bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determinants of Ceftazidime Clearance by Continuous Venovenous Hemofiltration and Continuous Venovenous Hemodialysis
Authors: Matzke Gary R. , Frye Reginald F. , Joy Melanie S. , Palevsky Paul M. 
Published: July 2002

ABSTRACT

Although several dosage adjustment regimens have been proposed, there is little quantitative information to guide the initiation of ceftazidime therapy in patients who are receiving continuous renal replacement therapy. To determine the clearance of ceftazidime by continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), we performed controlled clearance studies with stable hemodialysis patients with three hemofilters: a 0.6-m
2
acrylonitrile copolymer (AN69; Hospal) filter, a 2.1-m
2
polymethylmethacrylate filter (PMMA; Toray) filter and a 0.65-m
2
polysulfone (PS; Fresenius) filter. Subjects received 1,000 mg of ceftazidime intravenously prior to the start of a clearance study. The concentration of ceftazidime in multiple plasma and dialysate or ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (CI
diffusion
) and sieving coefficients of ceftazidime were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and the patient as a random effect. The fraction of ceftazidime bound to plasma proteins was 17% ± 7% (range, 10 to 25%). The clearances of ceftazidime, urea, and creatinine by CVVHD were essentially constant at blood flow rates of 75 to 250 ml/min for all three filters. Significant linear relationships (
P
< 0.0001) were observed between CI
diffusion
of ceftazidime and clearance of urea for all three filters: AN69 (slope = 0.83), PMMA (slope = 0.89), and PS (slope = 1.03). Ceftazidime clearance was membrane independent during CVVH and CVVHD. CVVH and CVVHD can significantly augment the clearance of ceftazidime. Dosing strategies for initiation of ceftazidime therapy in patients receiving CVVH and CVVHD are proposed.
Identification and Characterization of the Penicillin-Binding Protein 2a of
Streptococcus pneumoniae
and Its Possible Role in Resistance to β-Lactam Antibiotics
Authors: Zhao Genshi , Meier Timothy I. , Hoskins Joann , McAllister Kelly A. 
Published: July 2002

ABSTRACT

To further understand the role of penicillin-binding protein 2a (PBP 2a) of
Streptococcus pneumoniae
in penicillin resistance, we confirmed the identity of the protein as PBP 2a. The PBP 2a protein migrated electrophoretically to a position corresponding to that of PBP 2x, PBP 2a, and PBP 2b of
S. pneumoniae
and was absent in a
pbp2a
insertional mutant of
S. pneumoniae
. We found that the affinities of PBP 2a for penicillins were lower than for cephalosporins and a carbapenem. When compared with other
S. pneumoniae
PBPs, PBP 2a exhibited lower affinities for β-lactam antibiotics, especially penicillins. Therefore, PBP 2a is a low-affinity PBP for β-lactam antibiotics in
S. pneumoniae.
Dose-Dependent Pharmacokinetics of Amphotericin B Lipid Complex in Rabbits
Authors: Walsh Thomas J. , Jackson Andre J. , Lee James W. , Amantea Michael , Sein Tin , Bacher John , Zech Loren 
Published: July 2002

