bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of Gamete Recognition Proteins
Authors: Vacquier Victor D. 
Published: July 2002

REVIEW
Although fertilization has been studied for more than a century, the cell surface proteins mediating the process are only now becoming known. Gamete interaction in animals appears to be molecularly complex. Although it is difficult to generalize at present, diversity of structure may be a recurring theme in the evolution of fertilization proteins. Examples of rapid evolution of fertilization proteins by positive selection are known, and concerted evolution can influence the differentiation of gamete recognition proteins between closely related species.
Once-Daily Dosing in Dogs Optimizes Daptomycin Safety
Authors: Oleson F. B. , Berman C. L. , Kirkpatrick J. B. , Regan K. S. , Lai J.-J. , Tally F. P. 
Published: July 2002

ABSTRACT
Daptomycin is a novel lipopeptide antibiotic with potent bactericidal activity against most clinically important gram-positive bacteria, including resistant strains. Daptomycin has been shown to have an effect on skeletal muscle. To guide the clinical dosing regimen with the potential for the least effect on skeletal muscle, two studies were conducted with dogs to compare the effects of repeated intravenous administration every 24 h versus every 8 h for 20 days. The data suggest that skeletal-muscle effects were more closely related to the dosing interval than to either the maximum concentration of the drug in plasma or the area under the concentration-time curve. Both increases in serum creatine phosphokinase activity and the incidence of myopathy observed at 25 mg/kg of body weight every 8 h were greater than those observed at 75 mg/kg every 24 h despite the lower maximum concentration of drug in plasma. Similarly, the effects observed at 25 mg/kg every 8 h were greater than those observed at 75 mg/kg every 24 h at approximately the same area under the concentration-time curve from 0 to 24 h. Once-daily administration appeared to minimize the potential for daptomycin-related skeletal-muscle effects, possibly by allowing for more time between doses for repair of subclinical effects. Thus, these studies with dogs suggest that once-daily dosing of daptomycin in humans should have the potential to minimize skeletal-muscle effects. In fact, interim results of ongoing clinical trials, which have focused on once-daily dosing, appear to be consistent with this conclusion.
Consequences of Interaction of a Lipophilic Endotoxin Antagonist with Plasma Lipoproteins
Authors: Rose Jeffrey R. , Mullarkey Maureen A. , Christ William J. , Hawkins Lynn D. , Lynn Melvyn , Kishi Yoshito , Wasan Kishor M. , Peteherych Kathy , Rossignol Daniel P. 
Published: July 2002

ABSTRACT

E5531, a novel synthetic lipid A analogue, antagonizes the toxic effects of lipopolysaccharide, making it a potential intravenously administered therapeutic agent for the treatment of sepsis. This report describes the distribution of E5531 in human blood and its activity when it is associated with different lipoprotein subclasses. After in vitro incubation of [
14
C]E5531 with blood, the great majority (>92%) of material was found in the plasma fraction. Analysis by size-exclusion and affinity chromatographies and density gradient centrifugation indicates that [
14
C]E5531 binds to lipoproteins, primarily high-density lipoproteins (HDLs), with distribution into low-density lipoproteins (LDLs) and very low density lipoproteins (VLDLs) being dependent on the plasma LDL or VLDL cholesterol concentration. Similar results were also seen in a limited study of [
14
C]E5531 administration to human volunteers. The potency of E5531 in freshly drawn human blood directly correlates to increasing LDL cholesterol levels. Finally, preincubation of E5531 with plasma or purified lipoproteins indicated that binding to HDL resulted in a time-dependent loss of drug activity. This loss in activity was not observed with drug binding to LDLs or to VLDLs or chylomicrons. Taken together, these results indicate that E5531 binds to plasma lipoproteins, making its long-term antagonistic potency dependent on the plasma lipoprotein composition.
Efficacy of Linezolid in Experimental Otitis Media
Authors: Pelton S. I. , Figueira M. , Albut R. , Stalker D. 
Published: July 2002

