bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Ethanol on Fluoroquinolone Efficacy in a Rat Model of Pneumococcal Pneumonia
Authors: Olsen Keith M. , Gentry-Nielsen Martha , Yue Mei , Snitily Mary U. , Preheim Laurel C. 
Published: December 2005

ABSTRACT

This investigation compared the effect of ethanol on fluoroquinolone antibiotic efficacy and pharmacodynamics in an ethanol-fed rat model of pneumococcal pneumonia. Male Sprague-Dawley rats received a liquid diet containing 36% of total calories as ethanol. Paired controls (pair-fed controls) were fed a liquid diet without ethanol or received rat chow. Diets began 7 days before and continued for 10 days after transtracheal infections with 10 times the 50% lethal dose of type 3
Streptococcus pneumoniae
. Beginning 18 h after infection, the rats received once daily subcutaneous phosphate-buffered saline, levofloxacin, moxifloxacin, or trovafloxacin at 50 or 100 mg/kg of body weight. White blood cell counts were determined, blood samples were collected for culture, and mortality was recorded. Additional rats were killed on day 5 for pharmacodynamic studies and quantitative cultures of bronchoalveolar lavage fluid. Bacteremia occurred by day 3 in 20 of 22 untreated rats. All 22 untreated rats died by day 9. Moxifloxacin treatment was effective in all diet groups at both the 50- and 100-mg/kg doses. In contrast, 50-mg/kg doses of levofloxacin and trovafloxacin improved survival in ethanol-fed rats but were ineffective in chow-fed rats. High-dose trovafloxacin at 100 mg/kg was associated with increased mortality in pair-fed rats. The free-fraction area under the concentration-time curve/MIC ratio exceeded 50 with all antibiotics in the ethanol group but dropped below 30 with levofloxacin and trovafloxacin in the pair- and chow-fed rats, with higher mortality. Achievement of adequate antibiotic-free fraction area under the concentration-time curve/MIC ratios helps overcome ethanol-induced immune defects induced in experimental pneumococcal pneumonia.
Induction and Inhibition of Ciprofloxacin Resistance-Conferring Mutations in Hypermutator Bacteria
Authors: Cirz Ryan T. , Romesberg Floyd E. 
Published: December 2005

ABSTRACTThe emergence of drug-resistant bacteria poses a serious threat to human health. Bacteria often acquire resistance from a mutation of chromosomal genes during therapy. We have recently shown that the evolution of resistance to ciprofloxacin in vivo and in vitro requires the induction of a mutation that is mediated by the cleavage of the SOS repressor LexA and the associated derepression of three specialized DNA polymerases (polymerase II [Pol II], Pol IV, and Pol V). These results led us to suggest that it may be possible to design drugs to inhibit these proteins and that such drugs might be coadministered with antibiotics to prevent mutation and the evolution of resistance. For the approach to be feasible, there must not be any mechanisms through which bacteria can induce mutations and acquire antibiotic resistance that are independent of LexA and its repressed polymerases. Perhaps the most commonly cited mechanism to elevate bacterial mutation rates is the inactivation of methyl-directed mismatch repair (MMR). However, it is unclear whether this represents a LexA-independent mechanism or if the mutations that arise in MMR-deficient hypermutator strains are also dependent on LexA cleavage and polymerase derepression. In this work, we show that LexA cleavage and polymerase derepression are required for the evolution of clinically significant resistance in MMR-defectiveEscherichia coli. Thus, drugs that inhibit the proteins responsible for induced mutations are expected to efficiently prevent the evolution of resistance, even in MMR-deficient hypermutator strains.
First Detection of Metallo-β-Lactamase VIM-2 in
Pseudomonas aeruginosa
Isolates from Colombia
Authors: Villegas Maria Virginia , Lolans Karen , del Rosario Olivera Maria , Suarez Carlos José , Correa Adriana , Queenan Anne Marie , Quinn John P. 
Published: December 2005

