Addition of Tobramycin inhalation antibiotic treatment to standard IV antibiotic treatment for ventilator-associated pneumonia

INTRODUCTION AND RATIONALE

Approximately 9-27% of mechanically ventilated patients in the intensive care
unit (ICU) develop ventilator-associated pneumonia (VAP). Patients in whom VAP
develops have a higher mortality rate up to 50%, stay longer in the intensive
care unit (ICU), and require more resources than those without the disease.
Despite the availability of modern ICU care and modern antibiotics, the overall
clinical cure rate for VAP in randomized clinical trials is only 40%. The cure
rate for Pseudomonas aeruginosa is even lower (9). It is unclear why VAP cure
rates are so low.

There is a disappointing amount of data in the medical literature about the
effect of inhalation antibiotics. Almost all of the studies were observational
and did not have control groups
In one study, 38 patients were randomized to receive either endotracheally (ET)
sisomicin (aminoglycoside) or placebo added to systemic β-lactam/aminoglycoside
therapy. The cure rate was significantly better in the ET group (77 vs 45%).
This study from 1979 remains the largest randomized, placebo-controlled trial
of aerosolized antibiotics for treating VAP. Another prospective randomized
trial has also examined the impact of the adjunctive use of locally instilled
tobramycin with intravenous therapy in the treatment of VAP. Although the
addition of endotracheal tobramycin did not improve clinical outcome compared
with placebo, microbiologic eradication was significantly greater in the
patients receiving aerosolized antibiotics. The small number of patients in
this study suggests that more data are needed on this type of therapy before
determining its value.

The relatively poor response rates seen with intravenous therapy of VAP and the
emergence of MDR organisms makes new treatment options desirable. The ATS/IDSA
VAP guidelines recommend that *adjunctive therapy with an inhaled
aminoglycoside or polymyxin (colistin) for MDR Gram-negative pneumonia should
be considered, especially in patients who are not improving*. The
recommendations by the Society of Infectious Diseases Pharmacists are similar.

Does addition of inhalation tobramycin to standard IV treatment result in a
higher clinical cure rate than standard IV antibiotic treatment alone in
patients with ventilator-associated pneumonia.
The initial response to treatment will be evaluated after 3 days of
antimicrobial treatment at day 4.

A prospective double-blind randomized controlled trial
comparing Tobramycin inhalation antibiotic treatment and standard IV antibiotic
treatment with standard IV antibiotic treatment alone for ventilator-associated
pneumonia

Patients will receive Tobramycin inhalation (Bramitob) 300 mg 2 times daily
or placebo inhalation (identically packaged sterile saline) 2 times daily
besides IV antibiotic treatment

A number of pulmonary adverse events such as coughing and bronchospasm can
occur with outpatient use of aerosolized antibiotics. The only adverse events
reported in the aminoglycoside VAP studies were coughing and dizziness in four
patients. No other adverse events were reported. The vast majority of
aminoglycoside VAP reports used the intravenous formulation. A
preservative-free formulation of tobramycin for inhalation used in cystic
fibrosis may theoretically provide a better safety profile, but this has not
been studied widely in VAP patients.


Serumconcentrations need to be controlled in patients with renal dysfunction.
Tobramycin inhalation treatment needs to be stopped until trough level is < 2
microgram/ml (2 mg/l).When a patient is known to have a renal dysfunction, is
using nefrotoxic medication, has a serum creatinine level of > 180 micromol/l,
or in case of acute renal insufficiency or on dialysis than a trough level will
be determined. When the trough level is > 1 mg/l than tobramycin will not be
given until the trough level is < 1mg/l.

Benefit: possible reduction in mortality, length of treatment, improvement of
other important clinical outcome parameters, like clinical cure rate and
improved eradication of microorganisms.