Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia.
Luyt Charles-Edouard,Clavel Marc,Guntupalli Kalpalatha,Johannigman Jay,Kennedy John I,Wood Christopher,Corkery Kevin,Gribben Dennis,Chastre Jean
Critical care (London, England)
INTRODUCTION:Aminoglycosides aerosolization might achieve better diffusion into the alveolar compartment than intravenous use. The objective of this multicenter study was to evaluate aerosol-delivered amikacin penetration into the alveolar epithelial lining fluid (ELF) using a new vibrating mesh nebulizer (Pulmonary Drug Delivery System (PDDS), Nektar Therapeutics), which delivers high doses to the lungs. METHODS:Nebulized amikacin (400 mg bid) was delivered to the lungs of 28 mechanically ventilated patients with Gram-negative VAP for 7-14 days, adjunctive to intravenous therapy. On treatment day 3, 30 minutes after completing aerosol delivery, all the patients underwent bronchoalveolar lavage in the infection-involved area and the ELF amikacin concentration was determined. The same day, urine and serum amikacin concentrations were determined at different time points. RESULTS:Median (range) ELF amikacin and maximum serum amikacin concentrations were 976.1 (135.7-16127.6) and 0.9 (0.62-1.73) microg/mL, respectively. The median total amount of amikacin excreted in urine during the first and second 12-hour collection on day 3 were 19 (12.21-28) and 21.2 (14.1-29.98) microg, respectively. During the study period, daily through amikacin measurements were below the level of nephrotoxicity. Sixty-four unexpected adverse events were reported, among which 2 were deemed possibly due to nebulized amikacin: one episode of worsening renal failure, and one episode of bronchospasm. CONCLUSIONS:PDDS delivery of aerosolized amikacin achieved very high aminoglycoside concentrations in ELF from radiography-controlled infection-involved zones, while maintaining safe serum amikacin concentrations. The ELF concentrations always exceeded the amikacin minimum inhibitory concentrations for Gram-negative microorganisms usually responsible for these pneumonias. The clinical impact of amikacin delivery with this system remains to be determined. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT01021436.
10.1186/cc8206
Pharmacokinetics of high-dose nebulized amikacin in mechanically ventilated healthy subjects.
Ehrmann Stephan,Mercier Emmanuelle,Vecellio Laurent,Ternant David,Paintaud Gilles,Dequin Pierre-François
Intensive care medicine
OBJECTIVE:Nebulized amikacin may be an attractive option for the treatment of lung infections. Low systemic absorption may permit the use of high doses, leading to high lung concentrations without systemic toxicity. We evaluated the pharmacokinetics and safety of an optimized high-dose amikacin nebulization technique. DESIGN:in vitro and in vivo pharmacokinetic study. PATIENTS AND PARTICIPANTS:Six healthy volunteers (age 21-30 years, weight 49-68 kg). INTERVENTIONS:The Aeroneb Pro nebulizer with an Idehaler vertical spacer was evaluated in a bench study. Amikacin was administered intravenously (15[Symbol: see text]mg/kg) and nebulized (40, 50, and 60[Symbol: see text]mg/kg) during noninvasive pressure-support ventilation through a mouthpiece. MEASUREMENTS AND RESULTS:Median (interquartile range) in vitro inhaled fraction was 31% (30-32) and inhalable output was 681 mg/h (630-743). Serum concentrations after nebulization were less than or equal to those after infusion. The area under the serum concentration curve was significantly higher after infusion (138 mg h(-1)l(-1), 122-143) than after nebulization (49 mg h(-1)l(-1), 39-55, at 40 mg/kg; 63, 53-67 at 50; 66, 50-71, at 60). Peak serum concentration was also higher after infusion: 48 mg/l (45-49) after infusion compared to 8.2 (5.6-8.7), 9.2 (7.6-10.2), and 9.2 (5.2-10.3), respectively. Mean absorption times after nebulization were 2 h 24 min (2,07-2,45), 2 h 21 min (2,07-2,35), and 2 h 5 min (2,00-2,25), respectively. No side effect was observed. CONCLUSIONS:Nebulization of up to 60 mg/kg amikacin appears to be safe in healthy subjects and associated with lower serum concentrations than a 15 mg/kg infusion.
