bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of a Continuous-Culture Biofilm System To Study the Antimicrobial Susceptibilities of
Gardnerella vaginalis
and
Lactobacillus acidophilus
Authors: Muli F. , Struthers J. K. 
Published: October 2018

ABSTRACT

Gardnerella vaginalis
and
Lactobacillus acidophilus
have been shown to grow to high titers in a simple biofilm system. This system was used in the present investigation to compare the biofilm-eradicating concentrations (BECs) of amoxicillin, clindamycin, erythromycin, and metronidazole to standard tube MIC and minimum bactericidal concentration (MBC) results. With the lactobacillus, the BEC/tube MBC ratio was at least 16:1, while for
G. vaginalis
the ratio varied from 2:1 to 512:1. The simple continuous-culture system used in the present investigation is ideal for investigating the BEC for bacteria involved in complex ecological situations such as bacterial vaginosis and may be useful for the identification of the most effective and selective antibiotic therapy.
Pharmacokinetics and Safety of a New Parenteral Carbapenem Antibiotic, Biapenem (L-627), in Elderly Subjects
Authors: Kozawa Osamu , Uematsu Toshihiko , Matsuno Hiroyuki , Niwa Masayuki , Takiguchi Yoshiharu , Matsumoto Syouzou , Minamoto Masahiko , Niida Yoshito , Yokokawa Masahiro , Nagashima Satoru , Kanamaru Mitsutaka 
Published: October 2018

ABSTRACT

The pharmacokinetics and tolerability of a new parenteral carbapenem antibiotic, biapenem (L-627), were studied in healthy elderly volunteers aged 65 to 74 years (71.6 ± 2.7 years [mean ± standard deviation],
n
= 5; group B) and ≥75 years (77.8 ± 1.9 years,
n
= 5; group C), following single intravenous doses (300 and 600 mg), and compared with those of healthy young male volunteers aged 20 to 29 years (23.0 ± 3.5 years,
n
= 5; group A). The agent was well tolerated in all three age groups. Serial blood and urine samples were analyzed for biapenem to obtain key pharmacokinetic parameters by both two-compartment model-dependent and -independent methods. The maximum plasma concentration and area under plasma concentration-versus-time curve (AUC) increased in proportion to the dose in all three groups. Statistically significant age-related effects for AUC, total body clearance, and renal clearance (CL
R
) were found, while elimination half-life (
t
1/2β
) and percent cumulative recovery from urine of unchanged drug (% UR) remained unaltered (
t
1/2β
, 1.51 ± 0.42 [300 mg] and 2.19 ± 0.64 [600 mg] h [group A], 1.82 ± 1.14 and 1.45 ± 0.36 h [group B], and 1.75 ± 0.23 and 1.59 ± 0.18 h [group C]; %UR, 52.6% ± 3.0% [300 mg] and 53.1% ± 5.1% [600 mg] [group A], 46.7% ± 7.4% and 53.0% ± 4.8% [group B], and 50.1% ± 5.2% and 47.1% ± 7.6% [group C]). A significant linear correlation was observed between the CL
R
of biapenem and creatinine clearance at the dose of 300 mg but not at 600 mg. The steady-state volume of distribution tended to be decreased with age, although not significantly. Therefore, the age-related changes in parameters of biapenem described above were attributable to the combination of decreased lean body mass and lowered renal function of the elderly subjects. However, the magnitude of those changes does not necessitate dosage adjustment in elderly patients with normal renal function for their age.
Quantitative Structure-Activity Relationship Studies of a Series of Sulfa Drugs as Inhibitors of
Pneumocystis carinii
Dihydropteroate Synthetase
Authors: Johnson Theresa , Khan Ikhlas A. , Avery Mitchell A. , Grant Juliana , Meshnick Steven R. 
Published: October 2018

