- freely available
Nutrients 2012, 4(10), 1490-1503; doi:10.3390/nu4101490
Published: 16 October 2012
Abstract: Healthcare-associated infections (HAI) in preterm infants are a challenge to the care of these fragile patients. HAI-incidence rates range from 6 to 27 infections per 1000 patient-days. Most nosocomial infections are bloodstream infections and of these, the majority is associated with the use of central venous catheters. Many studies identified parenteral nutrition as an independent risk factor for HAI, catheter-associated bloodstream infection, and clinical sepsis. This fact and various published outbreaks due to contaminated parenteral nutrition preparations highlight the importance of appropriate standards in the preparation and handling of intravenous solutions and parenteral nutrition. Ready-to-use parenteral nutrition formulations may provide additional safety in this context. However, there is concern that such formulations may result in overfeeding and necrotizing enterocolitis. Given the risk for catheter-associated infection, handling with parenteral nutrition should be minimized and the duration shortened. Further research is required about this topic.
There has been an increase of preterm births (<37 weeks of gestation) in most countries worldwide over the past years . These patients are at risk for healthcare-associated infections (HAIs), in particular very low birth weight (VLBW, <1500 g birth weight) and extremely low birth weight (ELBW, <1000 g birth weight) infants. They require longer care in neonatology units, are exposed to more invasive devices, and have an immature immune system, as well as low levels of transplacentally acquired antibodies. Reported HAI-rates in neonatal care range from 6 to 27 per 1000 patient-days [2,3,4,5,6,7] and thus are higher than in other patient groups. Large cohort studies reported high mortality and impaired neurological development in neonates after HAI [8,9]. A study among 1051 neonates in a Brazilian neonatal intensive care unit (NICU) identiﬁed risk factors for HAI to include mechanical ventilation, inappropriate fraction of inspired oxygen, and duration of central venous catheterization .
Most nosocomial infections are due to bloodstream infections (BSIs) representing up to more than three-quarters of all HAI among neonates [7,11,12,13,14,15,16,17]. Most BSIs are associated with catheter use, in particular central lines such as peripherally inserted central catheters (PICC) and umbilical lines . A total of 205 neonates out of 2935 neonates in two NICUs in New York developed BSIs after a mean of 21.4 and 35.7 days of life in each NICU, respectively . Risk factors included low birth weight (with an additional 9% risk for each 100 g weight decrease), the presence of a central venous catheter (9.3-fold risk increase when compared to children without a catheter) and total parenteral nutrition (RR: 4.7). A Swiss study identified ELBW [OR: 2.24 (1.42–3.53); p < 0.001] and the use of parenteral nutrition (PN) [OR: 2.23 (1.10–4.55); p = 0.027] as the only two independent risk factors for BSI over 8 years . Median time-to-infection was seven days.
Central line-associated bloodstream infections (CLABSIs) extend hospital length of stay by an average of 7 days and result in attributable costs of 3700 to 29,000 USD per infection . A case-control study estimated extra-costs per neonate to 10,440 USD with 5.2 extra hospital days . BSI-attributed costs are particularly high in Candida infections, especially in ELBW infants .
2. Growth of Microorganisms in Parenteral Nutrition
2.1. Microorganisms in Parenteral Nutrition
Various in vitro studies tested the growth of micro-organisms in single compounds of PN, in total parenteral nutrition (TPN), or in total nutrient admixtures (TNA). Testing of 12 different pathogens (Staphylococcus epidermidis, Staphylococcus aureus, Enterobacter cloacae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Burkholderia cepacia, Flavobacterium spp., Staphylococcus saprophyticus, and Candida albicans) in a representative TNA of 17.6% glucose, 5% amino acids, and 4% lipid (pH 5.6, osmolality 1778) compared to a control solution of 5% dextrose in water at 4 °C, 25 °C, and 35 °C only grew C. albicans and S. saprophyticus in TNA at 25 °C and 35 °C and only after 24 to 48 h. The authors concluded that TNA was a poor growth medium for most nosocomial pathogens . While lipid emulsion and broth grew all tested organisms (Escherichia coli, Enterobacter cloacae, P. aeruginosa, S. aureus, and C. albicans) in another study, only C. albicans was found to proliferate in TPN . Candida albicans demonstrated significant growth regardless of fat contents (0% or 5%) in admixtures containing variable concentrations of dextrose in an in vitro study . Gram-negative microorganisms such as Klebsiella pneumoniae, E. coli, and P. aeruginosa were able to proliferate in TNA with glucose, amino acids, and lipid emulsion, but growth was impaired in conventional TPN without lipids . S. epidermidis was not able to proliferate in any admixture tested; however, C. albicans grew well in all admixtures. A recent study showed that the proliferation of S. epidermidis was not only affected by adding lipids to TPN, but also depended on glucose concentration and total non-nitrogen energy . Growth was also reduced by higher pH values (~8.4). An older study, on the other hand, found considerable growth of a number of Gram-positive and Gram-negative microorganisms in TPN without lipids . The same study looked at growth in catheters challenged with bacteria and flushed with TPN for three days, but did not find significant increase of growth over time.
2.2. Growth of Microorganisms on Catheters Used for Parenteral Nutrition
Staphylococcus epidermidis was cultured from 7 out of 9 catheters after lipid infusion but only from 3 out of 13 catheters after glucose-infusion (p = 0.016) in a rabbit model . Lipid but not glucose solutions containing low protein levels (0.1%–1.0%) supported the survival and growth of S. epidermidis. The reason for enhanced growth in the context of lipid administration is not clear. A modulation of the proinflammatory cytokine response to Staphylococcus epidermidis by lipids has been suggested . In a S. epidermidis sepsis model of whole cord blood cells from healthy infants, IL-6, IL-8, and TNF-α expression of CD14+ cells was signiﬁcantly enhanced upon addition of a 1% lipid formulation, while lower lipid concentrations had no remarkable effect. When glucose was added to whole cord blood cultures, a dose-dependent effect was demonstrated for IL-8 expression but not for other cytokines.
