bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamics of a New Triazole, Posaconazole, in a Murine Model of Disseminated Candidiasis
Authors: Andes D. , Marchillo K. , Conklin R. , Krishna Gopal , Ezzet Farkad , Cacciapuoti Anthony , Loebenberg David 
Published: December 2003

ABSTRACT

Previous in vivo studies have characterized the pharmacodynamic characteristics of two triazole compounds, fluconazole and ravuconazole. These investigations demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio is the critical pharmacokinetic-pharmacodynamic (PK-PD) parameter associated with treatment efficacy. Further analysis demonstrated that a free-drug triazole 24-h AUC/MIC ratio of 20 to 25 was predictive of treatment success in both experimental models and clinical trials. We used a neutropenic murine model of disseminated
Candida albicans
infection to similarly characterize the time course activity of the new triazole, posaconazole. The PK-PD parameters (percent time above MIC, AUC/MIC ratio, and peak serum drug level/MIC ratio) were correlated with in vivo efficacy, as measured by organism number in kidney cultures after 48 h of therapy. Kinetics and protein binding following oral posaconazole dosing were performed in neutropenic infected mice. Peak levels and AUC from 0 h to ∞ values were nonlinear over the 16-fold dose range studied. Serum drug elimination half-life ranged from 12.0 to 17.7 h. Protein binding was 99%. Single dose postantifungal effect studies demonstrated prolonged suppression of organism regrowth after serum posaconazole levels had fallen below the MIC. Treatment efficacy with the four dosing intervals studied was similar, supporting the AUC/MIC ratio as the PK-PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (AUC/MIC ratio
R
2
= 83%; peak serum drug/MIC ratio
R
2
= 85%; time that serum levels of posaconazole remained above the MIC
R
2
= 65%). Similar studies were conducted with 11 additional
C. albicans
isolates with various posaconazole susceptibilities (MIC, 0.015 to 0.12 μg/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The posaconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (6.12 to 26.7, mean ± SD = 16.9 ± 7.8,
P
value, 0.42). These free-drug AUC/MIC ratios are similar to those observed for other triazoles in this model.
Biofilm Formation by
Stenotrophomonas maltophilia
: Modulation by Quinolones, Trimethoprim-Sulfamethoxazole, and Ceftazidime
Authors: Di Bonaventura Giovanni , Spedicato Ilaria , D'Antonio Domenico , Robuffo Iole , Piccolomini Raffaele 
Published: December 2003

ABSTRACT

We investigated the in vitro effects of seven fluoroquinolones (ciprofloxacin, grepafloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, and rufloxacin), compared to those of trimethoprim-sulfamethoxazole (SXT) and ceftazidime on total biomass and cell viability of
Stenotrophomonas maltophilia
biofilm.
S. maltophilia
attached rapidly to polystyrene, within 2 h of incubation, and then biofilm formation increased over time, reaching maximum growth at 24 h. In the presence of fluoroquinolones at one-half and one-fourth the MIC, biofilm biomass was significantly (
P
< 0.01) reduced to 55 to 70% and 66 to 76% of original mass, respectively. Ceftazidime and SXT did not exert any activity. Biofilm bacterial viability was significantly reduced by all antibiotics tested at one-half the MIC. At one-fourth the MIC all antibiotics, except levofloxacin, significantly reduced viability. Treatment of preformed biofilms with bactericidal concentrations (500, 100, and 50 μg/ml) of all fluoroquinolones caused, except for norfloxacin, significant reduction of biofilm biomass to 29.5 to 78.8, 64.1 to 83.6, and 70.5 to 82.8% of original mass, respectively. SXT exerted significant activity at 500 μg/ml only. Ceftazidime was completely inactive. Rufloxacin exhibited the highest activity on preformed biofilm viability, significantly decreasing viable counts by 0.6, 5.4, and 17.1% at 500, 100, and 50 μg/ml, respectively. Our results show that (i) subinhibitory (one-half and one-fourth the MIC) concentrations of fluoroquinolones inhibit adherence of
S. maltophilia
to polystyrene and (ii) clinically achievable concentrations (50 and 100 μg/ml) of rufloxacin are able to eradicate preformed
S. maltophilia
biofilm.
Fungicidal Activity of Fluconazole against
Candida albicans
in a Synthetic Vagina-Simulative Medium
Authors: Moosa Mahomed-Yunus S. , Sobel Jack D. , Elhalis Hussain , Du Wenjin , Akins Robert A. 
Published: December 2003

