A new, potent, and placenta-permeable macrolide antibiotic, solithromycin, for the prevention and treatment of bacterial infections in pregnancy

Frontiers in Immunology

Volumn 7, Issue APR, 2016, Pages

  Keelan, Jeffrey A ^a   Payne, Matthew S ^a   Kemp, Matthew W ^a   Ireland, Demelza J ^a   Newnham, John P ^a  

^a UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

Author keywords

Intrauterine infection; Macrolide antibiotics; Mycoplasma; Pregnancy; Prelabor rupture of membranes; Ureaplasma

Indexed keywords

ANTIBIOTIC AGENT; AZITHROMYCIN; CLINDAMYCIN; ERYTHROMYCIN; METRONIDAZOLE; SOLITHROMYCIN;

AMNION; ANTIINFLAMMATORY ACTIVITY; ANTIMICROBIAL THERAPY; BACTERIAL COLONIZATION; BACTERIAL INFECTION; CLINICAL TRIAL (TOPIC); COMMUNITY ACQUIRED PNEUMONIA; DEVELOPMENTAL TOXICITY; DRUG EFFICACY; GESTATIONAL AGE; GONORRHEA; HUMAN; INTRAUTERINE INFECTION; MINIMUM INHIBITORY CONCENTRATION; NEWBORN MORBIDITY; NEWBORN MORTALITY; NONHUMAN; PHASE 3 CLINICAL TRIAL (TOPIC); PREGNANCY; PREGNANCY COMPLICATION; PREGNANCY OUTCOME; PREMATURE FETUS MEMBRANE RUPTURE; PREMATURE LABOR; PRENATAL DRUG EXPOSURE; PROTEIN SYNTHESIS; REPRODUCTIVE TOXICITY; REVIEW; RNA TRANSLATION; UREAPLASMA INFECTION; VAGINA FLORA; VAGINITIS;

EID: 84966715368     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2016.00111     Document Type: Review

References (117)

1. Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet (2008) 371:261-9. doi: 10.1016/S0140-6736(08)60136-1
2. Platt MJ. Outcomes in preterm infants. Public Health (2014) 128:399-403. doi:10.1016/j.puhe.2014.03.010
3. Strunk T, Inder T, Wang X, Burgner D, Mallard C, Levy O. Infection-induced inflammation and cerebral injury in preterm infants. Lancet Infect Dis (2014) 14:751-62. doi:10.1016/S1473-3099(14)70710-8
4. Bastek JA, Weber AL, McShea MA, Ryan ME, Elovitz MA. Prenatal inflammation is associated with adverse neonatal outcomes. Am J Obstet Gynecol (2014) 210:450.e1-10. doi:10.1016/j.ajog.2013
5. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med (2000) 342:1500-7. doi:10.1056/NEJM200005183422007
6. Iams JD, Papatsonis DN, van Geijn HP, Bleker OP, Ader HJ. The epidemiology of preterm birth. Clin Perinatol (2003) 30:651-64. doi:10.1016/S0095-5108(03)00101-5
7. Romero R, Espinoza J, Gonçalves LF, Kusanovic JP, Friel L, Hassan S. The role of inflammation and infection in preterm birth. Semin Reprod Med (2007) 25:21-39. doi:10.1055/s-2006-956773
8. Kim MJ, Romero R, Gervasi MT, Kim JS, Yoo W, Lee DC, et al. Widespread microbial invasion of the chorioamniotic membranes is a consequence and not a cause of intra-amniotic infection. Lab Invest (2009) 89:924-36. doi:10.1038/labinvest.2009.49
9. Romero R, Miranda J, Chaiworapongsa T, Chaemsaithong P, Gotsch F, Dong Z, et al. A novel molecular microbiologic technique for the rapid diagnosis of microbial invasion of the amniotic cavity and intra-amniotic infection in preterm labor with intact membranes. Am J Reprod Immunol (2014) 71(4):330-58. doi:10.1111/aji.12189
10. Romero R, Chaemsaithong P, Korzeniewski SJ, Tarca AL, Bhatti G, Xu Z, et al. Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response. J Perinat Med (2015) 44(1):5-22. doi:10.1515/jpm-2015-0045
11. Combs CA, Gravett M, Garite TJ, Hickok DE, Lapidus J, Porreco R, et al. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol (2014) 210:125.e1-15. doi:10.1016/j.ajog.2013.11.032
