bluuebunny/crossref_metadata_2025_split huggingface dataset:
Replacement of Broad-Spectrum Cephalosporins by Piperacillin-Tazobactam: Impact on Sustained High Rates of Bacterial Resistance
Authors: Bantar Carlos , Vesco Eduardo , Heft Claudia , Salamone Francisco , Krayeski Marcelo , Gomez Hernán , Coassolo María Alicia , Fiorillo Alejandro , Franco Diego , Arango Carina , Duret Fernando , Oliva María Eugenia 
Published: January 2004

ABSTRACT

We have previously observed a significant reduction of ceftriaxone resistance in
Proteus mirabilis
associated with an increase in the use of cefepime, along with a decrease in the consumption of broad-spectrum cephalosporins (CEP). However, we did not observe such a reduction with
Klebsiella pneumoniae
. Therefore, we sought to determine whether replacement of CEP by piperacillin-tazobactam might be useful in reducing sustained high rates of CEP resistance by this organism. We used a 6-month “before and after model”; during the second (intervention) period, most prescriptions of CEP were changed to piperacillin-tazobactam at the pharmacy. No additional barrier precautions were undertaken. During intervention, consumption of ceftazidime decreased from 17.73 to 1.14 defined daily doses (DDD) per 1,000 patient-days (
P
< 0.0001), whereas that of piperacillin-tazobactam increased from 0 to 30.57 DDD per 1,000 patient-days (
P
< 0.0001). The levels of resistance to CEP by
K. pneumoniae
and
P. mirabilis
decreased from 68.4 and 57.9% to 37.5 and 29.4%, respectively (
P
< 0.05). We conclude that replacement of ceftazidime by piperacillin-tazobactam might be a suitable strategy to decrease endemic CEP resistance by
K. pneumoniae
and
P. mirabilis
, even where there are high bacterial resistance rates and irrespective of any additional precautions for controlling nosocomial infection.
Antibody Array-Generated Profiles of Cytokine Release from THP-1 Leukemic Monocytes Exposed to Different Amphotericin B Formulations
Authors: Turtinen Lloyd W. , Prall David N. , Bremer Lindsay A. , Nauss Rachel E. , Hartsel Scott C. 
Published: January 2004

ABSTRACT

Cytokine antibody arrays were used to establish the profiles of cytokine release from THP-1 monocytes exposed to different amphotericin B (AMB) drug delivery systems. Fungizone (FZ) and Amphotec (ABCD) caused the release of significantly more inflammatory molecules and the release of inflammatory molecules at higher levels than either AmBisome (L-AMB) or Abelcet (ABLC) after 6 h of treatment. Specifically, tumor necrosis factor alpha (TNF-α), interleukin-8 (IL-8), GRO-(αβγ), monocyte chemoattractant protein-1 (MCP-1), RANTES, IL-10, and IL-6 were detected and semiquantified with a chemiluminscence imaging system. TNF-α, IL-8, and MCP-1 were the most predominant; however, little if any TNF-α was present in ABLC- or L-AMB-treated cultures. The TNF- α and IL-8 levels determined by quantitative enzyme-linked immunosorbent assay correlated with the relative cytokine levels measured by using the antibody arrays. Although the viabilities of THP-l monocytes in all AMB-treated cultures were similar by trypan blue exclusion, the amount of lactic dehydrogenase released was significantly larger in FZ- and ABCD-treated cultures than in L-AMB- and ABLC-treated cultures, indicating more membrane perturbations with those formulations. Membrane cation channel formation was also measured in model cholesterol-containing large unilamellar vesicles to directly assess the ion channel formation ability of the system. Only FZ and ABCD induced significant ion currents at concentrations less than 1.5 × 10
−5
M. These results may help provide rationales for the immediate cytokine-mediated side effects observed with FZ and ABCD and the reduced side effects observed with L-AMB and ABLC.
Oral Treatment of Cowpox and Vaccinia Virus Infections in Mice with Ether Lipid Esters of Cidofovir
Authors: Quenelle Debra C. , Collins Deborah J. , Wan W. Brad , Beadle James R. , Hostetler Karl Y. , Kern Earl R. 
Published: January 2004

