The Pediatric Infectious Disease Journal • Volume 32, Number 8, August 2013 www.pidj.com |
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ong-term central venous catheters(CVCs) are essential for modern pediatric practice. These devices terminate in a large central vein, usually the superior vena cava, and are used for administration of drugs, flu-ids and blood products; for blood collection and for hemodialysis. The most common, serious complication of CVC use is cen-tral line–associated bloodstream infection (CLABSI). Rates of CLABSI vary widely according to device type and patient popula-tion and can range from approximately 0.2 episodes per 1000 catheter-days in children with sickle cell disease to 11 per 1000 days in infants with intestinal insufficiency.1,2
The most common infecting organ-isms are coagulase-negative staphylococci (especially Staphylococcus epidermidis),
Staphylococcus aureus, Enterococcus spp.,
Escherichia coli, Klebsiella spp., other enteric Gram-negative bacteria and Candida
spp. Microorganisms are introduced predom-inantly through the hub during routine use or at the time of catheter insertion. After the first 14 days, intraluminal colonization is the most important source of infection.3 Important consequences of CLABSI include extended hospital stay (median of 12 days in 1 study), interruption of chemotherapy or other treat-ment, catheter removal (up to 50% of epi-sodes), intravascular thrombosis, endocardi-tis, sepsis (up to 10%c) and rarely death.4,5
Techniques to prevent CVC coloni-zation during insertion, such as maximum sterile barrier precautions, reduce the risk of CLABSI. After insertion, appropriate CVC dressings, careful catheter access technique, alcohol catheter caps and the use of prophylac-tic lock therapy with taurolidine, antibioprophylac-tic or preservative-containing heparin solution can reduce the risk of infection in some groups.6–9
This review focuses on the manage-ment of CLABSI in children, outside the neonatal period, who have long-term tun-neled CVCs (eg, Broviac or Hickman cath-eters, Bard Access Systems, Salt Lake City, Utah) or implantable ports (eg, Port-A-Cath, Smiths Medical, Dublin, Ohio). Major con-troversies include duration and choice of sys-temic antibiotic therapy, indications for cath-eter removal, screening for complications and the roles of adjunctive treatment and sec-ondary prevention techniques. This review assesses the available literature and identifies pragmatic treatment strategies based on the best available evidence basis. The Infectious Diseases Society of America guidelines, which focus predominantly on adult patients, are referenced where a consensus recommen-dation is required but evidence is limited or conflicting.
DIAGNOSIS AND DEFINITIONS
The classic presentation of CLABSI is the development of fever and chills immedi-ately after accessing a catheter that has been locked for some time. However, the range of clinical presentations is broad, and the cath-eter may not always be immediately consid-ered as the source of fever. Most episodes are not associated with any visible abnormality at the site of the catheter.3Unless an alternative source is iden-tified, all bloodstream infections in patients with a CVC are classified as CLABSI. This surveillance definition may overestimate the true number of infections that are attribut-able to the CVC. Therefore, when there is evidence to confirm that the colonized device is the true source of infection, the more specific diagnosis of catheter-related bloodstream infection (CRBSI) is used (Fig. 1).10 Confirmatory tests include culture of the catheter tip, quantitative blood cul-tures or differential time to positivity (DTP) of blood cultures drawn from different sites. Data from pediatric oncology patients sug-gest that up to one third of CLABSI epi-sodes are related to infections at other sites and are therefore not CRBSI.10 Definitive diagnosis of CRBSI can be important to identify those patients who might benefit from catheter removal or adjunctive therapy. CVC tip culture can identify CRBSI, but precludes salvage of the catheter.
