Abstract
Ureaplasma infection is associated with increased lung disease in high-risk neonates. Our goal was to determine the impact of antibiotic prophylaxis on Ureaplasma and oxygen-induced lung disease in newborn mice. In animal model development and prophylaxis experiments, pups were randomly assigned to either 0.8 or 0.21 inspired oxygen concentration [fraction of inspired oxygen (FiO2)] from 1 to 14 d of age and either Ureaplasma or 10 B media daily from 1 to 3 d. All pups were observed for growth and survival. Surviving pups had culture and PCR evaluated for blood, bronchoalveolar lavage, and lung, and lung weights, pathology, morphometry, histology, and immunohistochemistry were determined. In prophylaxis experiments, erythromycin, azithromycin, or normal saline was given for the first 3 d, and minimum inhibitory concentration and pharmacokinetics were determined. In model development, 0.8 FiO2 and Ureaplasma infection survival and growth were significantly decreased and lung edema and inflammation were significantly increased. In prophylaxis experiments, we observed significantly improved survival and growth with azithromycin versus normal saline controls, whereas erythromycin was not significantly different from controls, and decreased inflammatory response with azithromycin versus normal saline and erythromycin. In a neonatal mouse model of Ureaplasma and oxygen-induced lung disease, appropriate antibiotic prophylaxis improves survival and morbidity and decreases lung inflammation.
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Abbreviations
- BAL:
-
bronchoalveolar lavage
- BPD:
-
bronchopulmonary dysplasia
- FiO2:
-
inspired oxygen concentration
- MBC:
-
minimum bactericidal concentration
- MIC:
-
minimum inhibitory concentration
References
Cassell GH, Waites KB, Watson HL, Crouse DT, Harasawa R 1993 Ureaplasma urealyticum intrauterine infection: role in prematurity and disease in newborns. Clin Microbiol Rev 6: 69–87
Katz B, Patel P, Duffy L, Schelonka RL, Dimmitt RA, Waites KB 2005 Characterization of ureaplasmas isolated with and without bronchopulmonary dysplasia. J Clin Microbiol 43: 4852–4854
Zheng X, Watson HL, Waites KB, Cassell GH 1992 Serotype diversity and antigen variation among invasive isolates of Ureaplasma urealyticum from neonates. Infect Immun 60: 3472–3474
Pinna GS, Skevaki CL, Kafetzis DA 2006 The significance of Ureaplasma urealyticum as a pathogenic agent in the paediatric population. Curr Opin Infect Dis 19: 283–289
Van Waarde WM, Brus F, Okken A, Kimpen JL 1997 Ureaplasma urealyticum colonization, prematurity and bronchopulmonary dysplasia. Eur Respir J 10: 886–890
Waites KB, Katz B, Schelonka RL 2005 Mycoplasmas and ureaplasmas as neonatal pathogens. Clin Microbiol Rev 18: 757–789
Baier RJ, Loggins J, Kruger TE 2003 Failure of erythromycin to eliminate airway colonization with Ureaplasma urealyticum in very low birth weight infants. BMC Pediatr 3: 10
Mabanta CG, Pryhuber GS, Weinberg GA, Phelps DL 2003 Erythromycin for the prevention of chronic lung disease in intubated preterm infants at risk for, or colonized or infected with Ureaplasma urealyticum. Cochrane Database of Syst Rev CD003744
Waites KB, Crabb DM, Bing X, Duffy LB 2003 In vitro susceptibilities to and bactericidal activities of Garenoxacin (BMS-284756) and other antimicrobial agents against human mycoplasmas and ureaplasmas. Antimicrob Agents Chemother 47: 161–165
Barazzone C, Belin D, Piguet PF, Vassalli JD, Sappino A 1996 Plasminogen activator inhibitor-1 in acute hyperoxic mouse lung injury. J Clin Invest 98: 2666–2673
Warner BB, Stuart LA, Papes RA, Wispé JR 1998 Functional and pathological effects of prolonged hyperoxia in neonatal mice. Am J Physiol 275: L110–L117
Jiang W, Welty SE, Couroucli XI, Barrios R, Kondraganti SR, Muthiah K, Yu L, Avery SE, Moorthy B 2004 Disruption of the Ah receptor gene alters the susceptibility of mice to oxygen-mediated regulation of pulmonary and hepatic cytochromes P4501A expression and exacerbates hyperoxic lung injury. J Pharmacol Exp Ther 310: 512–519
Viscardi RM, Kaplan J, Lovchik JC, Ju RH, Hester L, Srinivas R, Hasday JD 2002 Characterization of a murine model of Ureaplasma urealyticum pneumonia. Infect Immun 70: 5721–5729
Rudd PT, Cassell GH, Waites KB, Davis JK, Duffy LB 1989 Ureaplasma urealyticum pneumonia: experimental production and demonstration of age-related susceptibility. Infect Immun 57: 918–925
Sinha A, Kathirvel M, Jiang W, Couroucli X, Barrios R, Moorthy B 2005 Attenuation of hyperoxic lung injury by the CYP1A inducer β-naphthoflavone. Toxicol Sci 87: 204–212
