Skip to main content
Download PDF
  • Review
  • Published:

Bench-to-bedside review: Challenges of diagnosis, care and prevention of central catheter-related bloodstream infections in children

Critical Care volume 17, Article number: 238 (2013) Cite this article

Abstract

Central venous catheters (CVCs) are indispensable in modern pediatric medicine. CVCs provide secure vascular access, but are associated with a risk of severe complications, in particular bloodstream infection. We provide a review of the recent literature about the diagnostic and therapeutic challenges of catheter-related bloodstream infection (CRBSI) in children and its prevention. Variations in blood sampling and limitations in blood culturing interfere with accurate and timely diagnosis of CRBSI. Although novel molecular testing methods appear promising in overcoming some of the present diagnostic limitations of conventional blood sampling in children, they still need to solidly prove their accuracy and reliability in clinical practice. Standardized practices of catheter insertion and care remain the cornerstone of CRBSI prevention although their implementation in daily practice may be difficult. Technology such as CVC impregnation or catheter locking with antimicrobial substances has been shown less effective than anticipated. Despite encouraging results in CRBSI prevention among adults, the goal of zero infection in children is still not in range. More high-quality research is needed in the field of prevention, accurate and reliable diagnostic measures and effective treatment of CRBSI in children.

Introduction

Central venous catheters (CVCs) are common and indispensable in modern pediatric medicine with an increasing number of patients requiring long-term vascular devices for various reasons. Common indications for CVC use are intensive care treatment with hemodynamic monitoring and infusion of vasoactive medication, hemodialysis as well as long-term use for chemotherapy, antibiotic treatment, parenteral nutrition (PEN) and replacement therapy for hematological or immunological diseases. CVCs provide secure vascular access, but they are also associated with catheter-related bloodstream infection (CRBSI) and central line-associated blood-stream infection (CLABSI), respectively. This review summarizes the recent literature about CRBSI and CLABSI in children focusing on long-term CVCs. The role of biofilm is discussed as well as measures for CRBSI prevention, diagnostic challenges in children, and the management of suspected infection.

Methodology

The literature search included PubMed with the search terms 'central venous catheter' and 'infection' with the limitation of age (children up to 18 years). Only articles published after 1999 and written in English were included. The title and abstract search focused on clinical studies, and only publications in line with all inclusion criteria were eligible for full-text review. Reference lists of reviews and clinical studies were used to retrieve additional literature from previous years. In total, 435 studies were retrieved for title and abstract sift in PubMed, and a total of 127 studies fulfilled the inclusion criteria for full-text review from which 95 studies were chosen for detailed qualitative assessment.

Results

CRBSI and CLABSI are multifactorial events with a reported incidence varying between 0.46 and 26.5 infections/1,000 catheter-days [1–4]. Infection rates vary with catheter types, indications, insertion sites, dwell times and patients' underlying disease. Implantable port systems have the most favorable risk, while infection rates are higher in tunneled catheters and nontunneled CVCs [5]. A number of risk factors for long-term catheters have been described such as PEN [3], young age (<2 to 3 years) [4, 6, 7], low bodyweight (<8 kg) [8], increasing number of lumens in tunneled catheters [7] and hematopoietic stem cell transplantation [1].

The most common microorganisms include coagulase-negative staphylococci (CoNS), Staphylococcus aureus, Escherichia coli, streptococci, enterococci, Candida albicans, Pseudomonas aeruginosa and Klebsiella pneumoniae [9, 10].

Multimodal prevention strategies

Avoiding contamination that would lead to subsequent CVC colonization is supposed to be the key element in decreasing the risk of CLABSI [11]. CLABSI occurs through extraluminal contamination (microorganisms migrating from the insertion site along the external of the catheter) or intraluminal contamination (pathogens migrating from the catheter hub through the lumen of the catheter) with subsequent colonization and biofilm formation [12]. While extraluminal contamination is supposed to be the most common mechanism of CLABSI with short-term catheters [13], the intraluminal route is believed to be the more prevalent route of infection with long-term catheters (duration >10 days) [14].

A number of studies demonstrate the effectiveness of implementing standardized procedures and care bundles for CVC insertion and CVC care on CLABSI or CRBSI reduction. Elements for prevention upon CVC insertion include the use of maximum sterile barrier precautions, (alcohol-based) chlorhexidine for skin antisepsis, a checklist to stop non-emergent insertion and establishing fully equipped insertion carts [15–21]. Elements for prevention in CVC care include standardization of dressing change, skin antisepsis and replacement of tubing, and improving workflow at the patient [9, 15–21]. Outcome reductions range from 70 to 83% using different strategies. No conclusion can be made for single interventions but only for the multimodal use of a defined set of procedures. Most studies applied a before-and-after study design and thus the quality of the studies is limited and the effectiveness in infection prevention may have been overestimated due to high baseline infection rates (7.8 to 8.6/1,000 days), but multimodal prevention strategies are still probably the most effective and important means of reducing CRBSI - especially for short-term catheters.

Biofilm formation in central venous catheters; prophylaxis and treatment aspects

Biofilm formation plays a major role in the pathophysiology of CRBSI. Biofilm acts both as a mechanical barrier and as an environment for genetic exchange and thereby contributes to protection from elimination by the innate host immune defense and to emerging antibiotic resistance. Biofilm formation is revealed to be a two-stepped process with initial adhesion of planktonic microorganisms and a subsequent maturation phase [22]. Bacterial expression of so-called microbial surface components recognizing adhesive matrix molecules has the capacity to bind to human matrix proteins such as fibrinogen or fibronectin [23]. Cofactors for the adhesion process are the presence of cations [24–26] and bacterial stress. The maturation phase of biofilm formation is characterized by intercellular aggregation and production of extracellular matrix leading to a typical three-dimensional structure. Bacterial lysis, DNA release and quorum-sensing systems play major roles in the development of the structure [27, 28].

Most vascular devices develop biofilm within 24 hours after insertion [22]. The occurrence of CRBSI is proportional to the occurrence of microorganisms on the catheter tip, supporting the theory that a critical level of colonization is necessary for the detachment of planktonic bacteria, embolization and systemic infection [29, 30]. The ability of a pathogen to form biofilm can be considered a virulence factor, as it is associated with mortality [31]. As metallic cations convey adherence of microorganisms to the surface of catheters, adhesion and thus biofilm formation is reduced by chelating agents [32–35]. In vitro studies found that ethylenediamine tetra-acetic acid, citrate and N-acetyl-cysteine effectively reduce proliferation of Staphylococcus epidermidis and C. albicans and even eradicate existing biofilm [36].

Preventive lock solutions

Lock solutions in CRBSI prevention were tested almost exclusively in long-term CVCs. A recent study among adult hemodialysis patients found catheter lifespan prolongation using a lock solution with a highly concentrated chelating agent (sodium citrate 46.7%) in the absence of antimicrobials [37]. CRBSI was not reduced. Similarly, a lock solution combining citrate 7%, methylene blue and paraben effectively reduced infection rates in a recent study among adult hemodialysis patients [38].

Antibiotic CVC locks versus heparin locks were found effective in adults by a recent systematic review (relative risk = 0.37/catheter-day (95% confidence interval = 0.30 to 0.47)) [39]. Only one randomized controlled trial (RCT) has compared a vancomycine lock with heparin in a predominantly pediatric population, reporting a reduction of bacteremia among non-neutropenic patients [40]. Two RCTs evaluated the effect of adding vancomycine to PEN infusions in neonates and found bacteremia and CVC colonization significantly reduced [41, 42]. In vitro studies suggested a synergistic effect by combining antibiotics, chelators and disinfectants [43–45]. A small proof-of-concept study confirmed the effectiveness of a lock solution combining minocycline and ethylene-diamine tetraacetic acid on infection rates and prolonged catheter survival as compared with heparin [46]. An additional small study reported a similar effect for minocycline/ethylenediamine tetraacetic acid among a small cohort of children with an implantable device [47]. There are no comparative studies between antibiotics alone and in combination with chelating agents.

Various non-antibiotic locking techniques have been proposed, such as taurolidine-citrate for hemodialysis catheters [48]. Taurolidine acts as a disinfectant, irreversibly damaging bacterial and fungal cell walls and disrupting biofilm, while citrate is a chelating agent [48]. Taurolidine-citrate locks reduced the incidence of bloodstream infection (BSI) due to Gram-negative organisms in two adult studies, but showed limited effect when BSI was caused by Gram-positive organisms [49, 50]. In contrast, a recent study among pediatric hematology patients reported reduced overall BSI incidence in the taurolidine group as compared with the heparin group [51]. The study was very small, however, which puts the finding into perspective.

