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Catheter Design Influences Recurrence of Catheter-Related Bloodstream Infection in Children With Cancer

Patricia M. Flynn, Brian Willis, Aditya H. Gaur, Jerry L. Shenep

From the Department of Infectious Diseases, St Jude Children’s Research Hospital; and the Department of Pediatrics and Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN.

Address reprint requests to Patricia M. Flynn, MD, Department of Infectious Diseases, St Jude Children’s Research Hospital, 332 N Lauderdale St, Memphis, TN 38105; e-mail: pat.flynn{at}stjude.org.

	ABSTRACT

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Purpose: Multiple studies have demonstrated that catheter-related bloodstream infections (CRBI) can be successfully treated without catheter removal (in situ therapy), but there is insufficient information available to determine if catheter design can influence the eradication of bacteremia or recurrence.

Patients and Methods: Bacteremic episodes in patients at St Jude Children’s Research Hospital between January 1996 and May 2001 were identified and patient records were reviewed.

Results: A total of 172 unique episodes of CRBI were identified. In situ therapy resulted in successful eradication of bacteremia in 87% of the episodes. Bacteremia recurred in 10% of the episodes. Although catheter design (Hickman and Broviac versus totally implantable central venous catheter) did not influence short-term eradication of bacteremia, totally implantable central venous catheters were significantly associated with recurrence of bacteremia (odds ratio, 10; 95% confidence interval, 3.1 to 33.3). In a multivariable analysis, this association between catheter design and recurrence remained statistically significant after adjustment for other factors that influenced recurrence in this study (isolation of coagulase-negative staphylococci and inadequate duration of initial antibiotic therapy).

Conclusion: This study demonstrates that patients with CRBI with a totally implantable central venous catheter in place are more likely to develop recurrent bacteremia. Management strategies to prevent recurrence in this setting should be explored.

	INTRODUCTION

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TUNNELED CENTRAL venous catheters, such as Hickman and Broviac catheters (H/Bs) and totally implantable central venous catheters (TIPs), are critical devices in the management of pediatric oncology patients.¹ Infection remains a serious complication.² TIPs have been demonstrated to have a lower overall rate of catheter-related bloodstream infection (CRBI) than H/Bs.^3–9 There have been many reports of successful in situ therapy in H/B CRBI,^3,6,10–20 but there is scant and conflicting information about in situ therapy in TIP CRBI. Initial reports suggested that bacteremias in patients with TIPs were more difficult to eradicate than in H/Bs, and it was hypothesized that this was related to adherence of microorganisms to the plastic material of the septum.²¹ Rubin et al²² recently reviewed the experience with septic infections in TIPs in pediatric patients and found similar success rates compared with historical success rates for H/Bs.

The purpose of this study was to examine the influence of catheter design on the outcome of the initial treatment of CRBI and recurrence of CRBI in a population of pediatric oncology patients.

	PATIENTS AND METHODS

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All positive blood cultures from the St Jude Children’s Research Hospital (SJCRH; Memphis, TN) Microbiology Laboratory between January 1996 and May 2001 were identified via a computerized search. During this time period, all samples for blood culture were collected using the Isolator 1.5 pediatric tube (Wampole, Cranberry, NJ) and processed according to the manufacturer’s directions. Microorganisms isolated from positive cultures were identified by standard microbiological methods. Quantitation of organisms was determined by the actual number of colonies present on the blood and chocolate agar plates and extrapolation to colony-forming units (CFU) per milliliter of blood. The maximum concentration of organisms reported was greater than 400 CFU/mL.

Patient Population
Patients who did not have an H/B or TIP at the time of the bacteremia, patients with catheters who only had peripheral-blood cultures or only catheter blood cultures obtained, patients who died within 72 hours of the first positive blood culture, and patients with a single positive blood culture for coagulase-negative staphylococci (CNS) were excluded.

