bluuebunny/crossref_metadata_2025 huggingface dataset:
Field emission from carbide film cathodes
Authors: Mackie W. A. , Xie Tianbao , Davis P. R.
Published: July 2002

We report here on experiments with the deposition of ZrC onto individual prefabricated W and Mo emitters and on field emission arrays using Mo and Si emitters. With observed field emission current densities greater than 1×108 A/cm2 and work functions approximately 1 eV lower than Mo or W, carbides make good candidates for low voltage microelectronic field emitter arrays. In addition, evaporation of ZrC films onto Mo and W single field emitter cathodes improves their emission stability and greatly improves beam confinement. Mo and W field emitters were individually fabricated and an appropriate quantity of ZrC was evaporated onto the emitter surface from a high-purity ZrC evaporation source. Several emitters prepared by this method have been tested. The uniformity of the emission pattern was checked by in situ field emission microscopy, both before and after carbide deposition, in order to verify that the surface of the emitter had been cleaned and smoothed. The deposited film was subjected to a variety of heating treatments, each of which was followed by examination of the emission pattern and determination of I–V characteristics. The results of these experiments indicate that work function reductions of the order of 1 eV can be achieved by the deposition of ZrC films onto W or Mo field emitters. The observed emission patterns indicate that the lowest film work functions occur on and around the (100) planes of the underlying Mo or W emitter. Beam confinement is therefore possible with carbide film deposition on Mo or W field emission cathodes. We also report on experiments with ZrC film deposition onto field emitter arrays with Mo and Si emitters. In the case of ZrC on a Spindt array of Mo cathodes we observed a decrease of operating voltage from 122 to 68 V for 100 μA emission current following ZrC deposition. The ratio of the Fowler–Nordheim slope for the ZrC layer to that for the cathode before deposition was approximately 0.68. These results seem consistent and very promising for the use of ZrC film on field emitters and field emitter arrays.
Characterization of exfoliated TaS2 thin films and the existence of charge density waves
Authors: Manivannan A. , Cabrera C. R. , Fujishima A.
Published: July 2002

Restacked single molecular layers of the layer compound TaS2 from suspensions was deposited on titanium substrates by using a lithium intercalation–exfoliation method. These exfoliated thin films on titanium substrates have been characterized by scanning electron microscopy and Raman spectroscopy, and x-ray diffraction techniques are also investigated for the existence of charge density wave (CDW) phases using scanning tunneling microscopy (STM). All these techniques revealed that TaS2 crystallites tend to orient mostly with their basal planes parallel to the titanium substrate. TaS2 thin films are chosen with the understanding that the CDW states could mostly be determined because of intralayer interactions in comparison to bulk single crystals where inter- and intralayer interactions are considered. STM images showed strong CDWs with a hexagonal array having periodicity of ∼12 Å and ‘‘corrugations’’ of ∼1.5 Å, respectively. The existence of a CDW superlattice, together with the surface atomic structure observed at room temperature, on these thin films (thickness, ca. 300 Å) of single layers, allows us to understand the intralayer effects on the CDWs. The existence of CDWs in these films was not observed by transmission electron microscopy even at 25 K.
Proximity correction algorithms and a co-processor based on regularized optimization. I. Description of the algorithm
Authors: Peckerar M. C. , Chang S. , Marrian C. R. K.
Published: July 2002

This is the first of a series of articles aimed at laying the foundations for construction of special purpose computing machinery for solving the proximity effect problem. In this article, we compare three different types of proximity correction approach (basic matrix inversion, gradient descent optimization, and optimization using a Shannon entropy regularizer). We show that entropy regularization does not result in physically unrealizable negative dose requests as does the matrix inversion and related methods, and always provides optimizations closer to target than those derived from ‘‘least-mean-square’’ type gradient descent. The implications of this approach for integrated co-processor design are outlined.
Direct observation of fullerene-adsorbed tips by scanning tunneling microscopy
Authors: Kelly K. F. , Sarkar Dipankar , Prato Stefano , Resh J. S. , Hale G. D. , Halas N. J.
Published: July 2002

We have succeeded in imaging individual C60 molecules that have been adsorbed onto the tunneling region of a scanning tunneling microscopy tip. The individual tip-adsorbed molecules are imaged by scanning the fullerene-adsorbed tip over a defect covered graphite surface. The defects are generated by low energy argon ion bombardment and protrude from the graphite surface. These nanometer-size defects serve as a surface tip array which inverse images the molecules adsorbed to the tip when the surface is scanned.
Application of scanning tunneling microscopy to determine the exact charge states of surface point defects
Authors: Chao K.-J. , Smith A. R. , Shih C. K.
Published: July 2002

We demonstrate a method for determining the charge state of surface arsenic vacancies on p-type GaAs(110) by using scanning tunneling microscopy. The method is based on the compensation between hole depletion at isolated arsenic vacancies and hole accumulation at ionized dopant atoms whose charge states are known a priori. Detailed analysis shows a one-to-one compensation between the charged vacancies and the ionized dopants, indicating the isolated arsenic vacancy charge of +1. This method can be extended to determine quantitative charge states of other point defects (positive or negative).
Chemical vapor deposition of TiSi2 using an industrial integrated cluster tool
Authors: Maury D. , Rostoll M. L. , Gayet P. , Regolini J. L.
Published: July 2002

