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

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

Gitelman-like Syndrome with Kanamycin Toxicity.

A 22 year-old lady with multi-drug-resistant pulmonary tuberculosis was on Kanamycin, Cycloserine, Ethionamide, Pyrazinamide and Moxifloxacin since more than two months. She presented with muscle cramps and carpopedal spasm. Investigation revealed hypokalemia and metabolic alkalosis. She also had hypomagnesemia, hypochloremia and hypocalciuria. Serum urea and creatinine levels were normal. Patient was treated with intravenous and oral potassium chloride. Kanamycin was stopped. Metabolic alkalosis and hypokalemia improved gradually over one month. Biochemical parameters were like Gitelman's syndrome but it reversed with stoppage of Kanamycin. Gitelman-like syndrome with Kanamycin toxicity has not been reported in literature previously.

Kanamycin inhibits daidzein metabolism and abilities of the metabolites to prevent bone loss in ovariectomized mice.

BACKGROUND: Daidzein is an isoflavone derived from soybeans that exerts preventive effects on bone loss in ovariectomized (OVX) animals. These effects have been correlated with increasing serum equol levels. In the present study, we investigated the effects of antibiotic intake on equol metabolism from daidzein, and the corresponding levels of bone loss in OVX mice. METHODS: Eight-week-old female ddY mice (n = 42) were either ovariectomized (OVX) or subjected to a sham operation (sham). OVX mice were then divided into six dietary subgroups: control diet (control), 0.3 % kanamycin diet (KN), 0.1 % daidzein diet (Dz), 0.1 % daidzein and 0.0375 % kanamycin diet (Dz+KN3.75), 0.1 % daidzein and 0.075 % kanamycin diet (Dz+KN7.5), and 0.1 % daidzein and 0.3 % kanamycin diet (Dz+KN30). The mice were fed their respective diets for 4 weeks. RESULTS: Uterine weight and femoral bone mineral density (BMD) were significantly lower in the OVX mice compared in the sham mice. No significant differences in uterine weight were observed among all OVX dietary subgroups. The Dz subgroup was found to exhibit higher plasma equol and O-desmethylangolensin (O-DMA) concentrations, as well as greater femoral BMD, compared to all other OVX subgroups. Furthermore, when compared to the Dz group, kanamycin intake decreased plasma equol and O-DMA concentrations, as well as femoral BMD in the OVX mice. CONCLUSIONS: These results suggest that kanamycin intake inhibited the conversion of daidzein to equol and O-DMA, blocking the preventive effects of daidzein on bone loss in OVX mice. Therefore, the bone-protective effects of daidzein intake may be predominantly associated with increased plasma concentrations of either equol or O-DMA.

Supporting cell characteristics in long-deafened aged mouse ears.

Significant sensory hair cell loss leads to irreversible hearing and balance deficits in humans and other mammals. Future therapeutic strategies to repair damaged mammalian auditory epithelium may involve inserting stem cells into the damaged epithelium, inducing non-sensory cells remaining in the epithelium to transdifferentiate into replacement hair cells via gene therapy, or applying growth factors. Little is currently known regarding the status and characteristics of the non-sensory cells that remain in the deafened auditory epithelium, yet this information is integral to the development of therapeutic treatments. A single high-dose injection of the aminoglycoside kanamycin coupled with a single injection of the loop diuretic furosemide was used to kill hair cells in adult mice, and the mice were examined 1 year after the drug insult. Outer hair cells are lost throughout the entire length of the cochlea and less than a third of the inner hair cells remain in the apical turn. Over 20% and 55% of apical organ of Corti support cells and spiral ganglion cells are lost, respectively. We examined the expression of several known support cell markers to investigate for possible support cell dedifferentiation in the damaged ears. The support cell markers investigated included the microtubule protein acetylated tubulin, the transcription factor Sox2, and the Notch signaling ligand Jagged1. Non-sensory epithelial cells remaining in the organ of Corti retain acetylated tubulin, Sox2 and Jagged1 expression, even when the epithelium has a monolayer-like appearance. These results suggest a lack of marked SC dedifferentiation in these aged and badly damaged ears.

