bluuebunny/crossref_metadata_2025 huggingface dataset:
Susceptibility of
Chlamydia trachomatis
to Chlorhexidine Gluconate Gel
Authors: Lampe M. F. , Ballweber L. M. , Stamm W. E.
Published: October 2018

To identify topical antimicrobial preparations which may be effective in preventing the transmission of sexually transmitted diseases, we examined the activity of chlorhexidine gluconate (CHG) against
Chlamydia trachomatis
. Chlamydial elementary bodies were incubated with dilutions of CHG gel for various times from 0 to 120 min. An aliquot of each dilution was further diluted and was inoculated onto McCoy cell monolayers in individual wells in a 96-well microtiter plate. The cultures were incubated for 48 h, and the chlamydial inclusions were stained and counted. CHG gel diluted fourfold (0.0625% CHG) killed
C. trachomatis
serovar D, and CHG gel diluted eightfold (0.0313% CHG) killed serovar F immediately upon exposure. CHG gel diluted 16-fold (0.0156% CHG) killed serovar D, and CHG gel diluted 32-fold (0.0078% CHG) killed serovar F after 120 min of exposure. Alteration of the pH over the range of from 4 to 8 did not significantly affect its activity. The addition of 10% whole human blood decreased the CHG gel activity at 0 min but had no significant effect after 120 min of exposure. We conclude that CHG gel may be effective topically against
C. trachomatis
at concentrations that can be used and under conditions that are found in the female genital tract and that further studies of its antimicrobial efficacy and toxicity in vivo are warranted.
NADPH Cytochrome P-450 Oxidoreductase and Susceptibility to Ketoconazole
Authors: Venkateswarlu K. , Kelly Diane E. , Manning Nigel J. , Kelly Steven L.
Published: October 2018

The phenotype of a strain of
Saccharomyces cerevisiae
containing a disruption of the gene encoding NADPH cytochrome P-450 oxidoreductase (
CPR
) was quantified biochemically and microbiologically, as were those of various transformants of this strain after expression of native CPR, cytochrome P-45051 (CYP51), and a fusion protein of CYP51-CPR (FUS). Only a 4-fold decrease in ergosterol biosynthesis was observed for the
cpr
strain, but ketoconazole sensitivity increased 200-fold, indicating hypersensitivity to the alternative electron donor system in
cpr
strains. Both phenotypes could be reversed in transformants expressing the CPR and FUS, indicating the availability of the CPR in FUS as well as the expressed native CPR for monoxygenase-associated reactions. The complementation of function was observed both in vitro and in vivo for the monoxygenases squalene epoxidase, CYP51, and CYP61 in the ergosterol biosynthesis pathway with which CPR is coupled. Overexpression of CYP51 and FUS produced different levels of ketoconazole resistance in wild-type cells, indicating that the availability of CPR may limit the potential of overproduction of CYP51 as a mechanism of resistance to azole antifungal agents.
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

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

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

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

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

The 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

Physiological 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

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

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

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

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

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

Human 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

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.
Treatment of Community-Acquired Acute Uncomplicated Urinary Tract Infection with Sparfloxacin versus Ofloxacin
Authors: Henry D. , Ellison W. , Sullivan J. , Mansfield D. L. , Magner D. J. , Dorr M. B. , Talbot G. H. , Group For The Sparfloxacin Multicenter Uuti Study
Published: October 2018

The efficacy and safety of a 3-day regimen of sparfloxacin were compared with those of a 3-day regimen of ofloxacin for the treatment of community-acquired acute uncomplicated urinary tract infections. Four hundred nineteen women were enrolled in a randomized, open-label, observer-blinded, multicenter study; 204 received sparfloxacin as a 400-mg loading dose on the first day and 200 mg once daily thereafter, and 215 received ofloxacin as 200 mg twice daily. A total of 383 patients met the criteria for clinical evaluability, and 174 were also bacteriologically evaluable; all treated patients were included in the safety analysis.Escherichia coli(86%) andStaphylococcus saprophyticus(4.6%) were the organisms most commonly isolated. Positive clinical responses were obtained 5 to 9 days after therapy in more than 92% of the patients in each group; sustained clinical cure rates 4 to 6 weeks after therapy were 78.3 and 76.9% in the sparfloxacin and ofloxacin groups, respectively. A positive bacteriologic response was observed in 98% of the bacteriologically evaluable patients in each treatment group at 5 to 9 days posttherapy and in 88.2 and 92.6% of the patients in the sparfloxacin and ofloxacin groups, respectively, 4 to 6 weeks after therapy. Almost 90% of all adverse events were of mild or moderate severity; the most frequent events at least possibly related to drug treatment were those common to the fluoroquinolones, namely, nausea, diarrhea, headache, insomnia, and photosensitivity. Photosensitivity was more frequent in the sparfloxacin group (6.9% versus 0.5% in the ofloxacin group); insomnia was more frequent in the ofloxacin group (3.7% versus 1.0% in the sparfloxacin group). These data suggest that a once-daily, 3-day regimen of sparfloxacin is effective and generally well tolerated in the treatment of acute uncomplicated urinary tract infections.
Identification of Elongation Factor 2 as the Essential Protein Targeted by Sordarins in
Candida albicans
Authors: Domínguez Juan Manuel , Martín J. Julio
Published: October 2018

