bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro Activities of Oral β-Lactams at Concentrations Achieved in Humans against Penicillin-Susceptible and -Resistant Pneumococci and Potential to Select Resistance
Authors: Thorburn Christine E. , Knott Sarah J. , Edwards David I. 
Published: October 2018

ABSTRACT

The β-lactam susceptibilities of 65 strains of
Streptococcus pneumoniae
for which penicillin MICs covered a broad range were assessed. The order of potency was amoxicillin (AMX) = amoxicillin-clavulanate (AMC) > penicillin G > cefpodoxime (CPO) > cefuroxime (CXM) > cefprozil > cefaclor > loracarbef > cefixime. No decrease in susceptibility was seen following repeated subculture of two penicillin-susceptible strains of
S. pneumoniae
in AMX, AMC, cefaclor, or loracarbef, whereas repeated exposure to CPO and CXM resulted in 4- to 32-fold decreases in susceptibility for both strains. When one of these strains was exposed to concentrations of CPO, CXM, AMX, and AMC achieved in the serum of humans following the administration of an oral dose, all agents were rapidly bactericidal, with no decrease in susceptibility up to 72 h. This was consistent with antibiotic concentrations exceeding the MICs for 100% of the dosing interval. For a penicillin-resistant strain, MICs were exceeded for 29% of the 12-h dosing interval for 500 mg of AMX, 42% of the interval for AMC with 875 mg of AMX and 125 mg of clavulanate (875/125 mg of AMC) 21% of the interval for 500 mg of CXM, and 0% of the interval for 200 mg of CPO. Consequently, only 875/125 mg of AMC produced a sustained bactericidal effect. A four- to eightfold reduction in susceptibility to CPO and CXM and cross-resistance with cefotaxime, but not penicillin or AMC, were selected following exposure to simulated serum CPO and CXM concentrations. In addition, AMX and AMC were the only agents which consistently produced a >99% reduction in bacterial numbers in time-kill studies using concentrations of antibiotic achieved in middle ear fluid for all three strains of penicillin-resistant
S. pneumoniae
tested.
Efficacy of MK-991 (L-743,872), a Semisynthetic Pneumocandin, in Murine Models of
Pneumocystis carinii
Authors: Powles Mary Ann , Liberator Paul , Anderson Jennifer , Karkhanis Yashwant , Dropinski James F. , Bouffard F. Aileen , Balkovec James M. , Fujioka Hisashi , Aikawa Masamichi , McFadden Diane , Schmatz Dennis 
Published: October 2018

ABSTRACT

In addition to its potent efficacy in animal models against
Candida
sp.,
Aspergillus fumigatus
, and
Histoplasma capsulatum
, the clinical candidate pneumocandin MK-991 (formerly L-743,872) was also extremely potent against
Pneumocystis carinii
in models of immune-compromised animals. MK-991 was approximately 14 times more potent than the original natural product lead, pneumocandin B
0
. The 90% effective dose (ED
90
) of MK-991 for cyst clearance in the rat model for pneumocystis was 0.011 mg/kg of body weight when delivered parenterally for 4 days twice a day (b.i.d.). In a mouse model, under the same experimental parameters, the ED
90
was 0.02 mg/kg. MK-991 was also effective orally, with an ED
90
for cyst clearance of 2.2 mg/kg against acute infection in rats (b.i.d. for 4 days). Complete prevention of
P. carinii
development was achieved in immunocompromised mice at a daily oral dose of 2.25 mg/kg. As reported previously for other pneumocandins and echinocandins, MK-991 selectively prevented the development of
P. carinii
cysts. When used as a prophylactic agent, neither stage of the organism appeared in the lungs of animals. In response to an acute infection, cysts were eliminated rapidly, while trophozoite forms persisted. Despite good efficacy as an oral agent in murine models, the low oral absorption of this class may limit the use of MK-991 to parenteral therapy.
Nucleoside Analog 1592U89 and Human Immunodeficiency Virus Protease Inhibitor 141W94 Are Synergistic In Vitro
Authors: Drusano G. L. , D’Argenio D. Z. , Symonds W. , Bilello P. A. , McDowell J. , Sadler B. , Bye A. , Bilello J. A. 
Published: October 2018

