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The New England Journal of Medicine Nov 2023Whether preventive inhaled antibiotics may reduce the incidence of ventilator-associated pneumonia is unclear. (Randomized Controlled Trial)
Randomized Controlled Trial
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.).
Topics: Adult; Humans; Amikacin; Double-Blind Method; Pneumonia, Ventilator-Associated; Respiration, Artificial; Treatment Outcome; Administration, Inhalation; Anti-Bacterial Agents; Critical Illness
PubMed: 37888914
DOI: 10.1056/NEJMoa2310307 -
Molecules (Basel, Switzerland) Dec 2017Aminoglycosides are a group of antibiotics used since the 1940s to primarily treat a broad spectrum of bacterial infections. The primary resistance mechanism against... (Review)
Review
Aminoglycosides are a group of antibiotics used since the 1940s to primarily treat a broad spectrum of bacterial infections. The primary resistance mechanism against these antibiotics is enzymatic modification by aminoglycoside-modifying enzymes that are divided into acetyl-transferases, phosphotransferases, and nucleotidyltransferases. To overcome this problem, new semisynthetic aminoglycosides were developed in the 70s. The most widely used semisynthetic aminoglycoside is amikacin, which is refractory to most aminoglycoside modifying enzymes. Amikacin was synthesized by acylation with the l-(-)-γ-amino-α-hydroxybutyryl side chain at the C-1 amino group of the deoxystreptamine moiety of kanamycin A. The main amikacin resistance mechanism found in the clinics is acetylation by the aminoglycoside 6'--acetyltransferase type Ib [AAC(6')-Ib], an enzyme coded for by a gene found in integrons, transposons, plasmids, and chromosomes of Gram-negative bacteria. Numerous efforts are focused on finding strategies to neutralize the action of AAC(6')-Ib and extend the useful life of amikacin. Small molecules as well as complexes ionophore-Zn or Cu were found to inhibit the acetylation reaction and induced phenotypic conversion to susceptibility in bacteria harboring the gene. A new semisynthetic aminoglycoside, plazomicin, is in advance stage of development and will contribute to renewed interest in this kind of antibiotics.
Topics: Amikacin; Anti-Bacterial Agents; Bacterial Infections; Genes, Bacterial; Gram-Negative Bacteria; Humans; Kanamycin Resistance
PubMed: 29257114
DOI: 10.3390/molecules22122267 -
The Journal of Antimicrobial... Oct 2016The objectives of this study were to identify the amikacin dosage regimens and drug concentrations consistent with good outcomes and to determine the drug exposures... (Review)
Review
OBJECTIVES
The objectives of this study were to identify the amikacin dosage regimens and drug concentrations consistent with good outcomes and to determine the drug exposures related to nephrotoxicity and ototoxicity.
METHODS
A literature review was conducted in Medline, EMBASE and the Cochrane Central Register of Controlled Trials. Full journal articles reporting randomized controlled trials, controlled clinical trials, interrupted time series trials, and controlled before and after studies involving amikacin therapeutic drug monitoring (TDM) and dose adjustment were considered for inclusion.
RESULTS
Seventeen studies for inclusion were identified, comprising 1677 participants. Amikacin doses ranged from 11 to 15 mg/kg/day with 13 studies using 15 mg/kg/day. Studies were generally designed to compare different aminoglycosides rather than to assess concentration-effect relationships. Only 11 papers presented data on target concentrations, rate of clinical cure and toxicity. Target peak concentrations ranged from 15 to 40 mg/L and target troughs were typically <10 or <5 mg/L. It was not clear whether these targets were achieved. Measured peaks averaged 28 mg/L for twice-daily dosing and 40-45 mg/L for once-daily dosing; troughs averaged 5 and 1-2 mg/L, respectively. Fifteen of the included studies reported rates of nephrotoxicity; auditory and vestibular toxicities were reported in 12 and 8 studies.