12. Romero R, Miranda J, Chaiworapongsa T, Korzeniewski SJ, Chaemsaithong P, Gotsch F, et al. Prevalence and clinical significance of sterile intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Reprod Immunol (2014) 72:458-74. doi:10.1111/aji.12296
13. Romero R, Miranda J, Kusanovic JP, Chaiworapongsa T, Chaemsaithong P, Martinez A, et al. Clinical chorioamnionitis at term I: microbiology of the amniotic cavity using cultivation and molecular techniques. J Perinat Med (2015) 43:19-36. doi:10.1515/jpm-2014-0249
14. DiGiulio DB. Diversity of microbes in amniotic fluid. Semin Fetal Neonatal Med (2012) 17:2-11. doi:10.1016/j.siny.2011.10.001
15. Mysorekar IU, Cao B. Microbiome in parturition and preterm birth. Semin Reprod Med (2014) 32:50-5. doi:10.1055/s-0033-1361830
16. Romero R, Hassan SS, Gajer P, Tarca AL, Fadrosh DW, Bieda J, et al. The vaginal microbiota of pregnant women who subsequently have spontaneous preterm labor and delivery and those with a normal delivery at term. Microbiome (2014) 2:18. doi:10.1186/2049-2618-2-18
17. DiGiulio DB, Romero R, Kusanovic JP, Gómez R, Kim CJ, Seok KS, et al. Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol (2010) 64:38-57. doi:10.1111/j.1600-0897.2010.00830.x
18. Mendz GL, Kaakoush NO, Quinlivan JA. Bacterial aetiological agents of intra-amniotic infections and preterm birth in pregnant women. Front Cell Infect Microbiol (2013) 3:58. doi:10.3389/fcimb.2013.00058
19. Pararas MV, Skevaki CL, Kafetzis DA. Preterm birth due to maternal infection: causative pathogens and modes of prevention. Eur J Clin Microbiol Infect Dis (2006) 25:562-9. doi:10.1007/s10096-006-0190-3
20. Payne MS, Bayatibojakhi S. Exploring preterm birth as a polymicrobial disease: an overview of the uterine microbiome. Front Immunol (2014) 5:595. doi:10.3389/fimmu.2014.00595
21. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science (2014) 345:760-5. doi:10.1126/science.1251816
22. Romero R, Miranda J, Chaemsaithong P, Chaiworapongsa T, Kusanovic JP, Dong Z, et al. Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med (2014) 28(12):1394-409. doi:10.3109/14767058.2014.958463
23. Capoccia R, Greub G, Baud D. Ureaplasma urealyticum, Mycoplasma hominis and adverse pregnancy outcomes. Curr Opin Infect Dis (2013) 26:231-40. doi:10.1097/QCO.0b013e328360db58
24. Kwak DW, Hwang HS, Kwon JY, Park YW, Kim YH. Co-infection with vaginal Ureaplasma urealyticum and Mycoplasma hominis increases adverse pregnancy outcomes in patients with preterm labor or preterm premature rupture of membranes. J Matern Fetal Neonatal Med (2014) 27:333-7. doi:10.3109/14767058.2013.818124
25. Murtha AP, Edwards JM. The role of Mycoplasma and Ureaplasma in adverse pregnancy outcomes. Obstet Gynecol Clin North Am (2014) 41:615-27. doi:10.1016/j.ogc.2014.08.010
26. Kasper DC, Mechtler TP, Reischer GH, Witt A, Langgartner M, Pollak A, et al. The bacterial load of Ureaplasma parvum in amniotic fluid is correlated with an increased intrauterine inflammatory response. Diagn Microbiol Infect Dis (2010) 67:117-21. doi:10.1016/j.diagmicrobio.2009.12.023
27. Kundsin RB, Leviton A, Allred EN, Poulin SA. Ureaplasma urealyticum infection of the placenta in pregnancies that ended prematurely. Obstet Gynecol (1996) 87:122-7. doi:10.1016/0029-7844(95)00376-2
28. Kirchner L, Helmer H, Heinze G, Wald M, Brunbauer M, Weninger M, et al. Amnionitis with Ureaplasma urealyticum or other microbes leads to increased morbidity and prolonged hospitalization in very low birth weight infants. Eur J Obstet Gynecol Reprod Biol (2007) 134:44-50. doi:10.1016/j.ejogrb.2006.09.013
