bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic In Vitro Antimalarial Activity of Omeprazole and Quinine
Authors: Skinner-Adams T. , Davis T. M. E. 
Published: October 2018

ABSTRACT
Previous studies have shown that the proton pump inhibitor omeprazole has antimalarial activity in vitro. The interactions of omeprazole with commonly used antimalarial drugs were assessed in vitro. Omeprazole and quinine combinations were synergistic; however, chloroquine and omeprazole combinations were antagonistic. Artemisinin drugs had additive antimalarial activities with omeprazole.
Emergence of Fluoroquinolone Resistance among Multiply Resistant Strains of
Streptococcus pneumoniae
in Hong Kong
Authors: Ho Pak-Leung , Que Tak-Lun , Tsang Dominic Ngai-Chong , Ng Tak-Keung , Chow Kin-Hung , Seto Wing-Hon 
Published: October 2018

ABSTRACT

The MICs of 17 antimicrobial agents for 181
Streptococcus pneumoniae
strains were determined by the E-test. Overall, 69.1% were penicillin resistant (MIC > 0.06 μg/ml). Resistance to ciprofloxacin (MIC > 2 μg/ml), levofloxacin (MIC > 2 μg/ml), or trovafloxacin (MIC > 1 μg/ml) was found in 12.1, 5.5, or 2.2% of the strains, respectively. These high rates of resistance raise concerns for the future.
A Mechanism for the Synergistic Antimalarial Action of Atovaquone and Proguanil
Authors: Srivastava Indresh K. , Vaidya Akhil B. 
Published: October 2018

ABSTRACT

A combination of atovaquone and proguanil has been found to be quite effective in treating malaria, with little evidence of the emergence of resistance when atovaquone was used as a single agent. We have examined possible mechanisms for the synergy between these two drugs. While proguanil by itself had no effect on electron transport or mitochondrial membrane potential (ΔΨ

m

), it significantly enhanced the ability of atovaquone to collapse ΔΨ

m

when used in combination. This enhancement was observed at pharmacologically achievable doses. Proguanil acted as a biguanide rather than as its metabolite cycloguanil (a parasite dihydrofolate reductase [DHFR] inhibitor) to enhance the atovaquone effect; another DHFR inhibitor, pyrimethamine, also had no enhancing effect. Proguanil-mediated enhancement was specific for atovaquone, since the effects of other mitochondrial electron transport inhibitors, such as myxothiazole and antimycin, were not altered by inclusion of proguanil. Surprisingly, proguanil did not enhance the ability of atovaquone to inhibit mitochondrial electron transport in malaria parasites. These results suggest that proguanil in its prodrug form acts in synergy with atovaquone by lowering the effective concentration at which atovaquone collapses ΔΨ

m

in malaria parasites. This could explain the paradoxical success of the atovaquone-proguanil combination even in regions where proguanil alone is ineffective due to resistance. The results also suggest that the atovaquone-proguanil combination may act as a site-specific uncoupler of parasite mitochondria in a selective manner.
OXA-17, a Further Extended-Spectrum Variant of OXA-10 β-Lactamase, Isolated from
Pseudomonas aeruginosa
Authors: Danel Franck , Hall Lucinda M. C. , Duke Brigid , Gur Deniz , Livermore David M. 
Published: October 2018

ABSTRACT

Pseudomonas aeruginosa
isolates 871 and 873 were isolated at Hacettepe University Hospital in Ankara and were highly resistant to ceftazidime (MIC, 128 μg/ml). Each produced three β-lactamases, with pIs of 5.3, 6.1, and 7.9. The β-lactamase with a pI of 5.3 was previously shown to be PER-1 enzyme. The antibiograms of the isolates were not entirely explained by production of PER-1 enzyme, insofar as ceftazidime resistance was incompletely reversed by clavulanate. The enzymes with pIs of 6.1 and 7.9 were therefore investigated. The enzyme with a pI of 6.1 proved to be a novel mutant of OXA-10, which we designated OXA-17, and had asparagine changed to serine at position 73 of the protein. When cloned into
Escherichia coli
XL1-blue, OXA-17 enzyme conferred greater resistance to cefotaxime, latamoxef, and cefepime than did OXA-10, but it had only a marginal (two- to fourfold) effect on the MIC of ceftazidime. This behavior contrasted with that of previous OXA-10 mutants, specifically OXA-11, -14, and -16, which predominately compromise ceftazidime. Extracted OXA-17 enzyme had relatively greater activity than OXA-10 against oxacillin, cloxacillin, and cefotaxime but, in terms of
k
cat
/

