bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of the Paradoxical Effect of Caspofungin in Therapy of Candidiasis
Authors: Clemons Karl V. , Espiritu Marife , Parmar Rachana , Stevens David A. 
Published: March 2006

ABSTRACT

Paradoxical growth of some
Candida albicans
isolates in the presence of caspofungin (CAS) in vitro has been demonstrated previously. We sought to determine whether a similar phenomenon occurred in vivo. A systemic model of candidiasis was studied in CD-1 mice by intravenous inoculation of different isolates of
C. albicans.
Infected animals were treated with CAS at various dosages (0.01 to 20 mg/kg) and CFU remaining in the kidneys determined. Four clinical isolates that showed paradoxical growth in vitro and one that did not were tested. Recovery of CFU from the kidneys showed that dosages of CAS at 0.1 mg/kg and above were efficacious in the reduction of
C. albicans
, but were not curative. Against isolates that show paradoxical growth in vitro, CAS was efficacious, but lacked dose responsiveness above 0.5 mg/kg against three of the four. One isolate, 95-68, showed paradoxical growth in vivo with significantly higher CFU recovered from mice given CAS at 20 mg/kg than those given CAS at 5 mg/kg, but the effect was not reproducible in a subsequent experiment. When CAS was given prophylactically and therapeutically, improved efficacy and cure rate were observed. Overall, these data indicate that CAS is highly efficacious against systemic murine candidiasis and a paradoxical effect was not reproducibly demonstrated in vivo.
Pharmacokinetics of Tenofovir Disoproxil Fumarate and Ritonavir-Boosted Saquinavir Mesylate Administered Alone or in Combination at Steady State
Authors: Chittick Gregory E. , Zong Jian , Blum M. Robert , Sorbel Jeffrey J. , Begley John A. , Adda Nathalie , Kearney Brian P. 
Published: March 2006

ABSTRACT

A phase I study was conducted to formally evaluate the steady-state pharmacokinetics (PK) of tenofovir disoproxil fumarate (TDF) and ritonavir (RTV)-boosted saquinavir mesylate (SQV) when coadministered in healthy volunteers. Forty subjects received multiple doses of TDF (300 mg, once daily) and SQV/RTV (1,000 mg/100 mg, twice daily) alone and together under steady-state conditions in an open-label, fixed sequence design. Blood samples for tenofovir (TFV) and SQV/RTV PK were drawn over respective 24- and 12-h dosing intervals, and drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Safety was assessed periodically by clinical and laboratory monitoring. Thirty-two subjects completed the study and were fully evaluable; three subjects discontinued participation in the study due to adverse events, three subjects withdrew for personal reasons, and two subjects withdrew because of inadequate venous access for blood sampling. Steady-state TFV PK were not significantly altered upon coadministration with SQV/RTV. Steady-state SQV (administered as SQV/RTV) AUC
tau
,
C
max
, and
C
tau
increased 29, 22, and 47%, respectively, upon coadministration with TDF, and all subjects achieved a
C
tau
of >100 ng/ml. These modestly increased SQV exposures are not clinically meaningful given its clinical use with RTV already results in >10-fold-higher SQV levels. Steady-state RTV AUC
tau
and
C
max
levels were not significantly altered, whereas
C
tau
was 23% higher upon coadministration of SQV/RTV and TDF. Thus, no clinically relevant interactions between TDF and RTV-boosted SQV were observed under conditions simulating clinical practice.
Time Course of Microbiologic Outcome and Gene Expression in
Candida albicans
during and following In Vitro and In Vivo Exposure to Fluconazole
Authors: Lepak A. , Nett J. , Lincoln L. , Marchillo K. , Andes D. 
Published: March 2006

