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.).

Pharmacovigilance of nephrotoxic drugs in neonates: the Pottel method for acute kidney injury detection in ELBW neonates.

BACKGROUND: Extremely low birth weight (ELBW) neonates (birth weight ≤ 1000 g) are at high risk to develop drug-induced acute kidney injury (AKI). However, we lack a pragmatic detection tool to capture their time-dependent (patho)physiologic serum creatinine (Scr) patterns. Pottel et al. suggested rescaling Scr by dividing Scr with the mean Scr value of the age- and sex-specific reference population. We explored if this Pottel method can detect drug-related nephrotoxicity in ELBW neonates. METHODS: A previously reported dataset on Scr changes in ELBW neonates exposed to ibuprofen, amikacin, or vancomycin was updated to calculate Pottel scores for every available Scr value in the first 28 postnatal days. We hereby used previously published postnatal age-specific 50th centile values in an ELBW population. Linear mixed models were applied, analyzing Pottel scores as response variable and continuous time (day), drug exposure, and interaction thereof in the explanatory model. RESULTS: Serum creatinine (n = 3231) observations in 201 ELBW neonates were collected. A statistically significant rise of Pottel scores was observed with ibuprofen starting from postnatal day 4. In addition, a cumulative effect of treatment with mean Pottel scores on day 0 of 1.020 and on day 3 during treatment of 1.106 (95% CI 1.068-1.145, p < 0.001) was observed, corrected for effect of antibiotics. Antibiotic administrations showed a small but statistically significant difference up to postnatal day 5. CONCLUSIONS: As rescaled Scr biomarker, the Pottel method showed a clear association with ibuprofen-exposed ELBW neonates, suggesting its applicability as a pragmatic bedside alternative tool to assess nephrotoxicity.

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.

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.

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.

Low-dose amikacin in the treatment of Multidrug-resistant Tuberculosis (MDR-TB).

BACKGROUND: The World Health Organization recommends intravenous amikacin for the treatment of MDR-TB at a dose of 15 mg/kg. However, higher doses are associated with significant toxicity. METHODS: Patients with MDR-TB treated at our institution receive amikacin at 8-10 mg/kg, with dose adjustment based on therapeutic drug monitoring. We conducted a retrospective cohort study of patients with MDR-TB who received amikacin between 2010 and 2016. RESULTS: Forty-nine patients were included in the study. The median starting dose of amikacin was 8.9 mg/kg (IQR 8, 10), and target therapeutic drug levels were achieved at a median of 12 days (IQR 5, 26). The median duration of amikacin treatment was 7.2 months (IQR 5.7, 8), and median time to sputum culture conversion was 1 month (IQR 1,2). Six patients (12.2%) experienced hearing loss based on formal audiometry testing (95% CI 4.6-24.8%); 22.2% had subjective hearing loss (95% CI 11.2-37.1%) and 31.9% subjective tinnitus (95% CI 19.1-47.1%). Ten patients (23%) had a significant rise in serum creatinine (95% CI 11.8-38.6%), but only 5 patients had a GFR < 60 at treatment completion. 84% of patients had a successful treatment outcome (95% CI 84-99%). CONCLUSIONS: Low dose amikacin is associated with relatively low rates of aminoglycoside-related adverse events. We hypothesize that low-dose amikacin can be used as a safe and effective treatment for MDR-TB in situations where an adequate regimen cannot be constructed with Group A and B drugs, and where careful monitoring for adverse events is feasible.

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.

A meta-analysis of the target trough concentration of gentamicin and amikacin for reducing the risk of nephrotoxicity.

