bluuebunny/crossref_metadata_2025 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

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

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

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

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

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

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

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

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

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

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

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

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

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.
The Interferon Inducer Ampligen [Poly(I)-Poly(C
12
U)] Markedly Protects Mice against Coxsackie B3 Virus-Induced Myocarditis
Authors: Padalko Elizaveta , Nuyens Dieter , De Palma Armando , Verbeken Erik , Aerts Joeri L. , De Clercq Erik , Carmeliet Peter , Neyts Johan
Published: December 2003

Viral replication, as well as an immunopathological component, is assumed to be involved in coxsackie B virus-induced myocarditis. We evaluated the efficacy of the interferon inducer Ampligen on coxsackie B3 virus-induced myocarditis in C3H/HeNHsd mice. The efficacy of Ampligen was compared with that of the interferon inducer poly(inosinic acid)-poly(cytidylic acid) [poly(IC)], alpha interferon 2b (INTRON A), and pegylated alpha interferon 2b (PEG-INTRON-α-2b). Ampligen at 20 mg/kg of body weight/day was able to reduce the severity of virus-induced myocarditis, as assessed by morphometric analysis, by 98% (
P
= 3.0 × 10
−8
). When poly(IC) was administered at 15 mg/kg/day, it reduced the severity of virus-induced myocarditis by 93% (
P
= 5.6 × 10
−5
). Alpha interferon 2b (1 × 10
5
U/day) and pegylated alpha interferon 2b (5 × 10
5
U/day) were less effective and reduced the severity of virus-induced myocarditis by 66% (
P
= 0.0009) and 78% (
P
= 0.0002), respectively. The observed efficacies of Ampligen and poly(IC) were corroborated by the observation that the drugs also markedly reduced the virus titers in the heart, as detected by (i) quantitative real-time reverse transcription-PCR and (ii) titration for infectious virus content. Whereas the electrocardiograms for untreated mice with myocarditis were severely disturbed, the electrocardiographic parameters were normalized in Ampligen- and poly(IC)-treated mice. Even when start of treatment with Ampligen was delayed until day 2 postinfection, a time at which lesions had already appeared in untreated control animals, a marked protective effect on the development of viral myocarditis (as assessed at day 6 postinfection) was still noted.
Vancomycin-Resistant
Staphylococcus aureus
Isolate from a Patient in Pennsylvania
Authors: Tenover Fred C. , Weigel Linda M. , Appelbaum Peter C. , McDougal Linda K. , Chaitram Jasmine , McAllister Sigrid , Clark Nancye , Killgore George , O'Hara Caroline M. , Jevitt Laura , Patel Jean B. , Bozdogan Bülent
Published: December 2003

A vancomycin-resistant
Staphylococcus aureus
(VRSA) isolate was obtained from a patient in Pennsylvania in September 2002. Species identification was confirmed by standard biochemical tests and analysis of 16S ribosomal DNA,
gyrA
, and
gyrB
sequences; all of the results were consistent with the
S. aureus
identification. The MICs of a variety of antimicrobial agents were determined by broth microdilution and macrodilution methods following National Committee for Clinical Laboratory Standards (NCCLS) guidelines. The isolate was resistant to vancomycin (MIC = 32 μg/ml), aminoglycosides, β-lactams, fluoroquinolones, macrolides, and tetracycline, but it was susceptible to linezolid, minocycline, quinupristin-dalfopristin, rifampin, teicoplanin, and trimethoprim-sulfamethoxazole. The isolate, which was originally detected by using disk diffusion and a vancomycin agar screen plate, was vancomycin susceptible by automated susceptibility testing methods. Pulsed-field gel electrophoresis (PFGE) of
Sma
I-digested genomic DNA indicated that the isolate belonged to the USA100 lineage (also known as the New York/Japan clone), the most common staphylococcal PFGE type found in hospitals in the United States. The VRSA isolate contained two plasmids of 120 and 4 kb and was positive for
mecA
and
vanA
by PCR amplification. The
vanA
sequence was identical to the
vanA
sequence present in Tn
1546
. A DNA probe for
vanA
hybridized to the 120-kb plasmid. This is the second VRSA isolate reported in the United States.
Linezolid Pharmacokinetics in Adult Patients with Cystic Fibrosis
Authors: Bosso John A. , Flume Patrick A. , Gray Susan L.
Published: December 2003