ABSTRACT

Pharmacodynamics (PD) considers the relationship between drug exposure and effect. The two factors that have been used to distinguish the PD behaviors of antimicrobials are the impact of concentration on the extent of organism killing and the duration of persistent microbiologic suppression (postantibiotic effect). The goals of these studies were (i) to examine the relationship between antimicrobial PD and gene expression and (ii) to gain insight into the mechanism of fluconazole effects persisting following exposure. Microarrays were used to estimate the transcriptional response of
Candida albicans
to a supra-MIC F exposure over time in vitro. Fluconazole at four times the MIC was added to a log-phase
C. albicans
culture, and cells were collected to determine viable growth and for microarray analyses. We identified differential expression of 18% of all genes for at least one of the time points. More genes were upregulated (
n
= 1,053 [16%]) than downregulated (174 [3%]). Of genes with known function that were upregulated during exposure, most were related to plasma membrane/cell wall synthesis (18%), stress responses (7%), and metabolism (6%). The categories of downregulated genes during exposure included protein synthesis (15%), DNA synthesis/repair (7%), and transport (7%) genes. The majority of genes identified at the postexposure time points were from the protein (17%) and DNA (7%) synthesis categories. In subsequent studies, three genes (
CDR1
,
CDR2
, and
ERG11
) were examined in greater detail (more concentration and time points) following fluconazole exposure in vitro and in vivo. Expression levels from the in vitro and in vivo studies were congruent.
CDR1
and
CDR2
transcripts were reduced during in vitro fluconazole exposure and during supra-MIC exposure in vivo. However, in the postexposure period, the mRNA abundance of both pumps increased.
ERG11
expression increased during exposure and fell in the postexposure period. The expression of the three genes responded in a dose-dependent manner. In sum, the microarray data obtained during and following fluconazole exposure identified genes both known and unknown to be affected by this drug class. The expanded in vitro and in vivo expression data set underscores the importance of considering the time course of exposure in pharmacogenomic investigations.
Novel Carbapenem-Hydrolyzing Oxacillinase OXA-62 from
Pandoraea pnomenusa
Authors: Schneider Ines , Queenan Anne Marie , Bauernfeind Adolf 
Published: March 2006

ABSTRACT

Pandoraea
spp. are gram-negative, glucose nonfermenting rods detectable in blood cultures and sputa of cystic fibrosis patients. They are resistant to various antibiotic groups, with imipenem being the only active β-lactam. We isolated an imipenem-resistant (MIC, 64 μg/ml)
Pandoraea pnomenusa
strain from a cystic fibrosis patient. Cloning and sequencing identified two β-lactamases of Bush group 2d, namely, the known OXA-33, located on an integron, and the novel carbapenem-hydrolyzing oxacillinase OXA-62. OXA-62 is only distantly related to other oxacillinases (OXA-50 being closest with 43% amino acid identity). It hydrolyzes penicillins, oxacillin, imipenem, and meropenem but not expanded-spectrum cephalosporins. The
bla
OXA-62
gene is chromosome located. No transposable elements were found in its genetic neighborhood. With OXA-62-specific primers,
bla
OXA-62
could be identified in all
P. pnomenusa
strains and appears to be species specific. This additional mechanism of carbapenem resistance further complicates the treatment of infections caused by
P. pnomenusa
.
Involvement of the MexXY-OprM Efflux System in Emergence of Cefepime Resistance in Clinical Strains of
Pseudomonas aeruginosa
Authors: Hocquet Didier , Nordmann Patrice , El Garch Farid , Cabanne Ludovic , Plésiat Patrick 
Published: March 2006

ABSTRACT

Cefepime (FEP) and ceftazidime (CAZ) are potent β-lactam antibiotics with similar MICs (1 to 2 μg/ml) for wild-type strains of
Pseudomonas aeruginosa
. However, recent epidemiological studies have highlighted the occurrence of isolates more resistant to FEP than to CAZ (FEP
r
/CAZ
s
profile). We thus investigated the mechanisms conferring such a phenotype in 38 clonally unrelated strains collected in two French teaching hospitals. Most of the bacteria (
n
= 32; 84%) appeared to stably overexpress the
mexY
gene, which codes for the RND transporter of the multidrug efflux system MexXY-OprM. MexXY up-regulation was the sole FEP resistance mechanism identified (
n
= 12) or was associated with increased levels of pump MexAB-OprM (
n
= 5) or MexJK (
n
= 2), synthesis of secondary β-lactamase PSE-1 (
n
= 10), derepression of cephalosporinase AmpC (
n
= 1), coexpression of both OXA-35 and MexJK (
n
= 1), or production of both PSE-1 and MexAB-OprM (
n
= 1). Down-regulation of the
mexXY
operon in seven selected strains by the plasmid-borne repressor gene
mexZ
decreased FEP resistance from two- to eightfold, thereby demonstrating the significant contribution of MexXY-OprM to the FEP
r
/CAZ
s
phenotype. The six isolates of this series that exhibited wild-type levels of the
mexY
gene were found to produce β-lactamase PSE-1 (
n
= 1), OXA-35 (
n
= 4), or both PSE-1 and OXA-35 (
n
= 1). Altogether, these data provide evidence that MexXY-OprM plays a major role in the development of FEP resistance among clinical strains of
P. aeruginosa
.
Antitrypanosomal and Antileishmanial Activities of Flavonoids and Their Analogues: In Vitro, In Vivo, Structure-Activity Relationship, and Quantitative Structure-Activity Relationship Studies
Authors: Tasdemir Deniz , Kaiser Marcel , Brun Reto , Yardley Vanessa , Schmidt Thomas J. , Tosun Fatma , Rüedi Peter 
Published: March 2006