INTRODUCTION: Antimicrobial resistance is one of the biggest threats to public health systems worldwide, and aminoglycosides are key drugs for treating drug-resistant infections. Because of the nephrotoxicity of aminoglycosides, therapeutic drug monitoring is recommended, but few studies of the target trough concentration (Cmin) have been reported. To address the problem, we performed a meta-analysis to confirm the target Cmin of aminoglycosides for minimizing the risk of nephrotoxicity. METHODS: We conducted a literature search using MEDLINE, the Cochrane Library, and Ichushi-Web. In the meta-analysis, nephrotoxicity was compared between the Cmin ≥2 mg/L and Cmin <2 mg/L groups for gentamicin and between the Cmin ≥10 mg/L and Cmin <10 mg/L groups for amikacin. RESULTS: No randomized controlled trials were reported for any of the drugs. Five observational studies involving 615 patients were reported for gentamicin, and two observational studies involving 159 patients were identified for amikacin. For gentamicin, Cmin <2 mg/L was linked to a significantly lower rate of nephrotoxicity than Cmin ≥2 mg/L (odds ratio [OR] = 0.22, 95% confidence interval [CI] = 0.12-0.40). For amikacin, Cmin <10 mg/L was associated with a significantly lower rate of nephrotoxicity than Cmin ≥10 mg/L (OR = 0.05, 95% CI = 0.01-0.21). CONCLUSIONS: Although further well-controlled studies with a low risk of bias are needed, the current meta-analysis demonstrated that Cmin <2 mg/L and Cmin <10 mg/L may reduce the risk of nephrotoxicity linked to gentamicin and amikacin, respectively.

Impact of Therapeutic Drug Monitoring on Once-Daily Regimen of Amikacin in Patients With Urinary Tract Infection: A Prospective Observational Study.

BACKGROUND: Amikacin is a semisynthetic antibiotic used in the treatment of gram-negative bacterial infections and has a narrow therapeutic index. Although therapeutic drug monitoring is recommended for amikacin, it is not routinely performed because of the use of a less toxic once-daily regimen. Only few studies have evaluated the role of therapeutic drug monitoring in patients treated with amikacin. The objective of our study was to find an association between the pharmacokinetic parameters of amikacin and the time required for a clinical cure, creatinine clearance, and frequency of ototoxicity in patients with urinary tract infection treated for 7 or more days. METHODS: A prospective study was conducted on patients with urinary tract infections who were administered amikacin for 7 or more days. Blood samples were obtained from the patients to measure the maximum drug concentration (Cmax) and trough concentration (Ctrough). Minimum inhibitory concentration (MIC) values were determined for patients with positive urine cultures. Serum creatinine levels were estimated every 3 days. The auditory assessment was performed using pure tone audiometry at baseline and weekly until the patients were discharged. Levels of amikacin were analyzed using a validated liquid chromatography-tandem mass spectrometry method. RESULTS: Of 125 patients analyzed, the median time required for a clinical cure was less in the group of patients who achieved a Cmax/MIC ratio ≥8 than it was in those who did not achieve this level [7 versus 8 days (P = 0.02)]. The Ctrough of amikacin was associated with the change in serum creatinine level (P = 0.01) and the incidence of nephrotoxicity (P = 0.004). CONCLUSIONS: In patients receiving short-term amikacin therapy, Cmax/MIC value can be used to predict the time required for a clinical cure. Ctrough can be used to predict the occurrence of nephrotoxicity in patients receiving amikacin therapy.

Engraftment of Human Stem Cell-Derived Otic Progenitors in the Damaged Cochlea.

Most cases of sensorineural deafness are caused by degeneration of hair cells. Although stem/progenitor cell therapy is becoming a promising treatment strategy in a variety of organ systems, cell engraftment in the adult mammalian cochlea has not yet been demonstrated. In this study, we generated human otic progenitor cells (hOPCs) from induced pluripotent stem cells (iPSCs) in vitro and identified these cells by the expression of known otic markers. We showed successful cell transplantation of iPSC-derived-hOPCs in an in vivo adult guinea pig model of ototoxicity. The delivered hOPCs migrated throughout the cochlea, engrafted in non-sensory regions, and survived up to 4 weeks post-transplantation. Some of the engrafted hOPCs responded to environmental cues within the cochlear sensory epithelium and displayed molecular features of early sensory differentiation. We confirmed these results with hair cell progenitors derived from Atoh1-GFP mice as donor cells. These mouse otic progenitors transplanted using the same in vivo delivery system migrated into damaged cochlear sensory epithelium and adopted a partial sensory cell fate. This is the first report of the survival and differentiation of hOPCs in ototoxic-injured mature cochlear epithelium, and it should stimulate further research into cell-based therapies for treatment of deafness.

Amikacin Pharmacokinetics in Terminal Stage of Hematological Malignancy.

