Gentamicin tympanoclysis: effects on the labyrinthine sensory cells

OBJECTIVES: The objective of the study was to determine whether a selective vestibular hair cell toxicity with sparing of the cochlear hair cells could be achieved by infusing different concentrations of gentamicin into the middle ears of adult cats. STUDY DESIGN: Prospective experimental animal study treating only the left ear of each cat, the right ear serving as individual control. METHODS: Gentamicin solution at concentrations of either 30 or 3 mg/mL was infused daily into the left middle ear of adult cats until overt ataxia occurred. After 1 month or 6 months, each cat was killed and its temporal bones prepared for optical microscopy. RESULTS: Animals treated with 30 mg/mL gentamicin until ataxic required a median of five daily doses. These animals had clear-cut cochlear basal turn hair cell losses accompanying toxic lesions in the utricle and cristae. In contrast, animals treated with 3 mg/mL gentamicin until ataxic required an average of 19 daily doses. These animals had lesions restricted to the utricle and cristae with sparing of the cochlea hair cells. Animals that failed to develop ataxia manifested neither lesions of the cochlear nor vestibular hair cells. CONCLUSION: Gentamicin tympanoclysis in the cat animal model, using a dilute solution and continued once daily until clinical ataxia occurs, is capable of producing selective vestibular hair cell toxicity while sparing cochlea hair cells.     

Neomycin-Induced Hair Cell Death and Rapid Regeneration in the Lateral Line of Zebrafish (<Emphasis Type="Italic">Danio rerio</Emphasis>)

Mechanoreceptive hair cells are extremely sensitive to aminoglycoside antibiotics, including neomycin. Hair cell survival was assessed in larval wild-type zebrafish lateral line neuromasts 4 h after initial exposure to a range of neomycin concentrations for 1 h. Each of the lateral line neuromasts was scored in live fish for the presence or absence of hair cells using the fluorescent vital dye DASPEI to selectively label hair cells. All neuromasts were devoid of DASPEI-labeled hair cells 4 h after 500 µM neomycin exposure. Vital DASPEI staining was proportional to the number of hair cells per neuromast identified in fixed larvae using immunocytochemistry for acetylated tubulin and phalloidin labeling. The time course of hair cell regeneration in the lateral line neuromasts was also analyzed following neomycin-induced damage. Regenerated hair cells were first observed using live DASPEI staining 12 and 24 h following neomycin treatment. The potential role of proliferation in regenerating hair cells was analyzed. A 1 h pulse-fix protocol using bromodeoxyuridine (BrdU) incorporation was used to identify S-phase cells in neuromasts. BrdU incorporation in neomycin-damaged neuromasts did not differ from control neuromasts 4 h after drug exposure but was dramatically upregulated after 12 h. The proliferative cells identified during a 1 h period at 12 h after neomycin treatment were able to give rise to new hair cells by 24–48 h after drug treatment. The results presented here provide a standardized preparation for studying and identifying genes that influence vertebrate hair cell death, survival, and regeneration following ototoxic insults.     

Sensitization to chloramphenicol; a persistent problem

A surprisingly high incidence of chloramphenicol sensitization is reported in 8 patients with periocular or periauricular dermatitis. In 6 of them, relevance was established to the use of topical chloramphenicol. Concurrent sensitization to polymyxin B sulphate was found in 2. The findings stress the fact that chloramphenicol allergy remains a persistent problem.     

Intravenous aminoglycoside usage and monitoring of patients with cystic fibrosis in Australia. What's new?

