International Journal of Infectious Diseases
Volume 14, Issue 7 , Pages e548-e552, July 2010

The efficacy of catheters coated with minocycline and rifampin in the prevention of catheter-related bacteremia in cancer patients receiving high-dose interleukin-2☆

  • R.F. Chemaly

      Affiliations

    • Departments of Infectious Diseases, Infection Control, and Employee Health, Unit 402, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 713 745 1116; fax: +1 713 745 6839.
    • ,
  • P.S. Sharma

      Affiliations

    • Departments of Infectious Diseases, Infection Control, and Employee Health, Unit 402, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA
    • ,
  • S. Youssef

      Affiliations

    • Departments of Infectious Diseases, Infection Control, and Employee Health, Unit 402, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA
    • ,
  • D. Gerber

      Affiliations

    • Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
    • ,
  • P. Hwu

      Affiliations

    • Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
    • ,
  • S.S. Hanmod

      Affiliations

    • Departments of Infectious Diseases, Infection Control, and Employee Health, Unit 402, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA
    • ,
  • Y. Jiang

      Affiliations

    • Departments of Infectious Diseases, Infection Control, and Employee Health, Unit 402, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA
    • ,
  • R.Y. Hachem

      Affiliations

    • Departments of Infectious Diseases, Infection Control, and Employee Health, Unit 402, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA
    • ,
  • I.I. Raad

      Affiliations

    • Departments of Infectious Diseases, Infection Control, and Employee Health, Unit 402, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA

Received 20 February 2009; received in revised form 17 July 2009; accepted 10 August 2009. published online 14 December 2009.

Corresponding Editor: Andy I.M. Hoepelman, Utrecht, the Netherlands

Article Outline

Summary 

High-dose interleukin-2 (HDIL-2) has proven to be an effective treatment for metastatic renal cell carcinoma and melanoma. Previous studies have shown an increase in catheter-related bacteremia (CRB) in patients on HDIL-2. The primary objective of this study was to evaluate the effectiveness of minocycline and rifampin-coated catheters (M/R-C) in reducing CRB in cancer patients on HDIL-2. This was a retrospective study where non-coated catheters (NC-C) and M/R-C were used for the administration of HDIL-2 before and after December 2004, respectively. Data collected included demographics, cancer type, catheter type, antibiotic prophylaxis, and infection rates. A total of 107 episodes of catheter use for HDIL-2 were evaluated in 78 patients (30 episodes in patients with M/R-C vs. 77 with NC-C). A total of nine episodes of CRB were identified, all in patients with NC-C (M/R-C 0% vs. NC-C 12%; p=0.06). The median time to bacteremia was 11 days (range 1–315 days). A log-rank test showed a trend that the M/R-C group had lower probability of getting CRB than the NC-C group (p=0.06). The use of M/R-C in patients on HDIL-2 therapy for advanced melanoma and renal cell carcinoma may have reduced the risk of CRB to nil. CRB still occurred despite antibiotic prophylaxis in patients with NC-C.

Keywords: Catheter-related bacteremia, IL-2 therapy, Melanoma, Renal cell carcinoma, Blood stream infection

 

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1. Introduction 

Patients with advanced melanoma and renal cell carcinoma (RCC) have a poor prognosis. In early studies, high-dose interleukin-2 (HDIL-2) therapy was found to have clinical efficacy in a subset of patients with cancer at an advanced stage. Interleukin-2 (IL-2) has played an important role in treating such patients, either alone or in combination with other chemo/immunotherapeutic agents and treatment strategies. In multiple clinical trials, IL-2 has been associated with a low, but consistent, rate of overall response of approximately 13–17% in metastatic melanoma1, 2, 3 and has consistently produced durable responses in a small percentage of patients with advanced RCC.4, 5, 6 However, the substantial toxicity and limited efficacy that is associated with IL-2 has narrowed its application to highly selected patients treated at specialized centers.7, 8

Numerous and significant toxicities attributed to the systemic administration of IL-2 have been reported.9, 10 Bacterial infections, mainly catheter-related staphylococcal bacteremia, have been observed by several investigators.11, 12, 13, 14, 15 Fortunately, only a minority of these infections lead to death.13 However, an increase in the number and duration of hospitalization occurs. Successful strategies to prevent or decrease the incidence of catheter-related staphylococcal bacteremia in patients receiving IL-2 have been used, including the prophylactic use of intravenous oxacillin,16 and oral novobiocin and rifampin.17 However, the use of intravenous oxacillin is associated with added costs and catheter manipulations, and the use of the novobiocin and rifampin regimen has been associated with intolerability in these patients.

