bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multicenter Study To Determine Antibody Concentrations and Assess the Safety of Administration of INH-A21, a Donor-Selected Human Staphylococcal Immune Globulin, in Low-Birth-Weight Infants
Authors: Capparelli Edmund V. , Bloom Barry T. , Kueser Tom J. , Oelberg David G. , Bifano Ellen M. , White Robert D. , Schelonka Robert L. , Pearlman Stephen A. , Patti Joseph , Hetherington Seth V. 
Published: September 2005

ABSTRACTNosocomial or late-onset sepsis is a common complication among premature infants, with a frequency inversely correlated with birth weight. Increased susceptibility to infection is due in part to an immature humoral (antibody-mediated) immune response. This study investigated the pharmacokinetics (PKs) and safety of a donor-selected specific intravenous immune globulin (IVIG) preparation, INH-A21 (Veronate), for prevention of sepsis in premature infants. Thirty-six infants weighing between 500 and 1,250 g during the first postnatal week were eligible to begin a series of up to four intravenous infusions of 500 or 750 mg/kg of body weight INH-A21. Blood samples were analyzed for antibodies against the Ser-Asp dipeptide repeat G (SdrG) and clumping factor A (ClfA) surface proteins of staphylococci. Sparse sampling and population PK analyses were performed to derive PK parameters. Following administration of the 500- and 750-mg/kg doses, the estimated average steady-state levels of anti-ClfA were 6.1 U/ml and 9.2 U/ml, respectively, and those of anti-SdrG were 5.2 U/ml and 7.7 U/ml, respectively. The elimination half-lives for anti-ClfA and anti-SdrG were 719 h and 701 h, respectively, and the clearances were 0.18 ml/h and 0.21 ml/h, respectively. In the final model, the values of the PK parameters were independent of gestational age. Both doses of INH-A21 were well tolerated, and the safety profile was similar to those of other IVIG preparations. These results suggest that a shorter dosing interval should be utilized between the first and second doses to achieve and maintain higher titers of anti-ClfA and anti-SdrG antibodies. Further studies examining INH-A21 for the prevention of late-onset sepsis in infants within the weight range studied are warranted.
Evaluation of LBM415 (NVP PDF-713), a Novel Peptide Deformylase Inhibitor, for Treatment of Experimental
Mycoplasma pneumoniae
Pneumonia
Authors: Fonseca-Aten Monica , Salvatore Christine M. , Mejías Asunción , Ríos Ana M. , Chávez-Bueno Susana , Katz Kathy , Gómez Ana M. , McCracken George H. , Hardy R. Doug 
Published: September 2005

ABSTRACT

Mycoplasma pneumoniae
is a major cause of community-acquired pneumonia. We evaluated the efficacy of LBM415, a novel peptide deformylase inhibitor antimicrobial agent, for the treatment of
M. pneumoniae
pneumonia in a mouse model. Eight-week-old BALB/c mice were intranasally inoculated once with 10
7
CFU of
M. pneumoniae
. Groups of mice were treated with LBM415 (50 mg/kg of body weight) or placebo subcutaneously daily for 13 days, starting 24 h after inoculation. Groups of mice were evaluated at the baseline; at days of treatment 1, 3, 6, and 13; and at 7 days after treatment. The MIC of LBM415 against
M. pneumoniae
was <0.005 μg/ml. LBM415-treated mice had significantly lower bronchoalveolar lavage fluid
M. pneumoniae
concentrations than placebo-treated mice on days 6 and 13 of treatment. Compared with placebo treatment, therapy with LBM415 significantly decreased lung histopathology scores at days 3, 6, and 13 of treatment and at 7 days after treatment. Airway obstruction was significantly lower in LBM415-treated mice than in placebo-treated mice on days 1, 3, and 6 of treatment and after 7 days of therapy, while airway hyperresponsiveness was significantly lower only on day 3 of therapy. The bronchoalveolar lavage fluid concentrations of tumor necrosis factor alpha, gamma interferon (IFN-γ), interleukin-6 (IL-6), IL-12, KC (functional IL-8), monocyte chemotactic protein 1, macrophage inflammatory protein 1α, monokine induced by IFN-γ, and IFN-inducible protein 10 were significantly reduced in LBM415-treated mice compared with the levels in placebo-treated mice. There were no differences in the bronchoalveolar lavage fluid concentrations of granulocyte-macrophage colony-stimulating factor, IL-1β, IL-2, IL-4, IL-5, and IL-10 between the two groups of mice. LBM415 therapy had beneficial microbiologic, histologic, respiratory, and immunologic effects on acute murine
M. pneumoniae
pneumonia.
Efficacy and Safety of a Novel Once-Daily Extended-Release Ciprofloxacin Tablet Formulation for Treatment of Uncomplicated Urinary Tract Infection in Women
Authors: Fourcroy Jean L. , Berner Bret , Chiang Yu-Kun , Cramer Marilou , Rowe Lynne , Shore Neal 
Published: September 2005

