bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of NorA Inhibitors on In Vitro Antibacterial Activities and Postantibiotic Effects of Levofloxacin, Ciprofloxacin, and Norfloxacin in Genetically Related Strains of
Staphylococcus aureus
Authors: Aeschlimann Jeffrey R. , Dresser Linda D. , Kaatz Glenn W. , Rybak Michael J. 
Published: October 2018

ABSTRACT

NorA is a membrane-associated multidrug efflux protein that can decrease susceptibility to fluoroquinolones in
Staphylococcus aureus
. To determine the effect of NorA inhibition on the pharmacodynamics of fluoroquinolones, we evaluated the activities of levofloxacin, ciprofloxacin, and norfloxacin with and without various NorA inhibitors against three genetically related strains of
S. aureus
(SA 1199, the wild-type; SA 1199B, a NorA hyperproducer with a
grlA
mutation; and SA 1199-3, a strain that inducibly hyperproduces NorA) using susceptibility testing, time-kill curves, and postantibiotic effect (PAE) methods. Levofloxacin had the most potent activity against all three strains and was minimally affected by addition of NorA inhibitors. In contrast, reserpine, omeprazole, and lansoprazole produced 4-fold decreases in ciprofloxacin and norfloxacin MICs and MBCs for SA 1199 and 4- to 16-fold decreases for both SA 1199B and SA 1199-3. In time-kill experiments reserpine, omeprazole, or lansoprazole increased levofloxacin activity against SA 1199-3 alone by 2 log
10
CFU/ml and increased norfloxacin and ciprofloxacin activities against all three strains by 0.5 to 4 log
10
CFU/ml. Reserpine and omeprazole increased norfloxacin PAEs on SA 1199, SA 1199B, and SA 1199-3 from 0.9, 0.6, and 0.2 h to 2.5 to 4.5, 1.1 to 1.3, and 0.4 to 1.1 h, respectively; similar effects were observed with ciprofloxacin. Reserpine and omeprazole increased the levofloxacin PAE only on SA 1199B (from 1.6 to 5.0 and 3.1 h, respectively). In conclusion, the NorA inhibitors dramatically improved the activities of the more hydrophilic fluoroquinolones (norfloxacin and ciprofloxacin). These compounds may restore the activities of these fluoroquinolones against resistant strains of
S. aureus
or may potentially enhance their activities against sensitive strains.
Antimicrobial Resistance of 1,113
Streptococcus pneumoniae
Isolates from Patients with Respiratory Tract Infections in Spain: Results of a 1-Year (1996–1997) Multicenter Surveillance Study
Authors: Baquero Fernando , García-Rodríguez José Angel , García de Lomas Juan , Aguilar Lorenzo ,   The Spanish Surveillance Group for Respiratory Pathogens
Published: October 2018

ABSTRACT

A nationwide susceptibility surveillance of 1,113
Streptococcus pneumoniae
isolates was carried out and found the following percentages of resistance: cefuroxime, 46%; penicillin, 37%; macrolides, 33%; aminopenicillins, 24%; cefotaxime, 13%; and ceftriaxone, 8%. A significant
(P
< 0.05) seasonality pattern for β-lactam antibiotics was observed. Resistance to macrolides was higher
(P
< 0.05) in middle-ear samples. Higher percentages of resistance to cefuroxime and macrolides were observed among penicillin-intermediate and -resistant strains, whereas high frequencies of resistance to aminopenicillins and expanded-spectrum cephalosporins were observed only among penicillin-resistant strains.
In Vitro Activities of Benflumetol against 158 Senegalese Isolates of
Plasmodium falciparum
in Comparison with Those of Standard Antimalarial Drugs
Authors: Pradines Bruno , Tall Adama , Fusai Thierry , Spiegel Andre , Hienne Remi , Rogier Christophe , Trape Jean Francois , Le Bras Jacques , Parzy Daniel 
Published: October 2018

