Original Article
Association of Intravenous Lipid Emulsion and Coagulase-Negative Staphylococcal Bacteremia in Neonatal Intensive Care Units
N Engl J Med 1990; 323:301-308August 2, 1990
- Abstract
- Abstract
Background and Methods.
Coagulase-negative staphylococci are now the chief cause of bacteremia in neonatal intensive care units. To investigate potential risk factors for this nosocomial infection, we conducted a case–control study among 882 infants treated in two neonatal intensive care units during 1982.
Results.
The 38 case patients and 76 controls were similar with respect to 27 indicators of the severity of the underlying illness. In addition, of the 20 potential risk factors for bacteremia that we investigated, only 2 met conventional criteria for causality. Infants with coagulase-negative staphylococcal bacteremia were 5.8 times as likely as controls (95 percent confidence interval, 4.1 to 8.3) to have received intravenous lipid emulsion before the onset of bacteremia. Because the use of lipids was common, 56.6 percent of all of the cases of nosocomial bacteremia could be attributed to lipid administration. Infants with bacteremia were also 3.5 times as likely as controls (95 percent confidence interval, 1.4 to 8.3) to have had a percutaneously inserted central venous catheter (attributable risk, 14.9 percent). The induction time for bacteremia after lipid administration, usually through peripheral catheters, was often less than one day. In contrast, the average induction period for nosocomial bacteremia associated with the use of central catheters, which were rarely used for lipid administration, was at least 5.5 days.
Similar analyses of data on an additional 31 neonates treated in 1988 confirmed the strong and apparently independent association of coagulase-negative staphylococcal bacteremia with the intravenous administration of lipids (adjusted odds ratio, 5.3; 95 percent confidence interval, 3.5 to 6.7).
Conclusions.
The risk of coagulase-negative staphylococcal bacteremia in infants in neonatal intensive care units can be attributed primarily to the intravenous administration of lipid emulsions. Since lipids are critical for the nutritional support of premature infants, further studies are needed to examine the pathogenesis and prevention of lipid-associated bacteremia. (N Engl J Med 1990; 323: 301–8.)
Media in This Article
Figure 1
Average Induction Times for Nosocomial Coagulase-Negative Staphylococcal Bacteremia, in Relation to Exposure to Intravenous Lipid Emulsions (Panel A), Percutaneously Inserted Peripheral Catheters for the Administration of Lipid Emulsions (Panel B), and Percutaneously Inserted Central Venous Catheters (Panel C).Table 1
Attributes, Signs, Diagnoses, and Laboratory Values Investigated as Indicators of the Severity of Illness among 38 Case Patients and 76 Controls.*Article Activity
- Article
Coagulase-negative staphylococci have become the most common blood-culture isolates in neonatal intensive care units.1 2 3 4 5 6 7 8 9 10 Many investigators have suggested that the use of intravascular catheters, particularly central venous catheters, is a major risk factor for staphylococcal bacteremia in infants.2 , 6 , 11 12 13 14 15 16 17 18 19 20 21 22 23 Intravascular catheters are used most often in very-low-birth-weight infants with long hospital stays, however, and two groups of investigators who adjusted for these potential confounding variables did not find that the catheters themselves were an independent cause of nosocomial coagulase-negative staphylococcal bacteremia.3 , 7 Instead, they found that specific types of intravenous fluids were associated with this bacteremia.3 , 7
In this study we determined the most important independent risk factors for nosocomial coagulasenegative staphylococcal bacteremia by examining the diagnostic, supportive, and therapeutic measures commonly used in neonatal intensive care units, while adjusting for birth weight and duration of hospitalization. We also considered other epidemiologic evidence of causality, including the relation between the risk of bacteremia and the duration of exposure and the consistency of associations during the course of hospitalization.
Methods
Population for Primary Observational Study (1982 Data Set)
All infants admitted to the neonatal intensive care units of the Joint Program in Neonatology at Brigham and Women's Hospital and Children's Hospital, Boston, in 1982 were included in this portion of the study. Their names, medical-record numbers, birth weights, and lengths of stay were obtained from a computerized registry maintained by the Joint Program in Neonatology. The length of the hospital stay was calculated from the date of birth. This information is referred to as the 1982 data set.
Population for Confirmatory Study (1988 Data Set)
A second data set was obtained from an ongoing pharmacoepidemiologic study. 24 The 1988 data set included information on lipid use among all infants admitted after April 15, 1987, to the Neonatal Intensive Care Unit at Brigham and Women's Hospital and discharged before August 15, 1988.
Microbiologic Data
Physicians obtained blood for culture when the neonates' clinical condition was suggestive of infection. Common indications were apnea, bradycardia, temperature instability, lethargy, or feeding difficulties; surveillance blood cultures were not performed. Most blood for cultures was obtained percutaneously, except for that taken through the umbilical-artery catheter at the time of catheter placement. The cultures were processed in conventional two-bottle broth blood-culture systems according to standard procedures. 25 The collection of microbiologic data has previously been described in detail.8 9 10 All culture results were obtained from original logbooks in the microbiology laboratories of the two hospitals. Among 1220 admissions in 1982, there were 76 infants with positive cultures: 50 (66 percent) with coagulasenegative staphylococci, 8 (10 percent) with group B streptococci (Streptococcus agalacliae), 6 (8 percent) with Staphylococcus aureus, 3 (4 percent) with Escherichia coli, 2 (3 percent) with Enterobacter cloacae, 2 (3 percent) with enterococci (Strep, faecalis), 2 (3 percent) with Candida albicans, and 1 each (1 percent each) with Klebsiella pneumoniae, Serratia marcescens, and α-hemolytic streptococci. The distribution of organisms among the 94 infants in the 1988 data set who had positive blood cultures was similar: 59 (63 percent) had coagulase-negative staphylococci; 15 (16 percent) had group B streptococci (Strep, agalactiae); 7 (7 percent) had Staph. aureus; 3 (3 percent) had α-hemolytic streptococci; 2 (2 percent) had Haemophilus influenzae; and 1 each (1 percent each) had Esch. coli, Ent. cloacae, enterococci (Strep. faecalis), Candida parapsilosis, Klebsiella oxytoca, Strep, pneumoniae, nonhemolytic streptococcus, and Clostridium perfringens.
Blood cultures that yielded only a single morphologic type or species of coagulase-negative staphylococci were taken as evidence of bacteremia due to that organism. Only the first positive culture for each subject was counted. Bacteremia that occurred within the first 48 hours of life was not considered to be nosocomial and was excluded from further analysis.8 9 10 11 , 26 27 28
Matching of Controls to Case Patients
Separate case–control studies were conducted, one for the 1982 data set and a second for the 1988 data set. In each study, two controls without bacteremia were matched to each patient with bacteremia. The controls were matched to the individual case patients according to hospital and birth weight within 100 g for infants weighing ≤2000 g at birth or within 10 percent for those weighing more than 2000 g at birth. The controls were also matched as closely as possible for the date of discharge (approximate date of discharge). Controls were also required to have been hospitalized at least as long as the interval from the birth of the case patient to the finding of the first positive blood culture. The latter date was used as the date of onset of bacteremia.
