Treatment subjects were identified from the population of patients with pulmonary NTM infections followed and treated at the Stanford University Medical Center Chest Clinic. All patients included in this series had a diagnosis of NTM infection that met the disease diagnostic criteria established in the 1997 ATS consensus statement[9
]. These patients had remained sputum culture positive despite a minimum of six months of standard oral therapy with a macrolide-based multi-drug regimen. All of the patients included in this case series were symptomatic and had radiographic evidence of nodular infiltrates, bronchiectasis and/or cavitary disease as outlined in Table . Institutional approval for inhaled amikacin delivery was obtained, as was informed consent from all study subjects.
Patients were treated with aerosolized amikacin as a single daily dose of 15 mg/kg administered using a DeVilbiss PulmoAide Compressor/Nebulizer system (DeVilbiss Health Care; Somerset, Pa) in addition to their concurrent oral antibiotic regimens. Amikacin therapy was anticipated to continue for the duration of their oral antibiotic course (estimated 12–18 month course). Patients were pre-treated with an albuterol meter dose inhaler, if they developed shortness of breath or cough with aerosolized amikacin administration.
An inhaled amikacin dose of 15 mg/kg/day was chosen with the following considerations: a) 15 mg/kg is the usual total daily IV dose for therapy with amikacin; b) the goal of inhaled amikacin therapy was to produce lung drug concentrations that significantly exceed minimum inhibitory concentration (MIC), with particular attention to patients with significant anatomic lung problems including bronchiectasis, where lung drug distribution may be much less uniform than in normal lung.
None of the study patients were currently receiving intravenous aminoglycoside therapy. Patients were monitored throughout therapy for evidence of nephrotoxicity, ototoxicity and vestibuar toxicity. Clinical improvement was determined on the basis of a combination of the following: symptomatic improvement, radiographic stabilization or improvement, and eradication of mycobacterium from sputum cultures. Sputum cultures were performed at 8 to 12 week intervals and were induced with hypertonic saline if the patient's cough was non-productive. Aerosolized amikacin was held for 24 hours prior to sputum induction for surveillance cultures.
Six patients with NTM pulmonary infections were treated with aerosolized amikacin at a dose of 15 mg/kg/day in addition to a concurrent standard oral macrolide based multi-drug regimen. Table outlines specific patient characteristics. All of the patients were women between the ages of 52 and 71 years. All had been treated previously with standard oral macrolide/rifamycin-based regimens and either had failed to respond or were unable to tolerate therapy due to side effects. Patient 4 was infected with a MAC species that was resistant to ethambutol and rifampin, necessitating a change in medications. All remained symptomatic despite prior interventions and had progressive or persistent symptoms including fatigue, cough, hemoptysis, dyspnea, and weight loss. None of the patients had known macrolide resistant NTM infections. Each had a different radiographic presentation on chest radiograph and CT. Patient 1 had primarily nodular infiltrates with mild multi-lobar bronchiectasis; patient 2 had severe multi-lobar bronchiectasis and cavitary nodules; patient 3 had multi-lobar bronchiectasis, centrilobular nodules and a history of a right middle lobe and lingual resection; patient 4 had mild multi-lobar bronchiectasis and diffuse centrilobular nodules; patient 5 had multi-lobar bronchiectasis, centrilobular nodules and a history of a left upper lobe wedge resection; patient 6 had focal bronchiectasis and bronchial wall thickening confined to the right upper and lower lobes. Patients received an average of 750 mg to 1000 mg/day of aerosolized amikacin based on weight.
Patients 1, 3, 4, 5 and 6 tolerated therapy well. They all noted an improvement in cough and fatigue with therapy and were sputum culture negative for NTM on follow-up cultures after 6 months of therapy. Patient 3 developed recurrent NTM disease after 6 months of culture-negative sputum. Her initial sputum cultures prior to initiating inhaled amikacin therapy revealed MAC; subsequent cultures have grown M. chelonae and M. gordonae. Patient 2 was unable to tolerate prolonged therapy with aerosolized amikacin and discontinued therapy after 4 months because of cough and inconvenience of administration. She continued to experience progressive symptoms after cessation of therapy and died of respiratory failure.
Side effects of therapy included voice hoarseness, sore throat (transient) and oral candidiasis. Two patients developed oral candidiasis on aerosolized amikacin therapy that was not responsive to Nystatin oral rinse. Both cases responded well to oral fluconazole therapy. Subsequent episodes of oropharyngeal problems were prevented with improved vigilance of mouth care (including mouth gargling as well as rinsing) after each dose administration. There was no evidence of nephrotoxicity, ototoxicity or vestibular toxicity with therapy.