bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antipneumococcal Activity of DK-507k, a New Quinolone,Compared with the Activities of 10 OtherAgents
Authors: Browne Frederick A. , Bozdogan Bülent , Clark Catherine , Kelly Linda M. , Ednie Lois , Kosowska Klaudia , Dewasse Bonifacio , Jacobs Michael R. , Appelbaum Peter C. 
Published: November 2003

ABSTRACT

Agar
dilution MIC determination was used to compare the activity of DK-507k
with those of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin,
sitafloxacin, amoxicillin, cefuroxime, erythromycin, azithromycin, and
clarithromycin against 113 penicillin-susceptible, 81
penicillin-intermediate, and 67 penicillin-resistant pneumococci (all
quinolone susceptible). DK-507k and sitafloxacin had the lowest MICs of
all quinolones against quinolone-susceptible strains (MIC at which
50% of isolates were inhibited [MIC
50
] and
MIC
90
of both, 0.06 and 0.125 μg/ml, respectively),
followed by moxifloxacin, gatifloxacin, levofloxacin, and
ciprofloxacin. MICs of β-lactams and macrolides rose with those
of penicillin G. Against 26 quinolone-resistant pneumococci with known
resistance mechanisms, DK-507k and sitafloxacin were also the most
active quinolones (MICs, 0.125 to 1.0 μg/ml), followed by
moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. Mutations
in quinolone resistance-determining regions of quinolone-resistant
strains were in the usual regions of the
parC
and
gyrA
genes. Time-kill testing showed that both DK-507k and
sitafloxacin were bactericidal against all 12 quinolone-susceptible and
-resistant strains tested at twice the MIC at 24 h. Serial
broth passages in subinhibitory concentrations of 10 strains for a
minimum of 14 days showed that development of resistant mutants
(fourfold or greater increase in the original MIC) occurred most
rapidly for ciprofloxacin, followed by moxifloxacin, DK-507k,
gatifloxacin, sitafloxacin, and levofloxacin. All parent strains
demonstrated a fourfold or greater increase in initial MIC in<50 days. MICs of DK-507k against resistant mutants were
lowest, followed by those of sitafloxacin, moxifloxacin, gatifloxacin,
ciprofloxacin, and levofloxacin. Four strains were subcultured in
subinhibitory concentrations of each drug for 50 days: MICs of DK-507k
against resistant mutants were lowest, followed by those of
sitafloxacin, moxifloxacin, gatifloxacin, levofloxacin, and
ciprofloxacin. Exposure to DK-507k and sitafloxacin resulted in
mutations, mostly in
gyrA
.
Antimicrobial Resistance in
Campylobacterjejuni
and
Campylobacter coli
Strains Isolated in 1991and 2001-2002 from Poultry and Humans in Berlin,Germany
Authors: Luber Petra , Wagner Jutta , Hahn Helmut , Bartelt Edda 
Published: November 2003

ABSTRACT

The
susceptibilities of 430
Campylobacter jejuni
strains and 79
C. coli
strains to six antimicrobial agents were tested and
analyzed. The two sets of strains originated from retail market chicken
and turkey samples and from humans, respectively, in Berlin, Germany.
Two groups of isolates, one dating from 1991 and the other dating from
2001-2002, were tested. Of the
Campylobacter
sp. isolates
recovered from humans in 2001-2002, 45.1% were resistant to
ciprofloxacin, 37.8% were resistant to tetracycline,
12.8% were resistant to ampicillin, and 50.0% were
resistant to trimethoprim-sulfamethoxazole. All isolates were
susceptible to gentamicin, while the overall rate of resistance to
erythromycin was 6.1%. During the 10 years between the two
sampling times, the rates of resistance to ciprofloxacin (
P
< 0.001), ampicillin (
P
= 0.035), and
tetracycline (
P
= 0.01) increased significantly among
strains isolated from humans. Furthermore, among human
C. coli
strains the rate of resistance to erythromycin rose from 7.1% in
1991 to 29.4% in 2001-2002. In comparison,
Campylobacter
sp. isolates from poultry already had high rates
of resistance in 1991. Different rates of resistance to tetracycline
among isolates from chickens and turkeys suggested the development of
resistance during antimicrobial treatment in food animals. Thus,
discrepancies in the antimicrobial resistance rates among
Campylobacter
isolates originating from poultry and humans
support the hypothesis that at least some of the resistant
Campylobacter
strains causing infection in humans come from
sources other than poultry
products.
GeneHunter, a Transposon Tool for Identificationand Isolation of Cryptic Antibiotic ResistanceGenes
Authors: Salipante Stephen J. , Barlow Miriam , Hall Barry G. 
Published: November 2003

