Antibiotic Lock Research Articles

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.

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. 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. 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. 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.

Does antibiotic lock therapy prevent catheter-associated bacteremia in hemodialysis?

Central venous catheter-related blood stream infection is a major cause of morbidity and mortality in patients with renal disease treated with hemodialysis. Antibiotic lock solutions can be effective in preventing this complication in patients with hemodialysis. Searching in Epistemonikos database, which is maintained by screening more than twenty databases, we identified eight systematic reviews including seventeen randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded that antibiotic lock solutions probably decrease catheter-related blood stream infection in hemodialysis patients.

Antibiotic lock therapy for the treatment of catheter colonization in pediatric cancer patients

Antibiotic lock therapy for the treatment of catheter colonization in pediatric cancer patients

Nosocomial infections in dialysis access.

Nosocomial infections in patients requiring renal replacement therapy have a high impact on morbidity and mortality. The most dangerous complication is bloodstream infection (BSI) associated with the vascular access, with a low BSI risk in arteriovenous fistulas or grafts and a comparatively high risk in central venous catheters. The single most important measure for preventing BSI is therefore the reduction of catheter use by means of early fistula formation. As this is not always feasible, prevention should focus on educational efforts, hand hygiene, surveillance of dialysis-associated events, and specific measures at and after the insertion of catheters. Core measures at the time of insertion include choosing the optimal site of insertion, the use of maximum sterile barrier precautions, adequate skin antisepsis, and the choice of catheter type; after insertion, access care needs to ensure hub disinfection and regular dressing changes. The application of antimicrobial locks is reserved for special situations. Evidence suggests that bundling a selection of the aforementioned measures can significantly reduce infection rates. The diagnosis of central line-associated BSI (CLABSI) is based on clinical signs and microbiological findings in blood cultures ideally drawn both peripherally and from the catheter. The prompt installation of empiric antibiotic treatment covering the most commonly encountered organisms is key regarding CLABSI treatment. Catheter removal is recommended in complicated cases or if cultures yield Staphylococcus aureus, enterococci, Pseudomonas or fungi. In other cases, guide wire exchange or catheter salvage strategies with antibiotic lock solutions may be acceptable alternatives.

Antibiotic lock therapy: review of technique and logistical challenges.

Antibiotic lock therapy (ALT) for the prevention and treatment of catheter-related bloodstream infections is a simple strategy in theory, yet its real-world application may be delayed or avoided due to technical questions and/or logistical challenges. This review focuses on these latter aspects of ALT, including preparation information for a variety of antibiotic lock solutions (ie, aminoglycosides, beta-lactams, fluoroquinolones, folate antagonists, glycopeptides, glycylcyclines, lipopeptides, oxazolidinones, polymyxins, and tetracyclines) and common clinical issues surrounding ALT administration. Detailed data regarding concentrations, additives, stability/compatibility, and dwell times are summarized. Logistical challenges such as lock preparation procedures, use of additives (eg, heparin, citrate, or ethylenediaminetetraacetic acid), timing of initiation and therapy duration, optimal dwell time and catheter accessibility, and risks of ALT are also described. Development of local protocols is recommended in order to avoid these potential barriers and encourage utilization of ALT where appropriate.

Usefulness of endoluminal catheter colonization surveillance cultures to reduce catheter-related bloodstream infections in hemodialysis

To evaluate the use of surveillance cultures (SCs) to prevent catheter-related bloodstream infections (CRBSIs) in asymptomatic hemodialysis (HD) patients. In 2011-2012, we conducted a prospective study of HD patients with tunneled cuffed central venous catheters (TCCs). Colonization of the catheter lumen was assessed every 15 days by inoculating ~5 mL endoluminal blood into aerobic culture bottles. Individual patients were triaged based on SC results: group 1 (negative); group 2 (coagulase-negative Staphylococcus [CoNS] with time-to-positivity (TTP) >14 hours); group 3 (CoNS with TTP ≤14 hours); and group 4 (any microorganism other than CoNS and any TTP). We studied 104 patients (129 TCCs). Median follow-up was 262.5 days (interquartile range [IR], 135.0-365.0). A total of 1,734 SCs were collected (median, 18 per patient; IR, 10.0-24.0), of which 1,634 (94.2%) were negative (group 1) and 100 (5.8%) were positive (group 2: 79; group 3: 12, group 4: 9). In groups 2 and 3, 19 TCCs required antibiotic lock therapy (ALT). In group 4, all patients received intravenous therapy and ALT. Under this protocol, there were 0.27 episodes of CRBSI per 1,000 catheter days compared with 1.65 (P < .001) prior to its implementation. SCs based on easily accessible samples proved useful in triaging HD patients at a high risk of infection.

