bluuebunny/crossref_metadata_2025_split huggingface dataset:
Searching for Extraterrestrial Civilizations
Authors: Kuiper T. B. H. , Morris M. 
Published: October 2006

We have argued that planning for a search for extraterrestrial intelligence should involve a minimum number of assumptions. In view of the feasibility (at our present level of understanding) of using nuclear fusion to effect interstellar travel at a speed of 0.1
c
, it appears unwarranted (at this time) to assume that it would not occur for at least some technologically advanced civilizations. One cannot even conclude that humans would not attempt this within the next few centuries. On the contrary, the most likely future situation, given the maintenance of technological growth and the absence of extraterrestrial interference, is that our civilization will explore and colonize our galactic neighborhood.

A comparison of the time scales of galactic evolution and interstellar travel leads to the conclusion that the galaxy is either essentially empty with respect to technological civilizations or extensively colonized. In the former instance, a SETI would be unproductive. In the latter, a SETI could be fruitful if a signal has been deliberately directed at the earth or at an alien outpost, probe, or communication relay station in our solar system. In the former case, an existing antenna would probably be sufficient to detect the signal. In the latter case, success would depend on the way in which the communications were coded.
Failure to detect a signal could permit any of the following conclusions: (i) the galaxy is devoid of technological civilizations, advanced beyond our own, (ii) such civilizations exist, but cannot (for some reason which is presently beyond our ken) engage in interstellar colonization, or (iii) such civilizations are not attempting overt contact with terrestrial civilizations and their intercommunications, if present, are not coded in a simple way. To plan at this time for a high-cost, large-array SETI based on the last two possibilities appears to be rather premature.
Telithromycin-Nonsusceptible Clinical Isolates of
Streptococcus pneumoniae
from Europe
Authors: Al-Lahham Adnan , Appelbaum Peter C. , van der Linden Mark , Reinert Ralf René 
Published: October 2006

ABSTRACT

Telithromycin-nonsusceptible pneumococcal clinical isolates (
n
= 17) were analyzed for their antimicrobial susceptibility, macrolide resistance mechanisms, and genetic relatedness. All strains showed the
erm
(B) genotype and showed a wide range of combinations of macrolide resistance mechanisms. The predominant clone (
n
= 7) was serotype 14, sequence type 143.
Hyaluronic Acid Binding Peptides Prevent Experimental Staphylococcal Wound Infection
Authors: Zaleski Kathleen J. , Kolodka Tadeusz , Cywes-Bentley Colette , McLoughlin Rachel M. , Delaney Mary L. , Charlton Bernard T. , Johnson Wendy , Tzianabos Arthur O. 
Published: October 2006

ABSTRACT

Staphylococcus aureus
is a major cause of surgical wound infections. The development of mechanisms of antimicrobial resistance by this and other bacterial pathogens has prompted the search for new approaches to treat infectious diseases. Hyaluronic acid binding peptides have been shown to modulate cellular trafficking during host responses and were assessed for their ability to treat and possibly prevent experimental surgical wound infections caused by
S. aureus
. Treatment with these peptides was highly efficacious in reducing the number of
S. aureus
cells at the wound site and ameliorated the inflammatory host response associated with these infections. These data suggest a novel approach for the treatment and prophylaxis of staphylococcal wound infections in the clinical setting.
Population Pharmacokinetics of Atazanavir in Patients with Human Immunodeficiency Virus Infection
Authors: Colombo Sara , Buclin Thierry , Cavassini Matthias , Décosterd Laurent A. , Telenti Amalio , Biollaz Jérôme , Csajka Chantal 
Published: October 2006

