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Persistent Catheter-Related Bacteremia: Clearance With Antibiotics and UrokinaseDavid P. Ascher, Braden A. Shoupe, David Maybee, and Gerald W. Fischer
A patient with terminal osteogenic sarcoma and catheter-related coagulase-negative staphylococcal bacteremia was treated with vancomycin and blood cultures were positive for 4 days documented with quantitative colony counts. Urokinase therapy was initiated and was associated with a transient bacteremia with markedly increased colony counts of coagulase-negative Staphylococcus prior to eradication of the catheter-related infection. We feel that the combination of urokinase and appropriate antibiotics may be an effective method to eradicate line-associated coagulase-negative staphylococcal infection in selected patients. This is a US government work. There are no restrictions on its use. INDEX WORDS: Central venous catheter-related bacteremia; urokinase. Central venous catheters (CVCs) are commonly used for prolonged venous access in many disease processes. Catheter-related bacteremia is a frequent complication of central venous catheters. If catheter-related bacteremia is persistent on appropriate antibiotics, current recommendations are to remove the line.1 We report a terminal cancer patient with persistent coagulase-negative staphylococcal catheter-related bacteremia that cleared after urokinase therapy was initiated.
Case ReportAn 18-year old black female was diagnosed in April 1987 with a left tibial osteosarcoma and underwent a limb-sparing procedure 1 month later. Her chemotherapy consisted of Cisplatin, Adriamycin, Bleomycin, Cytoxan, Methotrexate, and Actinomycin-D. She experienced significant morbidity with this therapy including restrictive pulmonary disease and a cardiomyopathy. In February 1989 she relapsed with a local recurrence of her osteosarcoma and developed unresectable pulmonary metastases. A subcutaneous infusion port was placed and chemotherapy consisting of Ifosfamide and VP-16 was initiated.She did well until August 1989, when she developed fever to 40.0°C. She denied any localizing symptoms, chills, rigors, or pleuritic chest pain. Her respirations were 25 breaths/min, pulse 132 beats/min, and blood pressure 107/65 mm Hg. Her physical examination was unremarkable with no tenderness, induration, or erythema over the port or catheter tract. Laboratory findings included a white blood cell count of 7.0 x 103/mL with 59% segmented neutrophils, 21% bands, 10% lymphocytes, 9% monocytes, and 1% eosinophiles. The urinalysis was normal. The chest roentgenogram showed widely metastatic disease but no acute infiltrates or effusions. Her CVC functioned well without evidence of occlusion. Peripheral and central nonradiometric BACTEC cultures (Becton-Dickinson, Cockeysville, MD) were obtained and vancomycin (40 mg/kg/d) and ceftazadime (150 mg/kg/d) were begun. Initial central blood cultures were positive for coagulase-negative Staphylococcus. Serial quantitative blood cultures (Isolator; Dupont, Wilmington, DE) from her central line were positive on the next 4 days while all peripheral cultures were negative (Table 1). Within 6 hours of antibiotic initiation, she defervesced and remained afebrile for the duration of the hospitalization. With the persistence of positive central blood cultures for coagulase-negative Staphylococcus, line removal was contemplated. Due to her ultimate prognosis, her anesthetic risk, and her need for continued central access, it was elected to attempt clearing the line through the use of urokinase and antibiotics. On the fourth hospital day, a volume of 2 mL of urokinase (2,500 units/mL) was administered and left in place for 3 hours. A follow-up quantitative blood culture through the central line yielded too numerous to count colonies of coagulase-negative Staphylococcus. The patient continued to be afebrile and had no clinical signs of bacteremia. The urokinase therapy was repeated daily for the next 4 days. All subsequent cultures were negative except for one central Isolator on the seventh hospital day that yielded 3 colonies of coagulase-negative Staphylococcus. She was discharged on the 11th hospital day to continue on home vancomycin therapy for a total 21-day course. She had no further difficulty with her line until 5 months later when she presented with fever. At that time she had a single central blood culture for coagulase-negative Staphylococcus. Her tumor continued to progress and she died in April 1990.