Central Venous Catheter Salvage in Home Parenteral Nutrition Catheter-Related Bloodstream Infections: Long-Term Safety and Efficacy Data.

Catheter-related bloodstream infections (CRBSIs) are a serious complication in the provision of home parenteral nutrition (HPN). Antibiotic salvage of central venous catheters (CVCs) in CRBSI is recommended; however, this is based on limited reports. We assessed the efficacy of antibiotic salvage of CRBSIs in HPN patients. All confirmed CRBSIs occurring in patients receiving HPN in a national intestinal failure unit (IFU), between 1993 and 2011, were analyzed. A standardized protocol involving antibiotic and urokinase CVC locks and systemic antibiotics was used. In total, 588 patients were identified with a total of 2134 HPN years, and 297 CRBSIs occurred in 137 patients (65 single and 72 multiple CRBSIs). The overall rate of CRBSI in all patients was 0.38 per 1000 catheter days. Most (87.9%) infections were attributable to a single microorganism. In total, 72.5% (180/248) of CRBSIs were salvaged when attempted (coagulase-negative staphylococcus, 79.8% [103/129], Staphylococcus aureus, 56.7% [17/30]; polymicrobial infections, 67.7% [21/30]; and miscellaneous, 66.1% [39/59]). CVC salvage was not attempted in 49 episodes because of life-threatening sepsis (n = 18), fungal infection (n = 7), catheter problems (n = 20), and CVC tunnel infection (n = 4). Overall, the CVC was removed in 33.7% (100/297) of cases. There were 5 deaths in patients admitted to the IFU for management of the CRBSI (2 severe sepsis at presentation, 3 metastatic infection). This is the largest reported series of catheter salvage in CRBSIs and demonstrates successful catheter salvage in most cases when using a standardized protocol.

Assessing phenotype and disease course in children with earlier onset of IBD (&lt;11 years). Data from two tertiary centres in the United Kingdom and Italy

Assessing phenotype and disease course in children with earlier onset of IBD (&lt;11 years). Data from two tertiary centres in the United Kingdom and Italy

Urinary metabolome of children with autism and pervasive developmental disorder not otherwise specified

Urinary metabolome of children with autism and pervasive developmental disorder not otherwise specified

No evidence of benefit from antibiotic lock therapy in pediatric oncology patients with central line-related bloodstream infection: results of a retrospective matched cohort study and review of the literature.

Long-term central venous catheters (CVCs) are essential to modern pediatric oncology practice, but central line-related bloodstream infection (CRBSI) is a frequent and important complication. CVC salvage is often attempted but treatment failure is common due to persistent infection, delayed catheter removal, or subsequent relapse of infection, which can be associated with significant morbidity and cost. Adjunctive antibiotic lock therapy (ALT) has been proposed to reduce the risk of treatment failure, but insufficient data are available to confirm efficacy of this intervention. We undertook a retrospective matched cohort study of ALT use for treatment of CRBSI in pediatric hematology/oncology patients at St. Jude Children's Research Hospital between 2006 and 2012. Thirty-eight eligible episodes of CRBSI treated with adjunctive ALT were identified and compared to 73 episodes treated with standard therapy (ST) alone, matched by catheter-type and organism. Overall, treatment failure was similar between ALT and ST groups (50.0 vs. 38.4%; P = 0.24), but the timing was different; in the ALT cohort, immediate CVC removal was less common (0.0 vs. 12.3%; P = 0.03) but delayed removal (4-13 days) and relapse of infection was more common (50.0 vs. 24.7%; P = 0.01). This retrospective study was unable to identify any benefit of adjunctive ALT in pediatric oncology patients with CRBSI. The available evidence does not support routine ALT use, and well-conducted prospective studies are needed.

Systematic review and meta-analysis on management of hemodialysis catheter-related bacteremia.

