Clinical utility of daptomycin in infective endocarditis caused by Gram-positive cocci

Gram-positive bacteria account for >80% of all cases of endocarditis. Currently, staphylococci are the leading cause of endocarditis worldwide. Daptomycin is the drug of choice for empirical antibiotic therapy of staphylococcal endocarditis due to its optimal activity both against meticillin-susceptible Staphylococcus aureus and meticillin-resistant S. aureus (MRSA) strains. Daptomycin has not been proven to be superior to vancomycin in the treatment of MRSA endocarditis. However, daptomycin should be considered the drug of choice for the treatment of MRSA endocarditis caused by strains with a vancomycin minimum inhibitory concentration (MIC) of 2 μg/mL, for heterogeneous vancomycin-intermediate S. aureus (hVISA) phenotypes and for glycopeptide-intermediate S. aureus (GISA) strains. Daptomycin is the drug of choice for rescue therapy in cases of MRSA endocarditis in which vancomycin has failed. The appropriate dose of daptomycin has not yet been established; however, for treatment of left-sided endocarditis the dose of daptomycin should be higher than the recommended dose of 6 mg/kg/day. Combination antibiotic therapy with daptomycin (e.g. combined with fosfomycin) is a promising treatment for MRSA endocarditis and warrants further investigation. In vivo studies show that daptomycin is superior to vancomycin in the treatment of meticillin-resistant coagulase-negative staphylococci experimental endocarditis, although clinical data are required. Daptomycin could represent an efficacious treatment for vancomycin-resistant Enterococcus faecium endocarditis. Finally, the pharmacokinetic profile of daptomycin makes it an excellent drug for outpatient parenteral antimicrobial therapy.     

Chitosan nanoparticles for daptomycin delivery in ocular treatment of bacterial endophthalmitis

Abstract

Context: Chitosan nanoparticles were prepared to encapsulate daptomycin and proposed as a delivery system of this antibiotic to the eye for the treatment of bacterial endophthalmitis.

Objective: The aim of this study was to develop daptomycin-loaded nanoparticles to apply directly to the eye, as a possible non-invasive and less painful alternative for the treatment of endophthalmitis, increasing the effectiveness of treatment and reducing toxicity associated with systemic administration.

Materials and methods: Nanoparticles were obtained by ionotropic gelation between chitosan and sodium tripolyphosphate (TPP). Physicochemical and morphological characteristics of nanoparticles were evaluated, as well as determination of antimicrobial efficiency of encapsulated daptomycin and stability of the nanoparticles in the presence of lysozyme and mucin.

Results: Loaded nanoparticles presented mean particle sizes around 200?nm, low polydispersity index, and positive zeta potential. Morphological examination by scanning electron microscopy (SEM) confirmed their small size and round-shaped structure. Encapsulation efficiency ranged from 80 to 97%. Total in vitro release of daptomycin was obtained within 4?h. Determination of minimum inhibitory concentrations (MICs) showed that bacteria were still susceptible to daptomycin encapsulated into the nanoparticles. Incubation with lysozyme did not significantly affect the integrity of the nanoparticles, although mucin positively affected their mucoadhesive properties.

Discussion and conclusion: The obtained nanoparticles have suitable characteristics for ocular applications, arising as a promising solution for the topical administration of daptomycin to the eye.     

Efficacy of daptomycin in complicated skin and skin-structure infections due to methicillin-sensitive and ‐resistant Staphylococcus aureus : results from the CORE Registry

ABSTRACT

Objective: To characterize postmarketing clinical experience with daptomycin in treating complicated skin and skin-structure infections (cSSSIs) due to cultureconfirmed MRSA and MSSA in real-life prescribing situations.

Research design and methods: The Cubicin Outcomes Registry and Experience 2004 (CORE 2004) is a multicenter observational registry involving 45 separate institutions, designed to characterize infection types, pathogens, and outcomes of patients who were treated with daptomycin. A subset analysis of the CORE 2004 data was conducted to characterize patients with cSSSI due to culture-confirmed MRSA and MSSA, but without bacteremia, endocarditis, osteomyelitis, or other significant infectious processes. Clinical information, including patient demographics, antibiotic treatments, and clinical outcome, was analyzed. Adverse event data were not collected in CORE 2004.

