bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro and In Vivo Activities of Novel 6-Methylidene Penems as β-Lactamase Inhibitors
Authors: Weiss William J. , Petersen Peter J. , Murphy Timothy M. , Tardio LuAnna , Yang Youjun , Bradford Patricia A. , Venkatesan Aranapakam M. , Abe Takao , Isoda Takeshi , Mihira Ado , Ushirogochi Hideki , Takasake Tsuyoshi , Projan Steve , O'Connell John , Mansour Tarek S. 
Published: November 2004

ABSTRACTNovel penem molecules with heterocycle substitutions at the 6 position via a methylidene linkage were investigated for their activities and efficacy as β-lactamase inhibitors. The concentrations of these molecules that resulted in 50% inhibition of enzyme activity were 0.4 to 3.1 nM for the TEM-1 enzyme, 7.8 to 72 nM for Imi-1, 1.5 to 4.8 nM for AmpC, and 14 to 260 nM for a CcrA metalloenzyme. All the inhibitors were more stable than imipenem against hydrolysis by hog and human dehydropeptidases. Piperacillin was combined with a constant 4-μg/ml concentration of each inhibitor for MIC determinations. The combinations reduced piperacillin MICs by 2- to 32-fold for extended-spectrum β-lactamase (ESBL)-producingEscherichia coliandKlebsiella pneumoniaestrains. The MICs for piperacillin-resistant (MIC of piperacillin, >64 μg/ml) strains ofEnterobacterspp.,Citrobacterspp., andSerratiaspp. were reduced to the level of susceptibility (MIC of piperacillin, ≤16 μg/ml) when the drug was combined with 4, 2, or 1 μg of these penem inhibitors/ml. Protection against acute lethal bacterial infections with class A and C β-lactamase- and ESBL-producing organisms in mice was also demonstrated with piperacillin plus inhibitor. Median effective doses were reduced by approximately two- to eightfold compared to those of piperacillin alone when the drug was combined with the various inhibitors at a 4:1 ratio. Pharmacokinetic analysis after intravenous administration of the various inhibitors showed mean residence times of 0.1 to 0.5 h, clearance rates of 15 to 81 ml/min/kg, and volumes of distribution between 0.4 and 2.5 liters/kg. The novel methylidene penem molecules inhibit both class A and class C enzymes and warrant further investigation for potential as therapeutic agents when used in combination with a β-lactam antibiotic.
Pharmacokinetics and Pharmacodynamics of Intravenous Levofloxacin at 750 Milligrams and Various Doses of Metronidazole in Healthy Adult Subjects
Authors: Sprandel Kelly A. , Schriever Christopher A. , Pendland Susan L. , Quinn John P. , Gotfried Mark H. , Hackett Suzanne , Graham Mary Beth , Danziger Larry H. , Rodvold Keith A. 
Published: November 2004

ABSTRACT

The purpose of this investigation was to evaluate the steady-state pharmacokinetics, pharmacodynamics, and safety of intravenous levofloxacin at 750 mg administered once daily combined with three different dosages of intravenous metronidazole (500 mg every 8 h [q8h], 1,000 mg q24h, and 1,500 mg q24h). Eighteen healthy adult subjects received all three combinations in a randomized, crossover fashion. Serial blood and urine samples were collected on the third day of each study period. The 24-h areas under the inhibitory (AUIC
0-24
) and bactericidal (AUBC
0-24
) curves of these three combination regimens were determined against clinical isolates of
Bacteroides fragilis
,
Bacteroides thetaiotaomicron
,
Peptostreptococcus asaccharolyticus
, and
Escherichia coli
. The mean concentrations of levofloxacin were not different between study periods and were similar to those previously published. The mean (± standard deviation) areas under the metronidazole plasma concentration-time curve (AUC
0-24
) for 1,500-mg q24h (338 ± 105 mg · h/liter) and 500-mg q8h (356 ± 68 mg · h/liter) regimens were not different (
P
> 0.05), but both were significantly higher than the 1,000-mg q24h AUC
0-24
(
P
< 0.05, 227 ± 57 mg · h/liter). Mean (± standard deviation) total body clearance and renal clearance values were similar among the 500-mg q8h, 1,000-mg q24, and 1,500-mg q24h regimens (62 ± 7, 67 ± 13, and 67 ± 14 and 11 ± 3, 12 ± 2, and 12 ± 5 ml/min/1.73 m
2
, respectively). Levofloxacin at 750 mg q24h plus metronidazole at 500 mg q8h or 1,500 mg q24h resulted in similar AUIC
0-24
and AUBC
0-24
values with one exception: the AUIC
0-24
for the 1,500-mg q24h regimen against
B. thetaiotamicron
was significantly higher (
P
< 0.05) than those of the other regimens. Overall, the combination of levofloxacin at 750 mg once daily and metronidazole at 500 mg q8h or 1,500 mg q24h appeared to have greater AUIC
0-24
and AUBC
0-24
values than did the 1,000-mg q24h regimen. All combination regimens of levofloxacin and metronidazole were well tolerated, and no serious drug-related adverse effects were reported. The pharmacokinetic, safety, and pharmacodynamic data from our study suggest that a once-daily regimen of intravenous levofloxacin at 750 mg and metronidazole at 1,500 mg warrants further clinical investigation.
National Surveillance of Antimicrobial Resistance in
Pseudomonas aeruginosa
Isolates Obtained from Intensive Care Unit Patients from 1993 to 2002
Authors: Obritsch Marilee D. , Fish Douglas N. , MacLaren Robert , Jung Rose 
Published: November 2004