ABSTRACT
Amphotericin B lipid complex (ABLC) was recently approved by the Food and Drug Administration for treatment of patients with invasive fungal infections who are intolerant of or refractory to conventional amphotericin B therapy. Little is known, however, about the pharmacokinetics of this new antifungal compound. We therefore investigated the pharmacokinetics of ABLC in comparison with those of conventional desoxycholate amphotericin B (DAmB) in rabbits. The pharmacokinetics of DAmB in a rabbit model were similar to those previously reported in humans. The pharmacokinetics of ABLC differed substantially from those of DAmB. Plasma amphotericin B levels following ABLC administration were 10 times lower than those following administration of an equal dosage of DAmB. The levels of ABLC in whole blood were approximately 40 times greater than those in plasma. The ABLC model differed from the DAmB model by (i) a dose- and time-dependent uptake and return between the plasma compartment and apparent cellular components of the blood-sediment compartment and (ii) time-dependent tissue uptake and return to plasma from serially connected compartments. Following infusion of ABLC, there was a nonlinear uptake into the apparent cellular components of the blood-sediment compartment. This uptake was related to the reciprocal of the integral of the total amount of drug infused (i.e., the more drug infused the greater the fractional uptake between 0.5 and 5 mg/kg of body weight for ABLC). The transfer of drug from plasma to the cellular components of the blood-sediment compartment resulted in initial uptake followed by rapid redistribution back to the plasma. The study describes a detailed model of the pharmacokinetics of ABLC and characterizes a potential role of the cellular components of the blood-sediment compartment in the distribution of this new antifungal compound in tissue.
Mutant Prevention Concentration as a Measure of Antibiotic Potency: Studies with Clinical Isolates of
Mycobacterium tuberculosis
Authors: Dong Yuzhi , Zhao Xilin , Kreiswirth Barry N. , Drlica Karl 
Published: July 2002

ABSTRACT

The mutant prevention concentration (MPC) of a C-8-methoxy fluoroquinolone exhibited a narrow distribution for 14 genetically diverse clinical isolates of
Mycobacterium tuberculosis
, indicating that results from single-isolate studies are likely to be representative. When one isolate was challenged with a variety of antituberculosis agents, C-8-methoxy fluoroquinolones were exceptional in having MPCs below the maximum concentration attained in serum by use of commonly recommended doses.
Mechanisms of Streptomycin Resistance: Selection of Mutations in the 16S rRNA Gene Conferring Resistance
Authors: Springer Burkhard , Kidan Yishak G. , Prammananan Therdsak , Ellrott Kerstin , Böttger Erik C. , Sander Peter 
Published: July 2002

ABSTRACT

Chromosomally acquired streptomycin resistance is frequently due to mutations in the gene encoding the ribosomal protein S12,
rpsL
. The presence of several rRNA operons (
rrn
) and a single
rpsL
gene in most bacterial genomes prohibits the isolation of streptomycin-resistant mutants in which resistance is mediated by mutations in the 16S rRNA gene (
rrs
). Three strains were constructed in this investigation:
Mycobacterium smegmatis rrnB
,
M. smegmatis rpsL
3+
, and
M. smegmatis rrnB rpsL
3+
.
M. smegmatis rrnB
carries a single functional
rrn
operon, i.e.,
rrnA
(comprised of 16S, 23S, and 5S rRNA genes) and a single
rpsL
+
gene;
M. smegmatis rpsL
3+
is characterized by the presence of two
rrn
operons (
rrnA
and
rrnB
) and three
rpsL
+
genes; and
M. smegmatis rrnB rpsL
3+
carries a single functional
rrn
operon (
rrnA
) and three
rpsL
+
genes. By genetically altering the number of
rpsL
and
rrs
alleles in the bacterial genome, mutations in
rrs
conferring streptomycin resistance could be selected, as revealed by analysis of streptomycin-resistant derivatives of
M. smegmatis rrnB rpsL
3+
. Besides mutations well known to confer streptomycin resistance, novel streptomycin resistance conferring mutations were isolated. Most of the mutations were found to map to a functional pseudoknot structure within the 530 loop region of the 16S rRNA. One of the mutations observed, i.e., 524G→C, severely distorts the interaction between nucleotides 524G and 507C, a Watson-Crick interaction which has been thought to be essential for ribosome function. The use of the single rRNA allelic
M. smegmatis
strain should help to elucidate the principles of ribosome-drug interactions.
DPC 681 and DPC 684: Potent, Selective Inhibitors of Human Immunodeficiency Virus Protease Active against Clinically Relevant Mutant Variants
Authors: Kaltenbach Robert F. , Trainor George , Getman Daniel , Harris Greg , Garber Sena , Cordova Beverly , Bacheler Lee , Jeffrey Susan , Logue Kelly , Cawood Pamela , Klabe Ronald , Diamond Sharon , Davies Marc , Saye Joanne , Jona Janan , Erickson-Viitanen Susan 
Published: July 2002