ABSTRACT

GeneHunter
is a transposon tool designed for the experimental activation and
identification of silent antibiotic resistance genes. The method
permits the identification of novel resistance genes that lack
previously identified homologues. Using
Salmonella enterica
serovar Typhimurium strain LT2 as a test organism for the in vivo
version of the GeneHunter method, we were able to activate, clone, and
identify two cryptic antibiotic resistance genes, the aminoglycoside
acetyltransferase
aac(6′)-Iaa
and the probable Mar-A
regulon activator
rma
. Because the method requires being able
to electroporate the host with an efficiency of at least
10
10
transformants per microgram, the in vivo method is not
applicable to most microorganisms. We therefore developed an in vitro
transposition method, showed that it can also recover the cryptic
rma
gene from S. enterica serovar Typhimurium strain LT2, and
showed that it is generally applicable to a variety of microorganisms
by using it to recover a cryptic metallo-β-lactamase gene from
the gram-positive organism
Bacillus cereus
. It is anticipated
that the GeneHunter method will be used to identify potential
resistance genes during the development and testing of novel
antibiotics, new variants of existing antibiotics, and drug inhibitor
combinations.
Molecular Mechanism of Terbinafine Resistance in
Saccharomycescerevisiae
Authors: Leber Regina , Fuchsbichler Sandra , Klobučníková Vlasta , Schweighofer Natascha , Pitters Eva , Wohlfarter Kathrin , Lederer Mojca , Landl Karina , Ruckenstuhl Christoph , Hapala Ivan , Turnowsky Friederike 
Published: November 2003

ABSTRACT

Ten
mutants of the yeast
Saccharomyces cerevisiae
resistant to the
antimycotic terbinafine were isolated after chemical or UV mutagenesis.
Molecular analysis of these mutants revealed single base pair exchanges
in the
ERG1
gene coding for squalene epoxidase, the target of
terbinafine. The mutants did not show cross-resistance to any of the
substrates of various pleiotropic drug resistance efflux pumps tested.
The
ERG1
mRNA levels in the mutants did not differ from those
in the wild-type parent strains. Terbinafine resistance was transmitted
with the mutated alleles in gene replacement experiments, proving that
single amino acid substitutions in the Erg1 protein were sufficient to
confer the resistance phenotype. The amino acid changes caused by the
point mutations were clustered in two regions of the Erg1 protein.
Seven mutants carried the amino acid substitutions F
402
L
(one mutant), F
420
L (one mutant), and P
430
S (five
mutants) in the C-terminal part of the protein; and three mutants
carried an L
251
F exchange in the central part of the
protein. Interestingly, all exchanges identified involved amino acids
which are conserved in the squalene epoxidases of yeasts and mammals.
Two mutations that were generated by PCR mutagenesis of the
ERG1
gene and that conferred terbinafine resistance mapped in
the same regions of the Erg1 protein, with one resulting in an
L
251
F exchange and the other resulting in an
F
433
S exchange. The results strongly indicate that these
regions are responsible for the interaction of yeast squalene epoxidase
with
terbinafine.
Novispirin G10-Induced Lung Toxicity in aKlebsiella pneumoniaeInfectionModel
Authors: Bartlett Karen H. , McCray Paul B. , Thorne Peter S. 
Published: November 2003