The most readily available technique to confirm CRBSI without catheter removal is the calculation of DTP between blood cultures drawn from the catheter and from a peripheral vein or separate lumen. In cases of true CRBSI, blood obtained through a col-onized lumen will usually indicate growth
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Copyright © 2013 by Lippincott williams & wilkins ISSn: 0891-3668/13/3208-0905
DOI: 10.1097/InF.0b013e3182996b6e
The Pediatric Infectious Disease Journal
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Copyright © 2013 by Lippincott williams & wilkins
0891-3668
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Treatment of CLABSI
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Pediatr Infect Dis J
Lippincott williams & wilkins
Hagerstown, MD
XXX
Central Line–associated Bloodstream Infection in
Children: An Update on Treatment
Joshua Wolf, MBBS, BA, FRACP,*† Nigel Curtis, MBBS, PhD, FRCPCH,†‡§ Leon J. Worth, MBBS, PhD, FRACP,¶
║
and Patricia M. Flynn, MD, MS*
From the *Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tn; †Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia; ‡Infec-tious Diseases Unit, Royal Children’s Hospital Melbourne, Parkville, Victoria, Australia; §Mur-doch Childrens Research Institute, Parkville, Vic-toria, Australia; ¶Victorian Healthcare Associated Infection Surveillance (VICnISS) Coordinating Centre, north Melbourne, Victoria, Australia; and ║Department of Infectious Diseases, Peter MacCallum Cancer Center, East Melbourne, Vic-toria, Australia.
The authors have no funding or conflicts of interest to disclose.
Correspondence to: Patricia M. Flynn, Department of Infectious Diseases, St. Jude Children’s Research Hospital, Mailstop 600, 262 Danny Thomas Pl, Memphis, Tn 38105. E-mail: pat.flynn@stjude.org.
CONTENTS
CLABSI in Children
EDITORIAL BOARD
Co-Editors: Delane Shingadia and Irja Lutsar
Board Members David Burgner (Melbourne, Australia)
Luisa Galli (Rome, Italy) Christiana Nascimento-Carvalho (Bahia, Brazil)
Ville Peltola (Turku, Finland)
Nicol Ritz (Basel, Switzerland) Ira Shah (Mumbai, India) Matthew Snape (Oxford, UK) George Syrogiannopoulos (Larissa, Greece)
Tobias Tenenbaum (Mannhein, Germany) Marc Terbruegge (Southampton, UK) Marceline van Furth (Amsterdam, The Netherlands)
before uncolonized lumens or peripheral blood because of high intraluminal micro-organism burden. To apply, identical vol-umes of blood must be collected for culture simultaneously from each site, and a con-tinuously monitored blood culture system is needed. In pediatric oncology patients who had simultaneous peripheral and central cul-tures, a DTP of ≥150 minutes had a speci-ficity of 100% and sensitivity of 89% for CRBSI. For cultures from both lumens of a double-lumen catheter, a DTP of ≥180 min-utes had a specificity of 94% and sensitivity of 61%.11,12 These data suggest that DTP can be confidently used to diagnose CRBSI, but that the negative predictive value is poor, especially when comparing 2 lumens of a double-lumen catheter.
To maximize the sensitivity and specificity of diagnosis in cases of suspected CRBSI, blood cultures should be collected from the catheter and from the peripheral blood before initiation of antibiotics.13 Blood should generally be collected from all lumens of a multilumen catheter (although there is an absence of data to support this consensus recommendation), as some can be uncolo-nized. Similarly, in patients with a single-lumen catheter, at least 2 sets of blood cul-tures should be collected through the CVC if a peripheral culture is not taken. normal skin flora are the most common causes of CLABSI and are also frequent blood culture contaminants. Therefore, definitive diagnosis of bloodstream infection with a common skin contaminant requires multiple positive cul-tures to exclude the possibility of contamina-tion during colleccontamina-tion or inoculacontamina-tion. If mul-tiple blood cultures have not been collected before antibiotics, a presumptive diagnosis of
CLABSI has to be made, leading to unnec-essary treatment in cases where the positive culture has resulted from contamination.
Peripheral blood should be collected in all cases of suspected CLABSI before antibiotics are started, but pediatricians often avoid this. There are a number of important situations in which peripheral blood culture aids management. One example is a patient with severe sepsis in whom catheter removal might limit venous access and compromise treatment. Another is attempted catheter salvage complicated by persistent bactere-mia during appropriate antibiotic therapy in which evidence that the catheter is not the primary focus could lead to earlier identi-fication of an intravascular focus such as endocarditis. Lastly, definitive diagnosis of CRBSI can support a decision to remove and replace a catheter in cases of S. aureus
or candida infection. All these situations can be difficult to predict at initial presentation.
After diagnosis of CLABSI, blood cultures should be collected daily until cul-tures from all lumens are negative. Further peripheral cultures may not be necessary if blood can be collected from all lumens of the catheter and the patient is clinically stable.
