Ototoxicity of a new glycopeptide, norvancomycin with multiple intravenous administrations in guinea pigs

Time courses of plasma concentration of a new glycopeptide, norvancomycin (NVCM) after single intravenous (iv) and intraperitoneal (ip) injection, and the peak plasma concentrations (Cmax's) of this drug at various doses after single iv injection were determined in guinea pigs. There were significant differences in pharmacokinetic parameters between the two routes of administration and the Cmax linearly increased with the dose used increasing. Guinea pigs with normal hearing were then used to investigate ototoxic liability of NVCM after multiple intravenous administrations (54, 108, 216mg/kg, qd for 14 days). Postrotatory vestibular nystagmus (PRN), auditory brainstem response (ABR) and electron microscopy (SEM TEM) results showed that, similarly to vancomycin, there was no functional or morphological evidence of ototoxicity of NVCM at the dose of 54, 108 mg/kg. In the high dose group (216 mg/kg), there was a 0 approximately 4 dB elevation of hearing threshold but no morphological changes. The results suggested that the ototoxicity of NVCM is absent or minimal after multiple iv administrations within this dose range.     

Isepamicin与六种氨基糖苷类体外抗菌活性研究

本文比较fsepamicin(ISP)、庆大霉素(GM)、地贝卡星(DKB)、乙基西索米星(NTL)、妥布霉素(TOB)、西索米星(SISO)与阿米卡星(AMK)的体外抗菌活性。金葡菌产酶株对上述抗生素的敏感性显较不产酶株为差,以ISP、NTL对金葡菌产酶株的作用最强。其平均MIC值分别为1.85和2.12mg/L;对革兰氏阴性杆菌的作用则以ISP和AMK为强。以ISP对各种细菌的MIC值最低0.32～3.39mg/L。TOB、GM、SISO、NTL与DKB对多数革兰氏阴性杆菌的作用相似,五者之间有很大程度交叉耐药。所测611株革兰氏阴性杆菌中对一种以上药物耐药者312株,占51％;其中对ISP和AMK仍敏感者分别为90.4％和91.7％,而对NTl、GM、TOB、DKB敏感者仅15～18％,本文讨论了细菌对氨基糖苷类的耐药机理及其临床意义。     

Four Weeks Inhalation Exposure to n-Heptane Causes Loss of Auditory Sensitivity in Rats

Abstract: The effects of exposure to 800 or 4000 p.p.m. of n-heptane, CAS No. [142-82-5]) 6 hr per day during a period of 28 days, on the function of the auditory system were examined by measurements of auditory brain stem response (ABR) in Long Evans rats. The ABR was measured simultaneously with both needle electrodes and implanted electrodes. The wave forms recorded with the two types of electrodes were similar, but the amplitudes were largest on the recordings with implanted electrodes. The overall ratio between the amplitudes obtained with implanted electrodes and with needle electrodes was 1.4 for peak la and 2.5 for peak IV of the ABR. The exposure to rc-heptane (4000 p.p.m.) reduced the amplitudes of components la and IV of the ABR. The reduction was most consistent for component IV and most pronounced at higher frequencies and intensities. The reduction in ABR corresponds to an increase in the auditory threshold of approximately 10 dB at all frequencies. Neither the latencies nor the interpeak latencies of components la and IV were changed. No significant changes in ABR were observed in the group exposed to 800 p.p.m. The mechanism behind the ototoxicity of organic solvents is discussed.     

Antibacterial activities and PK/PD parameters of aminoglycosides against recent clinical isolates of gram-negative rods

We examined antibacterial activities and PK/PD parameters of six kinds of aminoglycosides against seven bacterial species of clinical isolates in 2001. Aminoglycoseides examined were gentamicin (GM), dibekacin (DKB), tobramycin (TOB), amikacin (AMK), netilmicin (NTL), and isepamicin (ISP), and bacterial isolates used were each 50 strains of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii, Proteus spp., Serratia marcescens and Pseudomonas aeruginosa. All aminoglycosides showed good activities with low MICs against 6 species of Enterobacteriacea except S. marcescens. Eight strains (3.2%) among them were resistant to one or more aminoglycosides. Resistance to multiple aminoglycosides were detected in 16 strains (32%) of S. marcescens, among which 13 strains were resistant to AMK but susceptible to ISP. Three (6%) strains of P. aeruginosa were resistant to multiple drugs, one of which was resistant to all six aminoglycosides, and others were moderately susceptible to AMK and ISP, and susceptible to GM, AMK and ISP. Using a ratio of peak serum concentration to MIC90 (Cmax/MIC90) or a ratio of area under the curve to MIC90 (AUC/MIC90) as a pharmacokinetic and pharmacodynamic (PK/PD) parameter, we estimated the efficacy of the drug. An excellent effect of ISP, which was injected intramuscularly or intravenously at a dose of 400 mg, was expected for strains of Enterobacteriacea except S. marcescens. The Cmax/MIC90 ratios for S. marcescens were comparably higher in GM and ISP and that for P. aeruginosa were rather high in TOB when compared to other aminoglycosides. Another PK/PD parameter, AUC/MIC90 ratio, was high enough in NTL and ISP for Enterobacteriacea, suggesting good efficacy of these drugs. The (AUC/MIC90) ratios for S. marcescens were comparably high in GM and ISP, and that for P. aeruginosa were high in TOB, DKB, and ISP.     

