Antibiotic Lock Therapy for Port Catheter-Related Infections of Children with Acute Leukemia

Fatma Burçin Kurtipek1, Ayça Koca Yozgat1, Saliha Kanık Yüksek2, Dilek Kaçar1, Turan Bayhan1, Dilek Gürlek Gökçebay1, Aslınur Özkaya Parlakay2 and Neşe Yaralı1.

1 Ankara Bilkent City Hospital, Division of Paediatric Hematology and Oncology, Ankara, Turkey.
2 Ankara Bilkent City Hospital, Division of Paediatric Infectious Diseases, Ankara, Turkey.

Correspondence to: Fatma Burçin Kurtipek, Ankara Bilkent City Hospital, Division of Paediatric Hematology and Oncology. E-mail: burcindogan86@gmail.com

Published: September 01, 2024
Received: June 24, 2024
Accepted: August 17, 2024
Mediterr J Hematol Infect Dis 2024, 16(1): e2024072 DOI 10.4084/MJHID.2024.072

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction: Port catheters facilitate the administration of chemotherapy, antibiotics, blood products, fluid, and parenteral nutrition to pediatric patients with hematological malignancies. However, as its use has become widespread, local and systemic, catheter-related infections have emerged as important causes of morbidity and mortality. In our study, we aimed to evaluate the success of antibiotic lock therapy in port catheter-related infections of pediatric patients followed up with acute leukemia.
Methods: Port catheter cultures taken from a total of 182 pediatric patients with acute lymphoblastic/myeloblastic leukemia who were followed up at Ankara City Hospital Pediatric Hematology Clinic between August 2019 and August 2023 were evaluated retrospectively.
Results: Bacterial growth was identified in 739 port catheter culture specimens of 182 patients. Closure or removal of the port was required in 91, and removal of the port catheters in 49 patients due to port catheter-related infections. Antibiotic lock therapy was started in 56 patients with bacterial growth in the port catheter. With antibiotic lock therapy, port catheter-related infections of 42 patients were eradicated, and their catheters began to be used again. As a result, the port catheter-related infections of 42 of 56 (75%) patients whose ports were closed and also received systemic antibiotic therapy were eradicated, and no infection recurrence was observed.
Conclusion: Adding antibiotic lock therapy to systemic antibiotics in pediatric patients may be beneficial in terms of catheter salvage.

Introduction

Intravascular catheter-related bloodstream infections (CRBSI) are significant complications for leukemia patients with increased risk of morbidity and mortality, longer hospital stays, and higher costs.[1,2] Coagulase-negative Staphylococci (CoNS), Staphylococcus aureus, Enterococcus spp., and Klebsiella spp. are the most common pathogens responsible for CRBSI in children.[3] Microorganisms may be transmitted through the infected closure sites during catheter insertion or via hematological routes.[4] The risk of CRBSI is high in children receiving intensive chemotherapy and those carrying external or double-lumen catheters.[5] Although catheter removal is preferred to prevent the development of CRBSI, catheter salvage may be attempted in patients whose alternative venous access is challenging to construct and who continue to need a catheter for infusions.
Antibiotic lock therapy (ALT) is a treatment method in which high concentrations of antibiotics are delivered through the lumen of the catheter.[2] Microorganisms can migrate into the intraluminal space, forming a pathogenic biofilm resulting in the onset of CRBSI. In ALT, the catheter lumen is filled with a high concentration of antibiotics to maximize bactericidal activity and penetrate the pathogenic biofilm. The antibiotic concentration required to destroy causative microorganisms in the catheter lumen should be 100-1000 times the minimum inhibitor concentration.[6] Re-catheterization complications and costs can be prevented with the use of ALT. However, the catheter should be removed if the systemic intravenous antibiotics and ALT are unable to destroy the microorganisms.[1,7]
Data concerning the efficacy and safety of ALT in children are limited. In this study, we aim to determine its effectiveness in children with leukemia and identify factors affecting treatment outcomes.

