bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vivo Assessment of Drug Efficacy against
Plasmodium falciparum
Malaria: Duration of Follow-Up
Authors: Stepniewska Kasia , Taylor Walter R.J. , Mayxay Mayfong , Price Ric , Smithuis Frank , Guthmann Jean-Paul , Barnes Karen , Myint Hla Yin , Adjuik Martin , Olliaro Piero , Pukrittayakamee Sasithon , Looareesuwan Sornchai , Hien Tran Tinh , Farrar Jeremy , Nosten François , Day Nicholas P.J. , White Nicholas J. 
Published: October 2004

ABSTRACT

To determine the optimum duration of follow-up for the assessment of drug efficacy against
Plasmodium falciparum
malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years; 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in individual trials) but could be used to predict the true failure rate if either parasite genotyping was performed (
r
2
= 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up.
Heterologous Expression of the Enterococcal
vanA
Operon in Methicillin-Resistant
Staphylococcus aureus
Authors: Périchon Bruno , Courvalin Patrice 
Published: October 2004

ABSTRACT

Two methicillin- and vancomycin-resistant
Staphylococcus aureus
strains, MI-VRSA and PA-VRSA, and
Enterococcus faecalis
DMC83006B, considered to be the potential donor of glycopeptide resistance to MI-VRSA, were studied. MI-VRSA is highly resistant to both glycopeptides, whereas PA-VRSA displays low-level resistance to vancomycin and reduced susceptibility to teicoplanin. We have analyzed the expression of the
vanA
operon in the three clinical isolates. Determination of the relative amounts of late peptidoglycan precursors and quantification of the
d,d
-peptidase activities, in the absence or after induction by glycopeptides, revealed that the resistance genes were expressed at similarly high levels in the three strains. Glycopeptide resistance stability in the three strains was studied by replica plating. Resistance was lost at high frequency, ca. 50%, after overnight growth of PA-VRSA in the absence of antibiotics, whereas it was fully stable in MI-VRSA and
E. faecalis
DMC83006B. Induction of resistance by vancomycin was significantly delayed in PA-VRSA relative to MI-VRSA. Low-level glycopeptide resistance of
S. aureus
PA-VRSA is thus likely due to instability of the genetic element, plasmid or transposon, carrying the
vanA
operon associated with a longer lag phase before growth resumes after induction by vancomycin.
Activity of the New Triazole Derivative Albaconazole against
Trypanosoma
(
Schizotrypanum
)
cruzi
in Dog Hosts
Authors: Guedes Paulo Marcos da Matta , Urbina Julio A. , de Lana Marta , Afonso Luis C. C. , Veloso Vanja M. , Tafuri Washington L. , Machado-Coelho George L. L. , Chiari Egler , Bahia Maria Terezinha 
Published: October 2004

ABSTRACT

Albaconazole is an experimental triazole derivative with potent and broad-spectrum antifungal activity and a remarkably long half-life in dogs, monkeys, and humans. In the present work, we investigated the in vivo activity of this compound against two strains of the protozoan parasite
Trypanosoma
(
Schizotrypanum
)
cruzi
, the causative agent of Chagas' disease, using dogs as hosts. The
T. cruzi
strains used in the study were previously characterized (murine model) as susceptible (strain Berenice-78) and partially resistant (strain Y) to the drugs currently in clinical use, nifurtimox and benznidazole. Our results demonstrated that albaconazole is very effective in suppressing the proliferation of the parasite and preventing the death of infected animals. Furthermore, the parasitological, PCR, serological, and proliferative assay results indicated parasitological cure indices of 25 and 100% among animals inoculated with
T. cruzi
strain Y when they were treated with albaconazole at 1.5 mg/kg of body weight/day for 60 and 90 days, respectively. On the other hand, although albaconazole given at 1.5 mg/kg/day was very effective in suppressing the proliferation of the parasite in animals infected with the Berenice-78
T. cruzi
strain, no parasitological cure was observed among them, even when a longer treatment period (150 doses) was used. In conclusion, our results demonstrate that albaconazole has trypanocidal activity in vivo and is capable of inducing radical parasitological cure, although natural resistance to this compound was also indicated. Furthermore, the compound can be used in long-term treatment schemes (60 to 150 days) with minimal toxicity and thus represents a potentially useful candidate for the treatment of human Chagas' disease.
Rapid Direct Detection of Multiple Rifampin and Isoniazid Resistance Mutations in
Mycobacterium tuberculosis
in Respiratory Samples by Real-Time PCR
Authors: Marín Mercedes , de Viedma Darío García , Ruíz-Serrano María Jesús , Bouza Emilio 
Published: October 2004

