bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationship Between Fundamental Movement Skills and Physical Self-Perception Among Adolescent Girls
Authors: Rogers Vaimanino , Barnett Lisa M. , Lander Natalie
Published: October 2018

This study aimed to explore the relationship between fundamental movement skills (FMS) and multiple levels of physical self-perception among early adolescent girls. The Victorian FMS Teachers’ Manual was used to measure actual FMS. Perceptions were measured using the Physical Self-Perception Profile and the Perceived Movement Skill Competence Scale. Pearson’s correlations assessed the association between FMS and each level of physical self-perception. General linear models, adjusting for potential confounders, were conducted to explore the relationship between FMS and multiple levels of physical self-perception. A total of 173 Australian girls (M = 12.48 years,SD = .34) had complete data. Results found positive moderate and significant associations between actual FMS and physical self-perception, perceived sports competence, and, to a lesser degree, perceived FMS. Actual and perceived object control skill were also moderately associated, but there was no association between actual and perceived locomotor skill. After adjusting for potential confounders, FMS remained a significant predictor of each level of perception in each model, except for locomotor skill. These findings are important for future intervention development to improve both actual and perceived FMS, particularly in object control skill, which has been identified as a predictor of subsequent physical activity.
Hip Abductor and Adductor Muscles Activity Patterns During Landing After Anterior Cruciate Ligament Injury
Authors: Dashti Rostami Komeil , Naderi Aynollah , Thomas Abbey
Published: October 2018

Context:Hamstring and quadriceps activity adaptations are well known in individuals with anterior cruciate ligament deficiency (ACLD) and reconstructed (ACLR) to potentially compensate for knee joint instability. However, few studies have explored hip muscles activity patterns after ACL injury.Objective:To examine the activation characteristics of gluteus medius (GMED) and adductor longus in ACLR and ACLD subjects compared with controls.Design:Case–control study.Setting:Athletic training room and university lab.Participants:Twelve healthy and 24 ACL-injured (12 ACLR and 12 ACLD) recreationally active male volunteers.Interventions:Surface electromyography of the GMED and adductor longus were recorded during a single-leg vertical drop landing and normalized to maximum voluntary isometric contractions.Main Outcome Measures:Preparatory and reactive muscle activity and coactivation were analyzed from 100 milliseconds prior to initial contact to 250 milliseconds postcontact.Results:During reactive activity, ACL-injured (ACLR and ACLD) participants demonstrated significantly lower peak GMED activity compared with controls (F = 4.33,P = .02). In addition, ACLR participants exhibited significantly lower reactive GMED:adductor longus coactivation muscle activity compared with controls (F = 4.09,P = .03).Conclusion:Our findings suggest neuromuscular adaptations of the hip musculature are present in people at least 2 years from ACL injury. GMED activation exercises should be considered in designing rehabilitation programs for ACL-injured individuals.
Decoupled taxonomic and ecological recoveries from the Permo-Triassic extinction
Authors: Song Haijun , Wignall Paul B. , Dunhill Alexander M.
Published: October 2018

After the enormous Permian-Triassic mass extinction, marine animals high in the food chain recovered the most quickly.
Cryo-EM structure of
P. falciparum
circumsporozoite protein with a vaccine-elicited antibody is stabilized by somatically mutated inter-Fab contacts
Authors: Oyen David , Torres Jonathan L. , Cottrell Christopher A. , Richter King C. , Wilson Ian A. , Ward Andrew B.
Published: October 2018

An unprecedented spiral structure of the malarial CSP protein in complex with a protective antibody is revealed by cryo-EM.
Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2)
Authors: Cocco Emiliano , Javier Carmona F. , Razavi Pedram , Won Helen H. , Cai Yanyan , Rossi Valentina , Chan Carmen , Cownie James , Soong Joanne , Toska Eneda , Shifman Sophie G. , Sarotto Ivana , Savas Peter , Wick Michael J. , Papadopoulos Kyriakos P. , Moriarty Alyssa , Cutler Richard E. , Avogadri-Connors Francesca , Lalani Alshad S. , Bryce Richard P. , Chandarlapaty Sarat , Hyman David M. , Solit David B. , Boni Valentina , Loi Sherene , Baselga José , Berger Michael F. , Montemurro Filippo , Scaltriti Maurizio
Published: October 2018

Metastatic breast cancer patients with coexistent HER2 mutation and amplification respond to neratinib.
A nano stress reliever for sepsis
Authors: Shen Keyue
Published: October 2018

A peroxide scavenger nanoparticle reduces systemic inflammation in mouse models.
Comparison of Etest to broth microdilution method for testing Streptococcus pneumoniae susceptibility to levofloxacin and three macrolides
Authors: Hunt Gerardo S , Citron D M , Claros M C , Goldstein E J
Published: October 2018

When the Etest was compared to broth microdilution for susceptibility testing of Streptococcus pneumoniae, levofloxacin, erythromycin, and penicillin results correlated for both methods; azithromycin and clarithromycin showed discrepancies of > or = 2 dilutions for 95.8% and 31.5% of the isolates, respectively. Levofloxacin was active against 141 of 142 isolates (< or = 2.0 micrograms/ml), making it a potentially useful new fluoroquinolone.
Phase I study of intravenous ribavirin treatment of respiratory syncytial virus pneumonia after marrow transplantation
Authors: Lewinsohn D M , Bowden R A , Mattson D , Crawford S W
Published: October 2018