3. Sepsis in Neonates
Group B Streptococci were predominant (47%), followed by E. coli (23%), Staphylococcus spp. (13%) and Gram-negative rods other than E. coli (8%) in early-onset sepsis (sepsis in the first three days of life) in a long term surveillance of a US NICU . The most common organisms in late-onset sepsis (>3 days after birth) were coagulase-negative Streptococci (CoNS) (39%), followed by Escherichia coli (9%) and C. albicans (9%) . This finding was confirmed by others, with nearly all isolated CoNS (87%) being methicillin resistant .
4. Parenteral Nutrition Is a Risk for Late-Onset Sepsis
There is evidence that parenteral nutrition is associated with BSI. Nosocomial BSI due to parenteral nutrition is a potentially fatal complication with an attributable mortality rate of 11% in neonates . High mortality, high incidence densities of late-onset-sepsis and CLABSI, require efforts to reduce this risk as much as possible [2,18,33,34,35]. The reasons for parenteral nutrition being identified as a risk factor by a number of studies include contamination of infusates; however, a catheter may infect at any time during catheterization due to handling, which is exemplified by the fact that CoNS is the most common pathogen identified in neonatal CLABSI .
TPN-use was found to be a significant risk factor among preterm neonates in a small single center study in Australia [OR (CI 95%): 4.17 (1.37–12.7)] .
A retrospective study in Brazil among 948 neonates found parenteral nutrition significantly associated with HAI [OR (CI 95%): 6.35 (4.14–9.75); p < 0.01] .
A large Canadian study reported the results of a neonatal network of 16,538 infants . HAI was detected in 23.5% (765/3253) of VLBW infants and in 2.5% (329/13,244) of infants >1500 g. Multiple logistic regression analysis disclosed parenteral nutrition being a significant risk factor for neonates <1500 g [OR (CI 95%): 3.9 (3.0–5.2)] and >1500 g [OR (CI 95%): 5.1 (3.8–6.9)].
A Colombian group investigated risk factors for BSI due to Candida spp. in a single center. Prolonged hospitalization (p < 0.05), missing prenatal birth control (p < 0.05), and parenteral nutrition (p < 0.05) were associated with BSI due to Candida spp. .
Six hundred and eighty three neonates were included in a prospective single center study in Denmark. The overall incidence densities of HAI and BSIs were 8.8/1000 patient-days and 5.1/1000, respectively . Parenteral nutrition was found an independent and significant risk factor for BSIs [HR (CI 95%): 2.71 (1.27–5.79); p = 0.01].
A multicenter cohort study in six Italian NICUs reported an overall HAI incidence density of 6.9/1000 patient-days . Administration of parenteral nutrition [HR (CI 95%): 8.1 (3.2–20.5)] also was found an independent risk factor for HAI in neonates >1500 g.
Similar results were reported by Avila-Figueroa and colleagues (Mexico) who looked into BSI due to CoNS . They found that lipids were independently associated with subsequent BSI due to CoNS among other procedures at risk [OR (CI 95%): 9.4 (1.2–74.2)].
The overall rate of HAI in the NICU was 27/1000 patient-days in a Catalan study . The most significant predisposing risk factors for HAI were birth weight <1000 g [RR (CI 95%): 2.8 (1.0–8.0)], umbilical arterial catheterization [RR (CI 95%): 5.7 (1.1–28.5)] and parenteral nutrition [RR (CI 95%): 2.4 (1.2–4.6)].
4.9. Saudi Arabia
A single center study in Saudi Arabia reported total parenteral nutrition [OR (CI 95%): 5.62 (2.78–11.35)] significantly associated with HAI in a cohort of 401 neonates . The overall incidence density of nosocomial infections in this study was 13.7/1000 patient-days.
Parenteral nutrition was an independent and significant risk factor for bacteraemia and clinical sepsis [HR (CI 95%): 2.23 (1.10–4.55); p = 0.027] in a prospective single center study in Switzerland . The follow-up was eight years and included 1124 neonates exposed to a central line, such as a peripherally inserted central catheter (PICC) or an umbilical line.
4.11. The Netherlands
A prospective surveillance study over three years in a university medical center in the Netherlands enrolled 762 neonates . The BSI-incidence density was 14.9/1000 patient-days. The main risk factors for BSI were birth weight [HR (CI 95%): 1.79 (1.45–2.17)] and parenteral feeding with an all-in-one mixture produced by the in-hospital pharmacy [HR (CI 95%): 3.69 (2.03–6.69)].
4.12. United Kingdom
A single center study in a Level-II NICU in the United Kingdom revealed an overall sepsis rate of 77 per 1000 NICU admissions in 1612 neonates . Administration of TPN was the leading risk factor for late-onset sepsis (88%).
A prospective cohort study in a NICU in England over a study period of almost two years included 1367 neonates with a mean (±SD) gestational age of 31 weeks (±4.4) and birth weight of 1607 g (±817 g) . Significant adjusted risk factors were gestational age <26 weeks [IRR (CI 95%): 2.5 (1.7–3.8)] and the use of parenteral nutrition, whether administered centrally or peripherally [IRR (CI 95%): 14.2 (8.8–22.9); p < 0.001].
4.13. United States
A retrospective cohort study in the US did not identify specific genetic associations among twins, but the duration of TPN was found an independent risk factor for late-onset sepsis [Coeff (CI 95%): 0.041 (0.017–0.064); p < 0.001] . The same author tested risk factors for S. marcescens BSI in neonates in a matched case-control study. Interestingly, an association with parenteral nutrition was found for this pathogen only when the cohort was compared to neonates with E. coli-BSI [OR (CI 95%): 3.27 (1.20–8.92); p = 0.02] but not when compared to neonates without BSI .