Because the prophylactic use of intravenous oxacillin had been shown to decrease the frequency of staphylococcal bacteremia in patients receiving IL-2,13, 16 all patients with advanced melanoma or RCC who were admitted to our center for IL-2-based therapy over the last 5 years received an antibiotic regimen, mainly intravenous nafcillin for 48h, as a preventive measure for catheter-related bacteremia (CRB), although it is not the standard of care in many other institutions. Since the rate of methicillin-resistant Staphylococcus aureus (MRSA) infection and colonization is on the rise17 and the previous regimen of nafcillin prophylaxis has no activity against MRSA, another additional prophylactic strategy was needed. After December 2004, the use of long-term silicone catheters coated with minocycline and rifampin (M/R-C) (Spectrum; Cook Critical Care, Bloomington, IN, USA) was recommended in these patients in our institution, as also recommended by the published guidelines for the prevention of intravascular catheter-related infections in high-risk patients when the infection rate remains high.18 In this retrospective study, we report our experience with these antibiotic-coated catheters and their impact on the incidence of CRB when compared to the non-coated ones.

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2. Methods 

2.1. Patients 

This was a retrospective study where non-coated catheters (NC-C) and M/R-C, both non-tunneled, were used for the administration of HDIL-2; NC-C were used before December 2004 and M/R-C after December 2004. The study included patients with melanoma or RCC treated with IL-2 between December 1, 2003 and August 31, 2006. All patients were admitted to our institution and received antibiotic prophylaxis for up to 48h after the last dose of IL-2, mainly with nafcillin (in 67% of episodes). In addition, insertion site care remained the same during the study period and consisted of cleaning the site with 2% chlorhexidine gluconate and 70% isopropyl alcohol. Data collected included demographics, cancer type, catheter type, antibiotic prophylaxis, adverse events, systemic toxicities, and bacteremia rates. We retrospectively identified the cases of catheter-related infection from the microbiology databases, and compared them between the two groups. We also determined the outcome and complications of the episodes of catheter-related infections in these patients with RCC and melanoma treated with IL-2.

2.2. Definitions 

Definitions were based on the published guidelines for the management of intravascular catheter-related infections.19 In summary, catheter colonization was defined as the isolation of 15 colony-forming units (CFU) of any microorganism by semiquantitative culture (roll plate method) or 103 CFU by quantitative culture (e.g., sonication technique) from a catheter tip or subcutaneous segment in the absence of simultaneous clinical symptoms; or 10 CFU/ml of any organism from a blood culture drawn through the catheter during routine surveillance in the absence of fever. Local catheter-related infection was defined as exit site infection as demonstrated by purulent drainage from the catheter site yielding a microorganism, with or without concomitant blood stream infection (BSI), or erythema, tenderness, and swelling within 2cm of the catheter exit site, and colonization of the catheter if removed. CRB was considered probable if the patient had an indwelling central venous catheter (CVC) with at least one positive blood culture from the peripheral vein, with clinical manifestations of infection (i.e., fever, chills, and/or hypotension), and no apparent source for the BSI except the catheter, whereby the isolated organism was considered as an organism likely to cause catheter-related infections (such as staphylococci, diphtheroids/Corynebacterium, Bacillus spp, Stenotrophomonas, Klebsiella, Enterobacter, Acinetobacter, Achromobacter). For patients with a blood culture positive for coagulase-negative staphylococci, either two positive blood cultures or a quantitative blood culture with ≥15 colonies/ml were required.20 If more than one positive culture was identified, they should have been drawn within 48h of one another and should have been positive for the same microbial organism (same species and similar antimicrobial susceptibility profile). CRB was considered definite if the patient fulfilled all the criteria for probable CRB plus at least one of the following: a positive semiquantitative (>15 CFU/catheter segment) or quantitative (>103 CFU/catheter segment) culture whereby the same organism (species and antibiogram) was isolated from the catheter segment and peripheral blood; simultaneous quantitative blood cultures from the catheter and peripheral vein revealing a ratio >5:1 (CVC vs. peripheral); indicative differential time to positivity (that is, the blood culture obtained through the CVC became positive at least 2h earlier than a positive simultaneous blood culture obtained from a peripheral vein).

