bluuebunny/crossref_metadata_2025_split huggingface dataset:
Daptomycin Is Highly Efficacious against Penicillin-Resistant and Penicillin- and Quinolone-Resistant Pneumococci in Experimental Meningitis
Authors: Cottagnoud Philippe , Pfister Marc , Acosta Fernando , Cottagnoud Marianne , Flatz Lukas , Kühn Felix , Müller Hans-Peter , Stucki Armin 
Published: September 2004

ABSTRACT

The penetration of daptomycin, a new lipopeptide antibiotic, into inflamed meninges ranged between 4.37 and 7.53% (mean, 5.97%). Daptomycin was very efficacious in the treatment of experimental pneumococcal meningitis, producing a decrease of −1.20 ± 0.32 Δlog
10
CFU/ml · h in the bacterial titer of
Streptococcus pneumoniae
against a penicillin-resistant strain and of −0.97 ± 0.32 Δlog
10
CFU/ml · h against a penicillin- and quinolone-resistant strain found in cerebrospinal fluid (CSF). For both strains, daptomycin was significantly superior to the standard regimen of a combination of ceftriaxone with vancomycin, sterilizing 9 of 10 CSF samples after 4 h. In vitro, daptomycin produced highly bactericidal activity in concentrations above the MIC.
Mechanism of Resistance to Several Antimicrobial Agents inSalmonellaClinical Isolates Causing Traveler's Diarrhea
Authors: Cabrera Roberto , Ruiz Joaquím , Marco Francesc , Oliveira Inés , Arroyo Margarita , Aladueña Ana , Usera Miguel A. , Jiménez De Anta M. Teresa , Gascón Joaquím , Vila Jordi 
Published: September 2004

ABSTRACTThe evolution of antimicrobial resistance inSalmonellaisolates causing traveler's diarrhea (TD) and their mechanisms of resistance to several antimicrobial agents were analyzed. From 1995 to 2002, a total of 62Salmonellastrains were isolated from stools of patients with TD. The antimicrobial susceptibility to 12 antibiotics was determined, and the molecular mechanisms of resistance to several of them were detected as well. The highest levels of resistance were found against tetracycline and ampicillin (21 and 19%, respectively), followed by resistance to nalidixic acid (16%), which was mainly detected from 2000 onward. Molecular mechanisms of resistance were analyzed in 16 isolates. In these isolates, which were resistant to ampicillin, two genes encoding β-lactamases were detected:oxa-1(one isolate) andtem-like (seven isolates [in one strain concomitantly with acarb-2]). Resistance to tetracycline was mainly related totetA(five cases) and totetBandtetG(one case each). Resistance to chloramphenicol was related to the presence of thefloRandcmlAgenes and to chloramphenicol acetyltransferase activity in one case each. Different genes encoding dihydrofolate-reductases (dfrA1,dfrA12,dfrA14, anddfrA17) were detected in trimethoprim-resistant isolates. Resistance to nalidixic acid was related to the presence of mutations in the amino acid codons 83 or 87 of thegyrAgene. Further surveillance of theSalmonellaspp. causing TD is needed to detect trends in their resistance to antimicrobial agents, as we have shown in our study with nalidixic acid. Moreover, such studies will lead to better treatment and strategies to prevent and limit their spread.
A 7-Deaza-Adenosine Analog Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic Properties
Authors: Olsen David B. , Eldrup Anne B. , Bartholomew Linda , Bhat Balkrishen , Bosserman Michele R. , Ceccacci Alessandra , Colwell Lawrence F. , Fay John F. , Flores Osvaldo A. , Getty Krista L. , Grobler Jay A. , LaFemina Robert L. , Markel Eric J. , Migliaccio Giovanni , Prhavc Marija , Stahlhut Mark W. , Tomassini Joanne E. , MacCoss Malcolm , Hazuda Daria J. , Carroll Steven S. 
Published: September 2004

