High-dose cytarabine plus gemtuzumab ozogamicin as consolidation therapy in patients with favorable- or intermediate-risk acute myeloid leukemia.

Previous prospective randomized trials have investigated the efficacy of gemtuzumab ozogamicin in the frontline treatment of acute myeloid leukemia (AML). We evaluated the efficacy of high-dose cytarabine with GO as consolidation therapy in 20 patients with favorable- or intermediate-risk AML in first complete remission. They included six patients with wild-type nucleophosmin (NPM1) core binding factor (CBF), ten with NPM1-mutated non-CBF, and four with wild-type NPM1 non-CBF. The median follow-up for the entire cohort was 62.0 months. The three-year overall survival (OS) and relapse-free survival (RFS) rates were 72.2% and 77.8%, respectively. OS and RFS were significantly higher for NPM1-mutated non-CBF AML than for wild-type NPM1 non-CBF AML (p = 0.001). We also examined the CD33 single-nucleotide polymorphism (SNP) rs12459419, which has been reported to influence the therapeutic efficacy of GO and CD33 expression. The CD33 expression ratio was higher in CD33 SNP C/C than in C/T (83.1% vs. 49.8%, p = 0.035), but 3-year OS and RFS did not differ significantly. These results suggest that consolidation therapy with high-dose cytarabine plus GO is highly effective in transplant-ineligible elderly patients and may be a reasonable treatment, especially for NPM1-mutated AML.

Azacitidine and gemtuzumab ozogamicin as post-transplant maintenance therapy for high-risk hematologic malignancies.

Disease recurrence remains the principal cause of treatment failure after allogeneic hematopoietic stem cell transplantation. Post-transplant maintenance therapy with azacitidine (AZA) is promising to prevent relapse but the outcomes are unsatisfactory in patients at high risk of recurrence. Herein, we evaluated the outcome in patients who received AZA and gemtuzumab ozogamicin (GO), anti-CD33 antibody-calicheamicin conjugate, as post-transplant maintenance therapy. Twenty-eight patients with high-risk hematologic malignancies harboring CD33-positive leukemic blasts received the maintenance therapy. AZA (30 mg/m2) was administered for 7 days, followed by GO (3 mg/m2) on day 8. The maximum number of cycles was 4. At transplant, 21 patients (75.0%) had active disease. Their 2-year overall survival, disease-free survival, relapse, and non-relapse mortality rates were 53.6%, 39.3%, 50.0%, and 10.7%, respectively. Of these patients, those with minimal residual disease at the start of maintenance therapy (n = 9) had a higher recurrence rate (66.7% vs. 42.1% at 2 years, P = 0.069) and shorter disease-free survival (11.1% vs. 52.6% at 2 years, P = 0.003). Post-transplant maintenance therapy with AZA and GO was generally tolerable but more than half of the patients eventually relapsed. Further improvements are needed to prevent relapse after transplantation in patients with high-risk hematologic malignancies.

Vestibular Hypofunction Secondary to Topical Use of Aminoglycosides in Ears with Perforated Tympanic Membrane.

INTRODUCTION: The objective of this study was to identify and clinically characterize patients treated in an Otoneurology Unit who experienced vestibular ototoxicity as a result of using aminoglycoside ear drops during outbreaks of superinfection in chronic otitis media. MATERIAL AND METHODS: An observational retrospective study was conducted, including patients with perforated eardrums who developed vestibular ototoxicity within the past 10 years following the application of topical ear aminoglycosides in a tertiary referral center. The study encompassed the assessment of the clinical presentation, treatment, quality of life, and evolution after treatment of the identified individuals. RESULTS: During the study period, 6 patients, aged between 33 and 71 years, developed vestibular ototoxicity following the use of topical aminoglycoside drops due to infection flares in chronic otitis media. All cases involved the use of gentamicin. Two cases were unilateral, and 4 were unilateral. The onset of symptoms occurred within one to four weeks of using the drops, resulting in all patients experiencing instability without vertigo attacks. After discontinuing the drops and undergoing vestibular rehabilitation, 4 patients experienced sequelae, with 2 patients (both with bilateral vestibular hypofunction) suffering significant impairment in their quality of life. CONCLUSIONS: Vestibular ototoxicity due to the topical application of aminoglycosides during acute exacerbations of chronic otitis media is a rare occurrence. However, given its potential for severe consequences and the fact that we are still encountering patients with this condition, healthcare professionals should explore alternative antibacterial agents that offer similar efficacy.