Response to treatment was defined as the resolution of all clinical and microbiological manifestations of catheter-related infection, and failure to treatment was defined as persistence of the clinical signs and symptoms of the infection and positive microbiological data.

2.3. Statistics 

The episodes of catheter use were divided into those using M/R-C and those using NC-C. The categorical variables were compared by Chi-square test or Fisher's exact test, as appropriate. The continuous variables were compared by Wilcoxon rank sum test as the data departed from normal distribution. The overall probability for CRB was estimated by Kaplan–Meier approach for the two types of episodes, respectively, and the two probabilities were compared by a log-rank test. For each episode, the patient was followed up for 400 days. For patients whose catheter was removed due to other reasons during the follow-up time period, their times were regarded as censored observations. The statistical significance was set at p≤0.05. All the statistical analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, NC, USA).

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3. Results 

Seventy-eight consecutive patients treated with HDIL-2-based therapy were identified for a total of 107 episodes of catheter use between December 1, 2003 and August 31, 2006. Most of the patients who received HDIL-2-based therapy had RCC (61%). In 30 episodes, M/R-C were used, whereas NC-C were used in the remaining 77 episodes. For these two types of episode, patient baseline characteristics were evaluated and were all comparable except for a trend towards higher age in patients with M/R-C (Table 1). All patients received antibiotic prophylaxis, mainly with intravenous nafcillin for 48h after the last dose of IL-2 (67% of the episodes), followed by clindamycin (15% of episodes), and levofloxacin (13% of episodes).

Table 1. Characteristics of the patients who had minocycline and rifampin-coated catheters (M/R-C) and those who had non-coated catheters (NC-C)
CharacteristicsPatients who had M/R-CPatients who had NC-Cp-Value
(30 episodes)(77 episodes)
n (%)n (%)
Age (years), median (range)55 (28–66)51 (26–66)0.086
Gender 0.13
Female7 (23)30 (39)
Male23 (77)47 (61)
Race >0.99
White26 (87)67 (87)
Non-white4 (13)10 (13)
Type of cancer 0.73
Melanoma11 (37)31 (40)
Renal cell carcinoma19 (63)46 (60)
Prophylaxis 0.14
Nafcillin17 (57)55 (71)
Other antibiotics13 (43)22 (29)
Days of catheter stay, median (range)55 (5–227)42 (5–393)0.81a
Catheter-related bacteremia0 (0)9 (12)0.06b

aThe calculations were only limited to those patients whose catheter was removed during our study period.

bThe p-value was calculated from a two-sided Fisher's exact test.

A total of nine episodes of CRB were identified (six were probable and three definite), all in patients with NC-C (M/R-C 0% vs. NC-C 12%; p=0.06). The nine bacteremia episodes occurred in seven patients between September 2004 and July 2005, with three of the episodes occurring before December 1, 2004. The median time to bacteremia was 11 days (range 1–315 days). There was no difference between patients with and without bacteremia in the number of courses of IL-2 and whether nafcillin or another type of antibiotic was used for prophylaxis (all p>0.4) (Table 2). Interestingly, eight out of nine CRB (89%) occurred in patients with advanced RCC, while only one episode occurred in a patient with melanoma (p=0.086). Moreover, in three out the nine episodes of bacteremia, the blood cultures grew more than one pathogen. The causative pathogens for CRB included methicillin-resistant coagulase-negative Staphylococcus (3), Stenotrophomonas maltophilia (2), MRSA, Pseudomonas aeruginosa, Enterococcus sp, Flavimonas sp, Citrobacter sp, Escherichia coli and Enterobacter cloacae (one each). In the nine episodes of bacteremia, patients received prophylaxis with an antibiotic that had no activity against the pathogen(s) recovered from the blood. In addition, there was one episode of probable catheter-related candidemia (Candida parapsilosis) in a patient with M/R-C. When including this case in the analysis, 3% (1/30) of episodes in the M/R-C group involved a catheter-related infection compared to 12% (9/77) in the NC-C group (p=0.28). Kaplan–Meier analysis showed a trend towards better outcome in the M/R-C group (p=0.063) (Figure 1).