ABSTRACT

The 50% inhibitory concentration (IC
50
s) of benflumetol (range, 12.5 to 240 nM; mean, 55.1 nM) for 158 Senegalese isolates were evaluated. Ten isolates (6%) showed decreased susceptibility to benflumetol. Benflumetol was slightly more potent against chloroquine-resistant isolates (
P
< 0.025). No correlation or weak correlations in the responses to benflumetol and pyrimethamine, chloroquine, amodiaquine, artemether, quinine, and pyronaridine were observed, and these correlations are insufficient to suggest cross-resistance. Benflumetol may be an important alternative drug for the treatment of chloroquine-resistant malaria.
In Vivo Activities of Peptidic Prodrugs of Novel Aminomethyl Tetrahydrofuranyl-1β-Methylcarbapenems
Authors: Weiss William J. , Mikels Susan M. , Petersen Peter J. , Jacobus Nilda V. , Bitha Panayota , Lin Yang-I. , Testa Raymond T. 
Published: October 2018

ABSTRACTA series of novel aminomethyl tetrahydrofuranyl (THF)-1β-methylcarbapenems which have excellent broad-spectrum antibacterial activities exhibit modest efficacies against acute lethal infections (3.8 mg/kg of body weight againstEscherichia coliand 0.9 mg/kg againstStaphylococcus aureus) in mice when they are administered orally. In an effort to improve the efficacies of orally administered drugs through enhanced absorption by making use of a peptide-mediated transport system, several different amino acids were added at the aminomethyl THF side chains of the carbapenem molecules. The resulting peptidic prodrugs withl-amino acids demonstrated improved efficacy after oral administration, while thedforms were less active than the parent molecules. After oral administration increased (3 to 10 times) efficacy was exhibited with the alanine-, valine-, isoleucine-, and phenylalanine-substituted prodrugs against acute lethal infections in mice. Median effective doses (ED50s) of <1 mg/kg against infections caused byS. aureus,E. coli,Enterobacter cloacae, or penicillin-susceptibleStreptococcus pneumoniaewere obtained after the administration of single oral doses. Several of the peptidic prodrugs were efficacious againstMorganella morganii,Serratia marcescens, penicillin-resistantS. pneumoniae, extended-spectrum β-lactamase-producingKlebsiella pneumoniae, andE. coliinfections, with ED50s of 1 to 14 mg/kg by oral administration compared with ED50s of 14 to >32 mg/kg for the parent molecules. In general, the parent molecules demonstrated greater efficacy than the prodrugs against these same infections when the drugs were administered by the subcutaneous route. The parent molecule was detectable in the sera of mice after oral administration of the peptidic prodrugs.
In Vitro and In Vivo Activities of NS-718, a New Lipid Nanosphere Incorporating Amphotericin B, against
Aspergillus fumigatus
Authors: Otsubo Takakazu , Maesaki Shigefumi , Hossain Mohammad Ashraf , Yamamoto Yoshihiro , Tomono Kazunori , Tashiro Takayoshi , Seki Junzo , Tomii Yoshifumi , Sonoke Satoru , Kohno Shigeru 
Published: October 2018

ABSTRACT

We evaluated the in vitro and in vivo potencies of a new lipid nanosphere that incorporates amphotericin B (AmB), NS-718, against
Aspergillus fumigatus
. The in vitro activity of NS-718 (the MIC at which 90% of strains are inhibited [MIC
90
], 0.25 μg/ml) against 18 isolates of
A. fumigatus
was similar to that of deoxycholate AmB (D-AmB; Fungizone; MIC
90
, 0.25 μg/ml), but NS-718 was more potent than liposomal AmB (L-AmB; AmBisome; MIC
90
, 1.0 μg/ml). The in vivo efficacy of NS-718 in a rat model of invasive pulmonary aspergillosis was compared with those of D-AmB and L-AmB. A low dose (1 mg/kg of body weight) of L-AmB was ineffective (survival rate, 0%), although equivalent doses of D-AmB and NS-718 were more effective (survival rate, 17%). However, a higher dose of NS-718 (3 mg/kg) was more effective (survival rate, 100%) than equivalent doses of D-AmB and L-AmB (survival rate, 0%). To explain these differences, pharmacokinetic studies showed higher concentrations of AmB in the plasma of rats treated with NS-718 than in the plasma of those treated with D-AmB. Our results suggest that NS-718, a new preparation of AmB, is a promising antifungal agent with activity against pulmonary aspergillosis.
Two-Step Acquisition of Resistance to the Teicoplanin-Gentamicin Combination by VanB-Type
Enterococcus faecalis
In Vitro and in Experimental Endocarditis
Authors: Lefort Agnès , Baptista Marina , Fantin Bruno , Depardieu Florence , Arthur Michel , Carbon Claude , Courvalin Patrice 
Published: October 2018

