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William M Mega, Melanie Doyle-Eisele, Robert T Cass, Corwin F Kostrub, Robert L Sherwood, Matthew A Metz, Ryan T Cirz
The efficacy of plazomicin for pneumonic plague was evaluated in a non-human primate model. African Green monkeys challenged with a lethal aerosol of Yersinia pestis [median (range) of 98 (15-331) LD50s] received placebo (n=12) or 'humanized' dose regimens (6.25, 12.5 or 25mg/kg every 24h) of plazomicin (n=52) after the onset of fever for a duration of 5 or 10days. All animals treated with placebo died, while 36 plazomicin-treated animals survived through study end. The majority (33/36) were either in the 10-day (high-/mid-/low-dose) or 5-day high-dose groups...
August 27, 2016: Bioorganic & Medicinal Chemistry
Matthew E Falagas, Andreas D Mavroudis, Konstantinos Z Vardakas
INTRODUCTION: A real concern in the medical community is the increasing resistance of bacteria, especially that of Gram-negative types. New antibiotics are currently under clinical development, promising to tackle severe infections caused, especially, by multi-drug resistant (MDR) bacteria and broaden the armamentarium of clinicians. AREAS COVERED: We searched PUBMED and GOOGLE databases. Combinations of already approved β-lactams or monobactams with new β-lactamase inhibitors [imipenem-cilastatin/MK-7655 (relebactam), meropenem/RPX7009 (vaborbactam), ceftaroline/avibactam, aztreonam/avibactam], new β-lactams (S-649266, BAL30072), aminoglycosides (plazomicin), quinolones (finafloxacin) and tetracyclines (eravacycline) were included in the review...
August 2016: Expert Review of Anti-infective Therapy
Joshua T Thaden, Jason M Pogue, Keith S Kaye
Antimicrobial resistance has been identified by the World Health Organization as "one of the three greatest threats to human health." Gram negative bacteria in particular drive this alarming trend. Carbapenem-resistant Enterobacteriaceae (CRE) such as Escherichia coli, Klebsiella pneumoniae, and Enterobacter species are of particular importance as they are associated with poor clinical outcomes and are common causes for a variety of infections including bacteremia, urinary tract infection, intra-abdominal infections and pneumonia...
July 6, 2016: Virulence
Adamantia Liapikou, Antoni Torres
INTRODUCTION: Hospital-acquired pneumonia (HAP) is one of the leading nosocomial infections worldwide and is associated with an elevated morbidity and mortality and increased hospital costs. Nevertheless, prompt and adequate antimicrobial treatment is mandatory following VAP development, especially in the face of multidrug resistant pathogens. AREAS COVERED: We searched Pubmed and site reports in English language of phase III clinical trials, between 2000-2016 referring to the antibiotic treatment of nosocomial pneumonia...
September 2016: Expert Opinion on Emerging Drugs
Ghady Haidar, Ammar Alkroud, Shaoji Cheng, Travis M Churilla, Bryce M Churilla, Ryan K Shields, Yohei Doi, Cornelius J Clancy, M Hong Nguyen
We compared the in vitro activities of gentamicin (GEN), tobramycin (TOB), amikacin (AMK), and plazomicin (PLZ) against 13 Enterobacter isolates possessing both Klebsiella pneumoniae carbapenemase and extended-spectrum β-lactamase (KPC+/ESBL+) with activity against 8 KPC+/ESBL-, 6 KPC-/ESBL+, and 38 KPC-/ESBL- isolates. The rates of resistance to GEN and TOB were higher for KPC+/ESBL+ (100% for both) than for KPC+/ESBL- (25% and 38%, respectively), KPC-/ESBL+ (50% and 17%, respectively), and KPC-/ESBL- (0% and 3%, respectively) isolates...
September 2016: Antimicrobial Agents and Chemotherapy
Yohei Doi, Jun-Ichi Wachino, Yoshichika Arakawa
Aminoglycoside-producing Actinobacteria are known to protect themselves from their own aminoglycoside metabolites by producing 16S ribosomal RNA methyltransferase (16S-RMTase), which prevents them from binding to the 16S rRNA targets. Ten acquired 16S-RMTases have been reported from gram-negative pathogens. Most of them posttranscriptionally methylate residue G1405 of 16S rRNA resulting in high-level resistance to gentamicin, tobramycin, amikacin, and plazomicin. Strains that produce 16S-RMTase are frequently multidrug-resistant or even extensively drug-resistant...
