bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of Fluconazole MICs with Clinical Outcome in Cryptococcal Infection
Authors: Aller A. I. , Martin-Mazuelos E. , Lozano F. , Gomez-Mateos J. , Steele-Moore L. , Holloway W. J. , Gutiérrez M. J. , Recio F. J. , Espinel-Ingroff A. 
Published: July 2002

ABSTRACT

We have correlated the in vitro results of testing the susceptibility of
Cryptococcus neoformans
to fluconazole with the clinical outcome after fluconazole maintenance therapy in patients with AIDS-associated cryptococcal disease. A total of 28 isolates of
C. neoformans
from 25 patients (24 AIDS patients) were tested. The MICs were determined by the broth microdilution technique by following the modified guidelines described in National Committee for Clinical Standards (NCCLS) document M27-A, e.g., use of yeast nitrogen base medium and a final inoculum of 10
4
CFU/ml. The fluconazole MIC at which 50% of isolates are inhibited (MIC
50
) and MIC
90
, obtained spectrophotometrically after 48 h of incubation, were 4 and 16 μg/ml, respectively. Of the 25 patients studied, 4 died of active cryptococcal disease and 2 died of other causes. Therapeutic failure was observed in five patients who were infected with isolates for which fluconazole MICs were ≥16 μg/ml. Four of these patients had previously had oropharyngeal candidiasis (OPC); three had previously had episodes of cryptococcal infection, and all five treatment failure patients had high cryptococcal antigen titers in either serum or cerebrospinal fluid (titers, >1:4,000). Although 14 of the 18 patients who responded to fluconazole therapy had previously had OPC infections, they each had only a single episode of cryptococcal infection. It appears that the clinical outcome after fluconazole maintenance therapy may be better when the infecting
C. neoformans
strain is inhibited by lower concentrations of fluconazole for eradication (MICs, <16 μg/ml) than when the patients are infected with strains that require higher fluconazole concentrations (MICs, ≥16 μg/ml). These findings also suggest that the MICs determined by the modified NCCLS microdilution method can be potential predictors of the clinical response to fluconazole therapy and may aid in the identification of patients who will not respond to fluconazole therapy.
Evaluation of Voriconazole Pharmacodynamics Using Time-Kill Methodology
Authors: Klepser Michael E. , Malone Dennis , Lewis Russell E. , Ernst Erika J. , Pfaller Michael A. 
Published: July 2002

ABSTRACT

Voriconazole is an investigational azole antifungal agent with activity against a variety of fungal species, including fluconazole-susceptible and -resistant
Candida
species and
Cryptococcus neoformans
. In this study, we employed in vitro time-kill methods to characterize the relationship between concentrations of voriconazole and its fungistatic activity against
Candida albicans
,
Candida glabrata
,
Candida tropicalis
, and
C. neoformans
. Isolates were exposed to voriconazole concentrations ranging from 0.0625 to 16 times the MIC, and the viable colony counts were determined over time. The 50 and 90% effective concentrations (EC
50
and EC
90
, respectively) were determined at 8, 12, and 24 h following the addition of voriconazole. At each time point, near-maximal fungistatic activity, as indicated by the EC
90
, was noted at a drug concentration of approximately three times the MIC. Additionally, EC
50
and EC
90
did not change over time, thus suggesting that the rate of activity was not improved by increasing concentrations. Voriconazole exhibits non-concentration-dependent pharmacodynamic characteristics in vitro.
Efficacy of Oral Cochleate-Amphotericin B in a Mouse Model of Systemic Candidiasis
Authors: Santangelo Rosaria , Paderu Padmaja , Delmas Guillaume , Chen Zi-Wei , Mannino Raphael , Zarif Leila , Perlin David S. 
Published: July 2002