Respiratory syncytial virus (RSV) pneumonia in marrow transplant recipients is associated with significant mortality. Ribavirin is a nucleoside analog with activity against RSV and in its aerosolized formulation is the only drug approved for treatment of RSV pneumonia in the United States. The clinical use of aerosolized ribavirin has been limited by caregivers' concerns about drug exposure and potential teratogenic effects. Since there is lack of proven efficacy and safety of the aerosolized ribavirin in this setting, we performed a phase I study of intravenous ribavirin treatment. Between November 1993 and May 1994, 10 patients with clinically significant RSV pneumonia at the Fred Hutchinson Cancer Research Center were enrolled. Only 2 of the 10 survived (20%; 95% CI, 3-56). Two of the 10 patients developed acute hemolysis that necessitated discontinuation of the medication. In conclusion, treatment of marrow transplant recipients with RSV pneumonia with intravenous ribavirin did not improve mortality compared with historical controls treated with the aerosolized drug.
Species selectivity of new siderophore-drug conjugates that use specific iron uptake for entry into bacteria
Authors: Diarra M S , Lavoie M C , Jacques M , Darwish I , Dolence E K , Dolence J A , Ghosh A , Ghosh M , Miller M J , Malouin F
Published: October 2018

Siderophores selectively bind ferric iron and are involved in receptor-specific iron transport into bacteria. Several types of siderophores were synthesized, and growth-promoting or inhibitory activities when they were conjugated to carbacephalosporin, erythromycylamine, or nalidixic acid were investigated. Overall, 11 types of siderophores and 21 drug conjugates were tested against seven different bacterial species: Escherichia coli, Bordetella bronchiseptica, Pasteurella multocida, Pasteurella haemolytica, Streptococcus suis, Staphylococcus aureus, and Staphylococcus epidermidis. In some species, the inhibitory activities of the drug conjugates were associated with the ability of the bacteria to use the siderophore portion of the molecules for growth promotion in disc diffusion tests (0.04 mumol of conjugate or siderophore per disc). E. coli used catechol-based siderophore portions as well as hydroxamate-based tri-delta-OH-N-OH-delta-N-acetyl-L-ornithine ferric iron ligands for growth under iron-restricted conditions achieved by supplemental ethylenediamine di (O-hydroxyphenylacetic acid) (100 micrograms/ml) and was sensitive to carbacephalosporin conjugated to these siderophore types (up to a 34-mm-diameter inhibition zone). B. bronchiseptica used desferrioxamine B and an isocyanurate-based or trihydroxamate in addition to catechol-based siderophore portions for promotion but was not inhibited by beta-lactam conjugates partly because of the presence of beta-lactamase. P. multocida and P. haemolytica did not use any of the synthetic siderophores for growth promotion, and the inhibitory activities of some conjugates seemed partly linked to their ability to withhold iron from these bacteria, since individual siderophore portions showed some antibacterial effects. Individual siderophores did not promote S. suis growth in restrictive conditions, but the type of ferric iron ligands attached to beta-lactams affected inhibitory activities. The antibacterial activities of the intracellular-acting agents erythromycylamine and nalidixic acid were reduced or lost, even against S. aureus and S. epidermidis, when the agents were conjugated to siderophores. Conjugate-resistant E. coli mutants showed the absence of some iron-regulated outer membrane proteins in gel electrophoresis profiles and in specific phage or colicin sensitivity tests, implying that the drugs used outer membrane receptors of ferric complexes to get into cells.
Susceptibility of Helicobacter pylori to bactericidal properties of medium-chain monoglycerides and free fatty acids
Authors: Petschow B W , Batema R P , Ford L L
Published: October 2018

Previous studies have shown that various short- and medium-chain free fatty acids (FFAs) and their corresponding monoacylglycerol esters (MGs) have antibacterial activity in vitro against primarily gram-positive bacteria. More recent studies have also shown that the growth of Helicobacter spp. is inhibited by linoleic acid and arachidonic acid. The purpose of the present study was to evaluate the susceptibility of Helicobacter pylori to the in vitro bactericidal properties of medium-chain MGs and FFAs. Incubation of H. pylori with saturated MGs, ranging in carbon chain length from C10:0 to C14:0, at 1 mM caused a 4-log-unit or greater reduction in the number of viable bacteria after exposure for 1 h. Lower levels of bactericidal activity were observed with C9:0, C15:0, and C16:0 MGs. In contrast, lauric acid (C12:0) was the only medium-chain saturated FFA with bactericidal activity against H. pylori. The MGs and FFAs were bactericidal after incubation for as little as 15 min at neutral or acidic pHs. Higher levels of MGs and FFAs were required for bactericidal activity in the presence of higher amounts of protein in liquid diets. We also found that the frequency of spontaneous development of resistance by H. pylori was higher for metronidazole and tetracycline (10(-5) to 10(-6)) than for C10:0 MG, C12:0 MG, and C12:0 FFA (< 10(-8)). Collectively, our data demonstrate that H. pylori is rapidly inactivated by medium-chain MGs and lauric acid and exhibits a relatively low frequency of spontaneous development of resistance to the bactericidal activity of MGs. Further studies are needed to establish whether MGs may be useful either alone or with other known therapeutic agents in the management of H. pylori infections in humans.
Pharmacokinetics of conventional formulation versus fat emulsion formulation of amphotericin B in a group of patients with neutropenia
Authors: Ayestarán A , López R M , Montoro J B , Estíbalez A , Pou L , Julià A , López A , Pascual B
Published: October 2018