Background: The aim of this study was to determine the current situation regarding aminoglycoside use and monitoring in patients with cystic fibrosis (CF) throughout Australia.
Methods: A questionnaire was sent out to all CF units. Information gathered included patient characteristics, aminoglycoside use, dosing, therapeutic drug-monitoring methods, toxicity monitoring and incidence of occurrence.
Results: Responses were obtained from 27 of the 28 units identified. Tobramycin was the aminoglycoside of choice. All but three centres were using once-daily dosing for aminoglycoside administration. Initial dosing in tobramycin-naïve patients was based on bodyweight (range 7–12 mg/kg). Patients being readmitted were mainly prescribed the dose that they had received on their previous admission. All units gave i.v. doses by infusion with five units using bolus dosing as well. The method of therapeutic drug monitoring varied greatly. A computer programme was used by 15 units. Toxicity monitoring usually coincided with therapeutic drug monitoring. Nephrotoxicity was reported as having occurred in 13 units and ototoxicity in 15 units. The highest incidence of toxicity was ototoxicity in 20% of patients in one CF unit.
Conclusion: Aminoglycoside dosing regimens have changed since the last survey was carried out in 1999. There has been an increase in the use of once-daily dosing from 54 to 88% of units. The reporting of both ototoxicity and renal toxicity has also increased (from 27 to 75% and from 19 to 65%, respectively). Standardization of management protocols for antibiotic use and patient monitoring may help reduce the risk of cumulative toxicity to aminoglycosides in CF patients.     

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

IntroductionAntimicrobial resistance is one of the biggest threats to public health systems worldwide, and aminoglycosides are key drugs for treating drug-resistant infections. Because of the nephrotoxicity of aminoglycosides, therapeutic drug monitoring is recommended, but few studies of the target trough concentration (Cmin) have been reported. To address the problem, we performed a meta-analysis to confirm the target Cmin of aminoglycosides for minimizing the risk of nephrotoxicity.MethodsWe conducted a literature search using MEDLINE, the Cochrane Library, and Ichushi-Web. In the meta-analysis, nephrotoxicity was compared between the Cmin ≥2 mg/L and Cmin <2 mg/L groups for gentamicin and between the Cmin ≥10 mg/L and Cmin <10 mg/L groups for amikacin.ResultsNo randomized controlled trials were reported for any of the drugs. Five observational studies involving 615 patients were reported for gentamicin, and two observational studies involving 159 patients were identified for amikacin. For gentamicin, Cmin <2 mg/L was linked to a significantly lower rate of nephrotoxicity than Cmin ≥2 mg/L (odds ratio [OR] = 0.22, 95% confidence interval [CI] = 0.12–0.40). For amikacin, Cmin <10 mg/L was associated with a significantly lower rate of nephrotoxicity than Cmin ≥10 mg/L (OR = 0.05, 95% CI = 0.01–0.21).ConclusionsAlthough further well-controlled studies with a low risk of bias are needed, the current meta-analysis demonstrated that Cmin <2 mg/L and Cmin <10 mg/L may reduce the risk of nephrotoxicity linked to gentamicin and amikacin, respectively.     

Aminoglycoside usage and monitoring in a Saudi Arabian teaching hospital: a ten-year laboratory audit

BACKGROUND AND OBJECTIVE: In 1989, a therapeutic drug monitoring service was established in Assir Central Hospital, Abha, Saudi Arabia, by the Department of Clinical Pharmacology and Therapeutics of the College of Medicine, King Saud University Abha Branch (now King Khalid University). We report a 10-year follow-up of the results of monitoring the commonly used aminoglycosides (amikacin, gentamycin and tobramycin) obtained from our adult patients on first monitoring. METHOD: Two educational seminars for doctors and nurses were conducted 6 months before the initiation of this study. Drug assay requests were made on specially designed forms. Drug dosages were determined by the attending physicians. Samples for peak and trough drug level determinations were drawn after the fourth dose. The results of first time monitoring were sent to the wards with appropriate comments for dosage modifications where indicated. RESULTS: The results for 2022 patients were analysed. Of these, 929, 899 and 194 were for amikacin, gentamycin and tobramycin, respectively. Therapeutic trough concentrations were 71.2%, 28.3% and 28.3% of patients on amikacin, gentamycin and tobramycin, respectively. A total of 8.8%, 17.6% and 11.9% had trough concentrations considered toxic for amikacin, gentamycin and tobramycin, respectively. Peak therapeutic concentrations were achieved in 31.6%, 42.3% and 39.7% of patients on amikacin, gentamycin and tobramycin. A total of 53.3% of patients on amikacin, 50.3% on gentamycin and 57.2% on tobramycin had peak serum drug concentrations in the subtherapeutic range. Toxic concentrations were noticed mainly in patients aged over 60 years and in the critically ill in the intensive care, coronary care and bums units of the hospital. CONCLUSION: To be cost-effective, intensive therapeutic monitoring of aminoglycosides in adults should continue to be monitored mainly for the old and sick patients in critical care units to optimize patient management.     