1982 Data Set
In 1982, 882 of the 1220 infants admitted to one of the intensive care units survived and remained in the unit for more than 48 hours and thus were at risk for nosocomial infection. Forty-five of these patients (5.1 percent) had nosocomial bacteremia with coagulasenegative staphylococci. There was a strong association between this type of infection and low birth weight.8 9 10 All seven infants in this data set who weighed less than 700 g at birth had nosocomial bacteremia with coagulase-negative staphylococci; thus, there were no uninfected controls for these infants.10 Therefore, neonates with birth weights of less than 700 g had to be excluded from analysis in the 1982 data set, leaving 38 triads (each consisting of 1 case patient and 2 controls).
1988 Data Set
In the 1988 data set, 905 neonates met the criteria for inclusion. Of these, 33 (3.6 percent) had nosocomial bacteremia with coagulase-negative staphylococci. A pair of matched controls was available for 31 of the 33 case patients. The remaining 2 infants with bacteremia were the heaviest of the 33, and there were no similarly sized control infants who had been hospitalized for sufficient lengths of time.
Factors Assessed for the 1982 Data Set
Data on 27 indicators of the severity of the underlying illness, including clinical signs, diagnoses, and laboratory values (Table 1Table 1
Attributes, Signs, Diagnoses, and Laboratory Values Investigated as Indicators of the Severity of Illness among 38 Case Patients and 76 Controls.* ), and on 20 therapeutic measures that were possible risk factors for nosocomial bacteremia (Table 2Table 2
Potential Risk Factors for Nosocomial Coagulase-Negative Staphylococcal Bacteremia in 38 Case Patients and 76 Controls.) were abstracted from the medical records of the case patients and controls. The presence or absence of all study variables according to the day of hospitalization was recorded for all triads for all hospital days before the day of onset of bacteremia in the case patient. We quantified the effects of variables for which there were at least five triads of infants discordant for the exposure. We divided the peripheral venous catheters into two groups, depending on whether or not they had ever been used to administer intravenous lipid emulsion.Factors Assessed for the 1988 Data Set
The 1988 data set contained the same information on hospitals, birth weights, dates of hospitalization, blood-culture results, and intravenous lipid use as the 1982 data set. Information on other potential risk factors, included in Tables 1 and 2, such as exposure to intravascular catheters, was not available in this second, independent data set.
Epidemiologic Analysis
Analyses were carried out separately on the 1982 and the 1988 data sets. Each triad of one infant with bacteremia and two matched controls formed a stratum. First, we partitioned chi-square and calculated the MantelHaenszel summary-estimates-of-exposure odds ratios, chi, and test-based 95 percent confidence intervals for the variables listed in Tables 1 and 2.29 30 31 Second, for variables with odds ratios of more than 2.0, the effect of the duration of exposure and the consistency of the effects over time were investigated.32 , 33 To calculate relations between the risks and the duration of exposure, the infants in the triads were restratified, and the Mantel extension test for linear trend was employed. Finally, for variables with odds ratios of more than 2.0, matched triads were stratified according to the week of hospitalization in order to investigate the consistency of effect during the first five weeks of hospitalization and to obtain summary estimates of effect adjusted for time.29 , 31 , 34 , 35
Exposure variables for which there was both a significant linear relation between the risk of bacteremia and the duration of exposure and a consistent effect throughout hospitalization were further investigated to estimate the probable induction times from the beginning of exposure to the onset of bacteremia. We ordered the matched triads by defining the hospital day on which bacteremia was noted as time zero for each triad and then computed separate MantelHaenszel summary-exposure odds ratios for exposure to these variables using increasingly larger blocks of time before the bacteremia was noted. Cumulative calculations were carried out beginning with the day of bacteremia and progressing backward at one-day intervals (0.5, 1.5, 2.5, and so on) up to a total of 7.5 days of exposure before the onset of bacteremia, to search for the intervals with the largest cumulative odds ratios.32
The effect of the independent variables on the risk of nosocomial bacteremia in the 1982 data set was further investigated by adjusting for the effect of each on the other variables. Estimates of etiologic fractions were computed from risk ratios and proportions of case patients exposed to specific risk factors, according to standard methods.29 The effect of the use of intravenous lipid emulsions in the 1988 data set was assessed in a similar manner, except that data on the use of intravascular venous catheters were not available.*
Results
The 1982 Data Set
The Study Population
Both the case patients and the controls appeared to be seriously but comparably ill before the onset of nosocomial bacteremia in the case patients.* The infants with bacteremia and their matched controls had similarly low average birth weights: 1401 and 1423 g, respectively. On average, nosocomial coagulase-negative staphylococcal bacteremia occurred in the case patients on the 21st hospital day. Other general characteristics of these infants have been described previously.10 Two thirds of the study infants had apnea and bradycardia, and half had a depressed platelet count or an elevated proportion of immature neutrophils in the differential white-cell count.36 , 37
Three quarters of the infants had umbilical-artery catheters placed in order to monitor arterial blood gases, and almost all had peripheral venous catheters. Most received nutritional support in the form of glucose and protein, and about half also received intravenous lipid emulsions. About three quarters of the controls and the case patients were intubated and mechanically ventilated for an average of about 10 days before the onset of bacteremia in the case patients. Approximately three quarters of the babies had had an average of two previous episodes of suspected bacteremia in which blood cultures were negative (cultures obtained within 48 hours of an episode of suspected infection) before the onset of bacteremia in the case patients.9 , 10 Approximately 90 percent had received antibiotics for an average period of more than a week.
Initial Survey of Factors Indicating the General Severity of Underlying Illness
After adjustment for birth weight, hospital, and durationof hospitalization before the onset of bacteremia, there were no significant differences between case patients and controls and no odds ratios of more than 2.0 for any of the variables indicating the general severity of underlying illness (listed in Table 1).* Data on mortality in these infants have been published elsewhere.10 All 76 controls and 37 of the 38 case patients with bacteremia survived, again confirming that the two groups had a relatively similar degree of underlying illness.
*See NAPS document no. 04785 for seven pages of supplementary material. Order from NAPS c/o Microfiche Publications, P.O. Box 3513. Grand Central Station, New York, NY 10163–3513. Remit in advance (in U.S. funds only) $7.75 for photocopies or $4 for microfiche. Outside the United States and Canada add postage of $4.50 ($1.50 for microfiche postage). There is an invoicing fee ($15) for orders not prepaid.
Initial Survey of Potential Risk Factors for Nosocomial Coagulase-Negative Staphylococcal Bacteremia
The 20 variables listed in Table 2 may be causes of bacteremia as well as indicators of the severity of underlying disease. The case patients and the controls differed significantly or had adjusted summary-exposure odds ratios of more than 2.0 for six of these variables: exposure to nonumbilical arterial catheters, exposure to nonumbilical central venous catheters, intravenous administration of lipid emulsions, exposure to peripheral venous catheters used to administer lipid emulsions, previous antibiotic therapy, and breastmilk feeding.* These six factors were therefore analyzed further.