ABSTRACT

Sulfone and sulfanilamide sulfa drugs have been shown to inhibit dihydropteroate synthetase (DHPS) isolated from
Pneumocystis carinii
. In order to develop a pharmacophoric model for this inhibition, quantitative structure-activity relationships (QSAR) for sulfa drugs active against DHPS have been studied. Accurate 50% inhibitory concentrations were collected for 44 analogs, and other parameters, such as partition coefficients and molar refractivity, were calculated. Conventional multiple regression analysis of these data did not provide acceptable QSAR. However, three-dimensional QSAR provided by comparative molecular field analysis did give excellent results. Upon removal of poorly correlated analogs, a data set of 36 analogs, all having a common NHSO
2
group, provided a cross-validated
r
2
value of 0.699 and conventional
r
2
value of 0.964. The resulting pharmacophore model should be useful for understanding and predicting the binding of DHPS by new sulfa drugs.
Antiviral Activities of 9-
R
-2-Phosphonomethoxypropyl Adenine (PMPA) and Bis(isopropyloxymethylcarbonyl)PMPA against Various Drug-Resistant Human Immunodeficiency Virus Strains
Authors: Srinivas Ranga V. , Fridland Arnold 
Published: October 2018

ABSTRACT

9-
R
-2-Phosphonomethoxypropyl adenine (PMPA) is an acyclic nucleoside phosphonate analog that has demonstrated efficacy against human immunodeficiency virus (HIV). We recently described the synthesis, metabolism, and biological activities of bis(isopropyloxymethylcarbonyl)PMPA [bis(poc)PMPA] as an orally bioavailable prodrug for PMPA. Among a large panel of drug-resistant HIV type 1 variants, only the K65R virus was resistant to PMPA. K65R virus also showed reduced susceptibility to bis(poc)PMPA, although the prodrug could still inhibit these viruses at submicromolar, nontoxic concentrations. Among a panel of seven primary clinical isolates from patients with diverse treatment histories, only one isolate showed reduced susceptibility to PMPA and was found to carry three mutations (M41L, T69N, R73K) in its reverse transcriptase catalytic domain.
In Vitro Activity of a New Ketolide Antibiotic, HMR 3647, against
Chlamydia pneumoniae
Authors: Roblin Patricia M. , Hammerschlag Margaret R. 
Published: October 2018

ABSTRACT

The in vitro activities of HMR 3647, roxithromycin, erythromycin, and azithromycin against 19 strains of
Chlamydia pneumoniae
were tested. The MIC at which 90% of the isolates are inhibited and the minimum bactericidal concentration at which 90% of the isolates are killed of HMR 3647 were 0.25 μg/ml (range, 0.015 to 2 μg/ml). Nine recently obtained clinical isolates from children with pneumonia were more susceptible (MICs, 0.015 to 0.0625 μg/ml) than older strains that had been passaged more extensively.
Antimicrobial Susceptibilities of Group B Streptococci Isolated between 1992 and 1996 from Patients with Bacteremia or Meningitis
Authors: Fernandez Marisol , Hickman Melissa E. , Baker Carol J. 
Published: October 2018

ABSTRACT
In vitro testing of 229 group B streptococcal isolates from a variety of patients with invasive infections indicated uniform penicillin G susceptibility. However, 17 (7.4%) isolates were resistant to erythromycin and 8 (3.4%) were resistant to clindamycin. These results support the continued use of penicillin G as the drug of choice for the treatment and prevention of group B streptococcal disease.
Selection and Characterization of β-Lactam–β-Lactamase Inactivator-Resistant Mutants following PCR Mutagenesis of the TEM-1 β-Lactamase Gene
Authors: Vakulenko Sergei B. , Geryk Bruce , Kotra Lakshmi P. , Mobashery Shahriar , Lerner Stephen A. 
Published: October 2018