K
m

, it had lower catalytic efficiency against most β-lactams. The enzyme with a pI of 7.9 was shown by gene sequencing to be OXA-2.
Erythromycin-Resistant
Neisseria gonorrhoeae
and Oral Commensal
Neisseria
spp. Carry Known rRNA Methylase Genes
Authors: Roberts Marilyn C. , Chung Whasun O. , Roe Darcie , Xia Minsheng , Marquez Carolina , Borthagaray G. , Whittington William L. , Holmes King K. 
Published: October 2018

ABSTRACT

Two
Neisseria gonorrhoeae
isolates from Seattle and two isolates from Uruguay were resistant to erythromycin (MIC, 4 to 16 μg/ml) and had reduced susceptibility to azithromycin (MIC, 1 to 4 μg/ml) due to the presence of the self-mobile rRNA methylase gene(s)
ermF
or
ermB
and
ermF
. The two Seattle isolates and one isolate from Uruguay were multiresistant, carrying either the 25.2-MDa
tetM
-containing plasmid (Seattle) or a β-lactamase plasmid (Uruguay). Sixteen commensal
Neisseria
isolates (10
Neisseria perflava
-
N. sicca
, 2
N. flava
, and 4
N. mucosa
) for which erythromycin MICs were 4 to 16 μg/ml were shown to carry one or more known rRNA methylase genes, including
ermB
,
ermC
, and/or
ermF
. Many of these isolates also were multiresistant and carried the
tetM
gene. This is the first time that a complete transposon or a complete conjugative transposon carrying an antibiotic resistance gene has been described for the genus
Neisseria
.
In Vivo Efficacies of Combinations of β-Lactams, β-Lactamase Inhibitors, and Rifampin against
Acinetobacter baumannii
in a Mouse Pneumonia Model
Authors: Wolff Michel , Joly-Guillou Marie-Laure , Farinotti Robert , Carbon Claude 
Published: October 2018

ABSTRACT

The effects of various regimens containing combinations of β-lactams, β-lactam inhibitor(s), and rifampin were assessed in a recently described mouse model of
Acinetobacter baumannii
pneumonia (M. L. Joly-Guillou, M. Wolff, J. J. Pocidalo, F. Walker, and C. Carbon, Antimicrob. Agents Chemother. 41:345–351, 1997). Two aspects of the therapeutic response were studied: the kinetics of the bactericidal effect (treatment was initiated 3 h after intratracheal inoculation, and bacterial counts were determined over a 24-h period) and survival (treatment was initiated 8 h after inoculation, and the cumulative mortality rate was assessed on day 5). Two clinical strains were used: a cephalosporinase-producing strain (SAN-94040) and a multiresistant strain (RCH-69). For SAN-94040 and RCH-69, MICs and MBCs (milligrams per liter) were as follows: ticarcillin, 32, 64, 256, and >256, respectively; ticarcillin-clavulanate, 32, 64, and 512, and >512, respectively; imipenem, 0.5, 0.5, 8, and 32, respectively; sulbactam, 0.5, 0.5, 8, and 8, respectively; and rifampin, 8, 8, 4, and 4, respectively. Against SAN-94040, four regimens, i.e., imipenem, sulbactam, imipenem-rifampin, and ticarcillin-clavulanate (at a 25/1 ratio)-sulbactam produced a true bactericidal effect (≥3-log
10
reduction of CFU/g of lung). The best survival rate (i.e., 93%) was obtained with the combination of ticarcillin-clavulanate-sulbactam, and regimens containing rifampin provided a survival rate of ≥65%. Against RCH-69, only regimens containing rifampin and the combination of imipenem-sulbactam had a true bactericidal effect. The best survival rates (≥80%) were obtained with regimens containing rifampin and sulbactam. These results suggest that nonclassical combinations of β-lactams, β-lactamase inhibitors, and rifampin should be considered for the treatment of nosocomial pneumonia due to
A. baumannii
.
In Vitro Activities of Designed Antimicrobial Peptides against Multidrug-Resistant Cystic Fibrosis Pathogens
Authors: Schwab Ute , Gilligan Peter , Jaynes Jesse , Henke David 
Published: October 2018