ABSTRACT

Rapid detection of resistance in
Mycobacterium tuberculosis
can optimize the efficacy of antituberculous therapy and control the transmission of resistant
M. tuberculosis
strains. Real-time PCR has minimized the time required to obtain the susceptibility pattern of
M. tuberculosis
strains, but little effort has been made to adapt this rapid technique to the direct detection of resistance from clinical samples. In this study, we adapted and evaluated a real-time PCR design for direct detection of resistance mutations in clinical respiratory samples. The real-time PCR was evaluated with (i) 11 clinical respiratory samples harboring bacilli resistant to isoniazid (INH) and/or rifampin (RIF), (ii) 10 culture-negative sputa spiked with a set of strains encoding 14 different resistance mutations in 10 independent codons, and (iii) 16 sputa harboring susceptible strains. The results obtained with this real-time PCR design completely agreed with DNA sequencing data. In all sputa harboring resistant
M. tuberculosis
strains, the mutation encoding resistance was successfully detected. No mutation was detected in any of the susceptible sputa. The test was applied only to smear-positive specimens and succeeded in detecting a bacterial load equivalent to 10
3
CFU/ml in sputum samples (10 acid-fast bacilli/line). The analytical specificity of this method was proved with a set of 14 different non-
M. tuberculosis
bacteria. This real-time PCR design is an adequate method for the specific and rapid detection of RIF and INH resistance in smear-positive clinical respiratory samples.
Mutations of
Pneumocystis jirovecii
Dihydrofolate Reductase Associated with Failure of Prophylaxis
Authors: Nahimana Aimable , Rabodonirina Meja , Bille Jacques , Francioli Patrick , Hauser Philippe M. 
Published: October 2004

ABSTRACT

Most drugs used for prevention and treatment of
Pneumocystis jirovecii
pneumonia target enzymes involved in the biosynthesis of folic acid, i.e., dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). Emergence of
P. jirovecii
drug resistance has been suggested by the association between failure of prophylaxis with sulfa drugs and mutations in DHPS. However, data on the occurrence of mutations in DHFR, the target of trimethoprim and pyrimethamine, are scarce. We examined polymorphisms in
P. jirovecii
DHFR from 33 patients diagnosed with
P. jirovecii
pneumonia who were receiving prophylaxis with a DHFR inhibitor (
n
= 15), prophylaxis without a DHFR inhibitor (
n
= 11), or no prophylaxis (
n
= 7). Compared to the wild-type sequence present in GenBank, 19 DHFR nucleotide substitution sites were found in 18 patients with 3 synonymous and 16 nonsynonymous mutations. Of 16 amino acid changes, 6 were located in positions conserved among distant organisms, and five of these six positions are probably involved in the putative active sites of the enzyme. Patients with failure of prophylaxis, including a DHFR inhibitor, were more likely to harbor nonsynonymous DHFR mutations than those who did not receive such prophylaxis (9 of 15 patients versus 2 of 18;
P
= 0.008). Analysis of the rate of nonsynonymous versus synonymous mutations was consistent with selection of amino acid substitutions in patients with failure of prophylaxis including a DHFR inhibitor. The results suggest that
P. jirovecii
populations may evolve under selective pressure from DHFR inhibitors, in particular pyrimethamine, and that DHFR mutations may contribute to
P. jirovecii
drug resistance.
Potential for Interactions between Caspofungin and Nelfinavir or Rifampin
Authors: Stone Julie A. , Migoya Elizabeth M. , Hickey Lisa , Winchell Gregory A. , Deutsch Paul J. , Ghosh Kalyan , Freeman Amanda , Bi Sheng , Desai Rajesh , Dilzer Stacy C. , Lasseter Kenneth C. , Kraft Walter K. , Greenberg Howard , Waldman Scott A. 
Published: October 2004