2,3-Dihydroxybenzoic acid attenuates kanamycin-induced volume reduction in mouse utricular type I hair cells.

The aminoglycoside kanamycin is a commonly used antibiotic, but unfortunately it is oto- and nephrotoxic in large doses. The negative effects are thought to be due to the formation of free radicals which is why strong antioxidants and iron chelators like 2,3-dihydroxybenzoic acid (DHB) are of great interest. This study estimates cellular quantitative changes in the utricular macula of mice following systemic treatment with kanamycin alone or in combination with DHB. The animals were injected with either saline, kanamycin or kanamycin + DHB for 15 days and perfusion fixed three weeks after last injection. Total volume of the utricle, as well as total number of hair and supporting cells, were estimated on light microscopic sections. Total volume and mean volume of hair cell types I and II and supporting cells were estimated on digital transmission electron micrographs. Total volume of the utricular macula, hair cell type I and supporting cells decreased significantly in animals injected with kanamycin but not in animals co-treated with DHB. Hair and supporting cell numbers remained unchanged in all three groups. In conclusion, the kanamycin-induced volume reduction of type I hair cells was attenuated by DHB.

Tanshinone (Salviae miltiorrhizae extract) preparations attenuate aminoglycoside-induced free radical formation in vitro and ototoxicity in vivo.

Antioxidant therapy protects against aminoglycoside-induced ototoxicity in animal models. A clinically suitable antioxidant must not affect the therapeutic efficacy of aminoglycosides or exhibit any side effects of its own. In addition, the treatment should be inexpensive and convenient in order to be implemented in developing countries where the use of aminoglycosides is most common. Standardized Salviae miltiorrhizae extracts (Danshen) are used clinically in China and contain diterpene quinones and phenolic acids with antioxidant properties. We combined in vitro and in vivo approaches to investigate the effect of a clinically approved injectable Danshen solution on aminoglycoside-induced free radical generation and ototoxicity. In vitro, Danshen inhibited gentamicin-dependent lipid peroxidation (formation of conjugated dienes from arachidonic acid), as well as the gentamicin-catalyzed formation of superoxide (in a lucigenin-based chemiluminescence assay) and hydroxyl radicals (oxidation of N,N-dimethyl-p-nitrosoaniline). Danshen extracts were then administered to adult CBA mice receiving concurrent treatment with kanamycin (700 mg/kg of body weight twice daily for 15 days). Auditory threshold shifts induced by kanamycin (approximately 50 dB) were significantly attenuated. Danshen did not reduce the levels in serum or antibacterial efficacy of kanamycin. These results suggest that herbal medications may be a significantly underexplored source of antidotes for aminoglycoside ototoxicity. Such traditional medicines are widely used in many developing countries and could become an easily accepted and inexpensive protective therapy.

Efficacy and safety of sparfloxacin in combination with kanamycin and ethionamide in multidrug-resistant pulmonary tuberculosis patients: preliminary results.

SETTING: Department of tuberculosis and chest diseases of a tertiary referral tuberculosis institute in New Delhi, India. OBJECTIVE: To study the efficacy and safety of sparfloxacin, in combination with kanamycin (for the initial 3-4 months) and ethionamide, in multidrug-resistant (MDR) pulmonary tuberculosis patients. DESIGN: Prospective, uncontrolled study of nine patients with pulmonary tuberculosis who had received adequate anti-tuberculosis treatment with first-line drugs, including supervised category II treatment regimen as per World Health Organization guidelines for 5 months, and were still sputum smear acid-fast bacilli positive. It was planned to give them kanamycin (initial 3-4 months), ethionamide and sparfloxacin for 2 years. RESULTS: All nine patients achieved sputum conversion within 6 months. Seven patients converted within 3.5 months, two of these within 1 month. All patients reported improvement in clinical symptoms, and chest X-ray improved in seven patients. Four patients developed mild to moderate phototoxicity. Eight patients have completed treatment for an average of 19 months (range 15-24 months), and are still under follow-up. One patient defaulted after 7 months of treatment. CONCLUSIONS: In MDR-TB patients, sparfloxacin, along with other anti-tuberculosis drugs, appears to be effective and safe. Mild to moderate phototoxicity is common. However, the long-term results, including relapses, are still awaited.