ABSTRACTMammalian cathelicidins are a class of innate antimicrobial peptides isolated from leukocytes and epithelial cells that aid host defense against bacterial infections. Synthetic analogs of cathelicidins offer the promise of potent broad-spectrum antimicrobial efficacy. We developed a combined lung infection and ex vivo whole-blood assay model to characterize the toxicity and efficacy of synthetic cathelicidin-derived peptides. Male C57BL/6 mice were administered saline orKlebsiella pneumoniaeby intratracheal instillation. Five hours later, theKlebsiella-infected mice were instilled with saline, tobramycin (1 mg/kg of body weight or 10 mg/kg), novispirin G10 (0.4 mg/kg), or a combination of tobramycin (1 mg/kg) and G10 (0.4 mg/kg). At 24 h, bronchoalveolar lavage fluid (BAL) was collected for analysis of culturable bacteria and for markers of inflammation and lung toxicity. Blood samples were analyzed for circulating cytokines. Recovery ofKlebsiellafrom the lung, recruitment of neutrophils, and production of interleukin-6 (IL-6) in BAL samples were highly correlated (r= 0.68 and 0.84, respectively;P< 0.01). Animals treated with G10 or G10 plus tobramycin had increased hemoglobin (P< 0.001) and protein (P< 0.001) levels compared to those forKlebsiella-infected or tobramycin-alone-treated animals. The levels of circulating IL-6 in mice infected withKlebsiellawere 1000- to 10,000-fold higher than in the noninfected controls. The highest levels of IL-6 were measured in mice given G10 alone or in combination with tobramycin. These studies demonstrated that G10 was relatively nontoxic in saline-treated mice but was highly toxic in mice infected withKlebsiella. This finding establishes the importance of investigating candidate antimicrobial agents in an in vivo infection model.
Phase II, Randomized, Double-Blind, Placebo-Controlled Studies of Ruprintrivir Nasal Spray 2-Percent Suspension for Prevention and Treatment of Experimentally Induced Rhinovirus Colds in Healthy Volunteers
Authors: Hayden Frederick G. , Turner Ronald B. , Gwaltney Jack M. , Chi-Burris Kathy , Gersten Merril , Hsyu Poe , Patick Amy K. , Smith George J. , Zalman Leora S. 
Published: November 2003

ABSTRACTHuman rhinovirus (HRV) infections are usually self-limited but may be associated with serious consequences, particularly in those with asthma and chronic respiratory disease. Effective antiviral agents are needed for preventing and treating HRV illnesses. Ruprintrivir (Agouron Pharmaceuticals, Inc., San Diego, Calif.) selectively inhibits HRV 3C protease and shows potent, broad-spectrum anti-HRV activity in vitro. We conducted three double-blind, placebo-controlled clinical trials in 202 healthy volunteers to assess the activity of ruprintrivir in experimental HRV infection. Subjects were randomized to receive intranasal ruprintrivir (8 mg) or placebo sprays as prophylaxis (two or five times daily [2×/day or 5×/day] for 5 days) starting 6 h before infection or as treatment (5×/day for 4 days) starting 24 h after infection. Ruprintrivir prophylaxis reduced the proportion of subjects with positive viral cultures (for 5×/day dosing groups, 44% for ruprintrivir treatment group versus 70% for placebo treatment group [P= 0.03]; for 2×/day dosing groups, 60% for ruprintrivir group versus 92% for placebo group [P= 0.004]) and viral titers but did not decrease the frequency of colds. Ruprintrivir treatment reduced the mean total daily symptom score (2.2 for ruprintrivir treatment group and 3.3 for the placebo treatment group [P= 0.014]) by 33%. Secondary endpoints, including viral titers, individual symptom scores, and nasal discharge weights, were also reduced by ruprintrivir treatment. Overall, ruprintrivir was well tolerated; blood-tinged mucus and nasal passage irritation were the most common adverse effects reported. Pharmacokinetic analysis of plasma and nasal ruprintrivir concentrations revealed intranasal drug residence with minimal systemic absorption. Results from these studies in experimental rhinoviral infection support continued investigation of intranasal ruprintrivir in the setting of natural HRV infection.
Evolutionary Models of the Emergence ofMethicillin-Resistant
Staphylococcusaureus
Authors: Robinson D. Ashley , Enright Mark C. 
Published: November 2003

