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Catheter-related bloodstream infections with coagulase-negative staphylococci: are antibiotics necessary if the catheter is removed?

Catheter-related bloodstream infections with coagulase-negative staphylococci: are antibiotics... Background: Catheter-related bloodstream infections (CRBSI) with coagulase-negative Staphylococci (CoNS) are a common source of hospital-acquired bloodstream infections. The main objective of this study was to elucidate the role of systemic antibiotic therapy in the setting of catheter removal in adult patients with CoNS-CRBSI. Methods: We conducted a retrospective cohort study on patients with CoNS-CRBSI diagnosed between 2008 and 2016 with follow-up for up to 12 months. The main inclusion criterion was a removed intravascular catheter with quantitative catheter tip culture growing CoNS and the same CoNS identified in the blood culture of a given patient. Outcomes were non-resolved infection (i.e. either presence of prolonged bacteremia or symptoms attributed to CoNS-CRBSI > 2 days after catheter removal), recurrence, mortality and length of hospitalization after catheter removal. We compared outcomes between a group with antibiotic treatment prescribed according to current IDSA guidelines (≥5days, “treatment” group) and a “no-treatment” group. Results: Our study population comprised 184 CoNS-CRBSI episodes. Seventy-six percent received antibiotic treatment ≥5 days, while 17% did not receive therapy. Non-resolved infections were absent from the patients who did not receive antibiotics. Severe neutropenia, hematologic cancer and immunosuppression were significantly more frequent in the treatment group. The subgroup analysis with 32 matched pairs showed no significant difference in frequency of non-resolved infection (0% in the no-treatment vs 15.6% in the ≥5 days treatment group, p = 0.06). The remaining outcomes were similar in the two groups. Conclusions: Our findings indicate that withholding antimicrobial therapy in CoNS-CRBSI is neither associated with short-term complications nor with long-term recurrences. Keywords: Intravascular catheter, Central venous catheter, Coagulase-negative staphylococci, CRBSI Background catheter-related infections [2, 3]. CoNS-CRBSI and CoNS Catheter-related bloodstream infections (CRBSI) are the bacteremia increase the duration of hospitalization, inten- leading subset of hospital-acquired bloodstream infections sive care unit (ICU) length of stay, morbidity and therapy- (BSI) [1]. In Europe, BSI can be found in 1–3.1 cases per related costs [4–6]. However, CoNS are considered 1000 patient-days, 60% of which are catheter-associated low-virulence microorganisms and data on outcomes in [1, 2]. Coagulase-negative staphylococci (CoNS) are the terms of mortality due to these infections have been con- most frequent etiology of BSI, especially in the setting of flicting [5, 7, 8]. Few studies have examined the role of antibiotic treat- * Correspondence: niccolo.buetti@gmail.com ment in CoNS bacteremias. The heterogeneity of these Ursula Patricia Hebeisen and Andrew Atkinson contributed equally to this studies precludes any conclusion regarding efficacy. A work. small study suggested that early antimicrobial treatment Department of Infectious Diseases, University Hospital Bern, Freiburgstrasse, 3010 Bern, Switzerland might reduce the clinical impact of CoNS-CRBSI [5], Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 2 of 8 whereas other researchers concluded that administering catheter removal was a selection criterion for our study. adequate antibiotics was irrelevant for outcomes [9]. An- Moreover, additional culture tip reports of another other recent analysis postulated that adequate empirical catheter tip with CoNS in the same patient within 7 therapy is not a requirement as long as the primary days after catheter removal were interpreted as dupli- focusisremoved [7]. Current guidelines question the cate and therefore excluded. need for treating these infections [10–12]. In particular, for uncomplicated CoNS-CRBSI, the Infectious Dis- Clinical, catheter and microbiological data eases Society of America (IDSA) guideline recommends Data on included patients were obtained through review of antibiotic treatment for 5–7 days in the setting of cath- their electronic medical records using a standardized data eter removal [10]. However, thesameguidelinehigh- collection tool. For each episode demographic features, site lights that some experts recommend no antibiotic of CRBSI onset, department at time of onset, underlying therapy in patients without intravascular prosthetic ma- chronic diseases including the Charlson Comorbidity Index terial unless fever and/or bacteremia persist after cath- (CCI) [14] and immunosuppression (due to medication, eter withdrawal, thus leaving the choice to treat or not chemotherapy or illness), and presence of orthopedic hard- to treat these infections open [10]. To our knowledge, ware or intravascular prosthetic material (other than intra- there has never been a direct comparison of clinical vascular catheters) were recorded. Clinical, catheter and outcomes in patients with CoNS-CRBSI treated with or microbiological data collected included: local exit-site in- without antibiotic agents. The main objective of this fection signs, systemic symptoms (e.g., fever), severe neu- study was to elucidate the role of systemic antibiotic tropenia (leucocyte count < 0.5 G/L), type of catheter, therapy in the setting of catheter removal in adult pa- catheter site and dwell-time, number of blood cultures tients with CoNS-CRBSI. drawn during an episode, number of positive blood cul- tures and resistance patterns of CoNS. Methods Theantibiotictherapywasconsideredadequateif it Study design and population included at least one antibiotic (e.g., vancomycin) to We performed a retrospective cohort study on patients which the isolate was susceptible and the treatment was with