bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acyclovir Levels in Serum and Cerebrospinal Fluid after Oral Administration of Valacyclovir
Authors: Lycke Jan , Malmeström Clas , Ståhle Lars 
Published: July 2003

ABSTRACT
The possible involvement of herpesviruses in the pathogenesis of multiple sclerosis (MS) was recently investigated in a clinical trial of valacyclovir in patients with MS. As an important part of that survey we performed an independent pharmacokinetic study in order to determine the concentration of acyclovir in cerebrospinal fluid (CSF). The concentrations of acyclovir in serum and CSF were measured at steady state after 6 days of oral treatment with 1,000 mg of valacyclovir three times a day. Samples were obtained from 10 patients with MS. All patients had normal renal function, and none had signs of a damaged blood-CSF barrier. The maximum concentration of acyclovir in serum was reached after 1 to 3 h (mean ± standard deviation [SD], 27.1 ± 5.6 μM), and the minimum concentration in serum was 3.1 ± 1.1 μM (mean ± SD). The acyclovir concentrations in CSF at 2 and 8 h were essentially stable, with the mean ± SD levels being 2.5 ± 0.9 and 2.3 ± 0.7 μM, respectively. Similar levels were recorded in serum and CSF samples from five other MS patients after 6 months of oral treatment with valacyclovir at identical dosages. The area under the concentration-time curve (AUC) for acyclovir in CSF to the AUC for acyclovir in serum (CSF/serum AUC ratio) was approximately 20%. We conclude that the improved bioavailability previously reported for valacyclovir in plasma results in higher concentrations in CSF, while the CSF/serum AUC ratio remains constant.
Gatifloxacin and Ethionamide as the Foundation for Therapy of Tuberculosis
Authors: Cynamon Michael H. , Sklaney Mary 
Published: July 2003

ABSTRACT
The use of gatifloxacin (GAT) in combination with ethionamide (ETA) with or without pyrazinamide (PZA) for a 12-week treatment period followed by an 8-week observation period was evaluated in a model of tuberculosis in mice. Mice treated with GAT at 300 mg/kg of body weight in combination with ETA (25 mg/kg) for 5 days per week had sterile lungs, whereas mice treated with GAT (100 mg/kg) and ETA (25 mg/kg) had about 10 CFU/lung; however, there was regrowth of the organisms in both groups at the end of the observation period. When PZA (450 mg/kg 5 days per week) was added to the high-dose GAT-ETA regimen, no viable mycobacteria were present after the 8-week observation period. GAT in combination with ETA and PZA has great promise for the treatment of tuberculosis.
Effective Immunomodulatory Treatment ofEscherichia coliExperimental Sepsis with Thalidomide
Authors: Giamarellos-Bourboulis Evangelos J. , Poulaki Helen , Kostomitsopoulos Nikolaos , Dontas Ismene , Perrea Despina , Karayannacos Panayotis E. , Giamarellou Helen 
Published: July 2003

