bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of RNA Synthesis as a Therapeutic Strategy against
Aspergillus
and
Fusarium
: Demonstration of In Vitro Synergy between Rifabutin and Amphotericin B
Authors: Clancy Cornelius J. , Yu Yue C. , Lewin Alfred , Nguyen M. Hong 
Published: October 2018

ABSTRACT

We investigated the in vitro antifungal activity of amphotericin B, alone and in combination with rifabutin, an inhibitor of bacterial RNA polymerase, against 26 clinical isolates of
Aspergillus
and 25 clinical isolates of
Fusarium
. Synergy or additivism between these drugs was demonstrated against all isolates tested. Amphotericin B MICs were reduced upon combination with rifabutin from a mean of 0.65 μg/ml to a mean of 0.16 μg/ml against
Aspergillus
, and from a mean of 0.97 μg/ml to a mean of 0.39 μg/ml against
Fusarium
(
P
< 0.000001 for both). Similarly, the MICs of rifabutin were reduced upon combination with amphotericin B from a mean of >32 μg/ml to a mean of 1.1 μg/ml against both fungi (
P
< 0.000001 for both). These positive interactions were corroborated by a colony count study with two
Fusarium
isolates, for which treatment with the combination of subinhibitory concentrations of amphotericin B (at concentrations 2- and 4-fold less than the MIC) and rifabutin (at concentrations ranging from 4- to 64-fold less than the MIC) resulted in 3.2-log reductions in colony counts compared to those after treatment with either drug alone. Inhibition of RNA synthesis was shown to be the mechanism of antifungal activity. These results suggest that inhibition of fungal RNA synthesis might be a potential target for antifungal therapy.
Introduction of the
mec
Element (Methicillin Resistance) into
Staphylococcus aureus
Alters In Vitro Functional Activities of Fibrinogen and Fibronectin Adhesins
Authors: Vaudaux Pierre E. , Monzillo Vincenza , Francois Patrice , Lew Daniel P. , Foster Tim J. , Berger-Bächi Brigitte 
Published: October 2018

ABSTRACT

Some methicillin-resistant strains of
Staphylococcus aureus
are defective in the production of major surface components such as protein A, clumping factor, or other important adhesins to extracellular matrix components which may play a role in bacterial colonization and infection. To evaluate the impact of methicillin resistance (
mec
) determinants on bacterial adhesion mediated by fibrinogen or fibronectin adhesins, we compared the in vitro attachment of two genetically distinct susceptible strains (NCTC8325 and Newman) to protein-coated surfaces with that of isogenic methicillin-resistant derivatives. All strains containing an intact
mec
element in their chromosomes were found to be defective in adhesion to fibrinogen and fibronectin immobilized on polymethylmethacrylate coverslips, regardless of the presence or absence of additional mutations in the
femA
,
femB
, or
femC
gene, known to decrease expression of methicillin resistance in
S. aureus
. Western ligand affinity blotting or immunoblotting of cell wall-associated adhesins revealed similar contents of fibrinogen- or fibronectin-binding proteins in methicillin-resistant strains compared to those of their methicillin-susceptible counterparts. In contrast to methicillin-resistant strains carrying a
mec
element in their genomes, methicillin-resistant strains constructed in vitro, by introducing the
mecA
gene on a plasmid, retained their adhesion phenotypes. In conclusion, the chromosomal insertion of the
mec
element into genetically defined strains of
S. aureus
impairs the in vitro functional activities of fibrinogen or fibronectin adhesins without altering their production. This effect is unrelated to the activity of the
mecA
gene.
Plasmid-Mediated Resistance to Expanded-Spectrum Cephalosporins among
Enterobacter aerogenes
Strains
Authors: Pitout Johann D. D. , Thomson Kenneth S. , Hanson Nancy D. , Ehrhardt Anton F. , Coudron Philip , Sanders Christine C. 
Published: October 2018

