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Effectiveness of β-Lactam Monotherapy vs Macrolide Combination Therapy for Children Hospitalized With Pneumonia.
Williams DJ, Edwards KM, Self WH, Zhu Y, Arnold SR, McCullers JA, Ampofo K, Pavia AT, Anderson EJ, Hicks LA, Bramley AM, Jain S, Grijalva CG
(2017) JAMA Pediatr 171: 1184-1191
MeSH Terms: Adolescent, Anti-Bacterial Agents, Child, Child, Preschool, Community-Acquired Infections, Drug Therapy, Combination, Hospitalization, Humans, Infant, Intensive Care Units, Pediatric, Length of Stay, Macrolides, Patient Readmission, Pneumonia, Bacterial, Propensity Score, Radiography, Treatment Outcome, beta-Lactams
Show Abstract · Added July 27, 2018
Importance - β-Lactam monotherapy and β-lactam plus macrolide combination therapy are both common empirical treatment strategies for children hospitalized with pneumonia, but few studies have evaluated the effectiveness of these 2 treatment approaches.
Objective - To compare the effectiveness of β-lactam monotherapy vs β-lactam plus macrolide combination therapy among a cohort of children hospitalized with pneumonia.
Design, Setting, and Participants - We analyzed data from the Etiology of Pneumonia in the Community Study, a multicenter, prospective, population-based study of community-acquired pneumonia hospitalizations conducted from January 1, 2010, to June 30, 2012, in 3 children's hospitals in Nashville, Tennessee; Memphis, Tennessee; and Salt Lake City, Utah. The study included all children (up to 18 years of age) who were hospitalized with radiographically confirmed pneumonia and who received β-lactam monotherapy or β-lactam plus macrolide combination therapy. Data analysis was completed in April 2017.
Main Outcomes and Measures - We defined the referent as β-lactam monotherapy, including exclusive use of an oral or parenteral second- or third-generation cephalosporin, penicillin, ampicillin, ampicillin-sulbactam, amoxicillin, or amoxicillin-clavulanate. Use of a β-lactam plus an oral or parenteral macrolide (azithromycin or clarithromycin) served as the comparison group. We modeled the association between these groups and patients' length of stay using multivariable Cox proportional hazards regression. Covariates included demographic, clinical, and radiographic variables. We further evaluated length of stay in a cohort matched by propensity to receive combination therapy. Logistic regression was used to evaluate secondary outcomes in the unmatched cohort, including intensive care admission, rehospitalizations, and self-reported recovery at follow-up.
Results - Our study included 1418 children (693 girls and 725 boys) with a median age of 27 months (interquartile range, 12-69 months). This cohort was 60.1% of the 2358 children enrolled in the Etiology of Pneumonia in the Community Study with radiographically confirmed pneumonia in the study period; 1019 (71.9%) received β-lactam monotherapy and 399 (28.1%) received β-lactam plus macrolide combination therapy. In the unmatched cohort, there was no statistically significant difference in length of hospital stay between children receiving β-lactam monotherapy and combination therapy (median, 55 vs 59 hours; adjusted hazard ratio, 0.87; 95% CI, 0.74-1.01). The propensity-matched cohort (n = 560, 39.5%) showed similar results. There were also no significant differences between treatment groups for the secondary outcomes.
Conclusions and Relevance - Empirical macrolide combination therapy conferred no benefit over β-lactam monotherapy for children hospitalized with community-acquired pneumonia. The results of this study elicit questions about the routine empirical use of macrolide combination therapy in this population.
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MeSH Terms
The use of fluorescently-tagged apoptolidins in cellular uptake and response studies.
Chong KM, Leelatian N, Deguire SM, Brockman AA, Earl D, Ihrie RA, Irish JM, Bachmann BO, Sulikowski GA
(2016) J Antibiot (Tokyo) 69: 327-30
MeSH Terms: A549 Cells, Biological Transport, Cell Line, Tumor, Flow Cytometry, Fluorescent Dyes, Humans, Macrolides, Staining and Labeling
Show Abstract · Added March 12, 2016
The apoptolidins are glycomacrolide microbial metabolites reported to be selectively cytotoxic against tumor cells. Using fluorescently tagged active derivatives we demonstrate selective uptake of these four tagged glycomacrolides in cancer cells over healthy human blood cells. We also demonstrate the utility of these five fluorescently tagged glycomacrolides in fluorescent flow cytometry to monitor cellular uptake of the six glycomacrolides and cellular response.
