bluuebunny/crossref_metadata_2025_split huggingface dataset:
Steady-State Pharmacokinetics of Abacavir in Plasma and Intracellular Carbovir Triphosphate following Administration of Abacavir at 600 Milligrams Once Daily and 300 Milligrams Twice Daily in Human Immunodeficiency Virus-Infected Subjects
Authors: Moyle Graeme , Boffito Marta , Fletcher Carl , Higgs Chris , Hay Phillip E. , Song Ivy H. , Lou Yu , Yuen Geoffrey J. , Min Sherene S. , Guerini Elena M. 
Published: February 2009

ABSTRACT

Abacavir (ABC) is administered either at 600 mg once daily (ABC 600 mg QD) or 300 mg twice daily (ABC 300 mg BID) in anti-human immunodeficiency virus (anti-HIV) combination therapy. Although ABC plasma pharmacokinetics following each regimen has been well defined, no study has directly compared the regimens with respect to pharmacokinetics of ABC's active intracellular anabolite, carbovir-triphosphate (CBV-TP). In an open-label, two-period, crossover study, 34 HIV-infected male and female subjects stabilized on antiretroviral regimens containing either ABC 600 mg QD or ABC 300 mg BID received their usual doses on days −1 and 1 and then switched regimens for days 2 to 11. Serial blood samples collected on days 1 and 11 were assayed for plasma ABC and intracellular CBV-TP concentrations using validated high-performance liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods. Analysis of variance with a mixed-effect model was performed for treatment and gender comparisons. In 27 evaluable subjects, the regimens provided bioequivalent ABC daily areas under the concentration-time curve from 0 to 24 h (AUC
0-24
) and comparable CBV-TP concentrations at the end of the dosing interval (
C
τ
). As expected, ABC QD resulted in 109% higher ABC maximum concentrations of drug in plasma (
C
max
) than did ABC BID. ABC QD also resulted in 32% higher CBV-TP AUC
0-24
and 99% higher CBV-TP
C
max
than did ABC BID. Females had a 38% higher weight-adjusted ABC AUC
0-24
and 81% higher weight-adjusted CBV-TP AUC
0-24
than did males. Virologic suppression was maintained during regimen switch, and no tolerability differences between regimens were observed. In conclusion, this study showed that ABC 600 mg QD and ABC 300 mg BID regimens led to similar intracellular CBV-TP
C
τ
values, thus providing pharmacokinetic support for the interchangeability of these two regimens. Women had higher intracellular CBV-TP exposure than did men.
Urinary Bactericidal Activity of Doripenem versus That of Levofloxacin in Patients with Complicated Urinary Tract Infections or Pyelonephritis
Authors: Wagenlehner Florian M. E. , Wagenlehner Christine , Redman Rebecca , Weidner Wolfgang , Naber Kurt G. 
Published: February 2009

ABSTRACT
The aim of this study was to investigate the urinary bactericidal titers (UBTs) and 24-h area under the UBT-versus-time curve (AUBT) of intravenous doripenem (500 mg every 8 h [q8h]), a new carbapenem, versus those of intravenous levofloxacin (250 mg q24h) in patients with complicated urinary tract infections (cUTIs) or pyelonephritis. UBTs and AUBTs are pharmacokinetic/pharmacodynamic parameters able to reflect the activity of an antimicrobial substance in the urine. Doripenem and levofloxacin show comparable urinary excretion of approximately 80% and are therefore registered for the treatment of UTIs. In order to assess and compare the urinary antimicrobial activities of the two substances, UBTs were investigated for 24 patients (10 treated with doripenem and 14 with levofloxacin) for 31 uropathogens and one control strain. Eight strains were tested for all patients and 27 only in the urine of the corresponding patient. Median UBTs (AUBTs) of doripenem for the uropathogens tested ranged between 1.5 and 65,536 (224 and 909,312) and were significantly higher than median UBTs (AUBTs) of levofloxacin, ranging between 0 and 128 (0 and 2,208). Eight microbiological failures were observed, three after doripenem treatment and five after levofloxacin treatment. For levofloxacin, microbiological failures correlated well with low UBTs and AUBTs, whereas for doripenem there was no correlation. From this study, a calculated target attainment rate for levofloxacin predicting therapeutic success in patients with UTIs approximated mean UBTs of 100 over 24 h or AUBTs of 2,240. Doripenem demonstrated excellent urinary bactericidal activity with the dose administered and appears to be a good alternative in the empirical treatment of cUTI.
Population Pharmacokinetics of High-Dose, Prolonged-Infusion Cefepime in Adult Critically Ill Patients with Ventilator-Associated Pneumonia
Authors: Nicasio Anthony M. , Ariano Robert E. , Zelenitsky Sheryl A. , Kim Aryun , Crandon Jared L. , Kuti Joseph L. , Nicolau David P. 
Published: February 2009