29. Oh KJ, Lee SE, Jung H, Kim G, Romero R, Yoon BH. Detection of Ureaplasmas by the polymerase chain reaction in the amniotic fluid of patients with cervical insufficiency. J Perinat Med (2010) 38:261-8. doi:10.1515/JPM.2010.040
30. Kemp MW. Preterm birth, intrauterine infection, and fetal inflammation. Front Immunol (2014) 5:574. doi:10.3389/fimmu.2014.00574
31. Kemp MW, Saito M, Kallapur SG, Jobe AH, Keelan JA, Li S, et al. Inflammation of the fetal ovine skin following in utero exposure to Ureaplasma parvum. Reprod Sci (2011) 18:1128-37. doi:10.1177/1933719111408114
32. Grigsby PL, Novy MJ, Sadowsky DW, Morgan TK, Long M, Acosta E, et al. Maternal azithromycin therapy for Ureaplasma intraamniotic infection delays preterm delivery and reduces fetal lung injury in a primate model. Am J Obstet Gynecol (2012) 207:475.e1-14. doi:10.1016/j.ajog.2012.10.871
33. Novy MJ, Duffy L, Axthelm MK, Sadowsky DW, Witkin SS, Gravett MG, et al. Ureaplasma parvum or Mycoplasma hominis as sole pathogens cause chorioamnionitis, preterm delivery, and fetal pneumonia in rhesus macaques. Reprod Sci (2009) 16:56-70. doi:10.1177/1933719108325508
34. Han YW, Shen T, Chung P, Buhimschi IA, Buhimschi CS. Uncultivated bacteria as etiologic agents of intra-amniotic inflammation leading to preterm birth. J Clin Microbiol (2009) 47:38-47. doi:10.1128/JCM.01206-08
35. Lamont RF. Advances in the prevention of infection-related preterm birth. Front Inflamm (2015) 16:566. doi:10.3389/fimmu.2015.00566
36. Bujold E, Morency AM. Antibiotics for the prevention of preterm birth. Aust N Z J Obstet Gynaecol (2008) 48:124-5. doi:10.1111/j.1479-828X.2007.00816.x
37. Simcox R, Sin WT, Seed PT, Briley A, Shennan AH. Prophylactic antibiotics for the prevention of preterm birth in women at risk: a meta-analysis. Aust N Z J Obstet Gynaecol (2007) 47:368-77. doi:10.1111/j.1479-828X.2007.00759.x
38. Morency AM, Bujold E. The effect of second-trimester antibiotic therapy on the rate of preterm birth. J Obstet Gynaecol Can (2007) 29:35-44. doi:10.1016/S1701-2163(16)32350-7
39. Brocklehurst P, Gordon A, Heatley E, Milan SJ. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev (2013) 1:CD000262. doi:10.1002/14651858.CD000262.pub4
40. Mercer B. Antibiotics in the management of PROM and preterm labor. Obstet Gynecol Clin North Am (2012) 39:65-76. doi:10.1016/j.ogc.2011.12.007
41. Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon P, Ota E. Antibiotic prophylaxis during the second and third trimester to reduce adverse pregnancy outcomes and morbidity. Cochrane Database Syst Rev (2015) 6:CD002250. doi:10.1002/14651858.CD002250.pub3
42. Lambert JA, John S, Sobel JD, Akins RA. Longitudinal analysis of vaginal microbiome dynamics in women with recurrent bacterial vaginosis: recognition of the conversion process. PLoS One (2013) 8:e82599. doi:10.1371/journal.pone.0082599
43. Ugwumadu A. Role of antibiotic therapy for bacterial vaginosis and intermediate flora in pregnancy. Best Pract Res Clin Obstet Gynaecol (2007) 21:391-402. doi:10.1016/j.bpobgyn.2007.01.001
44. McDonald HM, Brocklehurst P, Gordon A. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev (2007) (1):CD000262. doi:10.1002/14651858.CD000262.pub3
