Inhaled amikacin versus placebo to prevent ventilator-associated pneumonia: the AMIKINHAL double-blind multicentre randomised controlled trial protocol

IntroductionPre-emptive inhaled antibiotics may be effective to reduce the occurrence of ventilator-associated pneumonia among critically ill patients. Meta-analysis of small sample size trials showed a favourable signal. Inhaled antibiotics are associated with a reduced emergence of antibiotic resistant bacteria. The aim of this trial is to evaluate the benefit of a 3-day course of inhaled antibiotics among patients undergoing invasive mechanical ventilation for more than 3 days on the occurrence of ventilator-associated pneumonia.Methods and analysisAcademic, investigator-initiated, parallel two group arms, double-blind, multicentre superiority randomised controlled trial. Patients invasively ventilated more than 3 days will be randomised to receive 20 mg/kg inhaled amikacin daily for 3 days or inhaled placebo (0.9% Sodium Chloride). Occurrence of ventilator-associated pneumonia will be recorded based on a standardised diagnostic framework from randomisation to day 28 and adjudicated by a centralised blinded committee.Ethics and disseminationThe protocol and amendments have been approved by the regional ethics review board and French competent authorities (Comité de protection des personnes Ouest I, No.2016-R29). All patients will be included after informed consent according to French law. Results will be disseminated in international scientific journals.Trial registration numbersEudraCT 2016-001054-17 and NCT03149640.

Comparison of Inhaled Colistin with Inhaled Amikacin-Fosfomycin in the Treatment of Ventilator-Associated Pneumonia Caused by Extensively Drug-Resistant (XDR) Acinetobacter: A Clinical Trial

Background: This study aimed to compare the effects of inhaled colistin and inhaled amikacin-fosfomycin combination in the treatment of ventilator-associated pneumonia (VAP) caused by extensively drug-resistant (XDR) Acinetobacter. This clinical trial is the first study to evaluate the effect of inhaled fosfomycin on VAP in Iran. Methods: In this clinical trial, 60 patients with Acinetobacter VAP were divided into two groups of 30 patients. The empirical regimen changed to meropenem plus intravenous colistin in both groups. Inhaled colistin in the first group and inhaled amikacin-fosfomycin in the second group were added to the intravenous therapy. Next, the mortality rate, if any, duration of treatment success, and patient withdrawal from VAP were evaluated in the two groups. Results: Although the mean clinical pulmonary infection score (CPIS) before treatment was not significantly different between the two groups, the mean score of the amikacin-fosfomycin group was significantly lower at 72 hours and seven days after the onset of treatment and at the end of treatment. Based on the intra-group assessments, the CPIS in both groups was significantly reduced (P < 0.001). Also, in the inter-group assessments, the mean CPIS changes were significantly different between the two groups, and in the amikacin-fosfomycin group, a greater reduction in the CPIS was observed (P = 0.007). Conclusions: The findings of the present study showed that the use of amikacin-fosfomycin nebulization could lead to increased recovery and reduced treatment duration in patients with VAP, caused by drug-resistant Acinetobacter baumannii.

Outcomes of Inhaled Amikacin and Clofazimine-Containing Regimens for Treatment of Refractory Mycobacterium avium Complex Pulmonary Disease

Limited data are available regarding optimal treatment for refractory Mycobacterium avium complex-pulmonary disease (MAC-PD). We evaluated outcomes of inhaled amikacin (AMK) with clofazimine (CFZ) regimens as an add-on salvage therapy for refractory MAC-PD. We retrospectively analyzed 52 patients with refractory MAC-PD, characterized by persistently positive sputum cultures despite >6 months of treatment. Thirty-five (67%) patients had M. intracellulare-PD, and 17 (33%) patients had M. avium-PD. Twenty-seven (52%) patients received the salvage therapy for ≥12 months, whereas 25 (48%) patients were treated for <12 months due to adverse effects or other reasons. Seventeen (33%) patients had culture conversion: 10 (10/27) in the ≥12-month treatment group and seven (7/25) in the <12-month treatment group (p = 0.488). Microbiological cure, defined as maintenance of culture negativity, was achieved in 12 (23%) patients; six (6/12) with accompanying symptomatic improvement were considered to have reached cure. Clinical cure, defined as symptomatic improvement with <3 consecutive negative cultures, was achieved in three (6%) patients. Overall, 15 (29%) patients achieved favorable outcomes, including microbiological cure, cure, and clinical cure. Inhaled AMK with CFZ may provide favorable outcomes in some patients with refractory MAC-PD. However, given the adverse effects, more effective strategies are needed to maintain these therapeutic regimens.

Amikacin exposure and susceptibility of macrolide-resistant Mycobacterium abscessus

Mycobacterium abscessus is associated with antibiotic resistance and poor treatment outcomes. We described within-patient changes in M. abscessus resistance to clarithromycin and amikacin.Patients with amikacin exposure and a >50-month interval between M. abscessus isolates were identified. Antimicrobial susceptibility testing was performed on the first and last isolates by broth microdilution, and genetic markers of resistance were identified.16 patients were identified with a median amikacin exposure of 2.3 years (range 0.6–8.6 years). 15 patients also received macrolides (median 7.2 years, range 1.3–10.7 years). All initial isolates were resistant to clarithromycin (minimum inhibitory concentration (MIC) ≥8 µg·mL−1). Two patients had later susceptible isolates, which were of a different subspecies (M. abscessus subsp. massiliense) than the initial isolates (M. abscessus subsp. abscessus). All initial isolates were susceptible or intermediately resistant to amikacin, and only one patient had a resistant final isolate (MIC >64 µg·mL−1), accompanied by an A→G mutation at position 1408 of the 16S ribosomal RNA. Forced expiratory volume in 1 s decreased significantly over the study period, while smear quantity and the proportions of patients with elevated C-reactive protein or cavitary lesions all increased significantly.Despite prolonged, mostly inhaled amikacin exposure, development of amikacin resistance was uncommon in this patient population; however, disease progression continued.