Relation between the Duration of Exposure to Six Selected Risk Factors and the Risk of Nosocomial Bacteremia
There were significant relations between the risk of bacteremia and the duration of exposure to nonumbilical central venous catheters, intravenous lipid emulsions, peripheral catheters through which lipids were administered, and nonumbilical arterial catheters, although significant heterogeneity was observed for nonumbilical arterial catheters over the strata of birth weight and duration of hospitalization, indicating that the relation between bacteremia and exposure to such catheters was quite inconsistent among the groups of infants (Table 3Table 3
Association of Risk with Duration of Exposure to Selected Risk Factors before the Onset of Nosocomial Coagulase-Negative Staphylococcal Bacteremia in 38 Case Patients and 76 Controls.*).Consistency of Association of Risk Factors Throughout Hospitalization
The intravenous administration of lipid emulsions, exposure to peripheral catheters through which lipids were administered, exposure to nonumbilical central venous catheters, and previous antibiotic therapy were significantly and consistently associated with subsequent bacteremia (Table 4Table 4
Consistency of Effect, According to Week of Hospitalization, of Exposure to Selected Risk Factors before the Onset of Nosocomial Coagulase-Negative Staphylococcal Bacteremia in 38 Triads of Neonates and Summary Odds Ratio during Weeks of Hospitalization.). Exposure to nonumbilical arterial catheters was associated with bacteremia as well, but there was also significant heterogeneity in this association according to the week of hospitalization, indicating that this effect was not consistent over time.Exposure to Intravenous Lipid Emulsions and Nonumbilical Central Venous Catheters as Principal Risk Factors
Only exposure to intravenous lipid emulsions, peripheral catheters used for lipid administration, and the length of time in which the nonumbilical central venous catheter was in place had a clear linear association with bacteremia that was consistent throughout hospitalization. The effect of exposure to nonumbilical arterial catheters was inconsistent over time (heterogeneity of effect, P<0.05), and the linear relation between the risk of bacteremia and the duration of exposure was inconsistent for birth weight and duration of hospitalization (heterogeneity, P<0.05). Previous antibiotic therapy showed a possible linear relation with the occurrence of bacteremia (Table 3), but this relation was not statistically significant (P>0.05), although it did appear to be consistent over time.
Adjustment of the Effects of Intravenous Lipid Emulsions and Nonumbilical Central Venous Catheters for Each Other and for Antibiotic Exposure
The overall relative odds of nosocomial coagulasenegative staphylococcal bacteremia after the intravenous administration of lipid emulsion, adjusted for hospital, approximate date of discharge, birth weight, duration of hospital stay, week of hospitalization, and exposure to central venous catheters, was 5.8 (95 percent confidence interval, 4.1 to 8.3). The relative odds of nosocomial bacteremia after exposure to nonumbilical central venous catheters, adjusted similarly exexceptthat exposure to lipid emulsion was substituted for exposure to central venous catheters, was 3.5 (95 percent confidence interval, 1.4 to 8.3). The effect of each was significant, and the associations were strong (P<10-10 for lipids and P<5 X 10-3 for nonumbilical central venous catheters).
Because the effect of previous antibiotic therapy was not completely clear, we repeated the calculations after adjusting for previous antibiotic use. The relative odds for lipid exposure fell to 2.6 (95 percent confidence interval, 2.0 to 3.3), but the association remained strong (P<10-10). Similarly, the relative odds for exposure to nonumbilical central venous catheters decreased to 2.7 (95 percent confidence interval, 2.4 to 3.1) when adjusted for previous antibiotic therapy, but the strength of the association increased substantially (P<10-10), and the lower limit for this odds ratio actually increased from 1.4 to 2.4. Although it remains unclear whether these results should be adjusted for previous antibiotic therapy, such adjustment did not substantively alter the inference that exposure to lipid emulsions and exposure to nonumbilical central venous lines both appear to be important risk factors for nosocomial coagulase-negative staphylococcal bacteremia.
*See NAPS document no, 04785 for seven pages of supplementary material. Order from NAPS c/o Microfiche Publications, P.O. Box 3513, Grand Central Station, New York, NY 10163–3513. Remit in advance (in U.S. funds only) $7.75 for photocopies or $4 for microfiche. Outside the United States and Canada add postage of $4.50 ($1.50 for microfiche postage). There is an invoicing fee ($15) for orders not prepaid.
Proportion of Cases of Bacteremia Attributable to Exposure to Lipid Emulsions and Nonumbilical Central Venous Catheters
Intravenous lipid emulsions were administered to 68.4 percent of the case patients before bacteremia occurred; this high frequency of use, combined with the adjusted odds ratio of 5.8, yielded an attributable risk of 56.6 percent. Therefore, about half of all cases of nosocomial bacteremia with coagulase-negative staphylococci in these intensive care units could be attributed to lipid exposure. The use of nonumbilical central venous catheters was much less common: only 21.1 percent of patients with bacteremia were exposed. When combined with an adjusted odds ratio of 3.5, the risk attributable to this exposure was only 14.9 percent. Adjustment for previous antibiotic therapy did not have a substantial effect on these attributable risks.
Induction Periods for Nosocomial Bacteremia in Relation to Exposure to Lipid Emulsions and Nonumbilical Central Venous Catheters
Analyses of potential induction times for coagulasenegative staphylococcal bacteremia for the different risk factors, carried out with use of widening intervals of exposure before bacteremia occurred, are presented in Figure 1Figure 1
Average Induction Times for Nosocomial Coagulase-Negative Staphylococcal Bacteremia, in Relation to Exposure to Intravenous Lipid Emulsions (Panel A), Percutaneously Inserted Peripheral Catheters for the Administration of Lipid Emulsions (Panel B), and Percutaneously Inserted Central Venous Catheters (Panel C).. The position of the relative maximal risk ratio indicates the induction time with the greatest effect on bacteremia, whereas the absolute value of each risk ratio applies only to the subgroup of infants (triads) exposed to the particular risk factor within two days of the onset of bacteremia. The induction time for all cases of lipid-associated bacteremia was short; the shortest interval, 0.5 day, had the highest exposure odds ratio (odds ratio, 39) for bacteremia (Fig. 1A). The exposure odds ratio declined monotonically with longer intervals, indicating that concurrent or very recent infusion of lipids was necessary to induce nosocomial bacteremia. Lipids were almost always infused through peripheral catheters in 1982, and all infants in whom bacteremia developed during lipid administration had peripheral venous catheters in place. The relative odds of exposure to the peripheral catheter through which the lipids were infused (Fig. 1B) remained at the same high level for more than a day and then declined with the inclusion of increasingly longer intervals. Although the numbers are small, this suggests that a catheter had to be in place for a day or two before the infusion of lipids through it resulted in bacteremia.The average induction period for nosocomial coagulase-negative staphylococcal bacteremia not associated with lipid administration was much longer (Fig. 1C). Nonumbilical central venous catheters were inserted to administer concentrated dextrose solutions, but not lipids. In fact, only 2 of the 38 case patients had these long catheters in place during lipid administration. The odds of bacteremia after exposure to percutaneously inserted central venous catheters were relatively low (odds ratio, 4) for short induction periods, but the odds increased markedly with longer induction times and remained high (odds ratio, 9) beyond 5.5 days.
