Amikacin liposome inhalation suspension for Mycobacterium avium complex pulmonary disease: A subgroup analysis of Japanese patients in the randomized, phase 3, CONVERT study.

BACKGROUND: CONVERT, a randomized, active-controlled, global, Phase 3 trial demonstrated that patients with treatment-refractory Mycobacterium avium complex (MAC) pulmonary disease were more likely to achieve culture conversion with amikacin liposome inhalation suspension (ALIS) plus guideline-based therapy (GBT) versus those continuing on GBT alone. This subgroup analysis reports the efficacy and safety of ALIS in Japanese patients enrolled in CONVERT. METHODS: Japanese patients aged ≥20 years with treatment-refractory MAC pulmonary disease from Japanese sites were included. Patients were randomized to receive once-daily 590 mg ALIS + GBT or GBT alone; patients converting by Month 6 remained in the study to complete 12-month treatment followed by a 12-month off-treatment period. Nonconverters exited the study at Month 8. The primary endpoint was the proportion of patients achieving culture conversion by Month 6. RESULTS: Of the 59 Japanese patients screened, 48 were randomized to receive ALIS + GBT (n = 34) or GBT alone (n = 14), and 41/48 (85.4 %) were women. The mean (standard deviation) age of patients was 64.5 (8.6) years, and 83.3 % of patients had bronchiectasis at baseline. By Month 6, sputum culture conversion was cumulatively achieved in 9/34 (26.5 %) patients receiving ALIS + GBT versus none receiving GBT alone. Treatment-emergent adverse events were reported in 94.1 % and 100.0 % of patients receiving ALIS + GBT and GBT alone, respectively. No deaths were reported. CONCLUSIONS: The efficacy observed in the Japanese subpopulation was largely consistent with that in the overall CONVERT study population, with more patients achieving culture conversion with ALIS + GBT versus GBT alone. Safety profiles were similar between the overall population and the Japanese subpopulation. CLINICAL TRIAL REGISTRATION: NCT02344004.

Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia.

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.).

Comparison of Treatment Outcomes of Cavitary Mycobacterium avium Complex Pulmonary Disease with Streptomycin or Amikacin Use.

The comparative outcomes of specific aminoglycosides in cavitary type (fibrocavitary or cavitary nodular bronchiectatic type) Mycobacterium avium complex (MAC) pulmonary disease (PD) are unelucidated. We investigated the treatment outcomes with streptomycin or amikacin inclusion in the treatment regimen. From 2006 to 2020, 168 patients with cavitary MAC-PD who received guideline-based therapy (a three-drug oral antibiotic regimen with macrolide, ethambutol, and rifampin with an injectable aminoglycoside) for ≥1 year at a tertiary referral center in South Korea were retrospectively enrolled. We compared the rates of the culture conversion achievement of patients with streptomycin or amikacin use. Of the 168 participants, 127 patients (75.6%) received streptomycin and 41 (24.4%) received amikacin (median [interquartile range] treatment duration of 17.6 [14.2 to 25.2] and 17.0 [14.0 to 19.4] weeks, respectively). The overall culture conversion rate at treatment completion was 75.6% (127/168), and the rates were similar for the streptomycin-treated and amikacin-treated groups (74.8% [95/127] and 78.0% [32/41], respectively; P = 0.674). A multivariate analysis revealed that the achievement of culture conversion did not differ significantly with streptomycin or amikacin use (adjusted odds ratio, 1.086; 95% confidence interval, 0.425 to 2.777). The rate of adverse events was similar in the two groups. In conclusion, in cavitary MAC-PD, treatment with streptomycin-containing and amikacin-containing regimens results in similar rates of culture conversion achievement. IMPORTANCE We found that among the participants with cavitary MAC-PD who received guideline-based treatment for ≥1 year, the selection of either streptomycin or amikacin in the treatment regimen led to similar rates of culture conversion at treatment completion. In addition, the adverse reaction development rate did not differ significantly for streptomycin and amikacin. These findings suggest that either streptomycin or amikacin can be selected for the treatment of MAC-PD, according to the physician's or patient's preference, such as the route of administration.