45. Lamont RF, Nhan-Chang CL, Sobel JD, Workowski K, Conde-Agudelo A, Romero R. Treatment of abnormal vaginal flora in early pregnancy with clindamycin for the prevention of spontaneous preterm birth: a systematic review and metaanalysis. Am J Obstet Gynecol (2011) 205:177-90. doi:10.1016/j.ajog.2011.03.047
46. Payne MS, Feng Z, Li S, Doherty DA, Xu B, Li J, et al. Second trimester amniotic fluid cytokine concentrations, Ureaplasma sp. colonisation status and sexual activity as predictors of preterm birth in Chinese and Australian women. BMC Pregnancy Childbirth (2014) 14:340. doi:10.1186/1471-2393-14-340
47. Vouga M, Greub G, Prod'hom G, Durussel C, Roth-Kleiner M, Vasilevsky S, et al. Treatment of genital Mycoplasma in colonized pregnant women in late pregnancy is associated with a lower rate of premature labour and neonatal complications. Clin Microbiol Infect (2014) 20:1074-9. doi:10.1111/1469-0691.12686
48. Miura Y, Payne MS, Keelan JA, Noe A, Carter S, Watts R, et al. Maternal intravenous treatment with either azithromycin or solithromycin clears Ureaplasma parvum from the amniotic fluid in an ovine model of intrauterine infection. Antimicrob Agents Chemother (2014) 58(9):5413-20. doi:10.1128/AAC.03187-14
49. McCormack WM, Rosner B, Lee YH, Munoz A, Charles D, Kass EH. Effect on birth weight of erythromycin treatment of pregnant women. Obstet Gynecol (1987) 69:202-7
50. Ogasawara KK, Goodwin TM. Efficacy of azithromycin in reducing lower genital Ureaplasma urealyticum colonization in women at risk for preterm delivery. J Matern Fetal Med (1999) 8:12-6. doi:10.1002/(SICI)1520-6661(199901/02)8:1<12::AID-MFM3>3.0.CO;2-8
51. Gomez R, Romero R, Nien JK, Medina L, Carstens M, Kim YM, et al. Antibiotic administration to patients with preterm premature rupture of membranes does not eradicate intra-amniotic infection. J Matern Fetal Neonatal Med (2007) 20:167-73. doi:10.1080/14767050601135485
52. Kemp MW, Miura Y, Payne MS, Watts R, Megharaj S, Jobe AH, et al. Repeated maternal intramuscular or intraamniotic erythromycin incompletely resolves intrauterine Ureaplasma parvum infection in a sheep model of pregnancy. Am J Obstet Gynecol (2014) 211:134.e131-9. doi:10.1016/j.ajog.2014.02.025
53. Heikkinen T, Laine K, Neuvonen PJ, Ekblad U. The transplacental transfer of the macrolide antibiotics erythromycin, roxithromycin and azithromycin. Br J Obstet Gynaecol (2000) 107:770-5. doi:10.1111/j.1471-0528.2000.tb13339.x
54. Philipson A, Sabath LD, Charles D. Transplacental passage of erythromycin and clindamycin. N Engl J Med (1973) 288:1219-21. doi:10.1056/NEJM197306072882307
55. Keelan JA, Nitsos I, Saito M, Musk GC, Kemp MW, Timmins M, et al. Maternal-amniotic-fetal distribution of macrolide antibiotics following intravenous, intramuscular, and intraamniotic administration in late pregnant sheep. Am J Obstet Gynecol (2011) 204(546):e510-47. doi:10.1016/j.ajog.2011.02.035
56. Mushtaq A. Solithromycin to treat community-acquired pneumonia? Lancet Respir Med (2015) 3:429. doi:10.1016/S2213-2600(15)00188-5
57. Van Bambeke F, Tulkens PM. The role of solithromycin in the management of bacterial community-acquired pneumonia. Expert Rev Anti Infect Ther (2016) 14:311-24. doi:10.1586/14787210.2016.1138857
58. Farrell DJ, Mendes RE, Jones RN. Antimicrobial activity of solithromycin against serotyped macrolide-resistant Streptococcus pneumoniae isolates collected from U.S. medical centers in 2012. Antimicrob Agents Chemother (2015) 59:2432-4. doi:10.1128/AAC.04568-14