ABSTRACT

The efficacy and safety of a novel once-daily extended-release ciprofloxacin (ciprofloxacin ER) 500-mg dose were compared with those of an immediate-release ciprofloxacin (ciprofloxacin IR) 250-mg twice-daily dose, each administered orally for 3 days in the treatment of acute uncomplicated urinary tract infection (uUTI) in women. Adult female outpatients (mean age, 39 years) with clinical signs and symptoms of acute uUTI and a positive pretreatment urine culture (≥10
5
CFU/ml) were enrolled in a multicenter, randomized, double-blind, noninferiority trial. Patients were assessed at a test-of-cure visit (4 to 11 days posttreatment) and a late-posttreatment visit (4 to 6 weeks posttreatment) for microbiological and clinical outcomes and safety. The primary efficacy endpoint and microbiological eradication rate at the test-of-cure visit in the ciprofloxacin ER group (254/272; 93.4%) were noninferior to those in the ciprofloxacin IR group (225/251; 89.6%) (95% confidence interval [CI] of difference, −0.99%, 8.59%). Clinical-cure rates at the test-of-cure visit were 85.7% (233/272) for ciprofloxacin ER and 86.1% (216/251) for ciprofloxacin IR (95% CI of difference, −6.37%, 5.57%). At the late-posttreatment visit, microbiological and clinical outcomes were similar for the two treatments and consistent with test-of-cure results. Both treatments were well tolerated, but the frequencies of nausea and diarrhea were lower in the ciprofloxacin ER group than in the ciprofloxacin IR group (nausea, ER, 0.6%; IR, 2.2%;
P
= 0.033; diarrhea, ER, 0.2%; IR, 1.4%;
P
= 0.037). Once-daily ciprofloxacin ER was safe, effective, and noninferior to twice-daily ciprofloxacin IR in the treatment of acute uUTI. Additionally, ciprofloxacin ER was associated with significantly reduced frequencies of nausea and diarrhea.
Relationship between the Level of Acquired Resistance to Gentamicin and Synergism with Amoxicillin in
Enterococcus faecalis
Authors: Aslangul Elisabeth , Ruimy Raymond , Chau Françoise , Garry Louis , Andremont Antoine , Fantin Bruno 
Published: September 2005

