Nosocomial sepsis is a serious problem for neonates who are admitted for intensive care. It is associated with an increase in mortality, morbidity, and prolonged length of hospital stay. Thus, both the human and fiscal costs of these infections are high. Although the rate of nosocomial sepsis increases with the degree of both prematurity and low birth weight, no specific lab test has been shown to be very useful in improving our ability to predict who has a “real” blood-stream infection and, therefore, who needs to be treated with a full course of antibiotics. As a result, antibiotic use is double the rate of “proven” sepsis and we are facilitating the growth of resistant organisms in the neonatal intensive care unit. The purpose of this article is to describe simple changes in process, which when implemented, can reduce nosocomial infection rates in neonates and improve outcomes.
Effective strategies to prevent nosocomial sepsis must include continuous monitoring and surveillance of infection rates and distribution of pathogens; strategic nursery design and staffing; emphasis on staff accountability for incidence of nosocomial infections; programs to increase emphasis on hand-washing compliance; cautious insertion and handling of central venous catheters; minimizing central venous catheter duration; and prudent use of antimicrobial agents. Educational programs and feedback to NICU personnel improve compliance with infection control programs.1
The simplest strategy for decreasing nosocomial sepsis and the most difficult with which to achieve compliance is good hand hygiene.2, 3, 4, 5, 6 The rationale for hand washing is to reduce transient and resident microflora.7, 8, 9, 10, 11, 12, 13, 14 Several hand-washing products have been studied. The residual effect of chlorhexidine gluconate and Triclosan® appear to provide an advantage over other disinfectants.13, 15, 16, 17 Waterless alcohol products are equally effective in initial antisepsis and improve compliance.18, 19, 20 Ensuring that hand-washing techniques13, 17 (duration of wash, type of soap) are appropriate is important. In addition, locating hand-washing opportunities close to the site of care improves compliance and reduces the risk of crosscontamination. Several controlled trials of hand washing demonstrate that it is effective at reducing nosocomial infections.8, 21, 22, 23, 24, 25
Compliance with hand washing can be improved by reducing barriers19, 20, 21, 26, 27, 28, 29 and actively promoting compliance.17, 18, 19, 20, 30 Defining specific policies, which eliminate hand-related artificial fingernails and hand jewelry that spread infection, can help reduce infection rates. Several studies have shown that Pseudomonas outbreaks have been associated with long and artificial nails.31, 32 Artificial nails are also more often colonized with pathogenic organisms than natural nails.33, 34
Use of Human-milk Feedings
In a prospective controlled trial, neonates fed breast milk were less likely to become septic compared to formula-fed neonates.35 Hylander et al.36 showed that human-milk feedings reduced the odds of sepsis/meningitis compared to preterm milk feedings (OR=0.43; 95% CI: 0.23 to 0.81). The efficacy of breast milk also appears to be dose dependent and neonates for whom breast milk is the primary source of nutrition have fewer episodes of infection than when breast milk is only a small part of the daily nutrition.37
Meta-analysis of clinical trials in low-birth-weight neonates shows that prophylactic intravenous immunoglobulin administration resulted in a significant reduction in sepsis (clinical signs and symptoms of sepsis and positive blood culture for bacteria or fungi decreased by 3%) and the occurrence of serious infection (clinical signs and symptoms in conjunction with positive cultures from blood, cerebrospinal fluid, urine was decreased by 4%).38 However, the use of intravenous immunoglobulin is not associated with improvement in other important outcomes (necrotizing enterocolitis, intraventricular hemorrhage, or length of hospital stay); therefore, most authors do not recommend routine use of intravenous immunoglobulin to prevent nosocomial sepsis.38, 39, 40
Several design factors may reduce the incidence of nosocomial sepsis. Overcrowding, inadequate design of sinks and soap containers, inconvenient placement of supplies, improper maintenance of surface-covering materials (e.g., carpet), and poorly designed air flow/isolation facilities can also increase the occurrence of neonatal sepsis. Elements of a well-designed NICU, with respect to reduction of nosocomial infection, include: 120 to 180 ft2 per bed space, sinks within 20 ft of each bed, and having all commonly used equipment easily accessible at each bedside. Each NICU needs at least one isolation room with enough space for two commonly infected babies and an area for hand washing, gowning, and storage of clean and soiled materials located directly outside or immediately inside the entry door to the room.41 It is important to remember that good designs are of little value without good policies, and bad designs can largely be rescued with good policies.
