Diagnosis and Management of Neonatal Bacterial Sepsis: Current Challenges and Future Perspectives.

Sepsis remains the second cause of death among neonates after the pathological consequences of extreme prematurity. In this review we summarized knowledge about pathogens causing early-onset sepsis (EOS) and late-onset sepsis (LOS), the role of perinatal risk factors in determining the EOS risk, and the tools used to reduce unnecessary antibiotics. New molecular assays could improve the accuracy of standard blood cultures, providing the opportunity for a quick and sensitive tool. Different sepsis criteria and biomarkers are available to date, but further research is needed to guide the use of antibiotics according to these tools. Beyond the historical antibiotic regimens in EOS and LOS episodes, antibiotics should be based on the local flora and promptly modulated if specific pathogens are identified. The possibility of an antibiotic lock therapy for central venous catheters should be further investigated. In the near future, artificial intelligence could help us to personalize treatments and reduce the increasing trend of multidrug-resistant bacteria.

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

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.

A Local Experience of Antibiotic Lock Therapy as an Adjunctive Treatment for Central Venous Catheter-Related Bloodstream Infections in Pediatric Oncology and Hematology Patients.

BACKGROUND: One of the main drawbacks of tunneled central venous catheters (CVCs) is catheter-related bloodstream infections (CRBSIs). Antibiotic lock therapy (ALT) can be combined with systemic antibiotics to achieve catheter salvage. Our objectives are to describe cases of CRBSI and our experience with ALT in a pediatric oncology-hematology ward. METHODS: a retrospective descriptive study of pediatric CRBSI cases in a Spanish oncology-hematology unit from 2007 to 2017 was conducted. We collected demographic, clinical, and microbiological data from all patients. RESULTS: fifty-eight CRBSIs were diagnosed in thirty-nine patients; 72.9% of these patients were male, with a median age of 42.1 months. The main underlying diseases were leukemia/lymphoma (51.7%) and solid tumors (32.7%). Thirty-five (60.3%) CRBSIs were caused by Gram-positive cocci, of which 70.6% were coagulase-negative Staphylococci, and sixteen (27.6%) were caused by Gram-negative bacilli. We treated 41/58 (71%) cases with ALT. A total of 12/17 (71%) CVCs that were not treated with adjunctive ALT were removed, compared with 13/41 (32%) that were treated with ALT (relative risk (RR), 0.449; confidence interval (CI), 95%: 0.259-0.778, p = 0.004). Major reasons to remove the CVC in the CRBSI-ALT group were local insertion/pocket site infection (23%), persistent symptoms (23%), and infectious' relapses (15%). CONCLUSIONS: ALT was shown to be an effective approach to keeping the CVC in place, with no added adverse effects.

Antibiotic lock solutions as adjunct therapy for catheter-related blood stream infections in pediatric hemodialysis patients.

The predominant use of intravenous catheters as primary access type in the pediatric hemodialysis population is associated with an increased risk of catheter related blood stream infections. While strict adherence to catheter placement and long-term care guidelines have helped to decrease the incidence of these infections, blood stream infections remain an infection burden in pediatric patients with long term hemodialysis catheters. The formation of biofilms on the surfaces of these catheters has been shown to be a source of microbes causing blood stream infections. One of the strategies for preventing bacterial colonization, inhibiting microbial multiplication, and suppressing the seeding of these microbes from biofilms upon maturation, has been the use of antibiotic-based lock solutions in-between dialysis treatments. Although clinical guidelines for the use of antibiotic lock solutions are yet to be developed, available evidence suggests a beneficial role of antibiotic lock solutions in the management of catheter related blood stream infections. Additionally, a clear understanding of how biofilms are formed and their role in the pathogenesis of catheter related bloodstream infection will facilitate the development of solutions that can prevent biofilm formation and inhibit their multiplication, maturation and seeding into the bloodstream.

"Locking in" a rare pathogen.

