bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mefloquine Pharmacokinetic-Pharmacodynamic Models: Implications for Dosing and Resistance
Authors: Simpson Julie A. , Watkins Emmeline R. , Price Ric N. , Aarons Leon , Kyle Dennis E. , White Nicholas J. 
Published: July 2002

ABSTRACT
Antimalarial resistance develops and spreads when spontaneously occurring mutant malaria parasites are selected by concentrations of antimalarial drug which are sufficient to eradicate the more sensitive parasites but not those with the resistance mutation(s). Mefloquine, a slowly eliminated quinoline-methanol compound, is the most widely used drug for the treatment of multidrug-resistant falciparum malaria. It has been used at doses ranging between 15 and 25 mg of base/kg of body weight. Resistance to mefloquine has developed rapidly on the borders of Thailand, where the drug has been deployed since 1984. Mathematical modeling with population pharmacokinetic and in vivo and in vitro pharmacodynamic data from this region confirms that, early in the evolution of resistance, conventional assessments of the therapeutic response ≤28 days after treatment underestimate considerably the level of resistance. Longer follow-up is required. The model indicates that initial deployment of a lower (15-mg/kg) dose of mefloquine provides a greater opportunity for the selection of resistant mutants and would be expected to lead more rapidly to resistance than de novo use of the higher (25-mg/kg) dose.
Bactericidal Activities of Antibiotics against Intracellular
Francisella tularensis
Authors: Maurin M. , Mersali N. F. , Raoult D. 
Published: July 2002

ABSTRACT

MICs of many antibiotics for
Francisella tularensis
are low in axenic medium, whereas only aminoglycosides, tetracyclines, and fluoroquinolones are useful in treating tularemic patients. In an in vitro cell system, only these antibiotics, rifampin, and telithromycin were bactericidal against intracellular
F. tularensis
. These results correlate better with clinical data than MIC data do.
Substitutions in the Eyelet Region Disrupt Cefepime Diffusion through the
Escherichia coli
OmpF Channel
Authors: Simonet Valérie , Malléa Monique , Pagès Jean-Marie 
Published: July 2002

ABSTRACT

The
Escherichia coli
OmpF porin is a nonspecific channel involved in the membrane translocation of small hydrophilic molecules and especially in the passage of β-lactam antibiotics. In order to understand the dynamic of charged-compound uptake through bacterial porins, specific charges located in the
E. coli
OmpF channel were mutated. Substitutions G119D and G119E, inserting a protruding acidic side chain into the pore, decreased cephalosporin and colicin susceptibilities. Cefepime diffusion was drastically altered by these mutations. Conversely, substitutions R132A and R132D, changing a residue located in the positively charged cluster, increased the rate of cephalosporin uptake without modifying colicin sensitivity. Modelling approaches suggest that G119E generates a transverse hydrogen bond dividing the pore, while the two R132 substitutions stretch the channel size. These charge alterations located in the constriction area have differential effects on cephalosporin diffusion and substantially modify the profile of antibiotic susceptibility.
Delavirdine Susceptibilities and Associated Reverse Transcriptase Mutations in Human Immunodeficiency Virus Type 1 Isolates from Patients in a Phase I/II Trial of Delavirdine Monotherapy (ACTG 260)
Authors: Demeter L. M. , Shafer R. W. , Meehan P. M. , Holden-Wiltse J. , Fischl M. A. , Freimuth W. W. , Para M. F. , Reichman R. C. 
Published: July 2002

ABSTRACT
The development of human immunodeficiency virus type 1 resistance to delavirdine (DLV) was studied in subjects receiving DLV monotherapy. Phenotypic resistance developed in 28 of 30 subjects within 8 weeks. K103N and Y181C, which confer nonnucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance, were the predominant reverse transcriptase mutations. P236L, which confers DLV resistance but hypersensitivity to other NNRTIs, developed in <10% of isolates.
In Vitro Activities of Daptomycin, Vancomycin, Linezolid, and Quinupristin-Dalfopristin against Staphylococci and Enterococci, Including Vancomycin- Intermediate and -Resistant Strains
Authors: Rybak Michael J. , Hershberger Ellie , Moldovan Tabitha , Grucz Richard G. 
Published: July 2002

