bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ciclopirox Olamine Treatment Affects the Expression Pattern ofCandida albicansGenes Encoding Virulence Factors, Iron Metabolism Proteins, and Drug Resistance Factors
Authors: Niewerth Markus , Kunze Donika , Seibold Michael , Schaller Martin , Korting Hans Christian , Hube Bernhard 
Published: May 2003

ABSTRACTThe hydroxypyridone ciclopirox olamine belongs to the antimycotic drugs used for the treatment of superficial mycoses. In contrast to the azoles and other antimycotic drugs, its specific mode of action is only poorly understood. To investigate the mode of action of ciclopirox olamine on fungal viability, pathogenicity, and drug resistance, we examined the expression patterns of 47Candida albicansgenes in cells grown in the presence of a subinhibitory concentration (0.6 μg/ml) of ciclopirox olamine by reverse transcription-PCR. In addition, we used suppression-subtractive hybridization to further identify genes that are up-regulated in the presence of ciclopirox olamine. The expression of essential genes such asACT1was not significantly modified in cells exposed to ciclopirox olamine. Most putative and known virulence genes such as genes encoding secreted proteinases or lipases had no or only moderately reduced expression levels. In contrast, exposure of cells to ciclopirox olamine led to a distinct up- or down-regulation of genes encoding iron permeases or transporters (FTR1,FTR2,FTH1), a copper permease (CCC2), an iron reductase (CFL1), and a siderophore transporter (SIT1); these effects resembled those found under iron-limited conditions. Addition of FeCl3to ciclopirox olamine-treated cells reversed the effect of the drug. Addition of the iron chelator bipyridine to the growth medium induced similar patterns of expression of distinct iron-regulated genes (FTR1,FTR2). While serum-induced yeast-to-hyphal phase transition ofC. albicanswas not affected in ciclopirox olamine-treated cells in the presence of subinhibitory conditions, a dramatic increase in sensitivity to oxidative stress was noted, which may indicate the reduced activities of iron-containing gene products responsible for detoxification. Although theCandidadrug resistance genesCDR1andCDR2were up-regulated, no change in resistance or increased tolerance could be observed even after an incubation period of 6 months. This was in contrast to control experiments with fluconazole, in which the MICs for cells incubated with this drug had noticeably increased after 2 months. These data support the view that the antifungal activity of ciclopirox olamine may at least be partially caused by iron limitation. Furthermore, neither the expression of certain multiple-drug resistance genes nor other resistance mechanisms causedC. albicansresistance to this drug even after long-term exposure.
Voriconazole Inhibits Fungal Growth without Impairing Antigen Presentation or T-Cell Activation
Authors: Van Epps Heather L. , Feldmesser Marta , Pamer Eric G. 
Published: May 2003

ABSTRACTInvasive aspergillosis (IA) is the most common life-threatening invasive mold infection worldwide. The principal therapy for IA is amphotericin B, despite its known toxicity and immunosuppressive side effects. Studies in animal models of IA suggest a role for T lymphocytes in the pathology of the disease, although the precise role forAspergillus-specific T cells remains undefined. The isolation and characterization of T lymphocytes in animal models of IA are hampered by the rapid outgrowth of the fungus in cultures derived from infected organs. In the present study, we tested the abilities of the antifungal drugs caspofungin acetate and voriconazole to inhibit fungal growth in vitro as a means of maintaining cultures of T cells fromAspergillus-infected mice. We demonstrate that while both antifungal drugs are inhibitory, only voriconazole completely inhibited fungal growth, allowing long-term maintenance of T-cell cultures. In addition, voriconazole had no inhibitory effect on the activation and maturation of dendritic cells or the proliferation of T lymphocytes. Thus, voriconazole appears to be a promising agent for use in in vitro studies ofAspergillus-specific T lymphocytes in animal models of IA.
Worldwide Assessment of Linezolid's Clinical Safety and Tolerability: Comparator-Controlled Phase III Studies
Authors: Rubinstein Ethan , Isturiz Raul , Standiford Harold C. , Smith Leon G. , Oliphant Thomas H. , Cammarata Sue , Hafkin Barry , Le Vu , Remington Jack 
Published: May 2003

