(Chest. 2001;120:107S-113S.)
© 2001
American College of Chest Physicians
Administration of Aerosolized Antibiotics in Cystic Fibrosis Patients*
Richard B. Moss, MD, FCCP
*
From the Department of Pediatric Pulmonary Medicine, Stanford University Medical Center, Palo Alto, CA.
Correspondence to: Richard B. Moss, MD, FCCP, Pediatric Pulmonary Medicine, Stanford University Medical Center, 701 Welch Rd, Room 3328, Palo Alto, CA, CA 94304-5786; e-mail: rmoss{at}stanford.edu
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Abstract
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High rates of colonization and the challenge of managing
Pseudomonas aeruginosa infections in patients with
cystic fibrosis (CF) have necessitated a search for safe and effective
antibiotics. Currently, therapy with an aminoglycoside in combination
with a ß-lactam or a quinolone antibiotic is the standard.
Unfortunately, it is difficult to deliver high doses of these
antibiotics via the IV route without significant systemic adverse
events (AEs) (eg, ototoxicity and nephrotoxicity).
Recently, a reformulation of the aminoglycoside antibiotic tobramycin
has become available in a preservative-free, pH-adjusted solution for
inhalation by jet nebulizer. A 96-week series of clinical studies
including 520 patients, aged 
6 years, with moderate-to-severe CF
has evaluated the long-term safety and effectiveness of this
formulation. Patients received tobramycin solution for inhalation (TSI)
or placebo, which was administered in alternating cycles of 28-days-on
and 28-days-off therapy, plus their usual CF care for 6 months with
open-label follow-up extended to 2 years. Most AEs declined in
frequency with increasing TSI exposure. Patients receiving TSI spent 25
to 33% fewer days in the hospital. Following the initiation of TSI
treatment, patients experienced significant increases in
FEV1. FEV1 values were maintained above
baseline for the duration of the study series. Antibiotic
susceptibility of the bacterial isolates did not predict clinical
response. TSI was safe, well-tolerated, and effective for long-term
treatment (96 weeks) of P aeruginosa colonization and
infection in CF patients.
Key Words: aerosolized antibiotics • cystic fibrosis • Pseudomonas aeruginosa • tobramycin solution for inhalation
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Introduction
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A major
feature of cystic fibrosis (CF) lung disease is endobronchial
infection with the bacterium Pseudomonas aeruginosa. Early
in their lives, CF patients may be infected with Staphylococcus
aureus or Haemophilus influenzae, but by the age of 17
years, nearly 70% of CF patients have P aeruginosa present
in their sputum cultures.1
P aeruginosa, which
can be present at densities of 106 to
108 colony-forming units per gram of sputum, is
the major infectious burden in the airway of CF patients.2
Once established in CF patients, respiratory tract infections are not
eradicated by antibiotic therapy.
Respiratory disease in CF patients is characterized by the progressive
obstruction of the airways and loss of lung function due in large part
to inflammatory response to chronic bacterial infection. The loss of
pulmonary function resulting in respiratory failure is a primary cause
of death in CF patients. In the 1998 Cystic Fibrosis Patient Registry,
87.4% of registry deaths could be attributed to the loss of pulmonary
function.3
The presence of P aeruginosa is
associated with increased rates of lung function decline4
and is a significant independent predictor of mortality.5
The role of chronic inflammation in the pulmonary function decline of
CF patients has been confirmed by separate reports on the efficacy of
long-term anti-inflammatory agent therapy (ie,
ibuprofen6
and prednisone7
) in slowing lung
function decline. CF patients are prone to episodes of acute pulmonary
exacerbation, characterized by worsening symptoms of respiratory tract
infection accompanied by acute declines in lung function. The primary
cause of CF patient hospitalization is for the treatment of
exacerbations, with > 35% of patients hospitalized at least once
annually.1
The central role of P aeruginosa in CF lung disease has led
to the testing of intensive therapy with antipseudomonal
antibiotics to suppress infection,8
even in the absence of
pulmonary exacerbations. Among patients with well-established
infections, the suppression of P aeruginosa has been shown
to lead to decreases in sputum P aeruginosa density.
Although these decreases can be short-lived beyond the cessation of
therapy,9
lung function benefits from antibiotic therapy
can be maintained over extended periods.