ABSTRACT

Therapy for otitis media (OM) due to resistant
Streptococcus pneumoniae
(MIC of penicillin, ≥2.0 μg/ml) is challenging. Linezolid, an oxazolidinone, represent a new class of antimicrobial agents with excellent in vitro activity against penicillin-resistant
S. pneumoniae
; however, in vitro activity against nontypeable
Haemophilus influenzae
(NTHI) is limited. We evaluated its efficacy against experimental acute OM due to a multidrug-resistant
S. pneumoniae
isolate and two isolates of NTHI. The chinchilla model was utilized to evaluate the efficacy of linezolid against experimental infection due to
S. pneumoniae
or NTHI. Serum and middle ear antibiotic concentrations were determined, and sterilization of experimental OM was evaluated. Chinchillas were inoculated directly with
S. pneumoniae
into the superior bulla. Twenty-four hours after inoculation, all animals had positive middle ear and nasopharyngeal cultures. Animals were given linezolid at 25 mg/kg/dose twice a day (b.i.d.) by orogastric feeding tube or amoxicillin at 40 mg/kg/dose b.i.d. intramuscularly for 5 days. By day 5, all animals in the linezolid group had sterile middle ear cultures and eradication of
S. pneumoniae
from the nasopharynx. In the amoxicillin group, all nine animals remained middle ear and nasopharynx positive (
P
< 0.01). In animals inoculated with NTHI, 25 and 37.5 mg/kg b.i.d. failed to sterilize middle ear infection or eradicate colonization. Mean levels in middle ear fluid measured during experimental infection were 12.8 μg/ml at 2 to 6 h and 4.1 μg/ml at 16 to 17 h after orogastric dosing at 25 mg/kg. Linezolid achieved a high concentration in the middle ear during experimental OM. Linezolid eradicated multidrug-resistant
S. pneumoniae
from the middle ear and nasopharynx. Experimental infection and nasopharyngeal colonization due to NTHI persisted despite achievement of concentrations in the middle ear that were above the MIC (for NTHI).
Synergistic Antifungal Activities of Bafilomycin A
1
, Fluconazole, and the Pneumocandin MK-0991/Caspofungin Acetate (L-743,873) with Calcineurin Inhibitors FK506 and L-685,818 against
Cryptococcus neoformans
Authors: Del Poeta Maurizio , Cruz M. Cristina , Cardenas Maria E. , Perfect John R. , Heitman Joseph 
Published: July 2002

ABSTRACT

Cryptococcus neoformans
is an opportunistic fungal pathogen that causes life-threatening infections of the central nervous system. Existing therapies include amphotericin B, fluconazole, and flucytosine, which are limited by toxic side effects and the emergence of drug resistance. We recently demonstrated that the protein phosphatase calcineurin is required for growth at 37°C and virulence of
C. neoformans
. Because calcineurin is the target of potent inhibitors in widespread clinical use, cyclosporine and FK506 (tacrolimus), it is an attractive drug target for novel antifungal agents. Here we have explored the synergistic potential of combining the calcineurin inhibitor FK506 or its nonimmunosuppressive analog, L-685,818, with other antifungal agents and examined the molecular basis of FK506 action by using genetically engineered fungal strains that lack the FK506 target proteins FKBP12 and calcineurin. We demonstrate that FK506 exhibits marked synergistic activity with the H
+
ATPase inhibitor bafilomycin A
1
via a novel action distinct from calcineurin loss of function. FK506 also exhibits synergistic activity with the pneumocandin MK-0991/caspofungin acetate (formerly L-743,873), which targets the essential β-1,3 glucan synthase, and in this case, FK506 action is mediated via FKBP12-dependent inhibition of calcineurin. Finally, we demonstrate that FK506 and fluconazole have synergistic activity that is independent of both FKBP12 and calcineurin and may involve the known ability of FK506 to inhibit multidrug resistance pumps, which are known to export azoles from fungal cells. In summary, our studies illustrate the potential for synergistic activity of a variety of different drug combinations and the power of molecular genetics to define the mechanisms of drug action, as well as identify a novel action of FK506 that could have profound implications for therapeutic or toxic effects in other organisms, including humans.
Characterization of VIM-2, a Carbapenem-Hydrolyzing Metallo-β-Lactamase and Its Plasmid- and Integron-Borne Gene from a
Pseudomonas aeruginosa
Clinical Isolate in France
Authors: Poirel Laurent , Naas Thierry , Nicolas Delphine , Collet Louis , Bellais Samuel , Cavallo Jean-Didier , Nordmann Patrice 
Published: July 2002