Gemtuzumab ozogamicin plus midostaurin in combination with standard '7 + 3' induction therapy in newly diagnosed AML: Results from the SAL-MODULE phase I study.

We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.

Limited efficacy of 3 + 7 plus gemtuzumab ozogamycin in newly diagnosed fit intermediate genetic risk acute myeloid leukemia patients.

BACKGROUND: Gemtuzumab-ozogamycin (GO) is approved in combination with high-dose chemotherapy for treatment-naïve low- and intermediate-risk acute myeloid leukemia (AML). AIMS: In this retrospective real-life multicenter study, we reported efficacy and safety of GO plus high-dose chemotherapy in newly diagnosed AML patients. METHODS AND RESULTS: A total of 31 fit low- and intermediate-risk AML patients treated with GO-based regimens were retrospectively included in this real-life multicenter study, and results were compared with a control cohort treated with 3 + 7 alone. Complete remission (CR) rate after induction was 77%, and most responders (45%) underwent two GO-based consolidation, and minimal residual disease (MRD) negativity was observed in 17 cases (55%) after the end of consolidation. Low genetic risk was associated with increased CR rate compared with intermediate-risk AML (88% vs. 33%; p < .001), as well as prolonged overall survival (OS; hazard ratio, 0.16; 95% confidential interval, 0.02-0.89; p < .001). GO addition resulted in a survival benefit for low-risk AML (median OS not reached vs. 25 months; p = .19) while not for intermediate-risk subjects (10 vs. 13 months; p = .92), compared with the control group. Moreover, GO-treated patients experienced fever of unknown origin or sepsis in 42% or 36% of cases, respectively, with one death during induction due to septic shock, with similar rates compared with the control group (p = .3480 and p = .5297, respectively). No cases of veno-occlusive disease after allogeneic transplantation were observed. CONCLUSIONS: Our real-life multicenter study confirmed GO-based treatment efficacy with high MRD negativity rates in fit newly diagnosed AML patients, especially in those with low genetic risk and core binding factor, while limited benefits were observed in intermediate-risk AML. However, further validation on larger prospective cohorts is required.

A comparison of aminoglycoside antibiotic serum concentrations collected by peripheral veins and peripherally inserted central catheters in adults with cystic fibrosis.

BACKGROUND: People with cystic fibrosis (PwCF) are frequently hospitalized for treatment of pulmonary exacerbation. The Cystic Fibrosis Foundation Pulmonary Guidelines support the use of intravenous aminoglycosides with therapeutic drug monitoring for the treatment of pulmonary exacerbation due to Pseudomonas aeruginosa. Serum intravenous tobramycin concentrations are commonly collected by peripheral venipuncture (PV). Discomfort associated with collection of samples by PV prompts collection via PICC, but the accuracy of intravenous tobramycin serum levels collected by PICC has not been documented in adult PwCF. The primary study objective was to evaluate the difference between intravenous tobramycin serum levels collected by PV and PICC in adult PwCF. METHODS: The authors conducted a prospective case-control study of adult PwCF admitted to University of Utah Health for a pulmonary exacerbation receiving tobramycin by a single lumen PICC. The authors compared tobramycin peak and random serum levels collected by PV and PICC using a detailed flush and waste protocol. RESULTS: The authors analyzed a total of 19 patients with peripheral and PICC samples. The mean tobramycin peak collected by PV (27.2 mcg/mL) was similar to the mean peak collected by PICC (26.9 mcg/mL) (paired samples Wilcoxon signed-rank test, p = .94). The correlation coefficient was 0.88 (95% CI = 0.85-0.91, p < .001). CONCLUSION: Tobramycin serum samples collected by PICC appear to be similar in value to PV collections. Collecting aminoglycoside levels by PICC rather than PV may reduce patient discomfort and improve quality of life. Additional multicenter studies are needed to confirm these results.

