bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic-Pharmacodynamic Analysis of Lopinavir-Ritonavir in Combination with Efavirenz and Two Nucleoside Reverse Transcriptase Inhibitors in Extensively Pretreated Human Immunodeficiency Virus-Infected Patients
Authors: Hsu Ann , Isaacson Jeffrey , Brun Scott , Bernstein Barry , Lam Wayne , Bertz Richard , Foit Cheryl , Rynkiewicz Karen , Richards Bruce , King Martin , Rode Richard , Kempf Dale J. , Granneman G. Richard , Sun Eugene 
Published: December 2002

ABSTRACTThe steady-state pharmacokinetics and pharmacodynamics of two oral doses of lopinavir-ritonavir (lopinavir/r; 400/100 and 533/133 mg) twice daily (BID) when dosed in combination with efavirenz, plus two nucleoside reverse transcriptase inhibitors, were assessed in a phase II, open-label, randomized, parallel arm study in 57 multiple protease inhibitor-experienced but non-nucleoside reverse transcriptase inhibitor-naive human immunodeficiency virus (HIV)-infected subjects. All subjects began dosing of lopinavir/r at 400/100 mg BID; subjects in one arm increased the lopinavir/r dose to 533/133 mg BID on day 14. When codosed with efavirenz, the lopinavir/r 400/100 mg BID regimen resulted in lower lopinavir concentrations in plasma, particularlyCmin, than were observed in previous studies of lopinavir/r administered without efavirenz. Increasing the lopinavir/r dose to 533/133 mg increased the lopinavir area under the concentration-time curve over a 12-h dosing interval (AUC12),Cpredose, andCminby 46, 70, and 141%, respectively. The increase in lopinavirCmax(33%,) did not reach statistical significance. Ritonavir AUC12,Cmax,Cpredose, andCminvalues were increased 46 to 63%. The lopinavir predose concentrations achieved with the 533/133-mg BID dose were similar to those observed with lopinavir/r 400/100 mg BID in the absence of efavirenz. Results from univariate logistic regression analyses identified lopinavir and efavirenz inhibitory quotient (IQ) parameters, as well as the baseline lopinavir phenotypic susceptibility, as predictors of antiviral response (HIV RNA < 400 copies/ml at week 24); however, no lopinavir or efavirenz concentration parameter was identified as a predictor. Multiple stepwise logistic regressions confirmed the significance of the IQ parameters, as well as other baseline characteristics, in predicting virologic response at 24 weeks in this patient population.
Drug Targeting
Mycobacterium tuberculosis
Cell Wall Synthesis: Development of a Microtiter Plate-Based Screen for UDP-Galactopyranose Mutase and Identification of an Inhibitor from a Uridine-Based Library
Authors: Scherman Michael S. , Winans Katharine A. , Stern Richard J. , Jones Victoria , Bertozzi Carolyn R. , McNeil Michael R. 
Published: December 2002

ABSTRACT

A microtiter plate assay for UDP-galactopyranose mutase, an essential cell wall biosynthetic enzyme of
Mycobacterium tuberculosis
, was developed. The assay is based on the release of tritiated formaldehyde from UDP-galactofuranose but not UDP-galactopyranose by periodate and was used to identify a uridine-based enzyme inhibitor from a chemical library.
Site-Specific Mutagenesis Analysis of PBP 1A from a Penicillin-Cephalosporin-Resistant Pneumococcal Isolate
Authors: Smith Anthony M. , Klugman Keith P. 
Published: December 2002

ABSTRACT
Our mutagenesis study has investigated all amino acid mutations in the penicillin-binding domain of PBP 1A from Hungarian pneumococcal isolate 3191 to determine the importance of every mutation in the development of penicillin and cefotaxime resistance. Our data reveal that mutations at amino acid positions 574 to 577 and position 539 cause penicillin and cefotaxime resistance.
In Vitro Activities of ABT-773 and Other Antimicrobials against Human Mycoplasmas
Authors: Waites Ken B. , Crabb Donna M. , Duffy Lynn B. 
Published: December 2002

