bluuebunny/crossref_metadata_2025 huggingface dataset:
Genes Specific for the Biosynthesis of Clavam Metabolites Antipodal to Clavulanic Acid Are Clustered with the Gene for Clavaminate Synthase 1 in
Streptomyces clavuligerus
Authors: Mosher Roy H. , Paradkar Ashish S. , Anders Cecilia , Barton Barry , Jensen Susan E.
Published: October 2018

Portions of the
Streptomyces clavuligerus
chromosome flanking
cas1
, which encodes the clavaminate synthase 1 isoenzyme (CAS1), have been cloned and sequenced. Mutants of
S. clavuligerus
disrupted in
cvm1
, the open reading frame located immediately upstream of
cas1
, were constructed by a gene replacement procedure. Similar techniques were used to generate
S. clavuligerus
mutants carrying a deletion that encompassed portions of the two open reading frames,
cvm4
and
cvm5
, located directly downstream of
cas1
. Both classes of mutants still produced clavulanic acid and cephamycin C but lost the ability to synthesize the antipodal clavam metabolites clavam-2-carboxylate, 2-hydroxymethyl-clavam, and 2-alanylclavam. These results suggested that
cas1
is clustered with genes essential and specific for clavam metabolite biosynthesis. When a
cas1
mutant of
S. clavuligerus
was constructed by gene replacement, it produced lower levels of both clavulanic acid and most of the antipodal clavams except for 2-alanylclavam. However, a double mutant of
S. clavuligerus
disrupted in both
cas1
and
cas2
produced neither clavulanic acid nor any of the antipodal clavams, including 2-alanylclavam. This outcome was consistent with the contribution of both CAS1 and CAS2 to a common pool of clavaminic acid that is shunted toward clavulanic acid and clavam metabolite biosynthesis.
In Vitro Susceptibilities of Clinical Yeast Isolates to the New Antifungal Eberconazole Compared with Their Susceptibilities to Clotrimazole and Ketoconazole
Authors: Torres-Rodríguez Josep M. , Mendez Raúl , López-Jodra Olga , Morera Yolanda , Espasa Mateu , Jimenez Teresa , Lagunas Carme
Published: October 2018

The antifungal activity of eberconazole, a new imidazole derivative, against 124 clinical isolates of
Candida
comprising eight different species and to 34 isolates of
Cryptococcus neoformans
was compared to those of clotrimazole and ketoconazole. MICs of eberconazole, determined by the National Committee for Clinical Laboratory Standards standardized microbroth method, were equal to or lower than those of other azoles, especially for
Candida krusei
and
Candida glabrata
, which are usually resistant to triazoles.
Molecular Investigation of the Postantibiotic Effects of Clarithromycin and Erythromycin on
Staphylococcus aureus
Cells
Authors: Champney W. Scott , Tober Craig L.
Published: October 2018

The kinetics of recovery after inhibition of growth by erythromycin and clarithromycin were examined in
Staphylococcus aureus
cells. After inhibition for one mass doubling by 0.5 μg of the antibiotics/ml, a postantibiotic effect (PAE) of 3 and 4 h duration was observed for the two drugs before growth resumed. Cell viability was reduced by 25% with erythromycin and 45% with clarithromycin compared with control cells. Erythromycin and clarithromycin treatment reduced the number of 50S ribosomal subunits to 24 and 13% of the number found in untreated cells. 30S subunit formation was not affected. Ninety minutes was required for resynthesis to give the control level of 50S particles. Protein synthesis rates were diminished for up to 4 h after the removal of the macrolides. This continuing inhibition of translation was the result of prolonged binding of the antibiotics to the 50S subunit as measured by
14
C-erythromycin binding to ribosomes in treated cells. The limiting factors in recovery from macrolide inhibition in these cells, reflected as a PAE, are the time required for the synthesis of new 50S subunits and the slow loss of the antibiotics from ribosomes in inhibited cells.
Antimicrobial Activities of Amine- and Guanidine-Functionalized Cholic Acid Derivatives
Authors: Li Chunhong , Lewis Matthew R. , Gilbert Amy B. , Noel Mark D. , Scoville David H. , Allman Glenn W. , Savage Paul B.
Published: October 2018

Compounds in a series of cholic acid derivatives, designed to mimic the activities of polymyxin B and its derivatives, act as both potent antibiotics and effective permeabilizers of the outer membranes of gram-negative bacteria. Some of these compounds rival polymyxin B in antibacterial activity against gram-negative bacteria and are also very active against gram-positive organisms. Other compounds interact synergistically with hydrophobic antibiotics to inhibit bacterial growth.
In Vitro Antifungal Activity of Nikkomycin Z in Combination with Fluconazole or Itraconazole
Authors: Li R. K. , Rinaldi M. G.
Published: October 2018

Nikkomycins are nucleoside-peptide antibiotics produced by
Streptomyces
species with antifungal activities through the inhibition of chitin synthesis. We investigated the antifungal activities of nikkomycin Z alone and in combination with fluconazole and itraconazole. Checkerboard synergy studies were carried out by a macrobroth dilution procedure with RPMI 1640 medium at pH 6.0. At least 10 strains of the following fungi were tested:
Candida albicans
, other
Candida
spp.,
Cryptococcus neoformans
,
Coccidioides immitis
,
Aspergillus
spp., and dematiacious fungi (including
Exophiala jeanselmei
,
Exophiala spinifera
,
Bipolaris spicifera
,
Wangiella dermatitidis
,
Ochroconis humicola
,
Phaeoannellomyces werneckii
, and
Cladophialophora bantiana
), and 2 strains each of
Fusarium
,
Scedosporium
,
Paecilomyces
,
Penicillium
, and
Trichoderma
spp. A total of 110 isolates were examined. Inocula of fungal elements were standardized by hemacytometer counting or spectrophotometrically. MICs and minimum lethal concentrations (MLCs) were determined visually by comparison of growth in drug-treated tubes with growth in drug-free control tubes. Additive and synergistic interactions between nikkomycin and either fluconazole or itraconazole were observed against
C. albicans
,
Candida parapsilosis
,
Cryptococcus neoformans
, and
Coccidioides immitis
. Marked synergism was also observed between nikkomycin and itraconazole against
Aspergillus fumigatus
and
Aspergillus flavus
. No antagonistic interaction between the drugs was observed with any of the strains tested.
Subpopulations of
Helicobacter pylori
Are Responsible for Discrepancies in the Outcome of Nitroimidazole Susceptibility Testing
Authors: van der Wouden E. J. , de Jong A. , Thijs J. C. , Kleibeuker J. H. , van Zwet A. A.
Published: October 2018

