Omadacycline: A New Tetracycline Antibiotic

2018 ◽  
Vol 53 (5) ◽  
pp. 486-500 ◽  
Author(s):  
John A. Dougherty ◽  
Allana J. Sucher ◽  
Elias B. Chahine ◽  
Katherine C. Shihadeh
Keyword(s):  
Data Extraction ◽  
Phase 1 ◽  
Common Adverse Effect ◽  
Tetracycline Antibiotic ◽  
Search Terms ◽  
Study Selection ◽  
Alternative Treatment Option ◽  
Wide Range ◽  
Resistant Strains

Objective: To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosage, and administration of omadacycline, a new tetracycline antibiotic. Data Sources: A literature search through PubMed, Google Scholar, and clinicaltrials.gov was conducted (2008 to October 2018) using the search terms omadacycline and PTK-0796. Abstracts presented at recent conferences, prescribing information and information from the FDA and the manufacturer’s website were reviewed. Study Selection and Data Extraction: Preclinical data and published phase 1, 2, and 3 studies were evaluated. Data Synthesis: Omadacycline displays in vitro activity against a wide range of bacteria. Clinical trials have shown that omadacycline is noninferior to linezolid for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and noninferior to moxifloxacin for the treatment of community-acquired bacterial pneumonia (CABP). A loading dose of 200 mg intravenously (IV) once or 100 mg IV twice or 450 mg orally for two days is recommended followed by a maintenance dose of 100 mg IV or 300 mg orally once daily. No dosage adjustment is needed in patients with renal or hepatic impairment. Omadacycline is well tolerated, with nausea being a common adverse effect, but is associated with food and drug interactions. Relevance to Patient Care and Clinical Practice: Omadacycline is active against staphylococci, including methicillin-resistant strains, and streptococci, including tetracycline-resistant strains, as well as atypical bacteria. Omadacycline provides clinicians with an additional parenteral and oral option for the treatment of adults with ABSSSI and CABP. Conclusion: Omadacycline is an alternative treatment option for ABSSSI and CABP.

Stiripentol: A Novel Antiseizure Medication for the Management of Dravet Syndrome

2019 ◽  
Vol 53 (11) ◽  
pp. 1136-1144 ◽  
Author(s):  
Marcia L. Buck ◽  
Howard P. Goodkin
Keyword(s):  
English Language ◽  
Data Extraction ◽  
Phase 1 ◽  
The United States ◽  
Dravet Syndrome ◽  
Pathogenic Variants ◽  
Search Terms ◽  
Novel Approach ◽  
Study Selection ◽  
Refractory Seizures

Objective: To describe the pharmacology, efficacy, and safety of stiripentol in the treatment of refractory seizures in patients with Dravet syndrome. Data Sources: A search of the English language literature was conducted using PubMed and MEDLINE (1978 to April 2019) with the search terms stiripentol, Dravet syndrome, and refractory epilepsy. Other resources included article bibliographies, prescribing information, and relevant trials at https://clinicaltrials.gov/ . Study Selection and Data Extraction: All phase 1, 2, or 3 trials; observational studies; and retrospective studies were analyzed. Data Synthesis: In controlled studies, stiripentol has been shown to reduce seizure frequency by 50% or more in 40% to 70% of patients with Dravet syndrome. Reductions in seizure duration and episodes of status epilepticus have also been documented. Common adverse effects include somnolence and anorexia. Stiripentol inhibits the metabolism of clobazam and valproate, often requiring dose adjustment. Relevance to Patient Care and Clinical Practice: Stiripentol, a direct allosteric modulator of GABAA receptors, offers a novel approach to treatment in patients with Dravet syndrome, both with and without pathogenic variants of the sodium channel α-1 subunit gene, and potentially other refractory seizures. Although available outside the United States for a decade, it was only recently approved by the Food and Drug Administration for patients 2 years of age and older with Dravet syndrome taking clobazam. Conclusions: Stiripentol is an effective adjunctive therapy for reducing the frequency and duration of refractory seizures in patients with Dravet syndrome. Its role in the treatment of other refractory epilepsies requires further study.