59. Piccinelli G, Fernandes P, Bonfanti C, Caccuri F, Caruso A, De Francesco MA. In vitro activity of solithromycin against erythromycin-resistant Streptococcus agalactiae. Antimicrob Agents Chemother (2014) 58:1693-8. doi:10.1128/AAC.02210-13
60. Mallegol J, Fernandes P, Melano RG, Guyard C. Antimicrobial activity of solithromycin against clinical isolates of Legionella pneumophila serogroup 1. Antimicrob Agents Chemother (2014) 58:909-15. doi:10.1128/AAC.01639-13
61. Jensen JS, Fernandes P, Unemo M. In vitro activity of the new fluoroketolide solithromycin (CEM-101) against macrolide-resistant and -susceptible Mycoplasma genitalium strains. Antimicrob Agents Chemother (2014) 58:3151-6. doi:10.1128/AAC.02411-14
62. Rodgers W, Frazier AD, Champney WS. Solithromycin inhibition of protein synthesis and ribosome biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Antimicrob Agents Chemother (2013) 57:1632-7. doi:10.1128/AAC.02316-12
63. Mallegol J, Fernandes P, Seah C, Guyard C, Melano RG. Determination of in vitro activity of solithromycin at different pHs and its intracellular activity tested against clinical isolates of Neisseria gonorrhoeae from a laboratory collection. Antimicrob Agents Chemother (2013). doi:10.1128/AAC.00564-13
64. Wittlin S, Ekland E, Craft JC, Lotharius J, Bathurst I, Fidock DA, et al. In vitro and in vivo activity of solithromycin (CEM-101) against Plasmodium species. Antimicrob Agents Chemother (2012) 56:703-7. doi:10.1128/AAC.05039-11
65. Golparian D, Fernandes P, Ohnishi M, Jensen JS, Unemo M. In vitro activity of the new fluoroketolide solithromycin (CEM-101) against a large collection of clinical Neisseria gonorrhoeae isolates and international reference strains, including those with high-level antimicrobial resistance: potential treatment option for gonorrhea? Antimicrob Agents Chemother (2012) 56:2739-42. doi:10.1128/AAC.00036-12
66. Putnam SD, Sader HS, Farrell DJ, Biedenbach DJ, Castanheira M. Antimicrobial characterisation of solithromycin (CEM-101), a novel fluoroketolide: activity against staphylococci and enterococci. Int J Antimicrob Agents (2011) 37:39-45. doi:10.1016/j.ijantimicag.2010.08.021
67. Farrell DJ, Castanheira M, Sader HS, Jones RN. The in vitro evaluation of solithromycin (CEM-101) against pathogens isolated in the United States and Europe (2009). J Infect (2010) 61:476-83. doi:10.1016/j.jinf.2010.08.010
68. Still JG, Schranz J, Degenhardt TP, Scott D, Fernandes P, Gutierrez MJ, et al. Pharmacokinetics of solithromycin (CEM-101) after single or multiple oral doses and effects of food on single-dose bioavailability in healthy adult subjects. Antimicrob Agents Chemother (2011) 55:1997-2003. doi:10.1128/AAC.01429-10
69. Schranz J, Clark K, Marion A, Ghibellini G, Fernandes P. A phase 1 trial to evaluate the safety and pharmacokinetics of single doses of intravenous (IV) solithromycin (CEM-101) in healthy adult subjects. 21st European Congress of Clinical Microbiology of Infectious Diseases. Milan, Italy: Clinical Microbiology and Infection (2011). O95 p
70. Rodvold KA, Gotfried MH, Still JG, Clark K, Fernandes P. Comparison of plasma, epithelial lining fluid, and alveolar macrophage concentrations of solithromycin (CEM-101) in healthy adult subjects. Antimicrob Agents Chemother (2012) 56:5076-81. doi:10.1128/AAC.00766-12
