bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of the Metallo-β-Lactamase Determinant of
Acinetobacter baumannii
AC-54/97 Reveals the Existence of
bla
IMP
Allelic Variants Carried by Gene Cassettes of Different Phylogeny
Authors: Riccio Maria Letizia , Franceschini Nicola , Boschi Letizia , Caravelli Berardo , Cornaglia Giuseppe , Fontana Roberta , Amicosante Gianfranco , Rossolini Gian Maria 
Published: July 2002

ABSTRACT

The metallo-β-lactamase determinant of
Acinetobacter baumannii
AC-54/97, a clinical isolate from Italy that was previously shown to produce an enzyme related to IMP-1, was isolated by means of a PCR methodology which targets amplification of gene cassette arrays inserted into class 1 integrons. Sequencing revealed that this determinant was an allelic variant (named
bla
IMP-2
) of
bla
IMP
found in Japanese isolates and that it was divergent from the latter by 12% of its nucleotide sequence, which evidently had been acquired independently. Similar to
bla
IMP
,
bla
IMP-2
was also carried by an integron-borne gene cassette. However, the 59-base element of the
bla
IMP-2
cassette was unrelated to those of the
bla
IMP
cassettes found in Japanese isolates, indicating a different phylogeny for the gene cassettes carrying the two allelic variants. Expression of the integron-borne
bla
IMP-2
gene in
Escherichia coli
resulted in a significant decrease in susceptibility to a broad array of β-lactams (ampicillin, carbenicillin, cephalothin, cefoxitin, ceftazidime, cefepime, and carbapenems). The IMP-2 enzyme was purified from an
Escherichia coli
strain carrying the cloned determinant, and kinetic parameters were determined with several β-lactam substrates. Compared to IMP-1, the kinetic parameters of IMP-2 were similar overall with some β-lactam substrates (cefoxitin, ceftazidime, cefepime, and imipenem) but remarkably different with others (ampicillin, carbenicillin, cephaloridine, and meropenem), revealing a functional significance of at least some of the mutations that differentiate the two IMP variants. Present findings suggest that the environmental reservoir of
bla
IMP
alleles could be widespread and raise a question about the global risk of their transfer to clinically relevant species.
Pharmacokinetics of Gentamicin C
1
, C
1a
, and C
2
in Beagles after a Single Intravenous Dose
Authors: Isoherranen Nina , Lavy Eran , Soback Stefan 
Published: July 2002

ABSTRACT

The pharmacokinetics of gentamicin C
1
, C
2
, and C
1a
were studied in six beagles after administration of gentamicin at 4 mg/kg of body weight as a single intravenous bolus dose. Plasma concentrations of the gentamicin components were analyzed with a novel high-performance liquid chromatography method capable of identifying and quantifying each of the components. The pharmacokinetic analysis of the plasma concentration-versus-time data was performed using the noncompartmental approach. The results indicated significant differences in the pharmacokinetic characteristics between the gentamicin components C
1
, C
1a
, and C
2
. The mean residence times of gentamicin C
1
, C
1a
, and C
2
were 81 ± 13, 84 ± 12, and 79 ± 13 min (mean ± standard deviation), respectively. The half-lives of the respective components were 64 ± 12, 66 ± 12 and 63 ± 12 min. Clearance (CL) of gentamicin C
1
, 4.62 ± 0.71 ml min
−1
kg
−1
, was significantly higher (
P
= 0.0156) than CL of gentamicin C
1a
, 1.81 ± 0.26 ml min
−1
kg
−1
, and C
2
, 1.82 ± 0.25 ml min
−1
kg
−1
. Similarly, the volume of distribution at steady state (
V
ss
) of gentamicin C
1
, 0.36 ± 0.04 liter kg
−1
, was significantly higher (
P
= 0.0156) than the
V
ss
of gentamicin C
1a
, 0.14 ± 0.01 liter kg
−1
, and C
2
, 0.15 ± 0.02 liter kg
−1
. Tissue binding was considered the most likely cause for the difference. The difference may have clinical and toxicological significance.
Use of Drug Effect Interaction Modeling with Monte Carlo Simulation To Examine the Impact of Dosing Interval on the Projected Antiviral Activity of the Combination of Abacavir and Amprenavir
Authors: Drusano G. L. , D'Argenio D. Z. , Preston S. L. , Barone C. , Symonds W. , LaFon S. , Rogers M. , Prince W. , Bye A. , Bilello J. A. 
Published: July 2002

