bluuebunny/crossref_metadata_2025 huggingface dataset:
Antecedents and Consequences of Goal Incongruity on New Product Development in Five Countries: A Marketing View
Authors: Xie Jinhong , Song Michael , Stringfellow Anne
Published: July 2003

This article examines an important challenge to effective cross‐functional integration: goal incongruity among marketing, research and development (R&D), and manufacturing in new product development. We examine the effect of this incongruity as perceived by the marketing function on three components of cross‐functional integration: the harmony of cross‐functional relationships, the quality of cross‐functional information, and the level of cross‐functional involvement. We also examine how two types of managerially controllable variables affect goal incongruity: (1) factors that motivate functions to develop common goals; and (2) factors that facilitate the formation of such goals. We give special attention to the effect of national culture on the formation of common goals. Data collected from marketing managers in 1,083 firms in five culturally distinct areas—‐the United States, Great Britain, Japan, Hong Kong (a special administrative region of China), and mainland China—are used to test the hypothesized relationships. Our results underscore the importance of people‐side issues, and of national culture, in cross‐functional integration. Perceived goal incongruity among marketing, R&D, and manufacturing impairs all three components of cross‐functional integration. In United States and British firms, goal incongruity generally is attributed to motivational factors and in Japan and Hong Kong to facilitative factors. Finally, our results show that the two types of managerially controllable variables interact. For example, joint rewards and job rotation strengthen each other's tendency to reduce goal incongruity in all five samples. This suggests that job rotation promotes the development of joint goals more effectively when it is accompanied by a joint reward system.
Product differentiation in successive vertical oligopolies
Authors: Belleflamme Paul , Toulemonde Eric
Published: July 2003

Abstract.  This is a successive oligopoly model with two varieties of a final product. Downstream firms choose one variety to sell on a final market. Upstream firms specialize in the production of one input specifically designed for one variety, but they also produce the input for the other variety at an extra cost. We show that as more downstream firms choose one particular variety, more upstream firms specialize in the input specific to that variety, and vice‐versa. Multiple equilibria may result, and the softening effect of product differentiation on competition might not be strong enough to induce maximal differentiation. JEL Classification: L11, L13, L23
The closed‐loop effect and the profitability of horizontal mergers
Authors: Benchekroun Hassan
Published: July 2003

Abstract.  We study the profitability of horizontal mergers in a dynamic competition context with sticky prices. It is shown that, when firms use open‐loop strategies, a merger is profitable only if the share of the market that merges is significant enough. In the case where firms use closed‐loop strategies we provide a method to conduct analytically the study of the profitability of horizontal mergers. We first prove the existence of an equilibrium of the game when a subset of firms merges. When firms use feedback strategies, mergers are profitable even when the share of the market that merges is arbitrarily small. JEL Classification:D4, L13
R&D, innovation, and technological progress: a test of the Schumpeterian framework without scale effects
Authors: Zachariadis Marios
Published: July 2003

Abstract.  I use U.S. manufacturing industry data to estimate a system of three equations implied by a model of R&D‐induced growth in steady state. These equations relate R&D intensity to patenting, patenting to technological progress, and technological progress to economic growth. In each case, I find evidence of positive impact. Thus, I reject the null hypothesis that growth is not induced by R&D in favour of the Schumpeterian endogenous growth framework without scale effects. I also find strong support for technological spillovers from aggregate research intensity to industry‐level innovation success. JEL Classification: O40, O30
Decentralizing hydro power production
Authors: Ambec Stefan , Doucet Joseph A.
Published: July 2003

Abstract.  We analyse the production of electricity from n power stations in a dynamic model. Each power station's production of electricity is constrained by the quantity of water available to it (supply constraint) as well as limitations on reservoir capacity (storage constraint). We show that hydro power production can lead to two sources of welfare loss: suboptimal management of water resources and the exercise of market power. A monopolist minimizes the first source of inefficiency, whereas decentralized production in a competitive environment minimizes the second. The decision to introduce competition in hydropower production must account for these two opposite effects. JEL Classification: L11, Q48
Eco‐labelling scheme, environmental protection, and protectionism
Authors: Tian Huilan
Published: July 2003

Abstract.  In this paper a model of international duopoly is developed involving competition in both prices and levels of environmental friendliness, and the implications of government policies are studied. It is shown that, contrary to the conventional wisdom, a regulatory increase in the minimum required level of environmental friendliness of imported goods may harm the home firm and may result in a rise in the volume of imported goods. Whether consumers lose or gain from such a regulatory increase depends on consumption spillover effects. We also show that, under certain conditions, the duopoly's equilibrium choice of levels of environmental friendliness is socially optimal.JEL Classification: F00
Export‐market participation and productivity performance in Canadian manufacturing
Authors: Baldwin John R. , Gu Wulong
Published: July 2003

Abstract.  In this paper, we explore the linkages between export‐market participation and productivity performance in Canadian manufacturing plants. We also examine differences in the relationship between exporting and productivity for foreign‐controlled as opposed to domestic‐controlled plants, and between younger and older plants. Export participation is associated with improved productivity. The effect is much stronger for domestic‐controlled plants than for foreign‐controlled plants and for younger businesses than for older businesses. We interpret this as evidence that there is a learning effect associated with export activity but that the potential for improving productivity with entry to export markets differs across firms. JEL Classification: F1, O4
Product differentiation and the gains from trade under Bertrand duopoly
Authors: Clarke Roger , Collie David R
Published: July 2003

