bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid Bactericidal Activity of Daptomycin against Methicillin-Resistant and Methicillin-Susceptible
Staphylococcus aureus
Peritonitis in Mice as Measured with Bioluminescent Bacteria
Authors: Mortin Lawrence I. , Li Tongchuan , Van Praagh Andrew D. G. , Zhang Shuxin , Zhang Xi-Xian , Alder Jeff D. 
Published: February 2007

ABSTRACT

The rising rates of antibiotic resistance accentuate the critical need for new antibiotics. Daptomycin is a new antibiotic with a unique mode of action and a rapid in vitro bactericidal effect against gram-positive organisms. This study examined the kinetics of daptomycin's bactericidal action against peritonitis caused by methicillin-susceptible
Staphylococcus aureus
(MSSA) and methicillin-resistant
S. aureus
(MRSA) in healthy and neutropenic mice and compared this activity with those of other commonly used antibiotics. CD-1 mice were inoculated intraperitoneally with lethal doses of MSSA (Xen-29) or MRSA (Xen-1), laboratory strains transformed with a plasmid containing the
lux
operon, which confers bioluminescence. One hour later, the animals were given a single dose of daptomycin at 50 mg/kg of body weight subcutaneously (s.c.), nafcillin at 100 mg/kg s.c., vancomycin at 100 mg/kg s.c., linezolid at 100 mg/kg via gavage (orally), or saline (10 ml/kg s.c.). The mice were anesthetized hourly, and photon emissions from living bioluminescent bacteria were imaged and quantified. The luminescence in saline-treated control mice either increased (neutropenic mice) or remained relatively unchanged (healthy mice). In contrast, by 2 to 3 h postdosing, daptomycin effected a 90% reduction of luminescence of MSSA or MRSA in both healthy and neutropenic mice. The activity of daptomycin against both MSSA and MRSA strains was superior to those of nafcillin, vancomycin, and linezolid. Against MSSA peritonitis, daptomycin showed greater and more rapid bactericidal activity than nafcillin or linezolid. Against MRSA peritonitis, daptomycin showed greater and more rapid bactericidal activity than vancomycin or linezolid. The rapid decrease in the luminescent signal in the daptomycin-treated neutropenic mice underscores the potency of this antibiotic against
S. aureus
in the immune-suppressed host.
Competitive Inhibitors of the CphA Metallo-β-Lactamase from
Aeromonas hydrophila
Authors: Horsfall L. E. , Garau G. , Liénard B. M. R. , Dideberg O. , Schofield C. J. , Frère J. M. , Galleni M. 
Published: February 2007

ABSTRACT
Various inhibitors of metallo-β-lactamases have been reported; however, none are effective for all subgroups. Those that have been found to inhibit the enzymes of subclass B2 (catalytically active with one zinc) either contain a thiol (and show less inhibition towards this subgroup than towards the dizinc members of B1 and B3) or are inactivators behaving as substrates for the dizinc family members. The present work reveals that certain pyridine carboxylates are competitive inhibitors of CphA, a subclass B2 enzyme. X-ray crystallographic analyses demonstrate that pyridine-2,4-dicarboxylic acid chelates the zinc ion in a bidentate manner within the active site. Salts of these compounds are already available and undergoing biomedical testing for various nonrelated purposes. Pyridine carboxylates appear to be useful templates for the development of more-complex, selective, nontoxic inhibitors of subclass B2 metallo-β-lactamases.
Multiple Staphylococcal Cassette Chromosomes and Allelic Variants of Cassette Chromosome Recombinases in
Staphylococcus aureus
and Coagulase-Negative Staphylococci from Norway
Authors: Hanssen Anne-Merethe , Sollid Johanna U. Ericson 
Published: February 2007