Maximizing Pharmacodynamics with High-Dose Levofloxacin

2005 ◽  
Vol 40 (9) ◽  
pp. 777-788 ◽  
Author(s):  
Kurt A. Wargo ◽  
Nichole A. Wargo ◽  
Edward H. Eiland
Keyword(s):  
Adverse Effects ◽  
Data Extraction ◽  
Community Acquired Pneumonia ◽  
High Dose ◽  
Data Synthesis ◽  
Search Terms ◽  
Short Course ◽  
Study Selection ◽  
Dosage Formulation

Objective To review published literature of levofloxacin 750 mg for the treatment of community-acquired pneumonia (CAP), nosocomial-acquired pneumonia (NAP), and skin and skin-structure infections (SSSI) focusing on microbiology, pharmacokinetic, and pharmacodynamic parameters. Data Sources MEDLINE was searched for clinical trials and review articles (1966 to September 2004). Also included were data from the manufacturer. Search terms utilized were levofloxacin, pneumonia, skin infections, adverse effects, pharmacokinetics, pharmacodynamics, and resistance. Study Selection and Data Extraction All articles and product labeling regarding levofloxacin for the treatment of CAP, NAP, and SSSI were included for review. Data Synthesis Compared with the other currently marketed fluoroquinolones, levofloxacin demonstrates similar in vitro activity to a number of commonly identified microorganisms. Levofloxacin 750 mg has shown equivalency to various non-fluoroquinolone regimens for the treatment of NAP and SSSI. Furthermore, a short, 5-day course of levofloxacin 750 mg was similar in efficacy to a longer, 10-day course of levofloxacin 500 mg for the treatment of CAP. Adverse events associated with levofloxacin therapy are dose independent; therefore, the adverse effects seen with high-dose levofloxacin are comparable to lower doses. Conclusions The levofloxacin 750 mg dosage formulation is a logical option when evaluating the antimicrobial armamentarium commonly utilized for the empiric treatment of CAP, NAP, and SSSI. Pharmacodynamic parameters are optimized and resistance is minimized when high-dose, short-course therapy is implemented.

Meropenem/Vaborbactam, the First Carbapenem/β-Lactamase Inhibitor Combination

2018 ◽  
Vol 52 (8) ◽  
pp. 769-779 ◽  
Author(s):  
Jonathan C. Cho ◽  
Monika T. Zmarlicka ◽  
Kristy M. Shaeer ◽  
Joe Pardo
Keyword(s):  
English Language ◽  
Clinical Success ◽  
Data Extraction ◽  
Phase Iii ◽  
Klebsiella Pneumoniae Carbapenemase ◽  
Preclinical Phase ◽  
Study Selection ◽  
Tract Infections ◽  
Lactamase Inhibitor

Objective: To review the pharmacology, spectrum of activity, pharmacokinetics, pharmacodynamics, safety, efficacy, administration, and considerations for clinical use of meropenem/vaborbactam (M/V). Data Sources: A literature search using PubMed and clinicaltrials.gov (June 2013 to December 2017) was conducted using the search terms meropenem, vaborbactam, RPX7009, biapenem, RPX2003, and carbavance. References from relevant articles and conference abstracts were also reviewed. Study Selection and Data Extraction: Preclinical, phase I studies, and phase III studies written in the English language were evaluated. Data Synthesis: M/V is a novel carbapenem/β-lactamase inhibitor antimicrobial with in vitro activity against nearly 99% of Klebsiella pneumoniae carbapenemase–producing Enterobacteriaceae. M/V is approved for the treatment of adults with complicated urinary tract infections (cUTIs), including pyelonephritis. In a phase III cUTI trial (TANGO I), 98.4% of patients treated with M/V experienced overall clinical success compared with 94% of patients treated with piperacillin/tazobactam (95% CI = 0.7 to 9.1). When compared with best available therapy for carbapenem-resistant Enterobacteriaceae (CRE) infections in TANGO II, patients receiving M/V were more likely to achieve clinical cure at both the end of therapy (64.3% vs 33.3%, P = 0.04) as well as at the test of cure (57.1% vs 26.7%, P = 0.04). The most common adverse effects associated with M/V were headache, infusion-site reactions, and diarrhea. Conclusion: M/V has a valuable role in the treatment of CRE and should be used judiciously to preserve its use for resistant infections.

scholarly journals Commercial tobacco and indigenous peoples: a stock take on Framework Convention on Tobacco Control progress

2018 ◽  
Vol 28 (5) ◽  
pp. 574-581 ◽  
Author(s):  
Raglan Maddox ◽  
Andrew Waa ◽  
Kelley Lee ◽  
Patricia Nez Henderson ◽  
Genevieve Blais ◽  
...  
Keyword(s):  
New Zealand ◽  
Tobacco Control ◽  
Indigenous Peoples ◽  
Tobacco Use ◽  
Data Extraction ◽  
Indigenous Populations ◽  
High Rate ◽  
Search Terms ◽  
Study Selection ◽  
Indigenous Participation