ABSTRACT

Improved treatments for chronic hepatitis C virus (HCV) infection are needed due to the suboptimal response rates and deleterious side effects associated with current treatment options. The triphosphates of 2′-
C
-methyl-adenosine and 2′-
C
-methyl-guanosine were previously shown to be potent inhibitors of the HCV RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of viral RNA in cells. Here we demonstrate that the inclusion of a 7-deaza modification in a series of purine nucleoside triphosphates results in an increase in inhibitory potency against the HCV RdRp and improved pharmacokinetic properties. Notably, incorporation of the 7-deaza modification into 2′-
C
-methyl-adenosine results in an inhibitor with a 20-fold-increased potency as the 5′-triphosphate in HCV RdRp assays while maintaining the inhibitory potency of the nucleoside in the bicistronic HCV replicon and with reduced cellular toxicity. In contrast, while 7-deaza-2′-
C
-methyl-GTP also displays enhanced inhibitory potency in enzyme assays, due to poor cellular penetration and/or metabolism, the nucleoside does not inhibit replication of a bicistronic HCV replicon in cell culture. 7-Deaza-2′-
C
-methyl-adenosine displays promising in vivo pharmacokinetics in three animal species, as well as an acute oral lethal dose in excess of 2,000 mg/kg of body weight in mice. Taken together, these data demonstrate that 7-deaza-2′-
C
-methyl-adenosine is an attractive candidate for further investigation as a potential treatment for HCV infection.
Mutant Prevention Concentrations for Single-Step Fluoroquinolone-Resistant Mutants of Wild-Type, Efflux-Positive, or ParC or GyrA Mutation-Containing
Streptococcus pneumoniae
Isolates
Authors: Smith Heather J. , Walters Michael , Hisanaga Tamiko , Zhanel George G. , Hoban Daryl J. 
Published: September 2004

ABSTRACT

Three fluoroquinolone-susceptible and five fluoroquinolone-resistant (two with ParC Ser79Phe mutations, one with a GyrA Ser81Phe mutation, and two that were efflux positive)
Streptococcus pneumoniae
isolates were exposed to one, two, four, eight, and sixteen times the MICs of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin. Mutational frequencies were calculated at each multiple of the MIC for which growth was observed. Mutant prevention concentrations (MPCs) and the multiple of the MIC at the MPC (MP
MIC
) were evaluated. All resulting mutants were sequenced for quinolone resistance-determining region changes in GyrA and ParC and were evaluated for reserpine-sensitive efflux. The MPC order was generally ciprofloxacin > levofloxacin > gatifloxacin > moxifloxacin > gemifloxacin. The MP
MIC
order varied depending on the genetic constitution of the original isolates from which the mutants were generated. For those mutants created from fluoroquinolone-susceptible isolates (those that had wild-type ParC and GyrA and were efflux negative), the MP
MIC
order was ciprofloxacin = moxifloxacin > gemifloxacin > levofloxacin > gatifloxacin. The MP
MIC
s of each fluoroquinolone for mutants created from isolates with a ParC mutation (with wild-type GyrA and efflux negative) were similar. A similar occurrence was observed with the mutants created from the efflux-positive isolates (with wild-type ParC and GyrA). The MP
MIC
order for the mutants created from the isolate with a GyrA mutation (with wild-type ParC and efflux negative) was ciprofloxacin = gemifloxacin > levofloxacin = moxifloxacin > gatifloxacin. Gatifloxacin, levofloxacin, and moxifloxacin may be intrinsically more able to prevent the development of resistance by fluoroquinolone-susceptible isolates, isolates that are efflux positive, or isolates that carry a GyrA mutation. However, once a ParC mutation is present, the MPC increases dramatically for all fluoroquinolones.
Efficacy of PLD-118, a Novel Inhibitor of
Candida
Isoleucyl-tRNA Synthetase, against Experimental Oropharyngeal and Esophageal Candidiasis Caused by Fluconazole-Resistant
C. albicans
Authors: Petraitis Vidmantas , Petraitiene Ruta , Kelaher Amy M. , Sarafandi Alia A. , Sein Tin , Mickiene Diana , Bacher John , Groll Andreas H. , Walsh Thomas J. 
Published: September 2004