ABSTRACT

A population pharmacokinetic model of cefepime was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP). A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups—26 for the initial model and 6 for model validation. Serum samples of cefepime were collected at steady state. Nonparametric adaptive grid population modeling was employed using a two-compartment
K
slope
pharmacokinetic model relating the elimination rate constant (
K
10
) to renal function, as defined by creatinine clearance (CL
CR
), and central distribution volume (
V
1
) to total body weight (TBW). The final model was described by the following equations:
K
10
= 0.0027 × CL
CR
+ 0.071 h
−1
and
V
1
= TBW × 0.21 liter/kg. The median intercompartmental transfer constants
K
12
and
K
21
were 0.780 h
−1
and 0.472 h
−1
, respectively. Using these median parameter estimates, the bias, precision, and coefficient of determination for the initial model were 11.3 μg/ml, 24.0 μg/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of −1.64 μg/ml, 17.1 μg/ml, and 62%, respectively. Time-concentration profiles were assessed for various dosing regimens, using 5,000-patient Monte Carlo simulations. Among the regimens, the likelihoods of 2 g every 8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 μg/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.
Intracellular Activity of Antibiotics in a Model of Human THP-1 Macrophages Infected by a
Staphylococcus aureus
Small-Colony Variant Strain Isolated from a Cystic Fibrosis Patient: Pharmacodynamic Evaluation and Comparison with Isogenic Normal-Phenotype and Revertant Strains
Authors: Nguyen Hoang Anh , Denis Olivier , Vergison Anne , Theunis Anne , Tulkens Paul M. , Struelens Marc J. , Van Bambeke Françoise 
Published: February 2009

ABSTRACT

Small-colony variant (SCV) strains of
Staphylococcus aureus
show reduced antibiotic susceptibility and intracellular persistence, potentially explaining therapeutic failures. The activities of oxacillin, fusidic acid, clindamycin, gentamicin, rifampin, vancomycin, linezolid, quinupristin-dalfopristin, daptomycin, tigecycline, moxifloxacin, telavancin, and oritavancin have been examined in THP-1 macrophages infected by a stable thymidine-dependent SCV strain in comparison with normal-phenotype and revertant isogenic strains isolated from the same cystic fibrosis patient. The SCV strain grew slowly extracellularly and intracellularly (1- and 0.2-log CFU increase in 24 h, respectively). In confocal and electron microscopy, SCV and the normal-phenotype bacteria remain confined in acid vacuoles. All antibiotics tested, except tigecycline, caused a net reduction in bacterial counts that was both time and concentration dependent. At an extracellular concentration corresponding to the maximum concentration in human serum (total drug), oritavancin caused a 2-log CFU reduction at 24 h; rifampin, moxifloxacin, and quinupristin-dalfopristin caused a similar reduction at 72 h; and all other antibiotics had only a static effect at 24 h and a 1-log CFU reduction at 72 h. In concentration dependence experiments, response to oritavancin was bimodal (two successive plateaus of −0.4 and −3.1 log CFU); tigecycline, moxifloxacin, and rifampin showed maximal effects of −1.1 to −1.7 log CFU; and the other antibiotics produced results of −0.6 log CFU or less. Addition of thymidine restored intracellular growth of the SCV strain but did not modify the activity of antibiotics (except quinupristin-dalfopristin). All drugs (except tigecycline and oritavancin) showed higher intracellular activity against normal or revertant phenotypes than against SCV strains. The data may help rationalizing the design of further studies with intracellular SCV strains.
Intracellular Activity of Antibiotics in a Model of Human THP-1 Macrophages Infected by a
Staphylococcus aureus
Small-Colony Variant Strain Isolated from a Cystic Fibrosis Patient: Study of Antibiotic Combinations
Authors: Nguyen Hoang Anh , Denis Olivier , Vergison Anne , Tulkens Paul M. , Struelens Marc J. , Van Bambeke Françoise 
Published: February 2009

