Treatment Of Serious Infections Research Articles

Insights into Key Interactions between Vancomycin and Bacterial Cell Wall Structures.

Vancomycin is a glycopeptide antibiotic used for the treatment of serious infections by Gram-positive pathogens. Vancomycin inhibits cell wall biosynthesis by targeting the d-Ala-d-Ala terminus of peptidoglycan (PG). The highly cross-linked heptapeptide aglycon structure of vancomycin is the d-Ala-d-Ala binding site. The first residue of vancomycin is N-methyl-leucine, which is crucial for the dipeptide binding. The removal of N-methyl-leucine by Edman degradation results in desleucyl-vancomycin devoid of antimicrobial activities. To investigate the function of N-methyl-leucine for the dipeptide binding in vancomycin, molecular dynamics simulations of vancomycin and three N-terminus-modified vancomycin derivatives: desleucyl-vancomycin, vancomycinNtoC, and vancomycinSar, binding to a PG unit of the sequence l-Ala-d-iso-Gln-l-Lys-d-Ala-d-Ala with an intact pentaglycine bridge structure attached to the bridge link of l-Lys were carried out. Glycopeptide–PG binding interactions were characterized by root-mean-square-deviation contour analysis of atomic positions in vancomycin and its three analogues bound to a PG unit. The overall sampling space for four glycopeptide–PG complexes shows four distinct distributions with a continuous change between the conformational spaces. The hydrogen bond analyses show that multiple hydrogen bonds between the d-Ala-d-Ala and the vancomycin aglycon structure strengthened the dipeptide binding. The simulations revealed that the removal or chemical modification of N-methyl-leucine significantly weakens the dipeptide binding to the aglycon structure and provides interesting structural insights into glycopeptide–PG binding interactions.

Hospital Outbreak of a Colistin-Resistant, NDM-1- and OXA-48-Producing Klebsiella pneumoniae: High Mortality from Pandrug Resistance.

Colistin resistance causes substantial problems in the treatment of serious infections with carbapenem-resistant (CR) gram-negative bacteria. In this study, we report a fatal hospital outbreak from the spread of a pandrug-resistant Klebsiella pneumoniae clone. An outbreak investigation was conducted after consecutive isolation of nine CR-K. pneumoniae (CR-Kp) strains from eight patients in two intensive care units of a university hospital within 2 weeks. Carbapenem and colistin resistance genes were investigated with PCR, clonal relationships of isolates were studied with pulse-field gel electrophoresis, and multilocus sequence types were determined. The outcomes of the affected patients were analyzed. Genotyping showed a predominant CR-Kp clone consisting of seven strains from six patients. These strains were in ST11 type, an international high-risk clone. They were resistant to all antimicrobials, including colistin, and positive for NDM-1 and OXA-48 carbapenemases, but negative for plasmid-borne colistin resistance genes. One patient had colonization and the remaining five died due to the infection within mean 12 days. No environmental or staff links could be established, and the outbreak was stopped by augmenting infection-control measures. Colistin-resistant K. pneumoniae could clonally expand in the hospital setting, and this spread might be associated with high mortality due to the lack of an appropriate treatment option. Immediate implementation of infection-control measures may be the best way to limit fatal consequences of the spread of such incurable pathogens.

Identification of Drug-Repellent Encoded Genes (Efflux pump) in Pseudomonas aeruginosa Isolated from Stool Samples, Kerman Province

Introduction: Pseudomonas aeruginosa is one of the important bacteria for nosocomial infections; particularly in patients with immune deficiency. For the treatment of serious infections caused by these bacteria, antibiotics such as aminoglycosides many, quinolones and beta-lactams are used. However the emergence and spread of resistant nosocomial strains of resistance have been reported. Nowadays, efflux pump has been proposed as an important mechanism of resistance to antibiotics in bacteria. Materials & methods: In this cross-sectional study, 60 clinical isolates of P.aeruginosa were collected from fecal samples from laboratories in Kerman province. All isolates were approved with the phenotype and biochemical tests. The disk diffusion method was performed according to CLSI (Clinical and Laboratory Standards Institute). Multiplex-PCR tests were performed for detection of efflux pumps genes (mexA, mexB, mexR) using specific primers. Findings: All the 60 fecal isolates of P..aeruginosa were confirmed by biochemical tests. The greatest sensitivity was observed for ceftizoxime 55(91.7%), imipenem, 54(90%), meropenem, 48(80%) and ciprofloxacin 40(66.7%). The greatest resistance were determined to antibiotics cefepime 36(60%) and ciprofloxacin 19(31.7%). The highest frequency was observed of Mex B gene in 59(98.3%) of the isolates. Discussion & conclusions: Rapid diagnosis of Pseudomonas aeruginosa in clinical samples is more than important for initiation of treatment. In general, the use of multiplex polymerase chain reaction for detection of antibiotic-resistant P. aeruginosa is very important in clinical samples of patients.