Selective chemical vapor deposition of TiSi2 for contacts and interconnects in 0.25 μm and below design rule devices has been performed from TiCl4/DCS/H2 chemistry using an industrial integrated cluster tool. Selectivity on oxide and nitride and a resistivity of around 16 μ cm have been obtained. The growth rates obtained on doped/undoped, poly/mono Si are almost identical. The grain size on poly Si is around 0.10 μm. Loading effect has been observed and corrected by the gas mixture. This chemical vapor deposition (CVD) technique has thus been used in a 0.25 μm complementary metal–oxide–semiconductor technology and the results are compared with the standard salicide (solid phase reaction) and elevated source/drain/gate (with selective epitaxy) followed by the salicide. The results show that CVD is a most promising process for the 0.2 μm technology with higher values for the transistor saturation current.
Experimental evidence of two-dimensional–three-dimensional transition in the Stranski–Krastanow coherent growth
Authors: Berti M. , Drigo A. V. , Rossetto G. , Torzo G.
Published: July 2002

The two-dimensional (2D)–three-dimensional (3D) transition has been studied for InAs and InP layers grown on (001) GaAs substrates by metalorganic vapor pressure epitaxy at different growth temperatures and growth rates. The combined use of scanning force microscopy and of Rutherford backscattering spectrometry allowed the determination of the surface morphology of the samples and of their equivalent layer thickness with a precision better than 0.1 monolayers (ML). The critical thickness for the 2D–3D transition has been found to occur after a deposition of (1.2±0.1) ML for InAs/GaAs and after a deposition of (2.2±0.2) ML for InP/GaAs, independently of the temperature and of the growth rate. For coverages slightly exceeding 1 ML, for InAs, and 2 ML, for InP, the surface of the samples appears partially covered by small bi-dimensional structures (platelets). The dimensions of the platelets appear to be independent of the system under study and consequently of the misfit. Moreover, their distribution on the surface appears to be strongly different from that of the islands after the 3D transition so that they cannot strictly be viewed as island precursors, as previously suggested.
Influence of silicon tip arrays on effective work function of diamond
Authors: Yuan G. , Jin C. C. , Zhang B. L. , Jiang H. , Zhou T. M. , Ning Y. Q. , Wang Y. Z. , Wang W. B. , Jin Y. X. , Ji H. , Gu C. Z.
Published: July 2002

The diamond films were deposited on silicon tip arrays by the microwave plasma chemical vapor deposition technique. The field emission property of diamond films deposited on tips (D tips) was compared with that of diamond on silicon wafers (D wafer). It shows that the effective work function becomes large at the high electrical field for the D tip sample, and that can be explained as an effect of the diamond films being in a breakdown state.
Parameters for improving reliability of full color field emission display devices
Authors: Kim J. M. , Hong J. P. , Choi J. H. , Ryu Y. S. , Hong S. S.
Published: July 2002

Field emission display devices of 100 mm×100 mm×2.4 mm in size are fully developed with the 80 cd/m2 of brightness. Full color real images are characterized by using structural analysis and electron trajectory profiles. No cross talk between pixels is confirmed by a simulation and a process integration. As a reliable process integration, phosphor screening integration of full color phosphors and conditions of high vacuum packaging are extensively investigated as a basis of mass production. In addition, the electrical reliability with a phosphor effect due to an electron excitation is studied with a lifetime test at various condition. Especially, the stability inside narrow vacuum space between anode and cathode plates is fully demonstrated with various process control parameters.
Novel approach to atomic force lithography
Authors: Hu S. , Altmeyer S. , Hamidi A. , Spangenberg B. , Kurz H.
Published: July 2002

A two-layer resist system consisting of 3 nm titanium and 65 nm polymethylmethacrylate (PMMA) has been developed to expand the potential of mechanical atomic force microscope nanolithography. Approximately 20 nm wide structures have been grooved in an ultrathin Ti film. The realized Ti patterns were transferred into the PMMA bottom layer by an reactive ion etching (RIE) process in oxygen. Finally, 30 nm wide and 45 nm deep grooves, and arrays of holes with a period of 55 nm, which are 20–30 nm in diameter and 45 nm in depth, have been fabricated in silicon by a second RIE step in a SF6+O2 gas mixture.
Resist design for resolution limit of KrF imaging towards 130 nm lithography
Authors: Azuma T. , Kawamura D. , Matsunaga K. , Shiobara E. , Tanaka S. , Onishi Y.
Published: July 2002

A strategy of resist design for the resolution limit of KrF imaging is investigated, and then the possibility of 130 nm lithography using KrF imaging is discussed. An extremely thin resist in a thickness of less than 150 nm was developed for KrF imaging at the resolution limit. The resist could overcome crucial problems of nanoedge roughness as well as degraded resist profiles without sacrificing resolution capability even when reducing the resist thickness to extreme limits. Moreover, a resist thickness of 80 nm could narrowly perform 130 nm lithography using an unconventional KrF imaging system featuring a numerical aperture of 0.6 and a partial coherency of 0.75 with 2/3 annular aperture, without using any phase shift mask technologies.
Electron beam lithography process for advanced optical masks
Authors: Hayashi Naoya , Kurihara Masa-aki , Segawa Toshikazu , Yokoyama Toshifumi , Abe Tsukasa
Published: July 2002

