Vestibular Toxicity Research Articles

P23-04 In vivo investigation of the vestibular toxicity of industrial aromatic solvents in rats

P23-04 In vivo investigation of the vestibular toxicity of industrial aromatic solvents in rats

Effects of Cross-linked Hyaluronic Acid in a Rat Model of Vestibular and Cochlear Toxicity.

To investigate the effects of cross-linked hyaluronic acid (CLHA) in an experimental model of vestibulotoxicity and cochleotoxicity. Twenty-eight female Wistar albino rats (200-250 g) were divided into four groups. Group A received 0.06 mL of 13.33 mg/mL gentamicin, Group B received 0.06 mL of CLHA, Group C received 0.03 mL of 26.66 mg/mL gentamicin and 0.03 mL CLHA, and Group D received 0.06 mL of 0.09% saline. All groups underwent auditory brainstem response testing at 4-32 kHz, signal-to-noise ratio of distortion product otoacoustic emission measurements at 1.5-8 kHz and vestibular tests on days 0,1,7,10. The rats were sacrificed, and their labyrinths were histologically assessed and scored. The hearing thresholds of Groups A and C were similar and significantly higher than those of the other groups at all frequencies, beginning from day 1. The vestibular and histological scores of Groups A and C were similar and significantly higher than those of the other groups from day 1. The audiological results, vestibular scores, and histological scores of Groups B and D were similar, except for a temporary middle ear effusion and hearing threshold shift in Group B. No significant deterioration was observed in the audiological, vestibular, and histological analyses of Groups B and D. That both Group A and Group C similarly showed worsening audiological, vestibular, and histological tests suggests that CLHA did not alter the pharmacokinetics and histologic results of gentamicin.

A Prospective Study on the Vestibular Toxicity of Gentamicin in a Clinical Setting.

Gentamicin is a widely used aminoglycoside with ototoxicity as a known adverse effect. Because of the difficulty in clinical recognition, the prevalence of gentamicin ototoxicity in practice is thought to be higher than reported. This study aimed to prospectively assess the effect of gentamicin on vestibular function and whether ototoxicity is underrecognized. Single-center, prospective, nonblinded trial. Inpatient tertiary hospital setting followed by vestibular outpatient clinic review. Forty-eight patients undergoing a urologic procedure were recruited, with 24 and 17 patients having one or two follow-up tests, respectively, after initial gentamicin administration. Single dose of gentamicin during a urologic procedure. Gains for the vestibuloocular reflex (VOR) were measured using the video head impulse test before receiving gentamicin and at two other timepoints after gentamicin. The gains in VOR were then compared with previous testing sessions to determine if there was a deterioration after gentamicin use. Before receiving gentamicin, the gains for horizontal VOR were measured for 48 patients. The gains were measured a second time for 24 patients at varying durations postgentamicin (1-56 d) and a third time for 17 patients (14-152 d) postgentamicin. The mean VOR gain for Timepoints 1, 2, and 3 were 0.72 ± 0.13, 0.75 ± 0.16, and 0.79 ± 0.18, respectively. Linear-mixed model with repeated-measure analysis revealed no significant difference in VOR gain between Timepoints 1 and 2 ( p = 0.19). There was no significant effect observed on mean VOR gain decrement after a single dose of gentamicin.

Vestibular dose correlates with dizziness after radiosurgery for the treatment of vestibular schwannoma

