Efficacy of Antimicrobial Lock Solutionsagainst Catheter-Related Infections in Hemodialysis Patients

Introduction: Hemodialysis patientsare at increased risk of catheter-related bloodstream infections (CRBSI) and catheter thrombosis asdialysis requires regular access to blood circulation through catheters. Antimicrobial Locking Solutions (ALS) containing anticoagulants and antimicrobial agents (antibiotic/non-antibiotic) are used to seal catheters in order to prevent thrombosis and CRBSI. Purpose: The investigation of internationalclinical studies regarding the efficacy and safety of the various ALS treatments for CRBSI in hemodialysis patients (HD patients) comparing to conventional approaches such as heparin treatment or catheter removal. Methodology: The review included prospective or retrospective clinical studies, randomized clinical trials or cohort studies published since 2015. Publications were retrieved from the “Pubmed”, “Google Scholar” and “Elsevier” databases using ‘catheter’, ‘catheter removal’, ‘hemodialysis’ ‘bacteremia’, ‘antimicrobial lock therapy’as key words. Results: 17 articles were found to meet the criteria for this systematic review. These studies investigated locking solutions containing various antibiotic (Cefazolin, Gentamicin, Vancomycin, Cotrimoxazole, Daptomycin, Trimethoprim) or/and non-antibiotic agents (Citrate, taurolidine, ethanol, urokinase, Cathasept) +/anticoagulants, single or in various combinations. The main objective of these studies was to identify the efficacy of ALS with respect to CRBSI risk rates, catheter exchange rates and related adverse effects. Conclusions: Antimicrobial Locking Therapy appears significantly beneficial forHD patients as it reduces CRBSI risk and prolongs catheter survival at considerable rates, so it should be seriously considered for systematic useagainst catheter-related infections. Further researchis required to establish safe and effective prevention and therapeutic protocols as alternatives to catheter removal practices.


Introduction
The appropriate maintenance of central venous catheters (CVC) is integral for the efficacy and safety of hemodialysiswhich requires systematic catheterization for bloodstream access (Dang et al., 2019). Catheter thrombosis or catheter-related bloodstream infections (CRBSI) are common complications for patients undergoing hemodialysis (Sofroniadou et al., 2017). The probability of blood stream infection (bacteremia) when using dialysis catheters increases exponentially as it reaches significant percentages in only a few weeks (Böhlke et al., 2015). Bacteremia may lead to the rapid deterioration of patients' health as it causes significant clinical signs such as hemodynamic instability, fever, nausea / vomiting and mental disorder .Consequently, bacteremia increases morbidity, hospitalization frequency, medical cost and mortality (Leistner et al., 2014). Therefore, research in the field of prevention and treatment of CRBSI is imperative for the health management of HD patients.
Antimicrobial Lock Solutions (ALS) containing anticoagulants and antimicrobial agents (Arechabala, 2018;Labriola, 2017). Although sealing catheters with anticoagulants, such as heparin, is standard for thrombosis prevention, the efficacy of ALS concerning their potential to reduce CRBSI risk requires further investigation. Antibiotics commonly used in ALS are gentamicin, tobramycin, minocycline, cefotaxime, vancomycin and cefazolin, with gentamicin being one of the most extensively studied (Cooney et al., 20014;Golestaneh & Mokrzycki, 2018). Non-antibiotic agents commonly used in ALS are sodium citrate, taurolidine, EDTA and ethanol (Arechabala, 2018;Dang et al., 2019). Prophylactic use of ALS combining anticoagulants with anti-microbials (antibiotic or non-antibiotic) has been associated with a significant reduction in CRBSI risk by 60%-70% (Böhlke et al., 2015;Sun et al., 2020). Moreover, ALS approaches present advantages such as reduced mortality, prevention of biofilm formation and broad range of antimicrobial activity, without risking catheter dysfunction or creation of resistant microbial strains (Raad et al., 2016). The objective of this study was to investigate thesafety and efficacy of the variousALS in the scope to explore the possibilities to endorse the systematic use of ALS for CRBSI prevention and treatment. To this end, this systematic review aims to assess the international literature on antimicrobial lock treatment of dialysis catheters based on data collected throughclinical studies. The assessment includes the identification of the various antimicrobial agents used in locking solutions and the various protocolsfor ALS treatments.