ABSTRACT

Amphotericin B (AMB) remains the principal therapeutic choice for deep mycoses. However, its application is limited by toxicity and a route of administration requiring slow intravenous injection. An oral formulation of this drug is desirable to treat acute infections and provide prophylactic therapy for high-risk patients. Cochleates are a novel lipid-based delivery system that have the potential for oral administration of hydrophobic drugs. They are stable phospholipid-cation crystalline structures consisting of a spiral lipid bilayer sheet with no internal aqueous space. Cochleates containing AMB (CAMB) inhibit the growth of
Candida albicans
, and the in vivo therapeutic efficacy of CAMB administered orally was evaluated in a mouse model of systemic candidiasis. The results indicate that 100% of the mice treated at all CAMB doses, including a low dosage of 0.5 mg/kg of body weight/day, survived the experimental period (16 days). In contrast, 100% mortality was observed with untreated mice by day 12. The fungal tissue burden in kidneys and lungs was assessed in parallel, and a dose-dependent reduction in
C. albicans
from the kidneys was observed, with a maximum 3.5-log reduction in total cell counts at 2.5 mg/kg/day. However, complete clearance of the organism from the lungs, resulting in more than a 4-log reduction, was observed at the same dose. These results were comparable to a deoxycholate AMB formulation administered intraperitoneally at 2 mg/kg/day (
P
< 0.05). Overall, these data demonstrate that cochleates are an effective oral delivery system for AMB in a model of systemic candidiasis.
In Vitro Antiproliferative Effects and Mechanism of Action of the New Triazole Derivative UR-9825 against the Protozoan ParasiteTrypanosoma(Schizotrypanum)cruzi
Authors: Urbina Julio A. , Lira Renee , Visbal Gonzalo , Bartrolí Javier 
Published: July 2002

ABSTRACTWe describe the in vitro antiproliferative effects of the new triazole derivative UR-9825 against the protozoan parasiteTrypanosoma(Schizotrypanum)cruzi, the causative agent of Chagas' disease in Latin America. The compound was found to be extremely active against the cultured (epimastigote) form of the parasite, equivalent to that present in the reduviid vector, with a MIC of 30 nM, a concentration 33-fold lower than that required with the reference compound ketoconazole. At that MIC, growth arrest coincided with depletion of the parasite's 4,14-desmethyl endogenous sterols (ergosterol, 24-ethylcholesta-5,7,22-trien-3b-ol, and precursors) and their replacement by methylated sterols (lanosterol, 24-methylenedihydrolanosterol, and obtusifoliol), as revealed by high-resolution gas chromatography coupled with mass spectrometry. This indicated that the primary mechanism of action of UR-9825 was inhibition of the parasite's sterol C14α demethylase, as seen with other azole derivatives. The phospholipid composition of growth-arrested epimastigotes was also altered, when compared to controls, with a significant increase in the content of phosphatidylethanolamine and phosphatidylserine and a concomitant reduction of the content of phosphatidylcholine. The clinically relevant intracellular amastigote form, grown in cultured Vero cells at 37°C, was even more sensitive to UR-9825, with a MIC of 10 nM, comparable to that for ketoconazole. The results showed that UR-9825 is among the most potent azole derivatives tested against this parasite and support in vivo studies with this compound.
Susceptibilities of
Haemophilus influenzae
and
Moraxella catarrhalis
to ABT-773 Compared to Their Susceptibilities to 11 Other Agents
Authors: Credito Kim L. , Lin Gengrong , Pankuch Glenn A. , Bajaksouzian Saralee , Jacobs Michael R. , Appelbaum Peter C. 
Published: July 2002