Medical records of all remaining patients with a positive blood culture were abstracted to obtain demographic information (age, race or ethnicity, and sex), underlying diagnosis, determination of catheter type, dates of placement and removal, organism colony count at the time of CRBI, clinical management of the episode of CRBI, presence of exit site or tunnel tract infection, adjuvant therapy with thrombolytics or dwell therapy, presence of sepsis requiring admission to the intensive care unit, antibiotic therapy, and outcome.

Routine Management of Catheters
Patients with newly placed H/Bs or TIPs and their families were trained in the maintenance of the catheter before hospital discharge. Patients with H/Bs cleaned the catheter site three times a week using povidone-iodine swabs. After placement of triple-antibiotic ointment, a dry gauze dressing was placed. Catheters were flushed once daily with a solution containing 10 U heparin/mL. TIPs were flushed once monthly with a solution containing 100 U heparin/mL.

Assignment of Relatedness to Catheter
Careful review of the quantitation of bacteremia was undertaken to determine the relationship of the episode of bacteremia to the catheter. Cultures were considered to be paired if they were obtained within 3 hours of each other and before appropriate antibiotic therapy administration. If more than one organism was isolated from a culture, the overall sum of the organisms was used. A CRBI occurred when the quantity of organisms identified in blood obtained via the catheter was at least five times that of the paired blood specimen obtained via a peripheral vein.¹⁷

When the H/B had two lumens, the highest number of organisms was used in this calculation. In the absence of a peripheral culture, a CRBI was diagnosed if bacterial concentration in one lumen was at least five times that of the other lumen in patients with double-lumen H/B. We also considered the repeated isolation of CNS from the same lumen of a catheter as evidence of a CRBI.¹⁷

Non-CRBI was diagnosed if the ratio of bacterial concentration in catheter blood compared with peripheral blood was less than five-fold.

Management of CRBI
Standard antibiotic combinations are used at SJCRH for the management of fever and neutropenia. Because of the familiarity with these agents, they are also the first used in the event of a suspected CRBI. In most cases, initial therapy for a suspected CRBI, regardless of neutrophil count, consisted of vancomycin and ceftazidime. Therapy was considered appropriate in this study if the isolated organism was susceptible to one or more of the administered antibiotics using standard laboratory susceptibility testing. Recommended therapy for patients diagnosed with CRBI included a minimum of 10 days of antibiotic therapy administered through the catheter.¹⁶

Definitions
Exit site infection was defined as erythema, induration, or drainage within 2 cm of the catheter exit site or edge of the portal. Tunnel tract infection was defined as erythema, induration, or drainage along the tunnel tract and beyond 2 cm from the catheter exit site or portal edge. Outcome of the episode was defined as a success if the CRBI resolved with specific antibiotic therapy, repeat blood culture obtained via the catheter demonstrated no growth, and the catheter was maintained. Failure occurred if positive blood cultures persisted for more than 3 days, necessitating removal of the catheter. No attempt at in situ therapy was considered if the catheter was removed before the patient received 72 hours of appropriate antibiotic therapy. All episodes of CRBI were assigned one of these outcomes.

Among those episodes with initial success, a recurrence was defined by documentation of a second or subsequent episode of CRBI with the same organism and susceptibility pattern within 1 year of the initial CRBI.

Data Analysis
Continuous data were assessed using the t test or the Wilcoxon rank sum test. For categorical data, the ² statistic or the Fisher’s exact test was used. Recurrence was assessed both as a categorical variable and in a time-to-event analysis. Observation period continued until catheter removal, death of the patient, or at 365 days after the diagnosis of the initial CRBI. The log-rank test was used to compare survival times between the different catheter designs. For all analyses, was set at .05. All analyses were performed using SAS, Version 8.0 (SAS Institute Inc, Cary, NC).

This study was approved by the SJCHR Institutional Review Board.