ABSTRACT
In a companion paper (H. A. Nguyen et al., Antimicrob. Agents Chemother. 53:1434-1442, 2009), we showed that vancomycin, oxacillin, fusidic acid, clindamycin, linezolid, and daptomycin are poorly active against the intracellular form of a thymidine-dependent small-colony variant (SCV) strain isolated from a cystic fibrosis patient and that the activity of quinupristin-dalfopristin, moxifloxacin, rifampin, and oritavancin remains limited (2- to 3-log CFU reduction) compared to their extracellular activity. Antibiotic combination is a well-known strategy to improve antibacterial activity, which was examined here against an intracellular SCV strain using combinations with either rifampin or oritavancin. Time-kill curve analysis using either concentrations that caused a static effect for each antibiotic individually or concentrations corresponding to the maximum concentration in human serum showed largely divergent effects that were favorable when antibiotics were combined with rifampin at low concentrations only and with oritavancin at both low and high concentrations. The nature of the interaction between rifampin, oritavancin, and moxifloxacin was further examined using the fractional maximal effect method, which allows categorization of the effects of combinations when dose-effect relationships are not linear. Rifampin and oritavancin were synergistic at all concentration ratios investigated. Oritavancin and moxifloxacin were also synergistic but at high oritavancin concentrations only. Rifampin and moxifloxacin were additive. This approach may help in better assessing and improving the activity of antibiotics against intracellular SCV strains.
Chlamydia trachomatis
Laboratory Strains versus Recent Clinical Isolates: Implications for Routine Microbicide Testing
Authors: Skinner M. C. , Stamm W. E. , Lampe M. L. 
Published: February 2009

ABSTRACT

A topical microbicide that women can use to prevent sexually transmitted diseases (STDs) is essential, and many microbicide candidates are being tested for activity against human immunodeficiency virus and other STDs, including
Chlamydia trachomatis
. Screening assays for assessing the activity of microbicides against
C. trachomatis
are typically done with laboratory-adapted strains, but it is possible that recent clinical isolates may have different susceptibilities to microbicides, as has been seen with
Neisseria gonorrhoeae
and
Lactobacillus
spp. (B. J. Moncla and S. L. Hillier, Sex. Transm. Dis. 32:491-494, 2005). We utilized three types of microbicides to help define this aspect of our assay to test microbicides against
C. trachomatis
in vitro. To simulate conditions of transmission, we used an assay that we previously developed in which we exposed chlamydial elementary bodies to microbicides prior to contact with epithelial cells. We first determined the toxicity of microbicides to the cells used to culture
Chlamydia trachomatis
in the assay and, if necessary, modified the assay to eliminate toxicity at the concentrations tested. We compared the sensitivities of recent clinical isolates of
Chlamydia trachomatis
versus laboratory strains of the same serovar and found major differences in sensitivity to nonoxynol-9 (non-9), but only minor differences were seen with the other microbicides. We thus conclude that when assessing activity of potential topical microbicides versus the obligate intracellular bacteria
C. trachomatis
, the use of recent clinical isolates may not be necessary to draw a conclusion about a microbicide's effectiveness. However, it is important to keep in mind that differences (like those seen with non-9) are possible and that clinical isolates could be included in later stages of testing.
Azithromycin in
Pseudomonas aeruginosa
Biofilms: Bactericidal Activity and Selection of
nfxB
Mutants
Authors: Mulet Xavier , Maciá María D. , Mena Ana , Juan Carlos , Pérez José L. , Oliver Antonio 
Published: February 2009

ABSTRACT

Azithromycin (AZM) has shown promising results in the treatment of
Pseudomonas aeruginosa
chronic lung infections such as those occurring in cystic fibrosis (CF) patients. We evaluated the effect of hypermutation and alginate hyperproduction on the bactericidal activity and resistance development to AZM in
P. aeruginosa
biofilms. Strains PAO1, its
mucA
mutant (PAOMA), and their respective
mutS
-deficient hypermutable derivatives (PAOMS and PAOMSA) were used. Biofilms were incubated with several AZM concentrations for 1, 2, 4, or 7 days, and the numbers of viable cells were determined. During the first 2 days, AZM showed bactericidal activity for all the strains, but in extended AZM incubation for strain PAOMS and especially strain PAOMSA, a marked increased in the number of viable cells was observed, particularly at 4 μg/ml. Biofilms formed by the lineages recovered from the 7-day experiments showed enhanced AZM resistance. Furthermore, most of the independent lineages studied, including those obtained from biofilms treated with AZM concentrations as low as 0.5 μg/ml, showed MexCD-OprJ hyperexpression and mutations in
nfxB
. The role of
nfxB
mutation in AZM resistance was further confirmed through the characterization of
nfxB
and
mexD
knockout mutants. Results from this work show that, although AZM exhibits bactericidal activity against
P. aeruginosa
biofilms, resistant mutants are readily selected and that, furthermore, they frequently show cross-resistance to other unrelated antipseudomonal agents such as ciprofloxacin or cefepime but hypersusceptibility to others such as imipenem or tobramycin. Therefore, these results should help guide the selection of appropriate antipseudomonal therapies in CF patients under AZM maintenance treatment.
Antistaphylococcal Activity of Dihydrophthalazine Antifolates, a Family of Novel Antibacterial Drugs
Authors: Clark Catherine , Ednie Lois M. , Lin Gengrong , Smith Kathy , Kosowska-Shick Klaudia , McGhee Pamela , Dewasse Bonifacio , Beachel Linda , Caspers Patrick , Gaucher Bérangère , Mert Gürkan , Shapiro Stuart , Appelbaum Peter C. 
Published: February 2009