ABSTRACTAtazanavir (ATV) is a new azapeptide protease inhibitor recently approved and currently used at a fixed dose of either 300 mg once per day (q.d.) in combination with 100 mg ritonavir (RTV) or 400 mg q.d. without boosting. ATV is highly bound to plasma proteins and extensively metabolized by CYP3A4. Since ATV plasma levels are highly variable and seem to be correlated with both viral response and toxicity, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the ATV pharmacokinetic profile in a target population of HIV patients, to characterize interpatient and intrapatient variability, and to identify covariates that might influence ATV disposition. A population analysis was performed with NONMEM with 574 plasma samples from a cohort of 214 randomly selected patients receiving ATV. A total of 346 randomly collected ATV plasma levels and 19 full concentration-time profiles at steady state were available. The pharmacokinetic parameter estimates were an oral clearance (CL) of 12.9 liters/h (coefficient of variation [CV], 26%), a volume of distribution of 88.3 liters (CV, 29%), an absorption rate constant of 0.405 h−1(CV, 122%), and a lag time of 0.88 h. A relative bioavailability value was introduced to account for undercompliance due to infrequent follow-ups (0.81; CV, 45%). Among the covariates tested, only RTV significantly reduced CL by 46%, thereby increasing the ATV elimination half-life from 4.6 h to 8.8 h. The pharmacokinetic parameters of ATV were adequately described by a one-compartment population model. The concomitant use of RTV improved the pharmacokinetic profile. However, the remaining high interpatient variability suggests the possibility of an impact of unmeasured covariates, such as genetic traits or environmental influences. This population pharmacokinetic model, together with therapeutic drug monitoring and Bayesian dosage adaptation, can be helpful in the selection and adaptation of ATV doses.
Novel Streptomycin Resistance Gene from
Mycobacterium fortuitum
Authors: Ramón-García Santiago , Otal Isabel , Martín Carlos , Gómez-Lus Rafael , Aínsa José A. 
Published: October 2006

ABSTRACT

We have isolated the
aph
(
3
")
-Ic
gene, encoding an aminoglycoside 3"-
O
-phosphotransferase [APH(3")-Ic], from a genomic library of an environmental
Mycobacterium fortuitum
strain, selecting for streptomycin resistance. APH(3")-Ic phosphorylates and inactivates streptomycin. Similar genes have been described in
Streptomyces griseus
and plasmid RSF1010. It is also present in some
M. fortuitum
clinical isolates.
Macrolide and Azithromycin Use Are Linked to Increased Macrolide Resistance in
Streptococcus pneumoniae
Authors: Bergman Miika , Huikko Solja , Huovinen Pentti , Paakkari Pirkko , Seppälä Helena ,   Finnish Study Group for Antimicrobial Resistance (FiRe Network)
Published: October 2006

ABSTRACT

The connection between regional rates of antimicrobial resistance in
Streptococcus pneumoniae
and regional antimicrobial use in Finland was investigated. During the 6-year study period of 1997 to 2002, a total of 31,609
S. pneumoniae
isolates were tested for penicillin resistance and a total of 23,769 isolates were tested for macrolide resistance in 18 central hospital districts in Finland. The regional macrolide resistance rates were compared with the local use of (i) all macrolides pooled and (ii) azithromycin. The penicillin resistance levels were compared with the consumption data for (i) penicillins, (ii) cephalosporins, (iii) all beta-lactams pooled, and (iv) all macrolides pooled. A statistically significant association between macrolide resistance and total use of macrolides and the use of azithromycin was found. Moreover, total use of beta-lactams and total use of cephalosporins were significantly connected to low-level penicillin resistance. A statistically significant association between penicillin-nonsusceptible isolates and penicillin or total macrolide consumption was not found. In conclusion, total macrolide use and azithromycin use are associated with increased macrolide resistance, and beta-lactam use and cephalosporin use are connected to increased low-level penicillin resistance in
S. pneumoniae
. Unnecessary prescribing of macrolides and cephalosporins should be avoided.
Randomized, Open-Label, Comparative Study of Piperacillin-Tazobactam Administered by Continuous Infusion versus Intermittent Infusion for Treatment of Hospitalized Patients with Complicated Intra-Abdominal Infection
Authors: Lau William K. , Mercer David , Itani Kamal M. , Nicolau David P. , Kuti Joseph L. , Mansfield Debra , Dana Adrian 
Published: October 2006