	RESULTS

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During the targeted period, there were 543 episodes of bacteremia identified from microbiology records. As stated in Patients and Methods, 227 episodes were excluded because the patient did not have an H/B or TIP (n = 25), only peripheral-blood cultures were obtained (n = 4), only cultures via the catheter were obtained (n = 113), the patient died within 72 hours (n = 2), or there was a single positive blood culture for CNS (n = 83). An additional 107 episodes were excluded because the medical records were not available (n = 9), the patient had received antibiotic therapy before obtaining blood cultures (n = 1), or a diagnosis of non-CRBI was made (n = 97). The remaining 209 episodes met the study definition of CRBI.

Among the 209 episodes of CRBI, 22 episodes were recurrent bacteremias (18 first recurrences and four subsequent recurrences) and 15 represented second or subsequent CRBIs with a different organism. Thus, there were 172 episodes of first-time CRBI for a patient and catheter combination in 167 patients (five patients had separate episodes of CRBI with different catheters in place). The characterization of these 172 episodes as CRBI included 119 episodes diagnosed using comparative quantitative blood cultures, 48 episodes diagnosed using comparative quantitative cultures from two lumens of a Hickman catheter, and eight episodes diagnosed with repeated culture of CNS. Additional analyses are limited to these 172 episodes.

Patient Characteristics
Demographics, underlying diagnoses, and catheter type are shown in Table 1. Patient characteristics were assessed as a function of catheter type. There were no significant differences demonstrated in age, race or ethnicity, sex, underlying diagnosis, history of bone marrow transplantation, and clinical features of catheter-related infection between patients with bacteremia who had a TIP versus those with an H/B. Because of the small number of patients with superficial infections or receiving thrombolytic or dwell therapy, no additional analysis was performed using these variables.

Role of Patient, CRBI Characteristics, and Catheter Type in Successful Eradication of Bacteremia
In addition to catheter design, we evaluated sex, race or ethnicity, age, underlying diagnosis, previous allogeneic bone marrow transplantation, organism isolated, organism colony count, and sepsis. No differences were demonstrated between the treatment successes and failures on the basis of these features.

Appropriate antibiotic therapy was administered for a median of 10 days (range, 3 to 40 days) in the treatment successes and 16.5 days (range, 2 to 27 days) in the treatment failures (P > .05).

Outcome of the initial treatment was assessed by catheter type. Among the 19 infections with a TIP in place, 18 (95%) were eradicated. Among patients with an H/B, 131 of 138 (95%) infections were eradicated. Thus, there was no difference demonstrated in the initial response rate on the basis of catheter design.

Recurrent Bacteremia
Among the 149 successful episodes of short-term eradication of CRBI, there were 18 episodes of recurrent CRBI within 1 year. Table 3 demonstrates the patient, clinical, and treatment characteristics of the initial episode in each recurrence. Staphylococcus epidermidis was the most common isolate in recurrent bacteremias (nine episodes). Episodes of recurrent bacteremia were diagnosed a median of 63 days after the initial episode (range, 10 to 244 days): a median of 63 days (range, 10 to 244 days) for H/Bs and a median of 70 days (range, 21 to 191 days) for TIPs (P > .05).

Role of Other Characteristics of the Study Population
There was no significant difference demonstrated between the continued successes and recurrence of CRBI on the basis of age, sex, race or ethnicity, underlying diagnosis group, prior bone marrow transplantation, or clinical symptoms of sepsis. We were also unable to demonstrate a significant difference between recurrence and continued success on the basis of organism colony count (when considered either as a continuous variable, P = .34, or a categorical variable [< 100, 100 to 400, or > 400 CFU/mL], P = .32).

The role of S epidermidis and other CNS in recurrence of CRBI was also evaluated. S epidermidis or other CNS were isolated during the initial bacteremia in 10 of 18 episodes of recurrence but from only 30 of 131 episodes without demonstrated recurrence (OR, 4.7; 95% CI, 1.68 to 13.1; P = .002 for S epidermidis and OR, 4.2; 95% CI, 1.53 to 11.6; P = .003 for any CNS).

