Lock Therapy for Treatment and Prevention of Catheter-related Infections

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Catheters are important devices for children. Currently, with the increase in survival rates of children with severe chronic diseases, such as solid organ transplants or very low birth weight, the availability of catheters may be a determining factor in survival. Therefore, the use of antimicrobial lock therapy (ALT) to prevent or treat catheter infection may be of vital importance. Central line–related bloodstream infection (CRBSI) is a confirmed bloodstream infection in a patient with a central line placed or withdrawn within the previous 48 hours, in which the catheter is the source of the infection.1,2 A confirmed infection is mostly considered if the same organism grows from a central venous catheter (CVC) at least 120 minutes before a percutaneous blood culture is obtained simultaneously.3,4 Central line–associated bloodstream infection (CLABSI) is defined as bacteremia in a subject with a CVC in place but not necessarily related to the device. This concept is often used in epidemiologic studies.2 Lumens of inserted catheters become coated with fibrin, platelets, and other biologic compounds, to which bacteria may adhere, multiply, and surround with an extracellular matrix, forming a biofilm that protects them from antibiotics.5,6 Biofilm development occurs more frequently in the lumen of long-term CVC, and bacterial hematogenous dissemination may occur from this biofilm colonization.7 ALT is the instillation of high concentrations of antibiotic (100–1000 times the minimal inhibitory concentration) or antiseptic agent, with/without anticoagulant, into the lumen of the catheter to dwell for a length of time, to prevent or treat a CRBSI.6,8,9 In vitro studies have demonstrated that many antibiotics and combinations are stable and maintain high drug concentrations for periods of time, with the ability to eliminate catheter colonization.6,8 These studies have provided information about dosages, heparin combination and dwell time although they differed in concentrations. The Table shows the most used antimicrobials for ALT. TABLE. - Most Common Lock Solutions* Described in the Literature Antimicrobial class Antimicrobial Concentration Heparin† Comments Cephalosporins Cefazolin‡ 5–10 mg/mL 10–100 U/mL 1000–5000 U/mL in some protocols (especially associated with gentamicin) Ceftazidime§ 2–5 mg/mL 100–5000 U/mL 10–100 U/mL of heparin in some protocols9 Penicillins Ampicillin 2–10 mg/mL 10–5000 U/mL Aminoglicosides‖ Amikacin 5 mg/mL No Amikacin 50 mg in 1 mL; dissolve 1 mL in 9 mL of normal saline Amikacin¶ 1,5–2 mg/mL 20 U/mL Up to 2500 U/mL of heparin in some protocols9 Gentamicin# 1–5 mg/mL 10–20 U/mL Up to 2500 U/mL of heparin in some protocols9 Gentamicin 40 mg/2 mL; dissolve 2 mL in 6 mL of normal salineIt may precipitate with heparin at higher doses Glucopeptides Teicoplanin 10 mg/mL 2500 U/mL 10–100 U/m of heparin in some protocols9 Dissolve teicoplanin in heparinIt may precipitate when combined with other antimicrobials Teicoplainin 2 mg/mL 10 U/mL Vancomycin‖ 2–5 mg/mL 10–100 U/mL 2500–5000 U/mL in some protocols Fluoroquinolones Ciprofloxacin 2 mg/mL No It may precipitate with heparin Levofloxacin 5 mg/mL No It may precipitate with heparin Lipopeptides Daptomycin 1–5 g/mL 100–5000 U/mL Dilute in Ringer lactate** Oxazolidinones Linezolid 2 mg/mL 10–100 U/mL Antifungals Caspofungin 2–3 mg/mL No Precipitates with heparin Micafungin 1 mg/mL 100 U/mL Amphotericin B 2–5 mg/mL No 10–100 U/m of heparin in some protocols9 Ethanol 70% No 7.5-mL sterile water + 18.75 mL 98% ethanol10 or 0.4-mL 0.9% sodium chloride + 1-ml 98% ethanol11 Prophylaxis of CRBSI with taurolidine Taurolidine (%) Brand name Citrate†† Heparin Comments 2% Nutrilock … … Used in neonates (also as CRBSI treatment)12 1.35% Taurolock 4% Used in children as prophylaxis13 1.35% Taurolock 4% 100 U/mL Used in children as prophylaxis13 Antimicrobial lock solutions used at the authors’ institution (Gregorio Marañón Hospital) Antimicrobial Concentration Heparin Cefazolin 10 mg/mL 100 U/mL Vancomycin 2 mg/mL 100 U/mL Daptomycin 5 mg/mL 100 U/mL Linezolid 2 mg/mL 10 U/mL Amikacin 2 mg/mL 20 U/mL Ciprofloxacin 2 mg/mL … Micafungin 1 mg/mL 100 U/mL Amphotericin B 2 mg/mL … Ethanol 40%‡‡ 20 U/mL *Ideally, the lock solution should be prepared as unidosis in the pharmacy service. Most experience with antibiotic lock solutions is for CLABSI/CRBSI therapy rather than for prevention.