ABSTRACTLinezolid, an oxazolidinone antibiotic, has 100% oral bioavailability and favorable activities against gram-positive pathogens including multidrug-resistant staphylococci, enterococci, and pneumococci. Safety assessments were conducted for 2,046 linezolid-treated patients and 2,001 comparator drug-treated patients from seven controlled clinical trials comparing the activities of linezolid and comparator drugs against nosocomial and community-acquired pneumonia, skin and skin structure infections, and methicillin-resistant staphylococcal infections. Drug-related adverse events were primarily transient. The most frequent (≥2%) adverse events caused by linezolid and the comparator drugs were diarrhea (4.3 and 3.2%, respectively;P= 0.074), nausea (3.4 and 2.3%, respectively;P= 0.036), and headache (2.2 and 1.3%, respectively;P= 0.047). Treatment discontinuations due to drug-related events (2.4 and 1.9%, respectively), serious adverse events (11.4 and 10.6%, respectively), and deaths (4.8 and 4.9%, respectively) were similar. No clinically significant drug-related hematologic events were reported, and laboratory safety data were comparable. In the first 6 months of postmarketing surveillance, hematologic abnormalities were reported in 0.1% of linezolid-treated patients, but no irreversible blood dyscrasias were documented. The risk for transient, reversible hematologic effects from treatment with linezolid should be considered together with the clinical benefits associated with its use.
Antimicrobial Resistance of Invasive Pneumococci in Finland in 1999-2000
Authors: Pihlajamäki Marja , Jalava Jari , Huovinen Pentti , Kotilainen Pirkko 
Published: May 2003

ABSTRACT

The resistance patterns and macrolide resistance mechanisms of 910 Finnish invasive pneumococci isolated during 1999 and 2000 were studied. Macrolide resistance was detected in 6.9% of isolates. Penicillin resistance was detected in 1.5% of isolates, and penicillin intermediate resistance was detected in 4.0% of isolates. Active macrolide efflux, mediated by the
mef
(A) gene, was the most common macrolide resistance mechanism. Four macrolide-resistant isolates had mutations in rRNA or ribosomal protein L22.
Tanshinone (
Salviae miltiorrhizae
Extract) Preparations Attenuate Aminoglycoside-Induced Free Radical Formation In Vitro and Ototoxicity In Vivo
Authors: Wang Ai-Mei , Sha Su-Hua , Lesniak Wojciech , Schacht Jochen 
Published: May 2003

ABSTRACT

Antioxidant therapy protects against aminoglycoside-induced ototoxicity in animal models. A clinically suitable antioxidant must not affect the therapeutic efficacy of aminoglycosides or exhibit any side effects of its own. In addition, the treatment should be inexpensive and convenient in order to be implemented in developing countries where the use of aminoglycosides is most common. Standardized
Salviae miltiorrhizae
extracts (Danshen) are used clinically in China and contain diterpene quinones and phenolic acids with antioxidant properties. We combined in vitro and in vivo approaches to investigate the effect of a clinically approved injectable Danshen solution on aminoglycoside-induced free radical generation and ototoxicity. In vitro, Danshen inhibited gentamicin-dependent lipid peroxidation (formation of conjugated dienes from arachidonic acid), as well as the gentamicin-catalyzed formation of superoxide (in a lucigenin-based chemiluminescence assay) and hydroxyl radicals (oxidation of N,N-dimethyl-
p
-nitrosoaniline). Danshen extracts were then administered to adult CBA mice receiving concurrent treatment with kanamycin (700 mg/kg of body weight twice daily for 15 days). Auditory threshold shifts induced by kanamycin (approximately 50 dB) were significantly attenuated. Danshen did not reduce the levels in serum or antibacterial efficacy of kanamycin. These results suggest that herbal medications may be a significantly underexplored source of antidotes for aminoglycoside ototoxicity. Such traditional medicines are widely used in many developing countries and could become an easily accepted and inexpensive protective therapy.
Effects of Pyrimidine and Purine Analog Combinations in the Duck Hepatitis B Virus Infection Model
Authors: Seignères Béatrice , Martin Perrine , Werle Bettina , Schorr Olivier , Jamard Catherine , Rimsky Laurence , Trépo Christian , Zoulim Fabien 
Published: May 2003