Prospective evaluation of single-dose aminoglycosides for treatment of complicated cystitis in the emergency department.

BACKGROUND: Antimicrobial resistance among Enterobacterales continues to be a growing problem, particularly in those with urinary infections. Previous studies have demonstrated safety and efficacy with the use of single-dose aminoglycosides in uncomplicated cystitis. However, data in complicated infections are limited. Single-dose aminoglycosides may provide a convenient alternative for those with or at risk for resistant pathogens causing complicated urinary infections, especially when oral options are unavailable due to resistance, allergy, intolerance, or interactions with other medications. This study evaluated the safety and effectiveness of single-dose aminoglycosides in treatment of complicated cystitis in the emergency department (ED). METHODS: This was a multicenter, prospective study performed between July 2022 and March 2023 of patients who met criteria for complicated cystitis and were otherwise stable for discharge at an academic ED. Primary outcomes were clinical or microbiologic failure within 14 days of treatment. Safety was assessed by review of adverse events. Descriptive statistics were used. RESULTS: Thirteen patients were included. Complicating factors were male sex (n = 4), kidney stone (n = 2), urinary catheter (n = 6), recent urologic procedure (n = 1), urinary hardware (n = 1), antibiotic allergy precluding use of alternate oral options (n = 4), immunocompromised status (n = 2), and <1-year history of multidrug-resistant organisms on urine culture (n = 8). Eleven patients (85%) had positive urine cultures in the preceding 12 months with no oral antimicrobial option. Eight patients (62%) received amikacin (median dose 15 mg/kg), four patients (31%) received gentamicin (median dose 5 mg/kg), and one patient (8%) received tobramycin (5 mg/kg) for treatment. Ten patients (77%) reported resolved urinary symptoms after treatment and 11 patients (85%) reported no new urinary symptoms since discharge. No patient required hospital admission for treatment failure, and no adverse events were noted. CONCLUSIONS: Single-dose aminoglycosides appear to be a reasonably effective and safe treatment for complicated cystitis, which avoided hospital admission in this cohort.

Single versus combination intravenous anti-pseudomonal antibiotic therapy for people with cystic fibrosis.

BACKGROUND: The choice of antibiotic, and the use of single or combined therapy are controversial areas in the treatment of respiratory infection due to Pseudomonas aeruginosa in cystic fibrosis (CF). Advantages of combination therapy include wider range of modes of action, possible synergy and reduction of resistant organisms; advantages of monotherapy include lower cost, ease of administration and reduction of drug-related toxicity. Current evidence does not provide a clear answer and the use of intravenous antibiotic therapy in CF requires further evaluation. This is an update of a previously published review. OBJECTIVES: To assess the effectiveness of single compared to combination intravenous anti-pseudomonal antibiotic therapy for treating people with CF. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search of the Group's Trials Register: 07 October 2020. We also searched online trials registries on 16 November 2020. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing a single intravenous anti-pseudomonal antibiotic with a combination of that antibiotic plus a second anti-pseudomonal antibiotic in people with CF. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We assessed the certainty of the data using GRADE. MAIN RESULTS: We identified 59 trials, of which we included eight trials (356 participants) comparing a single anti-pseudomonal agent to a combination of the same antibiotic and one other. There was a wide variation in the individual antibiotics used in each trial. In total, the trials included seven comparisons of a beta-lactam antibiotic (penicillin-related or third generation cephalosporin) with a beta-lactam-aminoglycoside combination and three comparisons of an aminoglycoside with a beta-lactam-aminoglycoside combination.  There was considerable heterogeneity amongst these trials, leading to difficulties in performing the review and interpreting the results. These results should be interpreted cautiously. Six of the included trials were published between 1977 and 1988; these were single-centre trials with flaws in the randomisation process and small sample size. Overall, the methodological quality was poor and the certainty of the evidence ranged from low to moderate. The review did not find any differences between monotherapy and combination therapy in either the short term or in the long term for the outcomes of different lung function measures, bacteriological outcome measures, need for additional treatment, adverse effects, quality of life or symptom scores. AUTHORS' CONCLUSIONS: The results of this review are inconclusive. The review raises important methodological issues. There is a need for an RCT which needs to be well-designed in terms of adequate randomisation allocation, blinding, power and long-term follow-up. Results need to be standardised to a consistent method of reporting, in order to validate the pooling of results from multiple trials.