The pharmacokinetics of many drugs are altered in patients with cystic fibrosis (CF), often necessitating different dosage requirements than those used in non-CF patients. The objective of this study was to determine the pharmacokinetics of linezolid, an antibiotic with good activity against gram-positive organisms such as methicillin-resistant
Staphylococcus aureus
, in patients with CF so that dosage requirements could be established. Twelve adult patients (6 male) ranging in age from 22 to 39 years were studied. A single 600-mg dose was administered intravenously over 0.5 h, and plasma samples were collected at 0 (predose), 0.5, 0.75, 1, 2, 4, 8, and 24 h. Linezolid concentrations were determined with a validated high-performance liquid chromatography assay. Pharmacokinetic parameters were estimated using standard noncompartmental methods. Blood chemistry and hematologic indices were determined before and after the study for safety purposes. All patients completed the study without encountering any adverse reactions. The pharmacokinetic parameters, while variable, with half-lives varying from 1.76 to 8.36 h, were similar to those previously described in other populations. Mean (± standard deviation) values for pharmacokinetic parameters of interest were as follows: elimination rate constant, 0.21 (0.11) h
−1
; half-life, 4.41 (2.43); volume of distribution at steady state, 0.87 (0.19) liters/kg of body weight; and total body clearance, 0.12 (0.06) liters/h/kg. No patient would have achieved the pharmacodynamic target of an area under the concentration-time curve/MIC ratio of 83 h for pathogens for which the MIC was 4 μg/ml. Patients with inadequate clinical responses to linezolid may require more frequent dosing.
Local Variants of Staphylococcal Cassette Chromosome
mec
in Sporadic Methicillin-Resistant
Staphylococcus aureus
and Methicillin-Resistant Coagulase-Negative Staphylococci: Evidence of Horizontal Gene Transfer?
Authors: Hanssen Anne-Merethe , Kjeldsen Gry , Sollid Johanna U. Ericson
Published: December 2003

The
mecA
gene in
Staphylococcus aureus
is located on the genetic element staphylococcal cassette chromosome (SCC). Different SCC
mec
s have been classified according to their putative recombinase genes (
ccrA
and
ccrB
) and overall genetic composition. Clinical isolates of coagulase-negative staphylococci (CoNS;
n
= 39) and
S. aureus
(
n
= 20) from Norway, India, Italy, Finland, the United States, and the United Kingdom were analyzed by pulsed-field gel electrophoresis, which showed that most isolates were genetically unrelated. Cluster analyses of 16S rRNA gene and
pta
sequences confirmed the traditional biochemical species identification. The
mecI
,
mecR1
,
mecA
, and
ccrAB
genes were detected by PCRs, identifying 19 out of 20
S. aureus
and 17 out of 39 CoNS isolates as carriers of one of the three published
ccrAB
pairs. New variants of SCC
mec
were identified, as well as CoNS isolates containing
ccrAB
genes without the
mec
locus.
ccrAB
and
mec
PCRs were verified by hybridization. Sequence alignments of
ccrAB
genes showed a high level of diversity between the
ccrAB
alleles from different isolates, i.e., 94 to 100% and 95 to 100% homology for
ccrAB1
and
ccrAB2
, respectively. All of the
ccrAB3
genes identified were identical. Genetically unique and sporadic methicillin-resistant
S. aureus
(MRSA) contained local variants of
ccrAB
gene pairs identical to those found in MR-CoNS but different from those in MRSA from other regions. Allelic variants of
ccrAB
in isolates from the same geographic region showed sequence conservation independent of species. The species-independent sequence conservation found suggests that there is a closer genetic relationship between
ccrAB2
in Norwegian staphylococci than between
ccrAB2
sequences in international MRSA and Norwegian MRSA. This might indicate that different staphylococcal species acquire these genes locally by horizontal gene transfer.
Pyridines and Pyrimidines Mediating Activity against an Efflux-Negative Strain of
Candida albicans
through Putative Inhibition of Lanosterol Demethylase
Authors: Buurman Ed T. , Blodgett April E. , Hull Kenneth G. , Carcanague Daniel
Published: December 2003

