bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ocular Distribution of Intravenously Administered Lipid Formulations of Amphotericin B in a Rabbit Model
Authors: Goldblum David , Rohrer Kaspar , Frueh Beatrice E. , Theurillat Regula , Thormann Wolfgang , Zimmerli Stefan 
Published: November 2002

ABSTRACT
Little is known about the ocular penetration of amphotericin B (AMB) and its lipid formulations, the current drug of choice in fungal endophthalmitis. The ocular distribution of AMB lipid complex (ABLC), liposomal AMB (L-AMB), and AMB deoxycholate (D-AMB) was studied in a rabbit model. D-AMB (1 mg/kg of body weight/day), ABLC (5 mg/kg/day), or L-AMB (5 mg/kg/day) was given intravenously to rabbits as a single dose or as repeated daily doses on 7 consecutive days after induction of unilateral uveitis by intravitreal injection of endotoxin. AMB concentrations in aqueous humor, vitreous humor, and plasma were determined by high-pressure liquid chromatography 16 h after administration of a single dose or 24 h after the last of seven doses. After single-dose administration, L-AMB achieved at least eightfold-higher AMB concentrations in the aqueous of inflamed eyes than ABLC or D-AMB (1.21 ± 0.58 μg/ml versus 0.14 ± 0.04 and 0.11 ± 0.09 μg/ml, respectively). At that time point no drug was detectable in the vitreous. After 7 days of treatment, the concentration of AMB in the vitreous was higher after treatment with L-AMB (0.47 ± 0.21 μg/ml) than after treatment with ABLC (0.27 ± 0.18 μg/ml) and D-AMB (0.16 ± 0.04 μg/ml). Similarly, AMB concentration in the aqueous was higher after repeated doses of L-AMB (0.73 ± 0.43 μg/ml) than after repeated doses of ABLC (0.03 ± 0.02 μg/ml) or D-AMB (0.13 ± 0.06 μg/ml). No AMB was detected in noninflamed eyes. Following systemic administration, AMB distribution to the eye is inflammation dependent and occurs sequentially, first to the aqueous and then to the vitreous. Compared to D-AMB and ABLC, L-AMB reaches higher drug concentrations in both ocular compartments.
Target Site Concentrations of Ciprofloxacin after Single Intravenous and Oral Doses
Authors: Brunner Martin , Staβ Heino , Möller Jan-Georg , Schrolnberger Claudia , Erovic Boban , Hollenstein Ursula , Zeitlinger Markus , Eichler Hans Georg , Müller Markus 
Published: November 2002

ABSTRACT

To characterize the potential of ciprofloxacin penetration into human soft tissues following intravenous (i.v.) and oral (p.o.) administration, we measured the free ciprofloxacin concentrations in interstitial space fluid of skeletal muscle and subcutaneous adipose tissue by microdialysis. In addition, ciprofloxacin concentrations were measured in cantharis-induced skin blisters, saliva, and capillary plasma and were compared to the total concentrations in venous plasma. Furthermore, a pharmacodynamic in vitro model was used to simulate in vivo pharmacokinetics in bacterial culture. Eight healthy volunteers received ciprofloxacin in an open randomized crossover fashion either as a single i.v. infusion of 400 mg over 60 min or as a single p.o. dose of 500 mg. For both tissues the mean areas under the concentration-time curves (AUCs) for interstitial space fluid (AUC
interstitial fluid
s) were significantly lower than the corresponding AUC
plasma
s, with AUC
interstitial fluid
/AUC
plasma
ratios ranging from 0.38 to 0.68. For skeletal muscle, the AUC
interstitial fluid
was significantly higher after administration of 400 mg i.v. than after administration of 500 mg p.o., with a ratio of the AUC after p.o. administration/AUC after i.v. administration of 0.64. The ratio of the concentration in skeletal muscle/concentration in plasma increased over the entire observation period, implying that ciprofloxacin concentrations were not at steady state. The ratio of the concentration in skin blister fluid/concentration in plasma reached values above 4, indicating a preferential penetration of ciprofloxacin into inflamed lesions. The concentrations in saliva and capillary blood were similar to the corresponding total levels in plasma. In vitro both in vivo ciprofloxacin concentration-time profiles were equally effective against select bacterial strains. In conclusion, single-dose administration of two bioequivalent dosage forms of ciprofloxacin might lead to differences in target site pharmacokinetics. These differences, however, are not related to a difference in target site pharmacodynamics.
Resistance to Pentamidine in
Leishmania mexicana
Involves Exclusion of the Drug from the Mitochondrion
Authors: Basselin Mireille , Denise Hubert , Coombs Graham H. , Barrett Michael P. 
Published: November 2002