Infants with CoNS-BSI were 5.8 times (CI 95%: 4.1–8.3) as likely as those in the control group to have received intravenous lipid emulsion before the onset of bacteraemia in a case-controlled study including 882 infants treated in two NICUs in the USA .
The differences in the risk of PICC-placement in the upper as compared to the lower extremities was investigated in a large preterm population in the USA [median gestational age and weight: 28 (CI 95%: 25.5–30); 937 (CI 95%: 760–360)] . The incidence densities of the upper and lower extremities were 7.1/1000 catheter-days and 4.8/1000, respectively. However, administration of lipid-containing parenteral nutrition was significantly longer (46 days) in neonates with catheter-related BSI (CRBSI) as compared to neonates without CRBSI (25 days; p < 0.01).
5. Outbreaks Due to Contaminated Parenteral Nutrition
Various outbreaks due to contaminated parenteral nutrition are reported in the literature. Outbreaks vary in size, time span, and pathogens. Interestingly, most outbreaks are due to contamination by Gram-negative bacteria (Table 1). The most likely time point for contamination appears to be within the span of PN-preparation. For yeasts however, days of TPN-administration seems to be more predictive [51,52]. Two outbreaks among adults due to contaminated TPN-products further illustrate the potential harm of contaminated preparations: A multistate outbreak of S. marcescens BSIs linked to contaminated MgSO4 that was distributed nationally by a compounding pharmacy . The outbreak included 18 confirmed and 7 probable adult cases in California and New Jersey. Another outbreak due to S. marcescens involved 19 patients in six hospitals in Alabama, US. Nine deaths were related to contaminated parenteral nutrition preparations from a compounding pharmacy. The identical strain of S. marcescens was cultured from a tap water faucet in the pharmacy which was used to rinse production equipment . Other outbreaks have been described (Table 1), most of them confirmed by pulsed-field gel-electrophoresis [55,56,57,58,59], ribotyping , or by an identical antibiotic susceptibility testing .
|Table 1. Published outbreaks among neonates related to parenteral nutrition.|
|Author||Ref.||Pathogens||n||Deaths||Confirmation 1||PN-preparation||Most likely way of contamination|
|Maltezou||||Serratia marcescens||57||9||Epidemiology||On ward||Preparation|
|Arslan||||Serratia marcescens||7||0||Culture/PFGE||On ward||Preparation|
|Bou||||Leuconostoc mesenteroides||11 (42)||3 of 42||Epidemiology||Hospital pharmacy||Preparation|
|De Vegas||||Acinetobacter RUH 1139||24||ND||Culture/PFGE||Hospital pharmacy||Handling on ward|
|Perniola||||Rhodotorula mucilaginosa||4||0||Epidemiology||Not specified||Not specified|
|Habsah||||Pantoea spp.||8||7||Culture/AB||Hospital pharmacy||Preparation|
|Doit||||Burkholderia cepacia||8||ND||Culture/Ribotype||manufacturer||Contaminated rubber stoppers|
|Aragao||||Pichia anomala||4||0||Epidemiology||Hospital pharmacy||Handling on ward|
|Tresoldi||||Enterobacter cloacae||11||7||Culture/PFGE||Hospital pharmacy||Preparation|
|Archibald||||Enterobacter cloacae & Pseudomonas aeruginosa||6||2||Epidemiology||On ward||Preparation|
ND: not determined; 1 Confirmation of the pathogen is done either by PFGE (pulsed-field gel-electrophoresis [PFGE]; ribotyping, identical antibiotic susceptibility testing [AB]), or by an epidemiological association.
6. Compounding Is a Risk for Contamination
If complicated transfers of the medium from vials and ampoules to intravenous bags are performed, even with stringent aseptic technique, the TNA-contamination rate is estimated at about 5.2% . Although performed under laminar flow by trained personnel in a pharmacy, transfer sets for compound pumps showed growth after 24 h with skin contaminants . A clinical-oriented study looking at differential methods of neonatal intravenous fat emulsion preparation found contamination in 3.3% when emulsions were repackaged in syringes before use . In a Mexican NICU-study mixtures made by nurses were more likely to be contaminated than commercial preparations [OR (CI 95%): 3.1 (1.1–8.5); p = 0.037] .
Individual tailored TNA should be prepared every day with strict aseptic technique in the pharmacy, not in the ward, and stored in a refrigerator at 4 °C . The solutions prepared in such a way are stable for 96 h. Current practice standards require parenteral preparations to be compounded in a clean room to minimize microbial contamination. Proper storage, refrigeration, and infusion time of no more than 24 h reduce the chance of microbial contamination or growth in parenteral nutrition formulation . Minimum requirements for compounding vary from country to country but mostly include the use of a Class A/Class 100 laminar flow cabinet either operated in a Class B/Class 1000 or a relatively uncontrolled environment .
7. Ready-to-Use Formulation in Preterm Infants
Large hospitals perform pharmacy compounding to all-in-one admixtures rather than using commercial formula in compartment bags. While in adults, ready-to-use admixtures have become standard, most parenteral nutrition preparations for neonates are still compounded in local pharmacies [70,71]. In adults, ready-to-use multichamber bags containing three sterilized macronutrient solutions in separate chambers of a single, closed plastic system are widely available and have been used for many years [72,73]. Standardized solutions can be also used in infants once they tolerate mild or moderate variations in nutritional intake [74,75,76,77,78,79]. However, there are still concernsabout ready-to-use preparations in preterms. Many neonatologists consider customized admixtures prepared by the pharmacy superior to ready-to-use preparations to provide optimal nutrition although standardized parenteral nutrition solutions in combination with early promotion of enteral feeding with human milk have been associated with improved nutritional support in very preterm infants [79,80].
