Investigation the effects of 2-aminoethoxydiphenyl borate (2-APB) on aminoglycoside nephrotoxicity.

Investigation the protective effect of transient receptor potential channel modulator 2-Aminoethoxydiphenyl Borate (2-APB) on aminoglycoside nephrotoxicity caused by reactive oxygen species, calcium-induced apoptosis and inflammation was aimed. Forty Wistar rats were divided (n=8) as follows: Control group; DMSO group; 2-APB group; Gentamicin group (injected 100 mg/kg gentamicin intramuscularly for 10 days); Gentamicin+ 2-APB group (injected 2 mg/kg 2-APB intraperitoneally, then after 30 minutes 100 mg/kg gentamicin was injected intramuscularly for 10 days). Blood samples were collected for biochemical analyses, kidney tissue samples were collected for light, electron microscopic and immunohistochemical investigations. In gentamicin group glomerular degeneration, tubular dilatation, vacuolization, desquamation of tubular cells and hyaline cast formation in luminal space and leukocyte infiltration were seen. Disorganization of microvilli of tubular cells, apical cytoplasmic blebbing, lipid accumulation, myelin figure like structure formation, increased lysosomes, mitochondrial swelling and disorganization of cristae structures, apoptotic changes and widening of intercellular space were found. TNF-α, IL-6 and caspase 3 expressions were increased. BUN and creatinine concentrations were increased. Increase in MDA levels and decrease in SOD activities were determined. Even though degeneration still continues in gentamicin+2-APB treatment group, severity and the area it occupied were decreased and the glomerular and tubule structures were generally preserved. TNF-α, IL-6, caspase 3 immunoreactivities and BUN, creatinine, MDA concentrations were reduced and SOD activities were increased markedly compared to gentamicin group. In conclusion, it has been considered that 2-APB can prevent gentamicin mediated nephrotoxicity with its anti-oxidant, anti-apoptotic and anti-inflammatory effects.

Incidence of acute kidney injury (AKI) and its impact on patient outcomes among adult hospitalized patients with carbapenem-resistant Gram-negative infections who received targeted treatment with a newer ß-lactam or ß-lactam/ß-lactamase inhibitor-, polymyxin- or aminoglycoside-containing regimen.

BACKGROUND: Limited comparative data exist on acute kidney injury (AKI) risk and AKI-associated outcomes in hospitalized patients with carbapenem-resistant Gram-negative infections (CR-GNIs) treated with a newer ß-lactam/ß-lactam-ß-lactamase inhibitor (BL/BL-BLI)-, polymyxin (PB)- or aminoglycoside (AG)-containing regimen. This study quantified the risk of AKI and AKI-related outcomes among patients with CR-GNIs treated with a newer BL/BL-BLI-, PB- or AG-containing regimen. METHODS: A multicentre, retrospective, observational study was performed (2016-20). The study included adult hospitalized patients with (i) baseline estimated glomerular filtration rates ≥30 mL/min/1.73 m2; (ii) CR-GN pneumonia, complicated urinary tract infection or bloodstream infection; and (iii) receipt of newer BL/BL-BLI, PG or AG within 7 days of index CR-GN culture for ≥3 days. Outcomes included AKI, in-hospital mortality and hospital costs. RESULTS: The study included 750 patients and most (48%) received a newer BL/BL-BLI. The median (IQR) treatment duration was 8 (5-11), 5 (4-8) and 7 (4-8) days in the newer BL/BL-BLI group, AG group and PB group, respectively. The PB group had the highest adjusted AKI incidence (95% CI) (PB: 25.1% (15.6%-34.6%) versus AG: 8.9% (5.7%-12.2%) versus newer BL/BL-BLI: 11.9% (8.1%-15.7%); P = 0.001). Patients with AKI had significantly higher in-hospital mortality (AKI: 18.5% versus 'No AKI': 5.6%; P = 0.001) and mean hospital costs (AKI: $49 192 versus 'No AKI': $38,763; P = 0.043). CONCLUSIONS: The AKI incidence was highest among PB patients and patients with AKI had worse outcomes. Healthcare systems should consider minimizing the use of antibiotics that augment AKI risk as a measure to improve outcomes in patients with CR-GNIs.