Main outcome measure: Clinical success (cured or improved) or failure was assessed at the end of daptomycin treatment.

Results: A total of 165 patients were identified, including 145 patients (87.9%) with MRSA and 20 patients (12.1%) with MSSA infections. Most patients received daptomycin at a dosage of 4–6?mg/kg intravenously and at a frequency of once every 24?h. Daptomycin dosing frequency was adjusted to once every 48?h or thrice weekly in all seven patients who had received hemodialysis. Prior antibiotic therapy had been administered to 121/163 (74.2%) patients and concomitant antibiotic therapy to 65/165 (39.4%) of patients. Clinical success was achieved with daptomycin in 89.1% of patients overall, including 89.7% and 85.0% of those with MRSA and MSSA, respectively. Among patients with a successful outcome, the total days of daptomycin therapy (median days: MRSA = 13.0, MSSA = 11.0) and the days to clinical response (median days: MRSA = 3.5, MSSA = 2.0) were not significantly different for MRSA and MSSA patients (p = 0.27 and p = 0.15 respectively, median test).

Conclusions: Given the limitations of this registry which include its retrospective nature; limited numbers of MSSA patients; and lack of specific information on adverse events, type and duration of prior antibiotic therapy, timing and duration of concomitant antibiotic therapy, concomitant surgical interventions, and possible on-therapy dosing adjustments), daptomycin appeared effective in postmarketing clinical practice in the treatment of cSSSI caused by MRSA and MSSA.     

Characterisation of a Staphylococcus aureus strain with progressive loss of susceptibility to vancomycin and daptomycin during therapy

Following an initial response to vancomycin therapy, a patient with meticillin-resistant Staphylococcus aureus (MRSA) bacteraemia developed endocarditis, failed a second course of vancomycin and then failed daptomycin therapy. An increase in the vancomycin minimum inhibitory concentrations of four consecutive MRSA blood isolates from 2 μg/mL to 8 μg/mL was shown by Etest. Population analysis of four successive blood culture isolates recovered over the 10-week period showed that the MRSA strain became progressively less susceptible to both vancomycin and daptomycin. Retrospectively, the macro Etest method using teicoplanin indicated a decrease in vancomycin susceptibility in the second blood isolate. The patient improved after treatment with various courses of trimethoprim/sulfamethoxazole, quinupristin/dalfopristin and linezolid. Early detection of vancomycin-heteroresistant S. aureus isolates, which appeared to have clinical significance in this case, continues to be a challenge for the clinical laboratory. Development of suitable practical methods for this should be given priority. Concurrent development of resistance to vancomycin and daptomycin, whilst rare, must be considered in a patient who is unresponsive to daptomycin following vancomycin therapy.     

达托霉素治疗复杂皮肤软组织感染的药物经济学评价

目的：评价达托霉素治疗复复杂性皮肤软组织感染(cSSTIs)的临床效果、安全性及经济性,为临床用药提供参考。方法：计算机检索中文和英文数据库,收集相关随机对照试验(RCT),进行临床治愈率和不良反应的meta分析及药物经济学分析。结果：共纳入6 篇RCT,共计820 例患者。Meta 分析结果显示,达托霉素组的临床治愈率与万古霉素组差异无统计学意义[RR=1.01, 95%CI(0.94, 1.08),P=0.88],达托霉素组的临床治愈率与替考拉宁组差异也无统计学意义[RR=1.02, 95%CI(0.90, 1.15),P=0.77]。达托霉素组与万古霉素、替考拉宁的的不良反应发生率相似。最小成本法分析结果显示,达托霉素治疗组的成本为9218.25元,万古霉素治疗组的成本为4138.60元,替考拉宁组为4429.34元,敏感性分析表明结果稳定。结论：对于cSSTIs患者,与万古霉素和替考拉宁相比,达托霉素并不具有经济性。但随着医疗保险政策的变化,达托霉素的经济学特征可能会翻转,还有待进一步研究。     

Eradication of methicillin-resistant Staphylococcus aureus infection by nanoliposomes loaded with gentamicin and oleic acid

Context: Methicillin-resistant Staphylococcus aureus (MRSA) infection with its high incidence is responsible for nosocomial infections. MRSA strains resistant to multiple antibiotics have emerged increasingly. Recently, combination therapy and efficient drug delivery systems are developed to treat infections.