庆大霉素耳中毒后血管纹HSP70 mRNA的表达及川芎嗪的保护作用

目的研究川芎嗪(TMP)对庆大霉素(GM)中毒豚鼠耳蜗血管纹热休克蛋白HSP70 mRNA表达的影响。方法应用原位杂交、图像分析技术并结合听脑干反应(ABR)的测试,观察TMP对GM耳中毒豚鼠耳蜗血管纹HSP70 mRNA表达的影响。结果GM组耳蜗血管纹ABR阈值为(36.55±6.13)dB,TMP+GM组对应值为(21.09±4.50)dB,二组之间差异有显著意义(P<0.01);GM组耳蜗血管纹HSP70 mRNA表达的平均灰度值为(89.31±1.47)dB,TMP+GM组对应值为(94.16±2.15)dB,二组之间差异有显著意义(P<0.01)。各组HSP70 mRNA表达与ABR阈值高度相关(r=-0.8734~-0.9841,P<0.001)。结论HSP70在耳蜗血管纹细胞的转录和翻译是不同的,TMP减少耳蜗血管纹HSP70 mRNA表达,改善听功能。     

Nitric oxide synthase inhibitor suppresses the ototoxic side effect of cisplatin in guinea pigs

Cisplatin is known to cause inner ear damage (ototoxicity). The role of inducible nitric oxide synthase (iNOS) in the cochlea of guinea pigs after injections of cisplatin or a combination of cisplatin and NOS inhibitor (NG-nitro-L-arginine methyl ester, L-NAME) i.p. was examined electro-and immunohistochemically. The auditory brain stem responses (ABR) were measured prior to injection and 3 days after the injection. Three days after injection, the cochleas were examined immunohistochemically for iNOS. We found that iNOS was expressed in the cisplatin- and L-NAME/ cisplatin-treated cochlea. The threshold shift of ABR was significant in the cisplatin group, whereas it was decreased in the L-NAME/cisplatin group. iNOS catalyzed high NO levels lead to inner ear dysfunction. Our results indicate that iNOS mediates the ototoxicity of cisplatin.     

Surveillance of antimicrobial activity of Pseudomonas aeruginosa isolated in the Kinki district

The antimicrobial activity of 18 antimicrobial agents were measured for the 500 Pseudomonas aeruginosa strains that had been isolated from various clinical specimens in 17 medical institutions in the Kinki district from April to July of 2008. The antimicrobial activity was excellent in the order of tobramycin (TOB), arbekacin (ABK), doripenem (DRPM), gentamicin (GM) and amikacin (AMK). Susceptible rate that was interpreted by Clinical and Laboratory Standards Institute (CLSI) was high in the order of AMK, TOB, tazobactam/piperacillin (TAZ/PIPC), DRPM, ABK. Also, the difference in susceptible rate was observed between departments, materials and institutions. Multidrug resistant strains were only 12 (2.4%) but strains that had resistance to 2 agents were 48 (9.6%), therefore, implementation of further surveillance should be continued.     

