bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of High-Dose Amoxicillin-Clavulanate against Experimental Respiratory Tract Infections Caused by Strains of
Streptococcus pneumoniae
Authors: Woodnutt Gary , Berry Valerie 
Published: October 2018

ABSTRACT

The purpose of the present investigation was to determine if the efficacy of amoxicillin-clavulanate against penicillin-resistant
Streptococcus pneumoniae
could be improved by increasing the pediatric amoxicillin unit dose (90 versus 45 mg/kg of body weight/day) while maintaining the clavulanate unit dose at 6.4 mg/kg/day. A rat pneumonia model was used. In that model approximately 6 log
10
CFU of one of four strains of
S. pneumoniae
(amoxicillin MICs, 2 μg/ml [one strain], 4 μg/ml [two strains], and 8 μg/ml [one strain]) were instilled into the bronchi of rats. Amoxicillin-clavulanate was given by computer-controlled intravenous infusion to approximate the concentrations achieved in the plasma of children following the administration of oral doses of 45/6.4 mg/kg/day or 90/6.4 mg/kg/g/day divided every 12 h or saline as a control for a total of 3 days. Infusions continued for 3 days, and 2 h after the cessation of infusion, bacterial numbers in the lungs were significantly reduced by the 90/6.4-mg/kg/day equivalent dosage for strains for which amoxicillin MICs were 2 or 4 μg/ml. The 45/6.4-mg/kg/day equivalent dosage was fully effective only against the strain for which the amoxicillin MIC was 2 μg/ml and had marginal efficacy against one of the two strains for which amoxicillin MICs were 4 μg/ml. The bacterial load for the strain for which the amoxicillin MIC was 8 μg/ml was not reduced with either dosage. These data demonstrate that regimens which achieved concentrations in plasma above the MIC for at least 34% of a 24-h dosing period resulted in significant reductions in the number of viable bacteria, indicating that the efficacy of amoxicillin-clavulanate can be extended to include efficacy against less susceptible strains of
S. pneumoniae
by increasing the amoxicillin dose.
Vancomycin-Dependent
Enterococcus faecalis
Clinical Isolates and Revertant Mutants
Authors: Van Bambeke Françoise , Chauvel Murielle , Reynolds Peter E. , Fraimow Henry S. , Courvalin Patrice 
Published: October 2018

ABSTRACT

Three vancomycin-dependent clinical isolates of
Enterococcus faecalis
of the VanB type were studied by determining (i) the sequence of the
ddl
gene encoding the host
d
-Ala:
d
-Ala ligase and the
vanS
B
-
vanR
B
genes specifying the two-component regulatory system that activates transcription of the
vanB
operon, (ii) the level of expression of resistance genes by using
dd
-dipeptidase activity as a reporter, and (iii) the proportions of the peptidoglycan precursors synthesized. Each strain had a mutation in
ddl
leading to an amino acid substitution (D295 to V; T316 to I) or deletion (DAK251-253 to E) at invariant positions in
d
-Ala:
d
-Ala,
d
-Ala:
d
-Lac, and
d
-Ala:
d
-Ser ligases. These mutations resulted in impaired host
d
-Ala:
d
-Ala ligases since only precursors terminating in
d
-Ala-
d
-Lac were synthesized under vancomycin-inducing conditions. Two types of vancomycin-independent revertants of one isolate were obtained in vitro after growth in the absence of vancomycin: (i) vancomycin-resistant, teicoplanin-susceptible mutants had a 6-bp insertion in the host
ddl
gene, causing the E251-to-EYK change that restored
d
-Ala:
d
-Ala ligase activity, (ii) constitutive vancomycin-resistant, teicoplanin-resistant mutants had substitutions (S232 to F or E247 to K) in the vicinity of the autophosphorylation site of the VanS
B
sensor and produced exclusively precursors ending in
d
-Ala-
d
-Lac. Vancomycin- and teicoplanin-dependent mutants obtained by growth in the presence of teicoplanin had an 18-bp deletion in VanS
B
, affecting residues 402 to 407 and overlapping the G2 ATP binding domain. The rapid emergence of vancomycin-independent revertants in vitro suggests that interruption of vancomycin therapy may not be sufficient to cure patients infected with vancomycin-dependent enterococci.
Type II Topoisomerase Mutations in Ciprofloxacin-Resistant Strains of
Pseudomonas aeruginosa
Authors: Mouneimné Hyam , Robert Jérome , Jarlier Vincent , Cambau Emmanuelle 
Published: October 2018