ABSTRACT

Fluconazole (FLZ) has emerged as a highly successful agent in the management of systemic infections of
Candida
. Cure rates for symptomatic candidiasis following single 150-mg FLZ dose therapy exceed 90%. In vitro, however, FLZ is fungistatic only in a narrow pH range and is not effective at vaginal pH, 4.2. This study evaluated the effect of FLZ on
Candida albicans
under in vitro conditions resembling the vaginal microenvironment, using vagina-simulative medium (VS). We found that FLZ was fungicidal for
C. albicans
in VS, but not in other media at the same pH, 4.2. In VS, FLZ was fungicidal at concentrations of ≥8 μg/ml and reduced viability by greater than 99.9%. Analysis of the components of VS indicated that 17 mM acetic acid, a concentration achieved in the vagina, was responsible for the synergistic, fungicidal effect. This effect was not seen at neutral pH. Other substrates were not effective substitutes for acetic acid; however, short-chained carboxylic acids, glyoxylate and malonate, were effective. Most strains of
C. albicans
that were resistant to FLZ under standard conditions were killed by FLZ plus acetate. Other species of
Candida
were also killed, except
C. krusei
and
C. glabrata
. This study shows that FLZ has fungicidal activity for
Candida
species under in vitro conditions that mimic the vaginal microenvironment. This raises the possibility that FLZ may also have fungicidal effects during treatment of vaginal candidiasis. Elucidating the mechanism by which FLZ and acetate interact may disclose vulnerable pathways that could be exploited in drug development.
Antimicrobial Susceptibility and Synergy Studies of
Stenotrophomonas maltophilia
Isolates from Patients with Cystic Fibrosis
Authors: San Gabriel Pablo , Zhou Juyan , Tabibi Setareh , Chen Yunhua , Trauzzi Marco , Saiman Lisa 
Published: December 2003

ABSTRACT

Stenotrophomonas maltophilia
is a newly emerging pathogen being detected with increasing frequency in patients with cystic fibrosis (CF). The impact of this multidrug-resistant organism on lung function is uncertain. The optimal treatment for
S. maltophilia
in CF patients is unknown. We studied the in vitro activity of ten antimicrobial agents, and conducted synergy studies by using checkerboard dilutions of eight pairs of antimicrobial agents against strains isolated from 673 CF patients from 1996 to 2001. This represents approximately 7 to 23% of the CF patients in the United States who harbor
S. maltophilia
annually. Doxycycline was the most active agent and inhibited 80% of 673 initial patient isolates, while trimethoprim-sulfamethoxazole inhibited only 16%. High concentrations of colistin proved more active than high concentrations of tobramycin and gentamicin. Serial isolates (
n
= 151) from individual patients over time (median, 290 days) showed minimal changes in resistance. Synergistic or additive activity was demonstrated by trimethoprim-sulfamethoxazole paired with ticarcillin-clavulanate (65% of strains), ciprofloxacin paired with ticarcillin-clavulanate (64% of strains), ciprofloxacin paired with piperacillin-tazobactam (59% of strains), trimethoprim-sulfamethoxazole paired with piperacillin-tazobactam (55% of strains), and doxycycline paired with ticarcillin-clavulanate (49% of strains). In all, 522 (78%) isolates were multidrug resistant (i.e., resistant to all agents in two or more antimicrobial classes) but 473 (91%) of these were inhibited by at least one antimicrobial combination (median, four; range, one to eight). To determine appropriate treatment for patients with CF, it is important to monitor the prevalence, antimicrobial susceptibility, and clinical impact of
S. maltophilia
in this patient population.
Evolution of Human Immunodeficiency Virus Type 1 (HIV-1) Resistance Mutations in Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) in HIV-1-Infected Patients Switched to Antiretroviral Therapy without NNRTIs
Authors: Joly Véronique , Descamps Diane , Peytavin Gilles , Touati Fatiha , Mentre France , Duval Xavier , Delarue Séverine , Yeni Patrick , Brun-Vezinet Françoise 
Published: December 2003