A case of drug-induced organizing pneumonia caused by amikacin liposome inhalation suspension.

Inhaled liposomal antimicrobials are known to cause hypersensitivity pneumonitis. Amikacin liposome inhalation suspension (ALIS) is a promising novel antimicrobial agent against refractory Mycobacterium avium complex infections. The frequency of drug-induced lung injury caused by ALIS is relatively high. To date, no reports of ALIS-induced organizing pneumonia diagnosed by bronchoscopy are available. We report a case of a 74-year-old female patient presenting with non-tuberculous mycobacterial pulmonary disease (NTM-PD). She was treated with ALIS for refractory NTM-PD. Fifty-nine days after starting ALIS, the patient developed a cough, and her chest radiographs indicated deterioration. She was diagnosed with organizing pneumonia based on pathological findings of the lung tissues obtained by bronchoscopy. After switching from ALIS to amikacin infusion, her organizing pneumonia improved. It is difficult to distinguish between organizing pneumonia and an exacerbation of NTM-PD based on chest radiography alone. Therefore, it is essential to perform an active bronchoscopy for diagnosis.

Adjunctive inhaled amikacin in infants with Ventilator-Associated Pneumonia optimizes the complex antimicrobial therapy: pilot study.

BACKGROUND AND AIM: VAP remains the second leading cause of death among the patients with nosocomial infections and its incidence varies significantly from 5% to 60% reaching on average 10 %. It is of crucial importance to develop novel treatment approaches and optimize the existing ones. Thus, the aim of this pilot study was to study the laboratory-microbiological effect of inhaled aminoglycosides in a complex treatment of patients with ventilator-associatedpneumonia(VAP).  Methods: To study the laboratory-microbiological effect of adjunctive inhaled aminoglycosides in the treatment of VAP, twenty enrolled patients were randomly subdivided into 2 groups (n=10). Amikacin was administered via a nebulizer starting from the first day of VAP manifestation. Inhalations were performed BID for 7 days via a nebulizer integrated into the breathing circuit. We assessed: cell membrane alterations in leukocytes, Annexin V/7-AAD staining for leukocytes, ROS detection assay for leukocytes. RESULTS: Adjunctive administration of inhaled amikacin reduced the fluorescence intensity ratio more efficiently compared with the intravenous antimicrobial treatment with no aerosolized amikacin following both 48 h and 96 h of treatment. The amount of dead necrotic annexin V-negative, 7-AAD-positive leukocytes was significantly lower under the use of inhaled amikacin than at the beginning of treatment. Conclusions In this pilot study, we found that administration of aerosolized amikacin combined with the systemic antimicrobial therapy improves the clinical outcome of patients with VAP, effective early microbial decrease in the sputum, reduces reactive oxygen species generation in leukocytes and the degree of leukocyte apoptosis and necrosis, decreases VAP-mediated cell membrane alterations of circulating leukocytes.

Population pharmacokinetic/pharmacodynamic evaluations of amikacin dosing in critically ill patients undergoing continuous venovenous hemodiafiltration.

OBJECTIVES: The pharmacokinetics/pharmacodynamics (PK/PD) of amikacin in critically ill patients undergoing continuous venovenous hemodiafiltration (CVVHDF) are poorly described, and appropriate dosing is unclear in this patient population. This study aimed to develop a population PK model of amikacin and to provide systemic PK/PD evaluations for different dosing regimens in CVVHDF patients. METHODS: One hundred and sixty-one amikacin concentration observations from thirty-three CVVHDF patients were pooled to develop the population PK model. Monte Carlo simulations were performed to assess the PK/PD index-based efficacy (Cmax/minimal inhibitory concentration (MIC) > 8 and AUC/MIC > 58.3), nonrisk of drug resistance (T>MIC > 60%) and risk of toxicity (trough concentration > 5 mg/l) for different dosing regimens. KEY FINDINGS: A two-compartment model adequately described the concentration data of amikacin. A loading dose of at least 25 mg/kg amikacin is needed to reach the efficacy targets in CVVHDF patients for an MIC of 4 mg/l, and the studied doses could not provide adequate drug exposure and T>MIC > 60% for an MIC ≥ 8 mg/l. The risk of toxicity for amikacin was unacceptably high for the patient population with low clearance. CONCLUSIONS: Our study demonstrated that a loading dose of 25-30 mg/kg amikacin is needed to provide adequate PK/PD target attainment in CVVHDF patients for an MIC ≤ 4 mg/l.