71. Lemaire S, Van Bambeke F, Tulkens PM. Cellular accumulation and pharmacodynamic evaluation of the intracellular activity of CEM-101, a novel fluoroketolide, against Staphylococcus aureus, Listeria monocytogenes, and Legionella pneumophila in human THP-1 macrophages. Antimicrob Agents Chemother (2009) 53:3734-43. doi:10.1128/AAC.00203-09
72. Llano-Sotelo B, Dunkle J, Klepacki D, Zhang W, Fernandes P, Cate JH, et al. Binding and action of CEM-101, a new fluoroketolide antibiotic that inhibits protein synthesis. Antimicrob Agents Chemother (2010) 54:4961-70. doi:10.1128/AAC.00860-10
73. Fernandez-Brando R, Yamaguchi N, Tahoun A, McAteer SP, Gillespie T, Wang D, et al. Type 3 secretion-dependent sensitivity of Escherichia coli O157 to specific ketolides. Antimicrob Agents Chemother (2015) 60:459-70. doi:10.1128/AAC.02085-15
74. Waites KB, Crabb DM, Duffy LB. Comparative in vitro susceptibilities of human Mycoplasmas and Ureaplasmas to a new investigational ketolide, CEM-101. Antimicrob Agents Chemother (2009) 53:2139-41. doi:10.1128/AAC.00090-09
75. Furfaro LL, Spiller OB, Keelan JA, Payne MS. In vitro activity of solithromycin and its metabolites, CEM-214 and N-acetyl-CEM-101, against 100 clinical Ureaplasma spp. isolates compared with azithromycin. Int J Antimicrob Agents (2015) 46:319-24. doi:10.1016/j.ijantimicag.2015.04.015
76. McGhee P, Clark C, Kosowska-Shick KM, Nagai K, Dewasse B, Beachel L, et al. In vitro activity of CEM-101 against Streptococcus pneumoniae and Streptococcus pyogenes with defined macrolide resistance mechanisms. Antimicrob Agents Chemother (2010) 54:230-8. doi:10.1128/AAC.01123-09
77. Roblin PM, Kohlhoff SA, Parker C, Hammerschlag MR. In vitro activity of CEM-101, a new fluoroketolide antibiotic, against Chlamydia trachomatis and Chlamydia (Chlamydophila) pneumoniae. Antimicrob Agents Chemother (2010) 54:1358-9. doi:10.1128/AAC.01343-09
78. Oldach D, Clark K, Schranz J, Das A, Craft JC, Scott D, et al. Randomized, double-blind, multicenter phase 2 study comparing the efficacy and safety of oral solithromycin (CEM-101) to those of oral levofloxacin in the treatment of patients with community-acquired bacterial pneumonia. Antimicrob Agents Chemother (2013) 57:2526-34. doi:10.1128/AAC.00197-13
79. Hook EW III, Golden M, Jamieson BD, Dixon PB, Harbison HS, Lowens S, et al. A phase 2 trial of oral solithromycin 1200 mg or 1000 mg as single-dose oral therapy for uncomplicated gonorrhea. Clin Infect Dis (2015) 61:1043-8. doi:10.1093/cid/civ478
80. Jamieson BD, Ciric S, Fernandes P. Safety and pharmacokinetics of solithromycin in subjects with hepatic impairment. Antimicrob Agents Chemother (2015) 59:4379-86. doi:10.1128/AAC.04652-14
81. Keelan JA, Pugazhenthi K. Trans-placental passage and anti-inflammatory effects of solithromycin in the human placenta. Placenta (2014) 35:1043-8. doi:10.1016/j.placenta.2014.09.009
82. Keelan JA, Kemp MW, Payne MS, Johnson D, Stock SJ, Saito M, et al. Maternal administration of solithromycin, a new, potent, broad-spectrum fluoroketolide antibiotic, achieves fetal and intra-amniotic antimicrobial protection in a pregnant sheep model. Antimicrob Agents Chemother (2014) 58:447-54. doi:10.1128/AAC.01743-13
83. Bahat Dinur A, Koren G, Matok I, Wiznitzer A, Uziel E, Gorodischer R, et al. Fetal safety of macrolides. Antimicrob Agents Chemother (2013) 57:3307-11. doi:10.1128/AAC.01691-12
