bluuebunny/crossref_metadata_2025_split huggingface dataset:
A New Ketolide, HMR 3004, Active against Streptococci Inducibly Resistant to Erythromycin
Authors: Rosato Adriana , Vicarini Hubert , Bonnefoy Alain , Chantot Jean-François , Leclercq Roland 
Published: October 2018

ABSTRACT

HMR 3004 is a new hydrazono ketolide characterized by a 3-keto function instead of the cladinose moiety. The effect of this antimicrobial agent on inducible and constitutive macrolide-lincosamide-streptogramin B (MLS
B
) resistance was tested in a
lacZ
reporter system under control of several
ermAM
-like attenuator variants. For one constitutively resistant
Streptococcus agalactiae
strain, three inducibly resistant
Streptococcus pneumoniae
strains, and one inducibly resistant
Enterococcus faecalis
strain, the attenuators fused with
lacZ
were cloned into the shuttle plasmid pJIM2246 and the plasmid was introduced into
Staphylococcus aureus
RN4220. For the wild-type attenuators, HMR 3004 was a very weak inducer, unlike its cladinose counterpart RU 6652 and erythromycin. As expected, for the fusion originating from the constitutively resistant
S. agalactiae
strain, the level of uninduced β-galactosidase synthesis was high. For one
S. pneumoniae
attenuator, mutations in the 3′ end of the attenuator that weakened the stem-loop structure that sequesters the ribosome-binding site and start codon for
ermAM
methylase could explain the high level of uninduced β-galactosidase produced. For streptococci, the activity of HMR 3004 correlated with the basal level of β-galactosidase synthesized. The weak inducer activity of HMR 3004 explained its activity against inducibly MLS
B
-resistant
S. pneumoniae
but did not correlate with the moderate activity of the antibiotic against inducibly resistant
E. faecalis.
Moxifloxacin in the Therapy of Experimental Pneumococcal Meningitis
Authors: Schmidt H. , Dalhoff A. , Stuertz K. , Trostdorf F. , Chen V. , Schneider O. , Kohlsdorfer C. , Brück W. , Nau R. 
Published: October 2018

ABSTRACT

The activity of moxifloxacin (BAY 12-8039) against a
Streptococcus pneumoniae
type 3 strain (MIC and minimum bactericidal concentration [MBC] of moxifloxacin, 0.06 and 0.25 μg/ml, respectively; MIC and MBC of ceftriaxone, 0.03 and 0.06 μg/ml, respectively) was determined in vitro and in a rabbit model of meningitis. Despite comparable bactericidal activity, 10 μg of moxifloxacin per ml released lipoteichoic and teichoic acids less rapidly than 10 μg of ceftriaxone per ml in vitro. Against experimental meningitis, 10 mg of moxifloxacin per kg of body weight per ml reduced the bacterial titers in cerebrospinal fluid (CSF) almost as rapidly as ceftriaxone did (mean ± standard deviation, −0.32 ± 0.14 versus −0.39 ± 0.11 Δlog CFU/ml/h). The activity of moxifloxacin could be described by a sigmoid dose-response curve with a maximum effect of −0.33 ΔlogCFU/ml/h and with a dosage of 1.4 mg/kg/h producing a half-maximal effect. Maximum tumor necrosis factor activity in CSF was observed later with moxifloxacin than with ceftriaxone (5 versus 2 h after the initiation of treatment). At 10 mg/kg/h, the concentrations of moxifloxacin in CSF were 3.8 ± 1.2 μg/ml. Adjunctive treatment with dexamethasone at 1 mg/kg prior to the initiation of antibiotic treatment only marginally reduced the concentrations of moxifloxacin in CSF (3.3 ± 0.6 μg/ml). In conclusion, moxifloxacin may qualify for use in the treatment of
S. pneumoniae
meningitis.
Screening for Novel Antimicrobials from Encoded Combinatorial Libraries by Using a Two-Dimensional Agar Format
Authors: Silen Joy L. , Lu Amy T. , Solas Dennis W. , Gore Medini A. , Maclean Derek , Shah Nikil H. , Coffin Jill M. , Bhinderwala Naseema S. , Wang Yongwen , Tsutsui Ken T. , Look Gary C. , Campbell David A. , Hale Ron L. , Navre Marc , DeLuca-Flaherty Camille R. 
Published: October 2018