2 Communities
2 Members
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8 MeSH Terms
Fluorescent probes of the apoptolidins and their utility in cellular localization studies.
DeGuire SM, Earl DC, Du Y, Crews BA, Jacobs AT, Ustione A, Daniel C, Chong KM, Marnett LJ, Piston DW, Bachmann BO, Sulikowski GA
(2015) Angew Chem Int Ed Engl 54: 961-4
MeSH Terms: Antineoplastic Agents, Apoptosis, Cell Line, Tumor, Fluorescent Dyes, Humans, Lipid Peroxidation, Macrolides, Microscopy, Confocal, Pyrones
Show Abstract · Added January 20, 2015
Apoptolidin A has been described among the top 0.1% most-cell-selective cytotoxic agents to be evaluated in the NCI 60 cell line panel. The molecular structure of apoptolidin A consists of a 20-membered macrolide with mono- and disaccharide moieties. In contrast to apoptolidin A, the aglycone (apoptolidinone) shows no cytotoxicity (>10 μM) when evaluated against several tumor cell lines. Apoptolidin H, the C27 deglycosylated analogue of apoptolidin A, displayed sub-micromolar activity against H292 lung carcinoma cells. Selective esterification of apoptolidins A and H with 5-azidopentanoic acid afforded azido-functionalized derivatives of potency equal to that of the parent macrolide. They also underwent strain-promoted alkyne-azido cycloaddition reactions to provide access to fluorescent and biotin-functionalized probes. Microscopy studies demonstrate apoptolidins A and H localize in the mitochondria of H292 human lung carcinoma cells.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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4 Members
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9 MeSH Terms
Concerted, highly asynchronous, enzyme-catalyzed [4 + 2] cycloaddition in the biosynthesis of spinosyn A; computational evidence.
Hess BA, Smentek L
(2012) Org Biomol Chem 10: 7503-9
MeSH Terms: Biocatalysis, Cyclization, Macrolides, Phosphorus-Oxygen Lyases, Quantum Theory, Saccharopolyspora
Show Abstract · Added February 15, 2016
A theoretical study has been carried out on model systems to study a recently reported, (Nature, 2011, 473, 109) biosynthetic, [4 + 2] cycloaddition catalyzed by a stand-alone enzyme (the cyclase SpnF). It was suggested in this paper that SpnF is the first known example of a Diels-Alderase (DA). In the present study, for a model system of the substrate a transition structure was found with density functional calculations (DFT). In addition, the intrinsic reaction coordinate calculations indicated that the transition structure is that of a concerted, but highly asynchronous, DA reaction. Based on the DFT and Møller-Plesset second order calculations the activation energy was estimated to be about 15 kcal mol(-1). The results of a natural population analysis indicated that there is significant charge transfer in the transition state, and it is proposed that possibly the enzyme plays a dual role of not only folding the substrate into the proper conformation for the DA reaction to occur, but also lowering its activation energy by stabilization of the highly polarized transition structure.
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6 MeSH Terms
Toll-like receptor 2 mediates fatal immunopathology in mice during treatment of secondary pneumococcal pneumonia following influenza.