10.1007/s00134-007-0935-1
Use of nebulized liposomal amphotericin B and posaconazole as antifungal prophylaxis in patients with severe SARS-CoV2 infection in intensive care unit.
Infection
PURPOSE:COVID-19 associated pulmonary aspergillosis (CAPA) is common and linked with high fatality rates. To assess the impact on the incidence and outcome of CAPA of an antifungal prophylaxis (AFP) we compared two cohorts of COVID-19 patients admitted to intensive care units (ICU) in Brescia, Italy, from January to August 2021. METHODS:The study cohort included all mechanically ventilated patients observed between April 2021 and August 2021 with SARS-CoV-2-pneumonia, who received AFP with oral posaconazole (200 mg every 6 h) and nebulized liposomal amphotericin B (50 mg every 2 weeks) from ICU admission to 7 days after discharge or, if applicable, until tracheostomy removal. The control cohort included COVID-19 patients admitted to the same ICU between January and March 2021 who did not receive any AFP. Subjects with CAPA at ICU admission were excluded. RESULTS:We included 270 patients, of whom 64 (23.7%) received AFP. In patients in the study group, CAPA-related mortality was significantly reduced (29% vs. 48% p = 0.04), as well as the incidence of CAPA (3.1% vs 12.1%, p = 0.03). Patients who developed CAPA were older (mean of 70-y-old vs 63-y-old, p < 0.001). One subject discontinued posaconazole due to an adverse reaction. Among the 46 patients who received it, only one patient reached an effective plasma concentration of posaconazole. CONCLUSION:AFP was associated with reduced incidence and mortality from CAPA and was well tolerated in patients with severe COVID-19. Posaconazole concentrations below the efficacy threshold in almost all patients may be attributable to drug interactions and prompt further studies to define its clinical significance.
10.1007/s15010-024-02234-9
Inhaled Antifungal Agents for the Treatment and Prophylaxis of Pulmonary Mycoses.
Liao Qiuying,Lam Jenny K W
Current pharmaceutical design
Pulmonary mycoses are associated with high morbidity and mortality. The current standard treatment by systemic administration is limited by inadequate local bioavailability and systemic toxic effects. Aerosolisation of antifungals is an attractive approach to overcome these problems, but no inhaled antifungal formulation is currently available for the treatment of pulmonary mycoses. Hence, the development of respirable antifungals formulations is of interest and in high demand. In this review, the recent advances in the development of antifungal formulations for pulmonary delivery are discussed, including both nebulised and dry powder formulations. Although the clinical practices of nebulised parenteral amphotericin B and voriconazole formulations (off-label use) are reported to show promising therapeutic effects with few adverse effects, there is no consensus about the dosage regimen (e.g. the dose, frequency, and whether they are used as single or combination therapy). To maximise the benefits of nebulised antifungal therapy, it is important to establish standardised protocol that clearly defines the dose and specifies the device and the administration conditions. Dry powder formulations of antifungal agents such as itraconazole and voriconazole with favourable physicochemical and aerosol properties are developed using various powder engineering technologies, but it is important to consider their suitability for use in patients with compromised lung functions. In addition, more biological studies on the therapeutic efficacy and pharmacokinetic profile are needed to demonstrate their clinical potential.
10.2174/1381612826666210101153547
Nebulised colistin for ventilator-associated pneumonia prevention.
Karvouniaris Marios,Makris Demosthenes,Zygoulis Paris,Triantaris Apostolos,Xitsas Stelios,Mantzarlis Konstantinos,Petinaki Efthimia,Zakynthinos Epaminondas
The European respiratory journal
We evaluated whether prophylactic nebulised colistin could reduce ventilator-associated pneumonia (VAP) rates in an intensive care unit (ICU) setting with prevalent multidrug-resistant (MDR) bacteria.We used a single-centre, two-arm, randomised, open-label, controlled trial in a 12-bed ICU in the University Hospital of Larissa, Greece. Patient inclusion criteria included mechanical ventilation of >48 h. The two arms consisted of prophylaxis with 500 000 U colistin (Col group) or normal saline (NS group), thrice daily, for the first 10 ICU days or until extubation. The primary outcome of the study was the 30-day VAP incidence.In total, 168 patients entered the study. VAP incidence was not different between Col and NS group patients (14 (16.7%) versus 25 (29.8%), respectively, p=0.07). Regarding the secondary outcomes, the intervention resulted in a lower VAP incidence density rate (11.4 versus 25.6, respectively, p<0.01), and less Gram-negative bacteria-VAP (p=0.03) and MDR-VAP (p=0.04). Among VAP patients (n=39), prophylaxis with inhaled colistin improved ICU survival (p=0.016). There was no evidence of increased resistance to colistin or multidrug resistance.Our findings suggest that nebulised colistin had no significant effect on VAP incidence.
