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1.
PAPER CURRENT
Comparative Pharmacodynamics of Telavancin and Vancomycin in the Neutropenic Murine Thigh and Lung Infection Models against Staphylococcus aureus [Experimental Therapeutics] (2017)
The American Society for Microbiology (ASM)
Publication Date: 2017-06-28
Description: The pharmacodynamics of telavancin and vancomycin were compared using neutropenic murine thigh and lung infection models. Four Staphylococcus aureus strains were included. The telavancin MIC ranged from 0.06 to 0.25 mg/liter, and the vancomycin MIC ranged from 1 to 4 mg/liter. The plasma pharmacokinetics of escalating doses (1.25, 5, 20, and 80 mg/kg of body weight) of telavancin and vancomycin were linear over the dose range. Epithelial lining fluid (ELF) pharmacokinetics for each drug revealed that penetration into the ELF mirrored the percentage of the free fraction (the fraction not protein bound) in plasma for each drug. Telavancin (0.3125 to 80 mg/kg/6 h) and vancomycin (0.3125 to 1,280 mg/kg/6 h) were administered by the subcutaneous route in treatment studies. Dose-dependent bactericidal activity against all four strains was observed in both models. A sigmoid maximum-effect model was used to determine the area under the concentration-time curve (AUC)/MIC exposure associated with net stasis and 1-log 10 kill relative to the burden at the start of therapy. The 24-h plasma free drug AUC ( f AUC)/MIC values associated with stasis and 1-log kill were remarkably congruent. Net stasis for telavancin was noted at f AUC/MIC values of 83 and 40.4 in the thigh and lung, respectively, and 1-log kill was noted at f AUC/MIC values of 215 and 76.4, respectively. For vancomycin, the f AUC/MIC values for stasis were 77.9 and 45.3, respectively, and those for 1-log kill were 282 and 113, respectively. The 24-h ELF total drug AUC/MIC targets in the lung model were very similar to the 24-h plasma free drug AUC/MIC targets for each drug. Integration of human pharmacokinetic data for telavancin, the results of the MIC distribution studies, and the pharmacodynamic targets identified in this study suggests that the current dosing regimen of telavancin is optimized to obtain drug exposures sufficient to treat S. aureus infections.
Print ISSN: 0066-4804
Electronic ISSN: 1098-6596
Topics: Biology , Medicine
2.
PAPER CURRENT
Publication Date: 2017-06-28
Description: The MONOD ANRS 12206 trial was designated to assess simplification of a successful lopinavir (LPV)-based antiretroviral treatment in HIV-infected children younger than 3 years of age using efavirenz (EFV; 25 mg/kg of body weight/day) to preserve the class of protease inhibitors for children in that age group. In this substudy, EFV concentrations were measured to check the consistency of an EFV dose of 25 mg/kg and to compare it with the 2016 FDA recommended dose. Fifty-two children underwent blood sampling for pharmacokinetic study at 6 months and 12 months after switching to EFV. We applied a Bayesian approach to derive EFV pharmacokinetic parameters using the nonlinear mixed-effect modeling (NONMEM) program. The proportion of midinterval concentrations 12 h after drug intake ( C 12 h ) corresponding to the EFV therapeutic pharmacokinetic thresholds (1 to 4 mg/liter) was assessed according to different dose regimens (25 mg/kg in the MONOD study versus the 2016 FDA recommended dose). With both the 25 mg/kg/day dose and the 2016 FDA recommended EFV dose, simulations showed that the majority of C 12 h values were within the therapeutic range (62.6% versus 62.8%). However, there were more children underexposed with the 2016 FDA recommended dose (11.6% versus 1.2%). Conversely, there were more concentrations above the threshold of toxicity with the 25 mg/kg dose (36.2% versus 25.6%), with C 12 h values of up to 15 mg/liter. Only 1 of 52 children was switched back to LPV because of persistent sleeping disorders, but his C 12 h value was within therapeutic ranges. A high EFV dose of 25 mg/kg per day in children under 3 years old achieved satisfactory therapeutic effective levels. However, the 2016 FDA recommended EFV dose appeared to provide more acceptable safe therapeutic profiles. (This study has been registered at ClinicalTrials.gov under identifier NCT01127204.)
Print ISSN: 0066-4804
Electronic ISSN: 1098-6596
Topics: Biology , Medicine
3.
