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Long-Term Silicone Central Venous Catheters Impregnated With Minocycline and Rifampin Decrease Rates of Catheter-Related Bloodstream Infection in Cancer Patients: A Prospective Randomized Clinical Trial

From the Departments of Infectious Diseases, Infection Control and Employee Health, Sarcoma Medical Oncology, Infusion Therapy Surgical Oncology, Biostatistics, and Leukemia, Division of Infectious Diseases, The University of Texas M.D. Anderson Cancer Center and Veterans Affairs Medical Center, Houston, TX

Address reprint requests to Hend A. Hanna, MD, MPH, The University of Texas M.D. Anderson Cancer Center, Department of Infectious Diseases, Infection Control, and Employee Health (Unit 402), 1515 Holcombe Blvd, Houston, TX 77030; e-mail: hhanna{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To evaluate the efficacy of long-term nontunneled silicone catheters impregnated with minocycline and rifampin (M-R) in reducing catheter-related bloodstream infections.

PATIENTS AND METHODS: This prospective, randomized, double-blind clinical trial was conducted at M.D. Anderson Cancer Center, a tertiary care hospital in Houston, TX. All patients in the trial had a malignancy.

RESULTS: Between September 1999 and May 2002, 356 assessable catheters were used: 182 M-R and 174 nonimpregnated. The patients' characteristics were comparable between the two study groups. The mean (± standard deviation) duration of catheterization with M-R catheters was comparable to that of nonimpregnated catheters (66.21 ± 30.88 v 63.01 ± 30.80 days). A total of 17 catheter-related bloodstream infections occurred during the course of the study. Three were associated with the use of M-R catheters and 14 were associated with the nonimpregnated catheters, with a rate of catheter-related bloodstream infection of 0.25 and 1.28/1,000 catheter-days, respectively (P = .003). Gram-positive cocci accounted for the majority of the organisms causing the infections. There were no allergic reactions associated with M-R catheters.

CONCLUSION: Long-term nontunneled central venous catheters impregnated with minocycline and rifampin are efficacious and safe in reducing catheter-related bloodstream infections in cancer patients.

	INTRODUCTION

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Central venous catheterization is an essential intervention in patients with malignancies for the administration of chemotherapeutic agents, total parenteral nutrition, blood products, antibiotics, electrolytes, fluids, and other medications. There is little doubt, if any, that central venous catheters (CVC) have contributed to patients' convenience and better quality of life by allowing for outpatient intravenous therapy and home parenteral therapy. Despite the obvious advantages of these devices, central venous catheterization can be complicated by catheter-related bloodstream infection, a problem associated with significant morbidity and mortality.^1-3

Catheter-related infection is often preceded by bacterial or fungal colonization of the catheter.⁴ Most indwelling CVCs become colonized with microorganisms, as was proven through scanning and transmission electron microscopy.⁵ These microorganisms are capable of adhering to catheter surfaces and embedding in a layer of biofilm, which is produced by the organism as well as the host itself.⁶ Many intervention measures have been found to decrease catheter-related infections. These measures include aseptic techniques for handling the catheters, skin disinfection, use of ports, antimicrobial catheters, and antibiotic lock solutions.^7-14

Short-term polyurethane CVCs impregnated with antimicrobial combinations, such as chlorhexidine and silver sulfadiazine or minocycline and rifampin (M-R), have been shown in clinical trials to reduce the rates of catheter colonization and catheter-related bloodstream infections.^15-17 In this current study, we compared the rates of bloodstream infection associated with long-term nontunneled silicone catheters impregnated with M-R versus nonimpregnated long-term silicone catheters inserted in cancer patients.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Patients and Study Plan
This prospective, randomized, double-blind study was conducted at M.D. Anderson Cancer Center, Houston, TX, a tertiary care cancer hospital. The trial, which was approved by M.D. Anderson's institutional review board, started in September 1999 and ended in May 2002. All patients provided written informed consent. Patients included in the study were adult patients with cancer who required new insertion of a nontunneled peripherally inserted CVC (PICC) or subclavian catheter (single or double lumen) with use anticipated to be greater than 7 days and who were available to be followed up for up to a 100-day period. Patients who were allergic to rifampin or tetracyclines as well as pregnant women were excluded from the study.

