bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Dispositions of Ofloxacin in Human Head, Axillary, and Pubic Hairs
Authors: Kosuge Kazuhiro , Uematsu Toshihiko , Araki Sei-Ichi , Matsuno Hiroyuki , Ohashi Kyoichi , Nakashima Mitsuyoshi 
Published: October 2018

ABSTRACTThe distribution of ofloxacin (OFLX) along the shaft of each of three hair types, i.e., head, axillary and pubic, was investigated and compared among five healthy male volunteers 1 to 4 months after ingestion of OFLX for 1 or 2 days (total dose, 200 or 600 mg). Five strands of each hair type were sectioned together into successive 0.5-cm lengths starting from the dermal end, over a length of ≤6 cm, and the OFLX concentration in each hair section was measured by high-pressure liquid chromatography with fluorescence detection. The distribution of OFLX along the head hair shaft was narrow, having a single peak even 3 to 4 months after administration, suggesting a rather uniform growth rate among hair strands. On the other hand, the OFLX distribution along axillary or pubic hair shafts tended to be broad, even having two apparent peaks, and the growth rate did not seem uniform. Since axillary hair seemed to stop growing after having gained a length of ≤4 to 5 cm, it was suggested to enter a resting stage after the growth of ≤3 cm over the 2 to 4 months after OFLX incorporation. These findings indicate that head hair is the most suitable for analysis of individual drug use and the larger growth rate and cycle stage variabilities of strands of the other types of hair should be taken into account.
Pregnancy Outcome Following Gestational Exposure to Fluoroquinolones: a Multicenter Prospective Controlled Study
Authors: Loebstein Ronen , Addis Antonio , Ho Elaine , Andreou Roseann , Sage Suzanne , Donnenfeld Alan E. , Schick Betsy , Bonati Maurizio , Moretti Myla , Lalkin Arieh , Pastuszak Anne , Koren Gideon 
Published: October 2018

ABSTRACT

Concerns regarding the teratogenicity of fluoroquinolones have resulted in their restricted use during gestation. This is despite an increasing need for their use due to emerging bacterial resistance. The objectives of the present investigation were to evaluate pregnancy and fetal outcomes following maternal exposure to fluoroquinolones and to examine whether in utero exposure to quinolones is associated with clinically significant musculoskeletal dysfunctions. We prospectively enrolled and followed up 200 women exposed to fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin) during gestation. Pregnancy outcome was compared with that for 200 controls matched for age and for smoking and alcohol consumption habits. Controls were exposed to nonteratogenic, nonembryotoxic antimicrobial agents matched by indication, duration of therapy (±3 days), and trimester of exposure. Rates of major congenital malformations did not differ between the group exposed to quinolones in the first trimester (2.2%) and the control group (2.6%) (relative risk, 0.85; 95% confidence interval, 0.21 to 3.49). Women treated with quinolones had a tendency for an increased rate of therapeutic abortions compared with the rate among women exposed to nonteratogens (relative risk, 4.50; 95% confidence interval, 0.98 to 20.57), resulting in lower live-birth rates (86 versus 94%;
P
= 0.02). The rates of spontaneous abortions, fetal distress, and prematurity and the birth weight did not differ between the groups. Gross motor developmental milestone achievements did not differ between the children of the mothers in the two groups. We concluded that the use of fluoroquinolones during embryogenesis is not associated with an increased risk of major malformations. There were no clinically significant musculoskeletal dysfunctions in children exposed to fluoroquinolones in utero. The higher rate of therapeutic abortions observed in quinolone-exposed women compared to that for their controls may be secondary to the misperception of a major risk related to quinolone use during pregnancy.
Lysostaphin Treatment of Experimental Methicillin-Resistant
Staphylococcus aureus
Aortic Valve Endocarditis
Authors: Climo Michael W. , Patron Roberto L. , Goldstein Beth P. , Archer Gordon L. 
Published: October 2018

