC> or =8 mg/L in both groups. No short- or long-term changes in audiology or serum creatinine were found in either group. After 10 days of IV therapy, the urinary enzyme N-acetyl-beta-d-glucosaminidase/creatinine ratios increased in both groups (P0.05). This increase was greater in the Conv compared to the Mono group (P < 0.05). We conclude that this pilot study indicates once-daily tobramycin therapy to be as effective and safe as conventional 8-hourly tobramycin/ceftazidime therapy. Combination antibacterial therapy appears to offer no clinical advantage over once-daily tobramycin monotherapy. Tobramycin once-daily monotherapy is a potential alternative to conventional IV antibacterial therapy which deserves further investigation, including the impact on susceptibility of PA to tobramycin.