bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bacterial Pathogens Isolated from Patients with Bloodstream Infection: Frequencies of Occurrence and Antimicrobial Susceptibility Patterns from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 1997)
Authors: Pfaller Michael A. , Jones Ronald N. , Doern Gary V. , Kugler Kari , Group The Sentry Participants 
Published: October 2018

ABSTRACT

The SENTRY Program was established in January 1997 to measure the predominant pathogens and antimicrobial resistance patterns of nosocomial and community-acquired infections over a broad network of sentinel hospitals in the United States (30 sites), Canada (8 sites), South America (10 sites), and Europe (24 sites). During the first 6-month study period (January to June 1997), a total of 5,058 bloodstream infections (BSI) were reported by North American SENTRY participants (4,119 from the United States and 939 from Canada). In both the United States and Canada,
Staphylococcus aureus
and
Escherichia coli
were the most common BSI isolates, followed by coagulase-negative staphylococci and enterococci.
Klebsiella
spp.,
Enterobacter
spp.,
Pseudomonas aeruginosa
,
Streptococcus pneumoniae
, and β-hemolytic streptococci were also among the 10 most frequently reported species in both the United States and Canada. Although the rank orders of pathogens in the United States and Canada were similar, distinct differences were noted in the antimicrobial susceptibilities of several pathogens. Overall, U.S. isolates were considerably more resistant than those from Canada. The differences in the proportions of oxacillin-resistant
S. aureus
isolates (26.2 versus 2.7% for U.S. and Canadian isolates, respectively), vancomycin-resistant enterococcal isolates (17.7 versus 0% for U.S. and Canadian isolates, respectively), and ceftazidime-resistant
Enterobacter
sp. isolates (30.6 versus 6.2% for U.S. and Canadian isolates, respectively) dramatically emphasize the relative lack of specific antimicrobial resistance genes (
mecA
,
vanA
, and
vanB
) in the Canadian microbial population. Among U.S. isolates, resistance to oxacillin among staphylococci, to vancomycin among enterococci, to penicillin among pneumococci, and to ceftazidime among
Enterobacter
spp. was observed in both nosocomial and community-acquired pathogens, although in almost every instance the proportion of resistant strains was higher among nosocomial isolates. Antimicrobial resistance continues to increase, and ongoing surveillance of microbial pathogens and resistance profiles is essential on national and international scales.
Molecular Basis of In Vivo Resistance to Sulfadoxine-Pyrimethamine in African Adult Patients Infected with
Plasmodium falciparum
Malaria Parasites
Authors: Basco Leonardo K. , Tahar Rachida , Ringwald Pascal 
Published: October 2018

ABSTRACT

In vitro sulfadoxine and pyrimethamine resistance has been associated with point mutations in the dihydropteroate synthase and dihydrofolate reductase domains, respectively, but the in vivo relevance of these point mutations has not been well established. To analyze the correlation between genotype and phenotype, 10 Cameroonian adult patients were treated with sulfadoxine-pyrimethamine and followed up for 28 days. After losses to follow-up (
n
= 1) or elimination of DNA samples due to mixed parasite populations with pyrimethamine-sensitive and pyrimethamine-resistant profiles (
n
= 3), parasite genomic DNA from day 0 blood samples of six patients were analyzed by DNA sequencing. Three patients who were cured had isolates characterized by a wild-type or mutant dihydrofolate reductase gene (with one or two mutations) and a wild-type dihydropteroate synthase gene. Three other patients who failed to respond to sulfadoxine-pyrimethamine treatment carried isolates with triple dihydrofolate reductase gene mutations and either a wild-type or a mutant dihydropteroate synthase gene. Three dihydrofolate reductase gene codons (51, 59, and 108) may be reliable genetic markers that can accurately predict the clinical outcome of sulfadoxine-pyrimethamine treatment in Africa.
Pharmacokinetics of the Protease Inhibitor KNI-272 in Plasma and Cerebrospinal Fluid in Nonhuman Primates after Intravenous Dosing and in Human Immunodeficiency Virus-Infected Children after Intravenous and Oral Dosing
Authors: Mueller Brigitta U. , Anderson Barry D. , Farley Maureen Q. , Murphy Robert , Zuckerman Judy , Jarosinski Paul , Godwin Karen , McCully Cindy L. , Mitsuya Hiroaki , Pizzo Philip A. , Balis Frank M. 
Published: October 2018