ABSTRACT

We studied the evolution of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations among 29 human immunodeficiency virus type 1 (HIV-1)-infected patients who experienced virologic failure when receiving an NNRTI-containing regimen (nevirapine, delavirdine, or efavirenz) and subsequently switched to antiretroviral therapy without NNRTIs. Genotypic resistance was determined from plasma samples collected at the time of NNRTI withdrawal (baseline) and during follow-up. At baseline, 83% of patients had more than two thymidine analog resistance mutations (TAMs), and all had NNRTI resistance mutations. Mutations at codons 103, 181, and 190 were found in 62, 62, and 34% of the patients, respectively. Follow-up samples were available after a median time of 6 months in all patients and at 12 months in 22 patients. The mean number of resistance mutations to NNRTIs was significantly lower at months 6 (1.34 ± 1.04) and 12 (1.18 ± 1.05) than at month 0 (2.03 ± 1.02) (
P
< 0.009). The percentages of patients with at least one NNRTI resistance mutation were 100, 76, and 73% at baseline, month 6, and month 12, respectively (
P
< 0.0044). Overall, 70% of the patients had a mutation at codon 103 or 181 at month 12. The mean number of TAMs did not vary significantly during follow-up. Our data show that, in the context of maintained antiretroviral therapy, NNRTI resistance mutations persist in two-thirds of the patients in spite of NNRTI withdrawal. These results argue for the low impact of NNRTI resistance mutations on viral fitness and suggest that resistance mutations to different classes of drugs are associated on the same genome, at least in some of the resistant strains.
Equivalent Steady-State Pharmacokinetics of Lamivudine in Plasma and Lamivudine Triphosphate within Cells following Administration of Lamivudine at 300 Milligrams Once Daily and 150 Milligrams Twice Daily
Authors: Yuen Geoffrey J. , Lou Yu , Bumgarner Nancy F. , Bishop Jim P. , Smith Glenn A. , Otto Victoria R. , Hoelscher David D. 
Published: December 2003