ABSTRACT

Nosocomial infections caused by
Pseudomonas aeruginosa
in critically ill patients are often difficult to treat due to resistance to multiple antimicrobials. The purpose of this study was to evaluate antimicrobial resistance among
P. aeruginosa
isolates from intensive care unit patients in the United States from 1993 to 2002 by using the Intensive Care Unit Surveillance Study database. Over the 10-year period, susceptibility of 13,999 nonduplicate isolates of
P. aeruginosa
was analyzed. From 1993 to 2002, nationwide increases in antimicrobial resistance were greatest for ciprofloxacin, imipenem, tobramycin, and aztreonam. Rates of multidrug resistance (resistance to ≥3 of the following drugs: ceftazidime, ciprofloxacin, tobramycin, and imipenem) increased from 4% in 1993 to 14% in 2002. The lowest dual resistance rates were observed between aminoglycosides or fluoroquinolones with piperacillin-tazobactam while the highest were for those that included β-lactams and ciprofloxacin. Ongoing surveillance studies are crucial in monitoring antimicrobial susceptibility patterns and selecting empirical treatment regimens.
Metabolism of the Anti-Hepatitis C Virus Nucleoside β-
d
-
N
4
-Hydroxycytidine in Different Liver Cells
Authors: Hernandez-Santiago Brenda I. , Beltran Thierry , Stuyver Lieven , Chu Chung K. , Schinazi Raymond F. 
Published: November 2004

ABSTRACT

β-
d
-
N
4
-Hydroxycytidine (NHC) was found to have selective anti-hepatitis C virus (HCV) activity in the HCV replicon system (clone A). The intracellular metabolism of tritiated NHC was investigated in the HCV replicon system, Huh-7 cells, HepG2 cells, and primary human hepatocytes. Incubation of cells with 10 μM radiolabeled NHC demonstrated extensive and rapid phosphorylation in all liver cells. Besides the 5′-mono, -di-, and -triphosphate metabolites of NHC, other metabolites were characterized. These included cytidine and uridine mono-, di-, and triphosphates. UTP was the predominant early metabolite in Huh-7 cells and primary human hepatocytes, suggesting deamination of NHC as the primary catabolic pathway. The intracellular half-lives of radiolabeled NHC-triphosphate and of CTP and UTP derived from NHC incubation in Huh-7 cells were calculated to be 3.0 ± 1.3, 10.4 ± 3.3, and 13.2 ± 3.5 h (means ± standard deviations), respectively. Studies using monkey and human whole blood demonstrated more-rapid deamination and oxidation in monkey cells than in human cells, suggesting that NHC may not persist long enough in plasma to be delivered to liver cells.
A Radio Frequency Electric Current Enhances Antibiotic Efficacy against Bacterial Biofilms
Authors: Caubet R. , Pedarros-Caubet F. , Chu M. , Freye E. , de Belém Rodrigues M. , Moreau J. M. , Ellison W. J. 
Published: November 2004

ABSTRACT

Bacterial biofilms are notably resistant to antibiotic prophylaxis. The concentration of antibiotic necessary to significantly reduce the number of bacteria in the biofilm matrix can be several hundred times the MIC for the same bacteria in a planktonic phase. It has been observed that the addition of a weak continuous direct electric current to the liquid surrounding the biofilm can dramatically increase the efficacy of the antibiotic. This phenomenon, known as the bioelectric effect, has only been partially elucidated, and it is not certain that the electrical parameters are optimal. We confirm here the bioelectric effect for
Escherichia coli
biofilms treated with gentamicin and with oxytetracycline, and we report a new bioelectric effect with a radio frequency alternating electric current (10 MHz) instead of the usual direct current. None of the proposed explanations (transport of ions within the biofilm, production of additional biocides by electrolysis, etc.) of the direct current bioelectric effect are applicable to the radio frequency bioelectric effect. We suggest that this new phenomenon may be due to a specific action of the radio frequency electromagnetic field upon the polar parts of the molecules forming the biofilm matrix.
Impact of High-InoculumStaphylococcus aureuson the Activities of Nafcillin, Vancomycin, Linezolid, and Daptomycin, Alone and in Combination with Gentamicin, in an In Vitro Pharmacodynamic Model
Authors: LaPlante Kerry L. , Rybak Michael J. 
Published: November 2004