Confirmatory Analysis of 1988 Data Set
The findings of the analyses of the 1988 data set were similar to those for the 1982 data set. The case patients and the controls had similar low average birth weights: 1166 and 1168 g, respectively. On average, nosocomial coagulase-negative staphylococcal bacteremia occurred among the case patients on the 16th hospital day. Repeat computations parallel to those used for Tables 3 and 4 for the 31 triads of infants in this independent data set indicated that there was a significant association between the exposure to intravenous lipid emulsion and the occurrence of nosocomial coagulase-negative staphylococcal bacteremia, and there was again a significant relation between the risk of bacteremia and the duration of exposure (P = 0.014) without significant departure from linearity or significant heterogeneity.* The relative odds of nosocomial coagulase-negative staphylococcal bacteremia after exposure to intravenous lipid emulsions, adjusted for hospital, approximate date of discharge, birth weight, duration of hospital stay, and week of hospitalization, was 5.3 (95 percent confidence interval, 3.5 to 6.7), confirming the important effect of lipids as a risk factor for nosocomial bacteremia. Because the 1988 data set did not include data on intravascular catheters, this estimate could not be further adjusted for the presence of catheters and corresponds to the summary value (odds ratio, 4.0) for the effect of lipids (Table 4).
Possible Effects of Excluded Case Patients
We also investigated the risk factors for the seven infants with bacteremia who weighed less than 700 g at birth and who were excluded from the 1982 data set because no uninfected controls could be found for them. All seven received intravenous lipids, and two had peripherally inserted central venous catheters. Since exposure to both lipids and central catheters was higher among the 7 excluded case patients than it was among the 38 included case patients, it seems likely that the odds ratios and etiologic fractions given above underestimate the true effect of lipids and central venous catheters in causing bacteremia. We also investigated the risk factors for the two case patients with the highest birth weights, who were excluded from the 1988 analysis for lack of appropriate uninfected controls. One of these case patients received lipids. Since intravenous lipid administration is less common in the care of larger infants, it appears likely that the calculated odds ratio of 5.3 is again an underestimate of the true effect of lipids in causing bacteremia.
Discussion
The infants that we studied were typical of those treated in many neonatal intensive care units. Extreme prematurity, severe respiratory distress, and fragile clinical status led these infants to be exposed to the many diagnostic and supportive procedures thatare possible risk factors for bacteremia.2 , 3 , 6 , 7 , 11 12 13 14 15 16 17 18 19 20 21 22 23 Of all the potential risk factors we investigated, only the administration of intravenous lipid emulsions and the use of nonumbilical central venous catheters fulfilled all of Hill's criteria as risk factors for nosocomial bacteremia due to coagulase-negative staphylococci.32 , 33 , 38 Both had a large effect, and the associations were also strong, especially considering the small number of study subjects. Exposure to intravenous lipid emulsion was common, whereas the use of nonumbilical central venous catheters was relatively rare. As a result, the overall effect of lipid use as a determinant of nosocomial bacteremia (attributable risk, 56.6 percent) was far greater than that of nonumbilical central catheters (attributable risk, 14.9 percent). In our intensive care units in 1982, lipid emulsions were almost always administered through peripheral venous catheters made of polytetrafluoroethylene (Teflon), but the catheters themselves were not associated with nosocomial bacteremia in the absence of lipid administration.* The association between the use of lipid emulsion and the risk of nosocomial bacteremia was confirmed by the demonstration of a remarkably similar odds ratio in a new data set obtained nearly six years later. This association has also been observed by other investigators who adjusted for birth weight and the duration of hospitalization.7
Although lipid emulsions at room temperature support the rapid proliferation of a wide variety of neonatal pathogens, including coagulase-negative staphylococci,7 , 39 40 41 we doubt that the association between lipid administration and coagulase-negative staphylococcal bacteremia can be explained by contamination of the lipids before they were administered. Lipids were administered from syringes that were prepared daily in microbiologically monitored laminar air-flow hoods and were sampled periodically for sterility. These syringes were refrigerated when not in use and discarded after 24 hours. These procedures virtually precluded a systematic, prolonged problem of contamination.
In considering the pathogenesis of lipid-associated coagulase-negative staphylococcal bacteremia, an informative analogy can be found in reports of nosocomial fungemia in neonates caused by Malassezia furfur, a lipid-requiring yeast that is also a commensal frequently found on the skin of infants.42 43 44 When lipids are administered through a colonized catheter, malassezia flourishes, ultimately leading to invasion of the bloodstream and even total occlusion of the catheter.45 Virtually all infants in our intensive care units have heavy skin colonization with coagulase-negative staphylococci within the first week of life,46 and plasmid analysis has revealed that the majority of strains recovered from the blood and skin of neonates with bacteremia are identical.47 Bacteria from the skin travel along the outside of percutaneously inserted catheters, quickly taking up residence on their intravascular segments.23 , 48 The colonization of catheters may be greater for strains of coagulase-negative staphylococci that elaborate slime49 or express a polysaccharide adhesin.50
The lipids and the Teflon catheter together may be viewed as a system for the generation of bacteremia. Catheters can be colonized within one or two days (Fig. 1B), perhaps even within minutes.48 When rich nutrient growth mediums, such as lipids, are then infused through the colonized catheter, only a few hours of rapid growth are required for the numbers of coagulase-negative staphylococci to reach a level sufficient to invade the bloodstream (Fig. 1A). Lipids themselves are deposited in the catheter, slowing the rate of flow and occasionally even completely blocking the lumen.51 In addition, lipid emulsions appear to impede the function of neutrophils and macrophages, facilitating microbial invasion.52
If nutrient growth mediums in the form of lipids are not infused through the catheter, then bacterial growth in the catheter is much slower, and the same process requires almost a week to produce bacteremia (Fig. 1C). It is interesting that umbilical arterial and venous catheters were commonly used in the study population, but neither was a major cause of nosocomial coagulase-negative staphylococcal bacteremia. Both were inserted very soon after birth, before the skin of most babies had time to become colonized by coagulase-negative staphylococci. Moreover, these catheters were not used to administer lipids, the apparent "fuel" for rapid bacterial growth and infection.
We have demonstrated a strong association between lipid administration through peripheral venous catheters made of Teflon and coagulase-negative staphylococcal bacteremia in neonates. Even so, the benefits of intravenous therapy, including lipid administration, in the care of critically ill very-low-birthweight infants clearly outweigh the risks. nutritional support for these smallest neonates has contributed to a severalfold increase in survival,8 and although these bacteremias result in longer hospital stays, they are not associated with measurable excess mortality.10 Further investigation of this problem seems warranted, because lipids are a critical component of the nutritional support of premature neonates, but lipid administration through a Teflon catheter also appears to be a potentially controllable risk factor for nosocomial coagulase-negative staphylococcal bacteremia in this population. The use of catheters made of other materials or delivery systems that reduce the opportunity for coagulase-negative staphylococci to come in contact with lipids deserves investigation.
*See NAPS document no. 04785 for seven pages of supplementary material. Order from NAPS c/o Microfiche Publications, P.O. Box 3513, Grand Central Station, New York, NY 10163–3513. Remit in advance (in U.S. funds only) $7.75 for photocopies or $4 for microfiche, Outside the United States and Canada add postage of $4.50 ($1.50 for microfiche postage). There is an invoicing fee ($15) for orders not prepaid.
Supported in part by the U.S. Veterans Affairs Career Development Program and the Health Services Research and Development Program, and by a grant (FDU-0O0315) from the Food and Drug Administration. Dr. Platt is a Burroughs Wellcome Scholar in Pharmacoepidemiology.
Presented in part at the 62nd annual meeting of the American Epidemiological Society, Tampa, Florida, March 17, 1989.