BackgroundStereotactic radiosurgery (SRS) has been recognized as a first-line treatment option for small to moderate sized vestibular schwannoma (VS). Our aim is to evaluate the impact of SRS doses and other patient and disease characteristics on vestibular function in patients with VS.MethodsData on VS patients treated with single-fraction SRS to 12 Gy were retrospectively reviewed. No dose constraints were given to the vestibule during optimization in treatment planning. Patient and tumor characteristics, pre- and post-SRS vestibular examination results and patient-reported dizziness were assessed from patient records.ResultsFifty-three patients were analyzed. Median follow-up was 32 months (range, 6–79). The median minimum, mean and maximum vestibular doses were 2.6 ± 1.6 Gy, 6.7 ± 2.8 Gy, and 11 ± 3.6 Gy, respectively. On univariate analysis, Koos grade (p = 0.04; OR: 3.45; 95% CI 1.01–11.81), tumor volume (median 6.1 cm3; range, 0.8–38; p = 0.01; OR: 4.85; 95% CI 1.43–16.49), presence of pre-SRS dizziness (p = 0.02; OR: 3.98; 95% CI 1.19–13.24) and minimum vestibular dose (p = 0.033; OR: 1.55; 95% CI 1.03–2.32) showed a significant association with patient-reported dizziness. On multivariate analysis, minimum vestibular dose remained significant (p = 0.02; OR: 1.75; 95% CI 1.05–2.89). Patients with improved caloric function had received significantly lower mean (1.5 ± 0.7 Gy, p = 0.01) and maximum doses (4 ± 1.5 Gy, p = 0.01) to the vestibule.ConclusionsOur results reveal that 5 Gy and above minimum vestibular doses significantly worsened dizziness. Additionally, mean and maximum doses received by the vestibule were significantly lower in patients who had improved caloric function. Further investigations are needed to determine dose-volume parameters and their effects on vestibular toxicity.

An in vitro model to assess the peripheral vestibulotoxicity of aromatic solvents

Epidemiological and experimental studies indicate that a number of aromatic solvents widely used in the industry can affect hearing and balance following chronic exposure. Animal studies demonstrated that long-term exposure to aromatic solvents directly damages the auditory receptor within the inner ear: the cochlea. However, no information is available on their effect on the vestibular receptor, which shares many structural features with the cochlea and is also localized in inner ear. The aim of this study was to use an in vitro approach to assess and compare the vestibular toxicity of different aromatic solvents (toluene, ethylbenzene, styrene and ortho-, meta-, para-xylene), all of which have well known cochleotoxic properties. We used a three-dimensional culture model of rat utricles (“cysts”) with preserved functional sensory and secretory epithelia, and containing a potassium-rich (K+) endolymph-like fluid for this study. Variations in K+ concentrations in this model were considered as biomarkers of toxicity of the substances tested. After 72 h exposure, o-xylene, ethylbenzene and styrene decreased the K+ concentration by 78 %, 37 % and 28 %, respectively. O- xylene and styrene both caused histopathological alterations in secretory and sensory epithelial areas after 72 h exposure, whereas no anomalies were observed in ethylbenzene-exposed samples.These in vitro results suggest that some widely used aromatic solvents might have vestibulotoxic properties (o-xylene, styrene and ethylbenzene), whereas others may not (p-xylene, m-xylene, toluene). Our results also indicate that variations in endolymphatic K+ concentration may be a more sensitive marker of vestibular toxicity than histopathological events. Finally, this study suggests that cochleotoxic solvents might not be necessarily vestibulotoxic, and vice versa.

Ototoxicity after chemoradiotherapy for nasopharyngeal carcinoma

: Successful nasopharyngeal carcinoma (NPC) treatment increases the survival rate and increases the late toxicity of chemoradiotherapy in survivors. Ototoxicity is the most common severe late sequelae after treatment. Both cochlear toxicity and vestibular toxicity have a significant negative impact on the quality of life. The hearing loss may begin as early as after the completion of radiotherapy (RT). Determination of rate of hearing loss after treatment completion is varied, depending on many factors, such as ototoxicity grading scales, follow-up period, treatment modalities, RT techniques. Prevalence of vestibular toxicity and tinnitus are also varied, depending on subjective or objective findings, types of vestibular function tests, or questionnaire. Successful ototoxicity monitoring involves the effort of healthcare professional teamwork. Permanent damage to the hearing and balance system can be decreased by early identification and promptly appropriate actions. Currently, there is no otoprotective agent recommended routinely to prevent ototoxicity after chemotherapy or radiation therapy. Rehabilitation options may improve the symptom disability but not restore the damage. The patient care team should be aware of the early identification of the ototoxicity. Effective tools for monitoring reveal abnormalities before the presence of audiovestibular symptoms. Once the ototoxicity was detected, the patient care team should consider starting appropriate actions to prevent progression and permanent damage. This article presents factors associated with an increased risk of hearing loss after treatment, ototoxicity grading scales, and tools of ototoxicity monitoring.

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

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. 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 30days 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. 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±96mg*hr/L, 29.9±12.7mg/L, and 0.35±0.66mg/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 . 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.