The pharmacokinetics of amphotericin B administered in a conventional 5% dextrose (glucose) (5% D) solution and in a 20% fat emulsion formulation (Intralipid; 20% IL) were compared in 16 patients (mean age, 42 years [range, 18 to 70 years]) who had been hospitalized for hematological malignancies and with proven or suspected fungal infections. All of the patients received 50 mg (approximately 1 mg/kg of body weight per day) of amphotericin B daily in random order, either as a 50-ml lipid emulsion (20% IL) (group I) or in 500 ml of 5% D (group II). Five serum samples were taken during the 24 h after drug administration, and the levels of amphotericin B were measured by high-pressure liquid chromatography. Serum amphotericin B concentrations declined rapidly during the first 6 h, and subsequent measurements revealed a slow terminal elimination phase in both groups. The maximum serum amphotericin B concentration was significantly lower when the drug was administered in 20% IL (1.46 +/- 0.61 versus 2.83 +/- 1.17 micrograms/ml; P = 0.02). The area under the concentration-time curve from 0 to 24 h was also much lower in group I (17.22 +/- 11.15 versus 28.98 +/- 15.46 micrograms.h/ml). The half-life of the distribution phase was approximately three times longer in group I (2.92 +/- 2.34 h versus 0.64 +/- 0.24 h; P = 0.011). Conversely, the half-lives of the elimination phase were approximately equal in the two groups (11.44 +/- 5.18 versus 15.23 +/- 5.25 h). The mean residence times were also similar in both groups (19.41 +/- 11.13 versus 19.65 +/- 7.86 h). The clearance and the steady-state volume of distribution of amphotericin B in group I were about twice as great as those in group II (62.97 +/- 35.51 versus 33.01 +/- 14.33 ml/kg/h and 1,043.92 +/- 512.10 versus 562.32 +/- 152.05 ml/kg [P = 0.034], respectively). Finally, the volume of distribution in the central compartment was greater in group I than in group II (618.17 +/- 231.80 versus 328.19 +/- 151.71 ml/kg; P = 0.013), but there were no differences in the volume of distribution in the peripheral compartment (425.75 +/- 352.87 versus 234.14 +/- 75.92 ml/kg). These results suggest that amphotericin B has a different pharmacokinetic profile when it is administered in 20% IL than when it is administered in the standard 5% D form and that the main difference is due to a clear-cut difference in the steady-state volume of distribution, especially that in the central compartment.
Antiviral efficacy in vivo of the anti-human immunodeficiency virus bicyclam SDZ SID 791 (JM 3100), an inhibitor of infectious cell entry
Authors: Datema R , Rabin L , Hincenbergs M , Moreno M B , Warren S , Linquist V , Rosenwirth B , Seifert J , McCune J M
Published: October 2018

SID 791, a bicyclam inhibiting human immunodeficiency virus (HIV) replication in vitro by blocking virus entry into cells, is an effective inhibitor of virus production and of depletion of human CD4+ T cells in HIV type 1-infected SCID-hu Thy/Liv mice. Steady levels of 100 ng of SID 791 or higher per ml in plasma resulted in statistically significant inhibition of p24 antigen formation. Daily injections of SID 791 caused a dose-dependent decrease in viremia, and this inhibition could be potentiated by coadministration of zidovudine or didanose. The present study suggests that SID 791 alone or in combination with licensed antiviral agents may decrease the virus load in HIV-infected patients and, by extension, that the infectious cell entry step is a valid target for antiviral chemotherapy of HIV disease. The SCID-hu Thy/Liv model in effect provides a rapid means of assessing the potential of compounds with novel modes of antiviral action, as well as the potential of antiviral drug combinations.
MDL 74,968, a new acyclonucleotide analog: activity against human immunodeficiency virus in vitro and in the hu-PBL-SCID.beige mouse model of infection
Authors: Bridges C G , Taylor D L , Ahmed P S , Brennan T M , Hornsperger J M , Navé J F , Casara P , Tyms A S
Published: October 2018

The novel acyclonucleotide derivative of guanine, 9-[2-methylidene-3-(phosphonomethoxy)propyl] guanine (MDL 74,968), had antiviral activity comparable to those of 9-(2-phosphonomethoxyethyl) adenine (PMEA) and 2',3'-dideoxyinosine against laboratory strains of both human immunodeficiency virus (HIV) types 1 and 2 cultured in MT-4 cells and several clinical HIV isolates cultured in human peripheral blood mononuclear cells (PBMCs). MDL 74,968 was at least fourfold less toxic than PMEA to MT-4 cells or PBMCs, thereby producing a more favorable in vitro selectivity index for the former compound. Studies of acute toxicity in CD-1 mice showed that MDL 74,968 was not toxic at doses of 1,600 mg/kg of body weight via the intraperitoneal route or at doses of 500 mg/kg via the intravenous route. Furthermore, no adverse effects of MDL 74,968 were apparent when mice were treated at doses of 200 mg/kg twice daily for 5 days. Treatment by continuous subcutaneous infusion of MDL 74,968 or PMEA at the daily dose of 20 mg/kg in the hu-PBL-SCID.beige murine model of HIV infection significantly reduced the severity of infection compared with that in placebo-treated controls. Quantitation of virus recovery by endpoint titration of spleen cells in coculture with mitogen-activated PBMCs demonstrated that MDL 74,968 as well as PMEA significantly reduced the amount of virus (P < 0.02). Moreover, by using DNA extracted from spleens, the mean HIV:HLA PCR product ratio, which takes into account individual variation in immune system reconstitution, were 0.50 and 0.40 for MDL 74,968 and PMEA treatments, respectively, whereas animals receiving the placebo control had significantly higher levels of HIV proviral DNA (mean 0.78; P < 0.02). Taken together, these promising findings suggest that an orally bioavailable prodrug of MDL 74,968 should be developed for the treatment of HIV infection.
Therapy of visceral leishmaniasis due to Leishmania infantum: experimental assessment of efficacy of AmBisome
Authors: Gangneux J P , Sulahian A , Garin Y J , Farinotti R , Derouin F
Published: October 2018