ABSTRACT

The emergence of multidrug-resistant pathogens renders antibiotics ineffective in the treatment of lung infections in patients with cystic fibrosis (CF). Designed antimicrobial peptides (DAPs) are laboratory-synthesized peptide antibiotics that demonstrate a wide spectrum of antibacterial activity. Optimal conditions for susceptibility testing of these peptides have not yet been established. Medium composition is clearly a major factor influencing the results and reproducibilities of susceptibility tests. Using time-kill assays, we tested the effects of different media and buffers on the bactericidal activities of the peptides D2A21 and D4E1 on
Staphylococcus aureus
ATCC 29213 and
Pseudomonas aeruginosa
ATCC 27853. Each peptide at 1 and 5 μM was incubated with bacteria in the different media and buffers. Both peptides were most active in Tris-HCl buffer against
S. aureus
and
P. aeruginosa
. Among the more complex media tested, modified RPMI medium was the medium in which the peptides demonstrated the highest activity, while it supported the growth of the bacteria. The broth microdilution technique was used to test the activities of D2A21 and D4E1 in modified RPMI medium against multidrug-resistant pathogens from patients with CF. The MICs of DAPs for methicillin-resistant
S. aureus
ranged from 0.25 to 4 μg/ml, those for multidrug-resistant
P. aeruginosa
ranged from 0.125 to 4 μg/ml, those for
Stenotrophomonas maltophilia
ranged from 0.5 to 32 μg/ml, and those for
Burkholderia cepacia
ranged from 32 to ≥64 μg/ml. When the activity of peptide D2A21 was compared with that of the tracheal antimicrobial peptide (TAP), D2A21 had greater potency than TAP against
P. aeruginosa
. In addition, no difference in the MICs of D2A21 was seen when it was tested in nutrient broth supplemented with NaCl at different concentrations. Thus, DAPs are a class of salt-insensitive antibiotics potentially useful in the treatment of CF patients harboring multidrug-resistant
P. aeruginosa
.
Cloning and Nucleotide Sequence Determination of the Entire
mec
DNA of Pre-Methicillin-Resistant
Staphylococcus aureus
N315
Authors: Ito T. , Katayama Y. , Hiramatsu K. 
Published: October 2018

ABSTRACT

In methicillin-resistant
Staphylococcus aureus
, the methicillin resistance gene
mecA
is localized within a large chromosomal region which is absent in the methicillin-susceptible
S. aureus
chromosome. The region, designated
mec
DNA, is speculated to have originated from the genome of another bacterial species and become integrated into the chromosome of the
S. aureus
cell in the past. We report here cloning and determination of the structure of the entire
mec
DNA sequence from a Japanese
S. aureus
strain, N315. The
mec
DNA was found to be 51,669 bp long, including terminal inverted repeats of 27 bp and a characteristic pair of direct repeat sequences of 15 bp each: one is situated in the right extremity of
mec
DNA, and the other is situated outside the
mec
DNA and abuts the left boundary of
mec
DNA. The integration site of
mec
DNA was found to be located in an open reading frame (ORF) of unknown function, designated
orfX
. Clusters of antibiotic resistance genes were noted in
mec
DNA carried by transposon Tn
554
and an integrated copy of plasmid pUB110. Both the transposon and plasmid were integrated in the proximity of the
mecA
gene, the latter being flanked by a pair of insertion sequence IS
431
elements. Many ORFs other than those encoding antibiotic resistance were considered nonfunctional because of the acquired mutations or partial deletions found in the ORFs. Two ORFs potentially encoding novel site-specific recombinases were found in
mec
DNA. However, there was no ORF that might encode
mec
DNA-specific transposase or integrase proteins, indicating that the
mec
DNA is not a transposon or a bacteriophage in nature.
Antimicrobial Susceptibility and Composition of Microcosm Dental Plaques Supplemented with Sucrose
Authors: Pratten J. , Wilson M. 
Published: October 2018

ABSTRACT

The aims of this study were to evaluate the effects of repeated chlorhexidine gluconate (CHG) pulsing on the viability and bacterial composition of microcosm dental plaques derived from human saliva. The biofilms were grown on bovine enamel discs in a constant-depth film fermentor fed with an artificial saliva which was supplemented thrice daily with sucrose. The microcosm plaques had total viable anaerobic counts of 5 × 10
8
CFU per mm
2
and consisted of 12%
Actinomyces
spp., 85% streptococci, and 0.2%
Veillonella
spp. When pulsed twice daily with 0.2% CHG, there was an immediate 1.3-log
10
reduction in the total viable (anaerobic) count. However, as pulsing continued, the viable counts recovered, and after 4 days, the anaerobic count reached its pre-CHG-pulsing level, although the bacterial composition of the biofilms had changed. The results of this study show that twice-daily pulsing with 0.2% CHG over a 4-day period was ineffective at reducing the total anaerobic viable count of the biofilms but did alter their bacterial composition.
Multiple Resistant Phenotypes of
Candida albicans
Coexist during Episodes of Oropharyngeal Candidiasis in Human Immunodeficiency Virus-Infected Patients
Authors: Lopez-Ribot Jose L. , McAtee Robert K. , Perea Sofia , Kirkpatrick William R. , Rinaldi Michael G. , Patterson Thomas F. 
Published: October 2018