Abstract.  In the literature on the welfare effects of free trade under imperfect competition, one important case seems to have been overlooked, and that is the Bertrand duopoly model with differentiated products. Although many authors have analysed the welfare effects of free trade under Cournot duopoly and demonstrated the possibility of losses from trade, there has been no thorough analysis of the welfare effects of free trade under Bertrand duopoly. In this article we present a thorough analysis of the welfare effects of free trade under Bertrand duopoly with differentiated products, and it is shown that there are always gains from trade. JEL Classification: F12
International capital flows under asymmetric information and costly monitoring: implications of debt and equity financing
Authors: Neumann Rebecca M.
Published: July 2003

Abstract.  The impact of increased equity trade on a small open economy is examined. Stochastic second‐period output depends on first‐period investment. Owing to information asymmetries, domestic agents cannot reveal credibly the level of first‐period investment to international financiers. Consistent with recent proposals to strengthen the international financial system, domestic firms choose to incur self‐monitoring costs to increase capital inflows. As an alternative to borrowing, domestic agents may sell ownership claims to second‐period output. When equity claims convey information, equity trade is preferred to international borrowing, consistent with developing economies’ observed reliance on international equity relative to debt in recent years. JEL Classification: F41, G15
Smuggling, non‐fundamental uncertainty, and parallel market exchange rate volatility
Authors: Barnett Richard Clay
Published: July 2003

Abstract.  We explore a model where smuggling and a parallel currency market arise, owing to government restrictions that prevent agents from legally holding foreign exchange. Despite such restrictions, agents are able to diversify their savings, holding both domestic and parallel foreign cash, basing their portfolio allocation on current and prospective parallel exchange rates. We attribute movements in parallel rates to non‐fundamental uncertainty. The model generates equilibria with both positive and negative parallel premia and correlations between illegal trade and the premium. The model has the novel implication that currency speculation drives smuggling, affecting real activities in all sectors of the economy. JEL classification: F31
Growth and unemployment in a shirking efficiency wage model
Authors: Alexopoulos Michelle
Published: July 2003

Abstract.  The relationship between growth and unemployment in a general equilibrium shirking efficiency wage model is explored. In contrast to past work on this subject, detected shirkers are not dismissed but instead incur a monetary punishment. As a result of this modification, the model can account for a stable rate of unemployment when there is positive population growth and/or technological growth in the economy. Moreover, I show that institutions and policies that limit the ability of firms to punish detected shirkers or restrict their use of discretionary bonuses can increase unemployment and reduce the economy's long run growth rate. JEL Classification: E0, J41
Goods market responses to trade shocks and trade and wages decompositions
Authors: Abrego Lisandro , Whalley John
Published: July 2003

Abstract.  Trade and wages literature asks whether trade or technology has been the major factor behind increases in wage inequality in OECD countries since the 1980s. In this literature, little attention has been paid to how goods market responses to trade shocks affect conclusions. Using an Armington heterogeneous goods trade model we capture demand side effects, and show how trade shocks affecting the price of unskilled‐intensive importable goods can be absorbed on the demand side of goods markets, with little or no impact on relative wage rates. No wage impact occurs if the elasticity of substitution in preferences between imports and import substitutes is one. As this elasticity increases, trade plays an ever larger role in explaining wage inequality changes, and as the elasticity goes below one the sign of the effect changes. We present some results of general equilibrium decompositions of total wage change into trade and technology components using UK data. We suggest that since many import demand elasticity estimates are in the neighbourhood of one, there is a prima facie case that goods market considerations further lower the significance of trade as an explanation of recent trends in OECD wage inequality beyond that claimed in the literature.
High Precision Microscale Bending by Pulsed and CW Lasers
Authors: Zhang X. Richard , Xu Xianfan
Published: July 2003

This paper discusses high precision microscale laser bending and the thermomechanical phenomena involved. The use of a pulsed and a CW laser for microscale bending of ceramics, silicon, and stainless steel is demonstrated. For each laser, experiments are conducted to find out the relation between bending angles and laser operation parameters. Changes of the ceramics surface composition after laser irradiation are analyzed using an electron probe microanalyzer (EPMA). Results obtained by the pulsed and the CW laser are compared, and it is found that the CW laser produces more bending than the pulsed laser does. However, the pulsed laser causes much less surface composition change and thermomechanical damage to the targets. Numerical calculations based on the thermo-elasto-plastic theory are carried out and the results are used to explain the phenomena observed experimentally.
Reversal of Mefloquine and Quinine Resistance in
Plasmodium falciparum
with NP30
Authors: Ciach Michelle , Zong Kathleen , Kain Kevin C. , Crandall Ian
Published: July 2003

Quinoline resistance in malaria is frequently compared with P-glycoprotein-mediated multidrug resistance (
mdr
) in mammalian cells. We have previously reported that nonylphenolethoxylates, such as NP30, are potential
Plasmodium falciparum
P-glycoprotein substrates and drug efflux inhibitors. We used in vitro assays to compare the ability of verapamil and NP30 to sensitize two parasite isolates to four quinolines: chloroquine (CQ), mefloquine (MF), quinine (QN), and quinidine (QD). NP30 was able to sensitize (reversal, >80%)
P. falciparum
to MF, QN, QD, and, to a lesser extent, CQ. The presence of 2 μM verapamil had no effect on mefloquine resistance; however, the presence of verapamil modulated the activities of QN and QD in a manner parallel to that observed for CQ. Genetic analysis of putative quinoline resistance genes did not suggest an association between known point mutations in
pfcrt
and
pfmdr1
and NP30 sensitization activity. We conclude that the sensitization action of NP30 is distinct both phenotypically and genotypically from that of verapamil.
Leishmania donovani
Resistance to Miltefosine Involves a Defective Inward Translocation of the Drug
Authors: Pérez-Victoria F. Javier , Castanys Santiago , Gamarro Francisco
Published: July 2003

