|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2000 American Society for Clinical Oncology Prevention of Central Venous Catheter–Related Infections and Thrombotic Events in Immunocompromised Children by the Use of Vancomycin/Ciprofloxacin/Heparin Flush Solution: A Randomized, Multicenter, Double-Blind TrialFrom the Department of Pediatrics, Medical College of Wisconsin, Children’s Hospital of Wisconsin, Milwaukee, WI; and DeVos Children’s Hospital, Grand Rapids, MI. Address reprint requests to Kelly J. Henrickson, MD, Department of Pediatrics, Midwest Athletes Against Childhood Cancer Fund Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226; email kellj{at}mcw.edu
PURPOSE: To determine whether an antibiotic flush solution containing vancomycin, heparin, and ciprofloxacin (VHC) can prevent the majority of line infections. PATIENTS AND METHODS: A prospective double-blind study was performed comparing VHC to vancomycin and heparin (VH) to heparin alone in 126 pediatric oncology patients. RESULTS: The 153 assessable lines resulted in 36,944 line days studied. There were 58 blood stream infections (43 Gram-positive, 14 Gram-negative, and one fungal). Forty were defined as line infections (31 heparin, three VH, six VHC). The time to develop a line infection was significantly increased using either antibiotic flush (VH, P = .011; VHC, P = .036). The rate of total line infections (VH, P = .004; VHC, P = .005), Gram-positive line infections (VH, P = .028; VHC, P = .022), and Gram-negative line infections (VH, P = .006; VHC, P = .003) was significantly reduced by either VH or VHC. Sixty-two (41%) of the lines developed 119 occlusion episodes (heparin, 3.99 per 1,000 line days; VHC, 1.75 per 1,000 line days; P = .0005). Neither antibiotic could be detected after flushing, and no adverse events were detected, including increased incidence of vancomycin-resistant Enterococcus colonization or disease. CONCLUSION: The use of either VH or VHC flush solution significantly decreased the complications associated with the use of tunneled central venous lines in immunocompromised children and would save significant health care resources.
PROLONGED VASCULAR access has become necessary for a large number of patients who require parenteral nutrition, chemotherapy, blood products, or antimicrobial therapy. This access is usually achieved through the use of tunneled central venous catheters (TCVCs; eg, Broviac, Hickman; Bard Access Systems, Salt Lake City, UT). A major complication of the use of TCVCs is infection.1-16 These infections can lead to serious morbidity and death, especially in pediatric oncology patients.1,2 Most catheter-associated infections are caused by Gram-positive (GP) organisms, in particular coagulase-negative staphylococci, but Gram-negative (GN) organisms still account for up to 28% of these infections.1-5,10,14 Only two prospective, blinded, placebo-controlled studies have been conducted that had statistical power.14,17 Both demonstrated that antibiotic-containing flush solutions (vancomycin and heparin [VH]) used in these lines are effective in preventing TCVC-associated infections caused by organisms sensitive to vancomycin. Ciprofloxacin is an antibiotic effective in killing an extensive spectrum of GN bacteria. To determine whether an antibiotic flush solution containing vancomycin, heparin, and ciprofloxacin (VHC) can prevent the majority of central venous line infections in pediatric immunocompromised patients, a prospective double-blind study was performed comparing VHC to VH to heparin alone (standard therapy).
The study was conducted at two medical centers. Inclusion criteria included the following: (1) age less than 20 years; (2) presence of a primary or secondary immunodeficiency; (3) placement of a TCVC as part of planned care or a current TCVC; and (4) expected substantial periods in which the TCVC was to be capped. Patients with totally implanted catheters (eg, Port-a-Cath; Sims Deltec, Inc, St Paul, MN) were excluded. Patients who were critically ill and who had a TCVC placed (or in place) but remained critically ill with continuous fluids running through their TCVC were not eligible for this study until they stabilized and it was expected that they would be able to have their TCVC capped. Patients who met the aforementioned criteria were asked to participate. After informed consent had been documented, the patients were assigned to one of three ranks depending on underlying disease and intended therapeutic plan: (1) risk 1: patients who were expected to require few admissions for fever and neutropenia (eg, standard-risk acute lymphatic leukemia, localized tumors, many brain tumors, infants with neuroblastoma, and so on); (2) risk 2: patients who were expected to have more frequent hospitalizations (eg, high- or very high-risk acute lymphatic leukemia, acute nonlymphoblastic leukemia, nonlocalized tumors, relapsed malignancy, or any patient with nonneoplastic-related immunodeficiency requiring a TCVC [eg, human immunodeficiency virus, severe combined immunodeficiency syndrome]); and (3) risk 3: all nonautologous bone marrow transplant patients and solid organ transplant recipients. The patients were then were randomized to one of three arms in the following fashion: VHC (one), VH (one), heparin (two). This provided 1:1 assignment into experimental versus control groups. The randomization was performed blindly and was designed to be balanced in each study group by risk (ie, equal numbers of patients from each risk group). Randomization took place in the pharmacy such that no investigator or nurse was aware of the type of flush being used. The designated flush solution was used for the entire study or the life of the TCVC. If a second TCVC was placed, the patient was rerandomized at that point. The VH (vancomycin 25 µg/mL, heparin 9.73 IU/mL) and VHC (VH plus ciprofloxacin 2 µg/mL) solutions were made in each institution’s pharmacy according to