ABSTRACT

Once-daily administration of 300 mg of lamivudine in combination with other antiretroviral agents has been proposed as a possible way to optimize anti-human immunodeficiency virus (HIV) treatment and to facilitate adherence. A single-center, randomized, two-way, crossover study was conducted in 60 healthy subjects to compare the steady-state pharmacokinetics of lamivudine in plasma and its putative active anabolite, lamivudine 5′-triphosphate (lamivudine-TP), in peripheral blood mononuclear cells (PBMCs) following 7 days of treatment with lamivudine at 300 mg once daily and 7 days of the standard regimen of 150 mg twice daily. Serial blood samples were collected over 24 h for determination of plasma lamivudine concentrations by liquid chromatography-mass spectrometry and intracellular lamivudine-TP concentrations in peripheral blood mononuclear cells by high-performance liquid chromatography/radioimmunoassay methods. Pharmacokinetic parameters were calculated based on lamivudine and lamivudine-TP concentration-time data. Regimens were considered bioequivalent if 90% confidence intervals (CI) for the ratio (once daily/twice daily) of geometric least-squares (GLS) means for lamivudine and lamivudine-TP pharmacokinetic values fell within the acceptance range of 0.8 to 1.25. Steady-state plasma lamivudine pharmacokinetics following the once- and twice-daily regimens were bioequivalent with respect to the area under the drug concentration-time curve from 0 to 24 h at steady state (AUC
24,ss
) (GLS mean ratio, 0.94; 90% CI, 0.92, 0.97) and average plasma lamivudine concentration over the dosing interval (
C
ave,ss
) (GLS mean ratio, 0.94; 90% CI, 0.92, 0.97). Steady-state intracellular lamivudine-TP pharmacokinetics after the once- and twice-daily regimens were bioequivalent with respect to AUC
24,ss
(GLS mean ratio, 0.99; 90% CI, 0.88, 1.11),
C
ave,ss
(GLS mean ratio, 0.99; 90% CI, 0.88, 1.11), and maximum lamivudine concentration (
C
max,ss
) (GLS mean ratio, 0.93; 90% CI, 0.81, 1.07). Lamivudine-TP trough concentrations were modestly lower (by 18 to 24%) during the once-daily regimen; the clinical importance of this is unclear, given the large intersubject variability in values that was observed (coefficient of variation, 48 to 124%). Once-daily lamivudine was as well tolerated as the twice-daily regimen. Overall, the results of this study suggest that for key AUC-related parameters, lamivudine at 300 mg once daily is pharmacokinetically equivalent to lamivudine at 150 mg twice daily.
Pharmacokinetics and Safety of Single Oral Doses of Emtricitabine in Human Immunodeficiency Virus-Infected Children
Authors: Wang Laurene H. , Wiznia Andrew A. , Rathore Mobeen H. , Chittick Gregory E. , Bakshi Saroj S. , Emmanuel Patricia J. , Flynn Patricia M. 
Published: December 2003

ABSTRACT

Emtricitabine (FTC; Emtriva), a potent deoxycytidine nucleoside reverse transcriptase inhibitor, has recently been approved by the U.S. Food and Drug Administration for the treatment of human immunodeficiency virus (HIV) infection. In adults, FTC has demonstrated linear kinetics over a wide dose range, and FTC 200 mg once a day (QD) is the recommended therapeutic dose. A phase I open-label trial was conducted in children to identify an FTC dosing regimen that would provide comparable plasma exposure to that observed in adults at 200 mg QD. Two single oral doses of FTC (60 and 120 mg/m
2
, up to a maximum of 200 mg, in solutions) were evaluated in HIV-infected children aged <18 years old. Children ≥6 years old also received a third dose of ∼120 mg/m
2
in capsules. A total of 25 children (two <2 years old, eight 2 to 5 years old, eight 6 to 12 years old, and seven 13 to 17 years old) received at least two doses of FTC. Single escalating oral doses of FTC were well tolerated and produced dose-proportional plasma drug concentrations in children. The FTC pharmacokinetics was comparable between adults and children 22 months to 17 years of age. The capsule formulation provided ∼20% higher plasma FTC exposure than the solution formulation. Using plasma area under the concentration-time curve (AUC) data at the 120-mg/m
2
dose, it is projected (based on dose proportionality) that a 6-mg/kg dose (up to a maximum of 200 mg) of FTC would produce plasma AUCs in children comparable to those in adults given a 200-mg dose (i.e., median of ∼10 h·μg/ml). This pediatric FTC dose is being evaluated in long-term phase II therapeutic trials in HIV-infected children.
In Vitro Pharmacodynamic Activities of ABT-492, a Novel Quinolone, Compared to Those of Levofloxacin against
Streptococcus pneumoniae
,
Haemophilus influenzae
, and
Moraxella catarrhalis
Authors: Gunderson Shana M. , Hayes Robert A. , Quinn John P. , Danziger Larry H. 
Published: December 2003