ABSTRACT

The use of combinations of anti-human immunodeficiency virus (anti-HIV) agents targeted to different molecular targets will most likely result in increased viral suppression and may also delay or prevent the emergence of resistant HIV strains. The purpose of the present study was to develop information on the in vitro anti-HIV activities of combinations of the reverse transcriptase inhibitor 1592U89 and the protease inhibitor 141W94 to help guide the choice of dosages in clinical trials. Triplicate in vitro dose-response matrices were prepared with MT-2 cells infected with HIV type 1 (HIV-1) strain IIIB. In order to account for the effects of protein binding, tissue culture medium with 10% fetal bovine serum was supplemented with the human serum proteins α
1
acid glycoprotein (1 mg/ml) and albumin (40 mg/ml). The three-dimensional drug interaction surface for 1592U89 and 141W94 was constructed with the program MacSynergy II. As analyzed relative to a Bliss Independence null reference model, this combination was synergistic, with volumes of synergy exceeding 100 (99% confidence). Analysis of the data set with a fully parametric form of an equation for the quantitation of drug interaction developed by Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol. Rev. 47:331–385, 1995) resulted in an interaction term statistically significantly greater than 0.0, indicating true synergy. Both methods concur that this combination is significantly synergistic. These data, with favorable findings from phase I/II trials for each drug alone, suggest that the combination of 1592U89 plus 141W94 should be further evaluated in clinical trials.
Characterization of a PSE-4 Mutant with Different Properties in Relation to Penicillanic Acid Sulfones: Importance of Residues 216 to 218 in Class A β-Lactamases
Authors: Sabbagh Yves , Thériault Esther , Sanschagrin François , Voyer Normand , Palzkill Timothy , Levesque Roger C. 
Published: October 2018

ABSTRACTClass A β-lactamases are inactivated by the suicide inactivators sulbactam, clavulanic acid, and tazobactam. An examination of multiple alignments indicated that amino acids 216 to 218 differed among class A enzymes. By random replacement mutagenesis of codons 216 to 218 in PSE-4, a complete library consisting of 40,864 mutants was created. The library of mutants with mutations at positions 216 to 218 in PSE-4 was screened on carbenicillin and ampicillin with the inactivator sulbactam; a collection of 14 mutants was selected, and theirblagenes were completely sequenced. Purified wild-type and mutant PSE-4 β-lactamases were used to measure kinetic parameters. One enzyme, V216S:T217A:G218R, was examined for its peculiar pattern of inhibition. There was an increase in theKmfrom 68 μM for the wild type to 271 μM for the mutant for carbenicillin and 33 to 216 μM for ampicillin. Relative to the wild-type PSE-4 enzyme, 37- and 30-fold increases inKivalues were observed for the mutant enzyme for sulbactam and tazobactam, respectively. The results that were obtained suggested that positions 216 to 218 are important for interactions with penicillanic acid sulfone inhibitors. In contrast, V216 and A217 in the TEM-1 class A β-lactamase do not tolerate amino acid residue substitutions. However, for the PSE-4 β-lactamase, 11 of 14 mutants from the library of mutants with mutations at positions 216 to 218 whose sequences were determined had substitutions at position 216 (G, R, A, S) and position 217 (A, S). The data showed the importance of residues 216 to 218 in their atomic interactions with inactivators in the PSE-4 β-lactamase structure.
Salmonella enteritidis
: AmpC Plasmid-Mediated Inducible β-Lactamase (DHA-1) with an
ampR
Gene from
Morganella morganii
Authors: Barnaud Guilene , Arlet Guillaume , Verdet Charlotte , Gaillot Olivier , Lagrange Philippe H. , Philippon Alain 
Published: October 2018

ABSTRACT

DHA-1, a plasmid-mediated cephalosporinase from a single clinical
Salmonella enteritidis
isolate, conferred resistance to oxyimino-cephalosporins (cefotaxime and ceftazidime) and cephamycins (cefoxitin and moxalactam), and this resistance was transferable to
Escherichia coli
HB101. An antagonism was observed between cefoxitin and aztreonam by the diffusion method. Transformation of the transconjugant
E. coli
strain with plasmid pNH5 carrying the
ampD
gene (whose product decreases the level of expression of
ampC
) resulted in an eightfold decrease in the MIC of cefoxitin. A clone with the same AmpC susceptibility pattern with antagonism was obtained, clone
E. coli
JM101(pSAL2-ind), and its nucleotide sequence was determined. It contained an open reading frame with 98.7% DNA sequence identity with the
ampC
gene of
Morganella morganii
. DNA sequence analysis also identified a gene upstream of
ampC
whose sequence was 97% identical to the partial sequence of the
ampR
gene (435 bp) from
M. morganii
. The gene encoded a protein with an amino-terminal DNA-binding domain typical of transcriptional activators of the LysR family. Moreover, the intercistronic region between the
ampC
and
ampR
genes was 98% identical to the corresponding region from
M. morganii
DNA. AmpR was shown to be functional by enzyme induction and a gel mobility-shift assay. An
ampG
gene was also detected in a Southern blot of DNA from the
S. enteritidis
isolate. These findings suggest that this inducible plasmid-mediated AmpC type β-lactamase, DHA-1, probably originated from
M. morganii.
Activities of Gatifloxacin Compared to Those of Seven Other Agents against Anaerobic Organisms
Authors: Ednie Lois M. , Jacobs Michael R. , Appelbaum Peter C. 
Published: October 2018