Miltefosine (hexadecylphosphocholine [HePC]) is the first drug approved for the oral treatment of visceral leishmaniasis. As part of a study on the mechanisms of action of this drug and on the rates of resistance to this drug, we have been working in vitro with an
Leishmania donovani
line that was previously shown to be 15-fold more resistant to HePC. We have studied the accumulation of [
14
C]HePC by
L. donovani
promastigotes and have found a drastic reduction (>95%) in the ability of the resistant line to internalize the drug. Binding of HePC to the plasma membrane and drug efflux from preloaded cells were similar in both drug-sensitive and -resistant lines, and no [
14
C]HePC metabolism was evident in either line. Resistant parasites were also unable to take up other short-chain phospholipid analogs, independently of their polar head group, even though endocytosis remained unaltered. Finally, HePC uptake was temperature and energy dependent and sensitive to the thiol-reactive agent
N
-ethylmaleimide. We propose that inward translocation of a short-chain phospholipid across the plasma membrane may exist in
Leishmania
promastigotes and that such activity is defective in the resistant line.
Candida albicans
Mutations in the Ergosterol Biosynthetic Pathway and Resistance to Several Antifungal Agents
Authors: Sanglard Dominique , Ischer Françoise , Parkinson Tania , Falconer Derek , Bille Jacques
Published: July 2003

The role of sterol mutations in the resistance of
Candida albicans
to antifungal agents has not been thoroughly investigated. Previous work reported that clinical
C. albicans
strains resistant to both azole antifungals and amphotericin B were defective in
ERG3
, a gene encoding sterol Δ
5,6
-desaturase. It is also believed that a deletion of the lanosterol 14α-demethylase gene,
ERG11
, is possible only under aerobic conditions when
ERG3
is not functional. We tested these hypotheses by creating mutants by targeted deletion of the
ERG3
and
ERG11
genes and subjecting those mutants to antifungal susceptibility testing and sterol analysis. The homozygous
erg3
/
erg3
mutant created, DSY1751, was resistant to azole derivatives, as expected. This mutant was, however, slightly more susceptible to amphotericin B than the parent wild type. It was possible to generate
erg11
/
erg11
mutants in the DSY1751 background but also, surprisingly, in the background of a wild-type isolate with functional
ERG3
alleles under aerobic conditions. This mutant (DSY1769) was obtained by exposure of an
ERG11
/
erg11
heterozygous strain in a medium containing 10 μg of amphotericin B per ml. Amphotericin B-resistant strains were obtained only from
ERG11
/
erg11
heterozygotes at a frequency of approximately 5 × 10
−5
to 7 × 10
−5
, which was consistent with mitotic recombination between the first disrupted
erg11
allele and the other remaining functional
ERG11
allele. DSY1769 was also resistant to azole derivatives. The main sterol fraction in DSY1769 contained lanosterol and eburicol. These studies showed that
erg11
/
erg11
mutants of a
C. albicans
strain harboring a defective
erg11
allele can be obtained in vitro in the presence of amphotericin B. Amphotericin B-resistant strains could therefore be selected by similar mechanisms during antifungal therapy.
Molecular Cloning and Characterization of an ABC Multidrug Efflux Pump, VcaM, in Non-O1
Vibrio cholerae
Authors: Huda Nazmul , Lee Eun-Woo , Chen Jing , Morita Yuji , Kuroda Teruo , Mizushima Tohru , Tsuchiya Tomofusa
Published: July 2003

A gene responsible for multidrug resistance was cloned from the chromosomal DNA of non-O1
Vibrio cholerae
NCTC 4716 by using as a host drug-hypersensitive
Escherichia coli
strain KAM32, which lacks major multidrug efflux pumps.
E. coli
cells transformed with the gene showed elevated levels of resistance to a number of structurally dissimilar drugs, such as tetracycline, norfloxacin, ciprofloxacin, doxorubicin, daunomycin, 4′,6-diamidino-2-phenylindole, and Hoechst 33342. We determined the nucleotide sequence and found one open reading frame. We designated the gene
vcaM
. The deduced product, VcaM, seems to be a polypeptide with 619 amino acid residues (69 kDa) that has a putative topology of six transmembrane segments in the N-terminal hydrophobic domain, followed by an ATP binding domain in the C-terminal hydrophilic region. The sequence of VcaM was shown to be similar to those of human multidrug resistance proteins P-glycoprotein MDR1 and lactococcal LmrA, which are driven by ATP. The efflux of Hoechst 33342 and doxorubicin from cells possessing VcaM was detected. The efflux activity was inhibited by reserpine and sodium
o-
vanadate, which are potent inhibitors of MDR1 and LmrA. Thus, we conclude that VcaM is a member of the family of multidrug efflux pumps of the ATP binding cassette type and the first experimentally proven example of a multidrug efflux pump of this family in gram-negative bacteria.
Resistance to Antimalarials in Southeast Asia and Genetic Polymorphisms in
pfmdr1
Authors: Pickard Amy L. , Wongsrichanalai Chansuda , Purfield Anne , Kamwendo Deborah , Emery Kathryn , Zalewski Christy , Kawamoto Fumihiko , Miller R. Scott , Meshnick Steven R.
Published: July 2003