published guidelines.18,19 All patients/parents were instructed in appropriate line care as determined by the Children’s Hospital of Wisconsin. At the time of randomization, a pharmacist assigned them to group X (VH), Y (heparin), or Z (VHC). All individuals (patients, parents, floor, and emergency department nurses) involved in flushing a child’s TCVC were informed of the child’s participation in this study and flush code. Extra bottles of all three flush solutions (labeled X, Y, and Z) were available throughout the hospital and in the pharmacy to facilitate use. The child and his/her parents were asked to contact the researcher/research nurse within 12 hours of when they began to show signs of infection, illness, and/or fever. Each of these episodes was evaluated and monitored by the research staff, and an "event" form was completed. The physician in charge of the patient for his/her acute illness was responsible for obtaining or ordering the appropriate laboratory tests and cultures. All study patients were evaluated in the following manner if they had a fever (38.3°C x 1 [oral or axillary temperature] or 38.0°C x 2 over at least 1 hour). Nonneutropenic patients (absolute neutrophil count [ANC] > 1,000/µL and not decreasing) who appeared nontoxic and were diagnosed with otitis media, streptococcal pharyngitis, impetigo, urinary tract infection, or other localized non–line-related infections were treated with oral antibiotics. A culture was obtained from suspected sites of localized infection when possible, but no cultures related to their TCVC were taken. In addition, nontoxic patients thought to have viral respiratory infections had no cultures taken related to their TCVC. Examination of bacterial and fungal cultures of the exit site and quantitative blood cultures from all ports of the TCVC and a peripheral vein was performed on patients with any evidence of TCVC site infection or no source for their fever. Moderately neutropenic patients (ANC 500 to 1,000/µL and not decreasing, or > 1,000/µL and decreasing to < 1,000/µL) were evaluated in the same fashion as nonneutropenic patients except that the TCVC site was inspected in all patients and cultured if evidence of tenderness, erythema, and/or purulence was found. Quantitative blood cultures were drawn from all ports of the TCVC in all patients, and in those without an obvious source for their fever or with evidence of TCVC site infection, a peripheral quantitative blood cultures was drawn. Severely neutropenic patients (ANC < 500/µL, or 500 to 1,000/µL and decreasing) or patients with toxic clinical appearance or bacteria obtained from the TCVC were evaluated in the same fashion as moderately neutropenic patients and in addition had a bacterial and fungal swab taken from the TCVC exit site, and before beginning intravenous antibiotics, a quantitative blood culture was taken from all ports of the TCVC and a peripheral vein. The event forms were completed after the appropriate culture and laboratory results had been obtained. This usually occurred after the event was over. Each event was classified using the following definitions, remembering that all patients evaluated were either febrile and appeared toxic, neutropenic, or nonneutropenic without an obvious source for their fever. 1. Definite TCVC-related bacteremia: Blood specimens obtained from the TCVC immediately before beginning antibiotic therapy are culture-positive, whereas blood specimens obtained from a peripheral vessel are culture-negative, or the concentration of bacteria isolated from the TCVC is at least 10 times greater than the concentration of bacteria isolated from a simultaneously sampled peripheral vessel.1 1a. Probable TCVC-related bacteremia: Blood specimens obtained from the TCVC are culture-positive, and no peripheral culture was performed before starting antibiotics. 1b. Possible TCVC-related bacteremia: Blood specimens obtained from the TCVC and peripheral vessel are culture positive but not quantitated or quantitated and off scale. 2. Bacteremia not related to the TCVC: Blood specimens obtained from the TCVC and a peripheral-blood vessel are both culture-positive, and the concentration of bacteria isolated from the peripheral vessel is similar to the concentration isolated from the TCVC (concentrations within 10-fold), or two blood cultures from a peripheral vessel are positive, and blood from the TCVC is culture-negative. 3. Contaminated blood culture: Blood specimens obtained from either the TCVC or peripheral-blood vessel contain less than 10 colonies of GP organisms or less than five colonies of GN organisms; in addition but less frequently, a single blood specimen obtained from a peripheral vessel is culture-positive for coagulase-negative Staphylococcus or alpha hemolytic streptococcus, and repeat culture is negative. 4. TCVC site infection: Bacteria or fungus is isolated from specimens taken from the insertion site of the TCVC. 5. Presumed TCVC site infection: Tenderness, erythema, and/or purulence at the insertion site that improves with antimicrobic therapy. 6. Presumed TCVC tunnel infection: Erythema and/or tenderness along the catheter tunnel. 7. Occlusion: Inability to draw through or infuse into a TCVC. Standard blood cultures, quantitative blood cultures, catheter tip cultures, and vancomycin-resistant enterococci (VRE) cultures were all performed at the Children’s Hospital of Wisconsin and DeVos Children’s Hospital using standard methods. Every effort was made to have the catheter tips cultured on removal. All episodes of line occlusion (including use of urokinase/streptokinase) were monitored and recorded. Peripheral ciprofloxacin levels were drawn on random patients after flushing the TCVC with the patient’s study solution and analyzed by high-performance liquid chromatography (George J. Krol, PhD, Bayer Corp, West Haven, CT). Surveillance cultures were routinely performed during the last year of the study to search for VRE.