ABSTRACTA sensitive lawn-based format has been developed to screen bead-tethered combinatorial chemical libraries for antimicrobial activity. This method has been validated with beads linked to penicillin V via a photocleavable chemical linker in several analyses including a spike-and-recover experiment. The lawn-based screen sensitivity was modified to detect antibacterial compounds of modest potency, and a demonstration experiment with a naive combinatorial library of over 46,000 individual triazines was evaluated for antibacterial activity. Numerous hits were identified, and both active and inactive compounds were resynthesized and confirmed in traditional broth assays. This demonstration experiment suggests that novel antimicrobial compounds can be easily identified from very large combinatorial libraries of small, nonpeptidic compounds.
Contribution of β-Lactamases to β-Lactam Susceptibilities of Susceptible and Multidrug-Resistant
Mycobacterium tuberculosis
Clinical Isolates
Authors: Segura C. , Salvadó M. , Collado I. , Chaves J. , Coira A. 
Published: October 2018

ABSTRACT

The β-lactamases in 154 clinical
Mycobacterium tuberculosis
strains were studied. Susceptibilities to β-lactam antibiotics, their combination with clavulanate (2:1), and two fluoroquinolones were determined in 24
M. tuberculosis
strains susceptible to antimycobacterial drugs and in nine multiresistant strains. All 154
M. tuberculosis
isolates showed a single chromosomal β-lactamase pattern (pI 4.9 and 5.1).
M. tuberculosis
β-lactamase hydrolyzes cefotaxime with a maximum rate of 22.5 ± 2.19 IU/liter (strain 1382). Neither amoxicillin, carbenicillin, cefotaxime, ceftriaxone, nor aztreonam was active alone. Except for aztreonam, β-lactam combinations with clavulanate produced better antimycobacterial activity.
In Vitro Susceptibilities of 27 Rickettsiae to 13 Antimicrobials
Authors: Rolain J. M. , Maurin M. , Vestris G. , Raoult D. 
Published: October 2018

ABSTRACT

The MICs of 13 antibiotics (doxycycline, thiamphenicol, rifampin, amoxicillin, gentamicin, co-trimoxazole, ciprofloxacin, pefloxacin, ofloxacin, erythromycin, josamycin, clarithromycin, and pristinamycin) were determined for 27 available rickettsial species or strains. We used two in vitro cell culture methods described previously: the plaque assay and the microplaque colorimetric assay. Our results confirm the susceptibilities of rickettsiae to doxycycline, thiamphenicol, and fluoroquinolones. Beta-lactams, aminoglycosides, and co-trimoxazole were not active. Typhus group rickettsiae were susceptible to all macrolides tested, whereas the spotted fever group rickettsiae,
R. bellii
, and
R. canada
were more resistant, with josamycin, a safe alternative for the treatment of Mediterranean spotted fever, being the most effective compound. Strain Bar 29,
R. massiliae
,
R. montana
,
R. aeschlimannii
, and
R. rhipicephali
, which are members of the same phylogenetic subgroup, were more resistant to rifampin than the other rickettsiae tested. Heterogeneity in susceptibility to rifampin, which we report for the first time, may explain in vivo discrepancies in the effectiveness of this antibiotic for the treatment of rickettsial diseases. We hypothesize that rifampin resistance and erythromycin susceptibility may reflect a divergence during the evolution of rickettsiae.
Antiretroviral Efficacy and Pharmacokinetics of Oral Bis(isopropyloxycarbonyloxymethyl)9-(2-Phosphonylmethoxypropyl)adenine in Mice
Authors: Naesens Lieve , Bischofberger Norbert , Augustijns Patrick , Annaert Pieter , Van den Mooter Guy , Arimilli Murty N. , Kim Choung U. , De Clercq Erik 
Published: October 2018

