bluuebunny/crossref_metadata_2025_split huggingface dataset:
Animal and Human Multidrug-Resistant, Cephalosporin-Resistant
Salmonella
Isolates Expressing a Plasmid-Mediated CMY-2 AmpC β-Lactamase
Authors: Winokur P. L. , Brueggemann A. , DeSalvo D. L. , Hoffmann L. , Apley M. D. , Uhlenhopp E. K. , Pfaller M. A. , Doern G. V. 
Published: July 2002

ABSTRACT

Salmonella
spp. are important food-borne pathogens that are demonstrating increasing antimicrobial resistance rates in isolates obtained from food animals and humans. In this study, 10 multidrug-resistant, cephalosporin-resistant
Salmonella
isolates from bovine, porcine, and human sources from a single geographic region were identified. All isolates demonstrated resistance to cephamycins and extended-spectrum cephalosporins as well as tetracycline, chloramphenicol, streptomycin, and sulfisoxazole. Molecular epidemiological analyses revealed eight distinct chromosomal DNA patterns, suggesting that clonal spread could not entirely explain the distribution of this antimicrobial resistance phenotype. However, all isolates encoded an AmpC-like β-lactamase, CMY-2. Eight isolates contained a large nonconjugative plasmid that could transform
Escherichia coli
. Transformants coexpressed cephalosporin, tetracycline, chloramphenicol, streptomycin, and sulfisoxazole resistances. Plasmid DNA revealed highly related restriction fragments though plasmids appeared to have undergone some evolution over time. Multidrug-resistant, cephalosporin-resistant
Salmonella
spp. present significant therapeutic problems in animal and human health care and raise further questions about the association between antimicrobial resistance, antibiotic use in animals, and transfer of multidrug-resistant
Salmonella
spp. between animals and man.
Protection against Lipopolysaccharide-Induced Death by Fluoroquinolones
Authors: Khan Anis A. , Slifer Teri R. , Araujo Fausto G. , Suzuki Yasuhiro , Remington Jack S. 
Published: July 2002

ABSTRACT

Because fluoroquinolones have an immunomodulatory effect on cytokine production by lipopolysaccharide (LPS)-treated human monocytes, we examined the effect of fluoroquinolones on the survival of mice injected with a lethal dose of LPS. Trovafloxacin (100 mg/kg), ciprofloxacin (250 mg/kg), and tosufloxacin (100 mg/kg) protected 75% (
P
= 0.0001), 25% (
P
= 0.002), and 50% (
P
= 0.002), respectively, of mice against death. The fluoroquinolones significantly reduced serum levels of interleukin-6 and tumor necrosis factor alpha in LPS-treated mice. The protective effects of fluoroquinolones in LPS-induced shock in mice may also occur in humans.
ampR
Gene Mutations That Greatly Increase Class C β-Lactamase Activity in
Enterobacter cloacae
Authors: Kuga Akio , Okamoto Ryoichi , Inoue Matsuhisa 
Published: July 2002

ABSTRACT

The
ampC
and
ampR
genes of
Enterobacter cloacae
GN7471 were cloned into pMW218 to yield pKU403. Four mutant plasmids derived from pKU403 (pKU404, pKU405, pKU406, and pKU407) were isolated in an AmpD mutant of
Escherichia coli
ML4953 by selection with ceftazidime or aztreonam. The β-lactamase activities expressed by pKU404, pKU405, pKU406, and pKU407 were about 450, 75, 160, and 160 times higher, respectively, than that expressed by the original plasmid, pKU403. These mutant plasmids all carried point mutations in the
ampR
gene. In pKU404 and pKU405, Asp-135 was changed to Asn and Val, respectively. In both pKU406 and pKU407, Arg-86 was changed to Cys. The ease of selection of AmpR mutations at a frequency of about 10
−6
in this study strongly suggests that derepressed strains, such as AmpD or AmpR mutants, could frequently emerge in the clinical setting.
Bloodstream Infections Due to
Candida
Species: SENTRY Antimicrobial Surveillance Program in North America and Latin America, 1997-1998
Authors: Pfaller M. A. , Jones R. N. , Doern G. V. , Sader H. S. , Messer S. A. , Houston A. , Coffman S. , Hollis R. J. ,   The SENTRY Participant Group
Published: July 2002