Metronidazole susceptibility testing by E test was compared to that by disk diffusion for 263
Helicobacter pylori
isolates and to that by breakpoint agar dilution for 90
H. pylori
isolates. In 5% and 6% of the cases, respectively, results were discrepant. For each of 52 clinical isolates an E test was performed on 10 separate colonies. Subpopulations of resistant and susceptible bacteria were found in five cases. From three isolates, each colony was subcultured and tested up to 10 times. All but 1 of 292 tests showed the same result. We conclude that the E test is reliable and that subpopulations are responsible for discordant results.
In Vitro Anti-Human Immunodeficiency Virus Activities of
Z
- and
E
-Methylenecyclopropane Nucleoside Analogues and Their Phosphoro-
l
-Alaninate Diesters
Authors: Uchida Hiroyuki , Kodama Eiichi N. , Yoshimura Kazuhisa , Maeda Yosuke , Kosalaraksa Pope , Maroun Victor , Qiu Yao-Ling , Zemlicka Jiri , Mitsuya Hiroaki
Published: October 2018

Nucleoside analogues with a
Z
- or an
E
-methylenecyclopropane moiety were synthesized and examined for activity against human immunodeficiency virus type 1 (HIV-1) in vitro. The addition of a methyl phenyl phosphoro-
l
-alaninate moiety to modestly active analogues resulted in potentiation of their anti-HIV-1 activity. Two such compounds, designated QYL-685 (with 2,6-diaminopurine) and QYL-609 (with adenine), were most potent against HIV-1 in vitro, with 50% inhibitory concentrations of 0.034 and 0.0026 μM, respectively, in MT-2 cell-based assays. Both compounds were active against zidovudine-resistant, didanosine-resistant, and multi-dideoxynucleoside-resistant infectious clones in vitro. Further development of these analogues as potential therapies for HIV-1 infection is warranted.
Pharmacokinetic-Pharmacodynamic Contributions to the Convulsant Activity of Fluoroquinolones in Rats
Authors: Delon Annie , Bouquet Serge , Huguet Francois , Brunet Valerie , Courtois Philippe , Couet William
Published: October 2018

The in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs’ ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ’s epileptogenic risk.
Nomenclature for New Tetracycline Resistance Determinants
Authors: Levy Stuart B. , McMurry Laura M. , Barbosa Teresa M. , Burdett Vickers , Courvalin Patrice , Hillen Wolfgang , Roberts Marilyn C. , Rood Julian I. , Taylor Diane E.
Published: October 2018

Letters of the English alphabet have heretofore been used to name tetracycline resistance determinants. Since all 26 letters have now been used, a nomenclature employing numerals is recommended for future determinants, and one laboratory has offered to coordinate the assignment of numerals.
Safety and Efficacy of Intravenous Zanamivir in Preventing Experimental Human Influenza A Virus Infection
Authors: Calfee David P. , Peng Amy W. , Cass Lindsey M. , Lobo Monica , Hayden Frederick G.
Published: October 2018

Zanamivir is a potent inhibitor of influenza A and B virus neuraminidases and is active topically in experimental and natural human influenza. We conducted this double-blinded, placebo-controlled study to evaluate the safety and efficacy of intravenously administered zanamivir. Susceptible volunteers were randomized to receive either saline or zanamivir (600 mg) intravenously twice daily for 5 days beginning 4 h prior to intranasal inoculation with ∼10
5
50% tissue culture infectious doses (TCID
50
) of influenza A/Texas/36/91 (H1N1) virus. Reductions in the frequency of viral shedding (0% versus 100% in placebo,
P
< 0.005) and seroconversion (14% versus 100% in placebo,
P
< 0.005) and decreases in viral titer areas under the curve (0 versus 11.6 [median] log
10
TCID
50
· day/ml in placebo,
P
< 0.005) were observed in the zanamivir group, as were reductions in fever (14% versus 88% in placebo,
P
< 0.05), upper respiratory tract illness (0% versus 100% in placebo,
P
< 0.005), total symptom scores (1 versus 44 [median] in placebo,
P
< 0.005), and nasal-discharge weight (3.9 g versus 17.5 g [median] in placebo,
P
< 0.005). Zanamivir was detectable in nasal lavage samples collected on days 2 and 4 (unadjusted median concentrations, 10.5 and 12.0 ng/ml of nasal wash, respectively). This study demonstrates that intravenously administered zanamivir is distributed to the respiratory mucosa and is protective against infection and illness following experimental human influenza A virus inoculation.
Molecular Characterization of TEM-59 (IRT-17), a Novel Inhibitor-Resistant TEM-Derived β-Lactamase in a Clinical Isolate of
Klebsiella oxytoca
Authors: Bermudes H. , Jude F. , Chaibi E. B. , Arpin C. , Bebear C. , Labia R. , Quentin C.
Published: October 2018