Amikacin-induced acute kidney injury in mechanically ventilated critically ill patients with sepsis.

In this retrospective cohort study, we aimed to evaluate the incidence, risk factors and outcomes of amikacin-induced acute kidney injury (AKI) in critically ill patients with sepsis. A total of 311 patients were included in the study. Of them, 83 (26.7%) had amikacin-induced AKI. In model 1, the multivariable analysis demonstrated concurrent use of colistin (OR 25.51, 95%CI 6.99-93.05, p< 0.001), presence of septic shock during amikacin treatment (OR 4.22, 95%CI 1.76-10.11, p=0.001), and Charlson Comorbidity Index (OR 1.14, 95%CI 1.02-1.28, p=0.025) as factors independently associated with an increased risk of amikacin-induced AKI. In model 2, the multivariable analysis demonstrated concurrent use of at least one nephrotoxic agent (OR 1.95, 95%CI 1.10-3.45; p=0.022), presence of septic shock during amikacin treatment (OR 3.48, 95%CI 1.61-7.53; p=0.002), and Charlson Comorbidity Index (OR 1.12, 95%CI 1.01-1.26; p=0.037) as factors independently associated with an increased risk of amikacin-induced AKI. In conclusion, before amikacin administration, the risk of AKI should be considered, especially in patients with multiple complicated comorbid diseases, septic shock, and those receiving colistin therapy.

Systematic review of high-dose amikacin regimens for the treatment of Gram-negative infections based on EUCAST dosing recommendations.

BACKGROUND: Updated European Committee on Antimicrobial Susceptibility Testing (EUCAST) amikacin breakpoints for Enterobacterales and Pseudomonas aeruginosa included revised dosing recommendations of 25-30 mg/kg to achieve key pharmacokinetic/pharmacodynamic parameters, higher than recommended in the British National Formulary. The objectives of this review were to identify clinical evidence for high-dose amikacin regimens and to determine drug exposures that are related to adverse events and toxicity. METHODS: The literature search was conducted in October 2021 and updated in May 2022 using electronic databases for any study reporting adult participants treated with amikacin at doses ≥20 mg/kg/day. Reference lists of included papers were also screened for potential papers. Data were extracted for pharmacokinetic parameters and clinical outcomes, presented in a summary table and consolidated narratively. Meta-analysis was not possible. Each study was assessed for bias before, during and after the intervention using the ROBINS-I tool. RESULTS: Nine studies (total 501 participants in 10 reports) were identified and included, eight of which were observational studies. Assessment of bias showed substantial flaws. Dosing regimens ranged from 25 to 30 mg/kg/day. Six studies adjusted the dose in obesity when participants had a body mass index of ≥30 kg/m2. Target peak serum concentrations ranged from 60 mg/L to 80 mg/L and 59.6-81.8% of patients achieved these targets, but there was no information on clinical outcomes. Two studies reported the impact of high-dose amikacin on renal function. No studies reporting auditory or vestibular toxicity were identified. CONCLUSION: All included papers were limited by a significant risk of bias, while methodological and reporting heterogeneity made drawing conclusions challenging. Lack of information on the impact on renal function or ototoxicity means high-dose regimens should be used cautiously in older people. There is a need for a consensus guideline for high-dose amikacin to be written. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42021250022).

Amikacin liposome and Mycobacterium avium complex: A systematic review.

