bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and Efficacy of Multilamellar Liposomal Nystatin against Disseminated Candidiasis in Persistently Neutropenic Rabbits
Authors: Groll Andreas H. , Petraitis Vidmantas , Petraitiene Ruta , Field-Ridley Aida , Calendario Myrna , Bacher John , Piscitelli Stephen C. , Walsh Thomas J. 
Published: October 2018

ABSTRACT

The activity of liposomal nystatin (L-Nys) against subacute disseminated candidiasis was investigated in persistently neutropenic rabbits. Antifungal therapy was administered for 10 days starting 24 h after intravenous inoculation of 10
3
blastoconidia of
Candida albicans
. Responses to treatment were assessed by the quantitative clearance of the organism from blood and tissues. Treatments consisted of L-Nys at dosages of 2 and 4 mg/kg of body weight/day (L-Nys2 and L-Nys4, respectively) amphotericin B deoxycholate at 1 mg/kg/day (D-AmB), and fluconazole at 10 mg/kg/day (Flu). All treatments were given intravenously once daily. Compared to the results for untreated but infected control animals, treatment with L-Nys2, L-Nys4, D-AmB, and Flu resulted in a significant clearance of the residual burden of
C. albicans
from the kidney, liver, spleen, lung, and brain (
P
< 0.0001 by analysis of variance). When the proportion of animals infected at at least one of the five tissue sites studied was evaluated, a dose-dependent response to treatment with L-Nys was found (
P
< 0.05). Compared to D-AmB-treated rabbits, mean serum creatinine and blood urea nitrogen levels at the end of therapy were significantly lower in animals treated with L-Nys2 (
P
< 0.001) and L-Nys4 (
P
< 0.001 and
P
< 0.01, respectively). L-Nys was less nephrotoxic than conventional amphotericin B and had dose-dependent activity comparable to that of amphotericin B for the early treatment of subacute disseminated candidiasis in persistently neutropenic rabbits.
Use of Pharmacodynamic Indices To Predict Efficacy of Combination Therapy In Vivo
Authors: Mouton Johan W. , van Ogtrop Marc L. , Andes David , Craig William A. 
Published: October 2018

ABSTRACT

Although combination therapy with antimicrobial agents is often used, no available method explains or predicts the efficacies of these combinations satisfactorily. Since the efficacies of antimicrobial agents can be described by pharmacodynamic indices (PDIs), such as area under the concentration-time curve (AUC), peak level, and the time that the concentration is above the MIC (time>MIC), it was hypothesized that the same PDIs would be valid in explaining efficacy during combination therapy. Twenty-four-hour efficacy data (numbers of CFU) for
Pseudomonas aeruginosa
in a neutropenic mouse thigh model were determined for various combination regimens: ticarcillin-tobramycin (
n
= 41 different regimens), ceftazidime-netilmicin (
n
= 60), ciprofloxacin-ceftazidime (
n
= 59), netilmicin-ciprofloxacin (
n
= 38) and for each of these agents given singly. Multiple regression analysis was used to determine the importance of various PDIs (time>MIC, time>0.25× the MIC, time>4× the MIC, peak level, AUC, AUC/MIC, and their logarithmically transformed values) during monotherapy and combination therapy. The PDIs that best explained the efficacies of single-agent regimens were time>0.25× the MIC for beta-lactams and log AUC/MIC for ciprofloxacin and the aminoglycosides. For the combination regimens, regression analysis showed that efficacy could best be explained by the combination of the two PDIs that each best explained the response for the respective agents given singly. A regression model for the efficacy of combination therapy was developed by use of a linear combination of the regression models of the PDI with the highest
R
2
for each agent given singly. The model values for the single-agent therapies were then used in that equation, and the predicted values that were obtained were compared with the experimental values. The responses of the combination regimens could best be predicted by the sum of the responses of the single-agent regimens as functions of their respective PDIs (e.g., time>0.25× the MIC for ticarcillin and log AUC/MIC for tobramycin). The relationship between the predicted response and the observed response for the combination regimens may be useful for determination of the presence of synergism. We conclude that the PDIs for the individual drugs used in this study are class dependent and predictive of outcome not only when the drugs are given as single agents but also when they are given in combination. When given in combination, there appears to be a degree of synergism independent of the dosing regimen applied.
Development of a New Experimental Model of Penicillin-Resistant
Streptococcus pneumoniae
Pneumonia and Amoxicillin Treatment by Reproducing Human Pharmacokinetics
Authors: Piroth Lionel , Martin Laurent , Coulon Alexis , Lequeu Catherine , Duong Michel , Buisson Marielle , Portier Henri , Chavanet Pascal 
Published: October 2018