ABSTRACT

Trypanosomiasis and leishmaniasis are important parasitic diseases affecting millions of people in Africa, Asia, and South America. In a previous study, we identified several flavonoid glycosides as antiprotozoal principles from a Turkish plant. Here we surveyed a large set of flavonoid aglycones and glycosides, as well as a panel of other related compounds of phenolic and phenylpropanoid nature, for their in vitro activities against
Trypanosoma brucei rhodesiense
,
Trypanosoma cruzi
, and
Leishmania donovani
. The cytotoxicities of more than 100 compounds for mammalian L6 cells were also assessed and compared to their antiparasitic activities. Several compounds were investigated in vivo for their antileishmanial and antitrypanosomal efficacies in mouse models. Overall, the best in vitro trypanocidal activity for
T. brucei rhodesiense
was exerted by 7,8-dihydroxyflavone (50% inhibitory concentration [IC
50
], 68 ng/ml), followed by 3-hydroxyflavone, rhamnetin, and 7,8,3′,4′-tetrahydroxyflavone (IC
50
s, 0.5 μg/ml) and catechol (IC
50
, 0.8 μg/ml). The activity against
T. cruzi
was moderate, and only chrysin dimethylether and 3-hydroxydaidzein had IC
50
s less than 5.0 μg/ml. The majority of the metabolites tested possessed remarkable leishmanicidal potential. Fisetin, 3-hydroxyflavone, luteolin, and quercetin were the most potent, giving IC
50
s of 0.6, 0.7, 0.8, and 1.0 μg/ml, respectively. 7,8-Dihydroxyflavone and quercetin appeared to ameliorate parasitic infections in mouse models. Generally, the test compounds lacked cytotoxicity in vitro and in vivo. By screening a large number of flavonoids and analogues, we were able to establish some general trends with respect to the structure-activity relationship, but it was not possible to draw clear and detailed quantitative structure-activity relationships for any of the bioactivities by two different approaches. However, our results can help in directing the rational design of 7,8-dihydroxyflavone and quercetin derivatives as potent and effective antiprotozoal agents.
Overexpression of the
MDR1
Gene Is Sufficient To Confer Increased Resistance to Toxic Compounds in
Candida albicans
Authors: Hiller Davina , Sanglard Dominique , Morschhäuser Joachim 
Published: March 2006

ABSTRACT

Overexpression of
MDR1
, which encodes a membrane transport protein of the major facilitator superfamily, is one mechanism by which the human fungal pathogen
Candida albicans
can develop increased resistance to the antifungal drug fluconazole and other toxic compounds. In clinical
C. albicans
isolates, constitutive
MDR1
overexpression is accompanied by the upregulation of other genes, but it is not known if these additional alterations are required for Mdr1p function and drug resistance. To investigate whether
MDR1
overexpression is sufficient to confer a drug-resistant phenotype in
C. albicans
, we expressed the
MDR1
gene from the strong
ADH1
promoter in
C. albicans
laboratory strains that did not express the endogenous
MDR1
gene as well as in a fluconazole-resistant clinical
C. albicans
isolate in which the endogenous
MDR1
alleles had been deleted and in a matched fluconazole-susceptible isolate from the same patient. Forced
MDR1
overexpression resulted in increased resistance to the putative Mdr1p substrates cerulenin and brefeldin A, and this resistance did not depend on the additional alterations which occurred during drug resistance development in the clinical isolates. In contrast, artificial expression of the
MDR1
gene from the
ADH1
promoter did not enhance or only slightly enhanced fluconazole resistance, presumably because Mdr1p expression levels in the transformants were considerably lower than those observed in the fluconazole-resistant clinical isolate. These results demonstrate that
MDR1
overexpression in
C. albicans
is sufficient to confer resistance to some toxic compounds that are substrates of this efflux pump but that the degree of resistance depends on the Mdr1p expression level.
Impaired Target Site Penetration of Vancomycin in Diabetic Patients following Cardiac Surgery
Authors: Skhirtladze Keso , Hutschala Doris , Fleck Tatjana , Thalhammer Florian , Ehrlich Marek , Vukovich Thomas , Müller Markus , Tschernko Edda M. 
Published: March 2006