Since its identification as a unique species in 1982, Escherichia hermannii has only recently been implicated as a pathogenic organism in human diseases. Literature search indicates removal of hemodialysis catheter as being essential to the success of treatment for bacteremia with this organism. However, having no alternative access for hemodialysis led to the attempt to salvage the catheter with the use of Antibiotic lock therapy. This case highlights Antibiotic lock therapy as an indication in Escherichia hermanii Catheter related Bloodstream infection.

Investigating the risk factors for antibiotic lock therapy failure in pediatric cancer: a single center retrospective analysis.

BACKGROUND: Catheter-related bloodstream infection (CRBSI) is one of the most common complications of central lines. Data concerning the effectiveness and safety of antibiotic lock therapy (ALT), especially in pediatric hematology and oncology patients, have not yet reached sufficient levels of evidence. We aimed to share our center`s experience on ALT in pediatric cancer and to investigate the causes of ALT failure. METHODS: All cases with CRBSI and treated with ALT administiration in children with cancer between January 2015 and May 2019 were reviewed. Patients characteristics, laboratory and clinical findings, treatments, outcome of ALT, recurrences and reinfections were recorded. Patients with successful and unsuccessful ALT outcomes were compared in order to identify the risk factors for ALT failure. RESULTS: Sixteen eligible CRBSI treated with adjunctive ALT were identified. The most common pathogens were coagulase negative staphylococci (8/16, 50%). Treatment failure was observed in 31.2% (5/16). Younger age alone was an independent risk factor for treatment failure (0.9 vs 6.8 years, p = 0.038). Recurrence and reinfection rates were 23.1% and 16.7%. Mild bleeding occured in two cases (12.5%) and occlusion causing catheter removal was seen in one (6.3%). CONCLUSIONS: ALT was found to be a safe modality with a success rate of 68.8% in children with cancer at our center and younger age was an independent risk factor for treatment failure. Future studies with larger sample sizes are needed to determine the factors affecting the ALT outcome, especially in childhood malignancies.

An analysis of totally implantable central venous port system infections in an urban tertiary referral center.

A frequent complication of central venous port systems (CVP) is infection (CVP-I), either local (CVP-LI) or a life-threatening blood stream infection (CVP-BSI). We examined the course of CVP-I including results of an antibiotic eradication attempt of CVP-BSI. We investigated adults with CVP-I from 2010 to 2018 who had to undergo port explantation or were treated by a combination of systemic antibiotics and antibiotic lock therapy (ALT). In nine years we diagnosed 206 CVP-I (CVP-LI: 52; CVP-BSI: 152). In 146 patients with CVP-I the port system was primary explanted, while 56 patients received antibiotics/ALT. 79% of Gram negative pathogens and 50% of coagulase negative staphylococci (CoNS) were eradicated. Failure of antibiotic treatment was more often associated with short time span since CVP implantation, neutropenia and polymicrobial infection. All patients with non-neoplastic disease survived, while 18/173 patients (10%) with underlying malignant disease had a fatal outcome in the same hospital stay.

Clinical profile and outcome of antibiotic lock therapy for bloodstream infections in pediatric hematology/oncology patients in a tertiary care hospital, Karachi, Pakistan.

BACKGROUND: Intravascular catheters are susceptible to infections, thus requiring catheter removal and leading to increased morbidity and costs. Antibiotic lock therapy (ALT) is a therapeutic technique that is used to salvage the catheter. The aim of this study was to evaluate the outcome of antibiotic lock therapy in bloodstream infections in pediatric hematology/oncology patients in a tertiary care hospital, Karachi. METHODS: A retrospective review was performed from January 2013 to December 2017 of pediatric hematology/oncology patients with bloodstream infections and who received ALT at Aga Khan University Hospital. All cases of polymicrobial infections, catheter removal, or malfunction before the completion of ALT were excluded. Descriptive analysis was carried out using SPSS version 20. RESULTS: A total of nine hematology/oncology patients were eligible. The catheter was salvaged in 7/9 (77.8%) children, and in 2/9 (22.2%) cases, catheter was removed because of persistent bacteremia. The most common organism isolated was Staphylococcus non-aureus species (33.3%). Relapse with a similar pathogen occurred in 2 (22.2%) patients and 2 (22.2%) of them developed an exit-site infection. CONCLUSION: In our experience, in almost two thirds of the cases, the catheter was salvaged, but disappointingly, relapses were high when the infection was due to Staphylococcus spp. Although this is a small study, our results show that ALT can be a potential safe adjunctive strategy to treat catheter-related bloodstream infections (CRBSI). However, we need larger prospective studies to test the safety and efficacy of ALT to develop specific ALT recommendations and guidelines particularly in children.