PAPER CURRENT
New Aspects of the Interplay between Penicillin Binding Proteins, murM, and the Two-Component System CiaRH of Penicillin-Resistant Streptococcus pneumoniae Serotype 19A Isolates from Hungary [Mechanisms of Resistance] (2017)
The American Society for Microbiology (ASM)
Publication Date: 2017-06-28
Description: The Streptococcus pneumoniae clone Hungary 19A -6 expresses unusually high levels of β-lactam resistance, which is in part due to mutations in the MurM gene, encoding a transferase involved in the synthesis of branched peptidoglycan. Moreover, it contains the allele ciaH232 , encoding the histidine kinase CiaH (M. Müller, P. Marx, R. Hakenbeck, and R. Brückner, Microbiology 157:3104–3112, 2011, https://doi.org/10.1099/mic.0.053157-0 ). High-level penicillin resistance primarily requires the presence of low-affinity (mosaic) penicillin binding protein (PBP) genes, as, for example, in strain Hu17, a closely related member of the Hungary 19A -6 lineage. Interestingly, strain Hu15 is β-lactam sensitive due to the absence of mosaic PBPs. This unique situation prompted us to investigate the development of cefotaxime resistance in transformation experiments with genes known to play a role in this phenotype, pbp2x , pbp1a , murM , and ciaH , and penicillin-sensitive recipient strains R6 and Hu15. Characterization of phenotypes, peptidoglycan composition, and CiaR-mediated gene expression revealed several novel aspects of penicillin resistance. The murM gene of strain Hu17 ( murM Hu17 ), which is highly similar to murM of Streptococcus mitis , induced morphological changes which were partly reversed by ciaH232. murM Hu17 conferred cefotaxime resistance only in the presence of the pbp2x o f strain Hu17 ( pbp2x Hu17 ). The ciaH232 allele contributed to a remarkable increase in cefotaxime resistance in combination with pbp2x Hu17 and pbp1a of strain Hu17 ( pbp1a Hu17 ), accompanied by higher levels of expression of CiaR-regulated genes, documenting that ciaH232 responds to PBP1a Hu17 -mediated changes in cell wall synthesis. Most importantly, the proportion of branched peptides relative to the proportion of linear muropeptides increased in cells containing mosaic PBPs, suggesting an altered enzymatic activity of these proteins.
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Electronic ISSN: 1098-6596
Topics: Biology , Medicine
4.
PAPER CURRENT
Multihospital Occurrence of Pan-Resistant Klebsiella pneumoniae Sequence Type 147 with an ISEcp1-Directed blaOXA-181 Insertion in the mgrB Gene in the United Arab Emirates [Epidemiology and Surveillance] (2017)
The American Society for Microbiology (ASM)
Publication Date: 2017-06-28
Description: The emergence of pan-resistant Klebsiella pneumoniae strains is an increasing concern. In the present study, we describe a cluster of 9 pan-resistant K. pneumoniae sequence type 147 (ST147) isolates encountered in 4 patients over nearly 1 year in 3 hospitals of the United Arab Emirates (UAE). The isolates exhibited highly similar genotypes. All produced chromosomally encoded OXA-181, and the majority also produced the NDM-5 carbapenemase. As with the previously described single isolate from the UAE, MS6671, the mgrB was disrupted by a functional, IS Ecp1 -driven bla OXA-181 insertion causing resistance to carbapenems. The mutation was successfully complemented with an intact mgrB gene, indicating that it was responsible for colistin resistance. bla NDM-5 was located within a resistance island of an approximately 100-kb IncFII plasmid carrying ermB , mph (A), bla TEM-1B , rmtB , bla NDM-5 , sul1 , aadA2 , and dfrA12 resistance genes. Sequencing this plasmid (pABC143-NDM) revealed that its backbone was nearly identical to that of plasmid pMS6671E from which several resistance genes, including bla NDM-5 , had been deleted. More extensive similarities of the backbone and the resistance island were found between pABC143C-NDM and the bla NDM-5 -carrying IncFII plasmids of two K. pneumoniae ST147 isolates from South Korea, one of which was colistin resistant, and both also produced OXA-181. Notably, one of these strains was isolated from a patient transferred from the UAE. Our data show that this pan-resistant clone has an alarming capacity to maintain itself over an extended period of time and is even likely to be transmitted internationally.
Print ISSN: 0066-4804
Electronic ISSN: 1098-6596
Topics: Biology , Medicine
5.
PAPER CURRENT
Correlation between gyrA and CmeR Box Polymorphism and Fluoroquinolone Resistance in Campylobacter jejuni Isolates in China [Mechanisms of Resistance] (2017)
The American Society for Microbiology (ASM)
Publication Date: 2017-06-28
Description: Sequence analysis of 79 ciprofloxacin-resistant Campylobacter jejuni isolates collected in China showed resistance-related sequence variations in gyrA and CmeR-Box. All the isolates contain an identical Thr-86-Ile substitution in GyrA. Several novel CmeR-Box variations, including point substitutions, deletion, and insertion, were identified. The point insertion or deletion led to dramatically reduced binding of CmeR to the cmeABC promoter, which significantly increases the expression of cmeABC and contributes to the high fluoroquinolone resistance.
Print ISSN: 0066-4804
Electronic ISSN: 1098-6596
Topics: Biology , Medicine
6.