ABSTRACT

PLD-118, formerly BAY 10-8888, is a synthetic antifungal derivative of the naturally occurring β-amino acid cispentacin. We studied the activity of PLD-118 in escalating dosages against experimental oropharyngeal and esophageal candidiasis (OPEC) caused by fluconazole (FLC)-resistant
Candida albicans
in immunocompromised rabbits. Infection was established by fluconazole-resistant (MIC > 64 μg/ml) clinical isolates from patients with refractory esophageal candidiasis. Antifungal therapy was administered for 7 days. Study groups consisted of untreated controls; animals receiving PLD-118 at 4, 10, 25, or 50 mg/kg of body weight/day via intravenous (i.v.) twice daily (BID) injections; animals receiving FLC at 2 mg/kg/day via i.v. BID injections; and animals receiving desoxycholate amphotericin B (DAMB) i.v. at 0.5 mg/kg/day. PLD-118- and DAMB-treated animals showed a significant dosage-dependent clearance of
C. albicans
from the tongue, oropharynx, and esophagus in comparison to untreated controls (
P
≤ 0.05,
P
≤ 0.01,
P
≤ 0.001, respectively), while FLC had no significant activity. PLD-118 demonstrated nonlinear plasma pharmacokinetics across the investigated dosage range, as was evident from a dose-dependent increase in plasma clearance and a dose-dependent decrease in the area under the plasma concentration-time curve. The biochemical safety profile was similar to that of FLC. In summary, PLD-118 demonstrated dosage-dependent antifungal activity and nonlinear plasma pharmacokinetics in treatment of experimental FLC-resistant oropharyngeal and esophageal candidiasis.
DB75, a Novel Trypanocidal Agent, Disrupts Mitochondrial Function in
Saccharomyces cerevisiae
Authors: Lanteri Charlotte A. , Trumpower Bernard L. , Tidwell Richard R. , Meshnick Steven R. 
Published: September 2004

ABSTRACT

The aromatic diamidines represent a class of compounds with broad-spectrum antimicrobial activity; however, their development is hindered by a lack of understanding of their mechanism of antimicrobial action. DB75 [2,5-bis(4-amidinophenyl)furan] is a trypanocidal aromatic diamidine that was originally developed as a structural analogue of the antitrypanosomal agent pentamidine. DB289, a novel orally active prodrug of DB75, is undergoing phase IIb clinical trials for early-stage human African trypanosomiasis,
Pneumocystis jiroveci carinii
pneumonia, and malaria. The purpose of this study was to investigate mechanisms of action of DB75 using
Saccharomyces cerevisiae
as a model organism. The results of this investigation suggest that DB75 inhibits mitochondrial function. Yeast cells relying upon mitochondrial metabolism for energy production are especially sensitive to DB75. DB75 localizes (by fluorescence) within the mitochondria of living yeast cells and collapses the mitochondrial membrane potential in isolated yeast mitochondria. Furthermore, addition of DB75 to yeast cells or isolated rat liver mitochondria results in immediate uncoupling of oxidative phosphorylation and subsequent inhibition of respiration. We conclude that the mitochondrion is a cellular target of DB75 in yeast cells and anticipate that the results of this study will aid in the target-based design of new antimicrobial aromatic diamidines.
Rifalazil Treats and Prevents Relapse of
Clostridium difficile
-Associated Diarrhea in Hamsters
Authors: Anton Pauline M. , O'Brien Michael , Kokkotou Efi , Eisenstein Barry , Michaelis Arthur , Rothstein David , Paraschos Sophia , Kelly Ciáran P. , Pothoulakis Charalabos 
Published: September 2004

