bluuebunny/crossref_metadata_2025_split huggingface dataset:
Granulocyte Colony-Stimulating Factor Enhances Endotoxin-Induced Decrease in Biliary Excretion of the Antibiotic Cefoperazone in Rats
Authors: Nadai Masayuki , Matsuda Izumi , Wang Li , Itoh Akio , Naruhashi Kazumasa , Nabeshima Toshitaka , Asai Masaki , Hasegawa Takaaki 
Published: October 2018

ABSTRACTWe have recently reported that endotoxin (lipopolysaccharide [LPS]) derived fromKlebsiella pneumoniaedramatically decreased the biliary excretion of the β-lactam antibiotic cefoperazone (CPZ), which is primarily excreted into the bile via the anion transport system, in rats. The present study was designed to investigate the effect of human recombinant granulocyte colony-stimulating factor (G-CSF), which is reported to be beneficial in experimental models of inflammation, on the pharmacokinetics and biliary excretion of CPZ in rats. CPZ (20 mg/kg of body weight) was administered intravenously 2 h after the intravenous injection of LPS (250 μg/kg). G-CSF was injected subcutaneously at 12 μg/kg for 3 days and was administered intravenously at a final dose of 50 μg/kg 1 h before LPS injection. Peripheral blood cell numbers were also measured. LPS dramatically decreased the systemic and biliary clearances of CPZ and the bile flow rate. Pretreatment with G-CSF enhanced these decreases induced by LPS. The total leukocyte numbers were increased in rats pretreated with G-CSF compared to the numbers in the controls, while the total leukocyte numbers were decreased (about 3,000 cells/μl) by treatment with LPS. Pretreatment with G-CSF produces a deleterious effect against the LPS-induced decrease in biliary secretion of CPZ, and leukocytes play an important role in that mechanism.
Pharmacodynamic Analysis of the Activity of Quinupristin-Dalfopristin against Vancomycin-Resistant
Enterococcus faecium
with Differing MBCs via Time-Kill-Curve and Postantibiotic Effect Methods
Authors: Aeschlimann Jeffrey R. , Rybak Michael J. 
Published: October 2018

ABSTRACT

Quinupristin-dalfopristin (Q-D) is a new water-soluble, semisynthetic antibiotic that is derived from natural streptogramins and that is combined in a 30:70 ratio. A number of studies have described the pharmacodynamic properties of this drug, but most have investigated only staphylococci or streptococci. We evaluated the relationship between Q-D, quinupristin (Q), and/or dalfopristin (D) susceptibility parameters and antibacterial activities against 22 clinical isolates of vancomycin-resistant
Enterococcus faecium
(VREF) by using the concentration-time-kill-curve method and by measuring postantibiotic effects. Q-D, Q, and D MICs and minimum bactericidal concentrations (MBCs) ranged from 0.125 to 1 and 0.25 to 64, 8 to 512 and >512, and 2 to 8 and 8 to 512 μg/ml, respectively. There were no significant relationships between susceptibilities to the individual components and the susceptibilities to the Q-D combination product. In the time-kill-curves studies, Q-D at a concentration of 6 μg/ml was at least bacteriostatic against all VREF tested. There was increased activity against more susceptible isolates when the isolates were grouped either by Q-D MBCs or by Q MICs. By multivariate regression analyses, the percent change in the inoculum from that at the baseline was significantly correlated with the Q MIC (
R
= 0.74;
P
= 0.008) and the Q-D concentration-to-MBC ratio (
R
= 0.58;
P
= 0.02) and was inversely correlated with the Q-D MBC-to-MIC ratio (
R
= 0.68;
P
= 0.003). A strong correlation existed between the killing rate and the Q-D concentration-to-MBC ratio (
R
= 0.99;
P
< 0.0001). Time to 99.9% killing was best correlated with the Q-D MBC (
R
= 0.96;
P
< 0.0001). The postantibiotic effect ranged from 0.2 to 3.2 h and was highly correlated with the Q-D concentration-to-MBC ratio (
R
= 0.96;
P
< 0.0001) and was less highly correlated with the Q MIC (
R
= 0.42;
P
= 0.04). Further study of these relationships with in vitro or in vivo infection models that simulate Q-D pharmacokinetics should further define the utility of these pharmacodynamic parameters in the prediction of Q-D activity for the treatment of VREF infections in humans.
Glycopeptide Antibiotic Resistance Genes in Glycopeptide-Producing Organisms
Authors: Marshall C. G. , Lessard I. A. D. , Park I.-S. , Wright G. D. 
Published: October 2018