Computer-generated randomization numbers were used to identify each catheter in the two study groups. Each catheter was sterilized and placed in an assembled sterile catheter tray which in turn was individually wrapped in identical wrappings and shipped to the hospital in large cartons. Each carton contained six catheters, each in its own tray; three were impregnated with M-R and three were uncoated (control). When an eligible patient was identified, a wrapped catheter tray was removed from the carton in the order in which trays were placed according to the randomization scheme. Stratification was done according to the type of catheter prescribed to be inserted in each patient (ie, PICC or subclavian CVC). This method was used to randomly assign all types of catheters used in the study, PICC and CVC. Patients, microbiologists, and other research personnel involved in the evaluation of outcome were blinded to the type of catheter used.

Catheter Types
The silicone catheters (Cook Critical Care, Bloomington, IN) used throughout this clinical trial were single-lumen PICC (5.0 French and 60 cm in length) and nontunneled single- and double-lumen subclavian CVC (7.0 French or 9.0 French and 20 to 25 cm in length). Catheters used in the two study groups were identical in material and size, except for the impregnation of the test arm with M-R.

Catheter Insertion and Maintenance
Subclavian catheters were inserted into the subclavian vein and PICCs were inserted through the antecubital fossa into the basilic or cephalic vein. Catheter insertions were performed under maximal sterile barrier precautions, as previously described elsewhere, using gowns, masks, sterile gloves, and full sterile drapes.⁸ During the course of the study, patients came to the hospital at least once a week for dressing change at the infusion therapy department. Study team personnel inspected the catheters and evaluated insertion sites for redness, tenderness, and the presence of any discharge. Catheters remained in place until either they were no longer needed or the occurrence of an adverse event that necessitated the removal of the catheter, such as suspected catheter-related infection, mechanical malfunction, or occlusion. The decision to remove the catheter was made by the patient's primary care physician. Study personnel worked closely with the patients' physicians, who determined the need to remove the catheters.

Patient Evaluation and Cultures
After catheter insertion, patients were followed up until the catheter was removed or up to 100 days, whichever occurred first. During the course of the study and at the onset of fever or when catheter-related bloodstream infection was suspected, quantitative blood cultures were obtained simultaneously through the catheter and from a peripheral vein. On catheter removal, a 5- to 7-cm length of the catheter tip and subcutaneous catheter segment were cultured semiquantitatively by the roll plate method¹⁸ and quantitatively by the sonication method.¹⁹ When catheters remained in place beyond the study's 100-day period, a blood sample was drawn through the catheter at the end of the 100 days and quantitative blood cultures were performed. Organisms were identified according to standard microbiologic techniques.

Insertion Site Cultures and Susceptibility
Skin swab cultures of the catheter insertion sites with subsequent susceptibility of isolated organisms were performed randomly on some patients immediately before catheter insertion and at catheter removal. The results of before-insertion and at-removal susceptibility patterns were compared to ascertain whether the use of catheters impregnated with M-R increased the chance of the emergence of resistance to either or both antibiotics. Susceptibility testing was conducted using a microtiter broth dilution method according to the guidelines of the National Committee for Clinical Laboratory Standards Document M7-A5.²⁰ The minimal inhibitory concentration (MIC) was defined as the lowest concentration of each antimicrobial agent that inhibited visible growth after 16 to 20 hours of incubation at 35°C.

Durability of Impregnated Catheters
The residual antimicrobial activity of removed impregnated catheters was tested by the modified Kirby-Bauer technique^21,22 to determine the antibiotic durability of impregnated catheters. A 2-cm segment of the aseptically removed impregnated catheters was embedded onto a Mueller-Hinton II agar plate inoculated with methicillin-resistant Staphylococcus aureus organisms that had previously caused catheter-related bloodstream infection. The plate was then incubated at 37°C for 24 hours. The zone of inhibition was determined by measuring the distance (in millimeters) of clear zone perpendicular to the midpoint of the catheter segment.