ABSTRACT

To overcome the low oral bioavailability of the highly potent and selective antiretroviral agent (
R
)-9-(2-phosphonylmethoxypropyl)adenine (PMPA), a new lipophilic ester derivative, i.e., the bis(isopropyloxycarbonyloxymethyl)-ester [bis(POC)-PMPA], was prepared. The usefulness of bis(POC)-PMPA as an oral prodrug for PMPA was investigated in the intestinal mucosa Caco-2 cell monolayer model. The total transport of bis(POC)-PMPA was 2.7%, whereas it was less than 0.1% for PMPA. Bis(POC)-PMPA was considerably metabolized inside the epithelial cells, since the majority of the compound was recovered after transport in the form of the monoester metabolite [mono(POC)-PMPA]. In contrast, bis(POC)-PMPA was relatively resistant to degradation at the luminal side of the Caco-2 cells. Pharmacokinetic studies with mice showed that the oral bioavailability of bis(POC)-PMPA (calculated from the curves of the concentration of free PMPA in plasma) was 20%. Neither bis(POC)-PMPA nor mono(POC)-PMPA could be recovered in plasma, suggesting the efficient release of the active drug PMPA after oral administration of bis(POC)-PMPA. Severe combined immunodeficient (SCID) mice infected with Moloney murine sarcoma virus (MSV) and treated orally with bis(POC)-PMPA for 5 or 10 days (dosages, 50, 100, or 200 mg of PMPA equivalent per kg of body weight per day) showed a significant delay in MSV-induced tumor appearance and tumor-associated death. The antiviral efficacy of oral bis(POC)-PMPA was related to the dosage and treatment period and was not significantly different from that of subcutaneous PMPA given at an equivalent dose. The favorable pharmacokinetic profile, marked antiviral efficacy, and low toxicity make bis(POC)-PMPA an attractive oral prodrug of PMPA that should be further pursued in clinical studies with patients infected with human immunodeficiency virus or hepatitis B virus.
Pharmacokinetic Evaluation of Amphotericin B in Lung Tissue: Lung Lymph Distribution after Intravenous Injection and Airspace Distribution after Aerosolization and Inhalation of Amphotericin B
Authors: Koizumi Tomonobu , Kubo Keishi , Kaneki Toshimichi , Hanaoka Masayuki , Hayano Toshihide , Miyahara Takayuki , Okada Kazuyoshi , Fujimoto Keisaku , Yamamoto Hiroshi , Kobayashi Toshio , Sekiguchi Morie 
Published: October 2018

ABSTRACT
We have studied the pharmacokinetics of amphotericin B (AmB) in lung lymph circulation and bronchial-wash fluid after intravenous infusion and inhalation, respectively. For two experiments with awake sheep, we used lung lymph fistulas and tracheotomy. In experiment 1, AmB concentrations in plasma and lung lymph after intravenous infusion of AmB (1 mg/kg of body weight) over 1.5 h were measured. The mean peak in plasma level was 756.0 ± 188.8 ng/ml at 3 h after the start of infusion, and the level then decreased gradually to 194.8 ± 28.9 ng/ml at 24 h. The stable and maximal levels in lung lymph last 5 to 9 h after the start of AmB infusion. The concentrations in lung lymph after 9 h were slightly higher than those in plasma. Thus, the lung lymph-to-plasma ratio of AmB concentrations increased gradually during infusion, and the ratio was more than 1.0 after the end of infusion, suggesting that AmB could be easily moved from plasma to pulmonary interstitium and/or lung lymph circulation. In another experiment, 5 or 30 mg of aerosol AmB was inhaled, and the concentration of AmB in the bronchial-wash fluid was determined by bronchoalveolar lavage. The peak AmB concentration in the fluid was observed at 0.5 h. After that, AmB was slowly eliminated over 24 h. The area under the concentration-time curve for 30 mg of inhaled AmB was higher than that for 5 mg, but maximum concentrations of AmB in serum for 5 and 30 mg were almost similar. These observations identify the pharmacokinetic characteristics of AmB in the lung and may provide a new insight into the strategy for clinical treatment of fungal pneumonia.
Genotypic and Phenotypic Characterization of Human Immunodeficiency Virus Type 1 Variants Isolated from AIDS Patients after Prolonged Adefovir Dipivoxil Therapy
Authors: Mulato A. S. , Lamy P. D. , Miller M. D. , Li W.-X. , Anton K. E. , Hellmann N. S. , Cherrington J. M. 
Published: October 2018