New aminoglycoside antibiotics

Importance of the field: Nosocomial infections caused by multi-drug resistant (MDR) Gram-negative bacteria are on the increase, often with few or no therapeutic options for treatment. Historically, a successful approach to generate novel antibiotics has been the chemical modification of existing classes, addressing deficiencies such as resistance mechanisms, safety profile or pharmacokinetic parameters. Aminoglycosides (AGs) represent one of the five clinically-used classes (AGs, β-lactams, quinolones, tetracyclines and sulfonamides) with activity against Gram-negative bacteria.

Areas covered in this review: A summary of the AG patent literature between the beginning of 2005 and February 2010 with the main focus on novel AG analogs with potential for therapeutic activity against MDR Gram-negative pathogens.

What the reader will gain: Overview of the patent literature in the aminoglycoside field during the past 5 years including an assessment of the therapeutic potential for the derivatives described.

Take home message: A few companies and academic groups have recently reawakened the dormant field of AG antibiotics, successfully applying novel technologies. So far, this has yielded one clinical candidate, ACHN-490, currently undergoing a Phase II evaluation in complicated urinary tract infections.     

Hypersensitivity to inhaled TOBI following reaction to gentamicin

Cystic fibrosis (CF) is the most common autosomal-recessive disease in Caucasians. Colonization with Pseudomonas aeruginosa (P. aeruginosa) of the CF airways causes deterioration of pulmonary status. TOBI (Tobramycin solution for inhalation) is an inhaled antibiotic that can improve the pulmonary disease. We report on a 9-year old boy with CF who developed a rash following a course of IV gentamicin. The rash resolved after its discontinuation. However, the rash returned all over his body, with the start of inhalation of TOBI therapy. We desensitized the patient using escalating doses of inhaled TOBI. He tolerated the procedure well, and continues to be on TOBI 9 months after desensitization on a once-a-day regimen.     

Combination therapy for carbapenem-resistant Gram-negative bacteria

The emergence of resistant to carbapenems Gram-negative bacteria (CR GNB) has severely challenged antimicrobial therapy. Many CR GNB isolates are only susceptible to polymyxins; however, therapy with polymyxins and other potentially active antibiotics presents some drawbacks, which have discouraged their use in monotherapy. In this context, along with strong pre-clinical evidence of benefit in combining antimicrobials against CR GNB, the clinical use of combination therapy has been raised as an interesting strategy to overcome these potential limitations of a single agent. Polymyxins, tigecycline and even carbapenems are usually the cornerstone agents in combination schemes. Optimization of the probability to attain the pharmacokinetic/pharmacodynamic targets by both cornerstone drug and adjuvant drug is of paramount importance to achieve better clinical and microbiological outcomes. Clinical evidence of the major drugs utilized in combination schemes and how they should be prescribed considering pharmacokinetic/pharmacodynamic characteristics against CR GNB will be reviewed in this article.     

克雷伯属菌耐药元件检测及指标与样本聚类分析

目的探讨耐药克雷伯属菌获得性耐药相关基因和可移动遗传元件的关系以及与菌株间的亲缘关系。方法收集20株从患者标本中分离的耐药克雷伯属菌,用PCR法分析67种水平转移获得的β-内酰胺类、氨基糖苷类、喹诺酮类获得性耐药基因和12种接合性质粒、转座子、插入序列、整合子等可移动元件标志基因,再对检测结果作指标聚类分析(UPGMA法)和样本聚类分析(neighbour-joining法)。结果 20株耐药克雷伯属菌共检出6种β-内酰胺类、5种氨基糖苷类、4种喹诺酮类耐药基因和8种可移动遗传元件的遗传标志;指标聚类分析提示,KPC与ISKpn6高度相关联,SHV与IS26高度相关联;样本聚类分析显示,4号与18号株、15号与20号株分别为克隆传播。结论克雷伯属菌耐药元件检测可揭示菌株耐药的遗传学背景。