ABSTRACT

Soft tissue infections constitute a serious complication following surgery in diabetic patients and frequently require the administration of vancomycin. However, despite antibiotic treatment, mortality of patients with postoperative infections remains high and might be related to an impaired penetration of anti-infective agents to target tissues. Therefore, the present study was designed to measure vancomycin tissue concentrations in six diabetic and six nondiabetic patients after cardiac surgery. Vancomycin was administered as a continuous intravenous infusion at an infusion rate of 80 to 120 mg/h. Vancomycin concentrations in soft tissues and plasma were measured in all patients during steady state as “therapeutic window” concentrations in plasma by microdialysis on day 8 ± 4 after initiation of vancomycin treatment. Vancomycin tissue concentrations in diabetic patients were significantly lower than in nondiabetics (3.7 mg/liter versus 11.9 mg/liter;
P
= 0.002). The median vancomycin
tissue
/vancomycin
plasma
concentration ratio was 0.1 in diabetic patients and 0.3 in nondiabetics (
P
= 0.002). Our study demonstrated that vancomycin penetration into target tissues is substantially impaired in diabetic patients versus nondiabetics. Insufficient tissue concentrations could therefore possibly contribute to failure of antibiotic treatment and the development of antimicrobial resistance in diabetic patients.
Pharmacodynamics of a New Cephalosporin, PPI-0903 (TAK-599), Active against Methicillin-Resistant
Staphylococcus aureus
in Murine Thigh and Lung Infection Models: Identification of an In Vivo Pharmacokinetic-Pharmacodynamic Target
Authors: Andes D. , Craig W. A. 
Published: March 2006

ABSTRACT

PPI-0903 is a new cephalosporin with broad-spectrum activity, including beta-lactam-resistant
Streptococcus pneumoniae
and
Staphylococcus aureus
. We used the neutropenic murine thigh and lung infection models to examine the pharmacodynamic characteristics of PPI-0903. Serum drug levels following four fourfold-escalating single doses of PPI-0903 were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were determined after doses of 1.56, 6.25, 25, and 100 mg/kg of body weight in mice infected with
S. pneumoniae
ATCC 10813,
S. aureus
ATCC 29213, or
Escherichia coli
ATCC 25922. Dose fractionation studies over a 24-h dose range of 0.39 to 1,600 mg/kg were administered every 3, 6, 12, or 24 hours. Nonlinear regression analysis was used to determine which pharmacokinetic-pharmacodynamic (PK-PD) index (total and free 65% drug) best correlated with CFU/thigh at 24 h. Similar to other beta-lactam antibiotics, PPI-0903 produced short to modest in vivo PAEs with either
S. pneumoniae
or
E. coli
. The percent time that serum concentrations were above the MIC (%T>MIC) was the PK-PD index that best correlated with efficacy (
R
2
= 84 to 88% for the three organisms, compared with 9 to 41% for peak/MIC and 30 to 82% for the area under the concentration-time curve/MIC). In subsequent studies we used the neutropenic murine thigh infection model to determine if the magnitude of the free-drug %T>MIC needed for efficacy of PPI-0903 varied among pathogens (including resistant strains). Mice infected with one of five isolates of
S. pneumoniae
, four isolates of
S. aureus
, or four gram-negative bacilli were treated for 24 h with 0.10 to 400 mg/kg of PPI-0903 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h and to produce a reduction in the burden of organisms from the start of therapy by 1 and 2 log
10
CFU/thigh. MICs ranged from 0.008 to 1 μg/ml. Mean free-drug %T>MICs ± the standard deviation associated with the static effect endpoint for
S. pneumoniae
,
S. aureus
, and gram-negative isolates were 39 ± 9, 26 ± 8, and 32 ± 6, respectively. Methicillin and penicillin resistance did not alter the magnitude of free-drug %T>MIC required for efficacy. The free-drug %T>MIC necessary for efficacy was slightly reduced in animals with normal neutrophil counts. Treatment effect was similar in both the thigh and lung infection models. The pharmacodynamic characteristics of PPI-0903 are similar to those of other compounds within the cephalosporin class.
Phosphorothioate Oligonucleotides Inhibit Human Immunodeficiency Virus Type 1 Fusion by Blocking gp41 Core Formation
Authors: Vaillant Andrew , Juteau Jean-Marc , Lu Hong , Liu Shuwen , Lackman-Smith Carol , Ptak Roger , Jiang Shibo 
Published: March 2006