All data from this study were entered into a relational database for analysis at the Medical College of Wisconsin. No prospective analysis was performed. An interim analysis was planned and performed by a statistician not involved in the clinical study. The statistical methods used were the
One hundred twenty-six patients (28 VH, 64 heparin, 34 VHC) with 154 TCVCs were enrolled between October 1993, and May 1997. Twenty patients had their line removed and were off study, then needed a new line and re-enrolled. Seven patients had two lines at the same time. Each of these patients received the same flush solution. One patient died before receiving any study drug and was not assessable. Seventy-one percent of all eligible patients were approached. The majority of those not approached were because of staff not being available. Sixty-four percent of those approached were enrolled onto the study. Reasons for not enrolling included no reason given (42%), overwhelmed with cancer diagnosis (11%), lived out of area (10%), wanted prefilled syringes (11%), did not want peripheral blood drawn (8%). The majority of the study population were pediatric oncology patients who had a TCVC placed for chemotherapy. Forty-four percent had acute leukemia, 40% had solid tumors, and 7% had bone marrow transplants. Table 1 lists the demographic information by solution. There were no statistically significant demographic differences between the three flush groups. Because the number of patients in each risk group did not allow analysis based on risk, all three risk groups were combined as planned in the original power calculations.
The 153 assessable TCVCs resulted in 36,944 line days studied (35 VH, 80 heparin, 38 VHC). The median number of line days per patient was 200 to 247 (Table 1). There were 489 events evaluated, resulting in 58 blood stream infections (43 GP, 14 GN, and one fungal; Table 2). Eighty organisms were recovered from these positive cultures (14 mixed infections): 58 GP (72%), 20 GN (25%), and two fungal (3%; Table 3). Fourteen blood stream infections met the definition of definite TCVC infection, 21 met the definition for probable infection, and five met the definition for possible infection. No organism recovered from the blood was resistant to either vancomycin or ciprofloxacin.
The TCVC infection rate (possible to definite) in the control group (heparin) was 1.72 per 1,000 line days. There were 31 TCVC infections in the heparin group (12 definite; Table 2), three TCVC infections in the VH group (one definite), and six TCVC infections in the VHC group (one definite, one fungal). The time to definite TCVC infection or possible to definite TCVC infection was significantly increased using either antibiotic flush (VH, P = .063 and VHC, P = .036, Fig 1; VH, P = .011 and VHC, P = .036, Fig 2). The rate of total definite, possible to definite, GP possible to definite, and GN TCVC infections were dramatically reduced by either VH or VHC (Table 2).
Sixty-two (41%) of the TCVCs developed 119 occlusion episodes. The occlusion rate in the control group (heparin) was 3.99 per 1,000 line days. Occlusion episodes were significantly reduced in the VHC group (1.75 per 1,000 line days; P = .0005) but not in the VH group (Table 2). Of the 119 occlusion episodes, only six had a positive blood culture within 48 hours of the occlusion. Two were contaminates, and one was a bacteremia unrelated to the TCVC. The remaining three episodes included two definite TCVC infections (VH and heparin) and one probable TCVC infection (heparin).