Source Information
From the Channing Laboratory, Department of Medicine (J.F., R.P.), the Department of Newborn Medicine (M.F.E.), and the Infection Control Unit (R.P.), Brigham and Women's Hospital, Boston; the Brockton/West Roxbury Veterans Affairs Medical Center, West Roxbury, Mass. (J.F., N.E.S.); the Division of Infectious Diseases and the Infection Control Program (D.A.G., D.G.S.) and the Division of Newborn Medicine (M.F.E.), Children's Hospital and Harvard Medical School, Boston; and the Department of Epidemiology, Harvard School of Public Health, Boston (J.F.). Address reprint requests to Dr. Freeman (152) at the West Roxbury VA Hospital, 1400 Veterans of Foreign Wars Pky., West Roxbury, MA 02132.
- References
References
1
Battisti
CrossRef | Web of Science | Medline2
Munson
CrossRef | Web of Science | Medline3
Fleer
CrossRef | Medline4
Baumgart
Web of Science | Medline5
Cainen
CrossRef | Web of Science | Medline6
DonowitZ
CrossRef | Web of Science | Medline7
Schmidt 8
Freeman
CrossRef | Web of Science | Medline9
Sidebottom
Web of Science | Medline10
Freeman
Web of Science | Medline11
Nelson JD. The neonate. In: Donowitz LG, ed. Hospital-acquired infection in the pediatric patient. Baltimore: Williams & Wilkins, 1988:273–94.
12
Scott
CrossRef | Web of Science | Medline13
Sarrut
Medline14
Balagtas
Web of Science | Medline15
Krauss
Medline16
Cochran
Web of Science | Medline17
Vidyasagar
CrossRef | Web of Science | Medline18
Neal
Web of Science | Medline19
Bard
CrossRef | Web of Science | Medline20
Adams
Web of Science | Medline21
Peter
CrossRef | Web of Science | Medline22
Crossley
CrossRef | Web of Science | Medline23
Maki DG. Infections associated with intravascular lines. In: Remington JS, Swartz MN, eds. Current clinical topics in infectious diseases. Vol. 3. New York: McGraw-Hill, 1982:309–63.
24
Platt
Medline25
Lennette EH, Balows A, Hausler WJ Jr. Shadomy HJ, eds. Manual of clinical microbiology. 4th ed. Washington, D.C.: American Society for Microbiology, 1985.
26
Hemming
Full Text | Web of Science | Medline27
Goldmann
CrossRef | Web of Science | Medline28
Freeman
CrossRef | Medline29
Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic research: principles and quantitative methods. Belmont, Calif.: Lifetime Learning Publications, 1982.
30
Rothman KJ, Boice JD Jr. Epidemiologic analysis with a programmable calculator. Boston: Epidemiology Resources, 1979.
31
Snedecor GW, Cochran WG. Statistical methods. 7th ed. Ames: Iowa State University Press, 1980.
32
Rothman KJ. Modern epidemiology. Boston: Little, Brown, 1986.
33
Hill AB. Principles of medical statistics. 9th ed. New York: Oxford University Press, 1971.
34
Mantel
Medline35
Peto
CrossRef | Web of Science36
Manroe
CrossRef | Web of Science | Medline37
Rodwell
CrossRef | Web of Science | Medline38
Feinstein
CrossRef | Web of Science | Medline39
Weese-Mayer
CrossRef | Web of Science | Medline40
Melly
Web of Science | Medline41
Crocker
CrossRef | Web of Science | Medline42
Bell
CrossRef | Web of Science | Medline43
Powell
CrossRef | Web of Science | Medline44
Long
Web of Science | Medline45
Azimi
CrossRef | Web of Science | Medline46
Goldmann
CrossRef | Web of Science | Medline47
Valvano
CrossRef | Web of Science | Medline48
Cooper
Web of Science | Medline49
Quie
CrossRef | Web of Science | Medline50
Tojo
CrossRef | Web of Science | Medline51
Pennington
CrossRef | Web of Science | Medline52
Fischer
CrossRef | Web of Science | Medline
- Citing Articles (95)
Citing Articles
1
David A. Munson, Jacquelyn R. Evans. 2012. Health Care–Acquired Infections in the Nursery. , 551-564.
CrossRef2
Brenda B. Poindexter, Scott C. Denne. 2012. Parenteral Nutrition. , 963-971.
CrossRef3
Eric C. Eichenwald. 2012. Care of the Extremely Low-Birthweight Infant. , 390-404.
CrossRef4
M. F. Cury-Boaventura, R. Gorjão, T. Martins de Lima, J. Fiamoncini, A. B. P. Godoy, F. C. Deschamphs, F. G. Soriano, R. Curi. (2011) Effect of medium/ω-6 long chain triglyceride-based emulsion on leucocyte death and inflammatory gene expression. Clinical & Experimental Immunology 165:3, 383-392
CrossRef5
Ike Njere, Saidul Islam, Deborah Parish, Jauro Kuna, Alireza S. Keshtgar. (2011) Outcome of peripherally inserted central venous catheters in surgical and medical neonates. Journal of Pediatric Surgery 46:5, 946-950
CrossRef6
Victor Nizet, Jerome O. Klein. 2011. Bacterial Sepsis and Meningitis. , 222-275.
CrossRef7
Victor Nizet, John S. Bradley. 2011. Staphylococcal Infections. , 489-515.
CrossRef8
Jinlin Wu, Dezhi Mu. (2011) Vascular catheter-related complications in newborns. Journal of Paediatrics and Child Healthno-no
CrossRef9
Richard J. Powers, David W. Wirtschafter. (2010) Decreasing Central Line Associated Bloodstream Infection in Neonatal Intensive Care. Clinics in Perinatology 37:1, 247-272
CrossRef10
Christoph Härtel, Berit Haase, Kathryn Browning-Carmo, Corinna Gebauer, Evelyn Kattner, Angela Kribs, Hugo Segerer, Norbert Teig, Axel von der Wense, Christian Wieg, Egbert Herting, Wolfgang Göpel. (2009) Does the Enteral Feeding Advancement Affect Short-term Outcomes in Very Low Birth Weight Infants?. Journal of Pediatric Gastroenterology and Nutrition 48:4, 464-470
CrossRef11
A. Borghesi, M. Stronati. (2008) Strategies for the prevention of hospital-acquired infections in the neonatal intensive care unit. Journal of Hospital Infection 68:4, 293-300
CrossRef12
A. Holmes, C.J. Doré, A. Saraswatula, K.B. Bamford, M.S. Richards, R. Coello, N. Modi. (2008) Risk factors and recommendations for rate stratification for surveillance of neonatal healthcare-associated bloodstream infection. Journal of Hospital Infection 68:1, 66-72
CrossRef13
(2007) Empfehlung zur Prävention nosokomialer Infektionen bei neonatologischen Intensivpflegepatienten mit einem Geburtsgewicht unter 1500 g. Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 50:10, 1265-1303
CrossRef14
Tobias Strunk, Peter Richmond, Karen Simmer, Andrew Currie, Ofer Levy, David Burgner. (2007) Neonatal immune responses to coagulase-negative staphylococci. Current Opinion in Infectious Diseases 20:4, 370-375
CrossRef15
Melanie Wirtitsch, Barbara Wessner, Andreas Spittler, Erich Roth, Thomas Volk, Lucas Bachmann, Michael Hiesmayr. (2007) Effect of different lipid emulsions on the immunological function in humans: A systematic review with meta-analysis. Clinical Nutrition 26:3, 302-313
CrossRef16
Bai-Horng Su, Hsin-Yang Hsieh, Hsiao-Yu Chiu, Hsiao-Chuan Lin, Hung-Chih Lin. (2007) Nosocomial infection in a neonatal intensive care unit: A prospective study in Taiwan. American Journal of Infection Control 35:3, 190-195
CrossRef17
ELENA CARESTA, AGOSTINO PIERRO, MOTI CHOWDHURY, MARK J. PETERS, MARCO PIASTRA, SIMON EATON. (2007) Oxidation of Intravenous Lipid in Infants and Children With Systemic Inflammatory Response Syndrome and Sepsis. Pediatric Research 61:2, 228-232
CrossRef18
Maria Fernanda Cury-Boaventura, Carla Cristine Kanunfre, Renata Gorjão, Thaís Martins de Lima, Rui Curi. (2006) Mechanisms involved in Jurkat cell death induced by oleic and linoleic acids. Clinical Nutrition 25:6, 1004-1014
CrossRef19
Catherine M. Crill, Michael C. Storm, Michael L. Christensen, Charles T. Hankins, M. Bruce Jenkins, Richard A. Helms. (2006) Carnitine supplementation in premature neonates: Effect on plasma and red blood cell total carnitine concentrations, nutrition parameters and morbidity. Clinical Nutrition 25:6, 886-896
CrossRef20
Hannah Piper, Tom Jaksic, Patrick Javid. 2006. Nutrition and Wound Healing at the Age Extremes. , 301-326.