Table 2. Characteristics of patients with or without catheter-related bacteremia (CRB)
Patients who got CRBPatients who did not get CRBp-Value
(9 episodes)(98 episodes)
n (%)n (%)
Age (years), median (range)51 (28–53)53 (26–66)0.16
Gender >0.99
Female3 (33)34 (35)
Male6 (67)64 (65)
Race >0.99
White8 (89)85 (87)
Non-white1 (11)13 (13)
Type of cancer 0.086
Melanoma1 (11)41 (42)
Renal cell carcinoma8 (89)57 (58)
Prophylaxis 0.47
Nafcillin5 (56)67 (68)
Other antibiotics4 (44)31 (32)
Days of catheter stay, median (range)42 (10–253)42 (5–393)0.47
Type of catheter
M/R-C0 (0)30 (31)0.06
NC-C9 (100)68 (69)

M/R-C, minocycline and rifampin-coated catheters; NC-C non-coated catheters.

  • View full-size image.
  • Figure 1. 

    Kaplan–Meier estimates of being free from catheter-related bacteremia for patients who had minocycline and rifampin-coated catheters (M/R-C) and those who had non-coated catheters (NC-C) (p=0.063).

In addition, two episodes of catheter colonization secondary to coagulase-negative staphylococci occurred in two patients who had no signs or symptoms of infection; both had the M/R-C. A third patient with NC-C had positive blood cultures for S. aureus with the same colony counts from the indwelling CVC and peripheral blood and a simultaneous positive culture for the same organism taken from an infected deep wound on the right arm, which was deemed to be the source of the bacteremia.

In eight out of the nine episodes, patients had to be admitted to the hospital for fever and chills and were subsequently diagnosed with CRB. In one episode, the patient was already in the hospital for HDIL-2 therapy. The mean length of stay for these complications was 6 days (range 3–11 days). In one episode, the patient developed extravascular complications with soft tissue abscesses secondary to MRSA; the same pathogen was isolated from blood. All patients received appropriate intravenous followed by oral antibiotics, with a mean duration of 14 days (range 8–21 days). There was no relapse of bacteremia documented and all patients survived.

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4. Discussion 

In this study, antimicrobial long-term silicone catheters coated with minocycline and rifampin showed a trend towards prevention of CRB in cancer patients treated with HDIL-2. The M/R-C not only prevented staphylococcal and Gram-positive CRB, but also resulted in the prevention of Gram-negative bacteremia. Such interventions were not associated with any adverse events or systemic toxicities.

Bacterial infections, particularly catheter-related staphylococcal bacteremia, are a major complication associated with high-dose interleukin therapy given alone or in combination with other treatments in cancer, as well as in other immunocompromised patients.12, 13, 14, 15 Several investigators have reported a high rate of bacteremia ranging from 19% to 41%, which is usually caused by staphylococci and often associated with the CVC in immunocompromised patients receiving HDIL-2 therapy.12, 13, 14, 21 This high rate of staphylococcal infection has been attributed to a defect in neutrophil chemotaxis caused by interleukin, which is reversible four weeks after completion of this biotherapy.11 Further data suggest that IL-2 induces the release of human necrosis factor, which could be the direct cause of this defect.22, 23

Several prophylactic strategies have been applied to prevent or decrease the incidence of bacteremia, particularly staphylococcal bacteremia, in patients receiving HDIL-2, including the prophylactic use of intravenous oxacillin16 and oral novobiocin and rifampin.21 However, the use of intravenous oxacillin is associated with added cost, catheter manipulation, and particularly the emergence of oxacillin-resistant staphylococcal organisms, such as MRSA.24 At our center, a combination of oral antibiotics consisting of novobiocin and rifampin has been used and shown to decrease the risk of catheter-related bacteremia associated with HDIL-2 therapy in cancer patients.21 However, this systemic oral antibiotic combination was found to be associated with a high rate (54%) of nausea and vomiting, and 35% of the patients who were put on this prophylaxis could not tolerate these drugs because of the severe nausea and vomiting.