Healthcare associated infections are a permanent challenge in neonates. In particular, preterm infants are at risk for infection due to an immature immune system and lower levels of transplacental antibodies. The majority of nosocomial infections are due to CLABSI, which are associated with prolonged hospital stay causing significant attributable costs. TPN and TNA have been identified as independent risk factors for HAI, BSI or sepsis by many studies. The body of evidence is uncontested and robust. These findings have a strong pathophysiological background as TPN with lipids promote the growth of a wide spectrum of microorganisms that is even further increased by human serum. In particular, Candida species can grow rapidly in almost all TPN solutions regardless of acidity and lipid content. Some bacterial species may grow in lipid-containing TNA unless the pH-value is extreme , but they poorly grow in parenteral nutrition without lipids due to the acidity of the solution .
Maintaining sterility of nutritional admixtures for parenteral use upon preparation is of utmost importance. Regulations and recommendations have been issued to assure the quality of the final product. Despite compounding in the pharmacy under strict aseptic technique, outbreaks due to contaminated admixtures have been reported. Given the high CLABSI incidence in neonates associated with high attributable mortality, further prevention efforts are required. Although many neonatologists still have concerns about the suitability of ready-to-use preparations on nutritional levels, such products may offer a better safety profile in terms of infections. The risk for CLABSI through prolonged catheterization and parenteral nutrition might be further reduced by encouraging enteral feeding. Current data do not provide evidence that delayed induction of progressive enteral feeding or slow advancement of enteral feed volumes reduces the risk of NEC in VLBW infants. On the other hand, delaying induction and increasing the volume of enteral feeds at slower rather than faster rates results in several days delay in regaining birth weight and establishing full enteral feeds [83,84]. Rapid advancement of enteral feeding may reduce the duration of parenteral nutrition and catheter dwell time and, thus, such an approach may be favored. It was not the scope of the review to comment on the risks and benefits of accelerated enteral feeding. However, a recent randomized controlled trial suggests that such a strategy may even contribute to the prevention of HAI and in particular of CLABSI and clinical sepsis .
Conflict of Interest
Walter Zingg received support from the European Commission (EC, FP7 Collaborative project-241928), the Swiss National Foundation (SNF; CRSI33_125408/1), and Baxter Inc.; Maria Martin received support from the European Commission (EC, FP7 Collaborative project-241928). The funding agencies had no role in the preparation, review or approval of the manuscript. The authors have no conflict of interest.
- Blencowe, H.; Cousens, S.; Oestergaard, M.Z.; Chou, D.; Moller, A.B.; Narwal, R.; Adler, A.; Vera Garcia, C.; Rohde, S.; Say, L.; et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: A systematic analysis and implications. Lancet 2012, 379, 2162–2172. [Google Scholar]
- Zingg, W.; Posfay-Barbe, K.M.; Pittet, D. Healthcare-associated infections in neonates. Curr. Opin. Infect. Dis. 2008, 21, 228–234. [Google Scholar] [CrossRef]
- Stover, B.H.; Shulman, S.T.; Bratcher, D.F.; Brady, M.T.; Levine, G.L.; Jarvis, W.R. Nosocomial infection rates in us children’s hospitals’ neonatal and pediatric intensive care units. Am. J. Infect. Control 2001, 29, 152–157. [Google Scholar] [CrossRef]
- Hentschel, J.; Brungger, B.; Studi, K.; Muhlemann, K. Prospective surveillance of nosocomial infections in a Swiss NICU: Low risk of pneumonia on nasal continuous positive airway pressure? Infection 2005, 33, 350–355. [Google Scholar] [CrossRef]
- Schwab, F.; Geffers, C.; Barwolff, S.; Ruden, H.; Gastmeier, P. Reducing neonatal nosocomial bloodstream infections through participation in a national surveillance system. J. Hosp. Infect. 2007, 65, 319–325. [Google Scholar] [CrossRef]
- Posfay-Barbe, K.M.; Zerr, D.M.; Pittet, D. Infection control in paediatrics. Lancet Infect. Dis. 2008, 8, 19–31. [Google Scholar] [CrossRef]
- Mireya, U.A.; Marti, P.O.; Xavier, K.V.; Cristina, L.O.; Miguel, M.M.; Magda, C.M. Nosocomial infections in paediatric and neonatal intensive care units. J. Infect. 2007, 54, 212–220. [Google Scholar] [CrossRef]
- Stoll, B.J.; Hansen, N.I.; Adams-Chapman, I.; Fanaroff, A.A.; Hintz, S.R.; Vohr, B.; Higgins, R.D. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004, 292, 2357–2365. [Google Scholar] [CrossRef]
