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Comparing success rates in central venous catheter salvage for catheter-related bloodstream infections in adult patients on home parenteral nutrition: a systematic review and meta-analysis

ABSTRACT Background Catheter-related bloodstream infection (CRBSI) is a life-threatening complication of parenteral nutrition. Therefore, optimal management, ideally with catheter salvage, is required to maintain long-term venous access. Objectives We aimed to evaluate successful catheter salvage rates in patients on home parenteral nutrition (HPN). Methods Studies were retrieved from medical databases, conference proceedings, and article reference lists. Data were collected relating to clinical outcomes of 3 treatments: systemic antibiotics, antimicrobial lock therapy (ALT), and catheter exchange. ORs and 95% CIs were calculated from a mixed logistic effects model. Results From 10,036 identified publications, 28 met the inclusion criteria (22 cohort studies, 5 case-control studies, and 1 randomized clinical trial), resulting in a total of 4911 CRBSIs. To achieve successful catheter salvage, the addition of an antimicrobial lock solution was superior to systemic antibiotics alone (OR: 1.75; 95% CI: 1.21, 2.53; P = 0.003). Recurrence of infection was less common in studies that used ALT than in those that used systemic antibiotics alone (OR: 0.26; 95% CI: 0.11, 0.61; P = 0.002). The catheter exchange group was excluded from multilevel regression analysis because only 1 included study applied this treatment. Successful salvage rates were highest for coagulase-negative staphylococci, followed by Gram-negative rods and Staphylococcus aureus . Conclusions The addition of an antimicrobial lock solution seems beneficial for successful catheter salvage in HPN-dependent patients with a CRBSI. Future prospective randomized studies should identify the most effective and pathogen-specific strategy. This review was registered at www.crd.york.ac.uk/PROSPERO as CRD42018102959.


Introduction
Catheter-related bloodstream infection (CRBSI) is a frequent and life-threatening complication in patients receiving home parenteral nutrition (HPN). HPN is a life-sustaining therapy in patients who suffer from intestinal failure (IF) and hence cannot meet their nutritional and/or fluid requirements by enteral intake owing to underlying conditions that limit gastrointestinal absorption (1). HPN is administered systemically via a central venous access device, mostly in the form of a central venous catheter (CVC) or an implantable port. Although HPN is generally lifesaving in these patients, its use is also associated with the risk of infectious and noninfectious catheter-related complications (2). Of these, CRBSI is the most common and is a potentially life-threatening complication. CRBSIs can lead to CVC removal. Multiple CVC removals are associated with venous stenosis and thrombosis which, in turn, can lead to the permanent loss of vascular access. When this occurs, the patient may eventually require a small bowel transplantation (3,4).
The impact that recurrent CVC removal can have on future venous access implies that catheter salvage should be attempted wherever possible in HPN-dependent patients with CRBSI. Whereas guidelines recommend CVC removal in most cases of CRBSI, catheter salvage aims to retain the CVC with the use of appropriate catheter lock therapy and systemic antibiotics, usually for ≥10-14 d (5,6). Catheter salvage is attractive because it obviates the inconveniences and risks of CVC replacement, especially in those patients who have limited remaining venous access or who cannot tolerate prolonged periods without HPN (7). Catheter removal, on the other hand, reduces the risk of infection recurrence, persistent bacteremia, and metastatic infection (8)(9)(10)(11). However, the appropriateness of catheter salvage in specific situations remains contentious (5,6,12,13). Current European HPN guidelines recommend attempting CVC salvage solely in patients with uncomplicated infections arising from Staphylococcus aureus, coagulase-negative staphylococci (CNS), and Gram-negative bacilli (12). The Infectious Diseases Society of America (IDSA) guidelines advocate catheter removal or replacement as a first-line approach to CRBSI (5). All guidelines agree on removing the CVC in patients who are hemodynamically unstable, for CRBSIs caused by yeasts, or in cases of complicated infections such as endocarditis, septic thrombosis, and other metastatic infections (5,12,14). However, the recommended treatment for certain high-virulence bacteria (e.g., S. aureus and Pseudomonas aeruginosa) remains controversial. For instance, whereas the IDSA recommends CVC removal in case of S. aureus and Gram-negative infections (5), some IF expert centers report high rates of successful catheter salvage with these bacteria (15)(16)(17).
In addition to the indications for CVC salvage, several other uncertainties exist around CRBSI management. One of these is the added value of an antimicrobial lock solution next to conventional systemic antibiotic treatment and another is the option of guidewire exchange instead of catheter removal; antimicrobial lock solution consists of high concentrations of an antimicrobial agent (often combined with an anticoagulant) instilled into the catheter lumen. Guidewire exchange is a technique that has previously been reported in studies mainly concerning hemodialysis patients (18). This technique involves the insertion of a guidewire through the infected CVC into the vein, followed by removal of the infected catheter and placement of a new catheter over the guidewire. However, the optimal strategy to salvage a catheter remains unclear owing to the lack of well-designed randomized clinical trials (RCTs).
Because current guidelines (5,6,12,14,19) vary in their recommendations, we conducted, to our knowledge, the first systematic review to appraise the available evidence on CRBSI management specifically in adult patients on HPN support, focusing on the safety and efficacy of available CRBSI management approaches with successful catheter salvage as the outcome. These data should lead to more consistent recommendations for CRBSI management between the different international societies.