ABSTRACT

Although vancomycin and metronidazole effectively treat
Clostridium difficile
-associated diarrhea and colitis (CDAD), their use is associated with a high incidence of relapsing
C. difficile
infection. Rifalazil is a new benzoxazinorifamycin that possesses activity against
Mycobacterium tuberculosis
and gram-positive bacteria. Here we compared rifalazil and vancomycin for effectiveness in preventing or treating clindamycin-induced cecitis in a hamster model of CDAD. Golden Syrian hamsters were injected subcutaneously with clindamycin phosphate (10 mg/kg), followed 24 h later by
C. difficile
gavage. Hamsters received by gavage for 5 days vehicle, vancomycin (50 mg/kg), or rifalazil (20 mg/kg) either simultaneously with (prophylactic protocol) or 24 h after
C. difficile
administration (treatment protocol). While all vehicle-administered animals became moribund within 48 h of
C. difficile
administration, no rifalazil- or vancomycin-treated animals in either protocol showed signs of morbidity after 7 days. Ceca of rifalazil-treated animals showed absence of epithelial cell damage, significantly reduced congestion and edema, and less, but not statistically significantly less, neutrophil infiltration compared to those of vehicle-treated animals. In contrast, vancomycin-treated animals demonstrated severe epithelial cell damage and mildly reduced congestion and edema. Moreover, hamsters relapsed and tested
C. difficile
toxin positive (by enzyme-linked immunosorbent assay) 10 to 15 days after discontinuation of vancomycin treatment. None of the rifalazil-treated hamsters showed signs of disease or presence of toxins in their feces 30 days after discontinuation of treatment. Our results indicate that once daily rifalazil may be superior to vancomycin for curative treatment of CDAD.
Tetracycline Resistance inChlamydia suisMediated by Genomic Islands Inserted into the Chlamydialinv-Like Gene
Authors: Dugan Jae , Rockey Daniel D. , Jones Loren , Andersen Arthur A. 
Published: September 2004

ABSTRACTMany strains ofChlamydia suis, a pathogen of pigs, express a stable tetracycline resistance phenotype. We demonstrate that this resistance pattern is associated with a resistance gene,tet(C), in the chlamydial chromosome. Four related genomic islands were identified in seven tetracycline-resistantC. suisstrains. All resistant isolates carry the structural genetet(C) and the tetracycline repressor genetetR(C). The islands share significant nucleotide sequence identity with resistance plasmids carried by a variety of different bacterial species. Three of the fourtet(C) islands also carry a novel insertion sequence that is homologous to the IS605family of insertion sequences. In each strain, the resistance gene and associated sequences are recombined into an identical position in a gene homologous to theinvgene of the yersiniae. These genomic islands represent the first examples of horizontally acquired DNA integrated into a natural isolate of chlamydiae or within any other obligate intracellular bacterium.
Mechanisms of Resistance in Multiple-Antibiotic-Resistant
Escherichia coli
Strains of Human, Animal, and Food Origins
Authors: Sáenz Yolanda , Briñas Laura , Domínguez Elena , Ruiz Joaquim , Zarazaga Myriam , Vila Jordi , Torres Carmen 
Published: September 2004

ABSTRACT

Seventeen multiple-antibiotic-resistant nonpathogenic
Escherichia coli
strains of human, animal, and food origins showed a wide variety of antibiotic resistance genes, many of them carried by class 1 and class 2 integrons. Amino acid changes in MarR and mutations in
marO
were identified for 15 and 14
E. coli
strains, respectively.
Determination of Susceptibilities of 26Leptospirasp. Serovars to 24 Antimicrobial Agents by a Broth Microdilution Technique
Authors: Murray Clinton K. , Hospenthal Duane R. 
Published: September 2004

ABSTRACTThe MICs of 24 antimicrobials for 26Leptospiraspp. serovars were determined using a broth microdilution technique. The MICs at which 90% of isolates tested were inhibited (MIC90s) of cefepime, imipenem-cilastatin, erythromycin, clarithromycin, and telithromycin were all ≤0.01 μg/ml. The MIC90s of amoxicillin, aztreonam, cefdinir, chloramphenicol, and penicillin G were ≥3.13 μg/ml. Many antimicrobials have excellent in vitro activity againstLeptospira.
Correlation between In Vitro Susceptibility of
Scedosporium apiospermum
to Voriconazole and In Vivo Outcome of Scedosporiosis in Guinea Pigs
Authors: Capilla Javier , Guarro Josep 
Published: September 2004

ABSTRACT

We have evaluated the efficacy of voriconazole (VRC) in a systemic infection by
Scedosporium apiospermum
in immunodepressed guinea pigs. Animals were infected with two strains; one required a VRC MIC of 0.5 to 1 μg/ml, common for this fungus, and the other required a high MIC (8 μg/ml), unusual in this species. VRC prolonged survival and reduced fungal load in kidney and brain tissues of the animals infected with the first strain but was unable to prolong survival or to reduce fungal load in brain tissue for the latter strain.
Prevalence of Mutations within the Quinolone Resistance-Determining Region of
gyrA
,
gyrB
,
parC
, and
parE
and Association with Antibiotic Resistance in Quinolone-Resistant
Salmonella enterica
Authors: Eaves Deborah J. , Randall Luke , Gray Douglas T. , Buckley Antony , Woodward Martin J. , White Allan P. , Piddock Laura J. V. 
Published: September 2004