The first step in ergosterol biosynthesis in
Saccharomyces cerevisiae
consists of the condensation of two acetyl coenzyme A (acetyl-CoA) moieties by acetoacetyl-CoA thiolase, encoded by
ERG10
. The inhibition of the sterol pathway results in feedback activation of
ERG10
transcription. A cell-based reporter assay, in which increased
ERG10
transcription results in elevated specific β-galactosidase activity, was used to find novel inhibitors of ergosterol biosynthesis that could serve as chemical starting points for the development of novel antifungal agents. A class of pyridines and pyrimidines identified in this way had no detectable activity against the major fungal pathogen
Candida albicans
(MICs > 64 μg · ml
−1
). However, a strain of
C. albicans
lacking the Cdr1p and Cdr2p efflux pumps was sensitive to the compounds (with MICs ranging from 2 to 64 μg · ml
−1
), suggesting that they are efficiently removed from wild-type cells. Quantitative analysis of sterol intermediates that accumulated during growth inhibition revealed the accumulation of lanosterol at the expense of ergosterol. Furthermore, a clear correlation was found between the 50% inhibitory concentration at which the sterol profile was altered and the antifungal activity, measured as the MIC. This finding strongly suggests that the inhibition of growth was caused by a reduction in ergosterol synthesis. The compounds described here are a novel class of antifungal pyridines and pyrimidines and the first pyri(mi)dines to be shown to putatively mediate their antifungal activity against
C. albicans
via lanosterol demethylase.
In Vitro Activities of Tigecycline against Erythromycin-Resistant
Streptococcus pyogenes
and
Streptococcus agalactiae
: Mechanisms of Macrolide and Tetracycline Resistance
Authors: Betriu C. , Culebras E. , Rodríguez-Avial I. , Gómez M. , Sánchez B. A. , Picazo J. J.
Published: December 2003

The activity of tigecycline was tested against erythromycin-resistant streptococci (107
Streptococcus pyogenes
and 98
Streptococcus agalactiae
strains). The presence of erythromycin and tetracycline resistance genes was determined by PCR. Among
S. pyogenes
strains the most prevalent gene was
mef
(A) (91.6%). The
erm
(B) gene was the most prevalent (65.3%) among
S. agalactiae
strains. Tigecycline proved to be very active against all the isolates tested (MIC at which 90% of the isolates tested were inhibited, 0.06 μg/ml), including those resistant to tetracycline.
bla
VIM-7
, an Evolutionarily Distinct Metallo-β-Lactamase Gene in a
Pseudomonas aeruginosa
Isolate from the United States
Authors: Toleman Mark A. , Rolston Kenneth , Jones Ronald N. , Walsh Timothy R.
Published: December 2003

As part of the CANCER Antimicrobial Surveillance Program in North America, a
Pseudomonas aeruginosa
isolate, strain 07-406, was shown to possess a metallo-β-lactamase, designated VIM-7.
bla
VIM-7
is located on a 24-kb plasmid which can be readily transferred into
Enterobacteriaceae
and other pseudomonads. This is the first report of a mobile metallo-β-lactamase gene,
bla
VIM-7
, being detected within the United States.
Comparison of In Vitro Activities of Ketolides, Macrolides, and an Azalide against the SpirocheteBorrelia burgdorferi
Authors: Hunfeld Klaus-Peter , Wichelhaus Thomas A. , Rödel Rebecca , Acker Georg , Brade Volker , Kraiczy Peter
Published: December 2003