Methods
The systematic review and meta-analysis were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (20). For the report format, we followed the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Before conducting this systematic review, the protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42018102959).

Search strategy
Our research question was: "What is the most efficacious and safest management approach (intervention) to accomplish high catheter salvage rates (outcome) in adult patients on home parenteral nutrition with catheter-related bloodstream infection (population)?" The following databases were searched from inception through March 2021: PubMed, Excerpta medica database (Embase), Cochrane library (Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science. The search strategy was composed by experts in the field and included the following terms: "parenteral nutrition," "home infusion," "catheter," and "infection." Because of the large variety and interchangeability of terms used for the outcomes of CBRSI management, we did not incorporate terms related to the outcome in our search strategy. Supplemental Table 1  lists of all relevant guidelines and reviews were manually searched to identify additional relevant studies. When needed, we contacted the authors of the included publications by e-mail to further clarify their data. We also included studies in languages other than English and translated these articles into English.

Study selection
Articles retrieved from the literature search were first deduplicated using filters and export formats, as described by Bramer et al. (21). The remaining articles were imported into an online software program (Covidence 2018) to screen the abstracts for eligibility. Two independent reviewers (MG and CP) screened the titles and abstracts of the retrieved citations. The full texts of potentially eligible articles were reviewed to identify relevant studies for inclusion. Studies were included when they focused on managing bloodstream infections from central venous access devices in adult patients receiving HPN.

Inclusion criteria
1) Adult patients (>17 y old) receiving HPN with a bacterial CRBSI; 2) use of either systemic antibiotics, antimicrobial lock therapy (ALT), and/or catheter exchange as the CRBSI management approach; 3) evaluation of treatment efficacy (i.e., successful catheter salvage, recurrence rates, and/or infectious complications).

Main exclusion criteria
1) Use of ALT for prevention only; 2) use of catheter removal as the sole management approach.
In addition, studies that only involved patients with previous CRBSI treatment failure or infectious complications were excluded. Studies incorporating different patient populations were only included if the text outlined that patients on parenteral nutrition were included. Studies only containing children were excluded in order to limit the heterogeneity of the patient population and because of expected differences in CRBSI etiology, diagnosis, and management (22,23). When distinct publications had partly overlapping data due to the same patients' inclusion, the results were either combined or collected from the most extensive study to avoid duplicate data. Selected studies included interventional clinical trials and case-control and observational cohort studies.

