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

 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 indis- pensable in modern pediatric medicine with an increas- ing 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, hemo- dialysis as well as long-term use for chemotherapy, antibiotic treatment, parenteral nutrition (PEN) and re- placement 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 dress- ing 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 inter- ventions 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 strate- gies 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 patho- physiology 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 com- ponents 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-dimen- sional structure. Bacterial lysis, DNA release and quorum-sensing systems play major roles in the develop- ment of the structure [27,28].

Most vascular devices develop biofilm within 24 hours after insertion [22]. The occurrence of CRBSI is propor- tional to the occurrence of microorganisms on the catheter tip, supporting the theory that a critical level of colonization is necessary for the detachment of plank- tonic 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 con- centrated 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 reduc- tion 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, irre- versibly 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 sulfa- diazine or antibiotics [55-58] and the use of chlor- hexidine-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]. Further- more, 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

		Potential					Level of
Intervention	Method	mechanism	Risk of harm	Population	Results	Comments	evidencea

Care and management bundles [12,15-21]	Education Skin antisepsis Daily reassessment of indication	Preventing contamination	None	Patients in pediatric ICUs [15-18,21] Pediatric cardiac ICU [20]	Outcome reductions: 70 to 83%	No assessment of individual steps High baseline infection rates	2b
Impregnated dressing [59-61]	Chlorhexidine	Preventing contamination	Reported toxicity in children	Adults in ICUs [59] Neonates [60,61]	Hazard ratio = 0.402 (95% CI = 0.186 to 0.868) for CRBSI compared with conventional dressing	Only two pediatric studies (neonates) [60,61]	(1b)b
Antibiotic- impregnated catheters [58,60-62]	Minocycline / rifampicin	Preventing biofilm formation	Antibiotic resistance	All patients in RCTs requiring a CVC [58, 62] Adults requiring a CVC, >50% treated in ICUs [60]	RR = 0.26 to 0.39 for CRBSI compared with standard catheter	Unknown cost–benefit in children Limited availability for pediatric use	(1a)b
Non-antibiotic- impregnated catheters [58,60,62,63]	Heparin coating	Preventing biofilm formation	Resistance Anaphylaxis	Pediatric ICU [63]	Hazard ratio = 0.11 (95% CI = 0.04 to 0.31) compared with standard catheter	Unknown cost–benefit in children Limited availability for pediatric use	1b (1a)b
	Chlorhexidine– silver sulfadiazine coating			All patients in RCTs requiring a CVC [58,62] Adults requiring a CVC, >50% treated in ICUs [60]	Conflicting interpretations of results		–
Antibiotic lock [39,40]	Vancomycine; minocycline; gentamycine; cefotaxim	High antibiotic concentrations Penetrating and disrupting	Antibiotic resistance	Adults and children with end- stage renal disease undergoing hemodialysis [39]	RR = 0.37/day (95% CI = 0.30 to 0.47) compared with heparin (systematic review of all antibiotic locks; adult)	Long indwelling times may compromise feasibility Only one predominantly	1b (1a)b
	Vancomycine			Patients with various malignancies and single lumen CVC, predominantly children [40]	Significantly reduced number of febrile and bacteremic episodes among non- neutropenic cancer patients		–
						pediatric
						study with
						questionable
						choice of
						outcome
Non-antibiotic lock [37,51,52, 117,118]	Chelating agents	Protein denaturation Disruption of biofilm	Systemic adverse events Catheter damage	Adults with acute renal failure undergoing hemodialysis in ICUs [37]	Chelating agents: no significant results. Only adult studies	Long indwelling times may compromise feasibility	(1b)b
	Taurolidine– citrate			Children with various malignancies requiring a CVC [51]	Taurolidine–citrate: significantly reduced risk of CRBSI		1b
	Ethanol			Pediatric patients receiving PEN [52] Adult, hematologic patients [117,118]	Ethanol: no reduction in CRBSI		1b

CI, confidence interval; CRBSI, catheter-related bloodstream infection; CVC, central venous catheter; PEN, parenteral nutrition; RCT, randomized controlled trial; RR, relative risk. aLevel of evidence refers to Oxford Centre for Evidence-based Medicine Levels of Evidence, March 2009 [http://www.cebm.net/index.aspx?o=1025]. bLevel of evidence extrapolated from studies among adults.