The requirements for advanced optical masks have been tightened according to the accelerated lithography roadmap for semiconductor manufacturing. The accuracy of the optical mask may be affected by the pattern exposure tools, the materials, and the processes. Higher acceleration voltage e-beam pattern exposure was evaluated with a chemically amplified resist. With the higher acceleration voltage e-beam system, proximity effect correction is needed to control the critical dimension (CD). CD linearity is maintained down to 400 nm for different kinds of patterns by adopting the 50 kV e-beam system and proximity effect correction. The results show that the method is an attractive candidate for fabrication of next generation optical masks. Dry etching is effective in achieving small feature sizes, such as optical proximity correction (OPC), with high pattern fidelity. Loading effects were evaluated, and inductively coupled plasma dry etching was found to be stable against those effects. Fabrication of the OPC pattern designed for a 0.15 μm rule device was demonstrated with these methods.
Surface enhancement by shallow carbon implantation for improved adhesion of diamond-like coatings
Authors: Malaczynski Gerard W. , Elmoursi Alaa A. , Leung Chi H. , Hamdi Aboud H. , Campbell Albert B.
Published: July 2002

A surface layer of metal carbides provides an excellent interface to achieve a highly adherent diamond-like carbon (DLC) coating. A plasma immersion ion implantation based procedure is described which delivers a high retained dose of implanted carbon at the surface of aluminum alloys. This proposed implantation procedure employs a low target bias of only 10–12 kV, a pulse repetition rate of around 5 kHz, and a duty cycle of 25%. The resultant shallow implantation profile, followed by an argon sputter cleaning, is continued until a saturated carbon matrix is brought to the surface providing an excellent interface for subsequent growth of DLC. At a carbon retained dose above 1018 atoms/cm2, the DLC adhesion exceeds the coating’s cohesion strength. Regardless of the silicon content in the aluminum, the coating produced by this method required tensile strengths typically exceeding 150 MPa to separate an epoxy coated stud from the coating in a standard pull test. Improved DLC adhesion was also observed on chromium and titanium. The reported tensile strength is believed to meet the majority of industrial applications.
In situ reflectance difference spectroscopy of II–VI compounds: A real time study of N plasma doping during molecular beam epitaxy
Authors: Stifter D. , Schmid M. , Hingerl K. , Bonanni A. , Garcia-Rocha M. , Sitter H.
Published: July 2002

Reflectance difference spectroscopy (RDS) has been performed during the growth and nitrogen-doping process of II–VI layers fabricated by molecular beam epitaxy (MBE). To the MBE chamber, equipped with an electron cyclotron resonance cell for N plasma generation, a RDS system has been attached via a normal incidence viewport which allows the acquisition of spectra during the doping process in the spectral range from 1.5 to 5.5 eV. ZnTe (001) surfaces have been studied under varying exposure conditions, like Zn, Te, and/or N plasma flux onto the sample surface. Furthermore, RDS features in the vicinity of the E1 and E1+Δ1 transitions were used to optimize online the doping performance of the N plasma cell by varying the source parameters, like N pressure and input power. Doping induced surface processes and surface saturation with activated N species have been investigated. Ex situ measured spectra are compared with in situ acquired data to study the surface Fermi level pinning occurring at ambient pressures. Finally, in situ acquired RDS data of δ-doped ZnSe are presented.
CTCF, a Candidate
Trans
-Acting Factor for X-Inactivation Choice
Authors: Chao Wendy , Huynh Khanh D. , Spencer Rebecca J. , Davidow Lance S. , Lee Jeannie T.
Published: July 2002

In mammals, X-inactivation silences one of two female X chromosomes. Silencing depends on the noncoding gene,
Xist
(
i
nactive
X
-
s
pecific
t
ranscript), and is blocked by the antisense gene,
Tsix
. Deleting the choice/imprinting center in
Tsix
affects X-chromosome selection. Here, we identify the insulator and transcription factor, CTCF, as a candidate
trans
-acting factor for X-chromosome selection. The choice/imprinting center contains tandem CTCF binding sites that function in an enhancer-blocking assay. In vitro binding is reduced by CpG methylation and abolished by including non-CpG methylation. We postulate that
Tsix
and CTCF together establish a regulatable epigenetic switch for X-inactivation.
Experimental Detection of Tetranitrogen
Authors: Cacace F. , de Petris G. , Troiani A.
Published: July 2002

Tetranitrogen (N
4
), which has been the subject of great theoretical interest, has been prepared from the N
4
+
cation and positively detected as a gaseous metastable molecule with a lifetime exceeding 1 microsecond in experiments based on neutralization-reionization mass spectrometry. An examination of the geometry of N
4
+
and the fragmentation pattern of the
14
N
2
15
N
2
neutral molecule has revealed that the latter is characterized by an open-chain geometry with two distinct, closely bound N
2
units joined by a longer weaker bond.
Ending Polio Immunization
Authors: Hull Harry F. , Aylward R. Bruce
Published: July 2002

The World Health (WHO) has implemented a plan to eradicate poliovirus that is widely viewed as having made enormous progress. If all goes as planned, polio will be eradicated on this planet by the year 2003. However, there is a debate, as highlighted in a pair of Policy Forums in this issue, over when vaccination against polio can be stopped. Dove and Racaniello believe that the reliance of the WHO on the live Sabin oral polio virus vaccine (OPV) means that there will be a continuing threat of release of potentially pathogenic virus into the environment. They are also concerned that the planned destruction of all wild-type polio stocks will not be possible. They recommend a switch to the inactivated polio vaccine. In response, Hull and Aylward set out the reasons for thinking that a switch from the OPV is not necessary and describe the studies being sponsored by the WHO to determine how and when immunization can safely be ended.
A Rare-Earth Phosphor Containing One-Dimensional Chains Identified Through Combinatorial Methods
Authors: Danielson Earl , Devenney Martin , Giaquinta Daniel M. , Golden Josh H. , Haushalter Robert C. , McFarland Eric W. , Poojary Damodara M. , Reaves Casper M. , Weinberg W. Henry , Wu Xin Di
Published: July 2002