BACKGROUND: The influence of cancer cachexia on the pharmacokinetics of and kidney injury caused by amikacin remains unclear. This study investigated whether the pharmacokinetics of amikacin and the risk of kidney injury are altered with the progression of cancer cachexia. METHODS: A retrospective analysis was conducted using therapeutic drug monitoring data obtained from 52 cancer patients who received amikacin intravenously for infection(s). The patients were classified into 2 groups based on the status of cachexia using a consensus definition: noncachexia group (n = 31) and cachexia group (n = 21). Differences in amikacin pharmacokinetics and occurrence of kidney injury were compared between the 2 groups. Amikacin pharmacokinetics was calculated based on a 1-compartment model using peak and trough concentrations measured clinically for therapeutic drug monitoring. In addition, intrapatient analysis was conducted based on patients who received amikacin treatments more than once during the study period to examine the alteration in amikacin pharmacokinetics with the progression of cancer cachexia. RESULTS: Systemic clearance of amikacin [median (range)] was significantly (P < 0.05) lower in the cachexia group [37.3 (11.2-87.3) (mL/min)] than in the noncachexia group [52.0 (19.1-133.4) (mL/min)]. In contrast, volume of distribution was significantly (P < 0.05) increased in the cachexia group [0.47 (0.20-1.45) L/kg] compared with the noncachexia group [0.32 (0.21-1.00) L/kg]. There was no difference in the occurrence of kidney injuries between the 2 groups. In an intrapatient analysis of the longitudinal alteration of amikacin pharmacokinetics, an approximately 50% reduction in clearance and 30% increase in volume of distribution were observed as cancer cachexia progressed. CONCLUSIONS: The present study suggests that progression of cancer cachexia may reduce amikacin clearance and increase the volume of distribution, but cancer cachexia does not increase amikacin-induced kidney injury.

Relationship between amikacin blood concentration and ototoxicity in low birth weight infants.

Amikacin (AMK) is used as empiric therapy for severe infections such as sepsis in low birth weight (LBW) infants. AMK administered once daily (OD) in adults is reported to be therapeutically effective and prevent side effects, however, evidence on AMK administration in LBW infants is limited, with no clear indications of effectiveness. We performed therapeutic drug monitoring analysis of 20 infants treated with AMK OD for severe infections such as bacteremia. Treatment effectiveness was admitted by the patients' medical records, and side effects of renal dysfunction and ototoxicity were investigated. The mean gestational age was 30.4 ± 5 weeks and mean body weight (Bw) was 1280.2 ± 809.8 g. The mean AMK dose was 14.1 ± 2.6 mg/kg and mean administration period was 10.1 ± 4.1 days. Blood concentration was measured 6.3 ± 2.3 days after AMK administration; mean peak and trough concentrations were 29.1 ± 7.5 µg/mL and 7.6 ± 6.9 µg/mL, respectively. Additionally, therapeutic effect was observed in all patients, and no significant change in serum creatinine (CRE) concentration (a marker of renal dysfunction) was observed, suggesting no renal dysfunction. Ototoxicity was observed in 4 patients, 3 of whom had trough concentrations ≥10 µg/mL. When we categorized patients into two groups using a trough cut-off value of 10 µg/mL, no difference in AMK dose was observed. However, there were significant differences in peak concentration, Bw, volume of distribution and CRE. Our findings suggest AMK trough concentration ≥10 µg/mL significantly affects ototoxicity in neonates.

Amikacin Inhalation as Salvage Therapy for Refractory Nontuberculous Mycobacterial Lung Disease.