The tolerance and efficacy of amphotericin B (AmB) deoxycholate (Fungizone) were compared with those of liposomal AmB (AmBisome) in a murine model of visceral leishmaniasis induced by Leishmania infantum. Control groups consisted of untreated mice and mice treated with a pentavalent antimonial (Glucantime). BALB/c mice were infected intravenously on day 0 with 10(7) promastigotes of L. infantum and then treated from day 7 to 17 (early treatment group) or from day 60 to 70 (delayed treatment group). The pentavalent antimonial was administered daily by intraperitoneal injection, whereas AmB formulations were administered intravenously on alternate days. On days 20, 60, and 120 (early treatment group) and on days 72 and 125 (delayed treatment group), parasite burdens in the liver, spleen, and lungs were determined by subculturings using a microtitration method. A dose range study showed that administration of AmBisome at the well-tolerated doses of 5 or 50 mg/kg of body weight completely eradicated the parasites from the tissues. At 0.8 mg/kg, AmBisome proved more efficacious than AmB deoxycholate administered at the same dose. We also compared the levels of AmB deoxycholate and AmBisome in plasma and tissue. Mice treated with AmBisome had levels of AmB in tissue much higher than did AmB deoxycholate-treated mice with persistent detectable levels 14 weeks after treatment. These results seem to account for the remarkable efficacy of the liposomal formulation of AmB in the treatment of visceral leishmaniasis due to L. infantum.
Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication
Authors: Deminie C A , Bechtold C M , Stock D , Alam M , Djang F , Balch A H , Chou T C , Prichard M , Colonno R J , Lin P F
Published: October 2018

Current treatments for human immunodeficiency virus (HIV) include both reverse transcriptase and protease inhibitors. Results from in vitro and clinical studies suggest that combination therapy can be more effective than single drugs in reducing viral burden. To evaluate compounds for combination therapy, stavudine (d4T), didanosine (ddI), or BMS-186,318, an HIV protease inhibitor, were combined with other clinically relevant compounds and tested in a T-cell line (CEM-SS) that was infected with HIV-RF or in peripheral blood mononuclear cells infected with a clinical HIV isolate. The combined drug effects were analyzed by the methods described by Chou and Talalay (Adv. Enzyme Regul. 22:27-55, 1984) as well as by Prichard et al. (Antimicrob. Agents Chemother. 37:540-545, 1993). The results showed that combining two nucleoside analogs (d4T-ddI, d4T-zidovudine [AZT], and d4T-zalcitabine [ddC]), two HIV protease inhibitors (BMS-186,318-saquinavir, BMS-186,318-SC-52151, and BMS-186,318-MK-639) or a reverse transcriptase and a protease inhibitor (BMS-186,318-d4T, BMS-186,318-ddI, BMS-186,318-AZT, d4T-saquinavir, d4T-MK-639, and ddI-MK-639) yielded additive to synergistic antiviral effects. In general, analysis of data by either method gave consistent results. In addition, combined antiviral treatments involving nucleoside analogs gave slightly different outcomes in the two cell types, presumably because of a difference in phosphorylation patterns. Importantly, no strong antagonism was observed with the drug combinations studied. These data should provide useful information for the design of clinical trials of combined chemotherapy.
Bioluminescence screening in vitro (Bio-Siv) assays for high-volume antimycobacterial drug discovery
Authors: Arain T M , Resconi A E , Hickey M J , Stover C K
Published: October 2018

Bioluminescence-based assays to indicate antimicrobial susceptibility have been developed and validated for recombinant strains of Mycobacterium tuberculosis, Mycobacterium bovis BCG, Mycobacterium avium, and Mycobacterium intracellulare expressing an integrated eukaryotic luciferase gene. MICs determined with these bioluminescence assays for several antimycobacterial agents, including isoniazid, ethambutol, rifampin, amikacin, streptomycin, ciprofloxacin, and clarithromycin, compared favorably with traditional BACTEC methods and visual estimations of the inhibitory end point. Assay methodology has been optimized for the analysis of large numbers of novel compounds and is simple, inexpensive, and labor efficient. The availability of these four recombinant mycobacteria has permitted a strategy for drug discovery employing the nonpathogenic BCG strain for mass screening purposes with subsequent confirmation of activity against the pathogenic mycobacteria. Furthermore, evidence suggests that the BCG-based screen may allow the direct identification of bactericidal agents.
Genetic basis for clarithromycin resistance among isolates of Mycobacterium chelonae and Mycobacterium abscessus
Authors: Wallace R J , Meier A , Brown B A , Zhang Y , Sander P , Onyi G O , Böttger E C
Published: October 2018

Resistance to clarithromycin among isolates of Mycobacterium chelonae and M. abscessus was observed in 18 of 800 (2.3%) patients tested between 1990 and 1995. Patients whose isolates were resistant had either disseminated disease or chronic lung disease, and the resistant isolates were recovered after clarithromycin monotherapy. Sequencing of the gene coding for the 23S rRNA peptidyltransferase region revealed a point mutation involving adenine at position 2058 (38%) or adenine at position 2059 (62%) in 20 of 20 relapse isolates from the first 13 patients identified. By pulsed-field gel electrophoresis or random amplified polymorphic DNA PCR, initial and relapse isolates were shown to have identical DNA patterns. M. chelonae and M. abscessus isolates were found to have only a single chromosomal copy of the rRNA operon, thus making them susceptible to single-step mutations. Thus, clarithromycin resistance in these species of rapidly growing mycobacteria relates to a point mutation in the gene coding for 23S rRNA and occurs in limited clinical situations, but was identified in almost 5% of isolates tested in 1995.
In vitro activities in new oxazolidinone antimicrobial agents against enterococci
Authors: Eliopoulos G M , Wennersten C B , Gold H S , Moellering R C
Published: October 2018