ABSTRACTSeveral studies have shown that phosphorothioate oligodeoxynucleotides (PS-ONs) have a sequence-independent antiviral activity against human immunodeficiency virus type 1 (HIV-1). It has also been suggested that PS-ONs inhibit HIV-1 by acting as attachment inhibitors that bind to the V3 loop of gp120 and prevent the gp120-CD4 interaction. Here we show that PS-ONs (and their fully 2′-O-methylated derivatives) are potent inhibitors of HIV-1-mediated membrane fusion and HIV-1 replication in a size-dependent, phosphorothioation-dependent manner. PS-ONs interact with a peptide derived from the N-terminal heptad repeat region of gp41, and the HIV-1 fusion-inhibitory activity of PS-ONs is closely correlated with their ability to block gp41 six-helix bundle formation, a critical step during the process of HIV-1 fusion with the target cell. These results suggest that the increased hydrophobicity of PS-ONs may contribute to their inhibitory activity against HIV-1 fusion and entry, because longer PS-ONs (≥30 bases) which have a greater hydrophobicity are more potent in blocking the hydrophobic interactions involved in the gp41 six-helix bundle formation and inhibiting the HIV-1-mediated cell-cell fusion than shorter PS-ONs (<30 bases). This novel antiviral mechanism of action of long PS-ONs has implications for therapy against infection by HIV-1 and other enveloped viruses with type I fusion proteins.
Protease-Stable Polycationic Photosensitizer Conjugates between Polyethyleneimine and Chlorin(e6) for Broad-Spectrum Antimicrobial Photoinactivation
Authors: Tegos George P. , Anbe Masahiro , Yang Changming , Demidova Tatiana N. , Satti Minahil , Mroz Pawel , Janjua Sumbul , Gad Faten , Hamblin Michael R. 
Published: March 2006

ABSTRACT

We previously showed that covalent conjugates between poly-
l
-lysine and chlorin(e6) were efficient photosensitizers (PS) of both gram-positive and gram-negative bacteria. The polycationic molecular constructs increased binding and penetration of the PS into impermeable gram-negative cells. We have now prepared a novel set of second-generation polycationic conjugates between chlorin(e6) and three molecular forms of polyethyleneimine (PEI): a small linear, a small cross-linked, and a large cross-linked molecule. The conjugates were characterized by high-pressure liquid chromatography and tested for their ability to kill a panel of pathogenic microorganisms, the gram-positive
Staphylococcus aureus
and
Streptococcus pyogenes
, the gram-negative
Escherichia coli
and
Pseudomonas aeruginosa
, and the yeast
Candida albicans
, after exposure to low levels of red light. The large cross-linked molecule efficiently killed all organisms, while the linear conjugate killed gram-positive bacteria and
C. albicans
. The small cross-linked conjugate was the least efficient antimicrobial PS and its remarkably low activity could not be explained by reduced photochemical quantum yield or reduced cellular uptake. In contrast to polylysine conjugates, the PEI conjugates were resistant to degradation by proteases such as trypsin that hydrolyze lysine-lysine peptide bonds, The advantage of protease stability combined with the ready availability of PEI suggests these molecules may be superior to polylysine-PS conjugates for photodynamic therapy of localized infections.
Comparative Analysis of Chromosome-Encoded Microcins
Authors: Poey María Eloisa , Azpiroz María F. , Laviña Magela 
Published: March 2006

ABSTRACT
Microcins are ribosomally synthesized peptide antibiotics that are produced by enterobacterial strains. Although the first studies concentrated on plasmid-encoded activities, in the last years three chromosome-encoded microcins have been described: H47, E492, and M. Here, a new microcin, I47, is presented as a fourth member of this group. Common features exhibited by chromosome-encoded microcins were searched for. The comparison of the genetic clusters responsible for microcin production revealed a preserved general scheme. The clusters essentially comprise a pair of activity-immunity genes which determine antibiotic specificity and a set of microcin maturation and secretion genes which are invariably present and whose protein products are highly homologous among the different producing strains. A strict functional relationship between the maturation and secretion pathways of microcins H47, I47, and E492 was demonstrated through genetic analyses, which included heterologous complementation assays. The peptide precursors of these microcins share a maturation process which implies the addition of a catecholate siderophore of the salmochelin type. Microcins thus acquire the ability to enter gram-negative cells through the catechol receptors. In addition, they employ a common mode of secretion to reach the external milieu by means of a type I export apparatus. The results presented herein lead us to propose that chromosome-encoded microcins constitute a defined subgroup of peptide antibiotics which are strictly related by their modes of synthesis, secretion, and uptake.