Otoprotection against aminoglycoside- and cisplatin-induced ototoxicity focusing on the upstream drug uptake pathway.

Aminoglycoside- and cisplatin-induced ototoxicity, which is a significant issue owing to the widespread use of these drugs in clinical practice, involves the entry of aminoglycosides and cisplatin into the endolymph and hair cells via specific channels or transporters, followed by reactive oxygen species (ROS) generation and hair cells apoptosis. Current strategies focalize primarily on interference with downstream ROS effects; however, recent evidence has demonstrated that inhibiting the uptake of aminoglycosides and cisplatin by hair cells is another promising strategy for tackling the upstream drug uptake pathway. With advances in structural biology, the conformations of certain aminoglycoside and cisplatin channels and transporters, such as the mechanoelectrical transduction channel and organic cation transporter-2, have been largely elucidated. These channels and transporters may become potential targets for the introduction of new otoprotective strategies. This review focuses on the strategies for inhibiting ototoxic drugs uptake by auditory hair cells and provides potential targets for recent developments in the field of otoprotection. Molecular dynamics (MD) simulations of these proteins could help identify the molecules that inhibit the uptake of aminoglycosides and cisplatin by hair cells. Integrating upstream drug uptake pathway targets and MD simulations may help dissect molecular mechanisms and develop novel otoprotective strategies for aminoglycoside- and cisplatin-induced ototoxicity.

Pharmacokinetics and safety of a single dose of telavancin in pediatric subjects 2-17 years of age.

Antimicrobial resistance increases infection morbidity in both adults and children, necessitating the development of new therapeutic options. Telavancin, an antibiotic approved in the United States for certain bacterial infections in adults, has not been examined in pediatric patients. The objectives of this study were to evaluate the short-term safety and pharmacokinetics (PK) of a single intravenous infusion of telavancin in pediatric patients. Single-dose safety and PK of 10 mg/kg telavancin was investigated in pediatric subjects >12 months to ≤17 years of age with known or suspected bacterial infection. Plasma was collected up to 24-h post-infusion and analyzed for concentrations of telavancin and its metabolite for noncompartmental PK analysis. Safety was monitored by physical exams, vital signs, laboratory values, and adverse events following telavancin administration. Twenty-two subjects were enrolled: 14 subjects in Cohort 1 (12-17 years), 7 subjects in Cohort 2 (6-11 years), and 1 subject in Cohort 3 (2-5 years). A single dose of telavancin was well-tolerated in all pediatric age cohorts without clinically significant effects. All age groups exhibited increased clearance of telavancin and reduced exposure to telavancin compared to adults, with mean peak plasma concentrations of 58.3 µg/mL (Cohort 1), 60.1 µg/mL (Cohort 2), and 53.1 µg/mL (Cohort 3). A 10 mg/kg dose of telavancin was well tolerated in pediatric subjects. Telavancin exposure was lower in pediatric subjects compared to adult subjects. Further studies are needed to determine the dose required in phase 3 clinical trials in pediatrics.

Clinical Pharmacogenomic MT-RNR1 Screening for Aminoglycoside-Induced Ototoxicity and the Post-Test Counseling Conundrum.

Aminoglycoside antibiotic exposure can result in ototoxicity and irreversible hearing loss among individuals that harbor the m.1555A>G variant in the mitochondrial 12S rRNA gene, MT-RNR1. Importantly, pre-emptive m.1555A>G screening has been shown to reduce the prevalence of pediatric aminoglycoside-induced ototoxicity; however, professional guidelines to support and guide post-test pharmacogenomic counseling in this context are not currently available. This Perspective highlights key issues with delivering MT-RNR1 results, including longitudinal familial care considerations and communicating m.1555A>G heteroplasmy.