ABSTRACT

We investigated the nature of the staphylococcal cassette chromosome
mec
(SCC
mec
) elements and cognate insertion sites in a collection of 42 clinical staphylococcal isolates of various species from Norway. The
ccr
and
mec
genes and the attachment sites (
attL
/
attR
) were identified by PCR, Southern blot hybridization, and DNA sequencing. We found 10 possibly new SCC
mec
types and one previously unreported variant of SCC
mec
type III (
mec
complex A,
ccrAB3
, and
ccrC7
) in
Staphylococcus epidermidis, Staphylococcus haemolyticus
, and
Staphylococcus hominis
. Eleven of 42 strains contained multiple copies of
ccr
, suggesting the presence of mosaic structures composed of multiple SCC elements.
S. haemolyticus
contained
ccrAB2
genes identical to those in
S. aureus
SCC
mec
type IV but lacked IS
1272
and
mec
regulators. Two new allelic
ccr
variants,
ccrC6
and
ccrC7
, were identified. Also, the presumed functional version of
ccrB1
was found in a
mecA
-positive
S. hominis
strain and in
mecA
-negative
S. epidermidis
and
S. hominis
strains. Only minor differences in direct repeats in the left and right boundaries (
attR
/
attL
) were observed, while there was more variation in the inverted repeats. Coagulase-negative staphylococci (CoNS) contained several representatives of different
ccr
complexes and thus seemed to harbor multiple or composite new types of SCC
mec
. The enormous diversity observed in the SCC
mec
elements implies a large SCC
mec
reservoir in CoNS.
Direct Inactivation of Human Immunodeficiency Virus Type 1 by a Novel Small-Molecule Entry Inhibitor, DCM205
Authors: Duong Yen T. , Meadows D. Christopher , Srivastava Indresh K. , Gervay-Hague Jacquelyn , North Thomas W. 
Published: February 2007

ABSTRACT
With more than 40 million people living with human immunodeficiency virus (HIV), there is an urgent need to develop drugs that can be used in the form of a topical microbicide to prevent infection through sexual transmission. DCM205 is a recently discovered small-molecule inhibitor of HIV type 1 (HIV-1) that is able to directly inactivate HIV-1 in the absence of a cellular target. DCM205 is active against CXCR4-, CCR5-, and dual-tropic laboratory-adapted and primary strains of HIV-1. DCM205 binds to the HIV-1 envelope glycoprotein, and competition studies map the DCM205 binding at or near the V3 loop of gp120. Binding to this site interferes with the soluble CD4 interaction. With its ability to disable the virus particle, DCM205 represents a promising new class of HIV entry inhibitor that can be used as a strategy in the prevention of HIV-1/AIDS.
In Vitro Activities of Various Antimicrobials Alone and in Combination with Tigecycline against Carbapenem-Intermediate or -Resistant
Acinetobacter baumannii
Authors: Scheetz Marc H. , Qi Chao , Warren John R. , Postelnick Michael J. , Zembower Teresa , Obias Arlene , Noskin Gary A. 
Published: February 2007

ABSTRACT

The activities of tigecycline alone and in combination with other antimicrobials are not well defined for carbapenem-intermediate or -resistant
Acinetobacter baumannii
(CIRA). Pharmacodynamic activity is even less well defined when clinically achievable serum concentrations are considered. Antimicrobial susceptibility testing of clinical CIRA isolates from 2001 to 2005 was performed by broth or agar dilution, as appropriate. Tigecycline concentrations were serially increased in time-kill studies with a representative of the most prevalent carbapenem-resistant clone (strain AA557; imipenem MIC, 64 mg/liter). The in vitro susceptibility of the strain was tested by time-kill studies in duplicate against the average free serum steady-state concentrations of tigecycline alone and in combination with various antimicrobials. Ninety-three CIRA isolates were tested and were found to have the following antimicrobial susceptibility profiles: tigecycline, MIC
50
of 1 mg/liter and MIC
90
of 2 mg/liter; minocycline, MIC
50
of 0.5 mg/liter and MIC
90
of 8 mg/liter; doxycycline, MIC
50
of 2 mg/liter and MIC
90
of ≥32 mg/liter; ampicillin-sulbactam, MIC
50
of 48 mg/liter and MIC
90
of 96 mg/liter; ciprofloxacin, MIC
50
of ≥16 mg/liter and MIC
90
of ≥16 mg/liter; rifampin, MIC
50
of 4 mg/liter and MIC
90
of 8 mg/liter; polymyxin B, MIC
50
of 1 mg/liter and MIC
90
of 1 mg/liter; amikacin, MIC
50
of 32 mg/liter and MIC
90
of ≥32 mg/liter; meropenem, MIC
50
of 16 mg/liter and MIC
90
of ≥128 mg/liter; and imipenem, MIC
50
of 4 mg/liter and MIC
90
of 64 mg/liter. Among the tetracyclines, the isolates were more susceptible to tigecycline than minocycline and doxycycline, according to FDA breakpoints (95%, 88%, and 71% of the isolates were susceptible to tigecycline, minocycline, and doxycycline, respectively). Concentration escalation studies with tigecycline revealed a maximal killing effect near the MIC, with no additional extent or rate of killing at concentrations 2× to 4× the MIC for tigecycline. Time-kill studies demonstrated indifference for tigecycline in combination with the antimicrobials tested. Polymyxin B, minocycline, and tigecycline are the most active antimicrobials in vitro against CIRA. Concentration escalation studies demonstrate that tigecycline may need to approach concentrations higher than those currently achieved in the bloodstream to adequately treat CIRA bloodstream infections. Future studies should evaluate these findings in vivo.
Role of Acidic pH in the Susceptibility of Intraphagocytic Methicillin-ResistantStaphylococcus aureusStrains to Meropenem and Cloxacillin
Authors: Lemaire Sandrine , Van Bambeke Françoise , Mingeot-Leclercq Marie-Paule , Glupczynski Youri , Tulkens Paul M. 
Published: February 2007