Resistance to antimalarial drugs is a public health problem worldwide. Molecular markers for drug-resistant malaria, such as
pfcrt
and
pfmdr1
polymorphisms, could serve as useful surveillance tools. To evaluate this possibility, sequence polymorphisms in
pfcrt
(position 76) and
pfmdr1
(positions 86, 184, 1034, 1042, and 1246) and in vitro drug sensitivities were measured for 65
Plasmodium falciparum
isolates from Thailand, Myanmar, Vietnam, and Bangladesh. The
pfcrt
Thr76 polymorphism was present in 97% of samples, consistent with observations that chloroquine resistance is well established in this region. Polymorphisms in
pfmdr1
clustered into four specific patterns: the wild type (category I), a Tyr86 polymorphism only (category II), a Phe184 polymorphism only (category III), and Phe184 in combination with Cys1034 and/or Asp1042 (category IV). Isolates in categories I and III were more sensitive to chloroquine and more resistant to mefloquine, artesunate, and artemisinin than isolates in categories II and IV (
P
≤ 0.01). Mefloquine resistance was significantly more common in category I and III isolates than in category II and IV isolates, with a prevalence ratio of 14.95 (95% confidence interval, 3.88 to 57.56). These categories identified mefloquine resistance with a sensitivity and a specificity of 94 and 91%, respectively. The
pfmdr1
gene copy number was measured by real-time PCR as a ratio of the amount of
pfmdr1
DNA to the amount of lactate dehydrogenase (
ldh
) DNA. Eight samples had
pfmdr1
DNA/
ldh
DNA ratios ≥3. The isolates in all 8 samples fell into categories I and III and were significantly more resistant to mefloquine, quinine, artemisinin, and artesunate and more sensitive to chloroquine than the isolates in the 57 samples with <3 copies of the gene (
P
≤ 0.001). Thus, measurement of
pfmdr1
mutations and gene copy number may be useful for surveillance of mefloquine-resistant malaria in Southeast Asia.
Molecular Mechanisms of Itraconazole Resistance in
Candida dubliniensis
Authors: Pinjon Emmanuelle , Moran Gary P. , Jackson Colin J. , Kelly Steven L. , Sanglard Dominique , Coleman David C. , Sullivan Derek J.
Published: July 2003

It has previously been shown that overexpression of the
CdMDR1
gene is a major contributor to resistance in fluconazole-resistant isolates of
Candida dubliniensis
. However, since CdMdr1p does not mediate transport of other azole drugs such as itraconazole, we investigated the molecular mechanisms of stable resistance to itraconazole obtained in three strains of
C. dubliniensis
(two with nonfunctional
CdCDR1
genes and one with functional
CdCDR1
genes) by serial exposure to this antifungal agent in vitro. Seven derivatives that were able to grow on agar medium containing 64 μg of itraconazole per ml were selected for detailed analysis. These derivatives were resistant to itraconazole, fluconazole, and ketoconazole but were not cross resistant to inhibitors.
CdMDR1
expression was unchanged in the seven resistant derivatives and their parental isolates; however, all seven derivatives exhibited increased levels of
CdERG11
expression, and six of the seven derivatives exhibited increased levels of
CdCDR1
expression compared to the levels of expression by their respective parental isolates. Except for one derivative, the level of rhodamine 6G efflux was decreased in the itraconazole-resistant derivatives compared to the level of efflux in their parental isolates, suggesting altered membrane properties in these derivatives. Analysis of their membrane sterol contents was consistent with a defective sterol C5,6-desaturase enzyme (CdErg3p), which was confirmed by the identification of mutations in the alleles (
CdERG3
) encoding this enzyme and their lack of functional complementation in a
Saccharomyces cerevisiae erg3
mutant. The results of this study show that the loss of function of CdErg3p was the primary mechanism of in vitro-generated itraconazole resistance in six of the seven the
C. dubliniensis
derivatives. However, the mechanism(s) of itraconazole resistance in the remaining seventh derivative has yet to be determined.
Acyclovir Levels in Serum and Cerebrospinal Fluid after Oral Administration of Valacyclovir
Authors: Lycke Jan , Malmeström Clas , Ståhle Lars
Published: July 2003

The possible involvement of herpesviruses in the pathogenesis of multiple sclerosis (MS) was recently investigated in a clinical trial of valacyclovir in patients with MS. As an important part of that survey we performed an independent pharmacokinetic study in order to determine the concentration of acyclovir in cerebrospinal fluid (CSF). The concentrations of acyclovir in serum and CSF were measured at steady state after 6 days of oral treatment with 1,000 mg of valacyclovir three times a day. Samples were obtained from 10 patients with MS. All patients had normal renal function, and none had signs of a damaged blood-CSF barrier. The maximum concentration of acyclovir in serum was reached after 1 to 3 h (mean ± standard deviation [SD], 27.1 ± 5.6 μM), and the minimum concentration in serum was 3.1 ± 1.1 μM (mean ± SD). The acyclovir concentrations in CSF at 2 and 8 h were essentially stable, with the mean ± SD levels being 2.5 ± 0.9 and 2.3 ± 0.7 μM, respectively. Similar levels were recorded in serum and CSF samples from five other MS patients after 6 months of oral treatment with valacyclovir at identical dosages. The area under the concentration-time curve (AUC) for acyclovir in CSF to the AUC for acyclovir in serum (CSF/serum AUC ratio) was approximately 20%. We conclude that the improved bioavailability previously reported for valacyclovir in plasma results in higher concentrations in CSF, while the CSF/serum AUC ratio remains constant.
Gatifloxacin and Ethionamide as the Foundation for Therapy of Tuberculosis
Authors: Cynamon Michael H. , Sklaney Mary
Published: July 2003