A clinical isolate of
Klebsiella oxytoca
(Kox 443) was found to have a low-level resistance to broad-spectrum penicillins (MICs of amoxicillin and ticarcillin, 256 and 32 μg/ml, respectively), without substantial potentiation by 2 μg of clavulanic acid per ml (amoxicillin- and ticarcillin-clavulanate, 128 and 8 μg/ml, respectively), while being fully susceptible to cephalosporins and other β-lactam antibiotics. These resistances were carried by a ca. 50-kb conjugative plasmid that encodes a single β-lactamase with a pI of 5.6. Compared to TEM-2, this enzyme exhibited a 3- to 30-fold higher

K
m

and a decreased maximal hydrolysis rate for β-lactams; higher concentrations of suicide inactivators (5- to 500-fold higher concentrations giving a 50% reduction in hydrolysis) were required for inhibition. Nucleotide sequence analysis revealed identity between the
bla
TEM
gene of Kox 443 and the
bla
TEM-2
gene, except for a single A-to-G change at position 590, leading to the amino acid change from Ser-130 Gly. This mutation has not been reported previously in the TEM type β-lactamases produced by clinical strains, and the novel enzyme was called TEM-59 (alternative name IRT-17). This is the first description of an inhibitor-resistant TEM-derived enzyme in the species
K. oxytoca.
Nonactin Biosynthesis: the Product of
nonS
Catalyzes the Formation of the Furan Ring of Nonactic Acid
Authors: Woo Anton J. , Strohl William R. , Priestley Nigel D.
Published: October 2018

Nonactin is the parent compound of a group of ionophore antibiotics, known as the macrotetrolides, produced by
Streptomyces griseus
subsp.
griseus
ETH A7796. Nonactin is a significant compound because of its inhibitory effects on the P170 glycoprotein-mediated efflux of chemotherapeutic agents in multiple-drug-resistant cancer cells. Nonactin is also significant in that it is a highly atypical polyketide. Very little is presently known about the genes of the nonactin biosynthesis cluster. In this paper we describe our efforts to establish a connection between the product of a gene from the nonactin biosynthesis cluster and a known biochemical transformation in nonactin biosynthesis. Nonactate synthase is the enzyme which catalyzes the formation of nonactic acid from an acyclic precursor in nonactin biosynthesis. We have synthesized the substrate for this enzyme and have detected the in vitro cyclization activity of the substrate in cell-free preparations of
S. griseus
subsp.
griseus
ETH A7796. Previous studies by R. Plater and J. A. Robinson (Gene 112:117–122, 1992) had suggested, based on sequence homology, that the product of a partial open reading frame found close to the tetranactin resistance gene of
S. griseus
could be the nonactate synthase. We have therefore cloned, sequenced, and heterologously expressed this full gene (
nonS
), and we have shown that the gene product, NonS, does indeed catalyze the formation of the furan ring of nonactic acid as hypothesized.
Lysostaphin Treatment of Experimental Aortic Valve Endocarditis Caused by a
Staphylococcus aureus
Isolate with Reduced Susceptibility to Vancomycin
Authors: Patron Roberto L. , Climo Michael W. , Goldstein Beth P. , Archer Gordon L.
Published: October 2018

The rabbit model of endocarditis was used to test the effectiveness of vancomycin and two different lysostaphin dosing regimens for the treatment of infections caused by a
Staphylococcus aureus
strain with reduced susceptibility to vancomycin (glycopeptide-intermediate susceptible
S. aureus
[GISA]). Vancomycin was ineffective, with no evidence of sterilization of aortic valve vegetations. However, rates of sterilization of aortic valve vegetations were significantly better for animals treated with either a single dose of lysostaphin (43%) or lysostaphin given twice daily for 3 days (83%) than for animals treated with vancomycin. Rabbits given a single dose of lysostaphin followed by a 3-day drug-free period had mean reductions in aortic valve vegetation bacterial counts of 7.27 and 6.63 log
10
CFU/g compared with those for untreated control rabbits and the vancomycin-treated group, respectively. We conclude that lysostaphin is an effective alternative for the treatment of experimental aortic valve endocarditis caused by a clinical VISA strain.
In Vitro Activities of the Everninomicin SCH 27899 and Other Newer Antimicrobial Agents against
Borrelia burgdorferi
Authors: Dever Lisa L. , Torigian Christine V. , Barbour Alan G.
Published: October 2018

The in vitro activity of the everninomicin antibiotic SCH 27899 against 17 isolates of
Borrelia
spp. was investigated. MICs ranged from 0.06 to 0.5 μg/ml. Time-kill studies with the B31 strain of
B. burgdorferi
demonstrated ≥3-log
10
-unit killing after 72 h with concentrations representing four times the MIC. The in vitro activity of four other newer antimicrobial agents, meropenem, cefepime, quinupristin-dalfopristin, and linezolid, was also tested against the B31 strain. Meropenem was the most potent of the latter agents, with an MIC of 0.125 μg/ml.
Improvement of In Vitro and In Vivo Antileishmanial Activities of 2′,6′-Dihydroxy-4′-Methoxychalcone by Entrapment in Poly(
d,l
-Lactide) Nanoparticles
Authors: Torres-Santos Eduardo Caio , Rodrigues José M. , Moreira Davyson L. , Kaplan Maria Auxiliadora C. , Rossi-Bergmann Bartira
Published: October 2018

The inhibition of intracellular
Leishmania amazonensis
growth by 2′,6′-dihydroxy-4′-methoxychalcone (DMC) isolated from
Piper aduncum
was further enhanced after encapsulation of DMC in polymeric nanoparticles. Encapsulated DMC also showed increased antileishmanial activity in infected BALB/c mice, as evidenced by significantly smaller lesions and fewer parasites in the lesions.
Identification of a Novel β-Lactamase Produced by
Xanthomonas campestris
, a Phytopathogenic Bacterium
Authors: Weng Shu-Fen , Chen Chun-Yi , Lee Yeong-Sheng , Lin Juey-Wen , Tseng Yi-Hsiung
Published: October 2018

