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Prevention of Coagulase-Negative Staphylococcal Central Venous Catheter–Related Infection Using Urokinase Rinses: A Randomized Double-Blind Controlled Trial in Patients With Hematologic Malignancies

Cornelis J. van Rooden, Emile F. Schippers, Henri F.L. Guiot, Renée M. Barge, Marcel M.C. Hovens, Felix J.M. van der Meer, Frits R. Rosendaal, Menno V. Huisman

From the Departments of General Internal Medicine/Endocrinology, Infectious Diseases, Haematology, and Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands

Corresponding author: Menno V. Huisman, MD, PhD, Department of General Internal Medicine/Endocrinology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC Leiden, the Netherlands; e-mail: M.V.Huisman{at}LUMC.nl

	ABSTRACT

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Purpose Fibrin deposition at the intraluminal surface of the indwelling part of the central venous catheter (CVC) surface increases the risk of CVC-related coagulase-negative staphylococci (CoNS) infection. Therefore, repetitive enzymatic dissolution of fibrin by urokinase might reduce the risk of CVC-related infection. We undertook this study to investigate whether three times weekly urokinase rinsing of CVC reduces the incidence or severity of CVC-related infections by CoNS in patients undergoing intensive cytotoxic treatment for hematologic malignancies.

Patients and Methods In a double-blind setting, all consecutive patients with a CVC were randomly allocated to receive either urokinase rinses (5 mL of 5,000 U/mL) or placebo (saline), both three times weekly.

Results The percentage of patients with at least one positive culture with CoNS was lower in patients receiving urokinase compared with patients receiving placebo (26% v 42%, respectively; relative risk [RR] = 0.61; 95% CI, 0.39 to 0.94). Major CVC-related CoNS infection occurred less frequently in patients receiving urokinase versus placebo (1.2% v 14.1%, respectively; RR = 0.09; 95% CI, 0.01 to 0.50). Secondary complications, including CVC-related thrombosis, were observed less frequently in the urokinase group compared with the placebo group (1.3% v 9.0%, respectively; RR = 0.14; 95% CI, 0.02 to 0.82). No severe bleeding complications attributable to urokinase were observed.

Conclusion Three times weekly urokinase rinsing reduces the incidence of CVC-related CoNS infection in patients treated with intensive cytotoxic therapy for hematologic malignancies, with acceptable safety.

	INTRODUCTION

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Central venous catheter (CVC)-related infection with coagulase-negative staphylococci (CoNS) remains a frequent cause of hospital-acquired infection, particularly in hematologic patients undergoing intensive chemotherapy despite preventive measures such as evidence-based CVC insertion practices.^1-3 CVC-related CoNS infections range in clinical severity and include, from least to most severe, colonization of the CVC, CVC-related local infection, CVC-related bloodstream infection, and CVC-related septicemia. In a minority of patients, suppressive antimicrobial therapy fails, leading to thrombosis, dissemination, and premature removal of the CVC.⁴

Migration of micro-organisms colonizing the skin at the insertion site into the cutaneous catheter tract finally reaching the catheter tip is a common route of infection for peripherally inserted, short-term catheters.⁵ In hematology patients undergoing intensive cytotoxic chemotherapy, the combination of mucositis and selective gut decontamination (including benzyl-penicillin prophylaxes) leads to colonization of the skin and the upper GI tract with penicillin-resistant CoNS. It has been shown that CVC-related infections with CoNS in these patients are frequently caused by the same colonizing strain of micro-organisms.⁶ Contamination of the catheter hub contributes substantially to intraluminal colonization of long-term CVCs.^7,8 Occasionally, catheters might become hematogenously seeded from another focus of infection or by infusate contamination.⁹

The presence of a thrombotic sheet favors adherence of various bacteria, including staphylococci.^10-12 Inspection by scanning electron microscopy of catheter tips, obtained after withdrawal of the CVC in hemato-oncology patients, revealed the presence of thrombotic biofilms even in patients without any clinical signs or symptoms of infection.¹³ In this biofilm, CoNS may surpass a critical amount, which causes local inflammation and release of CoNS in the bloodstream, resulting in fever and symptoms or signs of septicemia.^12,13

In a recent randomized study, low-dose unfractionated heparin by continuous infusion reduced the occurrence of catheter-related bloodstream infections.¹⁴ We hypothesized that serial enzymatic dissolution of the thrombus by urokinase would reduce the risk of CVC colonization and thus lead to a decrease of CVC-related CoNS infections. The aim of the present study was to examine whether regular application of urokinase could reduce the incidence and the severity of CVC-related infections by CoNS.