The comparative in vitro activities of two new oxazolidinone antimicrobial agents, U-100592 and U-100766, against 180 isolates of enterococci representing several resistance profiles were examined by using an agar dilution technique. The two oxazolidinones inhibited all isolates, including strains resistant to vancomycin, ampicillin, and minocycline, at concentrations between 1 and 4 micrograms/ml.
Antimicrobial susceptibilities of Campylobacter jejuni and Campylobacter coli to 12 beta-lactam agents and combinations with beta-lactamase inhibitors
Authors: Tajada P , Gomez-Graces J L , Alós J I , Balas D , Cogollos R
Published: October 2018

The in vitro activities of 12 beta-lactam agents against 100 thermophilic Campylobacter strains were tested. Beta-Lactamase production was detected in 88% of all strains tested. Clavulanic acid was the best inhibitor by susceptibility testing. The beta-lactams which displayed high levels of in vitro activity against Campylobacter isolates were imipenem, amoxicillin-clavulanic acid, and cefepime and, to a lesser degree, amoxicillin, ampicillin, and cefotaxime.
Novel mutation (K70E) in human immunodeficiency virus type 1 reverse transcriptase confers decreased susceptibility to 9-[2-(phosphonomethoxy)ethyl]adenine in vitro
Authors: Cherrington J M , Mulato A S , Fuller M D , Chen M S
Published: October 2018

9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), an acyclic nucleoside phosphonate analog, is active against several retroviruses and herpesviruses and has shown anti-human immunodeficiency virus (HIV) activity in clinical trials. Serial passage of HIV type 1 (strain IIIb, in MT2 cells in increasing concentrations of PMEA resulted in viruses with > 12-fold increases in their 50% inhibitory concentrations of PMEA compared with that for strain IIIb. Sequence analyses of these PMEA-selected viruses demonstrated the presence of a novel lysine-to-glutamic acid mutation at amino acid 70 (K70E) in HIV reverse transcriptase. A recombinant virus carrying the K70E mutation was constructed and showed a 10-fold increase in its 50% inhibitory concentrations of PMEA and 2',3'-dideoxy-3'-thiacytidine but showed wild-type susceptibility levels to 2',3'-dideoxycytosine, 2',3'-dideoxyinosine,2',3'-didehydro-2'3'-dideoxythymidine, 3'-azido-3'-deoxythymidine, foscarnet, and two additional phosphonates, 9-[(R)-2-(phosphonomethoxy)propyl]adenine and 9-[2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]adenine. Additionally, the K70E recombinant showed a minor reduction in growth kinetics compared with those of the wild-type virus in vitro.
Beta-lactamases and detection of beta-lactam resistance in Enterobacter spp
Authors: Pitout J D , Moland E S , Sanders C C , Thomson K S , Fitzsimmons S R
Published: October 2018

Enterobacter spp. are becoming increasingly frequent nosocomial pathogens, and beta-lactam-resistant strains are on the increase, especially among isolates recovered from intensive care units. Therefore, a study was designed to characterize the beta-lactamases produced by 80 isolates of E. cloacae, E. aerogenes, E. taylorae, E. gergoviae, E. sakazakii, E. asburiae, and E. agglomerans by induction studies, spectrophotometric hydrolysis assays, and isoelectric focusing. The ability of broth microdilution and disk diffusion susceptibility tests to detect resistance to 16 beta-lactam antibiotics among these species was also assessed. All species except E. agglomerans, E. gergoviae, and some isolates of E. sakazakii were found to produce a Bush group 1 cephalosporinase that was expressed inducibly or constitutively at high levels. In addition, some strains also produced a Bush group 2 beta-lactamase. In comparisons of broth microdilution and disk diffusion tests, disk diffusion tests failed to detect resistance in 1 of 25 isolates resistant to aztreonam and 2 of 30 isolates resistant to ceftazidime. These results indicate that species of Enterobacter can possess a variety of beta-lactamases that are responsible for beta-lactam resistance in this genus and that the disk diffusion test may occasionally miss resistance in some strains.
Antimicrobial susceptibility patterns of thermophilic Campylobacter spp. from humans, pigs, cattle, and broilers in Denmark
Authors: Aarestrup F M , Nielsen E M , Madsen M , Engberg J
Published: October 2018