Objective: The aim of the present study was to evaluate antibacterial activities of combination of oleic acid and gentamicin against MRSA, in both free and liposomal forms, and in comparison with vancomycin.

Materials and methods: The antibacterial activities against MRSA ATCC 43300 were assessed by the determination of minimum inhibitory concentration (MIC), MBC, and Fractional Inhibitory Concentration Index (FICI). The time-kill assays were performed to evaluate the potency of antibacterial agents. Nanoliposomal formulations of gentamicin, oleic acid, and combination of gentamicin with oleic acid were prepared by the dehydration–rehydration (DRV) method and characterized for size, zeta potential, and encapsulation efficiency.

Results: MIC values of gentamicin and oleic acid were 19.5 and >250?µg/ml, respectively. Synergetic effects were observed by the gentamicin and oleic acid combination; FICI was 0.5. Following incorporation of gentamicin into liposomal gentamicin and liposomal combination, the MIC values were reduced 15- and 27-fold, respectively. In comparison with vancomycin, liposomal combination was more effective in bacterial inhibition and killing. Liposomal combination was the most effective formula in time-kill study.

Discussion and conclusion: Liposomal formulation showed a higher antibacterial activity in comparison with the free forms and vancomycin. These carriers can improve antimicrobial activity as well as reducing the effective concentration required and inducing rapid bacterial clearance.     

玻璃体切除联合球内注入万古霉素+丁胺卡那霉素治疗眼内炎

目的　探讨玻璃体切除联合球内注入万古霉素 +丁胺卡那霉素治疗眼内炎的临床效果。方法　12 2例眼内炎患者接受玻璃体切除 ,同时球内注入万古霉素 (美国Lilly公司 ) 1mg/ 0 1ml,丁胺卡那霉素0 4mg/ 0 1ml,细菌培养 +药物敏感结果回报后 ,改用敏感药物静脉滴注。结果　联合用药组视力提高的例数较单纯注药组为多 ,眼球萎缩的例数减少 ,平均住院天数减少。结论　玻璃体切除联合球内注入万古霉素 +丁胺卡那霉素治疗眼内炎疗效肯定 ,对视网膜毒性小 ,值得推广应用     

Daptomycin versus vancomycin for complicated skin and skin structure infections: clinical and economic outcomes

STUDY OBJECTIVE: To assess the effect of daptomycin compared with vancomycin on the clinical and economic outcomes in patients with complicated skin and skin structure infections. DESIGN: Prospective, open-label study. SETTING: Level 1 trauma center in Detroit, Michigan. PATIENTS: Fifty-three adult patients with complicated skin and skin structure infections at risk for methicillin-resistant Staphylococcus aureus (MRSA) infection who were treated with daptomycin and a matched cohort of 212 patients treated with vancomycin. INTERVENTION: Patients in the prospective arm received intravenous daptomycin 4 mg/kg every 24 hours for at least 3 days but not more than 14 days. Historical controls received at least 3 days of vancomycin dosed to achieve trough concentrations of 5-20 microg/ml. MEASUREMENTS AND MAIN RESULTS: Outcomes evaluated included blinded assessments of clinical resolution, duration of therapy, and costs. The most common diagnoses were cellulitis (31%), abscess (22%), and both cellulitis with abscess (37%). Microbiology differed significantly between groups, with S. aureus found in 27 patients (51%) in the daptomycin group and 167 patients (79%) in the vancomycin group and MRSA in 22 (42%) and 159 (75%), respectively (p<0.001). The proportions of patients with clinical improvement or resolution of their infections on days 3 and 5 were 90% versus 70% and 98% versus 81% in the daptomycin versus vancomycin groups, respectively (p<0.01 for both comparisons), and 100% at the end of therapy in both groups. Among patients with complete resolution of their infections (41 patients [77%] with daptomycin vs 89 patients [42%] with vancomycin, p<0.05), median duration of intravenous therapy was 4 and 7 days, respectively, (p<0.001), and hospital costs were $5027 and $7552 (p<0.001). CONCLUSIONS: Patients receiving daptomycin achieved more rapid resolution of symptoms and clinical cure and had a decreased duration of inpatient therapy compared with those receiving vancomycin. This study suggests that daptomycin is a cost-effective alternative to vancomycin for complicated skin and skin structure infections.     