10.1183/13993003.02235-2014
Administration of antibiotics via the respiratory tract for the prevention of ICU-acquired pneumonia: a meta-analysis of comparative trials.
Falagas Matthew E,Siempos Ilias I,Bliziotis Ioannis A,Michalopoulos Argyris
Critical care (London, England)
INTRODUCTION:The administration of prophylactic antibiotics via the respiratory tract is one of several strategies for the prevention of ICU-acquired pneumonia. We systematically examined the available evidence regarding the effect of prophylactic antibiotics administered via the respiratory tract on the development of ICU-acquired pneumonia, mortality, colonization of the respiratory tract, emergence of antimicrobial resistance, and toxicity. METHODS:We searched the PubMed database (1/1950 to 9/2005) and references from relevant articles to identify trials that provided comparative data regarding the above-mentioned outcomes. Two investigators independently performed the data extraction to calculate the effect of the studied intervention on clinically relevant outcomes. RESULTS:8 comparative trials (5 randomized controlled trials (RCTs) and 3 non-randomized trials) studying gentamicin (3 trials) polymyxins (3 trials), tobramycin (1 trial), and ceftazidime (1 trial) that studied 1,877 patients were included in our meta-analysis. Our primary analysis that included the 5 RCTs, revealed that ICU-acquired pneumonia was less common in the group of patients that received the antibiotic prophylaxis (OR = 0.49, 95% CI 0.32-0.76). No difference in mortality was found between the compared groups (OR = 0.86, 95% CI 0.55-1.32). There were limited data to permit an analysis of colonization with Pseudomonas aeruginosa. A secondary analysis by adding the 3 non-randomized comparative trials did not reveal substantially different results regarding ICU-acquired pneumonia and mortality, while fewer patients were colonized with Pseudomonas aeruginosa in the group that received prophylaxis, compared to the group of patients that received no prophylaxis (OR = 0.51, 95% CI 0.30-0.86). No serious drug-related toxicity was noted. No meaningful systematic analysis of the evidence regarding the emergence of resistance could be performed in the studies included in our meta-analysis. CONCLUSIONS:The limited available evidence supports that prophylactic administration of antibiotics via the respiratory tract is associated with reduction of occurrence of ICU-acquired pneumonia. However, there is evidence from non-comparative studies that this preventive strategy may lead to an increase in the emergence of resistant bacteria. Thus, further investigation, at least in ICU patients at high risk for development of ICU-acquired pneumonia is warranted, including a more systematic evaluation of issues related to the emergence of resistance.
10.1186/cc5032
Inhaled Antibiotics for the Prevention of Respiratory Tract Infections in Children With a Tracheostomy.
Jutras Camille,Autmizguine Julie,Chomton Maryline,Marquis Christopher,Nguyen The Thanh-Diem,Roumeliotis Nadia,Emeriaud Guillaume
Frontiers in pediatrics
To describe the use of prophylactic inhaled antibiotics in children with a tracheostomy and assess if its use is associated with a reduction in exposition to broad-spectrum antibiotics and a lower risk of acquired respiratory tract infections. A case series study was performed in a tertiary care university affiliated hospital. All consecutive children (<18 years old) with a tracheostomy, hospitalized between January 2004 and November 2016, and treated with prophylactic inhaled antibiotics were identified. We analyzed the 3 month- period before and after initiation of prophylactic inhaled antibiotics and described exposure to broad spectrum antibiotics, the number of respiratory tract infections and the associated adverse events. Six children (median age: 11 months, range: 8-100) were included. One received colimycin, 3 received tobramycin and 2 were treated with both antibiotics in alternance. The median duration of treatment was 74 days (22-173) with one patient still being treated at the end of the study. Patients were exposed to systemic antibiotics for 18 days (2-49) in the 3 months preceding the treatment vs. 2 days (0-15) in the 3 months following the treatment initiation ( = 0.115). The number of respiratory tract infections went from median of 2 (0-3) to 1 (0-1) during the same periods ( = 0.07). Adverse events most commonly reported were cough ( = 2) and increased respiratory secretions post-inhalation ( = 4). Only one new bacterial resistance was observed. This series of consecutive cases underlines the need for future studies evaluating the potential benefit of prophylactic inhaled antibiotics in children with a tracheostomy.
