bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro Activities of DX-619 and Comparison Quinolones against Gram-Positive Cocci
Authors: Wickman Paul A. , Black Jennifer A. , Moland Ellen Smith , Thomson Kenneth S. 
Published: May 2006

ABSTRACT

The in vitro activity of the novel quinolone DX-619 was compared to those of currently available quinolones against U.S. clinical isolates of
Staphylococcus aureus
, coagulase-negative staphylococci,
Enterococcus
spp.,
Streptococcus pyogenes
, and
Streptococcus pneumoniae
. DX-619 was the most potent quinolone overall, indicating possible utility as an anti-gram-positive quinolone.
Analysis of the Loading and Hydroxylation Steps in Lankamycin Biosynthesis in
Streptomyces rochei
Authors: Arakawa Kenji , Kodama Kazuya , Tatsuno Satoshi , Ide Sayoko , Kinashi Haruyasu 
Published: May 2006

ABSTRACT

The biosynthetic gene cluster of lankamycin (LM), a 14-member macrolide antibiotic, is encoded on the 210-kb linear plasmid pSLA2-L in
Streptomyces rochei
7434AN4. LM contains a 3-hydroxy-2-butyl group at the C-13 position, which is different from an ethyl group in erythromycin. The following two possibilities could be considered for the origin of this starter moiety of LM biosynthesis: (i) an extra module exists in the biosynthetic gene cluster and loads an additional acetate molecule, or (ii) 3-hydroxy-2-butyrate or its equivalent is loaded and incorporated as a starter. The former possibility was eliminated by the complete sequencing of pSLA2-L, which showed no extra module. On the other hand, the latter was confirmed by incorporation of deuterium in [3-
2
H]
dl
-isoleucine into the C-14 position of LM. The timing of hydroxylation reactions at the C-15 and C-8 positions of LM was studied by constructing disruptants of two P450 hydroxylase genes,
lkmF
(
orf26
) and
lkmK
(
orf37
). The
lkmF
disruptant produced 8-deoxylankamycin, while the
lkmK
disruptant produced both 15-deoxylankamycin and 8,15-dideoxylankamycin. These results clearly showed that LkmF is a C-8 hydroxylase and LkmK is a C-15 hydroxylase in LM biosynthesis and in addition suggested the order of hydroxylation steps; namely, hydroxylation may occur at first at C-15 by LkmK and then at C-8 by LkmF.
Colistin Methanesulfonate Is an Inactive Prodrug of Colistin against
Pseudomonas aeruginosa
Authors: Bergen Phillip J. , Li Jian , Rayner Craig R. , Nation Roger L. 
Published: May 2006

ABSTRACT

There is a dearth of information on the pharmacodynamics of “colistin,” despite its increasing use as a last line of defense for treatment of infections caused by multidrug-resistant gram-negative organisms. The antimicrobial activities of colistin and colistin methanesulfonate (CMS) were investigated by studying the time-kill kinetics of each against a type culture of
Pseudomonas aeruginosa
in cation-adjusted Mueller-Hinton broth. The appearance of colistin from CMS spiked at 8.0 and 32 mg/liter was measured by high-performance liquid chromatography, which generated colistin concentration-time profiles. These concentration-time profiles were subsequently mimicked in other incubations, independent of CMS, by incrementally spiking colistin. When the cultures were spiked with CMS at either concentration, there was a substantial delay in the onset of the killing effect which was not evident until the concentrations of colistin generated from the hydrolysis of CMS had reached approximately 0.5 to 1 mg/liter (i.e., ∼0.5 to 1 times the MIC for colistin). The time course of the killing effect was similar when colistin was added incrementally to achieve the same colistin concentration-time course observed from the hydrolysis of CMS. Given that the killing kinetics of CMS can be accounted for by the appearance of colistin, CMS is an inactive prodrug of colistin with activity against
P. aeruginosa
. This is the first study to demonstrate the formation of colistin in microbiological media containing CMS and to demonstrate that CMS is an inactive prodrug of colistin. These findings have important implications for susceptibility testing involving “colistin,” in particular, for MIC measurement and for microbiological assays and pharmacokinetic and pharmacodynamic studies.
Genetic Changes That Correlate with Reduced Susceptibility to Daptomycin in
Staphylococcus aureus
Authors: Friedman Lisa , Alder Jeff D. , Silverman Jared A. 
Published: May 2006

