bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequence Analysis of the
gyrA
and
parC
Homologues of a Wild-Type Strain of
Vibrio parahaemolyticus
and Its Fluoroquinolone-Resistant Mutants
Authors: Okuda Jun , Hayakawa Eriko , Nishibuchi Mitsuaki , Nishino Takeshi 
Published: October 2018

ABSTRACT

Vibrio parahaemolyticus
causes seafood-borne gastroenteritis in humans. It is particularly important in Japan, where raw seafood is frequently consumed. Fluoroquinolone is one of the current drugs of choice for treating patients infected by
V. parahaemolyticus
because resistant strains are rarely found. To study a possible fluoroquinolone resistance mechanism in this organism, nucleotide sequences that are homologous to known
gyrA
and
parC
genes have been cloned from
V. parahaemolyticus
AQ3815 and sequenced by amplification with degenerate primers of the quinolone resistance-determining region (QRDR), followed by cassette ligation-mediated PCR. Open reading frames encoding polypeptides of 878 and 761 amino acid residues were detected in the
gyrA
and
parC
homologues, respectively. The
V. parahaemolyticus
GyrA and ParC sequences were most closely related to
Erwinia carotovora
GyrA (76% identity) and
Escherichia coli
ParC (69% identity) sequences, respectively. Ciprofloxacin-resistant mutants of AQ3815 were obtained on an agar medium by multistep selection with increasing levels of the quinolone. One point mutation only in the
gyrA
QRDR was detected among mutants with low- to intermediate-level resistance, while point mutations in both the
gyrA
and
parC
QRDRs were detected only in strains with high-level resistance. These results strongly suggest that, as in other gram-negative bacteria, GyrA and ParC are the primary and secondary targets, respectively, of ciprofloxacin in
V. parahaemolyticus
.
In Vitro Development of Resistance to Five Quinolones and Amoxicillin-Clavulanate in
Streptococcus pneumoniae
Authors: Davies Todd A. , Pankuch Glenn A. , Dewasse Bonifacio E. , Jacobs Michael R. , Appelbaum Peter C. 
Published: October 2018

ABSTRACT
The ability of 50 sequential subcultures in subinhibitory concentrations of ciprofloxacin, levofloxacin, grepafloxacin, sparfloxacin, trovafloxacin, and amoxicillin-clavulanate to select for resistance was studied for six penicillin-susceptible and four penicillin-intermediate pneumococci. Subculturing in ciprofloxacin, grepafloxacin, levofloxacin, and sparfloxacin led to selection of mutants requiring increased MICs for all 10 strains, with MICs rising from (i) 0.5 to 4.0 to (ii) 4.0 to 32.0 μg/ml after 7 to 12 passages for ciprofloxacin, from (i) 0.06 to 0.25 to (ii) 0.5 to 8.0 μg/ml after 5 to 23 passages for grepafloxacin, from (i) 0.5 to 1.0 to (ii) 4.0 to 64 μg/ml after 14 to 49 passages for levofloxacin, and from (i) 0.125 to 0.25 to (ii) 1.0 to 16.0 μg/ml after 8 to 26 passages for sparfloxacin. Subculturing in trovafloxacin led to increased MICs for eight strains, with MICs rising from (i) 0.06 to 0.125 to (ii) 0.5 to 8.0 μg/ml after 6 to 28 passages. Subculturing in amoxicillin-clavulanate led to raised MICs for only one strain, with the MIC rising from 0.015 to 0.125 μg/ml after 24 passages. Double mutations in both ParC and GyrA led to high-level quinolone resistance when ParC mutations were at S79. Trovafloxacin MICs were 1 to 2 μg/ml in double mutants with ParC mutations at positions other than S79 (e.g., D83). Mutations in ParE (at D435, R447, and E474) and GyrB (at S405, D406, and D435) were found in four and six mutants, respectively. In the presence of reserpine, 29 mutants had lower ciprofloxacin MICs (2 to 16 times lower), 8 mutants had lower levofloxacin MICs (2 times), and one mutant had a lower trovafloxacin MIC (2 times), suggesting the involvement of an efflux mechanism. In contrast to the case for quinolones, subculturing in the presence of amoxicillin-clavulanate did not select for resistance to this drug.
Pharmacokinetics of Rifapentine in Subjects Seropositive for the Human Immunodeficiency Virus: a Phase I Study
Authors: Keung Anther C.-F. , Owens Robert C. , Eller Mark G. , Weir Scott J. , Nicolau David P. , Nightingale Charles H. 
Published: October 2018