ABSTRACT

The activity of vancomycin and teicoplanin combined with gentamicin was investigated in vitro against strains of
Enterococcus faecalis
resistant to vancomycin and susceptible to teicoplanin (VanB type) and against mutants that had acquired resistance to teicoplanin by three different mechanisms. In vitro, gentamicin selected mutants with two- to sixfold increases in the level of resistance to this antibiotic at frequencies of 10
−6
to 10
−7
. Teicoplanin selected teicoplanin-resistant mutants at similar frequencies. Both mutations were required to abolish the activity of the gentamicin-teicoplanin combination. As expected, simultaneous acquisition of the two types of mutations was not observed. In therapy with gentamicin or teicoplanin alone, each selected mutants in three of seven rabbits with aortic endocarditis due to VanB-type
E. faecalis
BM4275. The vancomycin-gentamicin combination selected mutants that were resistant to gentamicin and to the combination. In contrast, the teicoplanin-gentamicin regimen prevented the emergence of mutants resistant to one or both components of the combination. These results suggest that two mutations are also required to suppress the in vivo activity of the teicoplanin-gentamicin combination.
Effect of Fasting on Temporal Variation in the Nephrotoxicity of Amphotericin B in Rats
Authors: LeBrun Michel , Grenier Louis , Bergeron Michel G. , Thibault Louise , Labrecque Gaston , Beauchamp Denis 
Published: October 2018

ABSTRACT

Evidence for temporal variation in the nephrotoxicity of amphotericin B was recently reported in experimental animals. The role of food in these variations was determined by studying the effect of a short fasting period on the temporal variation in the renal toxicity of amphotericin B. Twenty-eight normally fed and 28 fasted female Sprague-Dawley rats were used. Food was available ad libitum to the fed rats, while the fasted animals were fasted 12 h before and 24 h after amphotericin B injection to minimize stress for the animals. Water was available ad libitum to both groups of rats, which were maintained on a 14-h light, 10-h dark regimen (light on at 0600 h). Renal toxicity was determined by comparing the levels of excretion of renal enzyme and the serum creatinine and blood urea nitrogen (BUN) levels at the time of the maximal (0700 h) or the minimal (1900 h) nephrotoxicity after the intraperitoneal administration of a single dose of dextrose (5%; control group) or amphotericin B (50 mg/kg of body weight; treated group) to the rats. The nephrotoxicities obtained after amphotericin B administration at both times of day were compared to the nephrotoxicities observed for time-matched controls. In fed animals, the 24-h urinary excretion of
N
-acetyl-β-
d
-glucosaminidase and β-galactosidase was significantly higher when amphotericin B was injected at 0700 and 1900 h. The excretion of these two enzymes was reduced significantly (
P
< 0.05) in fasting rats, and this effect was larger at 0700 h (
P
< 0.05) than at 1900 h. The serum creatinine level was also significantly higher (
P
< 0.05) in fed animals treated at 0700 h than in fed animals treated at 1900 h. Fasting reduced significantly (
P
< 0.05) the increase in the serum creatinine level, and this effect was larger in the animals treated at 0700 h. Similar data were obtained for BUN levels. Amphotericin B accumulation was significantly higher (
P
< 0.05) in the renal cortexes of fed rats than in those of fasted animals, but there was no difference according to the time of injection. These results demonstrated that fasting reduces the nephrotoxicity of amphotericin B and that food availability is of crucial importance in the temporal variation in the renal toxicity of amphotericin B in rats.
Cloning, Expression, and Enzymatic Characterization of
Pseudomonas aeruginosa
Topoisomerase IV
Authors: Akasaka Takaaki , Onodera Yoshikuni , Tanaka Mayumi , Sato Kenichi 
Published: October 2018