The MICs of 16 antimicrobial agents were determined for 202 Campylobacter jejuni isolates, 123 Campylobacter coli isolates, and 6 Campylobacter lari isolates from humans and food animals in Denmark. The C. jejuni isolates originated from humans (75), broilers (95), cattle (29), and pigs (3); the C. coli isolates originated from humans (7), broilers (17), and pigs (99); and the C. lari isolates originated from broilers (5) and cattle (1). All isolates were susceptible to apramycin, neomycin, and gentamicin. Only a few C. jejuni isolates were resistant to one or more antimicrobial agents. Resistance to tetracycline was more common among C. jejuni isolates from humans (11%) than among C. jejuni isolates from animals (0 to 2%). More resistance to streptomycin was found among C. jejuni isolates from cattle (10%) than among those from humans (4%) or broilers (1%). A greater proportion of C. coli than of C. jejuni isolates were resistant to the other antimicrobial agents tested. Isolates were in most cases either coresistant to tylosin, spiramycin, and erythromycin or susceptible to all three antibiotics. More macrolide-resistant isolates were observed among C. coli isolates from swine (79%) than among C. coli isolates from broilers (18%) and humans (14%). Twenty-four percent of C. coli isolates from pigs were resistant to enrofloxacin, whereas 29% of C. coli isolates from humans and none from broilers were resistant. More resistance to streptomycin was observed among C. coli isolates from swine (48%) than among C. coli isolates from broilers (6%) or humans (0%). The six C. lari isolates were susceptible to all antimicrobial agents except ampicillin and nalidixic acid. This study showed that antimicrobial resistance was found only at relatively low frequencies among C. jejuni and C. lari isolates. Among C. coli isolates, especially from swine, there was a high level of resistance to macrolides and streptomycin. Furthermore, this study showed differences in the resistance to antimicrobial agents among Campylobacter isolates of different origins.
Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses
Authors: Chien S C , Rogge M C , Gisclon L G , Curtin C , Wong F , Natarajan J , Williams R R , Fowler C L , Cheung W K , Chow A T
Published: October 2018

The pharmacokinetics of once-daily oral levofloxacin (study A) or intravenous levofloxacin (study B) in 40 healthy male volunteers were investigated in two separate randomized, double-blind, parallel-design, placebo-controlled studies. Levofloxacin at 500 mg or placebo was administered orally or intravenously as a single dose on day 1; daily oral or intravenous dosing resumed on days 4 to 10. In a third study (study C), the comparability of the bioavailabilities of two oral and one intravenous levofloxacin formulations were investigated with 24 healthy male subjects in an open-label, randomized, three-way crossover study. Levofloxacin at 500 mg as a single tablet or an intravenous infusion was administered on day 1; following a 1-week washout period, subjects received the second regimen (i.e., the other oral formulation or the intravenous infusion); the third and final regimen was administered following a 1-week washout period. The concentrations of drug in plasma and urine were measured by validated high-pressure liquid chromatography methods. Pharmacokinetic parameters were estimated by noncompartmental methods. In both study A (oral levofloxacin) and study B (intravenous levofloxacin), steady state was attained within 48 h after the start of the multiple dosing on day 4. Levofloxacin pharmacokinetics were linear and predictable for the single and multiple 500-mg, once-daily oral and intravenous dosing regimens, and the values of the pharmacokinetic parameters for the oral and intravenous administrations were similar. Study C indicated that levofloxacin was rapidly and completely absorbed from the oral tablets, with mean times to the maximum concentration of drug in serum of approximately 1.5 h and mean absolute bioavailability of > or =99%. These results support the interchangeability of the oral and intravenous routes of levofloxacin administration.
Role of embB in natural and acquired resistance to ethambutol in mycobacteria
Authors: Alcaide F , Pfyffer G E , Telenti A
Published: October 2018

The mycobacterial embCAB operon encodes arabinosyl transferases, putative targets of the antimycobacterial agent ethambutol (EMB). Mutations in embB lead to resistance to EMB in Mycobacterium tuberculosis. The basis for natural, intrinsic resistance to EMB in nontuberculous mycobacteria (NTM) is not known; neither is the practical implication of resistance to EMB in the absence of embB mutations in M. tuberculosis well understood. The conserved embB resistance-determining region (ERDR) of a collection of 13 strains of NTM and 12 EMB-resistant strains of M. tuberculosis was investigated. Genotypes were correlated with drug susceptibility phenotypes. High-level natural resistance to EMB (MIC, . or =64 microg/ml) was associated with a variant amino acid motif in the ERDR of M. abscessus, M. chelonae, and M. leprae. Transfer of the M. abscessus emb allele to M. smegmatis resulted in a 500-fold increase in the MICs. In M. tuberculosis, embB mutations were associated with MICs of > or =20 microg/ml while resistance not associated with an ERDR mutation generally resulted in MICs of < or =10 microg/ml. These data further support the notion that the emb region determines intrinsic and acquired resistance to EMB and might help in the reassessment of the current recommendations for the screening and treatment of infections with EMB-resistant M. tuberculosis and NTM.
Characterization of fluoroquinolone-induced Achilles tendon toxicity in rats: comparison of toxicities of 10 fluoroquinolones and effects of anti-inflammatory compounds
Authors: Kashida Y , Kato M
Published: October 2018

Fluoroquinolone antibacterial agents have been reported to induce tendon lesions in juvenile rats. In the present study, we characterized fluoroquinolone-induced Achilles tendon lesions by comparing the effects of 10 fluoroquinolones and examining the potential of one of these antimicrobial agents, pefloxacin, to induce tendon lesions when coadministered with one of nine anti-inflammatory compounds. Among the 10 fluoroquinolones tested, fleroxacin and pefloxacin were the most toxic, inducing lesions at a dose of 100 mg/kg of body weight or more, while lomefloxacin, levofloxacin, and ofloxacin or sparfloxacin and enoxacin induced lesions at 300 mg/kg or more and 900 mg/kg, respectively. In contrast, norfloxacin, ciprofloxacin, and tosufloxacin had no effect even at the high dose of 900 mg/kg. The severity of the Achilles tendon lesions appeared to correlate with the structure of the substituent at the seventh position. Furthermore, pefloxacin-induced tendon lesions were inhibited by coadministration with dexamethasone and N-nitro-L-arginine methyl ester. Phenidone (1-phenyl-3-pyrazolidinone) and 2-(12-hydroxydodeca-5,10-diynyl)3,5,6-trimethyl-1,4-benzoqui none (AA861) also decreased the incidence of tendon lesions. In contrast, catalase, dimethyl sulfoxide, indomethacin, pyrilamine, and cimetidine did not modify these tendon lesions. These results suggest that nitric oxide and 5-lipoxigenase products partly mediate fluoroquinolone-induced tendon lesions.
Exposure-response relationships for saquinavir, zidovudine, and zalcitabine in combination therapy
Authors: Vanhove G F , Gries J M , Verotta D , Sheiner L B , Coombs R , Collier A C , Blaschke T F
Published: October 2018