ABSTRACT

The activity of the ketolide ABT-773 against
Haemophilus
and
Moraxella
was compared to those of 11 other agents. Against 210
Haemophilus influenzae
strains (39.0% β-lactamase positive), microbroth dilution tests showed that azithromycin and ABT-773 had the lowest MICs (0.5 to 4.0 and 1.0 to 8.0 μg/ml, respectively), followed by clarithromycin and roxithromycin (4.0 to >32.0 μg/ml). Of the β-lactams, ceftriaxone had the lowest MICs (≤0.004 to 0.016 μg/ml), followed by cefixime and cefpodoxime (0.008 to 0.125 and ≤0.125 to 0.25 μg/ml, respectively), amoxicillin-clavulanate (0.125 to 4.0 μg/ml), and cefuroxime (0.25 to 8.0 μg/ml). Amoxicillin was only active against β-lactamase-negative strains, and cefprozil had the highest MICs of all oral cephalosporins tested (0.5 to >32.0 μg/ml). Against 50
Moraxella catarrhalis
strains, all of the compounds except amoxicillin and cefprozil were active. Time-kill studies against 10
H. influenzae
strains showed that ABT-773, at two times the MIC, was bactericidal against 9 of 10 strains, with 99% killing of all strains at the MIC after 24 h; at 12 h, ABT-773 gave 90% killing of all strains at two times the MIC. At 3 and 6 h, killing by ABT-773 was slower, with 99.9% killing of four strains at two times the MIC after 6 h. Similar results were found for azithromycin, with slightly slower killing by erythromycin, clarithromycin, and roxithromycin, especially at earlier times. β-Lactams were bactericidal against 8 to 10 strains at two times the MIC after 24 h, with slower killing at earlier time periods. Most compounds gave good killing of five
M. catarrhalis
strains, with β-lactams killing more rapidly than other drugs. ABT-773 and azithromycin gave the longest postantibiotic effects (PAEs) of the ketolide-macrolide-azalide group tested (4.4 to >8.0 h), followed by clarithromycin, erythromycin, and roxithromycin. β-Lactam PAEs were similar and shorter than those of the ketolide-macrolide-azalide group for all strains tested.
RL-37, an Alpha-Helical Antimicrobial Peptide of the Rhesus Monkey
Authors: Zhao Chengquan , Nguyen Tung , Boo Lee Ming , Hong Teresa , Espiritu Cesar , Orlov Dmitri , Wang Wei , Waring Alan , Lehrer Robert I. 
Published: July 2002

ABSTRACT

Rhesus monkey bone marrow expresses a cathelicidin whose C-terminal domain comprises a 37-residue alpha-helical peptide (RL-37) that resembles human LL-37. Like its human counterpart, RL-37 rapidly permeabilized the membranes of
Escherichia coli
ML-35p and lysed liposomes that simulated bacterial membranes. When tested in media whose NaCl concentrations approximated those of extracellular fluids, RL-37 was considerably more active than LL-37 against staphylococci. Whereas human LL-37 contains five acidic residues and has a net charge of +6, rhesus RL-37 has only two acidic residues and a net charge of +8. Speculating that the multiple acidic residues of human LL-37 reduced its efficacy against staphylococci, we made a peptide (LL-37 pentamide) in which each aspartic acid of LL-37 was replaced by an asparagine and each glutamic acid was replaced by a glutamine. LL-37 pentamide's antistaphylococcal activity was substantially greater than that of LL-37. Thus, although the precursor of LL-37 is induced in human skin keratinocytes by injury or inflammation, its insufficiently cationic antimicrobial domain may contribute to the success of staphylococci in colonizing and infecting human skin.
In Vitro Activity of the Ketolide ABT-773
Authors: Barry Arthur L. , Fuchs Peter C. , Brown Steven D. 
Published: July 2002