An unusual luminescent inorganic oxide, Sr
2
CeO
4
, was identified by parallel screening techniques from within a combinatorial library of more than 25,000 members prepared by automated thin-film synthesis. A bulk sample of single-phase Sr
2
CeO
4
was prepared, and its structure, determined from powder x-ray diffraction data, reveals one-dimensional chains of edge-sharing CeO
6
octahedra, with two terminal oxygen atoms per cerium center, that are isolated from one another by Sr
2+
cations. The emission maximum at 485 nanometers appears blue-white and has a quantum yield of 0.48 ± 0.02. The excited-state lifetime, electron spin resonance, magnetic susceptibility, and structural data all suggest that luminescence originates from a ligand-to-metal Ce
4+
charge transfer.
Lateral Variations in Compressional/Shear Velocities at the Base of the Mantle
Authors: Wysession Michael E. , Langenhorst Amy , Fouch Matthew J. , Fischer Karen M. , Al-Eqabi Ghassan I. , Shore Patrick J. , Clarke Timothy J.
Published: July 2002

Observations of core-diffracted
P
(
P
diff
) and
SH
(
SH
diff
) waves recorded by the Missouri-to-Massachusetts (MOMA) seismic array show that the ratio of compressional (
P
) seismic velocities to horizontal shear (
SH
) velocities at the base of the mantle changes abruptly from beneath the mid-Pacific (

V
P

/

V
S

= 1.88, also the value predicted by reference Earth models) to beneath Alaska (

V
P

/

V
S

= 1.83). This change signifies a sudden lateral variation in material properties that may have a mineralogical or textural origin. A textural change could be a result of shear stresses induced during the arrival at the core of ancient lithosphere from the northern Pacific paleotrench.
Identification of Synergistic Signals Initiating Inner Ear Development
Authors: Ladher Raj K. , Anakwe Kelly U. , Gurney Austin L. , Schoenwolf Gary C. , Francis-West Philippa H.
Published: July 2002

Tissue manipulation experiments in amphibians more than 50 years ago showed that induction of the inner ear requires two signals: a mesodermal signal followed by a neural signal. However, the molecules mediating this process have remained elusive. We present evidence for mesodermal initiation of otic development in higher vertebrates and show that the mesoderm can direct terminal differentiation of the inner ear in rostral ectoderm. Furthermore, we demonstrate the synergistic interactions of the extracellular polypeptide ligands FGF-19 and Wnt-8c as mediators of mesodermal and neural signals, respectively, initiating inner ear development.
Activities of LY333328 and Vancomycin Administered Alone or in Combination with Gentamicin against Three Strains of Vancomycin-Intermediate
Staphylococcus aureus
in an In Vitro Pharmacodynamic Infection Model
Authors: Aeschlimann Jeffrey R. , Allen George P. , Hershberger Ellie , Rybak Michael J.
Published: July 2002

Staphylococcus aureus
with intermediate glycopeptide susceptibility (glycopeptide-intermediate
S. aureus
[GISA]) has been isolated from patients with apparent therapy failures. We studied the killing activity of vancomycin over a range of simulated conventional doses (1 to 1.5 g every 12 h) against three of these GISA strains in an in vitro pharmacodynamic infection model. We also studied the activity of a new glycopeptide (LY333328) at a simulated dose of 3 mg/kg of body weight every 24 h or 5 mg/kg every 24 h, as well as the potential for vancomycin and gentamicin synergy against these GISA strains. Four doses of vancomycin with or without gentamicin or two doses of LY333328 were administered over the 48-h study period. The vancomycin and LY333328 MICs and minimal bactericidal concentrations (MBCs) for the three GISA strains (strains 14379, 992, and Mu50) were 8 and 8 μg/ml and 1 and 2 μg/ml, respectively, for GISA 14379, 6 and 6 μg/ml and 1 and 1 μg/ml, respectively, for GISA 992, and 8 and 12 μg/ml and 2 and 8 μg/ml, respectively, for GISA Mu50. Vancomycin and LY333328 MICs and MBCs were 0.75 and 1.0 μg/ml and 1 and 1 μg/ml, respectively for a vancomycin-susceptible comparator strain (methicillin-resistant
S. aureus
[MRSA] 494). The addition of albumin to the growth medium increased the LY333328 MICs and MBCs approximately 8- to 16-fold. Vancomycin was bacteriostatic against the three GISA strains at doses of 1, 1.125, and 1.25 g every 12 h. Vancomycin was bactericidal at the dose of 1.5 g every 12 h against all strains; bactericidal activity occurred against the GISA strains at 8- to 10-fold lower ratios of the peak concentration to the MIC and the area under the concentration-time curve from time zero to 24 h (AUC
0–24
) to the MIC compared to those for the vancomycin-sensitive control strain. Overall, vancomycin activity was significantly correlated with the AUC
0–24
(
R
2
= 0.79;
P
< 0.001) by multiple stepwise regression analyses. The addition of gentamicin did not significantly affect killing activity against any strain. LY333328 was bactericidal against GISA strains 14379 and 992 and against MRSA 494 only with the 5-mg/kg/day dose simulations. The higher dose of LY333328 also prevented regrowth over the 48-h experiments for all strains tested. Higher doses of vancomycin (1.5 g every 12 h) and LY333328 (5 mg/kg every 24 h) may represent potential treatment options for infections caused by GISA strains.
Absolute Bioavailability and Disposition of (−) and (+) 2′-Deoxy- 3′-Oxa-4′-Thiocytidine (dOTC) following Single Intravenous and Oral Doses of Racemic dOTC in Humans
Authors: Smith Patrick F. , Forrest Alan , Ballow Charles H. , Martin David E. , Proulx Louise
Published: July 2002