Although guidelines recommend amikacin (AMK) inhalation therapy for difficult-to-treat nontuberculous mycobacterial lung disease (NTM-LD), data are limited regarding the safety and clinical efficacy of this salvage therapy. We retrospectively evaluated the treatment outcomes of 77 patients with refractory NTM-LD caused by Mycobacterium abscessus complex (MABC) or M. avium complex (MAC) who initiated AMK inhalation therapy between February 2015 and June 2016. MABC was the most common etiology (n = 48, 62%), followed by MAC (n = 20, 26%) and mixed infections (n = 9, 12%). Isolates with macrolide resistance and baseline AMK resistance were identified in 63 (82%) patients and 5 (6%) patients, respectively. At 12 months after AMK inhalation therapy, 49% of patients had symptomatic improvement, whereas 42% had radiological improvement. Conversion to a negative sputum culture occurred in 14 (18%) patients, and the culture conversion rate was higher in patients infected with macrolide-susceptible isolates (7/14, 50%) than in those infected with macrolide-resistant isolates (7/63, 11%) (P = 0.003). Significant decreases in sputum semiquantitative culture positivity occurred after AMK inhalation therapy (P < 0.001). On multivariate analysis, conversion to a negative sputum culture was associated with mixed infections (P = 0.009), a forced expiratory volume in 1 s of greater than 60% (P = 0.008), and the absence of macrolide resistance (P = 0.003). Thirty-eight percent of patients experienced adverse effects, with ototoxicity (n = 15) being the most common. AMK inhalation salvage therapy may improve the treatment responses in some patients with refractory NTM-LD. However, considering the common adverse effects, further evaluation of the optimal dosage and intervals for AMK inhalation therapy is needed.

Nebulized Versus IV Amikacin as Adjunctive Antibiotic for Hospital and Ventilator-Acquired Pneumonia Postcardiac Surgeries: A Randomized Controlled Trial.

OBJECTIVE: Nebulized antibiotics offer high efficacy due to significant local concentrations and safety with minimal blood levels. This study evaluates the efficacy and nephrotoxicity of nebulized versus IV amikacin in postcardiothoracic surgical patients with nosocomial pneumonia caused by multidrug-resistant Gram- negative bacilli. DESIGN: Prospective, randomized, controlled study on surgical patients divided into two groups. SETTING: Postcardiac surgery ICU. INTERVENTIONS: The first gtroup was administered IV amikacin 20 mg/kg once daily. The second group was prescribed amikacin nebulizer 400 mg twice daily. Both groups were co-administered IV piperacillin/tazobactam empirically. PATIENTS: Recruited patients were diagnosed by either hospital-acquired pneumonia or ventilator-associated pneumonia where 56 (42.1%) patients were diagnosed with hospital-acquired pneumonia, 51 (38.34%) patients were diagnosed with early ventilator-associated pneumonia, and 26 (19.54%) patients with late ventilator-associated pneumonia. MEASUREMENTS AND MAIN RESULTS: Clinical cure in both groups assessed on day 7 of treatment was the primary outcome. Efficacy was additionally evaluated through assessing the length of hospital stay, ICU stay, days on amikacin, days on mechanical ventilator, mechanical ventilator-free days, days to reach clinical cure, and mortality rate. Lower nephrotoxicity in the nebulized group was observed through significant preservation of kidney function (p < 0.001). Although both groups were comparable regarding length of hospital stay, nebulizer group showed shorter ICU stay (p = 0.010), lower number of days to reach complete clinical cure (p = 0.001), fewer days on mechanical ventilator (p = 0.035), and fewer days on amikacin treatment (p = 0.022). CONCLUSION: Nebulized amikacin showed better clinical cure rates, less ICU stay, and fewer days to reach complete recovery compared to IV amikacin for surgical patients with nosocomial pneumonia. It is also a less nephrotoxic option associated with less deterioration in kidney function.

Cefepime vs. cefoperazone/sulbactam in combination with amikacin as empirical antibiotic therapy in febrile neutropenia.