Hemodialysis catheter-related bacteremia is a common clinical problem with several management options. We performed a systematic review and meta-analysis to determine cure proportions with systemic antibiotics, antibiotic lock solution, and guidewire exchange. We searched databases and registries; conference proceedings from relevant medical societies; and article reference lists. Data regarding management approach, cure, follow-up, recurrence, complications, and microbiology were abstracted and pooled from 28 selected publications. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated from a mixed effects logistic regression model. In total, 1596 patients with tunneled hemodialysis catheter-related bacteremia were divided into groups on the basis of treatment with systemic antibiotics (n=697), antibiotic lock solution (n=546), or guidewire exchange (n=353). Antibiotic lock solution and guidewire exchange had similar cure proportions that were superior to systemic antibiotics alone (OR, 2.08; 95% CI, 1.25 to 3.45; P<0.01 for antibiotic lock solution; OR, 2.88; 95% CI, 1.82 to 4.55; P<0.001 for guidewire exchange versus systemic antibiotics). Cure proportions were highest for coagulase-negative staphylococci followed by gram-negative rods and Staphylococcus aureus. Among S. aureus infections, guidewire exchange led to a higher cure proportion than systemic antibiotics or antibiotic lock solution (OR, 3.33; 95% CI, 1.17 to 9.46; P=0.02; OR, 4.72; 95% CI, 1.79 to 12.46; P=0.002, respectively). Thus, results of this study suggest that tunneled hemodialysis catheter-related bacteremia should be treated with either guidewire exchange or antibiotic lock solution. Future studies should address prospectively whether one strategy is better than the other overall and for specific pathogens.

PH-Mediated Potentiation of Aminoglycosides Kills Bacterial Persisters and Eradicates In Vivo Biofilms

Limitations in treatment of biofilm-associated bacterial infections are often due to subpopulation of persistent bacteria (persisters) tolerant to high concentrations of antibiotics. Based on the increased aminoglycoside efficiency under alkaline conditions, we studied the combination of gentamicin and the clinically compatible basic amino acid L-arginine against planktonic and biofilm bacteria both in vitro and in vivo. Using Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli bioluminescent strains, we studied the combination of L-arginine and gentamicin against planktonic persisters through time-kill curves of late stationary-phase cultures. In vitro biofilm tolerance towards gentamicin was assessed using PVC 96 well-plates assays. Efficacy of gentamicin as antibiotic lock treatment (ALT) at 5 mg/mL at different pH was evaluated in vivo using a model of totally implantable venous access port (TIVAP) surgically implanted in rats. We demonstrated that a combination of gentamicin and the clinically compatible basic amino acid L-arginine increases in vitro planktonic and biofilm susceptibility to gentamicin, with 99% mortality amongst clinically relevant pathogens, i.e. S. aureus, E. coli and P. aeruginosa persistent bacteria. Moreover, although gentamicin local treatment alone showed poor efficacy in a clinically relevant in vivo model of catheter-related infection, gentamicin supplemented with L-arginine led to complete, long-lasting eradication of S. aureus and E. coli biofilms, when used locally. Given that intravenous administration of L-arginine to human patients is well tolerated, combined use of aminoglycoside and the non-toxic adjuvant L-arginine as catheter lock solution could constitute a new option for the eradication of pathogenic biofilms.

Long-term catheterization: current approaches in the diagnosis and treatment of port-related infections

Since the first description in 1982, totally implanted venous access ports have progressively improved patients’ quality of life and medical assistance when a medical condition requires the use of long-term venous access. Currently, they are part of the standard medical care for oncohematologic patients. However, apart from mechanical and thrombotic complications, there are also complications associated with biofilm development inside the catheters. These biofilms increase the cost of medical assistance and extend hospitalization. The most frequently involved micro-organisms in these infections are gram-positive cocci. Many efforts have been made to understand biofilm formation within the lumen catheters, and to resolve catheter-related infection once it has been established. Apart from systemic antibiotic treatment, the use of local catheter treatment (ie, antibiotic lock technique) is widely employed. Many different antimicrobial options have been tested, with different outcomes, in clinical and in in vitro assays. The stability of antibiotic concentration in the lock solution once instilled inside the catheter lumen remains unresolved. To prevent infection, it is mandatory to perform hand hygiene before catheter insertion and manipulation, and to disinfect catheter hubs, connectors, and injection ports before accessing the catheter. At present, there are still unresolved questions regarding the best antimicrobial agent for catheter-related bloodstream infection treatment and the duration of concentration stability of the antibiotic solution within the lumen of the port.