Outcome measures
The major outcome of interest was successful catheter salvage rates, with a distinction between: 1) Overall catheter salvage rate = ratio of successfully salvaged catheters to total CRBSIs. 2) Successful catheter attempt rate = ratio of successful salvage attempts according to the protocol to total salvage attempts.
The secondary outcomes comprised recurrence, infectious complications, mortality, and catheter salvage rates per pathogen type. The infecting pathogens were divided into 4 microbiological categories: CNS, S. aureus, Gram-negative rods (GNR), and polymicrobial.

Data extraction and risk of bias
Two reviewers (MG and CP) independently extracted data from each included study relating to patient and venous access characteristics, CRBSI management approach, microbiological results, reported outcomes, and follow-up duration. All included studies were appraised for methodological study quality using the Newcastle-Ottawa Scale (NOS) for cohort and case-control studies. This tool covers the evaluation of participant selection, comparability of groups, and assessment of outcome. The questions in these domains were adapted to our research topic (adequate follow-up of ≥30 d, loss to follow-up ≤ 20%, adequacy of the method to diagnose CRBSI, and risk of bias due to study design) (Supplemental Figure 1). A maximum of 9 points could be awarded to each study, with higher points representing a lower risk of bias. A qualitative assessment determined the main exclusion criteria for CVC salvage attempts and the limitations of each study separately (Supplemental Table 2). Any disagreements on data extraction or bias assessment were resolved through discussion with experts in the field (GJAW, CPB-R, SL, AB). None of the quality assessors were blinded. Study heterogeneity was assessed by the Cochrane Q test of heterogeneity and I 2 statistic. We examined the presence of publication bias by producing a funnel plot with Egger's statistical test of successful catheter salvage as outcome against study size for each treatment.

CRBSI definitions.
CRBSI. Based on the IDSA definition: positive blood cultures from catheter blood drawn from the catheter and a peripheral vein with a ratio of ≥3:1 (CVC vs. peripheral); and a differential period of CVC culture versus peripheral blood culture positivity of 2 h. Alternatively, and as per IDSA guidelines, a CRBSI was defined when the same organism was grown from ≥1 percutaneous blood culture and from the catheter tip (5).
Central line-associated bloodstream infection. This was defined based on the CDC guidelines (6,14). At least 1 of the following criteria should be present: 1) positive blood culture from a known pathogen, or 2) positive blood cultures from common skin commensal organisms and symptoms of infection with no other potential source of infection. Studies with stricter criteria than central line-associated bloodstream infection (CLABSI), such as positive blood cultures from both catheter and peripheral vein, were categorized as CLABSI because they were broad enough to meet CLABSI criteria but not strict enough to meet the CRBSI criteria.
No standard criteria. Studies that did not provide a proper definition or reference to a standard definition for infectious catheter-related complications were categorized as "no standard criteria."

1) Catheter salvage rate.
Defined by CVC status (retained or removed), clinical resolution, and no recurrence within 30 d of the previous CRBSI date.

2) Overall successful catheter salvage.
Calculation of catheter salvage rates, including all CRBSI cases (regardless of the reason for removal), according to Tribler et al. (24).

3) Successful catheter salvage attempt rate.
Calculation of catheter salvage rates, including only attempted catheter salvage cases according to protocol and/or guidelines.

Recurrence
• Recurrence was defined as any new CRBSI with the same microbial species and a comparable antibiogram occurring AddiƟonal records idenƟfied through cross-referencing n = 5 Screening of Ɵtle and abstract n = 10,041 Full-text assessment n = 289 Studies included for meta-analysis (n = 28)  within 30-90 d of the previous CRBSI date. Recurrence data beyond 90 d were not extracted (unless representing the only measure of recurrence), because recurrence beyond this point is considered unlikely to be significantly influenced by the primary treatment (24,25).
• New infection was defined as any new CRBSI with a different microbial species or different antibiograms from the former infection (24).