Reducing Intravascular Line-Related Infections
Line and line-connection contamination
Catheter-related sepsis has been shown to result from entry of microbes extraluminally via the skin at the insertion site and through the catheter hub after colonization of the hub during repeated manipulations.42, 43 Sepsis appearing within a short time period after catheter insertion is usually from skin contamination, while hub colonization results in bloodstream infection occurring after the first week of line duration. The same microorganism is often isolated from both the patient's skin and the catheter hub. This suggests that the health-care provider's hands may transfer skin flora to the inner surface of the catheter hub during hub manipulation and replacement of the infusion set and emphasizes the importance of good hand hygiene.44, 45, 46, 47
The design of line setups can influence the risk of infection and reducing the number of ports, decreasing the use of three-way stopcocks, and limiting the number of catheter lumens may decrease the occurrence of line sepsis.46, 47 Strategies that reduce the likelihood of line sepsis include: minimizing blood sampling by batching laboratory specimen draws;48 prepping of hubs with disinfectants;44, 49 use of an alternative hub design with an antiseptic chamber;50, 51, 52 and use of better hub connectors with needleless systems.
How the line is placed is equally important. Choosing a good site will reduce the number of percutaneous sticks required for successful placement of the line and decrease the likelihood of line contamination during the process. The skin should be carefully prepped before line placement. Available prep solutions include alcohol, povidone-iodine, and chlorhexidine gluconate. Garland et al.53 compared the efficacy of 0.5% chlorhexidine gluconate in 70% isopropyl alcohol to povidone-iodine in a nonrandomized prospective study in neonates. Chlorhexidine gluconate antisepsis was associated with decreased peripheral intravenous catheter colonization. In a prospective randomized trial of povidone-iodine, alcohol, and chlorhexidine gluconate in a surgical intensive care unit, chlorhexidine gluconate was associated with the lowest incidences of local catheter-related infection and bacteremia.54 The new guidelines from the US Department of Health and Human Services Centers for Disease Control suggest that 2% chlorhexidine gluconate-containing solutions are the agent of first choice in skin antisepsis for line insertion.42, 43
While placing a central venous catheter, the use of gown and gloves are both important. The concept of maximal barrier precautions stipulates the use of sterile cap, mask, gown, gloves, and drape. The rationale for this procedure is the reduction of contamination during the insertion process of the indwelling catheter. The benefits of this procedure have been demonstrated in prospective randomized trials in adult critical care patients.55, 56
Reducing the time the central line catheter is in place
The best method for reducing the risk of line infections is to reduce the duration of time that the central catheter is used.42, 43 Several studies show a direct correlation between the use and duration of deep lines and the incidence of sepsis in neonates.1, 57, 58, 59 In the largest of the studies, Chathas et al60 showed a critical time of 21 days, after which the risk for sepsis became significant. Most very-low-birth-weight infants will be close to full enteral calories by 21 days of age; thus, removing the central lines by 21 days is feasible. Introduction of early feedings with breast milk, consistent advancing of feeding volumes, and deciding to remove the deep lines in some infants before full enteral calories are introduced are important proactive strategies that can be used to reduce the risk of line sepsis.61, 62
Vancomycin prophylaxis for central lines
In meta-analysis, prophylactic use of vancomycin reduced blood-stream infection rates. In all five randomized-controlled trials reviewed, a decrease in the incidence of overall sepsis events and coagulase-negative Staphylococci sepsis events was reported. The authors conclude, however, that the clinical benefits are minimal and do not justify routine use of vancomycin prophylaxis.63 In addition, the risk of developing vancomycin resistance could not be conclusively disproved,63 and remains a concern with all strategies of prophylaxis with antimicrobial agents. Vancomycin-resistant enterococci are emerging as a serious problem, especially in immune-compromised patients and those admitted for intensive care.64, 65
Surface-coated central catheters
In adults, use of heparin-bonded central venous catheters reduced the nosocomial infection rate by 88%.66 Other materials that reduce bacterial adherence and the risk of colonization, when bonded to central venous catheters, include salicylic acid,43 silver,67, 68 and the glycopeptide, teicoplanin.69 Antiseptic bonding may also decrease the incidence of blood-stream infection. Agents used include cefazolin,70 iodine,71, 72 minocycline-rifampin73 and chlorhexidine-silver-sulfadiazine.74 Of note, none of these studies has involved neonates.43, 73, 74, 75, 76, 77 Until clinical studies documenting the efficacy, safety, and absence of emergence of antibiotic resistance in neonates are carried out, routine clinical use of catheters with antiseptic coatings is not warranted in the NICU.43
Removing the line when there is a positive culture
The outcome for patients whose central catheter is not removed after identification of pathogenic bacteria is worse than it is for those patients whose catheters are removed promptly.78, 79 One positive blood culture for Staphylococcus aureus or a Gram-negative rod warrants immediate central line removal in a neonate.78 In neonates who have just one positive central line culture for coagulase-negative Staphylococci, clinicians may attempt medical management without central catheter removal, but documentation of subsequent negative blood cultures is crucial.78, 79, 80, 81 In neonates who have four consecutive positive cultures or 4 or more days of positive cultures for coagulase-negative Staphylococci, the likelihood of successfully clearing the line is low78, 80 and, in some studies, there is evidence that the risk of end organ damage and poor outcome is high.78
Bloom et al.82 evaluated the performance of 52 NICUs on acquired infection, identified higher and lower centers, contrasted their processes, and isolated meaningful differences. Eight high and eight low centers were observed using the observation guide written from this rigorous evaluation process. The network average was 3.4 episodes/1000 patient days. The average of the high centers was 10.4 episodes/1000 patient days and the average of the low centers was 0.5 episodes/1000 patient days. In all, 15 meaningful differences were isolated. For example, "low" infection rate centers used two people or a closed endotracheal suction system and Tenderfoot® auto lancets for lab sampling; washed hands prior to each patient interaction; and had the intent to limit days for intravenous, central venous, and umbilical lines. In contrast, "high" infection rate centers used an open system for endotracheal suctioning, hand-held lancets, and gloves as a substitute for hand washing, and had no focus on a time limit for I.V.s, central or umbilical lines. These data suggest that simple process changes can reduce the occurrence of nosocomial sepsis.