Antibacterial effects of 18 medicinal plants used by the Khyang tribe in Bangladesh

Context: The resistance of bacteria to antibiotics is raising serious concern globally. Asian medicinal plants could improve the current treatment strategies for bacterial infections. The antibacterial properties of medicinal plants used by the Khyang tribe in Bangladesh have not been investigated.

Objective: The present study examines the antibacterial properties of 18 medicinal plants used by the Khyang tribe in day-to-day practice against human pathogenic bacteria.

Materials and methods: Leaves, bark, fruits, seeds, roots and rhizomes from collected plants were successively extracted with hexane, ethyl acetate and ethanol. The corresponding 54 extracts were tested against six human pathogenic bacteria by broth microdilution assay. The antibacterial mode of actions of phytoconstituents and their synergistic effect with vancomycin and cefotaxime towards MRSA was determined by time-killing assay and synergistic interaction assay, respectively.

Results and discussion: Hexane extract of bark of Cinnamomum cassia (L.) J. Presl. (Lauraceae) inhibited the growth of MRSA, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii with MIC values below 100 µg/mL. From this plant, cinnamaldehyde evoked at 4?×?MIC in 1?h an irreversible decrease of MRSA count Log10 (CFU/mL) from 6 to 0, and was synergistic with vancomycin for MRSA with fractional inhibitory concentration index of 0.3.

Conclusions: Our study provides evidence that the medicinal plants in Bangladesh have high potential to improve the current treatment strategies for bacterial infection.     

Tumour necrosis factor-alpha levels in aqueous humour and serum from patients with uveitis: the involvement of HLA-B27

SUMMARY

Objective: To study the local and systemic levels of the tumour necrosis factor-α in patients with active uveitis and to determine the implication of TNF-α in rheumatological uveitis and to observe if this relationship is more significant in the B27 positive patients.

Patients and methods: Patients were selected on the basis of a diagnosis of uveitis of any aetiology. Data from 23 patients were stratified into two categories according to the presence or absence of systemic rheumatic disease. The first group comprised nine patients with rheumatic disease; the second group contained 14 patients without rheumatic disease. The patients were also sub-classified into those who were HLA-B27 positive (14 patients) and those who were not. TNF-α levels in serum and aqueous humour from a group of 16 patients with uncomplicated cataracts were analysed as a control group.

Results: In the control group (n?=?16) the serum TNF-α concentration was 13.1?±?2.9pg/ml and the aqueous humour concentration of TNF-α was 0.56?±?1.53?pg/ml. In uveitis patients (n?=?23) the serum TNF-α concentration was 35.35?±?26.77?pg/ml and the aqueous humour concentration of TNF-α was 15.1?±?1.70?pg/ml (p?<?0.01). In HLA-B27 positive patients (n?=?9) the serum TNF-α concentration was 45.56?±?34.17?pg/ml and the aqueous humour concentration of TNF-α was 15.89?±?0.93?pg/ml. In HLA-B27 negative patients (n?=?14) the serum TNF-α concentration was 28.79?±?19.38?pg/ml and aqueous humour concentration of TNF-α was 14.57?±?1.91?pg/ml (p?<?0.01).

Conclusions: The concentration of TNF-α in aqueous humour in patients who are HLA-B27 positive is significantly greater than in those who are B27 negative. No significant differences in the concentrations of TNF-α in serum or aqueous humour in patients with or without rheumatic diseases were detected. TNF-α is a cytokine that may participate actively in the pathogenesis of clinical uveitis.     

Effectiveness and duration of daptomycin therapy in resolving clinical symptoms in the treatment of complicated skin and skin structure infections

ABSTRACT

Objective: Compare the rapidity of the resolution of clinical signs and symptoms of complicated skin and skin structure infections (cSSSIs) caused by Gram-positive organisms between daptomycin and comparator agents.

Patients and methods: A subset of South African patients with Gram-positive cSSSIs and no or one comorbid condition from two phase III clinical trials were included in the analysis. Patients were treated with daptomycin (n = 174) or comparator (penicillinase-resistant penicillins [n = 146] or vancomycin [n = 6]). The presence and severity of eight clinical signs and symptoms were evaluated at baseline, day 3 or 4 of treatment, end of therapy, and at test of cure (6–20 days after the last dose).