CrossRef21
Maria F. Cury-Boaventura, Renata Gorjão, Thaís Martins de Lima, Philip Newsholme, Rui Curi. (2006) Comparative toxicity of oleic and linoleic acid on human lymphocytes. Life Sciences 78:13, 1448-1456
CrossRef22
Philip L. Graham, Melissa D. Begg, Elaine Larson, Phyllis Della-Latta, Ari Allen, Lisa Saiman. (2006) Risk Factors for Late Onset Gram-Negative Sepsis in Low Birth Weight Infants Hospitalized in the Neonatal Intensive Care Unit. The Pediatric Infectious Disease Journal 25:2, 113-117
CrossRef23
Agnes van den Hoogen, Tannette G. Krediet, Cuno S.P.M. Uiterwaal, Jeroen F.G.A. Bolenius, Leo J. Gerards, André Fleer. (2006) In-line filters in central venous catheters in a neonatal intensive care unit. Journal of Perinatal Medicine 34:1, 71-74
CrossRef24
Rachel C. Orscheln, Henry R. Shinefield, Joseph W. St. Geme. 2006. Staphylococcal Infections. , 513-543.
CrossRef25
Debra L. Palazzi, Jerome O. Klein, Carol J. Baker. 2006. Bacterial Sepsis and Meningitis. , 247-295.
CrossRef26
W.C. van der Zwet, A.M. Kaiser, R.M. van Elburg, J. Berkhof, W.P.F. Fetter, G.A. Parlevliet, C.M.J.E. Vandenbroucke-Grauls. (2005) Nosocomial infections in a Dutch neonatal intensive care unit: surveillance study with definitions for infection specifically adapted for neonates. Journal of Hospital Infection 61:4, 300-311
CrossRef27
&NA;. (2005) 4. Lipids. Journal of Pediatric Gastroenterology and Nutrition 41:Supplement 2, S19-S27
CrossRef28
Michelle Versleijen, Hennie Roelofs, Frank Preijers, Dirk Roos, Geert Wanten. (2005) Parenteral lipids modulate leukocyte phenotypes in whole blood, depending on their fatty acid composition. Clinical Nutrition 24:5, 822-829
CrossRef29
A. García-de-Lorenzo, R. Denia, P. Atlan, S. Martinez-Ratero, A. Le Brun, D. Evard, G. Bereziat. (2005) Parenteral nutrition providing a restricted amount of linoleic acid in severely burned patients: a randomised double-blind study of an olive oil-based lipid emulsion v. medium/long-chain triacylglycerols. British Journal of Nutrition 94:02, 221
CrossRef30
Vladana Milisavljevic, Fann Wu, Jeannie Cimmotti, Janet Haas, Phyllis Della-Latta, Elaine Larson, Lisa Saiman. (2005) Genetic relatedness of Staphylococcus epidermidis from infected infants and staff in the neonatal intensive care unit. American Journal of Infection Control 33:6, 341-347
CrossRef31
Michael T. Brady. (2005) Health care–associated infections in the neonatal intensive care unit. American Journal of Infection Control 33:5, 268-275
CrossRef32
C. Auriti, L. Ravà, V. Di Ciommo, M.P. Ronchetti, M. Orzalesi. (2005) Short antibiotic prophylaxis for bacterial infections in a neonatal intensive care unit: a randomized controlled trial. Journal of Hospital Infection 59:4, 292-298
CrossRef33
Michael Christensen. 2005. Parenteral Formulations. , 279-302.
CrossRef34
J.-M. Reimund, G. Rahmi, G. Escalin, G. Pinna, G. Finck, C. D. Muller, B. Duclos, R. Baumann. (2005) Efficacy and safety of an olive oil-based intravenous fat emulsion in adult patients on home parenteral nutrition. Alimentary Pharmacology and Therapeutics 21:4, 445-454
CrossRef35
Eric C. Eichenwald. 2005. Care of the Extremely Low-Birth-Weight Infant. , 410-426.
CrossRef36
M. Millar. 2005. Microbial biofilms and clinical implants. , 619-636.
CrossRef37
Brenda B. Poindexter, Scott C. Denne. 2005. Parenteral Nutrition. , 1061-1070.
CrossRef38
Ira Adams-Chapman, Barbara J. Stoll. 2005. Nosocomial Infections in the Nursery. , 578-594.