ABSTRACT
Mechanism-based inactivators of β-lactamases are used to overcome the resistance of clinical pathogens to β-lactam antibiotics. This strategy can itself be overcome by mutations of the β-lactamase that compromise the effectiveness of their inactivation. We used PCR mutagenesis of the TEM-1 β-lactamase gene and sequenced the genes of 20 mutants that grew in the presence of ampicillin-clavulanate. Eleven different mutant genes from these strains contained from 1 to 10 mutations. Each had a replacement of one of the four residues, Met69, Ser130, Arg244, and Asn276, whose substitutions by themselves had been shown to result in inhibitor resistance. None of the mutant enzymes with multiple amino acid substitutions generated in this study conferred higher levels of resistance to ampicillin alone or ampicillin with β-lactamase inactivators (clavulanate, sulbactam, or tazobactam) than the levels of resistance conferred by the corresponding single-mutant enzymes. Of the four enzymes with just a single mutation (Ser130Gly, Arg244Cys, Arg244Ser, or Asn276Asp), the Asn276Asp β-lactamase conferred a wild-type level of ampicillin resistance and the highest levels of resistance to ampicillin in the presence of inhibitors. Site-directed random mutagenesis of the Ser130 codon yielded no other mutant with replacement of Ser130 besides Ser130Gly that produced ampicillin-clavulanate resistance. Thus, despite PCR mutagenesis we found no new mutant TEM β-lactamase that conferred a level of resistance to ampicillin plus inactivators greater than that produced by the single-mutation enzymes that have already been reported in clinical isolates. Although this is reassuring, one must caution that other combinations of multiple mutations might still produce unexpected resistance.
Antimicrobial Therapies for
Helicobacter pylori
Infection in Gnotobiotic Piglets
Authors: Krakowka Steven , Eaton K. A. , Leunk Robert D. 
Published: October 2018

ABSTRACT

Gnotobiotic piglets infected with
Helicobacter pylori
were treated with various antimicrobials as monotherapy and dual therapy, and the results were compared to those for piglets treated with a triple-therapy regimen (bismuth subsalicyclate at 5.7 mg/kg of body weight, metronidazole at 4.4 mg/kg, and amoxicillin at 6.8 mg/kg four times a day [QID]). Clearance of infection was assessed after 7 days of treatment, and eradication was assessed following 7 days of treatment and a 14-day posttreatment observation interval. Monotherapy with amoxicillin, clarithromycin, and ciprofloxacin cleared and eradicated the organism from porcine stomachs; monotherapy with metronidazole cleared the infection and eradicated it from some piglets. Metronidazole-resistant microbes were recovered from treated piglets which cleared but did not eradicate the infection. Monotherapy with bismuth subsalicylate, erythromycin, nitrofurantoin, and tetracycline in the dosage range of 5.0 to 7.1 mg/kg QID was less than 100% effective in clearance and eradication, in that these drugs cleared and/or eradicated the infection from some of the piglets but did not eradicate the infection from all of the piglets. Monotherapy with an H-2 receptor antagonist (ranitidine) or a proton pump inhibitor (omeprazole) was ineffective at either clearance or eradication. In vivo dose titrations with several effective monotherapies were performed to determine the lowest effective in vivo dose of drug. In piglets, eradication was associated with a statistically significant decline in serum
H. pylori
-specific immunoglobulin M (IgM) antibodies; the titers of both IgA and IgG also declined, but the values were not statistically significant. For many antimicrobials, piglets are more sensitive indicators of clearance and eradication than humans. These data establish the
H. pylori
-infected gnotobiotic piglet as a useful model for the identification of novel antimicrobials for the treatment of this disease and for drug assessment during preclinical evaluations.
Chloramphenicol Resistance in
Clostridium difficile
Is Encoded on Tn
4453
Transposons That Are Closely Related to Tn
4451
from
Clostridium perfringens
Authors: Lyras Dena , Storie Christine , Huggins Andrea S. , Crellin Paul K. , Bannam Trudi L. , Rood Julian I. 
Published: October 2018