Definitions
A bloodstream infection was considered to be catheter-related on the isolation of microorganisms from the bloodstream of a patient who had concurrent clinical manifestations of infection such as fever and chills in the absence of any other source of the bloodstream infection except the catheter, in addition to one of the following: (1) catheter colonized with at least 15 colony-forming units by roll plate or at least 1,000 colony-forming units by sonication^18,19 with the same organism isolated from the bloodstream, including same species and same antibiotic susceptibility profile; or (2) positive quantitative culture of blood drawn through the catheter, yielding a five-fold or greater colony count than a quantitative culture of concurrently drawn peripheral venous blood growing the same microorganism.

Statistical Considerations and Methods
This current study tested the hypothesis that long-term silicone catheters impregnated with M-R are more efficacious than nonimpregnated control catheters. On the basis of surveillance data collected at M.D. Anderson Cancer Center, we estimated the rates of colonization and infection of control catheters to be 14%. A total of 370 patients were to be enrolled onto the study, allowing for 12% nonassessable patients and approximately 165 assessable patients to be randomly assigned to each study arm. That would allow the detection of significant difference between the two study groups with 80% power and at a one-tailed significance level of 5%. One-tailed test was considered appropriate because the published clinical trials investigating short-term catheters impregnated with M-R concluded that these devices were more efficacious than uncoated catheters.^16,17,23,24

Differences in categoric dichotomous variables between the two study groups were determined using the ² test or the Fisher's exact test. The difference in the means of continuous variables was estimated by using Student's t test or Mann-Whitney U test. Time to catheter-related bloodstream infection in the two study groups was evaluated through the Kaplan-Meier method and was compared by the exact log-rank test. A multivariate logistic regression analysis was performed to control for the effect of multiple variables and their interactions and to determine which variables were associated with definite catheter-related bloodstream infection. Factors that were significant at a two-sided P value of .25 or less in univariate analysis were entered into the multiple logistic regression model and were tested for an independent effect through a backward elimination technique where variables were removed from the model one at a time until all remaining variables were statistically significant at the .05 level. Exact logistic regression was performed because some of the variables tested had sparse or unbalanced data between the two study arms. Although the study was designed with power computations based on one-sided test, the P values presented in this article are two-sided at the request of the editors for standardization of reporting, and P .05 was considered statistically significant. Analyses were performed using SPSS software (version 11.00; SPSS Inc, Chicago, IL) and LogXact-4 for Windows (version 4.1; Cytel Software Corp, Cambridge, MA).

	RESULTS

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Patient Characteristics
Between September 1999 and May 2002, a total of 371 catheters, 192 impregnated with M-R and 179 controls, were randomly assigned to be inserted in a total of 370 patients. There were 15 insertion attempts that ended up in failure to insert the study catheters. These 15 patients eventually received nonstudy catheters and were excluded from the study and the analysis. Ten of these 15 catheters that failed to be inserted were impregnated with M-R and five were control catheters. The study analysis included 356 catheters, 182 M-R and 174 controls, that were inserted in 355 patients. One patient received two control catheters at two separate occasions during the 2.5 years of the course of the study.

Of all study catheters, 239 (67%) were removed and cultured during the 100-day period of the study, 62 (17%) remained indwelling because they were still needed at the end of the study period, and 55 (15%) were either discarded at removal or lost to follow-up. At the end of the study period, blood cultures were performed of blood drawn through the 62 catheters that remained indwelling. The two study groups were comparable in terms of patients' characteristics as well as catheter characteristics (Tables 1 and 2). Patients in the two groups were similar in sex, age, underlying malignancy, bone marrow transplantation in the year before the enrollment in the study, and the presence of cardiopulmonary problems, neutropenia, thrombocytopenia, types of catheters used, and administration of drugs through the study catheters. Drugs used included systemic antibiotics, corticosteroids, hyperalimentation, blood transfusion, and interleukin-2. There were no allergic or hypersensitivity reactions as a result of the use of the M-R study catheters.