The relationship between isolation of these organisms and recurrence was investigated further using a stratified analysis. When the association of catheter type with recurrent infection was controlled for the isolation of S epidermidis, TIPs continued to have increased risk of recurrence (OR_adjusted, 7.1; 95% CI, 2.1 to 23.9; P = .001, Cochran Mantel Haenszel). The results were similar when controlled for isolation of any CNS (OR_adjusted, 7.4; 95% CI, 2.3 to 24.1; P = .0004, Cochran Mantel Haenszel).

Because the management of the initial CRBI can affect recurrence, we also evaluated the effect of duration of the initial antibiotic therapy. Among patients with no recurrence, initial therapy was given for a median of 10 days (range, 3 to 40 days) in comparison with patients who had a recurrence where therapy was given for a median of 9.5 days (range, 7 to 20 days; P = .01, Wilcoxon rank sum). When administration of 10 days of an antibiotic was considered as an appropriate duration of therapy, 72% of patients without recurrence and 50% of those with a recurrence received appropriate therapy (P = .05, ²). Likewise, in a stratified analysis controlling for duration of initial antibiotic therapy (treatment 10 v < 10 days), TIPs continued to have increased risk of recurrence (OR_adjusted, 8.8; 95% CI, 2.9 to 27.1; P < .0001, Cochran Mantel Haenszel).

Finally, when a multivariable analysis was used including catheter type, isolation of S epidermidis or CNS, and duration of antibiotic therapy, only catheter type remained independently associated with recurrence (P = .003 including S epidermidis and P = .002 including any CNS, respectively).

Time to Recurrence Analysis
Time to recurrence was generated for CRBIs by catheter type (TIP v H/B). Total number of follow-up days was 2,303 days for TIPs and 25,323 days for H/Bs. Time to recurrence is shown in Figure 1. TIPs were associated with shorter time to recurrence than were the H/Bs (P < .001).

View larger version (18K): [in this window] [in a new window]   Fig 1. Time to recurrence for totally implantable central venous catheters and Hickman/Broviac catheters (P < .001, log-rank test).

	DISCUSSION

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This study demonstrated that there is an increased recurrence of CRBI in pediatric patients who have TIPs in place compared with those who have H/Bs. This is the first study to demonstrate that catheter design may affect recurrence of infection. We speculate that the reason for the higher rate of recurrence lies in the design of the TIP. In comparison with the H/B, the TIP contains a portal that contains a vacant space below the septum. It is likely that cellular and coagulation-derived debris can accumulate within the dead space of the portal. Infusions of appropriate antibiotics are unlikely to clear organisms lodged in this debris. In comparison, the H/B has no dead space to allow the harbor of organism and all internal surfaces are in contact with infusates. It is possible that the mechanical action of flushing the catheter may also have a role in reducing the recurrence rate.

Prior investigators have suggested that intra- and extraluminal clots in TIPs may protect organisms from exposure to antibiotics and result in poor outcome, and also have suggested adjuvant therapy with urokinase or other thrombolytics.^23–27 We attempted to investigate this in our study but too few patients received thrombolytics to carry out a meaningful analysis.

An unexpected finding in this study was the relationship of CNS isolation to recurrence. These organisms are the most frequently isolated pathogen in episodes of CRBI. They are also the most common laboratory contaminant and frequently are resistant to a number of antibiotics. The ability to identify recurrence of these infections was based on the isolation of the same species with the same susceptibility patterns. Given the retrospective nature of this study, this is the only information available. Had this been a preplanned investigation or if isolates were available for genotyping, more precision in identifying recurrences with these organisms could have been achieved. Because all episodes with only one positive culture of CNS were removed from analysis, episodes analyzed were associated with at least two cultures yielding the same organism. This requirement raises the confidence level that the isolate was a pathogen and not a contaminant. Limitation to multiple positive cultures also may have been responsible for the unexpected predominance of Gram-negative isolates. Future studies should seek to perform molecular identity studies on paired isolates to confirm recurrence.