ABSTRACT

The increase of penicillin-resistant
Streptococcus pneumoniae
(PRSP) pneumonia results in a greater risk of antibiotic treatment failure. In vitro data are not sufficient predictors of clinical efficacy, and animal models may be insufficiently contributive, since they often use immunocompromised animals and do not always respect the human pharmacokinetics of antibiotics. We developed an experimental PRSP pneumonia model in immunocompetent rabbits, by using intrabronchial instillation of PRSP (MIC = 4 mg/liter), without any adjuvant. This reproducible model was used to assess amoxicillin efficacy by reproducing human serum pharmacokinetics following 1-g oral or intravenous administrations of amoxicillin every 8 h. Evaluation was performed by using clinical, CT scan, macroscopic, histopathologic, and microbiological criteria. Experimental pneumonia in untreated rabbits was similar to untreated severe human bacteremic untreated pneumonia; in both rabbits and humans, (i) cumulative survival was close to 50%, (ii) red or gray lung congestion and pleuritis were observed, and (iii) lung and spleen concentrations reached 5 and 4 log
10
CFU/g. A 48-h treatment resulted in a significant bacterial clearance in the lungs (1.53 versus 5.07 log
10
CFU/ml,
P
< 0.001) and spleen (1.00 versus 4.40 log
10
CFU/ml,
P
< 10
−6
) and a significant decrease in mortality (0% versus 50%,
P
= 0.02) in treated versus untreated rabbits. No difference was observed on macroscopic and histopathologic lesions between treated and untreated rabbits (
P
= 0.36 and 0.78, respectively). Similar results were obtained by using a fully penicillin-susceptible
S. pneumoniae
strain (MIC = 0.01 mg/liter). Our findings suggest that (i) this new model can be contributive in the evaluation of antibacterial agents and (ii) 1 g of amoxicillin three times a day may be sufficient to treat PRSP pneumonia in immunocompetent humans.
Anti-Kaposi’s Sarcoma and Antiangiogenic Activities of Sulfated Dextrins
Authors: Thornton Mark , Barkley Laura , Mason Justin C. , Shaunak Sunil 
Published: October 2018

ABSTRACTDelivery of the sulfated polysaccharide dextrin 2-sulfate by the intraperitoneal route to the lymphatic circulation resulted in a clinically significant improvement in Kaposi’s sarcoma in three patients. Our in vitro studies show that although sulfated dextrins do not interfere with the growth of isolated human umbilical vein endothelial cells, they do inhibit the morphological differentiation of endothelial cells into tubes as well as reduce new vessel formation in a placental angiogenesis assay. The antiangiogenic effect of dextrin 6-sulfate is greater than that of dextrin 2-sulfate and is independent of their anti-human immunodeficiency virus type 1 activities.
Antimicrobial Susceptibility Patterns of Enterococci Causing Infections in Europe
Authors: Schouten M. A. , Voss A. , Hoogkamp-Korstanje J. A. A. ,   The European VRE Study Group
Published: October 2018