ABSTRACT

The chloramphenicol resistance gene
catD
from
Clostridium difficile
was shown to be encoded on the transposons Tn
4453a
and Tn
4453b
, which were structurally and functionally related to Tn
4451
from
Clostridium perfringens
. Tn
4453a
and Tn
4453b
excised precisely from recombinant plasmids, generating a circular form, as is the case for Tn
4451
. Evidence that this process is mediated by Tn
4453
-encoded
tnpX
genes was obtained from experiments which showed that in
trans
these genes complemented a Tn
4451tnpXΔ1
mutation for excision. Nucleotide sequencing showed that the joint of the circular form generated by the excision of Tn
4453a
and Tn
4453b
was similar to that from Tn
4451
. These results suggest that the Tn
4453
-encoded TnpX proteins bind to similar DNA target sequences and function in a manner comparable to that of TnpX from Tn
4451
. Furthermore, it has been shown that Tn
4453a
and Tn
4453b
can be transferred to suitable recipient cells by RP4 and therefore are mobilizable transposons. It is concluded that, like Tn
4451
, they must encode a functional
tnpZ
gene and a target
oriT
or RS
A
site. The finding that related transposable elements are present in
C. difficile
and
C. perfringens
has implications for the evolution and dissemination of antibiotic resistance genes and the mobile elements on which they are found within the clostridia.
In Vitro Activities of Co-Amoxiclav at Concentrations Achieved in Human Serum against the Resistant Subpopulation of HeteroresistantStaphylococcus aureus: a Controlled Study with Vancomycin
Authors: Prieto J. , Aguilar L. , Giménez M. J. , Toro D. , Gómez-Lus M. L. , Dal-Ré R. , Balcabao I. P. 
Published: October 2018

ABSTRACTThe effects of concentrations that simulated those in human serum after a single intravenous dose of amoxicillin (2 g), amoxicillin-clavulanic acid (2,000 and 200 mg, respectively), or vancomycin (500 mg), on the viability and β-lactamase activity of two isogenic (β-lactamase and non-β-lactamase producer) heteroresistantStaphylococcus aureusstrains were studied in an in vitro pharmacodynamic model. A reduction of ≥97% of the initial inoculum was obtained with vancomycin and amoxicillin-clavulanic acid against both strains, with respect to the total bacterial population and the oxacillin-resistant subpopulation. The same pattern was observed with amoxicillin and the β-lactamase-negative strain. β-Lactamase activity in the β-lactamase-positive strain changed over time parallel to viability, decreasing with amoxicillin-clavulanic acid or vancomycin and increasing in the amoxicillin and control groups. Clavulanic acid concentrations achievable in serum that changed over time allowed amoxicillin to act against the β-lactamase-producing methicillin-resistantS. aureusto a similar extent as vancomycin.
Decreased Accumulation or Increased Isoleucyl-tRNA Synthetase Activity Confers Resistance to the Cyclic β-Amino Acid BAY 10-8888 in
Candida albicans
and
Candida tropicalis
Authors: Ziegelbauer Karl 
Published: October 2018

ABSTRACT

BAY 10-8888, a cyclic β-amino acid, exerts its antifungal activity by inhibition of isoleucyl-tRNA synthetase activity after accumulation to a millimolar concentration inside the cell. We have selected and characterized BAY 10-8888-resistant
Candida albicans
mutants. Reduced BAY 10-8888 accumulation as well as increased isoleucyl-tRNA synthetase activity was observed in these mutants. Some of the mutants were cross-resistant to cispentacin, a structurally related β-amino acid, while sensitivities to 5-fluorocytosine and fluconazole remained unchanged in all mutants. All except two in vitro-resistant mutants were pathogenic in a murine candidiasis model, and BAY 10-8888 failed to cure the infection. Furthermore, we have characterized BAY 10-8888 transport and isoleucyl-tRNA synthetase activity in several
Candida tropicalis
strains which showed MICs higher than those of other Candida strains. An analysis of the
C. tropicalis
strains revealed that intracellular concentrations of BAY 10-8888 were in the millimolar range, comparable to those for
C. albicans
. However, these isolates expressed isoleucyl-tRNA synthetase activities about fourfold higher than those for
C. albicans
. To test the possibility of resistance modeling, we determined the correlations between the intracellular concentration of BAY 10-8888, the specific activity of isoleucyl-tRNA synthetase, the number of free, i.e., noninhibited, isoleucyl-tRNA synthetase molecules/cell, and growth, assuming a linear relation. We found significant correlations between growth and the intracellular concentration of BAY 10-8888 and between growth and the number of free isoleucyl-tRNA synthetase molecules/cell, but not between growth and the specific activity of isoleucyl-tRNA synthetase.
Cefepime-Aztreonam: a Unique Double β-Lactam Combination for
Pseudomonas aeruginosa
Authors: Lister Philip D. , Sanders W. Eugene , Sanders Christine C. 
Published: October 2018