ABSTRACT

The uptake of [
3
H]pentamidine into wild-type and drug-resistant strains of
Leishmania mexicana
was compared. Uptake was carrier mediated. Pentamidine-resistant parasites showed cross-resistance to other toxic diamidine derivatives. A substantial decrease in accumulation of the drug accompanied the resistance phenotype, although the apparent affinity for pentamidine by its carrier was not altered when initial uptake velocity was measured. The apparent
V
max
, however, was reduced. An efflux of pentamidine could be measured in both wild-type and resistant cells. Only a relatively small proportion of the total accumulated pentamidine was available for efflux in wild-type cells, while in resistant cells the majority of loaded pentamidine was available for release. Pharmacological reagents which diminish the mitochondrial membrane potential reduced pentamidine uptake in wild-type parasites, and the mitochondrial membrane potential was shown to be reduced in resistant cells. A fluorescent analogue of pentamidine, 4′,6′-diamidino-2-phenylindole, accumulated in the kinetoplast of wild-type but not resistant parasites. These data together indicate that diamidine drugs accumulate in the
Leishmania
mitochondrion and that the development of the resistance phenotype is accompanied by lack of mitochondrial accumulation of the drug and its exclusion from the parasites.
Distribution of Extended-Spectrum β-Lactamases in Clinical Isolates of
Enterobacteriaceae
in Vietnam
Authors: Cao Van , Lambert Thierry , Nhu Duong Quynh , Loan Huynh Kim , Hoang Nguyen Kim , Arlet Guillaume , Courvalin Patrice 
Published: November 2002

ABSTRACT

Among 730
Escherichia coli
, 438
Klebsiella pneumoniae
, and 141
Proteus mirabilis
isolates obtained between September 2000 and September 2001 in seven hospitals in Ho Chi Minh City, Vietnam, 26.6% were resistant to ceftazidime, 30% were resistant to cefotaxime, 31.5% were resistant to ceftriaxone, 15.9% were resistant to cefoperazone, and 6% were resistant to cefepime. Resistance to imipenem was found in 5.6% of the isolates. In 55 strains producing extended-spectrum β-lactamases (32
E. coli
isolates, 13
K. pneumoniae
isolates, and 10
P. mirabilis
isolates), structural genes for VEB-1 (25.5%), CTX-M (25.5%), SHV (38.1%), and TEM (76.3%) enzymes were detected alone or in combination. Sequencing of the PCR products obtained from the
K. pneumoniae
isolates revealed the presence of
bla
VEB-1
,
bla
CTX-M-14
,
bla
CTX-M-17
,
bla
SHV-2
, and
bla
TEM-1
. Molecular typing of the strains with a similar resistance phenotype to broad-spectrum cephalosporins indicated polyclonal spread. IS
Ecp1
was presumably responsible for dissemination of the
bla
CTX-M-like
gene.
Mosaic-Like Structure of Penicillin-Binding Protein 2 Gene (
penA
) in Clinical Isolates of
Neisseria gonorrhoeae
with Reduced Susceptibility to Cefixime
Authors: Ameyama Satoshi , Onodera Shoichi , Takahata Masahiro , Minami Shinzaburo , Maki Nobuko , Endo Katsuhisa , Goto Hirokazu , Suzuki Hiroo , Oishi Yukihiko 
Published: November 2002

ABSTRACT

Neisseria gonorrhoeae
strains with reduced susceptibility to cefixime (MICs, 0.25 to 0.5 μg/ml) were isolated from male urethritis patients in Tokyo, Japan, in 2000 and 2001. The resistance to cephems including cefixime and penicillin was transferred to a susceptible recipient,
N. gonorrhoeae
ATCC 19424, by transformation of the penicillin-binding protein 2 gene (
penA
) that had been amplified by PCR from a strain with reduced susceptibility to cefixime (MIC, 0.5 μg/ml). The sequences of
penA
in the strains with reduced susceptibilities to cefixime were different from those of other susceptible isolates and did not correspond to the reported
N. gonorrhoeae penA
gene sequences. Some regions in the transpeptidase-encoding domain in this
penA
gene were similar to those in the
penA
genes of
Neisseria perflava
(
N. sicca
),
Neisseria cinerea
,
Neisseria flavescens
, and
Neisseria meningitidis
. These results showed that a mosaic-like structure in the
penA
gene conferred reductions in the levels of susceptibility of
N. gonorrhoeae
to cephems and penicillin in a manner similar to that found for
N. meningitidis
and
Streptococcus pneumoniae
.
A Novel Efflux System in Inducibly Erythromycin-Resistant Strains of
Streptococcus pyogenes
Authors: Giovanetti Eleonora , Brenciani Andrea , Burioni Roberto , Varaldo Pietro Emanuele 
Published: November 2002