Cost-effectiveness of implementing routine hearing screening using a tablet audiometer for pediatric cystic fibrosis patients receiving high-dose IV aminoglycosides.

BACKGROUND: Cystic fibrosis (CF) patients who receive high-dose aminoglycosides can acquire inner ear damage and subsequent hearing loss. There is no current standard protocol for assessing ototoxicity in CF centers in the United States. OBJECTIVE: To evaluate the cost-effectiveness of a pharmacist-implemented routine hearing screening for ototoxicity among pediatric patients using a clinically validated tablet audiometer to allow for earlier detection of hearing loss in an exploratory analysis. METHODS: A Markov decision-analytic model was developed to assess the cost-effectiveness of implementing routine screening with monthly cycles over a 3-year time horizon. The model measured the difference in promptly detected hearing loss, delayed detected hearing loss, and undetected hearing loss, compared with current screening practices. Model inputs were obtained through a comprehensive literature review. Primary model outcomes included total health care costs and quality-adjusted life-years (QALYs) gained with a 3% yearly discount. One-way, two-way, and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. RESULTS: In a hypothetical cohort of 100 patients, routine screening using a tablet audiometer increased promptly detected hearing loss by 8 patients. There was an incremental gain of 3.2 QALYs at an increased cost of $333,826 compared with current screening practices. This resulted in an incremental cost-effectiveness ratio (ICER) of $103,771 per QALY. In the 1-way sensitivity analysis, the ICER ranged between $64,345 and $258,830 per QALY. CONCLUSIONS: Using a tablet audiometer for routine hearing screening appears to be a cost-effective option at a $150,000 per QALY willingness-to-pay threshold when only considering the immediate benefits gained. This analysis did not examine the long-term effects of early detection in language development for pediatric patients. DISCLOSURES: Huang reports funding from the University of North Carolina and GlaxoSmithKline Health Outcomes Fellowship. GlaxoSmithKline had no involvement in the study creation, analysis, or manuscript composition. The other authors have nothing to disclose.

Prospective cohort study of ototoxicity in persons with cystic fibrosis following a single course of intravenous tobramycin.

INTRODUCTION: Aminoglycoside (AG) antibiotics, such as tobramycin, are known to be ototoxic but important clinically due to their bactericidal efficacy. Persons with cystic fibrosis (CF) are at risk for AG-induced ototoxicity due to the repeated use of intravenous (IV) tobramycin for the treatment of pulmonary exacerbations. While it is well-established that ototoxic hearing loss is highly prevalent in this clinical population, the progression of hearing loss over time remains unclear. Cumulative IV-AG dosing has been associated with a higher risk of ototoxic hearing loss, yet some individuals lose substantial hearing after a single IV-AG treatment, while others never seem to lose hearing. METHODS: 31 persons with CF (18 on IV tobramycin, 13 controls) were enrolled in an observational study. Pure-tone hearing thresholds (0.25-16 kHz) were measured at baseline (pre-treatment) and at follow-up for each subject. A hearing shift was determined using various metrics, and outcomes were compared to characterize changes in hearing bilaterally for both study groups. RESULTS: Comparison of pure-tone threshold shifts between baseline and follow-up audiograms following either a course of IV tobramycin (n = 18) or no intervening therapy (n = 13) demonstrated significant (p < 0.05) threshold shifts in all continuous metrics tested. CONCLUSION: A single course of IV tobramycin causes ototoxic hearing loss in some people with CF, which supports the need for routine ototoxicity monitoring and management in this clinical population. These findings also suggest that people with CF are a suitable population for clinical trials examining ototherapeutics in single IV-tobramycin treatment episodes.