Antibacterial activities of various aminoglycosides against clinically isolated methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) were isolated from samples collected from various patients during 1986, and antibacterial activities of 6 aminoglycosides (AGs) (netilmicin (NTL), gentamicin (GM), sisomicin (SISO), dibekacin (DKB), tobramycin (TOB) and amikacin (AMK] and 4 beta-lactam antibiotics (cefazolin (CEZ), cefmetazole (CMZ), cloxacillin (MCIPC) and methicillin (DMPPC) against these MRSA were evaluated. Among these 6 AGs, NTL was the most potent, and its MIC50 and MIC80 were 1.56 and 3.13 micrograms/ml, respectively. Antibacterial activities of GM, SISO, DKB and TOB were weak, and MIC50's of GM and DKB were both 100 micrograms/ml, while those of SISO and TOB were 50 and greater than 100 micrograms/ml, respectively. Frequency of highly resistant specimens to AMK was rather low and its MIC50 and MIC80 were 12.5 and 25 micrograms/ml, respectively. As for antibacterial activities of the above 4 beta-lactam antibiotics, the MIC50 and MIC80 of CMZ were 6.25 and 12.5 micrograms/ml, respectively, and therefore, its antibacterial activity to MRSA is relatively good. However, MIC50's of CEZ, MCIPC and DMPPC were all greater than 100 micrograms/ml, showing poor antibacterial activities. Recently, MRSA became a problem in various fields of clinical practice, and a number of literatures reporting refractory infections caused by MRSA have been published. Since MRSA is featured as multiply resistant bacteria, it is known that MRSA is resistant to the majority of existing antibiotics (penicillins, cephems, macrolides, AGs, etc.). In 1985, we reported results of our study concerning the antibacterial activities of a number of CEPs and some of AGs against multiply resistant S. aureus including MRSA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined effect of sulbactam/cefoperazone and other antibiotics against clinical isolates of multi-resistant strains. II. In vitro combined effects of sulbactam/cefoperazone with imipenem/cilastatin, cefuzonam, flomoxef, amikacin or tobramycin

We evaluated combined effects of sulbactam/cefoperazone (SBT/CPZ) with each of imipenem/cilastatin (IPM), cefuzonam, flomoxef, amikacin (AMK) and tobramycin (TOB) against 324 clinical strains. Through this study, we obtained the following results. 1. Against Serratia marcescens and Enterobacter cloacae, good synergism was obtained by combining SBT/CPZ with IPM, AMK, or TOB. 2. Against Pseudomonas aeruginosa, good synergism was obtained by combining SBT/CPZ with AMK or TOB. 3. When SBT/CPZ was used in combination with IPM, antagonism was observed among about 45% of strains of P. aeruginosa.     

Study on the drug sensitivity of multiple drug-resistant Staphylococcus aureus

Of clinically isolated Staphylococcus aureus showing resistance to multiple drugs among penicillins (PCs), cephem antibiotics (CEPs), aminoglycosides (AGs), minocycline (MINO) and fosfomycin (FOM), 64 strains were selected for the determination of MIC. Twenty-one drugs were used for the determination of MIC, with ampicillin (ABPC), cloxacillin (MCIPC), cephalothin (CET), cefazolin (CEZ), cefotiam (CTM), cefuroxime (CXM), cefamandole (CMD), cefotaxime (CTX), ceftizoxime (CZX), cefmenoxime (CMX), cefmetazole (CMZ), cefoxitin (CFX), latamoxef (LMOX), cefotetan (CTT), cefoperazone (CPZ), gentamicin (GM), dibekacin (DKB), tobramycin (TOB), amikacin (AMK), MINO, and FOM. MIC80 of each drug at 10(6) CFU/ml were: ABPC, MCIPC, CEZ, CTM, CXM, CTX, CZX, CMX, CFX, LMOX, CTT, CPZ, GM, DKB and TOB greater than 100 micrograms/ml; CET 50 micrograms/ml; CMD and AMK 25 micrograms/ml; CMZ 12.5 micrograms/ml; FOM 6.25 micrograms/ml; and MINO 0.78 micrograms/ml. The ratio of highly resistant strains with MIC greater than 100 micrograms/ml at 10(6) CFU/ml varied according to drug, and a difference tended to be seen in the degree of influence by resistant factors reflected upon MIC, e.g. drugs for which a high resistance of more than 50% was confirmed were ABPC, CXM, CZX, LMOX and TOB, and 20 approximately 30% MCIPC, CTM, CTX, CMX and CFX. MIC on MCIPC which has a correlation of structural activity with methicillin correlated with cephems (CEPs) resistance to a high degree, but many of the so-called new CEPs showed resistance even to the strains with a low MIC on MCIPC. It was assumed that CEPs resistant strains have multiple drug resistant factors based on the fact that such strains showed multiple drug resistance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative Ototoxicity of Dibekacin and Netilmicin in Guinea Pigs

Abstract: The cochleo- and vestibulotoxicity of dibekacin and netilmicin were compared in a guinea pig model. Both aminoglycosides were administered subcutaneously for 21 days at the dose level of 150 mg/kg/day. Control animals were injected with saline. Dibekacin-treated animals showed a significant (P<0.05) increase in the thresholds of the Preyer pinna reflex and the VIIIth nerve compound action potential in response to sound click stimulation. Moreover, a deterioration of the electrophysiologic auditory response and an almost complete suppression of the post-rotatory nystagmus were detected. In contrast, netilmicin did not induce any significant change in auditory and vestibular functions as compared to the control group. Our results demonstrated that netilmicin was devoid of ototoxicity in the guinea pig, while dibekacin provoked mild cochlear and severe vestibulotoxicity.     