The purpose of this study was to characterize the pharmacokinetics and determine the absolute bioavailability of 2′-deoxy-3′-oxa-4′-thiocytidine (dOTC) (BCH-10652), a novel nucleoside analogue reverse transcriptase inhibitor, in humans. dOTC belongs to the 4′-thio heterosubstituted class of compounds and is a 1:1 mixture of its two enantiomers, (−) and (+) dOTC. Twelve healthy adult male volunteers each received oral (800-mg) and intravenous (100-mg) doses of dOTC in two study periods separated by at least 7 days. Sixteen plasma samples were obtained over 72 h and assayed for (−) and (+) dOTC, and the resultant data fit by candidate pharmacokinetic models. Data were weighted by the fitted inverse of the observation variance; model discrimination was by AIC. The pharmacokinetic model was a linear, three compartment model, with absorption occurring during one to three first-order input phases, each following a fitted lag time. The model goodness-of-fit was excellent;
r
2
ranged from 0.995 to 1.0. The mean absolute bioavailabilities of (+) and (−) dOTC were 77.2% (coefficient of variation [given as a percentage] [CV%], 14) and 80.7% (CV%, 15), respectively. The median steady-state volume of distribution for (+) dOTC, 74.7 (CV%, 19.2) liters/65 kg, was greater than that for (−) dOTC, 51.7 (CV%, 16.7) liters/65 kg (
P
< 0.05). The median total clearance of (+) dOTC was less than that of (−) dOTC, 11.7 (CV%, 17.3) versus 15.4 (CV%, 18.6) liters/h/65 kg, respectively (
P
< 0.05). The intersubject variability of these parameters was very low. The median terminal half-life of (+) dOTC was 18.0 (CV%, 31.5) h, significantly longer than the 6.8 (CV%, 69.9) h observed for (−) dOTC (
P
< 0.01). No serious adverse events were reported during the study. These results suggest that dOTC is well absorbed, widely distributed, and well tolerated. The terminal half-lives indicate that dosing intervals of 12 to 24 h would be reasonable.
Monotherapy with a Broad-Spectrum Beta-Lactam Is as Effective as Its Combination with an Aminoglycoside in Treatment of Severe Generalized Peritonitis: a Multicenter Randomized Controlled Trial
Authors: Dupont H. , Carbon C. , Carlet J.
Published: July 2002

In a randomized trial conducted in 35 centers, we compared the clinical efficacy and safety of piperacillin plus tazobactam (TAZ) alone (monotherapy [MT]) versus those of TAZ combined with amikacin (AMK) (combined therapy [CT]) for the treatment of severe generalized peritonitis (SGP). Primary analysis consisted of blind assessment by an independent committee of the failure rate 30 days after the end of treatment in the modified intent-to-treat (ITT) analysis (mITT) population. Of the 241 patients with suspected SGP randomized into the study, 227 were eligible for ITT analysis, including 204 (99 in the MT group and 105 in the CT group) with confirmed SGP (mITT population). A total of 159 patients were eligible for per-protocol (PP) analysis. The clinical failure rates were equivalent in the mITT and PP populations (MT versus CT): 56 versus 52%, (odds ratio [OR] 0.87, 90% confidence interval [CI] = 0.6 to 1.27) for mITT and 49 versus 49% (OR = 1.03, 90% CI = 0.67 to 1.59) for PP analysis. Mortality rates (ITT population, 19%; PP population, 21%) and overall adverse event rates (ITT population, 55%; PP population, 54%) were also similar. Six patients (three in MT group and three in the CT group) developed acute renal failure. In conclusion, the addition of AMK to TAZ does not seem to be necessary for the treatment of SGP, even after adjustment for the simplified acute physiology score (SAPS II) and type of SGP.
Antimycobacterial Activities of Novel Levofloxacin Analogues
Authors: Kawakami Katsuhiro , Namba Kenji , Tanaka Mayumi , Matsuhashi Norikazu , Sato Kenichi , Takemura Makoto
Published: July 2002

In order to investigate structure-activity relationships between antimycobacterial activities and basic substituents at the C-10 position of levofloxacin (LVFX), we synthesized a series of pyridobenzoxazine derivatives by replacement of the
N
-methylpiperazinyl group of LVFX with various basic substituents. A compound with a 3-aminopyrrolidinyl group had one-half the activity of LVFX against
Mycobacterium avium
,
M. intracellulare
, and
M. tuberculosis
. Mono- and dimethylation of the 3-amino moiety of the pyrrolidinyl group increased the activities against
M. avium
and
M. intracellulare
but not those against
M. tuberculosis
. On the other hand, dialkylation at the C-4 position of the 3-aminopyrrolidinyl group enhanced the activities against
M. avium
,
M. intracellulare
, and
M. tuberculosis
. Thus, introduction of an
N
-alkyl or a
C
-alkyl group(s) into the 3-aminopyrrolidinyl group may contribute to an increase in potency against
M. avium
,
M. intracellulare
, and/or
M. tuberculosis
, probably through elevation of the lipophilicity. However, among the compounds synthesized, compound VII, which was a 2,8-diazabicyclo[4.3.0]nonanyl derivative with relatively low lipophilicity, showed the most potent activity against mycobacterial species: the activity was 4- to 32-fold more potent than that of LVFX and two to four times as potent as that of gatifloxacin. These results suggested that an increase in the lipophilicity of LVFX analogues in part contributed to enhancement of antimycobacterial activities but that lipophilicity of the compound was not a critical factor affecting the potency.
Pharmacokinetics-Pharmacodynamics of a Sordarin Derivative (GM 237354) in a Murine Model of Lethal Candidiasis
Authors: Aviles P. , Falcoz C. , San Roman R. , Gargallo-Viola D.
Published: July 2002