The
Xanthomonas campestris
pv. campestris 11 chromosome encodes a periplasmic β-lactamase of 30 kDa. Gene replacement and complementation confirmed the presence of this enzyme. Its deduced amino acid sequence shows identity and conserved domains between it and
Stenotrophomonas maltophilia
L2 and other Ambler class A/Bush group 2 β-lactamases. Southern hybridization detected a single homologous fragment in each of 12 other
Xanthomonas
strains, indicating that the presence of a β-lactamase gene is common among xanthomonads.
Unique Anti-Human Immunodeficiency Virus Activities of the Nonnucleoside Reverse Transcriptase Inhibitors Calanolide A, Costatolide, and Dihydrocostatolide
Authors: Buckheit Robert W. , White E. Lucile , Fliakas-Boltz Valerie , Russell Julie , Stup Tracy L. , Kinjerski Tracy L. , Osterling Mark C. , Weigand Ann , Bader John P.
Published: October 2018

(+)-Calanolide A (NSC 650886) has previously been reported to be a unique and specific nonnucleoside inhibitor of the reverse transcriptase (RT) of human immunodeficiency virus (HIV) type 1 (HIV-1) (M. J. Currens et al., J. Pharmacol. Exp. Ther., 279:645–651, 1996). Two isomers of calanolide A, (−)-calanolide B (NSC 661122; costatolide) and (−)-dihydrocalanolide B (NSC 661123; dihydrocostatolide), possess antiviral properties similar to those of calanolide A. Each of these three compounds possesses the phenotypic properties ascribed to the pharmacologic class of nonnucleoside RT inhibitors (NNRTIs). The calanolide analogs, however, exhibit 10-fold enhanced antiviral activity against drug-resistant viruses that bear the most prevalent NNRTI resistance that is engendered by amino acid change Y181C in the RT. Further enhancement of activity is observed with RTs that possess the Y181C change together with mutations that yield resistance to AZT. In addition, enzymatic inhibition assays have demonstrated that the compounds inhibit RT through a mechanism that affects both the

K
m

for dTTP and the
V
max
, i.e., mixed-type inhibition. In fresh human cells, costatolide and dihydrocostatolide are highly effective inhibitors of low-passage clinical virus strains, including those representative of the various HIV-1 clade strains, syncytium-inducing and non-syncytium-inducing isolates, and T-tropic and monocyte-tropic isolates. Similar to calanolide A, decreased activities of the two isomers were observed against viruses and RTs with amino acid changes at residues L100, K103, T139, and Y188 in the RT, although costatolide exhibited a smaller loss of activity against many of these NNRTI-resistant isolates. Comparison of cross-resistance data obtained with a panel of NNRTI-resistant virus strains suggests that each of the three stereoisomers may interact differently with the RT, despite their high degree of structural similarity. Selection of viruses resistant to each of the three compounds in a variety of cell lines yielded viruses with T139I, L100I, Y188H, or L187F amino acid changes in the RT. Similarly, a variety of resistant virus strains with different amino acid changes were selected in cell culture when the calanolide analogs were used in combination with other active anti-HIV agents, including nucleoside and nonnucleoside RT and protease inhibitors. In assays with combinations of anti-HIV agents, costatolide exhibited synergy with these anti-HIV agents. The calanolide isomers represent a novel and distinct subgroup of the NNRTI family, and these data suggest that a compound of the calanolide A series, such as costatolide, should be evaluated further for therapeutic use in combination with other anti-HIV agents.
Bactericidal Activity of Vancomycin in Cerebrospinal Fluid
Authors: Nagl Markus , Neher Claudia , Hager Josef , Pfausler Bettina , Schmutzhard Erich , Allerberger Franz
Published: October 2018

Intraventricular application of vancomycin is an effective therapeutic regimen for the treatment of shunt-associated staphylococcal ventriculitis. We examined the in vitro activity of vancomycin at high concentrations against
Staphylococcus aureus
ATCC 25923 and
Staphylococcus epidermidis
ATCC 12228 in human cerebrospinal fluid samples. Time-kill curves revealed equal efficacies for concentrations of 10, 100, and 300 μg/ml, and incubation times of 24 to 48 h were needed to achieve a 3 log
10
reduction of viable bacteria. A concentration of 5 μg/ml showed a slightly lower activity, but this difference was not significant. In an infant who was successfully treated for shunt-associated ventriculitis due to
S. epidermidis
by once-daily local administration of vancomycin (3 mg for 2 days and 5 mg for 4 days [0.5 to 0.8 mg/kg of body weight]) the in vivo kill kinetics were similar to those for the in vitro results. These results support time-dose regimens that provide trough vancomycin levels of 5 to 10 μg/ml.
Pharmacokinetics of Enrofloxacin and Danofloxacin in Plasma, Inflammatory Exudate, and Bronchial Secretions of Calves following Subcutaneous Administration
Authors: McKellar Quintin , Gibson Ian , Monteiro Ana , Bregante Miguel
Published: October 2018