ABSTRACT

The in vitro activities of ABT-773, azithromycin, erythromycin, and clindamycin were compared by testing 1,223 clinical isolates selected to represent different species and phenotypes. ABT-773 was particularly potent against staphylococci (the MIC at which 90% of the strains tested were inhibited [MIC
90
] was ≤0.06 μg/ml), including all strains that were macrolide resistant but clindamycin susceptible.
Streptococcus pneumoniae
and other streptococci were inhibited by low concentrations of ABT-773, and that included most erythromycin-resistant strains. Against
Haemophilus influenzae
, ABT-773 and azithromycin were similar in their antibacterial potency (MIC
90
, 4.0 and 2.0 μg/ml, respectively).
Hyperbaric Oxygen as an Adjunct in Zygomycosis: Randomized Controlled Trial in a Murine Model
Authors: Barratt Diana Marie , Van Meter Keith , Asmar Philip , Nolan Terry , Trahan Chris , Garcia-Covarrubias Lisardo , Metzinger Stephen E. 
Published: July 2002

ABSTRACT

Zygomycosis was induced by injecting CD-1 mice with 5 mg of intraperitoneal deferoxamine and then 10
6
CFU of intravenous and intrasinus
Rhizopus arrhizus
. The addition of hyperbaric oxygen (2.0 atm absolute twice daily) to amphotericin B did not improve survival over that achieved with amphotericin B and placebo air treatments.
In Vitro Activities of a New Ketolide, ABT-773, against Multidrug-Resistant Gram-Positive Cocci
Authors: Singh Kavindra V. , Malathum Kumthorn , Murray Barbara E. 
Published: July 2002

ABSTRACT

The in vitro activities of ABT-773 were evaluated against 324 strains of gram-positive bacteria, including multidrug-resistant
Staphylococcus
spp. and
Enterococcus
spp. ABT-773 had lower MIC ranges, MICs at which 50% of isolates are inhibited (MIC
50
s), and MIC
90
s than erythromycin or clindamycin for almost all isolates tested. The MICs of ABT-773 were also lower than those of quinupristin-dalfopristin (Q-D) for methicillin-susceptible
Staphylococcus aureus
,
Rhodococcus
spp., and
Streptococcus
spp., while the MICs of Q-D were lower than those of ABT-773 for methicillin-resistant
S. aureus
and
Enterococcus faecium
, including vancomycin-resistant isolates.
Resistance and Adaptation to Quinidine inSaccharomyces cerevisiae: Role ofQDR1(YIL120w), Encoding a Plasma Membrane Transporter of the Major Facilitator Superfamily Required for Multidrug Resistance
Authors: Nunes Patrı́cia A. , Tenreiro Sandra , Sá-Correia Isabel 
Published: July 2002

ABSTRACTAs predicted based on structural considerations, we show results indicating that the member of the major facilitator superfamily encoded bySaccharomyces cerevisiaeopen reading frameYIL120wis a multidrug resistance determinant. Yil120wp was implicated in yeast resistance to ketoconazole and quinidine, but not to the stereoisomer quinine; the gene was thus namedQDR1. Qdr1p was proved to alleviate the deleterious effects of quinidine, revealed by the loss of cell viability following sudden exposure of the unadapted yeast population to the drug, and to allow the earlier eventual resumption of exponential growth under quinidine stress. However,QDR1gene expression had no detectable effect on the susceptibility of yeast cells previously adapted to quinidine. Fluorescence microscopy observation of the distribution of the Qdr1-green fluorescent protein fusion protein in living yeast cells indicated that Qdr1p is a plasma membrane protein. We also show experimental evidence indicating that yeast adaptation to growth with quinidine involves the induction of active expulsion of the drug from preloaded cells, despite the fact that this antiarrhythmic and antimalarial quinoline ring-containing drug is not present in the yeast natural environment. However, we were not able to prove that Qdr1p is directly implicated in this export. Results clearly suggest that there are other unidentified quinidine resistance mechanisms that can be used in the absence ofQDR1.
C-Terminal Region of
Pseudomonas aeruginosa
Outer Membrane Porin OprD Modulates Susceptibility to Meropenem
Authors: Epp Simone F. , Köhler Thilo , Plésiat Patrick , Michéa-Hamzehpour Mehri , Frey Joachim , Pechère Jean-Claude 
Published: July 2002