ABSTRACT

The purpose of this randomized, multicenter, open-label study was to compare the continuous infusion of piperacillin-tazobactam with the standard intermittent infusion in 262 hospitalized patients with complicated intra-abdominal infections. Within 1 day of surgical intervention, eligible patients were randomized (1:1) to piperacillin-tazobactam 12 g/1.5 g administered continuously over 24 h or 3 g/0.375 g administered over 30 min intermittently every 6 h for 4 to 14 days. The demographics of the patients in the groups were similar, with a median APACHE II score of 7 and a median length of hospitalization of 7 days. Among 167 clinically evaluable patients, 86.4% and 88.4% of the patients treated with the continuous infusion and the intermittent infusion, respectively, were clinically cured or improved at the test-of-cure visit (
P
= 0.817). Bacteriological success was observed in 83.9% and 87.9% of patients (
P
= 0.597) in the two groups, respectively, and no differences in bacteriological response by pathogen were noted. Defervesence and white blood cell count normalization occurred in the majority of patients within 3 days and were similar between patients receiving the continuous infusion and those receiving the intermittent infusion. Drug-related adverse events were generally mild and were reported in similar numbers of patients in each arm of the trial. The results of this study support continuous infusion as a safe and reasonable alternate mode of administration of piperacillin-tazobactam for the treatment of complicated intra-abdominal infection.
Derivation of an In Vivo Drug Exposure Breakpoint for Flucytosine againstCandida albicansand Impact of the MIC, Growth Rate, and Resistance Genotype on the Antifungal Effect
Authors: Hope William W. , Warn Peter A. , Sharp Andrew , Howard Susan , Kasai Miki , Louie Arnold , Walsh Thomas J. , Drusano George L. , Denning David W. 
Published: October 2006

ABSTRACTDrug exposure or pharmacodynamic breakpoints refer to a magnitude of drug exposure which separates a population into groups with high and low probabilities of attaining a desired outcome. We used a pharmacodynamic model of disseminated candidiasis to define an in vivo drug exposure breakpoint for flucytosine (5FC) againstCandida albicans. The results were bridged to humans by using population pharmacokinetics and Monte Carlo simulation. An in vivo drug exposure breakpoint for 5FC was apparent when serum levels were above the MIC for 45% of the dosing interval. The Monte Carlo simulations suggested that using a human dose of 100 mg/kg of body weight/day in four divided doses, 5FC resistance was defined at an MIC of 32 mg/liter. Target attainment rates following administration of 25, 50, and 100 mg/kg/day were similar, suggesting that the use of a lower dose of 5FC is possible. Using six isolates ofC. albicanswith MICs ranging from 0.06 to >64 mg/liter, we also explored the influence that the MIC, the fraction of the dosing interval that the serum levels of 5FC remained above the MIC (T>MIC), the 5FC resistance genotype, and the in vivo growth rate had on the response to 5FC. The MIC and T>MIC were both critical measures affecting the generation of a drug effect but had no bearing on the magnitude of the maximal kill induced by 5FC. The in vivo growth rate was a critical additional determinant of the exposure-response relationship. There was a relationship between the 5FC resistance genotype and the exposure-response relationship.
In Vitro Cytotoxicity and Mitochondrial Toxicity of Tenofovir Alone and in Combination with Other Antiretrovirals in Human Renal Proximal Tubule Cells
Authors: Vidal Francesc , Domingo Joan Carles , Guallar Jordi , Saumoy Maria , Cordobilla Begoña , Sánchez de la Rosa Rainel , Giralt Marta , Álvarez Maria Luisa , López-Dupla Miguel , Torres Ferran , Villarroya Francesc , Cihlar Tomas , Domingo Pere 
Published: October 2006