10.3389/fped.2021.633039
Prophylactic Antibiotics Delivered Via the Respiratory Tract to Reduce Ventilator-Associated Pneumonia: A Systematic Review, Network Meta-Analysis, and Trial Sequential Analysis of Randomized Controlled Trials.
Critical care medicine
OBJECTIVES:To assess the effects of antibiotics delivered via the respiratory tract in preventing ventilator-associated pneumonia (VAP). DATA SOURCES:We searched PubMed, Scopus, the Cochrane Library, and ClinicalTrials.gov for studies published in English up to October 25, 2023. STUDY SELECTION:Adult patients with mechanical ventilation of over 48 h and receiving inhaled or instilled antibiotics (with control group) to prevent VAP were included. DATA EXTRACTION:Two independent groups screened studies, extracted the data, and assessed the risk of bias. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess the certainty/quality of the evidence. Results of a random-effects model were reported for overall and predefined subgroup meta-analyses. The analysis was primarily conducted on randomized controlled trials, and observational studies were used for sensitivity analyses. DATA SYNTHESIS:Seven RCTs with 1445 patients were included, of which six involving 1283 patients used nebulizers to deliver antibiotics. No obvious risk of bias was found among the included RCTs for the primary outcome. Compared with control group, prophylactic antibiotics delivery via the respiratory tract significantly reduced the risk of VAP (risk ratio [RR], 0.69 [95% CI, 0.53-0.89]), particularly in subgroups where aminoglycosides (RR, 0.67 [0.47-0.97]) or nebulization (RR, 0.64 [0.49-0.83]) were used as opposed to other antibiotics (ceftazidime and colistin) or intratracheal instillation. No significant differences were observed in mortality, mechanical ventilation duration, ICU and hospital length of stay, duration of systemic antibiotics, need for tracheostomy, and adverse events between the two groups. Results were confirmed in sensitivity analyses. CONCLUSIONS:In adult patients with mechanical ventilation for over 48 h, prophylactic antibiotics delivered via the respiratory tract reduced the risk of VAP, particularly for those treated with nebulized aminoglycosides.
10.1097/CCM.0000000000006323
Effect of antibiotics administered via the respiratory tract in the prevention of ventilator-associated pneumonia: A systematic review and meta-analysis.
Póvoa Frederico Castro Costa,Cardinal-Fernandez Pablo,Maia Israel Silva,Reboredo Maycon Moura,Pinheiro Bruno Valle
Journal of critical care
PURPOSE:We evaluated the effect of antibiotics administered via the respiratory tract to prevent the ventilator-associated pneumonia (VAP) in mechanically ventilated (MV) patients. METHODS:We searched relevant articles for trials that evaluated the impact of prophylactic antibiotics administered through the respiratory tract on the occurrence of VAP. The end-point was the occurrence of VAP in MV patients. RESULTS:We included 6 comparative trials involving 1158 patients (632 received prophylactic antibiotic). Our meta-analysis revealed that prophylactic antibiotics administered through the respiratory tract reduced the occurrence of VAP when compared to placebo or no treatment (OR 0.53; 95% CI 0.34-0.84). This effect was seen when the antibiotics were given by nebulization (OR 0.46; 95% CI 0.22-0.97), but not when they were administered by intratracheal instillation (OR 0.57; 95% CI 0.28-1.15). We did not find a significant difference between the compared groups in the intensive care unit (ICU) mortality (OR 0.89; 95% CI 0.64-1.25). Antibiotic prophylaxis did not impact occurrence of VAP due to multidrug resistant (MDR) pathogens (OR 0.67; 95% CI 0.17-2.62). CONCLUSIONS:Prophylactic antibiotics administered through the respiratory tract by nebulization reduce the occurrence of VAP, without a significant effect on either the ICU mortality or occurrence of VAP due to MDR pathogens.
10.1016/j.jcrc.2017.09.019
BAY41-6551 achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with Gram-negative pneumonia.