Results: Of the 326 patients included in this analysis, the clinical success rates between daptomycin and comparator treatments was comparable. Overall, the severity of symptoms in the daptomycin-treated patients improved more quickly (?p = 0.04) than comparator treatment. At the day 3/4 evaluation, of the eight signs and symptoms, severity significantly decreased for induration (?p = 0.03) and erythema (?p = 0.05); a statistical trend was noted for necrotic tissue (?p = 0.10) and edema (?p = 0.10) in daptomycin-treated patients. Daptomycin treatment resulted in a shorter median duration of therapy than those receiving comparator treatment (7 vs. 8 days, p < 0.0001). Both treatments were well tolerated.

Conclusion: Daptomycin produced a more rapid clinical improvement than comparators, as evidenced by significant reductions in the severity of induration and erythema, with a shorter duration of antibiotic therapy. However, this population was relatively young and healthy; therefore, these results may not be generalizable to all populations.     

Use of daptomycin to treat drug-resistant Gram-positive bone and joint infections

ABSTRACT

Objective: Drug-resistant, Gram-positive bacteria are a growing concern in treating bone and joint infections, including osteomyelitis. This report describes the experience in a series of cases of the use of a novel antibiotic, daptomycin, for the treatment of bone and joint infections.

Research design and methods: This retrospective analysis included patients from two medical centers diagnosed with Gram-positive bone and joint infections and treated with daptomycin.

Results: A total of 10 patients were included in this report, of which nine received previous antibiotic therapy, including vancomycin, linezolid, and quinupristin/dalfopristin. Methicillin-resistant Staphylococcus aureus was isolated from eight patients while the remaining patients were infected with enterococci or streptococci. All patients initially resolved the infection while undergoing daptomycin treatment and were discharged from the hospital. One patient was switched to ampicillin (after receiving daptomycin for 4 days) once the infection was identified due to vancomycin-susceptible enterococcus. However, one patient was readmitted after 18 days due to a clinical relapse, possibly caused by under-dosing of daptomycin.

Conclusion: Eight out of nine patients who received daptomycin for at least 8 days were successfully treated with the agent for Gram-positive bone and joint infections. Daptomycin was found to be well tolerated, even up to 44 days of treatment.     

Effects of sunitinib and bevacizumab on VEGF and miRNA levels on corneal neovascularization

Aim: To evaluate the effects of sunitinib (0.5?mg/ml) and bevacizumab (5?mg/ml) on VEGF-A, VEGFR-2 and microRNA (miRNA) levels on corneal neovascularization (CNV).

Methods: In this study, CNV was induced by silver nitrate application to the cornea, and 40 Albino male rats were equally divided into four subgroups:

Group 1 (sunitinib): After silver nitrate application to the cornea, 0.5?mg/ml sunitinib eyedrop was administered twice daily for two weeks (n?=?10).

Group 2 (bevacizumab): After silver nitrate application to the cornea, 5?mg/ml bevacizumab eyedrop was administered twice daily for two weeks (n?=?10).

Group 3 (control): After silver nitrate application to the cornea, normal saline eyedrop was administered twice daily for two weeks (n?=?10).

Group 4 (vehicle): After silver nitrate application to the cornea, 1% DMSO eyedrop was administered twice daily for two weeks (n?=?10).

After two weeks from the silver nitrate application, corneas were evaluated by hand-held biomicroscope for their vascularization status. Then, corneas were excised and the expression levels of VEGFR-2, VEGF-A and the common miRNA markers for neovascularization (miR-15?b, miR-16, miR-23a, miR-126, miR-188, miR-210, miR-221, miR-222, miR-410 and miR-423) were evaluated by real-time PCR.

Results: It was seen that the CNV was decreased in sunitinib- and bevacizumab-administered groups compared to the control and DMSO groups. Also, in comparison with the control group; VEGF-A expression was downregulated by nearly 0.75 times in sunitinib group and nearly 0.52 times in bevacizumab group. VEGFR-2 expression was downregulated by 0.89 times in sunitinib group and 0.68 times in bevacizumab group, compared to the control group. miR-15?b, miR-16 and miR-126 levels were statistically lower in sunitinib and bevacizumab groups, but miR-188 and miR-410 levels were two-fold higher compared to the control group. The miR-210 level was found higher only in sunitinib group compared to the control group. There were no statistically significant changes in miR-23a, miR-221, miR-222 and miR-423 levels among the groups.