Association of vancomycin with lipid vesicles

Antibiotics play a pivotal role in modern medicine for the treatment of bacterial infection in patients. Membrane defines the boundary between single cell and its environment and is a main target for antibacterial agents. To better understand the mechanism of antibiotics action on microbes, we utilized liposome as membrane mimic model to study antibiotics interaction with bacterial membrane by variety of biophysical methods. Isothermal calorimetry and fluorescence photometry experiments were performed to examine interaction between antibiotics and liposome. We found that vancomycin, one of the most important antibiotics for the treatment of serious infections by gram-positive bacteria, binds to the liposome. The association between the drug and the liposome does not involve the tail part of the lipids. Moreover, the binding affinity increases along with the increment of liposome size. Of three major lipid components, phosphatidylglycerol is the preferential target for vancomycin binding. We also showed that vancomycin associates with vesicle derived from Staphylococcus aureus membrane in a similar manner as the binding to liposome. Our data suggested that vancomycin associates with bacterial membrane through direct interaction with lipid head groups with the extent of the association depending very much on specific type of lipids and curvature of local membrane structure.

In Vitro Activity of Aztreonam-Avibactam against Enterobacteriaceae and Pseudomonas aeruginosa Isolated by Clinical Laboratories in 40 Countries from 2012 to 2015.

The combination of the monobactam aztreonam and the non-β-lactam β-lactamase inhibitor avibactam is currently in clinical development for the treatment of serious infections caused by metallo-β-lactamase (MBL)-producing Enterobacteriaceae, a difficult-to-treat subtype of carbapenem-resistant Enterobacteriaceae for which therapeutic options are currently very limited. The present study tested clinically significant isolates of Enterobacteriaceae (n = 51,352) and Pseudomonas aeruginosa (n = 11,842) collected from hospitalized patients in 208 medical center laboratories from 40 countries from 2012 to 2015 for in vitro susceptibility to aztreonam-avibactam, aztreonam, and comparator antimicrobial agents using a standard broth microdilution methodology. Avibactam was tested at a fixed concentration of 4 μg/ml in combination with 2-fold dilutions of aztreonam. The MIC90s of aztreonam-avibactam and aztreonam were 0.12 and 64 μg/ml, respectively, for all Enterobacteriaceae isolates; >99.9% of all isolates and 99.8% of meropenem-nonsusceptible isolates (n = 1,498) were inhibited by aztreonam-avibactam at a concentration of ≤8 μg/ml. PCR and DNA sequencing identified 267 Enterobacteriaceae isolates positive for MBL genes (NDM, VIM, IMP); all Enterobacteriaceae carrying MBLs demonstrated aztreonam-avibactam MICs of ≤8 μg/ml and a MIC90 of 1 μg/ml. Against all P. aeruginosa isolates tested, the MIC90 of both aztreonam-avibactam and aztreonam was 32 μg/ml; against MBL-positive P. aeruginosa isolates (n = 452), MIC90 values for aztreonam-avibactam and aztreonam were 32 and 64 μg/ml, respectively. The current study demonstrated that aztreonam-avibactam possesses potent in vitro activity against a recent, sizeable global collection of Enterobacteriaceae clinical isolates, including isolates that were meropenem nonsusceptible, and against MBL-positive isolates of Enterobacteriaceae, for which there are few treatment options.

WCK 5107 (Zidebactam) and WCK 5153 Are Novel Inhibitors of PBP2 Showing Potent "β-Lactam Enhancer" Activity against Pseudomonas aeruginosa, Including Multidrug-Resistant Metallo-β-Lactamase-Producing High-Risk Clones.