ABSTRACT

In vitro susceptibilities of 4,208 enterococci (83%
Enterococcus faecalis
isolates, 13.6%
Enterococcus faecium
isolates, and 3.4% isolates of other species) from patients in 27 European countries towards 16 antibiotics were determined. High-level resistance to gentamicin varied by country (range, 1 to 49%; mean, 22.6% ± 12.3%) and per species (19.7%
E. faecalis
isolates, 13.6%
E. faecium
isolates, 3.4% by other species). Vancomycin resistance was detected in 0.06%
E. faecalis
, 3.8%
E. faecium
, and 19.1% isolates of other species. All enterococci were susceptible to LY 333328 and everninomicin, and 25% of
E. faecalis
isolates and 85% of other enterococci were susceptible to quinupristin-dalfopristin. The MIC of moxifloxacin and trovafloxacin for ciprofloxacin-susceptible
E. faecalis
at which 90% of the isolates were inhibited was 0.25 to 0.5 μg/ml.
Postantibiotic Effects of Gatifloxacin against Gram-Positive and -Negative Organisms
Authors: Pankuch G. A. , Jacobs M. R. , Appelbaum P. C. 
Published: October 2018

ABSTRACT

Gatifloxacin pneumococcal, staphylococcal and enterococcal postantibiotic effects (PAEs) were 0.5 to 4.0 h, respectively. For
Escherichia coli
and
Pseudomonas aeruginosa
, PAEs were 2.2 to 4.8 h. Pneumococcal, staphylococcal, and enterococcal postantibiotic sub-MIC effects (PA-SMEs) (four times the MICs) were 3.7 to 8.6, 2.3 to 3.8, and 1.6 h, respectively, and
E. coli
and
P. aeruginosa
PA-SMEs were ≥9.6 and 4.4 h, respectively.
Activities of Fluoroquinolones against
Streptococcus pneumoniae
Type II Topoisomerases Purified as Recombinant Proteins
Authors: Morrissey Ian , George John 
Published: October 2018

ABSTRACT

Streptococcus pneumoniae
topoisomerase IV and DNA gyrase have been purified from a fluoroquinolone-susceptible
Streptococcus pneumoniae
strain, from first-step mutants showing low-level resistance to ciprofloxacin, sparfloxacin, levofloxacin, and ofloxacin, and from two clinical isolates showing intermediate- and high-level fluoroquinolone resistance by a gene cloning method that produces recombinant proteins from
Escherichia coli
. The concentrations of ciprofloxacin, sparfloxacin, levofloxacin, or ofloxacin required to inhibit wild-type topoisomerase IV were 8 to 16 times lower than those required to inhibit wild-type DNA gyrase. Furthermore, low-level resistance to these fluoroquinolones was entirely due to the reduced inhibitory activity of fluoroquinolones against topoisomerase IV. For all the laboratory strains, the 50% inhibitory concentration for topoisomerase IV directly correlated with the MIC. We therefore propose that with
S. pneumoniae
, ciprofloxacin, sparfloxacin, levofloxacin, and ofloxacin target topoisomerase IV in preference to DNA gyrase. Sitafloxacin, on the other hand, was found to be equipotent against either enzyme. This characteristic is unique for a fluoroquinolone. A reduction in the sensitivities of both topoisomerase IV and DNA gyrase are required, however, to achieve intermediate- or high-level fluoroquinolone resistance in
S. pneumoniae
.
Involvement of an Active Efflux System in the Natural Resistance of
Pseudomonas aeruginosa
to Aminoglycosides
Authors: Aires Julio Ramos , Köhler Thilo , Nikaido Hiroshi , Plésiat Patrick 
Published: October 2018