ABSTRACT

Four newly synthesized ether lipid esters of cidofovir (CDV), hexadecyloxypropyl-CDV (HDP-CDV), octadecyloxyethyl-CDV (ODE-CDV), oleyloxypropyl-CDV (OLP-CDV), and oleyloxyethyl-CDV (OLE-CDV), were found to have enhanced activities against vaccinia virus (VV) and cowpox virus (CV) in vitro compared to those of CDV. The compounds were administered orally and were evaluated for their efficacies against lethal CV or VV infections in mice. HDP-CDV, ODE-CDV, and OLE-CDV were effective at preventing mortality from CV infection when treatments were initiated 24 h after viral inoculation, but only HDP-CDV and ODE-CDV maintained efficacy when treatments were initiated as late as 72 h postinfection. Oral pretreatment with HDP-CDV and ODE-CDV were also effective when they were given 5, 3, or 1 day prior to inoculation with CV, even when each compound was administered as a single dose. Both HDP-CDV and ODE-CDV were also effective against VV infections when they were administered orally 24 or 48 h after infection. In animals treated with HDP-CDV or ODE-CDV, the titers of both CV and VV in the liver, spleen, and kidney were reduced 3 to 7 log
10
. In contrast, virus replication in the lungs was not significantly reduced. These data indicate that HDP-CDV or ODE-CDV given orally is as effective as CDV given parenterally for the treatment of experimental CV and VV infections and suggest that these compounds may be useful for the treatment of orthopoxvirus infections in humans.
Orally Active Fusion Inhibitor of Respiratory Syncytial Virus
Authors: Cianci Christopher , Yu Kuo-Long , Combrink Keith , Sin Ny , Pearce Bradley , Wang Alan , Civiello Rita , Voss Stacey , Luo Guangxiang , Kadow Kathy , Genovesi Eugene V. , Venables Brian , Gulgeze Hatice , Trehan Ashok , James Jennifer , Lamb Lucinda , Medina Ivette , Roach Julia , Yang Zheng , Zadjura Lisa , Colonno Richard , Clark Junius , Meanwell Nicholas , Krystal Mark 
Published: January 2004

ABSTRACT
BMS-433771 was found to be a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. It exhibited excellent potency against multiple laboratory and clinical isolates of both group A and B viruses, with an average 50% effective concentration of 20 nM. Mechanism-of-action studies demonstrated that BMS-433771 inhibits the fusion of lipid membranes during both the early virus entry stage and late-stage syncytium formation. After isolation of resistant viruses, resistance was mapped to a series of single amino acid mutations in the F1 subunit of the fusion protein. Upon oral administration, BMS-433771 was able to reduce viral titers in the lungs of mice infected with RSV. This new class of orally active RSV fusion inhibitors offers potential for clinical development.
Treatment of Advanced Human Immunodeficiency Virus Type 1 Disease with the Viral Entry Inhibitor PRO 542
Authors: Jacobson Jeffrey M. , Israel Robert J. , Lowy Israel , Ostrow Nancy A. , Vassilatos Linda S. , Barish Melanie , Tran Diep N. H. , Sullivan Brian M. , Ketas Thomas J. , O'Neill Tobias J. , Nagashima Kirsten A. , Huang Wei , Petropoulos Christos J. , Moore John P. , Maddon Paul J. , Olson William C. 
Published: January 2004

ABSTRACT

Viral entry inhibitors represent an emerging mode of therapy for human immunodeficiency virus type 1 (HIV-1) infection. PRO 542 (CD4-immunoglobulin G2) is a tetravalent CD4-immunoglobulin fusion protein that broadly neutralizes primary HIV-1 isolates. PRO 542 binds to the viral surface glycoprotein gp120 and blocks attachment and entry of virus into CD4
+
cells. Previously, PRO 542 demonstrated antiviral activity without significant toxicity when tested at single doses ranging to 10 mg/kg. In this study, 12 HIV-infected individuals were treated with 25-mg/kg single-dose PRO 542 and then monitored for safety, antiviral effects, and PRO 542 pharmacokinetics for 6 weeks. The study examined two treatment cohorts that differed in the extent of HIV-1 disease progression. PRO 542 at 25 mg/kg was well tolerated and demonstrated a serum half-life of 3 days. Statistically significant acute reductions in HIV-1 RNA levels were observed across all study patients, and greater antiviral effects were observed in the cohort of patients with more advanced HIV-1 disease. In advanced disease (HIV-1 RNA > 100,000 copies/ml; CD4 lymphocytes < 200 cells/mm
3
), PRO 542 mediated an 80% response rate and statistically significant ≈0.5 log
10
mean reductions in viral load for 4 to 6 weeks posttreatment. Similar findings were obtained in an analysis of all (
n
= 11) advanced disease patients treated to date with single doses of PRO 542 ranging from 1 to 25 mg/kg. In addition, a significant correlation was observed between antiviral effects observed in vivo and viral susceptibility to PRO 542 in vitro. The findings support continued development of PRO 542 for salvage therapy of advanced HIV-1 disease.
Pharmacokinetics of Saquinavir plus Low-Dose Ritonavir in Human Immunodeficiency Virus-Infected Pregnant Women
Authors: Acosta Edward P. , Bardeguez Arlene , Zorrilla Carmen D. , Van Dyke Russell , Hughes Michael D. , Huang Sharon , Pompeo Lisa , Stek Alice M. , Pitt Jane , Watts D. Heather , Smith Elizabeth , Jiménez Eleanor , Mofenson Lynne ,   the Pediatric AIDS Clinical Trials Group 386 Protocol Team
Published: January 2004