Enrofloxacin (2.5 mg/kg of body weight) and danofloxacin (1.25 mg/kg) were administered subcutaneously to ruminating calves (n= 8) fitted with subcutaneous tissue cages. Concentrations of enrofloxacin, its metabolite ciprofloxacin, and danofloxacin in blood (plasma), tissue cage exudate (following intracaveal injection of 0.3 ml of 1% [vol/wt] carrageenan), and bronchial secretions were measured by high-performance liquid chromatography (HPLC) and microbiological assay (enrofloxacin plus ciprofloxacin and danofloxacin). Mean maximum concentrations (Cmax) ± standard deviations of enrofloxacin (0.24 ± 0.08 μg/ml), ciprofloxacin (0.11 ± 0.03 [total, 0.34 ± 0.10] μg/ml), and danofloxacin (0.23 ± 0.05 μg/ml) were detected in the plasma of calves by HPLC. TheCmaxwere 0.49 ± 0.17 μg/ml (enrofloxacin equivalents) and 0.24 ± 0.03 μg/ml (danofloxacin) when they were measured by microbiological assay. MeanCmaxin exudate (HPLC) were 0.18 ± 0.07 μg/ml (enrofloxacin), 0.10 ± 0.04 μg/ml (ciprofloxacin), 0.27 ± 0.09 μg/ml (enrofloxacin plus ciprofloxacin), and 0.19 ± 0.05 μg/ml (danofloxacin), and concentrations in exudate exceeded those in plasma from 8 h (enrofloxacin and ciprofloxacin) or 6 h (danofloxacin) after drug administration. TheCmaxwere 0.34 ± 0.09 μg/ml (enrofloxacin equivalents) and 0.22 ± 0.04 μg/ml (danofloxacin) in exudate when they were measured by the microbiological assay. The maximum mean concentration achieved in bronchial secretions (HPLC) were 0.07 ± 0.04 μg/ml (enrofloxacin), 0.04 ± 0.07 μg/ml (ciprofloxacin), 0.10 ± 0.05 μg/ml (enrofloxacin plus ciprofloxacin), and 0.12 ± 0.09 μg/ml (danofloxacin). The maximum mean concentration in bronchial secretions from a limited number of animals from which samples were available for microbiological assay were 0.27 ± 0.11 μg/ml (n= 4 [enrofloxacin equivalents]) and 0.14 ± 0.02 μg/ml (n= 3 [danofloxacin]). With predictive models of efficacy (Cmax/MIC and area under the concentration-time curve/MIC ratios in plasma) forPasteurella multocida(MIC of enrofloxacin, 0.06 μg/ml [24]; MIC of danofloxacin, 0.06 μg/ml [6]), enrofloxacin produced scores of 8.17 and 52.00, respectively, compared to those of danofloxacin, which were 4.02 and 23.05, respectively. With the dosing rates recommended in some markets by manufacturers, enrofloxacin and danofloxacin achieved concentrations above the MICs for important pathogenic organisms in plasma, tissue cage exudate, and bronchial secretion. Since fluoroquinolones display concentration-dependent activities,Cmax/MIC ratios may be critical to efficacy. In the United States enrofloxacin is currently the only fluoroquinolone licensed for food animals and dosages for acute respiratory disease are 2.5 to 5 mg/kg for 3 days or 7.5 to 12.5 mg/kg once. The higher dosages on a single occasion are likely to conferCmax/MIC ratios that are associated with greater clinical efficacy.
Hydroxyurea Enhances the Activities of Didanosine, 9-[2-(Phosphonylmethoxy)ethyl]adenine, and 9-[2-(Phosphonylmethoxy)propyl]adenine against Drug-Susceptible and Drug-Resistant Human Immunodeficiency Virus Isolates
Authors: Palmer Sarah , Shafer Robert W. , Merigan Thomas C.
Published: October 2018

We assessed the effects of hydroxyurea (HU) at a concentration of 50 μM on the in vitro activities of 2′,3′-dideoxyinosine (ddI), 9-[2-(phosphonylmethoxy)ethyl]adenine (PMEA), and 9-[2-(phosphonylmethoxy)propyl]adenine (PMPA) against a wild-type human immunodeficiency virus (HIV) type 1 (HIV-1) laboratory isolate and a panel of five well-characterized drug-resistant HIV isolates. Fifty micromolar HU significantly increased the activities of ddI, PMEA, and PMPA against both the wild-type and the drug-resistant HIV-1 isolates. In fixed combinations, both ddI and PMEA were synergistic with HU against wild-type and drug-resistant viruses.
Penetration of Ciprofloxacin into the Interstitial Space of Inflamed Foot Lesions in Non-Insulin-Dependent Diabetes Mellitus Patients
Authors: Müller Markus , Brunner Martin , Hollenstein Ursula , Joukhadar Christian , Schmid Rainer , Minar Erich , Ehringer Herbert , Eichler Hans Georg
Published: October 2018

Interstitial ciprofloxacin concentrations were measured by microdialysis in inflamed foot lesions of non-insulin-dependent diabetes mellitus patients following intravenous administration of 0.2 g of ciprofloxacin. Interstitial ciprofloxacin concentrations were significantly lower than corresponding serum concentrations. There was no significant difference in the penetration of ciprofloxacin into inflamed and unaffected tissue (area under the concentration-time curve
infection
/area under the concentration-time curve
unaffected tissue
= 0.99 ± 0.15 [mean ± standard error],
n
= 6). Thus, inflammation appears to have little or no effect on the penetration of ciprofloxacin into tissue.
A New Point Mutation (P157S) in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 Confers Low-Level Resistance to (−)-β-2′,3′-Dideoxy-3′-Thiacytidine
Authors: Smith Robert A. , Klarmann George J. , Stray Kirsten M. , von Schwedler Uta K. , Schinazi Raymond F. , Preston Bradley D. , North Thomas W.
Published: October 2018

A P157S mutation in the reverse transcriptase (RT) of human immunodeficiency virus type 1 conferred fivefold resistance to (−)-β-2′,3′-dideoxy-3′-thiacytidine in cell culture. Interestingly, the P157S mutation resulted in increased sensitivity (two- to threefold) to 3′-azido-3′-deoxythymidine (AZT) and to (
R
)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). A similar increase in susceptibility to AZT and to PMPA was also conferred by the M184V mutation in RT.
Molecular Characterization of the SHV-11 β-Lactamase of
Shigella dysenteriae
Authors: Ahamed Jasimuddin , Kundu Manikuntala
Published: October 2018