ABSTRACT
Rifapentine is undergoing development for the treatment of pulmonary tuberculosis. This study was conducted to characterize the single-dose pharmacokinetics of rifapentine and its 25-desacetyl metabolite and to assess the effect of food on the rate and extent of absorption in participants infected with human immunodeficiency virus (HIV). Twelve men and four women, mean age, 38.6 ± 6.9 years, received a single 600-mg oral dose of rifapentine in an open-label, randomized two-way, complete crossover study. Each volunteer received rifapentine following a high-fat breakfast or during a fasting period. Serial blood samples were collected for 72 h and both rifapentine and its metabolite were assayed by a validated high-performance liquid chromatography method. Pharmacokinetics of rifapentine and 25-desacetylrifapentine were determined by noncompartmental methods. Mean (± the standard deviation) maximum concentrations of rifapentine in serum and areas under the curve from time zero to infinity following a high-fat breakfast were 14.09 ± 2.81 and 373.63 ± 78.19 μg/ml, respectively, and following a fasting period they were 9.42 ± 2.67 and 256.10 ± 86.39 μg · h/ml, respectively. Pharmacokinetic data from a previously published healthy volunteer study were used for comparison. Administration of rifapentine with a high-fat breakfast resulted in a 51% increase in rifapentine bioavailability, an effect also observed in healthy volunteers. Although food increased the exposure of these patients to rifapentine, the infrequent dosing schedule for the treatment of tuberculosis (e.g., once- or twice-weekly dosing) would be unlikely to lead to accumulation. Additionally, autoinduction has been previously studied and has not been demonstrated with this compound, unlike with rifabutin and rifampin. Rifapentine was well tolerated by HIV-infected study participants. The results of our study suggest that no dosage adjustments may be required for rifapentine in HIV-infected patients (Centers for Disease Control and Prevention classification A1, A2, B1, or B2) undergoing treatment for tuberculosis.
β-Lactamase Production and Antimicrobial Susceptibility of Oral Heterogeneous
Fusobacterium nucleatum
Populations in Young Children
Authors: Könönen E. , Kanervo A. , Salminen K. , Jousimies-Somer H. 
Published: October 2018

ABSTRACT

Oral
Fusobacterium nucleatum
populations from 20 young, healthy children were examined for β-lactamase production. Ten children (50%) harbored, altogether, 25 β-lactamase-positive
F. nucleatum
isolates that were identified as
F. nucleatum
subsp.
polymorphum
,
F. nucleatum
subsp.
nucleatum
, and
F. nucleatum
subsp.
vincentii
(J. L. Dzink, M. T. Sheenan, and S. S. Socransky, Int. J. Syst. Bacteriol. 40:74–78, 1990). In vitro susceptibility of these β-lactamase-producing and 26 non-β-lactamase-producing
F. nucleatum
isolates was tested with penicillin G, amoxicillin-clavulanic acid, tetracycline hydrochloride, metronidazole, trovafloxacin, and azithromycin. Except for penicillin G, the antimicrobials exhibited good activity against all
F. nucleatum
isolates.
Pharmacokinetics of a Clarithromycin Suspension Administered via Nasogastric Tube to Seriously Ill Patients
Authors: Fish Douglas N. , Abraham Edward 
Published: October 2018

ABSTRACT

The pharmacokinetics of clarithromycin and its 14-(
R
)-hydroxylated metabolite were studied on two separate occasions after nasogastric administration of 500 mg of a clarithromycin suspension to 16 seriously ill adults in an intensive care unit. The clarithromycin suspension appeared to be adequately absorbed, and the pharmacokinetics of neither clarithromycin nor 14-(
R
)-hydroxyclarithromycin differed significantly between the two dosing periods. No substantial differences in pharmacokinetics were observed compared to previously published studies of other adult populations. Minimal intrapatient variability of pharmacokinetic parameters was observed in these seriously ill patients.
Correlation between In Vitro Susceptibility Determined by E Test and Response to Therapy with Amphotericin B: Results from a Multicenter Prospective Study of Candidemia
Authors: Clancy Cornelius J. , Nguyen M. Hong 
Published: October 2018

ABSTRACT

Ninety-nine
Candida
bloodstream isolates underwent testing for susceptibility to amphotericin B by the E test, and the results were correlated with patients’ responses to amphotericin B. The MICs for isolates that were associated with therapeutic failure were significantly higher than the MICs for those associated with therapeutic success. A MIC of ≥0.38 μg/ml identified isolates likely to be associated with therapeutic failure.
Distribution and Antimicrobial Activity of Ciprofloxacin in Human Soft Tissues
Authors: Brunner Martin , Hollenstein Ursula , Delacher Simon , Jäger Dorothea , Schmid Rainer , Lackner Edith , Georgopoulos Apostoulos , Eichler Hans Georg , Müller Markus 
Published: October 2018