The relationship of CD4+ cell response, level of RNA in plasma, and quantitative peripheral blood mononuclear cell (PBMC) titer to apparent drug exposure was investigated by using data from AIDS Clinical Trial Group protocol 229, a multicenter randomized study. Patients received either saquinavir, zalcitabine, or a combination of both, along with open-label zidovudine. Approximately 100 patients were enrolled in each arm, and the primary study duration was 24 weeks. Individual drug exposure, the area under the concentration-time curve, was estimated by using population-based pharmacokinetic methods. Response was defined as the maximum increase in CD4+ cell count or the maximum decrease in RNA in plasma or PBMC titer adjusted for baseline CD4+ cell count, RNA in plasma, and PBMC titer, respectively. Regression of responses on exposure demonstrated an exposure effect for saquinavir which was significant for the maximum increase in CD4+ cell count and the decrease in RNA in plasma. For the PBMC titer, no significant relationship could be demonstrated but the results suggested a trend similar to that of the other response variables. For all three response variables, the slope of the saquinavir exposure response was greater with the triple combination (saquinavir, zidovudine, and zalcitabine) than with the combination of saquinavir and zidovudine, suggesting possible synergism between saquinavir and zalcitabine.
In vitro activities of beta-lactam-beta-lactamase inhibitor combinations against Stenotrophomonas maltophilia: correlation between methods for testing inhibitory activity, time-kill curves, and bactericidal activity
Authors: Muñoz Bellido J L , Muñoz Criado S , García García I , Alonso Manzanares M A , Gutiérrez Zufiaurre M N , García-Rodríguez J A
Published: October 2018

The activities of ampicillin, ampicillin-sulbactam, amoxicillin, amoxicillin-clavulanic acid, ticarcillin, ticarcillin-clavulanic acid, piperacillin, piperacillin-tazobactam, aztreonam, and aztreonam-clavulanic against Stenotrophomonas maltophilia strains for which the MICs of penicillins and commercially available beta-lactam-beta-lactamase inhibitor combinations were higher than the breakpoints usually recommended for Pseudomonas aeruginosa in commercially available broth microdilution methods were tested by the agar diffusion, agar dilution, and broth microdilution methods. Time-kill curve studies were performed when discrepancies between these methods were observed. The MICs obtained by the commercially available broth microdilution method, the agar dilution method, and the broth microdilution method were almost identical. Twenty-five percent of the strains tested showed inhibition diameters of > or =15 mm for ticarcillin-clavulanic acid, and 43.7% of the strains tested showed inhibition diameters of > or =18 mm for piperacillin-tazobactam by the agar diffusion method. The time-kill curves for these strains confirmed the results obtained by dilution methods. Aztreonam-clavulanic acid (2:1) at concentrations of < or =16 microg/ml inhibited all of these strains (MIC range, 1 to 16 microg/ml). The time-kill curves confirmed this activity. The addition of piperacillin to this combination did not modify the MICs. The combination aztreonam-clavulanic acid-ticarcillin was two- to fourfold more active than aztreonam-clavulanic acid alone. We studied the inhibitory and bactericidal activities of the two most active combinations (aztreonam-clavulanic acid and aztreonam-clavulanic acid-ticarcillin) against the standard inoculum and 10 and 50 times the standard inoculum. Inoculum modifications did not modify the MICs. Both combinations showed good bactericidal activity against the standard inoculum. With 10 times the standard inoculum, minimum bactericidal concentration (MBC) results were heterogeneous (for 55% of the strains, MBCs were between the MIC and 4-fold the MIC, and for 45% of the strains MBCs were between 8- and >32-fold the MIC). With 50 times the standard inoculum, MBCs were at least 32-fold the MICs for all the strains tested.
Use of a fluorescent probe to assess the activities of candidate agents against intracellular forms of Encephalitozoon microsporidia
Authors: Leitch G J , Scanlon M , Shaw A , Visvesvara G S , Wallace S
Published: October 2018

Microsporidia are obligate intracellular protozoan parasites. Three species of the genus Encephalitozoon are among the microsporidia that infect immunodeficient humans. These species, Encephalitozoon cuniculi, Encephalitozoon hellem, and Encephalitozoon intestinalis, all develop in a parasitophorous vacuole within a host cell. The present study describes a method that uses the fluorescent probe calcein and confocal microscopy to detect drug-induced effects in Encephalitozoon-infected green monkey kidney cells. The effects were as follows: (i) changes in parasite organization within the parasitophorous vacuole; (ii) swelling and gross morphological changes of parasite developing stages in situ; (iii) killing of developing parasite stages in situ, detected by their uptake of the fluorescent probe; and (iv) reduction in the viability of the host cell population, assessed by the loss of the probe. Verapamil and itraconazole were used to increase the vital dye loading by both uninfected and infected cells. Agents with known antimicrosporidial activity, albendazole and fumagillin, caused all three types of parasite changes at concentrations that had no detectable effect on host cell viability. The effective doses of albendazole and fumagillin that caused swelling and disorganization of parasite developing stages were 5 x 10(-7) and 10(-6) M respectively. Killing of developing stages was detected at 10-fold-higher concentrations for these agents and at 10(-5) M for metronidazole. This method can be used to screen candidate antimicrosporidial agents in infected cultured cells.
Fungicidal activity of cecropin A
Authors: DeLucca A J , Bland J M , Jacks T J , Grimm C , Cleveland T E , Walsh T J
Published: October 2018