ABSTRACT

The physiologic changes that occur during pregnancy make it difficult to predict antiretroviral pharmacokinetics (PKs), but few data exist on the PKs of protease inhibitors in human immunodeficiency virus (HIV)-infected pregnant women. The objective of the present study was to determine the PKs of ritonavir (RTV)-enhanced saquinavir (SQV) in HIV-infected pregnant women by an area under the curve (AUC)-targeted approach. A phase I, formal PK evaluation was conducted with HIV-infected pregnant woman during gestation, during labor and delivery, and at 6 weeks postpartum. The SQV-RTV regimen was 800/100 mg twice a day (b.i.d.), and nucleoside analogs were administered concomitantly. The SQV exposure targeted was an AUC at 24 h of 10,000 ng · h/ml. Participants were evaluated for 12-h steady-state PKs at each time period. Thirteen subjects completed the PK evaluations during gestation, 7 completed the PK evaluations at labor and delivery, and 12 completed the PK evaluations postpartum. The mean baseline weight was 67.4 kg, and the median length of gestation was 23.3 weeks. All subjects achieved SQV exposures in excess of the target AUC. The SQV AUCs at 12 h (AUC
12
s) during gestation (29,373 ± 17,524 ng · h/ml [mean ± standard deviation]), during labor and delivery (26,189 ± 22,138 ng · h/ml), and during the postpartum period (35,376 ± 26,379 ng · h/ml) were not significantly different. The mean values of the PK parameters for RTV were lower during gestation than during the postpartum period: for AUC
12
, 7,811 and 13,127 ng · h/ml, respectively; for trough concentrations, 376 and 632 ng/ml, respectively; and for maximum concentrations, 1,256 and 2,252 ng/ml, respectively (
P
≤ 0.05 for all comparisons). This is the first formal PK evaluation of a dual protease inhibitor regimen with HIV-infected pregnant women. The level of SQV exposure was sufficient at each time of evaluation. These data demonstrate large variability in SQV and RTV concentrations and suggest that RTV concentrations are altered by pregnancy. These PK results suggest that SQV-RTV at 800/100 mg b.i.d. appears to be a reasonable treatment option for this population.
Natural Variation of Drug Susceptibility in Wild-Type Human Immunodeficiency Virus Type 1
Authors: Parkin N. T. , Hellmann N. S. , Whitcomb J. M. , Kiss L. , Chappey C. , Petropoulos C. J. 
Published: January 2004

ABSTRACTWild-type viruses from the ViroLogic phenotype-genotype database were evaluated to determine the upper confidence limit of the drug susceptibility distributions, or “biological cutoffs,” for the PhenoSense HIV phenotypic drug susceptibility assay. Definition of the natural variation in drug susceptibility in wild-type human immunodeficiency virus (HIV) type 1 isolates is necessary to determine the prevalence of innate drug resistance and to assess the capability of the PhenoSense assay to reliably measure subtle reductions in drug susceptibility. The biological cutoffs for each drug, defined by the 99th percentile of the fold change in the 50% inhibitory concentration distributions or the mean fold change plus 2 standard deviations, were lower than those previously reported for other phenotypic assays and lower than the clinically relevant cutoffs previously defined for the PhenoSense assay. The 99th percentile fold change values ranged from 1.2 (tenofovir) to 1.8 (zidovudine) for nucleoside reverse transcriptase RT inhibitors (RTIs), from 3.0 (efavirenz) to 6.2 (delavirdine) for nonnucleoside RTIs, and from 1.6 (lopinavir) to 3.6 (nelfinavir) for protease inhibitors. To evaluate the potential role of intrinsic assay variability in the observed variations in the drug susceptibilities of wild-type isolates, 10 reference viruses with different drug susceptibility patterns were tested 8 to 30 times each. The median coefficients of variation in fold change for the reference viruses ranged from 12 to 18% for all drugs except zidovudine (32%), strongly suggesting that the observed differences in wild-type virus susceptibility to the different drugs is related to intrinsic virus variability rather than assay variability. The low biological cutoffs and assay variability suggest that the PhenoSense HIV assay may assist in defining clinically relevant susceptibility cutoffs for resistance to antiretroviral drugs.
Gag Non-Cleavage Site Mutations Contribute to Full Recovery of Viral Fitness in Protease Inhibitor-Resistant Human Immunodeficiency Virus Type 1
Authors: Myint Lay , Matsuda Masakazu , Matsuda Zene , Yokomaku Yoshiyuki , Chiba Tomoko , Okano Aiko , Yamada Kaneo , Sugiura Wataru 
Published: January 2004