Conclusion: Topical application of bevacizumab (5?mg/ml) and sunitinib (0.5?mg/ml) decreases the levels of VEGFR-2 and VEGF-A in CNV. Further studies are needed for detailed analysis of genes which are targeted by up- or downregulated miRNAs in this study.     

Effectiveness of a new tobramycin (0.3 % ) and dexamethasone (0.05 % ) formulation in the treatment of experimental Pseudomonas keratitis

ABSTRACT

Objective: To quantitatively determine, in a Pseudomonas keratitis model, the anti-inflammatory and bactericidal properties of a new formulation of tobramycin (0.3?%?) and dexamethasone (0.05?%?) that utilizes a xanthan gum vehicle.

Research methods: In a randomized and masked fashion, rabbit corneas (n?≥?16 eyes per group) were intrastromally injected with 10³ colony-forming units (CFU) of P. aeruginosa. Eyes were untreated or were administered a single drop every 15?min between 16 and 17?h postinfection (PI) and then a single drop every 30?min between 17 and 22?h PI, a total of 15 drops of either 0.1?%?dexamethasone and 0.3?%?tobramycin (TobraDex; Tdex) or a new formulation 0.3?%?tobramycin and 0.05?%?dexamethasone with xanthan gum (TobraDex ST; ST). Slit lamp examination scores (SLE?±?SEM) were derived from grading seven parameters at 22?h PI. Rabbits were sacrificed at 23?h PI and the log CFU?±?SEM per cornea was determined.

Results: Untreated eyes had SLE scores of 11.11?±?0.43 and had log CFU of 7.27?±?0.06. Eyes treated with Tdex, as compared to the untreated eyes, had significantly lower SLE scores (7.39?±?0.21, p?<?0.0001) and significantly fewer bacteria (6.32?±?0.29 log CFU, p?=?0.0213). Eyes treated with ST had a SLE score (6.56?±?0.19) that was significantly lower than both the untreated eyes (p?<?0.0001) and the eyes treated with Tdex (p?=?0.0124). Furthermore, eyes treated with ST had significantly fewer log CFU (5.78?±?0.30) than untreated eyes (p?=?0.0001) or eyes treated with Tdex (p?=?0.0434).

Conclusions: The ST formulation with xanthan gum demonstrated statistically superior anti-inflammatory and bactericidal properties as compared to Tdex.

Limitations: Variations in inoculation procedures produced limited eye-to-eye differences in the infection.     

Comparing the ocular surface effects of topical vancomycin and linezolid for treating bacterial keratitis

Background: Vancomycin is the gold standard in combination therapy for severe and resistant gram-positive keratitis and in particular for Methicillin-resistant Staphylococcus aureus (MRSA) infections. The aim of this study was to report the ocular surface toxicity and scoring in patients whose treatment shifted to topical linezolid/ceftazidime from topical vancomycin/ceftazidime due to their vancomycin intolerance.

Methods: A retrospective, interventional case series of bacterial keratitis was treated with topical linezolid (one drop of 0.2% solution per eye), administered hourly until epithelization and then gradually decreased. The number and extent of punctate epithelial erosions were noted across the entire surface of the cornea. Ocular discomfort was assessed by means of (a) patient-reported pain upon instillation of the medication (vancomycin/linezolid), (b) reported burning sensation between doses and (c) reported foreign-body sensation. No ocular surface toxicity related to linezolid use was noted. Patients were followed for at least 2 months after treatment between April and December 2013.

Results: Of the seven patients included in the study (age range: 2–88 years; five females, two males), complete epithelization and resolution was achieved in five patients. One patient was treated with linezolid after penetrating keratoplasty. The second culture of another patient with impending perforation despite linezolid/ceftazidime therapy yielded Fusarium spp., so he underwent tectonic keratoplasty. The mean ocular surface score was 9.4?±?1.6 during vancomycin treatment and 5.9?±?1.3 during linezolid treatment after discontinuation of vancomycin. The topical linezolid score was significantly lower (p?=?0.027).