PURPOSE: Beta lactams are standard empirical therapy for febrile neutropenia (FN). The aim of this study was to evaluate the efficacy and safety of cefepime monotherapy compared with cefoperazone/sulbactam plus amikacin (CS + A) for empirical treatment of high risk FN. METHODS: One hundred seventy-five patients with 336 FN episodes were randomized to receive either cefepime (2 g q8h for adults and 50 mg/kg q8h for children) or CS (2 g q8h for adults and 50 mg/kg q8h for children) plus amikacin (15 mg/kg once a day). Positive response was defined as afebrile within 72 h of starting antibiotics, persistent afebrile status more than 48 h and no requirement of second-line antibiotics and antifungal agents. RESULTS: Three hundred thirty-six episodes were assessable for efficacy (168 cefepime, 168 CS + A). The positive response to antibiotics was identical for cefepime (53%) and CS + A (53%). Positive response was similar in MDI (microbiologically documented infection), 50 vs. 35% (p = 0.248), CDI (clinically documented infection), 50 vs. 35% (p = 0.259), combination CDI + MDI, 25 vs. 15% (p = 0.400), FUO (fever of unknown origin), 68 vs. 72% (p = 0.577) respectively in the two groups. The successful discontinuation of antibiotics at 72 h in FUO was similar in both groups (60 vs. 59%, p = 0.544). Total drug-related adverse events were similar in both groups (8 vs. 6%) except renal dysfunction was high in CS + A (1 vs. 7 events). Mortality was the same between two groups (8 vs 7%). CONCLUSIONS: Cefepime monotherapy and CS + A had similar efficacy as first-line therapy for FN. Discontinuation of empirical antibiotics is safe and feasible approach in selected group of FUO patients.

A Prospective Trial of Nebulized Amikacin in the Treatment of Bronchiectasis Exacerbation.

BACKGROUND: Pseudomonas aeruginosa is the most common pathogenic bacteria in bronchiectasis (BE) patients. The availability and security of nebulized amikacin treatment are unknown. OBJECTIVE: The purpose of this study was to explore the efficiency and adverse effects of nebulized amikacin treatment for 2 weeks, administered as intravenous therapy during exacerbation of BE patients infected with P. aeruginosa. METHODS: A total of 143 patients with exacerbation of BE were screened between January 2013 and March 2016 at five tertiary hospitals in Shandong Province, China. The BE patients were diagnosed by high-resolution computed tomography scans, and all of them were confirmed to be infected with P. aeruginosa after sputum culture test. Seventy-four patients were assigned to the intervention group and received amikacin nebulization (0.2 g) treatment twice daily for 2 weeks along with intravenous antibiotic therapy. Sixty-nine patients were assigned to the control group and received standard antibiotic therapy alone. The primary outcome was the rate of bacterial eradication from the sputum, and the secondary outcomes were drug resistance and adverse effects. RESULTS: The bacterial eradication rate of sputum in the intervention group (51.4%) was significantly higher compared to that in the control group (23.2%) (χ2 = 14.211, p = 0.030). Drug sensitivity testing showed that there were 5 drug-resistant cases in the intervention group and 7 in the control group, which was not significantly different. Three patients dropped out of the trial due to adverse effects. None of the patients hat renal injury. CONCLUSIONS: Nebulized amikacin treatment is a safe treatment for exacerbation of BE and significantly increases the bacterial eradication rate of sputum.

Adverse Effects and Choice between the Injectable Agents Amikacin and Capreomycin in Multidrug-Resistant Tuberculosis.

The prolonged use of injectable agents in a regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) is recommended by the World Health Organization, despite its association with ototoxicity and nephrotoxicity. We undertook this study to look at the relative adverse effects of capreomycin and amikacin. We reviewed the case notes of 100 consecutive patients treated at four MDR-TB treatment centers in the United Kingdom. The median total duration of treatment with an injectable agent was 178 days (interquartile range [IQR], 109 to 192 days; n = 73) for those with MDR-TB, 179 days (IQR, 104 to 192 days; n = 12) for those with MDR-TB plus fluoroquinolone resistance, and 558 days (IQR, 324 to 735 days; n = 8) for those with extensively drug-resistant tuberculosis (XDR-TB). Injectable use was longer for those started with capreomycin (183 days; IQR, 123 to 197 days) than those started with amikacin (119 days; IQR, 83 to 177 days) (P = 0.002). Excluding patients with XDR-TB, 51 of 85 (60%) patients were treated with an injectable for over 6 months and 12 of 85 (14%) were treated with an injectable for over 8 months. Forty percent of all patients discontinued the injectable due to hearing loss. Fifty-five percent of patients experienced ototoxicity, which was 5 times (hazard ratio [HR], 5.2; 95% confidence interval [CI], 1.2 to 22.6; P = 0.03) more likely to occur in those started on amikacin than in those treated with capreomycin only. Amikacin was associated with less hypokalemia than capreomycin (odds ratio, 0.28; 95% CI, 0.11 to 0.72), with 5 of 37 (14%) patients stopping capreomycin due to recurrent electrolyte loss. There was no difference in the number of patients experiencing a rise in the creatinine level of >1.5 times the baseline level. Hearing loss is frequent in this cohort, though its incidence is significantly lower in those starting capreomycin, which should be given greater consideration as a first-line agent.