On-Demand and Low Dose Intratympanic Gentamicin for Meniere's Disease: A Customized Approach.

To evaluate the efficacy of on demand and low dose intratympanic gentamicin (ITG) in patients with intractable Meniere's disease (MD). Clinical chart review. Secondary care center. Subjects with MD who failed conventional treatment and underwent on demand ITG infiltration from June 2013 to December 2018. 0.4 to 0.5 ml of buffered gentamicin were administered through an intratympanic route. A total of 5 mg in case of low dose and 20 mg as a standard dose. Vertigo control, Meniere's Disease Functional Level Scale (MDFLS), Dizziness Handicap Inventory (DHI), and pure tone audiometry pre and posttreatment. Thirty-one patients, 16 women and 15 men with a mean age of 52.81 (22-79) years were included. The number of ITG injections ranged from 1 to 7, with a mean of 2.52 applications per patient. Mean interval between doses was 212.15 (21-1442) days. Average follow-up was 24.03 months. An improvement on MDFLS was seen on 77.4% (n = 24) patients. DHI score improved after gentamicin treatment (mean 55.23 versus 24.06, p ≤ 0.001). Thirty patients (96.8%) reached complete or substantial vertigo control. Only one patient did not achieve control. Hearing was preserved in 43.5% (n = 10) of analyzed audiograms, whereas 17.4% (n = 4) developed hearing loss greater than 20 dB, which was not statistically significant (p = 0.099). In our study, on demand and low dose ITG was effective for vertigo control in patients with intractable MD. Individualized therapy is recommended in all patients to minimize vestibular and cochlear toxicity.

Coding and Reimbursement for Cochleotoxicity and Vestibulotoxicity Services.

Because of the ICD-10 disease coding system transition that occurred in the United States in 2015, coding and billing for services on behalf of patients who experience cochlear and/or vestibular toxicity may be daunting and misunderstood. Coding and billing for any audiology procedure can be compelling; choosing the appropriate codes for these specific patients is critical not only for payment for services rendered but also for the national and global implications, given their utilization is tracked for mortality and morbidity statistics and potential policies.

Vestibular Toxicity: Causes, Evaluation Protocols, Intervention, and Management.

The loss of vestibular function, typically bilateral, due to chemical solvents and pharmacological agents is not rare and has been investigated and reported for many years. The successful treatment of bacterial infections and sepsis with IV antibiotics and cancer-fighting drugs like cisplatin makes the decision to use these life-saving drugs less of a debate, despite their potential deleterious effect on balance and equilibrium. The purpose of this article is to provide the reader with an overview of the more common substances found in industry and medicine which may decrease or permanently destroy peripheral and/or central vestibular function. A review of bedside and clinical evaluation protocols will be discussed as well as best practice intervention with balance retraining therapy. Finally, the role of the audiologist and opportunities for participation in an interdisciplinary approach to evaluation and management will be presented.

Vestibulotoxicity Associated With Platinum-Based Chemotherapy in Survivors of Cancer: A Scoping Review.

Background: Cochleotoxicity following the treatment with platinum-based chemotherapy is well documented. The potential for vestibulotoxicity is still unclear. This scoping review examined the extent of current research literature, summarized research findings and identified research gaps regarding vestibular-related adverse effects associated with platinum-based chemotherapy in survivors of cancer.Methods: Inclusion criteria followed the PICO principles: Participants, adult, and pediatric cancer patients of any cancer type; Intervention, platinum-based chemotherapy (such as cisplatin, carboplatin, and oxaliplatin); Control, none or any; Outcomes, vestibular-related adverse effects. English language articles published since 1978 were retrieved. Seventy-five eligible studies were identified from a systematic literature search, and relevant data were charted, collated, and summarized.Results: Testing for vestibulotoxicity predominately featured functional evaluation of the horizontal semicircular canal using the caloric and rotational tests. The rate of abnormal vestibular function test results after chemotherapy administration varied from 0 to 50%. The results of objective testing did not always correspond to patient symptoms. There is tentative support for patients with pre-existing loss of vestibular function to be more likely to experience vestibular toxicity after dosing with cisplatin.Conclusions: A number of studies reported significant evidence of vestibular toxicities associated with platinum-based chemotherapy, especially cisplatin. This scoping review emphasizes that vestibular toxicity needs more attention and comprehensive evaluation. Specifically, studies that analyse cumulative dose of platinum-based chemotherapy, affected sites of lesion in vestibular end organs, and the correlation and temporal patterns of cochlear and vestibular toxicity are needed.