ABSTRACT

It is well documented that human immunodeficiency virus type 1 (HIV-1) Gag cleavage site mutations (CSMs) emerge in conjunction with various HIV-1 mutations for protease inhibitor (PI) resistance and improve viral replication capacity, which is reduced by acquisition of the resistance. However, CSMs are not the only mutations that emerge in Gag during treatment; many mutations other than CSMs (non-CSMs) have been found to accumulate in the Gag region. In the present study we demonstrate the important role of Gag non-CSMs with regard to viral fitness recovery. We selected three Gag-protease sequences with different PI resistance-associated mutations and CSMs from patients with antiretroviral treatment failure. To clarify the significance of CSMs and non-CSMs, four types of recombinant viruses with different patterns in each sequence were constructed. These were the GP type (patient-derived Gag and protease), the P type (HXB2 Gag and patient-derived protease), the GP
−c
type (CSMs removed from the GP type), and the P
+c
type (CSMs in the HXB2 Gag frame and patient-derived protease). By comparison of these four types of recombinant viruses in each patient-derived Gag-protease sequence, we found that non-CSMs, which had no systematic pattern, make a significant contribution to viral fitness recovery. Our findings demonstrate a delicate interaction between the in vivo evolution of Gag and protease to evade drug selective pressure and the importance of Gag in evaluating drug-resistant viruses.
In Vitro Selection and Characterization of Resistance to Macrolides and Related Antibiotics in
Mycoplasma pneumoniae
Authors: Pereyre S. , Guyot C. , Renaudin H. , Charron A. , Bébéar C. , Bébéar C. M. 
Published: January 2004

ABSTRACT

Macrolide-resistant mutants of
Mycoplasma pneumoniae
were selected in vitro from the susceptible reference strain M129, by 23 to 50 serial passages in subinhibitory concentrations of macrolides and related antibiotics, erythromycin A, azithromycin, josamycin, clindamycin, quinupristin, quinupristin-dalfopristin, pristinamycin, and telithromycin. Mutants for which the MICs are increased could be selected with all antibiotics except the streptogramin B quinupristin. Portions of genes encoding 23S rRNA (domains II and V) and ribosomal proteins L4 and L22 of mutants were amplified by PCR, and their nucleotide sequences were compared to those of the susceptible strain M129. No mutation could be detected in domain II of 23S rRNA. Two point mutations in domain V of 23S rRNA, C2611A and A2062G, were selected in the presence of erythromycin A, azithromycin, josamycin, quinupristin-dalfopristin, and telithromycin. Mutants selected in the presence of clindamycin and telithromycin harbored a single amino acid change (H70R or H70L, respectively) in ribosomal protein L4, whereas insertions of one, two, or three adjacent glycines at position 60 (
M. pneumoniae
numbering) were selected in the presence of both streptogramin combinations. Telithromycin was the sole antibiotic that selected for substitutions (P112R and A114T) and deletions (
111
IPRA
114
) in ribosomal protein L22. Three sequential mutational events in 23S rRNA and in both ribosomal proteins were required to categorize the strain as resistant to the ketolide. Azithromycin and erythromycin A were the only selector antibiotics that remained active (MICs, 0.06 and 1 μg/ml, respectively) on their mutants selected after 50 passages.
Genotyping of
Plasmodium falciparum
Pyrimethamine Resistance by Matrix-Assisted Laser Desorption-Ionization Time-of-Flight Mass Spectrometry
Authors: Marks Florian , Meyer Christian G. , Sievertsen Jürgen , Timmann Christian , Evans Jennifer , Horstmann Rolf D. , May Jürgen 
Published: January 2004