ABSTRACT

Five
major lineages of methicillin-resistant
Staphylococcus aureus
(MRSA) have evolved since the introduction of methicillin for the
treatment of infections caused by penicillin-resistant
S.
aureus
in 1959. The clones of these lineages are responsible for
the vast majority of hospital-acquired MRSA disease globally. We have
constructed high-resolution evolutionary models for each lineage using
a parsimony approach with 15 partial gene sequences from 147
geographically diverse isolates. On the basis of these models, we infer
that MRSA has emerged at least 20 times upon acquisition of the
methicillin resistance determinant, which is carried on a mobile
genetic element called the staphylococcal cassette chromosome
mec
(SCC
mec
). The acquisition of SCC
mec
by
sensitive clones was four times more common than the replacement of one
SCC
mec
with another. Notably, SCC
mec
type IV was
found in twice as many clones as any other SCC
mec
type, and it
is this SCC
mec
type which is commonly found in clones from
patients with community-acquired MRSA disease. Our findings suggest
that most clones of MRSA arise by the acquisition of SCC
mec
type IV by methicillin-sensitive
isolates.
Pharmacodynamics of the New Des-F(6)-QuinoloneGarenoxacin in a Murine Thigh InfectionModel
Authors: Andes D. , Craig W. A. 
Published: November 2003

ABSTRACT

Garenoxacin
is a new des-F(6)-quinolone with broad-spectrum activity against both
gram-positive cocci and gram-negative bacilli. We used the neutropenic
murine thigh infection model to characterize the time course of
antimicrobial activity of garenoxacin and determine which
pharmacokinetic-pharmacodynamic (PK-PD) parameter best correlated with
efficacy. Serum drug levels following three fourfold-escalating
single-dose levels of garenoxacin were measured by microbiologic assay.
In vivo postantibiotic effects (PAEs) were determined after doses of 16
and 64 mg/kg of body weight. Mice had 10
6.5
to
10
6.7
CFU of
Streptococcus pneumoniae
strain ATCC
10813 or
Staphylococcus aureus
strain ATCC 33591 per thigh
when they were treated for 24 h with garenoxacin at a dose of
4 to 128 mg/kg/day fractionated for 3-, 6-, 12-, and 24-hour dosing
regimens. Nonlinear regression analysis was used to determine which
PK-PD parameter best correlated with the measurement of CFU/thigh at
24 h. Pharmacokinetic studies yielded peak/dose values of 0.2
to 0.3, area under the concentration-time curve (AUC)/dose values of
0.1 to 0.5, and half-lives of 0.7 to 1.6 h. Garenoxacin
produced in vivo PAEs of 1.4 to 8.2 h with
S.
pneumoniae
ATCC 10813, 7.6 to >12.4 h with
S.
aureus
ATCC 25923, and 0 to 1.5 h with
Klebsiella
pneumoniae
ATCC 43816. The 24-h AUC/MIC ratio was the PK-PD
parameter that best correlated with efficacy (
R
2
=
71 to 90% for the two organisms compared with 43 to
56% for the peak/MIC ratio and 47 to 75% for percent time
above the MIC [%
T
>MIC]).In subsequent studies we used the neutropenic murine thigh infection
model to determine if the magnitude of the AUC/MIC ratio needed for
efficacy of garenoxacin varied among pathogens (including resistant
strains). Mice had 10
5.9
to 10
7.2
CFU of 6
strains of
S. aureus
(2 methicillin resistant), 11 strains of
S. pneumoniae
(5 penicillin susceptible, 1 penicillin
intermediate, and 5 penicillin resistant, and of the resistant strains,
3 were also ciprofloxacin resistant), and 4 gram-negative
strains per thigh when treated for 24 h with 1 to 64 mg of
garenoxacin per kg every 12 h. A sigmoid dose-response model
was used to estimate the doses (mg/kg/24 h) required to achieve a net
bacteriostatic effect over 24 h. MICs ranged from 0.008 to 4μ
g/ml. The free drug 24-h AUC/MIC ratios for each static dose
(2.8 to 128 mg/kg/day) varied from 8.2 to 145. The mean 24-h AUC/MIC
ratios ± standard deviations for
S. pneumoniae
,
S.
aureus
, and gram-negative strains were 33 ± 18, 81±
37, and 33 ± 30, respectively. Methicillin,
penicillin, or ciprofloxacin resistance did not alter the magnitude of
the AUC/MIC ratio required for
efficacy.
PlasmidContent of a Vancomycin-Resistant
Enterococcus faecalis
Isolate from a Patient Also Colonized by
Staphylococcusaureus
with a VanAPhenotype
Authors: Flannagan Susan E. , Chow Joseph W. , Donabedian Susan M. , Brown William J. , Perri Mary B. , Zervos Marcus J. , Ozawa Yoshiyuki , Clewell Don B. 
Published: November 2003