84. Berard A, Sheehy O, Zhao JP, Nordeng H. Use of macrolides during pregnancy and the risk of birth defects: a population-based study. Pharmacoepidemiol Drug Saf (2015) 24(12):1241-8. doi:10.1002/pds.3900
85. Lund M, Pasternak B, Davidsen RB, Feenstra B, Krogh C, Diaz LJ, et al. Use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis: nationwide cohort study. BMJ (2014) 348:g1908. doi:10.1136/bmj.g1908
86. Eberly MD, Eide MB, Thompson JL, Nylund CM. Azithromycin in early infancy and pyloric stenosis. Pediatrics (2015) 135:483-8. doi:10.1542/peds.2014-2026
87. de Vries F. The difficulty in evaluating all findings in study on use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis. BMJ (2014) 349:g5201. doi:10.1136/bmj.g5201
88. Ludvigsson JF, Lundholm C, Ortqvist AK, Almqvist C. No association between macrolide treatment in infancy and later pyloric stenosis in Sweden. Eur J Epidemiol (2015). doi:10.1007/s10654-015-0114-6
89. Kallen BA, Otterblad Olausson P, Danielsson BR. Is erythromycin therapy teratogenic in humans? Reprod Toxicol (2005) 20:209-14. doi:10.1016/j.reprotox.2005.01.010
90. Crider KS, Cleves MA, Reefhuis J, Berry RJ, Hobbs CA, Hu DJ. Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Arch Pediatr Adolesc Med (2009) 163:978-85. doi:10.1001/archpediatrics.2009.188
91. Lin KJ, Mitchell AA, Yau WP, Louik C, Hernandez-Diaz S. Safety of macrolides during pregnancy. Am J Obstet Gynecol (2013) 208(221):e221-8. doi:10.1016/j.ajog.2012.12.023
92. Li M, Wang M, Donovan SM. Early development of the gut microbiome and immune-mediated childhood disorders. Semin Reprod Med (2014) 32:74-86. doi:10.1055/s-0033-1361825
93. Mueller NT, Bakacs E, Combellick J, Grigoryan Z, Dominguez-Bello MG. The infant microbiome development: mom matters. Trends Mol Med (2015) 21:109-17. doi:10.1016/j.molmed.2014.12.002
94. Prince AL, Antony KM, Ma J, Aagaard KM. The microbiome and development: a mother's perspective. Semin Reprod Med (2014) 32:14-22. doi:10.1055/s-0033-1361818
95. Faa G, Gerosa C, Fanni D, Nemolato S, van Eyken P, Fanos V. Factors influencing the development of a personal tailored microbiota in the neonate, with particular emphasis on antibiotic therapy. J Matern Fetal Neonatal Med (2013) 26(Suppl 2):35-43. doi:10.3109/14767058.2013.829700
96. Azad MB, Bridgman SL, Becker AB, Kozyrskyj AL. Infant antibiotic exposure and the development of childhood overweight and central adiposity. Int J Obes (Lond) (2014) 38:1290-8. doi:10.1038/ijo.2014.119
97. Azad MB, Konya T, Persaud RR, Guttman DS, Chari RS, Field CJ, et al. Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study. Br J Obstet Gynaecol (2015). doi:10.1111/1471-0528.13601
98. Lapin B, Piorkowski J, Ownby D, Freels S, Chavez N, Hernandez E, et al. Relationship between prenatal antibiotic use and asthma in at-risk children. Ann Allergy Asthma Immunol (2015) 114:203-7. doi:10.1016/j.anai.2014.11.014
99. Cox LM, Blaser MJ. Antibiotics in early life and obesity. Nat Rev Endocrinol (2015) 11:182-90. doi:10.1038/nrendo.2014.210
100. Metsälä J, Lundqvist A, Virta LJ, Kaila M, Gissler M, Virtanen SM. Prenatal and post-natal exposure to antibiotics and risk of asthma in childhood. Clin Exp Allergy (2015) 45:137-45. doi:10.1111/cea.12356
101. Ng PY, Ireland DJ, Keelan JA. Drugs to block cytokine signaling for the prevention and treatment of inflammation-induced preterm birth. Front Immunol (2015) 6:166. doi:10.3389/fimmu.2015.00166