Physiological assesment of vestibular function and toxicity in humans and animals

Physiological methods that can be similarly recorded in humans and animals have a major role in sensory toxicology, as they provide a bridge between human sensory perception data and the molecular and cellular data obtained in animal studies. Vestibular toxicity research lags well behind other sensory systems in many aspects, including the availability of methods for functional assessment in animals that could be robustly translated to human significance. Here we review the methods available for the assessment of vestibular function in both humans and laboratory animals, with an emphasis on their similarity or divergence, to highlight their potential utility for the predictive assessment of vestibular toxicity.

Treatment of peripheral vestibular dysfunction using photobiomodulation.

Gentamicin, which is still used in modern medicine, is a known vestibular toxic agent, and various degrees of balance problems have been observed after exposure to this pharmacologic agent. Photobiomodulation is a candidate therapy for vertigo due to its ability to reach deep inner ear organs such as the cochlea. Previous reports have suggested that photobiomodulation can improve hearing and cochlea function. However, few studies have examined the effect of photobiomodulation on balance dysfunction. We used a rat model to mimic human vestibulopathy resulting from gentamicin treatment and evaluated the effect of photobiomodulation on vestibular toxicity. Slow harmonic acceleration (SHA) rotating platform testing was used for functional evaluation and both qualitative and quantitative epifluorescence analyses of cupula histopathology were performed. Animals were divided into gentamicin only and gentamicin plus laser treatment groups. Laser treatment was applied to one ear, and function and histopathology were evaluated in both ears. Decreased function was observed in both ears after gentamicin treatment, demonstrated by low gain and no SHA asymmetry. Laser treatment minimized the damage resulting from gentamicin treatment as shown by SHA asymmetry and recovered gain in the treated ear. Histology results reflected the functional results, showing increased hair cell density and epifluorescence intensity in laser-treated cupulae.

Dose-dependent cochlear and vestibular toxicity of trans-tympanic cisplatin in the rat

In vivo studies are needed to study cisplatin ototoxicity and to evaluate candidate protective treatments. Rats and mice are the preferred species for toxicological and pharmacological pre-clinical research, but systemic administration of cisplatin causes high morbidity in these species. We hypothesized that trans-tympanic administration of cisplatin would provide a good model for studying its auditory and vestibular toxicity in the rat. Cisplatin was administered by the trans-tympanic route in one ear (50μl, 0.5–2mg/ml) of rats of both sexes and two different strains. Cochlear toxicity was corroborated by histological means. Vestibular toxicity was demonstrated by behavioral and histological analysis. Cisplatin concentrations were assessed in inner ear after trans-tympanic and i.v. administration. In all experiments, no lethality and only scant body weight loss were recorded. Cisplatin caused dose-dependent cochlear toxicity, as demonstrated by hair cell counts in the apical and middle turns of the cochlea, and vestibular toxicity, as demonstrated by behavioral analysis and hair cell counts in utricles. High concentrations of cisplatin were found in the inner ear after trans-tympanic administration. In comparison, i.v. administration resulted in lower inner ear concentrations. We conclude that trans-tympanic administration provides an easy, reproducible and safe model to study the cochlear and vestibular toxicity of cisplatin in the rat. This route of exposure may be useful to address particular questions on cisplatin induced ototoxicity and to test candidate protective treatments.

Septic Olecranon Bursitis caused by Non-tuberculous Mycobacteria, the Mayo Clinic Experience