The use of gatifloxacin (GAT) in combination with ethionamide (ETA) with or without pyrazinamide (PZA) for a 12-week treatment period followed by an 8-week observation period was evaluated in a model of tuberculosis in mice. Mice treated with GAT at 300 mg/kg of body weight in combination with ETA (25 mg/kg) for 5 days per week had sterile lungs, whereas mice treated with GAT (100 mg/kg) and ETA (25 mg/kg) had about 10 CFU/lung; however, there was regrowth of the organisms in both groups at the end of the observation period. When PZA (450 mg/kg 5 days per week) was added to the high-dose GAT-ETA regimen, no viable mycobacteria were present after the 8-week observation period. GAT in combination with ETA and PZA has great promise for the treatment of tuberculosis.
Effective Immunomodulatory Treatment ofEscherichia coliExperimental Sepsis with Thalidomide
Authors: Giamarellos-Bourboulis Evangelos J. , Poulaki Helen , Kostomitsopoulos Nikolaos , Dontas Ismene , Perrea Despina , Karayannacos Panayotis E. , Giamarellou Helen
Published: July 2003

Thalidomide, an agent which inhibits biosynthesis of tumor necrosis factor alpha (TNF-α) and which is used to treat a variety of chronic inflammatory conditions, was investigated as therapy for experimental sepsis. Sepsis was induced by intraperitoneal injection of 107CFU ofEscherichia coliper kg of body weight to 80 Wistar rats divided into four groups. Group A consisted of 24 control animals that did not receive any pretreatment, group B consisted of 18 vehicle-treated control animals pretreated with seed oil, group C consisted of 30 rats administered thalidomide diluted in seed oil at a dose of 50 mg/kg 30 min before bacterial challenge, and group D consisted of eight animals that were not challenged withE. colibut that were used for white blood cell count determination. Sepsis was determined by measurement of vital signs before and 6 h after bacterial challenge. After 6 h the animals were killed and blood was sampled for culture; white blood cell count determination; and determination of endotoxin (lipopolysaccharide), TNF-α, interleukin-1β (IL-1β), and IL-6 levels. The levels of these cytokines were also estimated in the supernatants of human monocytes pretreated with thalidomide after exposure to the isolate. Sepsis developed in all vehicle-treated control animals and controls by 6 h after bacterial challenge but in only 10 animals (33.3%) pretreated with thalidomide (P< 0.0001). Six hours after bacterial challenge all animals had similar levels of endotoxemia, IL-1β, and IL-6. The mean white blood cell count for groups A, B, and C were 5,631.1, 2,638.9, and 8,169.3 cells/μl, respectively (Pvalue between groups, <0.0001); the TNF-α levels were 77.3, 107.2, and 26.1 pg/ml, respectively (Pvalues between groups, <0.0001). Pretreatment of human monocytes with thalidomide prevented the secretion of TNF-α and IL-1β but not that of IL-6. It is concluded that thalidomide exerts a considerable anti-inflammatory effect by preventing evolution to sepsis and by decreasing the level of production of TNF-α and therefore deserves to be further evaluated in research for the therapy of sepsis.
Steady-State Plasma and Bronchopulmonary Concentrations of Intravenous Levofloxacin and Azithromycin in Healthy Adults
Authors: Rodvold Keith A. , Danziger Larry H. , Gotfried Mark H.
Published: July 2003

The purpose of this study was to compare the concentrations of levofloxacin and azithromycin in steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) after intravenous administration. Thirty-six healthy, nonsmoking adult subjects were randomized to either intravenous levofloxacin (500 or 750 mg) or azithromycin (500 mg) once daily for five doses. Venipuncture and bronchoscopy with bronchoalveolar lavage were performed in each subject at either 4, 12, or 24 h after the start of the last antibiotic infusion. The mean concentrations of levofloxacin and azithromycin in plasma were similar to those previously published. The dosing regimens of levofloxacin achieved significantly (P< 0.05) higher concentrations in steady-state plasma than azithromycin during the 24 h after drug administration. The respective mean (± standard deviation) concentrations at 4, 12, and 24 h in ELF for 500 mg of levofloxacin were 11.01 ± 4.52, 2.50 ± 0.97, and 1.24 ± 0.55 μg/ml; those for 750 mg of levofloxacin were 12.94 ± 1.21, 6.04 ± 0.39, and 1.73 ± 0.78 μg/ml; and those for azithromycin were 1.70 ± 0.74, 1.27 ± 0.47, and 2.86 ± 1.75 μg/ml. The differences in concentrations in ELF among the two levofloxacin groups and azithromycin were significantly (P< 0.05) higher at the 4- and 12-h sampling times. The respective concentrations in AM for 500 mg of levofloxacin were 83.9 ± 53.2, 18.3 ± 6.7, and 5.6 ± 3.2 μg/ml; those for 750 mg of levofloxacin were 81.7 ± 37.0, 78.2 ± 55.4, and 13.3 ± 6.5 μg/ml; and those for azithromycin were 650 ± 259, 669 ± 311, and 734 ± 770 μg/ml. Azithromycin achieved significantly (P< 0.05) higher concentrations in AM than levofloxacin at all sampling times. The concentrations in ELF and AM following intravenous administration of levofloxacin and azithromycin were higher than concentrations in plasma. Further studies are needed to determine the clinical significance of such high intrapulmonary concentrations in patients with respiratory tract infections.
Pharmacokinetics and Metabolism of [
14
C]Viramidine in Rats and Cynomolgus Monkeys
Authors: Lin Chin-Chung , Luu Kenneth , Lourenco David , Yeh Li-Tain
Published: July 2003