PAPER CURRENT
Identification of Mycobacterial Genes Involved in Antibiotic Sensitivity: Implications for the Treatment of Tuberculosis with {beta}-Lactam-Containing Regimens [Mechanisms of Resistance] (2017)
The American Society for Microbiology (ASM)
Publication Date: 2017-06-28
Description: In a Mycobacterium smegmatis mutant library screen, transposon mutants with insertions in fhaA , dprE2 , rpsT , and parA displayed hypersusceptibility to antibiotics, including the β-lactams meropenem, ampicillin, amoxicillin, and cefotaxime. Sub-MIC levels of octoclothepin, a psychotic drug inhibiting ParA, phenocopied the parA insertion and enhanced the bactericidal activity of meropenem against Mycobacterium tuberculosis in combination with clavulanate. Our study identifies novel factors associated with antibiotic resistance, with implications in repurposing β-lactams for tuberculosis treatment.
Print ISSN: 0066-4804
Electronic ISSN: 1098-6596
Topics: Biology , Medicine
7.
PAPER CURRENT
Mycobacterium tuberculosis Proteome Response to Antituberculosis Compounds Reveals Metabolic "Escape" Pathways That Prolong Bacterial Survival [Mechanisms of Resistance] (2017)
The American Society for Microbiology (ASM)
Publication Date: 2017-06-28
Description: Tuberculosis (TB) continues to be one of the most common bacterial infectious diseases and is the leading cause of death in many parts of the world. A major limitation of TB therapy is slow killing of the infecting organism, increasing the risk for the development of a tolerance phenotype and drug resistance. Studies indicate that Mycobacterium tuberculosis takes several days to be killed upon treatment with lethal concentrations of antibiotics both in vitro and in vivo . To investigate how metabolic remodeling can enable transient bacterial survival during exposure to bactericidal concentrations of compounds, M. tuberculosis strain H37Rv was exposed to twice the MIC of isoniazid, rifampin, moxifloxacin, mefloquine, or bedaquiline for 24 h, 48 h, 4 days, and 6 days, and the bacterial proteomic response was analyzed using quantitative shotgun mass spectrometry. Numerous sets of de novo bacterial proteins were identified over the 6-day treatment. Network analysis and comparisons between the drug treatment groups revealed several shared sets of predominant proteins and enzymes simultaneously belonging to a number of diverse pathways. Overexpression of some of these proteins in the nonpathogenic Mycobacterium smegmatis extended bacterial survival upon exposure to bactericidal concentrations of antimicrobials, and inactivation of some proteins in M. tuberculosis prevented the pathogen from escaping the fast killing in vitro and in macrophages, as well. Our biology-driven approach identified promising bacterial metabolic pathways and enzymes that might be targeted by novel drugs to reduce the length of tuberculosis therapy.
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Electronic ISSN: 1098-6596
Topics: Biology , Medicine
8.
PAPER CURRENT
In Vitro Activity of a Novel Glucan Synthase Inhibitor, SCY-078, against Clinical Isolates of Candida auris [Letters] (2017)
The American Society for Microbiology (ASM)
Publication Date: 2017-06-28
Print ISSN: 0066-4804
Electronic ISSN: 1098-6596
Topics: Biology , Medicine
9.
PAPER CURRENT
Novel Antibacterial Coating on Orthopedic Wires To Eliminate Pin Tract Infections [Experimental Therapeutics] (2017)
The American Society for Microbiology (ASM)
Publication Date: 2017-06-28
Description: Novel approaches to the prevention of microbial infections after the insertion of orthopedic external fixators are in great demand because of the extremely high incidence rates of such infections, which can reach up to 100% with longer implant residence times. Monolaurin is an antimicrobial agent with a known safety record that is broadly used in the food and cosmetic industries; however, its use in antimicrobial coatings of medical devices has not been studied in much detail. Here, we report the use of monolaurin as an antibacterial coating on external fixators for the first time. Monolaurin-coated Kirschner wires (K-wires) showed excellent antibacterial properties against three different bacterial strains, i.e., methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and Staphylococcus epidermidis . Approximately 6.0-log reductions of both planktonic and adherent bacteria were achieved using monolaurin-coated K-wires, but monolaurin-coated K-wires did not show any observable cytotoxicity with mouse osteoblast cell cultures. Overall, monolaurin-coated K-wires could be promising as potent antimicrobial materials for orthopedic surgery.
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Electronic ISSN: 1098-6596
Topics: Biology , Medicine
10.
PAPER CURRENT
Multicenter Study of Outcomes with Ceftazidime-Avibactam in Patients with Carbapenem-Resistant Enterobacteriaceae Infections [Clinical Therapeutics] (2017)
The American Society for Microbiology (ASM)
Publication Date: 2017-06-28
Description: Ceftazidime-avibactam is a novel cephalosporin–beta-lactamase inhibitor combination that is active against many carbapenem-resistant Enterobacteriaceae (CRE). We describe a retrospective chart review for 60 patients who received ceftazidime-avibactam for a CRE infection. In-hospital mortality was 32%, 53% of patients had microbiological cure, and 65% had clinical success. In this severely ill population with CRE infections, ceftazidime-avibactam was an appropriate option.
Print ISSN: 0066-4804
Electronic ISSN: 1098-6596
Topics: Biology , Medicine