ABSTRACT

The mechanism of high-level resistance to vancomycin in enterococci consists of the synthesis of peptidoglycan terminating in
d
-alanyl-
d
-lactate instead of the usual
d
-alanyl-
d
-alanine. This alternate cell wall biosynthesis pathway is ensured by the collective actions of three enzymes: VanH, VanA, and VanX. The origin of this resistance mechanism is unknown. We have cloned three genes encoding homologs of VanH, VanA, and VanX from two organisms which produce glycopeptide antibiotics: the A47934 producer
Streptomyces toyocaensis
NRRL 15009 and the vancomycin producer
Amycolatopsis orientalis
C329.2. The predicted amino acid sequences are highly similar to those found in VRE: 54 to 61% identity for VanH, 59 to 63% identity for VanA, and 61 to 64% identity for VanX. Furthermore, the orientations of the genes,
vanH
,
vanA
, and
vanX
, are identical to the orientations found in vancomycin-resistant enterococci. Southern analysis of total DNA from other glycopeptide-producing organisms,
A. orientalis
18098 (chloro-eremomycin producer),
A. orientalis
subsp.
lurida
(ristocetin producer), and
Amycolatopsis coloradensis
subsp.
labeda
(teicoplanin and avoparcin producer), with a probe derived from the
vanH
,
vanA
, and
vanX
cluster from
A. orientalis
C329.2 revealed cross-hybridizing DNA in all strains. In addition, the
vanH
,
vanA
,
vanX
cluster was amplified from all glycopeptide-producing organisms by PCR with degenerate primers complementary to conserved regions in VanH and VanX. Thus, this gene sequence is common to all glycopeptide producers tested. These results suggest that glycopeptide-producing organisms may have been the source of resistance genes in vancomycin-resistant enterococci.
New Trimethoprim-Resistant Dihydrofolate Reductase Cassette,
dfrXV
, Inserted in a Class 1 Integron
Authors: Adrian Peter V. , du Plessis Mignon , Klugman Keith P. , Amyes Sebastian G. B. 
Published: October 2018

ABSTRACT

The nucleotide sequence of a plasmid-borne trimethoprim resistance gene from a commensal fecal
Escherichia coli
isolate revealed a new dihydrofolate reductase gene,
dfrXV
, which occurred as a gene cassette integrated in a site-specific manner in a class 1 integron. The new gene shows 84% nucleotide identity and the predicted protein shows 90% amino acid identity with
dfrI
and DHFR type I, respectively. Genes for spectinomycin resistance,
aadA1
[
ant (3′′)-Ia
], and sulfonamide resistance,
sulI
, were located downstream of
dfrXV
in a manner identical to that in pLMO229.
Human Immunodeficiency Virus Type 1 cDNA Integration: New Aromatic Hydroxylated Inhibitors and Studies of the Inhibition Mechanism
Authors: Farnet C. M. , Wang B. , Hansen M. , Lipford J. R. , Zalkow L. , Robinson W. E. , Siegel J. , Bushman F. 
Published: October 2018