ABSTRACTTo design new strategies of antiviral therapy for chronic hepatitis B, we have evaluated the antiviral activity of the combination of amdoxovir (DAPD), emtricitabine [(−)FTC], and clevudine (l-FMAU) in the duck hepatitis B virus (DHBV) model. Using their triphosphate (TP) derivatives in a cell-free system expressing a wild-type active DHBV reverse transcriptase (RT), the three dual combinations exhibited a greater additive inhibitory effect on viral minus-strand DNA synthesis than the single drugs, according to the Bliss independence model. Both dual combinations with DAPD TP were the most efficient while the triple combination increased the inhibitory effect on the DHBV RT activity in comparison with the dual association, however, without additive effect. Postinoculation treatment of experimentally infected primary duck hepatocytes showed that dual and triple combinations potently inhibited viral DNA synthesis during treatment but did not inhibit the reinitiation of viral DNA synthesis after treatment cessation. Preinoculation treatment with the same combinations exhibited antiviral effects on intracellular viral DNA replication, but it was unable to prevent the initial covalently closed circular DNA (cccDNA) formation. Short-term in vivo treatment in acutely infected ducklings showed that the dual combinations were more-potent inhibitors of virus production than the single treatments, with thel-FMAU and FTC combination being the most potent. A longer administration ofl-FMAU and FTC for 4 weeks efficiently suppressed viremia and viral replication. However, no viral clearance from the liver was observed, suggesting that the enhanced antiviral effect of this combination was not sufficient for cccDNA suppression and HBV eradication from infected cells.
Pharmacokinetics and Pharmacodynamics of Cefepime in Patients with Various Degrees of Renal Function
Authors: Tam Vincent H. , McKinnon Peggy S. , Akins Ronda L. , Drusano George L. , Rybak Michael J. 
Published: May 2003

ABSTRACT

This study evaluated the pharmacokinetics of cefepime in 36 patients with different levels of renal function. Pharmacokinetic and pharmacodynamic parameters were calculated using samples obtained at steady state. Patients with creatinine clearance (CL
CR
) of >100 ml/min had more rapid clearance (CL) and a lower minimum concentration in serum (
C
min
).
C
min
in this group was found to be 3.3 ± 3.6 mg/liter (mean and standard deviation), compared to 19.5 ± 21.5 mg/liter in patients with a CL
CR
of between 60 and 100 ml/min (
P
= 0.025) and 14.0 ± 11.5 mg/liter in patients with a CL
CR
of <60 ml/min (
P
= 0.009). Patient data were also analyzed by the nonparametric expectation maximization method and Bayesian forecasting. The median volume of distribution in the central compartment was 27.08 liters. CL and CL
CR
were highly correlated (
P
= 0.00033) according to the equation CL= 0.324 liters/h + (0.0551 × CL
CR
). The median rate constants from the central compartment to the peripheral compartment and from the peripheral compartment to the central compartment were 12.58 and 41.09 h
−1
, respectively. The time-concentration profiles for 1,000 patients (CL
CR
s, 120, 60, and 30 ml/min) each receiving various dosing regimens were simulated by using Monte Carlo simulations. Standard dosing resulted in a
C
min
that was greater than or equal to the MIC in more than 80% of the simulated profiles with MICs ≤2 mg/liter. Current dosing recommendations may be suboptimal for monotherapy of infections due to less susceptible pathogens (e.g., those for which MICs are ≥4 mg/liter), particularly when CL
CR
exceeds 120 ml/min.
Clinical Pharmacokinetics of Cefamandole and Ceftazidime Administered by Continuous Intravenous Infusion
Authors: Berkhout J. , Visser L. G. , van den Broek P. J. , van de Klundert J. A. M. , Mattie H. 
Published: May 2003

ABSTRACT
In view of the results of animal studies as well as theoretical considerations, continuous administration of β-lactam antibiotics should be superior to intermittent administration because of the close relationship between efficacy and the duration of time in which the concentration of unbound antibiotics in plasma remains above the MIC. The aim of the present study was to establish the pharmacokinetic parameters of cefamandole and ceftazidime for patients receiving these cephalosporins by continuous infusion. The interindividual differences in the concentrations in plasma at the steady state were mainly attributable to variations in renal function, as estimated by the rate of creatinine clearance. Using these results, we derived formulas for both cephalosporins that can be used to determine on an individual basis the total daily dose needed to obtain a therapeutic concentration in plasma. These formulas were tested with a group of subsequent patients and proved to be practical and fairly reliable. For some patients, a correction for a possible underestimation of the renal clearance at presentation might be required.
Antimicrobial Resistance in Respiratory Tract
Streptococcus pneumoniae
Isolates: Results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002
Authors: Zhanel George G. , Palatnick Lorraine , Nichol Kimberly A. , Bellyou Tracy , Low Don E. , Hoban Daryl J. 
Published: May 2003