The pharmacokinetics of [
14
C]viramidine, a prodrug of ribavirin, were studied in rats (30 mg/kg of body weight) and monkeys (10 mg/kg) following intravenous (i.v.) and oral administration. The levels of oral absorption and bioavailabilities were 61.7 and 9.91%, respectively, in rats and 43.9 and 13.6%, respectively, in monkeys. Following i.v. administration, the elimination half-lives were 2.7 h in rats and 28.9 h in monkeys. Total body clearances were 14.0 liters/h/kg in rats and 1.23 liters/h/kg in monkeys; the apparent volumes of distribution were 15.6 liters/kg in rats and 18.6 liters/kg in monkeys. Following oral administration, viramidine was extensively converted to ribavirin, followed by further metabolism of ribavirin in both species, with a faster rate of metabolism in rats than in monkeys. In rats, excretion of total radioactivity in urine accounted for 77.0% of the i.v. dose and 60.8% of the oral dose, while in monkeys it accounted for 44.4% of the i.v. dose and 39.0% of the oral dose. The amount of unchanged viramidine and ribavirin in urine was small in both species after i.v. and oral administration of viramidine.
Novel Antimicrobial Peptides Derived from Flatfish Genes
Authors: Patrzykat Aleksander , Gallant Jeffrey W. , Seo Jung-Kil , Pytyck Jennifer , Douglas Susan E.
Published: July 2003

We report on the identification of active novel antimicrobials determined by screening both the genomic information and the mRNA transcripts from a number of different flatfish for sequences encoding antimicrobial peptides, predicting the sequences of active peptides from the genetic information, producing the predicted peptides chemically, and testing them for their activities. We amplified 35 sequences from various species of flatfish using primers whose sequences are based on conserved flanking regions of a known antimicrobial peptide from winter flounder, pleurocidin. We analyzed the sequences of the amplified products and predicted which sequences were likely to encode functional antimicrobial peptides on the basis of charge, hydrophobicity, relation to flanking sequences, and similarity to known active peptides. Twenty peptides were then produced synthetically and tested for their activities against gram-positive and gram-negative bacteria and the yeast
Candida albicans
. The most active peptide (with the carboxy-terminus amidated sequence GWRTLLKKAEVKTVGKLALKHYL, derived from American plaice) showed inhibitory activity over a concentration range of 1 to 8 μg/ml against a test panel of pathogens, including the intrinsically antibiotic-resistant organism
Pseudomonas aeruginosa
, methicillin-resistant
Staphylococcus aureus
, and
C. albicans.
The methods described here will be useful for the identification of novel peptides with good antimicrobial activities.
In Vitro and In Vivo Activities of Novel 2-(Thiazol-2-ylthio)-1β-Methylcarbapenems with Potent Activities against Multiresistant Gram-Positive Bacteria
Authors: Ueda Yutaka , Sunagawa Makoto
Published: July 2003

SM-197436, SM-232721, and SM-232724 are new 1β-methylcarbapenems with a unique 4-substituted thiazol-2-ylthio moiety at the C-2 side chain. In agar dilution susceptibility testing these novel carbapenems were active against methicillin-resistant
Staphylococcus aureus
(MRSA) and
Staphylococcus epidermidis
(MRSE) with a MIC
90
of ≤4 μg/ml. Furthermore, SM-232724 showed strong bactericidal activity against MRSA, in contrast to linezolid, which was bacteriostatic up to four times the MIC. SM-232724 showed good therapeutic efficacy comparable to those of vancomycin and linezolid against systemic infections of MRSA in cyclophosphamide-treated mice. The MICs of SM-197436, SM-232721, and SM-232724 for streptococci, including penicillin-intermediate and penicillin-resistant
Streptococcus pneumoniae
strains, ranged from ≤0.063 to 0.5 μg/ml. These drugs were the most active β-lactams tested against
Enterococcus faecium
, and the MIC
90
s for ampicillin-resistant
E. faecium
ranged between 8 and 16 μg/ml, which were slightly higher than the value for linezolid. However, time-kill assays revealed the superior bactericidal activity of SM-232724 compared to those of quinupristin-dalfopristin and linezolid against an
E. faecium
strain with a 4-log reduction in CFU at four times the MIC after 24 h of exposure to antibiotics. In addition, SM-232724 significantly reduced the numbers of bacteria in a murine abscess model with the
E. faecium
strain: its efficacy was superior to that of linezolid, although the MICs (2 μg/ml) of these two agents are the same. Among gram-negative bacteria, these three carbapenems were highly active against
Haemophilus influenzae
(including ampicillin-resistant strains),
Moraxella catarrhalis
, and
Bacteroides fragilis
, and showed antibacterial activity equivalent to that of imipenem for
Escherichia coli
,
Klebsiella pneumoniae
, and
Proteus
spp. Thus, these new carbapenems are promising candidates for agents to treat nosocomial bacterial infections by gram-positive and gram-negative bacteria, especially multiresistant gram-positive cocci, including MRSA and vancomycin-resistant enterococci.
Biological Activities of Synthetic Analogs of Halocidin, an Antimicrobial Peptide from the Tunicate
Halocynthia aurantium
Authors: Jang Woong Sik , Kim Chong Han , Kim Kyu Nam , Park Shin Yong , Lee Joon Ha , Son Seok Min , Lee In Hee
Published: July 2003

