Supportive Care in Cancer

, 15:95

A simplified method of antibiotic lock therapy for Broviac–Hickman catheters using a CLC 2000 connector device

Authors

    • Clinic of Pediatric Hematology and Oncology, Department of PediatricsUniversity of Padova
  • Mara Cavaliere
    • Clinic of Pediatric Hematology and Oncology, Department of PediatricsUniversity of Padova
  • Monica Spiller
    • Clinic of Pediatric Hematology and Oncology, Department of PediatricsUniversity of Padova
  • Lucia Rossi
    • Institute of Microbiology and VirologyUniversity of Padua
  • Laura Magagna
    • Clinic of Pediatric Hematology and Oncology, Department of PediatricsUniversity of Padova
  • Patrizia Gavin
    • Clinic of Pediatric Hematology and Oncology, Department of PediatricsUniversity of Padova
  • Michela Bonetto
    • Clinic of Pediatric Hematology and Oncology, Department of PediatricsUniversity of Padova
  • Modesto Carli
    • Clinic of Pediatric Hematology and Oncology, Department of PediatricsUniversity of Padova
Short Communication

DOI: 10.1007/s00520-006-0099-5

Cite this article as:
Cesaro, S., Cavaliere, M., Spiller, M. et al. Support Care Cancer (2007) 15: 95. doi:10.1007/s00520-006-0099-5

Abstract

Introduction

We report a simplified method of performing antibiotic lock therapy (ALT) based on a disposable central venous catheter (CVC) hub device, CLC 2000, enabling an open-ended CVC to be flushed with normal saline solution without heparin.

Methods

ALT was administered through a CLC 2000 connector for recurrent CVC-bloodstream infections (BSI) by the same organism in four patients and for CVC colonization in five patients.

Results

The antibiotic concentration obtained in the lumen of the CVC with ALT was 2,500-fold higher than the minimum inhibiting concentration of targeted bacteria for patients treated with vancomycin, 2,500–80,000-fold higher for patients treated with teicoplanin, and 10,000-fold higher for the patient treated with amikacin. All CVC-BSIs treated with ALT resulted in complete clinical and microbiological responses. No case of malfunction in withdrawing or flushing the CVC and no precipitation during the administration of the antibiotic solution was observed. No recurrence of CVC-BSI or CVC colonization by the same organism was diagnosed during subsequent follow-up, despite the fact that all patients had further periods of severe neutropenia. At the last follow-up, three CVCs had been removed for other infections (fever of unknown origin in two; fungemia in one), four CVCs had been removed at the end of therapy, and one CVC is still in situ 20 months after ALT.

Conclusions

In conclusion, a course of ALT is feasible in cancer patients with infected but much-needed CVCs before resorting to removal. The use of the CLC 2000 connector device simplifies the procedure for preparation and administration of ALT without compromising its efficacy.

Keywords

Lock-therapyBroviac–Hickman catheterCLC 2000HeparinPediatric malignancy

Introduction

Central venous catheters (CVC) have become an essential tool in the management of many patients in current medical practice. These devices provide reliable venous access for the administration of chemotherapeutic agents, blood products, parenteral nutrition, and antibiotics; moreover, they can be used for hemodialysis and for monitoring the hemodynamic status of patients [2]. The most frequent complication due to the use of these devices is infection. It has been calculated that the rate of CVC-related bloodstream infection (CVC-BSI) is 2.3–5.5 per 1,000 catheter days and that the attributable mortality is 12–25% [5, 15]. Despite appropriate systemic antibiotic treatment, CVC-BSI often necessitates prompt removal of the CVC [10, 11].

Many patients affected by cancer, AIDS, or gastrointestinal disease have poor venous access and depend on long-term CVCs to receive daily medications, parenteral nutrition, or dialysis. In these patients with much-needed CVCs, antibiotic lock therapy (ALT) has been considered a salvage technique to eradicate infection, enabling the CVC to be retained for longer periods of time [3, 8]. ALT consists of filling the CVC lumen with an antibiotic solution and allowing it to remain in situ for a period of time to sterilize the device. The advantage of this technique is the local use of a very high concentration of antibiotic, increasing its efficacy against bacteria and avoiding the potential side effects of systemic antibiotic treatment [12]. One potential drawback of antibiotic locks is the incompatibility of some antibiotics with the heparin solution used to flush CVCs. In this case, precipitation of the heparin and antibiotic mixture may render the ALT ineffective and expose the patient to other complications such as malfunction or complete occlusion of the CVC [1, 6, 7, 13].