INTRODUCTION: The prevalence of Mycobacterium avium complex (MAC) is increasing globally. Macrolide-based multidrug regimens have been recommended as the first-line treatment for patients with MAC pulmonary disease. However, developing macrolide resistance was associated with poor treatment outcomes and increased mortality. In 2018, the U.S. Food and Drug Administration approved liposomal amikacin for inhalation (LAI) to treat refractory MAC pulmonary disease. The current systematic review aimed to evaluate LAI's outcomes and adverse events in MAC pulmonary disease. METHODS: The systematic search was performed in PubMed/Medline, EMBASE, and the Cochrane Controlled Register of Trials (CENTRAL) up to March 8, 2022. The search terms included Mycobacterium avium complex, MAC, amikacin, and liposomal amikacin. RESULTS: After reviewing 1284 records, four papers met the inclusion criteria, including three clinical trials and one prospective cohort study. These studies showed that adding LAI to guideline-based therapies can increase sputum culture conversion rate and achieve early sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for three months after treatment) negative sputum culture. In addition, extended LAI use was a potential benefit in patients considered refractory to initial treatment. The most prevalent treatment-emergent adverse events (TEAE) reported in the LAI group were the respiratory TEAE. CONCLUSIONS: LAI could increase the sputum culture conversion rate and achieve early sustainable, durable negative sputum culture. However, additional large-scale research is required to confirm the results.

Evaluation of nephrotoxicity and ototoxicity following amikacin administration once daily or every 48 hours in neonates.

The purpose of this study was to evaluate the effects of once daily (OD) or every 48 hours (every-48-h) administration of amikacin (AMK) on renal function and ototoxicity in neonates. We investigated the frequency of nephrotoxicity and ototoxicity in neonates who received AMK OD or every-48-h from April 2015 to March 2021 and underwent dose evaluation by therapeutic drug monitoring (TDM). In addition, the relationships among birth weight, gestational age, AMK peak and trough values, total duration of AMK administration, and total AMK dose were examined separately for nephrotoxicity and ototoxicity. AMK was administered OD in 38 patients and every-48-h in 62 patients. Nephrotoxicity was observed in 8 patients on OD versus 36 patients on every-48-h administration (P < .001), and ototoxicity was observed in 2 patients on OD versus 12 patients on every-48-h administration (P = .192). For nephrotoxicity, only the trough value was relevant (P = .007). In terms of ototoxicity, there were no influencing factors. The risk of nephrotoxicity was higher with every-48-h AMK administration than with OD AMK administration, with nephrotoxicity depending on the trough value. However, compared with OD, the every-48-h group had lower body weight and possibly poorer original renal function. In addition, ototoxicity did not differ by administration method. Based on these results, every-48-h administration of AMK can be used as safely as OD by performing TDM and preventing high concentrations.

Clinicopathologic Findings in Chickens (Gallus gallus domesticus) Administered Amikacin Through Intravenous Regional Limb Perfusion.

Regional limb perfusion (RLP) has been used to treat cases of distal limb infections in avian species. Potentially nephrotoxic drugs, such as amikacin, may increase the risk of nephrotoxicity with RLP because of the presence of the renal portal system and direct venous blood flow from the pelvic limbs to the kidneys. In a randomized, blinded, placebo-controlled study, the safety of repeated amikacin administration (20 mg/kg q24h for 3 doses) via RLP was evaluated in healthy female chickens (Gallus gallus domesticus; n = 8 treatment, n = 8 saline control group). Plasma uric acid concentrations were not significantly elevated in treated birds compared with the control group at any time point following RLP. One week following the final RLP, birds were necropsied and the kidneys evaluated grossly and histologically. There was no significant difference in renal pathology scores between treated and control birds or between kidneys ipsilateral to the perfused limb and contralateral kidneys. This study concludes that RLP of amikacin at high doses produced no discernable renal pathology in healthy euhydrated chickens.

Impact of nephrotoxic drugs on urinary biomarkers of renal function in very preterm infants.