CoNS-CRBSI admitted to Bern University Hospital, initiated no later than 48 h after catheter removal. In a a 950-bed tertiary care hospital in Bern, Switzerland. subanalysis, we compared episodes treated according to Patients with CoNS-CRBSI were identified by match- current guidelines [3, 10–12, 15]versusepisodeswith- ing positive blood cultures and catheter tip data ex- out antibiotic treatment. tracted from the clinical microbiology lab database at the University of Bern. The inclusion criteria for this study were the following: (1) age ≥ 18 years, (2) a re- Follow-up and clinical outcomes moved short- or long-term intravascular catheter with a The patient charts during hospitalization and after cath- positive quantitative catheter tip culture, (3) the same eter removal were carefully reviewed. All microbiological CoNS (with an identical antibiogram) isolated from a data of a patient with CoNS-CRBSI were reviewed for a blood culture drawn 7 days before to 2 days after cath- 12-month follow-up period. eter removal and (4) admission to the hospital between It is still debated if mortality represents a reasonable 1 January 2008 and 31 December 2016. Patients with outcome measure for CoNS-CRBSI. In contrast to S. Staphylococcus lugdunensis infection were excluded. aureus and Gram-negative bacteremia [16], there is no standardized definition in the literature for treatment Episode definition success of these infections. Therefore, we modified a In general, an episode of CoNS-CRBSI had to fulfill the previously used definition to determine the primary out- IDSA criteria for definite CRBSI [10]: the same CoNS come [17]: A non-resolved infection was defined as pro- grows from at least 1 percutaneous blood culture and longed bacteremia (persistence of positive blood culture from the catheter tip, with a bacterial count of ≥10 with CoNS) or the presence of symptoms attributed to colony forming units (CFU) [13]. Moreover, patients CoNS-CRBSI (e.g., septic thrombosis, abscess) starting having solely positive blood cultures drawn from the more than 2 days after the catheter removal. catheter hub were only included if (1) local symptoms Secondary outcomes were hospital mortality, ICU ad- were documented (e.g., redness or swelling) or (2) sys- mission during an episode, length of hospital stay after temic symptoms (e.g., fever or chills) without another catheter removal, mortality during follow-up and recur- clinical focus were observed, thus qualifying at least for rence. Recurrence was defined as the occurrence of the a complicated “exit-site infection” or “possible CRBSI” same CoNS (bacteremia or growth of CoNS in a sterile [10]. CRBSI episodes diagnosed by differential time-to- site), within 1 week to 12 months after the date of the positivity were not considered for this analysis, as initial bacteremia or until death (modified from Raad Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 3 of 8 and colleagues [17]). We also collected adverse events again compared the groups using both descriptive statis- attributed to the antibiotic therapy. tics and by fitting the primary analysis model to this The study was approved by the regional ethics com- subgroup. Throughout, p-values < 0.05 were considered mittee (project number 2017–01827). statistically significant. All analyses were conducted using SPSS (Version 25) or R (Version 3.4.2). Statistical analysis Group comparisons for continuous variables were car- Results ried out using the Wilcoxon rank test, whereas for cat- During the study period, a total of 3′443 positive cath- egorial variables the χ2 or Fisher’s exact test were used. eter tips and 3′246 positive blood cultures with CoNS As primary analysis model, we fitted logistic regression were identified (see Fig. 1). Of these, 435 patients pre- models with the dependent variable being the presence sented a concurrent bacteremia with the same CoNS of non-resolved infection, and independent variables identified 7 days before to 48 h after catheter removal. treatment group (antibiotic treatment ≥5 days vs no Eighty-four CoNS episodes were excluded because they treatment), an indicator variable for age group, gender, revealed different resistance patterns, 78 were duplicates CCI, catheter type, department, severe neutropenia dur- and 73 had microbial counts per catheter segment that ing the episode, fever, and exit-site infection signs. were considered too low. Our study population thus We performed a post-hoc subgroup analysis to attempt comprised 184 CoNS-CRBSI episodes. to adjust for inherent imbalance between the patient populations in the two groups. We used both inverse Patient characteristics and antibiotic therapy probability weighting (results not shown) and propensity The clinical characteristics of patients with CoNS- score matching to create a subgroup with 32 matched CRBSI (n = 184) are illustrated in Table 1. The median pairs, 32 with treatment and 32 without treatment. To age was 61 years and patients were predominantly male calculate the scores, we fitted a logistic regression model (70%). Ninety-six percent (177) of CoNS-CRBSI were with treatment group as dependent variable, and an ex- hospital-acquired; 41% (75) and 21% (38) were detected tended set of independent variables to enable us to use in the hemato-oncological and internal medicine depart- all available information for the matching process. We ments, respectively. Comorbidities such as malignancy then used nearest neighbor matching to determine the (109, 59%), immunosuppression (98, 53%) and diabetes closest pairs. We visually checked the appropriateness of mellitus (40, 22%) were frequently encountered. The the pairings by plotting the first two principal compo- mean Charlson Comorbidity Index was 4 (range 0–12). nents from a principal components analysis using the Forty-nine patients (27%) had orthopedic hardware or same extended set of covariates (see Additional file 1: intravascular prosthetic material in place at