ABSTRACT

In enterococci, intrinsic low-level resistance to gentamicin does not abolish synergism with a cell wall-active antibiotic while high-level resistance due to acquired aminoglycoside-modifying enzymes does. To study the impact of intermediate levels of resistance to gentamicin (64 < MIC < 500 μg/ml), we selected in vitro three consecutive generations of mutants of
Enterococcus faecalis
JH2-2 with MICs of gentamicin at 128 μg/ml for G1-1477, 256 μg/ml for G2-1573, and 512 μg/ml for G3-1688.
E. faecalis
102, which is highly resistant to gentamicin by enzymatic inactivation was used as control. In in vitro killing curves experiments, gentamicin concentrations allowing bactericidal activity and synergism in combination with amoxicillin increased from 4 μg/ml (1/16th the MIC), 16 μg/ml (one-eighth the MIC), 64 μg/ml (one-quarter the MIC), and 256 μg/ml (one-half the MIC) for strains JH2-2, G1-1477, G2-1573 and G3-1688, respectively. As expected, no bactericidal effect of the combination or synergism could be obtained with strain 102. In rabbits with aortic endocarditis caused by strain G1-1477 or G2-1573, combination therapy with amoxicillin and gentamicin was significantly more active than amoxicillin alone (
P
< 0.05) but not in those infected with the strains G3-1688 and 102. Thus, intermediate levels of resistance to gentamicin was not associated with a loss of a beneficial effect of the gentamicin-amoxicillin combination in vivo even though higher concentrations of gentamicin were necessary to achieve in vitro synergism. Therefore, the use of an MIC of 500 μg/ml as a clinical cutoff limit to predict in vivo benefit of the combination remains a simple and effective tool.
Increase of Microcirculatory Blood Flow Enhances Penetration of Ciprofloxacin into Soft Tissue
Authors: Joukhadar Christian , Dehghanyar Pejman , Traunmüller Friederike , Sauermann Robert , Mayer-Helm Bernhard , Georgopoulos Apostolos , Müller Markus 
Published: September 2005

ABSTRACTThe present study addressed the effect of microcirculatory blood flow on the ability of ciprofloxacin to penetrate soft tissues. Twelve healthy male volunteers were enrolled in an analyst-blinded, clinical pharmacokinetic study. A single intravenous dose of 200 mg of ciprofloxacin was administered over a period of approximately 20 min. The concentrations of ciprofloxacin were measured in plasma and in the warmed and contralateral nonwarmed lower extremities. The microdialysis technique was used for the assessment of unbound ciprofloxacin concentrations in subcutaneous adipose tissue. Microcirculatory blood flow was measured by use of laser Doppler flowmetry. Warming of the extremity resulted in an increase of microcirculatory blood flow by approximately three- to fourfold compared to that at the baseline (P< 0.05) in subcutaneous adipose tissue. The ratio of the maximum concentration (Cmax) of ciprofloxacin for the warmed thigh to theCmaxfor the nonwarmed thigh was 2.10 ± 0.90 (mean ± standard deviation;P< 0.05). A combined in vivo pharmacokinetic (PK)-in vitro pharmacodynamic (PD) simulation based on tissue concentration data indicated that killing ofPseudomonas aeruginosa(ATCC 27853 and two clinical isolates) was more effective by about 2 log10CFU/ml under the warmed conditions than under the nonwarmed conditions (P< 0.05). The improvement of microcirculatory blood flow due to the warming of the extremity was paralleled by an increased ability of ciprofloxacin to penetrate soft tissue. Subsequent PK-PD simulations based on tissue PK data indicated that this increase in tissue penetration was linked to an improved antimicrobial effect at the target site.
Resistance to Antimicrobial Peptides and Stress Response in
Mycoplasma pulmonis
Authors: Fehri Lina Fassi , Sirand-Pugnet Pascal , Gourgues Géraldine , Jan Gwenaël , Wróblewski Henri , Blanchard Alain 
Published: September 2005

ABSTRACT

Antimicrobial peptides are widely distributed in nature, and in vertebrates, they play a key function in the innate immune defense system. It is generally agreed that these molecules may provide new antibiotics with therapeutic value. However, there are still many unsolved questions regarding the mechanisms underlying their antimicrobial activity as well as the mechanisms of resistance evolved by microorganisms against these molecules. The second point was addressed in this study. After determining the activity of 10 antimicrobial peptides against
Mycoplasma pulmonis
, a murine respiratory pathogen, the development of resistance was investigated. Following in vitro selection using subinhibitory concentrations of peptides, clones of this bacterium showing increased resistance to melittin or gramicidin D were obtained. For some of the clones, a cross-resistance was observed between these two peptides, in spite of their deep structural differences, and also with tetracycline. A proteomic analysis suggested that the stress response in these clones was constitutively activated, and this was confirmed by finding mutations in the
hrcA
gene; in mycoplasmas, bacteria which lack alternative sigma factors, the HrcA protein is supposed to play a key role as a negative regulator of heat shock proteins. By complementation of the
hrcA
mutants with the wild-type gene, the initial MICs of melittin and gramicidin D decreased to values close to the initial ones. This indicates that the resistance of
M. pulmonis
to these two antimicrobial peptides could result from a stress response involving HrcA-regulated genes.
In Vitro and In Vivo Antibacterial Activities of SM-216601, a New Broad-Spectrum Parenteral Carbapenem
Authors: Ueda Yutaka , Kanazawa Katsunori , Eguchi Ken , Takemoto Koji , Eriguchi Yoshiro , Sunagawa Makoto 
Published: September 2005