View larger version (18K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival curve. Proportions of catheters without infection. M-R, minocycline and rifampin.

Antibiotic Durability of Removed Catheters
A total of 154 M-R catheters were removed at the end of the 100-day study duration. Residual zones of inhibition against methicillin-resistant S aureus were determined for 120 of these removed catheters, as described above. These tested catheters had a mean dwell time of 68.2 days. The mean zone of inhibitions produced by the removed M-R segments over time are shown in Figure 2, showing that the M-R CVCs maintain a zone of inhibition of 10 mm for at least 35 days after insertion.

View larger version (15K): [in this window] [in a new window]   Fig 2. Durability of minocycline and rifampin catheters according to catheterization time. SD, standard deviation.

	DISCUSSION

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The use of long-term central venous catheterization has become an essential part of the management of chronically ill patients, such as cancer patients, patients requiring chronic hemodialysis as a result of renal failure, and organ or bone marrow transplant recipients. However, the wide use of these devices is associated with a risk of catheter-related infections. Previous studies found the infection rate associated with the use of long-term catheters in cancer patients to range from one to two episodes per 1,000 catheter-days.^25-28 Applying this rate of infection to the estimated 500,000 long-term CVCs that are inserted annually in the United States, and assuming that such long-term CVCs remain in place for an average of 100 days, the estimated number of catheter-related bloodstream infections in cancer patients would range from 50,000 and 100,000 annually.

This prospective randomized trial showed that nontunneled long-term silicone CVCs impregnated with M-R are safe and highly efficacious in preventing catheter-related bloodstream infections in cancer patients.

The practice of using maximal sterile barrier precautions, such as using sterile gloves, gowns, mask, and full drapes, during the insertion of central lines has been shown to reduce the rate of catheter-related bloodstream infections.⁸ During the course of this current study, all catheters were inserted under strict maximal sterile barrier precautions, because this is the standard of care at our institution. Nonetheless, the rate of catheter-related bloodstream infection in the control arm was still high at 8.0% (1.28 per 1,000 catheter-days). On the other hand, the M-R catheters were highly efficacious in decreasing the infection rate to 1.6% (0.25 per 1,000 catheter-days; P = .003). Recently the United States Centers for Disease Control and Prevention published guidelines for the prevention of intravascular catheter-related infections. They recommend the use of antimicrobial CVCs in adults for whom catheters are expected to remain in place for more than 5 days if rates of catheter-related bloodstream infection remain above the goal set by the individual institution after implementing aseptic measures, including maximal sterile barrier precautions.²⁹

The novel approach of coating catheters with antimicrobial combinations has been shown to be an efficacious preventive measure against catheter-related bloodstream infection. Short-term polyurethane catheters coated externally with the antiseptic combination of chlorhexidine/silver-sulfadiazine (CH-SS) were found to be more efficacious than control uncoated catheters in preventing catheter-related bloodstream infections.¹⁵ However, these catheters were shown in vitro to have a short-term antimicrobial activity that decreases over time, with a half-life of 3 days against S epidermidis.⁷ Therefore, the antimicrobial activity of such catheters would not be optimal for long-term catheterization, as was proven by a large randomized controlled trial that failed to demonstrate their efficacy when used in cancer patients for a longer mean duration of 20 days.³⁰ A second generation of catheters coated both externally and internally with CH-SS is now available. However, the zones of inhibition produced by this second generation catheters were shown to decrease to less than 10 mm in only 3 days.³¹ In addition, another in vitro study showed that their antimicrobial activity does not last beyond 14 days.³² This could be the reason why these second-generation catheters failed to decrease the risk of catheter-related bloodstream infection in two recent prospective randomized trials, even though they significantly reduced catheter colonization as compared with control uncoated catheters.^33,34

On the other hand, short-term polyurethane catheters impregnated intraluminally and extraluminally with M-R have demonstrated broad-spectrum activity, both in vitro and in vivo, against Gram-positive and Gram-negative bacteria.^7,16 When compared in a prospective, randomized, multicenter trial with first-generation CH-SS, catheters impregnated with M-R were 12 times less likely to be associated with catheter-related bloodstream infection and three times less likely to be colonized.¹⁷ In addition, their antimicrobial activity, as shown in this current study, was found to extend beyond 30 days, which could partly explain their superior efficacy when compared with the first-generation CH-SS.

