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.

Extended-Interval Aminoglycoside Administration for Children: A Meta-analysis

“…Twenty-four eligible studies [21][22][23][24][25][26][27][28][29][30][31][35][36][37][38][39][40][41][42][43][44][45][46][47] published between 1991 and 2003 were identified (Table 1). Aminoglycosides were used in different clinical settings (neonatal intensive care unit: 6 studies; cystic fibrosis: 3 studies; cancer: 5 studies; urinary tract infections: 4 studies; diverse infectious indications: 5 studies; pediatric intensive care unit: 1 study).…”

“…The pooled ototoxicity rates for studies that provided auditory testing results 21,23,25,[35][36][37][38][39][40]42,44,46,47 were 2.3% (10 of 436 cases) in the ODD arms and 2.0% (8 of 406 cases) in the MDD arms. The fixedeffects risk ratio was 1.06 (95% CI: 0.51-2.19; P ϭ .92) ( Table 3).…”

“…Many of them were published recently [21][22][23][24][25][26] or were not considered even in recent nonsystematic reviews. [27][28][29][30][31] The available randomized evidence may offer a rational basis for deciding on aminoglycoside dosing.…”

A Survey of Extended-Interval Aminoglycoside Dosing Practices in United States Adult Cystic Fibrosis Programs

“…This likely reflects the availability of well-designed safety and efficacy studies and meta-analyses evaluating tobramycin EID in this population, and the lack of published research studies assessing the use of gentamicin and amikacin EID in those with CF. 10,11,[13][14][15][16][17][18] As in the pediatric CF population, empiric dosing of tobramycin was most commonly prescribed at 10 mg/kg/d. 19 This practice is consistent with the dose used in a large, randomized, controlled, noninferiority study published in 2005.…”

“…8 In light of the emergence of safety and efficacy data in the CF population, the Cystic Fibrosis Foundation deemed once-daily aminoglycoside dosing as acceptable for Pseudomonas aeruginosa (grade C recommendation) in its September 2009 pulmonary exacerbation guidelines. [9][10][11][12][13][14][15][16][17][18] A 2009 survey of United States pediatric CF centers and affiliate programs distributed after the publication of these guidelines reported the use of EID (with once-daily or twice-daily dosing) in the pediatric CF population to be 94%, a significant increase from previous reports. 19 While empiric evidence suggests the use of EID of aminoglycosides to be increasingly common in the United States CF population, the prevalence of EID use across United States adult CF centers as well as the dosing and monitoring practices associated with this regimen following publication of the CF pulmonary exacerbation guidelines remain to be elicited.…”