ABSTRACT

An in vitro pharmacokinetic model was used to determine if aztreonam could enhance the pharmacodynamics of cefepime or ceftazidime against an isogenic panel of
Pseudomonas aeruginosa
164, including wild-type (WT), partially derepressed (PD), and fully derepressed (FD) phenotypes. Logarithmic-phase cultures were exposed to peak concentrations achieved in serum with 1- or 2-g intravenous doses, elimination pharmacokinetics were simulated, and viable bacterial counts were measured over three 8-h dosing intervals. In studies with cefepime and cefepime-aztreonam against the PD strain, samples were also filter sterilized, assayed for active cefepime, and assayed for nitrocefin hydrolysis activity before and after overnight dialysis. Against WT strains, the cefepime-aztreonam combination was the most active regimen, but viable counts at 24 h were only 1 log below those in cefepime-treated cultures. Against PD and FD strains, the antibacterial activity of cefepime-aztreonam was significantly enhanced over that of each drug alone, with 3.5 logs of killing by 24 h. Hydrolysis and bioassay studies demonstrated that aztreonam was inhibiting the extracellular cephalosporinase that had accumulated and was thus protecting cefepime in the extracellular environment. In contrast to cefepime-aztreonam, the pharmacodynamics of ceftazidime-aztreonam were not enhanced over those of aztreonam alone. Further pharmacodynamic studies with five other
P. aeruginosa
strains producing increased levels of cephalosporinase demonstrated that the enhanced pharmacodynamics of cefepime-aztreonam were not unique to the isogenic panel. The results of these studies demonstrate that aztreonam can enhance the antibacterial activity of cefepime against derepressed mutants of
P. aeruginosa
producing increased levels of cephalosporinase. This positive interaction appears to be due in part to the ability of aztreonam to protect cefepime from extracellular cephalosporinase inactivation. Clinical evaluation of this combination is warranted.
Antiviral Activity of a Selective Ribonucleotide Reductase Inhibitor against Acyclovir-Resistant Herpes Simplex Virus Type 1 In Vivo
Authors: Duan Jianmin , Liuzzi Michel , Paris William , Lambert Michelle , Lawetz Carol , Moss Neil , Jaramillo Jorge , Gauthier Jean , Déziel Robert , Cordingley Michael G. 
Published: October 2018

ABSTRACT

The present study reports the activity of BILD 1633 SE against acyclovir (ACV)-resistant herpes simplex virus (HSV) infections in athymic nude (
nu/nu
) mice. BILD 1633 SE is a novel peptidomimetic inhibitor of HSV ribonucleotide reductase (RR). In vitro, it is more potent than ACV against several strains of wild-type as well as ACV-resistant HSV mutants. Its in vivo activity was tested against cutaneous viral infections in athymic nude mice infected with the ACV-resistant isolates HSV type 1 (HSV-1)
dl
sptk and PAA
r
5, which contain mutations in the viral thymidine kinase gene and the polymerase gene, respectively. Following cutaneous infection of athymic nude mice, both HSV-1
dl
sptk and PAA
r
5 induced significant, reproducible, and persistent cutaneous lesions that lasted for more than 2 weeks. A 10-day treatment regimen with ACV given topically four times a day as a 5% cream or orally at up to 5 mg/ml in drinking water was partially effective against HSV-1 PAA
r
5 infection with a reduction of the area under the concentration-time curve (AUC) of 34 to 48%. The effects of ACV against HSV-1
dl
sptk infection were not significant when it was administered topically and were only marginal when it was given in drinking water. Treatment under identical conditions with 5% topical BILD 1633 SE significantly reduced the cutaneous lesions caused by both HSV-1
dl
sptk and PAA
r
5 infections. The effect of BILD 1633 SE against HSV-1 PAA
r
5 infections was more prominent and was inoculum and dose dependent, with AUC reductions of 96 and 67% against infections with 10
6
and 10
7
PFU per inoculation site, respectively. BILD 1633 SE also significantly decreased the lesions caused by HSV-1
dl
sptk infection (28 to 51% AUC reduction). Combination therapy with topical BILD 1633 SE (5%) and ACV in drinking water (5 mg/ml) produced an antiviral effect against HSV-1
dl
sptk and PAA
r
5 infections that was more than the sum of the effects of both drugs. This is the first report that a selective HSV RR subunit association inhibitor can be effective against ACV-resistant HSV infections in vivo.
Outer Membrane Profiles of Clonally Related
Klebsiella pneumoniae
Isolates from Clinical Samples and Activities of Cephalosporins and Carbapenems
Authors: Ardanuy Carmen , Liñares Josefina , Domínguez María Angeles , Hernández-Allés Santiago , Benedí Vicente J. , Martínez-Martínez Luis 
Published: October 2018