ABSTRACT

The in vitro activity of daptomycin was compared with those of vancomycin, linezolid, and quinupristin-dalfopristin against a variety (
n
= 203) of gram-positive bacteria, including methicillin-resistant
Staphylococcus aureus
and
S. epidermidis
(MRSA and MRSE, respectively), vancomycin-resistant enterococci (VRE), and vancomycin-intermediate
S. aureus
(VISA). Overall, daptomycin was more active against all organisms tested, except
Enterococcus faecium
and VISA, against which its activity was similar to that of quinupristin-dalfopristin. In time-kill studies with MRSA, MRSE, VRE, and VISA, daptomycin demonstrated greater bactericidal activity than all other drugs tested, killing ≥3 log CFU/ml by 8 h. Daptomycin may be a potential alternative drug therapy for multidrug-resistant gram-positive organisms and warrants further investigation.
Vancomycin and Oxacillin Synergy for Methicillin-Resistant Staphylococci
Authors: Domaracki Beth E. , Evans Ann M. , Venezia Richard A. 
Published: July 2002

ABSTRACT

An increase in oxacillin activity was observed against methicillin-resistant coagulase-negative staphylococci (MRCNS) and methicillin-resistant
Staphylococcus aureus
(MRSA) in the presence of a sub-MIC of vancomycin. Vancomycin and oxacillin were synergistic against 14 of 21 strains of MRCNS and MRSA. A pattern of enhanced killing was also supported by time-kill studies. These results suggest that combinations of sub-MICs of vancomycin and oxacillin may have therapeutic benefits against methicillin-resistant staphylococci.
Activity of the Novel Immunomodulatory Compound Tucaresol against Experimental Visceral Leishmaniasis
Authors: Smith Aden C. , Yardley Vanessa , Rhodes John , Croft Simon L. 
Published: July 2002

ABSTRACTTucaresol, a novel immunomodulator, was inactive againstLeishmania donovaniamastigotes in both peritoneal and bone marrow macrophages in vitro at concentrations between 100 and 1 μM, with toxicity to macrophages and parasites at 300 μM. However, againstL. donovaniin BALB/c mice at doses between 80 and 1.25 mg/kg of body weight administered once daily by the oral route during days 7 to 11 of infection, an optimal dose of 5 mg/kg produced a 43.8 to 62.4% suppression of liver amastigotes, with significantly reduced activity at the extremes of the dose range. This response was not related to levels of infection. No interaction with the standard pentavalent antimonial sodium stibogluconate (Pentostam) was observed during this period of infection. The optimum dose of 5 mg/kg was ineffective when administered during the first week of infection and was most effective against the liver infection when administered during weeks 2 to 3 of infection (42.3 to 46.8% inhibition) and against the splenic infection when administered during week 6 of infection (59.5% inhibition). The optimum dose of tucaresol againstL. donovaniin C57BL/6 mice was 5 mg/kg, which produced a 40.8 to 48.7% suppression of liver amastigotes when administered in a range of 80 to 1.25 mg/kg during days 7 to 11 of infection. The drug had no activity againstL. donovaniinfections in C.B-17scidmice when the same regimen was used.
In Vitro Activities of Membrane-Active Peptides Alone and in Combination with Clinically Used Antimicrobial Agents against
Stenotrophomonas maltophilia
Authors: Giacometti A. , Cirioni O. , Del Prete M. S. , Barchiesi F. , Fortuna M. , Drenaggi D. , Scalise G. 
Published: July 2002

ABSTRACT

The in vitro activities of buforin II, cecropin P1, and magainin II, alone and in combination with six clinically used antimicrobial agents, against 12 clinical isolates of
Stenotrophomonas maltophilia
were investigated. Antimicrobial activities were measured by MIC and time-kill studies. The isolates were susceptible to the peptides at concentrations in the range of 0.50 to 16 μg/ml. Synergy was observed when the peptides were combined with polymyxin E, meropenem, ceftazidime, piperacillin, and clarithromycin.
Molecular Basis of High-Level Ciprofloxacin Resistance in
Neisseria gonorrhoeae
Strains Isolated in Denmark from 1995 to 1998
Authors: Su Xiaohong , Lind Inga 
Published: July 2002