ABSTRACTHuman immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of many highly active antiretroviral therapy regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross-resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate to suppress preexisting resistant mutant variants and/or to inhibit de novo-generated resistant mutant variants. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at the trough. We have optimized a series of substituted sulfonamides and evaluated the inhibitors against laboratory strains and clinical isolates of HIV type 1 (HIV-1), including viruses with mutations in the protease gene. In addition, serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC90). Two compounds resulting from our studies, designated DPC 681 and DPC 684, are potent and selective inhibitors of HIV protease with IC90s for wild-type HIV-1 of 4 to 40 nM. DPC 681 and DPC 684 showed no loss in potency toward recombinant mutant HIVs with the D30N mutation and a fivefold or smaller loss in potency toward mutant variants with three to five amino acid substitutions. A panel of chimeric viruses constructed from clinical samples from patients who failed PI-containing regimens and containing 5 to 11 mutations, including positions 10, 32, 46, 47, 50, 54, 63, 71, 82, 84, and 90 had mean IC50values of <20 nM for DPC 681 and DPC 681, respectively. In contrast, marketed PIs had mean IC50values ranging from 200 nM (amprenavir) to >900 nM (nelfinavir).
Association of Genetic Mutations in
Plasmodium vivax dhfr
with Resistance to Sulfadoxine-Pyrimethamine: Geographical and Clinical Correlates
Authors: Imwong Mallika , Pukrittakayamee Sasithon , Looareesuwan Sornchai , Pasvol Geoffrey , Poirreiz Jean , White Nicholas J. , Snounou Georges 
Published: July 2002

ABSTRACT

Mutations in the
Plasmodium falciparum
gene (
dhfr
) encoding dihydrofolate reductase are associated with resistance to antifols.
Plasmodium vivax
, the more prevalent malaria parasite in Asia and the Americas, is considered antifol resistant. Functional polymorphisms in the
dhfr
gene of
P. vivax
(
pvdhfr
) were assessed by PCR-restriction fragment length polymorphism using blood samples taken from 125 patients with acute vivax malaria from three widely separated locations, Thailand (
n
= 100), India (
n
= 16), and Madagascar and the Comoros Islands (
n
= 9). Upon evaluation of the three important codons (encoding residues 57, 58, and 117) of
P. vivax dhfr
(
pvdhfr
), double- or triple-mutation genotypes were found in all but one case from Thailand (99%), in only three cases from India (19%) and in no cases from Madagascar or the Comoros Islands (
P
< 0.0001). The
dhfr
PCR products of
P. vivax
from 32 Thai patients treated with the antifolate sulfadoxine-pyrimethamine (S-P) were investigated. All samples showed either double (53%) or triple (47%) mutations. Following treatment, 34% of the patients had early treatment failures and only 10 (31%) of the patients cleared their parasitemias for 28 days. There were no significant differences in cure rates, but parasite reduction ratios at 48 h were significantly lower for patients whose samples showed triple mutations than for those whose samples showed double mutations (
P
= 0.01). The three mutations at the
pvdhfr
codons for residues 57, 58, and 117 are associated with high levels of S-P resistance in
P. vivax
. These mutations presumably arose from selection pressure.
Comparative Bactericidal Activities of Ciprofloxacin, Clinafloxacin, Grepafloxacin, Levofloxacin, Moxifloxacin, and Trovafloxacin against
Streptococcus pneumoniae
in a Dynamic In Vitro Model
Authors: Klepser Michael E. , Ernst Erika J. , Petzold C. Rosemarie , Rhomberg Paul , Doern Gary V. 
Published: July 2002