BackgroundThe health status and needs of indigenous populations of Australia, Canada and New Zealand are often compared because of the shared experience of colonisation. One enduring impact has been a disproportionately high rate of commercial tobacco use compared with non-indigenous populations. All three countries have ratified the WHO Framework Convention on Tobacco Control (FCTC), which acknowledges the harm caused to indigenous peoples by tobacco.Aim and objectivesWe evaluated and compared reporting on FCTC progress related to indigenous peoples by Australia, Canada and New Zealand as States Parties. The critiqued data included disparities in smoking prevalence between indigenous and non-indigenous peoples; extent of indigenous participation in tobacco control development, implementation and evaluation; and what indigenous commercial tobacco reduction interventions were delivered and evaluated.Data sourcesWe searched FCTC: (1) Global Progress Reports for information regarding indigenous peoples in Australia, Canada and New Zealand; and (2) country-specific reports from Australia, Canada and New Zealand between 2007 and 2016.Study selectionTwo of the authors independently reviewed the FCTC Global and respective Country Reports, identifying where indigenous search terms appeared.Data extractionAll data associated with the identified search terms were extracted, and content analysis was applied.ResultsIt is difficult to determine if or what progress has been made to reduce commercial tobacco use by the three States Parties as part of their commitments under FCTC reporting systems. There is some evidence that progress is being made towards reducing indigenous commercial tobacco use, including the implementation of indigenous-focused initiatives. However, there are significant gaps and inconsistencies in reporting. Strengthening FCTC reporting instruments to include standardised indigenous-specific data will help to realise the FCTC Guiding Principles by holding States Parties to account and building momentum for reducing the high prevalence of commercial tobacco use among indigenous peoples.

Dexrazoxane: A New Cardioprotective Agent

1998 ◽  
Vol 14 (5) ◽  
pp. 182-190 ◽  
Author(s):  
Beverly D Abbott ◽  
Cindy M Ippoliti
Keyword(s):  
Supportive Care ◽  
English Language ◽  
Bolus Dose ◽  
Cardiac Tissue ◽  
Data Extraction ◽  
Data Synthesis ◽  
Medline Search ◽  
Search Terms ◽  
Study Selection ◽  
Clinically Significant

Objective: To review the literature discussing the use of dexrazoxane (e.g., Zinecard, ICRF-187) to prevent doxorubicin-induced cardiotoxicity. Data Sources: Pertinent English-language reports of studies in humans were retrieved from a MEDLINE search (January 1980-January 1997); search terms included chelating agents, razoxane, dexrazoxane, Zinecard, ICRF-187, ADR-529, and ICRF-159. Study Selection: Representative articles discussing the chemistry, pharmacology, pharmacokinetics, dosing, and administration of dexrazoxane and those discussing clinical trials were selected. Data Extraction: Data were extracted and analyzed if the information was relevant and consistent. Studies were selected for review in the text on the basis of study design and clinical end points. Data Synthesis: Dexrazoxane is a chemoprotective agent developed to prevent cardiac tissue toxicity. Dexrazoxane exerts a cardioprotective effect with some clinically significant toxicities; it may also interfere with the antitumor activity of doxorubicin. Until there are sufficient data to support its use in first-line supportive care therapy, dexrazoxane should be reserved for use in patients responding to doxorubicin-based chemotherapy but who have risk factors for cardiac toxicity or have received a cumulative doxorubicin bolus dose of 300 mg/m2. Conclusions: The management of doxorubicin-induced cardiotoxicity has led to the development of supportive care drugs that specifically counteract the dose-limiting toxicities. Dexrazoxane may not completely eliminate the concern about doxorubicin-induced cardiotoxicity, but it may open new avenues for continuing doxorubicin-based chemotherapy.

scholarly journals In Vitro Antifungal Activities of a Series of Dication-Substituted Carbazoles, Furans, and Benzimidazoles

1998 ◽  
Vol 42 (10) ◽  
pp. 2503-2510 ◽  
Author(s):  
Maurizio Del Poeta ◽  
Wiley A. Schell ◽  
Christine C. Dykstra ◽  
Susan K. Jones ◽  
Richard R. Tidwell ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Candida Albicans ◽  
Fusarium Solani ◽  
Antifungal Agents ◽  
Antifungal Drugs ◽  
Inhibitory Compounds ◽  
Wide Range ◽  
Fluconazole Resistant ◽  
Resistant Strains