ABSTRACTEarly studies showed that methicillin-resistantStaphylococcus aureus(MRSA) strains are susceptible to β-lactams when they are exposed to pH ≤ 5.5 in broth. BecauseS. aureussurvives in the phagolysosomes of macrophages, where the pH may be acidic, we have examined the susceptibility of MRSA ATCC 33591 phagocytized by human THP-1 macrophages to meropenem (MEM) and cloxacillin (CLX). Using a pharmacodynamic model assessing key pharmacological (50% effective concentration and maximal efficacy) and microbiological (static concentration) descriptors of antibiotic activity, we show that intraphagocytic MRSA strains are as sensitive to MEM and CLX as methicillin-susceptibleS. aureus(MSSA; ATCC 25923). This observation was replicated in broth if the pH was brought to 5.5 and was confirmed with clinical strains. Electron microscopy showed that both the MRSA and the MSSA strains localized and multiplied in membrane-bounded structures (phagolysosomes) in the absence of β-lactams. Incubation of the infected macrophages with ammonium chloride (to raise the phagolysosomal pH) made MRSA insensitive to MEM and CLX. No difference was seen inmec,mecA,mecI,mecR1,femA, andfemBexpression (reversed transcription-PCR) or in PBP 2a content (immunodetection) in MRSA grown in broth at pH 5.5 compared with that in MRSA grown in broth at 7.4. The level of [14C]benzylpenicillin binding to cell walls prepared from a non-β-lactamase-producing MRSA clinical isolate was two times lower than that to cell walls prepared from MSSA ATCC 25923 at pH 7.4, but the levels increased to similar values for both strains at pH 5.5. These data suggest that the restoration of susceptibility of intraphagocytic of MRSA to MEM and CLX is due to the acidic pH prevailing in phagolysosomes and is mediated by an enhanced binding to penicillin-binding proteins.
In Vitro Activities of Isavuconazole and Other Antifungal Agents against
Candida
Bloodstream Isolates
Authors: Seifert H. , Aurbach U. , Stefanik D. , Cornely O. 
Published: February 2007

ABSTRACT

Isavuconazole is the active component of the new azole antifungal agent BAL8557, which is entering phase III clinical development. This study was conducted to compare the in vitro activities of isavuconazole and five other antifungal agents against 296
Candida
isolates that were recovered consecutively from blood cultures between 1995 and 2004 at a tertiary care university hospital. Microdilution testing was done in accordance with CLSI (formerly NCCLS) guideline M27-A2 in RPMI-1640 MOPS (morpholinepropanesulfonic acid) broth. The antifungal agents tested were amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole, and isavuconazole.
C. albicans
was the most common species, representing 57.1% of all isolates. There was no trend found in favor of non-
Candida albicans
species over time. In terms of MIC
50
s, isavuconazole was more active (0.004 mg/liter) than amphotericin B (0.5 mg/liter), itraconazole (0.008 mg/liter), voriconazole (0.03 mg/liter), flucytosine (0.125 mg/liter), and fluconazole (8 mg/liter). For isavuconazole, MIC
50
s/MIC
90
s ranged from 000.2/0.004 mg/liter for
C. albicans
to 0.25/0.5 mg/liter for
C. glabrata
. Two percent of isolates (
C. glabrata
and
C. krusei
) were resistant to fluconazole;
C. albicans
strains resistant to fluconazole were not detected. There were only two isolates with MICs for isavuconazole that were >0.5 mg/liter: both were
C. glabrata
isolates, and the MICs were 2 and 4 mg/liter, respectively. In conclusion, isavuconazole is highly active against
Candida
bloodstream isolates, including fluconazole-resistant strains. It was more active than itraconazole and voriconazole against
C. albicans
and
C. glabrata
and appears to be a promising agent against systemic
Candida
infections.
In Vivo Pharmacodynamic Activity of the Glycopeptide Dalbavancin
Authors: Andes David , Craig William A. 
Published: February 2007