ABSTRACT
Integration of the human immunodeficiency virus type 1 (HIV-1) cDNA is a required step for viral replication. Integrase, the virus-encoded enzyme important for integration, has not yet been exploited as a target for clinically useful inhibitors. Here we report on the identification of new polyhydroxylated aromatic inhibitors of integrase including ellagic acid, purpurogallin, 4,8,12-trioxatricornan, and hypericin, the last of which is known to inhibit viral replication. These compounds and others were characterized in assays with subviral preintegration complexes (PICs) isolated from HIV-1-infected cells. Hypericin was found to inhibit PIC assays, while the other compounds tested were inactive. Counterscreening of these and other integrase inhibitors against additional DNA-modifying enzymes revealed that none of the polyhydroxylated aromatic compounds are active against enzymes that do not require metals (methylases, a pox virus topoisomerase). However, all were cross-reactive with metal-requiring enzymes (restriction enzymes, a reverse transcriptase), implicating metal atoms in the inhibitory mechanism. In mechanistic studies, we localized binding of some inhibitors to the catalytic domain of integrase by assaying competition of binding by labeled nucleotides. These findings help elucidate the mechanism of action of the polyhydroxylated aromatic inhibitors and provide practical guidance for further inhibitor development.
Two 2-Hydroxy-3-Alkyl-1,4-Naphthoquinones with In Vitro and In Vivo Activities against
Toxoplasma gondii
Authors: Khan Anis A. , Nasr Mohamed , Araujo Fausto G. 
Published: October 2018

ABSTRACT

Two 3-alkyl-substituted 2-hydroxy-1,4-naphthoquinones, NSC 113452 (NSC52) and NSC 113455 (NSC55), were evaluated for activity against
Toxoplasma gondii
in vitro and in murine models of acute toxoplasmosis. In vitro, both NSC52 and NSC55 significantly inhibited intracellular replication of
T. gondii
. In vivo, each compound was examined alone and in combination with other drugs currently used for treatment of human toxoplasmosis. Although none of the compounds protected mice against death when administered orally, both were significantly protective when administered intraperitoneally. In addition, a significant increase in survival was observed when suboptimal doses of each compound were used in combination with suboptimal doses of pyrimethamine or sulfadiazine. These results indicate that combinations of NSC52 or NSC55 with pyrimethamine or sulfadiazine have promising activity against
T. gondii
.
Alterations in Topoisomerase IV and DNA Gyrase in Quinolone-Resistant Mutants of
Mycoplasma hominis
Obtained In Vitro
Authors: Bébéar Cécile M. , Renaudin Hélène , Charron Alain , Bové Joseph M. , Bébéar Christiane , Renaudin Joel 
Published: October 2018

ABSTRACT

Mycoplasma hominis
mutants were selected stepwise for resistance to ofloxacin and sparfloxacin, and their
gyrA
,
gyrB
,
parC
, and
parE
quinolone resistance-determining regions were characterized. For ofloxacin, four rounds of selection yielded six first-, six second-, five third-, and two fourth-step mutants. The first-step mutants harbored a single Asp426→Asn substitution in ParE. GyrA changes (Ser83→Leu or Trp) were found only from the third round of selection. With sparfloxacin, three rounds of selection generated 4 first-, 7 second-, and 10 third-step mutants. In contrast to ofloxacin resistance, GyrA mutations (Ser83→Leu or Ser84→Trp) were detected in the first-step mutants prior to ParC changes (Glu84→Lys), which appeared only after the second round of selection. Further analysis of eight multistep-selected mutants of
M. hominis
that were previously described (2) revealed that they carried mutations in ParE (Asp426→Asn), GyrA (Ser83→Leu) and ParE (Asp426→Asn), GyrA (Ser83→Leu) and ParC (Ser80→Ile), or ParC (Ser80→Ile) alone, depending on the fluoroquinolone used for selection, i.e., ciprofloxacin, norfloxacin, ofloxacin, or pefloxacin, respectively. These data indicate that in
M. hominis
DNA gyrase is the primary target of sparfloxacin whereas topoisomerase IV is the primary target of pefloxacin, ofloxacin, and ciprofloxacin.
Antifungal Activity of the Pradimicin Derivative BMS 181184 in the Treatment of Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits
Authors: Gonzalez Corina E. , Groll Andreas H. , Giri Neelam , Shetty Daiva , Al-Mohsen Ibrahim , Sein Tin , Feuerstein Erwin , Bacher John , Piscitelli Stephen , Walsh Thomas J. 
Published: October 2018