ABSTRACT

Resistance to expanded-spectrum cephalosporins commonly develops in
Enterobacter aerogenes
during therapy due to selection of mutants producing high levels of the chromosomal Bush group 1 β-lactamase. Recently, resistant strains producing plasmid-mediated extended-spectrum β-lactamases (ESBLs) have been isolated as well. A study was designed to investigate ESBL production among 31 clinical isolates of
E. aerogenes
from Richmond, Va., with decreased susceptibility to expanded-spectrum cephalosporins and a positive double-disk potentiation test. Antibiotic susceptibility was determined by standard disk diffusion and agar dilution procedures. β-Lactamases were investigated by an isoelectric focusing overlay technique which simultaneously determined isoelectric points (pIs) and substrate or inhibitor profiles. Decreased susceptibility to cefotaxime, ceftazidime, and aztreonam (MIC range, 1 to 64 μg/ml) was detected and associated with resistance to gentamicin and trimethoprim-sulfamethoxazole. All strains produced an inducible Bush group 1 β-lactamase (pI 8.3). Twenty-nine of the 31 isolates also produced an enzyme similar to SHV-4 (pI 7.8), while 1 isolate each produced an enzyme similar to SHV-3 (pI 6.9) and to SHV-5 (pI 8.2). The three different SHV-derived ESBLs were transferred by transconjugation to
Escherichia coli
C600N and amplified by PCR. Plasmid profiles of the clinical isolates showed a variety of different large plasmids. Because of the linkage of resistance to aminoglycosides and trimethoprim-sulfamethoxazole with ESBL production, it is possible that the usage of these drugs was responsible for selecting plasmid-mediated resistance to extended-spectrum cephalosporins in
E. aerogenes
. Furthermore, it is important that strains such as these be recognized, because they can be responsible for institutional spread of resistance genes.
Oral Administration of a Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071 Protects Mice and Ferrets against Influenza Infection
Authors: Mendel Dirk B. , Tai Chun Y. , Escarpe Paul A. , Li Weixing , Sidwell Robert W. , Huffman John H. , Sweet Clive , Jakeman Kenneth J. , Merson James , Lacy Steven A. , Lew Willard , Williams Matthew A. , Zhang Lijun , Chen Ming S. , Bischofberger Norbert , Kim Choung U. 
Published: October 2018

ABSTRACT
We have recently described GS 4071, a carbocyclic transition-state analog inhibitor of the influenza virus neuraminidase, which has potent inhibitory activity comparable to that of 4-guanidino-Neu5Ac2en (GG167; zanamivir) when tested against influenza A virus replication and neuraminidase activity in vitro. We now report that GS 4071 is active against several strains of influenza A and B viruses in vitro and that oral GS 4104, an ethyl ester prodrug which is converted to GS 4071 in vivo, is active in the mouse and ferret models of influenza virus infection. Oral administration of 10 mg of GS 4104 per kg of body weight per day caused a 100-fold reduction in lung homogenate viral titers and enhanced survival in mice infected with influenza A or B viruses. In ferrets, a 25-mg/kg dose of GS 4104 given twice daily reduced peak viral titers in nasal washings and eliminated constitutional responses to influenza virus infection including fever, increased nasal signs (sneezing, nasal discharge, mouth breathing), and decreased activity. Consistent with our demonstration that the parent compound is highly specific for influenza virus neuraminidases, no significant drug-related toxicity was observed after the administration of oral dosages of GS 4104 of up to 800 mg/kg/day for 14 days in nonclinical toxicology studies with rats. These results indicate that GS 4104 is a novel, orally active antiviral agent with the potential to be used for the prophylaxis and treatment of influenza A and B virus infections.
Relationship between Antimalarial Drug Activity, Accumulation, and Inhibition of Heme Polymerization in
Plasmodium falciparum
In Vitro
Authors: Hawley Shaun R. , Bray Patrick G. , Mungthin Mathirut , Atkinson Jill D. , O’Neill Paul M. , Ward Stephen A. 
Published: October 2018

ABSTRACT
We have investigated the contribution of drug accumulation and inhibition of heme polymerization to the in vitro activities of a series of antimalarial drugs. Only those compounds exhibiting structural relatedness to the quinolines inhibited heme polymerization. We could find no direct correlation between in vitro activity against chloroquine-susceptible or chloroquine-resistant isolates and either inhibition of heme polymerization or cellular drug accumulation for the drugs studied. However, in vitro activity against a chloroquine-susceptible isolate but not a chloroquine-resistant isolate showed a significant correlation with inhibition of heme polymerization when the activity was normalized for the extent of drug accumulation. The importance of these observations to the rational design of new quinoline-type drugs and the level of agreement of these conclusions with current views on quinoline drug action and resistance are discussed.
Pharmacokinetics and Bioavailability of the Anti-Human Immunodeficiency Virus Nucleotide Analog 9-[(
R
)2-(Phosphonomethoxy)Propyl]Adenine (PMPA) in Dogs
Authors: Cundy Kenneth C. , Sueoka Cathy , Lynch Geoffrey R. , Griffin Linda , Lee William A. , Shaw Jeng-Pyng 
Published: October 2018