An experimental study of electro-acupuncture on auditory impairment caused by kanamycin in guinea pigs.

Frequency following response (FFR) and auditory brain stem evoked potential response (ABR) were used to determine the auditory acuity in evaluating the effect of electro-acupuncture treatment of kanamycin-induced auditory impairment in guinea pigs. The succinate dehydrogenase (SDH) activity and morphological changes of the inner ear receptors were examined under the light and scanning electron microscope in cochlear spread preparations. The results showed that 1) electro-acupuncture was effective but no significant differences were found among the stimulating wave forms; 2) Tinggong (SI 19), Yifeng (SJ 17), Shenshu (UB 23), Sanyinjiao (Sp 6), Zhubin (K 9) and Waiguan (SJ 5) are all effective acupoints, especially the combination of Tinggong (SI 19), Sanyinjiao (Sp 6) and Zhubin (K 9) acupoints; 3) improvement in the cochlear function and excitability of the cortical and lower auditory center and increase of the mitochondrial SDH activity and energy supply in hair cells might contribute to the mechanism of the treatment.

[The impact of electrical stimulation on the functional status of cochlear nervous structures in cats with experimentally induced hearing disorders]. / Vliianie élektricheskoi stimuliatsii na funktsional'noe sostoianie nervnykh struktur ulitki koshki pri iskusstvennoi patologii slukha.

Effects of non-invasive electric stimulation on hearing were studied in cats with depressed periphery of the acoustic analyser. Experimental neurosensory hypoacusis was induced by large doses of canamycin (25-30 mg/kg). The hearing was assessed by short-latent stem and cortical long-latent evoked potentials (EP). Consideration was also given to changes in the amplitude of the wave V of short-latent EP in varying intensity of the sound stimulus. When deep suppression was reached, 8-day course of electric stimulation was started with registration of EP. It was found that canamycin elevates thresholds of identification of wave V of short-latent stem EP and thresholds of emergence of long-latent stem EP. The curve amplitude/intensity was also affected. The course of electrical stimulation returned the above parameters of the thresholds and the curve to the baseline levels. This is the evidence of therapeutic action of non-invasive electrical stimulation.

[Effects of poria cocos on ototoxicity induced by kanamycin in guinea-pigs].

In order to prevent the ototoxicity of kanamycin (KM), the effects of Poria Cocos (PC) on the ototoxicity induced by KM in guinea-pigs was observed by infusing the PC decoction into the guinea-pigs with comparing the difference in the general intoxicating symptom, prayer's reflex (PR) threshold, brainstem auditory evoked potentials (BAEPs) and the absence rate of outer hair cells in the first turn of cochlea. The results suggested that the ototoxicity of KM was retarded by giving the PC decoction. On 7th day after given KM, PR threshold of 4,6,8 kHz in the medicated group and control group were 4.7 +/- 1.5 dB, 5.7 +/- 2.4 dB, 2.7 +/- 1.2 dB and 10.5 +/- 3.2 dB, 12.1 +/- 3.7 dB, 8.5 +/- 2.7 dB respectively. BAEPs threshold on 13th day given KM raised 22.7 +/- 9.7 dB in the medicated group and 51.3 +/- 14.4 dB in control group. The absence rate of outer hair cells in first turn of cochlea were 39.4% and 67.4% respectively. The results suggested that PC might be antagonistic to the ototoxicity of KM in guinea-pigs.

[Treatment of ototoxic auditory damage caused by kanamycin with electroacupuncture at different acupoints].

We adopted the technique and method of integrating the morphology with function to select the effective acupoints for treatment of deafness. The results show that: (1) Tinggong (SI 19), Yifeng (TE 17), Waiguan (TE 5), Shenshu (UB 23), Sanyinjiao (SP 6) and Zhubin (KI 9) etc. are the effectine acupoints for the treatment of ototoxic auditory damage caused by drug, especially, the effect of Tinggong, Sanyinjiao and Zhubin etc, is much better; (2) electroacupuncture can promote audibility, improve SDH activity and relieve progressing injury of auditory hair cells, (3) FFR method has an important significance in the determination of ototoxic damage caused by drug.