ABSTRACT

The in vitro susceptibilities of 103
Mycoplasma pneumoniae
isolates, 14
Mycoplasma hominis
isolates, 12
Mycoplasma fermentans
isolates, and 24
Ureaplasma
species to ABT-773, an investigational ketolide, and seven other agents were determined. For
M. pneumoniae,
the ABT-773 MIC at which 90% of isolates are inhibited (MIC
90
; ≤0.001 μg/ml) was comparable to those of azithromycin, clarithromycin, and erythromycin and at least 128-fold lower than those of levofloxacin, gatifloxacin, moxifloxacin, and doxycycline. For
M. fermentans
, the ABT-773 MIC
90
(≤0.008 μg/ml) was 2- to 128-fold lower than those of all other agents tested. For
M. hominis
, the ABT-773 MIC
90
(0.031 μg/ml) was equivalent to that of moxifloxacin, 2-fold lower than those of gatifloxacin and clindamycin, and 16-fold lower than that of levofloxacin. ABT-773 was equally active against doxycycline-susceptible and doxycycline-resistant organisms. The ABT-773 MICs (0.016 μg/ml) for
Ureaplasma
species were the lowest of those of any drug tested. The MIC
90
was 4- to 64-fold lower than those of clarithromycin, azithromycin, and erythromycin and ≥16-fold lower than those of all three fluoroquinolones. Minimal bactericidal concentrations determined for a subgroup of organisms were ≤0.063 μg/ml for
M. pneumoniae
and 0.25 μg/ml for
M. fermentans
, but they were several dilutions higher for
M. hominis
and
Ureaplasma
spp. ABT-773 has great potential for further study for the treatment of infections due to mycoplasmas and ureaplasmas.
Escherichia coli
with a Self-Transferable, Multiresistant Plasmid Coding for Metallo-β-Lactamase VIM-1
Authors: Miriagou Vivi , Tzelepi Eva , Gianneli Dimitra , Tzouvelekis Leonidas S. 
Published: December 2002

ABSTRACT

An
Escherichia coli
strain exhibiting decreased susceptibility to carbapenems was isolated from a hospitalized patient in Greece. The strain carried a self-transferable plasmid coding for metallo-β-lactamase VIM-1.
bla
VIM-1
, along with
aacA7
,
dhfrI
, and
aadA
, was included as a gene cassette in a novel class 1 integron. A
Citrobacter freundii ampC
-derived gene, not associated with the integron, was also located in the same plasmid.
Antibiotic Susceptibilities of
Anaplasma
(
Ehrlichia
)
phagocytophilum
Strains from Various Geographic Areas in the United States
Authors: Maurin Max , Bakken Johan S. , Dumler J. Stephen 
Published: December 2002

ABSTRACT

We tested the antibiotic susceptibilities of eight strains of
Anaplasma phagocytophilum
(the agent of human granulocytic ehrlichiosis) collected in various geographic areas of the United States, including Minnesota, Wisconsin, California, and New York. The results are homogeneous and show that doxycycline, rifampin, and levofloxacin are the most active antibiotics against these strains in vitro.
Class 1 Integron-Borne Gene Cassettes in Multidrug-Resistant
Yersinia enterocolitica
Strains of Different Phenotypic and Genetic Types
Authors: Soto S. M. , Lobato M. J. , Mendoza M. C. 
Published: December 2002