水杨酸钠对顺铂所致耳毒性的保护作用

目的探讨水杨酸钠（SS）是否对顺铂（CDDP）所致的豚鼠耳毒性具有保护作用。方法将48只豚鼠随机分为4组：A组（对照组）、B组（SS组）、C组（CDDP组）、D组（SS＋CDDP组）,每组12只。对每组豚鼠右耳测用药前、后听性脑干反应（ABR）阈值;每组随机取6只耳蜗,通过免疫组化测定各组耳蜗螺旋神经节细胞（SGC）中Caspase-3的表达情况。结果 A组与B组用药后ABR阈值、SGC的Caspase-3表达量比较差异均无显著统计学意义（P〉0.05）;C、D组用药后ABR阈值、SGC的Caspase-3表达量明显高于A、B组（P〈0.05）;D组用药后ABR阈值、SGC的Caspase-3表达量明显低于C组（P〈0.05）。结论水杨酸钠对顺铂所致的耳毒性具有一定的保护作用。     

Antibacterial activity and ototoxicity in guinea pigs, and nephrotoxicity in rats of arbekacin

Arbekacin (HBK), 1-N[(S)-4-amino-2-hydroxybutyl]-3',4'-dideoxykanamycin B, showed broad antibacterial spectra against gram-positive and gram-negative bacteria including Pseudomonas aeruginosa. It was also effective against gentamycin- or tobramycin-resistant bacteria. HBK was resistant to various aminoglycoside-inactivating enzymes except for AAC (2') and AAC (6')-IV, both of which slowly inactivated it. Even at higher dosages (150 mg/kg i.m. or greater, which resulted in some deaths), HBK never decreased the pinna reflex in guinea pigs, while 150 mg/kg or more of dibekacin (DKB) or amikacin (AMK) caused loss of this reflex. HBK has less ototoxicity than do DKB and AMK. This was confirmed by histopathological examination of the inner ear. The degree of nephrotoxicity of HBK was suggested to be similar to that of DKB as judged from serum biochemical tests, urinalysis, and histopathological findings.     

The antimicrobial activity of sisomicin against fresh clinical isolates

Antimicrobial activities of sisomicin (SISO) against clinical isolates obtained in the second half of 1986 were investigated together with other 4 aminoglycosides (AGs) (gentamicin (GM), tobramycin (TOB), dibekacin (DKB), amikacin (AMK] and 2 cephems (cefotiam, cefotaxime), and were compared to the results reported in the period of late 1970's through early 1980's in Japan. 1. The incidence of SISO-resistant Staphylococcus aureus in the present study was 18% and is comparable to that of the other studies suggesting that the incidence of SISO resistant strains remains on the stable level. The incidence of SISO-resistant Pseudomonas aeruginosa showed the tendency of slight increase. 2. SISO-resistant strains of Enterobacter spp., Serratia marcescens and Citrobacter freundii did not show increase from the 1970/1980 levels. 3. Isolation rates of SISO-resistant indole(+) Proteus varied depending on strains. Isolation rates of SISO-resistant P. vulgaris and Morganella morganii were both as low as 4%, but that of Providencia rettgeri was as high as 60%. Refering to an American study reporting that the Genus Providencia including P. rettgeri showed high incidence of resistance to SISO as well as to GM or TOB, we pointed out that the antimicrobial activity of AGs against Genus Providencia should be evaluated separately from those of other indole(+) Proteus strains. 4. No SISO-resistant strains of Escherichia coli, Klebsiella pneumoniae or P. mirabilis were found. 5. SISO had good antimicrobial activity against most of the investigated species and SISO may still be regarded as one of the clinically useful AGs.     

WM88拮抗庆大霉素耳毒性实验观察

目的:初步了解WM88拮抗庆大霉素耳毒性的性能及其影响力.方法:设置庆大霉素组与庆大霉素加不同剂量WM88(10mg、20mg)的两组进行比较,观察听性脑干反应(ABR)阈值,眼震电图(ENG)的频率,了解其听功能及前庭功能的变化.仅结合耳蜗铺片琥珀酸脱氢酶(SDH)染色方法和扫描电镜观察耳蜗形态学变化.结果:听生理检查数据统计显示各组间无显著性差异;形态结果显示各组间无显著性差异.结论:本实验没有发现WM88对庆大霉素引起的耳蜗和前庭毒性有拮抗作用.     