Conclusions: Topical linezolid may be better tolerated, according to the mean ocular surface score, than topical vancomycin by some patients and can be considered an alternative for patients who do not well tolerate vancomycin.     

Management of cSSTIs:the role of daptomycin

ABSTRACT

Background: Skin and soft tissue infections (SSTIs) and complicated SSTIs (cSSTIs), particularly those caused by Gram-positive pathogens, are among the most common human bacterial infections The emergence of resistance to antibiotics such as methicillin and vancomycin has compromised treatment options for these infections and stimulated the search for new antimicrobial therapies. Daptomycin, the first in a class of agents known as cyclic lipopeptides, is a novel antibiotic with potent activity against most Grampositive pathogens, including methicillin‐ resistant Staphylococcus aureus.

Scope: This review examines the novel properties of daptomycin and describes its therapeutic efficacy and tolerability, particularly in the treatment of cSSTIs. The data search strategy included identification of original research papers, review articles, meeting reports and editorials by searches of MEDLINE and references from relevant articles.

Findings: In vitro studies have demonstrated that daptomycin has superior bactericidal activity compared with vancomycin and the newer anti-Gram-positive agents, quinupristin/dalfopristin and linezolid. Robust, randomised, phase III clinical trials have shown daptomycin to be effective and well tolerated for the treatment of cSSTIs caused by Gram-positive bacteria, with equivalent clinical success rates and a similar safety profile to those of comparator agents. Data from these studies suggest a trend toward shorter duration of therapy and faster resolution of symptoms with daptomycin.

Conclusions: Given the pressing need for new antibiotics to combat infections caused by Gram-positive organisms, and to overcome the problem of resistance to conventional antibiotics, daptomycin is a welcome addition to the treatment options for the management of cSSTIs.     

Magnesium lithospermate B reduces myocardial ischemia/reperfusion injury in rats via regulating the inflammation response

Abstract

Context: Magnesium lithospermate B (MLB), an active polyphenol acid of Danshen [Radix Salviae miltiorrhizae (Labiatae)], showed renoprotective, neuroprotective and myocardial salvage effects. Previous studies demonstrated that MLB could effectively suppress the production of cytokines and their associated signaling pathways in activated human T cells.

Objective: The purpose of this study was to examine the beneficial effects of MLB on myocardial ischemia/reperfusion (MI/R) injury and to explore its potential mechanisms related to anti-inflammation.

Materials and methods: Sprague–Dawley rats were grouped as sham group, model group and MLB-treated (15, 30 and 60?mg/kg) groups. Animals were subjected to MI/R injury by the occlusion of left anterior descending artery for 30?min followed by reperfusion for 3?h. At the end of reperfusion, blood samples were collected to determine the serum levels of cardiac troponin (cTnI), creatine kinase-MB (CK-MB), tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6). Hearts were harvested to assess infarct size, histopathological changes and the activity of myeloperoxidase (MPO). The expression of phosphor-IkB-α and phosphor-nuclear factor kappa B (NF-κB) were assayed by western blot.

Results: MLB administration significantly (p?<?0.05) reduced: (1) ST-segment elevation (0.23?mv), (2) the infarct size (22.5%), (3) histological scores of myocardial injury (1.67 score), (4) myocardial injury marker enzymes: cTnI (5.64?ng/ml) and CK-MB (49.57?ng/ml) levels, (5) pro-inflammatory cytokines: TNF-α (97.36?pg/ml), IL-1β (93.35?pg/ml) and IL-6 (96.84?pg/ml) levels, (6) MPO activity (1.82?U/mg), (7) phosphor-NF-κB (0.87) and phosphor-IkB-α (0.96) expression.

Discussion and conclusion: Our study provided evidence that MLB ameliorated the inflammatory process associated with MI/R injury via NF-κB inactivation.     