ABSTRACT

Carbapenem resistance rates in
Pseudomonas aeruginosa
isolates in Colombia, as in many South American countries, are high for reasons that remain unclear. From our nationwide network, we describe the first detection of the metallo-β-lactamase VIM-2 in clinical isolates of
P. aeruginosa
from multiple cities within Colombia. Metallo-β-lactamases were not detected in the two centers with the highest imipenem resistance rates. Clonality was noted in five of the eight centers with strains meeting the criteria for molecular typing. The high carbapenem resistance in
P. aeruginosa
in Colombia may be attributable to a combination of factors, including the presence of metallo-β-lactamases and nosocomial transmission.
Utility of Muropeptide Ligase for Identification of Inhibitors of the Cell Wall Biosynthesis Enzyme MurF
Authors: Baum Ellen Z. , Crespo-Carbone Steven M. , Abbanat Darren , Foleno Barbara , Maden Amy , Goldschmidt Raul , Bush Karen 
Published: December 2005

ABSTRACT

MurF is a key enzyme in the biosynthesis of the bacterial cell wall in both gram-positive and gram-negative bacteria. This enzyme has not been extensively exploited as a drug target, possibly due to the difficulty in obtaining one of the substrates, UDP-MurNAc-
l
-Ala-γ-
d
-Glu-
meso
-diaminopimelate, which is usually purified from bacteria. We have identified putative inhibitors of
Escherichia coli
MurF by a binding assay, thus bypassing the need for substrate. Inhibition of enzymatic activity was demonstrated in a high-performance liquid chromatography-based secondary assay with UDP-MurNAc-
l
-Ala-γ-
d
-Glu-diaminopimelate substrate prepared in a novel way by using muropeptide ligase enzyme to add UDP-MurNAc to synthetic
l
-Ala-γ-
d
-Glu-diaminopimelate; the substrate specificity of muropeptide ligase for peptides containing
l
-Lys in place of diaminopimelate was also investigated. Using the muropeptide ligase-generated MurF substrate, a thiazolylaminopyrimidine series of MurF enzyme inhibitors with 50% inhibitory concentration values as low as 2.5 μM was identified.
Activity of a New Oral Streptogramin, XRP2868, against Gram-Positive Cocci Harboring Various Mechanisms of Resistance to Streptogramins
Authors: Dupuis Michel , Leclercq Roland 
Published: December 2005

ABSTRACT

The antibacterial activity of XRP2868, a new oral streptogramin composed of a combination of RPR132552 (streptogramin A) and RPR202868 (streptogramin B), was evaluated against a collection of clinical gram-positive isolates with characterized phenotypes and genotypes of streptogramin resistance. The effects of genes for resistance to streptogramin A or B on the activity of XRP2868 and its components were also tested by cloning these genes individually or in various combinations in gram-positive recipient strains susceptible to quinupristin-dalfopristin. The species tested included
Staphylococcus aureus
, coagulase-negative staphylococci,
Enterococcus faecalis
,
Enterococcus faecium
,
Streptococcus pneumoniae
, and other species of streptococci. XRP2868 was generally fourfold more potent than quinupristin-dalfopristin against
S. aureus
,
E. faecium
, and streptococci and had activity against
E. faecalis
(MICs = 0.25 to 1 μg/ml). XRP2868 appeared to be affected by the same mechanisms of resistance as those to quinupristin-dalfopristin. Nevertheless, the strong activity of factor A of the oral streptogramin enabled the combination to be very potent against streptogramin-susceptible staphylococci, streptococci, and
E. faecium
(MICs = 0.03 to 0.25 μg/ml) and to retain low MICs against the strains harboring a mechanism of resistance to factor A or factor B of the streptogramin. However, the combination of mechanisms of resistance to factors A and B caused an increase in the MICs of XRP2868, which reached 1 to 4 μg/ml. As with the other streptogramins, there was a reduction in the bactericidal effect of XRPR2868 when the staphylococcal strains acquired a constitutively expressed
erm
gene.
Pharmacodynamics of a New Streptogramin, XRP 2868, in Murine Thigh and Lung Infection Models
Authors: Andes D. , Craig W. A. 
Published: December 2005