Elimination and Prevention of Microbial Colonization of Central Venous Catheters Using Antibiotic Lock Technique and NonLeachable Form of Catheter Surface Incorporated Antibiotic by Gamma Radiation

Aim: To test the efficacy of antibiotic lock technique (ALT) and catheter material modification for the eradication and prevention of biofilm formation on central venous catheters (CVCs). Methods: Four resistant clinical isolates, namely Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae and Candida tropicalis were used to study the effectiveness of ALT using levofloxacin (for bacteria) or fluconazole (for candida) to eliminate microbial biofilms. Moreover, with the aid of gamma radiation, gentamicin was covalently attached to the polyurethane catheter and the modified polymeric material was tested for their antimicrobial and anti-adherence properties. Results: The highest and lowest concentrations of levofloxacin tested (1024 and 64 mg/L) eliminated the biofilms of Pseudomonas aeruginosa and Acinetobacter baumannii after 3 and 10 days, respectively and after 1 and 7 days in case of Klebsiella pneumoniae, whereas Candida tropicalis biofilms were eliminated by fluconazole after 3 and 10 days. The modified polymeric material acquired antibacterial and anti- adherence properties. Conclusion: The results suggest that ALT and catheter modification could be effective for eradicating and preventing biofilm formation on CVCs.

Antibiotic lock shows survival advantage in haemodialysis patients

Antibiotic lock shows survival advantage in haemodialysis patients

Development of a Fourier transform infrared spectroscopy coupled to UV-Visible analysis technique for aminosides and glycopeptides quantitation in antibiotic locks

Antibiotic Lock technique maintains catheters' sterility in high-risk patients with long-term parenteral nutrition. In our institution, vancomycin, teicoplanin, amikacin and gentamicin locks are prepared in the pharmaceutical department. In order to insure patient safety and to comply to regulatory requirements, antibiotic locks are submitted to qualitative and quantitative assays prior to their release. The aim of this study was to develop an alternative quantitation technique for each of these 4 antibiotics, using a Fourier transform infrared (FTIR) coupled to UV-Visible spectroscopy and to compare results to HPLC or Immunochemistry assays. Prevalidation studies permitted to assess spectroscopic conditions used for antibiotic locks quantitation: FTIR/UV combinations were used for amikacin (1091-1115cm(-1) and 208-224nm), vancomycin (1222-1240cm(-1) and 276-280nm), and teicoplanin (1226-1230cm(-1) and 278-282nm). Gentamicin was quantified with FTIR only (1045-1169cm(-1) and 2715-2850cm(-1)) due to interferences in UV domain of parabens, preservatives present in the commercial brand used to prepare locks. For all AL, the method was linear (R(2)=0.996 to 0.999), accurate, repeatable (intraday RSD%: from 2.9 to 7.1% and inter-days RSD%: 2.9 to 5.1%) and precise. Compared to the reference methods, the FTIR/UV method appeared tightly correlated (Pearson factor: 97.4 to 99.9%) and did not show significant difference in recovery determinations. We developed a new simple reliable analysis technique for antibiotics quantitation in locks using an original association of FTIR and UV analysis, allowing a short time analysis to identify and quantify the studied antibiotics.

Management of infections related to totally implantable venous-access ports: challenges and perspectives

Use of totally implantable venous-access ports (TIVAPs) is standard practice for patients with diseases such as solid-tumour cancers, haematological malignancies, and chronic digestive diseases. Use of TIVAPs allows long-term administration of venotoxic compounds, improves patients' quality of life, and reduces the risk of infection. Microbial contamination, formation of pathogenic biofilms, and infection, however, are associated with morbidity, mortality, and increased health-care costs. Local and systemic complications or infections related to specific pathogens might lead to device removal. Alternatively, conservative treatment with combined systemic antibiotics and antibiotic lock therapy might be useful. We discuss in-vitro and in-vivo basic and clinical research findings on the epidemiology, diagnosis, and prevention of TIVAP-related infections, the current challenges to management, promising strategies, and some treatments in development that are likely to improve outcomes of TIVAP-related infections, with a particular focus on antibiotic lock therapy.