Zidebactam and WCK 5153 are novel β-lactam enhancers that are bicyclo-acyl hydrazides (BCH), derivatives of the diazabicyclooctane (DBO) scaffold, targeted for the treatment of serious infections caused by highly drug-resistant Gram-negative pathogens. In this study, we determined the penicillin-binding protein (PBP) inhibition profiles and the antimicrobial activities of zidebactam and WCK 5153 against Pseudomonas aeruginosa, including multidrug-resistant (MDR) metallo-β-lactamase (MBL)-producing high-risk clones. MIC determinations and time-kill assays were conducted for zidebactam, WCK 5153, and antipseudomonal β-lactams using wild-type PAO1, MexAB-OprM-hyperproducing (mexR), porin-deficient (oprD), and AmpC-hyperproducing (dacB) derivatives of PAO1, and MBL-expressing clinical strains ST175 (blaVIM-2) and ST111 (blaVIM-1). Furthermore, steady-state kinetics was used to assess the inhibitory potential of these compounds against the purified VIM-2 MBL. Zidebactam and WCK 5153 showed specific PBP2 inhibition and did not inhibit VIM-2 (apparent Ki [Kiapp] > 100 μM). MICs for zidebactam and WCK 5153 ranged from 2 to 32 μg/ml (amdinocillin MICs > 32 μg/ml). Time-kill assays revealed bactericidal activity of zidebactam and WCK 5153. LIVE-DEAD staining further supported the bactericidal activity of both compounds, showing spheroplast formation. Fixed concentrations (4 or 8 μg/ml) of zidebactam and WCK 5153 restored susceptibility to all of the tested β-lactams for each of the P. aeruginosa mutant strains. Likewise, antipseudomonal β-lactams (CLSI breakpoints), in combination with 4 or 8 μg/ml of zidebactam or WCK 5153, resulted in enhanced killing. Certain combinations determined full bacterial eradication, even with MDR MBL-producing high-risk clones. β-Lactam-WCK enhancer combinations represent a promising β-lactam "enhancer-based" approach to treat MDR P. aeruginosa infections, bypassing the need for MBL inhibition.

In Vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

Fosfomycin is a broad-spectrum agent with activity against Gram-positive and Gram-negative bacteria, including drug-resistant strains, such as extended-spectrum-beta-lactamase (ESBL)-producing and carbapenem-resistant (CR) Gram-negative rods. In the present study, the pharmacokinetic/pharmacodynamic (PK/PD) activity of ZTI-01 (fosfomycin for injection) was evaluated in the neutropenic murine thigh infection model against 5 Escherichia coli, 3 Klebsiella pneumoniae, and 2 Pseudomonas aeruginosa strains, including a subset with ESBL and CR phenotypes. The pharmacokinetics of ZTI-01 were examined in mice after subcutaneous administration of 3.125, 12.5, 50, 200, 400, and 800 mg/kg of body weight. The half-life ranged from 0.51 to 1.1 h, area under the concentration-time curve (AUC0-∞) ranged from 1.4 to 87 mg · h/liter, and maximum concentrations ranged from 0.6 to 42.4 mg/liter. Dose fractionation demonstrated the AUC/MIC ratio to be the PK/PD index most closely linked to efficacy (R2 = 0.70). Net stasis and bactericidal activity were observed against all strains. Net stasis was observed at 24-h AUC/MIC ratio values of 24, 21, and 15 for E. coli, K., pneumoniae and P. aeruginosa, respectively. For the Enterobacteriaceae group, stasis was noted at mean 24-h AUC/MIC ratio targets of 23 and 1-log kill at 83. Survival in mice infected with E. coli 145 was maximal at 24-h AUC/MIC ratio exposures of 9 to 43, which is comparable to the stasis exposures identified in the PK/PD studies. These results should prove useful for the design of clinical dosing regimens for ZTI-01 in the treatment of serious infections due to Enterobacteriaceae and Pseudomonas.

Genome-Wide Identification of Potential Drug Target in Enterobacteriaceae Family: A Homology-Based Method.