The three study groups were compared in terms of ANC at the time of the TCVC infection (Table 4) and the duration of neutropenia (ANC < 500/µL) before the infection. Four different parameters were compared: ANC < 100/µL (n = 11), ANC < 500/µL (n = 15), ANC > 500/µL (n = 24), and ANC > 1,000/µL (n = 19). There was no difference in the duration of neutropenia relative to infections in a particular study group. However, the ANC may have an effect on the rate of GP TCVC infections in the three flush populations. GP TCVC infections in patients with ANCs > 500/µL were almost completely prevented by either the VH or VHC (GP infection in the VH and VHC group/total GP infections = 12.5%; 95% confidence interval [CI], 1.6% to 38.4%). Similarly, in patients with TCVC infections and ANCs > 1,000/µL, no GP infections occurred in the VH and VHC groups (0%; 95% CI, 0% to 25%). However, in the GP TCVC infection population with ANCs < 500/µL, infections occurred in patients receiving VH and VHC with greater frequency than in those with ANCs
Sixteen patients were randomly tested for the presence of ciprofloxacin in their blood after flushing their line with their designated flush solution. After the study was unblinded, seven patients had VHC flushed through their TCVC and had a peripheral-blood sample analyzed. All seven patients had levels of ciprofloxacin that were less than the published sensitivity of the assay (< 0.05 µg/mL).20 Previously published work demonstrated that vancomycin could not be detected after flushing with VH solution.14 In addition, joint problems were assessed both subjectively and objectively at the beginning and at the end of the study for each patient. There was no association between use of VHC or VH with the presence of any joint problem. There were no cases of VRE recovered from any normally sterile site during the 3 2/3 years of the study. During the last year of the study, culture samples were analyzed in all 35 of the current patients (28% of total enrollment) to detect colonization with VRE. Sixteen patients were tested on initial enrollment in the study. One of these patients had VRE recovered from a rectal swab. This patient was placed on VH solution, and test results at the end of the study were VRE-negative. Sixteen patients received heparin solution and were tested 28 times for colonization during the study; results for all were negative. Ten patients received VH solution and were tested 25 times during the study. One of these patients had a rectal swab that was positive for VRE 4 months after beginning the VH flush. Results of six surveillance cultures performed over the next 4 months were negative. The patient’s results became positive again in the eighth month on study, but at the end of the study (same month), the patient’s results were negative. This patient demonstrated no evidence of disease from VRE at any time. Nine patients received VHC and were tested 17 times during the study; results for all were negative. The rate of VRE colonization was actually lower in the VH and VHC groups (5.26%) than in the general oncology population (7.14%; data not shown). There was no evidence that either VH or VHC flush increased the rate or amount of VRE colonization or disease in this patient population. Other complications such as exit site infections (n = 49) were equally distributed among the three groups (VH, n = 10; heparin, n = 24; VHC, n = 15). Tunnel track abnormalities or infections only occurred four times (heparin, n = 2; VHC, n = 2). Analysis of cultures of the catheter tips was performed on 30 TCVCs (VH, n = 8; heparin, n = 16; VHC, n = 6) and resulted in five positive cultures. The VH group had Staphylococcus aureus and Flavobacterium, the heparin group had S aureus and Corynebacterium, and the VHC group had S aureus. Twelve patients who were admitted for possible to definite TCVC infection were randomly selected to determine average cost for TCVC infections. Patients were admitted to the Children’s Hospital of Wisconsin between 1993 and 1997. The average length of stay was 11.5 days (range, 4 to 21 days). Hospital costs for these patients was $40,983 (range, $7,654 to $124,668). This equaled $3,563 per day. TCVC infections have been estimated to extend hospital stays by 7 to 14 days and add approximately $29,000 to the total hospital costs in adults.21 Using the low end of this estimate (7 days) to calculate the cost of one TCVC in this population (7 x $3563), the cost of a CVC infection was $24,946. This is close to the figure calculated for adults. However, if one wanted an even more conservative figure, one could use all of the short-stay admissions (< 7 days; n = 4) and calculate the average length of stay for a TCVC infection as 5 days ($1863 per day) at a cost of $9,318 per infection. Using these two calculations as a range, the cost-effectiveness of VHC or VH can be calculated. If an average pediatric oncology unit has 100 TCVC patients, then there would be 36,500 line days per year or 63 TCVC infections per year based on our observed rate of 1.72 infections per 1,000 line days in the heparin group. If the VH solution was used exclusively, there would be only 14 infections per year (245 to 343 fewer hospital days). This would save between $456,000 and $1,200,000 per year. If the VHC solution was used exclusively, there would be only 20 infections per year (not statistically different from VH). This would save between 215 and 301 hospital days and between $401,000 and $1,072,000 per year. In addition, the VHC solution would prevent 82 line occlusions compared with heparin alone for additional cost benefit. The actual cost differences for the VH ($3.10) and VHC ($4.40) solutions compared with the cost of heparin ($1.40) flushes is trivial. If produced in bulk, the VH and VHC flush solution costs could be reduced even further.
