Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Benefits of minocycline and rifampin-impregnated central venous catheters: A prospective, randomized, double-blind, controlled, multicenter trial.

Leon C, Ruiz-Santana S, Rello J, et al.

Intensive Care Med. 2004; 30:1891-1899 [abstract]

Reviewed by Asumthia S Jeyapalan, DO, Baylor College of Medicine, Houston TX

Review posted February 14, 2005

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I. What is being studied?:

The study objective:

To determine risk of catheter-related blood stream infection (CRBSI), catheter colonization, and catheter-related clinical infectious complications using minocycline and rifampin-impregnated central venous catheters compared to nonimpregnated catheters in critically ill patients.

The study design:

Prospective, randomized double blind controlled multicenter trial in Spain.

The patients included:

465 patients > 18 years of age admitted to 7 ICUs who required a central venous catheter at a new insertion site for ≥ 3 days

The patients excluded:

• Allergy to minocycline or rifampin
• Post randomization exclusion criteria:
  • Accidental loss of catheter post randomization
  • Catheter exchange over a guide wire
  • Lack of microbial cultures

The interventions compared:

All patients had implantation of a 7 French 20 cm long, uncuffed triple lumen polyurethane central venous catheter. Study catheters were impregnated with minocycline and rifampin and both interior and exterior surfaces had antimicrobial properties. Control catheters did not contain antibiotics.

The outcomes evaluated:

• Catheter colonization: growth of ≥ 15 cfu by roll plate or > 100 cfu by sonication
• Catheter contamination: < 15 cfu by roll plate method, or < 100 cfu by sonication and/or positive hub culture when there are no signs of infection at catheter site
• catheter-related blood stream infection: isolation of the same bacterial strain from the catheter segment and from one or more peripheral blood cultures in a clinically symptomatic septic patient with no other source of infection
• Local infection at insertion site: purulence at site
• catheter-related clinical infections complication: either local infection or catheter-related blood stream infection

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Catheter trays were wrapped in identical packages and randomly assigned by computer generated identification numbers in blocks of six.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes. 465 patients were enrolled, 228 to the minocycline and rifampin impregnated catheter group and 237 to the nonimpregnated catheter group. 41 patients (18%) from the minocycline and rifampin impregnated group were excluded from analysis secondary to administrative reasons, removal without notification, and death. Similarly 57 (25%) control patients were excluded secondary to the aforementioned reasons. The flow diagram (F.S1 in the electronic supplementary material) provides outcome data for those excluded from intention to treat analysis. Among those excluded from the impregnated catheter group, there was 1 case of sepsis, 0 cases of local infection, and 0 cases of catheter-related blood stream infection. Among those excluded from the control group, there were no cases of sepsis, local infection, or catheter-related blood stream infection.

Yes, since even those "excluded" were followed and their clinically significant outcomes reported (in the supplement). It does not appear likely that despite the number of dropouts, the dropout rate was different between the two groups, or that including the dropouts would have changed the study's main result.

Were patients analyzed in the groups to which they were randomized?

Yes. Results were analyzed based on rifampin and minocycline impregnated catheters and nonimpregnated catheters; there was no crossover between groups.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes. Neither health workers nor patients knew if they were receiving the rifampin and minocycline impregnated catheters versus the nonimpregnated catheters.

4. Were the groups similar at the start of the trial?

No. There were more neutropenic patients in the minocycline and rifampin impregnated catheters than in the nonimpregnated catheter group, but overall there were only 9 neutropenic patients included in the study. In terms of male/female ratio and type of patient and insertion site the groups were similar.

5. Aside from the experimental intervention, were the groups treated equally?

Although techniques for insertion and maintenance of all catheters were protocolized and duration of catheter use was similar in the two groups, the authors do not provide data on therapies other than the catheter that this heterogeneous group of patients received.

III. What were the results?

1. How large was the treatment effect?

There was no significant difference in catheter-related blood stream infection between the minocycline and rifampin impregnated catheter group and the nonimpregnated group. 6 patients (3.2%) in the impregnated group had a catheter-related blood stream infection versus 11 (6.1%) in the nonimpregnated group (Absolute risk reduction 2.9% with 95% CI 1.3-7.2%; NNT 34 with 95% CI 14-infinity, Relative risk 0.53 with 95% CI 0.2-1.44).