ABSTRACT
The agar dilution MIC was used to compare activities of gatifloxacin with those of ciprofloxacin, sparfloxacin, trovafloxacin, ampicillin, ampicillin-sulbactam, clindamycin, and metronidazole against 351 anaerobes. Overall MICs at which 50% of the isolates are inhibited and MICs at which 90% of the isolates are inhibited (in micrograms per milliliter) were as follows: gatifloxacin, 0.5 and 4; ciprofloxacin, 2 and 32; sparfloxacin, 2 and 8; trovafloxacin, 1 and 4; ampicillin, 1 and 64; ampicillin-sulbactam, 0.5 and 4; clindamycin, 0.125 and 8; and metronidazole, 1 and >16, respectively. Gatifloxacin MICs were similar to those of trovafloxacin in all organism groups.
Population Pharmacokinetics of Nevirapine, Zidovudine, and Didanosine in Human Immunodeficiency Virus-Infected Patients
Authors: Zhou Xiao-Jian , Sheiner Lewis B. , D’Aquila Richard T. , Hughes Michael D. , Hirsch Martin S. , Fischl Margaret A. , Johnson Victoria A. , Myers Maureen , Sommadossi Jean-Pierre ,   The National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators
Published: October 2018

ABSTRACTThe population pharmacokinetics of nevirapine (NVP), zidovudine (ZDV), and didanosine (ddI) were evaluated in a total of 175 patients infected with human immunodeficiency virus randomized to receive either a double combination of ZDV plus ddI or a triple combination of NVP plus ZDV plus ddI as a substudy of the AIDS Clinical Trials Group Protocol 241. Levels (approximating 3.5 determinations/patient) of the three drugs in plasma were measured during 44 of a total 48 weeks of study treatment, and a set of potential covariates was available for nonlinear mixed-effect modeling analysis. A one-compartment model with zero-order input and first-order elimination was fitted to the NVP data. Individual oral clearance (CL) and volume of distribution (V) averaged 0.0533 liters/h/kg of body weight and 1.17 liters/kg, respectively. Gender was the only covariate which significantly correlated with the CL of NVP. ZDV and ddI data were described by a two-compartment model with zero-order input and first-order elimination. Individual mean oral CL,VSS(volume of distribution at steady state), andVof ZDV were 1.84 liters/h/kg and 6.68 and 2.67 liters/kg, respectively, with body weight and age as correlates of CL and body weight as a correlate ofVSS. The average individual oral CL,VSS, andVof ddI were 1.64 liters/h/kg and 3.56 and 2.74 liters/kg, respectively, with body weight as a significant correlate of both CL andVSS. The relative bioavailability (F) of ZDV and ddI in the triple combination compared to that in the double combination was also evaluated. No significant effects of the combination regimens on theFof ddI were detected (FTRIPLE= 1.05 andFDOUBLE= 1 by definition), but theFof ZDV was markedly reduced by the triple combination, being only 67.7% of that of the double combination. Large (>50%) intraindividual variability was associated with both ZDV and ddI pharmacokinetics. Individual cumulative area under the plasma drug level-time curve of the three drugs was calculated for the entire study period as a measure of drug exposure based on the individual data and the final-model estimates of structural and statistical parameters.
Limited-Sampling Strategy Models for Itraconazole and Hydroxy-Itraconazole Based on Data from a Bioequivalence Study
Authors: Suarez-Kurtz Guilherme , Bozza Fernando A. , Vicente Flavio L. , Ponte Cristiano G. , Struchiner Claudio J. 
Published: October 2018