A β-lactamase with an
M
r
of 29,000 and a pI of 7.6 was partially purified from a clinical isolate of
Shigella dysenteriae
. The
bla
gene encoded the SHV-11 enzyme carrying the substitution Leu→Gln at position 35 and was linked to a strong promoter. This variant, unlike the prototype SHV-1 enzyme, hydrolyzed oxacillin, cloxacillin, and oxyiminocephalosporins such as cefotaxime.
Characterization and Quantitation of the Pharmacodynamics of Fluconazole in a Neutropenic Murine Disseminated Candidiasis Infection Model
Authors: Andes D. , van Ogtrop M.
Published: October 2018

We determined the pharmacodynamic parameter and the magnitude of that parameter that was predictive of the efficacy of fluconazole in the treatment of disseminated candidiasis. We used a neutropenic murine model of disseminated
Candida albicans
infection to characterize the time course of activity of fluconazole. Quantitation of colony counts in kidneys after 24 h of therapy with a wide range of doses and three dosing intervals was used to determine the dose required to achieve 50% of the maximal effect (ED
50
). The ED
50
was similar for each of the dosing intervals studied, supporting the area under the concentration-time curve (AUC) MIC ratio as the parameter that predicts the efficacy of fluconazole. Similar studies were performed with
C. albicans
strains for which fluconazole MICs are in the susceptible-dose-dependent range (MICs, 16 to 32 mg/liter). We found that the magnitude of the AUC/MIC ratio required to reach the ED
50
was similar for all three organisms studied, ranging from 12 to 25. When the pharmacokinetics of fluconazole in humans are considered, these AUC/MIC ratios would support in vitro susceptibility breakpoints of 8 mg/liter for dosages of 200 mg/day and susceptibility breakpoints of 16 to 32 mg/liter for dosages of 400 to 800 mg/day.
Prevalence and Mechanisms of Macrolide Resistance in Clinical Isolates of Group A Streptococci from Ontario, Canada
Authors: De Azavedo J. C. S. , Yeung R. H. , Bast D. J. , Duncan C. L. , Borgia S. B. , Low D. E.
Published: October 2018

A total of 3,205 group A streptoccal isolates were collected in 1997 through a private laboratory which serves community physicians in southern Ontario and which represents a population base of 6 million people. Nonsusceptibility to erythromycin was detected for 67 (2.1%) isolates both by disk diffusion and by broth microdilution. Of these, 47 (70%) were susceptible to clindamycin and were found by PCR to possess the
mef
gene. Of the other 20 strains, 18 and 2 showed inducible and constitutive resistance, respectively, to clindamycin. Nineteen of these strains were shown by PCR to possess the
ermTR
gene, and a single constitutively resistant strain harbored an
ermB
gene. Sixteen (24%) erythromycin-resistant strains were also resistant to tetracycline. All were susceptible to penicillin and chloramphenicol.
Sulfonamide Resistance in Clinical Isolates of
Campylobacter jejuni
: Mutational Changes in the Chromosomal Dihydropteroate Synthase
Authors: Gibreel Amera , Sköld Ola
Published: October 2018

The characterization of the genetic basis of sulfonamide resistance in
Campylobacter jejuni
was attempted. The resistance determinant from a sulfonamide-resistant strain of
C. jejuni
was cloned and was found to show 42% identity with the
folP
gene (which codes for dihydropteroate synthase, the target of sulfonamides) of the related bacterium
Helicobacter pylori
. The sequences of the areas surrounding the
folP
gene in
C. jejuni
showed similarity to those of the areas surrounding the corresponding gene in
H. pylori
. The
folP
gene of
C. jejuni
, which mediates the resistance, was observed to show particular features when it was compared to other known
folP
genes. One of these features is the presence of two pairs of direct repeats (15 and 27 bp) within the coding sequence of the gene. Comparison of the
C. jejuni folP
genes that mediate susceptibility and resistance revealed the occurrence of mutations that changed four amino acid residues. Resistance of
C. jejuni
to sulfonamides could be associated with one or several of these four mutational substitutions, which all occurred in the five different resistant isolates studied. The codon for one of these changed amino acids was found to be located in the second direct repeat within the coding sequence of the gene. The change made the repeat perfect. The transformation of both the resistance and the susceptibility variants of the gene into an
Escherichia coli folP
knockout mutant was found to complement the dihydropteroate synthase deficiency, confirming that the characterized sulfonamide resistance determinant codes for the
C. jejuni
dihydropteroate synthase enzyme. Kinetic measurements established different affinities of sulfonamide for the dihydropteroate synthase enzyme isolated from the resistant and susceptible strains. In conclusion, sulfonamide resistance in
C. jejuni
was shown to be associated with mutational changes in the chromosomally located gene for dihydropteroate synthase, the target of sulfonamides.
Activities of Clinafloxacin, Alone and in Combination with Other Compounds, against 45 Gram-Positive and -Negative Organisms for Which Clinafloxacin MICs Are High
Authors: Clark Catherine L. , Jacobs Michael R. , Appelbaum Peter C.
Published: October 2018

Time-kill studies indicated that clinafloxacin showed synergy after 24 h with ceftazidime, amikacin, and imipenem against 12, 8, and 10 of 33 gram-negative rods, respectively; with vancomycin, teicoplanin, cefotaxime, and amikacin against 3, 3, 1, and 1 of 9 staphylococci and enterococci, respectively; and with vancomycin, penicillin, and cefotaxime against 0, 2, and 2 of 3 pneumococci, respectively. The MICs of clinafloxacin alone for most strains were ≥1 μg/ml.
The Synergistic Bactericidal Mechanism of Simultaneous Treatment with a 222-Nanometer Krypton-Chlorine Excilamp and a 254-Nanometer Low-Pressure Mercury Lamp
Authors: Kang Jun-Won , Kang Dong-Hyun
Published: October 2018