ABSTRACT

ABT-492 is a novel quinolone with potent activity against gram-positive, gram-negative, and atypical pathogens, making this compound an ideal candidate for the treatment of community-acquired pneumonia. We therefore compared the in vitro pharmacodynamic activity of ABT-492 to that of levofloxacin, an antibiotic commonly used for the treatment of pneumonia, through MIC determination and time-kill kinetic analysis. ABT-492 demonstrated potent activity against penicillin-sensitive, penicillin-resistant, and levofloxacin-resistant
Streptococcus pneumoniae
strains (MICs ranging from 0.0078 to 0.125 μg/ml); β-lactamase-positive and β-lactamase-negative
Haemophilus influenzae
strains (MICs ranging from 0.000313 to 0.00125 μg/ml); and β-lactamase-positive and β-lactamase-negative
Moraxella catarrhalis
strains (MICs ranging from 0.001 to 0.0025 μg/ml), with MICs being much lower than those of levofloxacin. Both ABT-492 and levofloxacin demonstrated concentration-dependent bactericidal activities in time-kill kinetics studies at four and eight times the MIC with 10 of 12 bacterial isolates exposed to ABT-492 and with 12 of 12 bacterial isolates exposed to levofloxacin. Sigmoidal maximal-effect models support concentration-dependent bactericidal activity. The model predicts that 50% of maximal activity can be achieved with concentrations ranging from one to two times the MIC for both ABT-492 and levofloxacin and that near-maximal activity (90% effective concentration) can be achieved at concentrations ranging from two to five times the MIC for ABT-492 and one to six times the MIC for levofloxacin.
Risk Factors for Acquisition of Imipenem-Resistant
Acinetobacter baumannii
: a Case-Control Study
Authors: Lee Sang-Oh , Kim Nam Joong , Choi Sang-Ho , Kim Tae Hyong , Chung Jin-Won , Woo Jun-Hee , Ryu Jiso , Kim Yang Soo 
Published: December 2003

ABSTRACT

Risk factors for the nosocomial occurrence of imipenem-resistant
Acinetobacter baumannii
(IRAB) were determined. A case-control study design was used for a comparison of two groups of
A. baumannii
-positive patients with control patients. Nosocomial IRAB was isolated from the first group of
A. baumannii
-positive patients, and imipenem-susceptible
A. baumannii
(ISAB) was isolated from the second group. The control patients were randomly selected in a 4:1 ratio from the same medical or surgical services from which the
A. baumannii
-positive patients were receiving care when the isolation of IRAB occurred. Risk factors analyzed included demographic variables, comorbid conditions, variables related to hospitalization, and the antimicrobials used. IRAB was isolated from 104 patients, and ISAB was isolated from 387 patients between January and December 2000. The risk factors for IRAB were a previous intensive care unit (ICU) stay (odds ratio [OR], 21.54; 95% confidence interval [CI], 10.73 to 43.23) and prior exposure to imipenem (OR, 9.18; 95% CI, 3.99 to 21.13) or third-generation cephalosporins (OR, 2.11; 95% CI, 1.13 to 3.95). Risk factors for ISAB were a previous ICU stay (OR, 8.05; 95% CI, 5.67 to 11.44) and exposure to third-generation cephalosporins (OR, 2.07; 95% CI, 1.47 to 2.91). Our results suggest that the nosocomial occurrence of IRAB or ISAB is strongly related to an ICU stay, and IRAB occurrence may be favored by the selection pressure of imipenem.
Antimicrobial Activity of a Chelatable Poly(Arginyl-Histidine) Produced by the Ergot Fungus
Verticillium kibiense
Authors: Nishikawa Masanobu , Ogawa Ken'ichi 
Published: December 2003

ABSTRACT

We have recently developed a convenient method of screening a broad range of microorganisms that produce ε-poly-
l
-lysine (M. Nishikawa and K. Ogawa, Appl. Environ. Microbiol. 68:3575-3581, 2002). Using this method, we found an ergot fungus that secretes a charged polypeptide other than ε-poly-
l
-lysine. It was identified as a new species on the basis of its 28S rRNA sequence and was named
Verticillium kibiense
(formerly
Epichloe kibiensis
). Peptide sequencing and mass spectrometry revealed that the polypeptide is a linear peptide composed of repeated units of arginyl-histidine. The numbers of repeated units were in most cases five and in some cases four or six. This peptide showed activity against a broad range of bacteria and fungi but lost its activity under conditions of high ionic strength. Zinc and copper ions specifically changed the circular dichroism spectra of the peptide and restored the antimicrobial activity from abrogation under high ionic conditions, although these ions had no reinforcing effect on antimicrobial activity when they were added to solutions at a low ionic strength. The peptide labeled with fluorescein was able to permeate the cell membranes of target microbes, but its ability to permeate cell membranes decreased under conditions of high ionic strength. This decreased ability was partially recovered specifically by the addition of zinc and copper ions. These results indicate that poly(arginyl-histidine) is a cationic polypeptide characterized by specific metal binding and resistance to salts.
Escherichia coli
Mutators Present an Enhanced Risk for Emergence of Antibiotic Resistance during Urinary Tract Infections
Authors: Miller Keith , O'Neill Alexander John , Chopra Ian 
Published: December 2003