ABSTRACT

Fifteen isolates of
Klebsiella pneumoniae
producing extended-spectrum β-lactamases (ESBLs) isolated during a nosocomial outbreak were studied. The strains belonged to the same clonal type, as shown by pulsed-field gel electrophoretic analysis of chromosomal DNA. All the isolates were resistant to extended-spectrum cephalosporins, aztreonam, gentamicin, and fluoroquinolones and were susceptible to carbapenems, tobramycin, netilmicin, and amikacin. None of the isolates expressed the OmpK36 porin. Eight isolates, for which the MICs of cefoxitin were ≥64 μg/ml, showed a diminished level or no expression of a 35-kDa porin. The MICs of meropenem, cefotaxime, and cefpirome were three to eight times higher for porin-deficient isolates than for isolates expressing the 35-kDa porin, but the MICs of imipenem increased two times for porin-deficient isolates compared to those for isolates expressing the porin. This MIC increase reverted to a level similar to that for the parental strain when porin-deficient isolates were transformed with the gene coding for the
K. pneumoniae
porin OmpK36. It is concluded that the high level of resistance to cefoxitin and the increase in the MICs of meropenem, cefotaxime, and cefpirome for the ESBL-producing
K. pneumoniae
isolates studied are associated with porin deficiency.
Contribution of Outer Membrane Efflux Protein OprM to Antibiotic Resistance in
Pseudomonas aeruginosa
Independent of MexAB
Authors: Zhao Qixun , Li Xian-Zhi , Srikumar Ramakrishnan , Poole Keith 
Published: October 2018

ABSTRACT

A
Pseudomonas aeruginosa
strain carrying an insertion of an ΩHg interposon in the
mexB
gene (
mexB
::ΩHg; strain K879) produced markedly reduced but still detectable levels of OprM, the product of the third gene of the
mexAB-oprM
multidrug efflux operon. By using a
lacZ
transcriptional fusion vector, promoter activity likely responsible for OprM expression in the
mexB
::ΩHg mutant was identified upstream of
oprM
. Introduction of the
oprM
gene, but not the
mexAB
genes, into a
P. aeruginosa
multidrug-susceptible Δ
mexAB-oprM
mutant increased resistance to quinolones, cephalosporins, erythromycin, and tetracycline. A Δ
mexAB-oprM
strain carrying the
oprM
gene accumulated markedly less antibiotic than the deletion strain without
oprM
. Antibiotic accumulation by the MexAB
−
OprM
+
strain was markedly enhanced upon treatment of cells with the uncoupler carbonyl cyanide
m
-chlorophenylhydrazone (CCCP), indicating that MexAB-independent OprM function likely involves an efflux process. Moreover, pretreatment of cells with CCCP prior to the accumulation assay abrogated any differences in accumulation levels between the MexAB
−
OprM
+
and MexAB
−
OprM
−
strains, indicating that reduced drug accumulation by the OprM
+
strain (in the absence of CCCP) cannot be due to OprM-mediated reduction in outer membrane permeability. It appears, therefore, that OprM can be expressed and function in a drug efflux capacity independent of MexAB.