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Use of Tobramycin
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Tobramycin is the most frequently prescribed aminoglycoside for
the treatment of pulmonary infections in CF patients. Tobramycin is
frequently administered IV during periods of acute exacerbations.
Because the penetration of tobramycin into sputum is low following IV
administration, high doses are required to achieve concentrations
inhibitory to P aeruginosa. Moreover, the inactivation of
tobramycin in purulent sputum mandates the delivery of 10 to 25 times
the minimal inhibitory concentration (MIC) to achieve bacterial
killing.10
However, high doses of IV tobramycin increase
the risk of systemic adverse events (AEs) such as ototoxicity and
nephrotoxicity.
Aerosolized Tobramycin
Recently, a nonpyrogenic, preservative-free, pH-adjusted
formulation of tobramycin solution for inhalation (TSI) (TOBI; Chiron
Corporation; Emeryville, CA), administered via a jet nebulizer, has
become commercially available for use in CF patients. This product
allows the delivery of the antibiotic directly to the endobronchial
space in the lungs, while minimizing systemic exposure and the
associated risk of ototoxicity and nephrotoxicity.
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TSI Study Series
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The long-term safety and efficacy of TSI has been evaluated in a
96-week series involving 520 CF patients. The results of two
double-blind, placebo-controlled trials representing the first 24 weeks
of this series have been published previously.11
Patient Criteria
The selection criteria for the pivotal studies were chosen in
order to enroll CF patients who have P aeruginosa and
moderate-to-severe obstructive airway disease, but who were otherwise
in relatively stable condition at enrollment. Only CF patients > 6
years of age who had an FEV1 between 25% and
75% of predicted values and a sputum or throat culture yielding
P aeruginosa were eligible for enrollment. Patients were
excluded from the study if they had used any antipseudomonal antibiotic
within 14 days of receiving their initial dose of the study drug.
Patients also were excluded from the study if they had undergone a
respiratory culture positive for Burkholderia cepacia in the
previous 2 years, had compromised renal function, had hypersensitivity
to aminoglycosides, had a recent episode of hemoptysis, or were
pregnant at screening.
Study Design
This study series consisted of a randomized pivotal phase and an
open-label phase. The pivotal phase included two identical,
double-blind, placebo-controlled studies, each of 24 weeks’ duration.
The open-label phase included three sequential 24-week studies.
Throughout the series, patients could receive any and all standard
therapies for CF (ie, usual care), except for any inhaled
antibiotics other than TSI. Figure 1
illustrates the two phases.
In the randomized phase, patients were treated with either TSI, 300 mg
bid, or taste-masked placebo bid. In the open-label phase, all patients
received TSI, 300 mg bid. The study drug was administered twice daily
using a jet nebulizer (PARI LC PLUS; PARI Respiratory Equipment, Inc;
Richmond, VA) and a compressor (PulmoAid; DeVilbiss; Somerset, PA).
The overall design of each study is illustrated in Figure 2
. Each study consisted of three drug administration cycles. A cycle
included a 4-week on-drug period followed by a 4-week off-drug period.
Thus, each study included three 4-week on-drug periods and three 4-week
off-drug periods. The total length of this study series was 96 weeks.
Five hundred twenty patients were enrolled in the randomized phase of
the study series.11
Four hundred sixty-four patients completed the randomized phase. Of the
464 patients who completed the randomized phase, 396 entered the
open-label phase. A total of 242 patients completed all three of the
studies in the open-label phase for a total of up to 96 weeks of
intermittent TSI therapy.
Patient Demographics
Table 1
summarizes the patient demographics at the start of the randomized and
open-label phases.
Analysis
The safety and efficacy data from this study series have been
examined in two ways. First, ordinal data, such as those from pulmonary
function tests, can be analyzed by original treatment group using the
start of the randomized phase as a reference (eg, the
percentage change in FEV1 percent predicted from
baseline). This approach allows statistical analysis of the change from
baseline. Second, categoric data such as AEs may be evaluated in an
intent-to-treat analysis in which patients who received placebo in the
pivotal studies and subsequently switched to TSI are grouped with those
patients who received TSI from the start of the series. This approach
allows evaluation of the occurrence of events as a function of time
receiving TSI. In such analyses, time may be represented as discrete
3-cycle (12-week) blocks of exposure or by the number of weeks of
exposure, with the first dose of TSI as the baseline.