Data synthesis and statistical analysis
Studies were divided into 3 treatment groups: 1) systemic antibiotic treatment only, 2) systemic antibiotics with the addition of ALT, and 3) CVC exchange. For most observational cohort studies, a direct comparison of treatments was not possible. Therefore, study results were synthesized between the 3 treatment groups by comparing the catheter salvage rates (displayed in proportions) with the treatments considered in that study (26). A mixed logistic effects model was built with a studyspecific normal random effect that modified the mean log-odds for successful catheter salvage for the particular treatments. The treatment groups were included as a fixed effect and a studyspecific random effect that modeled the studies' heterogeneity. The differences in salvage rates between the treatments were evaluated using ORs with 95% CIs, and P values from the Wald test. For each treatment, each study was weighted by the number of patients receiving that treatment. The secondary outcomes were compared using the same methodology as described for the primary outcome. Heterogeneity was summarized for each of these outcomes using the χ 2 test and I 2 statistics (27). Publication bias was investigated by Egger's regression test and funnel plots (28). The Statistical Package for the Social Sciences (SPSS version 23, IBM Corp.) was used for the mixed-effects logistics analysis. The R statistical platform (version 4.0.5, www.r-project.org) was used to generate the forest plots (Meta package) (29) and funnel plots (Metafor package) (30).

Literature search
The initial search yielded 16,072 articles, but only 289 articles remained for full-text screening after deduplicating and exclusion by title and abstract (Figure 1). Five of these articles were found by screening the reference lists of relevant reviews. After full-text screening, 28 studies met the inclusion criteria for meta-analysis, representing 4911 CRBSIs (range: 8-1441) (15-17, 24, 31-54). All studies were published between 1981 and 2020. In addition, 16 case reports and 5 nonpublished studies were considered suitable for a narrative review. Supplemental Tables 3 and 4 summarize the list of included and most important excluded studies, including reasons for exclusion.
The remaining study was an RCT comparing ALT with placebo, both in addition to systemic antibiotic therapy (31).
Study duration ranged from 1 to >23 y and the patient followup time ranged from 7 to 540 d. A trend toward more ALT studies being published in the last decade was apparent (Supplemental Figure 3).

ALT.
All single-arm studies except 1 (40) used ALT in combination with systemic antibiotic treatment. Two case-control studies only administered systemic antibiotics to a selection of patients in the control group (33,37). Antibiotic lock solutions with vancomycin as an empiric lock solution were used most frequently, which was later changed according to sensitivity. One study used a lock containing taurolidine (41). Heparin was frequently added as an anticoagulant in the lock solution. Dosage, concentration, and duration of lock solutions varied highly among studies ( Table 3).

Systemic antibiotics.
The type of administered systemic antibiotics varied considerably among studies. Most studies mentioned empirical treatment according to IDSA guidelines with sensitivity-based adjustments. Several studies were unclear about administered antibiotics (17, 33-35, 39, 46, 47). Some studies used or reported notable percentages of inappropriate antibiotic treatments (32,37) or administered extended broad-spectrum empirical antibiotic treatment (44,48,49), probably because those studies were performed in regions with a high prevalence of multiresistant bacteria.

Catheter exchange.
Only 1 case-control study used CVC exchange as the CRBSI treatment (34). Because a low number of included studies per subgroup induces the risk of problems with collinearity, the CVC exchange group was excluded from the meta-regression subgroup analysis (55).
Primary endpoint: successful catheter salvage rates for CRBSI Figure 2 reports the results of the studies. Figure 2A shows a forest plot of pooled successful CVC salvage proportions for individual studies in each intervention type. The combined successful CVC salvage rate was 68% (95% CI: 64%, 72%). Figure 2B displays a subanalysis of studies using systemic antibiotics alone with a salvage rate of 60% (95% CI: 56%, 64%) compared with 73% (95% CI: 69%, 77%) for studies adding