- Benjamin, D.K., Jr.; Stoll, B.J.; Fanaroff, A.A.; McDonald, S.A.; Oh, W.; Higgins, R.D.; Duara, S.; Poole, K.; Laptook, A.; Goldberg, R. Neonatal candidiasis among extremely low birth weight infants: Risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics 2006, 117, 84–92. [Google Scholar] [CrossRef]
- Couto, R.C.; Pedrosa, T.M.; Tofani Cde, P.; Pedroso, E.R. Risk factors for nosocomial infection in a neonatal intensive care unit. Infect. Control Hosp. Epidemiol. 2006, 27, 571–575. [Google Scholar] [CrossRef]
- Contreras-Cuellar, G.A.; Leal-Castro, A.L.; Prieto, R.; Carvajal-Hermida, A.L. Device-associated infections in a Colombian neonatal intensive care unit. Rev. Salud Publica (Bogota) 2007, 9, 439–447. [Google Scholar]
- El-Nawawy, A.A.; Abd El-Fattah, M.M.; Metwally, H.A.; Barakat, S.S.; Hassan, I.A. One year study of bacterial and fungal nosocomial infections among patients in pediatric intensive care unit (PICU) in Alexandria. J. Trop. Pediatr. 2006, 52, 185–191. [Google Scholar]
- Balkhy, H.H.; Cunningham, G.; Chew, F.K.; Francis, C.; Al Nakhli, D.J.; Almuneef, M.A.; Memish, Z.A. Hospital- and community-acquired infections: A point prevalence and risk factors survey in a tertiary care center in Saudi Arabia. Int. J. Infect. Dis. 2006, 10, 326–333. [Google Scholar] [CrossRef]
- Couto, R.C.; Carvalho, E.A.; Pedrosa, T.M.; Pedroso, E.R.; Neto, M.C.; Biscione, F.M. A 10-year prospective surveillance of nosocomial infections in neonatal intensive care units. Am. J. Infect. Control 2007, 35, 183–189. [Google Scholar] [CrossRef]
- Elward, A.M.; Fraser, V.J. Risk factors for nosocomial primary bloodstream infection in pediatric intensive care unit patients: A 2-year prospective cohort study. Infect. Control Hosp. Epidemiol. 2006, 27, 553–560. [Google Scholar] [CrossRef]
- Ben Jaballah, N.; Bouziri, A.; Mnif, K.; Hamdi, A.; Khaldi, A.; Kchaou, W. Epidemiology of hospital-acquired bloodstream infections in a tunisian pediatric intensive care unit: A 2-year prospective study. Am. J. Infect. Control 2007, 35, 613–618. [Google Scholar] [CrossRef]
- Raka, L.; Zoutman, D.; Mulliqi, G.; Krasniqi, S.; Dedushaj, I.; Raka, N.; Ahmeti, S.; Shala, M.; Vishaj, A.; Elezi, Y. Prevalence of nosocomial infections in high-risk units in the university clinical center of Kosova. Infect. Control Hosp. Epidemiol. 2006, 27, 421–423. [Google Scholar] [CrossRef]
- Zingg, W.; Posfay-Barbe, K.M.; Pfister, R.E.; Touveneau, S.; Pittet, D. Individualized catheter surveillance among neonates: A prospective, 8-year, single-center experience. Infect. Control Hosp. Epidemiol. 2011, 32, 42–49. [Google Scholar] [CrossRef]
- Perlman, S.E.; Saiman, L.; Larson, E.L. Risk factors for late-onset health care-associated bloodstream infections in patients in neonatal intensive care units. Am. J. Infect. Control 2007, 35, 177–182. [Google Scholar] [CrossRef]
- Sengupta, A.; Lehmann, C.; Diener-West, M.; Perl, T.M.; Milstone, A.M. Catheter duration and risk of CLA-BSI in neonates with piccs. Pediatrics 2010, 125, 648–653. [Google Scholar] [CrossRef]
- Leroyer, A.; Bedu, A.; Lombrail, P.; Desplanques, L.; Diakite, B.; Bingen, E.; Aujard, Y.; Brodin, M. Prolongation of hospital stay and extra costs due to hospital-acquired infection in a neonatal unit. J. Hosp. Infect. 1997, 35, 37–45. [Google Scholar] [CrossRef]
- Zaoutis, T.E.; Heydon, K.; Localio, R.; Walsh, T.J.; Feudtner, C. Outcomes attributable to neonatal candidiasis. Clin. Infect. Dis. 2007, 44, 1187–1193. [Google Scholar] [CrossRef]
- Didier, M.E.; Fischer, S.; Maki, D.G. Total nutrient admixtures appear safer than lipid emulsion alone as regards microbial contamination: Growth properties of microbial pathogens at room temperature. JPEN J. Parenter. Enteral Nutr. 1998, 22, 291–296. [Google Scholar]
- Melly, M.A.; Meng, H.C.; Schaffner, W. Microbiol growth in lipid emulsions used in parenteral nutrition. Arch. Surg. 1975, 110, 1479–1481. [Google Scholar] [CrossRef]
- Rowe, C.E.; Fukuyama, T.T.; Martinoff, J.T. Growth of microorganisms in total nutrient admixtures. Drug Intell. Clin. Pharm. 1987, 21, 633–638. [Google Scholar]
- D’Angio, R.; Quercia, R.A.; Treiber, N.K.; McLaughlin, J.C.; Klimek, J.J. The growth of microorganisms in total parenteral nutrition admixtures. JPEN J. Parenter. Enteral Nutr. 1987, 11, 394–397. [Google Scholar] [CrossRef]
- Austin, P.D.; Hand, K.S.; Elia, M. Factors that influence Staphylococcus epidermidis growth in parenteral nutrition with and without lipid emulsion: A study framework to inform maximum duration of infusion policy decisions. Clin. Nutr. 2012. [Google Scholar] [CrossRef]
- Merlino, R.; Gaillard, J.L.; Fauchere, J.L.; Chaumont, P.; Droy-Lefaix, M.T.; Descamps, P.; Ricour, C.; Veron, M. In vitro quantitative model of catheter infection during simulated parenteral nutrition. J. Clin. Microbiol. 1988, 26, 1659–1664. [Google Scholar]