ABSTRACT

Seventy nine strains of
Yersinia enterocolitica
resistant to one or more antimicrobials were analyzed for integrons. Only class 1
sul1
integrons containing
aadA1a
(28 strains),
aadA1a-dfr1-sat1
(2 strains), and
dfr1-aadA1a
(1 strain) gene cassettes were found. The first two types were found in clinical isolates belonging to serotype O:3, biotypes 2 to 4, and eight combined ribotypes, and the third was found in the reference strain, CECT4054 (O:8). All screened resistance markers were found in strains with and without integrons (except for chloramphenicol resistance, encoded by
catA1
gene, which was only present in strains with integrons), but in different resistance profiles (R profiles). A profile (ampicillin, streptomycin, sulfadiazine, and trimethoprim resistance, encoded by the
tem1
,
aadA1a
,
sul1
, and
dfr1
genes, respectively) was found in strains, with and without integrons. Integrons and some of the resistance genes are located on plasmids with sizes ranging between 65 and 140 kb. This is the first report of class 1 integrons in
Y. enterocolitica.
In Vivo Antibacterial Activity of RWJ-54428, a New Cephalosporin with Activity against Gram-Positive Bacteria
Authors: Griffith David C. , Harford Laurie , Williams Robert , Lee Ving J. , Dudley Michael N. 
Published: December 2002

ABSTRACT

RWJ-54428 (MC-02,479) is a new cephalosporin with activity against resistant gram-positive organisms, including methicillin-resistant
Staphylococcus aureus
, vancomycin-resistant enterococci, and penicillin-resistant
Streptococcus pneumoniae
. The in vivo efficacy of RWJ-54428 was evaluated against gram-positive bacteria in four mouse models of infection. RWJ-54428 was effective in vivo against methicillin-susceptible and -resistant
S. aureus
in a mouse model of sepsis, with 50% effective doses being similar to those of vancomycin. In a single-dose neutropenic mouse thigh model of infection, RWJ-54428 at 30 mg/kg of body weight showed activity similar to that of vancomycin at 30 mg/kg against a strain of methicillin-resistant
S. aureus
. RWJ-54428 also showed a prolonged in vivo postantibiotic effect in this model. In a mouse model of pneumonia due to a penicillin-susceptible strain of
Streptococcus pneumoniae
, RWJ-54428 displayed efficacy and potency superior to those of penicillin G and cefotaxime. In a mouse model of pyelonephritis due to
Enterococcus faecalis
, RWJ-54428 had bactericidal effects similar to those of vancomycin and ampicillin, but at two- to threefold lower total daily doses. These studies show that RWJ-54428 is active in experimental mouse models of infection against gram-positive organisms, including strains resistant to earlier cephalosporins and penicillin G.
Lincomycin Resistance Mutations in Two Regions Immediately Downstream of the −10 Region of
lmr
Promoter Cause Overexpression of a Putative Multidrug Efflux Pump in
Bacillus subtilis
Mutants
Authors: Kumano Miyuki , Fujita Masaya , Nakamura Kouji , Murata Makiko , Ohki Reiko , Yamane Kunio 
Published: December 2002

ABSTRACT

We isolated 19 lincomycin-resistant
Bacillus subtilis
mutants by expressing
lmrB
encoding a putative multidrug efflux protein. Eighteen of the mutants altered at two regions (−3 to −1 and +15) immediately downstream of the −10 region of the
lmr
promoter increased
lmr
transcription in vivo and in vitro.
Fourteen-Member Macrolides Promote the Phosphatidylserine Receptor-Dependent Phagocytosis of Apoptotic Neutrophils by Alveolar Macrophages
Authors: Yamaryo Takeshi , Oishi Kazunori , Yoshimine Hiroyuki , Tsuchihashi Yoshiko , Matsushima Kouji , Nagatake Tsuyoshi 
Published: December 2002

