Long-term safety and efficacy of tobramycin in the management of cystic fibrosis

Figures & data

Table 1 Marketed inhaled antibiotics

Drug formulation/brand name	Inhalation device	Dose and posology
Aztreonam lysine IS (Cayston^®)	Altera^®	75 mg TID (on–off cycles)
Colistin IS
Colomycin^®	Variable	2,000,000 IU BID/TID
Promixin^®	I-neb ADD^®	1,000,000 IU BID
Colistin IP (Colobreathe^®)	Turbospin^®	1,662,500 IU BID
Tobramycin IS		300 mg BID (on–off cycles)
TOBI^®	Pari LC Plus^®
Bramitob^®	Pari LC Plus^®
Tobramycin IP (TOBI Podhaler^®)	Podhaler^® (T-326)	112 mg BID (on–off cycles) (four capsules, 28 mg)

Note: On–off cycles: 28 days on/28 days off.

Abbreviations: IS, inhalation solution; TID, three times a day; BID, twice a day; IP, inhalation powder.

Table 2 Clinical trials of inhaled tobramycin in chronic Pseudomonas aeruginosa infection

		Drug			Clinical trial
		Study	Type	Patients and age	Treatment schedule	Results	Adverse events
TIS	TIS 300 mg/5 mg	Ramsey et al^Citation23 Quittner and Buu^Citation24	DB, PC, MC	N=520 >6 years with chronic infection	TIS BID Three cycles	FEV1 increase in TIS group. P. aeruginosa sputum density reduced in TIS group.	Tinnitus (P<0.03).
		Moss^Citation3	OL	N=128 Adolescents with chronic infection	TIS BID 12 cycles	FEV1 increase. Hospital admission and IV antibiotic courses were reduced. Weight gain.	Tinnitus. No significant changes in serum creatinine levels. No aminoglycoside-induced hearing loss.
		Murphy et al^Citation25	OL, PG, MC	N=181 6–10 years with chronic infection	TIS BID Seven cycles	No significant FEV1 improvement.	Hoarseness.
		Lenoir et al^Citation26	DB, PC, PG, MC	N=59 >6 years with chronic infection	TIS BID One cycle	FEV1 increase in TIS group.	No significant changes in serum creatinine levels. No hearing loss.
	TIS, 4 mg	Chuchalin et al^Citation27	DB, PC, PG, MC	N=247 >6 years with chronic infection	TIS BID Three cycles	FEV1 increase in TIS group.	No.
	TIS 5 mg versus TIS 4 mg	Mazurek et al^Citation28	OL, MC	N=321 >6 years with chronic infection	TIS 4 mg BID, one cycle (treatment arm) TIS 5 mg BID, one cycle (control arm)	FEV1 improvement in both groups (differences not significant).	No.
TIP		Konstan et al^Citation29 (EVOLVE)	Cycle 1:DB, PC, MC Cycle 2: OL, MC	N=9S	TIP BID Three cycles	FEV1 improvement since the end of the first cycle.	SAE more frequent in the placebo group (lung disorders).
		Konstan et al^Citation30 (EAGER)	OL, AC, MC	N=517	TIP BID (T-326) TIS 5 mg BID (Pari LC Plus^®) Three cycles	FEV1 improvement similar in both groups.	More frequent in TIP group (differences not significant).
		Galeva et al^Citation31 Quittner et al^Citation32 (EDIT)	DB, PC	N=62 Naïve to inhaled antipseudomonal antibiotics	TIP BID, one cycle	FEV1 improvement in treatment group. P. aeruginosa sputum density reduced.	No.

Abbreviations: TIS, tobramycin inhaled solution; DB, double-blind; PC, placebo-controlled; MC, multicenter; N, number; BID, twice a day; FEV₁, forced expiratory volume in 1 second; P. aeruginosa, Pseudomonas aeruginosa; OL, open-label; IV, intravenous; PG, parallel-group; EVOLVE, Evaluate tobramycin inhaled dry powder efficacy trial; TIP, tobramycin inhaled powder; SAE, serious adverse events; EAGER, Establish a new gold standard efficacy and safety with tobramycin in cystic fibrosis trial; AC, active comparator; EDIT, Establish tobramycin dry powder efficacy in cystic fibrosis trial.

Figure 1 Flowchart of the clinical trials with tobramycin in CF.

Abbreviations: CF, cystic fibrosis; TIS, tobramycin inhaled solution; FEV₁, forced expiratory volume in 1 second; IV, intravenous; TIP, tobramycin inhaled powder; EVOLVE, Evaluate tobramycin inhaled dry powder efficacy trial; BID, twice a day; EAGER, Establish a new gold standard efficacy and safety with tobramycin in cystic fibrosis trial; EDIT, Establish tobramycin dry powder efficacy in cystic fibrosis trial; EPIC, Early Pseudomonas Infection Control trial; ELITE, EarLy Inhaled Tobramycin for Eradication trial.

Table 3 Clinical trials in new-onset Pseudomonas aeruginosa infection

Name	Type	Patients	Treatment schedule	Results	Adverse events
EPIC^Citation37	Interventional, Phase III, multicenter	N=305 1–12 years old	TIS 5 mg BID (28 days) either 15–20 mg/kg ciprofloxacin BID or placebo for the first 14 days, or culture-based therapy.	No differences in the exacerbation rates between cycled and culture-based groups or between ciprofloxacin and placebo.	Similar across groups. Respiratory events more common in ciprofloxacin groups.
ELITE^Citation38	Open-label, multicenter	N=88 >6 months	28 days with TIS BID (Pari LC Plus^® jet nebulizer). After 28 days, patients were randomized to 28 days off TIS or 28 days on TIS.	Median time to recurrence of infection similar in both groups. >90% patients free of infection.	Well tolerated.

Abbreviations: EPIC, Early Pseudomonas Infection Control trial; N, number; TIS, tobramycin inhaled solution; BID, twice a day; ELITE, EarLy Inhaled Tobramycin for Eradication trial.

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