ABSTRACT

An international program of surveillance of bloodstream infections (BSI) in the United States, Canada, and Latin America detected 306 episodes of candidemia in 34 medical centers (22 in the United States, 6 in Canada, and 6 in Latin America) in 1997 and 328 episodes in 34 medical centers (22 in the United States, 5 in Canada, and 7 in Latin America) in 1998. Of the 634 BSI, 54.3% were due to
Candida albicans
, 16.4% were due to
C. glabrata
, 14.9% were due to
C. parapsilosis
, 8.2% were due to
C. tropicalis
, 1.6% were due to
C. krusei
, and 4.6% were due to other
Candida
spp. The percentage of BSI due to
C. albicans
decreased very slightly in the United States between 1997 and 1998 (56.2 to 54.4%;
P
= 0.68) and increased in both Canada (52.6 to 70.1%;
P
= 0.05) and Latin America (40.5 to 44.6%;
P
= 0.67).
C. glabrata
was the second most common species observed overall, and the percentage of BSI due to
C. glabrata
increased in all three geographic areas between 1997 and 1998.
C. parapsilosis
was the third most prevalent BSI isolate in both Canada and Latin America, accounting for 7.0 and 18.5% of BSI, respectively. Resistance to fluconazole (MIC, ≥64 μg/ml) and itraconazole (MIC, ≥1.0 μg/ml) was observed infrequently in both 1997 (2.3 and 8.5%, respectively) and 1998 (1.5 and 7.6%, respectively). Among the different species of
Candida
, resistance to fluconazole and itraconazole was observed in
C. glabrata
and
C. krusei
, whereas isolates of
C. albicans
,
C. parapsilosis
, and
C. tropicalis
were all highly susceptible to both fluconazole (98.9 to 100% susceptible) and itraconazole (96.4 to 100% susceptible). Isolates from Canada and Latin America were generally more susceptible to both triazoles than U.S. isolates were. Continued surveillance appears necessary to detect these important changes.
Coordinate Suppression of Superantigen-Induced Cytokine Production and T-Cell Proliferation by a Small Nonpeptidic Inhibitor of Class II Major Histocompatibility Complex and CD4 Interaction
Authors: Krakauer Teresa 
Published: July 2002

ABSTRACTProinflammatory cytokines mediate the toxic effect of superantigenic staphylococcal exotoxins (SE). TJU103, a small nonpeptidic molecule that blocks the interaction between major histocompatibility complex class II and CD4 molecules inhibited SE-stimulated T-cell proliferation (by 92%) and production of tumor necrosis factor, interleukin 1β, interleukin 6, and gamma interferon (by 66, 56, 76, and 72%, respectively) by human peripheral blood mononuclear cells. These data suggest that TJU103 may be useful for mitigating the pathogenic effects of SE.
Clinical Efficacy of Intravenous followed by Oral Azithromycin Monotherapy in Hospitalized Patients with Community-Acquired Pneumonia
Authors: Plouffe Joseph , Schwartz Douglas B. , Kolokathis Antonia , Sherman Bruce W. , Arnow Paul M. , Gezon John A. , Suh Byungse , Anzuetto Antonio , Greenberg Richard N. , Niederman Michael , Paladino Joseph A. , Ramirez Julio A. , Inverso Jill , Knirsch Charles A. ,   the Azithromycin Intravenous Clinical Trials Group
Published: July 2002