- Shiro, H.; Muller, E.; Takeda, S.; Tosteson, T.D.; Goldmann, D.A.; Pier, G.B. Potentiation of Staphylococcus epidermidis catheter-related bacteremia by lipid infusions. J. Infect. Dis. 1995, 171, 220–224. [Google Scholar] [CrossRef]
- Haase, B.; Faust, K.; Heidemann, M.; Scholz, T.; Demmert, M.; Troger, B.; Herz, A.; Hartel, C. The modulatory effect of lipids and glucose on the neonatal immune response induced by Staphylococcus epidermidis. Inflamm. Res. 2011, 60, 227–232. [Google Scholar] [CrossRef]
- Bizzarro, M.J.; Raskind, C.; Baltimore, R.S.; Gallagher, P.G. Seventy-five years of neonatal sepsis at Yale: 1928–2003. Pediatrics 2005, 116, 595–602. [Google Scholar] [CrossRef]
- Hira, V.; Sluijter, M.; Estevao, S.; Horst-Kreft, D.; Ott, A.; de Groot, R.; Hermans, P.W.; Kornelisse, R.F. Clinical and molecular epidemiologic characteristics of coagulase-negative staphylococcal bloodstream infections in intensive care neonates. Pediatr. Infect. Dis. J. 2007, 26, 607–612. [Google Scholar] [CrossRef]
- Stoll, B.J.; Hansen, N.; Fanaroff, A.A.; Wright, L.L.; Carlo, W.A.; Ehrenkranz, R.A.; Lemons, J.A.; Donovan, E.F.; Stark, A.R.; Tyson, J.E.; et al. Late-onset sepsis in very low birth weight neonates: The experience of the NICHD neonatal research network. Pediatrics 2002, 110, 285–291. [Google Scholar] [CrossRef]
- Edwards, J.R.; Peterson, K.D.; Mu, Y.; Banerjee, S.; Allen-Bridson, K.; Morrell, G.; Dudeck, M.A.; Pollock, D.A.; Horan, T.C. National healthcare safety network (NHSN) report: Data summary for 2006 through 2008, issued December 2009. Am. J. Infect. Control 2009, 37, 783–805. [Google Scholar] [CrossRef]
- Geffers, C.; Baerwolff, S.; Schwab, F.; Gastmeier, P. Incidence of healthcare-associated infections in high-risk neonates: Results from the German surveillance system for very-low-birthweight infants. J. Hosp. Infect. 2008, 68, 214–221. [Google Scholar] [CrossRef]
- Kandasamy, Y. Infection control during administration of parenteral nutrition in preterm babies. Arch. Dis. Child. Fetal Neonatal Ed. 2009, 94, F78. [Google Scholar] [CrossRef]
- Tavora, A.C.; Castro, A.B.; Militao, M.A.; Girao, J.E.; Ribeiro Kde, C.; Tavora, L.G. Risk factors for nosocomial infection in a Brazilian neonatal intensive care unit. Braz. J. Infect. Dis. 2008, 12, 75–79. [Google Scholar] [CrossRef]
- Aziz, K.; McMillan, D.D.; Andrews, W.; Pendray, M.; Qiu, Z.; Karuri, S.; Lee, S.K. Variations in rates of nosocomial infection among Canadian neonatal intensive care units may be practice-related. BMC Pediatr. 2005, 5, 22. [Google Scholar] [CrossRef]
- Hartung de Capriles, C.; Mata-Essayag, S.; Azpiroz, A.; Ponente, A.; Magaldi, S.; Perez, C.; Rosello, A.; Colella, M.T.; Machuca, J. Neonatal candidiasis in Venezuela: Clinical and epidemiological aspects. Rev. Latinoam. Microbiol. 2005, 47, 11–20. [Google Scholar]
- Olsen, A.L.; Reinholdt, J.; Jensen, A.M.; Andersen, L.P.; Jensen, E.T. Nosocomial infection in a Danish neonatal intensive care unit: A prospective study. Acta Paediatr. 2009, 98, 1294–1299. [Google Scholar] [CrossRef]
- Auriti, C.; Ronchetti, M.P.; Pezzotti, P.; Marrocco, G.; Quondamcarlo, A.; Seganti, G.; Bagnoli, F.; De Felice, C.; Buonocore, G.; Arioni, C.; et al. Determinants of nosocomial infection in 6 neonatal intensive care units: An Italian multicenter prospective cohort study. Infect. Control Hosp. Epidemiol. 2010, 31, 926–933. [Google Scholar] [CrossRef]
- Avila-Figueroa, C.; Goldmann, D.A.; Richardson, D.K.; Gray, J.E.; Ferrari, A.; Freeman, J. Intravenous lipid emulsions are the major determinant of coagulase-negative staphylococcal bacteremia in very low birth weight newborns. Pediatr. Infect. Dis. J. 1998, 17, 10–17. [Google Scholar] [CrossRef]
- Mahfouz, A.A.; Al-Azraqi, T.A.; Abbag, F.I.; Al-Gamal, M.N.; Seef, S.; Bello, C.S. Nosocomial infections in a neonatal intensive care unit in south-western Saudi Arabia. East. Mediterr. Health J. 2010, 16, 40–44. [Google Scholar]
- Van der Zwet, W.C.; Kaiser, A.M.; van Elburg, R.M.; Berkhof, J.; Fetter, W.P.; Parlevliet, G.A.; Vandenbroucke-Grauls, C.M. Nosocomial infections in a Dutch neonatal intensive care unit: Surveillance study with definitions for infection specifically adapted for neonates. J. Hosp. Infect. 2005, 61, 300–311. [Google Scholar] [CrossRef]
- Haque, K.N.; Khan, M.A.; Kerry, S.; Stephenson, J.; Woods, G. Pattern of culture-proven neonatal sepsis in a district general hospital in the united kingdom. Infect. Control Hosp. Epidemiol. 2004, 25, 759–764. [Google Scholar]
- Holmes, A.; Dore, C.J.; Saraswatula, A.; Bamford, K.B.; Richards, M.S.; Coello, R.; Modi, N. Risk factors and recommendations for rate stratification for surveillance of neonatal healthcare-associated bloodstream infection. J. Hosp. Infect. 2008, 68, 66–72. [Google Scholar] [CrossRef]