Overall, catheter colonization was significantly less frequent in impregnated catheters (RR 0.57 with 95% CI 0.4-0.82). When the data is analyzed by catheter segment, colonization of the subcutaneous portion of impregnated catheters was significantly lower using semiquantitative culture methods (10.4% vs 25.1%, ARR 14.7%, NNT 7, RR 0.41 with 95% CI 0.25-0.7) but these differences were not significant when quantitative methods were used. Colonization of the catheter hub was not significantly different between the two groups (14.5% vs 22.4%, RR 0.65 with 95% CI 0.4-10.5).

In subgroup analysis, overall colonization with coagulase negative Staphylococcus species, was significantly less frequent in impregnated catheters (Quantitative method: 3.6 vs 17.6%, RR 0.21 with 95% CI 0.09-0.47, Semiquantitative method 6.8 vs 27.8%, RR 0.24 with 95% CI 0.13-0.45)

In addition, there was a statistically significant increase in Candida species colonization of the catheter in the minocycline and rifampin impregnated catheter group (Semiquantitative method 6.2 vs 1.1% Relative risk 5.84 with 95% CI 1.31-26.1; Quantitative method 5.2% vs 1.1% RR 4.87 with 95% CI 1.07-22.2).

There was no significant difference in the overall rate of catheter-related infectious complications between those who received impregnated catheters vs those who received standard catheters (RR 0.67 with 95% CI 0.31-1.44). However, subgroup analysis revealed a significant decrease in infection episodes per 1000 catheter days in the impregnated catheter group when only patients receiving TPN (n=135) were analyzed (RR 0.1 with 95% CI 0.01-0.76).

2. How precise was the estimate of the treatment effect?

In some of the subgroup analyses the wide confidence interval around the relative risk, such as for Candida colonization and TPN, probably reflect small numbers of affected patients.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Perhaps. This is a study done in adults and not children. In children we are more likely to place femoral central venous catheters than internal jugular or subclavian central venous catheters. Also, central venous catheters may remain in place longer than a mean of 9 days in our patient population. However, in the adolescent population subclavian catheters are more common and the duration would be similar.

2. Were all clinically important outcomes considered?

Yes. The primary outcome was catheter-related blood stream infection, however the authors did look at colonization and catheter-related clinical infectious complications.

3. Are the likely treatment benefits worth the potential harms and costs?

No. Based on the results of this study there is no difference between minocycline and rifampin impregnated catheters and nonimpregnated catheters in prevention of blood stream infection. Subgroup analysis within this study based on small numbers of affected patients suggests that minocycline/rifampin impregnated central venous catheters maybe associated with an increase in Candida colonization. However, the impregnated catheters may be protective against bacterial colonization. Additional study is needed to determine whether or not use of impregnated catheters may be associated with a reduction in catheter-related infection rates in specific high risk subpopulations. In the heterogeneous ICU population studied in this paper, the outcomes would not justify the added expense of the impregnated catheters.

The results of this study, however, should be put into the context of a large body of literature on this subject. Two systematic reviews found statistically and clinically significant reduction in rates of catheter-related bloodstream infections with the use of antibiotic-impregnated catheters (1, 2). In fact, the relative and absolute reduction in risk of CRBSI is similar in the current study as in these meta-analyses, but perhaps due to inadequate sample size, the current study's effect size was very imprecise and did not achieve statistical significance.

References:

1. Veenstra DL, Saint S, Somnath S, Lumley T, Sullivan SD. Efficacy of antiseptic-impregnated central venous catheters in preventing catheter-related bloodstream infection. A meta-analysis. JAMA;1999;281:261-267. [abstract]; PedsCCM EB Journal Club Review, by M. K. Moynihan Hardart
2. Marin MG, Lee JC, Skurnick JH. Prevention of nosocomial bloodstream infections: effectiveness of antimicrobial-impregnated and heparin-bonded central venous catheters. Crit Care Med. 2000 Sep;28(9):3332-8. [abstract]; PedsCCM EB Jounal Club Review by K Mistry

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