ABSTRACT
The activity of the pradimicin derivative BMS 181184 was evaluated in a model of invasive pulmonary aspergillosis in persistently neutropenic rabbits and compared with that of amphotericin B deoxycholate. BMS 181184 at total daily doses of 50 and 150 mg/kg of body weight was at least as effective as amphotericin B at 1 mg/kg once a day in conferring survival and had comparable activity in reducing organism-mediated tissue injury and excess lung weight. Although treatment at all dosing regimens of BMS 181184 resulted in significant reductions in fungal tissue burden compared to untreated controls, equivalence to amphotericin B occurred only at the higher dosage level. Similar observations were made in bronchoalveolar lavage fluid cultures obtained postmortem. Monitoring of the animals through ultrafast computerized tomography scan revealed a marked resolution of pulmonary lesions during treatment with BMS 181184. The compound was well tolerated at all dosing regimens, and no toxicity was noted. Pharmacokinetic studies revealed nonlinear drug disposition with increased clearance at higher dosages and some evidence for extravascular drug accumulation. BMS 181184 had excellent activity in the treatment of experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits, thus underscoring the potential of pradimicin derivatives in therapy of invasive aspergillosis in the neutropenic host.
Influence of Human Serum on Pharmacodynamic Properties of an Investigational Glycopeptide, LY333328, and Comparator Agents against
Staphylococcus aureus
Authors: Zhanel George G. , Kirkpatrick Iain D. C. , Hoban Daryl J. , Kabani Amin M. , Karlowsky James A. 
Published: October 2018

ABSTRACT

The MICs and MBCs of 15 antibiotics for two strains of
Staphylococcus aureus
were determined in Mueller-Hinton broth (MHB) and 90% serum–10% MHB. Subsequent experiments established that highly protein-bound antibiotics (≥80%), such as LY333328, demonstrated higher MICs and MBCs, less killing over an 8-h interval, and shorter postantibiotic effects in 90% serum–10% MHB than in MHB alone. Albumin was demonstrated to be almost solely responsible for changes in the aforementioned pharmacodynamic parameters of LY333328.
Control of
Candida albicans
Murine Vaginitis by Topical Administration of Polycarbophil-Econazole Complex
Authors: Ghelardi E. , Tavanti A. , Lupetti A. , Celandroni F. , Boldrini E. , Campa M. , Senesi S. 
Published: October 2018

ABSTRACT
The complexation of econazole with the mucoadhesive polycarbophil was found to significantly improve the therapeutic benefit of the drug in the topical treatment of experimental vaginal candidiasis in mice, while no difference in the antimycotic activity exerted by econazole and polycarbophil-econazole could be detected in vitro.
In Vitro Activity of the New Glycopeptide LY333328 against Multiply Resistant Gram-Positive Clinical Isolates
Authors: García-Garrote Fernando , Cercenado Emilia , Alcalá Luis , Bouza Emilio 
Published: October 2018

ABSTRACT

The in vitro activity of LY333328 was compared with those of vancomycin and teicoplanin against 425 gram-positive clinical isolates, including a variety of multiply resistant strains. LY333328 at ≤4 μg/ml inhibited all microorganisms tested, including methicillin- and teicoplanin-resistant staphylococci, glycopeptide-resistant enterococci, penicillin- and multiply resistant pneumococci, and
viridans
and beta-hemolytic streptococci.
Acetate-Mediated Growth Inhibition in Sterol 14α-Demethylation-Deficient Cells of
Candida albicans
Authors: Shimokawa Osamu , Nakayama Hiroaki 
Published: October 2018