Two ketolides, three macrolides, and one azalide were tested in vitro against 17 isolates of theB. burgdorferis.l. complex. As measured in micrograms per milliliter, activity was highest for cethromycin (MIC at which 90% of the tested isolates were inhibited [MIC90], 0.0019 μg/ml) and telithromycin (MIC90, 0.0078 μg/ml). Electron-microscope analysis and time-kill studies also supported enhanced effectiveness of both ketolides.
Chromosome-Encoded Ambler Class D β-Lactamase ofShewanella oneidensisas a Progenitor of Carbapenem-Hydrolyzing Oxacillinase
Authors: Poirel Laurent , Héritier Claire , Nordmann Patrice
Published: December 2003

A chromosome-encoded β-lactamase gene from aShewanella oneidensisreference strain was cloned and expressed inEscherichia coli. It encoded a carbapenem-hydrolyzing Ambler class D β-lactamase, OXA-54, that shared 92% amino acid identity with the plasmid-encoded carbapenem-hydrolyzing oxacillinase OXA-48 fromKlebsiella pneumoniae. This work suggests thatShewanellaspp. may produce the progenitor of oxacillinases compromising the efficacy of imipenem in clinically relevant gram-negative pathogens.
In Vitro Activities of DA-7867, a Novel Oxazolidinone, against Recent Clinical Isolates of Aerobic and Anaerobic Bacteria
Authors: Yong Dongeun , Yum Jong Hwa , Lee Kyungwon , Chong Yunsop , Choi Sung Hak , Rhee Jae Keol
Published: December 2003

In vitro activities of DA-7867, a novel oxazolidinone, were compared to those of linezolid and commonly used antimicrobials. DA-7867 had the lowest MIC for 90% of the aerobic gram-positive bacterial strains tested, ≤0.25 μg/ml, and it was more potent than linezolid.
Effects of Aspirin and Other Nonsteroidal Anti-Inflammatory Drugs on Biofilms and Planktonic Cells of
Candida albicans
Authors: Alem Mohammed A. S. , Douglas L. Julia
Published: December 2003

Prostaglandins are now known to be produced by
Candida albicans
and may play an important role in fungal colonization. Their synthesis in mammalian cells is decreased by inhibitors of the cyclooxygenase isoenzymes required for prostaglandin formation. In the present study, a catheter disk model system was used to investigate the effects of nonsteroidal anti-inflammatory drugs (all cyclooxygenase inhibitors) on biofilm formation by three strains of
C. albicans.
Seven of nine drugs tested at a concentration of 1 mM inhibited biofilm formation. Aspirin, etodolac, and diclofenac produced the greatest effects, with aspirin causing up to 95% inhibition. Celecoxib, nimesulide, ibuprofen, and meloxicam also inhibited biofilm formation, but to a lesser extent. Aspirin was active against growing and fully mature (48-h) biofilms; its effect was dose related, and it produced significant inhibition (20 to 80%) at pharmacological concentrations. Simultaneous addition of prostaglandin E
2
abolished the inhibitory effect of 25 or 50 μM aspirin. At 1 mM, aspirin reduced the viability of biofilm organisms to 1.9% of that of controls. Surviving cells had a wrinkled appearance, as judged by scanning electron microscopy, and consisted of both yeasts and hyphae. Treatment with other cyclooxygenase inhibitors, such as etodolac, resulted in biofilms that consisted almost entirely of yeast cells. In conventional assays for germ tube formation, these drugs produced significant inhibition, whereas aspirin had little effect. Our findings suggest that cyclooxygenase-dependent synthesis of fungal prostaglandin(s) is important for both biofilm development and morphogenesis in
C. albicans
and may act as a regulator in these physiological processes. Our results also demonstrate that aspirin possesses potent antibiofilm activity in vitro and could be useful in combined therapy with conventional antifungal agents in the management of some biofilm-associated
Candida
infections.
Efficacy of BB-83698, a Novel Peptide Deformylase Inhibitor, in a Mouse Model of Pneumococcal Pneumonia
Authors: Azoulay-Dupuis E. , Mohler J. , Bédos J. P.
Published: December 2003