ABSTRACTAn inflammation of the airway of patients with diffuse panbronchiolitis (DPB), is characterized by dense neutrophil infiltration. Resolution of the inflammation can be achieved by the removal of apoptotic neutrophils by human alveolar macrophages (AM) without liberating neutrophil proteases in the airway. To understand clinical efficacy for the treatment of DPB by 14- or 15-member macrolides, their effects on the phagocytosis of apoptotic neutrophils by AM were examined. Treatment of AM with erythromycin (ERY) or clarithromycin at clinically achievable levels significantly increased the levels of phagocytosis of apoptotic neutrophils. A serum factor was not essential for the enhancement by these 14-member macrolides. Of the antibiotics tested, these effects were specific for the 14-member macrolides and a 15-member macrolide, azithromycin, but not for the 16-member macrolides, clindamycin or β-lactam antibiotics. The enhanced phagocytosis of apoptotic neutrophils by ERY had no effect on the levels of interleukin-8 or tumor necrosis factor alpha production by lipopolysaccharide-stimulated AM after phagocytosis of the apoptotic neutrophils. The increased phagocytosis of apoptotic neutrophils by ERY was also found to be phosphatidylserine receptor-dependent for AM. These data indicate a novel anti-inflammatory action of 14-member and 15-member macrolides, and suggest that such antibiotics achieve clinical efficacy for patients with DPB, in part, through enhancing the nonphlogistic phagocytosis of apoptotic neutrophils by AM.
Mannopeptimycins, New Cyclic Glycopeptide Antibiotics Produced by
Streptomyces hygroscopicus
LL-AC98: Antibacterial and Mechanistic Activities
Authors: Singh M. P. , Petersen P. J. , Weiss W. J. , Janso J. E. , Luckman S. W. , Lenoy E. B. , Bradford P. A. , Testa R. T. , Greenstein M. 
Published: December 2002

ABSTRACT

Mannopeptimycins α, β, γ, δ, and ε are new cyclic glycopeptide antibiotics produced by
Streptomyces hygroscopicus
LL-AC98. Mannopeptimycins γ, δ, and ε, which have an isovaleryl substitution at various positions on the terminal mannose of the disaccharide moiety, demonstrated moderate to good antibacterial activities. Mannopeptimycin ε was the most active component against methicillin-resistant staphylococci and vancomycin-resistant enterococci (MICs, 2 to 4 μg/ml for staphylococci and streptococci and 4 to 32 μg/ml for enterococci), while mannopeptimycins γ and δ were two- to fourfold less active. Mannopeptimycins α and β, which lack the isovaleryl substitution and the disaccharide moiety, respectively, had poor antibacterial activities. The in vivo efficacies of the mannopeptimycins in
Staphylococcus aureus
mouse protection studies paralleled their in vitro activities. The median effective doses of mannopeptimycins γ, δ, and ε were 3.8, 2.6, and 0.59 mg/kg of body weight, respectively. The mannopeptimycins were inactive against cell wall-deficient
S. aureus
and caused spheroplasting of
Escherichia coli imp
similar to that observed with penicillin G in an osmotically protective medium. Mannopeptimycin δ rapidly inhibited [
3
H]
N
-acetylglucosamine incorporation into peptidoglycan in
Bacillus subtilis
and had no effect on DNA, RNA, or protein biosynthesis. On the basis of the observations presented above, an effect on cell wall biosynthesis was suggested as the primary mode of action for mannopeptimycin δ. The mannopeptimycins were inactive against
Candida albicans
, did not initiate hemolysis of human erythrocytes, and did not promote potassium ion leakage from
E. coli imp
, suggesting a lack of membrane damage to prokaryotic or eukaryotic cells.
VanD-Type Vancomycin-ResistantEnterococcus faecium10/96A
Authors: Depardieu Florence , Reynolds Peter E. , Courvalin Patrice 
Published: December 2002