Method
The search for international peer-reviewed publications for this systematic review was performed through the "Pubmed", "Google Scholar" and "Elsevier" digital databases. The objective of the search was to identify prospective or retrospective clinical studies, randomized clinical trials or cohort studies that involved the prevention or treatment of catheter-related infections in HD patients. The search involved the identification of the key words 'catheter', 'catheter removal', 'hemodialysis' 'bacteremia', 'antimicrobial locktherapy' in the titles of articles in any combination. The search parameters were set for articles from 2015 in the English language. This initial search resulted in n=1264 articles which were subsequently assessed with respect to specific exclusion criteria. According to these criteria n=815 articles were excluded as they did not comprise type of studies according to the criteria of the review. The excluded articles were mainly literature reviews, in-vitro studies or did not involve the application of ALS. The references of the excluded articles were further investigated although no additional eligible articles were identified. The remaining n=449 articles were further assessed in terms of relevancereading first through the titles, then the abstracts and finally the whole articles excluding n=218, n=168 and n=46 articles respectively. The majority of articles that were not considered eligible were incomplete in terms of data or involvednon-hemodialysis patients. The articles which were finally considered eligible for this review were n=17 (Figure 1).

Results
The selected articles included 4 systematic reviews and 13 prospective or retrospective studies and clinical trials. The articles, their type of study, their objectives and their results are presented in Table 1. Catheters with citrate lock solutions containing antimicrobial agents (citrate + gentamicin, citrate + taurolidine, and citrate + methylene blue + methylparaben + propylparaben) were more effective at the prevention of infections than heparin locks at a significant rate (P < 0.001, P = 0.003, and P = 0.008, respectively).Reduced bleeding episodes with citrate 'locking'. Böhlke et al., 2015 Systematic review, meta-analysis.
Investigation of prevention and surveillance protocols, diagnostic criteria and management of catheter-related infections in HD patients. Clinical studies Kanaa et al., 2015 Multicenter, randomized, controlled trial.
Assessment of Cathasept 4% locks comparing to heparin 5,000 U/mL locks with respect to catheter microbial colonization of the catheter, CRBSI rate, catheter patency, and biomarkers of inflammation and anemia in HD patients.
In 117 HD patients from 4 HD centers Cathasept locks significantly reduced catheter microbial colonization (0.14/1,000 catheter-days) comparing to heparin locks 1.08/1,000 catheter-days. Reduction in CRBSI rate (0.28/1,000 catheter-days) was not statistically significant comparing to heparin (0.68/1,000 catheter days) and resulted to more thrombotic incidents. Moghaddas et al., 2015 Multicenter, randomized controlled trial HD patients randomized to receive either heparin (2500 U/ml) or a mixture of 10 mg/ml cotrimoxazole (trimethoprim-based) and 2500 U/ml heparin as catheter lock solutions to determine differences in CRBSI risk ratios and catheter survival period.
In 87  In 464 HD catheters (231 TSC30 % group, 233 heparin group), the CRBSI-free survival of the TSC30 % group was significantly shorter. CRBSI-free survival was reduced only for subclavian CVCs. Functionality was not found significantly different between groups although survival was shorter for subclavian CVC locked with TSC30%. Differences may be related to anatomical effects and CVC design rather than locking effects. Sofroniadou, et al., 2017 Prospective, randomized, controlled study.
Investigation of ethanol lock solutions for the prevention of CRBSI in HD patients. Exit site infections, thrombotic and bleeding episodes were also investigated.
In 106 HD patients, 6 CRBSI incidents occurred in 6 of 52 patients in the taurolidine group and 18 incidents occurred in 13 of 54 patients in the citrate group, corresponding to 0.67 and 2.7 episodes of CRBSI per 1000 catheter days.Taurolidine-based lock solutions + heparin/urokinase significantly reduced CRBSI risk comparing to 4% citrate solutions. Vercaigne et al., 2017 Prospective, randomized, pilot study Assessment of 30% ethanol/4% sodium citrate and heparin 1000 units/mL locking solutions to identify and compare adverse effects, risk for CRBS and catheter functionality in HD patients. Ultimate objective to avoid catheter removal.