Sordarins are a new class of antifungal agents which selectively inhibit fungal protein synthesis (FPS) by impairing the function of elongation factor 2. The present study investigates possible correlations between sordarin pharmacokinetic (PK) properties and therapeutic efficacy, based on a murine model of invasive systemic candidiasis, and provides a rationale for dose selection in the first study of efficacy in humans. A significant correlation between PK parameters and the in vivo activity of GM 237354, taken as a representative FPS inhibitor, was demonstrated in a murine model of lethal systemic candidiasis. Area under the concentration-time curve (AUC) and maximum concentration of drug in serum (
C
max
) over 24 h were determined after a single GM 237354 subcutaneous (s.c.) dose (50 mg/kg of body weight) in healthy animals (no significant PK changes with infection were observed for other sordarin derivatives). These results have been used to simulate PK profiles obtained after several doses and/or schedules in animal therapy. A PK-pharmacodynamic (PD) parameter such as the time that serum drug concentrations remain above the MIC (
t
> MIC) was also determined. Treatment efficacies were evaluated in terms of the area under the survival time curve (AUSTC), using Kaplan-Meier survival analysis and in terms of kidney fungal burden (log CFU/gram) after s.c. doses of 2.5, 5, 10, 20, and 40 mg/kg every 4, 8, or 12 h (corresponding to total daily doses of 5 to 240 mg/kg). The results show all treatments to significantly prolong survival versus that of infected and nontreated controls (
P
< 0.05). Relationships between simulated PK and PK-PD parameters and efficacy were explored. A good correlation independent of the dosing interval was observed with AUC (but not
C
max
or
t
> MIC) and both AUSTC and kidney burden. Following repeated dosing every 8 h, AUC
50
(AUC at which 50% of the maximum therapeutic efficacy is obtained) was estimated as 21.7 and 37.1 μg · h/ml (total concentrations) for AUSTC and kidney burden using a sigmoid
E
max
and an inhibitory sigmoid
E
max
PK-PD model, respectively. For an efficacy target of 90% survival, AUC was predicted as 67 μg · h/ml. We conclude that the PK-PD approach is useful for evaluating relationships between PK parameters and efficacy in antifungal research. Moreover, the results obtained with this approach could be successfully applied to clinical studies.
In Vitro Activities of Six Fluoroquinolones against 250 Clinical Isolates of
Mycobacterium tuberculosis
Susceptible or Resistant to First-Line Antituberculosis Drugs
Authors: Ruiz-Serrano María Jesús , Alcalá Luis , Martínez Lucía , Díaz Marisol , Marín Mercedes , González-Abad María José , Bouza Emilio
Published: July 2002

Two hundred fifty isolates of
Mycobacterium tuberculosis
were evaluated for susceptibility to ciprofloxacin, ofloxacin, levofloxacin, grepafloxacin, trovafloxacin, and gemifloxacin (SB-265805). Levofloxacin, ciprofloxacin, and grepafloxacin showed the greatest activity (MIC for 90% of strains tested [MIC
90
] 1 μg/ml), although ofloxacin also showed good activity, with an MIC
90
of 2 μg/ml. Trovafloxacin and gemifloxacin showed lower in vitro activity, with MIC
90
s of 64 and 8 μg/ml, respectively.
Inhibitory Effects of Plant Polyphenoloxidase on Colonization Factors of
Streptococcus sobrinus
6715
Authors: Cowan M. M. , Horst E. A. , Luengpailin S. , Doyle R. J.
Published: July 2002

Exogenously added polyphenoloxidase (EC
1.14.18.1
), an enzyme which oxidizes tyrosine residues and is commonly found in many dietary components, abolished the aggregation of
Streptococcus sobrinus
6715 by high-molecular-weight dextran. The enzyme decreased glucan-binding lectin and/or glucosyltransferase I activities.
Development and Validation of Limited-Sampling Strategies for Predicting Amoxicillin Pharmacokinetic and Pharmacodynamic Parameters
Authors: Suarez-Kurtz Guilherme , Ribeiro Frederico Mota , Vicente Flávio L. , Struchiner Claudio J.
Published: July 2002

Amoxicillin plasma concentrations (
n
= 1,152) obtained from 48 healthy subjects in two bioequivalence studies were used to develop limited-sampling strategy (LSS) models for estimating the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (
C
max
), and the time interval of concentration above MIC susceptibility breakpoints in plasma (T>MIC). Each subject received 500-mg amoxicillin, as reference and test capsules or suspensions, and plasma concentrations were measured by a validated microbiological assay. Linear regression analysis and a “jack-knife” procedure revealed that three-point LSS models accurately estimated (
R
2
, 0.92; precision, <5.8%) the AUC from 0 h to infinity (AUC
0-∞
) of amoxicillin for the four formulations tested. Validation tests indicated that a three-point LSS model (1, 2, and 5 h) developed for the reference capsule formulation predicts the following accurately (
R
2
, 0.94 to 0.99): (i) the individual AUC
0-∞
for the test capsule formulation in the same subjects, (ii) the individual AUC
0-∞
for both reference and test suspensions in 24 other subjects, and (iii) the average AUC
0-∞
following single oral doses (250 to 1,000 mg) of various amoxicillin formulations in 11 previously published studies. A linear regression equation was derived, using the same sampling time points of the LSS model for the AUC
0-∞
, but using different coefficients and intercept, for estimating
C
max
. Bioequivalence assessments based on LSS-derived AUC
0-∞
's and
C
max
's provided results similar to those obtained using the original values for these parameters. Finally, two-point LSS models (
R
2
= 0.86 to 0.95) were developed for T>MICs of 0.25 or 2.0 μg/ml, which are representative of microorganisms susceptible and resistant to amoxicillin.
Identification and Characterization of New Inhibitors of the
Escherichia coli
MurA Enzyme
Authors: Baum Ellen Z. , Montenegro Deborah A. , Licata Lisa , Turchi Ignatius , Webb Glenda C. , Foleno Barbara D. , Bush Karen
Published: July 2002