ABSTRACT

Mutators may present an enhanced risk for the emergence of antibiotic resistance in bacteria during chemotherapy. Using
Escherichia coli
mutators as a model, we evaluated their ability to develop resistance to antibiotics routinely used for the treatment of urinary tract infections (UTIs). Under conditions that simulate therapeutic drug concentrations in humans, low-level resistance to trimethoprim, gentamicin, and cefotaxime emerged more frequently in mutators than normal strains. Resistance to trimethoprim in both cell types arose from a single point mutation in
folA
(Ile94→Leu) and cefotaxime resistance resulted from loss of outer membrane porin OmpF. The mechanisms of gentamicin resistance could not be defined, but resistance did not result from mutations in ribosomal protein L6 (
rplF
). Although similar mechanisms of low-level antibiotic resistance probably arise in these strains, mutators are a risk factor because the increased generation of mutants with low-level resistance enhances the opportunity for subsequent emergence of high-level resistance.
Growth-Inhibitory Effect of Heparin on
Babesia
Parasites
Authors: Bork Sabine , Yokoyama Naoaki , Ikehara Yuzuru , Kumar Sanjay , Sugimoto Chihiro , Igarashi Ikuo 
Published: December 2003

ABSTRACT

We examined the inhibitory effects of three heparins on the growth of
Babesia
parasites. The multiplication of
Babesia bovis
,
B. bigemina
,
B. equi
, and
B. caballi
in in vitro cultures and that of
B. microti
in vivo were significantly inhibited in the presence of heparins, as determined by light microscopy. Treatment with various concentrations of heparin showed complete clearance of the intracellular parasites. Interestingly, a higher percentage of abnormally multidividing
B. bovis
parasites was observed in the presence of low concentrations of heparin. Furthermore, fluorescein isothiocyanate-labeled heparin was preferably found on the surfaces of extracellular merozoites, as detected by confocal laser scanning microscopy. These findings indicate that the heparin covers the surfaces of babesial merozoites and inhibits their subsequent invasion of erythrocytes.
Flucytosine Resistance Is Restricted to a Single Genetic Clade of
Candida albicans
Authors: Pujol Claude , Pfaller Michael A. , Soll David R. 
Published: December 2003

ABSTRACT

Population studies have revealed that
Candida albicans
can be separated into five major clades, groups I, II, III, SA, and E. Groups SA and E are highly prevalent in South Africa and Europe, respectively, while group II is excluded from the southwestern portion of the United State. In each geographical locale, several clades exist side by side, suggesting little interclade recombination. These results suggest clade-specific phenotypes. In the present study we demonstrate that resistance to flucytosine (5FC MIC ≥ 32 μg/ml), an antifungal used for the treatment of systemic
C. albicans
infections, is restricted to clade I. In addition, while 97% of all strains for which 5FC MICs were ≥0.5 μg per ml were members of group I, only 3% were members of the other groups. 5FC MICs were ≥0.5 μg per ml for 72% of all group I isolates, while 5FC MICs were ≥0.5 μg per ml for only 2% of all non-group I isolates. These results demonstrate for the first time the clade specificity of a clinically relevant trait (5FC resistance) and suggest that while intraclade recombination may be common, interclade recombination is rare.