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Ken B. Waites - One of the best experts on this subject based on the ideXlab platform.
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Ureaplasma Transmitted From Donor Lungs Is Pathogenic After Lung Transplantation
The Annals of thoracic surgery, 2017Co-Authors: Ramiro Fernandez, Donna M. Crabb, Ken B. Waites, Amy E. Ratliff, Ankit BharatAbstract:Hyperammonemia is a highly fatal syndrome in lung recipients that is usually refractory to medical therapy. We recently reported that Infection by a Mollicute, Ureaplasma, is causative for hyperammonemia and can be successfully treated with antimicrobial agents. However, it remains unknown whether the pathogenic strain of Ureaplasma is donor or recipient derived. Here we provide evidence that donor-derived Ureaplasma Infection can be pathogenic. As such, we uncover a previously unknown lethal donor-derived opportunistic Infection in lung recipients. Given the high mortality associated with hyperammonemia, strategies for routine donor screening or prophylaxis should be further evaluated in prospective studies.
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Ureaplasma Infection-mediated release of matrix metalloproteinase-9 and PGP: a novel mechanism of preterm rupture of membranes and chorioamnionitis
Pediatric Research, 2016Co-Authors: Charitharth Vivek Lal, Ken B. Waites, Patricia L. Jackson, Thomas Prescott Atkinson, Ona Faye-petersen, Jegen Kandasamy, Joseph R. Biggio, Amit Gaggar, Namasivayam AmbalavananAbstract:Ureaplasma Infection-mediated release of matrix metalloproteinase-9 and PGP: a novel mechanism of preterm rupture of membranes and chorioamnionitis
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Disseminated Ureaplasma Infection as a cause of fatal hyperammonemia in humans
Science translational medicine, 2015Co-Authors: Ankit Bharat, Scott A Cunningham, G. R. Scott Budinger, Daniel Kreisel, Charl J. Dewet, Andrew E. Gelman, Ken B. Waites, Donna M. Crabb, Li Xiao, Sangeeta BhoradeAbstract:Hyperammonemia syndrome is a fatal complication affecting immunosuppressed patients. Frequently refractory to treatment, it is characterized by progressive elevations in serum ammonia of unknown etiology, ultimately leading to cerebral edema and death. In mammals, ammonia produced during amino acid metabolism is primarily cleared through the hepatic production of urea, which is eliminated in the kidney. Ureaplasma species, commensals of the urogenital tract, are Mollicutes dependent on urea hydrolysis to ammonia and carbon dioxide for energy production. We hypothesized that systemic Infection with Ureaplasma species might pose a unique challenge to human ammonia metabolism by liberating free ammonia resulting in the hyperammonemia syndrome. We used polymerase chain reaction, specialized culture, and molecular resistance profiling to identify systemic Ureaplasma Infection in lung transplant recipients with hyperammonemia syndrome, but did not detect it in any lung transplant recipients with normal ammonia concentrations. Administration of Ureaplasma-directed antimicrobials to patients with hyperammonemia syndrome resulted in biochemical and clinical resolution of the disorder. Relapse in one patient was accompanied by recurrent Ureaplasma bacteremia with antimicrobial resistance. Our results provide evidence supporting a causal relationship between Ureaplasma Infection and hyperammonemia, suggesting a need to test for this organism and provide empiric antimicrobial treatment while awaiting microbiological confirmation.
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transplacental transfer of azithromycin and its use for eradicating intra amniotic Ureaplasma Infection in a primate model
The Journal of Infectious Diseases, 2014Co-Authors: Edward P Acosta, Miles J Novy, Ken B. Waites, Peta L Grigsby, Kajal B Larson, Amanda Marie James, Mary C Long, Lynn B DuffyAbstract:Intrauterine Infections are an important and potentially preventable cause of preterm delivery. Such Infections cause the majority of very-low-birth-weight (VLBW) deliveries, which are characterized by a birth weight of <1500 g and delivery before 30 weeks of gestation. VLBW accounts for the highest rates of neonatal deaths, the most serious neonatal complications, and a disproportionate share of perinatal healthcare costs [1]. Intrauterine bacterial Infections can cause inflammation of the fetal membranes, chorion, and amnion (chorioamnionitis). Ureaplasma urealyticum and Ureaplasma parvum are the microorganisms most frequently isolated from placenta with chorioamnionitis in women with preterm labor (47%) [2, 3]. Moreover, these bacteria are also the most common organisms isolated from the respiratory tracts of preterm infants and have been associated with neonatal pneumonia, severe respiratory failure, and bronchopulmonary dysplasia [4–7]. Among newborn infants, the frequency and severity of Ureaplasma Infection varies inversely with gestational age and weight, occurring most frequently among preterm infants with VLBW [8]. Indeed, detection of Ureaplasmas in the chorioamnion is associated with delivery at <37 weeks gestational age [4, 9]. Intra-amniotic Infection (IAI) often manifests without the mother's knowledge, making accurate diagnosis difficult and early intervention challenging to forestall upregulation of proinflammatory mediators that precede preterm birth and also play an important role in fetal and neonatal sequelae. Eradicating Ureaplasma Infection in pregnant women with chorioamnionitis could delay delivery and prevent complications in newborns. While Ureaplasma species lack a cell wall and are therefore resistant to β-lactam antibiotics, these bacteria are susceptible to macrolides and fluoroquinolones [4]. Tetracycline resistance occurs in up to 50% of Ureaplasma clinical isolates because of the tetM transposon [4]. Isolated case reports demonstrate that it is possible to eradicate Ureaplasma species from the amniotic cavity by maternal administration of erythromycin [10]. However, in subsequent case reports, the rates of preterm delivery in treated versus untreated patients were similar, suggesting incomplete treatment or recolonization of the amniotic cavity [11]. While postnatal treatment with erythromycin is often ineffective at eliminating airway colonization with Ureaplasmas in VLBW infants [12–14], macrolides remain the treatment of choice, especially in pregnant women and neonates [15]. Azithromycin (AZI) is a 15-membered