Diagnosis of Complications
Resulting From CLABSI
Complicated catheter-associated infec-tions include tunnel or port pocket infection, endovascular infections such as endocarditis or suppurative thrombophlebitis and meta-static infections such as osteomyelitis and liver, spleen or brain abscess. Catheter-related skin and soft tissue infection can be identified by localized erythema, tenderness, fluctuance or swelling.13 An intravascular focus may be
identified when there is persistent bactere-mia or fungebactere-mia after CVC removal, despite appropriate antimicrobial therapy. Clinical signs, such as new murmur, peripheral stig-mata and cardiac failure or localized tender-ness and swelling of a limb, are often absent in infective endocarditis and suppurative thrombophlebitis, respectively.14,15
CATHETER SALVAGE
Catheter salvage is attractive in many cases because of the cost and inconvenience of replacement. However, catheter removal substantially reduces the risk of relapse, per-sistent bacteremia or fungemia, and meta-static infection.16 The risk of relapse differs by device and organism. For ports, the risk may be >50%, probably related to the com-plex structure and high internal surface area of the port housing.10
Salvage should not be attempted if the catheter is no longer essential for clini-cal care. Timely removal of the CVC is also indicated for infections complicated by sep-sis, tunnel or port pocket infection, endocar-ditis or suppurative thrombophlebitis, relapse of CLABSI with an identical organism, and infection with mycobacteria, fungi such as
Candida spp., S. aureus, Bacillus cereus and some multiresistant bacteria. with attempted catheter salvage, candida and mycobacteria CRBSIs have treatment failure rates over 70%, and S. aureus and B. cereus infections have relapse rates around 50% with poten-tially catastrophic complications.13,17 The catheter should therefore be removed in all the above cases, except where replacement will be so difficult that the high risk of treat-ment failure is considered justifiable.
It is appropriate to consider catheter salvage in other patients in view of the rela-tively high success rates of salvage therapy and potential hazards of CVC replacement. Catheter replacement is costly, carries risks associated with anesthesia and local trauma, does not reduce the risk of new CLABSI (the risk may actually be increased immediately after replacement) and venous occlusion can preclude future use of that insertion site.18 If salvage is attempted, the patient should be closely observed for the development of acute complications, persistent infection or sepsis. The catheter should be removed if complications develop or if bacteremia or fungemia persists after 72 hours of appropri-ate antibiotic therapy.13
After catheter removal, reinsertion of a new long-term CVC should ideally be delayed until blood cultures collected after removal are negative to prevent immediate contamination of the new device.13 This delay might be unnecessary for patients in whom clearance of bacteremia or fungemia is docu-mented before catheter removal. The absolute FIGURE 1. Categories of bloodstream infections.10 BSI indicates bloodstream infection.
risk of contamination of the new device is unknown in either case, so the decision of whether to delay reinsertion should take into account the potential clinical impact of either delayed reinsertion or colonization of the new catheter. The use of guidewire catheter exchange in the management of CLABSI is controversial. The technique has the benefit of reducing venous occlusion and mechanical complications of new device insertion, but it may be associated with contamination of the new catheter and can be technically difficult in young children.13 Guidewire replacement with an antimicrobial impregnated catheter could potentially be beneficial to prevent colonization of the new device. One retro-spective study of nontunneled impregnated devices reported excellent outcomes, but there are no prospective studies supporting the method, and appropriate devices for tun-neled use are not yet available.19
SYSTEMIC ANTIBIOTIC THERAPY
Empiric antibiotic therapy for sus-pected CLABSI should take into account the clinical condition of the patient, documented past colonization or infection with resistant organisms, known allergies and local resist-ance patterns. Initial therapy should usually be with vancomycin combined with a broad-spectrum agent active against Gram-negative bacteria including Pseudomonas aeruginosa, such as an aminoglycoside (eg, gentamicin), and antipseudomonal penicillin (eg, piper-acillin-tazobactam), or a cephalosporin (eg,ceftazidime or cefepime). If multiresistant Gram-negative infection is likely, the use of a carbapenem (eg, meropenem) should be considered. In patients with clinical sepsis, an additional third agent of a different antibi-otic class with activity against Gram-negative bacteria is recommended, until susceptibility results are available because of the risk of resistance. Although evidence is limited, it seems logical to administer treatment through all lumens of the CVC by splitting or rotating doses. Empiric therapy for fungal infection is not routinely recommended except in high-risk patients; considerations include severity of illness and presence of multiple risk fac-tors for candidemia, such as prolonged inten-sive care unit stay, administration of total parenteral nutrition, immunosuppression, prolonged antibiotic exposure, previous can-didemia without catheter removal and known candida colonization.20
Once the causative organism is iden-tified, targeted therapy should be selected based on susceptibility testing. Ideally, a sin-gle narrow spectrum agent should be used. If the catheter is retained, patients should receive 10–14 days of pathogen-specific systemic antibiotic therapy from the date of the first negative blood culture through each lumen of the catheter.13 A longer duration of therapy is indicated for cases complicated by endocarditis, suppurative thrombophlebitis or metastatic infection. Use of antibiotics, that have superior in vitro activity against biofilm bacteria, such as ciprofloxacin and rifamp(ic) in, has been proposed to potentially offer a
greater chance of eradication of infection, but there is currently no evidence that these drugs improve clinical outcomes. Rifampin should not be used as a single agent for the treatment of infection due to rapid develop-ment of antibiotic resistance.
