bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic Efficacy of Topically Applied KP-103 against Experimental Tinea Unguium in Guinea Pigs in Comparison with Amorolfine and Terbinafine
Authors: Tatsumi Yoshiyuki , Yokoo Mamoru , Senda Hisato , Kakehi Kazuaki 
Published: November 2002

ABSTRACTThe therapeutic efficacy of KP-103, a novel topical triazole, in a guinea pig tinea unguium model was investigated. Experimental tinea unguium and tinea pedis were produced by inoculation ofTrichophyton mentagrophytesSM-110 between the toes of the hind paw of guinea pigs. One percent solution (0.1 ml) of KP-103, amorolfine, or terbinafine was topically applied to the nails and whole sole of an infected foot once daily for 30 consecutive days, and terbinafine was also orally administered at a daily dose of 40 mg/kg of body weight for 30 consecutive days, starting on day 60 postinfection. The fungal burdens of nails and plantar skin were assessed using a new method, which makes it possible to recover infecting fungi by removing a carryover of the drug remaining in the treated tissues into the culture medium. Topically applied KP-103 inhibited the development of nail collapse, significantly reduced the fungal burden of the nails, and sterilized the infected plantar skin. On the other hand, topical amorolfine and topical or oral terbinafine were ineffective for tinea unguium, although these drugs eradicated or reduced the fungal burden of plantar skin. The in vitro activities of amorolfine and terbinafine againstT. mentagrophytesSM-110 were 8- and 32-fold, respectively, decreased by the addition of 5% keratin to Sabouraud dextrose broth medium. In contrast, the activity of KP-103 was not affected by keratin because its keratin affinity is lower than those of the reference drugs, suggesting that KP-103 largely exists in the nails as an active form that was not bound to keratin and diffuses in the nail without being trapped by keratin. The effectiveness of KP-103 against tinea unguium is probably due to its favorable pharmacokinetic properties in the nails together with its potent antifungal activity.
Effect of Auristatin PHE on Microtubule Integrity and Nuclear Localization in
Cryptococcus neoformans
Authors: Woyke Tanja , Roberson Robert W. , Pettit George R. , Winkelmann Günther , Pettit Robin K. 
Published: November 2002

ABSTRACT

The mechanism of action of the fungicidal peptide auristatin PHE was investigated in
Cryptococcus neoformans
. Since auristatin PHE causes budding arrest in
C. neoformans
(T. Woyke, G. R. Pettit, G. Winkelmann, and R. K. Pettit, Antimicrob. Agents Chemother.
45:
3580-3584, 2001), microtubule integrity and nuclear localization in auristatin PHE-treated cells were examined. Iterative deconvolution in conjunction with an optimized
C. neoformans
microtubule immunolabeling procedure enabled detailed visualization of the microtubule cytoskeleton in auristatin PHE-treated
C. neoformans
. The effect of auristatin PHE on
C. neoformans
microtubule organization was compared with that of the tubulin-binding agent nocodazole. Both drugs produced complete disruption first of cytoplasmic and then of spindle microtubules in a time- and concentration-dependent manner. Sub-MICs of auristatin PHE caused complete microtubule disruption within 4.5 h, while 1.5 times the nocodazole MIC was required for the same effect. For both drugs, disruption of microtubules was accompanied by blockage of nuclear migration and of nuclear and cellular division, resulting in cells arrested in a uninucleate, large-budded stage. Nocodazole and the linear peptide auristatin PHE are remarkably different in structure and spectrum of activity, yet on the cellular level, they have similar effects.
Mechanism by Which Mutations at His274 Alter Sensitivity of Influenza A Virus N1 Neuraminidase to Oseltamivir Carboxylate and Zanamivir
Authors: Wang Michael Z. , Tai Chun Y. , Mendel Dirk B. 
Published: November 2002