AEs
The incidence of most AEs remained constant or decreased with
increasing TSI exposure. Four adverse experiences (ie,
vomiting, fever, abdominal pain, and anorexia) were reported by
significantly more patients receiving placebo than those receiving TSI
(p 
0.05) during the pivotal studies (Fig 3
).11
As the length of TSI exposure increased, the rates of
these events declined further. The decrease in incidence of these
adverse experiences may reflect an improvement in some of the chronic
symptoms of CF with ongoing TSI therapy.
As reported by Ramsey et al,11
two AEs that were reported
by significantly (p 0.05) more TSI patients than placebo patients
during the pivotal studies were voice alteration and tinnitus (Fig 3) .
In the open-label phase, the incidence of voice alteration decreased
steadily with increasing TSI exposure (from 9.1 to 3.9%). Voice
alteration was usually mild to moderate in severity and tended to
improve during the off-drug part of each cycle. Although there was a
significant difference in the incidence of tinnitus between treatment
groups in the randomized part of the series, tinnitus was rare among
TSI-treated patients. The frequency of tinnitus never exceeded 3.5%
during the study series (Fig 3)
. During the study series, a total of 14
patients (12 adults and 2 adolescents) reported tinnitus. Most episodes
of tinnitus were transient and mild or moderate in severity. Audiology
testing showed that none of the 14 patients reporting tinnitus had
objective evidence of hearing loss, which was defined as a bilateral
decrease from baseline in hearing thresholds of 15 decibels at two
consecutive frequencies.
Effect on Renal Function
Mean serum creatinine levels were comparable between the TSI and
placebo groups at the start of the randomized phase. No clinically
significant changes in creatinine levels occurred over the course of
the study series. The mean values were within normal limits at all
observations.
Colonization by Other Organisms
Long-term antibiotic therapy may alter the composition of the lung
flora and lead to changes in the rates at which other potential
pathogens are isolated.12
Furthermore, the odds of
isolating rarely occurring organisms have been increased by
improvements in microbiological techniques that allow for the more
accurate identification of organisms. Thus, an accurate assessment of
the effect of TSI on the lung flora in CF patients is critical.
Microbiological data from this study series were analyzed to evaluate
whether long-term TSI treatment was associated with increased isolation
of Gram-negative organisms that are intrinsically resistant to
tobramycin (ie, Burkholderia cepacia,
Stenotrophomonas maltophilia, or Alcaligenes
xylosoxidans) or the fungus Aspergillus. The incidence of
isolation of B cepacia did not increase during up to 12
cycles (96 weeks) of TSI treatment.
The incidence of isolation of both S maltophilia and A
xylosoxidans was shown to increase over time, but the rate
of increase in isolation frequency was the same or greater during
24 weeks of placebo exposure, and, thus, these increases may be
independent of TSI exposure. The incidence of Aspergillus isolation
increased with increasing TSI exposure. No increase in the rate of
Aspergillus isolation was observed during the 24-week placebo exposure.
The clinical significance of the increase in Aspergillus isolation is
not known, but no increase in investigator-defined allergic
bronchopulmonary aspergillosis was found in 24 months of observation.
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Other Outcomes Measures
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Hospitalization
Hospitalization is a highly costly and disruptive aspect of the
traditional management of CF. During the initial randomized, controlled
trial, patients receiving placebo spent an average of 8 days in the
hospital. Following the initiation of TSI therapy, patients spent 25 to
33% fewer days in the hospital, suggesting a beneficial effect on
morbidity.
Hospitalization rates for CF patients are seasonal, with significantly
increased rates of hospital admission in autumn and winter when viral
superinfections are most common. Rates tend to decrease in spring and
summer. An analysis of the entire 96-week study series demonstrated
that in each season TSI-treated patients were hospitalized for a
smaller percentage of days than that observed in patients during 24
weeks of placebo exposure. The decreases in the percentage of days
hospitalized in each season of the first and second years of the study
series were comparable (Fig 4
).