ABSTRACT

Several new quinolones that exhibit enhanced in vitro activity against
Streptococcus pneumoniae
have been developed. Using a dynamic in vitro model, we generated time-kill data for ciprofloxacin, clinafloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin against three isolates of quinolone-susceptible
S. pneumoniae
. Three pharmacokinetic profiles were simulated for each of the study agents (0.1, 1, and 10 times the area under the concentration-time curve [AUC]). Target 24-h AUCs were based upon human pharmacokinetic data resulting from the maximal daily doses of each agent. Ciprofloxacin was the least active agent against all three isolates. With regimens that simulated the human 24-h AUC, ciprofloxacin resulted in an initial, modest decline in the numbers of CFU per milliliter; however, by 48 h the numbers of CFU per milliliter returned to or exceeded the starting inoculum. At the AUC, levofloxacin resulted in variable bacteriostatic and bactericidal activities against the isolates. The remaining agents yielded bactericidal (99.9% reduction) activity by 48 h with regimens that simulated the AUC. At 0.1 time the AUC ciprofloxacin and levofloxacin produced no inhibitory effect, grepafloxacin exhibited bacteriostatic activity, trovafloxacin had mixed static and cidal activities, and clinafloxacin and moxifloxacin caused significant reductions in the numbers of CFU per milliliter by 48 h. All six agents produced cidal activity at 10 times the AUC. In this dynamic in vitro model of infection, the quinolones demonstrated various degrees of activity against
S. pneumoniae
. The rank order of activity, with respect to bactericidal effect, was ciprofloxacin (least active) ≪ levofloxacin < grepafloxacin, trovafloxacin < clinafloxacin and moxifloxacin (most active). The rank order of the agents with respect to the selection of resistance was ciprofloxacin (most likely) > grepafloxacin, moxifloxacin, and trovafloxacin > levofloxacin > clinafloxacin.
Peptide Deformylase as an Antibacterial Drug Target: Assays for Detection of Its Inhibition in
Escherichia coli
Cell Homogenates and Intact Cells
Authors: Apfel Christian M. , Evers Stefan , Hubschwerlen Christian , Pirson Wolfgang , Page Malcolm G. P. , Keck Wolfgang 
Published: July 2002

ABSTRACT

An assay was developed to determine the activity of peptide deformylase (PDF) inhibitors under conditions as close as possible to the physiological situation. The assay principle is the detection of N-terminal [
35
S]methionine labeling of a protein that contains no internal methionine. If PDF is active, the deformylation of the methionine renders the peptide a substrate for methionine aminopeptidase, resulting in the removal of the N-terminal methionine label. In the presence of a PDF inhibitor, the deformylation is blocked so that the N-formylated peptide is not processed and the label is detected. Using this assay, it is possible to determine the PDF activity under near-physiological conditions in a cell-free transcription-translation system as well as in intact bacterial cells.
Activities of the Combination of Quinupristin-Dalfopristin with Rifampin In Vitro and in Experimental Endocarditis Due to
Staphylococcus aureus
Strains with Various Phenotypes of Resistance to Macrolide-Lincosamide-Streptogramin Antibiotics
Authors: Zarrouk Virginie , Bozdogan Bülent , Leclercq Roland , Garry Louis , Feger Celine , Carbon Claude , Fantin Bruno 
Published: July 2002