If the catheter is removed, patients should receive 10–14 days of appropriate sys-temic therapy. Oral therapy may be considered if an appropriate drug is available and intrave-nous access is difficult to maintain.21 A shorter 5- to 7-day treatment course is reasonable for CLABSI due to coagulase-negative staphylo-cocci if the catheter is removed and blood cul-tures clear promptly.13 There is no evidence to support the use of synergistic aminoglycoside in the absence of endocarditis.
TREATMENT FAILURE
Despite appropriate antibiotic therapy, treatment failure (persistent bacteremia, pre-mature device removal due to infection or relapse of infection) occurs in at least 25% of CLABSI episodes in which salvage is attempted. Relapse can occur many months after infection.10 Failure is highest in infec-tions caused by certain organisms (such as
S. aureus, Candida spp., Bacillus spp. and mycobacteria), tunnel and pocket infection, and in ports.13 This is attributable to biofilm, organized communities of microorganisms in a sessile state, predominantly on the lumi-nal surface of the catheter.3 Mechanisms of treatment failure are described in Figure 2.9 In addition to the risk of treatment failure, FIGURE 2. Mechanisms of treatment failure in CLABSI.
prior CLABSI increases the risk of future episodes.4 This might be associated with line-care technique, biofilm or catheter-associated thrombus acting as a nidus for reinfection, or the presence of multispecies biofilm.
CATHETER LOCK THERAPY
Catheter lock therapy (CLT) may be used in addition to systemic therapy with the aim of reducing treatment failure by targeting biofilm bacteria. A small dose of antimicro-bial agent is instilled to fill the catheter lumen (usually ≤1.5 mL) and is allowed to dwell for an extended period of time (usually hours to days). This permits high concentrations of antimicrobial agent at the site of infection and can be repeated in each lumen through-out the course of antibiotic treatment. For example, local vancomycin concentrations of up to 5 mg/mL, 1000 times higher than the usual minimum inhibitory concentration, are achievable. This targets intraluminal coloni-zation and would not be expected to improve outcomes for extraluminal colonization or infected catheter-associated thrombus. Spe-cific agents used for CLT are outlined below. Antibiotic lock therapy (ALT) with vancomycin, daptomycin, ceftriaxone, ami-noglycosides, ciprofloxacin and other agents, individually or in combination, have been reported. Published studies on ALT are het-erogeneous and mostly nonrandomized.8 One randomized study of vancomycin or ceftazi-dime lock therapy in addition to systemic antimicrobial therapy showed a nonsignifi-cant trend in the reduction of treatment fail-ure (33% versus 57%; P = 0.1) and relapse of infection (14% vs 39%; P = 0.06) in the treatment group.22 In adults, ALT seems to be well-tolerated with few adverse effects reported.Infectious Diseases Society of Amer-ica treatment guidelines for CLABSI recom-mend the routine use of adjunctive ALT for adults and children.13 However, the uptake of ALT use in pediatric practice seems to be inconsistent. This may be related to concerns about the development of antibiotic resist-ance, a limited range of studied antibiotics, a paucity of pediatric safety data, the potential for heparin overdose in infants, the need for prolonged dwell times and the lack of com-mercially available lock solutions. Antibiotic solutions for ALT are produced extempora-neously and usually admixed with heparin to prevent catheter occlusion. Recommended heparin concentrations vary from 0 to 5000 units/mL depending on the antibiotic, but high concentrations are contraindicated in small infants due to the risk of systemic anti-coagulation. More data are needed before a strong recommendation can be made on the routine use of adjunctive ALT in pediatrics,
and ALT should not be considered mandatory in children.13