ABSTRACT

The pharmacokinetics, bioavailability, and metabolism of the anti-human immunodeficiency virus nucleotide analog 9[(
R
)-2-(phosphonomethoxy)propyl]adenine (PMPA) were determined in beagle dogs following intravenous, intraperitoneal, and oral administration. Fasted male beagle dogs (
n
= 5) were pretreated with pentagastrin and received PMPA (10 mg/kg of body weight) by the intravenous and oral routes with a washout period of 1 week between doses. A further group of male dogs received PMPA as a single dose via the intravenous (1 mg/kg;
n
= 5) and the intraperitoneal (10 mg/kg;
n
= 3) routes, with 1-week washout period between doses. The concentrations of PMPA in plasma and urine were determined over 48 h postdosing by fluorescence derivatization and high-performance liquid chromatography (HPLC). The potential for metabolism or biliary excretion of PMPA was evaluated in a dog with a chronic indwelling bile cannula. Urine, feces, and bile were collected at intervals over 48 h following the intravenous administration of [
14
C]PMPA (10 mg/kg; 55 μCi/kg). The concentrations of PMPA in plasma after intravenous injection were best described by an open two-compartment model with a terminal half-life of approximately 10 h. PMPA was excreted unchanged in urine (70%); recovery in feces (0.42%) or bile (0.26%) was negligible. The plasma clearance of PMPA (0.28 ± 0.05 liter/h/kg) was substantially greater than the glomerular filtration rate in this species, suggesting active tubular secretion of PMPA. No metabolites of [
14
C]PMPA were observed in urine, feces, or bile on the basis of HPLC with radioactive flow detection. The remainder of the dose was probably excreted unchanged in urine beyond 48 h postdosing. The mean ± standard deviation observed bioavailabilities of PMPA following oral and intraperitoneal administration at 10 mg/kg were 17.1% ± 1.88% and 73.5% ± 10.5%, respectively.
Activities of Isoniazid Alone and in Combination with Other Drugs against
Mycobacterium avium
Infection in Beige Mice
Authors: Fattorini Lanfranco , Xiao Yan , Mattei Maurizio , Li Yongjun , Iona Elisabetta , Ricci Maria Luisa , Thoresen Ove Fredrik , Creti Roberta , Orefici Graziella 
Published: October 2018

ABSTRACT

Monotherapy with isoniazid or amikacin or clarithromycin or combinations of two of these drugs showed nil to modest therapeutic activity in beige mice infected with
Mycobacterium avium
. However, the combination of all three, isoniazid-amikacin-clarithromycin, markedly reduced CFUs in both spleens and lungs after 91 days of infection.
Cefepime versus Ceftriaxone for Empiric Treatment of Hospitalized Patients with Community-Acquired Pneumonia
Authors: Zervos M. , Nelson M. ,   the Cefepime Study Group
Published: October 2018

ABSTRACT

Effective empiric treatment of pneumonia requires antibiotic coverage against gram-negative and gram-positive pathogens, including drug-resistant isolates. We compared the safety and efficacy of intravenous (i.v.) cefepime (2 g administered every 12 h) to those of i.v. ceftriaxone (1 g administered every 12 h) for the empiric treatment of hospitalized patients with community-acquired pneumonia. Of the 115 patients randomized to the study, 86 (cefepime recipients,
n
= 40; ceftriaxone recipients,
n
= 46) were evaluated for clinical efficacy (clinically evaluated patients). Favorable clinical outcomes (cure or improvement) were comparable among clinically evaluated patients in the cefepime and ceftriaxone treatment arms (95.0 versus 97.8%, respectively; 95% confidence interval for treatment difference [data for ceftriaxone group minus data for cefepime group], −5.1 to +10.8%). The most common bacteria isolated from patients in both treatment groups were
Streptococcus pneumoniae
,
Haemophilus influenzae
, and
Staphylococcus aureus
. In clinically evaluated patients with a microbiologic response, all (100%) of the 32 pathogens from cefepime-treated patients and 97.4% (38 of 39) of the pathogens from ceftriaxone-treated patients were eradicated (documented or presumed eradication). The one persistent infection in the ceftriaxone group was caused by
Pseudomonas fluorescens
. Both treatments were well tolerated. Our data thus suggest that cefepime and ceftriaxone have comparable safety and efficacy for the treatment of pneumonia in hospitalized patients.
Effect of Dirithromycin onHaemophilus influenzaeInfection of the Respiratory Mucosa
Authors: Rutman Andrew , Dowling Ruth , Wills Peter , Feldman Charles , Cole Peter J. , Wilson Robert 
Published: October 2018