STRATEGIES THAT DO NOT APPEAR TO DECREASE NOSOCOMIAL INFECTION
While changes in process can reduce the frequency of nosocomial infection, a number of different approaches and processes have been studied and were not found to influence the occurrence of nosocomial infections. Ventilator circuit changes more often than one time per week were not associated with a decrease in pneumonia or sepsis.83 Changing the frequency of tracheal suctioning from every 4 hours to every 8 hours did not change pneumonia or blood-stream infection rate.84 In addition, the use of closed tracheal suctioning had no effect on the incidence of nosocomial pneumonia, when compared with the open-suction method in intensive care unit patients, and actually increased the incidence of tracheal colonization versus open circuit.85 A study in neonates also showed no benefit with regard to a reduction in infections.84 Gowning before entering the NICU has no effect on reducing nosocomial infection.86, 87, 88 Infusion of fresh-frozen plasma increased immunoglobulin G levels, but did not improve bacterial opsonification or decrease infection rates.89, 90, 91 Maintaining skin integrity is important, but overuse of emollients can increase the risk of infection.92, 93, 94, 95
TREATMENT DECISIONS FOR BLOOD-STREAM INFECTIONS
Who to Treat
Determining whom to treat and for how long are difficult clinical decisions and there is no consensus on how to establish as to who has life-threatening sepsis. While some authors report that inflammatory markers (interleukin-6,96, 97, 98 interleukin-8;99, 100, 101, 102, 103, 104, 105, 106 and C-reactive protein96, 107, 108, 109, 110, 111, 112) change with acquired infection in the premature infant, only two articles have suggested a laboratory methodology that could be used to decrease antibiotic exposure on the basis of specific criteria.104, 105
A specific antibiotic choice must be driven by hospital-specific guidelines based on the major causes of nosocomial sepsis and organism susceptibility patterns in that specific hospital. However, it is equally important to recognize that our choice of antimicrobial agents influences the types of neonatal sepsis and their antibiotic resistance patterns. De Man et al.113 investigated whether the emergence of resistant strains could be halted by modifying empirical antibiotic regimens. The authors assigned two similar NICUs to different empirical antibiotic regimens. In one NICU, penicillin G and tobramycin were used for early-onset septicemia; flucloxacillin and tobramycin were used for late-onset septicemia; and no broad-spectrum beta-lactam antibiotics, such as amoxicillin and cefotaxime, were used. In the other NICU, intravenous amoxicillin with cefotaxime was the empirical therapy. The relative risk for colonization with strains resistant to the empirical therapy was 18 times higher for the amoxicillin–cefotaxime regimen compared with the penicillin–tobramycin regimen (95% CI 5.6 to 58.0, p<0.01). The authors concluded that a regimen avoiding amoxicillin and cefotaxime reduces the resistance problem.113
A second common problem in the NICU is the overuse of vancomycin.114, 115 Stoll et al.,115 studying very low birth-weight neonates (401 to 1500 g), found that 56% of 6215 infants received at least one course of antibiotics started after day 3 of birth and 44% were treated with a course of vancomycin. Vancomycin use was inversely related to birth weight (401 to 500 g, 78%; 501 to 750 g, 75%; 751 to 1000 g, 60%; 1001 to 1250 g, 36%; 1251 to 1500 g, 18%). Interestingly, 30% of patients without culture-proven infection also received this drug.115
The question that remains to be answered is whether it is safe NOT to prescribe vancomycin at the time of the initial workup. Karlowicz et al.116 showed that coagulase-negative Staphylococcus is rarely fulminant and the mortality rate among neonates with coagulase-negative Staphylococci is no different from uninfected neonates.115 It may be reasonable to consider treating stable neonates with oxacillin or nafcillin instead of vancomycin for the 24 to 48 hours that it takes to identify a positive culture for coagulase-negative Staphylococci, but this approach should be subjected to prospective study before being utilized.116
An equally important issue is what antibiotics should be chosen to cover for the Gram-negative organisms — amikacin, tobramycin, or cephalosporin. Overuse of cephalosporins has been associated with the emergence of resistant organisms113 and higher rates of fungal infections.117 The current recommendation is to use an aminoglycoside in combination with oxacillin or nafcillin as Gram-positive coverage for neonates with suspected and not-yet-proven sepsis.