ABSTRACTThalidomide, an agent which inhibits biosynthesis of tumor necrosis factor alpha (TNF-α) and which is used to treat a variety of chronic inflammatory conditions, was investigated as therapy for experimental sepsis. Sepsis was induced by intraperitoneal injection of 107CFU ofEscherichia coliper kg of body weight to 80 Wistar rats divided into four groups. Group A consisted of 24 control animals that did not receive any pretreatment, group B consisted of 18 vehicle-treated control animals pretreated with seed oil, group C consisted of 30 rats administered thalidomide diluted in seed oil at a dose of 50 mg/kg 30 min before bacterial challenge, and group D consisted of eight animals that were not challenged withE. colibut that were used for white blood cell count determination. Sepsis was determined by measurement of vital signs before and 6 h after bacterial challenge. After 6 h the animals were killed and blood was sampled for culture; white blood cell count determination; and determination of endotoxin (lipopolysaccharide), TNF-α, interleukin-1β (IL-1β), and IL-6 levels. The levels of these cytokines were also estimated in the supernatants of human monocytes pretreated with thalidomide after exposure to the isolate. Sepsis developed in all vehicle-treated control animals and controls by 6 h after bacterial challenge but in only 10 animals (33.3%) pretreated with thalidomide (P< 0.0001). Six hours after bacterial challenge all animals had similar levels of endotoxemia, IL-1β, and IL-6. The mean white blood cell count for groups A, B, and C were 5,631.1, 2,638.9, and 8,169.3 cells/μl, respectively (Pvalue between groups, <0.0001); the TNF-α levels were 77.3, 107.2, and 26.1 pg/ml, respectively (Pvalues between groups, <0.0001). Pretreatment of human monocytes with thalidomide prevented the secretion of TNF-α and IL-1β but not that of IL-6. It is concluded that thalidomide exerts a considerable anti-inflammatory effect by preventing evolution to sepsis and by decreasing the level of production of TNF-α and therefore deserves to be further evaluated in research for the therapy of sepsis.
Steady-State Plasma and Bronchopulmonary Concentrations of Intravenous Levofloxacin and Azithromycin in Healthy Adults
Authors: Rodvold Keith A. , Danziger Larry H. , Gotfried Mark H. 
Published: July 2003

ABSTRACTThe purpose of this study was to compare the concentrations of levofloxacin and azithromycin in steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) after intravenous administration. Thirty-six healthy, nonsmoking adult subjects were randomized to either intravenous levofloxacin (500 or 750 mg) or azithromycin (500 mg) once daily for five doses. Venipuncture and bronchoscopy with bronchoalveolar lavage were performed in each subject at either 4, 12, or 24 h after the start of the last antibiotic infusion. The mean concentrations of levofloxacin and azithromycin in plasma were similar to those previously published. The dosing regimens of levofloxacin achieved significantly (P< 0.05) higher concentrations in steady-state plasma than azithromycin during the 24 h after drug administration. The respective mean (± standard deviation) concentrations at 4, 12, and 24 h in ELF for 500 mg of levofloxacin were 11.01 ± 4.52, 2.50 ± 0.97, and 1.24 ± 0.55 μg/ml; those for 750 mg of levofloxacin were 12.94 ± 1.21, 6.04 ± 0.39, and 1.73 ± 0.78 μg/ml; and those for azithromycin were 1.70 ± 0.74, 1.27 ± 0.47, and 2.86 ± 1.75 μg/ml. The differences in concentrations in ELF among the two levofloxacin groups and azithromycin were significantly (P< 0.05) higher at the 4- and 12-h sampling times. The respective concentrations in AM for 500 mg of levofloxacin were 83.9 ± 53.2, 18.3 ± 6.7, and 5.6 ± 3.2 μg/ml; those for 750 mg of levofloxacin were 81.7 ± 37.0, 78.2 ± 55.4, and 13.3 ± 6.5 μg/ml; and those for azithromycin were 650 ± 259, 669 ± 311, and 734 ± 770 μg/ml. Azithromycin achieved significantly (P< 0.05) higher concentrations in AM than levofloxacin at all sampling times. The concentrations in ELF and AM following intravenous administration of levofloxacin and azithromycin were higher than concentrations in plasma. Further studies are needed to determine the clinical significance of such high intrapulmonary concentrations in patients with respiratory tract infections.
Pharmacokinetics and Metabolism of [
14
C]Viramidine in Rats and Cynomolgus Monkeys
Authors: Lin Chin-Chung , Luu Kenneth , Lourenco David , Yeh Li-Tain 
Published: July 2003