ABSTRACT

Mechanisms of resistance to azoles in
Candida albicans
, the main etiologic agent of oropharyngeal candidiasis (OPC), include alterations in the target enzyme (lanosterol demethylase) and increased efflux of drug. Previous studies on mechanisms of resistance have been limited by the fact that only a single isolate from each OPC episode was available for study. Multiple isolates from each OPC episode were evaluated with oral samples plated in CHROMagar Candida with and without fluconazole to maximize detection of resistant yeasts. A total of 101 isolates from each of three serial episodes of OPC from four different patients were evaluated. Decreasing geometric means of fluconazole MICs with serial episodes of infection were detected in the four patients. However, 8-fold or larger (up to 32-fold) differences in fluconazole MICs were detected within isolates recovered at the same time point in 7 of 12 episodes. Strain identity was analyzed by DNA typing techniques and indicated that isolates from each patient represented mainly isogenic strains, but differed among patients. A Northern blot technique was used to monitor expression of
ERG11
(encoding lanosterol demethylase) and genes coding for efflux pumps. This analysis revealed that clinical isolates obtained from the same patient and episode were phenotypically heterogeneous in their patterns of expression of these genes involved in fluconazole resistance. These results demonstrate the complexity of the distribution of the molecular mechanisms of antifungal drug resistance and indicate that different subpopulations of yeasts may coexist at a given time in the same patient and may develop resistance through different mechanisms.
Combinations of Vancomycin and β-Lactams Are Synergistic against Staphylococci with Reduced Susceptibilities to Vancomycin
Authors: Climo Michael W. , Patron Roberto L. , Archer Gordon L. 
Published: October 2018

ABSTRACT

Evidence of synergism between combinations of vancomycin and β-lactam antibiotics against 59 isolates of methicillin-resistant staphylococci (
Staphylococcus aureus
,
Staphylococcus epidermidis
, and
Staphylococcus haemolyticus
) for which vancomycin MICs ranged from 1 to 16 μg/ml were tested by broth microdilution checkerboard, disk diffusion, agar dilution, and time-kill antimicrobial susceptibility tests. The combination of vancomycin and oxacillin demonstrated synergy by all test methods against 30 of 59 isolates; no antagonism was seen. Synergy with vancomycin was also found by modified disk diffusion testing for ceftriaxone, ceftazidime, cefpodoxime, and amoxicillin-clavulanate but not for aztreonam. Evidence of synergy correlated directly with vancomycin MICs. The efficacy of vancomycin given alone and in combination with nafcillin was tested in the rabbit model of experimental endocarditis caused by three clinical isolates of glycopeptide-intermediate-susceptible
S. aureus
(GISA) (isolates HIP5827, HIP5836, and MU50). Two of the GISA isolates (isolates MU50 and HIP5836) were extremely virulent in this model, with 27 of 42 (64%) animals dying during the 3-day trial. Therapy with either vancomycin or nafcillin given as a single agent was ineffective for animals infected with HIP5827 or MU50. However, the combination of vancomycin and nafcillin resulted in a mean reduction of 4.52 log
10
CFU/g of aortic valvular vegetations per g compared to the reduction for controls for animals infected with HIP5827 and a reduction of 4.15 log
10
CFU/g for animals infected with MU50. Renal abscesses caused by HIP5827 were sterilized significantly better with the combination of vancomycin and nafcillin than by either treatment alone. We conclude that the combination of vancomycin and β-lactams with antistaphylococcal activity is an effective regimen for the treatment of infections with clinical strains of staphylococci which demonstrate reduced susceptibility to glycopeptides.
Heteroresistance to Fluconazole and Voriconazole in
Cryptococcus neoformans
Authors: Mondon P. , Petter R. , Amalfitano G. , Luzzati R. , Concia E. , Polacheck I. , Kwon-Chung K. J. 
Published: October 2018