Ethanol locks, preferably at a concentration of 70%, have been studied mostly in children requiring PEN [52–54]. Ethanol appears to affect biofilm formation through protein denaturation [36]. A recent systematic review evaluated four studies among children treated by PEN and calculated a relative risk of 0.19 (95% confidence interval = 0.12 to 0.32) for CRBSI [52]. However, the included studies were heterogeneous, retrospective and small.

Impregnated catheters and dressings

In adults, technologies for infection prevention include catheters impregnated with chlorhexidine-silver sulfadiazine or antibiotics [55–58] and the use of chlorhexidine-impregnated dressings [59]. Availability of impregnated catheters for small children is limited and chlorhexidine-impregnated dressings were found to be causing contact dermatitis in neonates [60, 61]. Furthermore, no studies have been done for children other than neonates.

Two systematic reviews about the use of impregnated catheters in adults found only significant and substantial reductions in CRBSI for heparin-coated and antibiotic-impregnated catheters, while no benefits were identified for antiseptic CVCs, coated with chlorhexidine and silver sulphadiazine, or silver-impregnated CVCs. [57, 62]. The only RCT in children compared heparin-bonded against standard catheters [63]. Routine blood cultures were performed every 3 days and the catheters were cultured after removal. The hazard ratio for the endpoint of any positive culture result was 0.11 (95% confidence interval = 0.04 to 0.31) for children with heparin-bonded catheters.

Preventive strategies are summarized in Table 1.

Table 1 Strategies in the prevention of catheter-related bloodstream infections
Full size table

Thrombosis and infection

The association between catheter infection and thrombosis has been suggested repeatedly although the results of the older studies were never really confirmed and the more recent publication is limited by size [64–66]. Although some authors argue that infection precedes thrombosis, a recent pediatric study suggested that thrombotic occlusion rather precedes infection [67]. Although fibrin deposition may provoke infection [68], the vast majority of hypercoagulability disorders do not seem to predispose for CRBSI [69].

A recent Cochrane systematic review of 12 RCTs comparing the preventive administration of anti-thrombotic agents (heparin or vitamin K antagonists) against placebo in 3,611 pediatric cancer patients only found a nonsignificant trend towards decreased incidence of symptomatic deep vein thrombosis and a nonsignificant reduction of CRBSI [70]. Another Cochrane systematic review identified two studies about preventive urokinase flushing versus heparin flushing, and no significant CRBSI reduction was identified [71]. One of the included studies reported fewer occlusive events in the urokinase group but no BSI reduction [72].

In summary, the interplay between occlusion, infection and deep vein thrombosis remains unclear. Although pathophysiologically such association appears likely, no formal association has been demonstrated in children, most probably due to the fact that both events are relatively rare.

Catheter-related bloodstream infection diagnosis

Confirming CRBSI in children is challenging. According to guidelines, blood cultures should be taken both from the central catheter and from a peripheral vein upon clinical symptoms, and CRBSI is most likely when the colony count from the catheter is fivefold to 10-fold higher than the colony count from the peripheral vein, or when the differential time to positivity between the two blood culture samples exceeds 2 hours [73]. Peripheral sampling is painful and unpleasant, and thus is not routine practice in children. Blood culture sampling in children uses smaller volumes (1 to 3 ml compared with 10 to 20 ml in adults), and although specially enriched culture media are used, the chance of isolating live organisms drops below 70% as compared with adults [74, 75]. Correctly performed blood cultures are more likely to be positive [76]. Only two-thirds of the blood samples from infants <1 month old were adequate for culture, adequate being defined as containing an appropriate (age-related) volume of blood and being submitted in the correct blood culture bottle type. This information should prompt healthcare workers to be more careful when taking blood from neonates for blood culture [77]. If antibiotic treatment is initiated before sampling, the sensitivity of the test is further reduced [78]. Incubation times often exceeding 72 hours and low sensitivity due to blood sampling make traditional blood cultures a lengthy process to rule out BSI [79, 80].

As a consequence, new identification systems such as nucleic acid testing are promoted. Nucleic acid testing, which is based on pathogen lysis, nucleic acid extraction, purification, amplification and identification, can be used either to address a single pathogen of interest or to identify a large range of bacteria and fungi, even in a simultaneous process [81]. Techniques such as nucleic acid testing may serve to identify colonies isolated by culture or they may be applied directly to blood samples [81]. Protein-based identification via mass spectrometry by matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) is a rapid tool for pathogen identification, and is already widely established [82–84]. The technique uses mass spectral signals from clinical samples, which are compared with a reference database, thus allowing swift and accurate identification. MALDI-TOF has been shown to have limitations in the identification of some Gram-positive organisms or when the infection is polymicrobial [83]. However, prior culturing of organisms from clinical samples overcomes such limitation.

PCR-based diagnostics addressing housekeeping genes of microorganisms can theoretically be used directly in clinical material.

Quantitative detection of pathogen DNA without species identification may add information in confirming suspicion of CRBSI in children without prior culturing and can also detect bacterial DNA debris after initiation of antibiotic therapy [78, 85]. In one recent study, there was a dose-dependent association between the amount of bacterial DNA per microliter of blood and suspicion of confirmed BSI [86]. Concentrations >0.5 pg/μl had a high positive predictive value for CRBSI.

The most intensively studied clinical method of simultaneous, pathogen-specific diagnosis is SeptiFast (Roche, Mannheim, Germany), a multipathogen probe-based real-time PCR system targeting DNA sequences of the bacterial and fungal genome simultaneously, which allows the detection of 25 common pathogens from one single blood sample [87]. The sensitivity/ specificity values (60 to 95%/74 to 99%, depending on the pathogen) and positive predictive values of SeptiFast were superior to blood cultures in a number of studies, but the diagnostic value in clinical practice still awaits the results of large, well-designed clinical trials [81, 88, 89]. The test is rapid, but it identifies only a limited range of pathogens and does not provide information on antibiotic resistance, which is an important limitation in times of emerging resistance [87, 89].

Management of catheter-related bloodstream infection

Suspected CRBSI creates the dilemma of whether or not to remove the CVC. Guidelines recommend this decision is made based on individual, clinical judgment [59, 90]. The patient often still requires hemodynamic monitoring, fluid intake, PEN, and medication. CVC removal would therefore result in the insertion of a new catheter with the risk of mechanical and infectious complications and would expose the child to anesthesia. There is no RCT evaluating the evidence for early versus late CVC removal in neonates [91]. Only retrospective studies with conflicting conclusions are published [92–95].

CRBSI must always be treated with systemic antibiotics. However, while antibiotics are able to clear planktonic, free-floating microorganisms, their ability to eradicate biofilm-embedded organisms is limited due to low penetration into biofilm, changes in bacterial metabolism, antimicrobial resistance, and local alterations in the microenvironment of the biofilm that impair the activity of the antimicrobial agent [96]. To eradicate microorganisms embedded in biofilm, antibiotic concentrations would have to be 100-fold to 1,000-fold that required to kill free-floating organisms [97, 98]. High antibiotic concentrations instilled in the catheter lumen for hours or days alongside systemic antibiotic therapy have been used with success rates between 31 and 100% depending on the pathogen [99–106]. Most studies reported treatment durations of 14 days. Four small pediatric studies about antibiotic locks reported immediate success rates ranging from 83 to 100%, but no information about long-term effects was provided [107–110]. While inclusion criteria and choice of antibiotic vary greatly in these studies, the vast majority of infections in all studies are caused by CoNS.

In summary, attempts at CVC salvage are only recommended in uncomplicated CRBSI or CLABSI caused by bacteria that are neither too virulent nor too difficult to eradicate - predominantly CoNS or enterococci [23].

Alternative strategies for CVC treatment include nonspecific disinfectants such as hydrochloric acid (HCl). HCl is thought to disrupt biofilm through denaturation of protein components in the extracellular matrix, exposing the microorganisms to subsequent antibiotic treatment [111]. The instillation of 2 M HCl was described in 2004 for the first time [112]. Three cycles of HCl exposure for 10 minutes within 1 day in combination with systemic antibiotic therapy that took into account the susceptibility of the identified pathogen resolved the infection in 28 out of 42 (67%) patients with persistent CVC-related bacteremia, defined as positive blood cultures >48 hours after the initiation of antibiotics. Another study of HCl instillation using a similar protocol was able to prolong CVC survival as compared with a historical control [111].

Although of concern, there are no data about catheter damage due to HCl treatment [113].

Ethanol also acts as a nonspecific substance interfering with the biofilm matrix and has a direct disruptive effect on microorganisms [114]. Attempted catheter salvage by ethanol locks with dwell times between 12 and 24 hours have been reported to be successful in 67 to 88% of published observational studies and case reports [114–116]. A small RCT identified a reduced CRBSI incidence using a 70% ethanol lock in tunneled central lines among hematology patients [117]. A recent large RCT failed to show any significant reduction in the incidence of endoluminal CRBSI, however, and thus its true benefit remains uncertain [118]. This uncertainty is further supported by preliminary results of another large RCT including 359 long-term tunneled or implanted CVCs, which failed to show any benefit of a 50% ethanol lock for CRBSI prevention [119].