ABSTRACT

Streptococcus pyogenes
strains inducibly resistant (iMLS phenotype) to macrolide, lincosamide, and streptogramin B (MLS) antibiotics can be subdivided into three phenotypes: iMLS-A, iMLS-B, and iMLS-C. This study focused on inducibly erythromycin-resistant
S. pyogenes
strains of the iMLS-B and iMLS-C types, which are very similar and virtually indistinguishable in a number of phenotypic and genotypic features but differ clearly in their degree of resistance to MLS antibiotics (high in the iMLS-B type and low in the iMLS-C type). As expected, the iMLS-B and iMLS-C test strains had the
erm
(A) methylase gene; the iMLS-A and the constitutively resistant (cMLS) isolates had the
erm
(B) methylase gene; and a control M isolate had the
mef
(A) efflux gene.
mre
(A) and
msr
(A), i.e., other macrolide efflux genes described in gram-positive cocci, were not detected in any test strain. With a radiolabeled erythromycin method for determination of the intracellular accumulation of the drug in the absence or presence of an efflux pump inhibitor, active efflux of erythromycin was observed in the iMLS-B isolates as well as in the M isolate, whereas no efflux was demonstrated in the iMLS-C isolates. By the triple-disk (erythromycin plus clindamycin and josamycin) test, performed both in normal test medium and in the same medium supplemented with the efflux pump inhibitor, under the latter conditions iMLS-B and iMLS-C strains were no longer distinguishable, all exhibiting an iMLS-C phenotype. In conjugation experiments with an iMLS-B isolate as the donor and a Rif
r
Fus
r
derivative of an iMLS-C isolate as the recipient, transconjugants which shared the iMLS-B type of the donor under all respects, including the presence of an efflux pump, were obtained. These results indicate the existence of a novel, transferable efflux system, not associated with
mef
(A) or with other known macrolide efflux genes, that is peculiar to iMLS-B strains. Whereas the low-level resistance of iMLS-C strains to MLS antibiotics is apparently due to
erm
(A)-encoded methylase activity, the high-level resistance of iMLS-B strains appears to depend on the same methylase activity plus the new efflux system.
Genes Involved in Bacitracin Resistance in
Streptococcus mutans
Authors: Tsuda Hiromasa , Yamashita Yoshihisa , Shibata Yukie , Nakano Yoshio , Koga Toshihiko 
Published: November 2002

ABSTRACT

Streptococcus mutans
is resistant to bacitracin, which is a peptide antibiotic produced by certain species of
Bacillus
. The purpose of this study was to clarify the bacitracin resistance mechanism of
S. mutans
. We cloned and sequenced two
S. mutans
loci that are involved in bacitracin resistance. The
rgp
locus, which is located downstream from
rmlD
, contains six
rgp
genes (
rgpA
to
rgpF
) that are involved in rhamnose-glucose polysaccharide (RGP) synthesis in
S. mutans.
The inactivation of RGP synthesis in
S. mutans
resulted in an approximately fivefold-higher sensitivity to bacitracin relative to that observed for the wild-type strain Xc. The second bacitracin resistance locus comprised four
mbr
genes (
mbrA
,
mbrB
,
mbrC
, and
mbrD
) and was located immediately downstream from
gtfC
, which encodes the water-insoluble glucan-synthesizing enzyme. Although the bacitracin sensitivities of mutants that had defects in flanking genes were similar to that of the parental strain Xc, mutants that were defective in
mbrA
,
mbrB
,
mbrC
, or
mbrD
were about 100 to 120 times more sensitive to bacitracin than strain Xc. In addition, a mutant that was defective in all of the
mbrABCD
genes and
rgpA
was more sensitive to bacitracin than either the RGP or Mbr mutants. We conclude that RGP synthesis is related to bacitracin resistance in
S. mutans
and that the
mbr
genes modulate resistance to bacitracin via an unknown mechanism that is independent of RGP synthesis.
New Site of Modification of 23S rRNA Associated with Clarithromycin Resistance of
Helicobacter pylori
Clinical Isolates
Authors: Fontana Carla , Favaro Marco , Minelli Silvia , Criscuolo Anna Angela , Pietroiusti Antonio , Galante Alberto , Favalli Cartesio 
Published: November 2002