BACKGROUND: Following preterm birth, the immature kidney is exposed to several harmful conditions, with an increased risk of renal impairment. We aimed to assess urinary biomarkers of renal function in very preterm infants during early nephrotoxic treatments. METHODS: Infants ≤32 weeks' gestation and ≤1500 g were enrolled in this observational prospective study. Urine samples were collected on day 1(T1), 2-4(T2), 5-7(T3), 8-10(T4), 11-13(T5). The following urinary biomarkers were determined: osteopontin (uOPN), epidermal growth factor (uEGF), neutrophil gelatinase-associated lipocalin (uNGAL), cystatin C (uCysC). The infants were grouped according to their exposure to amikacin or ibuprofen during the study period and a between-group comparison of urinary biomarkers at each time point was performed. RESULTS: Thirty-six infants were included. Urinary CysC, uOPN, and uNGAL rose significantly during ibuprofen or amikacin treatment, while no difference was observed for uEGF. After adjustment for possible influencing factors, amikacin administration was associated with higher uCysC at T1 (p = 0.007) and T2 (p = 0.016), whereas ibuprofen increased uOPN (p = 0.001) and uNGAL concentration (p = 0.009) at T3. CONCLUSION: Nephrotoxic therapies induce molecule-specific change patterns of renal function biomarkers in treated preterm infants. Serial assessments of these biomarkers may aid to identify neonates at risk of renal impairment and to develop tailored therapeutic approaches. IMPACT: Despite the wide use of nephrotoxic therapies in neonatal settings, little is known on their effect on renal function biomarkers in preterm infants. This study describes molecule-specific change patterns of urinary biomarkers during ibuprofen and amikacin administration, suggesting underlying pathophysiological effects on renal function. Given their low analytical costs and non-invasive collection, the urinary biomarkers investigated in this study represent a promising strategy for serial monitoring of renal function in at-risk neonates and may aid the early detection of renal function impairment at different kidney levels during nephrotoxic treatments.

Emergency treatment with intermittent hemodialysis for amikacin overdose in a cat.

OBJECTIVE: To describe the safety and use of intermittent hemodialysis (IHD) for the emergency treatment of a cat with an amikacin overdose. CASE SUMMARY: A cat was accidentally administered 400 mg (97.5 mg/kg, IV) of amikacin. Four hours after the time of the overdose, a single emergency IHD session to remove amikacin was performed. The 4-hour IHD treatment allowed for the active removal of approximately 110 mg of amikacin. The plasma concentration of amikacin from the beginning to the end of the session decreased from approximately 160 µg/mL to a nontoxic concentration of 10 µg/mL. Following IHD treatment, the cat developed an International Renal Interest Society (IRIS) grade IV acute kidney injury (AKI) with a peak creatinine of 486 µmol/L (5.5 mg/dL) and was hospitalized for 4 days for supportive management of AKI. At the time of discharge, 4 days following the overdose, the AKI had resolved. NEW OR UNIQUE INFORMATION PROVIDED: This is the first report describing the use and safety of using IHD for emergency removal of amikacin overdose in a cat.

Assessment of the Effects of a High Amikacin Dose on Plasma Peak Concentration in Critically Ill Children.

OBJECTIVES: This study aimed to assess the incidence of amikacin plasma peak concentration (Cmax) below 60 mg·L-1 in critically ill children receiving an amikacin dosing regimen of 30 mg kg-1·day-1. Secondary objectives were to identify factors associated with low Cmax and to assess the incidence of acute kidney injury (AKI). METHODS: A retrospective observational study was performed in two French pediatric intensive care units. All admitted children who received 30 mg·kg-1 amikacin and had a Cmax measurement were eligible. Clinical and biological data, amikacin dose, and concentrations were collected. RESULTS: In total, 30 patients were included, aged from 3 weeks to 7 years. They received a median amikacin dosage of 30 mg kg-1·day-1 (range 29-33) based on admission body weight (BW), corresponding to 27 mg kg-1·day-1 (range 24-30) based on actual BW. Cmax was < 60 mg·L-1 in 21 (70%) children and none had a Cmax ≥ 80 mg·L-1. Among the 15 patients with a measured minimum inhibitory concentration (MIC), 13 (87%) had a Cmax/MIC ratio > 8. Univariate analysis showed that factors associated with Cmax < 60 mg·L-1 were high estimated glomerular filtration rate (p = 0.015) and low blood urea concentration (p = 0.001). AKI progression or occurrence was observed after amikacin administration in two (7%) and six (21%) patients, respectively. CONCLUSIONS: Despite the administration of the maximal recommended amikacin dose, Cmax was below the pharmacokinetic target in 70% of our pediatric population. Further studies are needed to develop a pharmacokinetic model in a population of critically ill children to optimize target attainment.