ABSTRACT

In Denmark surveillance of the in vitro susceptibility to ciprofloxacin of
Neisseria gonorrhoeae
was established in 1990. The proportion of
N. gonorrhoeae
strains with decreased susceptibility or resistance to ciprofloxacin (MIC ≥ 0.06 μg/ml) was low (0.3 to 2.3%) up to 1995. Between 1995 and 1998 the rate of less-susceptible and resistant strains rose from 6.9 to 13.2%. Among ciprofloxacin-resistant strains (MIC ≥ 1 μg/ml), 81% were highly resistant (MIC ≥ 4 μg/ml). Thirty-five
N. gonorrhoeae
strains (40 isolates) for which ciprofloxacin MICs were 4 to 32 μg/ml were investigated for the frequency and patterns of mutations within the
gyrA
and
parC
genes. The quinolone resistance-determining regions of the
gyrA
and
parC
genes were amplified by PCR, and the amplicons were directly sequenced. Alterations at Ser-91 and Asp-95 in GyrA and a single or double alteration in ParC were identified in 32 strains (91%). Ser-91-to-Phe and Asp-95-to-Gly alterations in GyrA were detected in 28 strains (80%). The most common ParC alteration, Asp-86 to Asn, was found in 19 strains (54%). The strains were analyzed for genetic relationship by pulsed-field gel electrophoresis (PFGE). The analysis showed that nine strains with the same mutation pattern in the
gyrA
and
parC
genes, originating from different geographical areas over 3 years, had the same PFGE patterns after
Spe
I as well as
Nhe
I digestion (only one strain with one band difference in the
Nhe
I pattern), suggesting that a resistant clone had spread worldwide. The results from this study strongly suggest that double
gyrA
mutations plus a
parC
mutation(s) play an important role in the development of high-level fluoroquinolone resistance in
N. gonorrhoeae
.
SHV-1 β-Lactamase Is Mainly a Chromosomally Encoded Species-Specific Enzyme in
Klebsiella pneumoniae
Authors: Chaves José , Ladona Margarita G. , Segura Concepción , Coira Amparo , Reig Roser , Ampurdanés Coral 
Published: July 2002

ABSTRACT

The nature of the SHV-1 β-lactamase gene was analyzed in 97 epidemiologically unrelated
Klebsiella pneumoniae
strains isolated from clinical samples. β-Lactamase bands that focused at a pI of 7.6 (SHV-1-type) in 74 strains, at a pI of 7.1 (LEN-1-type) in 13 strains, and at a pI of 5.4 (TEM-1-type) in 10 strains were detected by analytical isoelectric focusing (IEF). Among the 74 SHV-1-producing strains, 40 had, in addition to the pI 7.6 band, an additional band on IEF: 20 had a band with a pI of 7.1 and 20 had a band with a pI of 5.4. Most of the 74 SHV-1-producing strains (76.7%) carried plasmids. Transfer of β-lactam resistance by conjugation was possible in only 9.3% of the strains tested. SHV-1 gene-specific PCR-restriction fragment length polymorphism (PCR-RFLP) analysis of the chromosomal DNA was positive for 93 of the 97 strains and negative for only 4 of the 10 samples with
K. pneumoniae
TEM-1 producers. In an attempt to approximate the location of the SHV gene locus by endonuclease restriction analysis, RFLP analysis with Southern blotting of chromosomal DNA with a labeled SHV-1 fragment as a probe was used to study the 97 strains. A trial with
Eco
RI showed at least one positive hybridization band for 96 strains; two bands were detected for 8 strains. The hybridization was negative for only one TEM-1 β-lactamase-producing strain. DNA sequence analysis showed no differences in promoter regions or extra stop-triplet sequences; only point mutations determined different allelic variants. The novel SHV-type variants are designated SHV-32 and SHV-33. As a result of the RFLP and sequencing analyses, it can be postulated that the loci for SHV-1 and LEN-1 genes are arranged in tandem. Our results strongly support the hypothesis that the ancestor of the SHV-1 β-lactamase originated from the
K. pneumoniae
chromosome.
Binding Properties of a Peptide Derived from β-Lactamase Inhibitory Protein
Authors: Rudgers Gary W. , Huang Wanzhi , Palzkill Timothy 
Published: July 2002