The target for sordarins in
Candida albicans
has been elucidated. Kinetic experiments of sordarin inhibition as well as displacement experiments showed that the formation of a sordarin-target complex follows a reversible mechanism. Binding of tritiated drug to the target is enhanced in the presence of ribosomes. Isolation of the target by classical protein purification methods has allowed us to identify it as elongation factor 2. This is in agreement with the nature of sordarin derivatives as specific inhibitors of the elongation cycle within protein synthesis in yeasts.
Inhibition of Tumor Necrosis Factor Alpha Alters Resistance toMycobacterium aviumComplex Infection in Mice
Authors: Bala Shukal , Hastings Kenneth L. , Kazempour Kazem , Inglis Shelly , Dempsey Walla L.
Published: October 2018

Increased production of tumor necrosis factor alpha (TNF-α) appears to play an important role in the progression of human immunodeficiency virus disease. One treatment strategy being explored is the use of TNF-α inhibitors. TNF-α also appears to be important in conferring resistance to infections, and the inhibition of this cytokine may exacerbate the emergence of opportunistic pathogens, such asMycobacterium aviumcomplex (MAC). The present study examines the possibility that inhibition of TNF-α will increase the progression of disease in mice infected with MAC. C57BL/6 beige (bg/bg) mice have been shown to be highly susceptible to infection with MAC and are routinely used for testing of antimycobacterial drugs. However,bg/bgmice are known to exhibit impaired phagocyte and natural killer cell function. Since these cell types are important sources of TNF-α, the susceptibility of thebg/bgstrain to infection with MAC was compared with those of the heterozygous (bg/+) and wild-type (+/+) strains of C57BL/6 mice. The susceptibilities of thebg/bgandbg/+ strains of mice infected with MAC were found to be comparable. The +/+ strain was the least susceptible. Mycobacterial burden and serum TNF-α levels increased over time in all the strains of mice tested. Thebg/+ strain of C57BL/6 mice was then chosen to measure the activity of TNF-α antagonists. Treatment with dexamethasone decreased serum TNF-α levels and increased mycobacterial burden. Treatment with anti-TNF-α antibody or pentoxifylline did not significantly alter serum TNF-α levels but increased mycobacterial burden. Treatment with thalidomide neither consistently altered mycobacterial burden in the spleens or livers of infected mice nor affected serum TNF-α levels.
Absence of Effect of Rufloxacin on Theophylline Pharmacokinetics in Steady State
Authors: Kinzig-Schippers Martina , Fuhr Uwe , Cesana Marina , Müller Carola , Staib A. Horst , Rietbrock S. , Sörgel Fritz
Published: October 2018