ABSTRACT Aromatic dicationic compounds possess antimicrobial activity against a wide range of eucaryotic pathogens, and in the present study an examination of the structures-functions of a series of compounds against fungi was performed. Sixty-seven dicationic molecules were screened for their inhibitory and fungicidal activities againstCandida albicans and Cryptococcus neoformans. The MICs of a large number of compounds were comparable to those of the standard antifungal drugs amphotericin B and fluconazole. Unlike fluconazole, potent inhibitory compounds in this series were found to have excellent fungicidal activities. The MIC of one of the most potent compounds against C. albicans was 0.39 μg/ml, and it was the most potent compound against C. neoformans (MIC, ≤0.09 μg/ml). Selected compounds were also found to be active againstAspergillus fumigatus, Fusarium solani,Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. Since some of these compounds have been safely given to animals, these classes of molecules have the potential to be developed as antifungal agents.

scholarly journals Cobicistat Versus Ritonavir: Similar Pharmacokinetic Enhancers But Some Important Differences

2017 ◽  
Vol 51 (11) ◽  
pp. 1008-1022 ◽  
Author(s):  
Alice Tseng ◽  
Christine A. Hughes ◽  
Janet Wu ◽  
Jason Seet ◽  
Elizabeth J. Phillips
Keyword(s):  
English Language ◽  
Data Extraction ◽  
Therapeutic Index ◽  
Search Terms ◽  
Language Studies ◽  
Study Selection ◽  
Pharmacokinetic Properties ◽  
Medication Dose ◽  
Concomitant Medications ◽  
Potential Interactions

Objective: To describe properties of cobicistat and ritonavir; compare boosting data with atazanavir, darunavir, and elvitegravir; and summarize antiretroviral and comedication interaction studies, with a focus on similarities and differences between ritonavir and cobicistat. Considerations when switching from one booster to another are discussed. Data Sources: A literature search of MEDLINE was performed (1985 to April 2017) using the following search terms: cobicistat, ritonavir, pharmacokinetic, drug interactions, booster, pharmacokinetic enhancer, HIV, antiretrovirals. Abstracts from conferences, article bibliographies, and product monographs were reviewed. Study Selection and Data Extraction: Relevant English-language studies or those conducted in humans were considered. Data Synthesis: Similar exposures of elvitegravir, darunavir, and atazanavir are achieved when combined with cobicistat or ritonavir. Cobicistat may not be as potent a CYP3A4 inhibitor as ritonavir in the presence of a concomitant inducer. Ritonavir induces CYP1A2, 2B6, 2C9, 2C19, and uridine 5′-diphospho-glucuronosyltransferase, whereas cobicistat does not. Therefore, recommendations for cobicistat with comedications that are extrapolated from studies using ritonavir may not be valid. Pharmacokinetic properties of the boosted antiretroviral can also affect interaction outcome with comedications. Problems can arise when switching patients from ritonavir to cobicistat regimens, particularly with medications that have a narrow therapeutic index such as warfarin. Conclusions: When assessing and managing potential interactions with ritonavir- or cobicistat-based regimens, clinicians need to be aware of important differences and distinctions between these agents. This is especially important for patients with multiple comorbidities and concomitant medications. Additional monitoring or medication dose adjustments may be needed when switching from one booster to another.

FUZE clinical trial: a phase 2 study of Debio 1347 in FGFR fusion-positive advanced solid tumors irrespectively of tumor histology.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3157-TPS3157 ◽  
Author(s):  
David Michael Hyman ◽  
Lipika Goyal ◽  
Petros Grivas ◽  
Funda Meric-Bernstam ◽  
Josep Tabernero ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Tumor Type ◽  
Phase 2 ◽  
Alternative Treatment Option