The efficacy of BB-83698, a novel potent peptide deformylase inhibitor, was evaluated in a mouse model of acute pneumonia. The
Streptococcus pneumoniae
isolates tested included four virulent strains (one penicillin-susceptible wild-type strain, one macrolide-resistant strain, and two quinolone-resistant mutants [a mutant carrying mutations in ParC and GyrA and an efflux mutant] isogenic to the wild type) and two poorly virulent penicillin-resistant strains. Pneumonia was induced by intratracheal inoculation of 10
5
CFU (virulent strains) into immunocompetent mice or 10
7
CFU (less virulent strains) into leukopenic mice. Animals received three or six subcutaneous injections of antibiotics at 12- or 24-h intervals, with antibiotic treatment initiated at 3, 6, 12, or 18 h postinfection (p.i.). BB-83698 showed potent in vitro activity against all strains (MICs, 0.06 to 0.25 μg/ml). In the in vivo model, all control animals died within 2 to 5 days of infection. BB-83698 (80 mg/kg of body weight twice daily or 160 mg/kg once daily) protected 70 to 100% of the animals, as measured 10 days p.i., regardless of the preexisting resistance mechanisms. In contrast, the survival rates for animals treated with the comparator antibiotics were 30% for animals treated with erythromycin (100 mg/kg) and infected with the macrolide-resistant strain, 34% for animals treated with amoxicillin (200 mg/kg every 8 h) and infected with the penicillin-resistant strain, and 0 and 78% for animals treated with ciprofloxacin (250 mg/kg) and infected with the ParC and GyrA mutant and the efflux mutant, respectively. At 80 mg/kg, BB-83698 generated a peak concentration in lung tissue of 61.9 μg/ml within 1 h and areas under the concentration-times curves of 57.4 and 229.4 μg · h/ml for plasma and lung tissue, respectively. The emergence of
S. pneumoniae
isolates with reduced susceptibilities to BB-83698 was not observed following treatment with a suboptimal dosing regimen. In conclusion, the potent in vitro activity of BB-83698 against
S. pneumoniae
, including resistant strains, translates into good in vivo efficacy in a mouse pneumonia model.
Immunomodulatory Clarithromycin Treatment of Experimental Sepsis and Acute Pyelonephritis Caused by Multidrug-Resistant
Pseudomonas aeruginosa
Authors: Giamarellos-Bourboulis Evangelos J. , Adamis Theodoros , Laoutaris George , Sabracos Lambros , Koussoulas Vassilios , Mouktaroudi Maria , Perrea Despina , Karayannacos Panayotis E. , Giamarellou Helen
Published: December 2003

Clarithromycin was administered intravenously to 55 rabbits to evaluate its effect on experimental sepsis caused by multidrug-resistant
Pseudomonas aeruginosa
. Acute pyelonephritis was induced after ligation of the right ureter and injection of 10
8
CFU of the test isolate per kg of body weight into the renal pelvis. The animals were divided into six groups: group A, controls; group B, rabbits that received one intravenous dose of 80 mg of clarithromycin per kg concomitantly with bacterial challenge; group C, rabbits that received two doses of clarithromycin, the second one of which was given 2 h after the first one; group D, rabbits that received 15 mg of amikacin per kg; group E, rabbits that received one dose of clarithromycin and amikacin; and group F, rabbits that received two doses of clarithromycin and amikacin. Serum endotoxin levels were estimated by the QCL-1000
Limulus
amoebocyte lysate assay, tumor necrosis factor alpha (TNF-α) levels were measured by a bioassay, and malondialdehyde (MDA) levels were measured by the thiobarbiturate assay. Viable bacterial counts in various tissue samples were also assessed. The mean survival times of the animals in groups A, B, C, D, E, and F were 4.50, 7.69, 4.07, 4.55, 11.55, and 11.60 days, respectively (
P
= 0.033 for group D versus group F,
P
= 0.006 for group D versus group E,
P
= not significant for group B versus group E,
P
= 0.042 for group C versus group F). Serum endotoxin levels were similar between groups at all sampling times; TNF-α and MDA levels in groups B, C, E, and F decreased significantly over follow-up. The numbers of viable bacterial cells in the infected kidney were similar among the groups; those in the liver, spleen, lungs, and mesenteral lymph nodes were significantly decreased in groups B, E, and F compared to those in groups A and D. It is concluded that a prolongation of survival in animals with experimental sepsis caused by multidrug-resistant
P. aeruginosa
was achieved after coadministration of clarithromycin and amikacin and that the increased survival was probably attributable to the immunomodulatory properties of clarithromycin.
THE FISHER EFFECT: A SURVEY
Authors: COORAY ARUSHA
Published: December 2003