In 40 HD patientsrandomized to 30% ethanol/4% sodium citrate or heparin 1000 units/mL locking solution, catheter survival was longer in the ethanol/citrate group (2.8/1000 catheter days in the ethanol/citrate group, 1.5/1000 catheter days in the heparin group). Ethanol/sodium citrate locking appears more efficient in reducing CRBSI risk and avoiding catheter removal comparing to heparin locks. 113 cases of CRBSI were identified while monitoring 274 catheters in HD patients who receivedsystemic and lock therapy with Cephazolin and/or Vancomycin on the basis of antibiograms. In 40 episodes of S. aureus CRBSI, 34 were successfully treated (85%) avoiding catheter removal. In 19 episodes of MRSA and 21 of MSSA, 79% and 90% were successfully treated respectively. Recurrences were observed at 22% of the cases, 75% of which were treated successfully.

Bueloni et al., 2019
Prospective observational study in two dialysis centers.
In 65 HD patients in the gentamicin/cafazolin group and 62 HD patients in the taurolidine/citrate group, there was no significant difference between the two groups concerning CRBSI (p=0.18) or exit site infection rates (p=0.37).

Padilla-Orozco et al., 2019
Prospective cohort study Evaluation of the utility of a generalized and prolonged gentamicin-lock therapy in HD patients with respect to the reduction of CRBSI rates.
CRBSI rates were measured before and after and intervention of prolonged gentamicin lock therapy. CRBSI incidents were reduced significantly from 1.28 to 0.2 cases per 1,000 catheter-days (p = 0.001) especially with P. aeruginosa and other Gram-negative bacteria. Prolonged gentamicin was considered safe and effective. Wang et al., 2020 Retrospective, monocentric observational study Assessment of urokinase plasminogen activator (uPA)-based (+/antibiotics) comparing to heparin-based lock solutions on HD patient catheters with respect to CRBSI rates and adverse effects and in-vitro study involving the induction of biofilm formation in HD catheters to mimic CRBSI development. uPA +/-antibiotics was applied on the induced biofilms to study its antimicrobial and biofilm removing properties.
In 86 HD patients (34 heparin-based locks, 52 uPA-based locks +/antibiotics), uPA-based lock solutions were found more effective in treating coagulase-negative Staphylococci related CRBSI than other microorganisms without significant adverse effects. uPA+antibiotics presented better antimicrobial and antibiofilm properties than uPA alone or heparin-based lock solutions both in vitro and in vivo.

ALS Consistency
The ALS used in these studies contained various combinations of antibiotic and non-antibiotic agents. Concerning the non-antibiotic agents, heparin-based lock solutions were widely used throughout these studies, as heparin is systematically used to prevent catheter thrombosis and in many studies it was used in the control groups (Zhao et al., 2014;Zhao etal., 2018;Mai et al., 2019;Kanaa et al., 2015;Moghaddas et al., 2015;Rijnderset al., 2018;Wang et al., 2020).
Citrate-based lock solutions were also extensively studied (Mai et al., 2019;Winnicki et al., 2017;Barcellos et al., 2017). Citrate is a non-antibiotic agent often used in catheter lock solutions as an alternative to heparin due to its anticoagulant activity (Bruyère et al., 2014). Citrate was investigated in various combinations with antibiotics and other non-antibiotic agents such as Citrate/Gentamicin (Zhao et al., 2014), Citrate/Taurolidine +/-heparin (Zhao et al., 2014;Al-Ali et al., 2017;Winnickiet al., 2017;Bueloni et al., 2019), Citrate/Taurolidine/urokinase (Al-Ali et al., 2017;Winnicki et al.,2017) and Citrate/methylene blue/methylparaben/propylparaben (Zhao et al., 2014). Taurolidine, which is a synthetic non-antibiotic agent with broad antimicrobial and anticoagulant activity (Torres-Viera et al., 2000), is regularly used in catheter locks and it is commercially available in combination with citrate and heparin (Taurolock/Hep) or urokinase (Taurolock/U). These commercially available lock solutions with taurolidine were used in the studies by Al-Ali et al., 2017 andWinnickiet al., 2017 in various combinations and concentrations. Urokinase plasminogen activator (uPA) was investigated as a non-antibiotic agent in locking solutions for its thrombolytic properties in combination with antibiotics (Bonkain et al., 2017). Ethanol was also studied as an ALS component due to its antimicrobial properties in various concentrations and combinations (Sofroniadou, et al., 2017;Zhao et al., 2018). Cathasept (4% tetra-sodium EDTA) was also studied byKanaa et al., 2015 for its antimicrobial/anticoagulant properties.
