Prophylactic use of the probiotic strain Lactobacillus casei rhamnosus as part of a triple anti-infective regimen in very preterm infants during neonatal intensive care

Background. Probiotics are increasingly used in neonatal intensive care and prove to reduce rates of necrotizing enterocolitis (NEC), sepsis and all-cause mortality by meta-analyses. 

Objective. Aim of the study was to analyze the prophylactic use of the probiotic Lacto-bacillus casei rhamnosus (LCR) as part of a triple anti-infective treatment regimen in very preterm neonates in respect to com-plications and possible side effects. Setting. This was a study on 1169 very pre-term infants of 32 weeks of gestational age and less born between 2005 and 2015 who were admitted within the first 24 hours of life to the neonatal intensive care unit (NICU) and hospitalized for at least 7 days. Design. Retrospective observational STROBE compliant single-center cohort study

Intervention. All infants received a stand-ardized prophylactic anti-infective treat-ment regimen with enteral probiotics (LCR), antifungal agents, and oral genta-mycin over the study time starting at the first day of life.

Outcome measures. Perinatal and neonatal data were collected for descriptive analy-sis. Complications possibly avoided by the anti-infective regimen included NEC, late-onset sepsis (LOS), late-onset multiple or-gan dysfunction syndrome (MODS), and ventilator associated pneumonia (VAP). Main results. Eleven of 1169 infants 11 (0.9%) had diagnosis of NEC ≥ IIa, 141 (12.1%) exhibited at least one episode of LOS, 31 (2.7%) a VAP, and 44 (3.8%) a MODS. Those infants with complications were of younger gestational age (p<0.001), had lower birth weight (p<0.001), lower Apgar scores at 1/5/10 minutes (p<0.001), were more common SGA (p=0.007), had longer courses of mechanical ventilation and longer hospital stays and for longer time parenteral antibiotics (all p<0.001). Mortality rate was increased in infants having experienced complications (6.9 vs. 1.7%, p<0.001). 

Conclusions. Over an 11-year period, the use of the probiotic LCR as part of an anti-infective regimen was safe and resulted in low rates of NEC, LOS, VAP, and MODS compared to the literature. Those infants with complications had higher mortality rates.

very preterm infant; probiotics; Lactobacillus casei rhamnosus; necrotizing enterocolitis; multiple organ dysfunction syndrome; neonatal intensive care; ventila-tor associated pneumonia; late-onset sepsis; antibiotic-associated diarrhea 

1. Alberda C, Gramlich L, Meddings J, Field C, McCargar L, Kutsogiannis D, et al. Effects of probiotic therapy in critically ill patients: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 2007; 85: 816-23.

2. Apisarnthanarak A, Holzmann-Pazgal G, Hamvas A, Olsen MA, Fraser VJ. Ventilator-associated pneumonia in extremely preterm neonates in a neonatal intensive care unit: characteristics, risk factors, and outcomes. Pediatrics 2003; 112: 1283-9.

3. Yuan TM, Chen LH, Yu HM. Risk factors and outcomes for ventilator associated pneumonia in neonatal intensive care unit patients, J Perinat Med 2007; 35: 334-8.

4. Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM, Pollock DA, et al. NHSN annual update: antimicrobial- resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. Infect Control Hosp Epidemiol 2008; 29: 996-1011.

5. Bradley JS. Considerations unique to pediatrics for clinical trial design in hospital-acquired pneumonia and ventilator associated pneumonia. Clin Infect Dis 2010; 51(Suppl 1): S136-43.

6. Edwards JR, Peterson KD, Andrus ML, Dudeck MA, Pollock DA, Horan TC. National Healthcare Safety Network (NHSN) Report, data summary for 2006 through 2007, issued November 2008. Am J Infect Control 2008; 36: 609-26.

7. Dong Y, Speer CP. Late-onset neonatal sepsis: recent developments. Arch Dis Child Fetal Neonatal Ed 2015; 100: F257–F263.

8. AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 2014;(4): CD005496.

9. Garland SM, Tobin JM, Pirotta M, Tabrizi SN, Opie G, Donath S, et al. The ProPrems trial: investigating the effects of probiotics on late onset sepsis in very preterm infants. BMC Infect Dis 2011; 11: 210.

10. Nair V, Soraisham AS. Probiotics and prebiotics: role in prevention of nosocomial sepsis in preterm infants. Int J Pediatr 2013; 2013: 874726.