Risk of bias
Supplemental Table 7 provides an evaluation of the studies' quality and details the risk of bias within studies according to a modified NOS. Most studies had a low risk of bias, whereas 6 studies had a moderate (37,41,45,46,48) or high risk of bias (52). The overall median of the total NOS score was 6 out of 9. When the risk of bias was introduced as a covariate in the model for successful CVC salvage, its effect was not significant (P = 0.74). The funnel plot showed that successful salvage rates did not differ between small and large studies that used ALT in addition to systemic antibiotics as treatment (P = 0.17), indicating no evidence of publication bias ( Figure 5). However, funnel plot asymmetry was present in studies that used systemic antibiotics alone, mostly due to the absence of larger studies with higher salvage rates (P = 0.002).

Narrative review of gray literature (unpublished studies) and case reports
The majority of unpublished studies on CRBSI treatment in HPN patients address the efficacy and safety of catheter salvage by ALT in addition to systemic antibiotic treatment. Haneda et al. (56) reported a high efficacy of ALT with vancomycin (25 mg/mL, twice daily for 10-14 d) in 7 HPN patients suffering from a total of 10 CRBSIs. The treatment success rate was 90%, although 1 patient developed a recurrent CRBSI within 30 d. The causative pathogens of the CRBSIs in this study were not reported. ALT with vancomycin was also successful in 8 of 9 cases of CRBSIs caused by Bacillus cereus, a pathogen for which the IDSA guidelines would advise catheter removal (57). A retrospective analysis of the addition of ALT in 10 hematooncological patients (8 received HPN) with a port-infection revealed a high rate of CVC removal after CRBSI (58). Although intraluminal treatment with antibiotics was not attempted in all patients, the CVC was removed in 7 of 10 cases (5 cases of CNS, 4 cases of Gram-negative bacilli, and 1 case of methicillinsusceptible S. aureus). Udvarhelyi et al. (59) examined the catheter retention time during the implementation of their catheter preservation protocol. The time to catheter replacement was prolonged by a mean of 118.7 d. Three patients presented with recurrent CRBSIs, 1 of whom developed endocarditis during the third recurring CRBSI. This led to the policy of CVC removal after the occurrence of a second CRBSI. The unpublished study of Ward et al. (60) found that catheter salvage was more likely to fail in CRBSIs with S. aureus. Patients were treated with either systemic antibiotics only or in combination with ALT. Attempted catheter salvage was successful in 79% of the cases. The additional use of ALT resulted in similar salvage rates as intravenous antibiotic therapy alone. Of note, catheter salvage was not attempted (5 of 29 cases) when additional complications were present, such as septic shock, endocarditis, and repeated Teicoplanin (20), daptomycin (9), or meropenem (4). infections despite catheter salvage. The majority of the included case reports in this review related to cases with a complicated course of CRBSI including recurrent CRBSIs and rare causative pathogens. Also, the reported clinical outcomes differed widely. Therefore, we decided not to combine these results in our metaanalysis. Supplemental Tables 8 and 9 outline a summary of the patient characteristics and clinical outcomes of the included case reports.