the time of Figures S1-S2). Once this process was complete, we the index hospital admission. Of the 184 patients with Fig. 1 Data sources. CoNS, coagulase-negative Staphylococci; CFU, colony forming units Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 4 of 8 Table 1 Patient characteristics: all, with adequate antibiotic treatment according to current guidelines (≥5 days), and without antibiotic treatment Characteristic Total* Treatment ≥5 days No treatment p value (n = 184) (n = 140) (n = 32) Age, years, median (IQR) 61 (51–67) 62.5 (51–67.5) 57.5 (52–63) 0.254 Sex, male 128 (70%) 96 (69%) 24 (75%) 0.616 BMI, kg/cm , median (IQR) 26 (22–30) 26 (22–30) 25 (22–28.5) 0.535 Days in hospital, median (IQR) 29.5 (21–44) 31 (22–44) 28 (20–53.5) 0.783 Hospital-acquired CRBSI 177 (96%) 134 (96%) 32 (100%) 0.510 Department at time of diagnosis ICU 37 (20%) 24 (17%) 10 (31%) 0.118 Surgery 34 (19%) 26 (19%) 8 (25%) 0.563 Internal medicine 38 (21%) 22 (16%) 12 (38%) 0.011 Hemato-oncology 75 (41%) 68 (49%) 2 (6%) < 0.001 Comorbidities Malignancy 109 (59%) 91 (65%) 11 (34%) 0.003 Hematologic cancer 82 (45%) 74 (53%) 2 (6%) < 0.001 Solid cancer 27 (15%) 17 (12%) 9 (28%) 0.045 Immunosuppression 98 (53%) 85 (61%) 5 (16%) < 0.001 Chronic pulmonary disease 22 (12%) 15 (11%) 4 (13%) 1.000 Congestive heart failure 14 (8%) 10 (7%) 4 (13%) 0.521 Renal failure 22 (12%) 11 (8%) 7 (22%) 0.044 Cerebrovascular disease 11 (6%) 10 (7%) 1 (3%) 0.662 Diabetes mellitus 40 (22%) 28 (20%) 10 (31%) 0.251 CCI, median (range) 4 (0–12) 4 (0–12) 4 (1–10) 0.609 Any surgical treatment 74 (40) 52 (37%) 18 (56%) 0.074 Orthopedic hardware or intravascular prosthetic material Any device 49 (27%) 40 (29%) 8 (25%) 0.851 Orthopedic hardware 25 (14%) 19 (14%) 5 (16%) 0.984 Intravascular prosthetic material 25 (14%) 21 (15%) 4 (13%) 0.933 Clinical findings Exit-site infection signs 64 (35%) 56 (40%) 3 (9%) 0.002 Fever (> 38.2 °C) 130 (71%) 107 (76%) 17 (53%) 0.015 Septic shock 4 (2%) 3 (2%) 0 (0%) 0.931 Severe neutropenia° 78 (42%) 71 (51%) 1 (3%) < 0.001 Catheter characteristics Short-term catheter 170 (92%) 129 (92%) 30 (94%) 1.000 CVC 150 (82%) 116 (83%) 25 (78%) 0.709 Dwell time, median (IQR) 12 (9–17) 12 (9–17) 14 (9.5–20) 0.455 Long-term catheter 14 (8%) 11 (8%) 2 (6%) 1.000 Catheter site: jugular vein 138 (75%) 103 (74%) 26 (81%) 0.497 Microbiological data Positive blood cultures, median (IQR) 2 (1–3) 2 (2–3) 1 (1–2) < 0.001 Total of blood cultures drawn, 4(3–7) 5 (3–7) 2.5 (2–5) 0.001 median (range) ≥ 10′000 CFU on catheter tipª 124 (67%) 93 (66%) 22 (69%) 0.965 Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 5 of 8 Table 1 Patient characteristics: all, with adequate antibiotic treatment according to current guidelines (≥5 days), and without antibiotic treatment (Continued) Characteristic Total* Treatment ≥5 days No treatment p value (n = 184) (n = 140) (n = 32) CoNS resistant to oxacillin 143 (78%) 104 (74%) 30 (94%) 0.031 Antimicrobial therapy Vancomycin 135 (73%) 126 (90%) 0 (0%) Duration of adequate therapy, 10 (5–15) 13 (8–18) 0 (0) median (IQR) Abbreviations: IQR interquartile range, BMI body mass index, ICU intensive care unit, CCI Charlson comorbidity index, CVC central venous catheter, CFU colony forming units All values expressed as no. (%), unless otherwise indicated.*including all patients with ≥1 day treatment or no treatment. ° Severe neutropenia was defined as a leucocyte count < 0.5 G/L ª the remaining patients had a 1′000 CFU growth on their removed catheter tips CoNS-CRBSI, 71% (130) were diagnosed with fever, 35% Index was 4, 34% (11) of patients had a malignancy, and (64) presented local signs and 42% (78) were severely 25% (8) had orthopedic hardware or intravascular pros- neutropenic. Ninety-two percent of catheters (170) were thetic material in situ on admission. Severe neutropenia short-term intravascular catheters, most of them CVCs was infrequently observed (1, 3%) in this group. (150, 82%). In general, the two groups presented similar baseline Figure 2 shows the distribution of treatment duration characteristics (Table 1). Similar percentages regarding in our study group. Eighty-three percent of patients the presence of prosthetic material and catheter charac- (152) received adequate antibiotic therapy (Additional teristics were observed in both groups. However, file 1: Table S1) and 76% (140) were treated according to CoNS-CRBSI in the “no treatment” group were less fre- the current IDSA guidelines (i.e., at least 5–7 days). The quently observed in the hemato-oncologic department median duration of treatment was 10 (IQR, 5–15) days. (6% vs 49% in the “treatment” group, p < 0.001), had less Vancomycin was the most frequently administered ad- often hematologic cancer (6% vs 53%, p < 0.001), were equate antibiotic agent (135, 73%). less severely neutropenic (3% vs 51%, p < 0.001), and presented both fewer local (9% vs 40%, p = 0.002) and Patients without antibiotic therapy and comparison with systemic signs (53% vs 76%, p = 0.015). patients who received treatment ≥5 days Two groups of patients were created, one that received Evaluation of outcomes adequate therapy for ≥5 days and the other without anti- The mean follow-up time was 234 (SD ±155.1) days biotic therapy. Among patients without antibiotic treat- (Table 2). Of the 184 patients with CoNS-CRBSI, a ment (32, 17%, “no treatment” group in Table 1), CRBSI non-resolved infection was observed in 30 patients were most frequently observed in internal medicine de- (16%), with septic thrombosis being the most frequently partments (12, 38%). The median Charlson Comorbidity observed complication (25, 14%). Recurrences were Fig. 2 Distribution of the duration of antibiotic therapy (n = 184) Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 6 of 8 Table 2 Outcomes by duration of treatment (≥5 days vs. no treatment) Characteristic All patients Treatment ≥5 days No treatment p-value (n = 184) (n = 140) (n = 32) Primary outcome Non-resolved infection 30 (16%) 29 (21%) 0 (0%) 0.010 Septic thrombosis 25 (14%) 24 (17%) 0 (0%) 0.025 Prolonged bacteremia 4 (2%) 4 (3%) 0 (0%) 0.751 Abscess 2 (1%) 2 (1%) 0 (0%) 1.000 Secondary oucomes Recurrence (bacteremia) 8 (4%) 8 (6%) 0 (0%) 0.358 ICU admission 18 (10%) 15 (11%) 1 (3%) 0.111 Days to discharge, 13 (7–21) 15 (8–21) 11.5 (5–32) 0.253 median (IQR) Hospital mortality 22 (12%) 12 (9%) 6 (19%) 0.169 Mortality during follow-up 38 (21%) 26 (19%) 8 (25%) 0.563 Side effects 3 (2%) 3 (2%) Days of follow-up, 234.2 (±155.1) 241.2 (±152.3) 232.4 (±161.2) mean (±SD) Abbreviations: ICU intensive care unit, IQR interquartile range, SD standard deviation All values expressed as no. (%), unless otherwise indicated. including all patients with ≥1 day treatment or no treatment infrequently detected (8, 4%; all bacteremias) and no in those who received treatment according to guide- prosthetic material infections with CoNS were observed lines, p = 0.01). The subgroup analysis utilized propen- during the entire follow-up. Focusing on raw group sity scores and nearest neighbor matching to compare proportion comparisons, none of the patients without groups of similar patients with and without antibiotic antibiotic therapy experienced a non-resolved infec- treatment. The rates of outcomes approached each tion (0% infections in the no-treatment group vs 22% other after propensity score matched adjustment in terms of the non-resolved infection (0% vs 16%, p =0.06; Table 3 and Additional file 1: Figures S1-S2). The majority of the Table 3 Group comparisons following the nearest neighbor 32 patients chosen for these analyses were non-neutropenic matching process (31, 96.9%). Characteristic Treatment ≥5 days No Treatment p-value (n = 32) (n = 32) On the basis of univariate analyses, the secondary outcomes were similar in the two comparison groups Age mean (±SD) 58.0 (±15.7) 57.3 (±11.5) 0.892 (Table 2). In particular, no recurrence was observed Sex (mean) 26 (81%) 24 (75) 0.762 in the “no treatment” group. Side effects due to anti- ICU 11 (34%) 10 (31%) 1.000 biotic therapy were observed in only three of 32 pa- Internal medicine 11 (34%) 12 (38%) 1.000 tients (2%). Malignancy 13 (41%) 11 (34%) 0.796 Hematologic cancer 3 (9%) 2 (6%) 1.000 Discussion Our findings indicate that patients not receiving antibi- Immunosuppression 5 (16%) 5 (16%) 1.000 otics for CoNS-CRBSI after catheter removal experience Renal failure 5 (16%) 7 (22%) 0.749 a similarly low rate of complications as patients receiv- CCI, mean 4.3 4.1 0.109 ing ≥5 days of antibiotic therapy. This conclusion may Any surgical treatment 21 (66%) 18 (56%) 0.608 probably only be applied to non-neutropenic patients Orthopedic hardware or 10 (31%) 8 (25%) 0.781 given our results, which are supported by a neighbor intravascular prosthetic analysis and a principal components analysis for the pri- material mary outcome. Fever (> 38.2 °C) 19 (59%) 17 (53%) 0.801 To date, there are no well-designed and adequately pow- Catheter type: short-term 29 (91%) 30 (94%) 1.000 ered trials to compare the role of antibiotic therapy in Primary endpoint 5 (16%) 0 (0%) 0.062 CoNS-CRBSI following catheter removal. Accordingly, (Non-resolved Infection) practice often relies on prescriber preference and individual Abbreviations: SD standard deviation, ICU intensive care unit, CCI Charlson experience. The current IDSA guideline on catheter-related Comorbidity Index All values expressed as no. (%), unless otherwise indicated infections suggests prescribing antibiotic therapy for at least Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 7 of 8 5 to 7 days after catheter removal [10]. Other guidelines or Our study has several limitations. This was a small, reviews support similar recommendations [3, 11, 12, 15]. retrospective, single-center study and the results may Alternatively, patients with CoNS-CRBSI can be followed not be applicable to patients with severe neutropenia. without antibiotic administration if the patients have nei- However, the population included in the nearest neigh- ther orthopedic hardware nor intravascular prosthetic ma- bor analysis also included very ill patients and therefore terial in place. This strategy is based on expert opinion our conclusions may be applied to a variety of patient [10] and current recommendations (2009) are not based settings. Moreover, patients receiving ≥5 days of on relevant clinical evidence. Unfortunately, little progress antibiotic therapy showed higher risk of complications. has been made since that time to improve the evidence Following matching, this difference was reduced, with- base regarding antibiotic administration for CoNS-CRBSI. out statistical significance at the 5% level. The remaining In a retrospective study, Raad et al. concluded that difference might be explained by the presence of un- prolonged antibiotic treatment was not associated with measured confounders. Furthermore, patients without better resolution of bacteremia or significantly lower rate significant growth of CoNS on the catheter tip as well as of recurrence. However, in Raad’s study patients without CoNS-CRBSI diagnosed by differential time-to-positivity antibiotics were not separately analyzed [17]. In an ob- (without tip culture), were not included, which may have servational case-control study including patients with led to an underestimation of the total burden of CoNS- and without CoNS bacteremia, Molina et al. found an CRBSI. On one hand, no molecular typing was per- association between mortality and delay of appropriate formed for recurrences, which can lead to overesti- antibiotic treatment. However, worse outcomes related mation of this specific outcome; on the other hand, to inappropriate empirical treatment were observed irre- patients were not on defined clinical and follow-up pro- spective of whether patients had CoNS-BSI or not. A tocols, which may have led to an increased number of sub-analysis performed in only those patients with CoNS lost-to-follow-up