ABSTRACT

A total of 6,991 unique patient isolates of
Streptococcus pneumoniae
were collected from October 1997 to June 2002 from 25 medical centers in 9 of the 10 Canadian provinces. Among these isolates, 20.2% were penicillin nonsusceptible, with 14.6% being penicillin intermediate (MIC, 0.12 to 1 μg/ml) and 5.6% being penicillin resistant (MIC, ≥2 μg/ml). The proportion of high-level penicillin-resistant
S. pneumoniae
isolates increased from 2.4 to 13.8% over the last 3 years of the study, and the proportion of multidrug-resistant
S. pneumoniae
isolates increased from 2.7 to 8.8% over the 5-year period. Resistant rates (intermediate and resistant) among non-β-lactam agents were as follows: macrolides, 9.6 to 9.9%; clindamycin, 3.8%; doxycycline, 5.5%; chloramphenicol, 3.9%; and trimethoprim-sulfamethoxazole, 19.0%. Rates of resistance to non-β-lactam agents were higher among penicillin-resistant strains than among penicillin-susceptible strains. No resistance to vancomycin or linezolid was observed; however, 0.1% intermediate resistance to quinupristin-dalfopristin was observed. The rate of macrolide resistance (intermediate and resistant) increased from 7.9 to 11.1% over the 5 years. For the fluoroquinolones, the order of activity based on the MICs at which 50% of isolates are inhibited (MIC
50
s) and the MIC
90
s was gemifloxacin > clinafloxacin > trovafloxacin > moxifloxacin > grepafloxacin > gatifloxacin > levofloxacin > ciprofloxacin. The investigational compounds ABT-773 (MIC
90
, 0.008 μg/ml), ABT-492 (MIC
90
, 0.015 μg/ml), GAR-936 (tigecycline; MIC
90
, 0.06 μg/ml), and BMS284756 (garenoxacin; MIC
90
, 0.06 μg/ml) displayed excellent activities. Despite decreases in the rates of antibiotic consumption in Canada over the 5-year period, the rates of both high-level penicillin-resistant and multidrug-resistant
S. pneumoniae
isolates are increasing in Canada.
Antimicrobial Resistance in
Haemophilus influenzae
and
Moraxella catarrhalis
Respiratory Tract Isolates: Results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002
Authors: Zhanel George G. , Palatnick Lorraine , Nichol Kimberly A. , Low Don E. ,   The CROSS Study Group, Hoban Daryl J. 
Published: May 2003

ABSTRACT

A total of 7,566 unique patient isolates of
Haemophilus influenzae
and 2,314 unique patient isolates of
Moraxella catarrhalis
were collected between October 1997 and June 2002 from 25 medical centers in 9 of the 10 Canadian provinces. Among the 7,566
H. influenzae
isolates, 22.5% produced β-lactamase, while 92.4% of the 2,314
M. catarrhalis
isolates produced β-lactamase. The incidence of β-lactamase-producing
H. influenzae
isolates decreased significantly over the 5-year study period, from 24.2% in 1997-1998 to 18.6% in 2001-2002 (
P
< 0.01). The incidence of β-lactamase-producing
M. catarrhalis
isolates did not change over the study period. The overall rates of resistance to amoxicillin and amoxicillin-clavulanate for
H. influenzae
were 19.3 and 0.1%, respectively. The rank order of cephalosporin activity based on the MICs at which 90% of isolates were inhibited (MIC
90
s) was cefotaxime > cefixime > cefuroxime > cefprozil > cefaclor. On the basis of the MICs, azithromycin was more active than clarithromycin (14-OH clarithromycin was not tested); however, on the basis of the NCCLS breakpoints, resistance rates were 2.1 and 1.6%, respectively. Rates of resistance to other agents were as follows: doxycycline, 1.5%; trimethoprim-sulfamethoxazole, 14.2%; and chloramphenicol, 0.2%. All fluoroquinolones tested, including the investigational fluoroquinolones BMS284756 (garenoxacin) and ABT-492, displayed potent activities against
H. influenzae
, with MIC
90
s of ≤0.03 μg/ml. The MIC
90
s of the investigational ketolides telithromycin and ABT-773 were 2 and 4 μg/ml, respectively, and the MIC
90
of the investigational glycylcycline GAR-936 (tigecycline) was 4 μg/ml. Among the
M. catarrhalis
isolates tested, the resistance rates derived by using the NCCLS breakpoint criteria for
H. influenzae
were <1% for all antibiotics tested except trimethoprim-sulfamethoxazole (1.5%). In summary, the incidence of β-lactamase-positive
H. influenzae
strains in Canada is decreasing (18.6% in 2001-2002), while the incidence of β-lactamase-positive
M. catarrhalis
strains has remained constant (90.0% in 2001-2002).
Treatment with a Broad-Spectrum Cephalosporin versus Piperacillin-Tazobactam and the Risk for Isolation of Broad-Spectrum Cephalosporin-Resistant
Enterobacter
Species
Authors: Schwaber Mitchell J. , Graham Camilla S. , Sands Bruce E. , Gold Howard S. , Carmeli Yehuda 
Published: May 2003