ABSTRACT

XRP 2868 is a new streptogramin antibiotic with broad-spectrum activity against gram-positive cocci. We used the neutropenic murine thigh and lung infection models to characterize the time course of antimicrobial activity of XRP 2868 and determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy. Serum levels following four two- to fourfold-escalating single-dose levels of XRP 2868 were measured by liquid chromatography mass spectrometry assay. In vivo postantibiotic effects (PAEs) were determined after doses of 2.5, 10, and 40 mg/kg. Mice had 10
6.8
to 10
8.4
CFU/thigh of strains of
Streptococcus pneumoniae
ATCC 10813 or
Staphylococcus aureus
ATCC 29213 at the start of therapy when treated for 24 h with 2.5 to 640 mg/kg/day of XRP 2868 fractionated for 3-, 6-, 12-, and 24-h dosing regimens. Nonlinear regression analysis was used to determine which PK/PD parameter best correlated with CFU/thigh at 24 h. Pharmacokinetic studies exhibited peak dose values of 0.03 to 0.07, area under the concentration-time curve (AUC) dose values of 0.02 to 0.07, and half-lives of 0.35 to 1.27 h. XRP 2868 produced in vivo PAEs of 0.5 to 3.4 h with
S. pneumoniae
strain ATCC 10813 and −1.5 to 10.7 h with
S. aureus
strain ATCC 29213. The 24-h AUC/MIC was the PK/PD parameter that best correlated with efficacy. In subsequent studies, we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC needed for the efficacy of XRP 2868 varied among pathogens (including resistant strains). Mice had 10
6.1
to 10
7.8
CFU/thigh of four isolates of
S. aureus
(three methicillin-susceptible and one methicillin-resistant strain) and nine isolates of
S. pneumoniae
(one penicillin-susceptible, four penicillin-intermediate, and four penicillin-resistant strains) when treated for 24 h with 0.16 to 640 mg/kg of XRP 2868 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h. MICs ranged from 0.06 to 0.25 μg/ml. The 24-h AUC/MICs for each static dose (20.7 to 252 mg/kg/day) varied from 3 to 70. Mean 24-h AUC/MICs ± standard deviations (SDs) for
S. pneumoniae
and
S. aureus
isolates were 14 ± 10 and 31 ± 16, respectively. Beta-lactam and macrolide resistance did not alter the magnitude of AUC/MIC required for efficacy.
AsnB Is Involved in Natural Resistance of
Mycobacterium smegmatis
to Multiple Drugs
Authors: Ren Huiping , Liu Jun 
Published: December 2005

ABSTRACT

Mycobacteria are naturally resistant to most common antibiotics and chemotherapeutic agents. The underlying molecular mechanisms are not fully understood. In this paper, we describe a hypersensitive mutant of
Mycobacterium smegmatis
, MS 2-39, which was isolated by screening for transposon insertion mutants of
M. smegmatis
mc
2
155 that exhibit increased sensitivity to rifampin, erythromycin, or novobiocin. The mutant MS 2-39 exhibited increased sensitivity to all three of the above mentioned antibiotics as well as fusidic acid, but its sensitivity to other antibiotics, including isoniazid, ethambutol, streptomycin, chloramphenicol, norfloxacin, tetracycline, and β-lactams, remained unchanged. Uptake experiment with hydrophobic agents and cell wall lipid analysis suggest that the mutant cell wall is normal. The transposon insertion was localized within the
asnB
gene, which is predicted to encode a glutamine-dependent asparagine synthetase. Transformation of the mutant with wild-type
asnB
of mc
2
155 or
asnB
of
Mycobacterium tuberculosis
complemented the drug sensitivity phenotype. These results suggest that AsnB plays a role in the natural resistance of mycobacteria.
Resistance to Erythromycin and Telithromycin in
Streptococcus pyogenes
Isolates Obtained between 1999 and 2002 from Greek Children with Tonsillopharyngitis: Phenotypic and Genotypic Analysis
Authors: Grivea Ioanna N. , Al-Lahham Adnan , Katopodis George D. , Syrogiannopoulos George A. , Reinert Ralf René 
Published: December 2005