11. Morgan J, Bombell S, McGuire W. Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants.Cochrane Database Syst Rev 2013; 3: CD000504. 

12. Sweeney B, Puri P, Reen DJ. Induction and modulation of apoptosis in neonatal monocytes by polyunsaturated fatty acids. J Pediatr Surg 2007; 42: 620-8.

13. Flidel-Rimon O, Friedman S, Lev E, Juster-Reicher A, Amitay M, Shinwell ES. Early enteral feeding and nosocomial sepsis in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2004; 89: F289–92.

14. Resch B, Leonhardt K, Urlesberger B. Efficacy of a triple anti-infective regimen for prevention of complications in critically ill term neonates. Iran J Pediatr 2018; 28: e64845.

15. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978; 187: 1-7.

16. Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986; 33: 179-201.

17. Goldstein B, Giroir B, Randolph A. International consensus conference on pediatric sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005; 6: 2-8.

18. Cetinkaya M, Köksal N, Özkan H. A new scoring system for evaluation of multiple organ dysfunction syndrome in premature in-fants. Am J Crit Care 2012; 21: 328-37.

19. Hofer N, Müller W, Resch B. Non-infectious conditions and gestational age influence C-reactive protein values in newborns during the first 3 days of life. Clin Chem Lab Med 2011; 49: 297-302.

20. Grylack LJ, Scanlon JW. Oral gentamicin therapy in the prevention of neonatal necrotizing enterocolitis: a controlled double-blind trial. Am J Dis Child 1978; 132: 1192-4.

21. Egan EA, Mantilla G, Nelson RM, Eitzman DV. A prospective controlled trial of oral kanamycin in the prevention of neonatal ne-crotizing enterocolitis. J Pediatr 1976; 89: 467-70.

22. Birck MM, Nguyen DN, Cilieborg MS, Kamal SS, Nielsen DS, Damborg P, et al. Enteral but not parenteral antibiotics enhance gut function and prevent necrotizing enterocolitis in formula-fed newborn preterm pigs. Am J Physiol Gastrointest Liver Physiol 2016; 310: G323-33.

23. Al-Hosni M, Duenas M, Hawk M, Stewart LA, Borghese RA, Cahoon M, et al. Probiotics-supplemented feeding in extremely low-birth-weight infants. J Perinatol 2012; 32: 253-9.

24. Bin-Nun A, Bromiker R, Wilschanski M, Kaplan M, Rudensky B, Caplan M, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. J Pediatr 2005; 147: 192-6.

25. Braga TD, da Silva GA, de Lira PI, de Carvalho Lima M. Efficacy of Bifidobacterium breve and Lactobacillus casei oral supplementa-tion on necrotizing enterocolitis in very-low-birth-weight preterm infants: a double-blind, randomized, controlled trial. Am J Clin Nutr 2011; 93: 81-6.

26. Costalos C, Skouteri V, Gounaris A, Sevastiadou S, Triandafilidou A, Ekonomidou C, et al. Enteral feeding of premature infants with Saccharomyces boulardii. Early Hum Dev 2003; 74: 89–96.

27. Dani C, Biadaioli R, Bertini G, Martelli E, Rubaltelli FF. Probiotics feeding in prevention of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in preterm infants. A prospective double-blind study. Biol Neonate 2002; 82: 103–8.

28. Demirel G, Erdeve O, Celik IH,Dilmen U. Saccharomyces boulardii for prevention of necrotizing enterocolitis in preterm infants: A randomized, controlled study. Acta Paediatr 2013; 102: e560-5.

29. Fernández-Carrocera LA, Solis-Herrera A, Cabanillas-Ayón M, Gallardo-Sarmiento RB, García-Pérez CS, Montaño-Rodríguez R, et al. Double-blind, randomised clinical assay to evaluate the efficacy of probiotics in preterm newborns weighing less than 1500 g in the prevention of necrotizing enterocolitis. Arch Dis Child Fetal Neonatal Ed 2013; 98: F5-9.

30. Kitajima H, Sumida Y, Tanaka R, Yuki N, Takayama H, Fujimura M. Early administration of Bifidobacterium breve to preterm in-fants: randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 1997; 76: F101-7.

31. Lin HC, Su BH, Chen AC, Lin TW, Tsai CH, Yeh TF, et al. Oral probiotics reduce the incidence and severity of necrotizing enterocol-itis in very low birth weight infants. Pediatrics 2005; 115: 1-4.