Contamination of pathogenic microorganisms in water plays an important role in inducing outbreaks of food-borne illness by causing cross-contamination in foods. Thus, proper disinfection of water before use in food production is essential to prevent outbreaks of food-borne illness. As technologies capable of selecting UV radiation wavelengths (such as UV-LEDs and excilamps) have been developed, wavelength combination treatment with UV radiation, which is widely used in water disinfection systems, is actively being studied. In this regard, we have confirmed synergistic bactericidal effects in combination with 222-nm and 254-nm wavelengths and have identified mechanisms for this. This study clearly analyzed the mechanism of synergistic bactericidal effect by wavelength combination treatment, which has not been attempted in other studies. Therefore, it is also expected that these results will play an important role as baseline data for future research on, as well as industrial applications for, the disinfection strategy of effective wavelength combinations.
The Genetic Transformation of Chlamydia pneumoniae
Authors: Shima Kensuke , Wanker Maximilian , Skilton Rachel J. , Cutcliffe Lesley T. , Schnee Christiane , Kohl Thomas A. , Niemann Stefan , Geijo Javier , Klinger Matthias , Timms Peter , Rattei Thomas , Sachse Konrad , Clarke Ian N. , Rupp Jan
Published: October 2018

The absence of tools for the genetic manipulation ofC. pneumoniaehas hampered research into all aspects of its biology. In this study, we established a novel reproducible method forC. pneumoniaetransformation based on a plasmid shuttle vector system. We constructed aC. pneumoniaeplasmid backbone shuttle vector, pRSGFPCAT-Cpn. The construct expresses the red-shifted green fluorescent protein (RSGFP) fused to chloramphenicol acetyltransferase inC. pneumoniae.C. pneumoniaetransformants stably retained pRSGFPCAT-Cpn and expressed RSGFP in epithelial cells, even in the absence of chloramphenicol. The successful transformation inC. pneumoniaeusing pRSGFPCAT-Cpn will advance the field of chlamydial genetics and is a promising new approach to investigate gene functions inC. pneumoniaebiology. In addition, we demonstrated that pRSGFPCAT-Cpn overcame the plasmid species barrier without the need for recombination with an endogenous plasmid, indicating the potential probability of horizontal chlamydial pathogenic gene transfer by plasmids between chlamydial species.
Identification of a Shared Cytochrome p4502E1 Epitope Found in Anesthetic Drug-Induced and Viral Hepatitis
Authors: McCarthy Elisa K. , Vakos Amanda , Cottagiri Merylin , Mantilla Joel J. , Santhanam Lakshmi , Thomas David L. , Amzel L. Mario , Rose Noel R. , Njoku Dolores B.
Published: October 2018

Drug-induced hepatitis is the leading reason that an approved drug is removed from the commercial market. Halogenated anesthetics can induce hepatitis in susceptible persons, and cytochrome p4502E1 (CYP2E1) enzymes responsible for their metabolism induce antibodies in addition to hepatitis. CYP2E1 antibodies detected in anesthetic hepatitis patients have been detected in patients with viral hepatitis, suggesting that these different forms of hepatitis could develop immune reactions to a common segment or epitope of CYP2E1. We have found a common MHC-restricted CYP2E1 epitope in anesthetic and viral hepatitis that is a dominant epitope in anesthetic hepatitis and is significantly associated with fibrosis in patients with viral hepatitis. Along with conformational epitopes, our identification of MHC-restricted CYP2E1 epitopes can be used to develop specific diagnostic tests for drug-induced or viral hepatitis or associated fibrosis or to predict individuals at risk for developing these diseases or their sequelae.
Ascites with hepatic extravasation of total parenteral nutrition (TPN) secondary to umbilical venous catheter (UVC) malposition in an extremely preterm baby
Authors: Pegu Satyaranjan , Murthy Poornima
Published: October 2018

The ease of access and advantages of a secure central line makes use of umbilical venous catheter (UVC) and umbilical artery catheters a part of the standard of care in the extremely premature babies in the neonatal intensive care unit. However, there are complications associated with their use. One of the uncommon complications reported is total parenteral nutrition (TPN) ascites secondary to vessel perforation or hepatic erosion by the tip of the catheter due to malposition of a UVC. We present here a case of such catheter perforation causing ascites and right hepatic collection of TPN in a 28-week-old infant. Abdominal paracentesis was therapeutic by relieving the distension as well as confirming the presence of parenteral nutrition in the peritoneal cavity.
Topical glyceryl trinitrate for the treatment of tendinopathies: a systematic review
Authors: Challoumas Dimitris , Kirwan Paul D , Borysov Dmytro , Clifford Christopher , McLean Michael , Millar Neal L
Published: October 2018

Objective

To produce a best evidence synthesis of the clinical effects of topical glyceryl trinitrate (GTN) in the treatment of tendinopathies.

Design

A systematic review of published randomised controlled trials (RCTs) of the use of GTN in patients with tendinopathy.

Data sources

MEDLINE, Embase, Scopus and CINAHL from database inception to January 2018.

Methods

We examined RCTs comparing the effects of topical GTN with either placebo or other treatments on tendinopathy. Overall quality of each eligible study was determined based on a combined assessment of internal validity, external validity and precision. The level of evidence for each assessed parameter was rated based on the system by van Tulderet al.

Results

A total of 10 eligible RCTs were identified including patients with tendinopathy of the rotator cuff (n=4), wrist extensors (n=3), Achilles (n=2) and patellar (n=1) tendons. For all tendinopathies, improvements in pain were significant when comparing GTN versus placebo in the short term (<8 weeks; poor evidence). Significant improvements in midterm outcomes for treatment with GTN versus placebo included the following: patient satisfaction (strong evidence); chances of being asymptomatic with activities of daily living (strong evidence); range of movement (moderate evidence); strength (moderate evidence); pain (at night and with activity; poor evidence) and local tenderness (poor evidence). Patients treated with topical GTN reported a higher incidence of headaches than those who received placebo (moderate evidence).

