Beyond sepsis: Staphylococcus epidermidis is an underestimated but significant contributor to neonatal morbidity

Figures & data

Table 1. The proportion of culture-proven late-onset sepsis due to coagulase-negative Staphylococci, predominantly Staphylococcus epidermidis, among different geographical areas.

Region	Birth year	Design	Population	No. of LOS cases	% of LOS due to CONS	Ref
Developed countries
Netherland	2008-2014	SC	GA < 32 wk	86	77.9	Claessens et al.,^32 2017
			and/or VLBW
Canada	2015	MC	GA < 32 wk	429	58.9	CNN,^33 2016
France	1997	MC	GA 22-32 wk	816	46.0	Mitha et al.,^34 2013
Australia	2005-2016	SC	Neonates in	146	39.8	Gowda et al.,^35 2017
			NICU
South Korea	2013-2014	MC	VLBW	442	38.3	Lee et al.,^9 2015
USA	2000-2011	MC	ELBW	2000-2005: 2083	50.0	Greenberg et al.,^36 2017
				2006-2011: 1728	57.0
UK	2002-2011	SC	VLBW	2002-2007: 379	26.7	Davis et al.^37 2015
				2008-2011: 378	14.1
Germany	2012-2014	MC	VLBW	133	13.0	Tröger et al.,^38 2016
Developing countries
Poland	2009-2011	MC	VLBW	304	62.5	Wójkowska-Mach et al.,^39 2014
Ghana	2010-2013	SC	Neonates in	1039	52.8	Labi et al.,^40 2016
			NICU
China	1990-2014	SC	Neonates in	587	49.8	Lu et al.,^41 2016
			NICU
Turkey	2003-2010	SC	GA < 37wk	86	40.0	Ozkan et al.,^42 2014
Malaysia	2010	MC	VLBW	562	25.6	Boo et al.,^43 2016

CONS: coagulase negative Staphylococci; LOS: late-onset sepsis; MC: multiple centers; NICU: neonatal intensive care unit; SC: single center; VLBW: very low birth weight.

Table 2. In vitro and in vivo studies reporting neonatal host inflammatory responses to Staphylococcus epidermidis.

Study	Bacterial strain	Preparation	Patient population	Intervention	Results
			Cell or animal type
In vitro experiments
Strunk et al.,^78 2012	SE 1457	Heat-killed	GA<30wk, 31-33 wk, 37-41 wk	6 h	IL-1β, IL-6, IL-8, TNF-α↑with GA
		10^8cfu/ml	Cord & adult peripheral MNCs		Adult level TLR2 expression & phagocytosis
Mohamed et al.,^79 2007	SE PT 9657	Heat-killed	Healthy term infants	4 h	IL-1β, IL-6, IL-8, TNF-α↑with time
		10^3cfu/ml	Cord & adult peripheral WBC		Pro-inflammatory effect: SE <E.coli & GBS
Tatad et al.,^80 2008	Clinical isolate	Heat-killed	Healthy term & preterm infants	18 h	IL-6, IL-8, IL-10, IL-12↑ similar to adult
		10^4cfu/ml	Cord & adult peripheral WBC		Inflammatory response: preterm > term
Härtel et al.,^81 2007	ATCC 12228	Live bacteria	Term & preterm infants	24 h	IL-6, TNF-α↑with GA
	Strain 94B080	1cfu:1 WBC &	Neonatal peripheral WBC		Pro-inflammatory effect: BF^+ strain<BF^- strain
	Strain 94B575	10 cfu:1 WBC			IL-10, TGF-β expression independent of GA
Peoples et al.,^82 2009	Clinical isolate	Heat-killed	Healthy term & preterm infants	18 h	IL-6, IL-10↑> adult
		10^4 cfu/ml	Cord & adult peripheral WBC		IL-8, IL-12, INF-NK, INF-T↑ similar to adult
					Inflammatory response: preterm=term
Haase et al.,^83 2011	ATCC 12228	Live bacteria	Healthy term & preterm infants	1 h	TNF-α, IL-6, IL-8↑
	Strain 94B080	1cfu:1 WBC	Cord WBC		Pro-inflammatory effect: BF^+ strain>BF^- strain
	Strain 94B575
Björkqvist et al.,^77 2004	Clinical isolate	Live bacteria	Healthy term & preterm infants	30 min	Oxidative burst intensity: preterm < term
		10 cfu:1 PMNL	Neonatal peripheral PMNLs		SE similar to GBS
Ivarsson et al.,^104 2013	Clinical isolate	Live bacteria	Vascular endothelial cells	18 h	IL-8, ICAM-1 ↑
		10^4cfu/ml	Small airway epithelial cells		Pro-inflammatory effect: SE > SA
Hussain et al.,^105 2013	Strain 94B080	Live bacteria	Bronchial epithelial cells	36 h	TNF-α, IL-6, IL-8 and iNOS↑ with time
		10^4cfu/ml			Expression of ENaC and CFTR↑
In vivo experiments
Kronforst et al.,^87 2012	SE 1457	Live bacteria	C57BL/6 WT mice	48 h	At 2 h:
		up to 2×10^9 cfu/ml	< 24 h old		IL-1β, IL-6, TNF-α, TLR2↑ with inoculum
					At 24 h & 48 h:
					Inoculum-dependent neonatal weight loss
Bi et al.,^86 2015	SE 1457	Live bacteria	C57BL/6J WT mice	72 h	At 6 h:
		1×10^8cfu/ml	< 24 h old		IL-6, CCL2, CXCL1, IL-12↑ in blood & brain
					Caspase-3 & TLR2 mRNA ↑ in the brain
					At 24 h:
					PMNLs↑ in blood & cerebral spinal fluid
					White and grey matter impairment

BF: biofilm; cfu: colony forming unit; CFTR: cystic fibrosis transmembrane conductance regulator; ENaC: Epithelial Na+ channel; GA: gestational age; GBS: group B Streptococcus; ICAM-1: intercellular adhesion molecular-1; IL: interleukin; INF: interferon; MNCs: mononuclear cells; NK: natural killer; PMNLs: polymorphonuclear leucocytes; SA: Staphylococcus aureus; SE: Staphylococcus epidermidis; TLR: Toll-like receptor; TGF: transforming growth factor; TNF: tumor necrosis factor; WBC: whole blood cell; WT: wild type.

Figure 1. Putative mechanisms of Staphylococcus epidermidis-induced neonatal inflammatory response and consecutive organ injuries. PIA: polysaccharide intercellular adhesin; PSMs: phenol-soluble modulins; SCCmec: staphylococcal chromosome cassette mec; IS: insertion sequence; TNF-α: tumor necrosis factor-α; IL: interleukin; CNS: central nervous system; iNOS: inducible nitric oxide synthase; ICAM-1: intercellular adhesion molecule-1.