The relationship between CNS isolation and catheter type has not been explored previously; there is no prior information to link this organism to any catheter type preferentially. In this study we demonstrated disparate distribution of CNS isolates between the catheter types. Among TIPs, 58% of isolates were CNS compared with only 18% of isolates in H/Bs. It can be speculated that the intimate contact between the needle puncturing the TIP and the superficial skin is a direct pathway for the organism to gain entry to the TIP. Continued inflammation of the skin over the portal may further enhance the ability of CNS to infect patients with TIPs. In this study, we did not assess the skin over the portal nor determine the timing of portal access before CRBI. Additional investigation of this difference in isolated organisms is required.

A difference in short-term eradication of bacteremia among the catheter types studied was not demonstrated. The observation of similar short-term success between the two catheter designs in this study supports the previously reported findings of Rubin et al.²² These authors also report recurrences in four of the 36 initial successes, a rate of recurrence similar to that demonstrated in our study. They do not report the recurrence rate in H/Bs, which makes our study the first comparison of catheter design and its role in recurrence.

This study was limited by the reporting mechanism of the laboratory. Because 400 CFU was the maximum number of organisms reported from a culture, it is possible that we misclassified some true catheter-related infections as non–catheter-related infections if the number of organisms in the peripheral blood was moderately high. This misclassification bias was applicable to all catheter designs and thus had a nondifferential influence.

In addition, during the observation period for this study, there was widespread use of double-lumen H/Bs with fewer TIPs placed. This likely is due to the preference of double-lumen catheters for all patients who have acute myelocytic leukemia, or are anticipated to require a transplantation. The fewer TIPs included in this study also may be due to a lower rate of initial CRBI in patients with TIPs. Because of this difference, there was a smaller sample size in the TIP group, providing approximately one tenth the duration of follow-up observation days in patients with this type of catheter in place.

The medical implications of the results of this study include options for the initial and subsequent management of CRBI in TIPs in an effort to reduce recurrence. Close adherence to the duration of antibiotic therapy according to national treatment guidelines should be practiced; a minimum of 10 to 14 days of antibiotic therapy should be administered.¹⁷ It is logical that both dwell and thrombolytic therapy would improve outcome by improving access of the initial antibiotic therapy to organisms sequestered in cellular and coagulation-derived debris in the dead space. This study, which is based on historical data, does not support or refute this recommendation; a prospective trial could better define the optimal therapy for CRBIs in TIPs. As observed by Rubin et al,²² recurrent episodes of CRBI were successfully treated with repeat courses of antibiotic therapy without significant adverse outcome for the patient except for hospitalization for treatment. In those patients who have a catheter in place for a limited time to receive chemotherapy or bone marrow transplantation, they may still successfully maintain their catheter throughout the period of need. On the basis of this study, patients who have CNS CRBI with a TIP have a higher risk of recurrence and may benefit from therapies such as dwell therapy, urokinase, or antibiotic-containing flush solutions.

This study has demonstrated that there are similar rates of initial short-term success in eradication of CRBI in patients with either TIPs or H/Bs. However, in patients with TIPs, recurrent CRBIs are more likely to occur. Initial isolation of CNS may also contribute to the increased risk of recurrence and additional investigation is warranted.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	ACKNOWLEDGMENTS

 
We thank Drs. Stephen B. Kritchevsky, Andy Bush, and Fred F. Barrett for their suggestions for this project and its interpretation.

	NOTES

 
Supported in part by the American Lebanese Syrian Associated Charities (ALSAC) and the Cancer Center Support CORE Grant P30 CA21765.

	REFERENCES

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6. Mirro J Jr, Rao BN, Stokes DC, et al: A prospective study of Hickman/Broviac catheters and implantable ports in pediatric oncology patients. J Clin Oncol 7:214–222, 1989[Abstract]

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Submitted March 3, 2003; accepted July 3, 2003.

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