ABSTRACT

The delineation of optimal regimens for combinations of agents is a difficult problem, in part because, to address it, one needs to (i) have effect relationships between the pathogen in question and the drugs in the combination, (ii) have knowledge of how the drugs interact (synergy, antagonism, and additivity), and (iii) address the issue of true between-patient variability in pharmacokinetics for the drugs in the population. We have developed an approach which employs a fully parametric assessment of drug interaction using the equation of W. R. Greco, G. Bravo, and J. C. Parsons (Pharmacol. Rev. 47:331–385, 1995) to generate an estimate of effects for the two drugs and have linked this approach to a population simulator, using Monte Carlo methods, which produce concentration-time profiles for the drugs in combination. This software automatically integrates the effect over a steady-state dosing interval and produces an estimate of the mean effect over a steady-state interval for each simulated subject. In this way, doses and schedules can be easily evaluated. This software allows for a rational choice of dose and schedule for evaluation in clinical trials. We evaluated different schedules of administration for the combination of the nucleoside analogue abacavir plus the human immunodeficiency virus type 1 protease inhibitor amprenavir. Amprenavir was simulated as either 800 mg every 8 h (q8h) or 1,200 mg q12h, each along with 300 mg q12h of abacavir. Both regimens produced excellent effects over the simulated population of 500 subjects, with average percentages of maximal effect (as determined from the in vitro assays) of 90.9% ± 11.4% and 80.9% ± 18.6%, respectively. This difference is statistically significant (
P
≪ 0.001). In addition, 68.8 and 46.0% of the population had an average percentage of maximal effect which was greater than or equal to 90% for the two regimens. We can conclude that the combination of abacavir plus amprenavir is a potent combination when it is given on either schedule. However, the more fractionated schedule for the protease inhibitor produced significantly better effects in combination. Clinicians need to explicitly balance the improvement in antiviral effect seen with the more fractionated regimen against the loss of compliance attendant to the use of such a regimen. This approach may be helpful in the preclinical evaluation of multidrug anti-infective regimens.
Antibacterial Action of Structurally Diverse Cationic Peptides on Gram-Positive Bacteria
Authors: Friedrich Carol L. , Moyles Dianne , Beveridge Terry J. , Hancock Robert E. W. 
Published: July 2002

ABSTRACT

Antimicrobial cationic peptides are ubiquitous in nature and are thought to be a component of the first line of defense against infectious agents. It is widely believed that the killing mechanism of these peptides on bacteria involves an interaction with the cytoplasmic membrane. Cationic peptides from different structural classes were used in experiments with
Staphylococcus aureus
and other medically important gram-positive bacteria to gain insight into the mechanism of action. The membrane potential-sensitive fluorophore dipropylthiacarbocyanine was used to assess the interactions of selected antimicrobial peptides with the cytoplasmic membrane of
S. aureus
. Study of the kinetics of killing and membrane depolarization showed that, at early time points, membrane depolarization was incomplete, even when 90% or more of the bacteria had been killed. CP26, a 26-amino-acid α-helical peptide with a high MIC against
S. aureus
, still had the ability to permeabilize the membrane. Cytoplasmic-membrane permeabilization was a widespread ability and an action that may be necessary for reaching an intracellular target but in itself did not appear to be the killing mechanism. Transmission electron microscopy of
S. aureus
and
Staphylococcus epidermidis
treated with CP29 (a 26-amino-acid α-helical peptide), CP11CN (a 13-amino-acid, proline- and tryptophan-rich peptide), and Bac2A-NH
2
(a linearized version of the 12-amino-acid loop peptide bactenecin) showed variability in effects on bacterial structure. Mesosome-like structures were seen to develop in
S. aureus
, whereas cell wall effects and mesosomes were seen with
S. epidermidis
. Nuclear condensation and abherrent septation were occasionally seen in
S. epidermidis
. Our experiments indicated that these peptides vary in their mechanisms of action and that the mechanism of action likely does not solely involve cytoplasmic-membrane permeabilization.
Mutations in 23S rRNA and Ribosomal Protein L4 Account for Resistance in Pneumococcal Strains Selected In Vitro by Macrolide Passage
Authors: Tait-Kamradt A. , Davies T. , Cronan M. , Jacobs M. R. , Appelbaum P. C. , Sutcliffe J. 
Published: July 2002