ABSTRACT

KNI-272 is a human immunodeficiency virus (HIV) protease inhibitor with potent activity in vitro. We studied the pharmacokinetics of KNI-272 in the plasma and cerebrospinal fluid (CSF) of a nonhuman primate model and after intravenous and oral administration to children with HIV infection. Plasma and CSF were sampled over 24 h after the administration of an intravenous dose of 50 mg of KNI-272 per kg of body weight (approximately 1,000 mg/m
2
) to three nonhuman primates. The pharmacokinetics of KNI-272 were also studied in 18 children (9 males and 9 females; median age, 9.4 years) enrolled in a phase I trial of four dose levels of KNI-272 (100, 200, 330, and 500 mg/m
2
per dose given four times daily). The plasma concentration-time profile of KNI-272 in the nonhuman primate model was characterized by considerable interanimal variability and rapid elimination (clearance, 2.5 liters/h/kg; terminal half-life, 0.54 h). The level of drug exposure achieved in CSF, as measured by the area under the KNI-272 concentration-time curve, was only 1% of that achieved in plasma. The pharmacokinetics of KNI-272 in children were characterized by rapid elimination (clearance, 276 ml/min/m
2
; terminal half-life, 0.44 h), limited (12%) and apparently saturable bioavailability, and limited distribution (volume of distribution at steady state, 0.11 liter/kg). The concentrations in plasma were maintained above a concentration that is active in vitro for less than half of the 6-h dosing interval. There was no significant increase in CD4 cell counts or decrease in p24 antigen or HIV RNA levels. The pharmacokinetic profile of KNI-272 may limit the drug’s efficacy in vivo. It appears that KNI-272 will play a limited role in the treatment of HIV-infected children.
Enhanced Bioavailability of Itraconazole in Hydroxypropylβ-Cyclodextrin Solution versus Capsules in Healthy Volunteers
Authors: Barone Joseph A. , Moskovitz Bruce L. , Guarnieri Joseph , Hassell Alan E. , Colaizzi John L. , Bierman Robert H. , Jessen Lois 
Published: October 2018

ABSTRACT

The bioavailabilities and bioequivalences of single 200-mg doses of itraconazole solution and two capsule formulations were evaluated in a crossover study of 30 male volunteers. The two capsule formulations were bioequivalent. The bioavailabilities of the solutions itraconazole and hydroxyitraconazole were 30 to 33% and 35 to 37% greater, respectively, than those of either capsule. However, the maximum concentrations of the drug in plasma (
C
max
), the times to
C
max
, and the terminal half-lives were comparable for all three formulations. These data indicate that the bioavailabilities of itraconazole and hydroxyitraconazole are enhanced when administered as an oral solution instead of capsules.
Plasma Lipoprotein Distribution of Liposomal Nystatin Is Influenced by Protein Content of High-Density Lipoproteins
Authors: Cassidy Shawn M. , Strobel Frank W. , Wasan Kishor M. 
Published: October 2018

ABSTRACTThe plasma lipoprotein distribution of free nystatin (Nys) and liposomal nystatin (L-Nys) in human plasma samples with various lipoprotein lipid and protein concentrations and compositions was investigated. To assess the lipoprotein distributions of Nys and L-Nys, human plasma was incubated with Nys and L-Nys (equivalent to 20 μg/ml) for 5 min at 37°C. The plasma was subsequently partitioned into its lipoprotein and lipoprotein-deficient plasma fractions by step-gradient ultracentrifugation, and each fraction was analyzed for Nys content by high-pressure liquid chromatography. The lipid and protein contents and compositions of each fraction were determined with enzymatic kits. Following the incubation of Nys and L-Nys in human plasma the majority of Nys recovered within the lipoprotein fractions was recovered from the high-density lipoprotein (HDL) fraction. Incorporation of Nys into liposomes consisting of dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol significantly increased the percentage of drug recovered within the HDL fraction. Furthermore, it was observed that as the amount of HDL protein decreased the amounts of Nys and L-Nys recovered within this fraction decreased. These findings suggest that the preferential distribution of Nys and L-Nys into plasma HDL may be a function of the HDL protein concentration.
Acquisition of Certain Streptomycin-Resistant (str) Mutations Enhances Antibiotic Production in Bacteria
Authors: Hosoya Yoshiko , Okamoto Susumu , Muramatsu Hideyuki , Ochi Kozo 
Published: October 2018