ABSTRACT

Pseudomonas aeruginosa
COL-1 was identified in a blood culture of a 39-year-old-woman treated with imipenem in Marseilles, France, in 1996. This strain was resistant to β-lactams, including ureidopenicillins, ticarcillin-clavulanic acid, cefepime, ceftazidime, imipenem, and meropenem, but remained susceptible to the monobactam aztreonam. The carbapenem-hydrolyzing β-lactamase gene of
P. aeruginosa
COL-1 was cloned, sequenced, and expressed in
Escherichia coli
DH10B. The deduced 266-amino-acid protein was an Ambler class B β-lactamase, with amino acid identities of 32% with B-II from
Bacillus cereus
; 31% with IMP-1 from several gram-negative rods in Japan, including
P. aeruginosa
; 27% with CcrA from
Bacteroides fragilis
; 24% with BlaB from
Chryseobacterium meningosepticum
; 24% with IND-1 from
Chryseobacterium indologenes
; 21% with CphA-1 from
Aeromonas hydrophila
; and 11% with L-1 from
Stenotrophomonas maltophilia
. It was most closely related to VIM-1 β-lactamase recently reported from Italian
P. aeruginosa
clinical isolates (90% amino acid identity). Purified VIM-2 β-lactamase had a pI of 5.6, a relative molecular mass of 29.7 kDa, and a broad substrate hydrolysis range, including penicillins, cephalosporins, cephamycins, oxacephamycins, and carbapenems, but not monobactams. As a metallo-β-lactamase, its activity was zinc dependent and inhibited by EDTA (50% inhibitory concentration, 50 μM). VIM-2 conferred a resistance pattern to β-lactams in
E. coli
DH10B that paralleled its in vitro hydrolytic properties, except for susceptibility to ureidopenicillins, carbapenems, and cefepime.
bla
VIM-2
was located on a ca. 45-kb plasmid that in addition conferred resistance to sulfamides and that was not self-transmissible either from
P. aeruginosa
to
E. coli
or from
E. coli
to
E. coli. bla
VIM-2
was the only gene cassette located within the variable region of a novel class 1 integron, In56, that was weakly related to the
bla
VIM-1
-containing integron. VIM-2 is the second carbapenem-hydrolyzing metalloenzyme characterized from a
P. aeruginosa
isolate outside Japan.
Comparison of Nikkomycin Z with Amphotericin B and Itraconazole for Treatment of Histoplasmosis in a Murine Model
Authors: Goldberg Janet , Connolly Patricia , Schnizlein-Bick Carol , Durkin Michelle , Kohler Stephen , Smedema Melinda , Brizendine Edward , Hector Richard , Wheat Joseph 
Published: July 2002