ABSTRACT

The mechanisms responsible for macrolide resistance in
Streptococcus pneumoniae
mutants, selected from susceptible strains by serial passage in azithromycin, were investigated. These mutants were resistant to 14- and 15-membered macrolides, but resistance could not be explained by any clinically relevant resistance determinant [
mef
(A),
erm
(A),
erm
(B),
erm
(C),
erm
(TR),
msr
(A),
mph
(A),
mph
(B),
mph
(C),
ere
(A),
ere
(B)]. An investigation into the sequences of 23S rRNAs in the mutant and parental strains revealed individual changes of C2611A, C2611G, A2058G, and A2059G (
Escherichia coli
numbering) in four mutants. Mutations at these residues in domain V of 23S rRNA have been noted to confer erythromycin resistance in other species. Not all four 23S rRNA alleles have to contain the mutation to confer resistance. Some of the mutations also confer coresistance to streptogramin B (C2611A, C2611G, and A2058G), 16-membered macrolides (all changes), and clindamycin (A2058G and A2059G). Interestingly, none of these mutations confer high-level resistance to telithromycin (HMR-3647). Further, two of the mutants which had no changes in their 23S rRNA sequences had changes in a highly conserved stretch of amino acids (
63
KPWRQKGTGRAR
74
) in ribosomal protein L4. One mutant contained a single amino acid change (G69C), while the other mutant had a 6-base insert, resulting in two amino acids (S and Q) being inserted between amino acids Q67 and K68. To our knowledge, this is the first description of mutations in 23S rRNA genes or ribosomal proteins in macrolide-resistant
S. pneumoniae
strains.
Analysis of
rdxA
and Involvement of Additional Genes Encoding NAD(P)H Flavin Oxidoreductase (FrxA) and Ferredoxin-Like Protein (FdxB) in Metronidazole Resistance of
Helicobacter pylori
Authors: Kwon Dong-Hyeon , El-Zaatari Fouad A. K. , Kato Mototsugu , Osato Michael S. , Reddy Rita , Yamaoka Yoshio , Graham David Y. 
Published: July 2002

ABSTRACT

Metronidazole (Mtz) is a critical ingredient of modern multidrug therapies for
Helicobacter pylori
infection. Mtz resistance reduces the effectiveness of these combinations. Although null mutations in a
rdxA
gene that encodes oxygen-insensitive NAD(P)H nitroreductase was reported in Mtz-resistant
H. pylori
, an intact
rdxA
gene has also been reported in Mtz-resistant
H. pylori
, suggesting that additional Mtz resistance mechanisms exist in
H. pylori
. We explored the nature of Mtz resistance among 544 clinical
H. pylori
isolates to clarify the role of
rdxA
inactivation in Mtz resistance and to identify another gene(s) responsible for Mtz resistance in
H. pylori
. Mtz resistance was present in 33% (181 of 544) of the clinical isolates. There was marked heterogeneity of resistance, with Mtz MICs ranging from 8 to ≥256 μg/ml.
rdxA
inactivation resulted in Mtz MICs of up to 32 μg/ml for 6 Mtz-sensitive
H. pylori
strains and 128 μg/ml for one Mtz-sensitive strain. Single or dual (with
rdxA
) inactivation of genes that encode ferredoxin-like protein (designated
fdxB
) and NAD(P)H flavin oxidoreductase (
frxA
) also increased the MICs of Mtz for sensitive and resistant strains with low to moderate levels of Mtz resistance.
fdxB
inactivation resulted in a lower level of resistance than that from
rdxA
inactivation, whereas
frxA
inactivation resulted in MICs similar to those seen with
rdxA
inactivation. Further evidence for involvement of the
frxA
gene in Mtz resistance included the finding of a naturally inactivated
frxA
but an intact
rdxA
in an Mtz-resistant strain, complementation of Mtz sensitivity from an Mtz-sensitive strain to an Mtz-resistant strain or vice versa by use of naturally inactivated or functional
frxA
genes, respectively, and transformation of an Mtz-resistant
Escherichia coli
strain to an Mtz sensitive strain by a naturally functional
frxA
gene but not an inactivated
frxA
gene. These results are consistent with the hypothesis that null mutations in
fdxB
,
frxA
, or
rdxA
may be involved in Mtz resistance.
Antimicrobial Evaluation of
N
-Alkyl Betaines and
N
-Alkyl-
N
,
N
-Dimethylamine Oxides with Variations in Chain Length
Authors: Birnie Christine R. , Malamud Daniel , Schnaare Roger L. 
Published: July 2002