Karlström A, Heston SM, Boyd KL, Tuomanen EI, McCullers JA
(2011) J Infect Dis 204: 1358-66
MeSH Terms: Animals, Anti-Bacterial Agents, Female, Immunologic Factors, Lung, Macrolides, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neutrophils, Orthomyxoviridae Infections, Pneumonia, Pneumococcal, Streptococcus pneumoniae, Toll-Like Receptor 2, Treatment Outcome, beta-Lactams
Show Abstract · Added March 20, 2014
Host inflammatory responses contribute to the significant immunopathology that occurs during treatment of secondary bacterial pneumonia following influenza. We undertook the present study to determine the mechanisms underlying disparate outcomes in a mouse model with β-lactam and macrolide antibiotics. Lysis of superinfecting bacteria by ampicillin caused an extensive influx of neutrophils into the lungs resulting in a consolidative pneumonia, necrotic lung damage, and significant mortality. This was mediated through Toll-like receptor (TLR) 2 and was independent of TLR4 and the Streptococcus pneumoniae cytotoxin pneumolysin. Treatment with azithromycin prevented neutrophil accumulation and rescued mice from subsequent mortality. This effect was independent of the antibacterial activity of this macrolide since dual therapy with ampicillin and azithromycin against an azithromycin-resistant strain also was able to cure secondary pneumonia. These data suggest that strategies for eliminating bacteria without lysis coupled with immunomodulation of inflammation should be pursued clinically.
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17 MeSH Terms
Light-induced isomerization of apoptolidin a leads to inversion of C2-C3 double bond geometry.
Bachmann BO, McNees R, Melancon BJ, Ghidu VP, Clark R, Crews BC, Deguire SM, Marnett LJ, Sulikowski GA
(2010) Org Lett 12: 2944-7
MeSH Terms: Cell Line, Tumor, Cell Survival, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Macrolides, Molecular Conformation, Pyrones, Stereoisomerism, Structure-Activity Relationship, Ultraviolet Rays
Show Abstract · Added March 7, 2014
The isolation, characterization, and cytotoxicity against H292 cells of apoptolidin G are reported. Apoptolidin G is shown to be derived by a light-induced isomerization of the C2-C3 carbon-carbon double bond of apoptolidin A.
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11 MeSH Terms
S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes that involves BNIP3.
Ghavami S, Eshragi M, Ande SR, Chazin WJ, Klonisch T, Halayko AJ, McNeill KD, Hashemi M, Kerkhoff C, Los M
(2010) Cell Res 20: 314-31
MeSH Terms: Adenine, Apoptosis, Autophagy, Autophagy-Related Protein 12, Autophagy-Related Protein 5, Calgranulin A, Calgranulin B, Cell Line, Humans, Lysosomes, Macrolides, Membrane Proteins, Microtubule-Associated Proteins, Mitochondria, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Proto-Oncogene Proteins, Reactive Oxygen Species, Small Ubiquitin-Related Modifier Proteins, Vacuolar Proton-Translocating ATPases
Show Abstract · Added March 12, 2014
The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosis-inducing activity in various cells of different origins. Here, we present evidence that the underlying molecular mechanisms involve both programmed cell death I (PCD I, apoptosis) and PCD II (autophagy)-like death. Treatment of cells with S100A8/A9 caused the increase of Beclin-1 expression as well as Atg12-Atg5 formation. S100A8/A9-induced cell death was partially inhibited by the specific PI3-kinase class III inhibitor, 3-methyladenine (3-MA), and by the vacuole H(+)-ATPase inhibitor, bafilomycin-A1 (Baf-A1). S100A8/A9 provoked the translocation of BNIP3, a BH3 only pro-apoptotic Bcl2 family member, to mitochondria. Consistent with this finding, DeltaTM-BNIP3 overexpression partially inhibited S100A8/A9-induced cell death, decreased reactive oxygen species (ROS) generation, and partially protected against the decrease in mitochondrial transmembrane potential in S100A8/A9-treated cells. In addition, either DeltaTM-BNIP3 overexpression or N-acetyl-L-cysteine co-treatment decreased lysosomal activation in cells treated with S100A8/A9. Our data indicate that S100A8/A9-promoted cell death occurs through the cross-talk of mitochondria and lysosomes via ROS and the process involves BNIP3.
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20 MeSH Terms
Combined chemical and biosynthetic route to access a new apoptolidin congener.