Concerning the antibiotics used in the studies included in this review, they were investigated either as single components or in combinations +/-anticoagulants in ALS such as Cefazolin/Gentamicin/heparin (Bueloni et

Objectives of the Studies
Concerning the main objective of the studies, the majority aimed at the investigation of the efficacy of lock solutions to prevent or treat catheter related infections in HD patients in the scope to prolong catheter survival and avoid catheter exchange. More specifically, all the meta-analyses (Zhao et al., 2014;Böhlke et al., 2015;Zhao et al., 2018;Mai et al., 2019) aimed to investigate the effect of various lock solutions on the CRBSI risk patients with the ultimate objective to identify potential prevention/therapeutic protocols (Böhlke et al., 2015). The investigation was either aiming to compare specific non-antibiotic lock solutions (Zhao et al., 2014;Zhao et al., 2018;Mai et al., 2019) against heparin-based controls or to compare the most commonly used antibiotic/non-antibiotic ALS against each other in various combinations (Böhlke et al., 2015). Other relevant objectives which were common among these meta-analyses wereto assess catheter flow rate and dialysis efficiency, exit-site infection, adverse effects such as catheter-relatedthrombosis, bleeding and clinical side-effects, rate of thrombolytic treatment requirement (Zhao et al., 2014), catheter types and insertion sites (Böhlke et al., 2015;Barcellos et al., 2017;Zhao et al., 2018), catheter CRBSI-free survival, catheter duration and all-cause mortality (Zhao et al., 2014;Mai et al., 2019). The meta-analyses also assessed the heterogeneity, the sample size and the publication bias of the studies they included.The aforementionedobjectives were also common among most of the clinical studies included in this review. Secondary objectives which were distinctive in specific clinical studies werethe investigation of biomarkers for inflammation and anemia (Kanaa et al., 2015), the CRBSI risk assessment for specific microorganism (Yen et al., 2015;Mandolfo et al., 2019;Wang et al., 2020), the cost-effectiveness of specific treatments (Winnicki et al., 2017), differences with respect to catheter insertion sites (Barcellos et al., 2017) and the anti-biofilm properties of antimicrobial/anticoagulant agents in certain ALS treatments (Wang et al., 2020).

Study Results
The 4 meta-analyses in this study concerning the efficacy of ALS for the prevention or treatment of CRBSI in HD patients agree thatlocking therapy appears to have significant potential benefits. The reviews concluded that overall ALS therapy reduces CRBSI risk and prolongs catheter survival without profound adverse effects on the patients' health or dialysis efficiency. More specifically, citrate-based ALS +/-antibiotics were found to significantly reduce the risk for CRBSI comparing to heparin locks, without increasing bleeding or catheter thrombosis incidents (Zhao et al., 2014;Böhlke et al., 2015;Mai et al., 2019). Ethanol locking was also found to reduce the risk of bacteremia in HD patients at a significant rates (Zhao et al., 2018). All reviews though emphasize that in order to endorse the systematic use of ALS against CRBSI, further research is required as no prevention protocols and diagnostic criteria are yet established. Furthermore, concerning the use of ALS as an effective alternative to avoid catheter removal, current research is not yet conclusive. Böhlke et al. (2015) in particular claim in their review that catheter removal was found to be the most effective approach to treat CRBSI while certain adverse effects that might be related to systematic ALS treatment, such as hypocalcaemia or aminoglycoside ototoxicity, should be seriously taken into account.