ABSTRACT

Candida albicans
is a fungus thought to be viable in the presence of a deficiency in sterol 14α-demethylation. We showed in a strain of this species that the deficiency, caused either by a mutation or by an azole antifungal agent, made the cells susceptible to growth inhibition by acetate included in the culture medium. Studies with a mutant demonstrated that the inhibition was complete at a sodium acetate concentration of 0.24 M (20 g/liter) and was evident even at a pH of 8, the latter result indicating the involvement of acetate ions rather than the undissociated form of acetic acid. In fluconazole-treated cells, sterol profiles determined by thin-layer chromatography revealed that the minimum sterol 14α-demethylation-inhibitory concentrations (MDICs) of the drug, thought to be the most important parameter for clinical purposes, were practically identical in the media with and without 0.24 M acetate and were equivalent to the MIC in the acetate-supplemented medium. The acetate-mediated growth inhibition of azole-treated cells was confirmed with two additional strains of
C. albicans
and four different agents, suggesting the possibility of generalization. From these results, it was surmised that the acetate-containing medium may find use in azole susceptibility testing, for which there is currently no method capable of measuring MDICs directly for those fungi whose viability is not lost as a result of sterol 14α-demethylation deficiency. Additionally, the acetate-supplemented agar medium was found to be useful in detecting reversions from sterol 14α-demethylation deficiency to proficiency.
Characterization of Dihydrofolate Reductase Genes from Trimethoprim-Susceptible and Trimethoprim-Resistant Strains of
Enterococcus faecalis
Authors: Coque Teresa M. , Singh Kavindra V. , Weinstock George M. , Murray Barbara E. 
Published: October 2018

ABSTRACT

Enterococci are usually susceptible in vitro to trimethoprim; however, high-level resistance (HLR) (MICs, >1,024 μg/ml) has been reported. We studied
Enterococcus faecalis
DEL, for which the trimethoprim MIC was >1,024 μg/ml. No transfer of resistance was achieved by broth or filter matings. Two different genes that conferred trimethoprim resistance when they were cloned in
Escherichia coli
(MICs, 128 and >1,024 μg/ml) were studied. One gene that coded for a polypeptide of 165 amino acids (MIC, 128 μg/ml for
E. coli
) was identical to
dfr
homologs that we cloned from a trimethoprim-susceptible
E. faecalis
strain, and it is presumed to be the intrinsic
E. faecalis dfr
gene (which causes resistance in
E. coli
when cloned in multiple copies); this gene was designated
dfrE
. The nucleotide sequence 5′ to this
dfr
gene showed similarity to thymidylate synthetase genes, suggesting that the
dfr
and
thy
genes from
E. faecalis
are located in tandem. The
E. faecalis
gene that conferred HLR to trimethoprim in
E. coli
, designated
dfrF
, codes for a predicted polypeptide of 165 amino acids with 38 to 64% similarity with other dihydrofolate reductases from gram-positive and gram-negative organisms. The nucleotide sequence 5′ to
dfrF
did not show similarity to the
thy
sequences. A DNA probe for
dfrF
hybridized under high-stringency conditions only to colony lysates of enterococci for which the trimethoprim MIC was >1,024 μg/ml; there was no hybridization to plasmid DNA from the strain of origin. To confirm that this gene causes trimethoprim resistance in enterococci, we cloned it into the integrative vector pAT113 and electroporated it into RH110 (
E. faecalis
OG1RF::Tn
916
ΔEm) (trimethoprim MIC, 0.5 μg/ml), which resulted in RH110 derivatives for which the trimethoprim MIC was >1,024 μg/ml. These results indicate that
dfrF
is an acquired but probably chromosomally located gene which is responsible for in vitro HLR to trimethoprim in
E. faecalis
.
Increase in Quinolone Resistance in a
Haemophilus influenzae
Strain Isolated from a Patient with Recurrent Respiratory Infections Treated with Ofloxacin
Authors: Vila Jordi , Ruiz Joaquim , Sanchez Ferran , Navarro Ferran , Mirelis Beatriz , de Anta M. Teresa Jimenez , Prats Guillem 
Published: October 2018