Mechanism of Cisplatin Ototoxicity: Antioxidant System

Abstract: The dose and duration limiting toxic effects of cisplatin are ototoxicity and nephrotoxicity. While several studies have attempted to shed some light on the causes of nephrotoxicity, the reasons for ototoxicity induced by cisplatin are poorly understood. Therefore, this investigation was undertaken to delineate the potential mechanisms underlying cisplatin ototoxicity. The role of glutathione (GSH), oxidized glutathione (GSSG) and malondialdehyde levels, and antioxidant enzyme activities [superoxide dismutase, catalase, GSH peroxidase, and GSH reductase] were examined in cochlear toxicity following an acute dose of cisplatin. Male Wistar rats were treated with various doses of cisplatin. Pretreatment auditory brain stem evoked responses (ABR) were performed and then post-treatment ABRs and endocochlear potentials were also performed after three days. Acute cochlear toxicity (ototoxicity) was evidenced as elevated hearing thresholds and prolonged wave I latencies in response to various stimuli (clicks and tone bursts at 2, 8, 16 and 32 kHz) on ABRs. The endocochlear potentials were reduced (50% control) in cisplatin-treated rats as compared to control animals. The rats were sacrified and cochleae isolated. The GSH, GSSG and malondialdehyde levels, and antioxidant enzyme activities were determined. Cisplatin ototoxicity correlated with a decrease in cochlear GSH [0.45±0.012 nmol/mg] after cisplatin administration compared to 0.95±012 nmol/mg in control cochleae (P<0.05). Superoxide dismutase, catalase activities and malondialehyde levels were significantly increased in the cochleae of cisplatin injected rats. Cochlear GSH-peroxidase and GSH reductase activity significantly decreased after cisplatin administration. Alterations in the activity of antioxidant enzymes, an increase in malondialdehyde levels, and depletion of cochlear GSH suggest a role for reactive oxygen species mediated damage of the cochlea in cisplatin toxicity. These biochemical changes were accompanied by the elevation of ABR threshold that appears to correlate well with alterations in antioxidant systems which could be the cause of cisplatin ototoxicity.     

眼震电图对桥小脑角胆脂瘤致三叉神经痛的诊断价值

探讨眼震电图对诊断继发于桥小脑角胆脂瘤三叉神经痛的意义。方法：对６１例三叉神经痛患者进行术前系列ＥＮＧ和脑干电反应测听及颅脑ＣＴ检查。结果：原发性三叉神经痛患者３项检测均正常，而继发性尤其是继发于桥小脑角胆脂瘤患者的检测可出现异常结果，以ＥＮＧ最为敏感。结论：在三叉神经痛型的桥小脑角胆脂瘤诊断中，ＥＮＧ是较敏感的检测方法。     

Evaluation of the mutagenicity of aminoglycoside antibiotics in Salmonella typhimurium and Saccharomyces cerevisiae.

The mutagenicity of aminoglycoside antibiotics (KM, AKM, DKB, RSM, AMK, GM, TOB) has been studied in cells of the bacteria Salmonella typhimurium and in the yeast Saccharomyces cerevisiae. The bacterial strains (Ames') monitor reverse mutation (point mutation) and the yeast strain D5 monitors mitotic crossing-over, mitotic gene conversion and point mutation. None of these antibiotics demonstrated any mutagenic activities in either the bacteria or the yeast.     

加减味耳聋左慈丸对耳蜗琥珀酸脱氢酶的保护作用

目的:观察中药方剂"耳聋左慈丸"加减味对庆大霉素(GM)耳毒性的防治作用,并探讨其作用机制.方法:用脑干听觉诱发电位(BAEP)的方法检测GM耳中毒豚鼠听阈的变化;用组织化学的方法检测耳蜗毛细胞线粒体内琥珀酸脱氢酶(SDH)的变化.结果:该中药方剂能降低GM引起的听觉反应阈的上升幅度,减轻GM对耳蜗毛细胞SDH损害,降低了对毛细胞的损伤.结论:该中药方剂具有明显保护耳蜗毛细胞SDH,降低GM的耳毒性的作用.保护耳蜗毛细胞线粒体SDH,维持了毛细胞的能量代谢及其功能,从而减轻了毛细胞损伤,这可能是该方剂降低GM耳毒性的机制之一.