ABSTRACTPhysiological differentiation (including antibiotic production) in microorganisms usually starts when cells encounter adverse environmental conditions and is frequently accompanied by an increase in the accumulation of intracellular ppGpp. We have found that the acquisition of certain streptomycin-resistant (str) mutations enables cells to overproduce antibiotics, demonstrating an increase in productivity 5- to 50-fold greater than that of wild-type strains. The frequency of such antibiotic-overproducing strains among thestrmutants was shown to range from 3 to 46%, as examined with several strains of the generaStreptomyces,Bacillus, andPseudomonas. Analysis ofstrmutants fromBacillus subtilisMarburg 168 revealed that a point mutation occurred within therpsLgene, which encodes the ribosomal protein S12, changing Lys-56 (corresponding to Lys-43 inEscherichia coli) to Asn, Arg, Thr, or Gln. Antibiotic productivity increased in a hierarchical manner depending upon which amino acid residue replaced Lys at this position. ThestrA1mutation, a genetic marker frequently used for mapping, had no effect on antibiotic productivity even though it was found to result in an amino acid alteration of Lys-56 to Ile. Gene replacement experiments with thestralleles demonstrated unambiguously that thestrmutation is responsible for the antibiotic overproductivity observed. These results offer a rational approach for improving the production of antibiotic (secondary metabolism) from microorganisms.
Pharmacokinetics, Safety, and Tolerability of Ascending Single Doses of Moxifloxacin, a New 8-Methoxy Quinolone, Administered to Healthy Subjects
Authors: Stass H. , Dalhoff A. , Kubitza D. , Schühly U. 
Published: October 2018

ABSTRACT

The pharmacokinetics of moxifloxacin were investigated in six studies after oral administration of 50, 100, 200, 400, 600, and 800 mg. Eight healthy male volunteers were included in each study. With doses of up to 200 mg the study was performed as a double-blind, randomized group comparison (
n
= 6 verum and
n
= 2 matched placebo); with the higher doses the study was conducted with a double-blind, randomized, crossover design. Safety and tolerability were assessed by evaluation of vital signs, electrocardiograms, electroencephalograms, clinical chemistry parameters, results of urinalysis, and adverse events. The drug was well tolerated. The concentrations of moxifloxacin in plasma, urine, and saliva were determined by a validated high-pressure liquid chromatography assay with fluorescence detection. In addition, plasma and urine samples were analyzed by a bioassay. A good correlation between both methods was seen, indicating an absence of major active metabolites. The mean maximum concentrations of moxifloxacin in plasma (
C
max
) ranged from 0.29 mg/liter (50-mg dose) to 4.73 mg/liter (800-mg dose) and were reached 0.5 to 4 h following drug administration. After reaching the
C
max
, plasma moxifloxacin concentrations declined in a biphasic manner. Within 4 to 5 h they fell to about 30 to 55% of the
C
max
, and thereafter a terminal half-life of 11 to 14 h accounted for the major part of the area under the concentration-time curve (AUC). During the absorption phase concentrations in saliva were even higher than those in plasma, whereas in the terminal phase a constant ratio of the concentration in saliva/concentration in plasma of between 0.5 and 1 was observed, indicating a correlation between unbound concentrations in plasma and levels in saliva (protein binding level, approximately 48%). AUC and
C
max
increased proportionally to the dose over the whole range of doses investigated. Urinary excretion amounted to approximately 20% of the dose. Data on renal clearance (40 to 51 ml/min/1.73 m
2
) indicated partial tubular reabsorption of the drug. The pharmacokinetic parameters derived from compartmental and noncompartmental analyses were in good agreement. The kinetics could be described best by fitting the data to a two-compartment body model.
Overexpression of the
marA
or
soxS
Regulatory Gene in Clinical Topoisomerase Mutants of
Escherichia coli
Authors: Oethinger Margret , Podglajen Isabelle , Kern Winfried V. , Levy Stuart B. 
Published: October 2018