ABSTRACT

Alkyl betaines and alkyl dimethylamine oxides have been shown to have pronounced antimicrobial activity when used individually or in combination. Although several studies have been conducted with these compounds in combinations, only equimolar concentrations of the C
12
/C
12
and C
16
/C
14
chain lengths for the betaine and the amine oxide, respectively, have been investigated. This study investigates the antimicrobial activity of a wide range of chain lengths (C
8
to C
18
) for both the betaine and amine oxide and attempts to correlate their micelle-forming capabilities with their biological activity. A broth microdilution method was used to determine the MICs of these compounds singly and in various molar ratio combinations. Activity against both
Staphylococcus aureus
and
Escherichia coli
was investigated. Antimicrobial activity was found to increase with increasing chain length for both homologous series up to a point, exhibiting a cutoff effect at chain lengths of approximately 16 for betaine and 14 for amine oxide. Additionally, the C
18
oleyl derivative of both compounds exhibited activity in the same range as the peak alkyl compounds. Critical micelle concentrations were correlated with MICs, inferring that micellar activity may contribute to the cutoff effect in biological activity.
Identification and Characterization of Inhibitors of Multidrug Resistance Efflux Pumps in
Pseudomonas aeruginosa
: Novel Agents for Combination Therapy
Authors: Lomovskaya Olga , Warren Mark S. , Lee Angela , Galazzo Jorge , Fronko Richard , Lee May , Blais Johanne , Cho Deidre , Chamberland Suzanne , Renau Tom , Leger Roger , Hecker Scott , Watkins Will , Hoshino Kazuki , Ishida Hiroko , Lee Ving J. 
Published: July 2002

ABSTRACT

Whole-cell assays were implemented to search for efflux pump inhibitors (EPIs) of the three multidrug resistance efflux pumps (MexAB-OprM, MexCD-OprJ, MexEF-OprN) that contribute to fluoroquinolone resistance in clinical isolates of
Pseudomonas aeruginosa
. Secondary assays were developed to identify lead compounds with exquisite activities as inhibitors. A broad-spectrum EPI which is active against all three known Mex efflux pumps from
P. aeruginosa
and their close
Escherichia coli
efflux pump homolog (AcrAB-TolC) was discovered. When this compound, MC-207,110, was used, the intrinsic resistance of
P. aeruginosa
to fluoroquinolones was decreased significantly (eightfold for levofloxacin). Acquired resistance due to the overexpression of efflux pumps was also decreased (32- to 64-fold reduction in the MIC of levofloxacin). Similarly, 32- to 64-fold reductions in MICs in the presence of MC-207,110 were observed for strains with overexpressed efflux pumps and various target mutations that confer resistance to levofloxacin (e.g.,
gyrA
and
parC
). We also compared the frequencies of emergence of levofloxacin-resistant variants in the wild-type strain at four times the MIC of levofloxacin (1 μg/ml) when it was used either alone or in combination with EPI. In the case of levofloxacin alone, the frequency was ∼10
−7
CFU/ml. In contrast, with an EPI, the frequency was below the level of detection (<10
−11
). In summary, we have demonstrated that inhibition of efflux pumps (i) decreased the level of intrinsic resistance significantly, (ii) reversed acquired resistance, and (iii) resulted in a decreased frequency of emergence of
P. aeruginosa
strains that are highly resistant to fluoroquinolones.
In Vitro Antimicrobial Activities of Bakuchiol against Oral Microorganisms
Authors: Katsura Harumi , Tsukiyama Ryo-Ichi , Suzuki Akiko , Kobayashi Makio 
Published: July 2002