CONCLUSIONS
This systematic review found little published evidence to support an optimal dosage regimen or TDM targets for amikacin therapy. The use of alternative approaches, such as consensus opinion and a review of current practice, will be required to develop guidelines to maximize therapeutic outcomes and minimize toxicity with amikacin.
Topics: Adult; Amikacin; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Humans; Interrupted Time Series Analysis; Treatment Outcome
PubMed: 27494904
DOI: 10.1093/jac/dkw250 -
American Journal of Respiratory and... Dec 2018Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by complex (MAC). To evaluate the... (Randomized Controlled Trial)
Randomized Controlled Trial
Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by complex (MAC). To evaluate the efficacy and safety of daily amikacin liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease. Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6. Enrolled patients (ALIS + GBT, = 224; GBT-alone, = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08-8.57; < 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00-7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively. Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT02344004).
Topics: Administration, Inhalation; Amikacin; Anti-Bacterial Agents; Female; Humans; Liposomes; Lung Diseases; Male; Middle Aged; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Prospective Studies; Treatment Outcome
PubMed: 30216086
DOI: 10.1164/rccm.201807-1318OC -
BMJ Open Sep 2021Pre-emptive inhaled antibiotics may be effective to reduce the occurrence of ventilator-associated pneumonia among critically ill patients. Meta-analysis of small sample...
INTRODUCTION
Pre-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 ANALYSIS
Academic, 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 DISSEMINATION
The 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 NUMBERS
EudraCT 2016-001054-17 and NCT03149640.
Topics: Administration, Inhalation; Amikacin; Double-Blind Method; Humans; Multicenter Studies as Topic; Pneumonia, Ventilator-Associated; Randomized Controlled Trials as Topic; Respiration, Artificial; Treatment Outcome
PubMed: 34521664
DOI: 10.1136/bmjopen-2020-048591 -
Journal of Pharmacy Practice Dec 2014Aminoglycosides are among the oldest antibiotics available to treat serious infections caused by primarily, Gram-negative bacteria. The most commonly utilized parenteral... (Review)
Review
Aminoglycosides are among the oldest antibiotics available to treat serious infections caused by primarily, Gram-negative bacteria. The most commonly utilized parenteral agents in this class include gentamicin, tobramycin and amikacin. Aminoglycosides are concentration-dependent, bactericidal agents that undergo active transport into the cell where they inhibit protein synthesis on the 30S subunit of the bacterial ribosome. As the use of aminoglycosides became more widespread, the toxic effects of these agents, most notably ototoxicity and nephrotoxicity, became more apparent. When other, safer, antimicrobial agents became available, the use of aminoglycosides sharply declined. The development of multi-drug resistance among bacteria has now lead clinicians to reexamine the role of the aminoglycosides in the treatment of serious infections. This review will revisit the mechanism and risk factors for the development of aminoglycoside-induced nephrotoxicity, as well as strategies to prevent patients from developing nephrotoxicity.
Topics: Amikacin; Anti-Bacterial Agents; Gentamicins; Humans; Kidney Diseases; Tobramycin
PubMed: 25199523
DOI: 10.1177/0897190014546836 -
Expert Review of Respiratory Medicine Aug 2014Arikace™ is a novel formulation of inhaled liposomal amikacin that can penetrate deep within airway secretions and within Pseudomonas aeruginosa biofilms, making it an... (Review)
Review
Arikace™ is a novel formulation of inhaled liposomal amikacin that can penetrate deep within airway secretions and within Pseudomonas aeruginosa biofilms, making it an attractive therapeutic option for the treatment of cystic fibrosis (CF) pulmonary infections. Initial Phase I and Phase II studies in CF patients with chronic P. aeruginosa infection demonstrated that Arikace™ was a safe drug that resulted in significant improvements in lung function after 14-28 days of treatment. Phase III studies of inhaled liposomal amikacin compared to tobramycin inhalation solution in CF patients with P. aeruginosa infection revealed a comparable increase in forced expiratory volume in 1 second at the end of three cycles. In addition, inhaled liposomal amikacin has other potential applications in the management of difficult-to-treat pulmonary infections. A Phase II trial is currently underway to study the use of Arikace™ for the treatment of recalcitrant nontuberculous mycobacterial lung disease.