ABSTRACT

To overcome the antibiotic resistance mechanism mediated by β-lactamases, small-molecule β-lactamase inhibitors, such as clavulanic acid, have been used. This approach, however, has applied selective pressure for mutations that result in β-lactamases no longer sensitive to β-lactamase inhibitors. On the basis of the structure of β-lactamase inhibitor protein (BLIP), novel peptide inhibitors of β-lactamase have been constructed. BLIP is a 165-amino-acid protein that is a potent inhibitor of TEM-1 β-lactamase (
K

i

= 0.3 nM). The cocrystal structure of TEM-1 β-lactamase and BLIP indicates that residues 46 to 51 of BLIP make critical interactions with the active site of TEM-1 β-lactamase. A peptide containing this six-residue region of BLIP was found to retain sufficient binding energy to interact with TEM-1 β-lactamase. Inhibition assays with the BLIP peptide reveal that, in addition to inhibiting TEM-1 β-lactamase, the peptide also inhibits a class A β-lactamase and a class C β-lactamase that are not inhibited by BLIP. The crystal structures of class A and C β-lactamases and two penicillin-binding proteins (PBPs) reveal that the enzymes have similar three-dimensional structures in the vicinity of the active site. This similarity suggests that the BLIP peptide inhibitor may have a broad range of activity that can be used to develop novel small-molecule inhibitors of various classes of β-lactamases and PBPs.
Dicyclic and Tricyclic Diaminopyrimidine Derivatives as Potent Inhibitors of
Cryptosporidium parvum
Dihydrofolate Reductase: Structure-Activity and Structure-Selectivity Correlations
Authors: Nelson Richard G. , Rosowsky Andre 
Published: July 2002

ABSTRACT

A structurally diverse library of 93 lipophilic di- and tricyclic diaminopyrimidine derivatives was tested for the ability to inhibit recombinant dihydrofolate reductase (DHFR) cloned from human and bovine isolates of
Cryptosporidium parvum
(J. R. Vásquez et al., Mol. Biochem. Parasitol. 79:153–165, 1996). In parallel, the library was also tested against human DHFR and, for comparison, the enzyme from
Escherichia coli
. Fifty percent inhibitory concentrations (IC
50
s) were determined by means of a standard spectrophotometric assay of DHFR activity with dihydrofolate and NADPH as the cosubstrates. Of the compounds tested, 25 had IC
50
s in the 1 to 10 μM range against one or both
C. parvum
enzymes and thus were not substantially different from trimethoprim (IC
50
s, ca. 4 μM). Another 25 compounds had IC
50
s of <1.0 μM, and 9 of these had IC
50
s of <0.1 μM and thus were at least 40 times more potent than trimethoprim. The remaining 42 compounds were weak inhibitors (IC
50
s, >10 μM) and thus were not considered to be of interest as drugs useful against this organism. A good correlation was generally obtained between the results of the spectrophotometric enzyme inhibition assays and those obtained recently in a yeast complementation assay (V. H. Brophy et al., Antimicrob. Agents Chemother. 44:1019–1028, 2000; H. Lau et al., Antimicrob. Agents Chemother. 45:187–195, 2001). Although many of the compounds in the library were more potent than trimethoprim, none had the degree of selectivity of trimethoprim for
C. parvum
versus human DHFR. Collectively, the results of these assays comprise the largest available database of lipophilic antifolates as potential anticryptosporidial agents. The compounds in the library were also tested as inhibitors of the proliferation of intracellular
C. parvum
oocysts in canine kidney epithelial cells cultured in folate-free medium containing thymidine (10 μM) and hypoxanthine (100 μM). After 72 h of drug exposure, the number of parasites inside the cells was quantitated by indirect immunofluorescence microscopy. Sixteen compounds had IC
50
s of <3 μM, and five of these had IC
50
s of <0.3 μM and thus were comparable in potency to trimetrexate. The finding that submicromolar concentrations of several of the compounds in the library could inhibit in vitro growth of
C. parvum
in host cells in the presence of thymidine (dThd) and hypoxanthine (Hx) suggests that lipophilic DHFR inhibitors, in combination with leucovorin, may find use in the treatment of intractable
C. parvum
infections.
Effects of Lansoprazole and Amoxicillin on Uptake of [
14
C]Clarithromycin into Gastric Tissue in Rats
Authors: Endo Hiromi , Yoshida Hideo , Ohmi Naoko , Higuchi Shohei 
Published: July 2002