ABSTRACTOseltamivir carboxylate is a potent and specific inhibitor of influenza neuraminidase (NA). An influenza A/H1N1 variant selected in vitro with reduced susceptibility to oseltamivir carboxylate contains a His274Tyr mutation. To understand the mechanism by which a His274Tyr mutation gives rise to drug resistance, we studied a series of NA variant proteins containing various substitutions at position 274. Replacement of His274 with larger side chain residues (Tyr or Phe) reduced the NA sensitivity to oseltamivir carboxylate. In contrast, replacement of His274 with smaller side chain residues (Gly, Asn, Ser, and Gln) resulted in enhanced or unchanged sensitivity to oseltamivir carboxylate. Previous studies have suggested that the slow-binding inhibition of NA by oseltamivir carboxylate is a result of the reorientation of Glu276. Loss of this slow-binding inhibition in the His274Tyr and His274Phe mutant NA but not in His274Asn, His274Gly, His274Ser, or His274Gln supports the conclusion that the conformational change of Glu276 is restricted in the His274Tyr and His274Phe mutant NA upon oseltamivir carboxylate binding. Interestingly, His274Asn, as well as His274Gly, His274Ser, and His274Gln, also displayed reduced sensitivity to zanamivir and its analogue, 4-amino-Neu5Ac2en. Substitution of His274 with Tyr in influenza A/Tokyo/3/67 (H3N2) recombinant NA did not affect the susceptibility to oseltamivir carboxylate. These data indicate that the volume occupied by the amino acid side chain at position 274 can influence the sensitivities of influenza N1 NA but not of N2 NA to both oseltamivir carboxylate and zanamivir.
Carbapenem Resistance in a Clinical Isolate of
Enterobacter aerogenes
Is Associated with Decreased Expression of OmpF and OmpC Porin Analogs
Authors: Yigit Hesna , Anderson Gregory J. , Biddle James W. , Steward Christine D. , Rasheed J. Kamile , Valera Lourdes L. , McGowan John E. , Tenover Fred C. 
Published: November 2002

ABSTRACT

We investigated the mechanism of imipenem resistance in
Enterobacter aerogenes
strain 810, a clinical isolate from the United States for which the imipenem MIC was 16 μg/ml and the meropenem MIC was 8 μg/ml. An imipenem-susceptible revertant, strain 810-REV, was obtained after multiple passages of the strain on nonselective media. For the revertant, the imipenem MIC was ≤1 μg/ml and the meropenem MIC was ≤0.25 μg/ml. Cefepime MICs also decreased from 8 to 1 μg/ml; however, the MICs of ceftazidime (≥128 μg/ml), cefoxitin (≥32 μg/ml), and cefotaxime (≥64 μg/ml) remained the same. The β-lactamase and porin profiles of the parent, the revertant, and carbapenem-susceptible type strain
E. aerogenes
ATCC 13048 were determined. Strains 810 and 810-REV each produced two β-lactamases with pIs of 8.2 and 5.4. The β-lactamase activities of the parent and revertant were similar, even after induction with subinhibitory concentrations of imipenem. While 810-REV produced two major outer membrane proteins of 42 and 39 kDa that corresponded to
Escherichia coli
porins OmpC and OmpF, respectively, the parent strain appeared to produce similar quantities of the 39-kDa protein (OmpF) but decreased amounts of the 42-kDa protein (OmpC). When the parent strain was grown in the presence of imipenem, the 42-kDa protein was not detectable by gel electrophoresis. However, Western blot analysis of the outer membrane proteins of the parent and revertant with polyclonal antisera raised to the OmpC and OmpF analogs of
Klebsiella pneumoniae
(anti-OmpK36 and anti-OmpK35, respectively) showed that strain 810 expressed only the 42-kDa OmpC analog in the absence of imipenem (the 39-kDa protein was not recognized by the anti-OmpF antisera) and neither the OmpC nor the OmpF analog in the presence of imipenem. The OmpC analog is apparently down-regulated in the presence of imipenem; however, 810-REV expressed both OmpC and OmpF analogs. These data suggest that imipenem resistance in
E. aerogenes
810 is primarily associated with the lack of expression of the analogs of the OmpC (42-kDa) and OmpF (39-kDa) outer membrane proteins, which also results in decreased susceptibility to meropenem and cefepime.
Identification of
vat
(E) in
Enterococcus faecalis
Isolates from Retail Poultry and Its Transferability to
Enterococcus faecium
Authors: Simjee S. , White D. G. , Wagner D. D. , Meng J. , Qaiyumi S. , Zhao S. , McDermott P. F. 
Published: November 2002