ABSTRACT

The topoisomerase IV subunit A gene,
parC
homolog, has been cloned and sequenced from
Pseudomonas aeruginosa
PAO1, with cDNA encoding the N-terminal region of
Escherichia coli parC
used as a probe. The homolog and its upstream gene were presumed to be
parC
and
parE
through sequence homology with the
parC
and
parE
genes of other organisms. The deduced amino acid sequence of ParC and ParE showed 33 and 32% identity with that of the
P. aeruginosa
DNA gyrase subunits, GyrA and GyrB, respectively, and 69 and 75% identity with that of
E. coli
ParC and ParE, respectively. The putative ParC and ParE proteins were overexpressed and separately purified by use of a fusion system with a maltose-binding protein, and their enzymatic properties were examined. The reconstituted enzyme had ATP-dependent decatenation activity, which is the main catalytic activity of bacterial topoisomerase IV, and relaxing activities but had no supercoiling activity. So, the cloned genes were identified as
P. aeruginosa
topoisomerase IV genes. The inhibitory effects of quinolones on the activities of topoisomerase IV and DNA gyrase were compared. The 50% inhibitory concentrations of quinolones for the decatenation activity of topoisomerase IV were from five to eight times higher than those for the supercoiling activities of
P. aeruginosa
DNA gyrase. These results confirmed that topoisomerase IV is less sensitive to fluoroquinolones than is DNA gyrase and may be a secondary target of new quinolones in wild-type
P. aeruginosa
.
Synergy of an Investigational Glycopeptide, LY333328, with Once-Daily Gentamicin against Vancomycin-Resistant
Enterococcus faecium
in a Multiple-Dose, In Vitro Pharmacodynamic Model
Authors: Zelenitsky S. A. , Booker B. , Laing N. , Karlowsky J. A. , Hoban D. J. , Zhanel G. G. 
Published: October 2018

ABSTRACT

The pharmacodynamics of an investigational glycopeptide, LY333328 (LY), alone and in combination with gentamicin, against one vancomycin-susceptible and two vancomycin-resistant
Enterococcus faecium
strains were studied with a multiple-dose, in vitro pharmacodynamic model (PDM). Dose-range data for the PDM studies were obtained from static time-kill curve studies. In PDM experiments conducted over 48 h, peak LY concentrations of 0.1× and 1× the MIC every 24 h and peak gentamicin concentrations of 18 μg/ml every 24 h (Gq24h) and 6 μg/ml every 8 h (Gq8h) were studied alone and in the four possible LY-gentamicin combinations. Compared to either antibiotic alone, LY-gentamicin combination regimens produced significantly higher apparent killing rates (KRs) calculated during the initial 2 h postdosing. The mean KRs for LY or gentamicin alone versus those for the LY-gentamicin combination regimens were 0.35 ± 0.55 log
10
CFU/ml/h (95% confidence interval [CI
95%
], 0 to 0.70) and 1.46 ± 0.71 log
10
CFU/ml/h (CI
95%
, 1.01 to 1.91), respectively (
P <
0.0001). Bacterial killing at 48 h (BK
48
), which was calculated by subtracting the bacterial counts at 48 h from the initial inoculum, with a negative value indicating net growth, was also significantly greater. The mean BK
48
s were −0.69 ± 0.44 log
10
CFU/ml (CI
95%
, −0.41 to −0.97) and 3.72 ± 2.28 log
10
CFU/ml (CI
95%
, 2.28 to 5.17) for LY or gentamicin alone versus LY-gentamicin combination regimens, respectively (
P
< 0.0001). None of the 12 regimens with LY or gentamicin alone but 75% (9 of 12) of the LY-gentamicin combination regimens were bactericidal. Eighty-three percent (10 of 12) of the LY-gentamicin combination regimens also demonstrated synergy. No significant differences between the pharmacodynamics of LY-gentamicin combination regimens containing Gq24h versus those containing Gq8h were detected.
Safety and Pharmacokinetics of Abacavir (1592U89) following Oral Administration of Escalating Single Doses in Human Immunodeficiency Virus Type 1-Infected Adults
Authors: Kumar Princy N. , Sweet Donna E. , McDowell James A. , Symonds William , Lou Yu , Hetherington Seth , LaFon Stephen 
Published: October 2018