ABSTRACTWe evaluated the impact of high (9.5 log10CFU/g) and moderate (5.5 log10CFU/g) inocula of methicillin-susceptible and -resistant Staphylococcus aureus(MSSA and MRSA, respectively) on the activities of nafcillin, linezolid, vancomycin, and daptomycin, alone and in combination with gentamicin in an in vitro pharmacodynamic model with simulated endocardial vegetations over 72 h. Human therapeutic dosing regimens for nafcillin, daptomycin, vancomycin, linezolid, and gentamicin were simulated. At a moderate inoculum, nafcillin (MSSA only), vancomycin, and daptomycin demonstrated equivalent and significant (P< 0.01) bactericidal (99.9% kill) activities (decreases of 3.34 ± 1.1, 3.28 ± 0.4, and 3.34 ± 0.8 log10CFU/g, respectively). Bactericidal activity was demonstrated at 4 h for nafcillin and daptomycin and at 32 h for vancomycin. Linezolid demonstrated bacteriostatic activity over the course of the study period. At a high inoculum, daptomycin exhibited bactericidal activity against both MSSA and MRSA by 24 h (decrease of 5.51 to 6.31 ± 0.10 log10CFU/g). Nafcillin (versus MSSA), vancomycin, and linezolid (MSSA and MRSA) did not achieve bactericidal activity throughout the 72-h experiment. The addition of gentamicin increased the rate of 99.9% kill to 8 h for daptomycin (P< 0.01) and 48 h for nafcillin (MSSA only) (P= 0.01). The addition of gentamicin did not improve the activity of vancomycin or linezolid for either isolate for the 72-h period. Overall, high-inoculumStaphylococcus aureushad a significant impact on the activities of nafcillin and vancomycin. In contrast, daptomycin was affected minimally and linezolid was not affected by inoculum.
n-6 Polyunsaturated Fatty Acids Enhance the Activities of Ceftazidime and Amikacin in Experimental Sepsis Caused by Multidrug-Resistant
Pseudomonas aeruginosa
Authors: Giamarellos-Bourboulis Evangelos J. , Mouktaroudi Maria , Adamis Theodoros , Koussoulas Vassilios , Baziaka Fotini , Perrea Despina , Karayannacos Panayotis E. , Giamarellou Helen 
Published: November 2004

ABSTRACT

Recent in vitro and ex vivo studies disclosed an enhancement of the activity of antimicrobials on multidrug-resistant
Pseudomonas aeruginosa
by n-6 polyunsaturated fatty acids (PUFAS); therefore their effect was evaluated in experimental sepsis in 60 rabbits. Solutions of gamma-linolenic acid (GLA) and arachidonic acid (AA) were administered intravenously with ceftazidime and amikacin in rabbits with sepsis caused by one multidrug-resistant isolate. Therapy was started after bacterial challenge in five groups comprising 12 animals in each group: A, normal saline; B, antimicrobials; C, 99% ethanol and antimicrobials; D, GLA and antimicrobials; and E, AA and antimicrobials. Blood was sampled for the estimation of levels of endotoxins in serum (lipopolysaccharide), leukocytes, tumor necrosis factor alpha (TNF-α) and antimicrobials. Animals were sacrificed 210 min after bacterial challenge for tissue cultures. All animals had considerable endotoxemia and evolved leukopenia. The number of viable cells in blood, lung, and mesenteric lymph nodes was significantly reduced in groups D and E compared to that in other groups. Levels of antimicrobials in serum were inadequate to achieve bacterial killing due to the level of resistance. n-6 PUFAs did not influence TNF-α. It is concluded that intravenous coadministration of n-6 PUFAs and antimicrobials enhanced antimicrobial bacterial killing in experimental sepsis caused by multidrug-resistant
P. aeruginosa
.
Evolution of Ciprofloxacin-Resistant
Staphylococcus aureus
in In Vitro Pharmacokinetic Environments
Authors: Campion Jeffrey J. , McNamara Patrick J. , Evans Martin E. 
Published: November 2004