ABSTRACT

Bakuchiol was isolated from the seeds of
Psoralea corylifolia
, a tree native to China with various uses in traditional medicine, followed by extraction with ether and column chromatography combined with silica gel and octyldecyl silane. In this study, the antimicrobial activities of bakuchiol against some oral microorganisms were evaluated in vitro. The cell growth of
Streptococcus mutans
was inhibited in a bakuchiol concentration-dependent manner, and growth of
S. mutans
was completely prevented by 20 μg of bakuchiol per ml. The bactericidal effect of bakuchiol on
S. mutans
was dependent on temperature and stable under the following conditions: sucrose, 0 to 10% (wt/vol); pH, 3.0 to 7.0; organic acids (3% [wt/vol] citric and malic acids). Bakuchiol showed bactericidal effects against all bacteria tested, including
S. mutans
,
Streptococcus sanguis
,
Streptococcus salivarius
,
Streptococcus sobrinus
,
Enterococcus faecalis
,
Enterococcus faecium
,
Lactobacillus acidophilus
,
Lactobacillus casei
,
Lactobacillus plantarum
,
Actinomyces viscosus
, and
Porphyromonas gingivalis
, with MICs ranging from 1 to 4 μg/ml and the sterilizing concentration for 15 min ranging from 5 to 20 μg/ml. Furthermore, bakuchiol was also effective against adherent cells of
S. mutans
in water-insoluble glucan in the presence of sucrose and inhibited the reduction of pH in the broth. Thus, bakuchiol would be a useful compound for development of antibacterial agents against oral pathogens and has great potential for use in food additives and mouthwash for preventing and treating dental caries.
Antimicrobial Susceptibilities of 1,730
Haemophilus influenzae
Respiratory Tract Isolates in Spain in 1998-1999
Authors: Marco Francesc , Garcı́a-de-Lomas Juan , Garcı́a-Rey César , Bouza Emilio , Aguilar Lorenzo , Fernández-Mazarrasa Carlos ,   The Spanish Surveillance Group for Respiratory Pathogens
Published: July 2002

ABSTRACT

A β-lactamase prevalence of 23% was found among 1,730
Haemophilus influenzae
isolates. Ampicillin susceptibility was 70%, and 12% of β-lactamase-negative strains presented diminished susceptibility to ampicillin (BLNAR phenotype). Susceptibility of 90% was found for cefaclor and clarithromycin, whereas it was nearly 100% for cefotaxime, cefixime, azithromycin, and cefuroxime. Ciprofloxacin-resistant (0.1%) and β-lactamase-positive amoxicillin/clavulanate-resistant (BLPACR) phenotypes (0.1%) are anecdotal so far.
Novel Tetracycline Resistance Gene,
tet
(32), in the
Clostridium
-Related Human Colonic Anaerobe K10 and Its Transmission In Vitro to the Rumen Anaerobe
Butyrivibrio fibrisolvens
Authors: Melville Claire M. , Scott Karen P. , Mercer Derry K. , Flint Harry J. 
Published: July 2002