June 2016: Infectious Disease Clinics of North America
Izabela Karpiuk, Stefan Tyski
This paper is the fourth in a series on the search for new antibacterial therapies, and covers new compounds belonging to the aminoglycoside, macrolide and tetracycline groups of antibiotics. The article describes eight new substances at the clinical trial stage of development. One of them is an aminoglycoside (plazomicin), four are macrolides, collectively known as ketolides (cethromycin, solithromycin, EDP-420 and EDP-788), and the remaining three are members of the tetracycline group (omadacycline, eravacycline, sarecycline)...
2015: Przegla̧d Epidemiologiczny
Ling-Shan Syue, Yen-Hsu Chen, Wen-Chien Ko, Po-Ren Hsueh
The continuing increase in multidrug-resistant organisms (MDROs) worldwide has created new challenges in treating complicated intra-abdominal infections (cIAIs). A number of novel antimicrobial agents have been developed against resistant pathogens. To target extended-spectrum β-lactamase (ESBL)-producing pathogens, novel β-lactam antibiotics, such as ceftolozane/tazobactam, ceftazidime/avibactam, aztreonam/avibactam, imipenem/relebactam and S-649266, are antimicrobial alternatives for cIAIs. Two new drugs, eravacycline and plazomicin, have activity against Klebsiella pneumoniae carbapenemase (KPC)-producing K...
April 2016: International Journal of Antimicrobial Agents
Shang-Yi Lin, Chung-Hao Huang, Wen-Chien Ko, Yen-Hsu Chen, Po-Ren Hsueh
INTRODUCTION: Treatment of complicated intra-abdominal infections (cIAIs) is becoming increasingly difficult because of the widespread emergence of multidrug-resistant organisms. AREAS COVERED: In this review, we discuss the effectiveness of several new antibiotics for the treatment of cIAIs, including new β-lactamase inhibitor combinations (BLICs) and tetracycline-class drugs, recently developed aminoglycosides and quinolones, and novel lipoglycopeptides and oxazolidinones...
2016: Expert Opinion on Pharmacotherapy
W V Kern
After some years of stagnation there have been several new successful developments in the field of antibacterial agents. Most of these new developments have been in conventional antibacterial classes. New drugs among the beta-lactam agents are methicillin-resistant Staphylococcus aureus (MRSA) active cephalosporins (ceftaroline and ceftobiprole) and new combinations of beta-lactam with beta-lactamase inhibitors (ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam and meropenem/RPX7009). New developments can also be observed among oxazolidinones (tedizolid, radezolid, cadazolid and MRX-I), macrolides/ketolides (modithromycin and solithromycin), aminoglycosides (plazomicin), quinolones (nemonoxacin, delafloxacin and avarofloxacin), tetracyclines (omadacycline and eravacycline) as well as among glycopeptides and lipopeptides (oritavancin, telavancin, dalbavancin and surotomycin)...
November 2015: Der Internist
Ilias Karaiskos, Maria Souli, Helen Giamarellou
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...
2015: Expert Opinion on Investigational Drugs
Iciar Rodríguez-Avial, Irene Pena, Juan J Picazo, Carmen Rodríguez-Avial, Esther Culebras
Carbapenemase-producing Enterobacteriaceae (CPE) cause serious infections and are associated with high mortality in part due to limited treatment options. The in vitro activities of the new aminoglycoside plazomicin and comparators were evaluated against a collection of 164 CPE (VIM-1, n=125; KPC-2, n=34; OXA-48, n=4; and IMP-22, n=1). MIC90 values of gentamicin, tobramycin and amikacin were 256, 64 and 16 mg/L, respectively. Plazomicin exhibited an MIC range of 0.12-4 mg/L with MIC50 and MIC90 values of 0...
December 2015: International Journal of Antimicrobial Agents
Matteo Bassetti, Elda Righi
PURPOSE OF REVIEW: Increasing rates of life-threatening infections due to multidrug-resistant (MDR) gram-negative bacteria, such as carbapenemase-producer strains, as well as pathogens that are resistant to all current therapeutic options, have been reported. The number of compounds that are currently being developed is still insufficient to control this global threat. We have reviewed the current available options for the treatment of MDR gram-negative infections, including combination regimens employing older antimicrobials and new compounds...