Ototoxicity in cystic fibrosis patients receiving intravenous tobramycin for acute pulmonary exacerbation: Ototoxicity following tobramycin treatment.

Aminoglycosides are commonly used to treat infections in CF patients and are highly ototoxic. The incidence of tobramycin-induced hearing loss, tinnitus, vertigo or dizziness (ototoxicity) varies widely from 0 to 56% secondary to variation in patient enrollment, dosing, audiometry, and ototoxic criteria. The aim of this study is to determine the incidence of ototoxicity after one course of once-daily IV tobramycin in CF patients. Adult CF patients with acute pulmonary exacerbations were enrolled on IV tobramycin (10 mg/kg/d, ≥10 days). Pure-tone audiometry was performed for standard and extended high frequencies in the sensitive range for ototoxicity (SRO). American-Speech-Language-Hearing-Association cochleotoxicity criteria were applied. Distortion product otoacoustic emissions (DPOAE) and the words-in-noise-test (WINT) were assessed. Tinnitus Functional Index (TFI) and Vertigo Symptoms Scale (VSS) were used. Eighteen CF patients, mean age 31.1 (18-59), were enrolled. The incidence of cochleotoxic change from baseline at 2 and 4 weeks post-treatment was 89% and 93%. For DPOAE, a measure of outer hair-cell function, the incidence of ≥5 dB decrease was 82% and 80%. For WINT, a measure of word recognition, the incidence of ≥10% decrease was 17% and 40%. For TFI, the incidence of ≥10pt increase was 12% and 8%, and for VSS, the incidence of ≥6pt increase was 0% and 8%. One course of IV tobramycin was sufficient to cause hearing loss and other ototoxic symptoms four weeks after treatment ended. Audiometric measures were more sensitive to ototoxic change than TFI & VSS. Age and duration of tobramycin treatment were not obvious factors for predicting ototoxicity.

[Antibiotic stewardship - recent developments]. / Aktuelle Entwicklungen im Bereich Antibiotic Stewardship.

Both in hospitals and outpatient settings, fewer fluoroquinolones have been prescribed in Germany in recent years. The consumption of cephalosporins also decreased somewhat in favor of penicillin derivatives. The aminoglycosides, which have only rarely been prescribed, can now be used again as a suitable alternative - but only parenterally - due to their relatively favorable activity and low resistance rates among typical urinary tract infection pathogens. In acute severe infection such as sepsis, addition, e. g. of tobramycin, to a suitable betalactam of a single dose has been discussed as a useful option, but the evidence for such a recommendation is weak. There is little news about the rational use of antibiotics in hematology-oncology patients. In the case of fever and neutropenia, the initial empirical regimens of choice remain piperacillin-tazobactam or a pseudomonas-active carbapenem as monotherapy. These betalactams should be given with extended infusion times, e. g. over 4 hours. Linezolid should be considered as a reserve drug and not be used empirically, but only in targeted therapy. With regard to an alleged penicillin allergy, the risk of true allergic reactions can be differentiated by careful taking of the history; on that ground patient subgroups can be defined that may be re-exposed without further allergological examinations.

Aminoglycosides in critically ill patients: which dosing regimens for which pathogens?