AMPs as Anti-biofilm Agents for Human Therapy and Prophylaxis.

Microbial cells show a strong natural tendency to adhere to surfaces and to colonize them by forming complex communities called biofilms. In this growth mode, biofilm-forming cells encase themselves inside a dense matrix which efficiently protects them against antimicrobial agents and effectors of the immune system. Moreover, at the physiological level, biofilms contain a very heterogeneous cell population including metabolically inactive organisms and persisters, which are highly tolerant to antibiotics. The majority of human infectious diseases are caused by biofilm-forming microorganisms which are responsible for pathologies such as cystic fibrosis, infective endocarditis, pneumonia, wound infections, dental caries, infections of indwelling devices, etc. AMPs are well suited to combat biofilms because of their potent bactericidal activity of broad spectrum (including resting cells and persisters) and their ability to first penetrate and then to disorganize these structures. In addition, AMPs frequently synergize with antimicrobial compounds and were recently reported to repress the molecular pathways leading to biofilm formation. Finally, there is a very active research to develop AMP-containing coatings that can prevent biofilm formation by killing microbial cells on contact or by locally releasing their active principle. In this chapter we will describe these strategies and discuss the perspectives of the use of AMPs as anti-biofilm agents for human therapy and prophylaxis.

Is antibiotic lock therapy effective for the implantable longterm catheter-related bloodstream infections in children?

Tural Kara T, Özdemir H, Erat T, Yahsi A, Aysev AD, Taçyildiz N, Ünal E, Ileri T, Ince E, Haskologlu S, Çiftçi E, Ince E. Is antibiotic lock therapy effective for the implantable long-term catheter-related bloodstream infections in children? Turk J Pediatr 2019; 61: 895-904. Catheter-related bloodstream infections (CRBSIs) are an important problem in pediatric patients with central venous catheters. This study aimed to determine the incidence of CRBSIs, responsible pathogens and outcomes of antibiotic lock treatment (ALT) in pediatric patients. Between January 2010 and November 2015 all hospitalized pediatric hematology, oncology and immunology patients diagnosed with CRBSIs were retrospectively analyzed. Seventy-eight CRBSI episodes were detected in 60 pediatric patients. The incidence of CRBSIs was 4.20/1000 catheter days. The most frequently detected pathogen was methicillin-resistant coagulase-negative Staphylococcus. Pseudomonas aeruginosa, Klebsiella spp., and Escherichia coli were other commonly isolated microorganisms. ALT was administered in 42 patients. The success rate of ALT was 81% (34/42). Catheter was removed without ALT in 36 episodes. Common reasons for catheter removal were sepsis and causative microorganisms which had high probability of biofilm formation. CRBSIs are an important cause of morbidity and mortality in pediatric patients. ALT is safe and effective. It is possible to obtain satisfactory results when ALT is used with intravenous systemic antibiotics for CRBSIs, though in some cases catheter removal is necessary. ALT helps to prevent unnecessary catheter removal in pediatric patients.

High-Dose Daptomycin Is Effective as an Antibiotic Lock Therapy in a Rabbit Model of Staphylococcus epidermidis Catheter-Related Infection.

Long-term catheter-related bloodstream infections (CRBSIs) involving coagulase-negative staphylococci are associated with poor patient outcomes, increased hospitalization, and high treatment costs. The use of vancomycin lock therapy has been an important step forward in treatment of these biofilms, although failures occur in 20% of patients. In this study, we report that a high dose of daptomycin lock therapy may offer a therapeutic advantage for these CRBSIs in just 24 h of treatment.