Mechanisms and Impact of Aminoglycoside-Induced Vestibular Deficits.

PURPOSE: Acquired vestibulotoxicity from hospital-prescribed medications such as aminoglycoside antibiotics affects as many as 40,000 people each year in North America. However, there are no current federally approved drugs to prevent or treat the debilitating and permanent loss of vestibular function caused by bactericidal aminoglycoside antibiotics. This review will cover our current understanding of the impact of, and mechanisms underlying, aminoglycoside-induced vestibulotoxicity and highlight the gaps in our knowledge that remain. CONCLUSIONS: Aminoglycoside-induced vestibular deficits have long-term impacts on patients across the lifespan. Additionally, the prevalence of aminoglycoside-induced vestibulotoxicity appears to be greater than cochleotoxicity. Thus, monitoring for vestibulotoxicity should be independent of auditory monitoring and encompass patients of all ages from young children to older adults before, during, and after aminoglycoside therapy.

Linezolid: a safer and effective substitute to aminoglycoside in the treatment of actinomycetoma by Nocardia species.

Actinomycetoma is chronic, suppurative, granulomatous infection caused by bacteria and requires prolonged antibiotic therapy preferrably in combinations. Nephrotoxicity is a common side effect of aminoglycosides used in the management of actinomycetoma. We report here two cases of actinomycetoma due to Nocardia species who received linezolid as a substitute to aminoglycosides after developing nephrotoxicity.

Neonatal nephrotoxic medication exposure and early acute kidney injury: results from the AWAKEN study.

BACKGROUND: We aimed to describe nephrotoxic medication exposure and investigate associations between exposure and acute kidney injury (AKI) in the neonatal intensive care unit during the first postnatal week. DESIGN/METHODS: Secondary analysis of the AWAKEN cohort. We evaluated nephrotoxic medication exposure during the first postnatal week and associations with AKI using time-varying Cox proportional hazard regressions models. Nephrotoxic medication exposure categories were defined as: no nephrotoxic medication, nephrotoxic medications excluding aminoglycosides, aminoglycoside alone, and aminoglycoside and another nephrotoxic medication. RESULTS: Of 2162 neonates, 1616 (74.7%) received ≥1 nephrotoxic medication. Aminoglycoside receipt was most common (72%). AKI developed in 211(9.8%) neonates and was associated with a nephrotoxic medication exposure (p < 0.01). Nephrotoxic medication exposures including a nephrotoxic medication excluding aminoglycoside (aHR 3.14, 95% CI 1.31-7.55) and aminoglycoside and  another nephrotoxic medication (aHR 4.79, 95% CI 2.19-10.50) were independently associated with AKI and severe AKI (stage 2/3), respectively. CONCLUSIONS: Nephrotoxic medication exposure in critically ill infants is common during the first postnatal week. Specific nephrotoxic medication exposure, principally aminoglycosides with another nephrotoxic medication, are independently associated with early AKI.

Relationship between antibiotic exposure and carbapenem-resistant Klebsiella pneumoniae infection within four types of control patients: A systematic review and meta-analysis.

OBJECTIVES: This study attempted to identify the relationship between antibiotic exposure and risk of carbapenem-resistant Klebsiella pneumoniae (CRKP) infection. METHODS: Antibiotic exposure was analysed as a risk factor for CRKP infection, cases of which were extracted from research articles indexed in PubMed, EMBASE, and the Cochrane Library. Relevant studies published until January 2023 were reviewed, and a meta-analysis was conducted on antibiotic exposure within four types of control groups, which comprised 52 studies. RESULTS: The four types of control groups included carbapenem-susceptible K. pneumoniae infections (CSKP; comparison 1); other infections, especially without CRKP infection (comparison 2); CRKP colonisation (comparison 3); and no infection (comparison 4). Carbapenems exposure and Aminoglycosides exposure were two risk factors common to the four comparison groups. Compared with the risk of CSKP infection, tigecycline exposure in bloodstream infections and quinolone exposure within 30 days were associated with an increased risk of CRKP infection. However, the risk of CRKP infection associated with tigecycline exposure in mixed (MIX) infections (infections involving two or more different infection sites) and quinolone exposure within 90 days was similar to the risk of CSKP infection. CONCLUSION: Carbapenems and Aminoglycosides exposure are likely risk factors for CRKP infection. Antibiotic exposure time as a continuous variable was not associated with the risk of CRKP infection, compared with the risk of CSKP infection. Tigecycline exposure in MIX infections and quinolone exposure within 90 days may not increase the risk of CRKP infection.

