Impact of Mitochondrial Targeting Antibiotics on Mitochondrial Function and Proliferation of Cancer Cells

Some marketed antibiotics can cause mitochondria dysfunction via inhibition of the mitochondrial translation process. There is great interest in exploiting such effects within a cancer setting. To enhance accumulation of antibiotics within the mitochondria of cancer cells, and therefore delivery of a greater potency payload, a mitochondrial targeting group in the form of a triphenylphosphonium (TPP) cation was appended via an alkyl chain length consisting of 7 to 11 carbons to the ribosomal antibiotics azithromycin and doxycycline. Using MDA-MB-231 cells, the effects of each subseries on mitochondrial translation, mitochondrial bioenergetics, and cell viability are described.     

预防性应用抗菌药物预防乳腺癌术后手术部位感染的荟萃分析

目的:探讨预防性应用抗菌药物对乳腺癌术后手术部位感染的预防作用。方法:以 “preoperative antibiotics/peri-operative antibiotics/prophylactic antibiotics”、 “surgical site infection/wound infection/postoperative complications” 、 “mastectomy/wide local excision/breast reconstruction/axillary dissection”为关键词，查找1966年至2016年PubMed、Cochrane Library、Embase、ScienceDirect、Wiley InterScience、Scopus和Ovid数据库的RCT，无语言限制。2位评价者评价每一项研究的质量并提取数据。结果:12项RCT共计4 267例患者被纳入该荟萃分析。分析发现，预防性使用抗菌药物组可以显著降低手术部位感染（OR=0.63，95%CI:0.49~0.81,P=0.000 2）。按不同给药方式做亚组分析后，发现采用静脉抗生素的亚组，SSI的累积发生率(5.5%)显著低于对照组(8.2%)(OR=0.65,95%CI:0.50~0.83,P=0.000 7)；按不同用药方案做亚组分析后，发现使用头孢地尼预防抗感染组发生SSI的累积发生率显著低于对照组(OR=0.54,95%CI:0.30~0.94,P=0.03)。结论:预防性使用抗菌药物可预防乳腺术后SSI的发生，进一步亚组分析提示采用静脉抗菌药物预防效果更佳，但由于亚组研究数量有限，仍需要更多高质量的RCT提供依据以建立最有效的预防方案和标准流程。     

Precision dosing software to optimize antimicrobial dosing: a systematic search and follow-up survey of available programs

BackgroundPrecision dosing programs are promising tools for optimising antimicrobial dosing. Selecting the ideal program for local application may be challenging due to the large variety of available programs with differing characteristics.ObjectivesThe objectives of this study were to systematically identify available precision dosing software programs to optimize antimicrobial dosing and describe the characteristics of each program. Details on the ability of programs to provide beta-lactam dosing support was also gathered.SourcesA systematic review search strategy was used to identify candidate software programs described in the literature in Embase and PubMed. A detailed survey was then developed to identify characteristics of programs, including details on the underlying methodology driving dosing software recommendations, interface characteristics, costs and regulatory affairs. Software developers from all identified programs were invited to participate in the survey.ContentThe systematic search results identified 18 programs. Fifteen developers responded to the survey (83%) and 11 programs provide dosing support for at least one beta-lactam. Fourteen programs can utilize measured drug concentrations to generate dosing recommendations, with 13 able to generate empiric dosing recommendations. Six programs integrate with local electronic health records and four are registered with at least one regulatory agency. Pharmacokinetic models in combination with Bayesian statistics is the most common methodology used to generate dosing recommendations, with 14 programs utilizing this method.ImplicationsThere was significant variability in the available antimicrobial profiles and characteristics among dosing software programs. As healthcare providers will differ in their requirements within their local settings, clinicians should use these findings to identify potential candidate programs and, if feasible, trial these to ensure they meet their specific requirements.     