ABSTRACT

The pharmacokinetics of [
14
C]viramidine, a prodrug of ribavirin, were studied in rats (30 mg/kg of body weight) and monkeys (10 mg/kg) following intravenous (i.v.) and oral administration. The levels of oral absorption and bioavailabilities were 61.7 and 9.91%, respectively, in rats and 43.9 and 13.6%, respectively, in monkeys. Following i.v. administration, the elimination half-lives were 2.7 h in rats and 28.9 h in monkeys. Total body clearances were 14.0 liters/h/kg in rats and 1.23 liters/h/kg in monkeys; the apparent volumes of distribution were 15.6 liters/kg in rats and 18.6 liters/kg in monkeys. Following oral administration, viramidine was extensively converted to ribavirin, followed by further metabolism of ribavirin in both species, with a faster rate of metabolism in rats than in monkeys. In rats, excretion of total radioactivity in urine accounted for 77.0% of the i.v. dose and 60.8% of the oral dose, while in monkeys it accounted for 44.4% of the i.v. dose and 39.0% of the oral dose. The amount of unchanged viramidine and ribavirin in urine was small in both species after i.v. and oral administration of viramidine.
Novel Antimicrobial Peptides Derived from Flatfish Genes
Authors: Patrzykat Aleksander , Gallant Jeffrey W. , Seo Jung-Kil , Pytyck Jennifer , Douglas Susan E. 
Published: July 2003

ABSTRACT

We report on the identification of active novel antimicrobials determined by screening both the genomic information and the mRNA transcripts from a number of different flatfish for sequences encoding antimicrobial peptides, predicting the sequences of active peptides from the genetic information, producing the predicted peptides chemically, and testing them for their activities. We amplified 35 sequences from various species of flatfish using primers whose sequences are based on conserved flanking regions of a known antimicrobial peptide from winter flounder, pleurocidin. We analyzed the sequences of the amplified products and predicted which sequences were likely to encode functional antimicrobial peptides on the basis of charge, hydrophobicity, relation to flanking sequences, and similarity to known active peptides. Twenty peptides were then produced synthetically and tested for their activities against gram-positive and gram-negative bacteria and the yeast
Candida albicans
. The most active peptide (with the carboxy-terminus amidated sequence GWRTLLKKAEVKTVGKLALKHYL, derived from American plaice) showed inhibitory activity over a concentration range of 1 to 8 μg/ml against a test panel of pathogens, including the intrinsically antibiotic-resistant organism
Pseudomonas aeruginosa
, methicillin-resistant
Staphylococcus aureus
, and
C. albicans.
The methods described here will be useful for the identification of novel peptides with good antimicrobial activities.
In Vitro and In Vivo Activities of Novel 2-(Thiazol-2-ylthio)-1β-Methylcarbapenems with Potent Activities against Multiresistant Gram-Positive Bacteria
Authors: Ueda Yutaka , Sunagawa Makoto 
Published: July 2003

ABSTRACT

SM-197436, SM-232721, and SM-232724 are new 1β-methylcarbapenems with a unique 4-substituted thiazol-2-ylthio moiety at the C-2 side chain. In agar dilution susceptibility testing these novel carbapenems were active against methicillin-resistant
Staphylococcus aureus
(MRSA) and
Staphylococcus epidermidis
(MRSE) with a MIC
90
of ≤4 μg/ml. Furthermore, SM-232724 showed strong bactericidal activity against MRSA, in contrast to linezolid, which was bacteriostatic up to four times the MIC. SM-232724 showed good therapeutic efficacy comparable to those of vancomycin and linezolid against systemic infections of MRSA in cyclophosphamide-treated mice. The MICs of SM-197436, SM-232721, and SM-232724 for streptococci, including penicillin-intermediate and penicillin-resistant
Streptococcus pneumoniae
strains, ranged from ≤0.063 to 0.5 μg/ml. These drugs were the most active β-lactams tested against
Enterococcus faecium
, and the MIC
90
s for ampicillin-resistant
E. faecium
ranged between 8 and 16 μg/ml, which were slightly higher than the value for linezolid. However, time-kill assays revealed the superior bactericidal activity of SM-232724 compared to those of quinupristin-dalfopristin and linezolid against an
E. faecium
strain with a 4-log reduction in CFU at four times the MIC after 24 h of exposure to antibiotics. In addition, SM-232724 significantly reduced the numbers of bacteria in a murine abscess model with the
E. faecium
strain: its efficacy was superior to that of linezolid, although the MICs (2 μg/ml) of these two agents are the same. Among gram-negative bacteria, these three carbapenems were highly active against
Haemophilus influenzae
(including ampicillin-resistant strains),
Moraxella catarrhalis
, and
Bacteroides fragilis
, and showed antibacterial activity equivalent to that of imipenem for
Escherichia coli
,
Klebsiella pneumoniae
, and
Proteus
spp. Thus, these new carbapenems are promising candidates for agents to treat nosocomial bacterial infections by gram-positive and gram-negative bacteria, especially multiresistant gram-positive cocci, including MRSA and vancomycin-resistant enterococci.
Biological Activities of Synthetic Analogs of Halocidin, an Antimicrobial Peptide from the Tunicate
Halocynthia aurantium
Authors: Jang Woong Sik , Kim Chong Han , Kim Kyu Nam , Park Shin Yong , Lee Joon Ha , Son Seok Min , Lee In Hee 
Published: July 2003