ABSTRACT

Triple therapy consisting of clarithromycin (CLR), lansoprazole (LPZ), and amoxicillin (AMZ) is effective as eradication therapy for patients with peptic ulcer disease and
Helicobacter pylori
infection. We evaluated the effects of LPZ and AMZ on the uptake of [
14
C]CLR into the gastric tissue of rats. After administration of [
14
C]CLR alone or in combination with LPZ and AMZ, the distributions of [
14
C]CLR in the main organs and gastrointestinal tissues were compared. LPZ and AMZ had no effect on the distribution of [
14
C]CLR in any tissue except gastric tissue. The concentration of radioactivity in gastric tissue was several times higher when [
14
C]CLR was administered orally together with LPZ than when it was administered alone. The gastric emptying of [
14
C]CLR became smaller in the case of the coadministration of LPZ. AMZ had no apparent influence on the disposition of [
14
C]CLR. After the intravenous administration of [
14
C]CLR, no effects of drug coadministration were evident. In vitro uptake of [
14
C]CLR into gastric tissue was enhanced in the case of a high-pH environment. The uptake was not influenced by the concurrent presence of LPZ and AMZ. These results suggest that the penetration of [
14
C]CLR possibly depends on elevated gastric pH, as gastric acid secretion was inhibited by LPZ, and this may be a primary factor in explaining why the concentration of [
14
C]CLR at the target site, gastric tissue, was enhanced by the coadministration of LPZ.
Dynamic and Heterogeneous Mutations to Fluconazole Resistance in
Cryptococcus neoformans
Authors: Xu Jianping , Onyewu Chiatogu , Yoell Heather J. , Ali Rabia Y. , Vilgalys Rytas J. , Mitchell Thomas G. 
Published: July 2002

ABSTRACT

Infections with the human pathogenic basidiomycetous yeast
Cryptococcus neoformans
are often treated with fluconazole. Resistance to this antifungal agent has been reported. This study investigated the patterns of mutation to fluconazole resistance in
C. neoformans
in vitro. The MIC of fluconazole was measured for 21 strains of
C. neoformans
. The MICs for these 21 strains differed (0.25 to 4.0 μg/ml), but the strains were selected for this study because they exhibited no growth on plates of yeast morphology agar (YMA) containing 8 μg of fluconazole per ml. To determine their mutation rates, six independent cultures from a single original colony were established for each of the 21 strains. Each culture was then spread densely on a YMA plate with 8 μg of fluconazole per ml. A random set of putative mutants was subcultured, and the MIC of fluconazole was determined for each mutant. The 21 strains evinced significant heterogeneity in their mutation rates. The MICs of the putative mutants ranged widely, from their original MIC to 64 μg of fluconazole per ml. However, for this set of 21 strains, there was no significant correlation between the original MIC for a strain and the mutation rate of that strain; the MIC for the mutant could not be predicted from the original MIC. These results suggest that dynamic and heterogeneous mutational processes are involved in generating fluconazole resistance in
C. neoformans
.
Antibiotic Susceptibilities of Genetically Characterized
Streptococcus milleri
Group Strains
Authors: Tracy Michael , Wanahita Anna , Shuhatovich Yevgeny , Goldsmith Elizabeth A. , Clarridge Jill E. , Musher Daniel M. 
Published: July 2002