CVCs impregnated with minocycline and rifampin have been shown to be highly efficacious in the prevention of CRB in high-risk critically ill as well as cancer patients.25, 26, 27, 28, 29, 30, 31 A recent meta-analysis of eight prospective randomized controlled studies showed that M/R-C are safe and effective in reducing the rate of catheter colonization and catheter-related blood stream infections (CRBSI).31 In addition, indwelling CVCs impregnated with minocycline and rifampin have been shown to have uniquely prolonged antimicrobial durability in serum, particularly directed against staphylococci, which extends to 2 months.29, 30 This prolonged activity has made them highly useful in coating long-term silicone CVCs used in cancer patients, as opposed to the other FDA approved antimicrobial catheters associated with short-term antimicrobial durability against staphylococci, such as the chlorhexidine–silver sulfadiazine-coated catheters.32, 33

Unlike the use of systemic antibiotics, such as intravenous oxacillin, glycopeptides or oral antibiotics such as rifampin with novobiocin, the use of M/R-C in the prevention of CRBSI has not been associated with any local or systemic adverse events or the emergence of resistant organisms.25, 26, 27, 28, 29, 30, 31 Several prospective randomized trials have evaluated the susceptibility of organisms at the catheter insertion site prior to the insertion of the M/R-C and after the prolonged use of such catheters, and did not show any decreased susceptibility.25, 26, 29, 30 Furthermore, several in vitro studies have shown that prolonged bacterial exposure to M/R-C did not affect the antimicrobial activity of these catheters.34, 35 An evaluation of the clinical experience of M/R-coated CVCs in bone marrow transplant recipients at the MD Anderson Cancer Center over a four-year period that included more than 27 000 catheter days, showed that staphylococci cultured from the skin insertion site and the catheter tip remained highly susceptible to minocycline and rifampin.28 To date, since their approval in 1997, no local or systemic adverse events have been reported or associated with the use of such catheters in patients worldwide.31

Several studies have evaluated the cost-effectiveness of CVCs impregnated with minocycline and rifampin and have found them to be cost-effective and cost-saving.25, 27, 36, 37 Hanna et al. reported that the use of M/R-C in critically ill cancer patients resulted in a net saving of at least $1 450 000 annually.27 Marciante et al. showed that the M/R-coated CVCs were more cost-effective than other antimicrobial CVCs, particularly if used for a period of two weeks or longer.36 Shorr et al. showed that the M/R-coated CVCs were associated with cost savings of $9600 per CRBSI and $81 cost saving per patient when compared with CVCs coated with chlorhexidine–silver sulfadiazine.37

On the other hand, a major limitation is the fact that the M/R-coated catheters are not effective in preventing catheter-related candidemia, as is evident in other studies,30, 38 including this study where a probable catheter-related candidemia caused by C. parapsilosis occurred in a patient with an M/R-C. However, given the fact that this catheter-related candidemia occurred more than 180 days following the insertion of the M/R-C, it might not imply that these catheters predispose for catheter-related candidemia, particularly since the antimicrobial durability of the M/R-C extends to only 50–60 days. Among the limitations of this study is its retrospective design and small sample size.

In conclusion, with the wide use of IL-2 therapy, particularly in cancer patients with melanoma and RCC, as well as its potential use in high-risk patients such as the HIV patient population,39 the systemic prophylaxis with intravenous antimicrobial therapy, such as oxacillin or nafcillin, continues to be associated with a relatively high rate of CRBSI. In this current study, the use of antimicrobial CVCs coated with minocycline and rifampin in this patient population showed a trend towards prevention of CRBSI caused by methicillin-resistant staphylococci and Gram-negative bacilli, and points to the need for further evaluation in a large randomized study. Furthermore, the future development of second-generation antimicrobial CVCs with broad-spectrum antibacterial and antifungal therapy needs to be pursued and evaluated in clinical trials.

Conflict of interest: Cook – Speakers’ Bureau, Consultant, Grants, Royalties related to patents licensed to Cook on which Dr. Raad is an inventor/co-inventor. American Medical Systems – Royalties related to patent licensed to AMS on which Dr. Raad is a co-inventor. Horizon Medical Products – Royalties related to patent licensed to HMP on which Dr. Raad is a co-inventor. TyRx – Royalties related to patent licensed to TyRx on which Dr. Raad is a co-inventor.

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☆ Presented in part at the 45th Annual Meeting of the Infectious Diseases Society of America, San Diego, CA, USA, October 4–7, 2007.

PII: S1201-9712(09)00341-5

doi:10.1016/j.ijid.2009.08.007

International Journal of Infectious Diseases
Volume 14, Issue 7 , Pages e548-e552, July 2010

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