Ethanol lock therapy (ELT) for the treatment of CLABSI has not been studied in published randomized trials. Ethanol pen-etrates biofilm and rapidly kills microorgan-isms, including common CLABSI pathogens such as S. aureus, S. epidermidis, Klebsiella pneumoniae, P. aeruginosa and Candida
spp., by protein denaturation. In vitro studies suggest that maximum killing occurs during the first 2 hours of exposure to 70% ethanol.23
One single-center retrospective review of pediatric oncology patients treated with and without ELT has been reported, which demonstrated a reduction in treatment failure, although this was not statistically significant. The small sample size and study design make these results difficult to apply broadly.24 Suc-cessful treatment of candida CRBSI using ELT has been reported in an uncontrolled series. This is interesting because of the his-torically poor outcomes of these infections.25 Other retrospective studies are uncontrolled and do not provide information about effi-cacy of the treatment.9
Episodes of self-limiting nausea, headache and taste of alcohol have been associated with ELT, but more serious side effects, such as respiratory distress, are rare. In 1 randomized study of ELT prophylaxis in adults, 5% of patients in the ELT arm discon-tinued the drug due to side effects compared with 0.5% in the placebo arm.26 These effects are likely reduced by minimizing the ELT dose and aspirating the lock after the dwell period and seem to be less common in chil-dren. Reports on catheter occlusion or intra-luminal clot formation during the use of ELT, especially in children, have raised concerns that ELT may contribute to occlusion, but the frequency and clinical significance of this are unknown.9 Routine adjunctive ELT for the treatment of CLABSI is not recommended at this time due to lack of evidence for efficacy and concern about possible harms.9
Hydrochloric acid lock therapy has been trialed as an adjunctive treatment for CLABSI in children with long-term CVCs. Two retrospective studies found an associa-tion between hydrochloric acid lock therapy use and successful catheter salvage,27,28 but one suggested an increase in mechanical
TABLE 1. The Bottom Line: Recommendations and Areas of Uncertainty for
the Management of CLABSI in Children
Diagnosis
• Blood cultures should be collected from at least 2 sites before initiation of antibiotics (ideally from all lumens of a multilumen CVC).
• Peripheral blood culture should be collected when possible.
• Differential time to positivity may help identify true catheter-related bloodstream infection. Catheter Salvage
• The CVC should be removed if:
○ It is no longer required for routine care;
○ Sepsis, tunnel or port pocket infection, endocarditis or suppurative thrombophlebitis are present;
○ The infection is with mycobacteria, Candida spp. or other fungi, Staphylococcus aureus, Bacillus cereus or some multiresistant bacteria.
• Catheter salvage is reasonable in other cases, but should be abandoned if complications develop, if there is persistent bacteremia after 72 hours or if the infection relapses after cessation of antibiotics. Systemic Antibiotic Therapy
• Patients with CLABSI should receive 10–14 days of appropriate antibiotic therapy from the date of the first negative blood culture.
• Longer therapy is warranted in cases of fungemia, endocarditis, suppurative thrombophlebitis or metastatic infection.
• If the catheter has been removed, shorter treatment may be appropriate in infections due to coagu-lase-negative staphylococci, but other organisms should be treated for 10–14 days.
Adjunctive Therapy
• Antibiotic lock therapy may be reasonable as adjunctive treatment for CLABSI.
• Other catheter lock therapies (CLT), such as ethanol, hydrochloric acid or taurolidine, should not be routinely used for the treatment of CLABSI.
Some Areas of Uncertainty
• What is the optimal duration of antibiotic therapy for uncomplicated CLABSI if the catheter is removed/if it is retained?