ABSTRACT

SM-216601 is a novel parenteral 1β-methylcarbapenem. In agar dilution susceptibility testing, the MIC of SM-216601 for 90% of the methicillin-resistant
Staphylococcus aureus
(MRSA) strains tested (MIC
90
) was 2 μg/ml, which was comparable to those of vancomycin and linezolid. SM-216601 was also very potent against
Enterococcus faecium
, including vancomycin-resistant strains (MIC
90
= 8 μg/ml). SM-216601 exhibited potent activity against penicillin-resistant
Streptococcus pneumoniae
, ampicillin-resistant
Haemophilus influenzae
,
Moraxella catarrhalis
,
Escherichia coli
,
Klebsiella pneumoniae
, and
Proteus mirabilis
, with MIC
90
s of less than 0.5 μg/ml, and intermediate activity against
Citrobacter freundii
,
Enterobacter cloacae
,
Serratia marcescens
, and
Pseudomonas aeruginosa
. The therapeutic efficacy of SM-216601 against experimentally induced infections in mice caused by
S. aureus
,
E. faecium
,
E. coli
, and
P. aeruginosa
reflected its in vitro activity and plasma level. Thus, SM-216601 is a promising candidate for nosocomial bacterial infections caused by a wide range of gram-positive and gram-negative bacteria, including multiresistant pathogens.
Inhibition of Hepatitis C Virus Replication by Antimonial Compounds
Authors: Hwang Der-Ren , Lin Ren-Kuo , Leu Guang-Zhou , Lin Tiao-Yin , Lien Tzu-Wen , Yu Ming-Chen , Yeh Chau-Ting , Hsu John T.-A. 
Published: September 2005

ABSTRACTChronic hepatitis C virus (HCV) infection is a worldwide health problem causing serious complications, such as liver cirrhosis and hepatoma. Alpha interferon (IFN-α) or its polyethylene glycol-modified form combined with ribavirin is the only recommended therapy. However, an alternative therapy is needed due to the unsatisfactory cure rate of the IFN-based therapy. Using a modified reporter assay based on the HCV subgenomic-replicon system, we found that sodium stibogluconate (SSG), a compound used for leishmania treatment, suppressed HCV replication. We have previously reported that SSG is effective at inhibiting HCV replication in a cell line permissive for HCV infection/replication and in an ex vivo assay using fresh human liver slices obtained from patients infected with HCV (26). In this study, we show that the SSG 50% inhibitory dose for HCV replication is 0.2 to 0.3 mg/ml (equivalent to 345 to 517 μM of Sb) in the HCV subgenomic-replicon system. We also found that SSG and IFN-α exert a strong synergistic anti-HCV effect in both the traditional isobologram analysis and the median effect principle (CalcuSyn analysis). The combination of SSG and IFN-α could sustain the antiviral response better than SSG or IFN-α alone. The results suggest that SSG may be a good drug candidate for use in combination with other therapeutics, such as IFN-α and ribavirin, to treat HCV infection.
Antistaphylococcal Activity of Ceftobiprole, a New Broad-Spectrum Cephalosporin
Authors: Bogdanovich Tatiana , Ednie Lois M. , Shapiro Stuart , Appelbaum Peter C. 
Published: September 2005