ABSTRACT

Dalbavancin is a lipoglycopeptide antibiotic with broad-spectrum activity against gram-positive cocci and a markedly prolonged serum elimination half-life. We used the neutropenic murine thigh and lung infection models to characterize the pharmacodynamics of dalbavancin. Single-dose pharmacokinetic studies demonstrated linear kinetics and a prolonged elimination half-life which ranged from 7.6 to 13.1 h over the dose range of 2.5 to 80 mg/kg of body weight. The level of protein binding in mouse serum was 98.4%. The time course of in vivo activity of dalbavancin over the same dose range was examined in neutropenic ICR Swiss mice infected with a strain of either
Streptococcus pneumoniae
or
Staphylococcus aureus
by using the thigh infection model. The burden of organisms for
S. pneumoniae
was markedly reduced over the initial 24 h of study, and organism regrowth was suppressed in a dose-dependent fashion for up to the entire 96 h of study following dalbavancin doses of 2.5 mg/kg or greater. Dalbavancin doses of 20 mg/kg or greater resulted in less killing of
S. aureus
but were still followed by a prolonged suppression of regrowth. Multiple-dosing-regimen studies with the same organisms were used to determined which of the pharmacodynamic indices (maximum concentration in serum [
C
max
]/MIC, area under the concentration-versus-time curve [AUC]/MIC, or the duration of time that levels in serum exceed the MIC) best correlated with treatment efficacy. These studies used a dose range of 3.8 to 480 mg/kg/6 days fractionated into 2, 4, 6, or 12 doses over the 144-h dosing period. Nonlinear regression analysis was used to examine the data fit with each pharmacodynamic index. Dalbavancin administration by the use of large, widely spaced doses was the most efficacious for both organisms. Both the 24-h AUC/MIC and the
C
max
/MIC parameters correlated well with the in vivo efficacy of treatment against
S. pneumoniae
and
S. aureus
(for 24-h AUC/MIC,
R
2
= 78 and 77%, respectively; for
C
max
/MIC,
R
2
= 90 and 57%, respectively). The free-drug 24-h AUC/MICs required for a bacteriostatic effect were 17 ± 7 for five
S. pneumoniae
isolates. A similar treatment endpoint for the treatment against five strains of
S. aureus
required a larger dalbavancin exposure, with a mean free-drug 24-h AUC/MIC of 265 ± 143. Beta-lactam resistance did not affect the pharmacodynamic target. The dose-response curves were relatively steep for both species; thus, the pharmacodynamic target needed to achieve organism reductions of 1 or 2 log
10
in the mice were not appreciably larger (1.3- to 1.6-fold). Treatment was similarly efficacious in neutropenic mice and in the lung infection model. The dose-dependent efficacy and prolonged elimination half-life of dalbavancin support the widely spaced regimens used in clinical trials. The free-drug 24-h AUC/MIC targets identified in these studies should be helpful for discerning rational susceptibility breakpoints. The current MIC
90
for the target gram-positive organisms would fall within this value.
Two New
dfr
Genes in Trimethoprim-Resistant Integron-Negative
Escherichia coli
Isolates
Authors: Grape M. , Sundström L. , Kronvall G. 
Published: February 2007

ABSTRACT

Two
Escherichia coli
isolates resistant to trimethoprim but negative for integrons carried two new resistance genes,
dfrA24
and
dfrA26
, remotely similar to one another and to the cassette-independent genes
dfrA8
and
dfrA9
. The
dfrA24
gene was not associated with known mobile elements, while
dfrA26
was associated with the CR1 common region.
Mutations in
fusA
Associated with Posttherapy Fusidic Acid Resistance in
Clostridium difficile
Authors: Norén T. , Åkerlund T. , Wullt M. , Burman L. G. , Unemo M. 
Published: February 2007

ABSTRACT

In silico, we identified
fusA
(2,067 bp) in
Clostridium difficile
630. Sequencing of
fusA
in posttherapy fusidic acid-resistant
C. difficile
isolates from 12 patients with
C. difficile
-associated diarrhea (CDAD) identified
fusA
mutations, one or two nonsynonymous substitutions, or in one case a deletion of one codon associated with resistance. Five of these mutations have previously been described in
fusA
of fusidic acid-resistant
Staphylococcus aureus
, but seven were novel
fusA
mutations. Fusidic acid monotherapy for CDAD seemed to rapidly select conserved resistant mutants.
Antiplasmodial Activity of Lauryl-Lysine Oligomers
Authors: Radzishevsky I. , Krugliak M. , Ginsburg H. , Mor A. 
Published: February 2007