All previously mentioned studies that investigated the efficacy of the novel approach of coating or impregnating catheters with either CH-SS or M-R have dealt with short-term polyurethane central venous catheterization. This current study is the first to investigate long-term catheterization using silicone catheters impregnated with M-R. The use of the M-R catheters was found to be an independent protective factor against catheter-related bloodstream infections. In this current study, the M-R impregnated long-term nontunneled silicone catheters were associated with a lower rate of catheter-related bloodstream infection (0.24 per 1,000 catheter-days) than previously reported with uncoated tunneled catheters used in cancer patients (2.77 per 1,000 catheter-days), as determined by Groeger et al¹⁰ from Memorial Sloan-Kettering Cancer Center. This is an important observation that, if validated by further prospective randomized trials, could prove valuable for cancer patients. At our institution, it is estimated that the cost of CVC insertion is approximately $1,190 for PICC and $1,326 for subclavian CVC, whereas it is approximately $6,502 for tunneled CVC and $7,076 for port. The low infection rate associated with the use of M-R long-term nontunneled silicone catheters and their lower cost of insertion in comparison with the added cost of a special intervention associated with tunneling does favor the antimicrobial nontunneled CVC as a cost-effective alternative to the currently used tunneled catheters.

With the use of catheters impregnated with antimicrobials, the potential for development of antimicrobial resistance after prolonged use has been debated and investigated. Repeated in vitro exposure of S epidermidis culture to CH-SS and M-R indicated small increases in the MIC, albeit more with the M-R than with the CH-SS.³⁵ However, so far, well-designed prospective, randomized clinical trials have failed to show any evidence of antimicrobial resistance developing after the use of M-R catheters.^16,17 Furthermore, after using the M-R CVC in bone marrow transplantation patients for more than 4 years and a total of 21,888 catheter-days, staphylococci isolated from the bone marrow transplantation patients remained highly susceptible to M-R.³⁶ Consistent with these previous findings, we failed to detect the development of antibiotic resistance after the long-term (mean dwelling time of 65 days) use of M-R silicone catheters in this current study. The absence of any detectable levels of minocycline or rifampin in the blood of patients with indwelling M-R CVCs suggests the low risk of systemic circulation of minocycline or rifampin and, hence, the low risk of development of systemic resistance. The issue of antibiotic resistance is of paramount importance, both clinically and economically, and hence continuous monitoring and surveillance is encouraged. However, given the low risk of emerging antibiotic resistance, further monitoring should not deter the clinician from using these highly efficacious antimicrobial catheters.

An evidence report and technical assessment was published by the Agency for Health Care Research and Quality and was aimed at improving patient safety practices.³⁷ The report lists 11 patient safety practices that were rated the highest among 79 reviewed practices. The use of antibiotic-impregnated CVCs to prevent catheter-related infections is recommended by the Agency for Health Care Research and Quality as one of the selected patient safety practices.

In conclusion, this prospective, randomized clinical trial showed that long-term silicone catheters impregnated with M-R were safe and efficacious in providing protection against catheter-related bloodstream infection in cancer patients. These impregnated long-term nontunneled silicone catheters could prove to be an attractive alternative to tunneled catheters in cancer patients, with much lower cost of insertion. However, that remains to be validated through well-designed and adequately powered prospective randomized trials.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received more than $2,000 per year from a company for either of the past 2 years: Issam Raad, Cook Critical Care; Rabih Darouiche, Cook Critical Care.

	NOTES

 
Supported in part by grant CS99-2221rm from Cook Critical Care.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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5. Raad I, Costerton W, Sabharwal U, et al: Ultrastructural analysis of indwelling vascular catheters: A quantitative relationship between luminal colonization and duration of placement. JID 168:400-407, 1993

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Submitted April 16, 2003; accepted May 4, 2004.

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