patients. bacteremia showed that appropriate empirical treatment or delay of appropriate treatment did not affect out- Conclusions comes [5]. Recently, Park et al. concluded that in- These limitations notwithstanding, our study clearly sug- appropriate empirical therapy does not lead to poor gests that managing CoNS-CRBSI in non-neutropenic outcomes in CoNS-CRBSI bacteremia [7]. The reten- patients without clinical evidence of local symptoms tion of an eradicable focus such as intravascular cath- solely with catheter removal appears to be an option eter, however, might adversely affect outcomes in with neither short-term complications nor long-term re- CoNS bacteremia. Moreover, that study population currences, even if orthopedic hardware or intravascular also included bacteremic patients without a CoNS- prosthetic material remain in place. To verify our find- CRBSI thus limiting the generalizability of their results ings and ensure patient safety, further investigations in to intravascular catheter infections [7]. Of note, all prospective randomized trials are needed. these studies included patients with catheter retention and none compared patient characteristics between the different groups in the setting of catheter removal Additional file as we did here. Our study clearly supports the option Additional file 1: Figure S1 Distribution of propensity scores post of following patients with CoNS-CRBSI without ad- matching process. Figure S2. Plot of the first two principal components ministering antibiotic treatment by providing the first with the full data set to determine the appropriateness of the matches direct comparison with the standard approach, anti- from the nearest neighbor process. Table S1. Characteristics and outcome of patients with antibiotic treatment (≥1 day) vs. patients biotic treatment. Interestingly, the presence of foreign without antibiotic treatment. (PDF 332 kb) bodies (e.g., orthopedic hardware or intravascular prosthetic material) did not influence the rate of late recurrences. To our knowledge, only one study has Abbreviations CCI: Charlson Comorbidity Index; CoNS: Coagulase-negative staphylococci; ever assessed the occurrence of recurrent CRBSI: Catheter-related bloodstream infections; ICU: Intensive Care Unit; CoNS-CRBSI [17], revealing that patients with cath- IDSA: Infectious Diseases Society of America eter retention were more likely to suffer from infec- tion recurrence. However, 1) only bacteremias were Acknowledgements reviewed without considering other metastatic foci, We thank Antoine Buetti, Paolo Mombelli and Elia Lo Priore for their editorial support. We thank Sara Droz (IFIK) for providing microbiological data. and 2) the role of antibiotics was not assessed in a Part of this work was presented at the ECCMID 2018 conference in sub-analysis. Reducing antibiotic use, in particular Madrid, Spain. vancomycin, may be effective in decreasing both sev- eral adverse effects in the short term [18, 19]and anti- Funding biotic resistance in the long term [20, 21]. No external founding was received. Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 8 of 8 Availability of data and materials 12. Timsit JF, Dubois Y, Minet C, et al. New challenges in the diagnosis, The datasets used and/or analyzed during the current study are available management, and prevention of central venous catheter-related infections. from the corresponding author on reasonable request. Semin Respir Crit Care Med. 2011;32:139–50. 13. Brun-Buisson C, Abrouk F, Legrand P, Huet Y, Larabi S, Rapin M. Diagnosis of Authors’ contributions central venous catheter-related sepsis. Critical level of quantitative tip NB, UH, JM conceived and designed the study. NB, UH, AA analyzed the cultures. Arch Intern Med. 1987;147:873–7. data. NB, UH, JM, AA wrote the manuscript. All authors contributed to the 14. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying discussion and reviewed the manuscript. All authors commented and prognostic comorbidity in longitudinal studies: development and validation. approved the final version of the paper. J Chronic Dis. 1987;40:373–83. 15. Timsit JF, Rupp M, Bouza E, et al. A state of the art review on optimal practices Ethics approval and consent to participate to prevent, recognize, and manage complications associated with intravascular The study was approved by the regional (Canton of Bern) ethics committee devices in the critically ill. Intensive Care Med. 2018;44(6):742–59. (project number 2017–01827). 16. Harris PNA, McNamara JF, Lye DC, et al. Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in Consent for publication adults: a consensus definition. Clin Microbiol Infect. 2017;23:533–41. Not applicable (no individual person’s data). 17. Raad I, Kassar R, Ghannam D, Chaftari AM, Hachem R, Jiang Y. Management of the catheter in documented catheter-related coagulase-negative Competing interests staphylococcal bacteremia: remove or retain? Clin Infect Dis. 2009;49:1187–94. The authors declare that they have no competing interests. 18. Hanrahan TP, Harlow G, Hutchinson J, et al. Vancomycin-associated nephrotoxicity in the critically ill: a retrospective multivariate regression analysis*. Crit Care Med. 2014;42:2527–36. Publisher’sNote 19. Forouzesh A, Moise PA, Sakoulas G. Vancomycin ototoxicity: a reevaluation Springer Nature remains neutral with regard to jurisdictional claims in in an era of increasing doses. Antimicrob Agents Chemother. 2009;53:483–6. published maps and institutional affiliations. 20. Barlam TF, Cosgrove SE, Abbo LM, et al. 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Guidelines of the Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. Enferm Infecc Microbiol Clin. 2007;25:111–30. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antimicrobial Resistance & Infection Control Springer Journals

Catheter-related bloodstream infections with coagulase-negative staphylococci: are antibiotics necessary if the catheter is removed?