ABSTRACT
Interstitial ciprofloxacin concentrations in soft tissues were measured by microdialysis following intravenous administration of 200 mg to each of eight healthy volunteers. Interstitial ciprofloxacin concentrations were significantly lower than corresponding total serum drug concentrations; the interstitium-to-serum concentration ratios ranged from 0.55 to 0.73. An in vitro simulation based on interstitial pharmacokinetics showed a substantially lower antimicrobial activity than did the simulation based on serum pharmacokinetics. Thus, ciprofloxacin concentrations at the site of effect may be subinhibitory although effective concentrations are attained in serum.
Intrapulmonary Concentrations of Pyrazinamide
Authors: Conte John E. , Golden Jeffrey A. , Duncan Sheila , McKenna Elaine , Zurlinden Elisabeth 
Published: October 2018

ABSTRACTThe objective of this study was to compare the steady-state plasma and intrapulmonary concentrations of orally administered pyrazinamide in normal volunteers and subjects with AIDS. Pyrazinamide was administered at 1 g once daily for 5 days to 40 adult volunteers (10 men with AIDS, 10 normal men, 10 women with AIDS, and 10 normal women). Subjects with AIDS and with more than four stools per day were excluded. Blood was obtained prior to administration of the first dose, 2 h after the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage, which were performed 4 h after the last dose. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method. The total number of alveolar cells (AC) was counted in a hemocytometer, and differential cell counting was performed after cytocentrifugation. Pyrazinamide was measured by high-performance liquid chromatography. The presence of AIDS or gender had no significant effect on the concentrations of pyrazinamide in plasma. The concentrations of pyrazinamide in ELF and AC were lower in the subjects with AIDS than in the subjects without AIDS, but the difference was not significant. The concentrations in plasma (mean ± standard deviation) were 25.1 ± 7.6 and 21.1 ± 6.8 μg/ml at 2 and 4 h after the last dose, respectively, and were not significantly different from the concentration (17.4 ± 16.9 μg/ml) in AC. The concentration of pyrazinamide in ELF was high (431 ± 220 μg/ml) and was approximately 4 to 40 times the reported MIC for pyrazinamide-susceptible strains ofMycobacterium tuberculosis. The high concentration of pyrazinamide in ELF may contribute in part to the effectiveness of the drug in treating pulmonary tuberculosis.
ACTG 260: a Randomized, Phase I-II, Dose-Ranging Trial of the Anti-Human Immunodeficiency Virus Activity of Delavirdine Monotherapy
Authors: Para Michael F. , Meehan Patricia , Holden-Wiltse Jeanne , Fischl Margaret , Morse Gene , Shafer Robert , Demeter Lisa M. , Wood Kenneth , Nevin Tom , Virani-Ketter Nzeera , Freimuth William W. 
Published: October 2018

ABSTRACT

ACTG 260 was an open-label, four-arm trial designed to study the safety and anti-human immunodeficiency virus (anti-HIV) activity of delavirdine monotherapy at three ranges of concentrations in plasma compared to those of control therapy with zidovudine or didanosine. Delavirdine doses were adjusted weekly until subjects were within their target trough concentration range (3 to 10, 11 to 30, or 31 to 50 μM). A total of 113 subjects were analyzed. At week 2, the mean HIV type 1 (HIV-1) RNA level declines among the subjects in the three delavirdine arms were similar (0.87, 1.08, and 1.02 log
10
for the low, middle, and high target arms, respectively), but by week 8, the subjects in the pooled delavirdine arms showed only a 0.10 log
10
reduction. In the subjects in the nucleoside arm, mean HIV-1 RNA level reductions at weeks 2 and 8 were 0.67 and 0.55 log
10
, respectively. Because viral suppression by delavirdine was not maintained, the trial was stopped early. Rash, which was usually self-limited, developed in 36% of subjects who received delavirdine. Delavirdine monotherapy has potent anti-HIV activity at 2 weeks, but its activity is time limited due to the rapid emergence of drug resistance.
Activity of Gatifloxacin Compared to Those of Five Other Quinolones versus Aerobic and Anaerobic Isolates from Skin and Soft Tissue Samples of Human and Animal Bite Wound Infections
Authors: Goldstein Ellie J. C. , Citron Diane M. , Merriam C. Vreni , TyRrell Kerin , Warren Yumi 
Published: October 2018