ABSTRACT

Salmonella enterica
isolates (
n
= 182) were examined for mutations in the quinolone resistance-determining region of
gyrA
,
gyrB
,
parC
, and
parE
. The frequency, location, and type of GyrA substitution varied with the serovar. Mutations were found in
parC
that encoded Thr57-Ser, Thr66-Ile, and Ser80-Arg substitutions. Mutations in the
gyrB
quinolone resistance-determining region were located at codon Tyr420-Cys or Arg437-Leu. Novel mutations were also found in
parE
encoding Glu453-Gly, His461-Tyr, Ala498-Thr, Val512-Gly, and Ser518-Cys. Although it is counterintuitive, isolates with a mutation in both
gyrA
and
parC
were more susceptible to ciprofloxacin than were isolates with a mutation in
gyrA
alone.
In Vitro Killing of Community-Associated Methicillin-Resistant
Staphylococcus aureus
with Drug Combinations
Authors: Shelburne Samuel A. , Musher Daniel M. , Hulten Kristina , Ceasar Heather , Lu Michael Y. , Bhaila Imran , Hamill Richard J. 
Published: September 2004

ABSTRACT

This study employs time-kill techniques to examine the most common drug combinations used in the therapy of methicillin-resistant
Staphylococcus aureus
(MRSA) infections, vancomycin plus either gentamicin or rifampin. Community-associated MRSA were more likely to be synergistically inhibited by combinations of vancomycin and gentamicin versus vancomycin alone compared to inhibition associated with hospital-acquired strains.
Alterations of Penicillin-Binding Proteins 1A, 2X, and 2B in
Streptococcus pneumoniae
Isolates for Which Amoxicillin MICs Are Higher than Penicillin MICs
Authors: Kosowska K. , Jacobs M. R. , Bajaksouzian S. , Koeth L. , Appelbaum P. C. 
Published: September 2004

ABSTRACT

Penicillin-binding proteins (PBPs) of 15 selected penicillin- and amoxicillin-resistant
Streptococcus pneumoniae
isolates (MICs of 2 to 8 and 8 to 16 μg/ml, respectively) were studied. In addition to typical changes in PBPs 1A and 2X, these strains had 10 unique changes in PBP 2B, including a
618
A-G substitution, which may be the key alteration associated with amoxicillin resistance.
Peptide Nucleic Acid-Mediated Competitive PCR Clamping for Detection of Rifampin-Resistant
Mycobacterium tuberculosis
Authors: Iwamoto Tomotada , Sonobe Toshiaki 
Published: September 2004

ABSTRACT

Peptide nucleic acid-mediated competitive PCR clamping, which can selectively amplify mutant alleles, was developed to detect mutations in four codons (513, 516, 526, and 531) of the
rpoB
gene in
Mycobacterium tuberculosis
strains. This simple method successfully identified the mutations in all 40 of the
M. tuberculosis
strains tested.
Antipneumococcal Activity of LBM415, a New Peptide Diformylase Inhibitor, Compared with Those of Other Agents
Authors: Ednie Lois M. , Pankuch Glenn , Appelbaum Peter C. 
Published: September 2004

ABSTRACT
The MICs of LBM415, a new peptide diformylase inhibitor, were evaluated and ranged from 0.03 to 4.0 μg/ml for 300 pneumococci, irrespective of their β-lactam, macrolide, and quinolone susceptibilities. By comparison, vancomycin, teicoplanin, linezolid, and quinupristin-dalfopristin were also active, with MICs ≤2.0 μg/ml. Gatifloxacin and moxifloxacin were the most active quinolones tested, while the MICs of the β-lactams rose with those of penicillin G. LBM415 at two times the MIC was bactericidal (99.9% killing) against six strains after 24 h.
Antistaphylococcal Activity of LBM415, a New Peptide Deformylase Inhibitor, Compared with Those of Other Agents
Authors: Credito Kim , Lin Gengrong , Ednie Lois M. , Appelbaum Peter C. 
Published: September 2004