The Enterobacteriaceae is a large family of Gram-negative, facultative anaerobic, non-spore forming rod-shaped bacteria that includes harmless and pathogenic organisms. The emergence and development of drug resistance in Enterobacteriaceae is complicating the treatment of serious infections. The aim of this study is to predict and characterize putative drug targets in Enterobacteriaceae family employing a homology-based computational method. The final putative drug targets were qualitatively characterized via cellular function prediction, subcellular localization prediction, broad-spectrum, and druggability analyses. Of 6,327 analyzed proteins, 35 proteins were selected as final putative drug targets in Enterobacteriaceae family. These putative drug targets were involved in different vital pathways like metabolism, biosynthesis of macromolecule, and cell division. Predicted drug targets were also localized in the cytoplasm and cytoplasmic membrane of the pathogen that acts as antimicrobial or vaccine targets. Of 35 drug targets, 5 targets were druggable and 30 targets were not druggable and were predicted as novel drug targets, which should be further evaluated to develop new antimicrobial. Thirteen drug targets were considered as broad-spectrum targets. It is expected that results of our study could facilitate the production of novel antibacterial for efficient treatment of infections caused by Enterobacteriaceae pathogens.

Design and Implementation of a Novel Web-Based E-Learning Tool for Education of Health Professionals on the Antibiotic Vancomycin.

BackgroundTraditional approaches to health professional education are being challenged by increased clinical demands and decreased available time. Web-based e-learning tools offer a convenient and effective method of delivering education, particularly across multiple health care facilities. The effectiveness of this model for health professional education needs to be explored in context.ObjectivesThe study aimed to (1) determine health professionals’ experience and knowledge of clinical use of vancomycin, an antibiotic used for treatment of serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and (2) describe the design and implementation of a Web-based e-learning tool created to improve knowledge in this area.MethodsWe conducted a study on the design and implementation of a video-enhanced, Web-based e-learning tool between April 2014 and January 2016. A Web-based survey was developed to determine prior experience and knowledge of vancomycin use among nurses, doctors, and pharmacists. The Vancomycin Interactive (VI) involved a series of video clips interspersed with question and answer scenarios, where a correct response allowed for progression. Dramatic tension and humor were used as tools to engage users. Health professionals’ knowledge of clinical vancomycin use was obtained from website data; qualitative participant feedback was also collected.ResultsFrom the 577 knowledge survey responses, pharmacists (n=70) answered the greatest number of questions correctly (median score 4/5), followed by doctors (n=271; 3/5) and nurses (n=236; 2/5; P<.001). Survey questions on target trough concentration (75.0%, 433/577) and rate of administration (64.9%, 375/577) were answered most correctly, followed by timing of first level (49%, 283/577), maintenance dose (41.9%, 242/577), and loading dose (38.0%, 219/577). Self-reported “very” and “reasonably” experienced health professionals were also more likely to achieve correct responses. The VI was completed by 163 participants during the study period. The rate of correctly answered VI questions on first attempt was 65% for nurses (n=63), 68% for doctors (n=86), and 82% for pharmacists (n=14; P<.001), reflecting a similar pattern to the knowledge survey. Knowledge gaps were identified for loading dose (39.2% correct on first attempt; 64/163), timing of first trough level (50.3%, 82/163), and subsequent trough levels (47.9%, 78/163). Of the 163 participants, we received qualitative user feedback from 51 participants following completion of the VI. Feedback was predominantly positive with themes of “entertaining,” “engaging,” and “fun” identified; however, there were some technical issues identified relating to accessibility from different operating systems and browsers.ConclusionsA novel Web-based e-learning tool was successfully developed combining game design principles and humor to improve user engagement. Knowledge gaps were identified that allowed for targeting of future education strategies. The VI provides an innovative model for delivering Web-based education to busy health professionals in different locations.

Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections.

Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated monosulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure-activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED50 of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.

Detection and analysis of different interactions between resistance mechanisms and carbapenems in clinical isolates of Klebsiella pneumoniae.