ABSTRACTMacrolides have properties other than their antibiotic action which may benefit patients with airway infections. We have investigated the effect of dirithromycin (0.125 to 8.0 μg/ml) on the interaction ofHaemophilus influenzaewith respiratory mucosa in vitro using human nasal epithelium, adenoid tissue, and bovine trachea. Dirithromycin did not affect the ciliary beat frequency of the nasal epithelium or the transport of mucus on bovine trachea, but dirithromycin (1 μg/ml) did reduce the slowing of the ciliary beat frequency and the damage to the nasal epithelium caused byH. influenzaebroth culture filtrate. Amoxicillin (2 μg/ml) did not reduce the effects of theH. influenzaebroth culture filtrate.H. influenzaeinfection of the organ cultures for 24 h caused mucosal damage and the loss of ciliated cells. Bacteria adhered to damaged epithelium and to a lesser extent to mucus and unciliated cells. Incubation ofH. influenzaewith dirithromycin at sub-MICs (0.125 and 0.5 μg/ml) prior to infection of the organ cultures did not reduce the mucosal damage caused by bacterial infection. By contrast, incubation of adenoid tissue with dirithromycin (0.125 to 1.0 μg/ml) for 4 h prior to assembling the organ culture reduced the mucosal damage caused by subsequentH. influenzaeinfection by as much as 50%. The number of bacteria adherent to the mucosa was reduced, although the tissue that had been incubated with dirithromycin (0.125 and 0.5 μg/ml) did not inhibit bacterial growth. This was achieved by a reduction in the amount of damaged epithelium to whichH. influenzaeadhered and a reduction in the density of bacteria adhering to mucus. We conclude that dirithromycin at concentrations achievable in vivo markedly reduces the mucosal damage caused byH. influenzaeinfection due to a cytoprotective effect.
In Vivo Activity of HSR-903, a New Fluoroquinolone, against Respiratory Pathogens
Authors: Yoshizumi Satoshi , Domon Haruki , Miyazaki Shuichi , Yamaguchi Keizo 
Published: October 2018

ABSTRACT

The in vivo activity of HSR-903, a new fluoroquinolone, against major bacteria which cause respiratory tract infections was evaluated. HSR-903 was active against experimental respiratory tract infections in mice challenged with penicillin-susceptible and penicillin-resistant
Streptococcus pneumoniae
and
Haemophilus influenzae
strains. Treatment with HSR-903 reduced the bacterial numbers in infected murine lungs. In accord with the pulmonary clearance results, the rates of survival for mice treated with HSR-903, sparfloxacin, levofloxacin, ciprofloxacin, and benzylpenicillin were 50, 30, 10, 0, and 0%, respectively, 14 days after being infected with penicillin-resistant
S. pneumoniae
. A pharmacokinetic study with pneumonic mice showed that the levels of HSR-903 in the lungs were seven to eight times higher than those in the plasma. These results indicate that clinical studies of HSR-903 against respiratory tract infections may be warranted.
In Vitro Evaluation of Drug Susceptibilities of
Babesia divergens
Isolates
Authors: Brasseur Philippe , Lecoublet Sophie , Kapel Nathalie , Favennec Loic , Ballet Jean J. 
Published: October 2018