ABSTRACT

The activity of gatifloxacin against 308 aerobes and 112 anaerobes isolated from bite wound infections was studied. Gatifloxacin was active at ≤0.016 μg/ml against all 148
Pasteurella
isolates (eight species and three subspecies) tested and all other aerobes tested, including
Actinobacillus-Haemophilus
spp.,
Eikenella corrodens
,
Neisseria weaveri
,
Weeksella zoohelcum
, staphylococci, and streptococci. Fusobacteria were sometimes resistant. Gatifloxacin MICs at which 90% of the isolates were inhibited were 0.125 μg/ml against
Bacteroides tectum
and
Prevotella
spp., 0.25 μg/ml against
Porphyromonas
spp., and 0.5 μg/ml against peptostreptococci.
Pharmacokinetics of Azithromycin Administered Alone and with Atovaquone in Human Immunodeficiency Virus-Infected Children
Authors: Ngo Leock Y. , Yogev Ram , Dankner Wayne M. , Hughes Walter T. , Burchett Sandra , Xu Jing , Sadler Brian , Unadkat Jashvant D. 
Published: October 2018

ABSTRACTTo evaluate if atovaquone (ATQ) interacts pharmacokinetically with azithromycin (AZ) in human immunodeficiency virus-infected children, 10 subjects (ages, 4 to 13 years) were randomized in a crossover study to receive AZ (5 mg/kg/day) alone (ALONE) or AZ (5 mg/kg/day) and ATQ (30 mg/kg/day) simultaneously (SIM) prior to receiving AZ and ATQ staggered by 12 h. Despite a lack of significant difference in the mean AZ pharmacokinetic parameters, the steady-state values of AZ’s area under the concentration-time curve from 0 to 24 h and maximum concentration in serum were consistently lower (n= 7 of 7) for the SIM regimen than they were for the ALONE regimen. A larger study will be required to determine if ATQ affects AZ pharmacokinetics and efficacy in a clinically significant manner.
In Vitro Activities of Pyronaridine, Alone and in Combination with Other Antimalarial Drugs, against
Plasmodium falciparum
Authors: Ringwald Pascal , Eboumbou Else Carole Moukoko , Bickii Jean , Basco Leonardo K. 
Published: October 2018

ABSTRACT
The in vitro activities of pyronaridine, alone and in combination with established antimalarial drugs, were assessed by isotopic microtest. Pyronaridine was highly active against all Cameroonian isolates. A positive correlation was observed between the response to pyronaridine and that to chloroquine. Drug combination studies showed synergy between pyronaridine and primaquine, additive effects with 4-aminoquinolines, and weak antagonism with dihydroartemisinin, antifolates, or amino alcohols.
Prospective Evaluation of the Effect of an Aminoglycoside Dosing Regimen on Rates of Observed Nephrotoxicity and Ototoxicity
Authors: Rybak Michael J. , Abate Betty J. , Kang S. Lena , Ruffing Michael J. , Lerner Stephen A. , Drusano George L. 
Published: October 2018

ABSTRACT

The nephrotoxicity and ototoxicity associated with once-daily versus twice-daily administration of aminoglycosides was assessed in patients with suspected or proven gram-negative bacterial infections in a randomized, double-blind clinical trial. Patients who received therapy for ≥72 h were evaluated for toxicity. Patients also received concomitant antibiotics as deemed necessary for treatment of their infection. Plasma aminoglycoside concentrations, prospective aminoglycoside dosage adjustment, and serial audiologic and renal status evaluations were performed. The probability of occurrence of a nephrotoxic event and its relationship to doses and daily aminoglycoside exposure served as the main outcome measurement. One hundred twenty-three patients were enrolled in the study, with 83 patients receiving therapy for at least 72 h. For 74 patients plasma aminoglycoside concentrations were available for analysis, and the patients formed the group evaluable for toxicity. The primary infectious diagnosis for the patients who were enrolled in the study were bacteremia or sepsis, respiratory infections, skin and soft tissue infections, or urosepsis or pyelonephritis. Of the 74 patients evaluable for toxicity, 39 received doses twice daily and 35 received doses once daily and a placebo 12 h later. Nephrotoxicity occurred in 6 of 39 (15.4%) patients who received aminoglycosides twice daily and 0 of 35 patients who received aminoglycosides once daily. The schedule of aminoglycoside administration, concomitant use of vancomycin, and daily area under the plasma concentration-time curve (AUC) for the aminoglycosides were found to be significant predictors of nephrotoxicity by multivariate logistic regression analysis (
P
≤ 0.001). The time to a nephrotoxic event was significantly influenced by vancomycin use and the schedule of administration, as assessed by Cox proportional hazards modeling (
P
≤ 0.002). The results of the multivariate logistic regression analysis and the Cox proportional hazards modeling demonstrate that both the probability of occurrence and the time to occurrence of aminoglycoside nephrotoxicity are influenced by the schedule on which the aminoglycoside is administered as well as by the concomitant use of vancomycin. Furthermore, this risk of occurrence is modulated by the daily AUC for aminoglycoside exposure. These data suggest that once-daily administration of aminoglycosides has a predictably lower probability of causing nephrotoxicity than twice-daily administration.
Roles of β-Lactamases and Porins in Activities of Carbapenems and Cephalosporins against
Klebsiella pneumoniae
Authors: Martínez-Martínez Luis , Pascual Alvaro , Hernández-Allés Santiago , Alvarez-Díaz Dolores , Suárez Ana Isabel , Tran John , Benedí Vicente Javier , Jacoby George A. 
Published: October 2018