ABSTRACT

We investigated the unusual susceptibility to meropenem observed for seven imipenem-resistant clinical isolates of
Pseudomonas aeruginosa
. These strains were genetically closely related, expressed OprD, as determined by Western blot analyses, and were resistant to imipenem (>5 μg/ml) but susceptible to meropenem (<1 μg/ml). The
oprD
genes from two isolates were entirely sequenced, and their deduced protein sequences showed 93% identity with that of OprD of strain PAO1. The major alteration consisted of the replacement of a stretch of 12 amino acids, located in putative external loop L7 of OprD, by a divergent sequence of 10 amino acid residues. The
oprD
gene variants and the wild-type
oprD
gene were cloned and expressed in a defined
oprD
mutant. The meropenem MICs for strains carrying the
oprD
genes from clinical isolates were four times lower than that for the strain carrying the wild-type
oprD
gene. Imipenem activities, however, were comparable for all strains. Furthermore, meropenem hypersusceptibility was obtained with a hybrid OprD porin that consisted of the PAO1
oprD
gene containing loop L7 from a clinical isolate. These results show that the C-terminal portion of OprD, in particular, loop L7, was responsible for the unusual meropenem hypersusceptibility. Competition experiments suggested that the observed OprD modifications in the clinical isolates did not affect antagonism between imipenem and the basic amino acid
l
-lysine. We further propose that shortening of putative loop L7 of the OprD porin by 2 amino acid residues sufficiently opens the porin channel to allow optimal penetration of meropenem and increase its activity. In contrast, this alteration would not affect susceptibility to a smaller carbapenem molecule, such as imipenem.
Multidrug-Resistant Strains of
Neisseria gonorrhoeae
in Greece
Authors: Mavroidi Angeliki , Tzouvelekis Leonidas S. , Kyriakis Kyriakos P. , Avgerinou Helen , Daniilidou Maria , Tzelepi Eva 
Published: July 2002

ABSTRACT

Eighty-seven out of 575 gonococci isolated in Greece from 1991 to 1998 belonged to serovar Bropyst and exhibited resistance to penicillin, tetracycline, erythromycin, and chloramphenicol. Conventional and molecular typing showed three clusters, A, B, and C, that were associated with networks of high- frequency transmitters (cluster A with homosexuals and clusters B and C with refugees from Eastern Europe). Study of one isolate revealed mutations in the
penA, mtrR
, and
porB
genes that may explain the multidrug-resistant phenotype.
Comparison of Fractional Inhibitory Concentration Index with Response Surface Modeling for Characterization of In Vitro Interaction of Antifungals against Itraconazole-Susceptible and -ResistantAspergillus fumigatusIsolates
Authors: Te Dorsthorst D. T. A. , Verweij P. E. , Meis J. F. G. M. , Punt N. C. , Mouton J. W. 
Published: July 2002