Short-course daptomycin lock and systemic therapy for catheter-related bloodstream infections: a retrospective cohort study in cancer patients with surgically implanted devices.

PURPOSE: Few in vivo studies have been reported describing efficacy and duration of antibiotic lock therapy (ALT) with daptomycin (DPT) for long-term catheter-related bloodstream infections (CRBSI) due to coagulase-negative staphylococci (CoNS). We retrospectively analysed the efficacy of short-course ALT with DPT in combination with systemic treatment (ST) for CoNS-associated CRBSI in our hospital. METHODS: Patients admitted for CoNS-associated CRBSI and treated with DPT as ALT and ST were retrospectively analysed. Success was defined as preservation of the catheter device 30 days after ending treatment. Catheter removal within 30 days of discontinuing treatment, for either microbiological documentation of CRBSI relapse or re-occurrence of unexplained fever, was considered as failure. RESULTS: Among 7610 patients admitted to the Departments of Internal Medicine/Infectious Diseases and Pneumology in Cannes from January 2013 to November 2015, we identified 28 episodes of CoNS-associated CRBSI. Seven patients died of cancer during follow-up. Thus, 21 episodes were analysed among 20 patients (median age 67 years, 12 males, all treated for neoplasia and carrying a port-a-cath® device). Staphylococcus epidermidis was the main agent responsible for CRBSI. Median duration of systemic and ALT DPT was 3 days, in combination with rifampin for 4 days and then generally followed by a switch to oral drugs, most frequently cotrimoxazole or linezolid, to achieve 14 median days of treatment. Clinical success and failure rates were 76% and 24%, respectively. CONCLUSIONS: Short-course DPT as ALT, combined with 14 days of ST, allowed conservative management of CoNS-associated CRBSI in surgically implanted-catheters in three-fourth of cases.

Daptomycin antibiotic lock therapy for hemodialysis patients with Gram-positive bloodstream infections following use of tunneled, cuffed hemodialysis catheters: retrospective single center analysis.

Catheter-related blood stream infection (CRBSI) is a major complication in hemodialysis patients. We assessed the efficacy of systemic daptomycin (DPT) plus DPT antibiotic lock therapy (DPT-ALT) for catheter salvage in patients with Gram-positive CRBSIs. This is a retrospective study of hemodialysis patients with tunneled and cuffed hemodialysis catheters. All patients were from a single institution in Taipei and received systemic DPT plus DPT-ALT for the treatment of Gram-positive CRBSI. Successful resolution of CRBSI was implemented. Resolution of fever within 48 hours, negative result of repeated blood cultures after resolution of fever, no clinical evidence of CRBSI relapse and no need for catheter removal were measured. Fifteen hemodialysis patients received DPT-ALT for CRBSI, nine with coagulase-negative Staphylococcus (CONS), two with methicillin-resistant Staphylococcus aureus (MRSA), three with methicillin-sensitive Staphylococcus aureus (MSSA) and one with polymicrobial infections. Systemic DPT plus DPT-ALT cured 11 patients (73.3%). Treatment failed in all three MRSA cases (two with MRSA and one with MRSA + Enterococcus faecalis). Retrospective design and small sample size were the limitations of this study. Systemic DPT plus DPT-ALT appears to be a promising treatment for CRBSI from CONS and MSSA, but not for MRSA CRBSI. Systemic DPT plus DPT-ALT should be considered for patients with CRBSIs caused by certain species.

Synergy of ambroxol with vancomycin in elimination of catheter-related Staphylococcus epidermidis biofilm in vitro and in vivo.