102. Keelan JA. Pharmacological inhibition of inflammatory pathways for the prevention of preterm birth. J Reprod Immunol (2011) 88:176-84. doi:10.1016/j.jri.2010.11.003
103. Ireland DJ, Kemp MW, Miura Y, Saito M, Newnham JP, Keelan JA. Intra-amniotic pharmacological blockade of inflammatory signalling pathways in an ovine chorioamnionitis model. Mol Hum Reprod (2015) 21:479-89. doi:10.1093/molehr/gav005
104. Stinson LF, Ireland DJ, Kemp MW, Payne MS, Stock SJ, Newnham JP, et al. Effects of cytokine-suppressive anti-inflammatory drugs on inflammatory activation in ex vivo human and ovine fetal membranes. Reproduction (2014) 147:313-20. doi:10.1530/REP-13-0576
105. De Silva D, Mitchell MD, Keelan JA. Inhibition of choriodecidual cytokine production and inflammatory gene expression by selective I-kappaB kinase (IKK) inhibitors. Br J Pharmacol (2010) 160:1808-22. doi:10.1111/j.1476-5381.2010.00839.x
106. Kobayashi Y, Wada H, Rossios C, Takagi D, Charron C, Barnes PJ, et al. A novel macrolide/fluoroketolide, solithromycin (CEM-101), reverses corticosteroid insensitivity via phosphoinositide 3-kinase pathway inhibition. Br J Pharmacol (2013) 169:1024-34. doi:10.1111/bph.12187
107. Kobayashi Y, Wada H, Rossios C, Takagi D, Higaki M, Mikura S, et al. A novel macrolide solithromycin exerts superior anti-inflammatory effect via NF-kappaB inhibition. J Pharmacol Exp Ther (2013) 345:76-84. doi:10.1124/jpet.112.200733
108. Cheung PS, Si EC, Hosseini K. Anti-inflammatory activity of azithromycin as measured by its NF-kappaB, inhibitory activity. Ocul Immunol Inflamm (2010) 18:32-7. doi:10.3109/09273940903359725
109. Desaki M, Okazaki H, Sunazuka T, Omura S, Yamamoto K, Takizawa H. Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-kappaB activation. Antimicrob Agents Chemother (2004) 48:1581-5. doi:10.1128/AAC.48.5.1581-1585.2004
110. Desaki M, Takizawa H, Ohtoshi T, Kasama T, Kobayashi K, Sunazuka T, et al. Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun (2000) 267:124-8. doi:10.1006/bbrc.1999.1917
111. Ghartey J, Bastek JA, Brown AG, Anglim L, Elovitz MA. Women with preterm birth have a distinct cervicovaginal metabolome. Am J Obstet Gynecol (2015) 212:776.e1-12. doi:10.1016/j.ajog.2015.03.052
112. Hyman RW, Fukushima M, Jiang H, Fung E, Rand L, Johnson B, et al. Diversity of the vaginal microbiome correlates with preterm birth. Reprod Sci (2013) 21:32-40. doi:10.1177/1933719113488838
113. Prince AL, Antony KM, Chu DM, Aagaard KM. The microbiome, parturition, and timing of birth: more questions than answers. J Reprod Immunol (2014) 104-105:12-19. doi:10.1016/j.jri.2014.03.006
114. Palacio M, Cobo T, Bosch J, Filella X, Navarro-Sastre A, Ribes A, et al. Cervical length and gestational age at admission as predictors of intra-amniotic inflammation in preterm labor with intact membranes. Ultrasound Obstet Gynecol (2009) 34:441-7. doi:10.1002/uog.6437
115. Holst RM, Jacobsson B, Hagberg H, Wennerholm UB. Cervical length in women in preterm labor with intact membranes: relationship to-intra-amniotic inflammation/microbial invasion, cervical inflammation and preterm delivery. Ultrasound Obstet Gynecol (2006) 28:768-74. doi:10.1002/uog.3837
116. Hassan S, Romero R, Hendler I, Gomez R, Khalek N, Espinoza J, et al. A sonographic short cervix as the only clinical manifestation of intra-amniotic infection. J Perinat Med (2006) 34:13-9
117. Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev (2013) 12:CD001058. doi:10.1002/14651858.CD001058.pub3