semisynthetic macrolide antibiotic in the azalide subclass with some structural similarity to erythromycin, but with a prolonged duration of action, improved tissue penetration, a more favorable side-effect profile, and extended range of antimicrobial coverage [16]. Previous cross-sectional studies indicated that transplacental passage of AZI occurs at low rates and that the levels found in fetal plasma (FP) reach 2.6% of the levels in maternal circulation [14, 17, 18]. Several studies have demonstrated that AZI concentrations in tissues of the respiratory tract, including lung tissue, were several-fold higher than circulating AZI concentrations, providing promise that AZI will be useful against Ureaplasmal Infections in fetal lung tissue [19–22]. However, because of the limited placental permeability of AZI, there is controversy about whether antenatal antibiotic interventions prevents preterm labor, prolong gestation, or otherwise improves perinatal outcomes [23–25]. The use of prenatal antibiotics is debated with regard to the treatments' ability to prevent early labor, prolong gestation, and improve perinatal health. Conflicting results in the literature may be attributed to potential confounders and variations in study design [26–29]. There is now an urgent need to study specific antibiotic regimens for defined pathogens, to evaluate placental transfer, understand the pharmacokinetics and pharmacodynamics, and establish biological plausibility for the treatment of intra-uterine Infections. In the rhesus monkey (Macaca mulatta), hemochorial placentation, endocrine characteristics, anatomy, and singleton fetus pregnancies are analogues to those of human pregnancy and therefore permit longitudinal pharmacokinetic studies with serial sampling of both maternal and fetal compartments that is not possible with human subjects [30]. We provided proof of concept for the use of a specific macrolide antibiotic to eradicate U. parvum from the amniotic cavity and fetal tissues in the rhesus monkey [31, 32]. This maternal treatment targets amniotic fluid (AF) proinflammatory pathways and results in prolongation of gestation and reduced fetal lung injury [32]. Our goal was to extend this study to characterize the pharmacokinetics and pharmacodynamics of AZI in the maternal, fetal, and intra-amniotic compartments through modeling and to explore the relationships between U. parvum eradication and AZI exposure.
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Suppression of Antimicrobial Peptide Expression by Ureaplasma Species
Infection and immunity, 2014Co-Authors: Li Xiao, Ken B. Waites, Donna M. Crabb, Yuling Dai, Yuying Chen, T. Prescott AtkinsonAbstract:Ureaplasma species commonly colonize the adult urogenital tract and are implicated in invasive diseases of adults and neonates. Factors that permit the organisms to cause chronic colonization or Infection are poorly understood. We sought to investigate whether host innate immune responses, specifically, antimicrobial peptides (AMPs), are involved in determining the outcome of Ureaplasma Infections. THP-1 cells, a human monocytoid tumor line, were cocultured with Ureaplasma parvum and U. urealyticum. Gene expression levels of a variety of host defense genes were quantified by real-time PCR. In vitro antimicrobial activities of synthetic AMPs against Ureaplasma spp. were determined using a flow cytometry-based assay. Chromosomal histone modifications in host defense gene promoters were tested by chromatin immunoprecipitation (ChIP). DNA methylation status in the AMP promoter regions was also investigated. After stimulation with U. parvum and U. urealyticum, the expression of cell defense genes, including the AMP genes (DEFB1, DEFA5, DEFA6, and CAMP), was significantly downregulated compared to that of TNFA and IL-8, which were upregulated. In vitro flow cytometry-based antimicrobial assay revealed that synthetic peptides LL-37, hBD-3, and hBD-1 had activity against Ureaplasma spp. Downregulation of the AMP genes was associated with chromatin modification alterations, including the significantly decreased histone H3K9 acetylation with U. parvum Infection. No DNA methylation status changes were detected upon Ureaplasma Infection. In conclusion, AMPs have in vitro activity against Ureaplasma spp., and suppression of AMP expression might be important for the organisms to avoid this aspect of the host innate immune response and to establish chronic Infection and colonization.
Namasivayam Ambalavanan - One of the best experts on this subject based on the ideXlab platform.
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Ureaplasma Infection-mediated release of matrix metalloproteinase-9 and PGP: a novel mechanism of preterm rupture of membranes and chorioamnionitis
Pediatric Research, 2017Co-Authors: Charitharth Vivek Lal, Thomas Prescott Atkinson, Ona Faye-petersen, Jegen Kandasamy, Joseph R. Biggio, Amit Gaggar, Patricia Jackson, Ken Waites, Namasivayam AmbalavananAbstract:Background: Premature rupture of membranes and preterm delivery are associated with Ureaplasma Infection . We hypothesized that Ureaplasma induced extracellular collagen fragmentation results in production of the tripeptide PGP (proline-glycine-proline), a neutrophil chemoattractant. PGP release from collagen requires matrix metalloproteases (MMP-8/MMP-9) along with a serine protease, prolyl endopeptidase (PE). Methods: Ureaplasma culture negative amniotic fluid (indicated preterm birth, n = 8; spontaneous preterm birth, n = 8) and Ureaplasma positive amniotic fluid (spontaneous preterm birth, n = 8) were analyzed by electro-spray ionization-liquid chromatography tandem mass spectrometry for PGP, and for MMP-9 by zymography. PE was evaluated in lysates of U. parvum serovar 3 (Up3) and U. urealyticum serovar 10 (Uu10) by western blotting and activity assay. Results: PGP and MMP-9 were increased in amniotic fluid from spontaneous preterm birth with positive Ureaplasma cultures, but not with indicated preterm birth or spontaneous preterm birth with negative Ureaplasma cultures. Human neutrophils cocultured with Ureaplasma strains showed increased MMP-9 activity. PE presence and activity were noted with both Ureaplasma strains. Conclusion: Ureaplasma spp. carry the protease necessary for PGP release, and PGP and MMP-9 are increased in amniotic fluid during Ureaplasma Infection, suggesting Ureaplasma spp. induced collagen fragmentation contributes to preterm rupture of membranes and neutrophil influx causing chorioamnionitis.