Ghidu VP, Ntai I, Wang J, Jacobs AT, Marnett LJ, Bachmann BO, Sulikowski GA
(2009) Org Lett 11: 3032-4
MeSH Terms: Actinomyces, Antineoplastic Agents, Drug Screening Assays, Antitumor, Glycosylation, Humans, Macrolides, Molecular Structure, Structure-Activity Relationship
Show Abstract · Added June 1, 2014
Glycosylation of a synthetic aglycone using precursor-directed biosynthesis is facilitated by a chemical ketosynthase "knockdown" of the apoptolidin producer Nocardiopsis sp. This synthetic approach facilitated the preparation of an unnatural disaccharide derivative of apoptolidin D that substantially restores cytotoxicity against H292 cells and deconvolutes the role of the decorating sugars in apoptolidin bioactivity.
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1 Members
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8 MeSH Terms
Synthesis and evaluation of the cytotoxicity of apoptolidinones A and D.
Ghidu VP, Wang J, Wu B, Liu Q, Jacobs A, Marnett LJ, Sulikowski GA
(2008) J Org Chem 73: 4949-55
MeSH Terms: Antineoplastic Agents, Cell Line, Tumor, Humans, Macrolides, Molecular Structure, Pyrones
Show Abstract · Added March 5, 2014
Apoptolidins A-D are microbial secondary metabolites shown to be selectively cytotoxic against several cancer cell lines and noncytotoxic against normal cells. Total syntheses of apoptolidinones A and D are reported. The efficient synthetic strategy leading to the apoptolidinones features construction of the common 20-membered macrolactone by an intramolecular Suzuki reaction and stereocontrolled aldol reactions establishing the C19/C20 and C22/C23 stereocenters. In contrast to apoptolidin A, the aglycones apoptolidinone A and D were shown to be noncytotoxic when evaluated against human lung cancer cells (H292).
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6 MeSH Terms
Heat shock protein 90 modulates endothelial nitric oxide synthase activity and vascular reactivity in the newborn piglet pulmonary circulation.
Aschner JL, Foster SL, Kaplowitz M, Zhang Y, Zeng H, Fike CD
(2007) Am J Physiol Lung Cell Mol Physiol 292: L1515-25
MeSH Terms: Adenosine Triphosphate, Animals, Animals, Newborn, Benzoquinones, Cells, Cultured, Cyclic GMP, Dicarbethoxydihydrocollidine, Endothelial Cells, Enzyme Inhibitors, HSP90 Heat-Shock Proteins, Lactams, Macrocyclic, Macrolides, Microcirculation, Nitric Oxide, Nitric Oxide Synthase Type III, Pulmonary Artery, Pulmonary Circulation, Superoxides, Swine, Vascular Resistance
Show Abstract · Added May 20, 2014
Heat shock protein 90 (Hsp90) binding to endothelial nitric oxide synthase (eNOS) is an important step in eNOS activation. The conformational state of bound Hsp90 determines whether eNOS produces nitric oxide (NO) or superoxide (O(2)(*-)). We determined the effects of the Hsp90 antagonists geldanamycin (GA) and radicicol (RA) on basal and ACh-stimulated changes in vessel diameter, cGMP production, and Hsp90:eNOS coimmunoprecipitation in piglet resistance level pulmonary arteries (PRA). In perfused piglet lungs, we evaluated the effects of GA and RA on ACh-stimulated changes in pulmonary arterial pressure (Ppa) and perfusate accumulation of stable NO metabolites (NOx(-)). The effects of GA and RA on ACh-stimulated O(2)(*-) generation was investigated in cultured pulmonary microvascular endothelial cells (PMVEC) by dihydroethidine (DHE) oxidation and confocal microscopy. Hsp90 inhibition with GA or RA reduced ACh-mediated dilation, abolished the ACh-stimulated increase in cGMP, and reduced eNOS:Hsp90 coprecipitation. GA and RA also inhibited the ACh-mediated changes in Ppa and NOx(-) accumulation rates in perfused lungs. ACh increased the rate of DHE oxidation in PMVEC pretreated with GA and RA but not in untreated cells. The cell-permeable superoxide dismutase mimetic M40401 reversed GA-mediated inhibition of ACh-induced dilation in PRA. We conclude that Hsp90 is a modulator of eNOS activity and vascular reactivity in the newborn piglet pulmonary circulation. Uncoupling of eNOS with GA or RA inhibits ACh-mediated dilation by a mechanism that involves O(2)(*-) generation.
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20 MeSH Terms