ABSTRACTWe assessed the in vitro toxicity of tenofovir (TFV) and compared it with those of zidovudine (AZT), didanosine (ddI), ritonavir (RTV), and lopinavir (LPV) alone and in combination in human renal proximal tubule epithelial cells (RPTECs). The cells were treated with various concentrations and combinations of the tested antiretrovirals for up to 22 days, and cytotoxicity was determined. In addition, we assessed the levels of mitochondrial DNA (mtDNA) and cytochrome oxidase II (COII) mRNA in RPTECs treated with reverse transcriptase inhibitors. TFV alone was not associated with significant cytotoxicity. ddI showed pronounced cytotoxicity that was greater than those of AZT (P= 0.002) and TFV (P= 0.0001). The combination of 10 μM RTV and 40 μM LPV significantly reduced RPTEC viability (P< 0.0001), and TFV tended to partially reduce this effect. TFV alone affected neither mtDNA nor COII mRNA levels, whereas ddI caused a profound depletion of mtDNA and a parallel reduction in COII mRNA expression. The effects of ddI, but not those of AZT, on mtDNA and COII mRNA were further enhanced in the presence of TFV, a finding consistent with the inhibition of ddI clearance by TFV. The addition of TFV to ddI or AZT appeared to slightly increase the COII mRNA/mtDNA ratio relative to that in cells treated with ddI or AZT alone. Together, these in vitro results indicate that combination with other antiretrovirals does not significantly increase the toxic potential of TFV in RPTECs.
Urinary Bactericidal Activity of Extended-Release Ciprofloxacin (1,000 Milligrams) versus Levofloxacin (500 Milligrams) in Healthy Volunteers Receiving a Single Oral Dose
Authors: Wagenlehner Florian M. E. , Kinzig-Schippers Martina , Tischmeyer Uwe , Wagenlehner Christine , Sörgel Fritz , Naber Kurt G. 
Published: October 2006

ABSTRACT

Twelve volunteers received a single oral dose of 1,000 mg extended-release (XR) ciprofloxacin versus 500 mg levofloxacin to assess urinary bactericidal titers (UBTs) against common uropathogens. Areas under UBT-time curves were significantly larger for
Proteus mirabilis
with XR ciprofloxacin and for staphylococci with levofloxacin.
Enhancement of Antimicrobial Activity against
Pseudomonas aeruginosa
by Coadministration of G10KHc and Tobramycin
Authors: Eckert Randal , Brady Keith M. , Greenberg E. Peter , Qi Fengxia , Yarbrough Daniel K. , He Jian , McHardy Ian , Anderson Maxwell H. , Shi Wenyuan 
Published: October 2006

ABSTRACT

Pseudomonas aeruginosa
is a common opportunistic human pathogen that is associated with life-threatening acute infections and chronic airway colonization during cystic fibrosis. Previously, we converted the wide-spectrum antimicrobial peptide novispirin G10 into a
s
electively-
t
argeted
a
nti
m
icrobial
p
eptide (STAMP), G10KHc. Compared to novispirin G10, the STAMP had an enhanced ability to kill
Pseudomonas mendocina
. In this study, we explored the activity of G10KHc against
P. aeruginosa
. G10KHc was found to be highly active (as active as tobramycin) against
P. aeruginosa
clinical isolates. Most interestingly, we observed a synergistic-like enhancement in killing activity when biofilms and planktonic cultures of
P. aeruginosa
were cotreated with G10KHc and tobramycin. The data indicate that the mechanism of enhanced activity may involve increased tobramycin uptake due to G10KHc-mediated cell membrane disruption. These results suggest that G10KHc may be useful against
P. aeruginosa
during acute and chronic infection states, especially when it is coadministered with tobramycin.
In Vitro Pharmacodynamics of Anidulafungin and Caspofungin against
Candida glabrata
Isolates, Including Strains with Decreased Caspofungin Susceptibility
Authors: Cota Jason , Carden Michael , Graybill John R. , Najvar Laura K. , Burgess David S. , Wiederhold Nathan P. 
Published: October 2006