ABSTRACT

Sixteen isolates of
Enterococcus faecalis
were recovered from retail poultry samples (seven chickens and nine turkeys) purchased from grocery stores in the greater Washington, D.C., area. PCR for known streptogramin resistance genes identified
vat
(E) in five
E. faecalis
isolates (three isolates from chickens and two isolates from turkeys). The
vat
(E) gene was transmissible on a ca. 70-kb plasmid, along with resistance to erythromycin, tetracycline, and streptomycin, by conjugation to
E. faecalis
and
Enterococcus faecium
recipient strains. DNA sequencing showed little variation between
E. faecalis vat
(E) genes from the chicken samples; however, one
E. faecalis vat
(E) gene from a turkey sample possessed 5 nucleotide changes that resulted in four amino acid substitutions. None of these substitutions in the
vat
(E) allele have previously been described. This is the first report of
vat
(E) in
E. faecalis
and its transferability to
E. faecium
, which indicates that
E. faecalis
can act as a reservoir for the dissemination of
vat
(E)-mediated streptogramin resistance to
E. faecium
.
Mechanisms of Decreased Susceptibility to Cefpodoxime in
Escherichia coli
Authors: Oliver Antonio , Weigel Linda M. , Rasheed J. Kamile , McGowan John E. , Raney Patti , Tenover Fred C. 
Published: November 2002

ABSTRACT

Cefpodoxime is one of five antimicrobial agents recommended by the National Committee for Clinical Laboratory Standards for screening isolates of
Klebsiella
spp. and
Escherichia coli
for extended-spectrum β-lactamase (ESBL) production. In a prior study, we noted that among 131
E. coli
isolates for which the MIC of at least one extended-spectrum cephalosporin (ESC) or aztreonam was ≥2 μg/ml (suggesting the presence of ESBL production), there were 59 isolates (45.0%) for which the MIC of cefpodoxime was 2 to 4 μg/ml (i.e., a positive ESBL screening test), but the MICs of ceftazidime, cefotaxime, and ceftriaxone were ≤1 μg/ml (below the ESBL screening breakpoint). Thus, the results appeared to be false-positive ESBL screening tests. These 59 isolates were divided into five phenotypic groups based on the susceptibility patterns of the organisms to a variety of β-lactam agents and further characterized. The first group (32 isolates) all produced a TEM-1 β-lactamase, and changes in the major outer membrane proteins were detected in representative strains. The second group (18 isolates) lacked
bla
TEM
but showed a number of porin changes; some also showed a modest elevation in production of the AmpC chromosomal β-lactamase. In the third phenotypic group (seven isolates) all expressed an OXA-30 β-lactamase. Some also harbored altered porins. The two remaining phenotypes each had a distinct pattern of porin changes with or without β-lactamase production. These data indicate that several factors are associated with decreased susceptibility to cefpodoxime in
E. coli
, but none of the mechanisms are related to ESBL production. Current screening methods produced false-positive ESBL results for these isolates. Such isolates should not be classified as containing ESBLs, nor should interpretations of ESCs or aztreonam susceptibility be changed to resistant on test reports for these isolates.
Occurrence of Newer β-Lactamases in
Klebsiella pneumoniae
Isolates from 24 U.S. Hospitals
Authors: Moland Ellen Smith , Black Jennifer A. , Ourada Jason , Reisbig Mark D. , Hanson Nancy D. , Thomson Kenneth S. 
Published: November 2002