ABSTRACT

Previous studies of the antibiotic susceptibility of
Streptococcus milleri
group organisms have distinguished among species by using phenotypic techniques. Using 44 isolates that were speciated by 16S rRNA gene sequencing, we studied the MICs and minimum bactericidal concentrations of penicillin, ampicillin, ceftriaxone, and clindamycin for
Streptococcus intermedius, Streptococcus constellatus,
and
Streptococcus anginosus
. None of the organisms was resistant to beta-lactam antibiotics, although a few isolates were intermediately resistant; one strain of
S. anginosus
was tolerant to ampicillin, and another was tolerant to ceftriaxone. Six isolates were resistant to clindamycin, with representation from each of the three species. Relatively small differences in antibiotic susceptibilities among species of the
S. milleri
group show that speciation is unlikely to be important in selecting an antibiotic to treat infection caused by one of these isolates.
CENTA as a Chromogenic Substrate for Studying β-Lactamases
Authors: Bebrone Carine , Moali Catherine , Mahy Florence , Rival Sandrine , Docquier Jean Denis , Rossolini Gian Maria , Fastrez Jacques , Pratt Rex F. , Frère Jean-Marie , Galleni Moreno 
Published: July 2002

ABSTRACT

CENTA, a chromogenic cephalosporin, is readily hydrolyzed by β-lactamases of all classes except for the
Aeromonas hydrophila
metalloenzyme. Although it cannot practically be used for the detection of β-lactamase-producing strains on agar plates, it should be quite useful for kinetic studies and the detection of the enzymes in crude extracts and chromatographic fractions.
Potent In Vitro Antimalarial Activity of Metacycloprodigiosin Isolated fromStreptomycesspectabilisBCC 4785
Authors: Isaka Masahiko , Jaturapat Amonlaya , Kramyu Jarin , Tanticharoen Morakot , Thebtaranonth Yodhathai 
Published: July 2002

ABSTRACTBioassay-guided fractionation of the extract from the fermentation broth ofStreptomycesspectabilisBCC 4785 led to the isolation of three principle antimalarial agents, metacycloprodigiosin, bafilomycin A1, and spectinabilin. Metacycloprodigiosin exhibited potent in vitro activity againstPlasmodiumfalciparumK1, with a 50% inhibitory concentration of 0.0050 ± 0.0010 μg/ml, while its cytotoxicity was much weaker.
Effects of Specific Antibodies against
Streptococcus pneumoniae
on Pharmacodynamic Parameters of β-Lactams in a Mouse Sepsis Model
Authors: Casal J. , Aguilar L. , Jado I. , Yuste J. , Giménez M. J. , Prieto J. , Fenoll A. 
Published: July 2002

ABSTRACT

A dose-ranging study to investigate the in vivo effects of the presence of specific antibodies on the efficacy of β-lactam treatment of sepsis caused by
Streptococcus pneumoniae
(non-β-lactam-susceptible serotype 6B isolate) was performed with a BALB/c mouse model. Hyperimmune serum was obtained from mice immunized with the heat-inactivated strain. The rate of mortality was 100% in nontreated animals in the absence of specific antibodies. A single injection of a one-half or one-quarter dilution of hyperimmune serum produced 60 to 40% survival rates. In the absence of specific antibodies, the minimal effective doses of amoxicillin and cefotaxime that produced survival rates of 100 and 80% were 25 and 50 mg/kg of body weight (three times a day for up to six doses), respectively. These doses produced times that the levels in serum remained above the MIC (Δ
T
> MICs) ≈30% of the dosing interval. When specific antibodies were present (by administration of a one-half or one-quarter dilution of hyperimmune serum), the minimal effective doses of the antibiotics were 3.12 and 6.25 mg/kg (≈8 times lower), with the Δ
T
> MICs being approximately 3 and 5% of the dosing interval for amoxicillin and cefotaxime, respectively. This in vivo combined pharmacodynamic effect offers possibilities that can be used to address penicillin resistance.