A phase IV study evaluating QT interval, pharmacokinetics, and safety following fractionated dosing of gemtuzumab ozogamicin in patients with relapsed/refractory CD33-positive acute myeloid leukemia.

PURPOSE: Gemtuzumab ozogamicin (GO) is indicated for treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). The QT interval, pharmacokinetics (PK), and immunogenicity following the fractionated GO dosing regimen have not been previously assessed. This phase IV study was designed to obtain this information in patients with R/R AML. METHODS: Patients aged ≥ 18 years with R/R AML received the fractionated dosing regimen of GO 3 mg/m2 on Days 1, 4, and 7 of each cycle, up to 2 cycles. The primary endpoint was mean change from baseline in QT interval corrected for heart rate (QTc). RESULTS: Fifty patients received ≥ 1 dose of GO during Cycle 1. The upper limit of the 2-sided 90% confidence interval for least squares mean differences in QTc using Fridericia's formula (QTcF) was < 10 ms for all time points during Cycle 1. No patients had a post-baseline QTcF > 480 ms or a change from baseline > 60 ms. Treatment-emergent adverse events (TEAEs) occurred in 98% of patients; 54% were grade 3-4. The most common grade 3-4 TEAEs were febrile neutropenia (36%) and thrombocytopenia (18%). The PK profiles of both conjugated and unconjugated calicheamicin mirror that of total hP67.6 antibody. The incidence of antidrug antibodies (ADAs) and neutralizing antibodies was 12% and 2%, respectively. CONCLUSION: Fractionated GO dosing regimen (3 mg/m2/dose) is not predicted to pose a clinically significant safety risk for QT interval prolongation in patients with R/R AML. TEAEs are consistent with GO's known safety profile, and ADA presence appears unassociated with potential safety issues. TRIAL REGISTRY: Clinicaltrials.gov ID: NCT03727750 (November 1, 2018).

Aminoglycoside-Related Nephrotoxicity and Ototoxicity in Clinical Practice: A Review of Pathophysiological Mechanism and Treatment Options.

Aminoglycosides are a class of medications used to treat certain bacterial infections, specifically gram-negative aerobes. These drugs can be used alone as first-line treatments or in combination with other medications. There can be many different formulations of aminoglycosides including oral, inhalants, intravascular, intramuscular, or intraventricular. There are many distinctive types of aminoglycosides, and although they provide excellent coverage, they can have a wide variety of side effects. The most prevalent side effects of aminoglycosides are nephrotoxicity and ototoxicity. Aminoglycoside-induced nephrotoxicity is concerning because of the effects that abnormal creatinine levels can have on other drugs and the potential for neurotoxicity. Fortunately, changes in renal function are typically reversible. The kidney is affected by the drug's ability to enter the proximal tubule and cause a buildup of phospholipids in the lysosomes, inhibiting their function. Exposure to aminoglycosides in utero can result in permanent ototoxicity. The mechanism of ototoxicity is through the drug's ability to freely pass into hair cells and cause reactive oxygen species to damage the mitochondria, resulting in cell death. There is not a substantial amount of research regarding the prevention and treatment of adverse effects of aminoglycosides. Future research on the mediation or modulation of these pathophysiological processes would expand their usage in modern medicine.