ABSTRACT

Halocidin is a heterodimer antimicrobial peptide previously isolated from the tunicate
Halocynthia aurantium
. Based on the larger monomer (18Hc) of halocidin, nine halocidin congeners, including a series of 6 peptides truncated successively from the carboxyl-terminal end of 18Hc and 3 analogs (18HcKK, K19Hc, and K19HcKK), which have lysine residues in place of two internal histidines or have a lysine added to the amino terminus of the 18Hc molecule, were prepared. Each peptide was also converted into a homodimeric version. The antimicrobial activities of halocidin congeners truncated from the C terminus were dramatically decreased, suggesting that the full length of 18Hc is required for maintaining its maximum antimicrobial activity. Dimer forms of halocidin congeners exhibited stronger antimicrobial activities than the monomer of the corresponding peptide. Four dimer peptides (di-18Hc, di-18HcKK, di-K19Hc, and di-K19HcKK) were analyzed for antimicrobial activities against 10 clinically isolated antibiotic-resistant bacteria in elevated concentrations of NaCl or MgCl
2
. Of the peptides studied here, di-K19Hc retained invariably strong activity against all bacteria in diverse conditions and also showed much reduced hemolytic activity against human erythrocytes.
Cefotaxime Acts Synergistically with Levofloxacin in Experimental Meningitis Due to Penicillin-Resistant Pneumococci and Prevents Selection of Levofloxacin-Resistant Mutants In Vitro
Authors: Kühn F. , Cottagnoud M. , Acosta F. , Flatz L. , Entenza J. , Cottagnoud P. 
Published: July 2003

ABSTRACT

Cefotaxime, given in two doses (each 100 mg/kg of body weight), produced a good bactericidal activity (−0.47 Δlog
10
CFU/ml · h) which was comparable to that of levofloxacin (−0.49 Δlog
10
CFU/ml · h) against a penicillin-resistant pneumococcal strain WB4 in experimental meningitis. Cefotaxime combined with levofloxacin acted synergistically (−1.04 Δlog
10
CFU/ml · h). Synergy between cefotaxime and levofloxacin was also demonstrated in vitro in time killing assays and with the checkerboard method for two penicillin-resistant strains (WB4 and KR4). Using in vitro cycling experiments, the addition of cefotaxime in sub-MIC concentrations (one-eighth of the MIC) drastically reduced levofloxacin-induced resistance in the same two strains (64-fold increase of the MIC of levofloxacin after 12 cycles versus 2-fold increase of the MIC of levofloxacin combined with cefotaxime). Mutations detected in the genes encoding topoisomerase IV (
parC
and
parE
) and gyrase (
gyrA
and
gyrB
) confirmed the levofloxacin-induced resistance in both strains. Addition of cefotaxime in low doses was able to suppress levofloxacin-induced resistance.
Risk Factors for New Detection of Vancomycin-Resistant Enterococci in Acute-Care Hospitals That Employ Strict Infection Control Procedures
Authors: Padiglione Alexander A. , Wolfe Rory , Grabsch Elizabeth A. , Olden Di , Pearson Stephen , Franklin Clare , Spelman Denis , Mayall Barrie , Johnson Paul D. R. , Grayson M. Lindsay 
Published: July 2003