ABSTRACT

Despite the discovery of novel β-lactamases such as extended-spectrum β-lactamases (ESBLs), imported AmpC, and carbapenem-hydrolyzing β-lactamases at least a decade ago, there remains a low level of awareness of their importance and how to detect them. There is a need to increase the levels of awareness of clinical laboratories about the detection of newer β-lactamases. Therefore, a study was conducted in 2000 to investigate the occurrence of these β-lactamases in
Klebsiella pneumoniae
isolates at 24 U.S. medical centers. To enhance the likelihood of detecting imported AmpC and carbapenem-hydrolyzing β-lactamases, participating laboratories were permitted to include archived strains (1996 to 2000) that were intermediate or resistant to either cefoxitin or imipenem. The β-lactamase production of 408 isolates positive by screening of 1,123 isolates was investigated by ESBL phenotypic confirmation tests; and for AmpC and carbapenem-hydrolyzing β-lactamases, three-dimensional tests, isoelectric focusing, β-lactamase inhibitor studies, spectrophotometric assays, induction assays, and molecular tests were used. ESBL-producing isolates were detected at 18 of the 24 sites (75%), imported AmpC-producing isolates were detected at 10 sites (42%), inducible imported AmpC-producing isolates were detected at 3 sites (12.5%), and a molecular class A carbapenem-hydrolyzing enzyme was detected at 1 site (4%). No class B or D carbapenem-hydrolyzing enzymes were detected. ESBLs and imported AmpC β-lactamases were detected at a significant number of sites, indicating widespread penetration of these enzymes into U.S. medical institutions. Because these enzymes may significantly affect therapeutic outcomes, it is vital that clinical laboratories be aware of them and be able to detect their occurrence.
Antimicrobial Susceptibilities of Diverse
Bacillus anthracis
Isolates
Authors: Coker Pamala R. , Smith Kimothy L. , Hugh-Jones Martin E. 
Published: November 2002

ABSTRACT

A test of 25 genetically diverse isolates of
Bacillus anthracis
was conducted to determine their susceptibility to seven clinically relevant antimicrobial agents. Etest strips (AB BIODISK, Solna, Sweden) were used to measure the MICs for the isolates. Using the National Committee for Clinical Laboratory Standards MIC breakpoints for staphylococci, three isolates were found to be resistant to penicillin and five were found to be resistant to cefuroxime. The penicillin-resistant isolates were negative for β-lactamase production. Continued surveillance of
B. anthracis
field isolates is recommended to monitor antimicrobial susceptibility.
In Vitro Activity of Micafungin (FK-463) against
Candida
spp.: Microdilution, Time-Kill, and Postantifungal-Effect Studies
Authors: Ernst Erika J. , Roling Ellen E. , Petzold C. Rosemarie , Keele Douglas J. , Klepser Michael E. 
Published: November 2002

ABSTRACT

We evaluated the in vitro activity of the new echinocandin antifungal micafungin against
Candida
spp. using microdilution and time-kill methods. Additionally, we examined the postantifungal effect (PAFE) of micafungin. Finally, we evaluated the effect of the addition of serum and plasma on the MIC of micafungin. Four
Candida albicans
isolates and two isolates of each
Candida glabrata
,
Candida krusei
, and
Candida tropicalis
were selected for testing. The MICs of micafungin were determined in RPMI 1640 medium buffered with morpholinepropanesulfonic acid alone and with the addition of 10, 20, and 50% human serum and plasma. MICs were determined by using two endpoints: a prominent reduction in growth (the MIC at which 80% of isolates are inhibited [MIC
80
]) and complete visual inhibition of growth (MIC
100
). The minimum fungicidal concentration (MFC) of micafungin for each isolate was also determined. Time-kill curves were determined for each isolate in RPMI 1640 medium with micafungin at concentrations ranging from 0.125 to 16 times the MIC
80
to assess the correlation between MIC
80
and fungicidal activity. PAFE studies were conducted with each isolate by using concentrations ranging between 0.25 and 4 times the MIC
80
. The MIC
80
s for the test isolates ranged from 0.0039 to 0.25 μg/ml. Overall, the addition of serum or plasma increased the MIC 6 to 7 doubling dilutions for
C. albicans
and 3 to 4 doubling dilutions for
C. krusei
and
C. tropicalis
. Micafungin time-kill studies demonstrated fungicidal activity at concentrations ranging from 4 to 16 times the MIC
80
. Micafungin is very potent agent against a variety of
Candida
spp., producing fungicidal activity against 7 of 10 isolates tested. A PAFE was observed against all isolates. The PAFE was influenced by the drug concentration, with the highest concentration resulting in the longest observed PAFE in each case. The highest concentration tested, four times the MIC, resulted in a PAFE of more than 9.8 h for 5 of 10 isolates tested (range, 0.9 to ≥20.1 h).
Antiviral Activities and Cellular Toxicities of Modified 2′,3′-Dideoxy-2′,3′-Didehydrocytidine Analogues
Authors: Stuyver Lieven J. , Lostia Stefania , Adams Marjorie , Mathew Judy S. , Pai Balakrishna S. , Grier Jason , Tharnish Phillip M. , Choi Yongseok , Chong Youhoon , Choo Hyunah , Chu Chung K. , Otto Michael J. , Schinazi Raymond F. 
Published: November 2002