ABSTRACT

Increasing resistance, recrudescences, and treatment failure have led to the replacement of chloroquine with the combination of pyrimethamine (PYR) and sulfadoxine (SDX) as the first-line antimalarial drugs for treatment of uncomplicated
Plasmodium falciparum
malaria in several areas where this disease is endemic. The development of resistance to PYR-SDX is favored by incomplete treatment courses or by subtherapeutic levels in plasma. PYR-SDX resistance has been associated with several single-nucleotide polymorphisms (SNPs) in the
P. falciparum
dihydrofolate reductase (
pfdhfr
) and the
P. falciparum
dihydropteroate synthetase (
pfdhps
) genes. We have established assays based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) that conveniently allow the identification of SNPs associated with PYR resistance. Variants occurring at codon positions 16, 51, 59, and 108 of the
pfdhfr
gene were analyzed by MALDI-TOF MS in synthetic oligonucleotides to determine the detection threshold. In addition, 63 blood samples from subjects with
P. falciparum
parasitemia of various degrees were analyzed. The results were compared to those obtained by DNA sequencing of the respective gene fragment. The results of MALDI-TOF MS and DNA sequencing were consistent in 40 samples. In 23 samples two or three
pfdhfr
variants were detected by MALDI-TOF assays, whereas DNA-sequencing revealed one variant only. Simultaneous detection of two different mutations by biplex assays was, in principle, feasible. As demonstrated by the example of PYR resistance, MALDI-TOF MS allows for rapid and automated high-throughput assessment of drug sensitivity in
P. falciparum
malaria.
TheybxIGene ofBacillus subtilis168 Encodes a Class D β-Lactamase of Low Activity
Authors: Colombo Maria-Luigi , Hanique Sophie , Baurin Stéphane L. , Bauvois Cédric , De Vriendt Kris , Van Beeumen Jozef J. , Frère Jean-Marie , Joris Bernard 
Published: January 2004

ABSTRACTTheybxIgene ofBacillus subtilis168 encodes a preprotein of 267 amino acid residues, including a putative signal peptide of 23 residues. The YbxI primary structure exhibits high similarity scores with two members of the superfamily of the serine penicillin-recognizing enzymes: the class D β-lactamases and the hydrophilic carboxy-terminal domains of the BlaR and MecR penicillin receptors. To determine the function and the activity of this putative penicillin-recognizing enzyme, we have subcloned theybxIgene in the pET-26b expression vector. Transformation ofEscherichia coliBL21(DE3) by the recombinant plasmid pCIP51 resulted in the export of the mature YbxI in the periplasm as a water-soluble protein. The recombinant protein was purified to 95% homogeneity. YbxI interacts with several β-lactam antibiotics and can hydrolyze some of them. YbxI is not inactivated by clavulanic acid. The YbxI function and its enzymatic activity inB. subtilisremain unknown. The acyl-enzyme obtained after incubation of YbxI with a fluorescent derivative of ampicillin can be detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, confirming that YbxI can be acylated by β-lactam antibiotics. YbxI does not hydrolyze some of the standard substrates ofd-alanyl-d-alanine peptidases, the targets of penicillin. YbxI belongs to the penicillin-recognizing enzyme family but has an activity intermediate between those of a penicillin-binding protein and a β-lactamase.
Plasmid-Mediated 16S rRNA Methylase in
Serratia marcescens
Conferring High-Level Resistance to Aminoglycosides
Authors: Doi Yohei , Yokoyama Keiko , Yamane Kunikazu , Wachino Jun-ichi , Shibata Naohiro , Yagi Tetsuya , Shibayama Keigo , Kato Haru , Arakawa Yoshichika 
Published: January 2004

ABSTRACT

Serratia marcescens
S-95, which displayed an unusually high degree of resistance to aminoglycosides, including kanamycins and gentamicins, was isolated in 2002 from a patient in Japan. The resistance was mediated by a large plasmid which was nonconjugative but transferable to an
Escherichia coli
recipient by transformation. The gene responsible for the aminoglycoside resistance was cloned and sequenced. The deduced amino acid sequence of the resistance gene shared 82% identity with RmtA, which was recently identified as 16S rRNA methylase conferring high-level aminoglycoside resistance in
Pseudomonas aeruginosa
. Histidine-tagged recombinant protein showed methylation activity against
E. coli
16S rRNA. The novel aminoglycoside resistance gene was therefore designated
rmtB
. The genetic environment of
rmtB
was further investigated. The sequence immediately upstream of
rmtB
contained the right end of transposon Tn
3
, including
bla
TEM
, while an open reading frame possibly encoding a transposase was identified downstream of the gene. This is the first report describing 16S rRNA methylase production in
S. marcescens
. The aminoglycoside resistance mechanism mediated by production of 16S rRNA methylase and subsequent ribosomal protection used to be confined to aminoglycoside-producing actinomycetes. However, it is now identified among pathogenic bacteria, including
Enterobacteriaceae
and
P. aeruginosa
in Japan. This is a cause for concern since other treatment options are often limited in patients requiring highly potent aminoglycosides such as amikacin and tobramycin.