Topics: Administration, Inhalation; Amikacin; Anti-Bacterial Agents; Cystic Fibrosis; Humans; Pseudomonas Infections; Pseudomonas aeruginosa; Respiratory Tract Infections; Treatment Outcome
PubMed: 24882271
DOI: 10.1586/17476348.2014.918507 -
PloS One 2023Tuberculosis stands as a prominent cause of mortality in developing countries. The treatment of tuberculosis involves a complex procedure requiring the administration of...
Tuberculosis stands as a prominent cause of mortality in developing countries. The treatment of tuberculosis involves a complex procedure requiring the administration of a panel of at least four antimicrobial drugs for the duration of six months. The occurrence of treatment failure after the completion of a standard treatment course presents a serious medical problem. The purpose of this study was to evaluate antimicrobial drug resistant features of Mycobacterium tuberculosis associated with treatment failure. Additionally, it aimed to evaluate the effectiveness of second line drugs such as amikacin, linezolid, moxifloxacin, and the efflux pump inhibitor verapamil against M. tuberculosis isolates associated with treatment failure. We monitored 1200 tuberculosis patients who visited TB centres in Lahore and found that 64 of them were not cured after six months of treatment. Among the M. tuberculosis isolates recovered from the sputum of these 64 patients, 46 (71.9%) isolates were simultaneously resistant to rifampicin and isoniazid (MDR), and 30 (46.9%) isolates were resistant to pyrazinamide, Resistance to amikacin was detected in 17 (26,5%) isolates whereas resistance to moxifloxacin and linezolid was detected in 1 (1.5%) and 2 (3.1%) isolates respectively. Among MDR isolates, the additional resistance to pyrazinamide, amikacin, and linezolid was detected in 15(23.4%), 4(2.6%) and 1(1.56%) isolates respectively. One isolate simultaneously resistant to rifampicin, isoniazid, amikacin, pyrazinamide, and linezolid was also identified. In our investigations, the most frequently mutated amino acid in the treatment failure group was Serine 315 in katG. Three novel mutations were detected at codons 99, 149 and 154 in pncA which were associated with pyrazinamide resistance. The effect of verapamil on the minimum inhibitory concentration of isoniazid and rifampicin was observed in drug susceptible isolates but not in drug resistant isolates. Rifampicin and isoniazid enhanced the transcription of the efflux pump gene rv1258 in drug susceptible isolates collected from the treatment failure patients. Our findings emphasize a high prevalence of MDR isolates linked primarily to drug exposure. Moreover, the use of amikacin as a second line drug may not be the most suitable choice in such cases.
Topics: Humans; Mycobacterium tuberculosis; Antitubercular Agents; Isoniazid; Pyrazinamide; Rifampin; Linezolid; Amikacin; Moxifloxacin; Tuberculosis, Multidrug-Resistant; Microbial Sensitivity Tests; Verapamil; Mutation
PubMed: 37883448
DOI: 10.1371/journal.pone.0293194 -
Brazilian Journal of Otorhinolaryngology 2022Aminoglycosides are widely known for their ototoxic side effects. Nevertheless, they are potent antibiotics used in the treatment of life-threatening conditions because...
INTRODUCTION
Aminoglycosides are widely known for their ototoxic side effects. Nevertheless, they are potent antibiotics used in the treatment of life-threatening conditions because of the current concern for antibiotic resistance. We hypothesized that creatine supplements which are believed to improve mitochondrial antioxidant defense system and maintain optimal energy homeostasis may improve the ototoxic side effects.
OBJECTIVE
This study aimed to investigate the protective effects of creatine monohydrate against ototoxicity induced by amikacin in rats in an experimental animal model, using distortion product otoacoustic emissions and auditory brainstem response.