ABSTRACT

Receipt of a broad-spectrum cephalosporin is a strong risk factor for isolation of broad-spectrum cephalosporin-resistant
Enterobacter
species, and yet the risk from other broad-spectrum β-lactams hydrolyzed by group 1 β-lactamases has not been well characterized. We compared the risk conferred by broad-spectrum cephalosporins to that conferred by piperacillin-tazobactam, alone or in combination with an aminoglycoside or a fluoroquinolone. A retrospective cohort was monitored from treatment onset until a broad-spectrum cephalosporin-resistant
Enterobacter
strain was isolated or the patient was discharged. There were 447 patients in the piperacillin-tazobactam group and 2,341 patients in the broad-spectrum cephalosporin group. Groups were similar in age (mean, 62.5 years). The piperacillin-tazobactam group had a smaller percentage of men (32% versus 44%,
P
< 0.001) and a lower rate of intensive care unit stay (25% versus 38%,
P
< 0.001) but a higher rate of surgery (41% versus 26%,
P
< 0.001). Groups differed in the distribution of comorbidities. Resistant
Enterobacter
strains were isolated from 62 patients, 2% in each group (hazard ratio [RR] = 1.02 [
P
= 0.95]). In multivariable analysis, risk was similar among treatment groups (RR = 0.71 [
P
= 0.32]). Intensive care unit stay and surgery were associated with increased risk (RR = 4.53 [
P
< 0.001] and RR = 1.97 [
P
= 0.015], respectively), fluoroquinolones were protective (RR = 0.24 [
P
= 0.003]), and aminoglycosides did not affect risk (RR = 0.98 [
P
= 0.95]). The protective effect of fluoroquinolones against isolation of broad-spectrum cephalosporin-resistant
Enterobacter
spp. and the equivalence in risk associated with piperacillin-tazobactam and broad-spectrum cephalosporins may have important clinical and epidemiologic implications.
Genetic and Phenotypic Variations of a ResistantPseudomonas aeruginosaEpidemic Clone
Authors: Hocquet Didier , Bertrand Xavier , Köhler Thilo , Talon Daniel , Plésiat Patrick 
Published: May 2003

ABSTRACTFrom May 1997 to December 2001, a serotype O:6 multidrug-resistant strain ofPseudomonas aeruginosacolonized or infected 201 patients in the University Hospital of Besançon (France). The susceptibility profile of this epidemic clone to fluoroquinolones and aminoglycosides was relatively stable during the outbreak but showed important isolate-to-isolate variations (up to 64-fold) in the MICs of β-lactams. Analysis of 18 genotypically related isolates selected on a quaterly basis demonstrated alterations in the two DNA topoisomerases II and IV (Thr83→Ile in GyrA and Ser87→Leu in ParC) and production of an ANT(2")-I enzyme. Although constitutively overproduced in these bacteria, the MexXY efflux system did not appear to contribute significantly to aminoglycoside resistance. β-Lactam resistance was associated with derepression of intrinsic AmpC β-lactamase (with isolate-to-isolate variations of up to 58-fold) and sporadic deficiency in a 46-kDa protein identified as the carbapenem-selective porin OprD. Of the 18 isolates, 14 were also found to overproduce the efflux system MexAB-OprM as a result of alteration of the repressor protein MexR (His107→Pro). However, complementation experiments with the clonedmexRgene demonstrated that MexAB-OprM contributed only marginally to β-lactam and fluoroquinolone resistance. Of the four isolates exhibiting wild-type MexAB-OprM expression despite the MexR alteration, two appeared to harbor secondary mutations in themexA-mexRintergenic region and one harbored secondary mutations in the putative ribosome binding site located upstream of themexAB oprMoperon. In conclusion, this study shows that many mechanisms were involved in the multiresistance phenotype of this highly epidemic strain ofP. aeruginosa. Our results also demonstrate that the clone sporadically underwent substantial genetic and phenotypic variations during the course of the outbreak, perhaps in relation to local or individual selective drug pressures.