ABSTRACT

Daptomycin is a lipopeptide antibiotic with potent activity against gram-positive bacteria. Complete-genome comparisons of laboratory-derived
Staphylococcus aureus
with decreased susceptibility to daptomycin and their susceptible parent were used to identify genes that contribute to reduced susceptibility to daptomycin. Selective pressure of growth in sublethal concentrations of daptomycin resulted in the accumulation of mutations over time correlating with incremental decreases in susceptibility. Single point mutations resulting in amino acid substitutions occurred in three distinct proteins: MprF, a lysylphosphatidylglycerol synthetase; YycG, a histidine kinase; and RpoB and RpoC, the β and β′ subunits of RNA polymerase. Sequence analysis of
mprF
,
yycF
,
yycG
,
rpoB
, and
rpoC
in clinical isolates that showed treatment-emergent increases in daptomycin MICs revealed point mutations in
mprF
and a nucleotide insertion in
yycG
, suggesting a role for these genes in decreased susceptibility to daptomycin in the hospital setting.
Activities of Ceftobiprole, a Novel Broad-Spectrum Cephalosporin, against
Haemophilus influenzae
and
Moraxella catarrhalis
Authors: Bogdanovich Tatiana , Clark Catherine , Ednie Lois , Lin Gengrong , Smith Kathy , Shapiro Stuart , Appelbaum Peter C. 
Published: May 2006

ABSTRACT

Ceftobiprole, a broad-spectrum pyrrolidinone-3-ylidenemethyl cephem currently in phase III clinical trials, had MICs between 0.008 μg/ml and 8.0 μg/ml for 321 clinical isolates of
Haemophilus influenzae
and between ≤0.004 μg/ml and 1.0 μg/ml for 49 clinical isolates of
Moraxella catarrhalis
. Ceftobiprole MIC
50
and MIC
90
values for
H. influenzae
were 0.06 μg/ml and 0.25 μg/ml for β-lactamase-positive strains (
n
= 262), 0.03 μg/ml and 0.25 μg/ml for β-lactamase-negative strains (
n
= 40), and 0.5 μg/ml and 2.0 μg/ml for β-lactamase-negative ampicillin-resistant strains (
n
= 19), respectively. Ceftobiprole MIC
50
and MIC
90
values for β-lactamase-positive
M. catarrhalis
strains (
n
= 40) were 0.12 μg/ml and 0.5 μg/ml, respectively, whereas the ceftobiprole MIC range for β-lactamase-negative
M. catarrhalis
strains (
n
= 9) was ≤0.004 to 0.03 μg/ml. Ceftriaxone MICs usually were generally at least twofold lower than those of ceftobiprole, whereas amoxicillin-clavulanate MICs usually were higher than those of ceftobiprole. Azithromycin and telithromycin had unimodal MIC distributions against
H. influenzae
, with MIC
90
values of azithromycin and telithromycin of 2 μg/ml and 4 μg/ml, respectively. Except for selected quinolone-nonsusceptible
H. influenzae
strains, moxifloxacin proved highly active, with MIC
90
values of 0.12 μg/ml. Time-kill analyses showed that ceftobiprole, ceftriaxone, cefpodoxime, amoxicillin-clavulanate, azithromycin, telithromycin, and moxifloxacin were bactericidal at 2× MIC by 24 h against all 10
H. influenzae
strains surveyed. Only modest increases in MICs were found for
H. influenzae
or
M. catarrhalis
clones after 50 serial passages in the presence of subinhibitory concentrations of ceftobiprole, and single-passage selection showed that the selection frequency of
H. influenzae
or
M. catarrhalis
clones with elevated ceftobiprole MICs is quite low.
In Vitro and In Vivo Activities of Rifampin, Streptomycin, Amikacin, Moxifloxacin, R207910, Linezolid, and PA-824 against
Mycobacterium ulcerans
Authors: Ji Baohong , Lefrançois Sébastien , Robert Jerome , Chauffour Aurélie , Truffot Chantal , Jarlier Vincent 
Published: May 2006