ABSTRACT

The potential for interactions between caspofungin and nelfinavir or rifampin was evaluated in two parallel-panel studies. In study A, healthy subjects received a 14-day course of caspofungin alone (50 mg administered intravenously [IV] once daily) (
n
= 10) or with nelfinavir (1,250 mg administered orally twice daily) (
n
= 9) or rifampin (600 mg administered orally once daily) (
n
= 10). In study B, 14 subjects received a 28-day course of rifampin (600 mg administered orally once daily), with caspofungin (50 mg administered IV once daily) coadministered on the last 14 days, and 12 subjects received a 14-day course of caspofungin alone (50 mg administered IV once daily). The coadministration/administration alone geometric mean ratio for the caspofungin area under the time-concentration profile calculated for the 24-h period following dosing [AUC
0-24
] was as follows (values in parentheses are 90% confidence intervals [CIs]): 1.08 (0.93-1.26) for nelfinavir, 1.12 (0.97-1.30) for rifampin (study A), and 1.01 (0.91-1.11) for rifampin (study B). The shape of the caspofungin plasma profile was altered by rifampin, resulting in a 14 to 31% reduction in the trough concentration at 24 h after dosing (
C
24h
), consistent with a net induction effect at steady state. Both the AUC and the
C
24h
were elevated in the initial days of rifampin coadministration in study A (61 and 170% elevations, respectively, on day 1) but not in study B, consistent with transient net inhibition prior to full induction. The coadministration/administration alone geometric mean ratio for the rifampin AUC
0-24
on day 14 was 1.07 (90% CI, 0.83-1.38). Nelfinavir does not meaningfully alter caspofungin pharmacokinetics. Rifampin both inhibits and induces caspofungin disposition, resulting in a reduced
C
24h
at steady state. An increase in the caspofungin dose to 70 mg, administered daily, should be considered when the drug is coadministered with rifampin.
Novel Approach to Characterization of Combined Pharmacodynamic Effects of Antimicrobial Agents
Authors: Tam Vincent H. , Schilling Amy N. , Lewis Russell E. , Melnick David A. , Boucher Adam N. 
Published: October 2004

ABSTRACT

There is considerable need for new modeling approaches in the study of combined antimicrobial effects. Current methods based on the Loewe additivity and Bliss independence models are associated with implicit assumptions about the interacting system. To circumvent these limitations, we propose an alternative approach to the quantification of pharmacodynamic drug interaction (PDI). Pilot time-kill studies were performed with 10
8
CFU of
Pseudomonas aeruginosa
/ml at baseline with meropenem or tobramycin alone. The studies were repeated with 25 concentration combinations of meropenem (0 to 64 mg/liter) and tobramycin (0 to 32 mg/liter) in a five-by-five array. The data were modeled with a three-dimensional response surface using effect summation as the basis of null interaction. The interaction index (Ii) is defined as the ratio of the volumes under the planes (VUP) of the observed and expected surfaces: VUP
observed
/VUP
expected
. Synergy and antagonism are defined as Ii values of <1 and >1, respectively. In all combinations, an enhanced killing effect was seen compared to that of either drug at the same concentration. The most significant synergism was observed between 1 and 5 mg/liter of meropenem and between 1 and 4 mg/liter of tobramycin; seven out of nine combinations had a >2-log drop compared to the more potent agent. The Ii was found to be 0.76 (95% confidence interval, 0.65 to 0.91) for the concentration ranges of the agents. The results corroborate previous data indicating that meropenem is synergistic with an aminoglycoside when used in combination against
P. aeruginosa
. Our parametric approach to quantifying PDI appears robust and warrants further investigations.
LB11058, a New Cephalosporin with High Penicillin-Binding Protein 2a Affinity and Activity in Experimental Endocarditis Due to Homogeneously Methicillin-Resistant
Staphylococcus aureus
Authors: Vouillamoz Jacques , Entenza José M. , Hohl Peter , Moreillon Philippe 
Published: October 2004