ABSTRACTAlthough the fractional inhibitory concentration (FIC) index is most frequently used to define or to describe drug interactions, it has some important disadvantages when used for drugs against filamentous fungi. This includes observer bias in the determination of the MIC and no agreement on the endpoints (MIC-0, MIC-1, or MIC-2 [≥95, ≥75, and ≥50% growth inhibition, respectively]) when studying drug combinations. Furthermore, statistical analysis and comparisons are troublesome. The use of a spectrophotometric method to determine the effect of drug combinations yields quantitative data and permits the use of model fits to the whole response surface. We applied the response surface model described by Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol. Rev. 47:331-385, 1995) to determine the interaction coefficient alpha (ICα) using a program developed for that purpose and compared the results with FIC indices. The susceptibilities of amphotericin B (AM), itraconazole (IT), and terbinafine (TB) were tested either alone or in combination against 10 IT-susceptible (IT-S) and 5 IT-resistant (IT-R) clinical strains ofAspergillus fumigatususing a modified checkerboard microdilution method that employs the dye MTT [3-(4,5-dimethyl-2-thiazyl)2,5-diphenyl-2H-tetrazolium bromide]. Growth in each well was determined by a spectrophotometer. FIC indices were determined and ICα values were estimated for each organism strain combination, and the latter included error estimates. Depending on the MIC endpoint used, the FIC index ranged from 1.016 to 2.077 for AM-IT, from 0.544 to 1.767 for AM-TB, and from 0.656 to 0.740 for IT-TB for the IT-S strains. For the IT-R strains the FIC index ranged from 0.308 to 1.767 for AM-IT, from 0.512 to 1.646 for AM-TB, and from 0.403 to 0.497 for IT-TB. The results indicate that the degree of interaction is not only determined by the agents themselves but also by the choice of the endpoint. Estimates of the ICα values showed more consistent results. Although the absolute FIC indices were difficult to interpret, there was a good correlation with the results obtained using the ICα values. The combination of AM with either IT or TB was antagonistic in vitro, whereas the combination of IT and TB was synergistic in vitro for both IT-S and IT-R strains. The use of response surface modeling to determine the interaction of drugs against filamentous fungi is promising, and more consistent results are obtained by this method than by using FIC indices.
Interaction between Polyamines and Bacterial Outer Membranes as Investigated with Ion-Selective Electrodes
Authors: Katsu Takashi , Nakagawa Hideki , Yasuda Keiko 
Published: July 2002

ABSTRACT

We analyzed the interaction between polyamines and the outer membrane of
Escherichia coli
cells using potentiometric measurements with Ca
2+
, tetraphenylphosphonium (TPP
+
), and K
+
electrodes. The Ca
2+
electrode was used to examine the ability of the polyamines to release Ca
2+
from the outer membrane. The TPP
+
electrode was used to examine the ability to permeabilize the outer membrane, since the uptake of TPP
+
was enhanced when the permeability barrier of the outer membrane was disrupted. The K
+
electrode was used to examine permeabilization in the cytoplasmic membrane by monitoring the efflux of K
+
in cytosol. Although Ca
2+
release was remarkably enhanced by increasing the number of amino groups in polyamines, no TPP
+
uptake was observed with polyamines of a simple structure, such as ethylenediamine, spermidine, and spermine. TPP
+
uptake was observed when appropriate lipophilic moieties were further attached to the polyamines with three or four amino groups, indicating that the existence of bulky moieties as well as the number of amino groups is important to induce outer membrane permeabilization. Thus, 1-naphthylacetylspermine and
N,N
′-bis[6-[[(2-methoxyphenyl)methyl]amino]hexyl]-1,8-octanediamine (methoctramine) were especially effective in increasing the permeability of the outer membrane of
E. coli
cells, being comparable to polymyxin B nonapeptide, a well-known cationic peptide showing such action.
Origin and Evolution of the AmpC β-Lactamases ofCitrobacter freundii
Authors: Barlow Miriam , Hall Barry G. 
Published: July 2002

ABSTRACTTo determine whether the widespread clinical use of β-lactams has been selective forCitrobacter freundii-derived alleles of plasmidampCgenes, we generated a Bayesian consensus phylogeny of the publishedampCsequences and compared the MICs of 16 β-lactam antibiotics forEscherichia colistrains containing cloned copies of theC. freundii ampCalleles. We found that for the majority of compounds investigated, there has been essentially no increase in β-lactam resistance conferred by those alleles. We also found thatampCalleles from the chromosomes of two β-lactam-sensitiveC. freundiistrains isolated in the 1920s, before the clinical use of antibiotics, were as effective at providing β-lactam resistance inE. colias were the plasmid-borne alleles from β-lactam-resistant clinical isolates. These results suggest that selection for increased resistance to β-lactam antibiotics has not been a significant force directing the evolution of theC. freundii ampCalleles found in β-lactam-resistant clinical isolates.