ABSTRACT

We evaluated the activities of quinupristin-dalfopristin (Q-D), alone or in combination with rifampin, against three strains of
Staphylococcus aureus
susceptible to rifampin (MIC, 0.06 μg/ml) and to Q-D (MICs, 0.5 to 1 μg/ml) but displaying various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics:
S. aureus
HM1054 was susceptible to quinupristin and dalfopristin (MICs of 8 and 4 μg/ml, respectively); for
S. aureus
RP13, the MIC of dalfopristin was high (MICs of quinupristin and dalfopristin for strain RP13, 8 and 32 μg/ml, respectively); and
S. aureus
HM1054R was obtained after conjugative transfer of macrolide-lincosamide-streptogramin B constitutive resistance to HM1054, and the MIC of quinupristin for this strain was high (MICs of quinupristin and dalfopristin, 64 and 4 μg/ml, respectively). In vitro time-kill curve studies showed no difference between Q-D and rifampin, at a concentration of four times the MIC, against the three strains. Rabbits with aortic endocarditis were treated 4 days with Q-D, rifampin, or their combination. In vivo, the combination was highly bactericidal and synergistic against strains susceptible to quinupristin (HM1054 and RP13) and sterilized 94% of the animals. In contrast, the combination was neither synergistic nor bactericidal against the quinupristin-resistant strain (HM1054R) and did not prevent the emergence of mutants resistant to rifampin. We conclude that the in vivo synergistic and bactericidal activity of the combination of Q-D and rifampin against
S. aureus
is predicted by the absence of resistance to quinupristin but not by in vitro combination studies.
Vancomycin and Ceftazidime Bioactivities Persist for at Least 2 Weeks in the Lumen in Ports: Simplifying Treatment of Port-Associated Bloodstream Infections by Using the Antibiotic Lock Technique
Authors: Haimi-Cohen Yishai , Husain Neghma , Meenan Jerry , Karayalcin Gungor , Lehrer Michael , Rubin Lorry G. 
Published: July 2002

ABSTRACT
The residual antibiotic concentration of vancomycin (2 mg/ml)- or ceftazidime (2 mg/ml)-heparin solutions instilled in ports in pediatric hematology-oncology patients 1 to 34 days earlier was measured. Antibiotic concentrations of ≥100 μg of either antibiotic per ml persisted for at least 21 days. For treatment of lumenal port infections, antibiotic-heparin dwell times of ≥2 weeks may be appropriate.
Contributions of the 8-Methoxy Group of Gatifloxacin to Resistance Selectivity, Target Preference, and Antibacterial Activity against
Streptococcus pneumoniae
Authors: Fukuda Hideyuki , Kishii Ryuta , Takei Masaya , Hosaka Masaki 
Published: July 2002

ABSTRACT

Gatifloxacin (8-methoxy, 7-piperazinyl-3′-methyl) at the MIC selected mutant strains that possessed
gyrA
mutations at a low frequency (3.7 × 10
−9
) from wild-type strain
Streptococcus pneumoniae
IID553. AM-1147 (8-methoxy, 7-piperazinyl-3′-
H
) at the MIC or higher concentrations selected no mutant strains. On the other hand, the respective 8-H counterparts of these two compounds, AM-1121 (8-
H
, 7-piperazinyl-3′-methyl) and ciprofloxacin (8-
H
, 7-piperazinyl-3′-
H
), at one and two times the MIC selected mutant strains that possessed
parC
mutations at a high frequency (>2.4 × 10
−6
). The MIC of AM-1147 increased for the
gyrA
mutant strains but not for the
parC
mutant strains compared with that for the wild-type strain. These results suggest that fluoroquinolones that harbor 8-methoxy groups select mutant strains less frequently and prefer DNA gyrase, as distinct from their 8-H counterparts. The in vitro activities of gatifloxacin and AM-1147 are twofold higher against the wild-type strain, eight- and twofold higher against the first-step
parC
and
gyrA
mutant strains, respectively, and two- to eightfold higher against the second-step
gyrA
and
parC
double mutant strains than those of their 8-H counterparts. These results indicate that the 8-methoxy group contributes to enhancement of antibacterial activity against target-altered mutant strains as well as the wild-type strain. It is hypothesized that the 8-methoxy group of gatifloxacin increases the level of target inhibition, especially against DNA gyrase, so that it is nearly the same as that for topoisomerase IV inhibition in the bacterial cell, leading to potent antibacterial activity and a low level of resistance selectivity.
Pharmacokinetics and Tissue Penetration of Linezolid following Multiple Oral Doses
Authors: Gee Thekli , Ellis Richard , Marshall Gillian , Andrews Jenny , Ashby Janet , Wise Richard 
Published: July 2002