ABSTRACT

LB11058 is a new synthetic cephalosporin with good affinity for staphylococcal penicillin-binding protein 2a (PBP2a). LB11058 was tested in vitro and in rats with experimental aortic endocarditis against three methicillin-resistant
Staphylococcus aureus
(MRSA) strains, one penicillinase-negative strain (strain COL), and two penicillinase-producing strains (COL-Bla+ and P8-Hom). The MICs of LB11058 for the organisms were 1 mg/liter. The MICs of vancomycin and ceftriaxone were 1 and ≥64 mg/liter, respectively. In population analysis profiles, none of the MRSA strains grew at ≥2 mg of LB11058/liter. Rats with endocarditis were treated for 5 days. LB11058 was highly bound to serum proteins in rats (≥98%). However, binding was saturable above a threshold of 250 mg/liter. Therefore, continuous concentrations of 250 mg/liter in serum were infused to ensure a free fraction (≥5 mg/liter) above the drug's MIC for the entire infusion period. Control treatments included simulation of human serum kinetics produced by intravenous vancomycin (1 g twice daily, free drug concentration above MIC, ≥90% of infusion period) or ceftriaxone (2 g/24 h, free drug concentrations above the MIC, 0% of infusion period). LB11058 successfully treated 10 of 10 (100%) and 13 of 14 (93%) of rats infected with COL-Bla+ and P8-Hom, respectively. This was comparable to vancomycin (sterilization of 8 of 12 [66%] and 6 of 8 [75%] rats, respectively). Ceftriaxone was inactive. Low concentrations of LB11058 (5 and 10 mg/liter, continuously infused) in serum were ineffective, as predicted by the pharmacodynamic parameters. At appropriate doses, LB11058 was highly effective both in vitro and in vivo. This finding supports the development of this beta-lactam with high PBP2a affinity for the treatment of MRSA infections.
Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults
Authors: DiCenzo Robert , Peterson Derick , Cruttenden Kim , Morse Gene , Riggs Garret , Gelbard Harris , Schifitto Giovanni 
Published: October 2004

ABSTRACTValproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C0) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC0-24s) of EFV (n= 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC0-8s of LPV (n= 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in meanC0and 8-h VPA concentrations versus the control (n= 11) were −1.0 (−9.4, 7.4) μg/ml and −2.1 (−11.1, 6.9) μg/ml for EFV (n= 10) and −5.0 (−13.2, 3.3) μg/ml and −6.7 (−17.6, 4.2) μg/ml for LPV/r (n= 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly influence trough concentrations of VPA.
Maternal-Fetal Transfer and Amniotic Fluid Accumulation of Nucleoside Analogue Reverse Transcriptase Inhibitors in Human Immunodeficiency Virus-Infected Pregnant Women
Authors: Chappuy Hélène , Tréluyer Jean-Marc , Jullien Vincent , Dimet Jérôme , Rey Elisabeth , Fouché Maria , Firtion Ghislaine , Pons Gérard , Mandelbrot Laurent 
Published: October 2004

ABSTRACT

This study was performed to investigate placental transfer of nucleoside analogue reverse transcriptase inhibitors (NRTIs) and their concentrations in amniotic fluid when given to human immunodeficiency virus (HIV)-infected pregnant women. A total of 100 HIV type 1-infected mothers receiving antiretroviral therapy, including one or more NRTIs, for clinical indications at the time of delivery were enrolled. Maternal blood samples and amniotic fluid were obtained during delivery or cesarean section, and paired cord blood samples were obtained by venipuncture immediately after delivery. Drug concentrations were measured by using high-performance liquid chromatography. A significant relationship between concentrations in maternal and cord plasma samples was found for zidovudine, lamivudine, stavudine, and didanosine. The ratio between the concentrations in cord and maternal plasma samples (
R
) was high for zidovudine (
R
= 1.22), its glucuronide metabolite (3′-azido-3′-deoxythymidine-β-
d
-glucuronide) (
R
= 1.01), stavudine (
R
= 1.32), lamivudine (
R
= 0.93), and abacavir (
R
= 1.03) and was low for didanosine (
R
= 0.38). The ratio between the concentrations in amniotic fluid and cord plasma samples was high for zidovudine (
R
= 2.24), its glucuronide metabolite (
R
= 2.83), stavudine (
R
= 4.87), and lamivudine (
R
= 3.99) and was lower for didanosine (
R
= 1.14). These findings indicate that most NRTIs cross the placenta by simple diffusion and are concentrated in the amniotic fluid, probably through fetal urinary excretion. The efficacy or toxicity of NRTIs may vary according to placental transfer.
Inhibition of Adherence and Killing of
Candida albicans
with a 23-Mer Peptide (Fn/23) with Dual Antifungal Properties
Authors: Klotz Stephen A. , Gaur Nand K. , Rauceo Jason , Lake Douglas F. , Park Y. , Hahm K. S. , Lipke Peter N. 
Published: October 2004