ABSTRACT

The contribution of regulatory genes to fluoroquinolone resistance was studied with clinical
Escherichia coli
strains bearing mutations in
gyrA
and
parC
and with different levels of fluoroquinolone resistance. Expression of
marA
and
soxS
was evaluated by Northern blot analysis of isolates that demonstrated increased organic solvent tolerance, a phenotype that has been linked to overexpression of
marA
,
soxS
, and
rob
. Among 25 cyclohexane-tolerant strains detected by a screen for increased organic solvent tolerance (M. Oethinger, W. V. Kern, J. D. Goldman, and S. B. Levy, J. Antimicrob. Chemother. 41:111–114, 1998), we found 5 Mar mutants and 4 Sox mutants. A further Mar mutant was detected among 11 fluoroquinolone-resistant, cyclohexane-susceptible
E. coli
strains used as controls. Comparison of the
marOR
sequences of clinical Mar mutants with that of
E. coli
K-12 (GenBank accession no.
M96235
) revealed point mutations in
marR
in all mutants which correlated with loss of repressor function as detected in a
marO
::
lacZ
transcriptional assay. We found four other amino acid changes in MarR that did not lead to loss of function. Two of these changes, present in 20 of the 35 sequenced
marOR
fragments, identified a variant genotype of
marOR
. Isolates with the same
gyrA
and
parC
mutations showed increased fluoroquinolone resistance when the mutations were accompanied by overexpression of
marA
or
soxS
. These data support the hypothesis that high-level fluoroquinolone resistance involves mutations at several chromosomal loci, comprising structural and regulatory genes.
Tn
5706
, a Transposon-Like Element from
Pasteurella multocida
Mediating Tetracycline Resistance
Authors: Kehrenberg Corinna , Werckenthin Christiane , Schwarz Stefan 
Published: October 2018

ABSTRACT

The 4,378-bp putative tetracycline resistance transposon Tn
5706
of
Pasteurella multocida
consists of an internal
tet
(H)-
tetR
resistance gene region which is flanked by almost identical insertion elements, IS
1596
and IS
1597
. Two reading frames for proteins of 70 and 228 amino acids were detected in each of these insertion sequence elements. The 228-amino-acid protein revealed homology to transposase proteins of gram-positive bacteria.
Leishmania infantum
: Lack of Parasite Resistance to Amphotericin B in a Clinically Resistant Visceral Leishmaniasis
Authors: Durand Remy , Paul Muriel , Pratlong Francine , Rivollet Daniele , Dubreuil-Lemaire Marie-Laure , Houin Rene , Astier Alain , Deniau Michele 
Published: October 2018

ABSTRACT

Amphotericin B (AmB) has been used as a second-line treatment of visceral leishmaniasis, particularly in human immunodeficiency virus-positive patients. AmB median effective doses (ED
50
s) were determined on an isolate obtained before any treatment and on a second isolate obtained 4 years later from the same AmB-treated patient. ED
50
s were similar (0.059 and 0.067 mg/kg of body weight, respectively), demonstrating the first evidence of AmB ED
50
stability of
Leishmania infantum
after a long-term drug exposure. An isoenzymatic study was performed in order to verify that the second isolate originated from the same parasite as the first isolate. The present case report showed that treatment failure was not due to parasite resistance in spite of a prolonged exposure to the drug.
Inhibitory Action of a Truncated Derivative of the Amphibian Skin Peptide Dermaseptin s3 on
Saccharomyces cerevisiae
Authors: Coote Peter J. , Holyoak Caroline D. , Bracey Dani , Ferdinando Dudley P. , Pearce James A. 
Published: October 2018

ABSTRACT

The inhibitory activity of a truncated derivative of the natural amphibian skin peptide dermaseptin s3-(1-16)-NH
2
[DS s3 (1-16)] against
Saccharomyces cerevisiae
was studied. Significant growth inhibition was observed after exposure to 3.45 μg of the peptide per ml at pH 6.0 and 7.0, with complete growth inhibition occurring at 8.63 μg of peptide per ml for all pH values tested. Using confocal scanning laser microscopy, we have shown that DS s3 (1-16) disrupted the yeast cell membrane resulting in the gross permeabilization of the cell to the nuclear stain ethidium bromide. However, the principal inhibitory action of the peptide was not due to disruption of intracellular pH homeostasis. Instead, growth inhibition by the peptide correlated with the efflux of important cellular constituents such as ADP, ATP, RNA, and DNA into the surrounding medium. The combination of DS s3 (1-16) with mild heating temperatures as low as 35°C significantly enhanced the inhibitory effect of the peptide (8.63 μg/ml), and at 45°C greater than 99% of the population was killed in 10 min. In summary, a derivative of a natural antimicrobial peptide has potential, either alone or in combination with mild heating, to prevent the growth of or kill spoilage yeast.
Activities of LL-37, a Cathelin-Associated Antimicrobial Peptide of Human Neutrophils
Authors: Turner Jeffrey , Cho Yoon , Dinh Nhu-Nguyen , Waring Alan J. , Lehrer Robert I. 
Published: October 2018