	PATIENTS AND METHODS

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Patients and Study Design
This study was a double-blind randomized trial comparing the effect of urokinase rinses three times weekly with placebo on the incidence of CVC-related infections. The study was performed at the Department of Hematology of the Leiden University Medical Center, a tertiary referral center for hematologic disease in the Netherlands. The study protocol was approved by the local medical ethical committee, and written informed consent was obtained from all participating patients. All patients receiving a CVC before intensive chemotherapy or conditioning for bone marrow transplantation or peripheral-blood stem-cell transplantation between January 1996 and February 1999 were eligible for enrollment onto the study. Inclusion criteria were an age of 18 years or older and admission to undergo intensive cytotoxic treatment associated with disruption of the mucosa and severe granulocytopenia (polymorphonuclear leukocytes < 0.1 x 10⁹/L) for at least 14 days. Patients with pre-existing bleeding disorders and patients treated with intravenous unfractionated heparin to prevent veno-occlusive disease were excluded. Patients with documented septicemia before the start of the study were also excluded.

CVCs were inserted via the subclavian or jugular vein by qualified physicians of the intensive care department. All CVCs were tunneled. The external infusion system was replaced daily by a new system, during which the CVC was locked with heparin (5,000 U/mL). The CVCs were used for administering cytotoxic drugs and supporting treatment (ie, fluids, blood products, parenteral feeding, and antimicrobial therapy); withdrawal of blood from the CVC for diagnostic purposes and monitoring was allowed. No antibiotic prophylaxis specifically for CVC-related infections was administered.

Intervention
After informed consent was obtained, patients were randomly allocated to receive rinses three times a week containing urokinase (25,000 U; 5 mL of 5,000 U/mL) or placebo (5 mL of saline 0.9%) slowly infused in 15 minutes. After infusion of the total volume, the remaining urokinase or placebo in the lumen of the CVC was left as lock for at least 30 minutes or longer until the catheter had to be used for clinical purposes. The first dose of study drug was administered before day 7 after insertion of the CVC. Aside from the study drug (urokinase v placebo), there were no other differences in CVC management, including medication and CVC locking with heparin. Random assignment was performed by using sealed envelopes, enclosing a code corresponding to the study patient. After closure of the study, the codes were broken.

Preventive Measures and Antimicrobial Therapy
Patients were nursed in single rooms. All patients were treated according to a local protocol to prevent infections with aerobic Gram-negative rods, Streptococcus viridans, and Candida species. Prophylactic treatment included neomycin (250 mg), polymyxin B (1.10⁶ U) orally once daily, pipemidic acid 400 mg orally bid, and amphotericin B 200 mg orally once daily and 10-mg chewing tablets orally once daily. After 10 days of treatment, the dosage of the regimen was reduced (half of the dosage in mg), except for the pipemidic acid. Additional prophylaxis was administered for short episodes or individual indications (eg, pipemidic acid replacement by oral ciprofloxacin or cotrimoxazole in patients still colonized with aerobic Gram-negative rods, or intravenous benzyl-penicillin as streptococcal prophylaxis during mucositis and granulocytopenia after cytarabine induction therapy). The choices of individual regimens were based on the results of microbial surveillance cultures.

Surveillance and Follow-Up
Starting the day after the insertion of the CVC, lock fluid was cultured routinely every second day as described previously.¹³ If surveillance CVC lock fluid culture yielded growth of micro-organisms (positive lock culture), then lock cultures were drawn daily.

At each episode of onset of fever (body temperature 38.5°C) or other symptoms or signs of infection (eg, hypotension, chills, hypothermia, or unexplained tachycardia), blood cultures were drawn, at least one via the CVC and one by standard venipuncture. At least two blood cultures were drawn on each consecutive day in all patients with clinical symptoms or signs of infection, until a causative micro-organism was isolated. In the presence of clinical signs of inflammation at the insertion site (ie, erythema, exudation, tenderness, warmth, or swelling), swab cultures were taken. Catheter tip cultures were not performed routinely but only to support the diagnosis of CVC-related infection. Micro-organisms were identified by current tests (DNAse testing), additional commercial ID 32 STAPH biochemical test strips (API; bioMerieux, Lyon, France), and antimicrobial sensitivity patterns. To demonstrate an epidemiologic relationship between staphylococci isolated from diagnostic cultures and those present on the skin and mucosal surfaces, typing was performed by a combination of biochemical properties (ID 32 STAPH), antimicrobial sensitivity patterns, and molecular biologic typing techniques. The criteria for establishing a diagnosis of CVC-related infection were adapted from previous studies and described previously.^13,15,16 Two entities were distinguished, local CVC-related infection and systemic CVC-related infection (Table 1). In case of a proven insertion site infection or CVC colonization, appropriate antimicrobial therapy was started. The CVC was left in place. If a single CVC lock fluid culture was positive, no treatment was started. In case of fever or other symptoms or signs of systemic infection, empirical therapy was started (ceftazidime 500 mg intravenously tid and teicoplanin 200 mg intravenously bid on day 1, qid on consecutive days). Empirical therapy was discontinued if blood cultures remained negative after 72 hours. If a systemic CVC-related septicemia was diagnosed, empirical therapy was adjusted to the most appropriate small-spectrum regimen. The CVCs were not removed routinely.