Niederman Michael S,Chastre Jean,Corkery Kevin,Fink James B,Luyt Charles-Edouard,García Miguel Sánchez
Intensive care medicine
PURPOSE:To conduct a multicenter, randomized, placebo-controlled, double-blind, phase II study of BAY41-6551 (NCT01004445), an investigational drug-device combination of amikacin, formulated for inhalation, and a proprietary Pulmonary Drug Delivery System, for the treatment of Gram-negative pneumonia in mechanically ventilated patients. METHODS:Sixty-nine mechanically ventilated patients with Gram-negative pneumonia, a clinical pulmonary infection score ≥6, at risk for multidrug-resistant organisms, were randomized to BAY41-6551 400 mg every 12 h (q12h), 400 mg every 24 h (q24h) with aerosol placebo, or placebo q12h for 7-14 days, plus standard intravenous antibiotics. The combined primary endpoint was a tracheal aspirate amikacin maximum concentration ≥6,400 μg/mL (25 × 256 μg/mL reference minimum inhibitory concentration) and a ratio of area under the aspirate concentration-time curve (0-24 h) to minimum inhibitory concentration ≥100 on day 1. RESULTS:The primary endpoint was achieved in 50% (6/12) and 16.7% (3/18) of patients in the q12h and q24h groups, respectively. Clinical cure rates, in the 48 patients getting ≥7 days of therapy, were 93.8% (15/16), 75.0% (12/16), and 87.5% (14/16) in the q12h, q24h, and placebo groups, respectively (p = 0.467). By the end of aerosol therapy, the mean number of antibiotics per patient per day was 0.9 in the q12h, 1.3 in the q24h, and 1.9 in the placebo groups, respectively (p = 0.02 for difference between groups). BAY41-6551 was well tolerated and attributed to two adverse events in one patient (mild bronchospasm). CONCLUSIONS:BAY41-6551 400 mg q12h warrants further clinical evaluation.
10.1007/s00134-011-2420-0
Amikacin-fosfomycin at a five-to-two ratio: characterization of mutation rates in microbial strains causing ventilator-associated pneumonia and interactions with commonly used antibiotics.
Montgomery A Bruce,Rhomberg Paul R,Abuan Tammy,Walters Kathie-Anne,Flamm Robert K
Antimicrobial agents and chemotherapy
The amikacin-fosfomycin inhalation system (AFIS), a combination of antibiotics administered with an in-line nebulizer delivery system, is being developed for adjunctive treatment of ventilator-associated pneumonia (VAP). The in vitro characterization of amikacin-fosfomycin (at a 5:2 ratio) described here included determining resistance selection rates for pathogens that are representative of those commonly associated with VAP (including multidrug-resistant strains) and evaluating interactions with antibiotics commonly used intravenously to treat VAP. Spontaneous resistance to amikacin-fosfomycin (5:2) was not observed for most strains tested (n, 10/14). Four strains had spontaneously resistant colonies (frequencies, 4.25 × 10(-8) to 3.47 × 10(-10)), for which amikacin-fosfomycin (5:2) MICs were 2- to 8-fold higher than those for the original strains. After 7 days of serial passage, resistance (>4-fold increase over the baseline MIC) occurred in fewer strains (n, 4/14) passaged in the presence of amikacin-fosfomycin (5:2) than with either amikacin (n, 7/14) or fosfomycin (n, 12/14) alone. Interactions between amikacin-fosfomycin (5:2) and 10 comparator antibiotics in checkerboard testing against 30 different Gram-positive or Gram-negative bacterial strains were synergistic (fractional inhibitory concentration [FIC] index, ≤ 0.5) for 6.7% (n, 10/150) of combinations tested. No antagonism was observed. Synergy was confirmed by time-kill methodology for amikacin-fosfomycin (5:2) plus cefepime (against Escherichia coli), aztreonam (against Pseudomonas aeruginosa), daptomycin (against Enterococcus faecalis), and azithromycin (against Staphylococcus aureus). Amikacin-fosfomycin (5:2) was bactericidal at 4-fold the MIC for 7 strains tested. The reduced incidence of development of resistance to amikacin-fosfomycin (5:2) compared with that for amikacin or fosfomycin alone, and the lack of negative interactions with commonly used intravenous antibiotics, further supports the development of AFIS for the treatment of VAP.