ABSTRACT

A mutant, named 11B, hypersusceptible to aminoglycosides, tetracycline, and erythromycin was isolated after Tn
501
insertion mutagenesis of
Pseudomonas aeruginosa
PAO1. Cloning and sequencing experiments showed that 11B was deficient in an, at that time, unknown active efflux system that contains homologs of MexAB. This locus also contained a putative regulatory gene,
mexZ
, transcribed divergently from the efflux operon. Introduction of a recombinant plasmid that carries the genes of the efflux system restored the resistance of 11B to parental levels, whereas overexpression of these genes strongly increased the MICs of substrate antibiotics for the PAO1 host. Antibiotic accumulation studies confirmed that this new system is an energy-dependent active efflux system that pumps out aminoglycosides. Furthermore, this system appeared to function with an outer membrane protein, OprM. While the present paper was being written and reviewed, genes with a sequence identical to our pump genes,
mexXY
of
P. aeruginosa
, have been reported to increase resistance to erythromycin, fluoroquinolones, and organic cations in
Escherichia coli
hosts, although efflux of aminoglycosides was not examined (Mine et al., Antimicrob. Agents Chemother. 43:415–417, 1999). Our study thus shows that the MexXY system plays an important role in the intrinsic resistance of
P. aeruginosa
to aminoglycosides. Although overexpression of MexXY increased the level of resistance to fluoroquinolones, disruption of the
mexXY
operon in
P. aeruginosa
had no detectable effect on susceptibility to these agents.
Erythromycin Inhibits Transcriptional Activation of NF-κB, but not NFAT, through Calcineurin-Independent Signaling in T Cells
Authors: Aoki Yosuke , Kao Peter N. 
Published: October 2018

ABSTRACTThe molecular mechanism of the anti-inflammatory effect of erythromycin (EM) was investigated at the level of transcriptional regulation of cytokine gene expression in T cells. EM (>10−6M) significantly inhibited interleukin-8 (IL-8) expression but not IL-2 expression from T cells induced with 20 ng of phorbol 12-myristate 13-acetate (PMA) per ml plus 2 μM calcium ionophore (P-I). In electrophoretic mobility shift assays EM at 10−7to 10−5M concentrations inhibited nuclear factor kappa B (NF-κB) DNA-binding activities induced by P-I. Reporter gene assays also showed that EM (10−5M) inhibited IL-8 NF-κB transcription by 37%. The inhibitory effects of EM on transcriptional activation of IL-2 and DNA-binding activity of nuclear factor of activated T cells (NFAT) were not seen in T cells. On the other hand, FK506, which is also a macrolide derivative, inhibited transcriptional activation of both NF-κB and NFAT more strongly than EM did. The mechanism of EM inhibition of transactivation of NF-κB was further investigated in transiently transfected T cells that express calcineurin A and B subunits. Expression of calcineurin did not render transactivation of NF-κB in T cells more resistant to EM, while the inhibitory effect of FK506 on transactivation of NF-κB was attenuated. These findings indicate that EM is capable of inhibiting expression of the IL-8 gene in T cells through transcriptional inhibition and that this inhibition is mediated through a non-calcineurin-dependent signaling event in T lymphocytes.
Specific Inhibition of the Eubacterial DNA Ligase by Arylamino Compounds
Authors: Ciarrocchi Giovanni , MacPhee Donald G. , Deady Les W. , Tilley Leann 
Published: October 2018

ABSTRACT

All known DNA ligases catalyze the formation of a phosphodiester linkage between adjacent termini in double-stranded DNA via very similar mechanisms. The ligase family can, however, be divided into two classes: eubacterial ligases, which require NAD
+
as a cofactor, and other ligases, from viruses, archaea, and eukaryotes, which use ATP. Drugs that discriminate between DNA ligases from different sources may have antieubacterial activity. We now report that a group of arylamino compounds, including some commonly used antimalarial and anti-inflammatory drugs and a novel series of bisquinoline compounds, are specific inhibitors of eubacterial DNA ligases. Members of this group of inhibitors have different heterocyclic ring systems with a common amino side chain in which the two nitrogens are separated by four carbon atoms. The potency, but not the specificity of action, is influenced by the DNA-binding characteristics of the inhibitor, and the inhibition is noncompetitive with respect to NAD
+
. The arylamino compounds appear to target eubacterial DNA ligase in vivo, since a
Salmonella
Lig
−
strain that has been rescued with the ATP-dependent T4 DNA ligase is less sensitive than the parental
Salmonella
strain.
In Vitro Susceptibilities of
Neisseria gonorrhoeae
to Fatty Acids and Monoglycerides
Authors: Bergsson Gudmundur , Steingrímsson Ólafur , Thormar Halldor 
Published: October 2018