The risk of developing a TCVC infection seems to be increased during the first few weeks a line is in place.4,12 Other risk factors include frequent manipulations and entry into the line, length of TCVC in young infants and toddlers, occlusive plastic dressings, poor aseptic technique, and perhaps even the composition of the catheter.22-25 Many different approaches have been attempted to decrease central venous catheter infections. Exit sites have been covered with different antimicrobial mixtures.26,27 In some cases this has decreased catheter-associated bacteremia, but some studies have shown increased fungal colonization and infection. Catheters have had disinfectants,28 antibiotics,29-36 and heparin31 incorporated or bonded onto their plastic. Some of these methods have demonstrated decreased infection rates, but none has become widely used. Most of these studies have been either in vitro or involved short-term nontunneled percutaneous central venous catheters. In particular, attachable silver-impregnated cuffs demonstrated decreased infection rates in short-term catheters but failed to protect TCVCs.37,38 In addition, some studies have demonstrated that the majority of antibiotics can come off the catheters in the first day.39 The use of antibiotic flush solutions to prevent TCVC infections has been studied for more than 14 years since, Keith Powell MD, first suggested this as a straightforward method for reducing one of the most common complications of central venous access in children.14,17-19,40-43 Yet 8 years after the publication of a blinded, prospective, controlled study demonstrating the efficacy of VH solution in preventing almost all GP TCVC infections in immunocompromised children, the use of VH is not widespread.14 The first purpose of our study was to validate the safety and efficacy of VH solution compared with heparin. Its second purpose was to demonstrate the safety and efficacy of a second-generation flush (VHC) that would broaden the prophylactic coverage of the VH solution to include GN organisms. Our results demonstrated that VH and VHC significantly prevent systemic TCVC infections. However, both solutions unexpectedly reduced the number of GN infections. Although TCVC infections directly cause serious morbidity and death in pediatric oncology patients,10,44,45 indirect costs to these children comes from the extra days of hospitalization, antibiotic use and toxicity, delay in specific therapy for their underlying disease, and need for TCVC replacement. Therefore, our finding of a significant increase in the time to first infection in children using VH or VHC and a significant decrease in the number of occlusion episodes in children using VHC offers even greater benefit than only reduced infections. Our data support the association between TCVC infection and thrombotic events. However, the mechanism of protection from thrombotic events demonstrated by VHC, and to a lesser degree by VH (15% reduction), is unclear. The majority (95%) of occlusive events was not associated with positive blood cultures. Interestingly, the decrease in occlusion episodes was demonstrated by a small number of patients with multiple episodes of occlusion. Only one of the 15 patients with more than two occlusion episodes were in the VHC group (heparin, n = 10; VH, n = 4). This suggests that there may be a link between repeat occlusion and preventable "culture-negative" TCVC colonization with bacteria. Three clinical trials evaluating VH and one evaluating VH-amikacin for the prevention of TCVC infections or subcutaneous port infections (Table 5)17,40-43 either lacked statistical power (n = 3) or used different definitions and analysis criteria (n = 3) to reach their conclusions. In 1995, Rackoff et al40 studied the VH solution in an unblinded study that was stopped before accumulating enough infections to evaluate. An additional confounding variable was that the VH was in multiple-dose vials, whereas the heparin was in unit-dose syringes.
Three clinical trials17,42,43 used the presence of bacteremia instead of specific TCVC infection as their end point for analysis. This is problematic because it includes many cases of bacteremia not associated with the TCVC and may include cases of contamination. A proven or definite TCVC infection requires either quantitative culture results or physical evidence of the catheter being the source of bacteremia/septicemia.1-3 We excluded 18 episodes of bacteremia from our analysis because they were clearly not related to the patient’s TCVC. Hickman/Broviac catheters seem to have a somewhat higher infection rate than totally implantable catheters (ports).1,4,5 Rubie et al42 retrospectively compared 1.5 years’ use of VH at a higher concentration than we used (50 µg/mL vancomycin, 100 IU heparin) with 3 years without use in patients with ports (Table 5). Although this was a large study that showed VH flush to be effective, it also suffers from being retrospective and having a broad definition of TCVC infection (ie, bacteremia). For these reasons, it is not directly comparable to our study. It is unknown how some variations in the concentrations of vancomycin and heparin might change the efficacy of this solution. VH 50 µg/mL (10 IU) and VH 25 µg/mL (100 IU) have been shown to be stable and active.19,46 However, there are clearly combinations of VH that either precipitate or significantly effect the activity of vancomycin.47 Daghistani et al43 studied a VH-amikacin flush but were unable to collect enough infections to have statistical power (Table 5). Barriga et al17 studied both pediatric and adult patients (7% of total) and combined the results. The age of the patient has been directly linked to the infection rate, with younger patients having higher rates.1,8-10 In addition, the concentration of heparin was much higher than that used in our study (25 IU/mL v 9.73 IU/mL). It cannot be determined whether these factors may have affected their results. Comparison of their flushes did not reach statistical significance, but there were twice as many infections in the heparin group (VH, n = 7; heparin, n = 16). Recently, it has been shown that pediatric oncology patients are at high risk for TCVC infections even when they are not neutropenic.13 Barriga et al17 analyzed their data by ANC and reported a significant difference between those with TCVC infections and ANCs less than 500/µL and those with ANCs greater than 500/µL, suggesting that VH was less protective at low