• Does splitting or rotating antibiotic doses through all lumens of the CVC reduce treatment failure? • Are biofilm-active antibiotics more effective than other antibiotics for the treatment of CLABSI? • Is CLT with ethanol, antibiotics, taurolidine or another solution beneficial in routine treatment of
CLABSI?
• Is secondary prophylaxis with CLT beneficial in routine management of CLABSI? • Should catheter reinsertion be delayed after removal of a CVC for infection?
• Can a colonized CVC be safely replaced with an antimicrobial impregnated device by guidewire exchange?
• Can ultrasound identification of asymptomatic catheter-associated thrombus help guide therapy for CLABSI?
complications (38% versus 19%; P = 0.3).28 The available data do not support the use of hydrochloric acid lock therapy for the treat-ment of CLABSI.
CARDIAC AND VASCULAR
IMAGING
Suppurative Thrombophlebitis
Suppurative thrombophlebitis, the presence of infected intravascular throm-bus, requires catheter removal and prolonged therapy (4–6 weeks), as well as anticoagula-tion in many cases. However, the routine use of imaging to screen for catheter-associated thrombosis in the absence of clinical symp-toms may be misleading. One prospective study found intravascular thrombus in 71% of all patients with CLABSI due to S. aureus, many of whom had no local signs of this, but the clinical impact of such asymptomatic blood clots is unknown.29 Another study used ultrasound to screen for catheter-associated thrombosis in all CLABSI episodes in adult patients with acute leukemia. Catheters were removed from patients with evidence of catheter-associated thrombus.30 The study reported that death from sepsis and catheter loss was less common in the intervention group compared with historical controls, but the study has a number of methodological problems and no children were included.Therefore, at present, venous imaging is recommended only when there are signs and symptoms of thrombosis or persistent bacteremia or fungemia after 72 hours of appropriate antibiotic therapy and catheter removal. Appropriate management of inci-dentally diagnosed, nonvenoocclusive, cath-eter-associated thrombus remains unclear; however, catheter removal with delayed reinsertion and consultation with a pediatric hematologist may be warranted.
Endocarditis
Patients with persistent unexplained bacteremia or fungemia >72 hours after appropriate antibiotic treatment and catheter removal and those with significant structural cardiac disease are at high risk of endocar-ditis.31 If patients have risk factors or have clinical signs of endocarditis, then echocardi-ography and consideration of empiric endo-carditis therapy are warranted. Adults with S. aureus CLABSI have a high risk of concomi-tant endocarditis, and so empiric treatment or presumptive exclusion of endocarditis by transesophageal echocardiography has been recommended.13 However, the risk of endo-carditis associated with S. aureus CLABSI seems to be much lower in children without specific risk factors (<3%).31 Children without preexisting cardiac risk factors who develop
S. aureus CLABSI therefore do not require
routine echocardiography in the absence of clinical signs of endocarditis or unexplained prolonged bacteremia.
SECONDARY PREVENTION
The long-term risk of CLABSI is increased in children with prior episodes.18 Patient or caregiver education and careful attendance to catheter care and access tech-niques may help prevent future episodes and should be provided in all cases. The use of heparin with preservatives reduces the risk of CLABSI, but benzyl alcohol should be avoided in newborn infants.23 In addition, specific sec-ondary prevention, such as prophylactic etha-nol, antibiotic or taurolidine lock therapy, may be beneficial, but there is no evidence for these specifically as secondary prophylaxis.7LOOKING AHEAD
Potential future CLABSI treatments include phage therapy, nanoparticles and other agents, which are directed against biofilm structural elements (eg, proteolytic enzymes and surfactants), are active against organisms within biofilm (eg, taurolidine, metal chelators and pilus synthesis inhibi-tors) or interfere directly with bacterial bio-film regulation (eg, nucleotide second mes-senger systems).32 It is unclear which of these will progress to human trials.
CONCLUSIONS
Despite the development of preventive measures to reduce risks of infection related to CVC insertion and maintenance, CLABSI continues to be a significant burden in pedi-atric populations. Current treatments have a high failure rate predominantly due to relapse and reinfection because of the difficulty in preventing and eradicating intraluminal bio-film. Some adjunctive therapies are likely to be beneficial, but current evidence to support these is limited. More research is needed to determine the optimal management of CLABSI in children and adolescents.
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