Transforming growth factor alpha treatment alters intracellular calcium levels in hair cells and protects them from ototoxic damage in vitro

To determine if transforming growth factor alpha (TGFα) pretreatment protects hair cells from aminoglycoside induced injury by modifying their intracellular calcium concentration, we assayed hair cell calcium levels in organ of Corti explants both before and after aminoglycoside (i.e. neomycin, 10⁻³M) exposure either with or without growth factor pretreatment. After TGFα (500ng/ml) treatment, the intracellular calcium level of hair cells showed a five-fold increase as compared to the levels observed in the hair cells of control cultures. After ototoxin exposure, calcium levels in hair cells of control explants showed an increase relative to their baseline levels, while in the presence of growth factors pretreatment, hair cells showed a relative reduction in calcium levels. Pretreatment of organ of Corti explants afforded significant protection of hair cell stereocilia bundle morphology from ototoxic damage when compared to explants exposed to ototoxin alone. This study correlates a rise in hair cell calcium levels with the otoprotection of hair cells by TGFα in organ of Corti explants.     

大肠埃希菌氨基糖苷酰基转移酶基因型研究

目的：了解大肠埃希菌的耐药谱、氨基糖苷酰基转移酶基因（aac）的分布规律及其与氨基糖苷类抗生素耐药的相关性。方法：琼脂稀释法测定无菌体液分离的44株大肠埃希菌对阿米卡星等12种抗生素的耐药性，聚合酶联反应（PCR）法测定酰基转移酶基因型aac（3）-Ⅰ、Ⅱ和aac（6’）-Ⅰ。结果：大肠埃希菌超广谱β-内酰胺酶（ESBLs）的发生率为45．45％（20／44），对亚胺培南（IPM）、关罗培南（MEM）的耐药率为0，对哌拉西林／他唑巴坦、头孢他啶的耐药率较低（〈20％），对左氟沙星、环丙沙星的耐药率较高（〉60％），对氨基糖苷类阿米卡星、庆大霉素、妥布霉素的耐药率分别为18．18％、56．82％、61．36％。氨基糖苷类耐药模式TG（妥布霉素、庆大霉素）〉TGA（妥布霉素、庆大霉素、阿米卡星）〉T（妥布霉素）〉G（庆大霉素），分别占36．36％、18．189／5、6．82％、2．27％。氨基糖苷酰基转移酶基因检出以aac（3）-Ⅱ最高，占52．27％（23／44），aac（6＇）-Ⅰ次之，占29．55％（13／44），aac（3）-Ⅱ和aac（6’）-Ⅰ同时检出者占15．91％（7／44），未检出aac（3）-Ⅰ。ESBLs阳性株的aac（3）-Ⅱ、aac（6’）-Ⅰ检出率分别为60％、50％，高于ESBLs阴性株的45．81％、12．51％。TG模式与其耐药基因aac（3）-Ⅱ符合率较高为93．75％（15／16）。结论：本地分离大肠埃希菌氨基糖苷类耐药模式以TG为主，酰基转移酶基因以aac（3）-Ⅱ为主，aac（6’）-Ⅰ次之，aac（3）-Ⅰ罕见。     

用药代动力学软件预测氨基糖苷类抗生素血浓度的准确性

目的 评价药代动力学软件(PKS)预测氨基糖苷类抗生素血浓度的准确性。方法 严重感染病人53例,静脉点滴氨基糖苷类抗生素q 6 h共3天。血药浓度测定用偏振荧光免疫测定法。用PKS软件Bayesian模式,以首次给药后峰和低浓度为反馈值,对以后每剂量的峰和谷浓度作预测。预测准确性和精确性用平均预测误差(ME)、均方预测误差(MSE)、均方预测误差平方根(RMSE)及其95％可信限表示。将24,48,72h峰、谷浓度实测值与预测值做配对t检验。结果 303次血药浓度实测值供预测。ME,MSE,RMSE及其95％可信限均在临床可接受范围内。24和48h峰浓度预测值和观察值间无显著差异(P>0.05),72 h组问差异有显著性(P<0.05)。上述3个时间点的谷浓度预测值和观察值间均有显著性差异(P<0.01)。结论 用PKS可准确预测氨基糖苷类静脉给药后4 8 h内每一剂量的峰浓度,但谷浓度预测受限。     

Plazomicin: an investigational therapy for the treatment of urinary tract infections

Introduction: Living in the ever-expanding era of multidrug-resistant (MDR), extensively drug-resistant (XDR), and even pandrug-resistant Gram-negative microorganisms, the medical community is facing the approaching fear of the “End of Antibiotics.” Plazomicin is a next-generation aminoglycoside designed to evade all clinically relevant aminoglycoside-modifying enzymes, the main mechanism of aminoglycoside resistance. A newer aminoglycoside active against several MDR-XDR microorganisms is herein presented and discussed.