TPS3157 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR fusions is implicated in many cancers. Debio 1347 is a selective oral inhibitor of FGFR 1-3 tyrosine kinases. It exhibited high antitumor activity in in vitro and in vivo tumor models with FGFR1-3 gene fusions. Preliminary data from an ongoing phase 1 trial show efficacy and tolerability in patients (pts) harboring FGFR 1-3 fusion irrespectively of tumor type. We present the design for a multicenter, basket, 2-stage, adaptive single arm Phase 2 trial investigating Debio 1347 in pts with solid tumors harboring FGFR1-3 fusion/rearrangement. Methods: Adults with locally advanced/unresectable or metastatic tumors with documented FGFR1-3 gene fusion/rearrangement who require systemic therapy and have progression after ≥1 prior standard treatment or have no satisfactory alternative treatment option are eligible. Three cohorts are included: biliary tract cancer (cohort 1), urothelial cancer (cohort 2) and all other solid tumors (cohort 3). Primary brain tumors are excluded. Other key exclusion criteria include prior treatment with FGFR1-3 selective inhibitor; clinically significant corneal/retinal disorder; history of calcium/phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification, and symptomatic/unstable brain metastases < 1 month before enrollment. Genomic screening of tumor tissue is done at local or central laboratory with post-hoc central confirmation by RNA sequencing. Eligible pts will receive Debio 1347, 80 mg PO once daily in 28-day cycles until occurrence of progression or unacceptable toxicity. Primary Endpoint is objective response rate (ORR) based on independent central review using RECIST v.1.1. The targeted sample size (N=125) will provide approximately 90% power to reject H0: ORR ≤ 15% at an overall 5% significance level based on an expected ORR of 30% in at least one of the cohorts. Secondary endpoints are: duration of response, disease control rate, progression-free survival, overall survival, safety, tolerability, and quality of life. An interim analysis for futility and homogeneity will be performed after 27 evaluable pts. PK sparse sampling is performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. Accrual is opened in US, EU, Asia and Australia. Clinical trial information: NCT03834220.

scholarly journals In Vitro and In Vivo Antibacterial Activities of SM-216601, a New Broad-Spectrum Parenteral Carbapenem

2005 ◽  
Vol 49 (10) ◽  
pp. 4185-4196 ◽  
Author(s):  
Yutaka Ueda ◽  
Katsunori Kanazawa ◽  
Ken Eguchi ◽  
Koji Takemoto ◽  
Yoshiro Eriguchi ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Antibacterial Activities ◽  
Multiresistant Pathogens ◽  
E Coli ◽  
Wide Range ◽  
Agar Dilution ◽  
Resistant Strains ◽  
Mrsa Strains

ABSTRACT SM-216601 is a novel parenteral 1β-methylcarbapenem. In agar dilution susceptibility testing, the MIC of SM-216601 for 90% of the methicillin-resistant Staphylococcus aureus (MRSA) strains tested (MIC90) was 2 μg/ml, which was comparable to those of vancomycin and linezolid. SM-216601 was also very potent against Enterococcus faecium, including vancomycin-resistant strains (MIC90 = 8 μg/ml). SM-216601 exhibited potent activity against penicillin-resistant Streptococcus pneumoniae, ampicillin-resistant Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, with MIC90s of less than 0.5 μg/ml, and intermediate activity against Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa. The therapeutic efficacy of SM-216601 against experimentally induced infections in mice caused by S. aureus, E. faecium, E. coli, and P. aeruginosa reflected its in vitro activity and plasma level. Thus, SM-216601 is a promising candidate for nosocomial bacterial infections caused by a wide range of gram-positive and gram-negative bacteria, including multiresistant pathogens.

Intrapulmonary Percussive Ventilation as a Lung Recruitment Strategy in Brain-Dead Organ Donors

2016 ◽  
Vol 27 (1) ◽  
pp. 84-89 ◽  
Author(s):  
Geralyn Lerg ◽  
Linda Shanta
Keyword(s):  
Data Extraction ◽  
Chest Physiotherapy ◽  
Lung Recruitment ◽  
Recruitment Strategy ◽  
Organ Donors ◽  
Safe Alternative ◽  
Data Synthesis ◽  
Search Terms ◽  
Study Selection ◽  
Donor Population

Objective: To determine the strength of the evidence evaluating the effectiveness of intrapulmonary percussive ventilation (IPV) as a safe alternative or adjunctive therapy to traditional chest physiotherapy (CPT) among potential organ donors. Data Sources: Literature search conducted from February 2015 to November 2015 using PubMed, Cumulative Index of Nursing and Allied Health Literature, Scopus, and bibliographies of pertinent articles. Search Terms: Intrapulmonary percussive ventilation, chest physiotherapy, chest wall oscillation, organ donors, and ventilation. Study Selection: Articles in English from 1994 to present directly compared IPV to CPT or conventional (no) therapy. Data Extraction: Association of Critical-Care Nurses Levels of Evidence was used to determine the strength of evidence. Level B and level C articles were reviewed. Data Synthesis: No studies were found using IPV in the donor population. Results from studies using IPV in other populations indicated IPV had no adverse effects, improved sputum clearance and oxygenation, and reduced atelectasis and pneumonia in patients with artificial airways. Conclusion: Intrapulmonary percussive ventilation may be a safe and effective alternative or adjunctive to CPT therapy and improve the number of lungs available for transplantation. Clinical research is essential to determine the effectiveness of this therapy for lung recruitment in the donor population.

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