Several quinolone antibacterial agents are known to inhibit the metabolism of theophylline, with the potential to cause adverse events due to raised theophylline concentrations during coadministration. A randomized crossover study was therefore conducted with 12 healthy male volunteers (ages, 23 to 34 years; body weight, 64 to 101 kg) to evaluate a possible interaction between rufloxacin and theophylline. Both drugs were administered at steady state. Following the administration of an oral loading dose of 400 mg on day 1, rufloxacin was given orally at 200 mg once daily on days 2 to 7 during one period only. During both periods, 146 mg of theophylline was administered orally twice daily for 3 days (which were days 4 to 6 of the rufloxacin coadministration period) and intravenously once the next morning to test for an interaction. Theophylline and rufloxacin concentrations were measured by reversed-phase high-pressure liquid chromatography, the pharmacokinetics of theophylline at steady state following administration of the last dose were calculated by compartment-model-independent methods. To compare the treatments, analysis of variance-based point estimates and 90% confidence intervals (given in parentheses) were calculated for the mean ratios of the pharmacokinetic parameters from the test (rufloxacin coadministration) over those from the reference (theophylline without rufloxacin) period. These were as follows: maximum concentration at steady state, 1.01 (0.96 to 1.07); area under the concentration-time curve from 0 to 12 h, 0.98 (0.94 to 1.02); half-life, 0.99 (0.95 to 1.03); total clearance at steady state, 1.02 (0.99 to 1.06); and volume of distribution in the elimination phase, 1.01 (0.97 to 1.05). In conclusion, rufloxacin did not affect theophylline pharmacokinetics at steady state. Therefore, therapeutic coadministration of rufloxacin and theophylline is not expected to cause an increased incidence of theophylline-related adverse events.
In Vitro Pharmacodynamic Studies of L-749,345 in Comparison with Imipenem and Ceftriaxone against Gram-Positive and Gram-Negative Bacteria
Authors: Odenholt Inga , Löwdin Elisabeth , Cars Otto
Published: October 2018

L-749,345 is a new parenteral carbapenem with a very long half-life similar to that of ceftriaxone. The aim of the present study was to investigate different pharmacodynamic parameters of L-749,345 in comparison with those of ceftriaxone and imipenem. The following studies were performed: (i) comparative studies of the MICs of L-749,345, imipenem, and ceftriaxone for 70 strains of gram-positive and gram-negative bacteria; (ii) comparative studies of the rate of killing of gram-positive and gram-negative bacteria by L-749,345, imipenem, and ceftriaxone; (iii) studies of the postantibiotic effects of L-749,345, imipenem, and ceftriaxone; and (iv) studies of the postantibiotic sub-MIC effects of L-749,345, imipenem, and ceftriaxone. Significantly lower MICs of L-749,345 compared with those of ceftriaxone were found for all gram-negative organisms except
Haemophilus influenzae
. The MICs of L-749,345 were similar to those of imipenem for all organisms except
Pseudomonas aeruginosa
and methicillin-resistant
Staphylococcus aureus
, for which the MICs of L-749,345 were higher. A concentration-dependent killing of methicillin-resistant
S. aureus
but not methicillin-susceptible strains was noted for both L-749,345 and imipenem. All three of the investigated drugs exhibited a postantibiotic effect against the gram-positive strains but exhibited no postantibiotic effect against the gram-negative strains.
Efficacy of Nikkomycin Z in the Treatment of Murine Histoplasmosis
Authors: Graybill John R. , Najvar Laura K. , Bocanegra Rosie , Hector Richard F. , Luther Michael F.
Published: October 2018

Immune-competent ICR and BALB/c athymic (nude) mice were infected intravenously with
Histoplasma capsulatum
and treated with either fluconazole or nikkomycin Z or 5% dextrose (controls). In immune-competent ICR mice, fluconazole and nikkomycin Z both prolonged survival when given at 5 mg/kg of body weight twice daily. When administered in doses as low as 2.5 mg/kg twice daily, nikkomycin Z reduced fungal counts in both the spleen and liver. When both drugs were combined, there was no antagonism, and in combined therapy spleen and liver counts were reduced more than for either drug alone. However, nikkomycin Z had no effect on brain fungal burden. In nude mice fluconazole and nikkomycin Z had an additive effect in prolongation of survival and reduction of liver and spleen burden. Nikkomycin Z is well tolerated, is at least as effective as fluconazole, and may interact beneficially with fluconazole for treatment of murine histoplasmosis.
Superior Efficacy of Liposomal Amphotericin B with Prolonged Circulation in Blood in the Treatment of Severe Candidiasis in Leukopenic Mice
Authors: van Etten Els W. M. , Snijders Susan V. , van Vianen Wim , Bakker-Woudenberg Irma A. J. M.
Published: October 2018