The results of the clinical studies in this review are generally in agreement with the results of the systematic reviews. A considerable percentage of the clinical studies that investigated the effect of various ALS +/-antibiotics comparing to heparin locks found that ALS reduced CRBSI risk at a significant rate without major adverse effects (Moghaddas et al., 2015;Rijnders et al., 2018;Padilla-Orozco et al., 2019;Wang et al., 2020) with the exception of the study of Kanaa et al. (2015) where Cathasept locking did not result at a significant reduction of CRBSI rate comparing to heparin although bacterial colonization was significantly reduced. Similarly, Sofroniadou et al. (2017) detected reduced CRBSI incidents with ethanol/heparin locks comparing to heparin control at non-significant rates. Moreover, Vercaigne et al. (2017) although identified reduced CRBSI risk using 30% ethanol/4% sodium citrate locks, the significance of their results cannot be determined as this was a small scale pilot study. It's worth mentioning that Barcellos et al. (2017) were the only to report reduced CRBSI-free catheter survival with locking therapy (citrate-based lock) comparing to heparin control although they conclude that their results might have been affected by anatomical andCVC design differences related to catheter insertion site. More specifically they report that reduced CRBSI-free catheter survival was detected only with subclavian catheters while no significant differences were detected with jugular catheters. Concerning the studies that aimed to investigate the use of ALS to avoid catheter removal, Yen et al. (2015) consider Daptomycin lock to be particularly promising similarly to Vercaigne et al. (2017)

Discussion
Currently, the CDC recommends ALS treatment only for HD patients with recurrent bloodstream infections as there are no conclusive data on the efficacy and safety of ALS for long-term preventative or therapeutic protocols. This review was designed in the view to investigate the prospects of recommending the systematic application of ALS against CRBSI for HD patients as an alternative to catheter removal. Catheter removal and exchange is a common practice for the treatment ofCRBSI (Böhlke et al., 2015) which can be quite challenging for patients on regular catheterizations such as HD patients, cancer patients or patients on parenteral nutrition (Hachem et al., 2018). ALS treatment is considered promising for systematic application as it appears to have not only significant effect on CRBSI rates (Sun et al., 2020) but also presents other considerable advantages such as cost-effectiveness (Leistner et al., 2014;Winnicki et al.,2017) and anti-biofilm properties. The microbial biofilm that is formed in the lumen of infected catheters is often resistant to systemic antibiotics, so biofilm prevention is essential for CRBSI treatment (Pérez-Granda et al., 2017;Wang et al., 2020). Moreover, antimicrobial agents in locking solution maintain prolonged, high concentration within the catheter lumen with minimal systemic absorption (Bookstaver et al., 2009) and therefore have not been associated with increased risk for the formation of resistant microbial strains (Raad et al., 2016). Apparently, the evaluation of the prospects for systematic use of ALS is imperative as it gjhs.ccsenet.org Global Journal of Health Science Vol. 13, No.4; may contribute significantly to the wellbeing of HD patients as well as all patients undergoing regular catheterizations.
Regarding the variouslock solutions currently investigated in this field of research and more specifically the commonly used non-antibiotic ALS components, citrate-based ALS are among the most extensively studied (Mai et al., 2019). According to the meta-analysis of Mai et al., citrate-based locking including antimicrobials reduces significantly CRBSI risk in HD patients comparing to conventional heparin locks without affecting the risk of catheter removal, the frequency of thrombolytic treatment, thrombocytopenia rates or all-cause mortality (Mai et al., 2019). This is consistent with the review of Zhao et al. where citrate + antimicrobials is found to reduce CRBSI risk in HD catheters but not citrate alone (Zhao et al., 2014). On the other hand Liu et al. found significant CRBSI reduction with citrate locks even without antimicrobials (Liu et al., 2015). Vercaigne et al. also report that citrate is potentially more effective than heparin in CRBSI prevention in their pilot study for HD patients (Vercaigne et al., 2017). Mai et al. claim that such inconsistencies are due to the fact that previous studies did not systematically considercritical parameters that may affect citrate efficacy such as catheter type or type of infection. For example, Mai et al. found that CRBIS risk is reduced with tunneled cuffed catheterscomparing to non-tunneledones while CRBSI occurrence is more closely related to S.aureus with citrate than heparin locking.Abe et al. also reported no significant difference to CRBSI rates with citrate comparing to heparin locks with non-tunneled catheters which are primarily used in Egypt for dialysis (Abe et al., 2018). Taking into account parameters such as type of catheter or infection in their review Mai et al., concluded that citrate alone does not seem to reduce CRBSI risk while further research is required for the establishment of specific locking protocols (Mai et al., 2019). Similarly, Barcellos et al. in their clinical trial on the effectiveness of citrate locks comparing to heparin concluded that their results were inconclusive as the insertion site of the catheter in HD patients seemed to affect significantly the CRBSI-free catheter survival. More specifically, CRBSI-free catheter survival did not differ significantly between citrate (-antimicrobials) and heparin locks with jugular vein catheters, which is consistent with the results of Zhao et al. and Mai et al., while with subclavian catheters CRBSI-free survival was significantly lower with citrate locks (Barcellos et al., 2017). Other studies on the efficacy of citrate locks against CRBSI highlight on the significance of asepticcatheter manipulation in accordance to CDC guidelines, as imperfect sterility may compromise locking efficiency (Cooney et al., 2020). To conclude, citrate may be an effective anticoagulant alternative to heparin and contribute to CRBSI risk reduction in combination with antimicrobials but further research is required for the standardization of detailed protocols (May et al., 2019).