METHODS
Twenty healthy rats were assigned to four groups (5 rats in each): the control group, the creatine monohydrate group, the amikacin group and the amikacin+creatine monohydrate group. The creatine monohydrate group received creatine at a dose of 2g/kg once daily via gastric gavage for 21 days. The amikacin group received amikacin at a dose of 600mg/kg by intramuscular injections once daily for 21 days. The amikacin+creatine monohydrate group received intramuscular injections of amikacin (600mg/kg) once daily for 21 days and creatine monohydrate (2g/kg) once daily via gastric gavage for 21 days. The control group received nothing. The distortion product otoacoustic emissions and auditory brainstem response measurements were performed on all rats on days 0, 7, 21.
RESULTS
Regarding auditory brainstem response values, a significant increase in the auditory threshold was observed in the amikacin group on day 21 (p< 0.001). The amikacin+creatine monohydrate group showed significantly lower levels of auditory brainstem response auditory thresholds on day 21 in comparison to the amikacin group (p< 0.001). Additionally, the control group and the amikacin+creatine monohydrate group did not differ significantly with respect to auditory brainstem response thresholds on treatment day 21 (p> 0.05). When we compare distortion product otoacoustic emissions values, there was no significant difference between the amikacin and amikacin+creatine monohydrate groups on day 7 (p> 0.05), However significantly greater distortion product otoacoustic emissions values were observed in the amikacin+creatine monohydrate group on day 21 compared to the amikacin group (p< 0.001).
CONCLUSION
Our findings demonstrate that creatine treatment protects against amikacin ototoxicity when given at a sufficient dose and for an adequate time period.
Topics: Amikacin; Aminoglycosides; Animals; Anti-Bacterial Agents; Antioxidants; Creatine; Evoked Potentials, Auditory, Brain Stem; Otoacoustic Emissions, Spontaneous; Ototoxicity; Rats
PubMed: 33121925
DOI: 10.1016/j.bjorl.2020.09.002 -
Journal of Global Antimicrobial... Sep 2023Mycobacterium avium (M. avium) complex bacteria cause opportunistic infections in humans. Treatment yields cure rates of 60% and consists of a macrolide, a rifamycin,...
OBJECTIVES
Mycobacterium avium (M. avium) complex bacteria cause opportunistic infections in humans. Treatment yields cure rates of 60% and consists of a macrolide, a rifamycin, and ethambutol, and in severe cases, amikacin. Mechanisms of antibiotic tolerance remain mostly unknown. Therefore, we studied the contribution of efflux and amikacin modification to antibiotic susceptibility.
METHODS
We characterised M. avium ABC transporters and studied their expression together with other transporters following exposure to clarithromycin, amikacin, ethambutol, and rifampicin. We determined the effect of combining the efflux pump inhibitors berberine, verapamil and CCCP (carbonyl cyanide m-chlorophenyl hydrazone), to study the role of efflux on susceptibility. Finally, we studied the modification of amikacin by M. avium using metabolomic analysis.
RESULTS
Clustering shows conservation between M. avium and M. tuberculosis and transporters from most bacterial subfamilies (2-6, 7a/b, 10-12) were found. The largest number of transporter encoding genes was up-regulated after clarithromycin exposure, and the least following amikacin exposure. Only berberine increased the susceptibility to clarithromycin. Finally, because of the limited effect of amikacin on transporter expression, we studied amikacin modification and showed that M. avium, in contrast to M. abscessus, is not able to modify amikacin.
CONCLUSION
We show that M. avium carries ABC transporters from all major families important for antibiotic efflux, including homologues shown to have affinity for drugs included in treatment. Efflux inhibition in M. avium can increase susceptibility, but this effect is efflux pump inhibitor- and antibiotic-specific. Finally, the lack of amikacin modifying activity in M. avium is important for its activity.
Topics: Humans; Amikacin; Mycobacterium avium; Clarithromycin; Ethambutol; Berberine; Anti-Bacterial Agents; Mycobacterium avium Complex; Membrane Transport Proteins; Mycobacterium tuberculosis; ATP-Binding Cassette Transporters
PubMed: 37453496
DOI: 10.1016/j.jgar.2023.07.007