Amikacin for the treatment of carbapenem-resistant Klebsiella pneumoniae infections: clinical efficacy and toxicity.

Infections by carbapenem-resistant Klebsiella pneumoniae (CRKp) are an increasing global threat with limited therapeutic options. Our objective was to evaluate clinical and microbiological outcomes of patients treated with amikacin for CRKp infections. We did a retrospective cohort of patients > 18 years old, with CRKp infections treated with amikacin in two tertiary care hospitals in Porto Alegre, Brazil. The impact of clinical factors, antibiotic treatment, and amikacin minimum inhibitory concentration (MIC) on patients' 30-day mortality was assessed. Microbiological clearance and nephrotoxicity (assessed by RIFLE score) were evaluated as secondary outcomes. A Cox regression analysis was done for mortality. We included 84 patients for analysis. Twenty-nine (34.5%) patients died in 30 days. Amikacin MIC values ranged from 0.125 to 8 µg/mL and did not influence on mortality, regardless of the prescribed dose of this antibiotic (P = 0.24). Bacterial clearance occurred in 17 (58.6%) of 29 patients who collected subsequent cultures. Two (16.6%) of the 12 persistently positive cultures changed the amikacin susceptibility profile from susceptible to intermediate. Twenty-nine (37.2%) patients developed acute kidney injury (AKI): risk 13, injury 11, and failure 5. Risk factors for AKI were higher baseline eGFR (P < 0.01) and combination therapy with colistin (P = 0.02). Comparing patients who received combination with colistin vs polymyxin B, AKI occurred in 60.0% vs 20.6%, respectively, P < 0.01. Fifteen of the 16 (16.6%) patients who developed renal injury or failure were receiving colistin. In conclusion, amikacin was an effective treatment for CRKp infections. Within susceptible range, amikacin MIC values did not influence on clinical outcomes. Combination therapy of amikacin and colistin was highly nephrotoxic and should be used with caution.

Antibiotic regimens for late-onset neonatal sepsis.

BACKGROUND: Neonatal sepsis is a major cause of morbidity and mortality. It is the third leading cause of neonatal mortality globally constituting 13% of overall neonatal mortality. Despite the high burden of neonatal sepsis, high-quality evidence in diagnosis and treatment is scarce. Due to the diagnostic challenges of sepsis and the relative immunosuppression of the newborn, many neonates receive antibiotics for suspected sepsis. Antibiotics have become the most used therapeutics in neonatal intensive care units, and observational studies in high-income countries suggest that 83% to 94% of newborns treated with antibiotics for suspected sepsis have negative blood cultures. The last Cochrane Review was updated in 2005. There is a need for an updated systematic review assessing the effects of different antibiotic regimens for late-onset neonatal sepsis. OBJECTIVES: To assess the beneficial and harmful effects of different antibiotic regimens for late-onset neonatal sepsis. SEARCH METHODS: We searched the following electronic databases: CENTRAL (2021, Issue 3); Ovid MEDLINE; Embase Ovid; CINAHL; LILACS; Science Citation Index EXPANDED and Conference Proceedings Citation Index - Science on 12 March 2021. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: We included RCTs comparing different antibiotic regimens for late-onset neonatal sepsis. We included participants older than 72 hours of life at randomisation, suspected or diagnosed with neonatal sepsis, meningitis, osteomyelitis, endocarditis, or necrotising enterocolitis. We excluded trials that assessed treatment of fungal infections. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We used the GRADE approach to assess the certainty of evidence. Our primary outcome was all-cause mortality, and our secondary outcomes were: serious adverse events, respiratory support, circulatory support, nephrotoxicity, neurological developmental impairment, necrotising enterocolitis, and ototoxicity. Our primary time point of interest was at maximum follow-up. MAIN RESULTS: We included five RCTs (580 participants). All trials were at high risk of bias, and had very low-certainty evidence. The five included trials assessed five different comparisons of antibiotics. We did not conduct a meta-analysis due to lack of relevant data. Of the five included trials one trial compared cefazolin plus amikacin with vancomycin plus amikacin; one trial compared ticarcillin plus clavulanic acid with flucloxacillin plus gentamicin; one trial compared cloxacillin plus amikacin with cefotaxime plus gentamicin; one trial compared meropenem with standard care (ampicillin plus gentamicin or cefotaxime plus gentamicin); and one trial compared vancomycin plus gentamicin with vancomycin plus aztreonam. None of the five comparisons found any evidence of a difference when assessing all-cause mortality, serious adverse events, circulatory support, nephrotoxicity, neurological developmental impairment, or necrotising enterocolitis; however, none of the trials were near an information size that could contribute significantly to the evidence of the comparative benefits and risks of any particular antibiotic regimen. None of the trials assessed respiratory support or ototoxicity. The benefits and harms of different antibiotic regimens remain unclear due to the lack of well-powered trials and the high risk of systematic errors. AUTHORS' CONCLUSIONS: Current evidence is insufficient to support any antibiotic regimen being superior to another. RCTs assessing different antibiotic regimens in late-onset neonatal sepsis with low risks of bias are warranted.