ABSTRACT

The emergence of clinical isolates of methicillin-resistant
Staphylococcus aureus
with reduced susceptibility to vancomycin has prompted a search for new and novel therapeutic agents active against
S. aureus
. Lysostaphin, a peptidase produced by
Staphylococcus simulans
, specifically cleaves the glycine-glycine bonds unique to the interpeptide cross-bridge of the
S. aureus
cell wall. The effectiveness of various regimens of dosing with intravenous lysostaphin was compared to that of vancomycin in the rabbit model of aortic valve endocarditis caused by a clinical methicillin-resistant
S. aureus
isolate. All animals were treated for a total of 3 days. The most active regimen, lysostaphin given three times daily, produced sterile vegetations in 10 of 11 treated rabbits, with a mean reduction in vegetation bacterial counts of 8.5 log
10
CFU/g compared to the counts in the untreated controls. In contrast, vancomycin given twice daily sterilized no vegetations and reduced vegetation bacterial counts by only 4.8 log
10
CFU/g. Lysostaphin given once daily was less effective, reducing mean vegetation bacterial counts by only 3.6 log
10
CFU/g, but the combination of lysostaphin once daily and vancomycin twice daily reduced the mean vegetation bacterial density by 7.5 log
10
CFU/g, a result that was significantly better than that for either regimen alone (
P
< 0.05). Lysostaphin was well tolerated by the rabbits, with no evidence of immunological reactions following up to 9 weeks of intravenous administration. We conclude that lysostaphin given alone or in combination with vancomycin is more effective in the treatment of experimental methicillin-resistant
S. aureus
aortic valve endocarditis than vancomycin alone.
Initial Concentration-Time Profile of Gentamicin Determines Efficacy against
Enterobacter cloacae
ATCC 13047
Authors: Rayner Craig R. , Ioannides-Demos Lisa L. , Brien Jo-Anne E. , Liolios Lisa L. , Spicer W. John 
Published: October 2018

ABSTRACT

In vitro studies were designed to investigate the influence of peak drug concentration (
C
max
), the area under the concentration-time curve (AUC), and, consequently, the trough concentration on the bactericidal effects of gentamicin against
Enterobacter cloacae
(MIC, 0.5 mg/liter) by simulating bolus versus infusion administration and bolus dosing with altered drug clearance. Bacteria in the lag phase were exposed to gentamicin concentration-time profiles modelling either bolus or infusion dosing (AUC constant,
C
max
changing) with 30-min postdose peak concentrations (
C
peak30
) of 4, 6, 8, and 10 mg/liter or bolus dosing with normal and double drug clearance (
C
max
constant, AUC changing) corresponding to normal clearance profiles with
C
peak30
of 6 and 8 mg/liter. Exposure to gentamicin caused early bactericidal effects apparent by 2 h, followed by variable bacteriostatic and recovery phases. Exposure to bolus profiles resulted in greater bactericidal activity than the corresponding infusion profile up to a
C
peak30
of 8 mg/liter. At a
C
peak30
of 10 mg/liter, there were no differences in bactericidal effect. Double clearance profiles had a reduced bactericidal effect at 6 mg/liter compared to the corresponding normal clearance profile, but no differences in bactericidal effect were observed for 8-mg/liter double and normal clearance profiles. These results suggest that the initial exposure (i.e., 0 to 30 min) is a more important determinant for bacterial killing than the AUC or trough concentration for this bacterium. Subject to confirmation of these findings with other gram-negative bacteria, to optimize aminoglycoside efficacy the initial exposure (
C
max
) should be maximized by giving higher doses or bolus administration at intervals which may not produce detectable trough concentrations. Clinical trials with a broad range of patients, especially those with higher clearance, would confirm these in vitro observations and define optimal dosing recommendations.
Oral Antimicrobial Prophylaxis in Bone Marrow Transplant Recipients: Randomized Trial of Ciprofloxacin versus Ciprofloxacin-Vancomycin
Authors: Ford Clyde D. , Reilly William , Wood John , Classen David C. , Burke John P. 
Published: October 2018

ABSTRACT

The optimal oral antimicrobial prophylactic regimen for bone marrow transplant recipients remains to be elucidated. We randomized 84 patients to receive either oral ciprofloxacin or ciprofloxacin plus vancomycin at hospital admission. Patients were monitored for bacteremias and clinical parameters, and stool and throat swab surveillance cultures were performed. The addition of vancomycin resulted in a significant decrease in the frequency of patients with surveillance cultures positive for coagulase-negative staphylococci (stool cultures, 44 versus 23%; throat swab cultures, 37 versus 19%) and alpha-hemolytic streptococci (throat swab cultures, 90 versus 60%). The frequencies of positivity for
Candida
spp. and gram-negative organisms on surveillance cultures were comparable. Despite these results, no differences in the incidences of bacteremias (12 of 41 versus 12 of 43 patients) or clinical parameters such as number of days to first fever, total number of febrile days, length of stay, and number of transfusions could be demonstrated. Because of a lack of efficacy of vancomycin and emerging problems with vancomycin-resistant isolates, vancomycin should not be used in oral antimicrobial prophylaxis regimens.
Postantibiotic Effect of Trovafloxacin against Gram-Positive and -Negative Organisms
Authors: Pankuch G. A. , Jacobs M. R. , Appelbaum P. C. 
Published: October 2018