ABSTRACT

The activities of anidulafungin and caspofungin against
Candida glabrata
were evaluated. MICs, 50% inhibitory concentrations (IC
50
values), and IC
90
values for anidulafungin were lower than those for caspofungin for 16 of 18 strains tested. Anidulafungin has potent in vitro activity against
C. glabrata
that is maintained against isolates with elevated caspofungin MICs.
Multiple Genetic Elements Carry the Tetracycline Resistance Gene
tet
(W) in the Animal Pathogen
Arcanobacterium pyogenes
Authors: Billington Stephen J. , Jost B. Helen 
Published: October 2006

ABSTRACT

The
tet
(W) gene is associated with tetracycline resistance in a wide range of bacterial species, including obligately anaerobic rumen bacteria and isolates from the human gut and oral mucosa. However, little is known about how this gene is disseminated and the types of genetic elements it is carried on. We examined tetracycline-resistant isolates of the animal commensal and opportunistic pathogen
Arcanobacterium pyogenes
, all of which carried
tet
(W), and identified three genetic elements designated ATE-1, ATE-2, and ATE-3. These elements were found in 25%, 35%, and 60% of tetracycline-resistant isolates, respectively, with some strains carrying both ATE-2 and ATE-3. ATE-1 shows characteristics of a mobilizable transposon, and the
tet
(W) genes from strains carrying this element can be transferred at low frequencies between
A. pyogenes
strains. ATE-2 has characteristics of a simple transposon, carrying only the resistance gene and a transposase, while in ATE-3, the
tet
(W) gene is associated with a streptomycin resistance gene that is 100% identical at the DNA level with the
aadE
gene from the
Campylobacter jejuni
plasmid pCG8245. Both ATE-2 and ATE-3 show evidence of being carried on larger genetic elements, but conjugation to other strains was not observed under the conditions tested. ATE-1 was preferentially associated with
A. pyogenes
strains of bovine origin, while ATE-2 and ATE-3 elements were primarily found in porcine isolates, suggesting that these elements may circulate in different environments. In addition, four alleles of the
tet
(W) gene, primarily associated with different elements, were detected among
A. pyogenes
isolates.
Adaptive Resistance and Differential Protein Expression ofSalmonella entericaSerovar Enteritidis Biofilms Exposed to Benzalkonium Chloride
Authors: Mangalappalli-Illathu Anil K. , Korber Darren R. 
Published: October 2006

ABSTRACTThe development of adaptive resistance ofSalmonella entericaserovar Enteritidis ATCC 4931 biofilms following exposure to benzalkonium chloride (BC) either continuously (1 μg ml−1) or intermittently (10 μg ml−1for 10 min daily) was examined. Biofilms adapted to BC over a 144-h period could survive a normally lethal BC challenge (500 μg ml−1for 10 min) and then regrow, as determined by increases in biofilm thickness, total biomass, and the ratio of the viable biomass to the nonviable biomass. Exposure of untreated control biofilms to the lethal BC challenge resulted in biofilm erosion and cell death. Proteins found to be up-regulated following BC adaptation were those involved in energy metabolism (TpiA and Eno), amino acid and protein biosynthesis (WrbA, TrxA, RplL, Tsf, Tuf, DsbA, and RpoZ), nutrient binding (FruB), adaptation (CspA), detoxification (Tpx, SodB, and a probable peroxidase), and degradation of 1,2-propanediol (PduJ and PduA). A putative universal stress protein (YnaF) was also found to be up-regulated. Proteins involved in proteolysis (DegQ), cell envelope formation (RfbH), adaptation (UspA), heat shock response (DnaK), and broad regulatory functions (Hns) were found to be down-regulated following adaptation. An overall increase in cellular protein biosynthesis was deduced from the significant up-regulation of ribosomal subunit proteins, translation elongation factors, and amino acid biosynthesis protein and down-regulation of serine endoprotease. The cold shock response, stress response, and detoxification are suggested to play roles in the adaptive resistance ofSalmonellaserovar Enteritidis biofilms to BC.
Genes Involved in Intrinsic Antibiotic Resistance of
Acinetobacter baylyi
Authors: Gomez Maria J. , Neyfakh Alexander A. 
Published: October 2006