ABSTRACT
The pharmacokinetics of multiple-dose linezolid were determined following administration of five 600-mg oral doses given every 12 h to each of six healthy male volunteers. Concentrations of the drug were determined in plasma and inflammatory blister fluid using high-pressure liquid chromatography. A mean peak concentration in plasma of 18.3 μg/ml (standard deviation [SD], 6.0) was attained at a mean time of 0.7 h (SD, 0.3) after the final dose. The penetration into the inflammatory fluid was 104% (SD, 20.7). A mean peak concentration of 16.4 μg/ml (SD, 10.6) was attained in the inflammatory fluid at 3 h (SD, 0.6) after the final dose. The elimination half-life from serum and inflammatory fluid was 4.9 (SD, 1.8) and 5.7 (SD, 1.7) h, respectively. The area under the concentration-time curve in plasma and blister fluid was 140.3 (SD, 73.1) and 155.3 (SD, 80.1) μg · h/ml, respectively. These data suggest that linezolid has good tissue penetration, and we can predict that it will be successful in the treatment of a variety of gram-positive infections.
Standardized Method for In Vitro Antifungal Susceptibility Testing of
Candida albicans
Biofilms
Authors: Ramage Gordon , Vande Walle Kacy , Wickes Brian L. , López-Ribot José L. 
Published: July 2002

ABSTRACT

Candida albicans
is implicated in many biomaterial-related infections. Typically, these infections are associated with biofilm formation. Cells in biofilms display phenotypic traits that are dramatically different from those of their free-floating planktonic counterparts and are notoriously resistant to antimicrobial agents. Consequently, biofilm-related infections are inherently difficult to treat and to fully eradicate with normal treatment regimens. Here, we report a rapid and highly reproducible microtiter-based colorimetric assay for the susceptibility testing of fungal biofilms, based on the measurement of metabolic activities of the sessile cells by using a formazan salt reduction assay. The assay was used for in vitro antifungal susceptibility testing of several
C. albicans
strains grown as biofilms against amphotericin B and fluconazole and the increased resistance of
C. albicans
biofilms against these antifungal agents was demonstrated. Because of its simplicity, compatibility with a widely available 96-well microplate platform, high throughput, and automation potential, we believe this assay represents a promising tool for the standardization of in vitro antifungal susceptibility testing of fungal biofilms.
Single-Dose Pharmacokinetics and Penetration of BMS 284756 into an Inflammatory Exudate
Authors: Wise R. , Gee T. , Marshall G. , Andrews J. M. 
Published: July 2002

ABSTRACT
The pharmacokinetics of a single dose of BMS 284756 were determined following oral administration of a 600-mg dose to eight healthy male volunteers. Concentrations of the drug were measured in plasma and a cantharidine-induced inflammatory exudate by a microbiological assay. The mean peak concentration in plasma of 10.4 μg/ml (standard deviation [SD], 1.3 μg/ml) was attained at a mean time of 1.2 h (SD, 0.5 h) after the dose. The penetration into the inflammatory exudate was 82% (SD, 15.7%). A mean peak concentration of 7.2 μg/ml (SD, 2.4 μg/ml) was attained in the inflammatory exudate at 5.3 h (SD, 1.5 h). The elimination half-lives from plasma and inflammatory fluid were 9.8 h (SD, 1.1 h) and 8.5 h (SD, 1.9 h), respectively. The areas under the concentration-time curves for plasma and inflammatory fluid were 96.7 μg · h/ml (SD, 10.3 μg · h/ml) and 77.9 μg · h/ml (SD, 19.2 μg · h/ml), respectively.