ABSTRACT

Vancomycin-resistant
Enterococcus faecalis
coisolated with vancomycin-resistant
(VanA)
Staphylococcus aureus
was found to contain two
plasmids, designated pAM830 (45 kb) and pAM831 (95 kb). pAM830, found
to be conjugative and closely related to the Inc18 family of
broad-host-range conjugative plasmids, encodes resistances to
vancomycin (via a Tn
1546
-like element) and erythromycin;
pAM831 encodes resistances to gentamicin, streptomycin, and
erythromycin.
BactericidalActivities of Daptomycin, Quinupristin-Dalfopristin, and Linezolidagainst Vancomycin-ResistantStaphylococcus aureusinan In Vitro Pharmacodynamic Model with SimulatedEndocardialVegetations
Authors: Cha Raymond , Brown William J. , Rybak Michael J. 
Published: November 2003

ABSTRACTIn search of treatment alternatives against vancomycin-resistantS. aureus(VRSA), an in vitro pharmacodynamic model with simulated endocardial vegetations incorporating protein and a high inoculum was used to simulate daptomycin, linezolid, quinupristin-dalfopristin, and vancomycin against the Michigan VRSA strain. Daptomycin and quinupristin-dalfopristin exhibited the greatest bacterial reductions, and all tested agents except vancomycin exhibited bactericidal activity against the VRSA.
InVitro Activity of Tigecycline against
Staphylococcusepidermidis
Growing in an Adherent-Cell BiofilmModel
Authors: Labthavikul Pornpen , Petersen Peter J. , Bradford Patricia A. 
Published: November 2003

ABSTRACT

The
activity of tigecycline against
Staphylococcus epidermidis
growing in an in vitro adherent-cell biofilm model was determined.
Tigecycline minimum bactericidal concentrations (MBCs) ranged from 1 to
8 μg/ml for
S. epidermidis
growing in a biofilm of
adherent cells, compared to MBCs of 0.12 to >32 μg/ml
for freely growing cells. The killing activity of tigecycline against
the adherent bacteria was at least fourfold better than that of
vancomycin and
daptomycin.
ComparativeIn Vitro Susceptibilities and Bactericidal Activities ofInvestigational Fluoroquinolone ABT-492 and Other Antimicrobial Agentsagainst Human Mycoplasmas andUreaplasmas
Authors: Waites Ken B. , Crabb Donna M. , Duffy Lynn B. 
Published: November 2003

ABSTRACT

We
determined in vitro susceptibilities for ABT-492 and other
antimicrobials against
Mycoplasma pneumoniae
,
Mycoplasma
fermentans
,
Mycoplasma hominis
, and
Ureaplasma
species. ABT-492 MICs were ≤1 μg/ml, and the agent was
bactericidal against selected isolates of
M. pneumoniae
and
M. hominis.
ABT-492 has potential for treatment of infections
due to these
microorganisms.
Genotypesof
Pneumocystis jiroveci
Isolates Obtained in Harare,Zimbabwe, and London, UnitedKingdom
Authors: Miller Robert F. , Lindley Austin R. , Ambrose Helen E. , Malin Adam S. , Wakefield Ann E. 
Published: November 2003