ABSTRACT

Abacavir (1592U89) is a nucleoside analog reverse transcriptase inhibitor that has been demonstrated to have selective activity against human immunodeficiency virus (HIV) in vitro and favorable safety profiles in mice and monkeys. A phase I study was conducted to evaluate the safety and pharmacokinetics of abacavir following oral administration of single escalating doses (100, 300, 600, 900, and 1,200 mg) to HIV-infected adults. In this double-blind, placebo-controlled study, subjects with baseline CD4
+
cell counts ranging from <50 to 713 cells per mm
3
(median, 315 cells per mm
3
) were randomly assigned to receive abacavir (
n
= 12) or placebo (
n
= 6). The bioavailability of the caplet formulation relative to that of the oral solution was also assessed with the 300-mg dose. Abacavir was well tolerated by all subjects; mild to moderate asthenia, abdominal pain, headache, diarrhea, and dyspepsia were the most frequently reported adverse events, and these were not dose related. No significant clinical or laboratory abnormalities were observed throughout the study. All doses resulted in mean abacavir concentrations in plasma that exceeded the mean 50% inhibitory concentration (IC
50
) for clinical HIV isolates in vitro (0.07 μg/ml) for almost 3 h. Abacavir was rapidly absorbed following oral administration, with the time to the peak concentration in plasma occurring at 1.0 to 1.7 h postdosing. Mean maximum concentrations in plasma (
C
max
) and the area under the plasma concentration-time curve from time zero to infinity (AUC
0–∞
) increased slightly more than proportionally from 100 to 600 mg (from 0.6 to 4.7 μg/ml for
C
max
; from 1.0 to 15.7 μg · h/ml for AUC
0–∞
) but increased proportionally from 600 to 1,200 mg (from 4.7 to 9.6 μg/ml for
C
max
; from 15.7 to 32.8 μg · h/ml for AUC
0–∞
). The elimination of abacavir from plasma was rapid, with an apparent elimination half-life of 0.9 to 1.7 h. Abacavir was well absorbed, with a relative bioavailability of the caplet formulation of 96% versus that of an oral solution (drug substance in water). In conclusion, this study showed that abacavir is safe and is well tolerated by HIV-infected subjects and demonstrated predictable pharmacokinetic characteristics when it was administered as single oral doses ranging from 100 to 1,200 mg.
Use of an Isogenic
Escherichia coli
Panel To Design Tests for Discrimination of β-Lactamase Functional Groups of
Enterobacteriaceae
Authors: Ehrhardt Anton F. , Sanders Christine C. , Moland Ellen S. 
Published: October 2018