Secondary end points in this study were CVC-related infections caused by other microbial pathogens, premature CVC removal, secondary CVC-related complications (metastatic infection or CVC-related thrombosis), non–CVC-related septicemia, major bleeding (within 1 week after the last urokinase dose), and death.

Statistical Analysis
The primary analysis was performed on an intent-to-treat basis. Cumulative incidences were calculated as the number of first events over time. Ninety-five percent CIs were calculated and based on binominal distributions. Differences in proportions between both groups were compared using the ² test, unless otherwise stated. Relative risks (RRs) were expressed as ratio of risk of an end point in the urokinase group divided by the risk in the saline group.

Sample size calculation was based on a pilot study indicating an absolute risk of 45% of CVC-associated CoNS infection. Using a two-sided = .05, with 80 patients per group, the study has a statistical power of 80% to detect a 50% reduction in risk of CVC-associated CoNS infection. Allowing for a dropout rate of approximately 10%, we aimed for inclusion of a total of 180 patients.

	RESULTS

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Patients
Of 181 consecutive patients, 20 patients meeting one or more of the following exclusion criteria were excluded: refusing informed consent (n = 7), pre-existing bleeding disorder (n = 5), prior heparin treatment (n = 4), and documented septicemia (n = 4). Of the 161 included patients, 83 patients were randomly allocated to receive urokinase, and 78 patients were allocated to receive saline (Table 2). After the random assignment procedure, one patient in the urokinase group withdrew informed consent for perceived adverse effects (infusion-related nausea) after receiving four doses of the allocated study drug (urokinase). The remaining 160 patients completed the study (82 patients in the urokinase group and 78 patients in the saline group.)

Non–CVC-Related Septicemia
The frequency of non–CVC-related septicemia was similar among patients who received urokinase (8.5%) and saline (9.0%). The microbial pathogens cultured (blood cultures) are listed in Table 4.

Secondary Complications
Two patients with CVC-related septicemia, both receiving saline, suffered from metastatic abscesses caused by CoNS. One of these patients had multiple systemic metastatic abscesses and pulmonary emboli, whereas the other patient had a metastatic infection of the knee joint. In six patients, CVC-related thrombosis was objectified by Doppler ultrasound or venography. All patients had previous CVC-related septicemia; thrombosis was caused by CoNS in five patients (saline group) and by C jeikeium in one patient (urokinase group). Overall, secondary CVC-related complications occurred less frequently in the patients receiving urokinase (urokinase group: one of 82 patients; saline group: seven of 78 patients; RR = 0.14; 95% CI, 0.02 to 0.82).

Adverse Effects of Urokinase
In the group of patients who received urokinase, one patient suffered from a major (fatal) cerebral hemorrhage 3 weeks after the last urokinase rinse, in combination with a low platelet count not reacting on platelet infusion. In the group receiving placebo, no major hemorrhage occurred. No allergies were observed. In one patient, urokinase treatment was ceased because of nausea immediately after administration (repetitively).

Fatalities
Six patients died during follow-up. Among the patients treated with urokinase, five deaths occurred, whereas in the group of patients on saline, one death was observed (RR = 4.8; 95% CI, 0.76 to 30.6).

One patient in the urokinase group died as a result of major cerebral bleed. The other causes of death included cardiac failure/cardiomyopathy (n = 1), septicemia with C albicans (n = 2), multiorgan failure after chemotherapy toxicity (n = 1), and graft-versus-host disease (n = 1).