ABSTRACT

The susceptibilities of three bovine and two human
Babesia divergens
isolates to antimicrobial agents were evaluated in vitro by a tritiated hypoxanthine incorporation assay. The MICs at which 50% of isolates are inhibited (MIC
50
s) for mefloquine (chlorhydrate), chloroquine (sulfate), quinine (chlorhydrate), clindamycin (phosphate), pentamidine (isethionate), phenamidine (isethionate) plus oxomemazine (chlorhydrate), lincomycin (chlorhydrate monohydrate), and imidocarb (dipropionate) were determined. Except for imidocarb, the MIC
50
s observed for the different isolates were close. Imidocarb and the combination of phenamidine plus oxomemazine exhibited the highest in vitro activity, while antimalarial agents such as mefloquine, choroquine, and quinine were inactive. Other drugs had intermediate activities. The data support further in vitro evaluation of antimicrobial agents active against
B. divergens
for the improvement of therapeutic strategies.
Prophylaxis of Acute Osteomyelitis with Absorbable Ofloxacin-Impregnated Beads
Authors: Nicolau David P. , Nie Lin , Tessier Pamela R. , Kourea Helen P. , Nightingale Charles H. 
Published: October 2018

ABSTRACT

We investigated the use of an ofloxacin-impregnated bioabsorbable composite for the prevention of acute
Staphylococcus aureus
osteomyelitis. New Zealand White rabbits were anesthetized, the femur was exposed, and a cortical hole was drilled. Animals were randomly given drug-free composites or ofloxacin-impregnated composites; the composites were placed at the site of injury, and the incision was closed. One hour later, all animals were intravenously inoculated with 5 × 10
4
CFU of
S. aureus
and observed for 28 days. Bone culture data revealed that
S. aureus
was isolated from 3 of 12 rabbits in the ofloxacin composite group and 9 of 11 animals in the control group (
P
= 0.02). Radiographic evaluation revealed that the drug-free group had a significantly (
P
= 0.01) greater degree of radiographic evidence of infection than the group given ofloxacin composites. Although a limited number of histologic samples were available, these data also paralleled the radiographic and culture data. This study demonstrates the effectiveness of the implantable ofloxacin bioabsorbable composites to prevent the development of acute osteomyelitis.
Activities and Time-Kill Studies of Selected Penicillins, β-Lactamase Inhibitor Combinations, and Glycopeptides against
Enterococcus faecalis
Authors: Hoellman Dianne B. , Visalli Melissa A. , Jacobs Michael R. , Appelbaum Peter C. 
Published: October 2018

ABSTRACT

The activities of piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, vancomycin, and teicoplanin were tested against 212
Enterococcus faecalis
strains (9 β-lactamase producers) by standard agar dilution MIC testing (10
4
CFU/spot). The MICs at which 50 and 90% of the isolates were inhibited (MIC
50
s and MIC
90
s, respectively) were as follows (μg/ml): piperacillin, 4 and 8; piperacillin-tazobactam, 4 and 8; ticarcillin, 64 and 128; ticarcillin-clavulanate, 64 and 128; ampicillin, 2 and 2; ampicillin-sulbactam, 1 and 2; vancomycin, 1 and 4; and teicoplanin, 0.5 and 1. Agar dilution MIC testing of the nine β-lactamase-positive strains with an inoculum of 10
6
CFU/spot revealed higher β-lactam MICs (piperacillin, 64 to >256 μg/ml; ticarcillin, 128 to >256 μg/ml; and ampicillin, 16 to 128 μg/ml); however, MICs with the addition of inhibitors were similar to those obtained with the lower inoculum. Time-kill studies of 15 strains showed that piperacillin-tazobactam was bactericidal (99.9% killing) for 14 strains after 24 h at four times the MIC, with 90% killing of all 15 strains at two times the MIC. After 12 and 6 h, 90% killing of 14 and 13 strains, respectively, was found at two times the MIC. Ampicillin gave 99.9% killing of 14 β-lactamase-negative strains after 24 h at eight times the MIC, with 90% killing of all 15 strains at two times the MIC. After 12 and 6 h, 90% killing of 14 and 13 strains, respectively, was found at two times the MIC. Killing by ticarcillin-clavulanate was slower than that observed for piperacillin-tazobactam, relative to the MIC. For the one β-lactamase-producing strain tested by time-kill analysis with a higher inoculum, addition of the three inhibitors (including sulbactam) to each of the β-lactams resulted in bactericidal activity at 24 h at two times the MIC. For an enzyme-negative strain, addition of inhibitors did not influence kinetics. Kinetics of vancomycin and teicoplanin were significantly slower than those of the β-lactams, with bactericidal activity against 6 strains after 24 h at eight times the MIC, with 90% killing of 12 and 14 strains, respectively, at four times the MIC. Slower-kill kinetics by both glycopeptides were observed at earlier periods.