Carbapenems are considered last-line agents for the treatment of serious infections caused by Klebsiella pneumoniae, and this microorganism may exhibit resistance to β-lactam antibiotics due to different mechanisms of resistance. We evaluated 27 isolates of K. pneumoniae resistant to carbapenems recovered from inpatients at the University Hospital of Santa Maria-RS from July 2013 to August 2014. We carried out antimicrobial susceptibility, carbapenemase detection, testing for the presence of efflux pump by broth microdilution and loss of porin by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Genetic similarity was evaluated by ERIC-PCR. High levels of resistance were verified by the minimum inhibitory concentration for the antimicrobials tested. The blaKPC gene was present in 89% of the clinical isolates. Blue-Carba and combined disk with AFB tests showed 100% concordance, while the combined disk test with EDTA showed a high number of false-positives (48%) compared with the gold-standard genotypic test. Four isolates showed a phenotypic resistance profile consistent with the overexpression of the efflux pump, and all clinical isolates had lost one or both porins. The ERIC-PCR dendrogram demonstrated the presence of nine clusters. The main mechanism of resistance to carbapenems found in the assessed isolates was the presence of the blaKPC gene.

Protective effect of apocynin against gentamicin-induced nephrotoxicity in rats.

Gentamicin (GNT) is an aminoglycoside antibiotic used for treatment of serious infections, and the nephrotoxic adverse effect is one of the main therapeutic limitations. This study aimed to investigate the possible protective effect of apocynin (APO) on nephrotoxicity induced by GNT in rats. Twenty-four rats were allocated into three groups: control, GNT (100 mg/kg, intraperitoneally (i.p.)), and GNT plus APO (10 mg/kg, i.p.). All rats were killed at the end of the experiment, and then the blood, urine, and kidneys samples were taken. GNT-induced nephrotoxicity was manifested by a significant ( p < 0.05) increase in the weight of kidney, 24-h urine volume, renal somatic index (RSI), protein in urine, serum lactate dehydrogenase (LDH), creatinine (Cr), blood urea nitrogen (BUN), renal Fas ligand (CD95), nitric oxide (NO), and malondialdehyde (MDA). Furthermore, a significant reduction in body weight, creatinine clearance (CCr), serum albumin, renal superoxide dismutase (SOD), and glutathione activities were detected when compared with the control rats. APO ameliorated the nephrotoxic effect and oxidative damage caused by GNT by improving tissue morphology and significantly decreasing 24-h urine volume, RSI, serum Cr, LDH and BUN, protein in urine, and renal content of MDA, CD95, and NO. Additionally, APO caused a significant elevation in renal SOD activity and CCr when compared with the GNT group. These results confirm that APO by its anti-inflammatory, antiapoptotic, and antioxidant effects can ameliorate GNT-induced nephrotoxicity.

A smart aminoglycoside hydrogel with tunable gel degradation, on-demand drug release, and high antibacterial activity

Aminoglycosides are a family of critically important antibiotics for the treatment of serious infections including multidrug-resistant pathogens. However, clinical use of aminoglycoside antibiotics is compromised by bacterial biofilm formation at subinhibitory concentrations or adverse side effects such as ototoxicity and nephrotoxicity at high antibiotic doses. Preparation of aminoglycoside formulation that allows on-demand drug delivery is a solution to this sticky issue. Here, we designed a new type of aminoglycoside hydrogels by cross-linking oxidized polysaccharides such as dextran, carboxymethyl cellulose, alginate, and chondroitin using aminoglycosides as cross-linkers. The hydrogel modulus, degradation rate and release kinetics can be precisely modulated by tailoring the aminoglycoside dose during gel formation. The aminoglycoside hydrogel showed fast gelation, self-healing and on-demand drug release behaviors, and high antibacterial activities in vitro and in vivo against both Gram-positive and Gram-negative bacteria. This study provides a facile and promising strategy to develop smart hydrogels for topical administration of aminoglycoside antibiotics.