ABSTRACTHuman neutrophils contain two structurally distinct types of antimicrobial peptides, β-sheet defensins (HNP-1 to HNP-4) and the α-helical peptide LL-37. We used radial diffusion assays and an improved National Committee for Clinical Laboratory Standards-type broth microdilution assay to compare the antimicrobial properties of LL-37, HNP-1, and protegrin (PG-1). Although generally less potent than PG-1, LL-37 showed considerable activity (MIC, <10 μg/ml) againstPseudomonas aeruginosa,Salmonella typhimurium,Escherichia coli,Listeria monocytogenes,Staphylococcus epidermidis,Staphylococcus aureus, and vancomycin-resistant enterococci, even in media that contained 100 mM NaCl. Certain organisms (methicillin-resistantS. aureus,Proteus mirabilis, andCandida albicans) were resistant to LL-37 in media that contained 100 mM NaCl but were susceptible in low-salt media.Burkholderia cepaciawas resistant to LL-37, PG-1, and HNP-1 in low- or high-salt media. LL-37 caused outer and inner membrane permeabilization ofE. coliML-35p. ChromogenicLimulusassays revealed that LL-37 bound toE. coliO111:B4 lipopolysaccharide (LPS) with a high affinity and that this binding showed positive cooperativity (Hill coefficient = 2.02). Circular dichroism spectrometry disclosed that LL-37 underwent conformational change in the presence of lipid A, transitioning from a random coil to an α-helical structure. The broad-spectrum antimicrobial properties of LL-37, its presence in neutrophils, and its inducibility in keratinocytes all suggest that this peptide and its precursor (hCAP-18) may protect skin and other tissues from bacterial intrusions and LPS-induced toxicity. The potent activity of LL-37 againstP. aeruginosa, including mucoid and antibiotic-resistant strains, suggests that it or related molecules might have utility as topical bronchopulmonary microbicides in cystic fibrosis.
Pharmacokinetic Profiles of High-Dose Intravenous Ciprofloxacin in Severe Sepsis
Authors: Lipman J. , Scribante J. , Gous A. G. S. , Hon H. , Tshukutsoane S. ,   The Baragwanath Ciprofloxacin Study Group
Published: October 2018

ABSTRACT
The pharmacokinetics of 400 mg of ciprofloxacin given intravenously (i.v.) every 8 h (q8h) in severely septic adults was documented in a multidisciplinary, tertiary referral intensive care unit (ICU). Sixteen evaluable patients (three pharmacokinetic profiles) without renal dysfunction and with severe sepsis were studied. Ciprofloxacin at a dosage of 400 mg given i.v. q8h was administered over 1 h. Plasma samples for assay (high-pressure liquid chromatography) were taken at timed intervals (preinfusion, at the end of infusion, and at 1, 2, 3, 5, and 7 h postinfusion) for first-dose kinetics (day 0 [D0]), D2, and between D6 and D8. All pharmacokinetic variables were calculated by noncompartmental methods. Standard intensive care was provided. Peak ciprofloxacin concentrations were as follows: D0, 6.01 ± 1.93 mg/liter; D2, 6.68 ± 2.01 mg/liter; and D6 to D8 6.45 ± 1.54 mg/liter. Trough levels were as follows: D0, 0.6 ± 0.5 mg/liter; D2, 0.7 ± 0.4 mg/liter; and D6 to D8 0.6 ± 0.4 mg/liter. The areas under the concentration curves (8 h) were as follows: D0, 13.3 ± 3.8 mg · h/liter; D2, 16.8 ± 5.4 mg · h/liter; and D6 to D8, 15.5 ± 4.7 mg · h/liter. No drug-related serious adverse events occurred. For 17 of 18 patients enrolled in the study, the causative organisms were susceptible to ciprofloxacin. One patient developed renal failure (non-drug related) after the administration of three doses of ciprofloxacin. One patient was infected with ciprofloxacin-resistant organisms on enrollment. Nine of 16 evaluable patients had clinical cures, and 8 had bacteriological cures. One patient developed a ciprofloxacin-resistant superinfection. In two patients the clinical course was indeterminate. Two bacteriological failures occurred. We conclude that in critically ill adults ciprofloxacin at a dosage of 400 mg given i.v. q8h is safe. Its pharmacokinetic profile provides bactericidal activity against most organisms encountered in an ICU. Except for some initial accumulation on D2, no further accumulation occurred in patients without renal failure. Ciprofloxacin should be administered i.v. at a dosage of 400 mg q8h for severe sepsis.