ABSTRACT

Trovafloxacin pneumococcal and staphylococcal postantibiotic effects (PAEs) were 0.7 to 1.8 and 0.7 to 2.4 h, respectively. For
Escherichia coli
and
Pseudomonas aeruginosa
, PAEs were 2.4 to 4.4 h. Pneumococcal and staphylococcal postantibiotic sub-MIC effects (PA-SMEs) (0.4 times the MIC) were 2.3 to 3.7 and 2.4 to >9.2 h, respectively, and
E. coli
PA-SMEs (0.3 times the MIC) were 6.8 to >12.0 h. For one
P. aeruginosa
strain, the PA-SME (0.4 times the MIC) was >10 h; in the other, rapid bactericidal activity precluded measurement.
Characterization of the 6′-
N
-Aminoglycoside Acetyltransferase Gene
aac(6′)-Iq
from the Integron of a Natural Multiresistance Plasmid
Authors: Centrón Daniela , Roy Paul H. 
Published: October 2018

ABSTRACT

The nucleotide sequence of a newly identified amikacin resistance gene,
aac(6′)-Iq
(551 bp), is reported. It has 68.4 and 94.4% homology with the
aac(6′)-Ia
gene and the recently described
aac(6′)-Ip
gene, respectively. Analysis of its flanking sequences indicated that it is in the first cassette of a class I integron and has an
attC
site (59-base element) 108 bp in length.
Erythromycin Inhibits Tumor Necrosis Factor Alpha and Interleukin 6 Production Induced by Heat-KilledStreptococcus pneumoniaein Whole Blood
Authors: Schultz Marc J. , Speelman Peter , Zaat Sebastian , van Deventer Sander J. H. , van der Poll Tom 
Published: October 2018

ABSTRACTTo determine the effects of penicillin and erythromycin on cytokine production induced by heat-killedStreptococcus pneumoniae(HKSP), we studied the effects of those drugs on cytokine production induced byS. pneumoniaein human whole blood in vitro and ex vivo. In whole blood in vitro, erythromycin, but not penicillin, caused a dose-dependent decrease in HKSP-induced production of tumor necrosis factor alpha (TNF) and interleukin 6 (IL-6), while the production of IL-10, IL-12, and gamma interferon was inhibited only at the highest erythromycin concentration tested (10−3M). The production of TNF and IL-6 in whole blood obtained from healthy subjects after a 30-min infusion of erythromycin (1,000 mg) was lower after ex vivo stimulation with HKSP than that in blood drawn before the infusion. Inhibition of TNF contributed to erythromycin-induced inhibition of IL-6 synthesis. Inhibition of TNF and IL-6 production by erythromycin may have a negative impact on host defense mechanisms during pneumococcal pneumonia.
Administration of Liposomal Agents and Blood Clearance Capacity of the Mononuclear Phagocyte System
Authors: van Etten Els W. M. , ten Kate Marian T. , Snijders Susan V. , Bakker-Woudenberg Irma A. J. M. 
Published: October 2018

ABSTRACT
As liposomes are cleared from the circulation to a substantial extent by the phagocytic cells of the mononuclear phagocyte system (MPS), there is a question whether administration of liposome-based therapeutic agents interferes with clearance of infectious organisms by the MPS from blood. In the present study, at first the effect of administration of three types of empty liposomes (devoid of drug), differing in blood residence time, on carbon clearance and bacterial clearance from blood was studied with mice. Classical liposomes (LIP A) and placebo liposomes with lipid composition as in AmBisome (LIP B) or as in Doxil (LIP C) were used. Liposomes were administered intravenously as a single dose. Second, the effect of multiple-dose administration of AmBisome on bacterial blood clearance was studied with rats. AmBisome was administered with two different dosage schedules. The blood clearance capacity of the MPS was monitored at different time points after the last liposome injection. It was shown that the carbon blood clearance capacity of the MPS was impaired only at a high lipid dose of empty classical liposomes. The bacterial blood clearance capacity was never impaired, not even after prolonged treatment with AmBisome administered in a clinically relevant regimen.
Fluconazole Resistance Associated with Drug Efflux and Increased Transcription of a Drug Transporter Gene,
PDH1
, in
Candida glabrata
Authors: Miyazaki Haruko , Miyazaki Yoshitsugu , Geber Antonia , Parkinson Tanya , Hitchcock Christopher , Falconer Derek J. , Ward Douglas J. , Marsden Katherine , Bennett John E. 
Published: October 2018