ABSTRACT

Two clinical isolates of extended-spectrum β-lactamase (ESBL)-producing
Klebsiella pneumoniae
were noted to be less susceptible than expected to imipenem. Both were missing outer membrane proteins that serve as channels for antibiotic entry. The role of β-lactamase in resistance was investigated by eliminating the original ESBL and introducing plasmids encoding various ESBLs and AmpC β-lactamase types, by studying the effect of an increased inoculum, and by evaluating interactions with β-lactamase inhibitors. The contribution of porin deficiency was investigated by restoring a functional
ompK36
gene on a plasmid. Plasmids encoding AmpC-type β-lactamases provided resistance to imipenem (up to 64 μg/ml) and meropenem (up to 16 μg/ml) in strains deficient in porins. Carbapenem resistance showed little inoculum effect, was not affected by clavulanate but was blocked by BRL 42715, and was diminished if OmpK36 porin was restored. Plasmids encoding TEM- and SHV-type ESBLs conferred resistance to cefepime and cefpirome, as well as to earlier oxyimino-β-lactams. This resistance was magnified with an increased inoculum, was blocked by clavulanate, and was also lowered by OmpK36 porin restoration. In addition, SHV-2 β-lactamase had a small effect on carbapenem resistance (imipenem MIC, 4 μg/ml, increasing to 16 μg/ml with a higher inoculum) when porins were absent. In
K. pneumoniae
porin loss can thus augment resistance provided either by TEM- or SHV-type ESBLs or by plasmid-mediated AmpC enzymes to include the latest oxyimino-β-lactams and carbapenems.
Reversal of Tetracycline Resistance Mediated by Different Bacterial Tetracycline Resistance Determinants by an Inhibitor of the Tet(B) Antiport Protein
Authors: Nelson Mark L. , Levy Stuart B. 
Published: October 2018

ABSTRACT

Active efflux is a useful strategy by which bacteria evade growth inhibition by antibiotics. Certain semisynthetic tetracycline (TC) analogs, substituted at the 13th carbon at C-6 on ring C of the TC molecule, blocked TC efflux as revealed in everted membrane vesicles from class B TC-resistant (Tc
r
)
Escherichia coli
(M. L. Nelson, B. H. Park, J. S. Andrews, V. A. Georgian, R. C. Thomas, and S. B. Levy, J. Med. Chem. 36:370–377, 1993). A representative C-13-substituted analog, 13-cyclopentylthio-5-OH-TC (13-CPTC), was shown to competitively inhibit TC translocation by the Tet(B) protein, blocking the uptake of TC into vesicles and therefore the efflux of TC from whole cells. Against Tc
r
E. coli
, 13-CPTC, when used in combination with doxycycline, produced synergistic inhibition of growth. 13-CPTC was shown to increase the uptake of [
3
H]TC into the resistant cells. 13-CPTC alone was a potent growth inhibitor against TC-susceptible (Tc
s
) and Tc
r
Staphylococcus aureus
and enterococci specifying class K or class L efflux-dependent TC resistance mechanisms or, unexpectedly, the class M ribosomal protection mechanism. These findings indicate that derivatives of TC, identified by their ability to block the Tet(B) efflux protein, can restore TC activity against Tc
r
bacteria bearing either of the two known resistance mechanisms. Blocking drug efflux and increasing intracellular drug concentrations constitute an effective approach to reversing TC resistance and may be generally applicable to other antibiotics rendered ineffective by efflux proteins.