IV Antipseudomonal Antibiotic Use
An alternative means of assessing patient outcome is by evaluation
of the use of additional forms of antipseudomonal therapy during
treatment. Following the initiation of TSI therapy, the number of
patients requiring IV antibiotic therapy was reduced by 20 to 25%
relative to that observed during 24 weeks of placebo exposure in the
pivotal trials (Fig 5
). Furthermore, the use of oral quinolone therapy was reduced
approximately 33% over the entire study series.
Change in Pulmonary Function
Change in pulmonary function is usually considered to be a primary
and clinically important outcome measure in CF patients. In the
randomized phase, TSI-treated patients had a sharp increase in
FEV1 values following the start of TSI therapy
(Fig 6
). By the end of the last on-drug period of the randomized phase
(ie, after 20 weeks of therapy), a treatment effect of
11.9% in FEV1 values was observed between
TSI-treated patients and placebo-treated patients.11
Following the initiation of TSI treatment, patients originally treated
with placebo also exhibited an improvement in
FEV1 values. In both original treatment groups,
FEV1 was maintained above baseline from the
initiation of TSI treatment to the end of the study series.
Improvements in FEV1 following the initiation of
TSI treatment and long-term maintenance of this improvement clearly
demonstrate the efficacy of TSI therapy.
Microbiological Response
The clinical response to TSI therapy cannot be predicted by
P aeruginosa isolate susceptibility. At the end of the
randomized phase, patients with isolates in the higher MIC categories
(ie, > 8 µg/mL) had smaller mean relative changes in
FEV1 percent predicted than those patients whose
highest MIC isolates were in the 8-µg/mL category (Fig
7). However, despite having isolates with tobramycin MIC values between
16 and 64 µg/mL, a similar percentage of patients had improved
FEV1 values when compared with those patients
whose isolates had MIC values of 8 µg/mL. The mean relative
change in FEV1 percent predicted appeared to be
independent of the tobramycin MIC at all other points in the series.
The mean improvement in FEV1 percent predicted
and the proportion of patients with positive clinical responses were
similar in all three MIC categories.
These findings suggest that the conventional definition of drug
resistance and sensitivity (ie, MIC breakpoint of 8 to 16
µg/mL) as determined by parenteral tobramycin therapy may not be
relevant for TSI. Rather, due to the high sputum levels achieved with
TSI, a new definition of susceptibility may need to be developed.
Apparently, modest decreases in P aeruginosa susceptibility
are not predictive of clinical efficacy for TSI for a 2-year period.
Subgroup Analysis
Treatment randomization was prospectively stratified using a
number of factors that permitted subgroup analysis. These factors
included the use of dornase alfa (Pulmozyme; Genentech; South San
Francisco, CA), disease severity, gender, and age. At the end of the
randomized phase (week 24), TSI patients in the age groups of patients
13 to 17 years and 18 years had significantly (p 0.05) greater
relative changes in FEV1 than did placebo
patients.13
Although FEV1 percent predicted
for TSI patients in the age group of patients 6 to 12 years was
improved substantially, the p value was 0.076 due to improvements in
the placebo-treated patients in this age group. Furthermore, TSI
patients in all subgroups defined by gender, disease severity, and
rhDNAse use had significant (p 0.05) improvements in
FEV1 percent predicted relative to
placebo-treated patients in these subgroups.
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Summary
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Similar to the results of the 6-month randomized,
placebo-controlled trial with TSI therapy,11
the long-term
(24-month) treatment data from the open-label extension study
demonstrated the following conclusions about TSI therapy:
- it provided sustained improvements in pulmonary function;
- it reduced the duration and frequency of hospitalization;
- it reduced the need for concomitant antipseudomonal therapy; and
- it is safe, effective, and well-tolerated in patients with CF.
In addition, the 24-month study also showed that pathogen
susceptibility was not a predictor of clinical effect.
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Footnotes
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The author is a paid consultant for PathoGenesis Corporation (Seattle,
WA), Genentech, Inc (South San Francisco, CA), and AeroGen, Inc
(Sunnyvale, CA).
Abbreviations: AE = adverse event;
CF = cystic fibrosis; MIC = minimal inhibitory concentration;
TSI = tobramycin solution for inhalation
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TOP
Abstract
Introduction