ABSTRACT

Cryptococcus neoformans
isolates that exhibited unusual patterns of resistance to fluconazole and voriconazole were isolated from seven isolates from two different geographical regions: one isolate from an Israeli non-AIDS patient and six serial isolates from an Italian AIDS patient who had suffered six recurrent episodes of cryptococcal meningitis. Each isolate produced cultures with heterogeneous compositions in which most of the cells were susceptible, but cells highly resistant to fluconazole (MICs, ≥64 μg/ml) were recovered at a variable frequency (7 × 10
−3
to 4.6 × 10
−2
). Evidence showed that this type of resistance is innate and is unrelated to drug exposure since the Israeli patient had never been treated with azoles or any other antimycotic agents. Analysis of clonal subpopulations of these two strains showed that they exhibited heterogeneous patterns of resistance. The number of subpopulations which grew on fluconazole or voriconazole agar declined progressively with increasing azole concentration without a sharp cutoff point. For the Italian serial isolates, the number of clonal populations resistant to fluconazole (64 μg/ml) and voriconazole (1 μg/ml) increased steadily, yielding the highest number for the isolate from the last episode. Attempts to purify a sensitive subpopulation failed, but clones highly resistant to fluconazole (100 μg/ml) and moderately resistant to voriconazole (1 μg/ml) always produced a homogeneous population of resistant cells. Upon maintenance on drug-free medium, however, the majority of the homogeneously resistant cells of these subclones lost their resistance and returned to the stable initial heteroresistant phenotype. The pattern of heteroresistance was not affected by the pH or osmolarity of the medium but was influenced by temperature. The resistance appeared to be suppressed at 35°C and was completely abolished at 40°C. Although heterogeneity in azole resistance among subpopulations of single isolates has been reported for
Candida
species, the transient changes in expression of resistance under different growth conditions reported here have not been observed in fungal pathogens.
Physiological Cost of Rifampin Resistance Induced In Vitro in
Mycobacterium tuberculosis
Authors: Billington O. J. , McHugh T. D. , Gillespie S. H. 
Published: October 2018

ABSTRACT

Drug-resistant
Mycobacterium tuberculosis
is a major threat to public health. In clinical practice, a limited number of resistance mutations in a short sequence of the beta subunit of RNA polymerase (encoded by
rpoB
) have been described. Spontaneous resistance to rifampin was induced in vitro in
M. tuberculosis
H37Rv (ATCC 9360). Only three resistance patterns could be detected by PCR–single-strand conformation polymorphism analysis. Sequence analysis revealed that Ser
531
→Leu arose most frequently, followed by His
526
→Arg and then either His
526
→Tyr or His
526
→Asp. The relative Darwinian fitness of all but one of the mutant genotypes was less than that of the susceptible parent and, for these mutations, there was a significant correlation between fitness and clinical isolation rate (regression analysis
P
= 0.026). The fitness deficit in some mutants was small, suggesting that there is little likelihood of a spontaneous reversion to susceptibility.
Moderate-Level Resistance to Glycopeptide LY333328 Mediated by Genes of the
vanA
and
vanB
Clusters in Enterococci
Authors: Arthur Michel , Depardieu Florence , Reynolds Peter , Courvalin Patrice 
Published: October 2018

ABSTRACT

Three of five natural plasmids carrying a wild-type
vanA
gene cluster did not confer LY333328 glycopeptide resistance on
Enterococcus faecalis
JH2-2 (MIC = 2 μg/ml). The two remaining plasmids conferred resistance to the drug (MIC, 8 μg/ml). The
vanB
gene cluster did not confer resistance to LY333328, since this antibiotic was not an inducer. Mutations in the

vanS
B

sensor gene that allowed induction by teicoplanin or constitutive expression of the
vanB
cluster led to LY333328 resistance (MIC, 8 to 16 μg/ml). Overproduction of the VanH, VanA, and VanX proteins for
d
-alanyl-
d
-lactate (
d
-Ala-
d
-Lac) synthesis and
d
-Ala-
d
-Ala hydrolysis was sufficient for resistance to LY333328 (MIC, 16 μg/ml). Mutations in the host
d
-Ala:
d
-Ala ligase contributed to LY333328 resistance in certain VanA- and VanB-type strains, but the MICs of the antibiotic did not exceed 16 μg/ml. Addition of
d
-2-hydroxybutyrate in the culture medium of mutants that did not produce the VanH
d
-lactate dehydrogenase led to incorporation of this
d
-2-hydroxy acid at the C-terminal ends of the peptidoglycan precursors and to LY333328 resistance (MIC, 64 μg/ml). The
vanZ
gene of the
vanA
cluster conferred resistance to LY333328 (MIC, 8 μg/ml) by an unknown mechanism. These data indicate that VanA- and VanB-type enterococci may acquire moderate-level resistance to LY333328 (MIC ≤ 16 μg/ml) in a single step by various mechanisms.