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Copyright © 2019 by The Author(s).
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Biomedicine; Medical Microbiology; Drug Resistance; Infectious Diseases
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10.1186/s13756-019-0474-x
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Abstract

Background: Catheter-related bloodstream infections (CRBSI) with coagulase-negative Staphylococci (CoNS) are a common source of hospital-acquired bloodstream infections. The main objective of this study was to elucidate the role of systemic antibiotic therapy in the setting of catheter removal in adult patients with CoNS-CRBSI. Methods: We conducted a retrospective cohort study on patients with CoNS-CRBSI diagnosed between 2008 and 2016 with follow-up for up to 12 months. The main inclusion criterion was a removed intravascular catheter with quantitative catheter tip culture growing CoNS and the same CoNS identified in the blood culture of a given patient. Outcomes were non-resolved infection (i.e. either presence of prolonged bacteremia or symptoms attributed to CoNS-CRBSI > 2 days after catheter removal), recurrence, mortality and length of hospitalization after catheter removal. We compared outcomes between a group with antibiotic treatment prescribed according to current IDSA guidelines (≥5days, “treatment” group) and a “no-treatment” group. Results: Our study population comprised 184 CoNS-CRBSI episodes. Seventy-six percent received antibiotic treatment ≥5 days, while 17% did not receive therapy. Non-resolved infections were absent from the patients who did not receive antibiotics. Severe neutropenia, hematologic cancer and immunosuppression were significantly more frequent in the treatment group. The subgroup analysis with 32 matched pairs showed no significant difference in frequency of non-resolved infection (0% in the no-treatment vs 15.6% in the ≥5 days treatment group, p = 0.06). The remaining outcomes were similar in the two groups. Conclusions: Our findings indicate that withholding antimicrobial therapy in CoNS-CRBSI is neither associated with short-term complications nor with long-term recurrences. Keywords: Intravascular catheter, Central venous catheter, Coagulase-negative staphylococci, CRBSI Background catheter-related infections [2, 3]. CoNS-CRBSI and CoNS Catheter-related bloodstream infections (CRBSI) are the bacteremia increase the duration of hospitalization, inten- leading subset of hospital-acquired bloodstream infections sive care unit (ICU) length of stay, morbidity and therapy- (BSI) [1]. In Europe, BSI can be found in 1–3.1 cases per related costs [4–6]. However, CoNS are considered 1000 patient-days, 60% of which are catheter-associated low-virulence microorganisms and data on outcomes in [1, 2]. Coagulase-negative staphylococci (CoNS) are the terms of mortality due to these infections have been con- most frequent etiology of BSI, especially in the setting of flicting [5, 7, 8]. Few studies have examined the role of antibiotic treat- * Correspondence: niccolo.buetti@gmail.com ment in CoNS bacteremias. The heterogeneity of these Ursula Patricia Hebeisen and Andrew Atkinson contributed equally to this studies precludes any conclusion regarding efficacy. A work. small study suggested that early antimicrobial treatment Department of Infectious Diseases, University Hospital Bern, Freiburgstrasse, 3010 Bern, Switzerland might reduce the clinical impact of CoNS-CRBSI [5], Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 2 of 8 whereas other researchers concluded that administering catheter removal was a selection criterion for our study. adequate antibiotics was irrelevant for outcomes [9]. An- Moreover, additional culture tip reports of another other recent analysis postulated that adequate empirical catheter tip with CoNS in the same patient within 7 therapy is not a requirement as long as the primary days after catheter removal were interpreted as dupli- focusisremoved [7]. Current guidelines question the cate and therefore excluded. need for treating these infections [10–12]. In particular, for uncomplicated CoNS-CRBSI, the Infectious Dis- Clinical, catheter and microbiological data eases Society of America (IDSA) guideline recommends Data on included patients were obtained through review of antibiotic treatment for 5–7 days in the setting of cath- their electronic medical records using a standardized data eter removal [10]. However, thesameguidelinehigh- collection tool. For each episode demographic features, site lights that some experts recommend no antibiotic of CRBSI onset, department at time of onset, underlying therapy in patients without intravascular prosthetic ma- chronic diseases including the Charlson Comorbidity Index terial unless fever and/or bacteremia persist after cath- (CCI) [14] and immunosuppression (due to medication, eter withdrawal, thus leaving the choice to treat or not chemotherapy or illness), and presence of orthopedic hard- to treat these infections open [10]. To our knowledge, ware or intravascular prosthetic material (other than intra- there has never