Abbreviations: P, peripheral; C, central; B, BACTEC; I, Isolator; CNS, coagulase-negative Staphylococcus; NEG, negative.
DiscussionThe use of central venous lines has become standard in the care of children with illnesses that require prolonged venous access including malignancies, HIV infection, and gastrointestinal diseases requiring hyperalimentation, and in premature infants. These catheters are associated with many complications including catheter-related infection and thrombotic occlusion. Catheter-related infections may be treated by line removal without antibiotic therapy, antibiotic administration through the involved catheter, or by line removal and systemic antibiotic administration. Catheter removal is generally indicated if the catheter is no longer required, the patient is septic with clinical instability with evidence of deterioration, or if there is persistent catheter-related bacteremia that is unable to be sterilized after 3 days of appropriate antibiotic administration.1 The present patient was clinically stable, but had 4 days of persistent low-level coagulase-negative staphylococcal catheter-related bacteremia which did not clear on therapeutic doses of vancomycin. She had a continued requirement for a CVC, and was not a surgical candidate for either line removal or reinstallation because of anesthetic risk. Thus, it was decided to use urokinase to remove the fibrin matrix in an attempt to sterilize her CVC with the antibiotic therapy.This method has previously been described in catheter-associated sepsis and in individuals who had occluded lines with no alternative site for access.2,3 Glynn et al describe seven patients who cleared a catheter-related bacteremia after serial urokinase treatments. Four of these seven were treated with antibiotics.2 Haffar et al were able to clear catheter-related bacteremia in only one of seven patients who received urokinase treatment.3 Problems with their retrospective study include: patients with questionable catheter-related bacteremia by present standards; the patients' catheters had no serial urokinase instillation; and antibiotics were only exclusively administered through the involved catheters in two patients, one of whom was cured. Antibiotic administration through an infected catheter is important in eradicating catheter-related bacteremia.1 The conclusion by Haffar et al that urokinase instillation is not an effective means by which to achieve catheter salvage in high-risk pediatric patients with catheter-related infections is weakened by the noted deficiencies in their methods. Urokinase has been widely used in the treatment of occluded CVCs.4 It activates plasminogen, which is converted to the proteolytic enzyme plasmin, which has the ability to dissolve fibrin clots. Urokinase is less antigenic than streptokinase, another thrombolytic enzyme. Coagulase-negative staphylococci are among the most frequently isolated organisms associated with CVC sepsis.1 Several studies have shown the preferential and progressive adherence of these staphylococci to catheter surfaces.5-7 These organisms also have been shown to cause surface erosion of the catheter, and may produce large quantities of a slimelike material.8,9 This slimelike material is glycocalyx fibrin matrix that further enhances adhesion of the organisms and may protect the organisms from host defenses and antibiotics. The theoretical basis for the use of urokinase in the present patient was: (1) to cause intense local fibrinolysis, mediated by the activation of plasminogen by urokinase; and (2) to lyse and expose any bacterial nesting within the glycocalyx or fibrin sheath to the reticuloendothelial system and systemic antibiotics. After urokinase instillation, a blood culture through the line had too numerous to count colony forming units of coagulase-negative staphylococci suggesting a release of bacteria trapped in the fibrin matrix. All but one of the serial daily blood cultures through the line thereafter remained sterile. This one central blood culture may have represented a small remaining nidus of CNS or it may have been a contaminant. She was followed for 5 months without any further episodes of coagulase-negative staphylococcal catheter-related infection. We report a case of persistent catheter-related bacteremia successfully cleared by urokinase therapy in combination with antibiotics. The quantitative cultures give supportive evidence for microorganisms nesting in a glycocalyx matrix protected from antibiotics and host defenses. We feel that the combination of urokinase and antibiotics may be an effective method to eradicate line-associated coagulase-negative staphylococci in selected patients with persistent line associated bacteremia, and may be an acceptable alternative to the removal of the long-term CVC.
References
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