ABSTRACT

We determined the sequences of the quinolone resistance-determining regions of
gyrA
,
gyrB
, and
parC
genes for 30 clinical strains of
Pseudomonas aeruginosa
resistant to ciprofloxacin that were previously complemented by wild-type
gyrA
and
gyrB
plasmid-borne alleles and studied for their coresistance to imipenem (E. Cambau, E. Perani, C. Dib, C. Petinon, J. Trias, and V. Jarlier, Antimicrob. Agents Chemother. 39:2248–2252, 1995). In the present study, we found mutations in type II topoisomerase genes for all strains. Twenty-eight strains had a missense mutation in
gyrA
(codon 83 or 87). Ten of them had an additional mutation in
parC
(codon 80 or 84), including a novel mutation of Ser-80 to Trp, but all were fully complemented by a plasmid-borne wild-type
gyrA
allele. The remaining two strains harbored the first
gyrB
mutation described in
P. aeruginosa
, leading to the substitution of phenylalanine for serine 464. The strains which had two mutations in type II topoisomerase genes (i.e.,
gyrA
and
parC
) were significantly more resistant to fluoroquinolones than those with a single mutation in
gyrA
or
gyrB
(geometric mean MICs of ciprofloxacin, 39.4 versus 10.9 μg/ml,
P
< 0.01; geometric mean MICs of sparfloxacin, 64.0 versus 22.6,
P
< 0.01). No mutant with a
parC
mutation alone was observed, which favors DNA gyrase being the primary target for fluoroquinolones. These results demonstrate that
gyrA
mutations are the major mechanism of resistance to fluoroquinolones for clinical strains of
P. aeruginosa
and that additional mutations in
parC
lead to a higher level of quinolone resistance.
Therapeutic Effect of Clarithromycin on a Transplanted Tumor in Rats
Authors: Sassa Kazuhiko , Mizushima Yutaka , Fujishita Takashi , Oosaki Rokuo , Kobayashi Masashi 
Published: October 2018

ABSTRACT

The therapeutic antitumor effect of clarithromycin (CAM) was examined with the 13762NF mammary adenocarcinoma and F-344 rat system. When CAM treatment at a dosage of 2 mg/kg of body weight orally for 21 days was commenced after inoculation of the tumor, no significant decrease in death rate was observed, although the loss in body weight was less than that in the untreated group. When tumor-bearing (TB) rats were treated with CAM in combination with carboplatin or cyclophosphamide, a significant decrease in the death rate was obtained, although neither treatment alone proved to be effective. A beneficial effect was also observed when CAM treatment was combined with surgical treatment. CAM showed no direct cytotoxicity to this tumor in vitro according to the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Spleen cells obtained from TB rats receiving CAM treatment showed a stronger tumor-neutralizing activity than those from rats which had not received CAM treatment (Winn assay). Enhanced induction of cytotoxic cells to allogeneic tumor was also observed in rats immunized with allogeneic tumor cells together with CAM treatment (
51
Cr release assay). The 13762NF tumor produces transforming growth factor-β (TGF-β), tumor necrosis factor alpha, and matrix metalloproteinase-9, and treatment of tumor cells with CAM in vitro for 24 h significantly inhibited the expression of the genes coding for these proteins (reverse transcription-PCR). Levels of expression of the TGF-β and interleukin-6 genes of spleen cells obtained from CAM-treated TB rats were both significantly lower than those of spleen cells from CAM-untreated TB rats. This study suggests that CAM has biological response modifier activities resulting in a beneficial therapeutic antitumor effect and might be useful for the treatment of human cancers.
Effect of Probenecid on the Renal Excretion Mechanism of a New Carbapenem, DA-1131, in Rats and Rabbits
Authors: Kim So H. , Kim Won B. , Lee Myung G. 
Published: October 2018

