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Accuracy of bacterial DNA testing for central venous catheter-associated bloodstream infection in children with cancer

Millar, M; Zhou, W; Skinner, R; Pizer, B; Hennessy, E; Wilks, M; Gilbert, RE; (2011) Accuracy of bacterial DNA testing for central venous catheter-associated bloodstream infection in children with cancer. Health Technology Assessment , 15 (7) pp. 1-138. 10.3310/hta15070. Green open access

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Abstract

Background Central venous catheters (CVCs) are widely used for children with cancer to infuse anticancer drugs and to administer complex drug and hydration schedules, blood products and parenteral nutrition. CVCs are required for up to 2 years during the cancer treatment. They are a major risk factor for bloodstream infection in this group of patients.Children undergoing treatment for cancer may develop bloodstream infection from a variety of sources, including the CVC. Although intravenous (i.v.) antibiotic treatment is required whatever the source of infection, distinguishing CVC-associated bloodstream infection from other sources is important as additional interventions may be required, such as antibiotic treatment given slowly or in higher concentrations to target intraluminal biofilm bacteria and, in some cases, removal of the CVC.Methods used in adults to distinguish the CVC from other sources of infection require additional blood sampling from a peripheral vein or removal of the CVC, which is not always acceptable for children. Another problem for the diagnosis of CVC infection in patients undergoing treatment for cancer is the widespread use of antibiotics for both prophylaxis and treatment, which reduce the sensitivity of blood culture, and other diagnostic methods that require recovery of viable microbes.Early and specific diagnosis of CVC-associated bloodstream infection has the potential to lead to more effective, CVC-targeted treatment and to reduce the risk of serious complications. Early targeted treatment, such as antibiotic locks, may also reduce the risk of CVC removal, thereby avoiding the operative risks and trauma of reinsertion.The overall aim of our study was to improve the detection and treatment of CVC-associated bloodstream infections in children with cancer admitted with fever. The study involved the evaluation of diagnostic accuracy of a quantitative molecular method for the detection of bacterial DNA (deoxyribonucleic acid), based solely on blood samples drawn through the CVC. We analysed the prognostic risk of CVC removal and duration of i.v. antibiotic treatment days in relation to presenting clinical features, blood culture results and bacterial DNA test results, and we carried out a series of systematic reviews of treatment options for CVC-associated infection. We evaluated the clinical effectiveness of different test treatment strategies to reduce i.v. antibiotic treatment days and unnecessary CVC removals, and, finally, we considered the implications of our findings for further research.Objectives1. To determine the diagnostic accuracy of a novel molecular test for CVC-associated infection in children with cancer admitted with fever.2. To determine the extent to which bacterial DNA and other prognostic markers discriminate between sequelae of CVC-associated infection, including CVC removal and duration of i.v. antibiotic treatment days.3. To conduct systematic reviews to determine the effectiveness of treatment options targeted at CVC-associated bloodstream infection.4. To survey current clinical practice to determine the use of antimicrobial locks for prophylaxis or treatment of CVC-associated infection and perceived barriers to their use.5. To estimate the potential benefits of different test-treatment strategies measured by i.v. antibiotic treatment days saved and avoidance of unnecessary CVC removals.MethodsThe diagnostic accuracy study involved eight paediatric oncology centres in the UK and was co-ordinated through the Children's Cancer and Leukaemia Group (CCLG). Children aged 0-18 years with a CVC or implanted CVC port considered to be required for a minimum of 3 months were invited to participate in the study. Eligible patients were enrolled when they presented with a febrile episode if they had not received i.v. antibiotic therapy during the preceding 2 weeks. Samples were collected at the time of presentation to hospital with fever for routine blood cultures and for bacterial DNA testing. Clinical data were collected at the time of admission and at 4 weeks after presentation using standard questionnaires. Definitions of CVC-associated infection were agreed before the start of the study and these allowed classification of fever episodes into probable, possible, unlikely and unclassifiable groups. The results of the accuracy study have been published [Millar et al. Molecular