ABSTRACT

The development of novel antibacterial agents is decreasing despite increasing resistance to presently available agents among common pathogens. Insights into relationships between pharmacodynamics and resistance may provide ways to optimize the use of existing agents. The evolution of resistance was examined in two ciprofloxacin-susceptible
Staphylococcus aureus
strains exposed to in vitro-simulated clinical and experimental ciprofloxacin pharmacokinetic profiles for 96 h. As the average steady-state concentration (
C
avg ss
) increased, the rate of killing approached a maximum, and the rate of regrowth decreased. The enrichment of subpopulations with mutations in
grlA
and low-level ciprofloxacin resistance also varied depending on the pharmacokinetic environment. A regimen producing values for
C
avg ss
slightly above the MIC selected resistant variants with
grlA
mutations that did not evolve to higher levels of resistance. Clinical regimens which provided values for
C
avg ss
intermediate to the MIC and mutant prevention concentration (MPC) resulted in the emergence of subpopulations with
gyrA
mutations and higher levels of resistance. A regimen producing values for
C
avg ss
close to the MPC selected
grlA
mutants, but the appearance of subpopulations with higher levels of resistance was diminished. A regimen designed to maintain ciprofloxacin concentrations entirely above the MPC appeared to eradicate low-level resistant variants in the inoculum and prevent the emergence of higher levels of resistance. There was no relationship between the time that ciprofloxacin concentrations remained between the MIC and the MPC and the degree of resistance or the presence or type of ciprofloxacin-resistance mutations that appeared in
grlA
or
gyrA
. Regimens designed to eradicate low-level resistant variants in
S. aureus
populations may prevent the emergence of higher levels of fluoroquinolone resistance.
Reduced Content of Lysyl-Phosphatidylglycerol in the Cytoplasmic Membrane Affects Susceptibility to Moenomycin, as Well as Vancomycin, Gentamicin, and Antimicrobial Peptides, in
Staphylococcus aureus
Authors: Nishi Hiromi , Komatsuzawa Hitoshi , Fujiwara Tamaki , McCallum Nadine , Sugai Motoyuki 
Published: November 2004

ABSTRACT

An association between moenomycin resistance and vancomycin intermediate resistance in
Staphylococcus aureus
was demonstrated previously. Thus, to elucidate the mechanism of vancomycin intermediate resistance, we searched for factors contributing to moenomycin resistance. Random Tn
551
insertional mutagenesis of methicillin-resistant
S. aureus
strain COL yielded three mutants with decreased susceptibilities to moenomycin. Correspondingly, these mutants also exhibited slightly decreased susceptibilities to vancomycin. Genetic analysis revealed that two of the mutants had Tn
551
insertions in the
fmtC
(
mprF
) gene, which is associated with the synthesis of lysyl-phosphatidylglycerol. The third Tn
551
insertion was located in the
lysC
gene, which is involved in the biosynthesis of lysine from aspartic acid. Consequently, mutations in both of these loci reduced the lysyl-phosphatidylglycerol content in the cell membrane, giving it a more negative net charge. The positively charged antibiotic gentamicin and cationic antimicrobial peptides such as β-defensins and CAP18 were more effective against the mutants. The levels of moenomycin and vancomycin binding to intact cells was also greater in the mutants than in the wild type, while the binding affinity was not altered when cells boiled in sodium dodecyl sulfate were used, indicating that both agents had higher affinities for the negatively charged membranes of the mutants. Therefore, the membrane charge of
S. aureus
appears to influence the efficacies of moenomycin, vancomycin, and other cationic antimicrobial agents.
Evaluation of Antibiotic Susceptibilities of
Ehrlichia canis
,
Ehrlichia chaffeensis
, and
Anaplasma phagocytophilum
by Real-Time PCR
Authors: Branger S. , Rolain J. M. , Raoult D. 
Published: November 2004