ANCs. However, they used a broad definition of bacteremia that could have included contaminants or bacteremia from sources other than the line. In addition, no data were provided on GN infections. We did not demonstrate a significant difference between the infections in the patients with ANCs less than 500/µL and those with ANCs greater than 500/µL (Table 4). The 11 GN TCVC infections demonstrated no variation in relationship to the patients’ ANC. It has been suggested that intraluminal colonization plays a decreased role in the generation of TCVC infections in neutropenic patients.17 Our data suggest that this is not true for GN infections and may be true for GP organisms, but if it occurs, it is only a moderate decrease. Furthermore, 69% of TCVC infections in this study would not be affected. We found no evidence of toxicity in the patients using either VH or VHC flush. This concurs with the previously reported clinical trials.17,40,42,43 Ciprofloxacin has been well tolerated with only minor side effects in adults (eg, fever, nausea, rash). It has had limited use in the pediatric population secondary to articular cartilage damage noted in rats and beagle puppies.48 An anecdotal report49 has documented teeth staining in neonates treated with ciprofloxacin and numerous other drugs, but no clear link to serious side effects in children has been established. In fact, several investigators have failed to demonstrate significant toxicity in children.50-53 The calculated serum level that may have occurred in study patients once each day (ie, peak with TCVC being flushed) was 104 (> 14,000) times less than the dose found to be toxic in animals. Similarly, the concentration of vancomycin that a study patient is exposed to is undetectable even immediately after flushing the TCVC.14 No other signs or symptoms attributable to vancomycin toxicity could be detected in any of the patients studied. Of perhaps more concern has been the increase in VRE among hospitalized patients throughout the United States. We believe that the use of VH or VHC will not increase either the development of VRE disease, spread of VRE to other patients, or colonization with VRE. Our two controlled trials have not detected any disease or any relationship between colonization and VH or VHC flush use. None of the other published studies on these solutions has demonstrated any relationship either.17,40,42,44 The use of VH or VHC in pediatric oncology would decrease the number of TCVC infections by 68% to 78%. This would save an average pediatric oncology unit (100 TCVC patients per year) between 1.2 to 1.4 million dollars per year (extrapolating from studies in adult patients21) or 0.4 to 1.2 million dollars based on patient charges in this study (data not shown). This does not include any saving based on decreased occlusion episodes. TCVCs have drastically improved the medical care of pediatric patients with malignancies and immunocompromised states. They have allowed for easy vascular access, decreased pain and suffering, and increased outpatient treatment. However, their high infection rate causes significant morbidity, mortality, and cost to both the patient and society. Methods to significantly decrease this infection rate are needed. We believe that this is the largest blinded and placebo-controlled multicenter trial reported to date that examined the prevention of TCVC infections in children. VH and VHC proved to decrease dramatically the amount of TCVC infections (both GP and GN) and the time to first infection. VHC decreased dramatically the number of occlusion episodes. We believe that children and adults with TCVC infections would greatly benefit from the use of one of these solutions. Furthermore, we believe that the use of these solutions would significantly reduce the direct cost of TCVC infections to society.
Supported by grants from the Children’s Hospital of Wisconsin and Children’s Hospital Foundation, Milwaukee, WI. We thank George J. Krol, PhD, for providing the ciprofloxacin levels; the nurses, oncologists, pharmacists, hospital personnel, and parents that allowed this study to proceed; Barbara Mohr for the VRE data on nonstudy oncology patients; and Dawn Schlechta for manuscript preparation.
1. Flynn PM: Vascular access device infections, in Patrick CC (ed): Infections in Immunocompromised Infants and Children. New York, NY,Churchill Livingstone, 1992, pp 289-298 2. Raad II, Bodey GP: Infectious complications of indwelling vascular catheters. Dis 15:197-210, 1992 3. Garner JS, Jarvis WR, Emori TG, et al: CDC definitions for nosocomial infections, 1988. Am J Infect Control 16:128-140, 1988[Medline] 4. Mirro J, 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] 5. Ingram J, Weitzman S, Greenberg ML, et al: Complications of indwelling venous access lines in the pediatric hematology patient: A prospective comparison of external venous catheters and subcutaneous ports. Am J Pediatr Hematol Oncol 13:130-136, 1991[Medline] 6. Darbyshire PJ, Weightman NC, Speller DCE: Problems associated with indwelling central venous catheters. Child 60:129-134, 1985 7. Viscoli C, Garaventa A, Boni L, et al: Role of broviac catheters in infections in children with cancer. Pediatr Infect Dis J 7:556-650, 1988[Medline] 8. Johnson PR, Decker MD, Edwards KM, et al: Frequency of broviac catheter infections in pediatric oncology patients. J Infect Dis 154:570-578, 1986[Medline] 9. Donowitz LG, Haley CE, Gregory WW, et al: Neonatal intensive care unit bacteremia: Emergence of Gram-positive bacteria as major pathgens. Am J Infect Control 15:141-147, 1987[Medline] 10. Decker MD, Edwards KM: Central venous catheter infections. Pediatr Clin North Am 35:579-612, 1988[Medline] 11. Prince A, Heller B, Levy J, et al: Management of fever in patients with central vein catheters. Pediatr Infect Dis 5:20-24, 1986[Medline] 12. King DR, Komer M, Hoffman J, et al: Broviac catheter sepsis: The natural history of an iatrogenic infection. J Pediatr Surg 20:728-733, 1985[Medline] 13. Gorelick MH, Owen WC, Seibel NL, et al: Lack of association between neutropenia and the incidence of bacteremia associated with indwelling catheter venous catheters in febrile pediatric cancer patients. Pediatr Infect Dis J 10:506-510, 1991[Medline] 14. Schwartz C, Henrickson KJ, Roghmann K, et al: Prevention of bacteremia attributed to luminal colonization of tunneled central venous catheters with vancomycin-susceptible organisms. J Clin Oncol 8:1591-1597, 1990[Abstract]
15.