Therapeutic strategies are summarized in Table 2.

Table 2 Treatment strategies for catheter-related bloodstream infections in children
Full size table

Discussion

Avoiding contamination upon catheter insertion and catheter care is the cornerstone of CRBSI prevention, and a number of studies support the positive effect of improved routine procedures in the topic [9, 15–21]. In pediatric settings, study designs are mostly quasi-experimental and neither high-quality studies nor robust analyses clearly document the effect of such interventions. This does not imply that best-practice procedures would not work, however, and it is most likely that they contribute notably to a reduced risk of infection. Documented declines in infection rates [21, 120–122] allow the assumption that good clinical practice is pivotal in CRBSI prevention. These results are largely based on short-term CVCs in adult and pediatric or neonatal ICUs.

Although the contribution of the individual steps of what is called best practice is uncertain, multimodal intervention strategies were effective even if the combination of the specific interventions varied across the studies [123]. Bringing the risk of infection to the attention of healthcare providers already positively impacts patient outcomes. This phenomenon, called the Hawthorne effect, contributes to the positive outcome of many CRBSI prevention programs and thus should always be taken into account when interpreting data from quality improvement studies - especially in open-label protocols and when using a historical control group.

Although best-practice procedures of catheter insertion and catheter care to prevent bacterial colonization have been proven effective in CRBSI prevention, the principal pathogenesis of CRBSI is related to the catheter material itself promoting colonization with microorganisms and the formation of biofilm. As eradicating biofilms is difficult, if not impossible, preventing attachment and limiting biofilm formation are crucial tasks alongside correct catheter care in achieving the goal of zero infection - especially with long-term indwelling devices.

Maintaining best practice may be challenging with long-term CVCs and thus prophylactic locks have been intensively studied in pediatric patients using both antibiotics [40–42] and other antimicrobial substances [52–55] attempting to prevent the formation of biofilm. Despite evidence supporting antibiotics in lock solutions [39], there has been some reluctance to recommend such locks in routine use due to growing emergence of multi-drug-resistant microorganisms [41, 42, 46, 47]. A recent systematic review of 16 studies with a total of 176,332 CVC-days reported only one single case of bacterial resistance, but the authors argued that only few studies thoroughly addressed this issue and none performed surveillance cultures or examined long-term effects (>12 months) [39]. As for catheter salvage upon suspected BSI, pediatric studies are limited in quantity and quality. They provide limited evidence in favor of highly concentrated antibiotic lock solutions with long indwelling times, although the studies vary in design and choice of antibiotic [107–110]. On the other hand, the vast majority of detected and successfully treated CRBSIs were caused by CoNS and thus the findings are in line with the advisory guidelines, which propose that an antibiotic lock may be envisaged in uncomplicated CRBSI due to CoNS and enterococci [56]. It is of interest that primary outcome was either a subsequent negative blood culture or the absence of subsequent positive blood cultures. Bearing in mind the limited reliability of blood culture sampling in children, such an outcome may over-estimate the treatment effect. A recent adult RCT failed to demonstrate a treatment effect because the calculated sample size was not achieved due to strict exclusion criteria [124]. Most frequently, patients were excluded because of permanent CVC use, which made an 8-hour to 12-hour lock impossible. This is frequently the case in children with CRBSI because the catheter may represent the only route of administration for fluids and nutrients, and the insertion of a temporary peripheral or central line may be technically difficult or undesirable due to anesthesia.

Prophylactic locks by non-antibiotic agents such as taurolidine-citrate [51], ethanol [52–54, 117–119, 125] and HCl [111, 112] have been shown effective in pediatric settings. However, such locks imply a risk of inadvertent flushing or spillover to the systemic circulation. Due to low body weight this has more serious consequences in children, particularly in neonates. Taurolidine-citrate locks containing 4% sodium citrate provoked adverse events such as nausea, vomiting, and abnormal taste sensations in 20% of the children, possibly due to spillover of citrate causing a drop in plasma concentrations of calcium and magnesium [51]. Possible adverse events at high concentrations such as 46.7%, as used in a successful trial [37], may include severe or even fatal arrhythmias due to electrolyte disturbances [126]. The side effects of ethanol are dose dependent and include dizziness, lightheadedness, tiredness, headache and liver toxicity [115]. In addition, disseminated intravascular coagulation and thrombosis have been reported as possible adverse events in children [53, 54]. Ethanol locks, like antibiotic locks, require long indwelling times and thus their use is limited given the short time potentially available for locking in children often having only a single catheter. Spillover of HCl may cause hemolysis [112]. Such complications have not yet been reported, but generally the possible risks of HCl remain insufficiently investigated.

Antimicrobial coating of CVCs is another means to prevent infection, and impregnations with antibiotics or heparin have been shown of benefit [55, 62, 63]. However, most studies are unblinded and only one study has been performed in children. The study compared heparin coating with nonimpregnated catheters, and although CRBSI data had been obtained the reported outcome was all-cause BSI, which weakens the findings [63]. Most studies looked at catheter colonization as a primary outcome, which is questionable since a catheter may contaminate on removal. In addition, impregnated catheter tips can leak antimicrobials into the agar plate and thus provoke false negative culture results [62].

While there is evidence to support the use of antibiotic locks for CRBSI prevention, data for non-antibiotic locks in children are absent and well-designed studies are necessary to address this issue.

Quick and accurate microbiological diagnosis upon suspected CRBSI is of pivotal importance in pediatric critical care, but is challenging. New molecular techniques are promising, but not without shortcomings [81]. Methods such as MALDI-TOF are primarily add-ons requiring prior cultivation and although they shorten the time of pathogen identification, they do not overcome the challenge of low sensitivity of blood cultures in children due to inconsistent blood sampling [83].

Rapid multiplex real-time PCR tests to be applied directly to clinical samples may reduce the time to diagnosis [81]. However, existing PCR-based methods have not overcome shortcomings such as limited spectra of identifiable pathogens, limited antibiotic resistance testing, central laboratory facility requirements, lack of 24-hour availability and cost issues [87, 88]. For the time being, PCR-based methods still require conventional culture being performed because susceptibility testing is paramount in today's emerging resistance. Ideally, PCR-based methods would be performed for rapid diagnosis of a pathogen, and blood cultures would be taken to confirm pathogen identification and to obtain antibiotic susceptibility. However, in pediatric and neonatal care settings, an additional sampling volume (for example, +1.5 ml for SeptiFast) may not be feasible due to practical limitations.

Strengths and limitations

While attempting to provide a broad review of the microbiological and clinical challenges with CVCs in children, long-term catheters appear to be over-represented compared with short-term CVCs, peripherally inserted central catheters and umbilical catheters. This imbalance is partially due to the fact that short-term catheters or CVCs in the neonatal ICUs are addressed often in best-practice multimodal improvement strategies while technical prevention methods were more probably applied to long-term catheters.

Some discussed results are based on various adult populations [37, 39, 55, 57, 59, 62]. Catheters used for adults are of different length, diameter and material than those used for children, and there is a considerable difference in the disease spectrum indicating CVC placement and use in children and adults. There are also age-related physiological differences, which may affect the risk of infections related to the devices, especially the immaturity of the immune system and therefore relative immune incompetence in children.

Finally, children may have their CVCs longer than adults due to different clinical treatment regimes (that is, conversion from central to peripheral administration of medicine with increasing age) or merely due to the fact that critically ill children have better survival rates compared with adults.

Keeping in mind all of the above allows few overall evidence-based conclusions, and as such this review may leave the impression that little has been achieved. This is not the case, however, as multiple promising strategies have been proposed and indicate possible directions for future research.

Conclusion

Despite increasing research activity in CRBSI prevention in the past years, the goal of zero infection is still not in range - not for adults, and even less so for children. Insertion and care bundles addressing behavior change are difficult to implement in many hospital settings, and technology such as locks and antimicrobial impregnation of catheters are less effective than anticipated and many of them were tested in small studies of limited quality and rarely in children. For the time being, physicians must live with the limitations of blood sampling in children upon suspicion of CRBSI. New molecular tests, although promising, must show their effectiveness and reliability in clinical practice. In general, more high-quality research is needed in the field of infection prevention in children. This does not only apply for CRBSI prevention, but is indeed true for the entire field of infection control.

Abbreviations

BSI:

bloodstream infection

CLABSI:

central line-associated bloodstream infection

CoNS:

coagulase-negative staphylococci

CRBSI:

catheter-related bloodstream infection

CVC:

central venous catheter

HCl:

hydrochloric acid

MALDI-TOF:

matrix-assisted laser desorption/ionization-time of flight

PCR:

polymerase chain reaction

PEN:

parenteral nutrition

RCT:

randomized controlled trial.