Halocidin is a heterodimer antimicrobial peptide previously isolated from the tunicate
Halocynthia aurantium
. Based on the larger monomer (18Hc) of halocidin, nine halocidin congeners, including a series of 6 peptides truncated successively from the carboxyl-terminal end of 18Hc and 3 analogs (18HcKK, K19Hc, and K19HcKK), which have lysine residues in place of two internal histidines or have a lysine added to the amino terminus of the 18Hc molecule, were prepared. Each peptide was also converted into a homodimeric version. The antimicrobial activities of halocidin congeners truncated from the C terminus were dramatically decreased, suggesting that the full length of 18Hc is required for maintaining its maximum antimicrobial activity. Dimer forms of halocidin congeners exhibited stronger antimicrobial activities than the monomer of the corresponding peptide. Four dimer peptides (di-18Hc, di-18HcKK, di-K19Hc, and di-K19HcKK) were analyzed for antimicrobial activities against 10 clinically isolated antibiotic-resistant bacteria in elevated concentrations of NaCl or MgCl
2
. Of the peptides studied here, di-K19Hc retained invariably strong activity against all bacteria in diverse conditions and also showed much reduced hemolytic activity against human erythrocytes.
Cefotaxime Acts Synergistically with Levofloxacin in Experimental Meningitis Due to Penicillin-Resistant Pneumococci and Prevents Selection of Levofloxacin-Resistant Mutants In Vitro
Authors: Kühn F. , Cottagnoud M. , Acosta F. , Flatz L. , Entenza J. , Cottagnoud P.
Published: July 2003

Cefotaxime, given in two doses (each 100 mg/kg of body weight), produced a good bactericidal activity (−0.47 Δlog
10
CFU/ml · h) which was comparable to that of levofloxacin (−0.49 Δlog
10
CFU/ml · h) against a penicillin-resistant pneumococcal strain WB4 in experimental meningitis. Cefotaxime combined with levofloxacin acted synergistically (−1.04 Δlog
10
CFU/ml · h). Synergy between cefotaxime and levofloxacin was also demonstrated in vitro in time killing assays and with the checkerboard method for two penicillin-resistant strains (WB4 and KR4). Using in vitro cycling experiments, the addition of cefotaxime in sub-MIC concentrations (one-eighth of the MIC) drastically reduced levofloxacin-induced resistance in the same two strains (64-fold increase of the MIC of levofloxacin after 12 cycles versus 2-fold increase of the MIC of levofloxacin combined with cefotaxime). Mutations detected in the genes encoding topoisomerase IV (
parC
and
parE
) and gyrase (
gyrA
and
gyrB
) confirmed the levofloxacin-induced resistance in both strains. Addition of cefotaxime in low doses was able to suppress levofloxacin-induced resistance.
Risk Factors for New Detection of Vancomycin-Resistant Enterococci in Acute-Care Hospitals That Employ Strict Infection Control Procedures
Authors: Padiglione Alexander A. , Wolfe Rory , Grabsch Elizabeth A. , Olden Di , Pearson Stephen , Franklin Clare , Spelman Denis , Mayall Barrie , Johnson Paul D. R. , Grayson M. Lindsay
Published: July 2003

Accurate assessment of the risk factors for colonization with vancomycin-resistant enterococci (VRE) among high-risk patients is often confounded by nosocomial VRE transmission. We undertook a 15-month prospective cohort study of adults admitted to high-risk units (hematology, renal, transplant, and intensive care) in three teaching hospitals that used identical strict infection control and isolation procedures for VRE to minimize nosocomial spread. Rectal swab specimens for culture were regularly obtained, and the results were compared with patient demographic factors and antibiotic exposure data. Compliance with screening was defined as “optimal” (100% compliance) or “acceptable” (minor protocol violations were allowed, but a negative rectal swab specimen culture was required within 1 week of becoming colonized with VRE). Colonization with VRE was detected in 1.56% (66 of 4,215) of admissions (0.45% at admission and 0.83% after admission; the acquisition time was uncertain for 0.28%), representing 1.91% of patients. No patients developed infection with VRE. The subsequent rate of new acquisition of VRE was 1.4/1,000 patient days. Renal units had the highest rate (3.23/1,000 patient days; 95% confidence interval [CI], 1.54 to 6.77/1,000 patient days).
vanB Enterococcus faecium
was the most common species (71%), but other species included
vanB Enterococcus faecalis
(21%),
vanA E. faecium
(6%), and
vanA E. faecalis
(2%). The majority of isolates were nonclonal by pulsed-field gel electrophoresis analysis. Multivariate analysis of risk factors in patients with an acceptable screening suggested that being managed by a renal unit (hazard ratio [HR] compared to the results for patients managed in an intensive care unit, 4.6; 95% CI, 1.2 to 17.0 [
P
= 0.02]) and recent administration of either ticarcillin-clavulanic acid (HR, 3.6; 95% CI, 1.1 to 11.6 [
P
= 0.03]) or carbapenems (HR, 2.8; 95% CI, 1.0, 8.0 [
P
= 0.05]), but not vancomycin or broad-spectrum cephalosporins, were associated with acquisition of VRE. The relatively low rates of colonization with VRE, the polyclonal nature of most isolates, and the possible association with the use of broad-spectrum antibiotics are consistent with either the endogenous emergence of VRE or the amplification of previously undetectable colonization with VRE among high-risk patients managed under conditions in which the risk of nosocomial acquisition was minimized.
Selection of Resistant
Streptococcus pneumoniae
during Penicillin Treatment In Vitro and in Three Animal Models
Authors: Knudsen Jenny Dahl , Odenholt Inga , Erlendsdottir Helga , Gottfredsson Magnus , Cars Otto , Frimodt-Møller Niels , Espersen Frank , Kristinsson Karl G. , Gudmundsson Sigurdur
Published: July 2003