Conclusions and relevance

Treatment of tendinopathies with topical GTN for up to 6 months appears to be superior to placebo and may therefore be a useful adjunct to the treating healthcare professions.
Oestrogen replacement improves bone mineral density in oligo-amenorrhoeic athletes: a randomised clinical trial
Authors: Ackerman Kathryn E , Singhal Vibha , Baskaran Charumathi , Slattery Meghan , Campoverde Reyes Karen Joanie , Toth Alexander , Eddy Kamryn T , Bouxsein Mary L , Lee Hang , Klibanski Anne , Misra Madhusmita
Published: October 2018

Objective

Normal-weight oligo-amenorrhoeic athletes (OAA) are at risk for low bone mineral density (BMD). Data are lacking regarding the impact of oestrogen administration on bone outcomes in OAA. Our objective was to determine the effects of transdermal versus oral oestrogen administration on bone in OAA engaged in weight-bearing activity.

Methods

121 patients with OAA aged 14–25 years were randomised to receive: (1) a 17β-estradiol transdermal patch continuously with cyclic oral micronised progesterone (PATCH), (2) a combined ethinyl estradiol and desogestrel pill (PILL) or (3) no oestrogen/progesterone (NONE). All participants received calcium and vitamin D supplementation. Areal BMD was assessed at the lumbar spine, femoral neck, total hip and total body less head using dual-energy X-ray absorptiometry at baseline, 6 and 12 months. Intention-to-treat (ITT) and completers analyses were performed.

Results

Randomised groups did not differ for age, body mass index or BMD Z-scores at baseline. For ITT analysis, spine and femoral neck BMD Z-scores significantly increased in the PATCH versus PILL (p=0.011 and p=0.021, respectively) and NONE (p=0.021 and p=0.033, respectively) groups, and hip BMD Z-scores significantly increased in the PATCH versus PILL group (p=0.018). Similar findings were noted in completers analysis.

Conclusion

Transdermal estradiol over 12 months improves BMD in young OAA, particularly compared with an ethinyl estradiol-containing contraceptive pill/oral contraceptives.

Trial registration number

NCT00946192; Pre-results
Tuberculosis preventive treatment: the next chapter of tuberculosis elimination in India
Authors: Moonan Patrick K , Nair Sreenivas A , Agarwal Reshu , Chadha Vineet K , Dewan Puneet K , Gupta Umesh D , Ho Christine S , Holtz Timothy H , Kumar Ajay M , Kumar Nishant , Kumar Prahlad , Maloney Susan A , Mase Sundari R , Oeltmann John E , Paramasivan C N , Parmar Malik M , Rade Kiran K , Ramachandran Ranjani , Rao Raghuram , Salhorta Virendra S , Sarin Rohit , Sarin Sanjay , Sachdeva Kuldeep S , Selvaraju Sriram , Singla Rupak , Surie Diya , Tonsing Jamhoih , Tripathy Srikanth P , Khaparde Sunil D
Published: October 2018

The End TB Strategy envisions a world free of tuberculosis—zero deaths, disease and suffering due to tuberculosis by 2035. This requires reducing the global tuberculosis incidence from >1250 cases per million people to <100 cases per million people within the next two decades. Expanding testing and treatment of tuberculosis infection is critical to achieving this goal. In high-burden countries, like India, the implementation of tuberculosis preventive treatment (TPT) remains a low priority. In this analysis article, we explore potential challenges and solutions of implementing TPT in India. The next chapter in tuberculosis elimination in India will require cost-effective and sustainable interventions aimed at tuberculosis infection. This will require constant innovation, locally driven solutions to address the diverse and dynamic tuberculosis epidemiology and persistent programme monitoring and evaluation. As new tools, regimens and approaches emerge, midcourse adjustments to policy and practice must be adopted. The development and implementation of new tools and strategies will call for close collaboration between local, national and international partners—both public and private—national health authorities, non-governmental organisations, research community and the diagnostic and pharmaceutical industry. Leading by example, India can contribute to global knowledge through operational research and programmatic implementation for combating tuberculosis infection.
Sociodemographic correlates of eating disorder subtypes among men and women in France, with a focus on age
Authors: Andreeva Valentina A , Tavolacci Marie-Pierre , Galan Pilar , Ladner Joel , Buscail Camille , Péneau Sandrine , Galmiche Marie , Hercberg Serge , Déchelotte Pierre , Julia Chantal
Published: October 2018

Background

On the population level, the association of age and other sociodemographic factors with eating disorders (ED) is unclear.

Methods

We used cross-sectional data from the French general population-based NutriNet-Santé e-cohort (n=49 603 adults; 76.3% women; mean age=50.4±14.6 years). ED were evaluated in 2014 with the 5-item SCOFF screening questionnaire and the Expali algorithmic tool. Likely cases of restrictive, bulimic, hyperphagic and other ED were the dependent variables. Age, marital status, education, occupation, physical activity and smoking were the independent variables. Associations were estimated via gender-stratified multivariable polytomous logistic regression.

Results

Among women, age displayed inverse linear associations with both restrictive and bulimic ED, underscoring 18–25 years as the most vulnerable period (adjusted OR=3.37, 95% CI: 2.24 to 5.08 for restrictive ED; adjusted OR=2.98, 95% CI: 2.37 to 3.74 for bulimic ED, respectively). A similar association was observed in men regarding bulimic ED. In women, age was not associated with hyperphagic ED for which living alone, low education, low physical activity, being a homemaker/disabled/unemployed/retired, a manual worker or a former/current smoker had increased importance. In men, 18–39 years emerged as the least vulnerable period regarding hyperphagic ED (adjusted OR=0.74, 95% CI: 0.56 to 0.99). Across gender, having postsecondary education had significant inverse associations with all except restrictive ED, whereas being a student had a significant positive association with restrictive ED.

Conclusions

The findings support gender-specific associations of age with four ED subtypes and could inform future prevention initiatives targeting specific ED among specific age groups.

Trial registration number

NCT03335644; Pre-results.