ABSTRACT

The effects of probenecid, an anion transport inhibitor, on the renal excretion mechanism of a new anionic carbapenem, DA-1131, were investigated after a 1-min intravenous infusion of DA-1131 at 100 mg/kg of body weight to rabbits and 50 mg/kg to rats with or without probenecid at 50 mg/kg for both species. In control rabbits, the renal clearance (CL
R
) of DA-1131 and the glomerular filtration rate based on creatinine clearance (CL
CR
) were 6.14 ± 2.09 and 2.26 ± 0.589 ml/min/kg, respectively. When considering the less than 10% plasma protein binding of DA-1131 in rabbits, renal tubular secretion of DA-1131 was observed in rabbits. The CL
R
of DA-1131 (3.87 ± 0.543 ml/min/kg) decreased significantly with treatment with probenecid in rabbits, indicating that the renal tubular secretion of DA-1131 was inhibited by probenecid. However, in control rats, the CL
R
of DA-1131 (5.80 ± 1.94 ml/min/kg) was comparable to the CL
CR
(4.29 ± 1.64 ml/min/kg), indicating that DA-1131 was mainly excreted by glomerular filtration in rats. Therefore, it could be expected that the CL
R
of DA-1131 could not be affected by treatment with probenecid in rats; this was proved by a similar CL
R
of DA-1131 with treatment with (6.93 ± 0.675 ml/min/kg) or without (5.80 ± 1.94 ml/min/kg) probenecid. Therefore, the renal secretion of DA-1131 is a factor in rabbits but is not a factor in rats.
Evaluation of Rifapentine in Long-Term Treatment Regimens for Tuberculosis in Mice
Authors: Lenaerts Anne M. J. A. , Chase Sharon E. , Chmielewski Alex J. , Cynamon Michael H. 
Published: October 2018

ABSTRACT

Besides direct bactericidal activity, long-term effectiveness is one of the most important features to consider when developing new drugs for chemotherapy. In this study, we evaluated the ability of rifapentine (RFP), in monotherapy and combination therapy, to completely eradicate a
Mycobacterium tuberculosis
infection and to prevent relapse posttreatment in a Swiss mouse model. The combination of RFP, isoniazid (INH), and pyrazinamide (PZA) administered daily resulted in an apparent clearance of
M. tuberculosis
organisms in the lungs and spleens of infected mice after 10 weeks of treatment. However, 3 months after the cessation of therapy, bacterial regrowth occurred in mice treated for a 12-week period, indicating a relapse of infection. In intermittent treatment regimens of RFP in combination with INH and PZA, sterilization was achieved when mice were treated two to five times per week for 9 weeks. Bacterial growth was still observed in the once-weekly treatment group. Our results show that mouse models can predict important parameters for new drugs. We stress the necessity for long-term posttreatment observation in animal models for the routine evaluation of new drugs for antituberculosis chemotherapy.
Characterization of the Chromosomal
aac(6′)-Iz
Gene of
Stenotrophomonas maltophilia
Authors: Lambert Thierry , Ploy Marie-Cécile , Denis François , Courvalin Patrice 
Published: October 2018