ABSTRACT

We determined MICs of antibiotics against
Anaplasma phagocytophilum
,
Ehrlichia chaffeensis
, and
Ehrlichia canis
by real-time quantitative PCR. The doubling times of the organisms were established: 19 h for
E. chaffeensis
, 26 h for
A. phagocytophilum
, and 28 h for
E. canis.
In comparison to the reference method for determining sensitivities, which uses Diff-Quick staining, our PCR assay was very sensitive and specific. We confirmed that doxycycline and rifampin are highly active against these bacteria and found variable susceptibilities to fluoroquinolones;
A. phagocytophilum
was susceptible, but
E. canis
and
E. chaffeensis
were only partly susceptible. β-Lactam compounds, cotrimoxazole, macrolide compounds, and telithromycin showed no activity against any of the three organisms. Thiamphenicol was found to be more active than chloramphenicol. For the first time, we showed that these three species have numerous point mutations in their 23S RNA genes, with those at positions 754, 2057, 2058, 2059, and 2611 (
Escherichia coli
numbering) known to confer resistance to macrolide compounds in other bacteria. The role of each of these mutations in resistance to these drugs should be investigated in the future. Our study confirms previous reports that quantitative PCR is a reliable method for determining antibiotic susceptibility; therefore, it might be useful for screening new drugs.
Atovaquone Maintenance Therapy Prevents Reactivation of Toxoplasmic Encephalitis in a Murine Model of Reactivated Toxoplasmosis
Authors: Dunay Ildiko R. , Heimesaat Markus M. , Bushrab Faris Nadiem , Müller Rainer H. , Stocker Hartmut , Arasteh Keikawus , Kurowski Michael , Fitzner Rudolf , Borner Klaus , Liesenfeld Oliver 
Published: November 2004

ABSTRACT

Acute therapy with pyrimethamine plus sulfadiazine is the treatment of choice for reactivated toxoplasmic encephalitis (TE). Acute therapy is followed by lifelong maintenance therapy (secondary prophylaxis) with the same drugs at lower dosages. The use of pyrimethamine plus sulfadiazine is hampered by severe side effects including allergic reactions and hematotoxicity. Alternative treatment regimens with pyrimethamine plus clindamycin or other antiparasitic drugs are less efficacious. Atovaquone nanosuspensions show excellent therapeutic effects for “acute” intravenous (i.v.) treatment of reactivated TE in a murine model. In the present study, the therapeutic efficacy of atovaquone for oral “maintenance” therapy was investigated. Mice with a targeted mutation in the interferon regulatory factor 8 gene were latently infected with
Toxoplasma gondii
, developed reactivated TE, and received acute i.v. therapy with atovaquone nanosuspensions. Mice were then treated orally with atovaquone suspension or other antiparasitic drugs to prevent relapse of TE. Maintenance therapy with atovaquone at daily doses of 50 or 100 mg/kg (body weight) protected mice against reactivated TE and death. This maintenance treatment was superior to standard therapy with pyrimethamine plus sulfadiazine. The latter combination was superior to the combination of pyrimethamine plus clindamycin. Inflammatory changes in the brain parenchyma and meninges, as well as parasite numbers, in the brains of mice confirmed the therapeutic efficacy of atovaquone for maintenance therapy. Atovaquone was detectable in sera, brains, livers, and lungs of infected mice by high-performance liquid chromatography and/or mass spectrometry. In conclusion, atovaquone appears to be superior to the standard maintenance therapy regimens in a murine model of reactivated TE. The therapeutic efficacy of atovaquone for maintenance therapy against TE should be further investigated in clinical trials.
β-Lactamase Gene Expression in a Penicillin-Resistant
Bacillus anthracis
Strain
Authors: Chen Yahua , Tenover Fred C. , Koehler Theresa M. 
Published: November 2004

ABSTRACT

Expression of the
bla1
and
bla2
genes in an archetypal
Bacillus anthracis
strain is insufficient for penicillin resistance. In a penicillin-resistant clinical isolate, both genes are highly transcribed, but
bla1
is the major contributor to high-level resistance to ampicillin. Differential expression of the
bla
genes is dependent upon strain background.
VanE-Type Vancomycin-Resistant
Enterococcus faecalis
Clinical Isolates from Australia
Authors: Abadía-Patiño Lorena , Christiansen Keryn , Bell Jan , Courvalin Patrice , Périchon Bruno 
Published: November 2004

ABSTRACT

Three distinct
Enterococcus faecalis
VanE-type isolates—BM4574, BM4575, and BM4576-obtained in Australia were studied. Expression of the resistance genes was constitutive in BM4575, probably due to a 2-bp deletion into the

vanS
E

gene, and inducible in BM4574 and BM4576. Transcription analysis of the
vanE
operons suggested that the five genes were cotranscribed from an initiation site located 25 bp upstream from the ATG start codon of
vanE
.
Need for Early Antifungal Treatment Confirmed in Experimental Disseminated
Candida albicans
Infection
Authors: MacCallum Donna M. , Odds Frank C. 
Published: November 2004

ABSTRACT

Groups of mice infected intravenously with
Candida albicans
were treated intraperitoneally with amphotericin B, caspofungin, or fluconazole, starting at intervals before and after challenge. Survival was longest and tissue burdens were most reduced with early treatment, and survival times fell proportionately as treatment was delayed, reinforcing clinical recommendations for the earliest possible initiation of antifungal therapy.