ANTECEDENTES: La sepsis neonatal es una causa importante de morbilidad y mortalidad. Es la tercera causa de mortalidad neonatal a nivel mundial y constituye el 13% de la mortalidad neonatal total. A pesar de la elevada carga de la sepsis neonatal, la evidencia de alta calidad en el diagnóstico y el tratamiento es escasa. Debido a las dificultades de diagnóstico de la sepsis y a la relativa inmunosupresión del neonato, muchos reciben antibióticos por sospecha de sepsis. Los antibióticos se han convertido en el tratamiento más utilizado en las unidades de cuidados intensivos neonatales, y los estudios observacionales realizados en países de ingresos altos indican que entre el 83% y el 94% de los neonatos tratados con antibióticos por sospecha de sepsis tienen hemocultivos negativos. La última revisión Cochrane se actualizó en 2005. Se necesita una revisión sistemática actualizada que evalúe los efectos de los diferentes regímenes de antibióticos para la sepsis neonatal de inicio tardío. OBJETIVOS: Evaluar los efectos beneficiosos y perjudiciales de diferentes regímenes antibióticos para la sepsis neonatal de inicio tardío. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en las siguientes bases de datos electrónicas: CENTRAL (2021, número 3); Ovid MEDLINE; Embase Ovid; CINAHL; LILACS; Science Citation Index EXPANDED y Conference Proceedings Citation Index ­ Science el 12 de marzo de 2021. También se buscaron ensayos controlados aleatorizados (ECA) y cuasialeatorizados en las bases de datos de ensayos clínicos y en las listas de referencias de artículos identificados. CRITERIOS DE SELECCIÓN: Se incluyeron ECA que compararon diferentes regímenes de antibióticos para la sepsis neonatal de inicio tardío. Se incluyeron participantes mayores de 72 horas de vida en el momento de la asignación al azar, con sospecha o diagnóstico de sepsis neonatal, meningitis, osteomielitis, endocarditis o enterocolitis necrosante. Se excluyeron los ensayos que evaluaron el tratamiento de las infecciones micóticas. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión, de forma independiente, evaluaron los estudios para inclusión, extrajeron los datos y evaluaron el riesgo de sesgo. Se utilizó el método GRADE para evaluar la certeza de la evidencia. El desenlace principal fue la mortalidad por todas las causas, y los desenlaces secundarios fueron: eventos adversos graves, asistencia respiratoria, apoyo circulatorio, nefrotoxicidad, deterioro del desarrollo neurológico, enterocolitis necrosante y ototoxicidad. El punto temporal principal de interés fue el seguimiento máximo. RESULTADOS PRINCIPALES: Se incluyeron cinco ECA (580 participantes). Todos los ensayos tuvieron alto riesgo de sesgo y evidencia de certeza muy baja. Los cinco ensayos incluidos evaluaron cinco comparaciones diferentes de antibióticos. No se realizó un metanálisis debido a la falta de datos relevantes. De los cinco ensayos incluidos, un ensayo comparó cefazolina más amikacina con vancomicina más amikacina; un ensayo comparó ticarcilina más ácido clavulánico con flucloxacilina más gentamicina; un ensayo comparó cloxacilina más amikacina con cefotaxima más gentamicina; un ensayo comparó meropenem con atención estándar (ampicilina más gentamicina o cefotaxima más gentamicina); y un ensayo comparó vancomicina más gentamicina con vancomicina más aztreonam. Ninguna de las cinco comparaciones encontró evidencia de una diferencia al evaluar la mortalidad por todas las causas, los eventos adversos graves, el apoyo circulatorio, la nefrotoxicidad, el deterioro del desarrollo neurológico o la enterocolitis necrosante; sin embargo, ninguno de los ensayos se acercó a un tamaño de información que pudiera contribuir significativamente a la evidencia de los beneficios y los riesgos comparativos de cualquier régimen antibiótico en particular. Ninguno de los ensayos evaluó la asistencia respiratoria o la ototoxicidad. Los efectos beneficiosos y perjudiciales de los diferentes regímenes de antibióticos aún no están claros debido a la falta de ensayos con un poder estadístico adecuado y al alto riesgo de errores sistemáticos. CONCLUSIONES DE LOS AUTORES: La evidencia actual no es suficiente para apoyar que un régimen de antibióticos sea superior a otro. Se justifica la realización de ECA con bajo riesgo de sesgo que evalúen diferentes regímenes antibióticos en la sepsis neonatal de inicio tardío.