ABSTRACTThe extensive interindividual variability in oral bioavailability of itraconazole prompted an assessment of the bioequivalence of two formulations marketed in Brazil, namely, Sporanox (reference) and Traconal (test). Eighteen healthy volunteers received single 200-mg oral doses of each formulation at 2-week intervals in a randomized, crossover protocol. The concentrations of itraconazole and hydroxy-itraconazole in plasma were measured by high-performance liquid chromatography, and the datum points (n= 396) were subsequently used to develop limited-sampling strategy models for estimation of the areas under the curve (AUCs) for both compounds. The 90% confidence intervals for individual percent ratios (test/reference formulations) of the maximum concentration of drug in serum, the AUC from 0 to 48 h and the AUC from time zero to infinity (AUC0–∞) for itraconazole and hydoxy-itraconazole were below the range of 80 to 125%, suggesting that these formulations are not bioequivalent. Linear regression analysis of the AUC0–∞against time and a “jackknife” validation procedure revealed that models based on three sampling times accurately predict (R2, >0.98; bias, <3%; precision, 3 to 7%) the AUC0–∞for each of the four formulation-compound pairs tested. Increasing the number of sampling points to more than three adds little to the accuracy of the estimates of AUC0–∞. The three-point models developed for the reference formulation were validated retrospectively and were found to predict within 2% the AUC0–∞reported in previous studies performed under similar protocols. In conclusion, the data in this study indicate (i) that the tested formulations are not bioequivalent when single doses are compared and (ii) that limited-sampling strategy models based on three points predict accurately the AUC0–∞s for itraconazole and hydroxy-itraconazole and could be a valuable tool in pharmacokinetic and bioequivalence studies of single oral doses of itraconazole.
Activity of HMR 3647 Compared to Those of Six Compounds against 235 Strains of
Enterococcus faecalis
Authors: Hoellman Dianne B. , Lin Gengrong , Jacobs Michael R. , Appelbaum Peter C. 
Published: October 2018

ABSTRACT

Agar dilution was used to test the activities of HMR 3647, erythromycin A, azithromycin, clarithromycin, roxithromycin, clindamycin, and quinupristin-dalfopristin against 235 strains of
Enterococcus faecalis
. HMR 3647 was the most active compound (MICs at which 50 and 90% of the isolates are inhibited [MIC
50
and MIC
90
, respectively] of 0.06 and 4.0 μg/ml, respectively). The MIC
50
and MIC
90
(with the MIC
50
given first and the MIC
90
given second; both in micrograms per milliliter) for other compounds were as follows: 4.0 and >32.0 for erythromycin A, 16.0 and >32.0 for azithromycin, 2.0 and >32 for clarithromycin, 32.0 and >32.0 for roxithromycin, 32.0 and >32.0 for clindamycin, and 8.0 and 16.0 for quinupristin-dalfopristin. All compounds were only bacteriostatic.
Experimental Evaluation of Second-Line Oral Treatments of Visceral Leishmaniasis Caused by
Leishmania infantum
Authors: Gangneux Jean-Pierre , Dullin Michael , Sulahian Annie , Garin Yves Jean-Francois , Derouin Francis 
Published: October 2018

ABSTRACT

In a murine model of
Leishmania infantum
visceral leishmaniasis, metronidazole, ketoconazole, fluconazole, itraconazole, and terbinafine were less effective than antimonial agents in reducing hepatic parasite load. Ketoconazole potentiated the effect of meglumine antimoniate reference therapy through its marked activity against spleen infection.
The New Ketolide HMR3647 Accumulates in the Azurophil Granules of Human Polymorphonuclear Cells
Authors: Miossec-Bartoli Christine , Pilatre Lydie , Peyron Pascale , N’Diaye Elsa-Noah , Collart-Dutilleul Véronique , Maridonneau-Parini Isabelle , Diu-Hercend Anita 
Published: October 2018