References

  1. Adler A, Yaniv I, Steinberg R, Solter E, Samra Z, Stein J, Levy I: Infectious complications of implantable ports and Hickman catheters in paediatric haematology-oncology patients. J Hosp Infect. 2006, 62: 358-365. 10.1016/j.jhin.2005.08.019.

    PubMed  CAS  Google Scholar 

  2. Fratino G, Molinari AC, Parodi S, Longo S, Saracco P, Castagnola E, Haupt R: Central venous catheter-related complications in children with oncological/hematological diseases: an observational study of 418 devices. Ann Oncol. 2005, 16: 648-654. 10.1093/annonc/mdi111.

    PubMed  CAS  Google Scholar 

  3. Onder AM, Kato T, Simon N, Rivera-Hernandez M, Chandar J, Montane B, Francoeur D, Salvaggi G, Tzakis AG, Zilleruelo G: Prevention of catheterrelated bacteremia in pediatric intestinal transplantation/short gut syndrome children with long-term central venous catheters. Pediatr Transplant. 2007, 11: 87-93. 10.1111/j.1399-3046.2006.00634.x.

    PubMed  Google Scholar 

  4. Pinon M, Bezzio S, Tovo PA, Fagioli F, Farinasso L, Calabrese R, Marengo M, Giacchino M: A prospective 7-year survey on central venous catheterrelated complications at a single pediatric hospital. Eur J Pediatr. 2009, 168: 1505-1512. 10.1007/s00431-009-0968-2.

    PubMed  CAS  Google Scholar 

  5. Maki DG, Kluger DM, Crnich CJ: The risk of bloodstream infection in adults with different intravascular devices: a systematic review of 200 published prospective studies. Mayo Clin Proc. 2006, 81: 1159-1171. 10.4065/81.9.1159.

    PubMed  Google Scholar 

  6. Ruebner R, Keren R, Coffin S, Chu J, Horn D, Zaoutis TE: Complications of central venous catheters used for the treatment of acute hematogenous osteomyelitis. Pediatrics. 2006, 117: 1210-1215. 10.1542/peds.2005-1465.

    PubMed  Google Scholar 

  7. Barrett AM, Imeson J, Leese D, Philpott C, Shaw ND, Pizer BL, Windebank KP, United Kingdom Children's Cancer Study Group; Paediatric Oncology Nurses Forum of the Royal College of Nursing: Factors influencing early failure of central venous catheters in children with cancer. J Pediatr Surg. 2004, 39: 1520-1523. 10.1016/j.jpedsurg.2004.06.020.

    PubMed  Google Scholar 

  8. Garcia-Teresa MA, Casado-Flores J, Delgado Dominguez MA, Roqueta-Mas J, Cambra-Lasaosa F, Concha-Torre A, Fernandez-Perez C, Spanish Central Venous Catheter Pediatric Study Group: Infectious complications of percutaneous central venous catheterization in pediatric patients: a Spanish multicenter study. Intensive Care Med. 2007, 33: 466-476. 10.1007/s00134-006-0508-8.

    PubMed  Google Scholar 

  9. Niedner MF, Huskins WC, Colantuoni E, Muschelli J, Ii JM, Rice TB, Brilli RJ, Miller MR: Epidemiology of central line-associated bloodstream infections in the pediatric intensive care unit. Infect Control Hosp Epidemiol. 2011, 32: 1200-1208. 10.1086/662621.

    PubMed  Google Scholar 

  10. Bizzarro MJ, Raskind C, Baltimore RS, Gallagher PG: Seventy-five years of neonatal sepsis at Yale: 1928-2003. Pediatrics. 2005, 116: 595-602. 10.1542/peds.2005-0552.

    PubMed  Google Scholar 

  11. Graham PL: Simple strategies to reduce healthcare associated infections in the neonatal intensive care unit: line, tube, and hand hygiene. Clin Perinatol. 2010, 37: 645-653. 10.1016/j.clp.2010.06.005.

    PubMed  Google Scholar 

  12. Miller SE, Maragakis LL: Central line-associated bloodstream infection prevention. Curr Opin Infect Dis. 2012, 25: 412-422. 10.1097/QCO.0b013e328355e4da.

    PubMed  Google Scholar 

  13. Guidet B, Nicola I, Barakett V, Gabillet JM, Snoey E, Petit JC, Offenstadt G: Skin versus hub cultures to predict colonization and infection of central venous catheter in intensive care patients. Infection. 1994, 22: 43-48. 10.1007/BF01780765.

    PubMed  CAS  Google Scholar 

  14. Salzman MB, Isenberg HD, Shapiro JF, Lipsitz PJ, Rubin LG: A prospective study of the catheter hub as the portal of entry for microorganisms causing catheter-related sepsis in neonates. J Infect Dis. 1993, 167: 487-490. 10.1093/infdis/167.2.487.

    PubMed  CAS  Google Scholar 

  15. Miller MR, Griswold M, Harris JM, Yenokyan G, Huskins WC, Moss M, Rice TB, Ridling D, Campbell D, Margolis P, Muething S, Brilli RJ: Decreasing PICU catheter-associated bloodstream infections: NACHRI's quality transformation efforts. Pediatrics. 2010, 125: 206-213. 10.1542/peds.2009-1382.

    PubMed  Google Scholar 

  16. Miller MR, Niedner MF, Huskins WC, Colantuoni E, Yenokyan G, Moss M, Rice TB, Ridling D, Campbell D, Brilli RJ, National Association of Children's Hospitals and Related Institutions Pediatric Intensive Care Unit Central Line-Associated Bloodstream Infection Quality Transformation Teams: Reducing PICU central line-associated bloodstream infections: 3-year results. Pediatrics. 2011, 128: e1077-e1083. 10.1542/peds.2010-3675.

    PubMed  Google Scholar 

  17. Ahmed SS, McCaskey MS, Bringman S, Eigen H: Catheter-associated bloodstream infection in the pediatric intensive care unit: a multidisciplinary approach. Pediatr Crit Care Med. 2012, 13: e69-e72. 10.1097/PCC.0b013e31820ac2e1.

    PubMed  Google Scholar 

  18. Bizzarro MJ, Sabo B, Noonan M, Bonfiglio MP, Northrup V, Diefenbach K, Central Venous Catheter Initiative Committee: A quality improvement initiative to reduce central line-associated bloodstream infections in a neonatal intensive care unit. Infect Control Hosp Epidemiol. 2010, 31: 241-248. 10.1086/650448.

    PubMed  Google Scholar 

  19. Bhutta A, Gilliam C, Honeycutt M, Schexnayder S, Green J, Moss M, Anand KJ: Reduction of bloodstream infections associated with catheters in paediatric intensive care unit: stepwise approach. BMJ. 2007, 334: 362-365. 10.1136/bmj.39064.457025.DE.

    PubMed  PubMed Central  Google Scholar 

  20. Costello JM, Morrow DF, Graham DA, Potter-Bynoe G, Sandora TJ, Laussen PC: Systematic intervention to reduce central line-associated bloodstream infection rates in a pediatric cardiac intensive care unit. Pediatrics. 2008, 121: 915-923. 10.1542/peds.2007-1577.

    PubMed  Google Scholar 

  21. Schulman J, Stricof R, Stevens TP, Horgan M, Gase K, Holzman IR, Koppel RI, Nafday S, Gibbs K, Angert R, Simmonds A, Furdon SA, Saiman L, New York State Regional Perinatal Care Centers: Statewide NICU central-lineassociated bloodstream infection rates decline after bundles and checklists. Pediatrics. 2011, 127: 436-444. 10.1542/peds.2010-2873.

    PubMed  Google Scholar 

  22. Raad I, Costerton W, Sabharwal U, Sacilowski M, Anaissie E, Bodey GP: Ultrastructural analysis of indwelling vascular catheters: a quantitative relationship between luminal colonization and duration of placement. J Infect Dis. 1993, 168: 400-407. 10.1093/infdis/168.2.400.

    PubMed  CAS  Google Scholar 

  23. Vaudaux P, Pittet D, Haeberli A, Lerch PG, Morgenthaler JJ, Proctor RA, Waldvogel FA, Lew DP: Fibronectin is more active than fibrin or fibrinogen in promoting Staphylococcus aureus adherence to inserted intravascular catheters. J Infect Dis. 1993, 167: 633-641. 10.1093/infdis/167.3.633.

    PubMed  CAS  Google Scholar 

  24. Banin E, Brady KM, Greenberg EP: Chelator-induced dispersal and killing of Pseudomonas aeruginosa cells in a biofilm. Appl Environ Microbiol. 2006, 72: 2064-2069. 10.1128/AEM.72.3.2064-2069.2006.

    PubMed  CAS  PubMed Central  Google Scholar 

  25. Lin MH, Shu JC, Huang HY, Cheng YC: Involvement of iron in biofilm formation by Staphylococcus aureus. PLoS One. 2012, 7: e34388-10.1371/journal.pone.0034388.