ABSTRACT

Adefovir dipivoxil [bis(pivaloyloxymethyl)-ester prodrug], an orally bioavailable prodrug of adefovir [9-(2-phosphonylmethoxyethyl)adenine], is currently in phase III clinical trials for the treatment of human immunodeficiency virus (HIV). In vitro experiments demonstrated that either a K65R or a K70E mutation in HIV reverse transcriptase (RT) was selected in the presence of adefovir, conferring a 16- or 9-fold decrease in susceptibility to adefovir, respectively. Previous data demonstrated that patients receiving adefovir dipivoxil monotherapy (125 mg daily) for 12 weeks experienced a median decrease in HIV RNA levels of 0.5 log
10
copies/ml and that resistance to adefovir dipivoxil did not arise during that period. In the present investigation, a further study was undertaken to investigate whether RT mutations developed among viruses from patients who completed the 12-week study and who opted to enroll in a maintenance phase of prolonged (6- to 12-month) adefovir dipivoxil therapy (120 mg daily). Concomitant treatment with antiretroviral agents was permitted during the maintenance phase. The median decreases in HIV RNA levels for patients who completed 6 or 12 months of maintenance-phase dosing were 0.6 and 1.14 log
10
copies/ml, respectively. The reductions in the HIV RNA levels were similar among patients who received adefovir dipivoxil with or without concomitant treatment with antiretroviral agents. Viruses from 8 of 29 patients dosed for up to 12 months developed RT mutations that were not present at baseline; these mutations may have been related to adefovir dipivoxil therapy. Viruses from two of the eight patients developed the K70E mutation while the patients were on therapy, but none of the viruses from patients developed the K65R RT substitution. Despite the development of RT mutations, sustained reductions (6 to 12 months) in viral load (≥0.7 log
10
copies/ml decrease from baseline) were observed in all eight patients.
Zidovudine Azido-Reductase in Human Liver Microsomes: Activation by Ethacrynic Acid, Dipyridamole, and Indomethacin and Inhibition by Human Immunodeficiency Virus Protease Inhibitors
Authors: Fayz Shirin , Inaba T. 
Published: October 2018

ABSTRACT

AZT (zidovudine, 3′-azido-3′-deoxythymidine), although metabolized primarily to AZT-glucuronide, is also metabolized to 3′-amino-3′-deoxythmidine (AMT) by reduction of the azide to an amine. The formation of the myelotoxic metabolite AMT has not been well characterized, but inhibition of AMT formation would be of therapeutic benefit. The aim of this study was to identify compounds that inhibit AMT formation. Using human liver microsomes under anaerobic conditions and [2-
14
C]AZT,

K
m

values of AZT azido-reductase, estimated by radio-thin-layer chromatography, were 2.2 to 3.5 mM (
n
= 3). Oxygen completely inhibited this NADPH-dependent reduction. Thirteen of the 28 compounds tested inhibited the formation of AMT. In addition to the CYP3A4 inhibitors ketoconazole, fluconazole, indinavir, ritonavir, and saquinavir, metyrapone strongly inhibited AMT formation. An unexpected finding was the more-than-twofold increase in AMT formation in the presence of ethacrynic acid, dipyridamole, or indomethacin. Such activation of toxic metabolite formation would impair drug therapy.
Antiherpesvirus Activities of (1′
S
,2′
R
)-9-{[1′,2′-Bis(hydroxymethyl)cycloprop-1′-yl]methyl}guanine (A-5021) in Cell Culture
Authors: Iwayama Satoshi , Ono Nobukazu , Ohmura Yuko , Suzuki Katsuya , Aoki Miho , Nakazawa Harumi , Oikawa Miki , Kato Tamamo , Okunishi Masahiko , Nishiyama Yukihiro , Yamanishi Koichi 
Published: October 2018