ABSTRACT

Seven antimicrobials were tested in vitro against 29 clinical isolates of
Mycobacterium ulcerans
. R207910 demonstrated the lowest MIC
50
and MIC
90
, followed by moxifloxacin (MXF), streptomycin (STR), rifampin (RIF), amikacin (AMK), linezolid (LZD), and PA-824. All but PA-824 demonstrated an MIC
90
significantly less than the clinically achievable peak serum level. Administered as monotherapy to mice, RIF, STR, AMK, MXF, R207910, and LZD demonstrated some degree of bactericidal activity, whereas PA-824 failed to prevent mortality and to reduce the mean number of CFU in the footpads. Because 4 or 8 weeks of treatment by the combinations RIF-MXF, RIF-R207910, and RIF-LZD displayed bactericidal effects similar to those of RIF-STR and RIF-AMK, these three combinations might be considered as orally administered combined regimens for treatment of Buruli ulcer. Taking into account the cost, potential toxicity, and availability, the combination RIF-MXF appears more feasible for application in the field; additional experiments with mice are warranted to define further its activity against
M. ulcerans
. In addition, a pilot clinical trial is proposed to test the efficacy of RIF-MXF for treatment of Buruli ulcer.
Antibody-Guided Alpha Radiation Effectively Damages Fungal Biofilms
Authors: Martinez L. R. , Bryan R. A. , Apostolidis C. , Morgenstern A. , Casadevall A. , Dadachova E. 
Published: May 2006

ABSTRACT

The use of indwelling medical devices—pacemakers, prosthetic joints, catheters—is rapidly growing and is often complicated by infections with biofilm-forming microbes that are resistant to antimicrobial agents and host defense mechanisms. We investigated for the first time the use of microbe-specific monoclonal antibodies (MAbs) as delivery vehicles for targeting biofilms with cytocidal radiation. MAb 18B7 (immunoglobulin G1 [IgG1]), which binds to capsular polysaccharides of the human pathogenic fungus
Cryptococcus neoformans
, penetrated cryptococcal biofilms, as shown by confocal microscopy. When the alpha radiation-emitter 213-Bismuth (
213
Bi) was attached to MAb 18B7 and the radiolabeled MAb was added to
C. neoformans
biofilms, there was a 50% reduction in biofilm metabolic activity. In contrast, when the IgM MAb 13F1 labeled with
213
Bi was used there was no penetration of the fungal biofilm and no damage. Unlabeled 18B7,
213
Bi-labeled nonspecific MAbs, and gamma and beta types of radiation did not have an effect on biofilms. The lack of efficacy of gamma and beta radiation probably reflects the radioprotective properties of polysaccharide biofilm matrix. Our results indicate that
C. neoformans
biofilms are susceptible to treatment with antibody-targeted alpha radiation, suggesting a novel option for the prevention or treatment of microbial biofilms on indwelling medical devices.
Fluoroquinolone-Resistant Urinary Isolates of
Escherichia coli
from Outpatients Are Frequently Multidrug Resistant: Results from the NorthAmerican Urinary Tract Infection Collaborative Alliance-QuinoloneResistance Study
Authors: Karlowsky James A. , Hoban Daryl J. , DeCorby Melanie R. , Laing Nancy M. , Zhanel George G. 
Published: May 2006