    PubMed  CAS  PubMed Central  Google Scholar 

  26. Hoffman LR, D'Argenio DA, MacCoss MJ, Zhang Z, Jones RA, Miller SI: Aminoglycoside antibiotics induce bacterial biofilm formation. Nature. 2005, 436: 1171-1175. 10.1038/nature03912.

    PubMed  CAS  Google Scholar 

  27. Jayaraman A, Wood TK: Bacterial quorum sensing: signals, circuits, and implications for biofilms and disease. Annu Rev Biomed Eng. 2008, 10: 145-167. 10.1146/annurev.bioeng.10.061807.160536.

    PubMed  CAS  Google Scholar 

  28. Otto M: Staphylococcal biofilms. Curr Top Microbiol Immunol. 2008, 322: 207-228. 10.1007/978-3-540-75418-3_10.

    PubMed  CAS  PubMed Central  Google Scholar 

  29. Leonidou L, Gogos CA: Catheter-related bloodstream infections: catheter management according to pathogen. Int J Antimicrob Agents. 2010, 36 (Suppl 2): S26-S32.

    PubMed  CAS  Google Scholar 

  30. Schachter B: Slimy business - the biotechnology of biofilms. Nat Biotechnol. 2003, 21: 361-365. 10.1038/nbt0403-361.

    PubMed  CAS  Google Scholar 

  31. Lin MH, Chang FR, Hua MY, Wu YC, Liu ST: Inhibitory effects of 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose on biofilm formation by Staphylococcus aureus. Antimicrob Agents Chemother. 2011, 55: 1021-1027. 10.1128/AAC.00843-10.

    PubMed  CAS  PubMed Central  Google Scholar 

  32. Raad II, Hachem RY, Hanna HA, Fang X, Jiang Y, Dvorak T, Sherertz RJ, Kontoyiannis DP: Role of ethylene diamine tetra-acetic acid (EDTA) in catheter lock solutions: EDTA enhances the antifungal activity of amphotericin B lipid complex against Candida embedded in biofilm. Int J Antimicrob Agents. 2008, 32: 515-518. 10.1016/j.ijantimicag.2008.06.020.

    PubMed  CAS  Google Scholar 

  33. Raad I, Chatzinikolaou I, Chaiban G, Hanna H, Hachem R, Dvorak T, Cook G, Costerton W: In vitro and ex vivo activities of minocycline and EDTA against microorganisms embedded in biofilm on catheter surfaces. Antimicrob Agents Chemother. 2003, 47: 3580-3585. 10.1128/AAC.47.11.3580-3585.2003.

    PubMed  CAS  PubMed Central  Google Scholar 

  34. Shah CB, Mittelman MW, Costerton JW, Parenteau S, Pelak M, Arsenault R, Mermel LA: Antimicrobial activity of a novel catheter lock solution. Antimicrob Agents Chemother. 2002, 46: 1674-1679. 10.1128/AAC.46.6.1674-1679.2002.

    PubMed  CAS  PubMed Central  Google Scholar 

  35. Bergan T, Klaveness J, Aasen AJ: Chelating agents. Chemotherapy. 2001, 47: 10-14. 10.1159/000048495.

    PubMed  CAS  Google Scholar 

  36. Venkatesh M, Rong L, Raad I, Versalovic J: Novel synergistic antibiofilm combinations for salvage of infected catheters. J Med Microbiol. 2009, 58 (Pt 7): 936-944.

    PubMed  CAS  Google Scholar 

  37. Hermite L, Quenot JP, Nadji A, Barbar SD, Charles PE, Hamet M, Jacquiot N, Ghiringhelli F, Freysz M: Sodium citrate versus saline catheter locks for non-tunneled hemodialysis central venous catheters in critically ill adults: a randomized controlled trial. Intensive Care Med. 2012, 38: 279-285. 10.1007/s00134-011-2422-y.

    PubMed  CAS  Google Scholar 

  38. Maki DG, Ash SR, Winger RK, Lavin P, AZEPTIC Trial Investigators: A novel antimicrobial and antithrombotic lock solution for hemodialysis catheters: a multi-center, controlled, randomized trial. Crit Care Med. 2011, 39: 613-620. 10.1097/CCM.0b013e318206b5a2.

    PubMed  CAS  Google Scholar 

  39. Yahav D, Rozen-Zvi B, Gafter-Gvili A, Leibovici L, Gafter U, Paul M: Antimicrobial lock solutions for the prevention of infections associated with intravascular catheters in patients undergoing hemodialysis: systematic review and meta-analysis of randomized, controlled trials. Clin Infect Dis. 2008, 47: 83-93. 10.1086/588667.

    PubMed  Google Scholar 

  40. Barriga FJ, Varas M, Potin M, Sapunar F, Rojo H, Martinez A, Capdeville V, Becker A, Vial PA: Efficacy of a vancomycin solution to prevent bacteremia associated with an indwelling central venous catheter in neutropenic and non-neutropenic cancer patients. Med Pediatr Oncol. 1997, 28: 196-200. 10.1002/(SICI)1096-911X(199703)28:3<196::AID-MPO8>3.0.CO;2-E.

    PubMed  CAS  Google Scholar 

  41. Kacica MA, Horgan MJ, Ochoa L, Sandler R, Lepow ML, Venezia RA: Prevention of Gram-positive sepsis in neonates weighing less than 1500 grams. J Pediatr. 1994, 125: 253-258. 10.1016/S0022-3476(94)70207-1.

    PubMed  CAS  Google Scholar 

  42. Spafford PS, Sinkin RA, Cox C, Reubens L, Powell KR: Prevention of central venous catheter-related coagulase-negative staphylococcal sepsis in neonates. J Pediatr. 1994, 125: 259-263. 10.1016/S0022-3476(94)70208-X.

    PubMed  CAS  Google Scholar 

  43. Sherertz RJ, Boger MS, Collins CA, Mason L, Raad II: Comparative in vitro efficacies of various catheter lock solutions. Antimicrob Agents Chemother. 2006, 50: 1865-1868. 10.1128/AAC.50.5.1865-1868.2006.

    PubMed  CAS  PubMed Central  Google Scholar 

  44. Raad I, Hanna H, Dvorak T, Chaiban G, Hachem R: Optimal antimicrobial catheter lock solution, using different combinations of minocycline, EDTA, and 25-percent ethanol, rapidly eradicates organisms embedded in biofilm. Antimicrob Agents Chemother. 2007, 51: 78-83. 10.1128/AAC.00154-06.

    PubMed  CAS  PubMed Central  Google Scholar 

  45. Sauer K, Steczko J, Ash SR: Effect of a solution containing citrate/Methylene Blue/parabens on Staphylococcus aureus bacteria and biofilm, and comparison with various heparin solutions. J Antimicrob Chemother. 2009, 63: 937-945. 10.1093/jac/dkp060.

    PubMed  CAS  Google Scholar 

  46. Chatzinikolaou I, Zipf TF, Hanna H, Umphrey J, Roberts WM, Sherertz R, Hachem R, Raad I: Minocycline-ethylenediaminetetraacetate lock solution for the prevention of implantable port infections in children with cancer. Clin Infect Dis. 2003, 36: 116-119. 10.1086/344952.

    PubMed  Google Scholar 

  47. Ferreira Chacon JM, Hato de Almeida E, de Lourdes Simoes R, Lazzarin C Ozorio V, Alves BC, Mello de Andrea ML, Santiago Biernat M, Biernat JC: Randomized study of minocycline and edetic acid as a locking solution for central line (port-a-cath) in children with cancer. Chemotherapy. 2011, 57: 285-291. 10.1159/000328976.

    PubMed  Google Scholar 

  48. Torres-Viera C, Thauvin-Eliopoulos C, Souli M, DeGirolami P, Farris MG, Wennersten CB, Sofia RD, Eliopoulos GM: Activities of taurolidine in vitro and in experimental enterococcal endocarditis. Antimicrob Agents Chemother. 2000, 44: 1720-1724. 10.1128/AAC.44.6.1720-1724.2000.

    PubMed  CAS  PubMed Central  Google Scholar 

  49. Solomon LR, Cheesbrough JS, Ebah L, Al-Sayed T, Heap M, Millband N, Waterhouse D, Mitra S, Curry A, Saxena R, Bhat R, Schulz M, Diggle P: A randomized double-blind controlled trial of taurolidine-citrate catheter locks for the prevention of bacteremia in patients treated with hemodialysis. Am J Kidney Dis. 2010, 55: 1060-1068. 10.1053/j.ajkd.2009.11.025.

    PubMed  CAS  Google Scholar 

  50. Filiopoulos V, Hadjiyannakos D, Koutis I, Trompouki S, Micha T, Lazarou D, Vlassopoulos D: Approaches to prolong the use of uncuffed hemodialysis catheters: results of a randomized trial. Am J Nephrol. 2011, 33: 260-268. 10.1159/000324685.