BackgroundNon-tuberculous mycobacteria (NTM) are a rare cause of septic olecranon bursitis (SOB) with few cases reported in the literature. Here we describe clinical outcomes and treatment modalities of 6 patients with SOB due to NTM infections.MethodsThis is a retrospective chart review of all adult patients treated at Mayo Clinic between January 2000 and June 2015 with SOB due to NTM.ResultsWe had 6 patients in our series. Patient characteristics are in Table 1. All patients receiving antibiotics (n = 5) required ≥12 weeks of therapy. 80% experienced severe side effects requiring either a change in regimen (n = 3) or discontinuation (n = 1). The most serious side effect was vestibular toxicity and hearing loss related to tobramycin usage. One patient did not receive antibiotics after surgical debridement and had resolution. Of the 5 patients who required debridement, none experienced complications from surgery. Anconeus muscle flap was required in 1 patient to avoid wound healing issues. All 6 patients achieved resolution of infection at the bursa, but relapse with the same organism at other sites was seen in 2 immunocompromised hosts.ConclusionSOB due to NTM infections are uncommon and challenging to treat. In our institution, Mycobacterium chelonae was the most frequently implicated organism. Proper microbiologic diagnosis is often delayed. These typically require extensive debridement and prolonged combination antimicrobial therapy. In some instances, more conservative measures may be considered. Although side effects are common, this treatment modality seems to produce clinical improvement. Relapse may be associated with immunosuppression and may occur at different sites.Table 1.Characteristics of 6 patients with SOB due to NTMNo.Sex Male5 Female1Immunosuppressed Poorly controlled IDDM1 Solid Organ Transplant1 Methotrexate and Corticosteroids1Bursa tissue culture growth M. chelonae 4 M. avium complex 1 M. gordonae and fortuitum 1Received antibiotics5Toxicity requiring change or stoppage4Underwent debridement5Complications related to debridement0Anconeous flap coverage1Resolution Surgery and antibiotics5 Relapse at remote site—no./total no.2/5 Surgery only1 Relapse—no./total no.0/1Disclosures All authors: No reported disclosures.

Strain and Sex Differences in the Vestibular and Systemic Toxicity of 3,3′-Iminodipropionitrile in Mice

The nitrile 3,3'-iminodipropionitrile (IDPN) causes a loss of hair cells in the vestibular epithelium of the inner ear in several species of both mammals and nonmammals. It is of interest as a model compound in ototoxicity and vestibular regeneration research, but its effects on the mouse, including the potential relevance of strain and sex differences for susceptibility, have not yet been thoroughly characterized. In this study, we compared the vestibular toxicity of IDPN in dose-response studies (0, 8, 12, 16, and 24 mmol/kg IDPN p.o.) in males and females of 2 different mouse strains (RjOrl:Swiss/CD-1 and 129S1/SvImJ). 3,3'-Iminodipropionitrile caused a dose-dependent loss of vestibular function in all sex and strain groups, as assessed by a specific battery of behavioral tests. However, large differences in systemic toxicity were recorded, with high systemic toxicity in 129S1 mice of both sexes compared to limited effects on the Swiss mice. Both male and female Swiss mice showed a marked increase of hindlimb stride width after exposure. The Swiss, but not the 129S1, mice treated with IDPN showed hyperactivity in the open field. The dose-response relationships in the behavioral effects were matched by the extent of hair cell loss assessed by scanning electron microscopy. Altogether, the data demonstrated prominent strain-dependent differences in the systemic toxicity of IDPN between 129S1 and Swiss mice, in contrast to no differences between the strains and small differences between the sexes in its vestibular toxicity. These results support the use of Swiss mice exposed to IDPN as a mouse lesion model for research in vestibular therapy and regeneration.

15th Annual Meeting of the Safety Pharmacology Society: Focus on traditional sensory systems

IntroductionThis report summarizes and comments key talks on the five traditional senses (ear, vestibular system, vision, taste, olfaction, and touch) which were delivered during the 2015 Annual Meeting of the Safety Pharmacology (SP) Society. Areas coveredThe functional observational battery (FOB) can detect major candidate drug liabilities only on ear, touch and vision. Anatomy, physiology, pharmacology, and pathology notions on each sensory system introduce speaker talks. Techniques for evaluating drug effects on hearing functions are reviewed. Nonclinical approaches to assess vestibular toxicity leading to balance deficits are presented. Retinal explants studied with multielectrode arrays allow the identification of drug liability sites on the retina. Routinely performed Safety Pharmacology assays are not powered to address candidate drug-induced disturbances on taste and smell. This weakness needs correction since unintended pharmacological impairment of these sensorial functions may have serious health consequences. Neuropathy produced by chemotherapeutic agents may cause multiple sensorial perception distortions. ConclusionsSafety Pharmacology studies should ensure the safety of any candidate drug on the five sensorial systems.