ABSTRACT

Ciprofloxacin-resistant
Escherichia coli
isolates (
n
= 1,858) from outpatient midstream urine specimens at 40 North American clinical
laboratories in 2004 to 2005 were frequently resistant to ampicillin
(79.8% of isolates) and trimethoprim-sulfamethoxazole (66.5%);
concurrent resistance to cefdinir (9.0%) or nitrofurantoin (4.0%) was
less common. Only 10.8% of isolates were resistant to ciprofloxacin
alone. Fluoroquinolone-resistant isolates of
E. coli
from
urine were frequently multidrug
resistant.
Molecular Validation of LpxC as an Antibacterial Drug Target in
Pseudomonas aeruginosa
Authors: Mdluli Khisimuzi E. , Witte Pamela R. , Kline Toni , Barb Adam W. , Erwin Alice L. , Mansfield Bryce E. , McClerren Amanda L. , Pirrung Michael C. , Tumey L. Nathan , Warrener Paul , Raetz Christian R. H. , Stover C. Kendall 
Published: May 2006

ABSTRACT

LpxC [UDP-3-
O-
(
R
-3-hydroxymyristoyl)-GlcNAc deacetylase] is a metalloamidase that catalyzes the first committed step in the biosynthesis of the lipid A component of lipopolysaccharide. A previous study (H. R. Onishi, B. A. Pelak, L. S. Gerckens, L. L. Silver, F. M. Kahan, M. H. Chen, A. A. Patchett, S. M. Galloway, S. A. Hyland, M. S. Anderson, and C. R. H. Raetz, Science 274:980-982, 1996) identified a series of synthetic LpxC-inhibitory molecules that were bactericidal for
Escherichia coli
. These molecules did not inhibit the growth of
Pseudomonas aeruginosa
and were therefore not developed further as antibacterial drugs. The inactivity of the LpxC inhibitors for
P. aeruginosa
raised the possibility that LpxC activity might not be essential for all gram-negative bacteria. By placing the
lpxC
gene of
P. aeruginosa
under tight control of an arabinose-inducible promoter, we demonstrated the essentiality of LpxC activity for
P. aeruginosa
. It was found that compound L-161,240, the most potent inhibitor from the previous study, was active against a
P. aeruginosa
construct in which the endogenous
lpxC
gene was inactivated and in which LpxC activity was supplied by the
lpxC
gene from
E. coli
. Conversely, an
E. coli
construct in which growth was dependent on the
P. aeruginosa lpxC
gene was resistant to the compound. The differential activities of L-161,240 against the two bacterial species are thus the result primarily of greater potency toward the
E. coli
enzyme rather than of differences in the intrinsic resistance of the bacteria toward antibacterial compounds due to permeability or efflux. These data validate
P. aeruginosa
LpxC as a target for novel antibiotic drugs and should help direct the design of inhibitors against clinically important gram-negative bacteria.
Antipneumococcal Activity of DW-224a, a New Quinolone, Compared to Those of Eight Other Agents
Authors: Kosowska-Shick Klaudia , Credito Kim , Pankuch Glenn A. , Lin Gengrong , Bozdogan Bülent , McGhee Pamela , Dewasse Bonifacio , Choi Dong-Rack , Ryu Jei Man , Appelbaum Peter C. 
Published: May 2006