ABSTRACT

The ever evolving resistance of the most virulent malaria parasite,
Plasmodium falciparum
, to antimalarials necessitates the continuous development of new drugs. Our previous analysis of the antimalarial activities of the hemolytic antimicrobial peptides dermaseptins and their acylated derivatives implicated the importance of hydrophobicity and charge for drug action. Following these findings, an oligoacyllysine (OAK) tetramer designed to mimic the characteristics of dermaseptin was synthesized and assessed for its antimalarial activity in cultures of
P. falciparum
. The tetramer inhibited the growth of different plasmodial strains at low micromolar concentrations (mean 50% inhibitory concentration [IC
50
], 1.8 μM). A structure-activity relationship study involving eight derivatives unraveled smaller, more potent OAK analogs (IC
50
s, 0.08 to 0.14 μM). The most potent analogs were the most selective, with selectivity ratios of 3 orders of magnitude. Selectivity was strongly influenced by the self-assembly properties resulting from interactions between hydrophobic OAKs, as has been observed with conventional antimicrobial peptides. Further investigations performed with a representative OAK revealed that the ring and trophozoite stages of the parasite developmental cycle were equally sensitive to the compound. A shortcoming of the tested compound was the need for long incubation times in order for it to exert its full effect. Nevertheless, the encouraging results obtained in this study regarding the efficiency and selectivity of some compounds establish them as leads for further development.
Tetracycline Resistance in Group A Streptococci: Emergence on a Global Scale and Influence on Multiple-Drug Resistance
Authors: Ayer Vanessa , Tewodros Wezenet , Manoharan Anand , Skariah Sini , Luo Feng , Bessen Debra E. 
Published: February 2007

ABSTRACT

A global sample of group A streptococci (GAS) revealed ≥80 separate acquisitions of tetracycline resistance. Of 244 clones, 38 and 25% displayed resistance to tetracycline and erythromycin, respectively; a relatively high proportion (15%) were resistant to both classes of drugs.
tet
(M) displayed a highly significant association with
erm
(B).
Candida albicans
and
Candida dubliniensis
Respond Differently to Echinocandin Antifungal Agents In Vitro
Authors: Jacobsen Mette D. , Whyte Julie A. , Odds Frank C. 
Published: February 2007

ABSTRACT

Candida dubliniensis
isolates tested for susceptibility to anidulafungin, caspofungin, and micafungin commonly showed artifactual regrowth and/or trailing effects with MIC tests done under conditions involving a high initial yeast concentration. The artifacts were less common with
Candida albicans
and seldom seen for either species under Clinical and Laboratory Standards Institute method M27-A test conditions.
A Complex Ergovaline Gene Cluster in Epichloë Endophytes of Grasses
Authors: Fleetwood Damien J. , Scott Barry , Lane Geoffrey A. , Tanaka Aiko , Johnson Richard D. 
Published: February 2007

ABSTRACT

Clavicipitaceous fungal endophytes of the genera
Epichloë
and
Neotyphodium
form symbioses with grasses of the subfamily Pooideae, in which they can synthesize an array of bioprotective alkaloids. Some strains produce the ergopeptine alkaloid ergovaline, which is implicated in livestock toxicoses caused by ingestion of endophyte-infected grasses. Cloning and analysis of a nonribosomal peptide synthetase (NRPS) gene from
Neotyphodium lolii
revealed a putative gene cluster for ergovaline biosynthesis containing a single-module NRPS gene,
lpsB
, and other genes orthologous to genes in the ergopeptine gene cluster of
Claviceps purpurea
and the clavine cluster of
Aspergillus fumigatus
. Despite conservation of gene sequence, gene order is substantially different between the
N. lolii
,
C. purpurea
, and
A. fumigatus
ergot alkaloid gene clusters. Southern analysis indicated that the
N. lolii
cluster was linked with previously identified ergovaline biosynthetic genes
dmaW
and
lpsA
. The ergovaline genes are closely associated with transposon relics, including retrotransposons and autonomous and nonautonomous DNA transposons. All genes in the cluster were highly expressed in planta, but expression was very low or undetectable in mycelia from axenic culture. This work provides a genetic foundation for elucidating biochemical steps in the ergovaline pathway, the ecological role of individual ergot alkaloid compounds, and the regulation of their synthesis in planta.