ABSTRACT

Ceftobiprole (formerly BAL9141), the active component of the prodrug BAL5788 (ceftobiprole medocaril), is a novel cephalosporin with expanded activity against gram-positive bacteria. Among 152
Staphylococcus aureus
isolates, including 5 vancomycin-intermediate and 2 vancomycin-resistant strains, MIC
50
and MIC
90
values for ceftobiprole were each 0.5 μg/ml against methicillin-susceptible strains and 2 μg/ml against methicillin-resistant strains. Against 151 coagulase-negative staphylococci (including 4 vancomycin-intermediate strains), MIC
50
and MIC
90
values were, respectively, 0.125 μg/ml and 1 μg/ml against methicillin-susceptible and 1 μg/ml and 2 μg/ml against methicillin-resistant strains. Teicoplanin was less active than vancomycin against coagulase-negative strains. Linezolid, quinupristin-dalfopristin, and daptomycin were active against all strains, whereas increased MICs for amoxicillin-clavulanate, cefazolin, minocycline, gentamicin, trimethoprim-sulfamethoxazole, levofloxacin, rifampin, mupirocin, fusidic acid, and fosfomycin were sometimes observed. At 2× MIC, ceftobiprole was bactericidal against 11 of 12 test strains by 24 h. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to select for clones with MICs >4 times those of the parents; the maximum MIC achieved for ceftobiprole after 50 passages (in 1 of 10 strains) was 8 μg/ml. Single-passage selections showed very low frequencies of resistance to ceftobiprole irrespective of genotype or phenotype; the maximal ceftobiprole MIC of recovered clones was 8 μg/ml.
Glycopeptide ResistancevanAOperons inPaenibacillusStrains Isolated from Soil
Authors: Guardabassi Luca , Perichon Bruno , van Heijenoort Jean , Blanot Didier , Courvalin Patrice 
Published: September 2005

ABSTRACTThe sequence and gene organization of thevanoperons in vancomycin (MIC of >256 μg/ml)- and teicoplanin (MIC of ≥32 μg/ml)-resistantPaenibacillus thiaminolyticusPT-2B1 andPaenibacillus apiariusPA-B2B isolated from soil were determined. Both operons had regulatory (vanRandvanS), resistance (vanH,vanA, andvanX), and accessory (vanY,vanZ, andvanW) genes homologous to the corresponding genes in enterococcalvanAandvanBoperons. ThevanAPToperon inP. thiaminolyticusPT-2B1 had the same gene organization as that ofvanAoperons whereasvanAPAinP. apiariusPA-B2B resembledvanBoperons due to the presence ofvanWupstream from thevanHAXcluster but was closer tovanAoperons in sequence. ReferenceP. apiariusstrains NRRL B-4299 and NRRL B-4188 were found to harbor operons indistinguishable fromvanAPAby PCR mapping, restriction fragment length polymorphism, and partial sequencing, suggesting that this operon was species specific. As in enterococci, resistance was inducible by glycopeptides and associated with the synthesis of pentadepsipeptide peptidoglycan precursors ending ind-Ala-d-Lac, as demonstrated byd,d-dipeptidase activities, high-pressure liquid chromatography, and mass spectrometry. The precursors differed from those in enterococci by the presence of diaminopimelic acid instead of lysine in the peptide chain. Altogether, the results are compatible with the notion thatvanoperons in soilPaenibacillusstrains and in enterococci have evolved from a common ancestor.
Kinetic Properties of Four Plasmid-Mediated AmpC β-Lactamases
Authors: Bauvois Cédric , Ibuka Akiko Shimizu , Celso Almeida , Alba Jimena , Ishii Yoshikazu , Frère Jean-Marie , Galleni Moreno 
Published: September 2005

ABSTRACT

The heterologous production in
Escherichia coli
, the purification, and the kinetic characterization of four plasmid-encoded class C β-lactamases (ACT-1, MIR-1, CMY-2, and CMY-1) were performed. Except for their instability, these enzymes are very similar to the known chromosomally encoded AmpC β-lactamases. Their kinetic parameters did not show major differences from those obtained for the corresponding chromosomal enzymes. However, the