ABSTRACT

DW-224a is a new broad-spectrum quinolone with excellent antipneumococcal activity. Agar dilution MIC was used to test the activity of DW-224a compared to those of penicillin, ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, gemifloxacin, amoxicillin-clavulanate, cefuroxime, and azithromycin against 353 quinolone-susceptible pneumococci. The MICs of 29 quinolone-resistant pneumococci with defined quinolone resistance mechanisms against seven quinolones and an efflux mechanism were also tested. DW-224a was the most potent quinolone against quinolone-susceptible pneumococci (MIC
50
, 0.016 μg/ml; MIC
90
, 0.03 μg/ml), followed by gemifloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. β-Lactam MICs rose with those of penicillin G, and azithromycin resistance was seen mainly in strains with raised penicillin G MICs. Against the 29 quinolone-resistant strains, DW-224a had the lowest MICs (0.06 to 1 μg/ml) compared to those of gemifloxacin, clinafloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. DW-224a at 2× MIC was bactericidal after 24 h against eight of nine strains tested. Other quinolones gave similar kill kinetics relative to higher MICs. Serial passages of nine strains in the presence of sub-MIC concentrations of DW-224a, moxifloxacin, levofloxacin, ciprofloxacin, gatifloxacin, gemifloxacin, amoxicillin-clavulanate, cefuroxime, and azithromycin were performed. DW-224a yielded resistant clones similar to moxifloxacin and gemifloxacin but also yielded lower MICs. Azithromycin selected resistant clones in three of the five parents tested. Amoxicillin-clavulanate and cefuroxime did not yield resistant clones after 50 days.
Pharmacokinetics and Safety of Oral Posaconazole in Neutropenic Stem Cell Transplant Recipients
Authors: Gubbins Paul O. , Krishna Gopal , Sansone-Parsons Angela , Penzak Scott R. , Dong Li , Martinho Monika , Anaissie Elias J. 
Published: May 2006

ABSTRACT

The pharmacokinetics of posaconazole oral suspension in neutropenic patients undergoing high-dose chemotherapy and stem cell transplantation were evaluated, and the association of plasma posaconazole exposure with the presence and severity of oral mucositis was explored in this nonrandomized, open-label, parallel-group, multiple-dose pharmacokinetic study. Thirty patients were enrolled and received one of three regimens (group I, 200 mg once daily; group II, 400 mg once daily; group III, 200 mg four times daily) for the duration of neutropenia. The mean total exposure for day 1, as shown by the area under the concentration-time curve from 0 to 24 h (AUC
0-24
), was 1.96 mg · h/liter in group I and was 51% higher in group II and in group III. Increases in AUC
0-24
and maximum plasma concentration (
C
max
) in groups II and III were dose related. The AUC
0-24
and
C
max
values on day 1 were similar between groups II and III. There was interpatient variability of up to 68% in the pharmacokinetic values for our study population. Steady state was attained by days 5 to 6. Average steady-state plasma posaconazole trough values were 192, 219, and 414 ng/ml in groups I, II, and III, respectively. The AUC
0-24
and apparent oral clearance increased by increasing dose and dosing frequency. Mucositis appeared to reduce exposure but did not significantly affect mean total posaconazole exposure (AUC and
C
max
) at steady state (
P
= 0.1483). Moreover, this reduction could be overcome by increasing the total dose and dosing frequency. Posaconazole was safe and well tolerated.
In Vitro Activities of 10 Combinations of Antifungal Agents against the Multiresistant Pathogen
Scopulariopsis brevicaulis
Authors: Cuenca-Estrella Manuel , Gomez-Lopez Alicia , Buitrago Maria J. , Mellado Emilia , Garcia-Effron Guillermo , Rodriguez-Tudela Juan L. 
Published: May 2006

ABSTRACT

The activities of 10 combinations of antifungal agents against 25 clinical isolates of
Scopulariopsis brevicaulis
were tested by the checkerboard technique. An average indifferent effect was detected for all combinations. Synergy was observed for some isolates and combinations, particularly with posaconazole-terbinafine (68% of strains), amphotericin B-caspofungin (60%), and posaconazole-caspofungin (48%).
In Vitro Activities of Posaconazole, Fluconazole, Itraconazole, Voriconazole, and Amphotericin B against a Large Collection of Clinically Important Molds and Yeasts
Authors: Sabatelli F. , Patel R. , Mann P. A. , Mendrick C. A. , Norris C. C. , Hare R. , Loebenberg D. , Black T. A. , McNicholas P. M. 
Published: May 2006