	DISCUSSION

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In this study, we have shown a benefit from urokinase in the prevention of CVC septicemia by CoNS. The number of severe infections with CoNS was significantly reduced by urokinase. This was most obvious regarding systemic CVC-related bloodstream infections, including septicemia. However, urokinase did not reduce the overall infection rate, including merely colonization and local exit infection. Furthermore, our results suggest that the risk for secondary complications (metastatic infections) and CVC-related thrombosis may also be reduced by urokinase. Two other studies have evaluated urokinase for the prevention of CVC-related complications.^17,18 In the first study, 105 patients with long-term indwelling CVCs were randomly treated with twice-daily unfractionated heparin flushes and additional urokinase (5,000 U once weekly) or standard unfractionated heparin flush (twice daily).¹⁷ Using the combined end point of CVC dysfunction and infection, patients receiving urokinase had a 6% rate of complications compared with a rate of 21% for patients on saline (P = .02). There were no complications noted from the urokinase administrations. In the second study, 100 patients undergoing chemotherapy or stem-cell transplantation were randomly assigned to either urokinase (5,000 U flush, twice weekly) or unfractionated heparin (50 U flush, twice weekly).¹⁸ The frequency of CVC-related septicemia in urokinase-treated patients (20%) was similar to that in patients receiving heparin (25%; P = .50). Also, other complications, including other types of CVC infection, CVC dysfunction, and thrombosis, were equally distributed among the two treatment groups. Several authors have reported that microbial pathogens adhere easily to thrombin sheaths.^10,11 Specifically, most strains of CoNS strongly bind to fibronectin, and some strains also bind to fibrin. Mehall et al¹² clearly demonstrated that the presence of a thrombin sheath promotes attachment of CoNS and contributes to the risk of CVC-related infection. Some in vivo studies reported a close association between thrombosis and infection.^15,19,20 Our results suggest that urokinase interferes in the process of infection by reducing the load of CoNS colonies attached to CVC thrombus systematically as a result of repetitive thrombolysis, rather than by preventing CVC colonization through microbial adhesion itself. As a consequence, progression to a critical mass of thrombus, with CoNS causing clinically relevant septicemia, is inhibited.

Alternative methods to prevent CVC-related infection may be antiseptic impregnated CVCs or anticoagulant prophylaxis. Although antiseptic impregnated CVCs have been shown to be effective in the prevention of CVC-related infection in the short term, the benefit is limited when used for more than 2 weeks.²¹ A reduction in infection has been reported in several studies for anticoagulant prophylaxis with unfractionated or low molecular weight heparin. In contrast to urokinase, which lyses clots, heparin prevents thrombus formation. Recently, in a randomized placebo-controlled study in patients with hemato-oncologic diseases, the continuous infusion of low-dose unfractionated heparin (100 U/kg/d) was effective in reducing the incidence of catheter-related bloodstream infections from 16.6% to 6.8% (RR = 0.41; 95% CI, 0.18 to 0.95).²² Bleeding was not different between the groups, and the doses of heparin did not prolong the activated partial thromboplastin time.

Some aspects of our findings warrant comment. First, we observed a lower incidence of CVC-related thrombosis in the group of patients receiving urokinase. Although in our study a low dose of urokinase (in nontherapeutic range) was used, potentially a developing clot could have been dissolved systematically. Because we did not evaluate our patients routinely with Doppler ultrasound or venography to assess thrombosis, the true incidence and risk reduction by urokinase for CVC-related thrombosis in our patients is unclear from this study. Second, we observed a nonsignificant higher number of deaths in the group of patients who received urokinase. One patient died from major cerebral bleeding 2 weeks after the last dose of urokinase. Considering the short half-life of urokinase and its clinical effect, this bleeding cannot be attributed to the urokinase administration. The other four deaths in the urokinase group were not regarded to be related to urokinase administration but, instead, were the result of adverse effects of disease or antileukemic treatment. Finally, the observed prevalence of infection in the placebo group was less than the prevalence we observed in a pilot study performed before this study (24.4% v 45%, respectively). This may be partially a result of the relatively small number of patients in the pilot study with inherent wide confidence limits. Alternatively, this lower prevalence may have been the result of better general preventive measures in the overall study population. In conclusion, administration of urokinase contributes to a clinically significant reduction in CVC-related septicemia caused by CoNS in patients treated for hematologic malignancies, although the total number of CVC-related infections was not reduced.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Cornelis J. van Rooden, Henri F.L. Guiot

Provision of study materials or patients: Henri F.L. Guiot, Renée M. Barge

Collection and assembly of data: Cornelis J. van Rooden, Emile F. Schippers, Henri F.L. Guiot, Renée M. Barge, Menno V. Huisman