Antimicrobial Efficacy of Doripenem Colistin Combination on Carbapenem - Resistant Acinetobacter Baumanii Isolates by E-Test Agar Dilution and Ultrastrastructural Methods

Background: Acinetobacter baumannii (A.baumannii) is a serious nosocomial pathogen and a threat for hospitalized patients especially in intensive care units (ICUs). Infections caused by the bacteria are difficult to treat owing to the frequent development of resistant strains which are mostly multidrug resistant (MDR). Emerging resistance to carbapenems is an alarming issue. As treatment options are limited so the discovery of new therapies, including combination therapy, is required. Doripenem is a new carbapenem, which is more stable against carbapenemases. Colistin remains a last line treatment for MDR A.baumannii and its combined use with cabapenems may present a possible strategy for treatment of serious bacterial infections. Objective: In this study we evaluated the efficacy and antibacterial activity of doripenem monotherapy versus doripenem combination therapy with colistin against carbapenem-resistant A. baumannii isolates in vitro. Methodology: Thirty two carbapenem non-susceptible A. baumannii clinical isolates were identified and antimicrobial susceptibility testing (AST) and minimum inhibitory concentration (MIC) determination were done by using VITEK2 compact system (bioMerieux, France). Phenotypic detection of MBLs was assessed using MBL E-test strips. Synergy testing was performed by agar dilution E-test method using doripenem E-test strips and colistin at 1/2 MIC values. Morphological changes were evaluated by scanning electron microscopy (SEM). Results: All 32 A. baaumannii isolates were resistant to carbapenems including doripenem and 23/32 (72%) were resistant to colistin. The colistin doripenem combination displayed synergy in (27/32; 84%) among carbapenem resistant isolates while antagonism was detected in 5/32 (16%). Metallo-f-lactamase (MBL) production was detected in 24 isolates (75%); however the MBL status did not affect the synergistic activity of the combination therapy. Electron microscopy on selected isolates showed major morphological changes after exposure of A. baumannii to doripenem and colistin combination confirming synergy between the 2 drugs. Conclusion: This study confirms the superiority of doripenem colistin combination at 1/2 MIC over doripenem or colistin monotherapy in both carbapenem resistant and carbapenem colistin resistant A. baumanni isolates. This combination could be a life-saving alternative for treatment of serious infections that improves the clinical outcome of critically ill patients in ICU. This should be further examined in clinical studies.

A case report on red man syndrome

Vancomycin is a glycopeptide antibiotic used for the treatment of serious infections caused by Gram-positive organism. Rapid infusion-related adverse drug reaction (ADR) of vancomycin is known as red man syndrome (RMS) or red neck syndrome. The manifestations of RMS are erythema, flushing, pruritis of the face, upper torso, and in severe cases dyspnea, chest pain, and hypotension. RMS occurs due to the release of histamine from degranulated mast cells and basophils. This histamine release is also associated with ciprofloxacin, amphotericin B, rifampicin, and teicoplanin. It can be prevented by slowing the infusion rate or pre-treatment with an H1- or H2-receptor antagonist.

Pharmacokinetics (PK) of Eravacycline in Subjects with Renal or Hepatic Impairment Compared with Healthy Subjects

BackgroundEravacycline (ERV) is a fluorocycline being developed for the treatment of serious infections, including those caused by multidrug-resistant pathogens. The PK of ERV in subjects with end stage renal disease (ESRD) or hepatic impairment (HI) were investigated.MethodsTwo multi-center studies were completed; one in subjects with ESRD and one in subjects with mild, moderate or severe HI based upon Child-Pugh scoring. Each included a cohort of healthy subjects (HS) matched by gender, age and BMI. A single IV dose of 1.5 mg/kg ERV was administered. PK parameters were calculated using standard non-compartmental methods and within study comparisons of PK for the ESRD and HI subjects were made with HS.ResultsThe following comparative AUCinf and Cmax values for ERV were observed:Conclusion Following a single IV dose of ERV, the systemic exposures in subjects with ESRD and mild or moderate hepatic impairment were similar to those observed in HS. The 2-fold increase in AUCinf observed in subjects with severe HI did not result in increased adverse events. Therefore, no dose adjustment should be required when ERV is given to subjects with either renal or hepatic impairment.Funded in whole or in part with Federal funds from the Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services, under Contract No HHSO100201200002C.Disclosures P. Horn, Tetraphase Pharmaceuticals: Employee, Salary; S. Redican, Tetraphase Pharmaceuticals: Employee, Salary; M. Olesky, Tetraphase Pharmaceuticals: Employee, Salary.Subjects Status (n)Ratio of geometric LS, Mean (%)90% CI for ratio (%)Intra- subject CV (%)ESRDAUC0-inf (ng*hours/ mL/kg)ESRD (6) vs. HS (6)96(82, 112)15Cmax (ng/mL)ESRD (6) vs. HS (6)109(82, 145)28HIAUC0-inf (ng*hours/ mL/kg)Mild (4) vs. HS (5)123(84, 180)34Moderate (5) vs. HS (5)138(96, 198)34Severe (6) vs. HS (5)210(149, 297)34Cmax (ng/mL)Mild (6) vs. HS (6)114(89, 145)25Moderate (6) vs. HS (6)116(91, 148)25Severe (6) vs. HS (6)120(94, 153)25For all groups, except severe HI, the 90% CI for the ratio of AUCinf and Cmax compared with HS contains 100%, indicating similar exposures. For subjects with severe HI, Cmax was similar to that in HS while AUCinf was about 2-fold higher. ERV was well tolerated with 2 or fewer subjects in any group reporting drug-related adverse events (1 subject with severe HI).