ABSTRACT

Sequential
Candida glabrata
isolates were obtained from the mouth of a patient infected with human immunodeficiency virus type 1 who was receiving high doses of fluconazole for oropharyngeal thrush. Fluconazole-susceptible colonies were replaced by resistant colonies that exhibited both increased fluconazole efflux and increased transcripts of a gene which codes for a protein with 72.5% identity to Pdr5p, an ABC multidrug transporter in
Saccharomyces cerevisiae
. The deduced protein had a molecular mass of 175 kDa and was composed of two homologous halves, each with six putative transmembrane domains and highly conserved sequences of ATP-binding domains. When the earliest and most azole-susceptible isolate of
C. glabrata
from this patient was exposed to fluconazole, increased transcripts of the
PDR5
homolog appeared, linking azole exposure to regulation of this gene.
Effect of Trovafloxacin on Production of Cytokines by Human Monocytes
Authors: Khan Anis A. , Slifer Teri R. , Remington Jack S. 
Published: October 2018

ABSTRACTAntibiotics have previously been shown to have immunomodulatory effects. We examined the effect of the broad-spectrum fluoroquinoline antibiotic trovafloxacin on cytokine synthesis by monocytes obtained from healthy human volunteers and stimulated with either lipopolysaccharide or gram-positive cells (heat-killedStaphylococcus aureus[Pansorbin]). Trovafloxacin levels achievable in humans suppressed in vitro synthesis of each of the cytokines analyzed, viz., interleukin-1α (IL-1α), IL-1β, IL-6, IL-10, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha. This effect was not due to direct effects of the drug on cellular viability; at these concentrations, trovafloxacin did not have demonstrable cytotoxicity for the monocytes, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Although similar patterns of suppression of cytokine synthesis were observed in samples obtained from the same volunteers on different days, there were significant day-to-day variations. These results reveal that trovafloxacin possesses significant immunomodulatory activity in vitro and suggest that suppression of acute-phase inflammatory responses may occur in vivo, elicited through trovafloxacin’s effect on cytokine synthesis by human monocytes.
Efficacy of NS-718, a Novel Lipid Nanosphere-Encapsulated Amphotericin B, against
Cryptococcus neoformans
Authors: Hossain Mohammad Ashraf , Maesaki Shigefumi , Kakeya Hiroshi , Noda Tetsuhiro , Yanagihara Katsunori , Sasaki Eisuke , Hirakata Yoichi , Tomono Kazunori , Tashiro Takayoshi , Kohno Shigeru 
Published: October 2018

ABSTRACT

In vitro and in vivo efficacies of NS-718, a lipid nanosphere-encapsulated amphotericin B (AMPH-B), have been studied. Of the tested AMPH-B formulations, NS-718 had the lowest MIC for
Cryptococcus neoformans
. In a murine model, low-dose therapy (0.8 mg/kg of body weight) with NS-718 showed higher efficacy than that with AmBisome. High-dose therapy (2.0 mg/kg) with NS-718 was much more effective than those with Fungizone and AmBisome. In mice treated with a high dose of NS-718, only a few yeast cells had grown in lung by 7 days after inoculation. A pharmacokinetic study showed higher concentrations of AMPH-B in lung following administration of NS-718 than after administration of AmBisome. Our results indicated that NS-718, a new AMPH-B formulation, is a promising antifungal agent for treatment of pulmonary cryptococcosis and could be the most effective antifungal agent against
C. neoformans
infections.
NorM, a Putative Multidrug Efflux Protein, of
Vibrio parahaemolyticus
and Its Homolog in
Escherichia coli
Authors: Morita Yuji , Kodama Kazuyo , Shiota Sumiko , Mine Tomoyuki , Kataoka Atsuko , Mizushima Tohru , Tsuchiya Tomofusa 
Published: October 2018

ABSTRACT

We found that cells of
Vibrio parahaemolyticus
possess an energy-dependent efflux system for norfloxacin. We cloned a gene for a putative norfloxacin efflux protein from the chromosomal DNA of
V. parahaemolyticus
by using an
Escherichia coli
mutant lacking the major multidrug efflux system AcrAB as the host and sequenced the gene (
norM
). Cells of
E. coli
transformed with a plasmid carrying the
norM
gene showed elevated energy-dependent efflux of norfloxacin. The transformants showed elevated resistance not only to norfloxacin and ciprofloxacin but also to the structurally unrelated compounds ethidium, kanamycin, and streptomycin. These results suggest that this is a multidrug efflux system. The hydropathy pattern of the deduced amino acid sequence of NorM suggested the presence of 12 transmembrane domains. The deduced primary structure of NorM showed 57% identity and 88% similarity with that of a hypothetical
E. coli
membrane protein, YdhE. No reported drug efflux protein in the sequence databases showed significant sequence similarity with NorM. Thus, NorM seems to be a novel type of multidrug efflux protein. We cloned the
ydhE
gene from
E. coli
. Cells of
E. coli
transformed with the cloned
ydhE
gene showed elevated resistance to norfloxacin, ciprofloxacin, acriflavine, and tetraphenylphosphonium ion, but not to ethidium, when MICs were measured. Thus, it seems that NorM and YdhE differ somehow in substrate specificity.
Efficacy of Trovafloxacin, a New Quinolone Antibiotic, in Experimental Staphylococcal Endocarditis Due to Oxacillin-Resistant Strains
Authors: Bayer Arnold S. , Li Cong , Ing Michael 
Published: October 2018