ABSTRACT

The
aac(6′)-Iz
gene of
Stenotrophomonas maltophilia
BM2690 encoding an aminoglycoside 6′-
N
-acetyltransferase was characterized. The gene was identified as a coding sequence of 462 bp corresponding to a protein with a calculated mass of 16,506 Da, a value in good agreement with that of ca. 16,000 found by in vitro coupled transcription-translation. Analysis of the deduced amino acid sequence indicated that the protein was a member of the major subfamily of aminoglycoside 6′-
N
-acetyltransferases. The enzyme conferred resistance to amikacin but not to gentamicin, indicating that it was an AAC(6′) of type I. The open reading frame upstream from the
aac(6′)-Iz
gene was homologous to the
fprA
gene of
Myxococcus xanthus
(61% identity), which encodes a putative pyridoxine (pyridoxamine) 5′-phosphate oxidase. Pulsed-field gel electrophoresis of total DNA from BM2690 and
S. maltophilia
ATTC 13637 digested with
Xba
I,
Dra
I, and
Spe
I followed by hybridization with rRNA and
aac(6′)-Iz
-specific probes indicated that the gene was located in the chromosome. The
aac(6′)-Iz
gene was detected by DNA-DNA hybridization in all 80 strains of
S. maltophilia
tested. The MICs of gentamicin against these strains of
S. maltophilia
were lower than those of amikacin, netilmicin, and tobramycin, indicating that production of AAC(6′)-Iz contributes to aminoglycoside resistance in
S. maltophilia
.
Pharmacokinetics of Isepamicin during Continuous Venovenous Hemodiafiltration
Authors: Breilh Dominique , Allaouchiche Bernard , Jaumain Hélène , Boulétreau Paul , Chassard Dominique , Malbec Isabelle , Ducint Dominique , Saux Marie-Claude 
Published: October 2018

ABSTRACT
The objective of this study was to analyze the pharmacokinetics of isepamicin during continuous venovenous hemodiafiltration. Six patients received 15 mg of isepamicin per kg of body weight. The mean isepamicin concentration peak in serum was 62.88 ± 18.20 mg/liter 0.5 h after the infusion. The elimination half-life was 7.91 ± 0.83 h. The mean total body clearance was 1.75 ± 0.28 liters/h, and dialysate outlet (DO) clearance was 2.76 ± 0.59 liters/h. The mean volume of distribution was 19.83 ± 2.95 liters. The elimination half-life, DO clearance, and volume of distribution were almost constant. In this group of patients, the initial dosage of 15 mg/kg appeared to be adequate, but the dosage interval should be determined by monitoring residual isepamicin concentrations in plasma.
Multicenter Study of In Vitro Susceptibility of the
Bacteroides fragilis
Group, 1995 to 1996, with Comparison of Resistance Trends from 1990 to 1996
Authors: Snydman D. R. , Jacobus N. V. , McDermott L. A. , Supran S. , Cuchural G. J. , Finegold S. , Harrell L. , Hecht D. W. , Iannini P. , Jenkins S. , Pierson Carl , Rihs J. , Gorbach S. L. 
Published: October 2018

ABSTRACT

Antimicrobial resistance, including plasmid-mediated resistance, among the species of the
Bacteroides fragilis
group is well documented. An analysis of the in vitro susceptibility of
B. fragilis
group species referred between 1995 and 1996 as well as during a 7-year (1990 to 1996), prospective, multicenter survey of over 4,000 clinical isolates of
B. fragilis
group species was undertaken to review trends in the percent resistance to and geometric mean MICs of the antibiotics tested. There was a trend toward a decrease in the geometric mean MICs of most β-lactam antibiotics, while the percent resistance to most agents was less affected. Within the species
B. fragilis
, the geometric mean MICs showed significant (
P
< 0.05) decreases for piperacillin-tazobactam, ticarcillin-clavulanate, piperacillin, ticarcillin, ceftizoxime, cefotetan, and cefmetazole; a significant increase was observed for clindamycin and cefoxitin. For the non-
B. fragilis
species, a significant decrease in the geometric mean MICs was observed for meropenem, ampicillin-sulbactam, ticarcillin-clavulanate, piperacillin, ticarcillin, ceftizoxime, and cefmetazole; a significant increase was observed for cefoxitin. Significant increases in percent resistance were observed within the
B. fragilis
strains for ticarcillin and ceftizoxime and within the non-
B. fragilis
isolates for cefotetan. Significant increases in percent resistance among all
B. fragilis
group species were observed for clindamycin, while imipenem showed no significant change in resistance trends. The trend analysis for trovafloxacin was limited to 3 years, since the quinolone was tested only in 1994, 1995, and 1996. During the 7 years analyzed, there was no resistance to metronidazole or chloramphenicol observed. The data demonstrate that resistance among the
B. fragilis
group species has decreased in the past several years, the major exception being clindamycin. The majority of the resistance decrease has been for the β-lactams in
B. fragilis
, compared to other species. The reasons for these changes are not readily apparent.
Decreased Azithromycin Susceptibility of
Neisseria gonorrhoeae
Due to
mtrR
Mutations
Authors: Zarantonelli Leticia , Borthagaray Graciela , Lee Eun-Hee , Shafer William M. 
Published: October 2018