ABSTRACT

The antiviral efficacies and cytotoxicities of 2′,3′- and 4′-substituted 2′,3′-didehydro-2′,3′-dideoxycytidine analogs were evaluated. All compounds were tested (i) against a wild-type human immunodeficiency virus type 1 (HIV-1) isolate (strain xxBRU) and lamivudine-resistant HIV-1 isolates, (ii) for their abilities to inhibit hepatitis B virus (HBV) production in the inducible HepAD38 cell line, and (iii) for their abilities to inhibit bovine viral diarrhea virus (BVDV) production in acutely infected Madin-Darby bovine kidney cells. Some compounds demonstrated potent antiviral activities against the wild-type HIV-1 strain (range of 90% effective concentrations [EC
90
s], 0.14 to 5.2 μM), but marked increases in EC
90
s were noted when the compounds were tested against the lamivudine-resistant HIV-1 strain (range of EC
90
s, 53 to >100 μM). The β-
l
-enantiomers of both classes of compounds were more potent than the corresponding β-
d
-enantiomers. None of the compounds showed antiviral activity in the assay that determined their abilities to inhibit BVDV, while two compounds inhibited HBV production in HepAD38 cells (EC
90
, 0.25 μM). The compounds were essentially noncytotoxic in human peripheral blood mononuclear cells and HepG2 cells. No effect on mitochondrial DNA levels was observed after a 7-day incubation with the nucleoside analogs at 10 μM. These studies demonstrate that (i) modification of the sugar ring of cytosine nucleoside analogs with a 4′-thia instead of an oxygen results in compounds with the ability to potently inhibit wild-type HIV-1 but with reduced potency against lamivudine-resistant virus and (ii) the antiviral activity of β-
d
-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine against wild-type HIV-1 (EC
90
, 0.08 μM) and lamivudine-resistant HIV-1 (EC
90
= 0.15 μM) is markedly reduced by introduction of a 3′-fluorine in the sugar (EC
90
s of compound 2a, 37.5 and 494 μM, respectively).
Mutagenically Separated PCR Assay for Rapid Detection of M41L and K70R Zidovudine Resistance Mutations in CRF01_AE (Subtype E) Human Immunodeficiency Virus Type 1
Authors: Myint Lay , Ariyoshi Koya , Yan Hua , Frater Alexander J. , Auwanit Wattana , Pathipvanith Panita , Yamada Kaneo , Matsuda Masakazu , Chiba Tomoko , Fujita Kazunori , McClure Myra , Weber Jonathan N. , Sugiura Wataru 
Published: November 2002