Methods

This retrospective study assessed 182 children with acute leukemia treated in the Ankara Bilkent City Hospital Pediatric Hematology Clinic between August 2019 and August 2023. The patient demographic and clinical characteristics, isolated microorganisms, and antibiotics used in lock therapies were examined. Duration, success or failure of ALT, catheter-related reinfections, catheter removal, and mortality data were collected from patients' electronic medical files.
In cases of febrile neutropenia (FN) (body temperature >37.5 ºC persisting for at least 2 hours or >38 ºC once), a blood sample was drawn from the peripheral vein and port catheter lumen for culture and empirical antimicrobial treatment was started. Systemic empiric antibiotic therapy was administered according to the Infectious Diseases Society of America (IDSA) guidelines that recommend the use of antipseudomonal broad-spectrum beta-lactamase antibiotics like piperacillin-tazobactam or cefepime.[8] After the causative microorganism was identified, the treatment might be modified if necessary. Glycopeptides were added to the treatment protocol in patients with severe mucositis, pneumonia, soft tissue infections, and methicillin-resistant S. aureus colonization.
Diagnosis of CRBSI was based on the updated 2009 version of IDSA Clinical and Practice guidelines for the diagnosis and management of intravascular catheter-related infections.[8] Accordingly, in cases where the same microorganism was detected in both the cultures of blood samples drawn from the catheter tip and peripheral blood if the microorganism was identified at least two hours earlier in the cultures of the blood samples drawn from the catheter, then the presence of CRBSI was considered. If nonpathogenic microorganisms of normal skin flora (CoNS, S. viridans, Propionibacterium spp., Bacillus spp.) were isolated from at least two blood cultures, it was accepted as CRBSI. The clinical signs of infection were noted simultaneously at the time when the blood culture samples were obtained.
Catheter removal was performed in catheter-related infections associated with S. aureus, Pseudomonas spp., fungi, and mycobacteria, all tunnel infections, complicated catheter-related infections, and severely septic patients. If the patient was clinically stable and the catheter removal was not required, ALT combined with systemic intravenous antibiotic therapy was used. In ALT, heparin (100 U/mL) with saline and vancomycin (5 mg/mL), gentamicin (1 mg/mL), amikacin (2 mg/mL), colistin (0.1 mg/mL) or trimethoprim-sulfamethoxazole (10 mg/mL) were used according to identified microorganisms.[8,9] The locking solution was introduced into the catheter lumen (usually 3 mL), and then the catheter was locked. This solution was renewed every 24 hours. Duration of ALT varied depending on the causative microorganisms as follows: Enterococcus spp.: 7-14 days; CoNS: 10s-14 days; gram-negative bacilli: 10-14 days.[8] Control catheter and peripheral blood cultures were taken after 72 hours of ALT.
Treatment failure was defined as persistent bacterial growth of the same microorganism in blood cultures obtained within 72 hours of ALT. If the same pathogen was isolated from the blood culture within three months, it was accepted as a relapse.[9] The catheter was removed if the fever persisted or a sterile blood culture could not be obtained. All patients were followed for at least six months after CRBSI was diagnosed.
This study was approved by the University of Health Sciences Ankara City Hospital Ethics Committee (ethics approval number: E2-23 -3816) and performed according to the World Medical Association Declaration of Helsinki Ethical Principles for Medical Research involving Human Subjects and its latest amendments.
Statistical analysis. Statistical analyses were performed using SPSS for Windows 16. Categorical variables were expressed as numbers and percentages, and numerical variables were defined using mean ± standard deviation, minimum–maximum, and median values. Survival curves were estimated according to the Kaplan-Meier method. Adjusted hazard ratio and 95% confidence interval were used to estimate survival. The level of statistical significance was set at p <0.05.

Results

The febrile neutropenia (FN) episodes of 182 children with acute leukemia were examined. Bacterial growth was detected in port catheter cultures in 91 FN episodes of 79 patients, including cases with acute myeloid leukemia (AML) (n:14) and acute lymphoblastic leukemia (ALL) (n:65). Demographic and clinical characteristics of patients are summarized in Table 1. CRBSI was detected in 34 female and 45 male patients. The mean age of the patients with CRBSI was 6.8 years (min-max: 1- 17 years).
Table 1
Table 1.  Demographic and Clinical Characteristics of Patients with CRBSI.
Patient management was individualized depending on the causative microorganism, the patient's clinical condition, and the catheter type. Ninety-two catheters of 35 patients (44.3%) were removed as soon as possible without using ALT due to the patient's unstable condition (hypotension, resistant fever, detection of fungal microorganisms) or the development of complicated catheter infections such as tunnel infection. The treatment algorithm for patients with catheter-related infections is summarized in Figure 1.
Figure 1
Figure 1.  Algorithm of patients with catheter infection.
Microorganisms growing on the catheters are listed in Table 2. The most frequently isolated pathogens were Staphylococci (46%), E. coli (19.6 %), and Klebsiella spp. (14.2 %). ALT was started against 56 catheter-related infections. Microorganisms growing in the catheter cultures are listed in Table 2. Upon identification of gram-positive bacteria in 28 and gram-negative bacteria in 28 catheters, vancomycin (n:28), amikacin (n:21), gentamicin (n:5), colistin (n:1), TMP-SMX (n:1) were used in the respective patients for the treatment of ALT. All patients also received appropriate systemic intravenous antibiotics together with ALT.
Table 2
Table 2.  The outcome of ALT therapy for CRBSI and related microorganisms.
Fourteen catheters (25%) were removed due to persistent bacterial growth after the 72nd hour of ALT or clinical deterioration of the patients while receiving ALT. A number of patients, indicated in bracket, infected with K. pneumonia (n:5), Staphylococcus spp (n:3), and P. aeruginosa (n:2), Achromobacter spp. (n:1), E. coli (n:1) required intensive care treatment due to hemodynamic instability. Seven of these patients died due to sepsis. Antibiotic lock treatment was applied to one patient in whom pseudomonas growth was detected in the catheter, and the port catheter was removed directly because the other patient had clinical instability. Port catheter blood culture became negative in 42 (75%) patients treated with ALT, and these catheters were reused. Recurrent infection with S. epidermidis was observed in one (1.7 %) patient. As a result, the therapeutic success rate of ALT was 75 percent. The outcomes of CRBSI and identified microorganisms are shown in Table 2. ALT was successful in the treatment of CoNS infections but failed in the treatment of infections caused by Acinetobacter spp.