ABSTRACT

The purpose of this study was to evaluate intravenous (i.v.) azithromycin followed by oral azithromycin as a monotherapeutic regimen for community-acquired pneumonia (CAP). Two trials of i.v. azithromycin used as initial monotherapy in hospitalized CAP patients are summarized. Clinical efficacy is reported from an open-label randomized trial of azithromycin compared to cefuroxime with or without erythromycin. Bacteriologic and clinical efficacy results are also presented from a noncomparative trial of i.v. azithromycin that was designed to give additional clinical experience with a larger number of pathogens. Azithromycin was administered to 414 patients: 202 and 212 in the comparative and noncomparative trials, respectively. The comparator regimen was used as treatment for 201 patients; 105 were treated with cefuroxime alone and 96 were given cefuroxime plus erythromycin. In the comparative trial, clinical outcome data were available for 268 evaluable patients with confirmed CAP at the 10- to 14-day visit, with 106 (77%) of the azithromycin patients cured or improved and 97 (74%) of the comparator patients cured or improved. Mean i.v. treatment duration and mean total treatment duration (i.v. and oral) for the clinically evaluable patients were significantly (
P
< 0.05) shorter for the azithromycin group (3.6 days for the i.v. group and 8.6 days for the i.v. and oral group) than for the evaluable patients given cefuroxime plus erythromycin (4.0 days for the i.v. group and 10.3 days for the i.v. and oral group). The present comparative study demonstrates that initial therapy with i.v. azithromycin for hospitalized patients with CAP is associated with fewer side effects and is equal in efficacy to a 1993 American Thoracic Society-suggested regimen of cefuroxime plus erythromycin when the erythromycin is deemed necessary by clinicians.
In Vitro Activity of Trovafloxacin Compared to Those of Five Antimicrobials against Mycoplasmas Including
Mycoplasma hominis
and
Ureaplasma urealyticum
Fluoroquinolone-Resistant Isolates That Have Been Genetically Characterized
Authors: Bebear C. M. , Renaudin H. , Charron A. , Gruson D. , Lefrancois M. , Bebear C. 
Published: July 2002

ABSTRACT

The in vitro activity of trovafloxacin against 125 strains of
Mycoplasma
species and
Ureaplasma urealyticum
, including fluoroquinolone-susceptible and fluoroquinolone-resistant species, was compared to those of other fluoroquinolones, doxycycline, and erythromycin. The MIC at which 90% of isolates are inhibited for all fluoroquinolone-susceptible strains was 0.25 μg/ml. Whatever the associated mutations, trovafloxacin exhibited greater activity than the other fluoroquinolones tested against fluoroquinolone-resistant
Mycoplasma hominis
and
U. urealyticum
isolates.
Pharmacokinetics of the New Ketolide Telithromycin (HMR 3647) Administered in Ascending Single and Multiple Doses
Authors: Namour F. , Wessels D. H. , Pascual M. H. , Reynolds D. , Sultan E. , Lenfant B. 
Published: July 2002

ABSTRACT
Telithromycin (HMR 3647) is a novel ketolide antimicrobial with good activity against both common and atypical respiratory pathogens, including many resistant strains. This randomized, three-period crossover study determined the dose proportionality of telithromycin pharmacokinetics after single and multiple dosing in healthy subjects. In each treatment period, subjects received a single oral dose of 400, 800 or 1,600 mg of telithromycin followed 4 days later by the same dose once daily for 7 days. Blood and urine samples were taken throughout the study for determination of pharmacokinetic parameters for telithromycin and RU 76363, its main metabolite. Telithromycin and RU 76363 achieved steady state within 2 to 3 days of once-daily dosing. A slight accumulation of telithromycin was observed after 7 days of therapy, with values of the area under the concentration-time curve from 0 to 24 h approximately 1.5 times higher than those achieved with the single dose. The pharmacokinetics of telithromycin and RU 76363 deviated moderately from dose proportionality. At a dose of 800 mg/day, telithromycin attained mean maximal and trough plasma concentrations of 2.27 and 0.070 mg/liter respectively. Elimination was biphasic; initial and terminal half-lives were 2.87 and 9.81 h for the 800-mg dose. Study medication was well tolerated, although adverse events tended to be more frequent at the 1,600-mg dose. This study showed that telithromycin was generally well tolerated and suggests that a once-daily 800-mg oral dose of telithromycin maintains an effective concentration in plasma for the treatment of respiratory tract infections involving the key respiratory pathogens.
β-Lactamase Inhibitors Derived from Single-Domain Antibody Fragments Elicited in the
Camelidae
Authors: Conrath Katja E. , Lauwereys Marc , Galleni Moreno , Matagne André , Frère Jean-Marie , Kinne Jörg , Wyns Lode , Muyldermans Serge 
Published: July 2002