ABSTRACT

A study was designed to determine if an isogenic panel of
Escherichia coli
strains containing many different β-lactamases could be used for the preliminary screening of a large number of β-lactam agents to identify which might be most useful in the development of a definitive test for specific β-lactamases found among the members of family
Enterobacteriaceae
. The susceptibilities of 46 strains, comprising the isogenic panel, to expanded-spectrum cephalosporins, cephamycins, and aztreonam were determined in the presence and absence of β-lactamase inhibitors in broth microdilution tests. The results indicated that strains producing extended-spectrum β-lactamases (ESBLs) could be distinguished from strains producing other Bush-Jacoby-Medeiros functional group 2 or group 1 β-lactamases. For strains producing group 1 β-lactamases, cefpodoxime and ceftazidime MICs were ≥4 μg/ml and addition of clavulanate did not reduce the MICs more than fourfold. For strains producing group 2 enzymes other than ESBLs, cefpodoxime and ceftazidime MICs were ≤2 μg/ml. With a single exception (ceftazidime for the strain producing SHV-3), among strains producing ESBLs, cefpodoxime and ceftazidime MICs were ≥4 μg/ml and addition of clavulanate reduced the MICs by more than eightfold. Cephamycins could also be used to discriminate between strains producing group 1 β-lactamases and ESBLs, since only the former required cefotetan concentrations as high as 8 μg/ml or cefoxitin concentrations of >16 μg/ml for inhibition. Other cephalosporins provided some discrimination between the various β-lactamase producers, although they were not as reliable as either cefpodoxime or ceftazidime. These results indicate the utility of an isogenic panel for identification of candidate drugs among many for further testing with clinical isolates of the family
Enterobacteriaceae
to determine the best agents for detection of specific β-lactamases in this family.
Pharmacodynamic Comparisons of Levofloxacin, Ciprofloxacin, and Ampicillin against
Streptococcus pneumoniae
in an In Vitro Model of Infection
Authors: Lacy Melinda K. , Lu Wen , Xu Xiaowei , Tessier Pamela R. , Nicolau David P. , Quintiliani Richard , Nightingale Charles H. 
Published: October 2018

ABSTRACT

The increasing frequency of penicillin-resistant pneumococcus continues to be of concern throughout the world. Newer fluoroquinolone antibiotics, such as levofloxacin, have shown enhanced in vitro activity against
Streptococcus pneumoniae
. In this study, the bactericidal characteristics and pharmacodynamic profiles of levofloxacin, ciprofloxacin, and ampicillin against four isolates of
S. pneumoniae
were compared by using an in vitro model of infection. Standard antibiotic dosing regimens which simulated the pharmacokinetic profile observed in humans were used. Control and treatment models were sampled for bacterial CFU per milliliter over the duration of each 24- or 48-h experiment. In addition, treatment models were sampled for MIC determinations and drug concentration. Regrowth of all isolates as well as an increase in MICs throughout the study period was observed in the ciprofloxacin experiments. A limited amount of regrowth was noted during levofloxacin therapy for one isolate; however, no change in MIC was detected for any isolate. Ampicillin showed rapid and sustained bactericidal activity against all isolates. In this study, ratios of effective fluoroquinolone area under the concentration-time curve (AUC):MIC values ranged from 30 to 55. Levofloxacin, owing to its larger AUC
0–24
values, has excellent and sustained activity against different pneumococcal strains superior to that of ciprofloxacin.
Evaluation of Bactericidal Activities of LY333328, Vancomycin, Teicoplanin, Ampicillin-Sulbactam, Trovafloxacin, and RP59500 Alone or in Combination with Rifampin or Gentamicin against Different Strains of Vancomycin-Intermediate
Staphylococcus aureus
by Time-Kill Curve Methods
Authors: Hershberger Ellie , Aeschlimann Jeffrey R. , Moldovan Tabitha , Rybak Michael J. 
Published: October 2018

ABSTRACT

This in vitro study evaluated the activities of vancomycin, LY333328, and teicoplanin alone and in combination with gentamicin, rifampin, and RP59500 against
Staphylococcus aureus
isolates with intermediate susceptibilities to vancomycin. Ampicillin-sulbactam and trovafloxacin were also evaluated. LY333328 and ampicillin-sulbactam resulted in bactericidal activity against all isolates. The combination of gentamicin with glycopeptides showed synergistic activity, while rifampin had no added benefit.