Discussion 

Antibiotic lock therapy has been described in the prevention of CRBSI, and treatment guidelines to sterilize the catheter lumen so as to prevent its removal have been stated.[10] However, a limited number of studies have investigated the efficacy and safety of ALT' in children with leukemia.[11] In most guidelines, eradication of CRBSI that persists despite 72 hours of appropriate antimicrobial therapy, infections with S. aureus, P. aeruginosa, fungi, or mycobacteria, and tunnel infections, port abscesses has been recommended. Salvage of the catheter is essential in many children who need continuous intravenous chemotherapies, antibiotics, and fluids and for whom it is difficult to create a new peripheral venous access. However, guidelines specify that for children affected with CRBSI under “unusual extenuating circumstances," the attempt to salvage the CVC is allowed. Therefore, the decision to salvage the catheter must be assessed on a case-by-case basis.[8] There are also reports of successful antibiotic lock therapy in cases of CRBSI caused by the pathogens mentioned above.[1,13] In our study, we also obtained successful results with antibiotic lock therapy in infections caused by S. aureus, Pseudomonas aeruginosa, and Acinetobacter baumanii.
In our study, CoNS, E. coli, and Klebsiella spp. were the most frequently isolated pathogens. Gram-positive and gram-negative microorganisms were identified in equal percentages (50%) of patients receiving ALT. S. epidermidis and other CoNSs were reported as the most common causative microorganisms in CRBSI due to skin contamination during catheter manipulations.[1,2,9,14]
In a meta-analysis involving adult and pediatric patients with CRBSI, coadministration of systemic antibiotic therapy and ALT achieved better outcomes than single systemic antibiotic therapy.[15] Catheter removal rate was higher (33%) in patients receiving the sole systemic antibiotic therapy than in those treated with sole ALT  (10%) and the recurrence rates in patients in the ALT group were significantly lower than those in the non-ALT group (30% vs  20%).[15] In a pediatric study, Kara et al. reported CoNS as the most common organism, and the therapeutic success rate of the ALT was 81 percent.[16]  In  Lafaurie et al. prospective adult study, continuous vancomycin lock therapy was administered for 88 patients and intermittent vancomycin lock therapy for 9 patients due to coagulase-negative staphylococci infection. This therapy was successful in 44 patients. They recommended that continuous lock therapy should be preferred to intermittent therapy because of recurring infection risk.[17] In the Okur et al. study, teicoplanin lock therapy was administered for port-related Coagulase-negative Staphylococci in pediatric oncology patients, and the overall port survival rate was found to be 72.7%. The author suggested that this therapy is effective and safe for catheter-related infections caused by methicillin-resistant coagulase-negative staphylococcus.[18]
In our study, 42 of 56 catheters of patients who received ALT were reused, and our ALT success rate was 75 percent. ALT might be given without systemic antibiotics for patients with multiple positive catheter blood cultures demonstrating the growth of CoNS and concurrent negative peripheral blood cultures.[19] ALT was used with systemic antibiotics in our patients with CoNS infection. The therapeutic success rate of ALT was 70% for CoNS infection; however, for gram-negative infections, the ALT was successful in 57 of the cases. In a retrospective pediatric study, 37 febrile attacks in 28 patients were examined. Gram-negative bacilli were determined to be the most common causative agent, and the therapeutic success rate of ALT was 67.6 percent.[20] In that study conducted by Signorino et al., the most common causative gram-negative agent was K. pneumoniae (n:6), and 3 catheters infected with this agent were saved. In our study, the most frequently detected gram-negative pathogen was E. coli (n:11), and we successfully eradicated E. coli from 7 contaminated catheters with ALT. 
In our study, the catheter removal rate was 53 percent. In a pediatric study,  Adler et al. reported that catheters were removed in  46% of their patients during 207 CRBSI episodes.[3] Another study reported that removal of the catheters was necessitated in  56.4% of CRBSI episodes.[12] The mortality rate has been reported to range from 1.9% to 11% in children with CRBSI.[2,21,22] In our study, the mortality rate was 7.6 percent.
Our study's limitations were its retrospective nature and small sample size. However, the most powerful aspect of this study is that we included only pediatric patients with hematological malignancies to ensure the homogeneity of the patient population.

Conclusions

CRBSI is a significant cause of morbidity and mortality in pediatric patients with acute leukemia. ALT is a safe strategy and helps prevent unnecessary catheter removals when administered with systemic therapy in pediatric patients with acute leukemia. Multi-center randomized controlled trials are required to support the available data.

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