ABSTRACT

Bacterial genes defining intrinsic resistance to antibiotics encode proteins that can be targeted by antibiotic potentiators. To find such genes, a transposon insertion library of
Acinetobacter baylyi
was screened with subinhibitory concentrations of various antibiotics to find supersusceptible mutants. A DNA microarray printer was used to replica plate 10,000 individual library clones to select mutants unable to grow at 1/10 the MICs of 12 different antibiotics. Transposon insertions in 11 genes were found to cause an eightfold or higher hypersusceptibility to at least one antibiotic. Most of the mutants identified exhibited hypersusceptibility to β-lactam antibiotics. These included mutants with disruptions of genes encoding proteins involved in efflux (
acrB
and
oprM
) as well as genes pertaining to peptidoglycan synthesis and modification (
ampD
,
mpl
, and
pbpG
). However, disruptions of genes encoding proteins with seemingly unrelated functions (
gph
,
argH
,
hisF, and ACIAD0795
) can also render cells hypersusceptible to β-lactam antibiotics. A knockout of
gshA
, involved in glutathione biosynthesis, enhanced the susceptibility to metronidazole, while a knockout of
recD
, involved in recombination and repair, made the bacteria hypersusceptible to ciprofloxacin. Disruption of
acrB
in
Escherichia coli
rendered the cells hypersusceptible to several antibiotics. However, knockout mutants of other homologous genes in
E. coli
showed no significant changes in antibiotic MICs, indicating that the intrinsic resistance genes are species specific.
In Vitro Activity of Ceftobiprole against Aerobic and Anaerobic Strains Isolated from Diabetic Foot Infections
Authors: Goldstein Ellie J. C. , Citron Diane M. , Merriam C. Vreni , Warren Yumi A. , Tyrrell Kerin L. , Fernandez Helen T. 
Published: October 2006

ABSTRACT

Against 443 aerobic and anaerobic bacteria isolated from diabetic foot infections, ceftobiprole MICs (μg/ml) at which 90% of the isolates tested were inhibited were as follows: methicillin-resistant
Staphylococcus aureus
, 1; methicillin-susceptible
S. aureus
and
Staphylococcus lugdunensis
, 0.5;
Anaerococcus prevotii
, 0.125;
Finegoldia magna
, 0.5;
Peptoniphilus asaccharolyticus
, 1;
Peptostreptococcus anaerobius
, 4;
Escherichia coli
and
Enterobacter
species, 0.125;
Klebsiella
species, 2; and
Pseudomonas aeruginosa
, 8.
Prevalence in the United States of
aac(6
′
)
-
Ib
-
cr
Encoding a Ciprofloxacin-Modifying Enzyme
Authors: Park Chi Hye , Robicsek Ari , Jacoby George A. , Sahm Daniel , Hooper David C. 
Published: October 2006

ABSTRACT

Among 313
Enterobacteriaceae
from the United States with a ciprofloxacin MIC of ≥0.25 μg/ml and reduced susceptibility to ceftazidime,
aac(6
′
)-Ib
was present in 50.5% of isolates, and of these, 28% carried the
cr
variant responsible for low-level ciprofloxacin resistance.
aac(6
′
)-Ib-cr
was geographically widespread, stable over time, most common in
Escherichia coli
, equally prevalent in ciprofloxacin-susceptible and -resistant strains, and not associated with
qnr
genes.