ABSTRACTNikkomycin Z was tested both in vitro and in vivo for efficacy againstHistoplasma capsulatum. Twenty clinical isolates were tested for susceptibility to nikkomycin Z in comparison to amphotericin B and itraconazole. The median MIC was 8 μg/ml with a range of 4 to 64 μg/ml for nikkomycin Z, 0.56 μg/ml with a range of 0.5 to 1.0 μg/ml for amphotericin B, and ≤0.019 μg/ml for itraconazole. Primary studies were carried out by using a clinical isolate ofH. capsulatumfor which the MIC of nikkomycin Z was greater than or equal to 64 μg/ml. In survival experiments, mice treated with amphotericin B at 2.0 mg/kg/dose every other day (QOD) itraconazole at 75 mg/kg/dose twice daily (BID), and nikkomycin Z at 100 mg/kg/dose BID survived to day 14, while 70% of mice receiving nikkomycin Z at 20 mg/kg/dose BID and none of the mice receiving nikkomycin Z at 5 mg/kg/dose BID survived to day 14. All vehicle control mice died by day 12. Fungal burden was assessed on survivors. Mice treated with nikkomycin Z at 20 and 100 mg/kg/dose BID had significantly higher CFUs per gram of organ weight in quantitative cultures and higher levels ofHistoplasmaantigen in lung and spleen homogenates than mice treated with amphotericin B at 2.0 mg/kg/dose QOD or itraconazole at 75 mg/kg/dose BID. Studies also were carried out with a clinical isolate for which the MIC of nikkomycin Z was 4 μg/ml. All mice treated with amphotericin B at 2.0 mg/kg/dose QOD; itraconazole at 75 mg/kg/dose BID; and nikkomycin Z at 100, 20, and 5 mg/kg/dose BID survived until the end of the study at day 17 postinfection, while 30% of the untreated vehicle control mice survived. Fungal burden assessed on survivors showed similar levels ofHistoplasmaantigen in lung and spleen homogenates of mice treated with amphotericin B at 2.0 mg/kg/dose QOD; itraconazole at 75 mg/kg/dose BID; and nikkomycin Z at 100, 20, and 5 mg/kg/dose BID. The three surviving vehicle control mice had significantly higher antigen levels in lung and spleen than other groups (P< 0.05). The efficacy of nikkomycin Z at preventing mortality and reducing fungal burden correlates with in vitro susceptibility.
Antibiotic Susceptibility Patterns of
Neisseria meningitidis
Isolates from Patients and Asymptomatic Carriers
Authors: Arreaza L. , de la Fuente L. , Vázquez J. A. 
Published: July 2002

ABSTRACT

The activities of seven antimicrobial agents used for treatment and prophylaxis of meningococcal disease was investigated against 901
Neisseria meningitidis
isolates, 112 of which were recovered from patients and 789 of which were recovered from asymptomatic carriers. The proportions of isolates with decreased susceptibility to penicillin were 55.3 and 39.0%, respectively. Penicillin- and ampicillin-intermediate strains were more common among serogroup C meningococci than among non-serogroup C meningococci from both patients and carriers.
Identification of a Plasmid-Borne Chloramphenicol-Florfenicol Resistance Gene in
Staphylococcus sciuri
Authors: Schwarz Stefan , Werckenthin Christiane , Kehrenberg Corinna 
Published: July 2002

ABSTRACT

The 16.5-kbp plasmid pSCFS1 from
Staphylococcus sciuri
mediated combined resistance to chloramphenicol and florfenicol. The gene responsible for this resistance property,
cfr
, was cloned and sequenced. The amino acid sequence of the Cfr protein revealed no homology to known acetyltransferases or efflux proteins involved in chloramphenicol and/or florfenicol resistance or to other proteins whose functions are known.
Antiviral Efficacy and Pharmacokinetics of Oral Adefovir Dipivoxil in Chronically Woodchuck Hepatitis Virus-Infected Woodchucks
Authors: Cullen John M. , Li Daniel H. , Brown Cynthia , Eisenberg Eugene J. , Cundy Kenneth C. , Wolfe Julie , Toole Jay , Gibbs Craig 
Published: July 2002