Molecular detection of aminoglycoside-modifying enzyme genes in Acinetobacter baumannii clinical isolates.

Acinetobacter baumannii is a major opportunistic pathogen in healthcare settings worldwide. In Iran, there are only few reports on the prevalence of aminoglycoside resistance genes among A. baumannii isolates. The aim of this study was to investigate the existence of aminoglycoside-modifying enzyme (AME) genes from A. baumannii strains collected at a university teaching hospital in Iran. One hundred A. baumannii strains were collected between 2014 and 2015 from hospitalized patients at Loghman Hakim Hospital, Tehran, Iran. Antimicrobial susceptibility was determined by disk diffusion method according to the Clinical and Laboratory Standards Institute recommendations. The DNA was extracted using a kit obtained from Bioneer Co. (Korea) and was used as a template for polymerase chain reaction. The most active antimicrobial agent against these strains was colistin. The rate of extended-spectrum cephalosporin resistance was 97%. The aadA1, aadB, aac(6')-Ib, and aac(3)-IIa genes were found in 85%, 77%, 72%, and 68% of A. baumannii isolates, respectively. This study showed a high prevalence rate of AME genes in A. baumannii. This prevalence rate has explained that further aminoglycoside resistance genes may have role in the resistance of clinical isolates of A. baumannii. Therefore, control and treatment of serious infections caused by this opportunistic pathogen should be given more consideration.

Efficacy of CD101, a Novel Echinocandin, in Mouse Models of Aspergillosis and Azole-Resistant Disseminated Candidiasis

Background: CD101 is a novel echinocandin with long-acting pharmacokinetics and exceptional stability in development for prevention and treatment of serious fungal infections. The in vivo efficacy of CD101 was evaluated using neutropenic mouse models of azole-resistant candidiasis and aspergillosis.Methods: An azole-resistant strain of Candida albicans (R357; resistant to fluconazole [Flu], voriconazole, and posaconazole but susceptible to amphotericin B [AmB] and echinocandins) isolated from human blood was used for the mouse candidiasis model. A test strain of Aspergillus fumigatus (ATCC 13073) was used for the mouse aspergillosis model. Mice were rendered neutropenic by cyclophosphamide and then infected by injections of C. albicans (105 CFU/mouse) or A. fumigatus (104 CFU/mouse) into the tail vein. Test articles were administered starting 2 hours after infection. In the mouse candidiasis model, groups of 5 mice each received one dose of AmB (3 mg/kg IV), Flu (20 mg/kg orally), or CD101 (3, 10 or 30 mg/kg by intraperitoneal administration [IP]). After 72 hours post-infection, mice were euthanized and C. albicans counts in kidney tissue (CFU/g) were measured. In the mouse aspergillosis model, groups of 10 mice each received one dose ofAmB (2 mg/kg IP) or CD101 (2 mg/kg IV and IP). Survival was monitored daily for 10 days. Differences between vehicle and test article groups were assessed for significance by one-way ANOVA followed byDunnett's test and Fisher's Exact test in the candidiasis and aspergillosis models, respectively.Results: One dose of CD101 3 mg/kg produced a >99.9% (or > 3-log; P<0.001) reduction in C. albicans CFU compared with vehicle through at least 72hours post-dose following a single IP dose.AmB showed similar, albeit less robust, efficacy (>99% or >2-log reduction in CFU; P<0.05), whereas fluconazole was less efficacious (83.9% or <2-log reduction in CFU). In the aspergillosis model, CD101 administered 2 mg/kg IV or IP showed similar efficacy to that ofAmB 2 mg/kg IP, both with significantly longer survival than vehicle (P<0.05; Figure).Conclusions: A single dose of CD101 3 mg/kg produced significant reduction in C. albicans burden compared with vehicle (P<0.001) in the neutropenic mouse model of azole-resistant candidiasis, demonstrating efficacy comparable, if not better, to that of AmB at the same dose. One dose of CD101 also demonstrated efficacy in the mouse model of aspergillosis. These data support the continued development of CD101 for treatment of serious infections caused by Candida, including azole-resistant strains, and Aspergillus spp. [Display omitted] DisclosuresOng:Cidara Therapeutics, Inc.: Employment. Bartizal:Cidara Therapeutics, Inc.: Employment, Other: Stockholder. Miesel:Eurofins Panlabs: Employment; Cidara Therapeutics, Inc: Research Funding.