Cairo MS, Spooner S, Sowden L, et al: Long-term use of indwelling multipurpose silastic catheters in pediatric cancer patients treated with aggressive chemotherapy. J Clin Oncol 4:784-788, 1986 16. Shapiro ED, Wald ER, Nelson KA, et al: Broviac catheter-related bacteremia in oncology patients. Am J Dis Child 136:679-681, 1982[Abstract] 17. Barriga FJ, Varas M, Potin M, et al: Efficacy of a vancomycin solution to prevent bacteremia associated with an indwelling central venous catheter in neutropenic and non-neutropenic cancer patients. Med Pediatr Oncol 28:196-200, 1997[Medline] 18. Henrickson KJ, Powell KR, Schwartz CL: A dilute solution of vancomycin and heparin retains antibacterial and anticoagulant activities. J Infect Dis 157:600-601, 1988 (letter)[Medline] 19. Henrickson KJ, Dunne WM: Modification of a central venous catheter flush solution improves in vitro antimicrobial activity. J Infect Dis 166:944-946, 1992[Medline] 20. Krol GJ, Benham BT: HPLC analysis of ciprofloxacin and ciprofloxacin metabolites in body fluids. J Pharm Biomed Anal 14:181-190, 1995[Medline] 21. Pittet D, Tarara D, Wenzel RP: Nosocomial bloodstream infection in critically ill patients: Excess length of stay, extra costs, and attributable mortality. JAMA 271:1598-1601, 1994[Abstract] 22. Conly JM, Grieves K, Peters B: A prospective, randomized study comparing transparent and dry gauze dressings for central venous catheters. J Infect Dis 159:310-319, 1989[Medline] 23. Linder LE, Curelaru I, Gustavsson B, et al: Material thrombogenicity in central venous catheterization: A comparison between soft, antebrachial catheters of silicone elastomer and polyurethane. J Parenteral Enteral Nutr 8:399-406, 1984[Abstract]
24.
Sheth NK, Franson TR, Rose HD, et al: Colonization of bacteria on polyvinyl chloride and Teflon intravascular catheters in hospitalized patients. J Clin Microbiol 18:1061-1063, 1983 25. Rotrosen D, Calderone RA, Edwards JE: Adherence of Candida species to host tissues and plastic surfaces. Rev Infect Dis 8:73-85, 1986[Medline] 26. Maki DG, Band JD: A comparative study of polyantibiotic and iodophor ointments in prevention of vascular catheter-related infection. Am J Med 70:739-744, 1981[Medline] 27. Maki DG, Ringer M, Alvarado CJ: Prospective randomised trial of povidone-iodine, alcohol, and chlorhexidine for prevention of infection associated with central venous and arterial catheters. Lancet 338:339-343, 1991[Medline] 28. Kingston D, Seal DV: Self-disinfecting plastics for intravenous catheters and prosthetic inserts. J Hyg Camb 96:185-198, 1986[Medline] 29. Kamal GD, Pfaller MA, Rempe LE, et al: Reduced intravascular catheter infection by antibiotic bonding. JAMA 265:2364-2368, 1991[Abstract] 30. Maki DG, Wheller SJ, Stolz SM, et al: Clinical trial of a novel antiseptic central venous catheter. Program and Abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC, American Society for Microbiology, 1991 (abstr 461) 31. Mermel L, Stolz S, Maki D, et al: Antimicrobial activity of intravascular catheters. Pediatric Research Program Issue. Baltimore, MD, American Academy of Pediatrics/American Society of Clinical Investigators/American Federation of Clinical Research Annual Meeting, 1992 (abstr A114) 32. Maki DG, Cobb L, Garman JK, et al: An attachable silver-impregnated cuff for prevention of infection with central venous catheters: A prospective randomized multicenter trial. Am J Med 85:307-314, 1988[Medline] 33. Flowers RH, Schwenzer KJ, Kopel RF, et al: Efficacy of an attachable subcutaneous cuff for the prevention of intravascular catheter-related infection. JAMA 261:878-883, 1989[Abstract] 34. Heard SO, Wagle M, Vijayakumar E, et al: Influence of triple-lumen central venous catheters coated with chlorhexidine and silver sulfadizine on the incidence of cather-related bacteremia. Arch Intern Med 158:81-87, 1998
35.