    PubMed  Google Scholar 

  51. Dumichen MJ, Seeger K, Lode HN, Kuhl JS, Ebell W, Degenhardt P, Singer M, Geffers C, Querfeld U: Randomized controlled trial of taurolidine citrate versus heparin as catheter lock solution in paediatric patients with haematological malignancies. J Hosp Infect. 2012, 80: 304-309. 10.1016/j.jhin.2012.01.003.

    PubMed  CAS  Google Scholar 

  52. Oliveira C, Nasr A, Brindle M, Wales PW: Ethanol locks to prevent catheter-related bloodstream infections in parenteral nutrition: a metaanalysis. Pediatrics. 2012, 129: 318-329. 10.1542/peds.2011-1602.

    PubMed  Google Scholar 

  53. Cober MP, Kovacevich DS, Teitelbaum DH: Ethanol-lock therapy for the prevention of central venous access device infections in pediatric patients with intestinal failure. JPEN J Parenter Enteral Nutr. 2011, 35: 67-73. 10.1177/0148607110362758.

    PubMed  Google Scholar 

  54. Wales PW, Kosar C, Carricato M, de Silva N, Lang K, Avitzur Y: Ethanol lock therapy to reduce the incidence of catheter-related bloodstream infections in home parenteral nutrition patients with intestinal failure: preliminary experience. J Pediatr Surg. 2011, 46: 951-956. 10.1016/j.jpedsurg.2011.02.036.

    PubMed  Google Scholar 

  55. Hockenhull JC, Dwan KM, Smith GW, Gamble CL, Boland A, Walley TJ, Dickson RC: The clinical effectiveness of central venous catheters treated with anti-infective agents in preventing catheter-related bloodstream infections: a systematic review. Crit Care Med. 2009, 37: 702-712. 10.1097/CCM.0b013e3181958915.

    PubMed  CAS  Google Scholar 

  56. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O'Grady NP, Raad II, Rijnders BJ, Sherertz RJ, Warren DK: Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009, 49: 1-45. 10.1086/599376.

    PubMed  CAS  PubMed Central  Google Scholar 

  57. Ramritu P, Halton K, Collignon P, Cook D, Fraenkel D, Battistutta D, Whitby M, Graves N: A systematic review comparing the relative effectiveness of antimicrobial-coated catheters in intensive care units. Am J Infect Control. 2008, 36: 104-117. 10.1016/j.ajic.2007.02.012.

    PubMed  Google Scholar 

  58. Raad I, Mohamed JA, Reitzel RA, Jiang Y, Raad S, Al Shuaibi M, Chaftari AM, Hachem RY: Improved antibiotic-impregnated catheters with extendedspectrum activity against resistant bacteria and fungi. Antimicrob Agents Chemother. 2012, 56: 935-941. 10.1128/AAC.05836-11.

    PubMed  CAS  PubMed Central  Google Scholar 

  59. Timsit JF, Mimoz O, Mourvillier B, Souweine B, Garrouste-Orgeas M, Alfandari S, Plantefeve G, Bronchard R, Troche G, Gauzit R, Antona M, Canet E, Bohe J, Lepape A, Vesin A, Arrault X, Schwebel C, Adrie C, Zahar JR, Ruckly S, Tournegros C, Lucet JC: Randomized controlled trial of chlorhexidine dressing and highly adhesive dressing for preventing catheter-related infections in critically ill adults. Am J Respir Crit Care Med. 2012, 186: 1272-1278. 10.1164/rccm.201206-1038OC.

    PubMed  CAS  Google Scholar 

  60. Levy I, Katz J, Solter E, Samra Z, Vidne B, Birk E, Ashkenazi S, Dagan O: Chlorhexidine-impregnated dressing for prevention of colonization of central venous catheters in infants and children: a randomized controlled study. Pediatr Infect Dis J. 2005, 24: 676-679. 10.1097/01.inf.0000172934.98865.14.

    PubMed  Google Scholar 

  61. Garland JS, Alex CP, Mueller CD, Otten D, Shivpuri C, Harris MC, Naples M, Pellegrini J, Buck RK, McAuliffe TL, Goldmann DA, Maki DG: A randomized trial comparing povidone-iodine to a chlorhexidine gluconateimpregnated dressing for prevention of central venous catheter infections in neonates. Pediatrics. 2001, 107: 1431-1436. 10.1542/peds.107.6.1431.

    PubMed  CAS  Google Scholar 

  62. Gilbert RE, Harden M: Effectiveness of impregnated central venous catheters for catheter related blood stream infection: a systematic review. Curr Opin Infect Dis. 2008, 21: 235-245. 10.1097/QCO.0b013e3282ffd6e0.

    PubMed  Google Scholar 

  63. Pierce CM, Wade A, Mok Q: Heparin-bonded central venous lines reduce thrombotic and infective complications in critically ill children. Intensive Care Med. 2000, 26: 967-972. 10.1007/s001340051289.

    PubMed  CAS  Google Scholar 

  64. Timsit JF, Farkas JC, Boyer JM, Martin JB, Misset B, Renaud B, Carlet J: Central vein catheter-related thrombosis in intensive care patients: incidence, risks factors, and relationship with catheter-related sepsis. Chest. 1998, 114: 207-213. 10.1378/chest.114.1.207.

    PubMed  CAS  Google Scholar 

  65. van Rooden CJ, Schippers EF, Barge RM, Rosendaal FR, Guiot HF, van der Meer FJ, Meinders AE, Huisman MV: Infectious complications of central venous catheters increase the risk of catheter-related thrombosis in hematology patients: a prospective study. J Clin Oncol. 2005, 23: 2655-2660.

    PubMed  Google Scholar 

  66. Raad II, Luna M, Khalil SA, Costerton JW, Lam C, Bodey GP: The relationship between the thrombotic and infectious complications of central venous catheters. JAMA. 1994, 271: 1014-1016. 10.1001/jama.1994.03510370066034.

    PubMed  CAS  Google Scholar 

  67. Journeycake JM, Buchanan GR: Catheter-related deep venous thrombosis and other catheter complications in children with cancer. J Clin Oncol. 2006, 24: 4575-4580. 10.1200/JCO.2005.05.5343.

    PubMed  Google Scholar 

  68. Darouiche RO: Device-associated infections: a macroproblem that starts with microadherence. Clin Infect Dis. 2001, 33: 1567-1572. 10.1086/323130.

    PubMed  CAS  Google Scholar 

  69. Musher D, Goldsmith E, Dunbar S, Tilney G, Darouiche R, Yu Q, Lopez JA, Dong JF: Association of hypercoagulable states and increased platelet adhesion and aggregation with bacterial colonization of intravenous catheters. J Infect Dis. 2002, 186: 769-773. 10.1086/342882.

    PubMed  CAS  Google Scholar 

  70. Akl EA, Vasireddi SR, Gunukula S, Yosuico VE, Barba M, Sperati F, Cook D, Schunemann H: Anticoagulation for patients with cancer and central venous catheters. Cochrane Database Syst Rev. 2011, 4: CD006468-

    PubMed  Google Scholar 

  71. Arora RS, Roberts R, Eden TO, Pizer B: Interventions other than anticoagulants and systemic antibiotics for prevention of central venous catheter-related infections in children with cancer. Cochrane Database Syst Rev. 2010, 12: CD007785-

    PubMed  Google Scholar 

  72. Dillon PW, Jones GR, Bagnall-Reeb HA, Buckley JD, Wiener ES, Haase GM, Children's Oncology Group: Prophylactic urokinase in the management of long-term venous access devices in children: a Children's Oncology Group study. J Clin Oncol. 2004, 22: 2718-2723. 10.1200/JCO.2004.07.019.

    PubMed  CAS  Google Scholar 

  73. Mermel LA, Farr BM, Sherertz RJ, Raad II, O'Grady N, Harris JS, Craven DE, Infectious Diseases Society of America; American College of Critical Care Medicine; Society for Healthcare Epidemiology of America: Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis. 2001, 32: 1249-1272. 10.1086/320001.

    PubMed  CAS  Google Scholar 

  74. Mermel LA, Maki DG: Detection of bacteremia in adults: consequences of culturing an inadequate volume of blood. Ann Intern Med. 1993, 119: 270-272. 10.7326/0003-4819-119-4-199308150-00003.

    PubMed  CAS  Google Scholar 

  75. Randolph AG, Brun-Buisson C, Goldmann D: Identification of central venous catheter-related infections in infants and children. Pediatr Crit Care Med. 2005, 6 (3 Suppl): S19-S24.

    PubMed  Google Scholar 

  76. Connell TG, Rele M, Cowley D, Buttery JP, Curtis N: How reliable is a negative blood culture result? Volume of blood submitted for culture in routine practice in a children's hospital. Pediatrics. 2007, 119: 891-896. 10.1542/peds.2006-0440.