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Ureaplasma Infection-mediated release of matrix metalloproteinase-9 and PGP: a novel mechanism of preterm rupture of membranes and chorioamnionitis
Pediatric Research, 2016Co-Authors: Charitharth Vivek Lal, Ken B. Waites, Patricia L. Jackson, Thomas Prescott Atkinson, Ona Faye-petersen, Jegen Kandasamy, Joseph R. Biggio, Amit Gaggar, Namasivayam AmbalavananAbstract:Ureaplasma Infection-mediated release of matrix metalloproteinase-9 and PGP: a novel mechanism of preterm rupture of membranes and chorioamnionitis
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Ureaplasma Infection-mediated release of matrix metalloproteinase-9 and PGP: a novel mechanism of preterm rupture of membranes and chorioamnionitis.
Pediatric research, 2016Co-Authors: Charitharth Vivek Lal, Thomas Prescott Atkinson, Ona Faye-petersen, Jegen Kandasamy, Joseph R. Biggio, Amit Gaggar, Patricia Jackson, Ken Waites, Namasivayam AmbalavananAbstract:Premature rupture of membranes and preterm delivery are associated with Ureaplasma Infection. We hypothesized that Ureaplasma induced extracellular collagen fragmentation results in production of the tripeptide PGP (proline-glycine-proline), a neutrophil chemoattractant. PGP release from collagen requires matrix metalloproteases (MMP-8/MMP-9) along with a serine protease, prolyl endopeptidase (PE). Ureaplasma culture negative amniotic fluid (indicated preterm birth, n = 8; spontaneous preterm birth, n = 8) and Ureaplasma positive amniotic fluid (spontaneous preterm birth, n = 8) were analyzed by electro-spray ionization-liquid chromatography tandem mass spectrometry for PGP, and for MMP-9 by zymography. PE was evaluated in lysates of U. parvum serovar 3 (Up3) and U. urealyticum serovar 10 (Uu10) by western blotting and activity assay. PGP and MMP-9 were increased in amniotic fluid from spontaneous preterm birth with positive Ureaplasma cultures, but not with indicated preterm birth or spontaneous preterm birth with negative Ureaplasma cultures. Human neutrophils cocultured with Ureaplasma strains showed increased MMP-9 activity. PE presence and activity were noted with both Ureaplasma strains. Ureaplasma spp. carry the protease necessary for PGP release, and PGP and MMP-9 are increased in amniotic fluid during Ureaplasma Infection, suggesting Ureaplasma spp. induced collagen fragmentation contributes to preterm rupture of membranes and neutrophil influx causing chorioamnionitis.
Miles J Novy - One of the best experts on this subject based on the ideXlab platform.
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maternal azithromycin therapy for Ureaplasma parvum intra amniotic Infection improves fetal hemodynamics in a non human primate model
American Journal of Obstetrics and Gynecology, 2020Co-Authors: Meredith A. Kelleher, Miles J Novy, Victoria H. J. Roberts, Christopher M. Novak, Terry K. Morgan, Antonio E. Frias, Juha Rasanen, Ahmet BaschatAbstract:BACKGROUND: Ureaplasma parvum Infection is a prevalent cause of intrauterine Infection that is associated with preterm birth, preterm premature rupture of membranes, the fetal inflammatory response syndrome and adverse postnatal sequelae. Elucidation of diagnostic and treatment strategies for Infection-associated preterm labor may improve perinatal and long-term outcomes for these cases. OBJECTIVE: This study assesses the effect of intra-amniotic Ureaplasma Infection on fetal hemodynamic and cardiac function and the impact of maternal antibiotic treatment on these outcomes. STUDY DESIGN: Chronically catheterized pregnant rhesus monkeys were assigned to control (n=6), intra-amniotic inoculation with Ureaplasma parvum (107 CFU/ml, IAI, n=15); and intra-amniotic Infection plus Azithromycin treatment (12.5 mg/kg BID I.V., IAI+AZI, n=8) groups. At ∼135days gestation (term=165 days), pulsed and color Doppler ultrasonography was utilized to obtain measurements of fetal hemodynamics (pulsatility index of umbilical artery, ductus venosus, descending aorta, ductus arteriosus, aortic isthmus, right pulmonary artery, middle cerebral artery and cerebro-placental ratio, and left and right ventricular cardiac outputs) and cardiac function (E/A ratio, Tei index). These indices were stratified by amniotic fluid pro-inflammatory mediator levels and cardiac histology. RESULTS: Umbilical and fetal pulmonary artery vascular impedances were significantly increased in IAI animals (p 1.1) than those with normal blood flow (p 1.6, p<0.05). Amniotic fluid IL-6 concentrations were elevated in cases of abnormal RCO/LCO ratio compared to normal cases (p<0.05). CONCLUSIONS: Fetal hemodynamic alterations were associated with intra-amniotic Ureaplasma Infection and ameliorated following maternal antibiotic treatment. Doppler ultrasonographic measurements merit continuing investigation as a diagnostic method to identify fetal cardiovascular and hemodynamic compromise associated with intrauterine Infection or inflammation, and in the evaluation of therapeutic interventions or clinical management of preterm labor.