Cecropin A (CA) fungicidal properties were explored. Nongerminated and germinated Aspergillus spp. and Fusarium spp. conidia were treated with CA. CA achieved complete lethality at < or = 25 microM (99 micrograms/ml) for germinating, but not nongerminating, conidia of Aspergillus spp. CA achieved total lethality for nongerminated and germinating conidia of Fusarium spp at 1.5 microM (6 micrograms/ml). MIC and minimal lethal concentration assays in buffered RPMI medium gave similar results.
Potent antifungal effects of a new derivative of partricin A in a murine model of cerebral cryptococcosis
Authors: Luna T , Mazzolla R , Romanò G , Blasi E
Published: October 2018

A new member of the polyene family, N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diaspartate (SPA), was investigated and was found to be more effective than amphotericin B (i) in vivo by enhancing mouse resistance to cryptococcal meningoencephalitis and (ii) in vitro by potentiating the anticryptococcal activity of murine microglial cells.
Effects of incubation temperature, inoculum size, and time of reading on broth microdilution susceptibility test results for amphotericin B fgainst Fusarium
Authors: Pujol I , Guarro J , Sala J , Riba M D
Published: October 2018

In vitro antifungal susceptibility testing for filamentous fungi remains unstandardized and is unreliable for determining adequate therapy. A study was performed to evaluate the effect of inoculum size (10(2), 10(3), 10(4), and 10(5) conidia/ml), incubation time (48 and 72 h), and temperature (25, 30, and 35 degrees C) on MICs of amphotericin B for Fusarium spp. (20 strains). The inoculum size showed the clearest effect: when the inoculum was varied from 10(2) to 10(5) conidia/ml, the geometric mean MICs showed increases of between 10- and 19-fold in all the combined conditions of temperature and incubation time assayed. Time of incubation had less effect (increases of between two- and threefold in approximately half of the geometric mean MICs), and temperature especially had little effect (the increases were no higher than twofold). The effects of interaction between inoculum size and temperature on MICs were not statistically significant, while the combined effects of inoculum size and time of reading and of time of reading and temperature produced systematic variation in MICs.
In vitro studies of activity of voriconazole (UK-109,496), a new triazole antifungal agent, against emerging and less-common mold pathogens
Authors: Radford S A , Johnson E M , Warnock D W
Published: October 2018

The in vitro activity of voriconazole was compared with that of itraconazole. Eighty-six isolates of pathogenic molds belonging to 23 species were tested by an agar dilution method in High Resolution medium. Voriconazole was more active than itraconazole against a number of hyaline molds, including several Fusarium spp. and Scedosporium prolificans. Voriconazole and itraconazole showed comparable good activity against several hyaline molds, including Penicillium marneffei and Scedosporium apiospermum, and a number of dematiaceous molds, including Bipolaris australiensis, Cladophialophora bantiana, several Exophiala spp., and several Fonsecaea spp. Our results suggest that voriconazole could be effective against a wide range of mold infections in humans.
1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity
Authors: Daluge S M , Good S S , Faletto M B , Miller W H , St Clair M H , Boone L R , Tisdale M , Parry N R , Reardon J E , Dornsife R E , Averett D R , Krenitsky T A
Published: October 2018

1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with a unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of a wide variety of analogs containing a cyclopentene substitution for the 2'-deoxyriboside of natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. 1592U89 was equivalent in potency to 3'-azido-3'-deoxythymidine (AZT) in human peripheral blood lymphocyte (PBL) cultures against clinical isolates of HIV type 1 (HIV-1) from antiretroviral drug-naive patients (average 50% inhibitory concentration [IC50], 0.26 microM for 1592U89 and 0.23 microM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combination with AZT, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor 141W94 in MT4 cells against HIV-1 (IIIB). 1592U89 was anabolized intracellularly to its 5'-monophosphate in CD4+ CEM cells and in PBLs, but the di- and triphosphates of 1592U89 were not detected. The only triphosphate found in cells incubated with 1592U89 was that of the guanine analog (-)-carbovir (CBV). However, the in vivo pharmacokinetic, distribution, and toxicological profiles of 1592U89 were distinct from and improved over those of CBV, probably because CBV itself was not appreciably formed from 1592U89 in cells or animals (<2%). The 5'-triphosphate of CBV was a potent, selective inhibitor of HIV-1 RT, with Ki values for DNA polymerases (alpha, beta, gamma, and epsilon which were 90-, 2,900-, 1,200-, and 1,900-fold greater, respectively, than for RT (Ki, 21 nM). 1592U89 was relatively nontoxic to human bone marrow progenitors erythroid burst-forming unit and granulocyte-macrophage CFU (IC50s, 110 microM) and human leukemic and liver tumor cell lines. 1592U89 had excellent oral bioavailability (105% in the rat) and penetrated the CNS (rat brain and monkey cerebrospinal fluid) as well as AZT. Having demonstrated an excellent preclinical profile, 1592U89 has progressed to clinical evaluation in HIV-infected patients.