10.1128/AAC.02779-13
Population pharmacokinetics of single-dose amikacin in critically ill patients with suspected ventilator-associated pneumonia.
Burdet C,Pajot O,Couffignal C,Armand-Lefèvre L,Foucrier A,Laouénan C,Wolff M,Massias L,Mentré F
European journal of clinical pharmacology
AIMS:Modifications of antimicrobials' pharmacokinetic parameters have been reported in critically ill patients, resulting in a risk of treatment failure. We characterized amikacin pharmacokinetic variability in critically ill patients with ventilator-associated pneumonia (VAP) and evaluated several dosing regimens. METHODS:We conducted a prospective multicenter study in critically ill patients with presumptive diagnosis of Gram-negative bacilli (GNB) VAP. Patients empirically received imipenem and a single-dose of amikacin, which was administered as a 30-min infusion (20 mg/kg). Concentrations were measured 0.5, 1, 8, 16, and 24 h after beginning of infusion. Pharmacokinetic parameters were estimated using a population approach. Main pharmacodynamic target was a ratio ≥ 10 between the concentration achieved 1 h after beginning of infusion (C 1h) and the minimal inhibitory concentration of the liable bacteria (MIC). We simulated individual C 1h for several dosing regimens by Monte Carlo method and computed C 1h/MIC ratios for MICs from 0.5 to 64 mg/L. RESULTS:Sixty patients (47 males), median (range) age, and body weight, 61.5 years (28-84) and 78 kg (45-126), respectively, were included. Amikacin median C 1h was 45 mg/L (22-87). Mean value (between-patients variability) for CL, V1, Q, and V2 were 4.3 L/h (31 %), 15.9 L (22 %), 12.1 L/h (27 %), and 21.4 L (47 %), respectively. CL increased with CrCL (p<0.001) and V1 with body weight (p<0.001) and PaO2/FIO2 ratio (p<0.001). With a 25 mg/kg regimen, the pharmacodynamic target was achieved in 20 and 96 % for a MICs of 8 and 4 mg/L, respectively. CONCLUSION:Amikacin clearance was decreased and its volume of distribution was increased as previously reported. A ≥ 25 mg/kg single-dose is needed for empirical treatment of GNB-VAP.
10.1007/s00228-014-1766-y
Amikacin nebulization for the adjunctive therapy of gram-negative pneumonia in mechanically ventilated patients: a systematic review and meta-analysis of randomized controlled trials.
Qin Jun-Ping,Huang Hui-Bin,Zhou Hua,Zhu Yuan,Xu Yuan,Du Bin
Scientific reports
Treatment of ventilated patients with gram-negative pneumonia (GNP) is often unsuccessful. We aimed to assess the efficacy and safety of nebulized amikacin (NA) as adjunctive therapy to systemic antibiotics in this patient population. PubMed, Embase, China national knowledge infrastructure, Wanfang, and the Cochrane database were searched for randomized controlled trials (RCTs) investigating the effect of NA as adjunctive therapy in ventilated adult patients with GNP. Heterogeneity was explored using subgroup analysis and sensitivity analysis. The Grading of recommendations assessment, development, and evaluation approach was used to assess the certainty of the evidence. Thirteen RCTs with 1733 adults were included. The pooled results showed NA had better microbiologic eradication (RR = 1.51, 95% CI 1.35 to 1.69, P < 0.0001) and improved clinical response (RR = 1.23; 95% CI 1.13 to 1.34; P < 0.0001) when compared with control. Meanwhile, overall mortality, pneumonia associated mortality, duration of mechanical ventilation, length of stay in ICU and change of clinical pneumonia infection scores were similar between NA and control groups. Additionally, NA did not add significant nephrotoxicity while could cause more bronchospasm. The use of NA adjunctive to systemic antibiotics therapy showed better benefits in ventilated patients with GNP. More well-designed RCTs are still needed to confirm our results.
10.1038/s41598-021-86342-8
Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial.