    PubMed  Google Scholar 

  77. Zingg W, Posfay-Barbe KM, Pittet D: Healthcare-associated infections in neonates. Curr Opin Infect Dis. 2008, 21: 228-234. 10.1097/QCO.0b013e3282fcec5f.

    PubMed  Google Scholar 

  78. Vandecasteele SJ, Van Eldere J, Merckx R, Peetermans WE: The effect of systemic antibiotics on the microbiological diagnosis of experimental foreign body infections caused by Staphylococcus epidermidis. Diagn Microbiol Infect Dis. 2004, 48: 89-95. 10.1016/j.diagmicrobio.2003.09.015.

    PubMed  CAS  Google Scholar 

  79. Leggieri N, Rida A, Francois P, Schrenzel J: Molecular diagnosis of bloodstream infections: planning to (physically) reach the bedside. Curr Opin Infect Dis. 2010, 23: 311-319.

    PubMed  CAS  Google Scholar 

  80. Shah SS, Downes KJ, Elliott MR, Bell LM, McGowan KL, Metlay JP: How long does it take to 'rule out' bacteremia in children with central venous catheters?. Pediatrics. 2008, 121: 135-141. 10.1542/peds.2007-1387.

    PubMed  Google Scholar 

  81. Afshari A, Schrenzel J, Ieven M, Harbarth S: Bench-to-bedside review: rapid molecular diagnostics for bloodstream infection - a new frontier?. Crit Care. 2012, 16: 222-10.1186/cc11202.

    PubMed  PubMed Central  Google Scholar 

  82. Kliem M, Sauer S: The essence on mass spectrometry based microbial diagnostics. Curr Opin Microbiol. 2012, 15: 397-402. 10.1016/j.mib.2012.02.006.

    PubMed  CAS  Google Scholar 

  83. La Scola B: Intact cell MALDI-TOF mass spectrometry-based approaches for the diagnosis of bloodstream infections. Expert Rev Mol Diagn. 2011, 11: 287-298.

    PubMed  CAS  Google Scholar 

  84. Carbonnelle E, Mesquita C, Bille E, Day N, Dauphin B, Beretti JL, Ferroni A, Gutmann L, Nassif X: MALDI-TOF mass spectrometry tools for bacterial identification in clinical microbiology laboratory. Clin Biochem. 2011, 44: 104-109. 10.1016/j.clinbiochem.2010.06.017.

    PubMed  CAS  Google Scholar 

  85. Millar M, Zhou W, Skinner R, Pizer B, Hennessy E, Wilks M, Gilbert RE: Accuracy of bacterial DNA testing for central venous catheter-associated bloodstream infection in children with cancer. Health Technol Assess. 2011, 15: 1-114.

    PubMed  CAS  Google Scholar 

  86. Millar MR, Johnson G, Wilks M, Skinner R, Stoneham S, Pizer B, Hemsworth S, Fogarty A, Steward C, Gilbert R, Hennessy EM: Molecular diagnosis of vascular access device-associated infection in children being treated for cancer or leukaemia. Clin Microbiol Infect. 2008, 14: 213-220. 10.1111/j.1469-0691.2007.01909.x.

    PubMed  CAS  Google Scholar 

  87. Dark P, Wilson C, Blackwood B, McAuley DF, Perkins GD, McMullan R, Gates S, Warhurst G: Accuracy of LightCycler® SeptiFast for the detection and identification of pathogens in the blood of patients with suspected sepsis: a systematic review protocol. BMJ Open. 2012, 2: e000392-10.1136/bmjopen-2011-000392.

    PubMed  PubMed Central  Google Scholar 

  88. Pasqualini L, Mencacci A, Leli C, Montagna P, Cardaccia A, Cenci E, Montecarlo I, Pirro M, di Filippo F, Cistaro E, Schillaci G, Bistoni F, Mannarino E: Diagnostic performance of a multiple real-time PCR assay in patients with suspected sepsis hospitalized in an internal medicine ward. J Clin Microbiol. 2012, 50: 1285-1288. 10.1128/JCM.06793-11.

    PubMed  CAS  PubMed Central  Google Scholar 

  89. Tschiedel E, Steinmann J, Buer J, Onnebrink JG, Felderhoff-Muser U, Rath PM, Dohna-Schwake C: Results and relevance of molecular detection of pathogens by SeptiFast - a retrospective analysis in 75 critically ill children. Klin Padiatr. 2012, 224: 12-16.

    PubMed  CAS  Google Scholar 

  90. O'Grady NP, Alexander M, Dellinger EP, Gerberding JL, Heard SO, Maki DG, Masur H, McCormick RD, Mermel LA, Pearson ML, Raad II, Randolph A, Weinstein RA: Guidelines for the prevention of intravascular catheterrelated infections. The Hospital Infection Control Practices Advisory Committee, Center for Disease Control and Prevention, U.S. Pediatrics. 2002, 110: e51-10.1542/peds.110.5.e51.

    PubMed  Google Scholar 

  91. Vasudevan C, McGuire W: Early removal versus expectant management of central venous catheters in neonates with bloodstream infection. Cochrane Database Syst Rev. 2011, 8: CD008436-

    PubMed  Google Scholar 

  92. Benjamin DK, Miller W, Garges H, Benjamin DK, McKinney RE, Cotton M, Fisher RG, Alexander KA: Bacteremia, central catheters, and neonates: when to pull the line. Pediatrics. 2001, 107: 1272-1276. 10.1542/peds.107.6.1272.

    PubMed  Google Scholar 

  93. Karlowicz MG, Furigay PJ, Croitoru DP, Buescher ES: Central venous catheter removal versus in situ treatment in neonates with coagulase-negative staphylococcal bacteremia. Pediatr Infect Dis J. 2002, 21: 22-27. 10.1097/00006454-200201000-00005.

    PubMed  Google Scholar 

  94. Greenberg RG, Moran C, Ulshen M, Smith PB, Benjamin DK, Cohen-Wolkowiez M: Outcomes of catheter-associated infections in pediatric patients with short bowel syndrome. J Pediatr Gastroenterol Nutr. 2010, 50: 460-462.

    PubMed  PubMed Central  Google Scholar 

  95. Dato VM, Dajani AS: Candidemia in children with central venous catheters: role of catheter removal and amphotericin B therapy. Pediatr Infect Dis J. 1990, 9: 309-314. 10.1097/00006454-199005000-00002.

    PubMed  CAS  Google Scholar 

  96. Aslam S: Effect of antibacterials on biofilms. Am J Infect Control. 2008, 36: S175.e9-e11. 10.1016/j.ajic.2008.10.002.

    Google Scholar 

  97. Gaillard JL, Merlino R, Pajot N, Goulet O, Fauchere JL, Ricour C, Veron M: Conventional and nonconventional modes of vancomycin administration to decontaminate the internal surface of catheters colonized with coagulase-negative staphylococci. JPEN J Parenter Enteral Nutr. 1990, 14: 593-597. 10.1177/0148607190014006593.

    PubMed  CAS  Google Scholar 

  98. Simon VC, Simon M: Antibacterial activity of teicoplanin and vancomycin in combination with rifampicin, fusidic acid or fosfomycin against staphylococci on vein catheters. Scand J Infect Dis Suppl. 1990, 72: 14-19.

    PubMed  CAS  Google Scholar 

  99. Messing B, Peitra-Cohen S, Debure A, Beliah M, Bernier JJ: Antibiotic-lock technique: a new approach to optimal therapy for catheter-related sepsis in home-parenteral nutrition patients. JPEN J Parenter Enteral Nutr. 1988, 12: 185-189. 10.1177/0148607188012002185.

    PubMed  CAS  Google Scholar 

  100. Messing B, Man F, Colimon R, Thuillier F, Beliah M: Antibiotic-lock technique is an effective treatment of bacterial catheter-related sepsis during parenteral nutrition. Clin Nutr. 1990, 9: 220-225. 10.1016/0261-5614(90)90023-L.

    PubMed  CAS  Google Scholar 

  101. Krishnasami Z, Carlton D, Bimbo L, Taylor ME, Balkovetz DF, Barker J, Allon M: Management of hemodialysis catheter-related bacteremia with an adjunctive antibiotic lock solution. Kidney Int. 2002, 61: 1136-1142. 10.1046/j.1523-1755.2002.00201.x.

    PubMed  Google Scholar 

  102. Longuet P, Douard MC, Arlet G, Molina JM, Benoit C, Leport C: Venous access port-related bacteremia in patients with acquired immunodeficiency syndrome or cancer: the reservoir as a diagnostic and therapeutic tool. Clin Infect Dis. 2001, 32: 1776-1783. 10.1086/320746.