ABSTRACT

Antiherpetic activity of (1′
S
,2′
R
)-9-{[1′,2′-bis(hydroxymethyl)cycloprop-1′-yl]methyl}guanine (A-5021) was compared with those of acyclovir (ACV) and penciclovir (PCV) in cell cultures. In a plaque reduction assay using a selection of human cells, A-5021 showed the most potent activity in all cells. Against clinical isolates of herpes simplex virus type 1 (HSV-1,
n
= 5) and type 2 (HSV-2,
n
= 6), mean 50% inhibitory concentrations (IC
50
s) for A-5021 were 0.013 and 0.15 μg/ml, respectively, in MRC-5 cells. Corresponding IC
50
s for ACV were 0.22 and 0.30 μg/ml, and those for PCV were 0.84 and 1.5 μg/ml, respectively. Against clinical isolates of varicella-zoster virus (VZV,
n
= 5), mean IC
50
s for A-5021, ACV, and PCV were 0.77, 5.2, and 14 μg/ml, respectively, in human embryonic lung (HEL) cells. A-5021 showed considerably more prolonged antiviral activity than ACV when infected cells were treated for a short time. The selectivity index, the ratio of 50% cytotoxic concentration to IC
50
, of A-5021 was superior to those of ACV and PCV for HSV-1 and almost comparable for HSV-2 and VZV. In a growth inhibition assay of murine granulocyte-macrophage progenitor cells, A-5021 showed the least inhibitory effect of the three compounds. These results show that A-5021 is a potent and selective antiviral agent against HSV-1, HSV-2, and VZV.
Determination of the Excitatory Potencies of Fluoroquinolones in the Central Nervous System by an In Vitro Model
Authors: Schmuck Gabriele , Schürmann Anja , Schlüter Gerhard 
Published: October 2018

ABSTRACT

Fluoroquinolones have been reported to induce central nervous system side effects, including seizures and psychiatric events. Although relatively rare in patients up to now, the proconvulsant activity depends on the chemical structure and might be a critical endpoint of some new representatives of this valuable class of antimicrobials. The electrophysiological determination of field potentials in the CA
1
region of the rat hippocampus slice allowed an assessment of the excitatory potential of fluoroquinolones and might be predictive for their neurotoxic potency in vivo. An optimization of this method and its extension to other fluoroquinolones resulted in a defined rank order. Well-known already-marketed quinolones as well as some fluoroquinolones under evaluation and development were used. The dose range tested was between 0.5 and 4 μmol/liter, which was comparable to the therapeutic concentration in the brain. All tested compounds increased the population spike amplitude in a concentration-dependent manner, and the resulting excitatory potency was highly dependent on the chemical structure, with compounds ranging from least to most excitatory as follows: ofloxacin, ciprofloxacin, nalidixic acid, moxifloxacin (= BAY × 8843), fleroxacin, lomefloxacin, enoxacin, clinafloxacin (much more excitatory than enoxacin), tosufloxacin, trovafloxacin, BAY 15-7828, and BAY × 9181 (much more excitatory than BAY 15-7828). The proposed hippocampus slice model not only is suitable for giving valuable alerts as to convulsive potential during candidate selection but also enables mechanistic investigations. These investigations pointed to the
N
-methyl-
d
-aspartate receptor as the probable target of the fluoroquinolone effects.
Dosing of Aminoglycosides To Rapidly Attain Pharmacodynamic Goals and Hasten Therapeutic Response by Using Individualized Pharmacokinetic Monitoring of Patients with Pneumonia Caused by Gram-Negative Organisms
Authors: Kashuba A. D. M. , Bertino J. S. , Nafziger A. N. 
Published: October 2018

ABSTRACT

Achieving a peak aminoglycoside concentration (
C
max
)/MIC of ≥10 within 48 h of initiation of therapy for pneumonia caused by gram-negative organisms results in a 90% probability of therapeutic response by day 7. Targeting an MIC of 1 μg/ml, empirical aminoglycoside loading doses of 348 (25th- to 75th-percentile range, 275 to 432) mg were calculated to obtain a
C
max
/MIC of 10 in our patient population. Individualized pharmacokinetic monitoring coupled with MIC data should determine subsequent dosing regimens to minimize the potential for toxicity and maximize the probability of clinical response.
Antimicrobial Susceptibility Testing of 59 Strains of
Campylobacter fetus
subsp.
fetus
Authors: Tremblay Carole , Gaudreau Christiane 
Published: October 2018