ABSTRACT

The increase in the level of quinolone resistance of
Haemophilus influenzae
clinical isolates during ofloxacin therapy of a patient with recurrent respiratory infections was investigated. The first isolate (MIC of ciprofloxacin of 2 μg/ml) and the second isolate (MIC of 32 μg/ml) belonged to the same clone, as shown by pulsed-field gel electrophoresis, and the increase in the resistance level was associated with a substitution in Ser-84 to Arg in the ParC protein. These results emphasize the potential risk of development of quinolone-resistant
H. influenzae
during fluoroquinolone therapy in patients with recurrent respiratory infection.
In Vitro Activities of Voriconazole, Fluconazole, and Itraconazole against 566 Clinical Isolates of
Cryptococcus neoformans
from the United States and Africa
Authors: Pfaller M. A. , Zhang J. , Messer S. A. , Brandt M. E. , Hajjeh R. A. , Jessup C. J. , Tumberland M. , Mbidde E. K. , Ghannoum M. A. 
Published: October 2018

ABSTRACT

We investigated the in vitro activity of voriconazole compared to those of fluconazole and itraconazole against 566 clinical isolates of
Cryptococcus neoformans
from Africa (164) and the United States (402). Isolates were obtained from cerebrospinal fluid (362), blood (139), and miscellaneous sites (65). Voriconazole (MIC at which 90% of the isolates are inhibited [MIC
90
], 0.12 to 0.25 μg/ml) was more active than either itraconazole (MIC
90
, 0.5 μg/ml) or fluconazole (MIC
90
, 8.0 to 16 μg/ml) against both African and U.S. isolates. Isolates inhibited by ≥16 μg of fluconazole per ml were almost all (99%) inhibited by ≤1 μg of voriconazole per ml. These results suggest that voriconazole may be useful in the treatment of cryptococcosis.
A 5-Year Surveillance Study of 44,691 Isolates of
Haemophilus influenzae
Project Beta-Alert 1993–1997
Authors: Derecola A. , Butler D. L. , Kaplan R. L. , Miller L. A. , Poupard J. A. 
Published: October 2018

ABSTRACT

Beta-Alert is a surveillance program developed in 1993 to monitor the percentage of β-lactamase-producing
Haemophilus influenzae
isolates obtained from specimens submitted to regional commercial laboratories. The results of this study demonstrate that levels of β-lactamase producers have remained between 31 and 38% in the United States over the past 5 years.
Two Pharmacodynamic Models for Assessing the Efficacy of Amoxicillin-Clavulanate against Experimental Respiratory Tract Infections Caused by Strains of
Streptococcus pneumoniae
Authors: Woodnutt Gary , Berry Valerie 
Published: October 2018

ABSTRACT

Two models of respiratory tract infection were used to investigate the pharmacodynamics of amoxicillin-clavulanate against
Streptococcus pneumoniae
. Eight strains of
S. pneumoniae
were used in a mouse model in which the animals were infected intranasally and were then treated with a range of doses and dose intervals. The time that the plasma amoxicillin concentration remained above the MIC (
T
>MIC) correlated well with bacterial killing, such that if
T
>MIC was below 20% there was no effect on bacterial numbers in the lungs. As
T
>MIC increased, the response, in terms of decreased bacterial load, improved and at
T
>MICs of greater than 35 to 40% of the dosing interval, bacteriological cure was maximal. On the basis of equivalent
T
>MICs, these data would suggest that in humans a dosage of 500 mg three times daily (t.i.d.) should have efficacy equal to that of a dosage of 875 mg twice daily (b.i.d.). This hypothesis was evaluated in a rat model in which amoxicillin-clavulanate was given by computer-controlled intravenous infusion to achieve concentrations that approximate the concentrations achieved in the plasma of humans following oral administration of 500/125 mg t.i.d. or 875/125 mg b.i.d. Infusions continued for 3 days and bacterial numbers in the lungs 2 h after the cessation of the infusion were significantly reduced (
P
< 0.01) by both treatments in strains of
S. pneumoniae
for which amoxicillin MICs were below 2 μg/ml. When tested against a strain of
S. pneumoniae
for which the amoxicillin MIC was 4 μg/ml, the simulated 500/125-mg dose was ineffective but the 875/125-mg dose demonstrated a small but significant (
P
< 0.01) reduction in bacterial numbers. These data confirm the findings in the mouse and indicate that amoxicillin-clavulanate administered at 875/125 mg b.i.d. would be as effective clinically as amoxicillin-clavulanate administered at 500/125 mg t.i.d.