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maternal azithromycin therapy for Ureaplasma parvum intraamniotic Infection improves fetal hemodynamics in a nonhuman primate model
American Journal of Obstetrics and Gynecology, 2020Co-Authors: Meredith A. Kelleher, Miles J Novy, Victoria H. J. Roberts, Christopher M. Novak, Antonio E. Frias, Juha Rasanen, Ahmet Baschat, Ji Yeon Lee, Terry Morgan, Irina BurdAbstract:BACKGROUND Ureaplasma parvum Infection is a prevalent cause of intrauterine Infection associated with preterm birth, preterm premature rupture of membranes, fetal inflammatory response syndrome, and adverse postnatal sequelae. Elucidation of diagnostic and treatment strategies for Infection-associated preterm labor may improve perinatal and long-term outcomes for these cases. OBJECTIVE This study assessed the effect of intraamniotic Ureaplasma Infection on fetal hemodynamic and cardiac function and the effect of maternal antibiotic treatment on these outcomes. STUDY DESIGN Chronically catheterized pregnant rhesus monkeys were assigned to control (n=6), intraamniotic inoculation with Ureaplasma parvum (107 colony-forming units/mL, n=15), and intraamniotic Infection plus azithromycin treatment (12.5 mg/kg twice a day intravenously, n=8) groups. At approximately 135 days' gestation (term=165 days), pulsed and color Doppler ultrasonography was used to obtain measurements of fetal hemodynamics (pulsatility index of umbilical artery, ductus venosus, descending aorta, ductus arteriosus, aortic isthmus, right pulmonary artery, middle cerebral artery and cerebroplacental ratio, and left and right ventricular cardiac outputs) and cardiac function (ratio of peak early vs late transmitral flow velocity [marker of ventricular function], Tei index [myocardial performance index]). These indices were stratified by amniotic fluid proinflammatory mediator levels and cardiac histology. RESULTS Umbilical and fetal pulmonary artery vascular impedances were significantly increased in animals from the intraamniotic inoculation with Ureaplasma parvum group (P 1.1) than in those with normal blood flow (P 1.6, P<.05). Amniotic fluid interleukin-6 concentrations were elevated in cases of abnormal right-to-left ventricular cardiac output ratios compared with those in normal cases (P<.05). CONCLUSION Fetal hemodynamic alterations were associated with intraamniotic Ureaplasma Infection and ameliorated after maternal antibiotic treatment. Doppler ultrasonographic measurements merit continuing investigation as a diagnostic method to identify fetal cardiovascular and hemodynamic compromise associated with intrauterine Infection or inflammation and in the evaluation of therapeutic interventions or clinical management of preterm labor.
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Maternal azithromycin therapy for Ureaplasma parvum intraamniotic Infection improves fetal hemodynamics in a nonhuman primate model.
American journal of obstetrics and gynecology, 2020Co-Authors: Meredith A. Kelleher, Miles J Novy, Victoria H. J. Roberts, Christopher M. Novak, Antonio E. Frias, Juha Rasanen, Ahmet Baschat, Ji Yeon Lee, Terry Morgan, Irina BurdAbstract:BACKGROUND Ureaplasma parvum Infection is a prevalent cause of intrauterine Infection associated with preterm birth, preterm premature rupture of membranes, fetal inflammatory response syndrome, and adverse postnatal sequelae. Elucidation of diagnostic and treatment strategies for Infection-associated preterm labor may improve perinatal and long-term outcomes for these cases. OBJECTIVE This study assessed the effect of intraamniotic Ureaplasma Infection on fetal hemodynamic and cardiac function and the effect of maternal antibiotic treatment on these outcomes. STUDY DESIGN Chronically catheterized pregnant rhesus monkeys were assigned to control (n=6), intraamniotic inoculation with Ureaplasma parvum (107 colony-forming units/mL, n=15), and intraamniotic Infection plus azithromycin treatment (12.5 mg/kg twice a day intravenously, n=8) groups. At approximately 135 days' gestation (term=165 days), pulsed and color Doppler ultrasonography was used to obtain measurements of fetal hemodynamics (pulsatility index of umbilical artery, ductus venosus, descending aorta, ductus arteriosus, aortic isthmus, right pulmonary artery, middle cerebral artery and cerebroplacental ratio, and left and right ventricular cardiac outputs) and cardiac function (ratio of peak early vs late transmitral flow velocity [marker of ventricular function], Tei index [myocardial performance index]). These indices were stratified by amniotic fluid proinflammatory mediator levels and cardiac histology. RESULTS Umbilical and fetal pulmonary artery vascular impedances were significantly increased in animals from the intraamniotic inoculation with Ureaplasma parvum group (P 1.1) than in those with normal blood flow (P 1.6, P
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transplacental transfer of azithromycin and its use for eradicating intra amniotic Ureaplasma Infection in a primate model
The Journal of Infectious Diseases, 2014Co-Authors: Edward P Acosta, Miles J Novy, Ken B. Waites, Peta L Grigsby, Kajal B Larson, Amanda Marie James, Mary C Long, Lynn B DuffyAbstract:Intrauterine Infections are an important and potentially preventable cause of preterm delivery. Such Infections cause the majority of very-low-birth-weight (VLBW) deliveries, which are characterized by a birth weight of <1500 g and delivery before 30 weeks of gestation. VLBW accounts for the highest rates of neonatal deaths, the most serious neonatal complications, and a disproportionate share of perinatal healthcare costs [1]. Intrauterine bacterial Infections can cause inflammation of the fetal membranes, chorion, and amnion (chorioamnionitis). Ureaplasma urealyticum and Ureaplasma parvum are the microorganisms most frequently isolated from placenta with chorioamnionitis in women with preterm labor (47%) [2, 3]. Moreover, these bacteria are also the most common organisms isolated from the respiratory tracts of preterm infants and have been associated with neonatal pneumonia, severe respiratory failure, and bronchopulmonary dysplasia [4–7]. Among newborn infants, the frequency and severity of Ureaplasma Infection varies inversely with gestational age and weight, occurring most frequently among preterm infants with VLBW [8]. Indeed, detection of Ureaplasmas in the chorioamnion is associated with delivery at <37 weeks gestational age [4, 9]. Intra-amniotic Infection (IAI) often manifests without the mother's knowledge, making accurate diagnosis difficult and