ABSTRACTVanD typeEnterococcus faecium10/96A is constitutively resistant to vancomycin and to low levels of teicoplanin by nearly exclusive synthesis of peptidoglycan precursors terminating ind-alanyl-d-lactate (L. M. Dalla Costa, P. E. Reynolds, H. A. Souza, D. C. Souza, M. F. Palepou, and N. Woodford, Antimicrob. Agents Chemother. 44:3444-3446, 2000). A G184S mutation adjacent to the serine involved in the binding ofd-Ala1 in thed-alanine:d-alanine ligase (Ddl) led to production of an impaired Ddl and accounts for the lack ofd-alanyl-d-alanine-containing peptidoglycan precursors. The sequence of thevanDgene cluster revealed eight open reading frames. The organization of this operon, assigned to a chromosomal location, was similar to those in other VanD type strains. The distal part encoded the VanHDdehydrogenase, the VanD ligase, and the VanXDdipeptidase, which were homologous to the corresponding proteins in VanD-type strains. Upstream from the structural genes for these proteins was thevanYDgene; a frameshift mutation in this gene resulted in premature termination of the encoded protein and accounted for the lack of penicillin-susceptibled,d-carboxypeptidase activity. Analysis of the translated sequence downstream from the stop codon, but in a different reading frame because of the frameshift mutation, indicated homology with penicillin binding proteins (PBPs) with a high degree of identity with VanYDfrom VanD-type strains. The 5′ end of the gene cluster contained thevanRD-vanSDgenes for a putative two-component regulatory system. Insertion of ISEfa4in thevanSDgene led to constitutive expression of vancomycin resistance. This new insertion belonged to the IS605family and was composed of two open reading frames encoding putative transposases of two unrelated insertion sequence elements, IS200and IS1341.
Contribution of the 8-Methoxy Group to the Activity of Gatifloxacin against Type II Topoisomerases of
Streptococcus pneumoniae
Authors: Kishii Ryuta , Takei Masaya , Fukuda Hideyuki , Hayashi Katsuhiko , Hosaka Masaki 
Published: December 2002

ABSTRACT

The inhibitory activities (50% inhibitory concentrations [IC
50
s]) of gatifloxacin and other quinolones against both DNA gyrase and topoisomerase IV of the wild-type
Streptococcus pneumoniae
IID553 were determined. The IC
50
s of 10 compounds ranged from 4.28 to 582 μg/ml against DNA gyrase and from 1.90 to 35.2 μg/ml against topoisomerase IV. The inhibitory activity against DNA gyrase was more varied than that against topoisomerase IV among fluoroquinolones. The IC
50
s for DNA gyrase of the 8-methoxy quinolones gatifloxacin and AM-1147 were approximately seven times lower than those of their 8-H counterparts AM-1121 and ciprofloxacin, whereas the IC
50
s for topoisomerase IV were 1.5 times lower. Moreover, the IC
50
ratios (IC
50
for DNA gyrase/IC
50
for topoisomerase IV) of gatifloxacin, AM-1147, and moxifloxacin, which possess 8-methoxy groups, were almost the same. The 8-methoxy quinolones showed higher antibacterial activity and less mutant selectivity against IID553 than their 8-H counterparts. These results suggest that the 8-methoxy group enhances both target inhibition, especially for DNA gyrase, leading to potent antipneumococcal activity and dual inhibition against both DNA gyrase and topoisomerase IV in the bacterial cell.
Regulation of Membrane Permeability by a Two-Component Regulatory System in
Pseudomonas aeruginosa
Authors: Wang Yanping , Ha Unhwan , Zeng Lin , Jin Shouguang 
Published: December 2002

ABSTRACT

Membrane impermeability is the major contributing factor to multidrug resistance in clinical isolates of
Pseudomonas aeruginosa
. By using laboratory strain PAK, a spontaneous
P. aeruginosa
mutant (mutant PAK1-3) whose membrane had reduced permeability and which displayed increased levels of resistance to various antibiotics, especially aminoglycosides, was isolated. By complementation of the mutant with a genomic clone library derived from wild-type strain PAK, a novel two-component regulatory system (PprA and PprB) was identified and was found to be able to increase the permeability of the bacterial membrane and render PAK1-3 sensitive to antibiotics. Furthermore, specific phosphorylation of the response regulator (PprB) by histidine kinase (PprA) was observed in vitro, demonstrating that they are cognate two-component regulatory genes. Introduction of a plasmid expressing the
pprB
gene into randomly chosen clinical isolates (
n
= 17) resulted in increased sensitivity to aminoglycosides in the majority of isolates (
n
= 13) tested. This is the first demonstration that
P. aeruginosa
membrane permeability can be regulated, providing an important clue in the understanding of the mechanism of membrane impermeability-mediated multidrug resistance in
P. aeruginosa
.
Dose-response patterns for vibration-induced white finger
Authors: Griffin M J , Bovenzi M , Nelson C M 
Published: December 2002