ABSTRACT

Since the late 1990s, the prevalence of erythromycin-resistant
Streptococcus pyogenes
has significantly increased in several European countries. Between January 1999 and December 2002, 1,577 isolates of
S. pyogenes
were recovered from children with tonsillopharyngitis living in various areas of Western Greece. Erythromycin resistance was observed in 379 (24%) of the 1,577 isolates. All erythromycin-resistant strains along with 153 randomly selected erythromycin-susceptible
S. pyogenes
isolates were tested for their antimicrobial susceptibility, resistance phenotypes, and genotypes. Representative isolates underwent
emm
gene sequence typing. Isolates with reduced susceptibility to telithromycin (MIC, ≥2 μg/ml) were studied for multilocus sequence type, L22, L4, and 23S rRNA mutations. Of the total 379 erythromycin-resistant isolates, 193 (50.9%) harbored the
mef
(A) gene, 163 (43%)
erm
(A), 1 (0.3%)
mef
(A) plus
erm
(A), and 22 (5.8%) the
erm
(B) gene. Among the erythromycin-susceptible isolates,
emm
1 (25%),
emm
2 (12.5%), and
emm
77 (12.5%) predominated. Furthermore, among the erythromycin-resistant isolates,
emm
4 (30.6%),
emm
28 (22.2%), and
emm
77 (12.5%) prevailed. Resistance to telithromycin was observed in 22 (5.8%) of the erythromycin-resistant isolates. Sixteen (72.7%) of the 22 isolates appeared to be clonally related, since all of them belonged to
emm
type 28 and multilocus sequence type 52. One of the well-known mutations (T2166C) in 23S rRNA, as well as a new one (T2136C), was detected in erythromycin- and telithromycin-resistant isolates. High incidence of macrolide resistance and clonal spread of telithromycin resistance were the characteristics of the Greek
S. pyogenes
isolates obtained from 1999 to 2002.
Topical Voriconazole as a Novel Treatment for Fungal Keratitis
Authors: Sponsel William , Chen Nancy , Dang Demi , Paris Gianmarco , Graybill John , Najvar Laura K. , Zhou Lei , Lam Kwok-Wai , Glickman Randolph , Scribbick Frank 
Published: December 2005

ABSTRACT

Paecilomyces lilacinus
is a fungal pathogen which is generally resistant to amphotericin B and certain other antifungals and is an uncommon cause of devastating fungal keratitis. In the present studies, we evaluated topical voriconazole as therapy for
P. lilacinus
keratitis in rabbits. Thirty eyes of 15 rabbits were studied. In five animals, the uninfected left eye was treated twice daily with voriconazole (drug control, uninfected eye). In these same animals, the right eye was infected with
P. lilacinus
but not treated with voriconazole (infection control eye). By day 5, the infection controls had lesions of >2.4 mm in diameter, with conjunctivitis and severe hypopyon, and were sacrificed. In the other 10 rabbits (voriconazole treatment), the right eyes were infected with
P. lilacinus
and treated with voriconazole beginning on day 3 after infection. Voriconazole therapy caused lesions to decrease during 8 days of therapy, after which rabbits were sacrificed (11 days postinfection). Hyphal masses were present in the control infected eyes and absent in treated infected eyes. Voriconazole was detected in all tissues of treated eyes. Topical voriconazole is effective treatment for
P. lilacinus
experimental keratitis, and it penetrates more deeply than the corneal tissue.
Global Transcriptome Analysis of the Responses of a Fluoroquinolone-Resistant
Streptococcus pneumoniae
Mutant and Its Parent to Ciprofloxacin
Authors: Marrer Estelle , Satoh A. Tatsuo , Johnson Margaret M. , Piddock Laura J. V. , Page Malcolm G. P. 
Published: December 2005