early intervention challenging to forestall upregulation of proinflammatory mediators that precede preterm birth and also play an important role in fetal and neonatal sequelae. Eradicating Ureaplasma Infection in pregnant women with chorioamnionitis could delay delivery and prevent complications in newborns. While Ureaplasma species lack a cell wall and are therefore resistant to β-lactam antibiotics, these bacteria are susceptible to macrolides and fluoroquinolones [4]. Tetracycline resistance occurs in up to 50% of Ureaplasma clinical isolates because of the tetM transposon [4]. Isolated case reports demonstrate that it is possible to eradicate Ureaplasma species from the amniotic cavity by maternal administration of erythromycin [10]. However, in subsequent case reports, the rates of preterm delivery in treated versus untreated patients were similar, suggesting incomplete treatment or recolonization of the amniotic cavity [11]. While postnatal treatment with erythromycin is often ineffective at eliminating airway colonization with Ureaplasmas in VLBW infants [12–14], macrolides remain the treatment of choice, especially in pregnant women and neonates [15]. Azithromycin (AZI) is a 15-membered semisynthetic macrolide antibiotic in the azalide subclass with some structural similarity to erythromycin, but with a prolonged duration of action, improved tissue penetration, a more favorable side-effect profile, and extended range of antimicrobial coverage [16]. Previous cross-sectional studies indicated that transplacental passage of AZI occurs at low rates and that the levels found in fetal plasma (FP) reach 2.6% of the levels in maternal circulation [14, 17, 18]. Several studies have demonstrated that AZI concentrations in tissues of the respiratory tract, including lung tissue, were several-fold higher than circulating AZI concentrations, providing promise that AZI will be useful against Ureaplasmal Infections in fetal lung tissue [19–22]. However, because of the limited placental permeability of AZI, there is controversy about whether antenatal antibiotic interventions prevents preterm labor, prolong gestation, or otherwise improves perinatal outcomes [23–25]. The use of prenatal antibiotics is debated with regard to the treatments' ability to prevent early labor, prolong gestation, and improve perinatal health. Conflicting results in the literature may be attributed to potential confounders and variations in study design [26–29]. There is now an urgent need to study specific antibiotic regimens for defined pathogens, to evaluate placental transfer, understand the pharmacokinetics and pharmacodynamics, and establish biological plausibility for the treatment of intra-uterine Infections. In the rhesus monkey (Macaca mulatta), hemochorial placentation, endocrine characteristics, anatomy, and singleton fetus pregnancies are analogues to those of human pregnancy and therefore permit longitudinal pharmacokinetic studies with serial sampling of both maternal and fetal compartments that is not possible with human subjects [30]. We provided proof of concept for the use of a specific macrolide antibiotic to eradicate U. parvum from the amniotic cavity and fetal tissues in the rhesus monkey [31, 32]. This maternal treatment targets amniotic fluid (AF) proinflammatory pathways and results in prolongation of gestation and reduced fetal lung injury [32]. Our goal was to extend this study to characterize the pharmacokinetics and pharmacodynamics of AZI in the maternal, fetal, and intra-amniotic compartments through modeling and to explore the relationships between U. parvum eradication and AZI exposure.
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Transplacental Transfer of Azithromycin and Its Use for Eradicating Intra-amniotic Ureaplasma Infection in a Primate Model
The Journal of infectious diseases, 2013Co-Authors: Edward P Acosta, Ken B. Waites, Peta L Grigsby, Kajal B Larson, Amanda Marie James, Mary C Long, Lynn B Duffy, Miles J NovyAbstract:Intrauterine Infections are an important and potentially preventable cause of preterm delivery. Such Infections cause the majority of very-low-birth-weight (VLBW) deliveries, which are characterized by a birth weight of
John P Newnham - One of the best experts on this subject based on the ideXlab platform.
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Ureaplasma parvum Serovar 3 Multiple Banded Antigen Size Variation after Chronic Intra-Amniotic Infection/Colonization
PloS one, 2013Co-Authors: James W Robinson, Samantha J Dando, Suhas G Kallapur, Ilias Nitsos, John P Newnham, Alan H Jobe, Graeme R Polglase, Jane J Pillow, Boris W Kramer, Diane PaytonAbstract:Ureaplasma species are the microorganisms most frequently associated with adverse pregnancy outcomes. The multiple banded antigen (MBA), a surface-exposed lipoprotein, is a key virulence factor of Ureaplasmas. The MBA demonstrates size variation, which we have shown previously to be correlated with the severity of chorioamnion inflammation. We aimed to investigate U. parvum serovar 3 pathogenesis in vivo, using a sheep model, by investigating: MBA variation after long term (chronic) and short term (acute) durations of in utero Ureaplasma Infections, and the severity of chorioamnionitis and inflammation in other fetal tissues. Inocula of 2 × 10(7) colony-forming-units (CFU) of U. parvum serovar 3 (Up) or media controls (C) were injected intra-amniotically into pregnant ewes at one of three time points: day 55 (69d Up, n = 8; C69, n = 4); day 117 (7d Up, n = 8; C7, n = 2); and day 121 (3d Up, n = 8; C3, n = 2) of gestation (term = 145-150d). At day 124, preterm fetuses were delivered surgically. Samples of chorioamnion, fetal lung, and umbilical cord were: (i) snap frozen for subsequent Ureaplasma culture, and (ii) fixed, embedded, sectioned and stained by haematoxylin and eosin stain for histological analysis. Selected fetal lung clinical Ureaplasma isolates were cloned and filtered to obtain cultures from a single CFU. Passage 1 and clone 2 Ureaplasma cultures were tested by western blot to demonstrate MBA variation. In acute durations of Ureaplasma Infection no MBA variants (3d Up) or very few MBA variants (7d Up) were present when compared to the original inoculum. However, numerous MBA size variants were generated in vivo (alike within contiguous tissues, amniotic fluid and fetal lung, but different variants were present within chorioamnion), during chronic, 69d exposure to Ureaplasma Infection. For the first time we have shown that the degree of Ureaplasma MBA variation in vivo increased with the duration of gestation.