[Comparison of vulnerability between avian and mammalian inner ears--electrophysiological and morphological studies].

In order to assess the vulnerability of the inner ear, auditory function and morphology of the inner ear were compared between adult budgerigars and adult guinea pigs. Budgerigars have been considered to have an excellent auditory-vocal system. Two experimental conditions were produced in each species; one by acoustic hyperstimulation (1500 Hz, 120 dBSPL) for 96 hours, the other by administration of kanamycin (200 mg/kg) for 7 weeks. Measurement of auditory evoked potentials (AEP) and observation of hair cells by electron microscopy were performed both immediately and 14 days after exposure. In the acoustic hyperstimulation experiment, AEPs of budgerigars showed less damage and better recovery than those of guinea pigs, probably because of morphological differences between the two species in hair and supporting cells. Electron microscopic observation on the budgerigars showed that a small part of the hair cell area was damaged and that regeneration of hair cells had occurred in this area 14 days after exposure. Such observations in guinea pigs revealed that outer hair cells had been damaged and replaced by supporting cells 14 days after exposure. In the kanamycin administration experiment, AEPs showed the same degree of damage and recovery in both species. This suggests that blood supply and drug transport to the inner ear are almost the same although the structure of the inner ear differs markedly between the two species. Electron microscopic observation did not show an apparent regeneration of hair cells 14 days after administration in the budgerigars. Guinea pigs had a tendency to show progressive damage of both auditory function and inner ear morphology even after the cessation of administration. Regeneration of hair cells in the budgerigar differed under both experimental conditions, suggesting that there is a difference in the mode of auditory disturbance between acoustic hyperstimulation and administration of kanamycin. In conclusion, resistance to acoustic hyperstimulation is higher in the avian inner ear than in the mammalian inner ear, while resistance to administration of kanamycin does not differ significantly between the two species.

The sensitive period and optimum dosage for induction of audiogenic seizure susceptibility by kanamycin in the Wistar rat.

The incidence and severity of audiogenic seizures in kanamycin (KM)-treated rat pups, from a Wistar strain which is inherently seizure-resistant, was analyzed as a function of (a) postnatal age at the time of KM injection (i.p.) and (b) KM dosage. The vigor of the pinna reflex response on postnatal day (PND) 28 was correlated with (a) age at the time of injection, (b) dosage and (c) individual audiogenic seizure severity scores on PND 28 or PND 32. The data indicate that PNDs 9-12 are the developmental period when the rat has its greatest sensitivity to induction of susceptibility to audiogenic seizures by KM. The pinna reflex data suggest that cochlear vulnerability to KM intoxication is also greatest during this period. The optimum dosage for the induction of susceptibility was 100 mg/kg X 4 days. Use of higher doses resulted in a reduction of both incidence and severity of audiogenic seizures. The pinna reflex generally exhibited a supranormal vigor in animals having the most severe seizures. The behavioral attributes of induced audiogenic seizures at postnatal ages of 28 and 32 days are described and discussed.

The aminoglycosides. Streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, sisomicin.

Despite their toxicity, the aminoglycosides remain useful and are often the first choice in the treatment of serious infections due to gram-negative bacilli. Nephrotoxicity has restricted the indications for neomycin to topical and oral use. Emergence of resistant organisms has limited the use of streptomycin to a few specific conditions. Gentamicin, tobramycin, and amikacin are effective against a broad spectrum of gram-negative bacilli including Pseudomonas aeruginosa. Amikacin is the aminoglycoside of choice when gentamicin resistance is prevalent.

Audiometric and histologic correlates of the interaction between kanamycin and subtraumatic levels of noise in the chinchilla.

Difficulty in assessment of potentiating interaction between noise-induced and kanamycin-induced injury of hearing is compounded by the great variability of intersubject response to the same drug dosage. However, in a given subject, response of the two cochleas to kanamycin intoxication may resonably be assumed to be symmetric. The present study was designed to utilize this similarity, in determining whether kanamycin intoxication would potentiate a normally subtraumatic noise stimulus. Under the experimental conditions outlined, it was found that after a dosage of 150 mg/kg/day of kanamycin given to a physiologic end point, normally subtraumatic noise caused consistent increas in hearing loss.