Matlow A, Th'ng C, Kovach D, Quinn P, Dunn M, Wang E 1998 Susceptibilities of neonatal respiratory isolates of Ureaplasma urealyticum to antimicrobial agents. Antimicrob Agents Chemother 42: 1290–1292
Bennett JV, Brodie JL, Benner EJ, Kirby WM 1966 Simplified, accurate method for antibiotic assay of clinical specimens. Appl Microbiol 14: 170–177
Stamler DA, Edelstein MA, Edelstein PH 1994 Azithromycin pharmacokinetics and intracellular concentrations in Legionella pneumophilia infected and uninfected guinea pigs and their alveolar macrophages. Antimicrob Agents Chemother 38: 217–222
Sanchez PJ, Regan JA 1988 Ureaplasma urealyticum colonization and chronic lung disease in low birth weight infants. Pediatr Infect Dis J 7: 542–546
Wang EE, Frayha H, Watts J, Hammerberg O, Chernesky MA, Mahony JB, Cassell GH 1988 The role of Ureaplasma urealyticum and other pathogens in the development of chronic lung disease of prematurity. Pediatr Infect Dis J 7: 547–551
Payne NR, Steinberg SS, Ackerman P, Chrenka BA, Sane SM, Anderson KT, Fangman JJ 1993 New prospective studies of the association of Ureaplasma urealyticum colonization and chronic lung disease. Clin Infect Dis 17: S117–S121
Cassell GH, Waites KB, Crouse DT, Rudd PT, Canupp KC, Stango S, Cutter GR 1988 Association of Ureaplasma urealyticum infection of the lower respiratory tract with chronic lung disease and death in very-low-birth-weight infants. Lancet 2: 240–245
Schelonka RL, Katz B, Waites KB, Benjamin DK Jr 2005 Critical appraisal of the role of Ureaplasma in the development of bronchopulmonary dysplasia with metaanalytic techniques. Pediatr Infect Dis J 24: 1033–1039
Colaizy TT, Morris CD, Lapidus J, Sklar RS, Pillers DA 2007 Detection of Ureaplasma DNA in endotracheal samples is associated with bronchopulmonary dysplasia after adjustment for multiple risk factors. Pediatr Res 61: 578–583
Viscardi RM, Hasday JD 2009 Role of Ureaplasma species in neonatal chronic lung disease: epidemiologic and experimental evidence. Pediatr Res( in press)
Kikuchi Y, Tateda K, Fuse ET, Matsumoto T, Gotoh N, Fukushima J, Takizawa H, Nagase T, Standiford TJ, Yamaguchi K 2009 Hyperoxia exaggerates bacterial dissemination and lethality in Pseudomonas aeruginosa pneumonia. Pulm Pharmacol Ther 22: 333–339
Crouse DT, Cassell GH, Waites KB, Foster JM, Cassady G 1990 Hyperoxia potentiates Ureaplasma urealyticum pneumonia in newborn mice. Infect Immun 58: 3487–3493
Manimtim WM, Hasday JD, Hester L, Fairchild KD, Lovchik JC, Viscardi RM 2001 Ureaplasma urealyticum modulates endotoxin-induced cytokine release by human monocytes derived from preterm and term newborns and adults. Infect Immun 69: 3906–3915
Talati AJ, Crouse DT, English BK, Newman C, Livingston L, Meals E 1998 Exogenous bovine surfactant suppresses tumor necrosis factor-alpha release by murine macrophages stimulated by genital mycoplasmas. J Infect Dis 178: 1122–1125
Ballard HO, Bernard P, Qualls J, Everson W, Shook LA 2007 Azithromycin protects against hyperoxic lung injury in neonatal rats. J Investig Med 55: 299–305
Goldenberg RL, Andrews WW, Goepfert AR, Faye-Petersen O, Cliver SP, Carlo WA, Hauth JC 2008 The Alabama Preterm Birth Study: umbilical cord blood Ureaplasma urealyticum and Mycoplasma hominis cultures in very preterm newborn infants. Am J Obstet Gynecol 198: 43.e1–43.e5
Jobe AH, Ikegami M 2001 Antenatal infection/inflammation and postnatal lung maturation and injury. Respir Res 2: 27–32
Kudoh S 1998 Erythromycin treatment in diffuse panbronchiolitis. Curr Opin Pulm Med 4: 116–121
Walsh WF, Stanky S, Lally KP, Stribley RE, Treece DP, McClesky F, Null DM 1991 Ureaplasma urealyticum demonstrated by open lung biopsy in newborns with chronic lung disease. Pediatr Infect Dis J 10: 823–827
Acknowledgements
We thank Travis Markham for the initial work on the animal infection model and Dr. E. O'Brian Smith for his assistance in statistical calculations. We also thank Dr. Bhagavatula Moorthy for his assistance with the design of the experiments and review of the manuscript.
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Supported by the Section of Neonatology and Department of Pediatrics at Baylor College of Medicine, Houston, TX.
Presented as an abstract at the Pediatric Academic Societies Meeting, Honolulu, Hawaii, May 3, 2008 and XXI European Congress of Perinatal Medicine, Istanbul, Turkey, September 12, 2008.
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Walls, S., Kong, L., Leeming, H. et al. Antibiotic Prophylaxis Improves Ureaplasma-Associated Lung Disease in Suckling Mice. Pediatr Res 66, 197–202 (2009). https://doi.org/10.1203/PDR.0b013e3181aabd34
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DOI: https://doi.org/10.1203/PDR.0b013e3181aabd34
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