ABSTRACT
HMR3647 is a semisynthetic representative of a new group of drugs, the ketolides, derived from erythromycin A. Since macrolides have been shown to accumulate in human polymorphonuclear cells (PMNs), we have investigated the ability of the molecule HMR3647 to enter human PMNs as well as other cell types, such as peripheral blood mononuclear cells and cell lines of hematopoietic and nonhematopoietic origin. In these experiments, HMR3647 was compared to erythromycin A, azithromycin, clarithromycin, and roxithromycin. Our results show that HMR3647 is specifically trapped in PMNs, where it is concentrated up to 300 times. In addition, it is poorly released by these cells, 80% of the compound remaining cell associated after 2 h in fresh medium. By contrast, it is poorly internalized and quickly released by the other cell types studied. This differs from the results obtained with the macrolide molecules, which behaved similarly in the different cells studied. In addition, subcellular fractionation of PMNs allowed us to identify the intracellular compartment where HMR3647 was trapped. In PMNs, more than 75% of the molecule was recovered in the azurophil granule fraction. Similarly, in NB4 cells differentiated into PMN-like cells, almost 60% of the molecules accumulated in the azurophil granule fraction. In addition, when HMR3647 was added to disrupted PMNs, 63% accumulated in the azurophil granules. Therefore, this study shows that the ketolide HMR3647 specifically accumulates in PMN azurophil granules, thus favoring its delivery to bacteria phagocytosed in these cells.
Sparfloxacin Selects Gyrase Mutations in First-Step
Mycoplasma hominis
Mutants, whereas Ofloxacin Selects Topoisonmerase IV Mutations
Authors: Kenny George E. , Young Patrick A. , Cartwright Frank D. , Sjöström Karen E. , Huang Wai M. 
Published: October 2018

ABSTRACT

The role of mutations in the genes for GyrA and ParC in quinolone resistance in
Mycoplasma hominis
was studied. Selection with sparfloxacin gave mutations at GyrA83 (Ser→Leu;
Escherichia coli
numbering) or GyrA87 (Glu→Lys), and mutants had increased levels of resistance to sparfloxacin (8- to 16-fold) but not to ofloxacin. Selection with ofloxacin gave changes at ParC80 (Ser→Ile) or ParC84 (Glu→Lys), and mutants were four- to eightfold more resistant to ofloxacin but not to sparfloxacin. Selection of second-step mutants from strains with ParC mutations with either quinolone yielded double mutants with additional mutations at GyrA83 (Ser→Trp or Ser→Leu) or GyrA87 (Glu→Lys). Second-step selection of GyrA mutants gave additional mutations at ParC80 (Ser→Ile) or ParC84 (Glu→Lys). Two-step mutants showed high levels of resistance to ofloxacin (MICs, 64 to 128 μg/ml) and moderate levels of resistance to sparfloxacin (MICs, 2 to 8 μg/ml). The primary target of ofloxacin in first-step mutants of
Mycoplasma hominis
was ParC, whereas that for sparfloxacin was GyrA.
Trends in Antimicrobial Resistance among Clinical Isolates of the
Bacteroides fragilis
Group from 1992 to 1997 in Montreal, Canada
Authors: Labbé Annie-Claude , Bourgault Anne-Marie , Vincelette Jean , Turgeon Pierre L. , Lamothe François 
Published: October 2018

ABSTRACT

The objective of the present study was to analyze the susceptibility profiles of 911 clinical strains of the
Bacteroides fragilis
group isolated from 1992 to 1997 in our institution in order to monitor susceptibility changes over time. Whereas the rates of resistance to metronidazole, imipenem, piperacillin-tazobactam, ticarcillin-clavulanic acid, penicillin, piperacillin, and cefoxitin remained essentially unchanged, there was a significant increase in the rates of resistance to clindamycin, which rose from 8.2% in 1992 to 19.7% in 1997 (
P
< 0.0004).
Bactericidal Activity and Postantibiotic Effect of Levofloxacin against Anaerobes
Authors: Pendland Susan L. , Diaz-Linares Mariela , Garey Kevin W. , Woodward Jennifer G. , Ryu Seonyoung , Danziger Larry H. 
Published: October 2018

ABSTRACT
The bactericidal activity and postantibiotic effect (PAE) of levofloxacin against nine anaerobes were determined. Levofloxacin at concentrations of the MIC and twice the MIC was bactericidal at 24 h to five of nine and nine of nine strains, respectively. The PAE of levofloxacin following a 2-h exposure ranged from 0.06 to 2.88 h.
Phenotypic Distinction in
Enterococcus faecium
and
Enterococcus faecalis
Strains between Susceptibility and Resistance to Growth-Enhancing Antibiotics
Authors: Butaye Patrick , Devriese Luc A. , Haesebrouck Freddy 
Published: October 2018

ABSTRACT

Susceptibility of
Enterococcus faecium
and
Enterococcus faecalis
strains from animals and foods to growth-promoting antibiotics used in animal feed was tested by the agar dilution technique. Acquired resistance to bacitracin, narasin, tylosin, and virginiamycin was seen for both species, and for
E. faecium
, resistance to avilamycin and avoparcin was also seen. Drawing the distinction between susceptibility and resistance based on frequency distributions of MICs was easy with avoparcin, avilamycin, and tylosin but difficult with virginiamycin and to some extent also with bacitracin and narasin.