Ethanol is another promising non-antibiotic catheter lock that is easily available, inexpensive, with wide antimicrobial properties that successfully penetrates microbial biofilm and does not facilitate the development of resistant microbial strains as opposed to antibiotic locks (Balestrino et al., 2009). Ethanol locking therapy for the prevention of bacteremia is associated with encouraging results in contemporary research. Sofroniadou et al. in their clinical study detected reduced CRBSI risk with ethanol/heparin locking comparing to heparin control although the mean cumulative infection-free catheter survivalwas not significantly different in the two groups (Sofroniadou et al., 2017). Zhao et al. report that ethanol locking decreases significantly the risk for CRBSIfor HD patients without significant adverse effects, although this result concerns only tunneled catheters (Zhao et al., 2018). Tunneled catheters are believed to offer better antimicrobial protection comparing to un-tunneled ones, so it is possible that ethanol cannot prevent bloodstream infections unless the major cause for CRBSI, which is the migration of microorganism from the skin to the bloodstream along the catheter, is eliminated (Timsit et al., 1999). This meta-analysis also points out that locking effect appears more beneficial with patients in higher risk for CRBSI, such as patients with hematological malignancy, while the protective effect of locking therapy is not easily measurable in patients with milder health conditions. Apparently, subgroup analysis is imperative for the accurate evaluation of the effectiveness of ethanol-based locking against CRBSI in HD patients as flawed research methodology may be masking results (Zhao et al., 2018).
Taurolidineis another antimicrobial agent that is commonly used in ALS due to its antibiofilm and antimicrobial properties against Gram-positive and Gram-negative bacteria including MRSE, CoNS and vancomycin-resistant enterococci, while it has not been associated with serious side effects or bacterial resistance (Torres-Viera et al., 2000). Liu et al. in their meta-analysis estimated a 66% reduction in CRBSI risk with taurolidine locks while Zwiechet al. reported a 77% decrease in their review (Liu et al., 2013;Zwiech et al., 2016). Norris et al. though, concluded that taurolidine is potentially beneficial against bloodstream infections in high risk cancer patients but further research is required for conclusive results (Norris et al., 2017). The more recent meta-analysis of Sun et al., for CRBSI risk in pediatric patients, reportsa significant reduction of CRBSI incidences with taurolidine locks but indicates that thequality of the studies included in their review was poor (Sun et al., 2020). No studies on taurolidine as a single antimicrobial agent in lock solutions specifically for HD patients were identified. Overall, the exact contribution of taurolidine as a single antimicrobial agents in locking solution against CRBSI is yet to be determined as large scale high-quality clinical trials are required (Sun et al., 2019).
Considerable research has also been done on the commercially available TauroLock™-Hep (taurolidine/heparin) and TauroLock™-U (taurolidine/citrate/urokinase) (Al-Ali et al., 2017;Winnicki et al., 2017). These studies though, focused primarily on the antithrombotic effect of urokinase in theTauroLock™-U. Urokinase plasminogen activator (uPA) is a fibrinolytic protease with thrombolytic properties which has been associated with reduced CRBSI incidents and improved catheter functionality (Bonkain et al., 2017). Both Al-Ali et al. and Winnichi et al. report reduced rates of all-causes catheter exchange concluding that Taurolock/U is a safe and effective lock solution for tunneled dialysis catheters (Al-Ali et al., 2017;Winnicki et al.,2017). These results were also corroborated by the studies of Bonkain et al. and Van Hulle et al. who report that urokinase locks are significantly efficient in preventing thrombotic dysfunction or restoring catheter functionality (Bonkain et al., 2017;Van Hulle et al., 2019). Finally, Wang et al. in their combined in vivo and in vitro study on hemodialysis catheter locks demonstrated that uPA locks have superior anti-thrombotic and anti-biofilm properties comparing to heparin locks while uPA combined with antibiotics also offers enhanced antimicrobial protection (Wang et al., 2020).