In leukopenic mice with severe systemic candidiasis, single-dose treatment (5 mg of amphotericin B [AMB]/kg of body weight) with long-circulating polyethylene glycol-coated AMB liposomes (PEG-AMB-LIP) resulted in zero mortality and a significant reduction in the number of viable
Candida albicans
in the kidney, whereas 70% mortality was seen in mice treated with five daily doses of AmBisome (5 mg of AMB/kg · day). When the first of five daily doses of AmBisome was combined with a single low dose of Fungizone (0.1 mg of AMB/kg), the efficacy was equal to that of PEG-AMB-LIP.
Microbicidal Activity of a New Silver-Containing Polymer, SPI-ARGENT II
Authors: Kampf Günter , Dietze Beate , Große-Siestrup Christian , Wendt Constanze , Martiny Heike
Published: October 2018

The survival of three bacterial species and
Candida albicans
was studied on SPI-ARGENT II. The immediate recovery from silver-impregnated polymer and control polymer (1 cm
2
) was ∼10
6
to 10
7
microorganisms. After incubation (37°C) and neutralization of silver with horse serum (5%), surviving organisms were recovered. The survival of the microorganisms on the polymer was not found to be influenced by the silver implantation.
A Ser315Thr Substitution in KatG Is Predominant in Genetically Heterogeneous Multidrug-Resistant
Mycobacterium tuberculosis
Isolates Originating from the St. Petersburg Area in Russia
Authors: Marttila Harri J. , Soini Hanna , Eerola Erkki , Vyshnevskaya Elena , Vyshnevskiy Boris I. , Otten Tatjana F. , Vasilyef Alexandr V. , Viljanen Matti K.
Published: October 2018

Parts of
katG
and
rpoB
from 27 Russian
Mycobacterium tuberculosis
isolates were sequenced to detect mutations causing resistance to isoniazid (INH) and rifampin (RMP), respectively. All 24 INH-resistant isolates had a mutated
katG
, and 22 of them (91.7%) carried a mutation coding for a Ser315Thr shift. An
rpoB
mutation was noted for each of the 21 RMP-resistant isolates, with Ser531Leu being the most prevalent change encoded. Only two isolates had identical IS
6110
fingerprints.
Activity and Diffusion of LY333328 in Experimental Endocarditis Due to Vancomycin-Resistant
Enterococcus faecalis
Authors: Saleh-Mghir Azzam , Lefort Agnès , Petegnief Yolande , Dautrey Sophie , Vallois Jean-Marie , Le Guludec Dominique , Carbon Claude , Fantin Bruno
Published: October 2018

The activity of LY333328 against
Enterococcus faecalis
JH2-2, which is susceptible to glycopeptides, and against its transconjugants
E. faecalis
BM4281 and BM4316, with VanB and VanA phenotypes, respectively, was investigated. LY333328 was active in vitro against the three strains, for which MICs were 2 μg/ml on agar and 0.25 μg/ml in broth. LY333328 was bactericidal in broth against
E. faecalis
JH2-2 and BM4281 at a concentration of 8 μg/ml and against BM4316 at a concentration of 30 μg/ml. The protein binding of LY333328 to rabbit serum was >99%, and the bactericidal activity of LY333328 in broth was reduced when it was tested in the presence of 90% rabbit serum. Autoradiographic studies performed in rabbits with enterococcal endocarditis showed that
14
[C]LY333328 was distributed heterogeneously throughout cardiac vegetations. In rabbits with aortic endocarditis, a regimen of 20 mg of LY333328 per kg of body weight administered intramuscularly twice a day for 5 days after a loading dose of 40 mg/kg was active against the three strains in vivo (
P
< 0.01), whereas vancomycin was not active against the VanB-type strain and teicoplanin was not active against the VanA-type strain. We conclude that the activity of LY333328 is not significantly modified by acquired resistance to glycopeptides in
E. faecalis
either in vitro or in experimental endocarditis.
Eradication by Ceftriaxone of
Streptococcus pneumoniae
Isolates with Increased Resistance to Penicillin in Cases of Acute Otitis Media
Authors: Gehanno P. , Nguyen L. , Barry B. , Derriennic M. , Pichon F. , Goehrs J. M. , Berche P.
Published: October 2018