ABSTRACT

For a panel of 153
Staphylococcus aureus
clinical isolates (including 13 vancomycin-intermediate or heterogeneous vancomycin-intermediate and 4 vancomycin-resistant strains), MIC
50
s and MIC
90
s of three novel dihydrophthalazine antifolates, BAL0030543, BAL0030544, and BAL0030545, were 0.03 and 0.25 μg/ml, respectively, for methicillin-susceptible strains and 0.03 and ≤0.25 μg/ml, respectively, for methicillin-resistant strains. For a panel of 160 coagulase-negative staphylococci (including 5 vancomycin-intermediate and heterogeneous vancomycin-intermediate strains and 7 linezolid-nonsusceptible strains), MIC
50
s and MIC
90
s were ≤0.03 and ≤0.06 μg/ml, respectively, for methicillin-susceptible strains and 0.06 and 0.5 μg/ml, respectively, for methicillin-resistant strains. Vancomycin was active against 93.0% of 313 staphylococci examined; linezolid was active against all
S. aureus
strains and 95.6% of coagulase-negative staphylococcus strains, whereas elevated MICs of clindamycin, minocycline, trimethoprim, and rifampin for some strains were observed. At 4× MIC, the dihydrophthalazines were bactericidal against 11 of 12 staphylococcal strains surveyed. The prolonged serial passage of some staphylococcal strains in the presence of subinhibitory concentrations of BAL0030543, BAL0030544, and BAL0030545 produced clones for which dihydrophthalazines showed high MICs (>128 μg/ml), although rates of endogenous resistance development were much lower for the dihydrophthalazines than for trimethoprim. Single-step platings of naïve staphylococci onto media containing dihydrophthalazine antifolates indicated considerable variability among strains with respect to preexistent subpopulations nonsusceptible to dihydrophthalazine antifolates.
Low Plasma Membrane Expression of the Miltefosine Transport Complex Renders
Leishmania braziliensis
Refractory to the Drug
Authors: Sánchez-Cañete María P. , Carvalho Luís , Pérez-Victoria F. Javier , Gamarro Francisco , Castanys Santiago 
Published: February 2009

ABSTRACT

Miltefosine (hexadecylphosphocholine, MLF) is the first oral drug with recognized efficacy against both visceral and cutaneous leishmaniasis. However, some clinical studies have suggested that MLF shows significantly less efficiency against the cutaneous leishmaniasis caused by
Leishmania braziliensis
. In this work, we have determined the cellular and molecular basis for the natural MLF resistance observed in
L
.
braziliensis
. Four independent
L
.
braziliensis
clinical isolates showed a marked decrease in MLF sensitivity that was due to their inability to internalize the drug. MLF internalization in the highly sensitive
L
.
donovani
species requires at least two proteins in the plasma membrane, LdMT, a P-type ATPase involved in phospholipid translocation, and its β subunit, LdRos3. Strikingly,
L
.
braziliensis
parasites showed highly reduced levels of this MLF translocation machinery at the plasma membrane, mainly because of the low expression levels of the β subunit, LbRos3. Overexpression of LbRos3 induces increased MLF sensitivity not only in
L
.
braziliensis
promastigotes but also in intracellular amastigotes. These results further highlight the importance of the MLF translocation machinery in determining MLF potency and point toward the development of protocols to routinely monitor MLF susceptibility in geographic areas where
L
.
braziliensis
might be prevalent.
Interconnections between Sigma B,
agr
, and Proteolytic Activity in
Staphylococcus aureus
Biofilm Maturation
Authors: Lauderdale Katherine J. , Boles Blaise R. , Cheung Ambrose L. , Horswill Alexander R. 
Published: February 2009