Discussion
This systematic review describes and compares the efficacy of 3 CRBSI management options for patients receiving HPN. These data show that successful catheter salvage can be achieved in the majority (68%) of HPN-dependent patients with a CRBSI, when catheter removal is not indicated. More importantly, the data indicate that ALT in addition to systemic antibiotics is superior to systemic antibiotic treatment alone for successful catheter salvage (OR: 1.75; 95% CI: 1.21, 2.53; P = 0.003).
The benefit of ALT in tandem with systemic antibiotics has previously been described in a systematic review and metaanalysis in hemodialysis patients, which mainly comprised casecontrol studies (61). In line with our findings, the authors concluded that the addition of an antimicrobial lock solution is superior to systemic antibiotics alone; however, lack of goodquality clinical trials precluded firm conclusions from being drawn. Likewise, the yield of randomized controlled clinical trials in our systematic search was low, with only 1 RCT included (31). Although a notable nonsignificant difference in salvage success rates was observed between ALT and placebo groups (57% compared with 33%; P = 0.10), this study was underpowered and ceased prematurely because of slow patient inclusion.
The IDSA guidelines for the diagnosis and management of CRBSI give 2 recommendations regarding the use of ALT as an adjunct therapy for catheter salvage: 1) it is advised that ALT is used (evidence B-II); 2) it is recommended to attempt catheter salvage in uncomplicated CRBSI involving long-term catheters due to pathogens other than S. aureus, P. aeruginosa, fungi, or mycobacteria, with the use of both systemic antibiotics and ALT (B-II). These recommendations are in keeping with our findings, because the lowest catheter salvage success rates were found in CRBSIs caused by S. aureus. Nevertheless, the addition of ALT still resulted in higher catheter salvage success rates than systemic antibiotic treatment alone. Two studies showed that successful salvage rates of >75% could be achieved even in CRBSIs caused by S. aureus (16,38). Caution may be required, however, because several of the included studies initially excluded catheter salvage in CRBSIs caused by S. aureus because of published guidelines and CVC removal within 72 h has been adopted as one of the key quality indicators for optimal S. aureus bacteremia management in antibiotic stewardship programs (62).
Only 1 study included in this meta-analysis used CVC exchange via a guidewire as CRBSI treatment (34). We did find 2 other studies that applied CVC exchange in patients receiving parenteral nutrition with our systematic search, but these only involved hospitalized patients (63,64). In our opinion, catheter exchange via a guidewire is only indicated on the rare occasions when a hemodynamically stable HPN patient with CRBSI cannot be successfully treated with antimicrobial therapy and options to obtain venous access are extremely limited.
Some of the studies included in our analysis also attempted CVC salvage in patients with nontunneled and peripherally inserted central catheters (PICCs) (35,48). It remains debatable as to whether CVC salvage for these devices is as appropriate as for tunneled CVCs and implanted ports, because nontunneled CVCs (including PICCs) themselves may carry a heightened risk of CRBSI acquisition (65)(66)(67).
CRBSIs caused by yeasts or fungi were not the scope of this review because CVC salvage is discouraged for these types of infections by all major international guidelines (5,12,14,68). In addition, there are limited clinical data to support the effectiveness of antifungal locks for patients with candidemia (69), and the use of such locks is currently not standard practice (5,12).
An important question that remains is the most effective composition and dose of the antimicrobial lock solution. There was wide variability in the reported concentrations and types of administered locks between the studies of this systematic review. Previous in vitro studies demonstrated that concentrations of lock solutions need to be ≥5 mg/mL, whereas several of the studies in this review used lower concentrations (15,16,36,38,42). It is also important to take reported dwell times into consideration which, unfortunately, were not reported in most of the included studies. Moreover, sufficient dwell time may be difficult to achieve if the catheter is used for parenteral nutrition infusion during the salvage protocol. Concerns also exist relating to the emergence of multiresistant bacteria resultant from antibiotic lock use, although data to support these concerns are currently lacking (70). Finally, limitations on lock availability between different countries may limit the choice available.
A major strength of our systematic review is its strict adherence to the PRISMA and MOOSE guidelines: the protocol was prepublished (PROSPERO registry); an up-to-date and extensive systematic literature search was performed; a structured risk of bias assessment was undertaken by 2 independent authors using the NOS, which is widely supported in observational research; the complete data set was controlled for mistakes by a second investigator; and case reports/series were excluded from the meta-analysis to minimize selection bias.