ABSTRACT

The in vitro activity of the novel triazole antifungal agent posaconazole (Noxafil; SCH 56592) was assessed in 45 laboratories against approximately 19,000 clinically important strains of yeasts and molds. The activity of posaconazole was compared with those of itraconazole, fluconazole, voriconazole, and amphotericin B against subsets of the isolates. Strains were tested utilizing Clinical and Laboratory Standards Institute broth microdilution methods using RPMI 1640 medium (except for amphotericin B, which was frequently tested in antibiotic medium 3). MICs were determined at the recommended endpoints and time intervals. Against all fungi in the database (22,850 MICs), the MIC
50
and MIC
90
values for posaconazole were 0.063 μg/ml and 1 μg/ml, respectively. MIC
90
values against all yeasts (18,351 MICs) and molds (4,499 MICs) were both 1 μg/ml. In comparative studies against subsets of the isolates, posaconazole was more active than, or within 1 dilution of, the comparator drugs itraconazole, fluconazole, voriconazole, and amphotericin B against approximately 7,000 isolates of
Candida
and
Cryptococcus
spp. Against all molds (1,702 MICs, including 1,423 MICs for
Aspergillus
isolates), posaconazole was more active than or equal to the comparator drugs in almost every category. Posaconazole was active against isolates of
Candida
and
Aspergillus
spp. that exhibit resistance to fluconazole, voriconazole, and amphotericin B and was much more active than the other triazoles against zygomycetes. Posaconazole exhibited potent antifungal activity against a wide variety of clinically important fungal pathogens and was frequently more active than other azoles and amphotericin B.
Targeting Antibacterial Agents by Using Drug-Carrying Filamentous Bacteriophages
Authors: Yacoby Iftach , Shamis Marina , Bar Hagit , Shabat Doron , Benhar Itai 
Published: May 2006

ABSTRACTBacteriophages have been used for more than a century for (unconventional) therapy of bacterial infections, for half a century as tools in genetic research, for 2 decades as tools for discovery of specific target-binding proteins, and for nearly a decade as tools for vaccination or as gene delivery vehicles. Here we present a novel application of filamentous bacteriophages (phages) as targeted drug carriers for the eradication of (pathogenic) bacteria. The phages are genetically modified to display a targeting moiety on their surface and are used to deliver a large payload of a cytotoxic drug to the target bacteria. The drug is linked to the phages by means of chemical conjugation through a labile linker subject to controlled release. In the conjugated state, the drug is in fact a prodrug devoid of cytotoxic activity and is activated following its dissociation from the phage at the target site in a temporally and spatially controlled manner. Our model target wasStaphylococcus aureus, and the model drug was the antibiotic chloramphenicol. We demonstrated the potential of using filamentous phages as universal drug carriers for targetable cells involved in disease. Our approach replaces the selectivity of the drug itself with target selectivity borne by the targeting moiety, which may allow the reintroduction of nonspecific drugs that have thus far been excluded from antibacterial use (because of toxicity or low selectivity). Reintroduction of such drugs into the arsenal of useful tools may help to combat emerging bacterial antibiotic resistance.
Microdialysis Study of Imipenem Distribution in Skeletal Muscle and Lung Extracellular Fluids of
Acinetobacter baumannii
-Infected Rats
Authors: Dahyot Claire , Marchand Sandrine , Pessini Greisiele Lorena , Pariat Claudine , Debaene Bertrand , Couet William , Mimoz Olivier 
Published: May 2006

ABSTRACT

The aim of this study was to investigate imipenem distribution in muscle and lung interstitial fluids of rats with
Acinetobacter baumannii
pulmonary infection. By combining microdialysis in blood and tissues, it was possible to demonstrate that free imipenem concentrations were virtually identical in blood, muscle, and lung.