ABSTRACTThe antiviral efficacy of orally administered adefovir dipivoxil was evaluated in an 18-week study (12 weeks of treatment and 6 weeks of recovery) conducted with woodchucks chronically infected with woodchuck hepatitis virus (WHV). Adefovir dipivoxil is a prodrug of adefovir designed to enhance its oral bioavailability. Following administration of 15 mg of adefovir dipivoxil per kg of body weight in four WHV-infected animals, the mean maximum concentration of adefovir in serum was 0.462 μg/ml, with an elimination half-life of 10.2 h, and the oral bioavailability of adefovir was estimated to be 22.9% (±11.2%). To study antiviral efficacy, the animals were divided into three groups. There were six animals each in a high-dose group (15 mg/kg/day) and a low-dose group (5 mg/kg/day). A vehicle control group consisted of five animals because WHV DNA was detectable only by PCR at the time of the study in one of the original six animals. Efficacy was evaluated by determining the levels of WHV DNA in serum. The geometric mean WHV DNA level for the high-dose group diminished by >40-fold (>1.6 log10) after 2 weeks of treatment and >300-fold (>2.5 log10) at 12 weeks. There was a >10-fold reduction in five of six low-dose animals by 2 weeks, but levels were unchanged in one animal. By 12 weeks of treatment there was a >45-fold (>1.6 log10) reduction of WHV DNA levels, and serum WHV DNA levels were below the limit of quantification in three of six animals. Viral DNA levels returned to pretreatment levels during the 6-week recovery period. There were no clinically significant changes in body weight, hematology, or serum chemistry values, including bicarbonate or lactate, in any of the treated animals. No histologic evidence of liver injury was apparent in the biopsies. Under the conditions of this study, adefovir dipivoxil was an effective antihepadnaviral agent.
Eradication of Biofilm-Forming
Staphylococcus epidermidis
(RP62A) by a Combination of Sodium Salicylate and Vancomycin
Authors: Polonio Roy E. , Mermel Leonard A. , Paquette Gregory E. , Sperry Jay F. 
Published: July 2002

ABSTRACT

Staphylococcus epidermidis
is a major cause of infections associated with indwelling medical devices. Biofilm production is an important virulence attribute in the pathogenesis of device-related infections. Therefore, elimination of these biofilms is an ideal treatment. Salicylate (5 mM) combined with 1 μg of vancomycin per ml inhibited biofilm formation by
S. epidermidis
(RP62A) by ≥99.9%. When biofilm-coated polystyrene beads were exposed to 5 mM sodium salicylate and 4 μg of vancomycin per ml (one-half the minimum biofilm eradication concentration), there was a >99.9% reduction in viable count.
Papillomavirus Microbicidal Activities of High-Molecular-Weight Cellulose Sulfate, Dextran Sulfate, and Polystyrene Sulfonate
Authors: Christensen Neil D. , Reed Cynthia A. , Culp Tim D. , Hermonat Paul L. , Howett Mary K. , Anderson Robert A. , Zaneveld Lourens J. D. 
Published: July 2002

ABSTRACTThe high-molecular-weight sulfated or sulfonated polysaccharides or polymers cellulose sulfate, dextran sulfate, and polystyrene sulfonate were tested for microbicidal activity against bovine papillomavirus type 1 (BPV-1) and human papillomavirus type 11 (HPV-11) and type 40 (HPV-40). In vitro assays included the BPV-1-induced focus-forming assay and transient infection of human A431 cells with HPVs. The compounds were tested for microbicidal activity directly by preincubation with virus prior to addition to cell cultures and indirectly by addition of virus to compound-treated cells and to virus-coated cells to test inactivation of the virus after virus-cell binding. The data indicated that all three compounds showed direct microbicidal activity with 50% effective concentrations between 10 to 100 μg/ml. These concentrations were nontoxic to cell cultures for both assays. When a clone of C127 cells was tested for microbicidal activity, approximately 10-fold-less compound was required to achieve a 50% reduction in BPV-1-induced foci than for the uncloned parental C127 cells. Pretreatment of cells with compound prior to addition of virus also demonstrated strong microbicidal activity with dextran sulfate and polystyrene sulfonate, but cellulose sulfate required several orders of magnitude more compound for virus inactivation. Polystyrene sulfonate prevented subsequent infection of HPV-11 after virus-cell binding, and this inactivation was observed up to 4 h after addition of virus. These data indicate that the polysulfated and polysulfonated compounds may be useful nontoxic microbicidal compounds that are active against a variety of sexually transmitted disease agents including papillomaviruses.
Clinafloxacin versus Piperacillin-Tazobactam in Treatment of Patients with Severe Skin and Soft Tissue Infections
Authors: Siami G. , Christou N. , Eiseman I. , Tack K. J. ,   the Clinafloxacin Severe Skin And Soft Tissue Infections Study Group
Published: July 2002