ABSTRACT

Streptococcus pneumoniae
M22 is a multidrug-resistant mutant selected after exposure of capsulated wild-type
S. pneumoniae
NCTC 7465 (strain M4) to ciprofloxacin. DNA microarray analysis comparing the gene expression profiles of strain M22 with those of strain M4 showed that strain M22 constitutively expressed 22 genes at levels higher than those observed in strain M4 under all conditions studied. These included the genes encoding the enzymes involved in branched-chain amino acid biosynthesis and two genes (
patA
and
patB
) with sequences suggestive of ABC transporter proteins. Expression of the
patA
and
patB
genes was induced by ciprofloxacin in both strains, but in strain M4 it only reached the levels observed in strain M22 after long incubation with high concentrations of ciprofloxacin. The altered expression profile observed with strain M22 suggested that the mutation or mutations acquired during resistance selection bring the cell into a state in which the expression of critical genes is preemptively altered to correct for the potential effects of ciprofloxacin on gene expression in the parent strain.
Single-Ascending-Dose Pharmacokinetics and Safety of the Novel Broad-Spectrum Antifungal Triazole BAL4815 after Intravenous Infusions (50, 100, and 200 Milligrams) and Oral Administrations (100, 200, and 400 Milligrams) of Its Prodrug, BAL8557, in Healthy Volunteers
Authors: Schmitt-Hoffmann Anne , Roos Brigitte , Heep Markus , Schleimer Michael , Weidekamm Erhard , Brown Tom , Roehrle Michael , Beglinger Christoph 
Published: December 2005

ABSTRACT
BAL8557 is the water-soluble prodrug of a novel antifungal triazole, BAL4815. BAL4815 is active against a broad spectrum of major opportunistic and pathogenic fungi, including strains that are resistant to other azoles. Cohorts of healthy male subjects received single-ascending oral (p.o.) doses of BAL8557 that were equivalent to 100, 200, or 400 mg of BAL4815 or single-ascending, 1-h constant-rate intravenous (i.v.) infusions of BAL8557 which were equivalent to 50, 100, or 200 mg of BAL4815. In each cohort, six subjects were randomly assigned to receive active drug and two subjects were assigned to receive the placebo. All doses were well tolerated, and no severe or serious adverse events occurred. Maximum plasma concentrations of BAL4815 were observed 1.5 to 3 h after p.o. drug intake or at the end of the 1-h infusion. After both routes of administration, values for maximum drug concentration observed in plasma and area under the concentration-time curve increased slightly more than proportionally to the administered dose. Mean elimination half-lives were particularly long (56 to 77 h after p.o. administration and 76 to 104 h after i.v. administration). The volume of distribution was large (155 to 292 liters after p.o. administration and 304 to 494 liters after i.v. administration) and systemic clearance was low (1.9 to 2.8 liter/h after p.o. administration and 2.8 to 5.0 liter/h after i.v. administration). Urinary recovery of BAL4815 was less than 0.4% of the infused dose. Based on the exposure data, oral bioavailability of BAL4815 is assumed to be very high. The pharmacokinetics of BAL4815 are well suited to maintaining concentrations of BAL4815 for a long period of time in the body and to enabling an effective treatment of systemic mycoses.
Multiple-Dose Pharmacokinetics and Safety of the New Antifungal Triazole BAL4815 after Intravenous Infusion and Oral Administration of Its Prodrug, BAL8557, in Healthy Volunteers
Authors: Schmitt-Hoffmann Anne , Roos Brigitte , Maares Jürgen , Heep Markus , Spickerman Jochen , Weidekamm Erhard , Brown Tom , Roehrle Michael 
Published: December 2005