ABSTRACT

A novel tetracycline resistance gene, designated
tet
(32), which confers a high level of tetracycline resistance, was identified in the
Clostridium-
related human colonic anaerobe K10, which also carries
tet
(W).
tet
(32) was transmissible in vitro to the rumen anaerobe
Butyrivibrio fibrisolvens
2221
R
. The predicted gene product of
tet
(32) has 76% amino acid identity with Tet(O). PCR amplification indicated that
tet
(32) is widely distributed in the ovine rumen and in porcine feces.
Antimicrobial Susceptibilities of 1,684
Streptococcus pneumoniae
and 2,039
Streptococcus pyogenes
Isolates and Their Ecological Relationships: Results of a 1-Year (1998–1999) Multicenter Surveillance Study in Spain
Authors: Pérez-Trallero E. , Fernández-Mazarrasa C. , Garcı́a-Rey C. , Bouza E. , Aguilar L. , Garcı́a-de-Lomas J. , Baquero F. ,   The Spanish Surveillance Group for Respiratory Pathogens
Published: July 2002

ABSTRACT

A nationwide multicenter susceptibility surveillance study which included 1,684
Streptococcus pneumoniae
and 2,039
S. pyogenes
isolates was carried out over 1 year in order to assess the current resistance patterns for the two most important gram-positive microorganisms responsible for community-acquired infections in Spain. Susceptibility testing was done by a broth microdilution method according to National Committee for Clinical Laboratory Standards M100-S10 interpretative criteria. For
S. pneumoniae
, the prevalences of highly resistant strains were 5% for amoxicillin and amoxicillin-clavulanic acid; 7% for cefotaxime; 22% for penicillin; 31% for cefuroxime; 35% for erythromycin, clarithromycin, and azithromycin; and 42% for cefaclor. For
S. pyogenes
, the prevalence of erythromycin resistance was 20%. Efflux was encountered in 90% of
S. pyogenes
and 5% of
S. pneumoniae
isolates that exhibited erythromycin resistance. Erythromycin resistance was associated with clarithromycin and azithromycin in both species, regardless of phenotype. Despite the different nature of the mechanisms of resistance, a positive correlation (
r
= 0.612) between the two species in the prevalence of erythromycin resistance was found in site-by-site comparisons, suggesting some kind of link with antibiotic consumption. Regarding ciprofloxacin, the MIC was ≥4 μg/ml for 7% of
S. pneumoniae
and 3.5% of
S. pyogenes
isolates. Ciprofloxacin resistance (MIC, ≥4 μg/ml) was significantly (
P
< 0.05) associated with macrolide resistance in both
S. pyogenes
and
S. pneumoniae
and with penicillin nonsusceptibility in
S. pneumoniae
.
Cefepime, Piperacillin-Tazobactam, and the Inoculum Effect in Tests with Extended-Spectrum β-Lactamase-Producing
Enterobacteriaceae
Authors: Thomson Kenneth S. , Moland Ellen Smith 
Published: July 2002

ABSTRACT

There is little information about the clinical effectiveness of cefepime and piperacillin-tazobactam in the treatment of infections caused by extended-spectrum β-lactamase (ESBL)-producing pathogens. Some inferences have been drawn from laboratory studies, which have usually involved only one or a few strains of ESBL-producing
Klebsiella pneumoniae
or
Escherichia coli
that produced only a limited range of ESBLs. Such studies are indirect, sometimes conflicting, indicators of efficacy. To extend previous laboratory findings, a study was designed to investigate organism-drug interactions by determining the in vitro activities of eight parenteral β-lactam agents against 82 clinical and laboratory strains of
Klebsiella
,
Escherichia
,
Enterobacter
,
Citrobacter
,
Serratia
,
Morganella
, and
Proteus
species that produced 22 different ESBLs, alone or in combination with other β-lactamases. Activities were determined in broth microdilution MIC tests using standard and 100-fold-higher inocula. An inoculum effect, defined as an eightfold or greater MIC increase on testing with the higher inoculum, was most consistently detected with cefepime, cefotaxime, and ceftriaxone and least frequently detected with meropenem and cefoteten. Piperacillin-tazobactam was intermediate between these two groups of agents. Although the inoculum effect is an in vitro laboratory phenomenon, if it has any predictive value in identifying increased risk of therapeutic failure in serious infections, these results support suggestions that cefepime may be a less-than-reliable agent for therapy of infections caused by ESBL-producing strains.