diagnosis of vascular access device-associated infection in children being treated for cancer or leukaemia. Clin Microbiol Infect 2008;14(3):213-20].The study of prognostic markers used the same data set as the diagnostic accuracy study, but with additional information up to 6 months after the presenting admission with fever. Analyses were restricted to the first episode of fever. Two test results were considered in all analyses in addition to the bacterial DNA results: these were blood culture and clinical signs of CVC-associated infection (fever, chills, rigors or hypotension associated with CVC manipulations).We conducted three systematic reviews to determine the effectiveness of early versus deferred CVC removal, antimicrobial locks for treating CVC-associated infection and antimicrobial locks for preventing CVC-associated infection. We also conducted a questionnaire survey of 18 oncology centres, in collaboration with CCLG members, to obtain information about current practice and problems perceived with using antimicrobial locks for prophylaxis or treatment of CVC-associated infection.We illustrated the potential benefits of different test-treatment strategies based on clinical signs of CVC infection or bacterial DNA results on admission prior to availability of blood culture results 48 hours later. We considered the treatment options of early removal of the CVC, early stopping of i.v. treatment for children at very low risk of bloodstream infection, antimicrobial lock treatment and standard care.ResultsThe accuracy study found that the bacterial DNA test detected two-thirds of children classified with probable CVC-associated infection and the specificity was 88% [95% confidence interval (CI) 84% to 92%]. Although high bacterial DNA concentrations were associated with subsequent CVC removal and duration of i.v. antibiotic treatment, the test did not improve the prediction of these outcomes over and above clinical signs of CVC-associated infection and blood culture results, although DNA was predictive of CVC removal and i.v. treatment duration on the day of admission, before blood culture results became available at 48 hours after sampling.the 352 days per 1000 children admitted (see Table 20) saved by stopping after a negative DNA test compared with 2 days later after a negative blood culture result, and cannot therefore infer whether these savings would justify the additional cost of DNA testing for all admitted children. The strategy of lock treatment for any child with a positive test would result in a moderate reduction in i.v. treatment days. The benefits would vary only marginally with or without the inclusion of DNA testing.Least benefits are to be gained from strategies involving early removal of the CVC, in terms of i.v. treatment days saved. These estimates are limited by a low event rate for recurrent i.v. treatment and CVC removal in high-risk children, and do not take into account the very high values placed by parents, children and clinicians on avoiding complications of CVC infection. There is some evidence that early CVC removal on day 1 would save more i.v. treatment days than removal on day 3, but at a cost of unnecessary CVC removal. Clinicians and patients would need to decide whether benefits in the order of 23 additional i.v. treatment days saved per additional CVC removed unnecessarily (385/17) would be an acceptable trade-off.ConclusionsThese crude analyses suggest that the largest reduction in adverse outcomes would result from a strategy of early discharge (48 hours post admission) for low-risk children. Moderate potential benefits would result from antibiotic lock treatment for all children with a positive test result, and least benefit would be derived from a strategy of early CVC removal. Bacterial DNA testing would add marginal benefits to these strategies that might not justify the costs of testing. These analyses are based on sparse data and on assumptions of treatment effectiveness that need to be evaluated in RCTs.

Type: Article
Title: Accuracy of bacterial DNA testing for central venous catheter-associated bloodstream infection in children with cancer
Open access status: An open access version is available from UCL Discovery
DOI: 10.3310/hta15070
Publisher version: http://www.hta.ac.uk/1449
Language: English
Additional information: © 2011 Queen's Printer and Controller of HMSO
Keywords: ANTIBIOTIC-LOCK TECHNIQUE, DOUBLE-BLIND TRIAL, STENOTROPHOMONAS-MALTOPHILIA BACTEREMIA, NEGATIVE STAPHYLOCOCCAL BACTEREMIA, TUNNELED HEMODIALYSIS CATHETERS, PROSPECTIVE RANDOMIZED-TRIALS, NON-NEUTROPENIC PATIENTS, IN-SITU TREATMENT, OF-THE-LITERATURE, RISK-FACTORS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Ortho and MSK Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Pop, Policy and Practice Prog
URI: http://discovery.ucl.ac.uk/id/eprint/1312974
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