The bacterial enzyme MurA catalyzes the transfer of enolpyruvate from phosphoenolpyruvate (PEP) to uridine diphospho-
N
-acetylglucosamine (UNAG), which is the first committed step of bacterial cell wall biosynthesis. From high-throughput screening of a chemical library, three novel inhibitors of the
Escherichia coli
MurA enzyme were identified: the cyclic disulfide RWJ-3981, the purine analog RWJ-140998, and the pyrazolopyrimidine RWJ-110192. When MurA was preincubated with inhibitor, followed by addition of UNAG and PEP, the 50% inhibitory concentrations (IC
50
s) were 0.2 to 0.9 μM, compared to 8.8 μM for the known MurA inhibitor, fosfomycin. The three compounds exhibited MICs of 4 to 32 μg/ml against
Staphylococcus aureus
; however, the inhibition of DNA, RNA, and protein synthesis in addition to peptidoglycan synthesis by all three inhibitors indicated that antibacterial activity was not due specifically to MurA inhibition. The presence of UNAG during the MurA and inhibitor preincubation lowered the IC
50
at least fivefold, suggesting that, like fosfomycin, the three compounds may interact with the enzyme in a specific fashion that is enhanced by UNAG. Ultrafiltration and mass spectrometry experiments suggested that the compounds were tightly, but not covalently, associated with MurA. Molecular modeling studies demonstrated that the compounds could fit into the site occupied by fosfomycin; exposure of MurA to each compound reduced the labeling of MurA by tritiated fosfomycin. Taken together, the evidence indicates that these inhibitors may bind noncovalently to the MurA enzyme, at or near the site where fosfomycin binds.
Eagle-Type Methicillin Resistance: New Phenotype of High Methicillin Resistance under
mec
Regulator Gene Control
Authors: Kondo Noriko , Kuwahara-Arai Kyoko , Kuroda-Murakami Hiroko , Tateda-Suzuki Eiko , Hiramatsu Keiichi
Published: July 2002

We report a novel phenotype of methicillin resistance, designated “Eagle-type” resistance, which is characteristic in its resistance to high concentrations of methicillin (64 to 512 μg/ml) and susceptibility to low concentrations of methicillin (2 to 16 μg/ml). The type of resistance was expressed in mutant strains selected with high concentrations (e.g., 128 to 512 μg/ml) of methicillin from the pre-methicillin-resistant
Staphylococcus aureus
strain N315, whose
mecA
gene transcription is strongly repressed by the
mecI
gene-encoded repressor protein MecI. The Eagle-type mutant strains harbored no mutation in the
mecI
gene or in the operator region of
mecA
gene to which MecI repressor is supposed to bind. In the representative Eagle-type strain h4, repression of
mecA
gene transcription and penicillin-binding protein 2′ production were found to be released by exposing the cells to a high concentration (128 μg/ml) of methicillin but not to lower concentrations (1 and 8 μg/ml) of methicillin. The strain h4 expressed paradoxical susceptibility (Eagle effect) to the cytokilling activity of methicillin. Experimental deletion of
mecI
gene from the chromosome of h4 by
mecI
-specific gene substitution converted its Eagle-type resistance to homogeneously high methicillin resistance. We cloned two novel genes, designated
hmrA
and
hmrB
, from genomic library of h4, which conferred Eagle-type resistance to N315 when introduced into the cell in multiple copies. The genes were shown to confer homogeneous methicillin resistance to the heterogeneously methicillin-resistant strain LR5 when they were introduced into on multicopy plasmids. This result strongly indicated that the genetic alteration responsible for the expression of the Eagle phenotype is identical, or equivalent in its effect, to the genetic alteration underlying heterogeneous-to-homogeneous conversion of methicillin resistance in
S. aureus
.
In Vivo Efficacy of Trovafloxacin against
Bacteroides fragilis
in Mixed Infection with either
Escherichia coli
or a Vancomycin-Resistant Strain of
Enterococcus faecium
in an Established-Abscess Murine Model
Authors: Stearne Lorna E. T. , Gyssens Inge C. , Goessens Wil H. F. , Mouton Johan W. , Oyen Wim J. G. , van der Meer Jos W. M. , Verbrugh Henri A.
Published: July 2002