CrossRef39
Jean-Marie Reimund, Olivier Scheer, Christian D Muller, Guillaume Pinna, Bernard Duclos, René Baumann. (2004) In vitro modulation of inflammatory cytokine production by three lipid emulsions with different fatty acid compositions. Clinical Nutrition 23:6, 1324-1332
CrossRef40
S. Tamilvanan. (2004) Oil-in-water lipid emulsions: implications for parenteral and ocular delivering systems. Progress in Lipid Research 43:6, 489-533
CrossRef41
Khalid N. Haque, M. Ajaz Khan, Sally Kerry, Jim Stephenson, Gretta Woods. (2004) Pattern of Culture‐Proven Neonatal Sepsis in a District General Hospital in the United Kingdom • . Infection Control and Hospital Epidemiology 25:9, 759-764
CrossRef42
Anucha Apisarnthanarak, Galit Holzmann‐Pazgal, Aaron Hamvas, Margaret A. Olsen, Victoria J. Fraser. (2004) Antimicrobial Use and the Influence of Inadequate Empiric Antimicrobial Therapy on the Outcomes of Nosocomial Bloodstream Infections in a Neonatal Intensive Care Unit • . Infection Control and Hospital Epidemiology 25:9, 735-741
CrossRef43
RA Lingen, W Baerts, ACM Marquering, GJHM Ruijs. (2004) The use of in-line intravenous filters in sick newborn infants. Acta Paediatrica 93:5, 658-662
CrossRef44
B. Hannie Eggink, Judith L. Rowen. (2003) Primary osteomyelitis and suppurative arthritis caused by coagulase-negative staphylococci in a preterm neonate. The Pediatric Infectious Disease Journal 22:6, 572-573
CrossRef45
Lisa Saiman. (2002) Risk factors for hospital-acquired infections in the neonatal intensive care unit. Seminars in Perinatology 26:5, 315-321
CrossRef46
Philip L. Graham. (2002) Staphylococcal and enterococcal infections in the neonatal intensive care unit. Seminars in Perinatology 26:5, 322-331
CrossRef47
Michael S.D. Agus, Tom Jaksic. (2002) Nutritional support of the critically ill child. Current Opinion in Pediatrics 14:4, 470-481
CrossRef48
LI-YIN CHIEN, YING MACNAB, KHALID AZIZ, WAYNE ANDREWS, DOUGLAS D. MCMILLAN, SHOO K. LEE. (2002) Variations in central venous catheter-related infection risks among Canadian neonatal intensive care units. The Pediatric Infectious Disease Journal 21:6, 505-511
CrossRef49
B. R. Thapa, Sujit Jagirdhar. (2002) Nutrition support in a surgical patient. The Indian Journal of Pediatrics 69:5, 411-415
CrossRef50
Tom Jaksic. (2002) Effective and efficient nutritional support for the injured child. Surgical Clinics of North America 82:2, 379-391
CrossRef51
D. L. Waitzberg, P. H. Lotierzo, A. F. Logullo, R. S. M. Torrinhas, C. C. A. Pereira, Rémy Meier. (2002) Parenteral lipid emulsions and phagocytic systems. British Journal of Nutrition 87:S1, S49
CrossRef52
SB Ainsworth, J Furness, AC Fenton. (2001) Randomized comparative trial between percutaneous longlines and peripheral cannulae in the delivery of neonatal parenteral nutrition. Acta Paediatrica 90:9, 1016-1020
CrossRef53
Ludo M. Mahieu, Jozef J. De Dooy, Aime O. De Muynck, Guillaume Van Melckebeke, Margareta M. Ieven, Patrick J. Van Reempts. (2001) Microbiology and Risk Factors for Catheter Exit‐Site and hub Colonization in Neonatal Intensive Care Unit Patients • . Infection Control and Hospital Epidemiology 22:6, 357-362
CrossRef54
L.M. Mahieu, J.J. De Dooy, A.E. Lenaerts, M.M. Ieven, A.O. De Muynck. (2001) Catheter manipulations and the risk of catheter-associated bloodstream infection in neonatal intensive care unit patients. Journal of Hospital Infection 48:1, 20-26
CrossRef55
Lisa A. Grohskopf, Dennis G. Maki, Annette H. Sohn, Ronda L. Sinkowitz‐Cochran, William R. Jarvis, Donald A. Goldmann. (2001) Reality Check: Should We Use Vancomycin for the Prophylaxis of Intravascular Catheter‐Associated Infections? • . Infection Control and Hospital Epidemiology 22:3, 176-179
CrossRef56
T. G. Krediet, L. J. Gerards, A. Fleer. (2000) Nosocomiale sepsis in de neonatale intensieve zorg. Tijdschrift voor kindergeneeskunde 68:3, 127-134
CrossRef57
SHARON B. BRODIE, KENNETH E. SANDS, JAMES E. GRAY, ROBERT A. PARKER, DONALD A. GOLDMANN, ROGER B. DAVIS, DOUGLAS K. RICHARDSON. (2000) Occurrence of nosocomial bloodstream infections in six neonatal intensive care units. The Pediatric Infectious Disease Journal 19:1, 56-65
CrossRef58
Paul B. Langevin, Nikolaus Gravenstein, Thomas J. Doyle, Steven A. Roberts, Stacy Skinner, Sharon O. Langevin, Paul A. Gulig. (1999) Growth of Staphylococcus aureus in Diprivan and Intralipid. Anesthesiology 91:5, 1394
CrossRef59
SAMIR S. SHAH, RICHARD A. EHRENKRANZ, PATRICK G. GALLAGHER. (1999) Increasing incidence of Gram-negative rod bacteremia in a newborn intensive care unit. The Pediatric Infectious Disease Journal 18:7, 591-595
CrossRef60
Anne G. Matlow, Ian Kitai, Haresh Kirpalani, Nicola H. Chapman, Mary Corey, Max Perlman, Paul Pencharz, Sue Jewell, Cindy Phillips‐Gordon, Richard Summerbell, E. Lee Ford‐Jones. (1999) A Randomized Trial of 72‐ Versus 24‐hour Intravenous Tubing Set Changes in Newborns Receiving Lipid Therapy • . Infection Control and Hospital Epidemiology 20:7, 487-493
CrossRef61
Lillian Sung, Karam Ramotar, Lindy M. Samson, Baldwin Toye. (1999) Bacteremia Due to Persistent Strains of Coagulase‐Negative Staphylococci in a Neonatal Intensive‐Care Unit • . Infection Control and Hospital Epidemiology 20:5, 349-351
CrossRef62
Wanten, Naber, Kruimel, Tool, Roos, Jansen. (1999) Influence of structurally different lipid emulsions on human neutrophil oxygen radical production. European Journal of Clinical Investigation 29:4, 357-363
CrossRef63
SADEGHI, WALLACE, CALDER. (1999) Dietary lipids modify the cytokine response to bacterial lipopolysaccharide in mice. Immunology 96:3, 404-410
CrossRef64
Esther Ocete, Angela Ruı́z-Extremera, Alejandro Goicoechea, Elisa Lozano, Concepción Robles, Maria Luisa Rey, Javier Salmerón. (1998) Low-dosage prophylactic vancomycin in central-venous catheters for neonates. Early Human Development 53, S181-S186
CrossRef65
A. Maas, P. Flament, A. Pardou, A. Deplano, M. Dramaix, M.J. Struelens. (1998) Central venous catheter-related bacteraemia in critically ill neonates: risk factors and impact of a prevention programme. Journal of Hospital Infection 40:3, 211-224
CrossRef66
I. Kurlat, G. Corral, F. Oliveira, G. Farinella, E. Alvarez. (1998) Infection control strategies in a neonatal intensive care unit in Argentina. Journal of Hospital Infection 40:2, 149-154
CrossRef67
R. JOHN BAIER, JOSEPH A. BOCCHINI, EDWIN G. BROWN. (1998) Selective use of vancomycin to prevent coagulase-negative staphylococcal nosocomial bacteremia in high risk very low birth weight infants. The Pediatric Infectious Disease Journal 17:3, 179-183