ABSTRACT
Small, soluble single-domain fragments derived from the unique variable region of dromedary heavy-chain antibodies (VHHs) against enzymes are known to be potent inhibitors. The immunization of dromedaries with the TEM-1 and BcII β-lactamases has lead to the isolation of such single-domain antibody fragments specifically recognizing and inhibiting those β-lactamases. Two VHHs were isolated that inhibit TEM-1 and one BcII inhibiting VHH was identified. All inhibitory VHHs were tight-binding inhibitors. The 50% inhibitory concentrations were determined for all inhibitors and they were all in the same range as the enzyme concentration used in the assay. Addition of the VHHs to the TEM-1 β-lactamase, expressed on the surface of bacteria, leads to a higher ampicillin sensitivity of the bacteria. This innovative strategy could generate multiple potent inhibitors for all types of β-lactamases.
Activity of Ertapenem (MK-0826) versus
Enterobacteriaceae
with Potent β-Lactamases
Authors: Livermore David M. , Oakton Karen J. , Carter Michael W. , Warner Marina 
Published: July 2002

ABSTRACT

Ertapenem (MK-0826; L-749,345), a new carbapenem with a long serum half-life, was tested, in vitro, against β-lactamase-producing bacteria. The new compound had a MIC at which 90% of the isolates were inhibited of 0.06 μg/ml for extended-spectrum β-lactamase (ESBL)-producing klebsiellas, compared with 0.5 μg/ml for imipenem, 16 μg/ml for cefepime, and >128 μg/ml for ceftazidime and piperacillin-tazobactam. MICs of ertapenem for AmpC-derepressed mutant
Enterobacteriaceae
were 0.015 to 0.5 μg/ml, whereas imipenem MICs were 0.25 to 1 μg/ml and those of cefepime were 0.5 to 4 μg/ml, and resistance to ceftazidime and piperacillin-tazobactam was generalized. Despite this good activity, the MICs of ertapenem for ESBL-positive klebsiellas mostly were two- to fourfold above those for ESBL-negative strains, and the MICs for AmpC-hyperproducing
Enterobacter cloacae
and
Citrobacter freundii
mutants exceeded those for the corresponding AmpC-basal mutants. These differentials did not increase when the inoculum was raised from 10
4
to 10
6
CFU/spot, contraindicating significant lability. Carbapenemase producers were also tested. The IMP-1 metallo-β-lactamase conferred substantial ertapenem resistance (MIC, 128 μg/ml) in a porin-deficient
Klebsiella pneumoniae
strain, whereas a MIC of 6 μg/ml was recorded for its porin-expressing revertant. SME-1 carbapenemase was associated with an ertapenem MIC of 2 μg/ml for
Serratia marcescens
S6, compared with <0.03 μg/ml for
Serratia
strains lacking this enzyme. In summary, ertapenem had good activity against strains with potent β-lactamases, except for those with known carbapenemases.
Biochemical-Genetic Characterization of the Chromosomally Encoded Extended-Spectrum Class A β-Lactamase from
Rahnella aquatilis
Authors: Bellais Samuel , Poirel Laurent , Fortineau Nicolas , Decousser Jean W. , Nordmann Patrice 
Published: July 2002