ABSTRACT

The susceptibility of
Neisseria gonorrhoeae
to several medium-chain fatty acids and their 1-monoglycerides was tested at a short inactivation time of 1 min. The results indicate that monocaprin, a monoglyceride of capric acid (10 carbon atoms, no double bonds), causes the fastest and most effective killing of all strains of
N. gonorrhoeae
tested.
Molecular Characterization of
rpoB
Mutations Conferring Cross-Resistance to Rifamycins on Methicillin-Resistant
Staphylococcus aureus
Authors: Wichelhaus Thomas A. , Schäfer Volker , Brade Volker , Böddinghaus Boris 
Published: October 2018

ABSTRACT

Mutations of the
rpoB
gene conferring resistance to rifampin were analyzed in 40 methicillin-resistant
Staphylococcus aureus
isolates obtained from six countries. Interestingly, the majority of clinical isolates showed multiple mutations within
rpoB
. The amino acid substitution 481His→Asn was the most prevalent one, capable of conferring low-level resistance on its own. Cross-resistance to rifampin, rifabutin, and rifapentine was demonstrated for all mutants identified. The level of resistance to rifamycins correlated with both the mutation position and type of amino acid substitution.
Potentiation of Vancomycin-Induced Histamine Release by Muscle Relaxants and Morphine in Rats
Authors: Shuto Hideki , Sueyasu Masanori , Otsuki Shuji , Hara Tomoko , Tsuruta Yuki , Kataoka Yasufumi , Oishi Ryozo 
Published: October 2018

ABSTRACT
The intravenous injection of vancomycin sometimes causes anaphylactoid reactions, in which histamine release may play a major role. These reactions are more frequently manifested when vancomycin is injected into anesthetized patients. We examined the vancomycin-induced histamine release and the interaction of vancomycin with muscle relaxants or opioid in rats. In an in vitro study with rat peritoneal mast cells, treatment with vancomycin at concentrations of greater than 1.25 mM produced significant histamine release. Tubocurarine, vecuronium, pancuronium, succinylcholine, and morphine up to concentrations of 0.25, 1, 5, 30, and 5 mM, respectively, produced no significant histamine release. However, the nonsignificant histamine release induced by 0.5 mM vancomycin was clearly enhanced by combining vancomycin with any of these agents. In the in vivo study, the intravenous injection of vancomycin significantly increased the plasma histamine levels in rats when vancomycin was injected at 200 mg/kg of body weight (63.2 ± 34.0 ng/ml [mean ± standard deviation]) but not when it was injected at 100 mg/kg (30.8 ± 20.2 ng/ml) compared with that in the saline-treated rats (22.5 ± 11.4 ng/ml). Although the subcutaneous administration of morphine (10 mg/kg) never increased the plasma histamine levels, the intravenous injection of vancomycin (100 mg/kg) 30 min after this morphine treatment markedly increased the plasma histamine levels (56.0 ± 26.9 ng/ml). These findings provide experimental evidence that the combination of muscle relaxants or an opioid with vancomycin may increase the risk of anaphylactoid reactions by enhancing the release of histamine.
Biochemical Characterization of Novel Tetrahydrofuranyl 1β-Methylcarbapenems: Stability to Hydrolysis by Renal Dehydropeptidases and Bacterial β-Lactamases, Binding to Penicillin Binding Proteins, and Permeability Properties
Authors: Yang Youjun , Testa Raymond T. , Bhachech Niraja , Rasmussen Beth A. , Bush Karen 
Published: October 2018