ABSTRACT
A rapid zidovudine (ZDV) resistance genotypic assay was developed based on the mutagenically separated PCR (MS-PCR) technique to detect two ZDV-resistant mutations, M41L and K70R in CRF01_AE (subtype E). Endpoint dilution analysis revealed that the newly constructed MS-PCR assay could successfully detect three to nine copies of human immunodeficiency virus type 1 template RNA. The test against wild-type and mutant template mixtures in different ratios demonstrated that the assay could detect 10% minor population, at least. Fifty-one subtype E clinical samples were analyzed by the newly constructed MS-PCR assay and direct nucleotide sequencing. The concordance of the two assays was 92 and 100% in codons 41 and 70, respectively. The MS-PCR assay is a rapid, simple, and inexpensive assay that is highly sensitive in detecting mutant targets, including minor populations. Thus, it could be used as a powerful tool for epidemiological surveillance of drug-resistant mutations in developing countries.
Synthetic Analogues of β-1,2 Oligomannosides Prevent Intestinal Colonization by the Pathogenic Yeast
Candida albicans
Authors: Dromer Françoise , Chevalier Reynald , Sendid Boualem , Improvisi Luce , Jouault Thierry , Robert Raymond , Mallet Jean Maurice , Poulain Daniel 
Published: November 2002

ABSTRACT

The pathogenic yeast
Candida albicans
displays at its cell surface β-1,2 oligomannosides (β-1,2-Mans). In contrast to the ubiquitous α-Mans, β-1,2-Mans bind to galectin-3, a major endogenous lectin expressed on epithelial cells. The specific role of β-1,2-Mans in colonization of the gut by
C. albicans
was assessed in a mouse model. A selected virulent strain of
C. albicans
(expressing more β-1,2-Man epitopes) induced more intense and sustained colonization than an avirulent strain (expressing less β-1,2-Man epitopes). Synthetic (Σ) β-and α-linked tetramannosides with antigenicities that mimicked the antigenicities of
C. albicans
-derived oligomannosides were then constructed. Oral administration of Σβ-1,2-Man (30 mg/kg of body weight) prior to inoculation with the virulent strain resulted in almost complete eradication of yeasts from stool samples, whereas administration of Σα-Man at the same dose did not. As most cases of human systemic candidiasis are endogenous in origin, this first demonstration that a synthetic analogue of a yeast adhesin can prevent yeast colonization in the gut opens the possibility of new prophylactic strategies.
Coadministration of Indinavir and Nelfinavir in Human Immunodeficiency Virus Type 1-Infected Adults: Safety, Pharmacokinetics, and Antiretroviral Activity
Authors: Riddler Sharon A. , Havlir Diane , Squires Kathleen E. , Kerr Brad , Lewis Ronald H. , Yeh Kuang , Wynne Linda Hawe , Zhong Ling , Peng Yahong , Deutsch Paul , Saah Alfred 
Published: November 2002

ABSTRACT

Combinations of protease inhibitors (PIs) can have potentially beneficial pharmacokinetic interactions, resulting in higher drug levels and less frequent dose administration. Indinavir (IDV) and nelfinavir (NFV) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) protease and are commonly prescribed antiretroviral agents. Pilot pharmacokinetic data suggested a bidirectional enhancing interaction between IDV and NFV. A phase II study was conducted to evaluate the safety, pharmacokinetics, and antiviral activity of IDV plus NFV given in a combination every 12 h in HIV-1-infected subjects. IDV plus NFV was given as a twice-daily regimen to 20 HIV-1-infected subjects who were PI naive (11 of 20 were antiretroviral naive). After week 18, nucleoside reverse transcriptase inhibitors were added to the treatment regimen in seven subjects. The enrolled subjects had a geometric mean baseline plasma HIV-1 RNA of 63,095 copies/ml and a mean CD4
+
cell count of 266 cells/mm
3
. Pharmacokinetic evaluations were performed at the following doses: IDV at 1,000 mg every 12 h (q12h) plus NFV at 750 mg q12h, IDV at 1,000 mg q12h plus NFV at 1,000 mg q12h, and IDV at 1,200 mg q12h plus NFV at 1,250 mg q12h. The coadministration of IDV plus NFV resulted in a modest inhibition of IDV elimination, resulting in a plasma profile of IDV 1200 mg q12h (with NFV at 1,250 mg q12h) that was comparable to the standard IDV dose of 800 mg q8h. In contrast, IDV had no apparent effect on the pharmacokinetic profile of NFV. The combination of IDV and NFV was generally well tolerated and resulted in sustained virologic suppression with 45% of the subjects having an HIV-1 RNA level in plasma of <400 copies/ml at week 72 (intent-to-treat).