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Ureaplasma parvum serovar 3 multiple banded antigen size variation after chronic intra amniotic Infection colonization
Faculty of Health; Institute of Health and Biomedical Innovation, 2013Co-Authors: James W Robinson, Samantha J Dando, Suhas G Kallapur, Ilias Nitsos, John P Newnham, Alan H Jobe, Graeme R Polglase, Jane J Pillow, Boris W Kramer, Diane PaytonAbstract:Ureaplasma species are the microorganisms most frequently associated with adverse pregnancy outcomes. The multiple banded antigen (MBA), a surface-exposed lipoprotein, is a key virulence factor of Ureaplasmas. The MBA demonstrates size variation, which we have shown previously to be correlated with the severity of chorioamnion inflammation. We aimed to investigate U. parvum serovar 3 pathogenesis in vivo, using a sheep model, by investigating: MBA variation after long term (chronic) and short term (acute) durations of in utero Ureaplasma Infections, and the severity of chorioamnionitis and inflammation in other fetal tissues. Inocula of 2x107 colony-forming-units (CFU) of U. parvum serovar 3 (Up) or media controls (C) were injected intra-amniotically into pregnant ewes at one of three time points: day 55 (69d Up, n=8; C69, n=4); day 117 (7d Up, n=8; C7, n=2); and day 121 (3d Up, n=8; C3, n=2) of gestation (term=145-150d). At day 124, preterm fetuses were delivered surgically. Samples of chorioamnion, fetal lung, and umbilical cord were: (i) snap frozen for subsequent Ureaplasma culture, and (ii) fixed, embedded, sectioned and stained by haematoxylin and eosin stain for histological analysis. Selected fetal lung clinical Ureaplasma isolates were cloned and filtered to obtain cultures from a single CFU. Passage 1 and clone 2 Ureaplasma cultures were tested by western blot to demonstrate MBA variation. In acute durations of Ureaplasma Infection no MBA variants (3d Up) or very few MBA variants (7d Up) were present when compared to the original inoculum. However, numerous MBA size variants were generated in vivo (alike within contiguous tissues, amniotic fluid and fetal lung, but different variants were present within chorioamnion), during chronic, 69d exposure to Ureaplasma Infection. For the first time we have shown that the degree of Ureaplasma MBA variation in vivo increased with the duration of gestation.
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intra amniotic Ureaplasma Infection adverse outcomes vary depending on gestation conference abstract
Journal of Paediatrics and Child Health, 2012Co-Authors: Jessica Norman, Samantha J Dando, Suhas G Kallapur, Ilias Nitsos, Matthew W Kemp, John P Newnham, Alan H Jobe, Christine L KnoxAbstract:Background: Ureaplasmas are the most prevalent bacteria isolated from preterm deliveries and the prognosis for neonates varies depending on the gestation at delivery. Ureaplasmas vary their surface-exposed antigen (MBA, a virulence mechanism) during chronic intra-amniotic Infections, but it is not known when changes first occur during gestation. Method: U. parvum serovar 3 (2x10e7CFU) was injected intra-amniotically (IA) into six experimental cohorts of pregnant ewes (of n=7), 3 days (d) or 7d before delivery at either: 100d, 124d or 140d gestation (term=145d). Control ewes received IA 10B broth. Fetuses were delivered surgically and Ureaplasmas cultured from amniotic fluid (AF), chorioamnion, fetal lung (FL) and umbilical cord. Ureaplasmas were tested by western blot to demonstrate MBA variation. Results: The highest number of Ureaplasmas were recovered from FL at 100d gestation after 3 days of Infection (p<0.03). Six of 7(86%) 100d–3d FL demonstrated an Ureaplasma MBA variant, but only 17% and 15% of FL showed an MBA variant after 3d Infection at 124d and 140d gestation respectively. Greatest variation of the MBA occurred in AF and FL at 124d gestation after 7d Infection. The least MBA variation was observed at 140d; however, at this time the most severe histological chorioamnionitis was observed. Conclusions: After intra-amniotic Ureaplasma injections, higher numbers of Ureaplasmas gained access to the FL at 100d gestation than observed at later gestations. This may exacerbate the adverse outcomes for neonates delivered early in gestation. In late gestation, Ureaplasma MBA variation was minimal, but chorioamnionitis was the most severe. Adverse pregnancy outcomes associated with IA Ureaplasma Infection may vary depending on the duration of gestation, the number of Ureaplasmas isolated from the fetal tissues and the degree of MBA variation.