ABSTRACT

From whole-cell DNA of a clinical isolate of the enterobacterial species
Rahnella aquatilis
, a β-lactamase gene was cloned that encoded a chromosomally encoded Ambler class A enzyme, RAHN-1. RAHN-1, with a pI of 7.2, shares 76, 73, and 71% amino acid identity with the extended-spectrum β-lactamase of chromosomal origin from
Serratia fonticola
and with the plasmid-mediated β-lactamases CTX-M-2 and CTX-M-1, respectively. The hydrolysis spectrum of the clavulanic acid-inhibited RAHN-1 was expanded to cephalosporins such as cefuroxime, cefotaxime, and ceftriaxone, but not to ceftazidime. Its expression was not inducible.
Antimicrobial Susceptibility Testing of Clinical Isolates of
Bordetella pertussis
from Northern California: Report from the SENTRY Antimicrobial Surveillance Program
Authors: Gordon Kelley A. , Fusco Judy , Biedenbach Douglas J. , Pfaller Michael A. , Jones Ronald N. 
Published: July 2002

ABSTRACT

Reports of an increased clinical incidence of pertussis and the development of resistance by
Bordetella pertussis
to erythromycin prompted the collection and testing of recent clinical isolates from patients in northern California against a range of antimicrobial agents by the Etest (AB BIODISK, Solna, Sweden) method. All isolates were fully susceptible to all eight agents tested (MIC, ≤0.38 μg/ml), including newer fluoroquinolones, such as gatifloxacin (MIC of which 90% of the isolates tested are inhibited, 0.006 μg/ml), which may be used in cases of adolescent or adult pertussis. Continued surveillance of
B. pertussis
isolates appears to be a prudent practice.
Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A
Authors: Desta Zeruesenay , Soukhova Nadia V. , Flockhart David A. 
Published: July 2002

ABSTRACTIsoniazid (INH) remains the most safe and cost-effective drug for the treatment and prophylaxis of tuberculosis. The use of INH has increased over the past years, largely as a result of the coepidemic of human immunodeficiency virus infection. It is frequently given chronically to critically ill patients who are coprescribed multiple medications. The ability of INH to elevate the concentrations in plasma and/or toxicity of coadministered drugs, including those of narrow therapeutic range (e.g., phenytoin), has been documented in humans, but the mechanisms involved are not well understood. Using human liver microsomes (HLMs), we tested the inhibitory effect of INH on the activity of common drug-metabolizing human cytochrome P450 (CYP450) isoforms using isoform-specific substrate probe reactions. Incubation experiments were performed at a single concentration of each substrate probe at itsKmvalue with a range of INH concentrations. CYP2C19 and CYP3A were inhibited potently by INH in a concentration-dependent manner. At 50 μM INH (∼6.86 μg/ml), the activities of these isoforms decreased by ∼40%. INH did not show significant inhibition (<10% at 50 μM) of other isoforms (CYP2C9, CYP1A2, and CYP2D6). To accurately estimate the inhibition constants (Kivalues) for each isoform, four concentrations of INH were incubated across a range of five concentrations of specific substrate probes. The meanKivalues (± standard deviation) for the inhibition of CYP2C19 by INH in HLMs and recombinant human CYP2C19 were 25.4 ± 6.2 and 13 ± 2.4 μM, respectively. INH showed potent noncompetitive inhibition of CYP3A (Ki= 51.8 ± 2.5 to 75.9 ± 7.8 μM, depending on the substrate used). INH was a weak noncompetitive inhibitor of CYP2E1 (Ki= 110 ± 33 μM) and a competitive inhibitor of CYP2D6 (Ki= 126 ± 23 μM), but the meanKivalues for the inhibition of CYP2C9 and CYP1A2 were above 500 μM. Inhibition of one or both CYP2C19 and CYP3A isoforms is the likely mechanism by which INH slows the elimination of coadministered drugs, including phenytoin, carbamazepine, diazepam, triazolam, and primidone. Slow acetylators of INH may be at greater risk for adverse drug interactions, as the degree of inhibition was concentration dependent. These data provide a rational basis for understanding drug interaction with INH and predict that other drugs metabolized by these two enzymes may also interact.
In Vivo Effect of α
1
-Acid Glycoprotein on Pharmacokinetics of Amprenavir, a Human Immunodeficiency Virus Protease Inhibitor
Authors: Sadler Brian M. , Gillotin Catherine , Lou Yu , Stein Daniel S. 
Published: July 2002