We report a simplified ALT that is based on a disposable CVC hub, the CLC 2000. This device enables an open-ended CVC to be flushed with normal saline solution so that ALT can be undertaken without heparin.

Patients and methods

The study was conducted from June 2003 to May 2005. The eligibility criteria were as follows: pediatric patients, aged 0–18 years, with a single or double lumen Broviac–Hickman CVC inserted to administer chemotherapy for a hematological or oncological disease who had developed recurrent CVC-BSI or CVC colonization, despite prior appropriate systemic antibiotic treatment, as defined by in vitro susceptibility tests. Moreover, a negative result of peripheral blood culture, if previously tested positive, was required before adoption of ALT.

CVC insertion and routine care

The CVC was inserted in the operating theatre using either an open or percutaneous approach according to standard procedures [4]. No systemic antibiotic prophylaxis was routinely given before insertion of the CVC or in the 24 h thereafter. Routine CVC care was handled by trained pediatric nurses and included flushing the CVC with 3 ml of heparinized solution (heparin, 200 IU/ml) at least twice a week, with weekly cleansing with a povidone–iodine solution and dressing the skin at the CVC exit site with sterile gauze. Strict aseptic techniques and scrupulous hand hygiene were always observed in handling the CVC.

Management of CVC-BSI

The definition, diagnosis and treatment of CVC-BSIs was according to published criteria [9, 11]. All febrile patients received prompt empiric treatment with the combination of teicoplanin and ceftazidime, while amikacin was added in the case of severe neutropenia (polymorphonuclear cells<0.5×109/l). Antibiotics were administered by brief intravenous infusion after dilution with 50 ml of 5% dextrose solution; continuous infusions of antibiotics were not used. When an organism was identified in the blood cultures, the antibiotic therapy was modified, as necessary, on the result of the sensitivity testing. The antibiotic therapy was continued until complete clinical and microbiological resolution of the CVC-BSI, i.e., defervescence of fever and resolution of neutropenia for at least 3 days if the patient was initially febrile or neutropenic, respectively; lack of chills or fever on routine flushing of the CVC; and at least two consecutive negative blood cultures drawn from the CVC. During antibiotic treatment, the patient was assessed daily for fever or any other symptoms; white blood count, C reactive protein, and blood culture were performed two times a week and at the end of the antibiotic therapy, respectively.

The adoption of ALT was intended as salvage of CVC in the following clinical situations: (a) recurrence of CVC-BSI by the same organism previously isolated and (b) CVC colonization, i.e., persistent positivity of blood cultures drawn from the CVC despite the administration of appropriate antibiotic treatment for at least 5–7 days, as defined by sensitivity testing. In contrast, prompt CVC removal was reserved for patients whose clinical condition deteriorated despite appropriate antibiotic therapy (high fever with chills and rigors, septic shock, seizures) or for patients at (or close to) the end of chemotherapy treatment for whom retention of the CVC was not considered a priority. To avoid any metastatic dissemination of bacteria to distant sites in neutropenic or febrile patients, ALT was used in combination with intravenous antibiotic administration until the CVC blood cultures became negative.

ALT was considered successful if (1) clinical and microbiological resolution of CVC-BSI was achieved, (2) no recurrence of infection by the same organism was diagnosed, or (3) removal of the CVC for a suspected or proven CVC-related infection was not needed within 30 days from the previous BSI.

Administration of ALT

To avoid the problem of stability described for the solution of antibiotic with low heparin concentration [7], ALT was administered using a CLC 2000 device (ICU Medical, San Clemente, CA, USA). This device has been designed to create a positive pressure when a syringe is disconnected from the line, forcing the flushing saline solution through the catheter distally and preventing the distal CVC from clot occlusion. This system allows a peripheral or central vascular line to be flushed with normal saline, avoiding the need for flushing with heparinized saline.

The antibiotic for ALT was chosen on the basis of the susceptibility of the organism isolated from the blood culture; then, it was diluted in normal saline to obtain the desired final concentration, i.e., vancomicin 5mg/ml, teicoplanin 10–40 mg/ml, amikacin 5 mg/ml, and amphotericin B 2.5 mg/ml [3, 12]. After flushing the CVC with normal saline, 2 ml of the antibiotic solution was locked into the CVC and left in situ for at least 12–24 h.