been a direct comparison of clinical vascular catheters) were recorded. Clinical, catheter and outcomes in patients with CoNS-CRBSI treated with or microbiological data collected included: local exit-site in- without antibiotic agents. The main objective of this fection signs, systemic symptoms (e.g., fever), severe neu- study was to elucidate the role of systemic antibiotic tropenia (leucocyte count < 0.5 G/L), type of catheter, therapy in the setting of catheter removal in adult pa- catheter site and dwell-time, number of blood cultures tients with CoNS-CRBSI. drawn during an episode, number of positive blood cul- tures and resistance patterns of CoNS. Methods Theantibiotictherapywasconsideredadequateif it Study design and population included at least one antibiotic (e.g., vancomycin) to We performed a retrospective cohort study on patients which the isolate was susceptible and the treatment was with CoNS-CRBSI admitted to Bern University Hospital, initiated no later than 48 h after catheter removal. In a a 950-bed tertiary care hospital in Bern, Switzerland. subanalysis, we compared episodes treated according to Patients with CoNS-CRBSI were identified by match- current guidelines [3, 10–12, 15]versusepisodeswith- ing positive blood cultures and catheter tip data ex- out antibiotic treatment. tracted from the clinical microbiology lab database at the University of Bern. The inclusion criteria for this study were the following: (1) age ≥ 18 years, (2) a re- Follow-up and clinical outcomes moved short- or long-term intravascular catheter with a The patient charts during hospitalization and after cath- positive quantitative catheter tip culture, (3) the same eter removal were carefully reviewed. All microbiological CoNS (with an identical antibiogram) isolated from a data of a patient with CoNS-CRBSI were reviewed for a blood culture drawn 7 days before to 2 days after cath- 12-month follow-up period. eter removal and (4) admission to the hospital between It is still debated if mortality represents a reasonable 1 January 2008 and 31 December 2016. Patients with outcome measure for CoNS-CRBSI. In contrast to S. Staphylococcus lugdunensis infection were excluded. aureus and Gram-negative bacteremia [16], there is no standardized definition in the literature for treatment Episode definition success of these infections. Therefore, we modified a In general, an episode of CoNS-CRBSI had to fulfill the previously used definition to determine the primary out- IDSA criteria for definite CRBSI [10]: the same CoNS come [17]: A non-resolved infection was defined as pro- grows from at least 1 percutaneous blood culture and longed bacteremia (persistence of positive blood culture from the catheter tip, with a bacterial count of ≥10 with CoNS) or the presence of symptoms attributed to colony forming units (CFU) [13]. Moreover, patients CoNS-CRBSI (e.g., septic thrombosis, abscess) starting having solely positive blood cultures drawn from the more than 2 days after the catheter removal. catheter hub were only included if (1) local symptoms Secondary outcomes were hospital mortality, ICU ad- were documented (e.g., redness or swelling) or (2) sys- mission during an episode, length of hospital stay after temic symptoms (e.g., fever or chills) without another catheter removal, mortality during follow-up and recur- clinical focus were observed, thus qualifying at least for rence. Recurrence was defined as the occurrence of the a complicated “exit-site infection” or “possible CRBSI” same CoNS (bacteremia or growth of CoNS in a sterile [10]. CRBSI episodes diagnosed by differential time-to- site), within 1 week to 12 months after the date of the positivity were not considered for this analysis, as initial bacteremia or until death (modified from Raad Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 3 of 8 and colleagues [17]). We also collected adverse events again compared the groups using both descriptive statis- attributed to the antibiotic therapy. tics and by fitting the primary analysis model to this The study was approved by the regional ethics com- subgroup. Throughout, p-values < 0.05 were considered mittee (project number 2017–01827). statistically significant. All analyses were conducted using SPSS (Version 25) or R (Version 3.4.2). Statistical analysis Group comparisons for continuous variables were car- Results ried out using the Wilcoxon rank test, whereas for cat- During the study period, a total of 3′443 positive cath- egorial variables the χ2 or Fisher’s exact test were used. eter tips and 3′246 positive blood cultures with CoNS As primary analysis model, we fitted logistic regression were identified (see Fig. 1). Of these, 435 patients pre- models with the dependent variable being the presence sented a concurrent bacteremia with the same CoNS of non-resolved infection, and independent variables identified 7 days before to 48 h after catheter removal. treatment group (antibiotic treatment ≥5 days vs no Eighty-four CoNS episodes were excluded because they treatment), an indicator variable for age group, gender, revealed different resistance patterns, 78 were duplicates