ABSTRACT

Observations from early clinical pharmacology studies of amprenavir, an inhibitor of human immunodeficiency virus type 1 (HIV-1) protease that is highly bound to human plasma proteins (∼90%), showed the single-dose pharmacokinetics of amprenavir to be variable between and within individuals. A cross-study analysis of various demographic, laboratory, and clinical covariates was therefore performed. Differences in amprenavir pharmacokinetics could be due to variable concentrations in α
1
-acid glycoprotein (AAG), the predominant plasma protein to which amprenavir binds. Therefore, AAG was considered an important factor to study since the literature suggested that AAG levels vary by race, age, and weight and following trauma or infection, including HIV disease. Pooled data from three single-dose studies analyzed by stepwise linear regression indicated that AAG concentrations significantly correlated with age and race and that only AAG concentrations were a significant predictor of amprenavir apparent total clearance (CL/F). A significant inverse linear relationship was found between AAG and amprenavir CL/F. Compared to white subjects, black subjects had significantly lower AAG concentrations and therefore significantly higher amprenavir CL/F. Although AAG has a significant influence on the variability of total drug pharmacokinetics, unbound, or free, drug concentrations are not affected by AAG concentrations. Incorrect conclusions could be drawn on the pharmacokinetics of highly protein-bound drugs if AAG concentration is not included in the analysis.
Overexpression and Characterization of the Chromosomal Aminoglycoside 2′-
N
-Acetyltransferase of
Providencia stuartii
Authors: Franklin Kristyn , Clarke Anthony J. 
Published: July 2002

ABSTRACT

The gene coding for aminoglycoside 2′-
N
-acetyltransferase Ia [AAC(2′)-Ia] from
Providencia stuartii
was amplified by PCR and cloned. The resulting construct, pACKF2, was transferred into
Escherichia coli
for overexpression of AAC(2′)-Ia as a fusion protein with an N-terminal hexa-His tag. The fusion protein was isolated and purified by affinity chromatography on Ni
2+
-nitrilotriacetic acid agarose and gel permeation chromatography on Superdex 75. Comparison of the specific activity of this enzyme with that of its enterokinase-digested derivative lacking the His tag indicated that the presence of the extra N-terminal peptide does not affect activity. The temperature and pH optima for activity of both forms of the 2′-
N
-acetyltransferase were 20°C and pH 6.0, respectively, while the enzymes were most stable at 15°C and pH 8.1. The Michaelis-Menten kinetic parameters for AAC(2′)-Ia at 20°C and pH 6.0 were determined using a series of aminoglycoside antibiotics possessing a 2′-amino group and a concentration of acetyl coenzyme A fixed at 10 times its
K

m

value of 8.75 μM. Under these conditions, gentamicin was determined to be the best substrate for the enzyme in terms of both
K

m

and
k
cat
/
K

m

values, whereas neomycin was the poorest. Comparison of the kinetic parameters obtained with the different aminoglycosides indicated that their hexopyranosyl residues provided the most important binding sites for AAC(2′)-Ia activity, while the enzyme exhibits greater tolerance further from these sites. No correlation was found between these kinetic parameters and MICs determined for
P. stuartii
PR50 expressing the 2′-
N
-acetyltransferase, suggesting that its true in vivo function is not as a resistance factor.