The safety and efficacy of high versus low vancomycin trough levels in the treatment of patients with infections caused by methicillin-resistant Staphylococcus aureus: a meta-analysis.

BackgroundRecent guidelines have recommended vancomycin trough levels of 15–20 mg/L for treatment of serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, high trough levels may increase risk of nephrotoxicity and mortality, and high vancomycin trough levels have not been well studied. This study was designed to combine safety and efficacy results from independent studies and to compare between high and low vancomycin trough levels in the treatment of MRSA-infected patients using meta-analysis.MethodsFrom 19 eligible studies, 9 studies were included in meta-analysis to compare clinical success between high and low vancomycin trough levels, while 10 and 11 studies met criteria for comparing trough levels and nephrotoxicity and trough levels and mortality, respectively. The PubMed/Medline, Web of Science, and Scopus databases, and hand searching were used to identify eligible studies dated up to March 2016. Of 2344 subjects with MRSA infection, 1036 were assigned to trough levels ≥15 mg/L and 1308 to trough levels <15 mg/L.ResultsHigh vancomycin trough levels were found to be associated with risk of nephrotoxicity (odds ratio [OR] 2.14, 95 % confidence interval [CI] 1.42–3.23 and adjusted OR 3.33, 95 % CI 1.91–5.79). There was no evidence of difference between high and low vancomycin trough levels for mortality (OR; 1.09; 95 % CI 0.75–1.60) or clinical success (OR 1.07; 95 % CI 0.68–1.68).ConclusionIn this study, high vancomycin trough levels were identified as an independent factor associated with risk of nephrotoxicity in MRSA-infected patients. Association between vancomycin trough levels and both adverse effects and clinical outcomes requires further study.Electronic supplementary materialThe online version of this article (doi:10.1186/s13104-016-2252-7) contains supplementary material, which is available to authorized users.

Multidrug-Resistant Staphylococcus aureus, India, 2013-2015.

To the Editor: Methicillin-resistant Staphylococcus aureus (MRSA) is a versatile pathogen capable of causing a wide variety of human diseases. Increased frequency of S. aureus infections imposes a high and increasing burden on healthcare resources. In many countries, MRSA infections in hospitals are common. Data from the National Nosocomial Infections Surveillance system suggest that, in the United States, incidence of nosocomial MRSA infections is steadily increasing and that these infections account for >60% of intensive care unit admissions (1,2). S. aureus has developed resistance to several antimicrobial drugs, including second- and third-line drugs. Only a few drugs, such as vancomycin (a glycopeptide), daptomycin (a lipopeptide), and linezolid (an oxazolidinone), have been approved for the treatment of serious infections caused by MRSA. Another drug, tigecycline (a glycylcycline), has shown good activity against MRSA strains in vitro (3). The epidemiology of MRSA is constantly changing, which results in variation in its drug-resistance patterns throughout regions and countries (4). Therefore, to support clinicians in preventing and treating infection, epidemiologic surveillance is essential. We report resistance patterns of S. aureus collected over 2 years (December 2013–November 2015) from blood samples of patients admitted to 1 hospital in Odisha, eastern India.