ABSTRACT

Isolates
of
Pneumocystis jiroveci
from sulfa-exposed and nonexposed
patients from London, United Kingdom, and Harare, Zimbabwe, were
genotyped. At the dihydropteroate synthase (DHPS) locus, there was
evidence of selection pressure from sulfa drug exposure, and reversal
of DHPS genotype ratios occurred when selection pressure was absent or
was
removed.
Prevalence of Extended-Spectrum β-Lactamase-Producing
Enterobacter cloacae
in the Asia-Pacific Region: Results from the SENTRY Antimicrobial Surveillance Program, 1998 to 2001
Authors: Bell J. M. , Turnidge J. D. , Jones R. N. ,   the SENTRY Asia-Pacific Participants
Published: November 2003

ABSTRACT

Enterobacter
cloacae
strains from hospitalized patients with a range of
infections were collected by 17 laboratories in the Asia-Pacific region
and South Africa. Isolates for which ceftriaxone MICs were above 1μ
g/ml and/or ceftazidime MICs were above 2 μg/ml, as
well as 46 strains for which ceftriaxone and/or ceftazidime MICs were
at or below these values, were screened for levels of extended-spectrumβ
-lactamase (ESBL) production through the use of broth
microdilution for the detection of clavulanate enhancement of the
activity of ceftriaxone, ceftazidime, and cefepime. Of the isolates
examined, ceftriaxone and/or ceftazidime had elevated MICs for
44%, of which 36% were ESBL positive. ESBL-positive
strains were commonly susceptible to piperacillin-tazobactam and more
frequently resistant to several other antimicrobials studied. A
cefepime MIC above 0.25 μg/ml had the highest sensitivity
(100%) and specificity (74%) for predicting the presence
of an
ESBL.
Effects of Unkei-to on FSH, LH and Estradiol in Anovulatory Young Women with Hyper- or Hypo-Functioning Conditions
Authors: Ushiroyama Takahisa , Hosotani Toshimitsu , Yamashita Yoshiki , Yamashita Hidetoshi , Ueki Minoru 
Published: November 2003

Eight weeks treatment with Unkei-to induced a significant increase in plasma follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol levels in hyper- (robust) and hypo- (asthenia) functioning patients with first- and second-grade amenorrhea. We observed no significant differences in the rate of change of these hormones between hyper- and hypo-functioning patients. Ovulation occurred in 61.3% and 66.7% of patients with first-grade amenorrhea, and in 27.3% and 22.4% of patients with second-grade amenorrhea, respectively. No significant difference was observed in the ovulation rate after an 8-week treatment with Unkei-to between hyper- and hypo-functioning patients. These results indicate that Unkei-to is effective in improving gonadotropin and estradiol secretion in the treatment of either hyper- or hypo-functioning anovulatory women.
Human Immunodeficiency Virus Hematology
Authors: Volberding Paul A. , Baker Kelty R. , Levine Alexandra M. 
Published: November 2003

AbstractThe advent of potent antiretroviral therapy has altered the expected natural history of human immunodeficiency virus (HIV) infection and of many previously associated opportunistic complications, including malignancies. At the same time, HIV suppression hasn’t affected all of these complications equally and the longer expected survival of infected patients may allow the development of newer complications. Additionally, the use of potent antiretroviral combination therapy may itself lead to hematological toxicities. Together these changes affect the consultation role of the hematology-oncology specialist in comprehensive HIV care and demand ongoing education.In Section I, Dr. Paul Volberding reviews the biology of antiretroviral drug development and the progression in discovering new agents as the viral life cycle is further elucidated. He briefly summarizes the process of combining agents to achieve the degree of viral suppression required for long-term clinical benefit.In Section II, Dr. Kelty Baker reviews the effects of HIV and its therapy on hematologic dyscrasia and clotting disorders. She summarizes how therapy may decrease certain previously common manifestations of HIV disease while adding new problems likely to result in referral to the hematologist. In addition, she addresses the role of secondary infections, such as parvovirus, in this spectrum of disorders.In Section III, Dr. Alexandra Levine discusses the still challenging aspects of HIV associated non-Hodgkin’s lymphoma and the association between HIV infection and Hodgkin’s disease. She addresses current controversies in the pathogenesis of HIV related lymphomas and summarizes a number of recent trials of combination chemotherapy, with or without monoclonal antibodies, in their management. Additionally, she reviews the complex relationship of HIV disease with multicentric Castleman’s disease and recent attempts to manage this disorder.