K
m

values of CMY-2 for cefuroxime, cefotaxime, and oxacillin were significantly decreased compared to those of the chromosomal AmpC enzymes. Finally, the susceptibility patterns of different
E. coli
hosts producing a plasmid- or a chromosome-encoded class C enzyme toward β-lactam antibiotics are mainly due to the overproduction of the β-lactamase in the periplasmic space of the bacteria rather than to a specific catalytic profile of the plasmid-encoded β-lactamases.
Antibacterial Activity of REP8839, a New Antibiotic for Topical Use
Authors: Critchley Ian A. , Young Casey L. , Stone Kimberley C. , Ochsner Urs A. , Guiles Joseph , Tarasow Ted , Janjic Nebojsa 
Published: September 2005

ABSTRACT

REP8839 is a novel methionyl-tRNA synthetase (MetS) inhibitor with potent antibacterial activity against clinical isolates of
Staphylococcus aureus
,
Streptococcus pyogenes
, and other clinically important gram-positive bacteria but little activity against gram-negative bacteria. All isolates of
S. aureus
, including strains resistant to methicillin, mupirocin, vancomycin, and linezolid were susceptible to REP8839 at concentrations of ≤0.5 μg/ml. REP8839 was also active against
Staphylococcus epidermidis
, including multiply resistant strains (MIC, ≤0.25 μg/ml). All
S. pyogenes
isolates were susceptible to REP8839 at concentrations of ≤0.25 μg/ml, suggesting that MetS2, a second enzyme previously identified in
Streptococcus pneumoniae
, was not present in this organism. REP8839 was highly bound to the protein of human serum, and activity was not greatly influenced by inoculum size but was affected by pH, exhibiting optimal antibacterial activity in a neutral medium rather than a weak acidic medium. Like mupirocin, REP8839 exhibited bacteriostatic activity against key pathogens. The emergence of mupirocin resistance in
S. aureus
highlights the need for a new topical antibiotic with the ability to inhibit high-level mupirocin-resistant strains and other emerging phenotypes, such as vancomycin-resistant and community-acquired methicillin-resistant isolates.
Ultrasonically Controlled Release of Ciprofloxacin from Self-Assembled Coatings on Poly(2-Hydroxyethyl Methacrylate) Hydrogels forPseudomonas aeruginosaBiofilm Prevention
Authors: Norris P. , Noble M. , Francolini I. , Vinogradov A. M. , Stewart P. S. , Ratner B. D. , Costerton J. W. , Stoodley P. 
Published: September 2005

ABSTRACTIndwelling prostheses and subcutaneous delivery devices are now routinely and indispensably employed in medical practice. However, these same devices often provide a highly suitable surface for bacterial adhesion and colonization, resulting in the formation of complex, differentiated, and structured communities known as biofilms. The University of Washington Engineered Biomaterials group has developed a novel drug delivery polymer matrix consisting of a poly(2-hydroxyethyl methacrylate) hydrogel coated with ordered methylene chains that form an ultrasound-responsive coating. This system was able to retain the drug ciprofloxacin inside the polymer in the absence of ultrasound but showed significant drug release when low-intensity ultrasound was applied. To assess the potential of this controlled drug delivery system for the targeting of infectious biofilms, we monitored the accumulation ofPseudomonas aeruginosabiofilms grown on hydrogels with and without ciprofloxacin and with and without exposure to ultrasound (a 43-kHz ultrasonic bath for 20 min daily) in an in vitro flow cell study. Biofilm accumulation from confocal images was quantified and statistically compared by using COMSTAT biofilm analysis software. Biofilm accumulation on ciprofloxacin-loaded hydrogels with ultrasound-induced drug delivery was significantly reduced compared to the accumulation of biofilms grown in control experiments. The results of these studies may ultimately facilitate the future development of medical devices sensitive to external ultrasonic impulses and capable of treating or preventing biofilm growth via “on-demand” drug release.