This multicenter, noncomparative, nonrandomized study evaluated the clinical efficacy and safety of ceftriaxone for treating acute otitis media in children following clinical failure of oral antibiotic therapy. Middle-ear fluid samples were collected on day 0 and on day 3, 4, or 5 (day 3 to 5) and were used to test whether ceftriaxone therapy can eradicate
Streptococcus pneumoniae
isolates with increased resistance to penicillin (MIC ≥ 1 mg/liter). At the first visit, on day 0, middle-ear fluid was sampled for bacteriological testing by tympanocentesis or otorrhea pus suction. Patients were administered 50 mg of ceftriaxone/kg of body weight/day, injected intramuscularly once daily, for 3 days. A second sample was collected by tympanocentesis if a pneumococcus isolate for which the MIC of penicillin was ≥1 mg/liter was detected in the day-0 sample and if the middle-ear effusion persisted on day 3 to 5. This second sample was tested for bacterial eradication. One hundred eighty-six children aged 5 months to 5 years, 10 months, with acute otitis media clinical failure were enrolled and treated in this trial. On day 10 to 12, 145 (83.8%) of the 173 patients evaluable for clinical efficacy were clinically cured. Of the 59 patients infected by pneumococci, 36 had isolates for which the MICs of penicillin were ≥1 mg/liter. Of those patients, on day 10 to 12, 32 (88.9%) were clinically cured. Middle-ear fluid samples collected by day 3 to 5 following the onset of treatment with ceftriaxone were sterile for 24 of the 27 (88.9%) patients who were infected as of day 0 by pneumococci for which the MICs of penicillin were ≥1 mg/liter and who were evaluable for bacteriological eradication. On day 10 to 12, 81.4% of
S. pneumoniae
-infected children and 87.5% of
Haemophilus influenzae
-infected children were clinically cured. No discontinuation of treatment due to adverse events, particularly due to local reactions at the injection site, were reported. Only 11 adverse events which had doubtful, probable, or possible links with the study treatment were recorded. Both the bacteriologically assessed eradication of pneumococci for which the MICs of penicillin were ≥1 mg/liter and the clinical cure rates demonstrate that ceftriaxone is of value in the management of acute otitis media unresponsive to previous oral antibiotic therapy.
Pharmacokinetics in Serum and Leukocyte Exposures of Oral Azithromycin, 1,500 Milligrams, Given over a 3- or 5-Day Period in Healthy Subjects
Authors: Amsden Guy W. , Nafziger Anne N. , Foulds George
Published: October 2018

The pharmacokinetics in serum and leukocyte (WBC) exposures of 1,500 mg of oral azithromycin administered as 3-day (500 mg/day, days 1 to 3) and 5-day (500 mg on day 1 and 250 mg/day on days 2 to 5) regimens were compared in 12 healthy volunteers. Serum, polymorphonuclear leukocytes, and mononuclear leukocytes were collected over a 12-day period from the start of each regimen. Results of the study indicate that the exposures of serum and both types of WBCs were similar with both regimens. Drug concentrations in day 12 WBCs were well above the MICs for all relevant community-acquired respiratory tract pathogens. Terminal half-lives in serum obtained by both regimens were essentially equal at 66 h and consistent with past reports. These results indicate that the standard 1,500-mg dose of oral azithromycin can be administered over either 5 or 3 days.
Identification of an Efflux Pump Gene,
pmrA
, Associated with Fluoroquinolone Resistance in
Streptococcus pneumoniae
Authors: Gill Martin J. , Brenwald Nigel P. , Wise Richard
Published: October 2018

An open reading frame (ORF) homologous to
norA
was insertionally inactivated with
cat
in a fluoroquinolone-resistant pneumococcus with an efflux phenotype; this inactivation caused reversion to drug sensitivity. The ORF product has 24% amino acid sequence identity each to NorA and Bmr, which suggests that it is a major facilitator system pump of the 12-transmembrane-segment class.
Metabolic Studies on BMS-200475, a New Antiviral Compound Active against Hepatitis B Virus
Authors: Yamanaka Gregory , Wilson Todd , Innaimo Steven , Bisacchi Gregory S. , Egli Peter , Rinehart J. Kent , Zahler Robert , Colonno Richard J.
Published: October 2018

BMS-200475 was recently shown to have potent antiviral activity against hepatitis B virus (50% effective concentration = 3.7 nM; 50% cytotoxic concentration = 30 μM). In metabolic studies in both HepG2 and hepatitis B virus-transfected 2.2.15 human hepatoma cell lines, the metabolism was similar, the primary products being the di- and triphosphates. The accumulation of triphosphate was rapid and detectable down to a 5 nM concentration of added drug. When cells were labeled at 25 μM, the intracellular triphosphate concentration attained 30 pmol/10
6
cells (∼30 μM). The intracellular half-life of the triphosphate was about 15 h. Compared with five other nucleoside analogs of medical interest (lamivudine, penciclovir, ganciclovir, acyclovir, and lobucavir), BMS-200475 was most efficiently phosphorylated to the triphosphate in HepG2 cells.
Close Association between Clearance of Recombinant Human Granulocyte Colony-Stimulating Factor (G-CSF) and G-CSF Receptor on Neutrophils in Cancer Patients
Authors: Terashi Kenji , Oka Mikio , Ohdo Shigehiro , Furukubo Taku , Ikeda Chizuko , Fukuda Minoru , Soda Hiroshi , Higuchi Shun , Kohno Shigeru
Published: October 2018