ABSTRACT

Resistance of
Helicobacter pylori
to clarithromycin occurs with a prevalence ranging from 0 to 15%. This has an important clinical impact on dual and triple therapies, in which clarithromycin seems to be the better choice to achieve
H. pylori
eradication. In order to evaluate the possibility of new mechanisms of clarithromycin resistance, a PCR assay that amplified a portion of 23S rRNA from
H. pylori
isolates was used. Gastric tissue biopsy specimens from 230 consecutive patients were cultured for
H. pylori
isolation. Eighty-six gastric biopsy specimens yielded
H. pylori
-positive results, and among these 12 isolates were clarithromycin resistant. The latter were studied to detect mutations in the 23S rRNA gene. Sequence analysis of the 1,143-bp PCR product (portion of the 23S rRNA gene) did not reveal mutation such as that described at position 2142 to 2143. On the contrary, our findings show, for seven isolates, a T-to-C transition at position 2717. This mutation conferred a low level of resistance, equivalent to the MIC for the isolates, selected using the E-test as well as using the agar dilution method: 1 μg/ml. Moreover, T2717C transition is located in a highly conserved region of the 23S RNA associated with functional sites: domain VI. This fact has a strong effect on the secondary structure of the 23S RNA and on its interaction with macrolide. Mutation at position 2717 also generated an
Hha
I restriction site; therefore, restriction analysis of the PCR product also permits a rapid detection of resistant isolates.
Low Frequencies of Resistance among
Staphylococcus
and
Enterococcus
Species to the Bactericidal DNA Polymerase Inhibitor
N
3
-Hydroxybutyl 6-(3′-Ethyl-4′-Methylanilino) Uracil
Authors: Butler Michelle M. , Skow Donna J. , Stephenson Ryan O. , Lyden Patrick T. , LaMarr William A. , Foster Kimberly A. 
Published: November 2002

ABSTRACT

The 6-anilinouracils (AUs) constitute a new class of bactericidal antibiotics selective against gram-positive (Gr
+
) organisms. The AU family of compounds specifically inhibits a novel target, replicative DNA polymerase Pol IIIC. Like other antibiotics, AUs can be expected to engender the development of resistant bacteria. We have used a representative AU and clinically relevant strains of
Staphylococcus aureu
s and
Enterococcus
to determine the frequency and mechanism(s) of resistance development. The frequency of resistance was determined by using
N
3
-hydroxybutyl 6-(3′-ethyl-4′-methylanilino) uracil (HBEMAU) and commercially available antibiotics at eight times the MICs. For all five Gr
+
organisms tested, the frequency of resistance to HBEMAU ranged from 1 × 10
−8
to 3 × 10
−10
. The frequencies of resistance to the antibiotics tested, including rifampin, gentamicin, and ciprofloxacin, were either greater than or equal to those for HBEMAU. In order to understand the mechanism of resistance, HBEMAU-resistant organisms were isolated. MIC assays showed that the organisms had increased resistance to AU inhibitors but not to other families of antibiotics. Inhibition studies with DNA polymerases from HBEMAU-sensitive and -resistant strains demonstrated that the resistance was associated with Pol IIIC. DNA sequence analysis of the entire
polC
genes from both wild-type and resistant organisms revealed that the resistant organisms had a sequence change that mapped to a single amino acid codon in all strains examined.
Pharmacokinetics and Efficacies of Liposomal and Conventional Formulations of Tobramycin after Intratracheal Administration in Rats with PulmonaryBurkholderia cepaciaInfection
Authors: Marier Jean-Francois , Lavigne Jean , Ducharme Murray P. 
Published: November 2002