CrossRef68
Robert S. Baltimore. (1998) Neonatal nosocomial infections. Seminars in Perinatology 22:1, 25-32
CrossRef69
CHUN-YAN YEUNG, HUNG-CHANG LEE, FU-YUAN HUANG, CHYONG-SHI WANG. (1998) Sepsis during total parenteral nutrition. The Pediatric Infectious Disease Journal 17:2, 135-142
CrossRef70
CARLOS AVILA-FIGUEROA, DONALD A. GOLDMANN, DOUGLAS K. RICHARDSON, JAMES E. GRAY, ANGELICA FERRARI, JONATHAN FREEMAN. (1998) Intravenous lipid emulsions are the major determinant of coagulase-negative staphylococcal bacteremia in very low birth weight newborns. The Pediatric Infectious Disease Journal 17:1, 10-17
CrossRef71
R.W.I. Cooke, J.A. Nycyk, H. Okuonghuae, V. Shah, V. Damjanovic, C.A. Hart. (1997) Low-dose vancomycin prophylaxis reduces coagulase-negative staphylococcal bacteraemia in very low birthweight infants. Journal of Hospital Infection 37:4, 297-303
CrossRef72
Paul Frost, David Bihari. (1997) The route of nutritional support in the critically ill: physiological and economical considerations. Nutrition 13:9, 58-63
CrossRef73
Felix D. Battistella, John T. Widergren, John T. Anderson, John K. Siepler, Jo C. Weber, Kathleen MacColl. (1997) A Prospective, Randomized Trial of Intravenous Fat Emulsion Administration in Trauma Victims Requiring Total Parenteral Nutrition. The Journal of Trauma: Injury, Infection, and Critical Care 43:1, 52-60
CrossRef74
Jens C. Möller, Isabel Nelskamp, Reinhard Jensen, Irwin Reiss, Martina Kohl, Sören Gatermann, Heiko Iven, Ludwig Gortner. (1997) Comparison of vancomycin and teicoplanin for prophylaxis of sepsis with coagulase negative staphylococci (CONS) in very low birth weight (VLBW) infants. Journal of Perinatal Medicine 25:4, 361-367
CrossRef75
A. Bach, J. Motsch. (1996) Infectious risks associated with the use of propofol. Acta Anaesthesiologica Scandinavica 40:10, 1189-1196
CrossRef76
A. R. Bedford-Russell. (1996) New modalities for treating neonatal infection. European Journal of Pediatrics 155:S2, S21-S24
CrossRef77
M. H. Alwaidh, L. Bowden, B. Shaw, S. W. Ryan. (1996) Randomised Trial of Effect of Delayed Intravenous Lipid Administration on Chronic Lung Disease in Preterm Neonates. Journal of Pediatric Gastroenterology & Nutrition 22:3, 303-306
CrossRef78
M. L. Moro, A. Toni, I. Stolfi, M. P. Carrieri, M. Braga, C. Zunin. (1996) Risk factors for nosocomial sepsis in newborn intensive and intermediate care units. European Journal of Pediatrics 155:4, 315-322
CrossRef79
Allan G. Jensen, Annette Kirstein, Ingrid Jensen, Jens Scheibel, Frank Espersen. (1996) A 6-month Prospective Study of Hospital-acquired Bacteremia in Copenhagen County. Scandinavian Journal of Infectious Diseases 28:6, 601-608
CrossRef80
David C. Wilson. (1995) Nutrition of the preterm baby. BJOG: An International Journal of Obstetrics and Gynaecology 102:11, 854-860
CrossRef81
V. Damjanovic, H.K.F. van Saene. (1995) Coagulase-negative staphylococcal sepsis in preterm neonates. The Lancet 346:8966, 51
CrossRef82
P. A. Cairns, D. C. Wilson, B. G. McClure, H. L. Halliday, M. McReid. (1995) Percutaneous central venous catheter use in the very low birth weight neonate. European Journal of Pediatrics 154:2, 145-147
CrossRef83
James P. Nataro, Linda Corcoran, Sharon Zirin, Sharon Swink, Norton Taichman, James Goin, Mary Catherine Harris. (1994) Prospective analysis of coagulase-negative staphylococcal infection in hospitalized infants. The Journal of Pediatrics 125:5, 798-804
CrossRef84
Fanaroff, Avroy A.Korones, Sheldon B.Wright, Linda L.Wright, Elizabeth C.Poland, Ronald L.Bauer, Charles B.Tyson, Jon E.Philips, Joseph B.Edwards, WilliamLucey, Jerold F.Catz, Charlotte S.Shankaran, SeethaOh, William. (1994) A Controlled Trial of Intravenous Immune Globulin to Reduce Nosocomial Infections in Very-Low-Birth-Weight Infants. New England Journal of Medicine 330:16, 1107-1113
Full Text85
P.C. Calder, E.J. Sherrington, J. Askanazi, E.A. Newsholme. (1994) Inhibition of lymphocyte proliferation in vitro by two lipid emulsions with different fatty acid compositions. Clinical Nutrition 13:2, 69-74
CrossRef86
Michael L. Christensen, Michael L. Hancock, Jami Gattuso, Craig A. Hurwitz, Clara Smith, John McCormick, B. S. Pharm, Joseph Mirro. (1993) Parenteral nutrition associated with increased infection rate in children with cancer. Cancer 72:9, 2732-2738
CrossRef87
Jiin-Haur Chuang, Chie-Song Shieh, Nyuk-Kong Chang, Wei-Jen Chen, Jer-Nan Lin. (1993) Role of parenteral nutrition in preventing malnutrition and decreasing bacterial translocation to liver in obstructive jaundice. World Journal of Surgery 17:5, 580-585
CrossRef88
L. LEIBOVICI, W. R. GRANSDEN, S. J. EYKYN, H. KONSIBERGER, M. DRUCKER, S. D. PITLIK, I. PHILLIPS. (1993) Clinical index to predict bacteraemia caused by staphylococci. Journal of Internal Medicine 234:1, 83-89
CrossRef89
George A. Gellert, Donnell P. Ewert, Nancie Bendana, Evra Smith, Consuelo Beck-Sague, Alvin Chin, J.Michael Miller, Gary Hancock, William Welch, Laurene Mascola. (1993) A cluster of coagulase-negative staphylococcal bacteremias associated with peripheral vascular catheter colonization in a neonatal intensive care unit. American Journal of Infection Control 21:1, 16-20
CrossRef90
Florian Linhardt, Wilma Ziebuhr, Peter Meyer, Wolfgang Witte, Jörg Hacker. (1992) Pulsed-field gel electrophoresis of genomic restriction fragments as a tool for the epidemiological analysis of Staphylococcus aureus and coagulase-negative staphylococci. FEMS Microbiology Letters 95:2-3, 181-185
CrossRef91
J.R. Thurn, K.B. Crossley, A. Gerdts, L. Baken. (1992) Dynamics of coagulase-negative staphylococcal colonization in patients and employees in a surgical intensive care unit. Journal of Hospital Infection 20:4, 247-255
CrossRef92
Edward E. Tredget, Yong Ming Yu. (1992) The metabolic effects of thermal injury. World Journal of Surgery 16:1, 68-79
CrossRef93
P. C. Sedman, C. W. Ramsden, T. G. Brennan, S. S. Somers, P. J. Guillou. (1991) Effects of different lipid emulsions on lymphocyte function during total parenteral nutrition. British Journal of Surgery 78:11, 1396-1399
CrossRef94
(1991) Lipid Emulsions and Bacteremia in the NICU. New England Journal of Medicine 324:4, 267-268
Full Text95
Klein, Jerome O., . (1990) From Harmless Commensal to Invasive Pathogen. New England Journal of Medicine 323:5, 339-340
Full Text
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