ABSTRACT

The biochemical properties of tetrahydrofuranyl (THF) carbapenems, carbapenems with THF substituents, were evaluated with respect to enzyme stability, binding to penicillin-binding proteins (PBPs), and penetration into gram-negative organisms. THF carbapenems showed increased stability to hog renal dehydropeptidases (DHPs) compared to that of imipenem or meropenem and were more stable to human DHP than imipenem (<10% hydrolysis compared to that for imipenem). THF carbapenems were stable to hydrolysis by all serine β-lactamases tested. CL 191,121, a prototype THF carbapenem, was more stable to hydrolysis by carbapenem-hydrolyzing serine β-lactamases such as IMI-1 and Sme-1 than imipenem, with a relative
k
cat
value of <20% for imipenem. Similar to imipenem and meropenem, THF carbapenems were not stable to the metallo β-lactamases CcrA and L1. However, CL 191,121 bound to all
Staphylococcus aureus
PBPs at concentrations that were less than or equal to the MICs. The THF carbapenems bound to PBPs from
Escherichia coli
and
Pseudomonas aeruginosa
, with the highest affinities being for PBPs 2 and 4, as noted with imipenem. The affinities for PBPs 1a and 1b in
E. coli
were reduced for the THF carbapenems compared to that for imipenem, even though the MICs of the THF carbapenems for
E. coli
strains were lower than those of imipenem. The penetrability of the THF carbapenems into
Serratia marcescens
S6, which produces the Sme-1 carbapenem-hydrolyzing β-lactamase, was 2.4 to 7.8 times less than that of imipenem. Compounds CL 190,294 and CL 188,624 showed good penetrability, with permeability coefficient values comparable to those of the rapidly penetrating agents cephaloridine, imipenem, meropenem, and biapenem. Decreased penetration into wild-type
P. aeruginosa
was suggested by the high MICs of the THF carbapenems (MICs, 16 to 32 μg/ml), despite equivalent or better binding to
P. aeruginosa
PBPs than that of imipenem. However, the MICs of the THF carbapenems for wild-type
P. aeruginosa
compared to that for an OprD2 mutant generally varied no more than 2-fold, but those of imipenem and other carbapenems differed 16-fold. These data indicated that THF carbapenems do not appear to enter through protein OprD2. In conclusion, the THF carbapenems exhibited stability to hydrolysis by renal DHPs and serine β-lactamases, exhibited strong binding to essential PBPs from
E. coli
and
S. aureus
, and penetrated gram-negative enteric bacteria at rates comparable to those for meropenem and biapenem.
Proteoglycan and Collagen Biochemical Variations during Fluoroquinolone-Induced Chondrotoxicity in Mice
Authors: Simonin Marie-Agnès , Gegout-Pottie Pascale , Minn Alain , Gillet Pierre , Netter Patrick , Terlain Bernard 
Published: October 2018

ABSTRACT

Although fluoroquinolone antibacterials have a broad therapeutic use, with a relatively low incidence of severe side effects, they have been reported to induce lesions in the cartilage of growing animals by a mechanism that remains unclear. This study was undertaken to determine the potentially deleterious effect of a high dose of pefloxacin (400 mg/kg of body weight) on two main constituents of cartilage in mice, i.e., proteoglycans and collagen. Variations in levels of proteoglycan anabolism measured by in vivo [
35
S]sulfate incorporation into cartilage and oxidative modifications of collagen assessed by detection of carbonyl derivatives were monitored after administration of pefloxacin. Treatment of mice with 1 day of pefloxacin treatment significantly decreased the rate of biosynthesis of proteoglycan for the first 24 h. However, no difference was observed after 48 h. The decrease in proteoglycan synthesis was accompanied by a marked drop in serum sulfate concentration and a concomitant increase in urinary sulfate excretion. The decrease in proteoglycan synthesis, also observed ex vivo, may suggest a direct effect of pefloxacin on this process, rather than it being a consequence of a low concentration of sulfate. On the other hand, treatment with pefloxacin for 10 days induced oxidative damage to collagen. In conclusion, this study demonstrates, for the first time, that pefloxacin administration to mice leads to modifications in the metabolism and integrity of extracellular proteins, such as collagen and proteoglycans, which may account for the side effects observed. These results offer new insights to explain quinolone-induced disorders in growing articular cartilage.