- Bizzarro, M.J.; Jiang, Y.; Hussain, N.; Gruen, J.R.; Bhandari, V.; Zhang, H. The impact of environmental and genetic factors on neonatal late-onset sepsis. J. Pediatr. 2011, 158, 234–238. [Google Scholar] [CrossRef]
- Bizzarro, M.J.; Dembry, L.M.; Baltimore, R.S.; Gallagher, P.G. Case-control analysis of endemic Serratia marcescens bacteremia in a neonatal intensive care unit. Arch. Dis. Child. Fetal Neonatal Ed. 2007, 92, F120–F126. [Google Scholar] [CrossRef]
- Freeman, J.; Goldmann, D.A.; Smith, N.E.; Sidebottom, D.G.; Epstein, M.F.; Platt, R. Association of intravenous lipid emulsion and coagulase-negative staphylococcal bacteremia in neonatal intensive care units. N. Engl. J. Med. 1990, 323, 301–308. [Google Scholar] [CrossRef]
- Hoang, V.; Sills, J.; Chandler, M.; Busalani, E.; Clifton-Koeppel, R.; Modanlou, H.D. Percutaneously inserted central catheter for total parenteral nutrition in neonates: Complications rates related to upper versus lower extremity insertion. Pediatrics 2008, 121, e1152–e1159. [Google Scholar] [CrossRef]
- Aragao, P.A.; Oshiro, I.C.; Manrique, E.I.; Gomes, C.C.; Matsuo, L.L.; Leone, C.; Moretti-Branchini, M.L.; Levin, A.S. Pichia anomala outbreak in a nursery: Exogenous source? Pediatr. Infect. Dis. J. 2001, 20, 843–848. [Google Scholar] [CrossRef]
- Perniola, R.; Faneschi, M.L.; Manso, E.; Pizzolante, M.; Rizzo, A.; Sticchi Damiani, A.; Longo, R. Rhodotorula mucilaginosa outbreak in neonatal intensive care unit: Microbiological features, clinical presentation, and analysis of related variables. Eur. J. Clin. Microbiol. Infect. Dis. 2006, 25, 193–196. [Google Scholar] [CrossRef]
- Sunenshine, R.H.; Tan, E.T.; Terashita, D.M.; Jensen, B.J.; Kacica, M.A.; Sickbert-Bennett, E.E.; Noble-Wang, J.A.; Palmieri, M.J.; Bopp, D.J.; Jernigan, D.B.; et al. A multistate outbreak of Serratia marcescens bloodstream infection associated with contaminated intravenous magnesium sulfate from a compounding pharmacy. Clin. Infect. Dis. 2007, 45, 527–533. [Google Scholar]
- Sacks, G.S. Microbial contamination of parenteral nutrition—how could it happen? JPEN J. Parenter. Enteral Nutr. 2011, 35, 432. [Google Scholar] [CrossRef]
- Arslan, U.; Erayman, I.; Kirdar, S.; Yuksekkaya, S.; Cimen, O.; Tuncer, I.; Bozdogan, B. Serratia marcescens sepsis outbreak in a neonatal intensive care unit. Pediatr. Int. 2012, 52, 208–212. [Google Scholar]
- Bou, G.; Luis Saleta, J.; Saez Nieto, J.A.; Tomas, M.; Valdezate, S.; Sousa, D.; Lueiro, F.; Villanueva, R.; Jose Pereira, M.; Llinares, P. Nosocomial outbreaks caused by Leuconostoc mesenteroides subsp. Mesenteroides. Emerg. Infect. Dis. 2008, 14, 968–971. [Google Scholar] [CrossRef]
- Campos, L.C.; Lobianco, L.F.; Seki, L.M.; Santos, R.M.; Asensi, M.D. Outbreak of Enterobacter hormaechei septicaemia in newborns caused by contaminated parenteral nutrition in Brazil. J. Hosp. Infect. 2007, 66, 95–97. [Google Scholar] [CrossRef]
- De Vegas, E.Z.; Nieves, B.; Araque, M.; Velasco, E.; Ruiz, J.; Vila, J. Outbreak of infection with Acinetobacter strain RUH 1139 in an intensive care unit. Infect. Control Hosp. Epidemiol. 2006, 27, 397–403. [Google Scholar] [CrossRef]
- Tresoldi, A.T.; Padoveze, M.C.; Trabasso, P.; Veiga, J.F.; Marba, S.T.; von Nowakonski, A.; Branchini, M.L. Enterobacter cloacae sepsis outbreak in a newborn unit caused by contaminated total parenteral nutrition solution. Am. J. Infect. Control 2000, 28, 258–261. [Google Scholar] [CrossRef]
- Doit, C.; Loukil, C.; Simon, A.M.; Ferroni, A.; Fontan, J.E.; Bonacorsi, S.; Bidet, P.; Jarlier, V.; Aujard, Y.; Beaufils, F.; et al. Outbreak of Burkholderia cepacia bacteremia in a pediatric hospital due to contamination of lipid emulsion stoppers. J. Clin. Microbiol. 2004, 42, 2227–2230. [Google Scholar]
- Habsah, H.; Zeehaida, M.; Van Rostenberghe, H.; Noraida, R.; Wan Pauzi, W.I.; Fatimah, I.; Rosliza, A.R.; Nik Sharimah, N.Y.; Maimunah, H. An outbreak of Pantoea spp. in a neonatal intensive care unit secondary to contaminated parenteral nutrition. J. Hosp. Infect. 2005, 61, 213–218. [Google Scholar] [CrossRef]
- Maltezou, H.C.; Tryfinopoulou, K.; Katerelos, P.; Ftika, L.; Pappa, O.; Tseroni, M.; Kostis, E.; Kostalos, C.; Prifti, H.; Tzanetou, K.; et al. Consecutive Serratia marcescens multiclone outbreaks in a neonatal intensive care unit. Am. J. Infect. Control 2012, 40, 637–642. [Google Scholar] [CrossRef]
- Archibald, L.K.; Ramos, M.; Arduino, M.J.; Aguero, S.M.; Deseda, C.; Banerjee, S.; Jarvis, W.R. Enterobacter cloacae and Pseudomonas aeruginosa polymicrobial bloodstream infections traced to extrinsic contamination of a dextrose multidose vial. J. Pediatr. 1998, 133, 640–644. [Google Scholar] [CrossRef]
- Trissel, L.A.; Gentempo, J.A.; Anderson, R.W.; Lajeunesse, J.D. Using a medium-fill simulation to evaluate the microbial contamination rate for USP medium-risk-level compounding. Am. J. Health Syst. Pharm. 2005, 62, 285–288. [Google Scholar]