ABSTRACTPatients (n= 409) with severe skin and soft tissue infections (SSTIs) were randomized to receive clinafloxacin or piperacillin-tazobactam (plus optional vancomycin for methicillin-resistant cocci), administered intravenously, with the option to switch to oral medication. Most patients had cellulitis, wound infections, or diabetic foot infections.Staphylococcus aureus,Enterococcus faecalis, andPseudomonas aeruginosawere the most common baseline pathogens. Fewer baseline pathogens were resistant to clinafloxacin (1.8%) than to piperacillin-tazobactam (6.2%) (P= 0.001). The clinafloxacin and piperacillin-tazobactam groups did not differ significantly in clinical cure rates (68.8 and 65.2%, respectively) or microbiologic eradication rates (61.5 and 57.2%). Clinafloxacin yielded higher eradication rates for all three of the most common pathogenic species, although no differences were statistically significant. Within the power of this study, the overall frequency of adverse events was similar (P= 0.577) in the two treatment groups. Drug-associated adverse events (P= 0.050) and treatment discontinuations (P= 0.052) were marginally more frequent in the clinafloxacin group, primarily due to phototoxicity in outpatients receiving clinafloxacin. Although most cases of phototoxicity were mild to moderate, four cases were reported as severe. In summary, clinafloxacin monotherapy was equivalent in effectiveness to therapy with piperacillin-tazobactam plus optional vancomycin in the treatment of hospitalized patients with severe SSTIs.
Mechanisms of Macrolide Resistance in Clinical Pneumococcal Isolates in France
Authors: Fitoussi Frederic , Doit Catherine , Geslin Pierre , Brahimi Naima , Bingen Edouard 
Published: July 2002

ABSTRACT

The genetic basis of macrolide resistance was investigated in a collection of 48 genotypically unrelated clinical isolates of
Streptococcus pneumoniae
obtained between 1987 and 1997 in France. All strains were resistant to erythromycin, clindamycin, and streptogramin B, exhibiting a macrolide-lincosamide-streptogramin B resistance phenotype, and harbored the
erm
(B) gene. None of the strains carried the
mef
(A) or
erm
(A) subclass
erm
(TR) gene.
Pharmacodynamics of Daptomycin in a Murine Thigh Model of
Staphylococcus aureus
Infection
Authors: Louie Arnold , Kaw Pamela , Liu Weiguo , Jumbe Nelson , Miller Michael H. , Drusano George L. 
Published: July 2002

ABSTRACT

Daptomycin is a lipopeptide antibiotic with activity against gram-positive bacteria, including
Staphylococcus aureus
. We defined the pharmacodynamic parameters that determine the activity of daptomycin for
S. aureus
using in vitro methods and the Craig (W. A. Craig, J. Redington, and S. C. Ebert, J. Antimicrob. Chemother. 27[Suppl. C]:29–40, 1991) neutropenic mouse thigh infection model. In Mueller-Hinton broth, the MICs for three
S. aureus
isolates were 0.1 to 0.2 μg/ml. In mouse serum, the MICs were 1.0 μg/ml. The protein binding of daptomycin was 90 to 92.5% in mouse serum. Single-dose intraperitoneal (i.p.) pharmacokinetic studies with infected mice showed a linear relationship between dose versus the maximum concentration of drug in serum and dose versus the area under the concentration-time curve (AUC). The serum half-life of daptomycin in infected mice was approximately 1.8 h. In single-dose, dose-ranging studies using mice, daptomycin showed a dose-response effect described by an inhibitory sigmoid
E
max
(maximum effect) curve (
r
= 0.974;
P
≪ 0.001). The density of
S. aureus
in untreated controls was 8.26 log
10
CFU/g, and the
E
max
was 3.97 log
10
CFU/g. The 50% effective dose (ED
50
) was 3.7 mg/kg of body weight i.p. and the stasis dose was 7.1 mg/kg. Dose fractionation studies at schedules of Q6h, Q12h, and Q24h, for total 24-h ED
30
, ED
60
, and ED
80
doses of 2.5, 5.6, and 15 mg/kg i.p., showed no difference in effect at each total 24-h dose level by schedule, indicating that the AUC/MIC ratio is the dynamically linked variable.