ABSTRACT

Single-dose azithromycin therapy has recently been used in Uruguay for the treatment of uncomplicated gonococcal infections. As part of an active surveillance study to monitor the emergence of antibiotic resistance in gonococcal isolates, we examined the levels of azithromycin susceptibility in 51 consecutive isolates obtained from males with uncomplicated gonococcal urethritis. Isolates with decreased susceptibility to azithromycin (MICs, 0.25 to 0.5 μg/ml) were common, and these isolates often displayed cross-resistance to hydrophobic antimicrobial agents (erythromycin and Triton X-100). Resistance to erythromycin and Triton X-100 is frequently due to overexpression of the
mtrCDE
-encoded efflux pump mediated by mutations in the
mtrR
gene, which encodes a transcriptional repressor that modulates expression of the
mtrCDE
operon. Accordingly, we questioned whether clinical isolates that express decreased azithromycin susceptibility harbor
mtrR
mutations. Promoter mutations that would decrease the level of expression of
mtrR
as well as a missense mutation at codon 45 in the
mtrR
-coding region that would result in a radical amino acid replacement within the DNA-binding motif of MtrR were found in these strains. When these mutations were transferred into azithromycin-susceptible strain FA19 by transformation, the susceptibility of gonococci to azithromycin was decreased by nearly 10-fold. The
mtrCDE
-encoded efflux pump system was responsible for this property since insertional inactivation of the
mtrC
gene resulted in enhanced susceptibility of gonococci to azithromycin. We conclude that the
mtrCDE
-encoded efflux pump can recognize azithromycin and that the emergence of gonococcal strains with decreased susceptibility to azithromycin can, in part, be explained by
mtrR
mutations.
In Vitro Induction of Human Immunodeficiency Virus Type 1 Variants Resistant to Phosphoralaninate Prodrugs of
Z
-Methylenecyclopropane Nucleoside Analogues
Authors: Yoshimura Kazuhisa , Feldman Ron , Kodama Eiichi , Kavlick Mark F. , Qiu Yao-Ling , Zemlicka Jiri , Mitsuya Hiroaki 
Published: October 2018

ABSTRACT

Two methylenecyclopropane nucleoside analogues with a phenylphosphoralaninate moiety, QYL-685 and QYL-609, exert potent and specific activities against human immunodeficiency virus type 1 strain LAI (HIV-1
LAI
) and HIV-2 in vitro. In this study, we induced HIV-1 variants resistant to QYL-685 by exposing HIV-1
LAI
to increasing concentrations of QYL-685. After 16 passages, the virus (HIV-1
P16
) was less sensitive to QYL-685 (104-fold), QYL-609 (>41-fold), and (−)-β-2′,3′-dideoxy-3′-thiacytidine (3TC) (>1,100-fold) than was HIV-1
LAI
and contained an M184I mutation. Two infectious clones, HIV-1
M184I
and HIV-1
M184V
, were resistant to QYL-685, QYL-609, and 3TC, confirming that the M184I mutation was responsible for the observed resistance. Viral-fitness analyses (competitive HIV-1 replication assays) revealed that in the absence of drugs, M184I and M184V conferred a replication disadvantage on the virus compared to the replication efficiency of the wild-type infectious clone (HIV-1
wt
). However, in the presence of QYL-685 (4 μM), HIV-1
M184I
and HIV-1
M184V
showed greater fitness than HIV-1
wt
. These data may provide structural and virological relevance with regard to the emergence of M184I and M184V substitutions in HIV-1.
Association of Alterations in ParC and GyrA Proteins with Resistance of Clinical Isolates of
Enterococcus faecium
to Nine Different Fluoroquinolones
Authors: Brisse Sylvain , Fluit Ad C. , Wagner Ulrich , Heisig Peter , Milatovic Dana , Verhoef Jan , Scheuring Sybille , Köhrer Karl , Schmitz Franz-Josef 
Published: October 2018