The Lancet. Infectious diseases
BACKGROUND:Treatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to established guidelines. Therefore, we aimed to investigate the efficacy of the combination drug device Amikacin Inhale as an adjunctive therapy to intravenous standard-of-care antibiotics for pneumonia caused by Gram-negative pathogens in intubated and mechanically ventilated patients. METHODS:INHALE was a prospective, double-blind, randomised, placebo-controlled, phase 3 study comprising two trials (INHALE 1 and INHALE 2) done in 153 hospital intensive-care units in 25 countries. Eligible patients were aged 18 years or older; had pneumonia that had been diagnosed by chest radiography and that was documented as being caused by or showing two risk factors for a Gram-negative, multidrug-resistant pathogen; were intubated and mechanically ventilated; had impaired oxygenation within 48 h before screening; and had a modified Clinical Pulmonary Infection Score of at least 6. Patients were stratified by region and disease severity (according to their Acute Physiology and Chronic Health Evaluation [APACHE] II score) and randomly assigned (1:1) via an interactive voice-recognition system to receive 400 mg amikacin (Amikacin Inhale) or saline placebo, both of which were aerosolised, administered every 12 h for 10 days via the same synchronised inhalation system, and given alongside standard-of-care intravenous antibiotics. All patients and all staff involved in administering devices and monitoring outcomes were masked to treatment assignment. The primary endpoint, survival at days 28-32, was analysed in all patients who received at least one dose of study drug, were infected with a Gram-negative pathogen, and had an APACHE II score of at least 10 at diagnosis. Safety analyses were done in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, numbers NCT01799993 and NCT00805168. FINDINGS:Between April 13, 2013, and April 7, 2017, 807 patients were assessed for eligibility and 725 were randomly assigned to Amikacin Inhale (362 patients) or aerosolised placebo (363 patients). 712 patients received at least one dose of study drug (354 in the Amikacin Inhale group and 358 in the placebo group), although one patient assigned to Amikacin Inhale received placebo in error and was included in the placebo group for safety analyses. 508 patients (255 in the Amikacin Inhale group and 253 in the placebo group) were assessed for the primary endpoint. We found no between-group difference in survival: 191 (75%) patients in the Amikacin Inhale group versus 196 (77%) patients in the placebo group survived until days 28-32 (odds ratio 0·841, 95% CI 0·554-1·277; p=0·43). Similar proportions of patients in the two treatment groups had a treatment-emergent adverse event (295 [84%] of 353 patients in the Amikacin Inhale group vs 303 [84%] of 359 patients in the placebo group) or a serious treatment-emergent adverse event (101 [29%] patients vs 97 [27%] patients). INTERPRETATION:Our findings do not support use of inhaled amikacin adjunctive to standard-of-care intravenous therapy in mechanically ventilated patients with Gram-negative pneumonia. FUNDING:Bayer AG.
10.1016/S1473-3099(19)30574-2
Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia.
The New England journal of medicine
BACKGROUND:Whether preventive inhaled antibiotics may reduce the incidence of ventilator-associated pneumonia is unclear. METHODS:In this investigator-initiated, multicenter, double-blind, randomized, controlled, superiority trial, we assigned critically ill adults who had been undergoing invasive mechanical ventilation for at least 72 hours to receive inhaled amikacin at a dose of 20 mg per kilogram of ideal body weight once daily or to receive placebo for 3 days. The primary outcome was a first episode of ventilator-associated pneumonia during 28 days of follow-up. Safety was assessed. RESULTS:A total of 850 patients underwent randomization, and 847 were included in the analyses (417 assigned to the amikacin group and 430 to the placebo group). All three daily nebulizations were received by 337 patients (81%) in the amikacin group and 355 patients (83%) in the placebo group. At 28 days, ventilator-associated pneumonia had developed in 62 patients (15%) in the amikacin group and in 95 patients (22%) in the placebo group (difference in restricted mean survival time to ventilator-associated pneumonia, 1.5 days; 95% confidence interval [CI], 0.6 to 2.5; P = 0.004). An infection-related ventilator-associated complication occurred in 74 patients (18%) in the amikacin group and in 111 patients (26%) in the placebo group (hazard ratio, 0.66; 95% CI, 0.50 to 0.89). Trial-related serious adverse effects were seen in 7 patients (1.7%) in the amikacin group and in 4 patients (0.9%) in the placebo group. CONCLUSIONS:Among patients who had undergone mechanical ventilation for at least 3 days, a subsequent 3-day course of inhaled amikacin reduced the burden of ventilator-associated pneumonia during 28 days of follow-up. (Funded by the French Ministry of Health; AMIKINHAL ClinicalTrials.gov number, NCT03149640; EUDRA Clinical Trials number, 2016-001054-17.).
10.1056/NEJMoa2310307