Pharmacokinetic (PK) and pharmacodynamic (PD) properties for the selection of resistant pneumococci were studied by using three strains of the same serotype (6B) for mixed-culture infection in time-kill experiments in vitro and in three different animal models, the mouse peritonitis, the mouse thigh, and the rabbit tissue cage models. Treatment regimens with penicillin were designed to give a wide range of T
>MIC
s, the amounts of time for which the drug concentrations in serum were above the MIC. The mixed culture of the three pneumococcal strains, 10
7
CFU of strain A (MIC of penicillin, 0.016 μg/ml; erythromycin resistant)/ml, 10
6
CFU of strain B (MIC of penicillin, 0.25 μg/ml)/ml, and 10
5
CFU of strain C (MIC of penicillin, 4 μg/ml)/ml, was used in the two mouse models, and a mixture of 10
5
CFU of strain A/ml, 10
4
CFU of strain B/ml, and 10
3
CFU of strain C/ml was used in the rabbit tissue cage model. During the different treatment regimens, the differences in numbers of CFU between treated and control animals were calculated to measure the efficacies of the regimens. Selective media with erythromycin or different penicillin concentrations were used to quantify the strains separately. The efficacies of penicillin in vitro were similar when individual strains or mixed cultures were studied. The eradication of the bacteria, independent of the susceptibility of the strain or strains or the presence of the strains in a mixture or on their own, followed the well-known PK and PD rules for treatment with β-lactams: a maximum efficacy was seen when the T
>MIC
was >40 to 50% of the observation time and the ratio of the maximum concentration of the drug in serum to the MIC was >10. It was possible in all three models to select for the less-susceptible strains by using insufficient treatments. In the rabbit tissue cage model, a regrowth of pneumococci was observed; in the mouse thigh model, the ratio between the different strains changed in favor of the less-susceptible strains; and in the mouse peritonitis model, the susceptible strain disappeared and was overgrown by the less-susceptible strains. These findings with the experimental infection models confirm the importance of eradicating all the bacteria taking part in the infectious process in order to avoid selection of resistant clones.
In Vivo Antibacterial Activity of S-3578, a New Broad-Spectrum Cephalosporin: Methicillin-Resistant
Staphylococcus aureus
and
Pseudomonas aeruginosa
Experimental Infection Models
Authors: Tsuji Masakatsu , Takema Morio , Miwa Hideaki , Shimada Jingoro , Kuwahara Shogo
Published: July 2003

The in vivo antibacterial activity of S-3578, a new parental cephalosporin, was compared with those of cefepime, ceftriaxone, ceftazidime, imipenem-cilastatin, and vancomycin. The efficacy of S-3578 against systemic infections caused by methicillin-resistant
Staphylococcus aureus
(MRSA) SR3637 (50% effective dose [ED
50
], 7.21 mg/kg of body weight) was almost the same as that of vancomycin. In contrast, cefepime and imipenem-cilastatin were less active against this pathogen (ED
50
s, >100 and >100 mg/kg, respectively). S-3578 was the most effective compound against penicillin-resistant
Streptococcus pneumoniae
SR20946 (ED
50
, 1.98 mg/kg). S-3578 (10 mg/kg) induced a significant reduction in the numbers of viable MRSA SR17764 and
Pseudomonas aeruginosa
SR10396 organisms in polymicrobial pulmonary infections. The therapeutic efficacy of S-3578 was more potent than that of the combination of vancomycin and ceftazidime. High levels of S-3578 were detected in plasma in vivo, and its efficacy against experimentally induced infections in mice caused by MRSA and
P. aeruginosa
reflected its potent in vitro activity. We conclude that S-3578 is a promising new cephalosporin for the treatment of infections caused by gram-positive and -negative bacteria, including MRSA and
P. aeruginosa.
Immunoenhancement Combined with Amphotericin B as Treatment for Experimental Visceral Leishmaniasis
Authors: Murray Henry W. , Brooks Elaine B. , DeVecchio Jennifer L. , Heinzel Frederick P.
Published: July 2003

To determine if stimulation of Th1-cell-associated immune responses, mediated by interleukin 12 (IL-12) and gamma interferon (IFN-γ), enhance the antileishmanial effect of amphotericin B (AMB),Leishmania donovani-infected BALB/c mice were first treated with (i) exogenous IL-12 to induce IFN-γ, (ii) agonist anti-CD40 monoclonal antibody (MAb) to maintain IL-12 and induce IFN-γ, or (iii) anti-IL-10 receptor (IL-10R) MAb to blockade suppression of IL-12 and IFN-γ. In animals with established visceral infection, low-dose AMB alone (two injections of 1 mg/kg of body weight; total dose, 2 mg/kg) killed 15 to 29% of liver parasites; by themselves, the immunointerventions induced 16 to 33% killing. When the interventions were combined, the leishmanicidal activities increased 3.4-fold (anti-CD40), 6.3-fold (anti-IL-10R), and 9-fold (IL-12) compared with the activities of AMB plus the control preparations; and overall killing (76 to 84%) approximated the 84 to 92% killing effect of 7.5-fold more AMB alone (three injections of 5 mg/kg; total dose, 15 mg/kg). These results suggest that strengthening the host Th1-cell response may be a strategy for the development of AMB-sparing regimens in visceral leishmaniasis.