Amikacin liposome inhalation suspension as a treatment for patients with refractory mycobacterium avium complex lung infection.

Introduction: Amikacin liposome inhalation suspension (ALIS) contains amikacin sulfate, an aminoglycoside antibacterial drug. It has been approved in the US as a combined antibiotic treatment for refractory MAC lung disease patients. ALIS, as an inhaled antibiotic, can deliver amikacin to the infected site effectively and reduce systemic toxicity.Areas covered: This article gives a summated review of the pharmacodynamics, pharmacokinetics, therapeutic efficacy, post-marketing surveillance, and regulatory affairs of ALIS as an add-on therapy for MAC lung disease in adults by analyzing data from preclinical studies, clinical trials and original studies. We systematically searched Medline/PubMed through October 2020.Expert opinion: Studies demonstrate that ALIS as an add-on treatment significantly improve the rate of sputum culture conversion in MAC lung disease patients compare to guideline-recommended therapy only. The ALIS treatment showed a similar risk of serious adverse events and a low chance of renal adverse events. However, ALIS was associated with more respiratory adverse events than guideline-recommended therapy only. There was not sufficient data to conclude that ALIS treatment can improve clinical outcomes; however, with the significant improvement in the microbiology outcome in MAC lung disease patients, ALIS showed its potential use as an adjunct treatment for treating MAC lung disease.

Laryngeal Injury Due to Amikacin Inhalation for Refractory Mycobacterium avium Complex Infection.

Inhaled antibiotics have long been used for chronic lung infections, especially in patients with cystic fibrosis and increasingly for non-cystic fibrosis bronchiectasis. Amikacin liposome inhalation suspension (ALIS) has emerged as a promising treatment for Mycobacterium avium complex infection refractory to oral antibiotics. However, despite its efficacy, nearly one-half of patients in phase II and III trials experienced dysphonia as a treatment-associated adverse effect. Here, we describe a patient who experienced severe, acute-onset laryngitis while receiving ALIS for refractory M avium complex infection, prompting discontinuation of ALIS therapy. This is the first report directly describing vocal fold injury due to such therapy. Given the high frequency of dysphonia reported with ALIS, this case highlights the potential severity of laryngeal toxicity, the importance of coordination of care for patients receiving inhaled antibiotics for chronic pulmonary disease, and the need for better insight into mechanisms of toxicity.