Cathasept (4% tetra-sodium EDTA) has also been studied for its anticoagulant and antimicrobial properties as a lock solution component (Kanaa et al., 2015;Hill et al., 2020). Cathasept has been reported to reduce CRBSI rates significantly in parenteral nutrition patients (Hill et al., 2020). Kanaa et al. in their clinical trial on HD patients, though they had detected significantly reduced microbial colonization in HD catheters with cathasept, they could not confirm a significant reduction in CRBSI rates comparing to heparin so they stressed the need for further research based on higher quality methodology (Kanaa et al., 2015). Quirt et al. in a more recent study on pediatric intestinal failure patients reported that according to their preliminary findings 4% tetrasodium EDTA solution effectivelyreduced catheter-related bloodstream infections and catheter flow (Quirt et al. 2021). EDTA (ethylenediaminetetraacetic acid) as the main component of cathasept and a chelating agent with known antimicrobial/anticoagulant/antibiofilm and blood vessel protective activity (Song & Zhang, 2020) has been extensively studied as a lock solution candidate (Hachem et al., 2018;Dang et al., 2019). More specifically, Dang et al. in their meta-analysis estimated that EDTA is the most effective against CRBSI and exit-site infection among 13 different lock solutions at a rate of 84.4%. EDTA has also been reported to complement successfully the antimicrobial activity of antibiotic-based locks (Raad et al., 2016;Rijnders et al., 2018). Although EDTA has been extensively studied as a catheter lock component, further research and subgroup analysis for the establishment of specific protocols is yet required (Dang et al. 2019).
Antibiotic lock solutions exhibit broad antimicrobial activity, reduce CRBSI and patients' mortality. The disadvantages of prolonged antibiotic locking though,include difficulty to infiltrate microbial biofilm in catheter lumen,increased risk for development of resistant microbial strains, systemic toxicity and catheter dysfunction (Golestaneh & Mokrzycki, 2018). Gentamicin has been reported to significantly reduce CRBSI risk and mortality hazard comparing to non-antibiotic locks in HD patients (Moore et al., 2014). Padilla-Orozco et al. concluded that gentamicin locks are significantly effective against hemodialysis catheter infections, especially with P. aeruginosa and other Gram-negative bacteria. Bolke et al. also identify the effectiveness of gentamicin-based locks against bloodstream infections in HD patients but raise concerns about the measurable levels of gentamicin in patients' plasma due to systemic absorption, which indicates a risk for development of gentamicin-resistant microbes (Böhlke et al., 2015). Concerning the studies comparing antibiotic-based to non-antibiotic locks, Moghaddas et al. (2015), Mandolfo et al. (2019) and Yen et al. (2015) identified significant or quite promising advantages with antibiotic locks using cotrimoxazol, daptomycin and caphazolin/vancomycin respectively. More specifically, Mandolfo et al. (2019) support that systematic antibiotic locking therapy should be seriously considered as a prophylactic practice for HD patients to reduce catheter removal rates. This view is corroborated by the review of Yahav et al. (2008) who concluded that antibiotic catheter locks should be considered as a routine clinical practice.On the other hand, Rijnders et al. (2018) and Bueloni et al. (2019) in their studies with trimethoprimand gentamicin/cefazolin respectively did not detect measurable differencescomparing to non-antibiotic locks. These inconsistencies highlight the need for further research based on subgroup analysis and high quality clinical trials as most researchers point out in recent relevant reviews (Böhlke et al., 2015;Dang et al., 2019;Sun et al., 2020).

Conclusion
The studies presented and analyzed in this review demonstrate encouraging emerging data on the application of antimicrobial lock solutions that could potentially be used systematically to reduce or treat CRBSI, prolong catheter survival and decrease the necessity for catheter removal in HD patients. These data although promising, are not yet conclusive and cannot fully support the endorsement of the systematic use of lock solutions to avoid gjhs.ccsenet.org Global Journal of Health Science Vol. 13, No.4; catheter removal, which is the primary response to catheter-related bloodstream infections. A significant number of researchers in this field of study identify the need for further research based on large scale, high quality clinical trials. More specifically, they emphasize on the heterogeneity among studies, the shortage of large scale trials and the likelihood for publication bias. The necessity for subgroup analysis is also emphasized as results may be biased in populations in higher risk for bloodstream infection. Type of catheter, type of microbial infection, catheter handling and catheter insertion site may also comprise independent parameters that should be considered in subgroup analysis as they may mask results. Overall, locking therapy appears to be a highly advantageous tool in the battle against thedetrimental effects of catheter related infections, so further research on the prospects of the various lock solutions is imperative as it might lead to a significant improvement in the wellbeing of HD patients.