Fidaxomicin-Associated Hypersensitivity Reactions: Report of a Morbilliform Drug Eruption.

PurposeWe report a probable case of morbilliform drug eruption secondary to fidaxomicin in a patient with Clostridioides difficile infection (CDI). Summary: A 62-year-old female presented to our institution's emergency department (ED) with symptoms consistent with Clostridioides difficile infection. The patient was prescribed 2 weeks of oral vancomycin for CDI prior to presentation. Given insufficient response to vancomycin, the patient was started on fidaxomicin with a planned 10-day course. After 2 doses of fidaxomicin, the patient developed a rash on her back that spread within 24 hours. The patient did not experience relief upon administration of a variety of medications for allergic reaction. Improvement was noted upon discontinuation of fidaxomicin. The Food and Drug Administration reports that < 2% of adults treated with fidaxomicin experience a rash as an adverse effect. Conclusion: Fidaxomicin was a probable cause of morbilliform drug eruption in our patient with CDI. The patient improved upon discontinuation of fidaxomicin.

Assessing the Risk of Nephrotoxicity Associated with Aminoglycosides in Brucellosis Patients: A Cross-sectional Study.

OBJECTIVE: The purpose of this study was to investigate renal function in patients with brucellosis before and at the end of gentamicin therapy. To ensure the safety of therapeutic doses of gentamicin, renal functions in brucellosis patients were monitored regarding drug serum levels and check for early detection biomarkers of nephrotoxicity. METHODS: In this cross-sectional study, 41 patients (25 men and 16 women, aged over 15 years) were included, with confirmed acute brucellosis that referred to Brucellosis Research Center in Hamadan, west of Iran between March 2018 to February 2019. At baseline before treatment (first step) and 7 days after gentamicin administration (second step), serum uric acid, blood urea nitrogen (BUN), serum and urine creatinine, erythrocyte sedimentation rate (ESR), quantitative C-reactive protein (CRP) and urinary ß2-microglobulin (ß2M) were measured. Gentamycin serum level due to the highest risk of nephrotoxicity with this drug in aminoglycoside class was also checked by HPLC method. The data were analyzed using SPSS version 22. RESULTS: The mean urinary ß 2M level, serum and urinary creatinine, uric acid, BUN, and quantitative CRP levels in the first step and second step, there were no statistical differences between the two steps. There was a correlation between urinary creatinine and ESR. In addition, a positive correlation was found between urinary ß2M and serum gentamicin level. ESR levels have been significantly reduced in the patients after the treatment compared to before it. CONCLUSION: Our findings confirm that gentamicin is safe at the dose of 5 mg/kg/day for one week intravenously in brucellosis patients.

Detecting mitochondrial mutations associated with aminoglycoside ototoxicity by noninvasive prenatal testing.

OBJECTIVES: Numerous diseases and disorders are associated with mitochondrial DNA (mtDNA) mutations, among which m.1555A > G and m.1494C > T mutations in the 12 S ribosomal RNA gene contribute to aminoglycoside-induced and nonsyndromic hearing loss worldwide. METHODS: A total of 76,842 qualified non-invasive prenatal (NIPT) samples were subjected to mtDNA mutation and haplogroup analysis. RESULTS: We detected 181 m.1555A > G and m.1494C > T mutations, 151 of which were subsequently sequenced for full-length mitochondrial genome verification. The positive predictive values for the m.1555A > G and m.1494C > T mutations were 90.78% and 90.00%, respectively, a performance comparable to that attained with newborn hearing screening. Furthermore, mitochondrial haplogroup analysis revealed that the 12 S rRNA 1555A > G mutation was enriched in sub-haplotype D5[p = 0, OR = 4.6706(2.81-7.78)]. CONCLUSIONS: Our findings indicate that the non-invasive prenatal testing of cell-free DNA obtained from maternal plasma can successfully detect m.1555A > G and m.1494C > T mutations.

Using a bedside test to detect genetic susceptibility to aminoglycoside-induced hearing loss: Has the future arrived?