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Intra-amniotic Ureaplasma Infection: Adverse outcomes vary depending on gestation [Conference Abstract]
Journal of Paediatrics and Child Health, 2012Co-Authors: Jessica A. Norman, Samantha J Dando, Suhas G Kallapur, Ilias Nitsos, Matthew W Kemp, John P Newnham, Alan H Jobe, Christine L KnoxAbstract:Background: Ureaplasmas are the most prevalent bacteria isolated from preterm deliveries and the prognosis for neonates varies depending on the gestation at delivery. Ureaplasmas vary their surface-exposed antigen (MBA, a virulence mechanism) during chronic intra-amniotic Infections, but it is not known when changes first occur during gestation. Method: U. parvum serovar 3 (2x10e7CFU) was injected intra-amniotically (IA) into six experimental cohorts of pregnant ewes (of n=7), 3 days (d) or 7d before delivery at either: 100d, 124d or 140d gestation (term=145d). Control ewes received IA 10B broth. Fetuses were delivered surgically and Ureaplasmas cultured from amniotic fluid (AF), chorioamnion, fetal lung (FL) and umbilical cord. Ureaplasmas were tested by western blot to demonstrate MBA variation. Results: The highest number of Ureaplasmas were recovered from FL at 100d gestation after 3 days of Infection (p
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Ureaplasma parvum multiple banded antigen mba size variation association with fetal inflammation in a sheep model conference abstract
Journal of Paediatrics and Child Health, 2011Co-Authors: James W Robinson, Suhas G Kallapur, Ilias Nitsos, John P Newnham, Alan H Jobe, Graeme R Polglase, Jane J Pillow, Christine L KnoxAbstract:Background: Ureaplasma species are the most prevalent isolates from women who deliver preterm. The MBA, a surface exposed lipoprotein, is a key virulence factor of Ureaplasmas. We investigated MBA variation after chronic and acute intra-amniotic (IA) Ureaplasma Infections. Method: U. parvum serovar 3 (2x104 colony-forming-units) was injected IA into pregnant ewes at: 55 days gestation (d, term = 145d) (n=8); 117d (n=8) and 121d (n=8). Fetuses were delivered surgically (124d) and Ureaplasmas cultured from amniotic fluid (AF), chorioamnion, fetal lung (FL) and umbilical cord were tested by western blot and PCR assays to demonstrate MBA and mba gene variation respectively. Tissue sections were sectioned and stained by haemotoxylin and eosin and inflammatory cell counts and pathology were reported (blinded to outcome). Results: Numerous MBA/mba variants were generated in vivo after chronic exposure to Ureaplasma Infection but after acute Infection no variants (3d) or very few variants (7d) were generated. Identical MBA variants were detected within the AF and FL but different Ureaplasma variants were detected within chorioamnion specimens. The severity of inflammation within chronically infected tissues varied between animals ranging from no inflammation to severe inflammation with/without fibrosis. Chorioamnion, FL and cord from the same animal demonstrated the same degree of inflammation. Conclusions: MBA/mba variation in vivo occurred after the initiation of the host immune response and we propose that Ureaplasmas vary the MBA antigen to evade the host immune response. In some animals there was no inflammation despite colonisation with high numbers of Ureaplasmas.
Suhas G Kallapur - One of the best experts on this subject based on the ideXlab platform.
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Role of Ureaplasma Respiratory Tract Colonization in Bronchopulmonary Dysplasia Pathogenesis: Current Concepts and Update
Clinics in perinatology, 2015Co-Authors: Rose M Viscardi, Suhas G KallapurAbstract:Respiratory tract colonization with the genital mycoplasma species Ureaplasma parvum and Ureaplasma urealyticum in preterm infants is a significant risk factor for bronchopulmonary dysplasia (BPD). Recent studies of the Ureaplasmal genome, animal Infection models, and human infants have provided a better understanding of specific virulence factors, pathogen-host interactions, and variability in genetic susceptibility that contribute to chronic Infection, inflammation, and altered lung development. This review provides an update on the current evidence supporting a causal role of Ureaplasma Infection in BPD pathogenesis. The current status of antibiotic trials to prevent BPD in Ureaplasma-infected preterm infants is also reviewed.
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Ureaplasma parvum Serovar 3 Multiple Banded Antigen Size Variation after Chronic Intra-Amniotic Infection/Colonization
PloS one, 2013Co-Authors: James W Robinson, Samantha J Dando, Suhas G Kallapur, Ilias Nitsos, John P Newnham, Alan H Jobe, Graeme R Polglase, Jane J Pillow, Boris W Kramer, Diane PaytonAbstract:Ureaplasma species are the microorganisms most frequently associated with adverse pregnancy outcomes. The multiple banded antigen (MBA), a surface-exposed lipoprotein, is a key virulence factor of Ureaplasmas. The MBA demonstrates size variation, which we have shown previously to be correlated with the severity of chorioamnion inflammation. We aimed to investigate U. parvum serovar 3 pathogenesis in vivo, using a sheep model, by investigating: MBA variation after long term (chronic) and short term (acute) durations of in utero Ureaplasma Infections, and the severity of chorioamnionitis and inflammation in other fetal tissues. Inocula of 2 × 10(7) colony-forming-units (CFU) of U. parvum serovar 3 (Up) or media controls (C) were injected intra-amniotically into pregnant ewes at one of three time points: day 55 (69d Up, n = 8; C69, n = 4); day 117 (7d Up, n = 8; C7, n = 2); and day 121 (3d Up, n = 8; C3, n = 2) of gestation (term = 145-150d). At day 124, preterm fetuses were delivered surgically. Samples of chorioamnion, fetal lung, and umbilical cord were: (i) snap frozen for subsequent Ureaplasma culture, and (ii) fixed, embedded, sectioned and stained by haematoxylin and eosin stain for histological analysis. Selected fetal lung clinical Ureaplasma isolates were cloned and filtered to obtain cultures from a single CFU. Passage 1 and clone 2 Ureaplasma cultures were tested by western blot to demonstrate MBA variation. In acute durations of Ureaplasma Infection no MBA variants (3d Up) or very few MBA variants (7d Up) were present when compared to the original inoculum. However, numerous MBA size variants were generated in vivo (alike within contiguous tissues, amniotic fluid and fetal lung, but different variants were present within chorioamnion), during chronic, 69d exposure to Ureaplasma Infection. For the first time we have shown that the degree of Ureaplasma MBA variation in vivo increased with the duration of gestation.