Central venous catheters are widely used in neonatal intensive care units (NICUs) nowadays. The commonest cause of catheter-related bloodstream infections (CRBSIs) is coagulase-negative staphylococci (CoNS). Ambroxol, an active metabolite of bromhexine, exhibits antimicrobial activity against strains producing biofilm and enhances the bactericidal effect of some antibiotic by breaking the structure of biofilm. In this study, we aimed to determine the effect of ambroxol with vancomycin on the biofilm of Staphylococcus epidermidis (S. epidermidis) in vitro and in vivo. In the in vitro study, the biofilm of S. epidermidis was assessed by XTT reduction assay and analysed by confocal laser scanning microscopy (CLSM). In the in vivo study, a rabbit model of CRBSIs was created by intravenous intubation with a tube covered with S. epidermidis biofilm. The rabbits received one of the following four treatments by means of antibiotic lock therapy: normal heparin, ambroxol, vancomycin, or vancomycin plus ambroxol each for 3 days. The microstructure of the biofilm was assessed by scanning electron microscopy (SEM). The number of bacterial colonies in the organs (liver, heart, and kidney) and on the intravenous tubes was measured on agar plates. Pathological changes in the organs (liver, heart, and kidney) were observed with Hematoxylin-Eosin staining. The ambroxol exhibits significant efficacy to potentiate the bactericidal effect of vancomycin on S. epidermidis biofilm both in vitro and in vivo. The antibiotic lock therapy using a combination of ambroxol and vancomycin reveals a high ability to eradicate S. epidermidis biofilms in vivo. These results provide the basis of a useful anti-infection strategy for the treatment of CRBSIs.

In vitro activity of gentamicin, vancomycin or amikacin combined with EDTA or l-arginine as lock therapy against a wide spectrum of biofilm-forming clinical strains isolated from catheter-related infections.

OBJECTIVES: Treatment of catheter-related bloodstream infections (CRBSI) is hampered by the characteristic tolerance of bacterial biofilms towards antibiotics. Our objective was to study the effect of the combination of antibiotics and the alkaline amino acid l-arginine or the cation chelator EDTA on the bacterial killing of in vitro biofilms formed by an array of clinical strains responsible for CRBSI and representative of epidemiologically relevant bacterial species. METHODS: Among 32 strains described in a previous clinical study, we focused on the most antibiotic-tolerant strains including CoNS (n = 4), Staphylococcus aureus (n = 4), Enterococcus faecalis (n = 2), Pseudomonas aeruginosa (n = 4) and Enterobacteriaceae (n = 4). We used an in vitro biofilm model (96-well plate assay) to study biofilm tolerance and tested various combinations of antibiotics and non-antibiotic adjuvants. Gentamicin, amikacin or vancomycin was combined with disodium EDTA or l-arginine for 24 h to reproduce the antibiotic lock therapy (ALT) approach. Killing of biofilm bacteria was measured by cfu quantification after a vigorous step of pipetting up and down in order to detach all biofilm bacteria from the surface of the wells. RESULTS: Both of our adjuvant strategies significantly increased the effect of antibiotics against biofilms formed by Gram-positive and Gram-negative bacterial pathogens. The combination of gentamicin + EDTA was active against all tested strains apart from one P. aeruginosa. The combination of gentamicin + l-arginine was active against most of the tested strains with the notable exception of CoNS for which no potentiation was observed. We also demonstrated that amikacin + EDTA was active against Gram-negative bacteria and that vancomycin + EDTA was active against Gram-positive bacteria. CONCLUSIONS: The addition of EDTA enhanced the activity of gentamicin, amikacin and vancomycin against biofilms formed by a wide spectrum of bacterial strains responsible for CRBSI.

ß-Lactam antibiotics and vancomycin inhibit the growth of planktonic and biofilm Candida spp.: an additional benefit of antibiotic-lock therapy?

The aim of this study was to evaluate the effects of cefepime, meropenem, piperacillin/tazobactam (TZP) and vancomycin on strains of Candida albicans and Candida tropicalis in planktonic and biofilm forms. Twenty azole-derivative-resistant strains of C. albicans (n=10) and C. tropicalis (n=10) were tested. The susceptibility of planktonic Candida spp. to the antibacterial agents was investigated by broth microdilution. The XTT reduction assay was performed to evaluate the viability of growing and mature biofilms following exposure to these drugs. Minimum inhibitory concentrations (MICs) ranged from 0.5 mg/mL to 2 mg/mL for cefepime, TZP and vancomycin and from 0.5 mg/mL to 1 mg/mL for meropenem and the drugs also caused statistically significant reductions in biofilm cellular activity both in growing and mature biofilm. Since all of the tested drugs are commonly used in patients with hospital-acquired infections and in those with catheter-related infections under antibiotic-lock therapy, it may be possible to obtain an additional benefit from antibiotic-lock therapy with these drugs, namely the control of Candida biofilm formation.