Comparison of In Vivo Transportability of Anti-Methicillin-Resistant Staphylococcus aureus (MRSA) Agents Into Intracellular and Extracellular Tissue Spaces in Rats

The pathogenic bacterium Staphylococcus aureus can penetrate host cells. However, intracellular S. aureus is not considered during antimicrobial agent selection in clinical chemotherapy because of the lack of information about drug transportability into cells in vivo. We focused on agents used to treat methicillin-resistant S. aureus (MRSA) (vancomycin, arbekacin, linezolid, and daptomycin) and indirectly assessed the drug levels in intracellular compartment using plasma, tissue homogenates, and interstitial fluid (ISF) samples from the skin of rats using the microneedle array technique. Lower drug levels were observed in the ISF than in the plasma for daptomycin but extracellular and intracellular drug levels were comparable. In contrast, vancomycin, arbekacin, and linezolid showed higher concentrations in the ISF than in the plasma. Intracellular transport was estimated only for arbekacin. Stasis of vancomycin in the ISF was also observed. These results suggest that both low vancomycin exposure against intracellular S. aureus infection and long-term subinhibitory drug levels in the ISF contribute to the failure of treatment and emergence of antibiotic resistance. Based on its pharmacokinetic characteristics in niche extravascular tissue spaces, arbekacin may be suitable for achieving sufficient clinical outcomes for MRSA infection because the drug is widely distributed in extracellular and intracellular compartments.     

The effect and safety of intravitreal injection of ranibizumab and bevacizumab on the corneal endothelium in the treatment of diabetic macular edema

Objective: To investigate the effect and safety of intravitreal injection (IVI) of bevacizumab and ranibizumab on corneal endothelial cell count and morphology in patients with diabetic macular edema.

Materials and methods: A total of 60 eyes from 60 consecutive patients who received 0.5?mg/0.05?ml IVIs of bevacizumab (n?=?30, IVB group) or 1.25?mg/0.05?ml ranibizumab (n?=?30, IVR group) for three consecutive months were investigated prospectively. Specular microscopy was performed to evaluate endothelial cell count, the percentage of hexagonal cells (pleomorphism), and the coefficient of variation of the cell size (polymegathism); optical biometry was performed to evaluate central corneal thickness. Results before injection and 1 month after the first and third injections were compared.

Results: The groups were matched for age (p?=?0.11) and gender (p?=?0.32). There was no significant difference in endothelial cell count (IVB group, p?=?0.66; IVR group, p?=?0.74), pleomorphism (IVB group, p?=?0.44; IVR group, p?=?0.88) and polymegathism (IVB group, p?=?0.21; IVR group, p?=?0.24) before injection or 1 month after the first and third injections. There was also no difference in central corneal thickness (IVB group, p?=?0.15; IVR group, p?=?0.58) before injection or 1 month after the first and third injections.

Conclusion: Monthly 1.25?mg/0.05?ml IVIs of bevacizumab or 0.5?mg/0.05?ml of ranibizumab for three consecutive months in the treatment of diabetic macular edema does not affect corneal morphology and has no harmful effects on the endothelium.     

Intravitreal administration of known phototoxicants in the rabbit fails to produce phototoxicity: implications for phototoxicity testing of intravitreally administered small molecule therapeutics

Context: Intravitreal (ITV) dosing has become a clinically important route of administration for the treatment of uveitis, endophthalmitis, retinal vein occlusion, diabetic macular edema and age-related macular degeneration. Despite this, there are no validated non-clinical models of phototoxicity for ITV products.

Objective: The objective of this study was to develop an ITV rabbit model of phototoxicity for use in assessing the photosafety of small molecules therapeutics.

Materials and methods: Dutch Belted rabbits were intravitreally injected bilaterally with four known phototoxicants: 8-methoxypsoralen, lomefloxacin, doxycycline and stannsoporfrin. Triescence®, a non-phototoxic triamcinolone acetonide steroid formulation designed for ITV administration, was used as a negative control. One eye was then irradiated with solar-simulated ultraviolet radiation for 30?min, 1?h after dosing, while the other eye was occluded, serving as a non-irradiated control.

Results: Despite the direct administration of known phototoxicants into the vitreous, no evidence of ocular phototoxicity was observed in any dose group. Direct (non-phototoxic) retinal toxicity was observed in the doxycycline dose group only.

Conclusion: These data suggest that the posterior segment of the rabbit eye is protected against phototoxicity by anatomical and/or physiological mechanisms, and is not a useful model for the assessment of phototoxicity of intravitreally administered molecules.