October 2015: Current Opinion in Critical Care
Esther Bettiol, Stephan Harbarth
Since 2010, awareness of the global threat caused by antimicrobial resistance (AMR) has risen considerably and multiple policy and research initiatives have been implemented. Research and development (R&D) of much-needed new antibiotics active against multiresistant pathogens is a key component of all programmes aiming at fighting AMR, but it has been lagging behind owing to scientific, regulatory and economic challenges. Although a few new antibiotics might be available in Switzerland in the next 5 years, these new agents are not based on new mechanisms of action and are not necessarily active against resistant pathogens for which there is the highest unmet medical need, i...
2015: Swiss Medical Weekly
Cristina García-Salguero, Iciar Rodríguez-Avial, Juan J Picazo, Esther Culebras
Nosocomial pathogens can be associated with a variety of infections, particularly in intensive care units (ICUs) and in immunocompromised patients. Usually these pathogens are resistant to multiple drugs and pose therapeutic challenges. Among these organisms, Acinetobacter baumannii is one of the most frequent being encountered in the clinical setting. Carbapenems are very useful to treat infections caused by these drug-resistant Gram-negative bacilli, but carbapenem resistance is increasing globally. Combination therapy is frequently given empirically for hospital-acquired infections in critically ill patients and is usually composed of an adequate beta-lactam and an aminoglycoside...
October 2015: Antimicrobial Agents and Chemotherapy
Matteo Bassetti, Elda Righi
BACKGROUND: Infections due to multidrug-resistant (MDR) bacteria are increasing both in hospitals and in the community and are characterized by high mortality rates. New molecules are in development to face the need of active compounds toward resistant gram-positive and gram-negative pathogens. In particular, the Infectious Diseases Society of America (IDSA) has supported the initiative to develop ten new antibacterials within 2020. Principal targets are the so-called ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacteriaceae)...
February 2015: Langenbeck's Archives of Surgery
Juan Pablo Horcajada, Julián Torre-Cisneros, Carmen Peña, María Carmen Fariñas
The emergence and spread of carbapenemase-producing Enterobacteriaceae is an important and very concerning problem. There is an urgent need of new antibimicrobials for treating these infections. Currently there are some options in the pipeline. Several new beta-lactamase and carbapenemase inhibitors as avibactam and MK-7655, combined with old or new betalactams are a very interesting option. Some combinations as ceftazidime-avibactam are in the late stages of clinical development and could reach the market in the next years...
December 2014: Enfermedades Infecciosas y Microbiología Clínica
Steven C Olsen, Steve A Carlson
Plazomicin is a next-generation aminoglycoside with a potentially unique set of clinical characteristics compared with other aminoglycosides. This study assessed the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of plazomicin against 15 clinical isolates as well as three reference strains representing Brucella abortus, Brucella melitensis and Brucella suis. These data were compared with those obtained for six other aminoglycosides and two aminocyclitols. Plazomicin and gentamicin were the only drugs demonstrating bactericidal activity towards two of the three Brucella spp...
January 2015: International Journal of Antimicrobial Agents
Garyphallia Poulakou, Matteo Bassetti, Elda Righi, George Dimopoulos
The spread of multidrug-resistant, extensively drug-resistant and pan-drug-resistant pathogens is causing an unprecedented public health crisis. The limited current therapeutic options led to the revival of two 'old' antibiotics - colistin and fosfomycin - for which a better understanding of their pharmacokinetics in the critically ill patient and in specific body compartments is required. Tigecycline's use in clinical practice for nonapproved indication based on its in vitro activity against problematic pathogens requires caution and probably higher doses...
2014: Future Microbiology
Chang-Seop Lee, Yohei Doi
The prevalence of carbapenem-resistant gram-negative bacterial pathogens (CRGNs) has increased dramatically during the last 10 years, but the optimal treatment for CRGN infections is not well established due to the relative scarcity of robust clinical data. The polymyxins remain the most consistently active agents against CRGNs in vitro. Tigecycline, based on its in vitro antibacterial spectrum, could also be considered as a therapeutic option in the treatment of infections caused by certain CRGNs. Other agents, including aminoglycosides, rifampin, trimethoprim-sulfamethoxazole, fosfomycin and fluoroquinolones, could be considered as monotherapy or combination therapy against CRGNs in appropriate contexts, as combination therapy with two or more in vitro active drugs appears to be more effective than monotherapy based on some clinical data...
September 2014: Infection & Chemotherapy
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