†Heparin is used to diminish the risk of CVC occlusion. There are several recommended concentrations, with no one completely standardized. Some authors recommend a maximum concentration of 100 U/mL to avoid adverse effects, except for aminoglycosides that may precipitate with lower heparin concentrations.9 5000 U/mL of heparin mostly for hemodialysis patients.6‡It may be combined with 1–5 mg/mL of gentamicin + 1000–5000 U/mL of heparin according to some studies.6§It may be combined with 2.5 mg/mL of vancomycin + 2500 U/mL of heparin according to some studies.6‖Lower penetration in biofilm than other antimicrobials: <70% vancomycin and <25% aminoglycosides.¶Different concentrations used (with and without heparin). It may be combined with 5 mg/mL of vancomycin or 1–10 mg/mL of teicoplanin + 5000 U/mL heparin (Bookstaver PB. PMID: 24296841).#Possible combination: vancomycin (2–25 mg/mL) + gentamicin (2–40 mg/mL) + heparin (100–5000 U/mL) (Bookstaver PB. PMID: 24296841).**It needs calcium to be active. Daptomycin (1 mg/mL) + gentamicin (3 mg/mL) without anticoagulant may be combined (Bookstaver PB. PMID: 24296841).††The FDA recommends a concentration of 4% for use in catheter locks.6‡‡It may have less adverse events than the 70% concentration, but the experience in efficacy is lower (Alonso B. PMID: 31283786).CLABSI indicates catheter-associated bloodstream infection; CRBSI, catheter-related bloodstream infection; CVC, central venous catheter; FDA, Food and Drug Administration. The antimicrobials for ALT must have1,6,8: high activity against biofilm, ability to achieve high concentrations, stability at room temperature, compatibility with anticoagulants and low resistance capacity. The solution must be prepared under sterile conditions, ideally in pharmacy services.4,9 Before using the CVC or replacing the antimicrobial, an amount equivalent to that administered should be aspirated and discarded to avoid infusion of microorganisms or antimicrobials/anticoagulants at high concentrations into the bloodstream.6 It is important to ensure the correct volume in children,9 usually 2–5 mL, depending on the type of catheter.3,8 LOCK SOLUTIONS FOR PREVENTION OF CATHETER-RELATED INFECTIONS Various strategies exist to prevent CLABSI/CRBSI. These typically target CLABSI/CRBSI pathogenesis, which primarily occurs via contamination of catheters at the insertion site and hub during manipulation.2 Intermittent catheter locking with 0.9% saline or heparin is the conventional practice for catheter maintenance.6,14 However, alternative lock solutions have been studied to prevent CRBSI, which aim to inhibit biofilm formation and bacterial growth within the CVC.14 Antibiotic-containing lock solutions, with/without anticoagulants, have demonstrated efficacy in reducing the risk of CRBSI, as evidenced by meta-analyses of randomized controlled trials (RCTs) conducted in various patient populations. Studies have shown effectiveness in patients undergoing hemodialysis,3,6 receiving cancer treatment6 and pediatric populations.14 Various antibiotics have been utilized in these RCTs; however, the optimal agent and its concentrations remain undefined. Thus, the evidence for any antibiotic, alone or in combination, is not strong enough to make any recommendations. Importantly, concerns about the emergence of resistant microorganisms with this antibiotic prophylaxis have led to extensive research on nonantibiotic alternatives,6,14 including ethanol, taurolidine, citrate and ethylenediaminetetraacetic acid. Taurolidine Taurolidine is a modified amino acid exh

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