ABSTRACT

Accurate assessment of the risk factors for colonization with vancomycin-resistant enterococci (VRE) among high-risk patients is often confounded by nosocomial VRE transmission. We undertook a 15-month prospective cohort study of adults admitted to high-risk units (hematology, renal, transplant, and intensive care) in three teaching hospitals that used identical strict infection control and isolation procedures for VRE to minimize nosocomial spread. Rectal swab specimens for culture were regularly obtained, and the results were compared with patient demographic factors and antibiotic exposure data. Compliance with screening was defined as “optimal” (100% compliance) or “acceptable” (minor protocol violations were allowed, but a negative rectal swab specimen culture was required within 1 week of becoming colonized with VRE). Colonization with VRE was detected in 1.56% (66 of 4,215) of admissions (0.45% at admission and 0.83% after admission; the acquisition time was uncertain for 0.28%), representing 1.91% of patients. No patients developed infection with VRE. The subsequent rate of new acquisition of VRE was 1.4/1,000 patient days. Renal units had the highest rate (3.23/1,000 patient days; 95% confidence interval [CI], 1.54 to 6.77/1,000 patient days).
vanB Enterococcus faecium
was the most common species (71%), but other species included
vanB Enterococcus faecalis
(21%),
vanA E. faecium
(6%), and
vanA E. faecalis
(2%). The majority of isolates were nonclonal by pulsed-field gel electrophoresis analysis. Multivariate analysis of risk factors in patients with an acceptable screening suggested that being managed by a renal unit (hazard ratio [HR] compared to the results for patients managed in an intensive care unit, 4.6; 95% CI, 1.2 to 17.0 [
P
= 0.02]) and recent administration of either ticarcillin-clavulanic acid (HR, 3.6; 95% CI, 1.1 to 11.6 [
P
= 0.03]) or carbapenems (HR, 2.8; 95% CI, 1.0, 8.0 [
P
= 0.05]), but not vancomycin or broad-spectrum cephalosporins, were associated with acquisition of VRE. The relatively low rates of colonization with VRE, the polyclonal nature of most isolates, and the possible association with the use of broad-spectrum antibiotics are consistent with either the endogenous emergence of VRE or the amplification of previously undetectable colonization with VRE among high-risk patients managed under conditions in which the risk of nosocomial acquisition was minimized.
Selection of Resistant
Streptococcus pneumoniae
during Penicillin Treatment In Vitro and in Three Animal Models
Authors: Knudsen Jenny Dahl , Odenholt Inga , Erlendsdottir Helga , Gottfredsson Magnus , Cars Otto , Frimodt-Møller Niels , Espersen Frank , Kristinsson Karl G. , Gudmundsson Sigurdur 
Published: July 2003

ABSTRACT

Pharmacokinetic (PK) and pharmacodynamic (PD) properties for the selection of resistant pneumococci were studied by using three strains of the same serotype (6B) for mixed-culture infection in time-kill experiments in vitro and in three different animal models, the mouse peritonitis, the mouse thigh, and the rabbit tissue cage models. Treatment regimens with penicillin were designed to give a wide range of T
>MIC
s, the amounts of time for which the drug concentrations in serum were above the MIC. The mixed culture of the three pneumococcal strains, 10
7
CFU of strain A (MIC of penicillin, 0.016 μg/ml; erythromycin resistant)/ml, 10
6
CFU of strain B (MIC of penicillin, 0.25 μg/ml)/ml, and 10
5
CFU of strain C (MIC of penicillin, 4 μg/ml)/ml, was used in the two mouse models, and a mixture of 10
5
CFU of strain A/ml, 10
4
CFU of strain B/ml, and 10
3
CFU of strain C/ml was used in the rabbit tissue cage model. During the different treatment regimens, the differences in numbers of CFU between treated and control animals were calculated to measure the efficacies of the regimens. Selective media with erythromycin or different penicillin concentrations were used to quantify the strains separately. The efficacies of penicillin in vitro were similar when individual strains or mixed cultures were studied. The eradication of the bacteria, independent of the susceptibility of the strain or strains or the presence of the strains in a mixture or on their own, followed the well-known PK and PD rules for treatment with β-lactams: a maximum efficacy was seen when the T
>MIC
was >40 to 50% of the observation time and the ratio of the maximum concentration of the drug in serum to the MIC was >10. It was possible in all three models to select for the less-susceptible strains by using insufficient treatments. In the rabbit tissue cage model, a regrowth of pneumococci was observed; in the mouse thigh model, the ratio between the different strains changed in favor of the less-susceptible strains; and in the mouse peritonitis model, the susceptible strain disappeared and was overgrown by the less-susceptible strains. These findings with the experimental infection models confirm the importance of eradicating all the bacteria taking part in the infectious process in order to avoid selection of resistant clones.
In Vivo Antibacterial Activity of S-3578, a New Broad-Spectrum Cephalosporin: Methicillin-Resistant
Staphylococcus aureus
and
Pseudomonas aeruginosa
Experimental Infection Models
Authors: Tsuji Masakatsu , Takema Morio , Miwa Hideaki , Shimada Jingoro , Kuwahara Shogo 
Published: July 2003