Modifications of antibiotic pharmacokinetic parameters have been reported in critically ill patients, resulting in a risk of treatment failure. We aimed to determine optimised amikacin (AMK), gentamicin (GEN) and tobramycin (TOB) intravenous dosing regimens in this patient population. Patients admitted to the medical ICU and treated with AMK, GEN or TOB were included. Analyses were performed using a parametric population approach. Monte Carlo simulations were performed and the probability of target attainment (PTA) was calculated using Cmax/MIC ≥ 8 and trough concentrations as targets. A total of 117 critically ill hospitalised patients were studied. Median values (interindividual variability, É·2) of clearance were 3.51 (0.539), 3.53 (0.297), 2.70 (0.339) and 5.07 (0.339) L/h for AMK, GEN, TOB, and TOB in cystic fibrosis (CF), respectively. Median values (É·2) of central volume of distribution were 30.2 (0.215), 20.0 (0.109) and 25.6 (0.177) L for AMK, GEN and TOB, respectively. Simulations showed that doses should be adjusted to actual body weight and creatinine clearance (CLCR) for AMK and GEN, and according to CLCR and presence of CF for TOB. In conclusion, our recommendations for treating Pseudomonas aeruginosa infections in this population include using initial doses of 35 mg/kg for AMK or 10 mg/kg for TOB (CF and non-CF patients). GEN demonstrated the best rates of target attainment against Staphylococcus aureus infections with a dose of 5 mg/kg. As high aminoglycoside doses are required in this population, efficacy and safety targets are conflicting and therapeutic drug monitoring remains an important tool to manage this issue.

Genetic testing in the acute setting: a round table discussion.

Genetic testing has historically been performed in the context of chronic disease and cancer diagnostics. The timelines for these tests are typically measured in days or weeks, rather than in minutes. As such, the concept that genetic information might be generated and then used to alter management in the acute setting has, thus far, not been feasible. However, recent advances in genetic technologies have the potential to allow genetic information to be generated significantly quicker. The m.1555A>G genetic variant is present in one in 500 individuals and predisposes to profound hearing loss following the administration of aminoglycoside antibiotics. These antibiotics are used frequently in cases of neonatal sepsis and it is estimated that approximately 180 neonates in the UK are at risk of antibiotic induced hearing loss each year because of this genetic change. Knowledge of this variant in the acute setting would allow clinicians to prescribe alternative antibiotics. The Pharmacogenetics to Avoid Loss of Hearing study will implement a genetic point of care test (POCT) for the m.1555A>G variant within two major UK based neonatal intensive care units. This represents the first trial of a genetic POCT aimed at altering management in the acute setting. This round table discussion outlines the novel ethical issues faced in the development of this trial and the legal barriers to implementation. We ask five stakeholders to provide their opinions on this trial and their perspectives on the concept of genetic testing in the acute setting.Trial registration numberISRCTN-13704894.

Exploring the Relationship between FEV1 Loss and Recovery and Aminoglycoside Pharmacokinetics in Adult Patients with Cystic Fibrosis: Implications for Clinical Dosing Strategies.

OBJECTIVE: Systemic aminoglycosides remain a cornerstone of treatment for cystic fibrosis (CF) pulmonary exacerbations (PEx); however, the impact of aminoglycoside pharmacokinetics (PK) on outcomes is not well defined in adult CF patients. Our objective was to assess the impact of increasing PK exposures on the clinical outcomes of PEx treatment in adult CF patients receiving high-dose and standard-dose extended-interval aminoglycosides. METHODS: We conducted a retrospective study of adult CF patients treated with an intravenous aminoglycoside for a PEx. Serum amikacin, gentamicin, and tobramycin levels and forced expiratory volume over 1 second (FEV1 ) data were used to evaluate exposure-response relationships. PK parameters were estimated using a Bayesian approach to obtain area under the curve (AUC)0-24 hr , maximum concentration (Cmax0-24 hr ), and minimum concentration (Cmin0-24 hr ) estimates. The primary efficacy end point was a 90% recovery of baseline FEV1 by 30 days posttreatment. Toxicity included signs or symptoms of ototoxicity, vestibular toxicity, or renal toxicity. Multivariate linear mixed-effects models of FEV1 were used for exposure-response analysis. RESULTS: The study included 51 patients who contributed 188 FEV1 observations. There were 3.0 ± 1.7 (mean ± SD) aminoglycoside concentrations per patient. The mean AUC0-24 hr , Cmax0-24 hr , and Cmin0-24 hr across all agents and patients were 156 ± 96 mg*hr/L, 29.9 ± 12.7 mg/L, and 0.35 ± 0.66 mg/L, respectively. A total of 42 amikacin-, gentamicin-, or tobramycin-treated patients contributed to the efficacy analysis, of whom 85.7% experienced recovery posttreatment. Of the 51 included patients, 6 (11.8%) experienced seven toxicity events. In exploratory exposure-response analyses, neither AUC0-24 hr nor Cmax0-24 hr was associated with FEV1 values after adjusting for clinical covariates and baseline FEV1 . CONCLUSIONS: Increasing aminoglycoside AUC0-24 hr and Cmax0-24 hr were not associated with FEV1 during PEx treatment. Although individualizing aminoglycoside dosing in adult CF patients is necessary to minimize toxicity risk, more work is needed to define optimally safe and effective dosing strategies for this population.