Results

During the study period, 55 episodes of febrile bacteremia were diagnosed in 41 patients, median age 7.4 years, range of 0.4–21 years; 23 were affected by acute leukemia, 8 were affected by non-Hodgkin lymphoma, 8 were affected by solid tumors, and 2 were affected by other hematological nonmalignant diseases. Nine patients, four girls and five boys, with a median age of 7 years (range 2–18), met the criteria for ALT. Seven patients had a double and two had a single lumen indwelling Broviac–Hickman CVC. Five patients were severely neutropenic at the time of ALT. The reason for the adoption of ALT was recurrent BSI in four patients (by Staphylococcus epidermidis in one patient, Pseudomonas aeruginosa in one patient, Corynebacterium sp. in one patient, and Trichosporum mucoides in one patient) and CVC colonization by S. epidermidis in five patients. The four patients classified as recurrent BSI had had previous BSIs by the same strain of the organism diagnosed 56 and 34 (this patient had had two previous BSIs with the same strain), 25, 11, and 8 days before the start of ALT. The intervals from the first positive blood culture and the start of ALT in each patient with CVC colonization were 34, 29, 13, and 8 days. Table 1 shows the main clinical characteristics of CVC-BSI treated with ALT.
Table 1

The main clinical characteristics of CVC-BSI treated with ALT are shown

Patient’ initials

Age/sex and diagnosis

Fever

Neutropenia

Reason for ALT

Organism

Antibiotic used and duration, (MIC)

30-day outcome

Reason for CVC removal (daysa)

G.M.

18/M ALL

Yes

Yes

Recurrent BSI

Staphylococcus epidermidis

Vancomycin, 5 mg/ml for 7 days (2 μg/ml)

Success

EOT (304)

M.F.

18/M ALL

No

Yes

CVC colonization

Staphylococcus epidermidis

Vancomycin, 5 mg/ml for 14 days (2 μg/ml)

Success

FUO (91)

C.G.

13/F ALL

No

No

CVC colonization

Staphylococcus epidermidis

Vancomycin, 5 mg/ml for 14 days (2 μg/ml)

Success

FUO (145)

C.M.

12/F ALL

Yes

Yes

Recurrent BSI

Pseudomonas aeruginosa

Amikacin 5 mg/ml for 11 days (≤0.5 μg/ml)

Success

EOT (365)

M.G.

2/F ALL

Yes

Yes

Recurrent BSI

Staphylococcus epidermidis

Teicoplanin, 40 mg/ml for 12 days (4 μg/ml)

Success

In situ (552)

C.N.

3/M BT

Yes

No

Recurrent BSI

Corynebacterium spp.

Teicoplanin, 40 mg/ml for 12 days (≤0.5 μg/ml)

Success

EOT (373)

P.J.

5/F NB

No

No

CVC colonization

Trichosporum mucoides

Amphotericin B, 2.5 mg/ml for 5 days (N.A.)

Success

Death (360)

T.C.

7/M ALL

No

No

CVC colonization

Staphylococcus epidermidis

Teicoplanin, 10 mg/ml for 7 days (2 μg/ml)

Success

EOT (341)

B.L.

4/M NB

No

No

CVC colonization

Staphylococcus epidermidis

Teicoplanin, 10 mg/ml for 7 days (4 μg/ml)

Success

Sepsis by Trichoderma sp. (71)

ALT antibiotic lock therapy, M male, F female, ALL acute lymphoblastic leukemia, BT brain tumors, NB neuroblastoma, MIC minimum inhibiting concentration, NA not available, EOT end of therapy

aDays from ALT

Among the six strains of S. epidermidis, four were methicillin-susceptible while two were methicillin-resistant. The minimum inhibiting concentration (MIC) for vancomycin and teicoplanin ranged from ≤1–2 μg/ml (median of 2) and from 4–8 μg/ml (median of 4), respectively. The strains of P. aeruginosa and Corynebacterium sp. showed a very susceptible profile to all tested antibiotics, and, in particular, their MICs for amikacin and teicoplanin, used in the ALT, were ≤0.5 and ≤2 μg/ml, respectively.

The antibiotic concentration obtained in the lumen of the CVC during ALT was 2,500-fold higher than the MIC in patients treated with vancomycin, 2,500–80,000-fold higher than the MIC in patients treated with teicoplanin, and 10,000-fold higher in the patient treated with amikacin (Table 1). All CVC-BSIs treated with ALT resulted in complete clinical and microbiological response, and all CVCs were still in situ 30 days after treatment. No case of malfunction in withdrawing or flushing the CVC and no precipitation during administration of the antibiotic solution was observed. After successful treatment with ALT, all nine patients continued with intensive or maintenance chemotherapy, and, in addition, two of them went on to allogeneic bone marrow transplantation. No recurrence of CVC-BSI or CVC colonization by the same strain of the organism was diagnosed in the subsequent follow-up, despite the fact that all patients had further periods of severe neutropenia.