Maki DG, Stolz SM, Wheeler S, et al: Prevention of central venous catheter-related bloodstream infection by use of an antiseptic-impregnanted catheter: A randomized, controlled trial. Ann Intern Med 127:257-266, 1997
36.
Raad I, Darouiche R, Dupuis J, et al: Central venous catheters coated with minocycline and rifampin for the prevention of catheter-related colonization and bloodstream infections: A randomized, double-blind trial. Ann Intern Med 127:267-274, 1997 37. Clementi E, Marie O, Arlet G, et al: Usefulness of an attachable silver impregnated cuff for prevention of catheter-related sepsis (CRS)? Program and Abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington DC, American Society for Microbiology, 1989 (abstr 460) 38. Groeger J, Lucas A, Brown A, et al: Silver-impregnated cuffs on Hickman catheters in cancer patients: A prospective randomized study of infectious morbidity. Programs and Abstracts of the 29th Interscience Conference on Antimicrobiol Agents and Chemotherapy. Washington, DC, American Society for Microbiology, 1989 (abstr 1079) 39. Bach A, Darby D, Bottiger B, et al: Retention of the antibiotic teicoplanin on a hydromer-coated central venous catheter to prevent bacterial colonization in postoperative surgical patients. Med 22:1066-1069, 1996 40. Rackoff WR, Weiman M, Jakobowski D, et al: A randomized, controlled trial of the efficacy of a heparin and vancomycin solution in preventing central venous catheter infections in children. J Pediatr 127:147-51, 1995[Medline] 41. Powell KR: Correction: Heparin-vancomycin solution to prevent central venous catheter infections. J Infect Dis 127:1008-1009, 1995 42. Rubie H, Juricic M, Claeyssens ,et al: Morbidity using subcutaneous ports and efficacy of vancomycin flushing in cancer. Dis Child 72:325-329, 1995 43. Daghistani D, Horn M, Rodriguez Z, et al: Prevention of indwelling central venous catheter sepsis. Med Pediatr Oncol 26:405-408, 1996[Medline] 44. Henrickson KJ, Shenep JL: Fulminating staphylococcus epidermidis bacteremia. Med J 83:231-234, 1990 45. Bender JW, Hughes WT: Fatal Staphylococcus epidermidis sepsis following bone marrow transplantation. Johns Hopkins Med J 146:13-15, 1980[Medline] 46. Yao JDC, Arkin CF, Karchmer AW: Vancomycin stability in heparin and total parenteral nutrition solutions: Novel approach to therapy of central venous catheter related infections. Enteral Nutr 16:268-274, 1992
47.
Barg NL, Supena RB, Fekety R: Persistent staphylococcal bacteremia in an intravenous drug abuser. Antimicrob Agents Chemother 29:209-211, 1986 48. Christ W, Lehnert T, Ulbrich B: Specific toxicologic aspects of the quinolones. Rev Infect Dis 10:S141-S146, 1988 49. Lumbiganon P, Pengswaa K, Sookpranee T: Ciprofloxacin in neonates and its possible adverse effect on the teeth. Pediatr Infect Dis J 6:932-935, 1991 50. Stutman HR: Summary of a workshop on ciprofloxacin use in patients with cystic fibrosis. Pediatr Infect Dis J 6:932-935, 1987 51. Schaad UB, Wedgwood-Krucko J: Efficacy and safety of ciprofloxacin in pediatric patients with cystic fibrosis. Rev Infect Dis 11:S118, 1989 (abstr) 52. Schaad UB, Sander E, Wedgwood J, Schaffner T: Morphologic studies for skeletal toxicity after prolonged ciprofloxacin therapy in two juvenile cystic fibrosis patients. Pediatr Infect Dis J 11:1047-1049, 1992[Medline] 53. Schaad UB: Role of the new quinolones in pediatric practice. Infect Dis J 11:1043-1046, 1992 Submitted July 12, 1999; accepted November 23, 1999. This article has been cited by other articles:
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
INTRODUCTION
2 test for proportions, the Kruskal-Wallis test for comparing the medians of continuous data, and the Fisher’s exact test. The Cox proportional hazards model was used to adjust for covariates when modeling time to first infection, and the Poisson regression model was used to adjust for covariates when modeling infection and occlusion rates. 
500/µL (41.7% of total GP infections; 95% CI, 15.2% to 72%). In patients with ANCs < 100/µL, infections occurred in the VH and VHC population a little less frequently than in those with ANCs less than 500/µL (37.5%; 95% CI, 8.5% to 75.5%) but still more than in those with ANC 