ABSTRACT

The
parC
and
gyrA
genes of 73 ciprofloxacin-resistant and 6 ciprofloxacin-susceptible
Enterococcus faecium
clinical isolates were partly sequenced. Alterations in ParC and GyrA, possibly in combination with other resistance mechanisms, severely restricted the in vitro activities of the nine quinolones tested. For all isolates, clinafloxacin and sitafloxacin showed the best activities.
Effects of Cilastatin on the Pharmacokinetics of a New Carbapenem, DA-1131, in Rats, Rabbits, and Dogs
Authors: Kim So H. , Kwon Jong W. , Kim Won B. , Lee Myung G. 
Published: October 2018

ABSTRACT

DA-1131, a new carbapenem antibiotic, undergoes renal metabolism by renal dehydropeptidase I (DHP-I), located on the brush border of the proximal tubular cell. Species differences with regard to the effects of cilastatin, a renal DHP-I inhibitor, were investigated after a 1-min intravenous infusion of DA-1131, with or without cilastatin, to rats, rabbits, and dogs. After intravenous infusion, the nonrenal clearance (CL
NR
) of DA-1131 was significantly slower in rats (3.00 versus 8.01 ml/min/kg) and rabbits (2.41 versus 6.77 ml/min/kg) when the drug was coadministered with cilastatin; this could be due to the slower metabolism of DA-1131 by rat and rabbit kidney DHP-I. This indicated that renal metabolism of DA-1131 by renal DHP-I was inhibited by cilastatin. However, coadministration with cilastatin to dogs did not affect the CL
NR
of DA-1131.
Potent Bacteriolytic Activity of Ritipenem Associated with a Characteristic Profile of Affinities for Penicillin-Binding Proteins of
Haemophilus influenzae
Authors: Inui Takashi , Oshida Tadahiro , Endo Toshio , Matsushita Tadahiro 
Published: October 2018

ABSTRACT

Ritipenem is highly bacteriolytic against
Haemophilus influenzae
. Bacterial lysis was shown after treatments with ritipenem and cefsulodin at their MICs and after treatments with fropenem and cefdinir at four times their MICs, indicated by decreases in the culture turbidities and by morphological changes of the destroyed cells. These β-lactams were preferentially bound to penicillin-binding protein (PBP) 1b. Ritipenem, fropenem, and cefsulodin exhibited poor affinities to PBPs 3a and 3b, but cefdinir showed high affinities to these PBPs. Microscopic examinations revealed that selective PBP 3 inhibitors, such as aztreonam and cefotaxime, inhibited lysis induced by ritipenem. These results suggest that the preferential inactivation of PBP 1b could be essential to induce the lysis of
H. influenzae
cells and that binding to PBPs 3a and 3b may interfere with lysis.
Potentiation of Artemisinin Activity against Chloroquine-Resistant
Plasmodium falciparum
Strains by Using Heme Models
Authors: Benoit-Vical Françoise , Robert Anne , Meunier Bernard 
Published: October 2018

ABSTRACT

The influence of different metalloporphyrin derivatives on the antimalarial activity of artemisinin was studied with two chloroquine-resistant strains of
Plasmodium falciparum
(FcB1-Colombia and FcM29-Cameroon) cultured in human erythrocytes. This potentiation study indicates that the manganese complex of
meso
-tetrakis(4-sulfonatophenyl)porphyrin has a significant synergistic effect on the activity of artemisinin against both
Plasmodium
strains.