Areas covered: Herein, the authors present the currently available information on plazomicin. This includes the current knowledge concerning plazomicin’s: mechanisms of action, in vitro activity and interactions, its pharmacokinetics, its clinical efficacy in complicated urinary tract infections (cUTIs) and acute pyelonephritis, and its toxicity issues.

Expert opinion: Plazomicin was developed to evade all clinically relevant aminoglycoside-modifying enzymes. Unfortunately, ribosomal enzymatic modification by ribosomal 16S-rRNA methyltransferases confers broad-spectrum high-level aminoglycoside resistance. Still, plazomicin demonstrates high activity against the Enterobacteriaceae including extended spectrum beta lactamase and most carbapenemase producers, as well as several of the non-fermenters. When compared to levofloxacin, the in vivo activity of plazomicin in complicated urinary tract infections (cUTIs) and in acute pyelonephritis in humans was very promising. Furthermore, regarding safety, no clinically significant effects on renal, vestibular, or cochlear function have been observed both at Phase I and II studies in humans, with mild to moderate adverse events being dose related. However, the authors believe that the real position of plazomicin in the MDR-XDR world will be revealed once pending Phase III studies are completed.     

Hemorrhagic death associated with a high titer factor V inhibitor

An acquired bleeding diathesis was first noted in a 51-year-old patient 11 days following an exploratory laparotomy. Laboratory studies indicated the cause of bleeding to be the development of a circulating anticoagulant which inhibited factor V activity. The inhibitor, an immunoglobulin of the IgG class, was separated by use of Sephadex G-200 filtration, disc electrophoresis, and isoelectric focusing. Despite vigorous immunosuppressive, antifibrinolytic, and replacement therapy, including the use of a "prothrombin complex" and plasmaphoresis, the bleeding diathesis could not be reversed and the patient died of hemorrhage. Although inhibitors to factor V are not usually associated with major life-threatening hemorrhage, this case demonstrates that the development of such an inhibitor can be an ominous finding. The use of an aminoglycoside antibiotic in this and other patients so reported may be one of the contributing causes to the development of such an inhibitor.     

How do I manage a patient with enterococcal bacteraemia?

BackgroundEnterococcal bacteraemia (EB) is common, particularly in the nosocomial setting, and its management poses a challenge for clinicians and microbiologists.ObjectivesThe aim was to summarize the more relevant features of EB and to provide a practical state-of-the-art on the topics that more directly affect its management.SourcesPubmed articles from inception to 31 May 2020.ContentThe following topics are covered: epidemiological, clinical and microbiological characteristics and factors associated with prognosis of EB; diagnosis and work-up, including the use of echocardiography to rule out endocarditis; antibiotic management with special focus on antimicrobial resistance and complicated EB; and the role of infectious disease consultation and the use of bundles in EB. In addition, three clinical vignettes are presented to illustrate the practical application of the guidance provided, and major gaps in the current evidence supporting EB management are discussed.ImplicationsEB is associated with large burdens of morbidity and mortality, particularly among fragile and immunosuppressed patients presenting complicated bacteraemia due to multidrug-resistant enterococci. Most cases of EB are caused by Enterococcus faecalis, followed by E. faecium. EB often presents as polymicrobial bacteraemia. Rapidly identifying patients at risk of EB is crucial for timely application of diagnostic techniques and empiric therapy. Early alert systems and rapid diagnostic techniques, such as matrix-assisted desorption ionization–time of flight mass spectrometry, especially if used together with infectious disease consultation within bundles, appear to improve management and prognosis of EB. Echocardiography is also key in the work-up of EB and should probably be more extensively used, although its exact indications in EB are still debated. Multidisciplinary approaches are warranted due to the complexity and severity of EB.     