ABSTRACT

Staphylococcus aureus
is a proficient biofilm former on host tissues and medical implants. We mutagenized
S. aureus
strain SH1000 to identify loci essential for
ica
-independent mechanisms of biofilm maturation and identified multiple insertions in the
rsbUVW-sigB
operon. Following construction and characterization of a
sigB
deletion, we determined that the biofilm phenotype was due to a lack of sigma factor B (SigB) activity. The phenotype was conserved in a
sigB
mutant of USA300 strain LAC, a well-studied community-associated methicillin-resistant
S. aureus
isolate. We determined that
agr
RNAIII levels were elevated in the
sigB
mutants, and high levels of RNAIII expression are known to have antibiofilm effects. By introducing an
agr
mutation into the SH1000 or LAC
sigB
deletion strain,
S. aureus
regained biofilm capacity, indicating that the biofilm phenotype was
agr
dependent. Protease activity is linked to
agr
activity and
ica
-independent biofilm formation, and we observed that the protease inhibitors phenylmethylsulfonyl fluoride and α-macroglobulin could reverse the
sigB
biofilm defect. Similarly, inactivating genes encoding both the aureolysin and Spl extracellular proteases in the
sigB
mutant restored biofilm capacity. Due to the growing link between murein hydrolase activity and biofilm maturation, autolysin zymography was performed, which revealed an altered profile in the
sigB
mutant; again, the phenotype could be repaired through protease inactivation. These findings indicate that the lack of SigB activity results in increased RNAIII expression, thus elevating extracellular protease levels and altering the murein hydrolase activity profile. Altogether, our observations demonstrate that SigB is an essential regulator of
S. aureus
biofilm maturation.
Generation of Antibody Responses to Pneumococcal Capsular Polysaccharides Is Independent of CD1 Expression in Mice
Authors: Moens Leen , Jeurissen Axel , Nierkens Stefan , Boon Louis , Van Kaer Luc , Kasran Ahmad , Wuyts Greet , Ceuppens Jan L. , Bossuyt Xavier 
Published: February 2009

ABSTRACTStreptococcus pneumoniaeis a bacterial microorganism that frequently causes serious infection, particularly in children and the elderly. Protection against infection withS. pneumoniaeis based mainly on the generation of antibodies to the pneumococcal capsular polysaccharides (caps-PS), but the mechanisms responsible for the generation of anticapsular antibodies remain incompletely understood. The aim of the present study was to evaluate the role of CD1-restricted T cells in the antibody response to caps-PS. When immunized with Pneumo23, wild-type mice and CD1 knockout mice on BALB/c and C57BL/6 backgrounds generated immunoglobulin M (IgM) and IgG antibody responses to soluble caps-PS that were comparable. Similar results were obtained after immunization with heat-inactivatedS. pneumoniae. The IgM and IgG antibody response of wild-type mice to Pneumo23 was not affected by an antagonizing monoclonal anti-CD1 antibody treatment. In summary, our data provide evidence that the antibody response to caps-PS is generated independently of CD1 expression.
Modelling of Infection by EnteropathogenicEscherichia coliStrains in Lineages 2 and 4 Ex Vivo and In Vivo by UsingCitrobacter rodentiumExpressing TccP
Authors: Girard Francis , Crepin Valérie F. , Frankel Gad 
Published: February 2009

ABSTRACTEnteropathogenicEscherichia coli(EPEC) strains colonize the human gut mucosa via attaching-and-effacing (A/E) lesion formation, while in vitro they employ diverse strategies to trigger actin polymerization. Strains belonging to the EPEC-1 lineage trigger strong actin polymerization via tyrosine phosphorylation of the type III secretion system (T3SS) effector Tir, recruitment of Nck, and activation of N-WASP. Strains belonging to EPEC-2 and EPEC-4 can trigger strong actin polymerization by dual mechanisms, since while employing the Tir-Nck pathway they can additionally activate N-WASP via the T3SS effectors TccP2 and TccP, respectively. It is currently not known if the ability to trigger actin polymerization by twin mechanisms increases in vivo virulence or fitness. Since mice are resistant to EPEC infection, in vivo studies are frequently done using the murine model pathogenCitrobacter rodentium, which shares with EPEC-1 strains the ability to induce A/E lesions and trigger strong actin polymerization via the Tir:Nck pathway. In order to model infections with EPEC-2 and EPEC-4, we constructedC. rodentiumstrains expressing TccP. Using a mouse intestinal in vitro organ culture model and oral gavage into C57BL/6 mice, we have shown that TccP can cooperate with Tir ofC. rodentium. The recombinant strains induced typical A/E lesions ex vivo and in vivo. Expression of TccP did not alterC. rodentiumcolonization dynamics or pathology. In competition with the wild-type strain, expression of TccP inC. rodentiumdid not confer a competitive advantage.