The pharmacodynamic and pharmacokinetic properties of trovafloxacin were studied in a standardized murine model of established subcutaneous abscesses. Daily dosing regimens of 37.5 to 300 mg/kg every 8 h (q8h) or every 24 h (q24h) were started 3 days after inoculation with mixtures containing either
Bacteroides fragilis-Escherichia coli
-autoclaved cecal contents (ACC) or
B. fragilis
–vancomycin-resistant
Enterococcus faecium
(VREF)–ACC. Treatment was continued for 3 or 5 days. The efficacy of treatment was determined by the decrease in abscess bacterial counts and abscess weights, as well as by the reduction in inflammation (biodistribution of
99m
Tc-HYNIC immunoglobulin G) compared to saline-treated controls. Trovafloxacin showed a significant dose-response effect on the bacterial counts, weight, and inflammation of
B. fragilis-E. coli
abscesses after 3 and/or 5 days of treatment. A maximum 3.4 and 3.1 log
10
reduction in CFU/abscess in the respective
B. fragilis
and
E. coli
bacterial counts was attained after 5 days of treatment with daily doses of 300 mg/kg. The peak serum concentration was more predictive for effect than the area under the concentration-time curve. The
C
max
was the pharmacodynamic index most predictive for success, and the efficacy of the q24h regimens was significantly better than the q8h regimens. The antibiotic was ineffective against the VREF in mixed infection with
B. fragilis
, while the killing of the anaerobe in the same combination was significantly less than in the
E. coli
combination (
P
< 0.05). We conclude that this is a useful model for studying the activity of antimicrobials for the treatment of small (<1-cm), undrainable, mixed-infection abscesses. In addition, we have shown for the first time that a decrease in bacterial numbers also leads to a reduction in both abscess weight and inflammation.
MexXY-OprM Efflux Pump Is Required for Antagonism of Aminoglycosides by Divalent Cations in
Pseudomonas aeruginosa
Authors: Mao Weimin , Warren Mark S. , Lee Angela , Mistry Anita , Lomovskaya Olga
Published: July 2002

Antagonism of aminoglycosides by divalent cations is well documented for
Pseudomonas aeruginosa
and is regarded as one of the problems in aminoglycoside therapy. It is generally considered that divalent cations interfere with uptake of aminoglycosides at both the outer and inner membranes. It has been demonstrated recently that aminoglycosides can be removed from cells of
P. aeruginosa
by the three-component multidrug resistance efflux pump MexXY-OprM. We sought to investigate the interplay between efflux and uptake in resistance to aminoglycosides in
P. aeruginosa
. To do so, we studied the effects of the divalent cations Mg
2+
and Ca
2+
on susceptibility to aminoglycosides in a wild-type strain of
P. aeruginosa
and in mutants either overexpressing or lacking the MexXY-OprM efflux pump. MICs of gentamicin, streptomycin, amikacin, apramycin, netilmicin, and arbekacin were determined in Mueller-Hinton broth in the presence of cations added at concentrations that varied from 0.125 to 8 mM. We found, unexpectedly, that while both Mg
2+
and Ca
2+
antagonized aminoglycosides (up to a 64-fold decrease in susceptibility at 8 mM), antagonism was seen only in the strains of
P. aeruginosa
that contained the functional MexXY-OprM efflux pump. Our results indicate that inhibition of the MexXY-OprM efflux pump should abolish the antagonism of aminoglycosides by divalent cations, regardless of its precise mechanism. This may significantly increase the therapeutic index of aminoglycosides and improve the clinical utility of this important class of antibiotics.
Molecular and Biochemical Characterization of Ambler Class A Extended-Spectrum β-Lactamase CGA-1 from
Chryseobacterium gleum
Authors: Bellais Samuel , Naas Thierry , Nordmann Patrice
Published: July 2002

Antibiotic susceptibility testing by disk diffusion of a
Chryseobacterium gleum
isolate, strain CIP 103039, showed a typical synergy image between clavulanic acid and expanded-spectrum cephalosporins. Shotgun cloning gave a recombinant plasmid in
Escherichia coli
that produced a β-lactamase, CGA-1, with a pI value of 8.9 that conferred resistance to most penicillins (except ureidopenicillins) and narrow-spectrum cephalosporins and an intermediate susceptibility to expanded-spectrum cephalosporins and aztreonam. The CGA-1 amino acid sequence shared only 60% amino acid identity with CME-1 and CME-2 from
Chryseobacterium meningosepticum
, the most closely related β-lactamases. CGA-1 was very likely chromosome encoded. It is a novel member of the PER subgroup of Ambler class A β-lactamases (Bush functional group 2be).
Oral Administration of Cyclopentane Neuraminidase Inhibitors Protects Ferrets against Influenza Virus Infection
Authors: Sweet Clive , Jakeman Kenneth J. , Bush Karen , Wagaman Pamela C. , Mckown Linda A. , Streeter Anthony J. , Desai-Krieger Daksha , Chand Pooran , Babu Yarlagadda S.
Published: July 2002

Several cyclopentane inhibitors of influenza virus neuraminidase that have inhibitory activities in tissue culture similar to those of zanamivir and oseltamivir have recently been described. These new inhibitors have been examined for efficacy against a virulent H3N2 influenza virus when administered orally to infected ferrets. Preliminary studies indicated that oral administration of BCX-1923, BCX-1827, or BCX-1812 (RWJ-270201) at a dose of 5 or 25 mg/kg of body weight was active in ferrets in reducing respiratory and constitutional signs and symptoms, but these antivirals affected virus titers in the upper and lower respiratory tracts only marginally. Of the three compounds, BCX-1812 seemed to be the most efficacious and was examined further at higher doses of 30 and 100 mg/kg. These doses significantly reduced peak virus titers in nasal washes and total virus shedding as measured by areas under the curve. Virus titers in lung homogenates were also reduced compared to those in controls, but the difference was not statistically significant. As was observed with BCX-1812 at lower doses, the nasal inflammatory cellular response, fever, and nasal signs were reduced while ferret activity was not, with activity remaining similar to uninfected animals.