As of January 31 2006, all but one CVC had been removed for one of the following reasons: fever of unknown origin in two patients after 91 and 145 days from ALT; CVC infection in one patient by the fungus Trichoderma longibrachiatum at 71 days from ALT; end of chemotherapy in four patients at 304, 341, 365, and 373 days from ALT; and death from progressive disease in one patient at 360 days from ALT. One CVC is still in situ for chemotherapy in a patient with acute lymphoblastic leukemia at 552 days from ALT.

Discussion

Most CVC-BSIs are caused by Gram-positive organisms, particularly coagulase-negative staphylococci and Staphylococcus aureus. Infection by Gram-negative bacilli and Candida species is also not infrequent [2, 8]. The organisms gain access to an intravascular catheter by four distinct pathways: the skin around the CVC insertion site, the catheter hub, microbial contamination of the infusate, and hematogenous seeding from other organs [2, 5]. The management of these infections is based on the administration of appropriate antibiotics and/or the removal of the CVC. The choice to remove the CVC depends on several factors, such as the needs of the patient, the type of pathogen, and the type of catheter. CVC removal is advisable in any patient with severe sepsis or septic shock or in patients with CVC-BSI due to Pseudomonas spp., Candida spp., Mycobacterium spp., and Corynebacterium j-k. Moreover, the removal of the line remains the mainstay of therapy in patients with peripherally inserted central lines [3, 8].

ALT is a promising method of treating CVC-BSI, although the experience is limited in pediatric onco-hematological patients. In a recent review of the literature, only 2 of 21 studies of ALT for CVC-BSI included pediatric patients, the total number of patients being 19/383 (5%) [12]. Several advantages can be anticipated from the use of antibiotic locks, including reduced hospitalization, the avoidance of side effects due to prolonged parenteral antibiotic therapy, and the potential for increased efficacy due to the high antibiotic concentration achievable in the lumen of CVC. One matter for discussion is the compatibility of heparin solution with antibiotics. Droste et al. found that a low concentration of heparin (<1,000 U/ml) is associated with antibiotic precipitation while a high concentration of heparin (≥3,500–10,000 U/ml) is compatible with a wider range of antibiotic concentrations. Moreover, the higher the concentration of antibiotics, the higher the concentration of heparin required to prevent precipitation [7]. Despite this, the use of high-dose heparin in cancer patients is usually avoided because of the risk of systemic heparinization, especially in children with low body weight.

To overcome the potential risks of precipitation and reduction in activity of the antibiotic–heparin solution, we have adopted the CLC 2000 device to perform ALT. This device has been designed to flush peripheral or central open-ended vascular lines with normal saline, without heparin, while maintaining a positive pressure to prevent the distal CVC from clot occlusion. Other advantages of the device are the potential for the reduced risk of needle-stick injuries by health care personnel in preparing the antibiotic heparin solution and, in general, the elimination of the risk of heparin-induced thrombocytopenia [14].

In our selected group of pediatric patients, ALT with a CLC 2000 device resulted in the eradication of all CVC-BSIs, and the patients still had their CVC in situ at 30 days from ALT. Interestingly, in one patient ALT was efficacious against CVC colonization by the fungus T. mucoides. This has been not been reported before, with only three successful cases and at least 20 failures for ALT against fungi having been reported to date [12]. All patients continued their planned chemotherapy and none of them has had a relapse of BSI-CVC by the same strain. In particular, six patients did not experience any further documented or suspected CVC-BSI, while in three patients the CVC was subsequently removed for fever of unknown origin (two patients) and for CVC-BSI by fungus (one patient). These data confirm that ALT is useful in helping to eradicate CVC-BSI in patients with much needed CVCs and in most cases results in a clear prolongation of the life of the CVC. Moreover, the use of the CLC 2000 device simplifies the preparation and administration of ALT without compromising its efficacy.

In conclusion, a course of ALT is feasible for CVC-BSI in cancer patients with infected but much-needed CVCs before resorting to removal of the line. The advantages of utilizing a CLC 2000 device deserve further assessment by a prospective controlled study.

Copyright information

© Springer-Verlag 2006