Amikacin use and therapeutic drug monitoring in adults: do dose regimens and drug exposures affect either outcome or adverse events? A systematic review.

The objectives of this study were to identify the amikacin dosage regimens and drug concentrations consistent with good outcomes and to determine the drug exposures related to nephrotoxicity and ototoxicity. A literature review was conducted in Medline, EMBASE and the Cochrane Central Register of Controlled Trials. Full journal articles reporting randomized controlled trials, controlled clinical trials, interrupted time series trials, and controlled before and after studies involving amikacin therapeutic drug monitoring (TDM) and dose adjustment were considered for inclusion. Seventeen studies for inclusion were identified, comprising 1677 participants. Amikacin doses ranged from 11 to 15 mg/kg/day with 13 studies using 15 mg/kg/day. Studies were generally designed to compare different aminoglycosides rather than to assess concentration-effect relationships. Only 11 papers presented data on target concentrations, rate of clinical cure and toxicity. Target peak concentrations ranged from 15 to 40 mg/L and target troughs were typically <10 or <5 mg/L. It was not clear whether these targets were achieved. Measured peaks averaged 28 mg/L for twice-daily dosing and 40-45 mg/L for once-daily dosing; troughs averaged 5 and 1-2 mg/L, respectively. Fifteen of the included studies reported rates of nephrotoxicity; auditory and vestibular toxicities were reported in 12 and 8 studies. This systematic review found little published evidence to support an optimal dosage regimen or TDM targets for amikacin therapy. The use of alternative approaches, such as consensus opinion and a review of current practice, will be required to develop guidelines to maximize therapeutic outcomes and minimize toxicity with amikacin.

Mania following use of ibogaine: A case series

Ibogaine is a naturally occurring hallucinogen with postulated anti-addictive qualities. While illegal domestically, a growing number of individuals have sought it out for treatment of opiate dependence, primarily in poorly regulated overseas clinics. Existing serious adverse events include cardiac and vestibular toxicity, though ours is the first report of mania stemming from its use. To report on a case series of psychiatric emergency room patients whose unregulated use of ibogaine resulted in mania in three patients with no prior diagnosis of bipolar illness. Review and summarize charts of three cases. Relevant literature was also reviewed for discussion. Two cases of reported ibogaine ingestion for self-treatment of addictions, and one for psycho-spiritual experimentation resulted in symptoms consistent with mania. No prior reports of mania were found in the literature, and the literature suggests growing popularity of ibogaine's use. The three cases presented demonstrate a temporal association between ibogaine ingestion and subsequent development of mania. In light of these cases, clinicians faced with a new onset mania may benefit from careful substance use and treatment history, specifically regarding opiates. In the vulnerable and often desperate addiction population, in particular, the number of patients seeking this treatment appears to be growing. We advise clinicians to be prepared for discussing the safety, efficacy, and paucity of good data regarding ibogaine with patients who may be considering its use. (Am J Addict 2015;24:203-205).

Aminoglycosides

Aminoglycoside antibiotics (AGAs) have proved an invaluable part of our antimicrobial armamentarium since their introduction into practice over 60 years ago. This review summarizes recent developments, defining their role in the context of the current global epidemic of antibiotic resistance, raising awareness of their toxicity profile, and highlighting current data on their utility as synergistic agents. Clinicians are facing an unprecedented threat from antibiotic resistance, resulting in an increased reliance on the addition of an AGA to provide adequate empirical cover in cases of severe sepsis. Concurrently, an increased awareness of the potential for severe disability, particularly from vestibular toxicity, has restrained directed therapy of AGAs to situations in which there are no appropriate alternatives. Their role as synergistic agents in the treatment of enterococcal endocarditis is currently under reevaluation, and new data have emerged on combination therapy for Pseudomonas aeruginosa bacteremia. AGAs are themselves coming under increasing threat from resistance, predominately from aminoglycoside modifying enzymes (mediating selective resistance) and 16S rRNA methyltransferases (conferring class-wide resistance). New agents and the development of alternate ways to circumvent resistance are likely to have important roles in future clinical care. Aminoglycosides retain an invaluable but well defined role, and will remain important agents into the foreseeable future.