Aminoglycosides are among the most commonly prescribed antibiotics in hospitalised Australian adults and children. A proportion of individuals with an underlying genetic predisposition to aminoglycoside-induced hearing loss (AIHL) can develop bilateral sensorineural hearing loss that is immediate and profound after just a single standard dose of an aminoglycoside. A recent publication described the use of a rapid point-of-care test (POCT) in a neonatal nursery in the United Kingdom for real-time detection of infants at risk of AIHL, in whom exposure to aminoglycosides could then be avoided. This proof of concept study should provide a catalyst for further development of similar assays that would be suitable for Australia's genetically diverse population. The barriers to mitigating the impact of AIHL on Australian children are not primarily technical, but involve a lack of data on the prevalence of the MT-RNR1 mutations in our current neonatal and paediatric populations and intensive care nurseries.

Incidence and associated risk factors for systemic drug levels with inhaled aminoglycoside therapy.

OBJECTIVES: To characterize the incidence of and risk factors for a detectable drug level (DDL) in patients that received inhaled aminoglycoside therapy. METHODS: This retrospective, single-centre study included adult patients who received at least one dose of an inhaled aminoglycoside with a drug level during inpatient hospitalization. Patients were excluded if they received an aminoglycoside intravenously within 7 days or if the drug level was not drawn within 4 h of the next dose. A repeated measures logistic regression model evaluated the association between potential risk factors and a DDL. RESULTS: Among 286 drug levels, 88 (30.8%) drug levels were detectable. In multivariable analysis, cystic fibrosis (CF) (OR: 3.03; 95% CI: 1.10-8.35), chronic kidney disease (CKD) (OR: 4.25; 95% CI: 1.84-9.83), lung transplant recipient (OR: 3.08; 95% CI: 1.09-8.73), mechanical ventilation (OR: 2.99; 95% CI: 1.25-7.15) and tobramycin (OR: 5.26; 95% CI: 2.35-11.78) were associated with higher odds of a DDL. Among those with a DDL, inhaled aminoglycoside type and drug level concentration were not associated with acute kidney injury (P = 0.161). CONCLUSIONS: Among 286 drug levels identified among inpatients receiving inhaled aminoglycoside therapy, 88 (30.8%) unique drug levels were detectable. Based on the results of this study, periodic trough concentrations should be considered for patients receiving inhaled aminoglycoside therapy with CF, CKD, lung transplantation, mechanical ventilation or tobramycin.

Aminoglycoside induced ototoxicity risk in the cystic fibrosis population: The utility of large-scale screening.

BACKGROUND: MT-RNR1 variants are a well-known cause of aminoglycoside-induced hearing loss (AIHL). Individuals with cystic fibrosis (CF) routinely receive aminoglycosides and are at high risk of AIHL. However, genetic testing before treatment is not routinely performed due to perceived rarity of risk, and cost ineffectiveness with traditional technologies. AIM: Assess the utility of large-scale screening for AIHL risk in the CF population, using digital droplet polymerase chain reaction (ddPCR), a novel and scalable low-cost molecular technique. METHODS: Using a clinically validated ddPCR assay, we performed retrospective testing on 122 and prospective testing on 32 individuals with CF for the two most common pathogenic variants associated with AIHL, MT-RNR1 m.1555 A > G and m.1494 C > T. Our study screened the largest known cohort of pediatric cases of CF (94/154) for these specific alterations. RESULTS: We identified two individuals positive for MT-RNR1 m.1555 A > G and no positives for m.1494 C > T. Of 32 prospective cases, 17 had aminoglycoside exposure. The positive case in our prospective group recently began inhaled tobramycin and denied hearing issues. The clinician adjusted to care for both the patient and sibling with CF (not included in cohort) who is presumed positive for m.1555 A > G due to the nature of mitochondrial inheritance. CONCLUSION: Our findings demonstrate the utility of pretreatment screening in the cystic fibrosis population for AIHL risk using ddPCR, a scalable and robust testing methodology at a fraction of the cost as compared to other sequencing-based methods. Therefore, the use of large-scale screening for AIHL risk in the cystic fibrosis community should be re-visited.