ABSTRACT

Therapeutic options for severe infections caused by strains of oxacillin-resistant
Staphylococcus aureus
(ORSA) and coagulase-negative staphylococci (ORSE) are very limited. With the increasing resistance of such strains to aminoglycosides, rifampin, and currently available quinolone agents, as well as the recent documentation of increasing resistance of ORSA to vancomycin (VANCO), new treatment alternatives are imperative. The in vivo efficacy of trovafloxacin (TROVA), a new quinolone agent with excellent antistaphylococcal activity in vitro, against experimental endocarditis (IE) due to β-lactamase-producing ORSA and ORSE strains (ORSA and ORSE IE) was evaluated. TROVA (25 mg/kg of body weight intravenously [i.v.] twice daily [b.i.d.]) was compared to VANCO (20 mg/kg i.v. b.i.d.) and two regimens of ampicillin-sulbactam (AMP-SUL; 200 mg/kg intramuscularly [i.m.] three times a day [t.i.d.] and 20 mg/kg i.m. b.i.d.), with all agents given for 3 or 6 days. AMP-SUL was included as a comparative treatment regimen because of its proven efficacy against experimental ORSA and ORSE IE. For both ORSA and ORSE IE, TROVA, AMP-SUL, and VANCO each reduced staphylococcal densities in vegetations compared to untreated controls (
P
< 0.01). For ORSA IE, TROVA was the most rapidly bactericidal agent—although not to a statistically significant degree—correlating with its superior bactericidal effect in vitro compared to those of VANCO and AMP-SUL.
Interactions between HMR 3647, a New Ketolide, and Human Polymorphonuclear Neutrophils
Authors: Vazifeh D. , Preira A. , Bryskier A. , Labro M. T. 
Published: October 2018

ABSTRACTHMR 3647, a new ketolide, is active upon intracellular pathogens. We previously demonstrated that HMR 3004 (RU 64004), another ketolide, is highly concentrated by human polymorphonuclear neutrophils (PMNs). This prompted us to evaluate whether the presence of a 3-keto group instead of anl-cladinose, a neutral sugar characteristic of erythromycin A derivatives, confers peculiar pharmacokinetic properties with regard to cellular accumulation and efflux. After incubation with the radiolabelled drug, HMR 3647 uptake was determined by a velocity gradient centrifugation technique. HMR 3647 was avidly concentrated by PMNs, without saturation, over a 3-h incubation period, with cellular-to-extracellular concentration ratios of 31 ± 4.2 at 5 min and up to 348 ± 27.1 at 180 min. About 60% of HMR 3647 was located in the granular compartment; less than 6% was associated with the membranes. HMR 3647 gradually egressed from loaded cells placed in drug-free medium. Uptake was dependent on environmental temperature (activation energy, 128 ± 9.4 kJ/mol) but not on extracellular pH. HMR 3647 displayed Michaelis-Menten saturation kinetics with a meanVmax of 2315 ng/2.5 × 106PMNs/5 min and a meanKmof 117 mg/liter (144 μM). As already observed with erythromycin A-derived macrolides, extracellular Ca2+was necessary for optimal uptake of HMR 3647. Interestingly, verapamil increased the uptake of HMR 3647 at 5 min, but this was followed by gradual inhibition at later incubation times, a phenomenon probably related to stimulation of drug efflux. The impact of intracellular accumulation of HMR 3647 on PMN functions was also investigated. In contrast to other erythromycin A derivatives, HMR 3647 only weakly triggered granule exocytosis, but it inhibited superoxide anion production in a time- and concentration-dependent manner, with concentrations which inhibited 50% of control response of 55 (67 μM) (5 min) and 30 (36 μM) (30 min) mg/liter for formyl-methionyl-leucyl-phenylalanine stimulation and 117 (143 μM) (5 min) and 44 (54 μM) (30 min) mg/liter for phorbol myristate acetate stimulation.