32. Lin HC, Hsu CH, Chen HL, Chung MY, Hsu JF, Lien RI, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics 2008; 122: 693-700.

33. Manzoni P, Mostert M, Leonessa ML, Priolo C, Farina D, Monetti C, et al. Oral supplementation with Lactobacillus casei subspe-cies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study. Clin Infect Dis 2006; 42: 1735-42.

34. Manzoni P, Rinaldi M, Cattani S, Pugni L, Romeo MG, Messner H, et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA 2009; 302: 1421-8.

35. Mihatsch WA, Vossbeck S, Eikmanns B, Hoegel J, Pohlandt F. Effect of Bifidobacterium lactis on the incidence of nosocomial infec-tions in very-low-birth-weight infants: a randomized controlled trial. Neonatology 2010; 98: 156-63.

36. Mohan R, Koebnick C, Schildt J, Schmidt S, Mueller M, Possner M, et al. Effects of Bifidobacterium lactis Bb12 supplementation on intestinal microbiota of preterm infants: a double-blind, placebo-controlled, randomized study. J Clin Microbiol 2006; 44: 4025-31.

37. Rojas MA, Lozano JM, Rojas MX, Rodriguez VA, Rondon MA, Bastidas JA, et al. Prophylactic probiotics to prevent death and noso-comial infection in preterm infants. Pediatrics 2012; 130: e1113–20.

38. Rougé C, Piloquet H, Butel MJ, Berger B, Rochat F, Ferraris L, et al. Oral supplementation with probiotics in very low-birth-weight preterm infants: a randomized, doubleblind, placebo-controlled trial. Am J Clin Nutr 2009; 89: 1828–35.

39. Samanta M, Sarkar M, Ghosh P, Ghosh JK, Sinha MK, Chatterjee S. Prophylactic probiotics for prevention of necrotizing enterocol-itis in very low birth weight newborns. J Trop Pediatr 2009; 55: 128–31.

40. Sari FN, Dizdar EA, Oguz S, Erdeve O, Uras N, Dilmen U. Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial. Eur J Clin Nutr 2011; 65: 434–9.

41. Stratiki Z, Costalos C, Sevastiadou S, Kastanidou O, Skouroliakou M, Giakoumatou A, et al. The effect of a bifidobacteria supplemented bovine milk on intestinal permeability of preterm infants. Early Hum Dev 2007; 83: 575-9.

42. Millar MR, Bacon C, Smith SL, Walker V, Hall MA. Enteral feeding of premature infants with Lactobacillus GG. Arch Dis Child 1993; 69: 483–7.

43. Deshpande G, Jape G, Rao S, Patole S. Benefits of probiotics in preterm neonates in low-income and medium-income countries: a systematic review of randomized controlled trials. BMJ Open 2017; 7: e017638.

44. Yu W, Sui W, Mu L, Yi W, Li H, Wei L, Yin W. Preventing necrotizing enterocolitis by food additives in neonates: a network meta-analysis revealing the efficacy and safety. Medicine (Baltimore) 2017; 96: e6652.

45. Sawh SC, Deshpande S, Jansen S, Reynaert CJ, Jones PM. Prevention of necrotizing enterocolitis with probiotics: a systematic review and mate-analysis. Peer J 2016; 4: e2429

46. Robinson J. Cochrane in context: probiotics for prevention of necrotizing enterocolitis in preterm infants. Evid Based Child Health 2014; 9: 672-4.

47. AlFaleh K, Anabrees J. Efficacy and safety of probiotics in preterm infants. J Neonatal Perinatal Med 2013; 6: 1-9.

48. Lee PL, Lee WT, Chen HL. Ventilator-associated pneumonia in low birth weight neonates at a neonatal intensive care unit: a retro-spective observational study. Pediatr Neonatol 2017; 58: 16-21.

49. Wynn JL, Kelly MS, Benjamin DK, Clark RH, Greenberg R, Benjamin DK Jr, Smith PB. Timing of Multiorgan Dysfunction among Hospitalized Infants with Fatal Fulminant Sepsis. Am J Perinatol 2017; 34: 633-9.

50. Reuman PD, Duckworth DH, Smith KL, Kagan R, Bucciarelli RL, Ayoub EM. Lack of effect of Lactobacillus on gastrointestinal bacte-rial colonization in premature infants. Pediatr Infect Dis J 1986; 5: 663-8.