ABSTRACT

BAL8557 is the water-soluble prodrug of BAL4815, a new broad-spectrum antifungal. Healthy male subjects were randomly assigned to four treatment cohorts to receive multiple oral doses or multiple 1-h constant-rate intravenous infusions of BAL8557. Loading doses of BAL8557 were equivalent to 100 mg (followed by once-daily maintenance doses of 50 mg) or 200 mg (followed by once-daily maintenance doses of 100 mg) of BAL4815. In each cohort, six subjects received active drug and two subjects received the placebo. Study duration was 21 days (oral) and 14 days (intravenous). All adverse events reported were mild or moderate, except one severe rhinitis event which was not related to trial medication. After both routes of administration, maximum drug concentration observed in plasma (
C
max
) and area under the concentration-time curve (AUC) values of BAL4815 increased proportionally to the administered dose. AUC values reflected a fourfold to fivefold accumulation of active drug in plasma during once-daily dosing, which is in line with the long elimination half-life of BAL4815 determined after the last administration (mean, 84.5 to 117 h). At steady state, the volume of distribution was large and amounted to 308 to 542 liters. Systemic clearance reached only 2.4 to 4.1 liter/h. At the levels obtained in the present study,
C
max
values of 2.56 and 2.55 μg/ml after oral and intravenous administrations, respectively, there was no indication of CYP3A4 induction or inhibition (as revealed by the urinary 6-β-hydroxycortisol/cortisol test). Based on AUC values after oral and intravenous administration, an excellent oral bioavailability can be predicted for BAL4815. Once-daily oral dosing of 50- or 100-mg equivalents of BAL8557 were recently demonstrated to be efficacious in a phase 2 study conducted with patients with esophageal candidiasis. These doses (preceded by adequate loading dose[s]) will be further explored in the treatment of systemic mycoses.
Pentamidine Is Active in a Neutropenic Murine Model of Acute Invasive Pulmonary Fusariosis
Authors: Lionakis Michail S. , Chamilos Georgios , Lewis Russell E. , Wiederhold Nathan P. , Raad Issam I. , Samonis George , Kontoyiannis Dimitrios P. 
Published: December 2005

ABSTRACT
We studied the efficacy of pentamidine (PNT) as prophylaxis or early treatment in acute pulmonary fusariosis in neutropenic mice. PNT-preexposed mice had significantly improved survival and reduced fungal burden compared to amphotericin B-preexposed and untreated mice. PNT-treated mice had increased survival but no difference in fungal burden versus untreated mice.
Molecular Genetic and Structural Modeling Studies of
Staphylococcus aureus
RNA Polymerase and the Fitness of Rifampin Resistance Genotypes in Relation to Clinical Prevalence
Authors: O'Neill A. J. , Huovinen T. , Fishwick C. W. G. , Chopra I. 
Published: December 2005

ABSTRACT

The adaptive and further evolutionary responses of
Staphylococcus aureus
to selection pressure with the antibiotic rifampin have not been explored in detail. We now present a detailed analysis of these systems. The use of rifampin for the chemotherapy of infections caused by
S. aureus
has resulted in the selection of mutants with alterations within the β subunit of the target enzyme, RNA polymerase. Using a new collection of strains, we have identified numerous novel mutations in the β subunits of both clinical and in vitro-derived resistant strains and established that additional, undefined mechanisms contribute to expression of rifampin resistance in clinical isolates of
S. aureus
. The fitness costs associated with rifampin resistance genotypes were found to have a significant influence on their clinical prevalence, with the most common clinical genotype (H
481
N, S
529
L) exhibiting no fitness cost in vitro. Intragenic mutations which compensate for the fitness costs associated with rifampin resistance in clinical strains of
S. aureus
were identified for the first time. Structural explanations for rifampin resistance and the loss of fitness were obtained by molecular modeling of mutated RNA polymerase enzymes.