Central Line–associated Bloodstream Infection in Children

Central Line–associated Bloodstream Infection in Children

Prevention and Treatment of Hemodialysis‐Related Bloodstream Infections

Despite improvements in the delivery of care, the annual all-cause mortality rate for end-stage renal disease (ESRD) patients is still around 220 deaths per 1000 at risk patient-years. Infection-related causes are second only to cardiovascular events as a cause for mortality among ESRD patients. Almost two-thirds of all ESRD patients will require hemodialysis and they are at the highest risk for bloodstream infections. An effective method for reducing bloodstream infections is increasing the use of fistula for dialysis access, but, for a significant number of patients, catheter access is inevitable. Several interventions have been studied that primarily involves the application of antimicrobials at the catheter exit site. Other interventions include the use of antibiotic lock solutions, which have resulted in the development of antibiotic resistance. Novel connecting devices may be of use in the future, but studies are still needed to show their efficacy at preventing catheter-related bloodstream infections among hemodialysis patients. As insertion sites can be limited in hemodialysis patients, treatment of certain catheter-related bloodstream infections can be amenable to catheter retention as long as both systemic antibiotic and antibiotic lock therapies are also initiated. Until more data are available, catheter removal followed by systemic therapy is preferred for infections involving Staphylococcus aureus, Pseudomonas species, Enterococcus species, and Candida species.

Antibiotic and other lock treatments for tunnelled central venous catheter-related infections in children with cancer.

The risk of developing a tunnelled central venous catheter (CVC)-related infection ranges between 0.1 and 2.3 per 1000 catheter days for children with cancer. These infections are difficult to treat with systemic antibiotics (salvage rate 24% - 66%) due to biofilm formation in the CVC. Lock treatments can achieve 100 - 1000 times higher concentrations locally without exposure to high systemic concentrations. Our objective was to investigate the efficacy of antibiotic and other lock treatments in the treatment of CVC-related infections in children with cancer compared to a control intervention. We also assessed adverse events of lock treatments. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, issue 3, 2011), MEDLINE/PubMed (1945 to August 2011) and EMBASE/Ovid (1980 to August 2011). In addition we searched reference lists from relevant articles and the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2006 to 2010), American Society of Clinical Oncology (ASCO) (from 2006 to 2010), the Multinational Association of Supportive Care in Cancer (MASCC) (from 2006 to 2011), the American Society of Hematology (ASH) (from 2006 to 2010) and the International Society of Thrombosis and Haematology (ISTH) (from 2006 to 2011). We scanned the ISRCTN Register and the National Institute of Health Register for ongoing trials (www.controlled-trials.com) (August 2011). Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing an antibiotic lock or other lock treatment (with or without concomitant systemic antibiotics) with a control intervention (other lock treatment with or without concomitant systemic antibiotics or systemic antibiotics alone) for the treatment of CVC-related infections in children with cancer. For the description of adverse events, cohort studies were also eligible for inclusion. Two authors independently selected studies, extracted data and performed 'Risk of bias' assessments of included studies. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. Two RCTs evaluated urokinase lock treatment with concomitant systemic antibiotics (n = 56) versus systemic antibiotics alone (n = 48), and one CCT evaluated ethanol lock treatment with concomitant systemic antibiotics (n = 15) versus systemic antibiotics alone (n = 13). No RCTs or CCTs evaluating antibiotic lock treatments were identified. All studies had methodological limitations and clinical heterogeneity between studies was present. We found no evidence of significant difference between ethanol or urokinase lock treatments with concomitant systemic antibiotics and systemic antibiotics alone regarding the number of participants cured, the number of recurrent CVC-related infections, the number of days until the first negative blood culture, the number of CVCs prematurely removed, ICU admission and sepsis. Not all studies were included in all analyses. No adverse events occurred in the five publications of cohort studies (one cohort was included in two publications) assessing this outcome; CVC malfunctioning occurred in three out of five publications of cohort studies assessing this outcome. No significant effect of urokinase or ethanol lock in addition to systemic antibiotics was found. However, this could be due to low power or a too-short follow-up. The cohort studies identified no adverse events; some cohort studies reported CVC malfunctioning. No RCTs or CCTs were published on antibiotic lock treatment alone. More well-designed RCTs are needed to further explore the effect of antibiotic or other lock treatments in the treatment of CVC-related infections in children with cancer.