ABSTRACT

The in vivo antibacterial activity of S-3578, a new parental cephalosporin, was compared with those of cefepime, ceftriaxone, ceftazidime, imipenem-cilastatin, and vancomycin. The efficacy of S-3578 against systemic infections caused by methicillin-resistant
Staphylococcus aureus
(MRSA) SR3637 (50% effective dose [ED
50
], 7.21 mg/kg of body weight) was almost the same as that of vancomycin. In contrast, cefepime and imipenem-cilastatin were less active against this pathogen (ED
50
s, >100 and >100 mg/kg, respectively). S-3578 was the most effective compound against penicillin-resistant
Streptococcus pneumoniae
SR20946 (ED
50
, 1.98 mg/kg). S-3578 (10 mg/kg) induced a significant reduction in the numbers of viable MRSA SR17764 and
Pseudomonas aeruginosa
SR10396 organisms in polymicrobial pulmonary infections. The therapeutic efficacy of S-3578 was more potent than that of the combination of vancomycin and ceftazidime. High levels of S-3578 were detected in plasma in vivo, and its efficacy against experimentally induced infections in mice caused by MRSA and
P. aeruginosa
reflected its potent in vitro activity. We conclude that S-3578 is a promising new cephalosporin for the treatment of infections caused by gram-positive and -negative bacteria, including MRSA and
P. aeruginosa.
Immunoenhancement Combined with Amphotericin B as Treatment for Experimental Visceral Leishmaniasis
Authors: Murray Henry W. , Brooks Elaine B. , DeVecchio Jennifer L. , Heinzel Frederick P. 
Published: July 2003

ABSTRACTTo determine if stimulation of Th1-cell-associated immune responses, mediated by interleukin 12 (IL-12) and gamma interferon (IFN-γ), enhance the antileishmanial effect of amphotericin B (AMB),Leishmania donovani-infected BALB/c mice were first treated with (i) exogenous IL-12 to induce IFN-γ, (ii) agonist anti-CD40 monoclonal antibody (MAb) to maintain IL-12 and induce IFN-γ, or (iii) anti-IL-10 receptor (IL-10R) MAb to blockade suppression of IL-12 and IFN-γ. In animals with established visceral infection, low-dose AMB alone (two injections of 1 mg/kg of body weight; total dose, 2 mg/kg) killed 15 to 29% of liver parasites; by themselves, the immunointerventions induced 16 to 33% killing. When the interventions were combined, the leishmanicidal activities increased 3.4-fold (anti-CD40), 6.3-fold (anti-IL-10R), and 9-fold (IL-12) compared with the activities of AMB plus the control preparations; and overall killing (76 to 84%) approximated the 84 to 92% killing effect of 7.5-fold more AMB alone (three injections of 5 mg/kg; total dose, 15 mg/kg). These results suggest that strengthening the host Th1-cell response may be a strategy for the development of AMB-sparing regimens in visceral leishmaniasis.