Data analysis and interpretation: Cornelis J. van Rooden, Emile F. Schippers, Henri F.L. Guiot, Renée M. Barge, Marcel M.C. Hovens, Felix J.M. van der Meer, Frits R. Rosendaal, Menno V. Huisman

Manuscript writing: Cornelis J. van Rooden, Emile F. Schippers, Henri F.L. Guiot, Renée M. Barge, Marcel M.C. Hovens, Felix J.M. van der Meer, Frits R. Rosendaal, Menno V. Huisman

Final approval of manuscript: Cornelis J. van Rooden, Emile F. Schippers, Henri F.L. Guiot, Renée M. Barge, Marcel M.C. Hovens, Felix J.M. van der Meer, Frits R. Rosendaal, Menno V. Huisman

	ACKNOWLEDGMENTS

 
We thank all the participating patients, nurses, and attending physicians for their cooperation.

	NOTES

 
Supported by Grant No. 99.146 from the Netherlands Heart Foundation (C.J.v.R.).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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6. Guiot HFL, Ballering HCM, van Gestel MH, et al: Epidemiology and clinical aspects of i.v. catheter-associated CNS infection: Evaluation of a typing system. Presented at 3rd International Conference of the Hospital Infection Society, London, United Kingdom, September 4-8, 1994

7. Raad II, Costerton W, Sabharwal U, et al: Ultrastructural analysis of indwelling vascular catheters: A quantitative relationship between luminal colonization and duration of placement. J Infect Dis 168:400-407, 1993[Medline]

8. Linares J, Sitges-Serra A, Garau J, et al: Pathogenesis of catheter sepsis: A prospective study with quantitative and semiquantitative cultures of catheter hub and segments. J Clin Microbiol 21:357-360, 1985[Abstract/Free Full Text]

9. Maki DG: Infections associated with intravascular lines, in Remington JS (ed): Current Clinical Topics in Infectious Diseases. New York, NY, McGraw-Hill, 1982, pp 309-363

10. Herrmann M, Vaudaux PE, Pittet D, et al: Fibronectin, fibrinogen, and laminin act as mediators of adherence of clinical staphylococcal isolates to foreign material. J Infect Dis 158:693-701, 1988[Medline]

11. Vaudaux P, Pittet D, Haeberli A, et al: Host factors selectively increase staphylococcal adherence on inserted catheters: A role for fibronectin and fibrinogen or fibrin. J Infect Dis 160:865-875, 1989[Medline]

12. Mehall JR, Saltzman DA, Jackson RJ, et al: Fibrin sheath enhances central venous catheter infection. Crit Care Med 30:908-912, 2002[CrossRef][Medline]

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14. Abdelkefi A, Ben Othman T, Kammoun L, et al: Prevention of central venous line-related thrombosis by continuous infusion of low-dose unfractionated heparin, in patients with haemato-oncological disease. Thromb Haemost 92:654-661, 2004[Medline]

15. Raad II, Bodey GP: Infectious complications of indwelling vascular catheters. Clin Infect Dis 15:197-208, 1992[Medline]

16. van Rooden CJ, Schippers EF, Barge RM, et al: Infectious complications of central venous catheters increase the risk of catheter-related thrombosis in hematology patients: A prospective study. J Clin Oncol 23:2655-2660, 2005[Abstract/Free Full Text]

17. Ray CE Jr, Shenoy SS, McCarthy PL, et al: Weekly prophylactic urokinase installation in tunneled central venous access devices. J Vasc Interv Radiol 10:1330-1334, 1999[Medline]

18. Solomon B, Moore J, Arthur C, et al: Lack of efficacy of twice-weekly urokinase in the prevention of complications associated with Hickman catheters: A multicenter randomised comparison of urokinase versus heparin. Eur J Cancer 37:2379-2384, 2001[CrossRef][Medline]

19. Xiang DZ, Verbeken EK, Van Lommel AT, et al: Composition and formation of the sleeve enveloping a central venous catheter. J Vasc Surg 28:260-271, 1998[CrossRef][Medline]

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22. Abdelkefi A, Torjman L, Ladeb S, et al: Randomized trial of prevention of catheter-related bloodstream infection by continuous infusion of low-dose unfractionated heparin in patients with hematologic and oncologic disease. J Clin Oncol 23:7864-7870, 2005[Abstract/Free Full Text]

Submitted March 19, 2007; accepted October 15, 2007.

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