Increased dosage requirements of tobramycin and gentamicin for treating Pseudomonas pneumonia in patients with cystic fibrosis

The pharmacokinetic behavior of tobramycin and gentamicin was evaluated in 27 patients who had cystic fibrosis (CF). A previously studied, age-matched group of 334 patients who had been treated with gentamicin and who did not have CF served as controls. The CF patients, who ranged in age from 2 to 32 years and who had normal renal function, received 36 treatment courses with either tobramycin (19) or gentamicin (17) to treat Pseudomonas pneumonia. Serum concentrations were determined after a 1.5-mg/kg dose to compute half-life (t 1/2), elimination rate constant (k), and apparent volume of distribution (V). From these values, doses were calculated to produce steady-state peak concentrations of 8.0 micrograms/ml with a dosing interval of every six hours. For tobramycin the mean (+/- SD) t1/2 was 1.0 (0.4) hours, V was 0.18 (0.06) l/kg, total body clearance (TBC) was 2.19 (0.71) ml/min/kg, and the calculated dose was 8.2 (2.1) mg/kg/day. For gentamicin t1/2 was 1.1 (0.5) hours, V was 0.20 (0.06) l/kg, TBC was 2.28 (0.89) ml/min/kg, and the calculated dose was 8.8 (2.4) mg/kg/day. The pharmacokinetic parameters were not statistically different between the two drugs, but the mean values of t1/2 and TBC of CF patients differed significantly from those of the control group. The calculated doses were larger than the manufacturer's maximum recommended dose of 7.5 mg/kg/day for 63% of tobramycin and 71% of gentamicin treatment courses. A dosing interval change to every four hours would have been appropriate in 28 of the 36 treatment courses (78%).(ABSTRACT TRUNCATED AT 250 WORDS)     

离子色谱法分析氨基糖苷类抗菌药物的质量标准研究进展

目的：综述各国药典中离子色谱法分析氨基糖苷类抗菌药物的质量标准进展情况。方法：介绍了氨基糖苷类抗菌药物的发展历程及离子色谱原理,概述了各国药典中氨基糖苷类抗菌药物的质量标准变迁,分析了各国药典离子色谱法在该类药物中的应用与质量标准沿革,并探讨了离子色谱法测定该类药物的发展趋势。结果与结论：氨基糖苷类抗菌药物的分析方法逐渐从薄层色谱法、高效液相色谱衍生化法、高效液相色谱-蒸发光散射法向离子色谱法发展,并日益成为该类抗菌药物较理想的质量控制方法,为今后氨基糖苷类抗菌药物的标准提高及质量控制提供了参考。     

Two-Stage Arthroplasty for Prosthetic Joint Infection : A Systematic Review of Acute Kidney Injury,Systemic Toxicity and Infection Control

Periprosthetic infections of hip and knee joints are now treated by two-stage revision arthroplasty with an infection control rate of 91%. The present systematic review studied the reported incidence of acute kidney injury (AKI) and infection recurrence from January 1989 to June 2012 to assess the risk–benefit ratio of antibiotic spacer use. Ten observational studies (n = 544 patients) with clinical outcomes showed an average incidence of AKI of 4.8%. The average reported persistence or recurrence rate of infection was 11% during a follow-up period that ranged from 13 to 108 months. The risk–benefit ratio presently favors treatment although there appears to be higher complication rates and incidence of AKI than previously reported. Marked heterogeneity in practice and lack of detail in reporting precluded more robust quantitative synthesis. Clinicians need to be aware of the potential risk of AKI, particularly in high-risk patients; practice patterns for the use of antibiotic spacers need to be standardized.     

Identification of FDA-Approved Drugs and Bioactives that Protect Hair Cells in the Zebrafish (Danio rerio) Lateral Line and Mouse (Mus musculus) Utricle

The hair cells of the larval zebrafish lateral line provide a useful preparation in which to study hair cell death and to screen for genes and small molecules that modulate hair cell toxicity. We recently reported preliminary results from screening a small-molecule library for compounds that inhibit aminoglycoside-induced hair cell death. To potentially reduce the time required for development of drugs and drug combinations that can be clinically useful, we screened a library of 1,040 FDA-approved drugs and bioactive compounds (NINDS Custom Collection II). Seven compounds that protect against neomycin-induced hair cell death were identified. Four of the seven drugs inhibited aminoglycoside uptake, based on Texas-Red-conjugated gentamicin uptake. The activities of two of the remaining three drugs were evaluated using an in vitro adult mouse utricle preparation. One drug, 9-amino-1,2,3,4-tetrahydroacridine (tacrine) demonstrated conserved protective effects in the mouse utricle. These results demonstrate that the zebrafish lateral line can be used to screen successfully for drugs within a library of FDA-approved drugs and bioactives that inhibit hair cell death in the mammalian inner ear and identify tacrine as a promising protective drug for future studies.