Aims:To investigate alternative relations between cumulative exposures to hand-transmitted vibration (taking account of vibration magnitude, lifetime exposure duration, and frequency of vibration) and the development of white finger (Raynaud’s phenomenon).Methods:Three previous studies have been combined to provide a group of 1557 users of powered vibratory tools in seven occupational subgroups: stone grinders, stone carvers, quarry drillers, dockyard caulkers, dockyard boilermakers, dockyard painters, and forest workers. The estimated total operating duration in hours was thus obtained for each subject, for each tool, and for all tools combined. From the vibration magnitudes and exposure durations, seven alternative measurements of cumulative exposure were calculated for each subject, using expressions of the form: dose = ∑amiti, whereaiis the acceleration magnitude on tooli,tiis the lifetime exposure duration for tooli, andm= 0, 1, 2, or 4.Results:For all seven alternative dose measures, an increase in dose was associated with a significant increase in the occurrence of vibration-induced white finger, after adjustment for age and smoking. However, dose measures with high powers of acceleration (m> 1) faired less well than measures in which the weighted or unweighted acceleration, and lifetime exposure duration, were given equal weight (m= 1). Dose determined solely by the lifetime exposure duration (without consideration of the vibration magnitude) gave better predictions than measures withmgreater than unity. All measures of dose calculated from the unweighted acceleration gave better predictions than the equivalent dose measures using acceleration frequency-weighted according to current standards.Conclusions:Since the total duration of exposure does not discriminate between exposures accumulated over the day and those accumulated over years, a linear relation between vibration magnitude and exposure duration seems appropriate for predicting the occurrence of vibration-induced white finger. Poorer predictions were obtained when the currently recommended frequency weighting was employed than when accelerations at all frequencies were given equal weight. Findings suggest that improvements are possible to both the frequency weighting and the time dependency used to predict the development of vibration-induced white finger in current standards.
Organisational justice and health of employees: prospective cohort study
Authors: Kivimäki M , Elovainio M , Vahtera J , Ferrie J E 
Published: December 2002

Aims:To examine the association between components of organisational justice (that is, justice of decision making procedures and interpersonal treatment) and health of employees.Methods:The Poisson regression analyses of recorded all-cause sickness absences with medical certificate and the logistic regression analyses of minor psychiatric morbidity, as assessed by the General Health Questionnaire, and poor self rated health status were based on a cohort of 416 male and 3357 female employees working during 1998–2000 in 10 hospitals in Finland.Results:Low versus high justice of decision making procedures was associated with a 41% higher risk of sickness absence in men (rate ratio (RR) 1.4, 95% confidence interval (CI) 1.1 to 1.8), and a 12% higher risk in women (RR 1.1, 95% CI 1.0 to 1.2) after adjustment for baseline characteristics. The corresponding odds ratios (OR) for minor psychiatric morbidity were 1.6 (95% CI 1.0 to 2.6) in men and 1.4 (95% CI 1.2 to 1.7) in women, and for self rated health 1.4 in both sexes. In interpersonal treatment, low justice increased the risk of sickness absence (RR 1.3 (95% CI 1.0 to 1.6) and RR 1.2 (95% CI 1.2 to 1.3) in men and women respectively), and minor psychiatric morbidity (OR 1.2 in both sexes). These figures largely persisted after control for other risk factors (for example, job control, workload, social support, and hostility) and they were replicated in initially healthy subcohorts. No evidence was found to support the hypothesis that organisational justice would represent a consequence of health (reversed causality).Conclusions:This is the first longitudinal study to show that the extent to which people are treated with justice in workplaces independently predicts their health.