Reduced Chance of Hearing Loss Associated with Therapeutic Drug Monitoring of Aminoglycosides in the Treatment of Multidrug-Resistant Tuberculosis.

Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our tuberculosis center, we used therapeutic drug monitoring (TDM) targeting preset pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto)toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of tuberculosis (TB) patients treated with amikacin or kanamycin in the period from 2000 to 2012. Patients with culture-confirmed multiresistant or extensively drug-resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study. Clinical data, including maximum concentration (Cmax), Cmin, and audiometry data, were extracted from the patients' medical charts. A total of 80 patients met the inclusion criteria. The mean weighted Cmax/MIC ratios obtained from 57 patients were 31.2 for amikacin and 12.3 for kanamycin. The extent of hearing loss was limited and correlated with the cumulative drug dose per kg of body weight during daily administration. At follow-up, 35 (67.3%) of all patients had successful outcome; there were no relapses. At a median dose of 6.5 mg/kg, a correlation was found between the dose per kg of body weight during daily dosing and the extent of hearing loss in dB at 8,000 Hz. These findings suggest that the efficacy at this lower dosage is maintained with limited toxicity. A randomized controlled trial should provide final proof of the safety and efficacy of TDM-guided use of aminoglycosides in MDR-TB treatment.

Gut-sparing treatment of urinary tract infection in patients at high risk of Clostridium difficile infection.

BACKGROUND: Recipients of faecal microbiota transplantation (FMT) in treatment of recurrent Clostridium difficile infection (RCDI) remain at markedly increased risk of re-infection with C. difficile with new antibiotic provocations. Urinary tract infections (UTIs) are common indications for antibiotics in these patients, often resulting in C. difficile re-infection. METHODS: We present a case series of 19 patients treated with parenteral aminoglycosides for UTI following FMT for RCDI. A 3 day outpatient regimen of once-daily intramuscular administration of gentamicin was used to treat 18 consecutive FMT recipients with uncomplicated UTI. One other patient was treated for a complicated UTI with intravenous amikacin. Profiling of 16S rRNA genes was used to track changes in faecal microbial community structure during this regimen in three patients. RESULTS: The protocol was highly effective in treating UTI symptoms. None of the patients suffered a re-infection with C. difficile The faecal microbial communities remained undisturbed by treatment with intramuscular administration of gentamicin. CONCLUSIONS: Despite falling out of favour in recent years, aminoglycoside antibiotics given parenterally have the advantage of minimal penetration into the gut lumen. A brief (3 day) course of parenteral gentamicin was safe and effective in curing UTI in patients at high risk of C. difficile infection without perturbing their gut microbiota.

Evaluation of the possible nephroprotective effects of vitamin E and rosuvastatin in amikacin-induced renal injury in rats.

Amikacin (AMIK) is an aminoglycoside antibiotic that possesses considerable nephrotoxic adverse effects. This study examined the protective effects of vitamin E (VIT. E) or rosuvastatin (ROSU) against AMIK-induced nephrotoxicity. For this purpose, eight groups of rats were used. Two control groups received saline and vehicle, AMIK group (1.2 g/kg, i.p.), VIT. E group (1000 mg/kg; p.o.), ROSU group (10 mg/kg; p.o.), AMIK + VIT. E group, AMIK + ROSU group, and combination group. The results showed that AMIK significantly increased serum levels of urea and creatinine. Meanwhile, serum levels of total protein and albumin were decreased. The kidney content of malondialdehyde was increased, whereas glutathione content and catalase activity were decreased. Tumor necrosis factor-α and nuclear transcriptional factor levels were increased. Conversely, administration of VIT. E and/or ROSU with AMIK ameliorated such damage and reduced DNA fragmentation, apoptosis, and necrosis. In conclusion, co-administration of VIT. E, ROSU, or their combination alleviated AMIK-induced nephrotoxicity.