Imidazolium salts as antifungal agents: strong antibiofilm activity against multidrug-resistant Candida tropicalis isolates.

UNLABELLED: The in vitro activity of the imidazolium salt C16 MImCl against planktonic and biofilm cells of multidrug-resistant isolates of Candida tropicalis was evaluated, both in solution and applied on a commercial catheter surface. This was determined by inhibition and susceptibility assays of biofilm and planktonic cells. In both cases, C16 MImCl prevented in vitro biofilm formation of C. tropicalis strains, including multidrug-resistant ones. Outstanding performances were observed, even at extremely low concentrations. Furthermore, this is the first report of the antifungal lock property of C16 MImCl, using a tracheal catheter as the test specimen to mimic a clinical in vivo condition. As such, C16 MImCl has been identified as a promising antimicotic pharmaceutical candidate for the treatment of candidiasis infections. SIGNIFICANCE AND IMPACT OF THE STUDY: The imidazolium salt 1-n-hexadecyl-3-methylimidazolium chloride (C16 MImCl) strongly prevents, in concentrations as low as 0·028 µg ml(-1) , the biofilm formation of multidrug-resistant Candida tropicalis isolates, either in solution or applied on the surface of commercial catheters. This presents an effective antimicotic candidate and alternative for invasive clinical procedure toolset asepsis.

Catheter-related bloodstream infections.

Central-venous-catheter-related bloodstream infections (CRBSIs) are an important cause of hospital-acquired infection associated with morbidity, mortality, and cost. Consequences depend on associated organisms, underlying pre-morbid conditions, timeliness, and appropriateness of the treatment/interventions received. We have summarized risk factors, pathogenesis, etiology, diagnosis, and management of CRBSI in this review.

Successful daptomycin lock therapy for implantable intra-arterial catheter infection in a patient with liver metastases of colon cancer.

There are no data on how to manage implantable intra-arterial catheter (IAC) infections. We report the case of a patient with liver metastases of colon cancer treated by regional intra-arterial chemotherapy who presented a suspected IAC-related infection, in whom daptomycin systemic treatment and lock therapy allowed to cure the IAC infection.

Daptomycin is effective as antibiotic-lock therapy in a model of Staphylococcus aureus catheter-related infection.

BACKGROUND: The effectiveness of daptomycin versus vancomycin for treating experimental methicillin-susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) catheter-related infection by antibiotic-lock technique was assessed. METHODS: One MSSA strain and one clinical MRSA isolate were used. A preliminary in vitro study determined the minimum biofilm eradication concentration (MBEC) of vancomycin and daptomycin. An intravenous catheter was implanted in New Zealand white rabbits. Infection was induced by 24 h locking the catheter with 0.3 mL of broth culture containing MSSA or MRSA. The 24 h of antibiotic-lock treatment groups were: control, vancomycin 10 mg/mL, daptomycin 5 mg/mL and daptomycin 50 mg/mL. RESULTS: Daptomycin showed greater in vitro activity than vancomycin against biofilm bacteria (MBECs of vancomycin and daptomycin for MSSA, >2000 mg/L and 7 mg/L; MRSA, >2000 mg/L and 15 mg/L). Daptomycin 5 mg/mL achieved significant reductions relative to vancomycin 10 mg/mL in log10 cfu recovered from catheter tips for both strains (P < 0.05). Only daptomycin 50 mg/mL achieved negative catheter tip cultures (up to 75% in MSSA and 85% in MRSA, P < 0.05), showing the greatest median log10 cfu reduction compared to controls (6.07 in MSSA and 6.59 in MRSA, P < 0.05). CONCLUSIONS: Daptomycin 50 mg/mL showed the highest activity against both strains biofilms.