The Fisher hypothesis has been a much debated topic. Over the years the hypothesis debated and the techniques used have changed. While the majority of early studies on the Fisher effect concentrated primarily on confirming the long and distributed lag in expectations formation, subsequent work saw the integration of the Fisher hypothesis with the theories of rational expectations and efficient markets. With the incorporation of these theories in the Fisher hypothesis, the methodological advances involved examining the time series properties of the variables in question. This survey reviews previous work from this perspective. In addition, the studies pertaining to developing economies and possible explanations for the failure of the Fisher effect are also reviewed.
PRICING BEHAVIOR OF A CONVENTIONAL RETAILER'S ONLINE-BRANCH
Authors: LU DING
Published: December 2003

This paper presents a simple model to interpret the business rationale for a conventional retailer with market power to develop its online business in the presence of an e-commerce rival. The model shows that the online branch of a conventional retailer tends to sell products at a higher price level than its dot.com rival. The participation of the conventional retailer in the online market may increase the average online prices. The conventional retailer will compete aggressively in price only when the cost-saving benefit of online sale is sufficiently large.
FORECASTING DAILY FOREIGN EXCHANGE RATE IN INDIA WITH ARTIFICIAL NEURAL NETWORK
Authors: PANDA CHAKRADHARA , NARASIMHAN V.
Published: December 2003

This study compares the efficiency of a non-linear model called artificial neural network with linear autoregressive and random walk models in the one-step-ahead prediction of daily Indian rupee/US dollar exchange rate. We find that neural network and linear autoregressive models outperform random walk model in in-sample and out-of-sample forecasts. The in-sample forecasting of neural network is found to be better than that of linear autoregressive model. As far as out-of-sample forecasting is concerned, the results are mixed and we do not find a "winner" model between neural network and linear autoregressive model. However, neural network is able to improve upon the linear autoregressive model in terms of sign predictions. In addition to this, we also find that the number of input nodes has greater impact on neural network's performance than the number of hidden nodes.
θ–PHYSICS: 0–vacuum versus π–vacuum
Authors: Aguado M. , Asorey M. , García-Alvarez D.
Published: December 2003

The behaviour of 0–vacuum and π–vacuum under CP symmetry is analyzed in two different families of quantum field theories: gauge theories in 4D and [Formula: see text] sigma models in 2D. In particular, the possibility of spontaneous CP symmetry breaking is analyzed by new continuum non-perturbative techniques. In the case of θ = 0–vacuum we find that the dependence of the vacuum energy density on θ around θ = 0 has not a first order cusp singularity, a missing requirement of the proof of the Vafa-Witten theorem. The result is based on the absence of Lee-Yang singularities for pure imaginary values of the θ–parameter. In the case of θ = π the result follows from the analysis of the nodal structure of the vacuum functional in the Schrödinger representation. The dynamics of both theories favors the localization of vacuum nodes at sphalerons instead of classical vacua as corresponds to parity even states. The existence of a dynamical level repulsion between parity even and parity odd states at low energies is the mechanism behind the absence of CP symmetry breaking in π–vacuum.
ONE AND QUASI-ONE DIMENSIONAL SPIN SYSTEMS
Authors: Ercolessi Elisa
Published: December 2003

Quantum spin models represent one of the most studied examples of application of low-dimensional field theories to condensed matter systems. In this paper we will review some chapters of this hystory, that dates back to the early '80, when Haldane put forward his by now famous conjecture on antiferromagnetic spin chains, and reaches the present days, with the most advanced applications of integrable models and conformal field theory.