ABSTRACT

The MICs of LBM415, a new peptide diformylase inhibitor, were ≤0.06 to 4.0 μg/ml for 258 isolates of
Staphylococcus aureus
and coagulase-negative staphylococci. LBM415 MICs were similar irrespective of whether the strains were methicillin susceptible or resistant. All strains were also susceptible to vancomycin, linezolid, ranbezolid, daptomycin, oritavancin, and quinupristin-dalfopristin. LBM415 at the MIC was bacteriostatic after 24 h.
Antistaphylococcal Activity of CB-181963 (CAB-175), an Experimental Parenteral Cephalosporin
Authors: Hoellman Dianne B. , Pankuch Glenn A. , Appelbaum Peter C. 
Published: September 2004

ABSTRACT

Among 265 methicillin-susceptible and -resistant staphylococci, CB-181963 (CAB-175) had a 50% minimum inhibitory concentration of 2 μg/ml and a 90% minimum inhibitory concentration of 4 μg/ml. All strains except two vancomycin-resistant
S. aureus
and 5 vancomycin-intermediate
S. aureus
strains were also susceptible to vancomycin and teicoplanin, and all were susceptible to linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin. Most methicillin-resistant strains were levofloxacin resistant. CB-181963 was bactericidal against all six methicillin-resistant strains at four times the MIC after 24 h.
Resistance Phenotypes and Genotypes of Erythromycin-Resistant
Streptococcus pneumoniae
Isolates in Beijing and Shenyang, China
Authors: Tiemei Zhao , Xiangqun Fang , Youning Liu 
Published: September 2004

ABSTRACT

Of a total of 192
Streptococcus pneumoniae
isolates, 149 (77.6%) were not susceptible to erythromycin. Of these 149 isolates, 117 (79.1%) contained the
erm
(B) gene, 16 (10.8%) contained the
mef
(A) gene, and 15 (10.1%) harbored both the
erm
(B) and
mef
(A) genes.
CARB-9, a Carbenicillinase Encoded in the VCR Region of
Vibrio cholerae
Non-O1, Non-O139 Belongs to a Family of Cassette-Encoded β-Lactamases
Authors: Petroni Alejandro , Melano Roberto G. , Saka Héctor A. , Garutti Alicia , Mange Laura , Pasterán Fernando , Rapoport Melina , Miranda Mariana , Faccone Diego , Rossi Alicia , Hoffman Paul S. , Galas Marcelo F. 
Published: September 2004

ABSTRACT

The gene
bla
CARB-9
was located in the
Vibrio cholerae
super-integron, but in a different location relative to
bla
CARB-7
. CARB-9 (pI 5.2) conferred β-lactam MICs four to eight times lower than those conferred by CARB-7, differing at Ambler's positions V97I, L124F, and T228K. Comparison of the genetic environments of all reported
bla
CARB
genes indicated that the CARB enzymes constitute a family of cassette-encoded β-lactamases.
Relationship between Phenotypic and Genotypic Florfenicol Resistance in
Escherichia coli
Authors: Singer Randall S. , Patterson Sheila K. , Meier Anne E. , Gibson Jessica K. , Lee Hannah L. , Maddox Carol W. 
Published: September 2004

ABSTRACT

This study evaluated the relationship between florfenicol resistance and
flo
genotypes in 1,987
Escherichia coli
isolates from cattle. The
flo
gene was detected in 164 isolates, all of which expressed resistance to florfenicol at MICs of ≥256 μg/ml. The florfenicol MICs for all isolates that lacked
flo
were ≤16 μg/ml.
AmpC β-Lactamase in an
Escherichia coli
Clinical Isolate Confers Resistance to Expanded-Spectrum Cephalosporins
Authors: Mammeri Hedi , Nazic Hasan , Naas Thierry , Poirel Laurent , Léotard Sophie , Nordmann Patrice 
Published: September 2004

ABSTRACT

Cloning, sequencing, and biochemical analysis identified a novel AmpC-type β-lactamase conferring resistance to extended-spectrum cephalosporins in an
Escherichia coli
clinical isolate. This enzyme, exhibiting 14 amino acid substitutions compared to a reference AmpC cephalosporinase of
E. coli
, hydrolyzed ceftazidime and cefepime significantly.