There remain several limitations to the interpretation of our findings. The most important limitation is that only 1 RCT could be included (31). This finding in itself highlights the lack of RCTs in evaluating CRBSI management in HPN-dependent patients, despite these being the most serious complication for this vulnerable group of patients. In addition, assessment of study quality using the NOS tool showed that one-quarter of the studies had a moderate or high risk of bias although, notably, this did  not affect our results based on regression meta-analysis. Strong heterogeneity was present when pooling the successful salvage rates of all intervention groups together. In the subanalysis dividing studies per type of intervention, heterogeneity decreased substantially, but moderate heterogeneity was still present in the systemic antibiotic group. Another limitation was the wide variation in reporting successful catheter salvage outcomes. As outlined earlier, some studies only attempted salvage for CNS infections, whereas others attempted salvage of all CRBSIs, regardless of pathogen. Furthermore, in the absence of a universally agreed-on definition of successful CVC salvage, different approaches were used by different authors of the studies included in this review. In our opinion, successful catheter salvage is only achieved when all of the following criteria are met: clinical resolution, negative blood cultures performed ≥48-72 h after antibiotic discontinuation (because of the long half-lives of several of the frequently used antibiotics), and no recurrence of infection with an identical strain for ≥2 mo. Notably, only 2 studies fulfilled these criteria (40,54). Although several studies performed control blood cultures at the end of antibiotic treatment, they only reported recurrence rates within <30 d (15,42,46,51). Furthermore, because different CRBSI definitions were used by studies, we endeavored to limit the impact of any potential misclassification bias by correcting for studies that used nonstandard definitions. In recent years, more ALT studies have been published and the approaches adopted to CRBSI diagnosis and management have also changed simultaneously in many centers; for example, there has been a recent paradigm shift toward shorter antibiotic treatment protocols for uncomplicated infections (71). These changes over time could lead to chronological time bias, resulting in a potential overestimation of the true benefit of the addition of ALT to systemic antibiotics. Funnel plots of published ALT studies showed no evident publication bias, but small studies were mainly included, and the few larger studies tended to have lower salvage rates. To overcome this issue, we weighted the analysis by study size and performed sensitivity analysis by excluding small studies of <10 patients. A final limitation of note is that some of the included studies had a primary purpose other than the treatment outcome of interest for this meta-analysis, which could have led to a degree of reporting bias. Despite the limitations outlined, this is the only meta-analysis that we know of on CBRSI management and catheter salvage in patients receiving HPN. Therefore, it is highly relevant to this population, where catheter preservation is the ultimate treatment goal. However, there is a clear need for additional high-quality clinical trials comparing the treatment options and also evaluating outcomes per pathogen. Additional topics that require welldesigned research are studies assessing the most effective and safe ALT composition, as well as the optimal treatment duration and dwell time.
We conclude that the addition of ALT to systemic antibiotic treatment is associated with increased successful catheter salvage rates compared with systemic antibiotic treatment alone for CRBSI management in patients receiving HPN. Although most of the included studies were retrospective cohort in design, limiting the strength of our findings, it is important to recognize that larger prospective multicenter studies will ultimately be difficult to perform considering the rarity of this condition and the ethical barriers to enrolling patients with a life-threatening infection into a trial where they may not receive the best possible care. Hence, there is a need for more pragmatic and innovative clinical trials overcoming these issues, such as adopting an adaptive trial design (72), in order to reliably evaluate the true benefit of antibiotics for catheter salvage in this vulnerable group of patients. We appreciate the work of the investigators who published the studies we have reviewed, with a special thanks to Darren R Linkin, University of Pennsylvania, who also provided additional data and analyses upon request. We thank Pim Lepelaars for his help with data visualization.
The authors' responsibilities were as follows-MG and CP: conceptualized the study, performed the investigation, and prepared and wrote the original draft; MG, CP, CPB-R, GJAW, and RPA: outlined the methodology; MG and RPA: conducted the statistical analysis; MG, CP, AB, SL, and GJAW: performed the risk of bias assessment; MG: performed the visualization and is the guarantor of the article; MG, CP, AB, CPB-R, SL, and GJAW: reviewed and edited the original draft; and all authors: read and approved the final manuscript. The authors report no conflicts of interest.

Data availability
The data used in the article that support the findings of this study are available from the corresponding author upon reasonable request.