Does Circadian Rhythm Affect the Pharmacokinetics of Once-Daily Tobramycin in Adults With Cystic Fibrosis?

BACKGROUND: In the era of multiple daily dosing of systemic aminoglycosides, a circadian rhythm in the clearance of these vital antibiotics has been demonstrated in animals and healthy volunteers. Over the past decade, once-daily dosing regimens have been proved to be less nephrotoxic and were therefore adopted worldwide for most indications requiring treatment with an aminoglycoside. In this study, the effect of the time of administration on the pharmacokinetics of once-daily tobramycin in adults with cystic fibrosis (CF) experiencing a pulmonary exacerbation was investigated. METHODS: In this open randomized study, patients with CF received intravenous tobramycin at 8:00 or 22:00 hours. Pharmacokinetic and kidney function parameters were compared between the 2 groups. RESULTS: Twenty-five patients were included. The mean weight-corrected clearances of tobramycin were 1.46 versus 1.43 mL/h*kg (P = 0.50) and mean volumes of distribution were 0.25 versus 0.27 L/kg (P = 0.54) for the 8:00 and 22:00 groups, respectively. In addition, no significant differences were detected in changes in estimated clearances of creatinine or tobramycin on day 1 and day 8 in the 8:00 or 22:00 group, indicating that there was no decline in clearance over time. At day 8 of therapy, the increase in serum blood urea nitrogen in the 22:00 group was significantly higher than that in the 8:00 group (1.8 versus 0.2 mmol/L, P = 0.015). CONCLUSIONS: The time of administration (8:00 versus 22:00) did not affect tobramycin pharmacokinetics in the adult CF population studied. The increase in serum blood urea nitrogen in the 22:00 group requires further investigation.

Intratympanic Treatment in Menière's Disease, Efficacy of Aminoglycosides Versus Corticosteroids in Comparison Studies: A Systematic Review.

OBJECTIVE: To compare the functional outcomes and complications of intratympanic gentamicin (ITG) versus intratympanic corticosteroids (ITC) in Menière's disease. DATA SOURCES: An electronic search was conducted in the Cochrane Library, PubMed, and Embase databases on February 3, 2019. Articles written in English, Dutch, German, French, or Turkish language were included. STUDY SELECTION: Study inclusion criteria were: 1) patients diagnosed with definite Menière's disease according to the criteria of the American Academy of Otolaryngology-Head and Neck Surgery, 2) treated with ITG or ITC in a comparison study, and 3) reported subjective and objective outcomes concerning Menière's disease. DATA EXTRACTION: The quality of eligible studies was assessed according to an adjusted version of the Cochrane Risk of Bias tool. The extracted data were study characteristics (study design, publication year, and number of relevant patients), patient's characteristics (sex and age), disease characteristics (uni or bilateral and duration of Menière's disease), treatment protocol, and different therapeutic outcomes (vertigo, tinnitus, aural fullness, and hearing loss). DATA SYNTHESIS: A total of eight articles were included for data extraction and analysis. For subjective outcomes, ITG was slightly favored compared to intratympanic corticosteroids. This was significant only in three studies (p < 0.05). For objective outcomes and complications, no significant differences were seen. CONCLUSIONS: The result of this systematic review shows some benefit of ITG over ITC for subjective outcomes and no difference regarding objective outcomes or complication rate. However, this superiority of ITG is rather weak. Both interventions can be effectively and safely used in controlling Menière's disease in acute situations.