    PubMed  CAS  Google Scholar 

  103. Ruiz-Valverde MP, Barbera JR, Segarra A, Capdevila JA, Evangelista A, Piera L: Successful treatment of catheter-related sepsis and extraluminal catheter thrombosis with vancomycin and fraxiparin without catheter removal. Nephron. 1997, 75: 354-355. 10.1159/000189561.

    PubMed  CAS  Google Scholar 

  104. Johnson DC, Johnson FL, Goldman S: Preliminary results treating persistent central venous catheter infections with the antibiotic lock technique in pediatric patients. Pediatr Infect Dis J. 1994, 13: 930-931. 10.1097/00006454-199410000-00015.

    PubMed  CAS  Google Scholar 

  105. Benoit JL, Carandang G, Sitrin M, Arnow PM: Intraluminal antibiotic treatment of central venous catheter infections in patients receiving parenteral nutrition at home. Clin Infect Dis. 1995, 21: 1286-1288. 10.1093/clinids/21.5.1286.

    PubMed  CAS  Google Scholar 

  106. Capdevila JA, Segarra A, Planes AM, Ramirez-Arellano M, Pahissa A, Piera L, Martinez-Vazquez JM: Successful treatment of haemodialysis catheterrelated sepsis without catheter removal. Nephrol Dial Transplant. 1993, 8: 231-234.

    PubMed  CAS  Google Scholar 

  107. Cuntz D, Michaud L, Guimber D, Husson MO, Gottrand F, Turck D: Local antibiotic lock for the treatment of infections related to central catheters in parenteral nutrition in children. JPEN J Parenter Enteral Nutr. 2002, 26: 104-108. 10.1177/0148607102026002104.

    PubMed  CAS  Google Scholar 

  108. De Sio L, Jenkner A, Milano GM, Ilari I, Fidani P, Castellano A, Gareri R, Donfrancesco A: Antibiotic lock with vancomycin and urokinase can successfully treat colonized central venous catheters in pediatric cancer patients. Pediatr Infect Dis J. 2004, 23: 963-965. 10.1097/01.inf.0000141740.82420.e6.

    PubMed  Google Scholar 

  109. McCarthy A, Rao JS, Byrne M, Breatnach F, O'Meara CA: Central venous catheter infections treated with teicoplanin. Eur J Haematol Suppl. 1998, 62: 15-17.

    PubMed  CAS  Google Scholar 

  110. Onder AM, Chandar J, Simon N, Diaz R, Nwobi O, Abitbol CL, Zilleruelo G: Comparison of tissue plasminogen activator-antibiotic locks with heparinantibiotic locks in children with catheter-related bacteraemia. Nephrol Dial Transplant. 2008, 23: 2604-2610. 10.1093/ndt/gfn023.

    PubMed  CAS  Google Scholar 

  111. Larsen LN, Malchau E, Kristensen B, Schroeder H: Hydrochloric acid treatment of tunneled central venous catheter infections in children with cancer. J Pediatr Hematol Oncol. 2011, 33: e64-e68. 10.1097/MPH.0b013e3181f6933d.

    PubMed  CAS  Google Scholar 

  112. Barbaric D, Curtin J, Pearson L, Shaw PJ: Role of hydrochloric acid in the treatment of central venous catheter infections in children with cancer. Cancer. 2004, 101: 1866-1872. 10.1002/cncr.20562.

    PubMed  CAS  Google Scholar 

  113. Carlsen EM, Severinsen S, Kehlet U, Schroeder H: The effect of 2 M hydrochloric acid on silicone rubber central venous catheters. J Pediatr Hematol Oncol. 2010, 32: e297-e298. 10.1097/MPH.0b013e3181e6264d.

    PubMed  CAS  Google Scholar 

  114. Valentine KM: Ethanol lock therapy for catheter-associated blood stream infections in a pediatric intensive care unit. Pediatr Crit Care Med. 2011, 12: e292-e296. 10.1097/PCC.0b013e318219267c.

    PubMed  Google Scholar 

  115. Dannenberg C, Bierbach U, Rothe A, Beer J, Korholz D: Ethanol-lock technique in the treatment of bloodstream infections in pediatric oncology patients with broviac catheter. J Pediatr Hematol Oncol. 2003, 25: 616-621. 10.1097/00043426-200308000-00006.

    PubMed  Google Scholar 

  116. Onland W, Shin CE, Fustar S, Rushing T, Wong WY: Ethanol-lock technique for persistent bacteremia of long-term intravascular devices in pediatric patients. Arch Pediatr Adolesc Med. 2006, 160: 1049-1053. 10.1001/archpedi.160.10.1049.

    PubMed  Google Scholar 

  117. Sanders J, Pithie A, Ganly P, Surgenor L, Wilson R, Merriman E, Loudon G, Judkins R, Chambers S: A prospective double-blind randomized trial comparing intraluminal ethanol with heparinized saline for the prevention of catheter-associated bloodstream infection in immunosuppressed haematology patients. J Antimicrob Chemother. 2008, 62: 809-815. 10.1093/jac/dkn284.

    PubMed  CAS  Google Scholar 

  118. Slobbe L, Doorduijn JK, Lugtenburg PJ, El Barzouhi A, Boersma E, van Leeuwen WB, Rijnders BJ: Prevention of catheter-related bacteremia with a daily ethanol lock in patients with tunnelled catheters: a randomized, placebo-controlled trial. PLoS One. 2010, 5: e10840-10.1371/journal.pone.0010840.

    PubMed  PubMed Central  Google Scholar 

  119. Crnich C, Duster M, Jones A, Maki D: Prospective randomized double-blind trial of an ethanol lock for prevention of CLABSI [Presentation K-1234]. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; San Francisco, CA. 2009, Overland Park, KS, USA: TriStar Publishing Inc

    Google Scholar 

  120. Pronovost P, Needham D, Berenholtz S, Sinopoli D, Chu H, Cosgrove S, Sexton B, Hyzy R, Welsh R, Roth G, Bander J, Kepros J, Goeschel C: An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med. 2006, 355: 2725-2732. 10.1056/NEJMoa061115.

    PubMed  CAS  Google Scholar 

  121. Centers for Disease Control and Prevention: Vital signs: central lineassociated blood stream infections - United States, 2001, 2008, and 2009. MMWR Morb Mortal Wkly Rep. 2011, 60: 243-248.

    Google Scholar 

  122. DePalo VA, McNicoll L, Cornell M, Rocha JM, Adams L, Pronovost PJ: The Rhode Island ICU collaborative: a model for reducing central lineassociated bloodstream infection and ventilator-associated pneumonia statewide. Qual Saf Health Care. 2010, 19: 555-561. 10.1136/qshc.2009.038265.

    PubMed  Google Scholar 

  123. Zingg W, Walder B, Pittet D: Prevention of catheter-related infection: toward zero risk?. Curr Opin Infect Dis. 2011, 24: 377-384. 10.1097/QCO.0b013e32834811ed.

    PubMed  Google Scholar 

  124. Rijnders BJ, Van Wijngaerden E, Vandecasteele SJ, Stas M, Peetermans WE: Treatment of long-term intravascular catheter-related bacteraemia with antibiotic lock: randomized, placebo-controlled trial. J Antimicrob Chemother. 2005, 55: 90-94.

    PubMed  CAS  Google Scholar 

  125. Mouw E, Chessman K, Lesher A, Tagge E: Use of an ethanol lock to prevent catheter-related infections in children with short bowel syndrome. J Pediatr Surg. 2008, 43: 1025-1029. 10.1016/j.jpedsurg.2008.02.026.

    PubMed  Google Scholar 

  126. Polaschegg HD, Sodemann K: Risks related to catheter locking solutions containing concentrated citrate. Nephrol Dial Transplant. 2003, 18: 2688-2690.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Bispebjerg Hospital, Copenhagen University Hospital, Bispebjerg Bakke 23, 2400, København NV, Denmark

    Susanne Janum

  2. Infection Control Program, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1211, Genève 14, Switzerland

    Walter Zingg

  3. Department of Anesthesiology, Juliane Marie Center, Rigshospitalet, Copenhagen University Hospital, Blegadmsvej 9, 2100, København Ø, Denmark

    Volker Classen & Arash Afshari

  4. Department of Pediatric and Intensive Care, Geneva University Hospitals, Rue Willy-Donzé 6, 1211, Genève 14, Switzerland

    Arash Afshari

Authors
  1. Susanne Janum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Walter Zingg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Volker Classen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arash Afshari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arash Afshari.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2

Rights and permissions

Reprints and permissions

About this article

Cite this article

Janum, S., Zingg, W., Classen, V. et al. Bench-to-bedside review: Challenges of diagnosis, care and prevention of central catheter-related bloodstream infections in children. Crit Care 17, 238 (2013). https://doi.org/10.1186/cc12730

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/cc12730

Keywords

Critical Care

ISSN: 1364-8535