ABSTRACT

The susceptibilities of 59
Campylobacter fetus
subsp.
fetus
isolates to eight antibiotics were studied by the agar dilution, E-test, and disk diffusion methods. None of the isolates were β-lactamase producers. All were susceptible to ampicillin, gentamicin, imipenem, and meropenem as determined by the three methods, with MICs at which 90% of the isolates are inhibited (MIC
90
s) (determined by agar dilution) of 2, 1, ≤0.06, and 0.12 μg/ml, respectively. Twenty-seven percent of the isolates were resistant to tetracycline, with complete agreement between the agar dilution and disk diffusion results. The MIC
90
s determined by agar dilution were 2 μg/ml for erythromycin, 1 μg/ml for ciprofloxacin, and 8 μg/ml for cefotaxime.
Energy-Dependent Accumulation of Fluoroquinolones in Quinolone-Resistant
Klebsiella pneumoniae
Strains
Authors: Martínez-Martínez Luis , García Isabel , Ballesta Sofía , Benedí Vicente Javier , Hernández-Allés Santiago , Pascual Alvaro 
Published: October 2018

ABSTRACT

The intracellular accumulation of norfloxacin and pefloxacin in
Klebsiella pneumoniae
was evaluated. The roles of lipopolysaccharide, capsule, and outer membrane proteins were not important for the intrabacterial accumulation of fluoroquinolones in isogenic strains with known outer membrane alterations. In fluoroquinolone-resistant clinical isolates also expressing GyrA alterations, an active efflux leading to decreased accumulation of the drugs enhanced their resistance to these agents.
In Vitro and In Vivo Activities of Moxifloxacin and Clinafloxacin against
Mycobacterium tuberculosis
Authors: Ji Baohong , Lounis Nacer , Maslo Caroline , Truffot-Pernot Chantal , Bonnafous Pascale , Grosset Jacques 
Published: October 2018

ABSTRACT

On 10% oleic acid–albumin–dextrose–catalase-enriched 7H11 agar medium, the MIC at which 90% of the isolates are inhibited for 20 strains of
Mycobacterium tuberculosis
was 0.5 μg of sparfloxacin (SPFX) or moxifloxacin (MXFX) per ml and 1.0 μg of clinafloxacin (CNFX) per ml, indicating that the in vitro activities of SPFX and MXFX were virtually identical and were slightly greater than that of CNFX. However, the in vivo activities of these drugs in a murine tuberculosis model differed considerably. Female Swiss mice were infected intravenously with 6.2 × 10
6
CFU of the H37Rv strain and treated for 4 weeks, beginning the next day after infection, with isoniazid (INH) serving as the positive control. By the criteria of 30-day survival rate, spleen weight, gross lung lesion, and mean number of CFU in the spleen, treatment with CNFX at up to 100 mg/kg of body weight six times weekly displayed no measurable effect against
M. tuberculosis
, whereas both SPFX and MXFX were effective; administration six times weekly of either of the latter two drugs demonstrated dosage-dependent bactericidal effects, as measured by enumeration of CFU in the spleens, and MXFX appeared more bactericidal than the same dosage of SPFX. Of the three fluoroquinolones, only MXFX at 100 mg/kg six times weekly appeared as bactericidal as INH at 25 mg/kg six times weekly. Thus, MXFX may be an important component of the newer combined regimens for treatment of tuberculosis.
Effects of Mutations in GrlA of Topoisomerase IV from
Staphylococcus aureus
on Quinolone and Coumarin Activity
Authors: Fournier Bénédicte , Hooper David C. 
Published: October 2018

ABSTRACT

The
grlA
genes of
Staphylococcus aureus
ISP794 (wild type), MT5224c4 (
grlA
[Phe-80]), MT5224c2 (
grlA
[Pro-116]), and MT111 (
grlA
[Glu-116]) were cloned in pSK950, a shuttle vector, and introduced into
S. aureus
strains derived from strain RN4220. The mutations at position 116 of GrlA (Ala→Pro or Glu) caused an increase in the level of fluoroquinolone resistance and a decrease in the level of coumarin susceptibility, whereas the mutation at position 80 (Ser→Phe) caused only an increase in the level of fluoroquinolone resistance. In multicopy alleles, both types of mutations were codominant for fluoroquinolone resistance, and mutations at position 116 were also codominant for coumarin resistance.