ABSTRACT

Candida albicans
adheres to host tissue and then proliferates in order to establish a commensal as well as a pathogenic state. Specific adherence to proteins is provided by several surface adhesins of
Candida
. Two well-studied proteins, Als1p and Als5p, do not require energy for adherence to occur (dead as well as living cells adhere) and have a multiplier effect of cell-cell aggregation that mediates the formation of microcolonies of
Candida
cells. The entire process is spontaneous, reversible, and stable for physiologically relevant chemical and physical forces. This adherence process is inhibited by the addition of free peptide ligands, including a 23-mer derived from fibronectin (Fn/23) that binds to the adhesins through H bond formation. Adherence was measured by determining the number of yeast cells that adhered to 90-μm-diameter polyethylene glycol (PEG) beads with a 7-mer peptide (KLRIPSV) synthesized on the surfaces of the beads. The concentration of the Fn/23 peptide that inhibited the adherence of cells to the peptide-coated beads by 50% was 4 to 5 μM, and the magnitudes of adherence were similar regardless of the presence or absence of physiologic salt concentrations. The minimum fungicidal concentration of Fn/23 was 2 to 4 μM in water, but there was no killing in physiologic salt concentrations. Peptides from the C and N termini or the center sequence of Fn/23 had no effect on inhibition of adherence and little effect on fungal viability. The fungicidal effect was similar to that seen with 23-, 19-, and 18-mer peptides derived from porcine myeloid cells, a
Helicobacter pylori
ribosomal protein, and a hybrid of cecropin and magainin, respectively. However, these fungicidal peptides did not inhibit
C. albicans
adherence to the peptide-coated PEG beads. This dual property of Fn/23, i.e., inhibition of adherence and killing of
C. albicans
, may provide important adjuvant effects in the treatment of disease caused by this fungus.
Delivery of Granulocyte-Macrophage Colony-Stimulating Factor in Bioadhesive Hydrogel Stimulates Migration of Dendritic Cells in Models of Human Papillomavirus-Associated (Pre)Neoplastic Epithelial Lesions
Authors: Hubert Pascale , Evrard Brigitte , Maillard Catherine , Franzen-Detrooz Elizabeth , Delattre Luc , Foidart Jean-Michel , Noël Agnes , Boniver Jacques , Delvenne Philippe 
Published: October 2004

ABSTRACTBecause of the central role of dendritic cells and/or Langerhans cells(DC/LC) in the induction of cellular immune responses, pharmacological agents that modulate the recruitment of these cells might have a clinical interest. The present study was designed to evaluate the capacity of several pharmaceutical formulations to topically deliver granulocyte-macrophage colony-stimulating factor (GM-CSF) on human papillomavirus (HPV)-associated genital (pre)neoplastic lesions. The formulations were evaluated for their bioactivity and for their potential to recruit DC in organotypic cultures of HPV-transformed keratinocytes. We found that a bioadhesive polycarbophil gel (Noveon) at pH 5.5 is able to maintain the bioactivity of GM-CSF at 4 or 37°C for at least 7 days, whereas a decreased activity of GM-CSF was observed when the molecule is included in other polymer gels. GM-CSF incorporated in the polycarbophil gel was also a potent factor in enhancing the colonization of DC into organotypic cultures of HPV-transformed keratinocytes since the infiltration of DC in the in vitro-formed (pre)neoplastic epithelium was very low under basal conditions and dramatically increased in the presence of GM-CSF gel. We next demonstrated that GM-CSF incorporated in polycarbophil gel induces the recruitment of human DC in a human (pre)neoplastic epithelium grafted into NOD/SCID mice. The efficacy of GM-CSF in this formulation was equivalent to that observed with liquid GM-CSF. These results suggest that GM-CSF incorporated in polycarbophil gel could play an important role in the recruitment of DC/LC in mucosal surfaces and be useful as a new immunotherapeutic approach for genital HPV-associated (pre)neoplastic lesions.