Bile salt metabolism is not the only factor contributing to Clostridioides (Clostridium) difficile disease severity in the murine model of disease

ABSTRACT

Susceptibility of patients to antibiotic-associated C. difficile disease is intimately associated with specific changes to gut microbiome composition. In particular, loss of microbes that modify bile salt acids (BSA) play a central role; primary bile acids stimulate spore germination whilst secondary bile acids limit C. difficile vegetative growth. To determine the relative contribution of bile salt (BS) metabolism on C. difficile disease severity, we treated mice with three combinations of antibiotics prior to infection. Mice given clindamycin alone became colonized but displayed no tissue pathology while severe disease, exemplified by weight loss and inflammatory tissue damage occurred in animals given a combination of five antibiotics and clindamycin. Animals given only the five antibiotic cocktails showed only transient colonization and no disease. C. difficile colonization was associated with a reduction in bacterial diversity, an inability to amplify bile salt hydrolase (BSH) sequences from fecal DNA and a relative increase in primary bile acids (pBA) in cecal lavages from infected mice. Further, the link between BSA modification and the microbiome was confirmed by the isolation of strains of Lactobacillus murinus that modified primary bile acids in vitro, thus preventing C. difficile germination. Interestingly, BSH activity did not correlate with disease severity which appeared linked to alternations in mucin, which may indirectly lead to increased exposure of the epithelial surface to inflammatory signals. These data confirm the role of microbial metabolic activity in protection of the gut and highlights the need for greater understanding the function of bacterial communities in disease prevention.     

门诊患儿就诊前抗生素使用现状的单中心调查

目的：调查我院儿科2018年3-4月门诊患儿就诊前抗生素使用现状。方法：由医师发放调查表，家属自愿如实填写。收集患儿年龄、性别、症状、就诊前是否服用抗生素、首剂抗生素与症状出现时限、服用时长、抗生素种类及来源等相关信息进行统计学分析。结果：入选的患儿共187例，使用抗生素者155例，占82.89%；未使用者32例，占17.11%。抗生素使用率细菌组与病毒组分别为81.43%、84.07%（P>0.05）；幼儿组、学龄前期组及学龄期组患儿抗生素使用率分别为88.46%、86.42%、84.61%，高于婴儿组（P<0.05）；单独使用者占85.16%，联合应用占14.84%。单独使用率由高到低分别为头孢菌素类58.71%、青霉素类21.93%、大环内酯类4.52%（P<0.05）。抗生素来源分别为药店购买（28.38%）、社区医师处方（27.10%）、家里储备（20.65%）、上次生病所剩（23.87%）4个途径（P>0.05）。首剂抗生素应用时限<12 h组应用率44.52%，明显高于12~24 h组的29.68%和>24 h组的25.81%（P <0.05）。结论：儿科患者就诊前抗生素应用存在滥用、不规范、不合理现象，应加强宣教及监管。     

Antibiotic therapy of life-threatening infectious diseases in the emergency department

Initial therapy in acutely ill septic patients is necessarily empiric. Although a specific etiologic infectious diagnosis is rarely made in an acute situation, a treatment decision must be made and must be developed from history, physical examination, and minimal laboratory and roentgen studies. Three life-threatening syndromes are discussed: febrile-neutropenic patients with cancer, immunosuppressed patients with fever and lung infiltrates, and patients with acute community-acquired meningitis.     

Lack of effect of ponsinomycin on the plasma pharmacokinetics of theophylline

Summary The influence of ponsinomycin on the pharmacokinetics of theophylline has been studied in 12 young healthy volunteers. They received 10 doses of theophylline 200 mg every 8 h p.o., successively in the absence and then in the presence of ponsinomycin. This new macrolide, structurally related to midecamycin, was given in the therapeutic dose of 800 mg b.d. for 5 days, starting 2 days before the second phase of treatment with theophylline.The pharmacokinetic parameters of theophylline, calculated from its plasma concentration at steady-state, were not affected by the co-treatment. In particular, there was no significant difference between the peak and trough plasma levels, apparent clearance or apparent elimination half-life of theophylline in the absence and the presence of ponsinomycin. Only renal clearance was slightly (27%) but significantly increased by the co-treatment. The results suggest that ponsinomycin would be a good choice if a macrolide antibiotic were needed in patients being treated with theophylline.     

Doxorubicin concentrations in plasma and myocardium and their respective roles in cardiotoxicity

Summary Three hours after the intravenous infusion of doxorubicin (3 mg/kg over 15 min) to anesthetized dogs, the drug concentration was found much higher in the myocardium than in the plasma (about 4,000 ng/g, i.e., 50 times higher). After the intravenous infusion of doxorubicin (1.5 mg/kg over 15 min) to conscious dogs, the drug concentration appeared to decline very slowly in the myocardium, since it was close to 200 ng/g at the 7th day, whereas the plasma concentration had fallen to zero, and the drug was still detected in the cardiac tissue 21 days after the administration. As myocardial concentrations of doxorubicin persist long after plasma clearance is complete, the hazards of repeated administration, based on plasma kinetic patterns, must be emphasized.