- Chung, K.; Head, G. Microbiologic quality-control study for the purpose of extending the use of transfer sets on the automix 3 + 3 and micromix automated total nutrient admixture compounding pumps. JPEN J. Parenter. Enteral Nutr. 2005, 29, 118–124. [Google Scholar] [CrossRef]
- Crill, C.M.; Hak, E.B.; Robinson, L.A.; Helms, R.A. Evaluation of microbial contamination associated with different preparation methods for neonatal intravenous fat emulsion infusion. Am. J. Health Syst. Pharm. 2010, 67, 914–918. [Google Scholar] [CrossRef]
- Macias, A.E.; Munoz, J.M.; Galvan, A.; Gonzalez, J.A.; Medina, H.; Alpuche, C.; Cortes, G.; Ponce-de-Leon, S. Nosocomial bacteremia in neonates related to poor standards of care. Pediatr. Infect. Dis. J. 2005, 24, 713–716. [Google Scholar] [CrossRef]
- Pesce-Hammond, H.; Wessel, J. The A.S.P.E.N Nutrition Support Practice Manual, 2nd ed.; American Society for Parenteral and Enteral Nutrition: Silver Spring, MD, USA, 2005; pp. 3–26. [Google Scholar]
- Allwood, M.C. Safe practices in parenteral nutrition compounding—An international consensus? Nutrition 1999, 15, 409–410. [Google Scholar] [CrossRef]
- Jetzer, J.; Maisonneuve, N.; Genton, L.; Muhlebach, S.; Pichard, C. Parenteral nutrition in the Swiss hospitals: A three years national survey. Rev. Med. Suisse Romande 2002, 122, 333–337. [Google Scholar]
- Pichard, C.; Muhlebach, S.; Maisonneuve, N.; Sierro, C. Prospective survey of parenteral nutrition in Switzerland: A three-year nation-wide survey. Clin. Nutr. 2001, 20, 345–350. [Google Scholar] [CrossRef]
- Bischoff, S.C.; Kester, L.; Meier, R.; Radziwill, R.; Schwab, D.; Thul, P. Organisation, regulations, preparation and logistics of parenteral nutrition in hospitals and homes; the role of the nutrition support team—Guidelines on Parenteral Nutrition, Chapter 8. Ger. Med. Sci. 2009, 7. [Google Scholar] [CrossRef]
- Muhlebach, S.; Franken, C.; Stanga, Z. Practical handling of AIO admixtures—Guidelines on Parenteral Nutrition, Chapter 10. Ger. Med. Sci. 2009, 7. [Google Scholar] [CrossRef]
- Iacobelli, S.; Bonsante, F.; Gouyon, J.B. Fluid and electrolyte intake during the first week of life in preterm infants receiving parenteral nutrition according current guidelines. Minerva Pediatr. 2010, 62, 203–204. [Google Scholar]
- Iacobelli, S.; Bonsante, F.; Vintejoux, A.; Gouyon, J.B. Standardized parenteral nutrition in preterm infants: Early impact on fluid and electrolyte balance. Neonatology 2010, 98, 84–90. [Google Scholar] [CrossRef]
- Lenclen, R.; Crauste-Manciet, S.; Narcy, P.; Boukhouna, S.; Geffray, A.; Guerrault, M.N.; Bordet, F.; Brossard, D. Assessment of implementation of a standardized parenteral formulation for early nutritional support of very preterm infants. Eur. J. Pediatr. 2006, 165, 512–518. [Google Scholar] [CrossRef]
- Skouroliakou, M.; Koutri, K.; Stathopoulou, M.; Vourvouhaki, E.; Giannopoulou, I.; Gounaris, A. Comparison of two types of TPN prescription methods in preterm neonates. Pharm. World Sci. 2009, 31, 202–208. [Google Scholar] [CrossRef]
- Smolkin, T.; Diab, G.; Shohat, I.; Jubran, H.; Blazer, S.; Rozen, G.S.; Makhoul, I.R. Standardized versus individualized parenteral nutrition in very low birth weight infants: A comparative study. Neonatology 2010, 98, 170–178. [Google Scholar] [CrossRef]
- Senterre, T.; Rigo, J. Optimizing early nutritional support based on recent recommendations in vlbw infants allows abolishing postnatal growth restriction. J. Pediatr. Gastroenterol. Nutr. 2011, 53, 532–542. [Google Scholar]
- Senterre, T.; Rigo, J. Reduction in postnatal cumulative nutritional deficit and improvement of growth in extremely preterm infants. Acta Paediatr. 2012, 101, e64–e70. [Google Scholar] [CrossRef]
- Kuwahara, T.; Kaneda, S.; Shimono, K.; Inoue, Y. Growth of microorganisms in total parenteral nutrition solutions without lipid. Int. J. Med. Sci. 2010, 7, 43–47. [Google Scholar]
- Kuwahara, T.; Shimono, K.; Kaneda, S.; Tamura, T.; Ichihara, M.; Nakashima, Y. Growth of microorganisms in total parenteral nutrition solutions containing lipid. Int. J. Med. Sci. 2010, 7, 101–109. [Google Scholar]
- Morgan, J.; Young, L.; McGuire, W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst. Rev. 2011. [Google Scholar] [CrossRef]
- Morgan, J.; Young, L.; McGuire, W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst. Rev. 2011. [Google Scholar] [CrossRef]
- Karagol, B.S.; Zenciroglu, A.; Okumus, N.; Polin, R.A. Randomized controlled trial of slow vs. rapid enteral feeding advancements on the clinical outcomes of preterm infants with birth weight 750–1250 g. JPEN J. Parenter. Enteral Nutr. 2012. [Google Scholar] [CrossRef]
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).