ABSTRACTThe objective of the present study was to determine the pharmacokinetics and efficacies of liposomal and conventional formulations of tobramycin againstBurkholderia cepaciain a model of chronic lung infection. Male Sprague-Dawley rats were inoculated intratracheally with 106CFU of a very resistant strain ofB. cepacia(strain BC 1368; MIC, 128 μg/ml) to establish lung infection. A 1,200-μg dose of tobramycin was administered intratracheally as a liposomal formulation and as a conventional formulation. Rats were anesthetized and exsanguinated by cardiac puncture at different times over 24 h to assess pulmonary tobramycin concentrations and the number of residual CFU. Pharmacokinetic parameters were calculated by using a two-compartment model with NONMEM. The mean half-life at the β phase (t1/2β) and the pulmonary exposure (the area under the concentration-time curve [AUC]) of liposomal tobramycin were 19.7 h (coefficient of variation [CV], 24.2%) and 6,811 μg · h/lungs (CV, 19.7%), respectively. The pharmacokinetics of conventional tobramycin were statistically different, with at1/2βand AUC of 12.9 h (CV, 31.4%) and 821 μg · h/lungs (CV, 15.0%), respectively. Pearson chi-square analyses were performed on residual CFU data distributed in the following categories: <103, 103to 105, and >105. Differences in CFU data between formulations showed a statistical trend (P< 0.10) when data from all time points were used, and statistically significant differences were found after 12 h (P< 0.05), with greater eradication achieved with the liposomal formulation. In conclusion, intratracheal administration of tobramycin in liposomes was associated with marked changes in the pharmacokinetics of the drug in the lung and an apparent trend for a prolonged efficacy againstB. cepacia. These results support the hypothesis that inhalation of liposomal tobramycin may improve the management of chronic pulmonary infections caused by resistant bacteria in patients with cystic fibrosis.
Ex Vivo Pharmacodynamics of Amoxicillin-Clavulanate against β-Lactamase-Producing
Escherichia coli
in a Yucatan Miniature Pig Model That Mimics Human Pharmacokinetics
Authors: Bronner Stéphane , Murbach Valérie , Peter Jean-Daniel , Levêque Dominique , Elkhaïli Hassan , Salmon Yves , Dhoyen Nathalie , Monteil Henri , Woodnutt Gary , Jehl François 
Published: November 2002

ABSTRACT

The objective of the present study was to investigate the potential bactericidal activity of amoxicillin-clavulanate against β-lactamase-producing
Escherichia coli
strains and to elucidate the extent to which enzyme production affects the activity. Six adult Yucatan miniature pigs received a single intravenous dose of 1.1 g of amoxicillin-clavulanate as an intravenous infusion over 30 min. The pharmacokinetic parameters were determined for the serum samples and compared to the published data for humans (2.2-g intravenous dose). The parameters were comparable for the two species, and therefore, the miniature pig constitutes a good model for pharmacodynamic study of amoxicillin-clavulanate. Therefore, the model was used in an ex vivo pharmacodynamic study of amoxicillin-clavulanate against four strains of
Escherichia coli
producing β-lactamases at different levels. The
E. coli
strains were cultured with serial dilutions (1:2 to 1:256) of the serum samples from the pharmacokinetic study, and the number of surviving bacteria was determined after 1, 3, and 6 h of exposure. Amoxicillin-clavulanate at concentrations less than the MIC and the minimal bactericidal concentration had marked bactericidal potency against the strain that produced low levels of penicillinase. For high-level or intermediate-level β-lactamase-producing strains, the existence of a clavulanate concentration threshold of 1.5 to 2 μg/ml, below which there was no bactericidal activity, was demonstrated. The index of surviving bacteria showed the existence of mixed concentration- and time-dependent actions of amoxicillin (in the presence of clavulanate) which varied as a function of the magnitude of β-lactamase production by the test strains. This study shows the effectiveness of amoxicillin-clavulanate against low- and intermediate-level penicillinase-producing strains of
E. coli
. These findings are to be confirmed in a miniature pig experimental infection model.
Benznidazole Treatment following AcuteTrypanosoma cruziInfection Triggers CD8+T-Cell Expansion and Promotes Resistance to Reinfection
Authors: Olivieri Bianca Perdigão , Cotta-de-Almeida Vinícius , Araújo-Jorge Tania 
Published: November 2002

ABSTRACTMany studies have shed light on the mechanisms underlying both immunoprotection and immune dysregulation arising afterTrypanosoma cruziinfection. However, little is known about the impact of benznidazole (N-benzyl-2-nitroimidazole acetamide), the drug available for clinical treatment of the infection, on the immune system in the infected host. In the present study we investigated the effect of benznidazole therapy on the lymphoid compartment during the course of experimentalT. cruziinfection. Although amelioration of a variety of clinical and parasitological signs was observed in treated mice, amelioration of splenocyte expansion was not detected. Interestingly, this sustained splenomegaly observed in benznidazole-treated mice showed a preferential expansion of CD8+T lymphocytes. Moreover, although benznidazole treatment blocked the expansion of recently activated CD4+and CD8+T cells seen in infected hosts, benznidazole treatment led to a selective expansion of effector and memory CD8+T lymphocytes in association with a lower rate of apoptosis. In addition, the surviving treated animals were protected from reinfection. Together, these data suggest that, in addition to its well-known direct role in blocking parasite replication in vivo, benznidazole appears to directly affect immune regulation inT. cruzi-infected hosts.