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is used to counter chemotherapy-induced neutropenia. Our previous study showed an inverse correlation between serum rhG-CSF levels and the number of circulating neutrophils in cancer patients (H. Takatani, H. Soda, M. Fukuda, M. Watanabe, A. Kinoshita, T. Nakamura, and M. Oka, Antimicrob. Agents Chemother. 40:988–991, 1996). The aim of this study was to clarify the relationship between rhG-CSF clearance and G-CSF receptors on circulating neutrophils. In five cancer patients receiving chemotherapy, a bolus dose of rhG-CSF (5 μg/kg) was injected intravenously during defined phases of posttreatment neutropenia and neutrophilia. Serum rhG-CSF levels were measured by a chemiluminescence enzyme immunoassay and analyzed by moment analysis. G-CSF receptors on neutrophils were detected by flow cytometry with biotinylated rhG-CSF. rhG-CSF clearance was significantly higher at neutrophilia than at neutropenia (1,497 ± 132 versus 995 ± 266 ml/h;
P
< 0.01). The percentage of G-CSF receptor-positive neutrophils, reflecting the number of G-CSF receptors per cell, was low at neutropenia without rhG-CSF therapy (44.5% ± 22.1%) and high at neutrophilia with rhG-CSF therapy (73.0% ± 11.4%;
P
< 0.01). rhG-CSF clearance closely correlated with the percentage of G-CSF receptor-positive neutrophils (
r
2
= 0.91;
P
< 0.0001) and neutrophil count (
r
2
= 0.72;
P
< 0.005). Our results indicate that, in cancer patients receiving chemotherapy, rhG-CSF increases the number of G-CSF receptors per cell as well as circulating neutrophil counts, resulting in modulation of its own clearance.
Evaluation of a Novel, Anti-Herpes Simplex Virus Compound, Acyclovir Elaidate (P-4010), in the Female Guinea Pig Model of Genital Herpes
Authors: Jennings R. , Smith T. L. , Myhren F. , Phillips J. , Sandvold M. L.
Published: October 2018

The antiviral effect of acyclovir elaidate in the female guinea pig model of genital herpes was investigated in a series of experiments. The antiherpesvirus effects of this novel compound, 9-(2′-[trans-9"-octadecenoyloxyl]ethoxymethyl)guanine (code no. P-4010), were studied in both primary and recurrent genital herpes in the female guinea pig, following oral gavage or intraperitoneal injection, with different formulations of the compound, and in comparison with acyclovir (ACV) or penciclovir (PCV). The results indicate that compound P-4010 has a greater capability than either ACV or PCV in reducing the clinical symptoms of primary genital herpes induced following the inoculation of herpes simplex virus type 2 (HSV-2) intravaginally into guinea pigs. In addition, the administration of P-4010 twice daily over a 10-day period by the intraperitoneal route (15 to 40 mg/kg of body weight/day) or by oral gavage (50 to 200 mg/kg/day), commencing 4 h subsequent to intravaginal HSV-2 infection, resulted in a degree of reduction in the incidence and severity of spontaneous, recurrent genital herpes in these animals. The findings are discussed in the light of the value and relevance of the female guinea pig model of genital herpes for the assessment of anti-herpes simplex virus compounds.
Low Plasma Cefepime Levels in Critically Ill Septic Patients: Pharmacokinetic Modeling Indicates Improved Troughs with Revised Dosing
Authors: Lipman J. , Wallis S. C. , Rickard C.
Published: October 2018

The pharmacokinetics of a 2-g bolus of cefepime were measured in critically ill patients with normal renal function. Variable and low trough plasma drug concentrations were found, and 8 of 10 patients had levels below the MIC at which 50% of the isolates are inhibited for
Pseudomonas aeruginosa
. Computer simulations predicted that continuous infusion and shorter dosing intervals would increase trough levels.