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Intra-amniotic Ureaplasma Infection: outcomes vary depending on gestation
2013Co-Authors: Jessica A. Norman, Samantha J Dando, Suhas G Kallapur, Ilias Nitsos, Alan H Jobe, Matthew Kemp, John Newnham, Christine L KnoxAbstract:Background: Ureaplasmas are the most prevalent bacteria isolated from preterm deliveries and the prognosis for neonates varies depending on the gestation at delivery. Ureaplasmas vary their surface-exposed antigen (MBA, a virulence mechanism) during chronic intra-amniotic Infections, but it is not known when changes first occur during gestation. Method: U. parvum serovar 3 (2x10e7CFU) was injected intra-amniotically (IA) into six experimental cohorts of pregnant ewes (of n=7), 3 days (d) or 7d before delivery at either: 100d, 124d or 140d gestation (term=145d). Control ewes received IA 10B broth. Fetuses were delivered surgically and Ureaplasmas cultured from amniotic fluid (AF), chorioamnion, fetal lung (FL) and umbilical cord. Ureaplasmas were tested by western blot to demonstrate MBA variation. Results: The highest number of Ureaplasmas were recovered from FL at 100d gestation after 3 days of Infection (p
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Ureaplasma parvum serovar 3 multiple banded antigen size variation after chronic intra amniotic Infection colonization
Faculty of Health; Institute of Health and Biomedical Innovation, 2013Co-Authors: James W Robinson, Samantha J Dando, Suhas G Kallapur, Ilias Nitsos, John P Newnham, Alan H Jobe, Graeme R Polglase, Jane J Pillow, Boris W Kramer, Diane PaytonAbstract:Ureaplasma species are the microorganisms most frequently associated with adverse pregnancy outcomes. The multiple banded antigen (MBA), a surface-exposed lipoprotein, is a key virulence factor of Ureaplasmas. The MBA demonstrates size variation, which we have shown previously to be correlated with the severity of chorioamnion inflammation. We aimed to investigate U. parvum serovar 3 pathogenesis in vivo, using a sheep model, by investigating: MBA variation after long term (chronic) and short term (acute) durations of in utero Ureaplasma Infections, and the severity of chorioamnionitis and inflammation in other fetal tissues. Inocula of 2x107 colony-forming-units (CFU) of U. parvum serovar 3 (Up) or media controls (C) were injected intra-amniotically into pregnant ewes at one of three time points: day 55 (69d Up, n=8; C69, n=4); day 117 (7d Up, n=8; C7, n=2); and day 121 (3d Up, n=8; C3, n=2) of gestation (term=145-150d). At day 124, preterm fetuses were delivered surgically. Samples of chorioamnion, fetal lung, and umbilical cord were: (i) snap frozen for subsequent Ureaplasma culture, and (ii) fixed, embedded, sectioned and stained by haematoxylin and eosin stain for histological analysis. Selected fetal lung clinical Ureaplasma isolates were cloned and filtered to obtain cultures from a single CFU. Passage 1 and clone 2 Ureaplasma cultures were tested by western blot to demonstrate MBA variation. In acute durations of Ureaplasma Infection no MBA variants (3d Up) or very few MBA variants (7d Up) were present when compared to the original inoculum. However, numerous MBA size variants were generated in vivo (alike within contiguous tissues, amniotic fluid and fetal lung, but different variants were present within chorioamnion), during chronic, 69d exposure to Ureaplasma Infection. For the first time we have shown that the degree of Ureaplasma MBA variation in vivo increased with the duration of gestation.
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intra amniotic Ureaplasma Infection adverse outcomes vary depending on gestation conference abstract
Journal of Paediatrics and Child Health, 2012Co-Authors: Jessica Norman, Samantha J Dando, Suhas G Kallapur, Ilias Nitsos, Matthew W Kemp, John P Newnham, Alan H Jobe, Christine L KnoxAbstract:Background: Ureaplasmas are the most prevalent bacteria isolated from preterm deliveries and the prognosis for neonates varies depending on the gestation at delivery. Ureaplasmas vary their surface-exposed antigen (MBA, a virulence mechanism) during chronic intra-amniotic Infections, but it is not known when changes first occur during gestation. Method: U. parvum serovar 3 (2x10e7CFU) was injected intra-amniotically (IA) into six experimental cohorts of pregnant ewes (of n=7), 3 days (d) or 7d before delivery at either: 100d, 124d or 140d gestation (term=145d). Control ewes received IA 10B broth. Fetuses were delivered surgically and Ureaplasmas cultured from amniotic fluid (AF), chorioamnion, fetal lung (FL) and umbilical cord. Ureaplasmas were tested by western blot to demonstrate MBA variation. Results: The highest number of Ureaplasmas were recovered from FL at 100d gestation after 3 days of Infection (p<0.03). Six of 7(86%) 100d–3d FL demonstrated an Ureaplasma MBA variant, but only 17% and 15% of FL showed an MBA variant after 3d Infection at 124d and 140d gestation respectively. Greatest variation of the MBA occurred in AF and FL at 124d gestation after 7d Infection. The least MBA variation was observed at 140d; however, at this time the most severe histological chorioamnionitis was observed. Conclusions: After intra-amniotic Ureaplasma injections, higher numbers of Ureaplasmas gained access to the FL at 100d gestation than observed at later gestations. This may exacerbate the adverse outcomes for neonates delivered early in gestation. In late gestation, Ureaplasma MBA variation was minimal, but chorioamnionitis was the most severe. Adverse pregnancy outcomes associated with IA Ureaplasma Infection may vary depending on the duration of gestation, the number of Ureaplasmas isolated from the fetal tissues and the degree of MBA variation.