Aminoglycosides use has a risk of acute kidney injury in patients without prior chronic kidney disease.

The outcome of acute kidney injury (AKI) as a result of aminoglycosides (AGs) use remains uncertain in patients without prior chronic kidney disease (CKD). Therefore, we explored the outcomes of AGs use on AKI episodes associated with renal recovery and progress in patients without prior CKD in Taiwan. This was a retrospective cohort study by using the Taipei Medical University Research Database from January 2008 to December 2019. 43,259 individuals without CKD who had received parenteral AGs were enrolled. The exposed and unexposed groups underwent propensity score matching for age, gender, patients in intensive care unit/emergency admission, and covariates, except serum hemoglobin and albumin levels. We identified an exposed group of 40,547 patients who used AGs (median age, 54.4 years; 44.3% male) and an unexposed group of 40,547 patients without AG use (median age, 55.7 years; 45.5% male). There was the risk for AKI stage 1 (adjusted hazard ratio [HR] 1.34; 95% confidence interval [CI] 1.00-1.79; p = 0.05) in patients that used AGs in comparison with the control subjects. Moreover, patients using AGs were significantly associated neither with the progression to acute kidney disease (AKD) stages nor with the progression to end-stage renal disease (ESRD) on dialysis. Further analyzed, there was an increased risk of AKI episodes for serum albumin levels less than 3.0 g/dL and hemoglobin levels less than 11.6 g/dL. Among patients without prior CKD, AGs-used individuals were associated with AKI risks, especially those at relatively low albumin (< 3.0 g/dL) or low hemoglobin (< 11.6 g/dL). That could raise awareness of AGs prescription in those patients in clinical practice.

Ototoxicity in childhood: Recommendations of the CODEPEH (Commission for the Early Detection of Childhood Hearing Loss) for prevention and early diagnosis.

Ototoxicity is defined as the damage, reversible or irreversible, produced in the inner ear by various substances that are called ototoxic and that can cause hearing loss and/or an alteration of the vestibular system. Permanent hearing loss significantly affects quality of life and is especially important in children. The lack or delay in its detection is frequent, since it often progresses in an inconspicuous manner until it affects communication and overall development. This impact can be minimized by following a strategy of audiological monitoring of ototoxicity, which allows for its early detection and treatment. This document recommends that children who are going to be treated with cisplatin or aminoglycosides be monitored. This CODEPEH review and recommendation document focuses on the early detection, prophylaxis, otoprotection, monitoring and treatment of ototoxicity caused by aminoglycosides and platinum-based antineoplastics in the paediatric population.

A phase III clinical trial evaluating efficacy and safety of minimal residual disease-based risk stratification for children with acute myeloid leukemia, incorporating a randomized study of gemtuzumab ozogamicin in combination with post-induction chemotherapy for non-low-risk patients (JPLSG-AML-20).

The purpose of this study is to establish a treatment with appropriate intensity for children (<16 years old at diagnosis) with de novo acute myeloid leukemia (excluding acute promyelocytic leukemia and myeloid leukemia associated with Down syndrome) according to a risk stratification based on recurrent leukemic cytogenetic abnormalities and flow-cytometric minimal residual disease at end of initial induction chemotherapy and to validate the safety and efficacy of gemtuzumab ozogamicin (GO)-combined post-induction chemotherapy for the non-low-risk (non-LR) patients. The primary endpoint of this phase III study is three-year disease-free survival rate, which will be compared between the GO and non-GO arms of the non-LR (intermediate-risk and high-risk [HR]) patients. All HR patients will be allocated to allogeneic hematopoietic stem cell transplantation in first remission. This trial has been registered at the Japan Registry of Clinical Trials (jRCTs041210015).