Duration of Treatment
Improved culture media and new technology integrated into blood culture systems have shortened the incubation time required to detect positive culture results. Investigators have shown a 97% to 100% yield at 48 hours for positivity of blood cultures.118, 119, 120, 121, 122, 123, 124, 125 These data suggest that in the absence of clinical signs of sepsis, which suggest that the blood culture is falsely negative, antibiotics can be stopped after 48 hours of treatment, if the blood culture is negative.
The best way to reduce the overuse of antibiotics in the NICU is to establish protocols that lead to the appropriate stopping of antibiotics in neonates whose cultures are negative and who have no evidence of sepsis after a 48-hour course of therapy.
NOSOCOMIAL CANDIDA SEPSIS
The incidence of candidemia is rising steadily, and Candida species are a leading cause of infectious mortality in the NICU.58, 115, 117, 126, 127, 128, 129 The cumulative incidence of candidemia in extremely low-birth-weight (<1000 g) infants is 4% to 15%.115, 117, 128 Candida blood-stream infection is associated with an attributable mortality of 38% and a crude mortality of 30% to 75%.58, 115, 117, 126, 127, 128, 129 Prompt diagnosis and initiation of antifungal therapy are crucial to survival across patient populations.117
Like other etiologies of neonatal sepsis, the current gold standard for the diagnosis of neonatal candidiasis is the blood culture. Unfortunately, while the blood culture is sensitive for bacterial pathogens, it is a poor diagnostic tool for invasive candidiasis. From animal models, the sensitivity of the blood culture to diagnose catheter-related candidemia and acute, disseminated, overwhelming candidiasis is approximately 80%, but the sensitivity of blood culture for transient candidemia is below 50%.130, 131 Data from autopsy studies indicate that the sensitivity of blood cultures to diagnose chronic disseminated and deep organ candidiasis is less than 50%.132, 133, 134, 135 Previous analyses of incidence and attributed mortality of neonatal candidiasis are based on the use of candidemia as equivalent to invasive candidiasis and may be misleading. Neonatal candidiasis diagnosed by blood-culture techniques underestimates the burden of disease.132, 133, 134, 136
There are two studies evaluating antifungal prophylaxis.128, 129 There have been no trials examining presumptive therapy or comparing prophylaxis with presumptive therapy. One of the two trials evaluating prophylaxis did not show substantial benefit.129) Rectal colonization was decreased, but infection rates were not changed. The other trial showed benefit, but the control group (N=50) had a very high rate of neonatal candidiasis — 18%. This rate of systemic candidal infection was higher than reported previously.129 Both of these studies were single-center studies that enrolled small numbers of neonates (N=100,128 and N=103,129 respectively). A high rate of the primary end point in the control group in a small single-center study suggests that the degree of estimated effect may be an overestimate.137
In general, prophylaxis exposes far more patients with much greater cumulative doses of antimicrobial agents than empirical therapy does. Antifungal prophylaxis, in those populations where it is currently indicated (patients who have received stem-cell transplantation, for example), reduces, but does not eliminate, invasive fungal infections, and in those children who receive antifungal prophylaxis, empirical antifungal therapy continues to show benefit.137
The primary modes of treatment are removal of any lines that are the source of infection, amphotericin, and 5-fluorocytosine in neonates with central nervous system involvement.138 Since the diagnosis of Candida sepsis is difficult to make, some authors suggest empirical therapy for high-risk neonates.117 End-organ evaluation of the neonate should include a lumbar puncture, echocardiogram, abdominal ultrasound, and ophthalmologic exam as these can influence the length of therapy and prognosis.139
Nosocomial sepsis is a serious and common problem for neonates who are admitted for intensive care because it is associated with an increase in mortality, morbidity, and prolonged length of hospital stay. It is, therefore, critically important to look for simple changes in processes of care (reducing barriers to hand washing, developing careful protocols for limiting the duration and contamination of central lines, improving the design of the NICU, and early feedings), which, when implemented, can help reduce the risk of nosocomial sepsis and improve outcomes.
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Clark, R., Powers, R., White, R. et al. Prevention and Treatment of Nosocomial Sepsis in the NICU. J Perinatol 24, 446–453 (2004). https://doi.org/10.1038/sj.jp.7211125
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