CCI, catheter type, department, severe neutropenia dur- and 73 had microbial counts per catheter segment that ing the episode, fever, and exit-site infection signs. were considered too low. Our study population thus We performed a post-hoc subgroup analysis to attempt comprised 184 CoNS-CRBSI episodes. to adjust for inherent imbalance between the patient populations in the two groups. We used both inverse Patient characteristics and antibiotic therapy probability weighting (results not shown) and propensity The clinical characteristics of patients with CoNS- score matching to create a subgroup with 32 matched CRBSI (n = 184) are illustrated in Table 1. The median pairs, 32 with treatment and 32 without treatment. To age was 61 years and patients were predominantly male calculate the scores, we fitted a logistic regression model (70%). Ninety-six percent (177) of CoNS-CRBSI were with treatment group as dependent variable, and an ex- hospital-acquired; 41% (75) and 21% (38) were detected tended set of independent variables to enable us to use in the hemato-oncological and internal medicine depart- all available information for the matching process. We ments, respectively. Comorbidities such as malignancy then used nearest neighbor matching to determine the (109, 59%), immunosuppression (98, 53%) and diabetes closest pairs. We visually checked the appropriateness of mellitus (40, 22%) were frequently encountered. The the pairings by plotting the first two principal compo- mean Charlson Comorbidity Index was 4 (range 0–12). nents from a principal components analysis using the Forty-nine patients (27%) had orthopedic hardware or same extended set of covariates (see Additional file 1: intravascular prosthetic material in place at the time of Figures S1-S2). Once this process was complete, we the index hospital admission. Of the 184 patients with Fig. 1 Data sources. CoNS, coagulase-negative Staphylococci; CFU, colony forming units Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 4 of 8 Table 1 Patient characteristics: all, with adequate antibiotic treatment according to current guidelines (≥5 days), and without antibiotic treatment Characteristic Total* Treatment ≥5 days No treatment p value (n = 184) (n = 140) (n = 32) Age, years, median (IQR) 61 (51–67) 62.5 (51–67.5) 57.5 (52–63) 0.254 Sex, male 128 (70%) 96 (69%) 24 (75%) 0.616 BMI, kg/cm , median (IQR) 26 (22–30) 26 (22–30) 25 (22–28.5) 0.535 Days in hospital, median (IQR) 29.5 (21–44) 31 (22–44) 28 (20–53.5) 0.783 Hospital-acquired CRBSI 177 (96%) 134 (96%) 32 (100%) 0.510 Department at time of diagnosis ICU 37 (20%) 24 (17%) 10 (31%) 0.118 Surgery 34 (19%) 26 (19%) 8 (25%) 0.563 Internal medicine 38 (21%) 22 (16%) 12 (38%) 0.011 Hemato-oncology 75 (41%) 68 (49%) 2 (6%) < 0.001 Comorbidities Malignancy 109 (59%) 91 (65%) 11 (34%) 0.003 Hematologic cancer 82 (45%) 74 (53%) 2 (6%) < 0.001 Solid cancer 27 (15%) 17 (12%) 9 (28%) 0.045 Immunosuppression 98 (53%) 85 (61%) 5 (16%) < 0.001 Chronic pulmonary disease 22 (12%) 15 (11%) 4 (13%) 1.000 Congestive heart failure 14 (8%) 10 (7%) 4 (13%) 0.521 Renal failure 22 (12%) 11 (8%) 7 (22%) 0.044 Cerebrovascular disease 11 (6%) 10 (7%) 1 (3%) 0.662 Diabetes mellitus 40 (22%) 28 (20%) 10 (31%) 0.251 CCI, median (range) 4 (0–12) 4 (0–12) 4 (1–10) 0.609 Any surgical treatment 74 (40) 52 (37%) 18 (56%) 0.074 Orthopedic hardware or intravascular prosthetic material Any device 49 (27%) 40 (29%) 8 (25%) 0.851 Orthopedic hardware 25 (14%) 19 (14%) 5 (16%) 0.984 Intravascular prosthetic material 25 (14%) 21 (15%) 4 (13%) 0.933 Clinical findings Exit-site infection signs 64 (35%) 56 (40%) 3 (9%) 0.002 Fever (> 38.2 °C) 130 (71%) 107 (76%) 17 (53%) 0.015 Septic shock 4 (2%) 3 (2%) 0 (0%) 0.931 Severe neutropenia° 78 (42%) 71 (51%) 1 (3%) < 0.001 Catheter characteristics Short-term catheter 170 (92%) 129 (92%) 30 (94%) 1.000 CVC 150 (82%) 116 (83%) 25 (78%) 0.709 Dwell time, median (IQR) 12 (9–17) 12 (9–17) 14 (9.5–20) 0.455 Long-term catheter 14 (8%) 11 (8%) 2 (6%) 1.000 Catheter site: jugular vein 138 (75%) 103 (74%) 26 (81%) 0.497 Microbiological data Positive blood cultures, median (IQR) 2 (1–3) 2 (2–3) 1 (1–2) < 0.001 Total of blood cultures drawn, 4(3–7) 5 (3–7) 2.5 (2–5) 0.001 median (range) ≥ 10′000 CFU on catheter tipª 124 (67%) 93 (66%) 22 (69%) 0.965 Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 5 of 8 Table 1 Patient characteristics: all, with adequate antibiotic treatment according to current guidelines (≥5 days), and without antibiotic treatment (Continued) Characteristic Total* Treatment ≥5 days No treatment p value (n = 184) (n = 140) (n = 32) CoNS resistant to oxacillin 143 (78%) 104 (74%) 30 (94%) 0.031 Antimicrobial therapy Vancomycin 135 (73%) 126 (90%) 0 (0%) Duration of adequate therapy, 10 (5–15) 13 (8–18) 0 (0) median (IQR) Abbreviations: IQR interquartile range, BMI body mass index, ICU intensive care unit, CCI Charlson comorbidity index, CVC central venous catheter, CFU colony forming units All values expressed as no. (%), unless otherwise indicated.*including all patients with ≥1 day treatment or no treatment. ° Severe neutropenia was defined as a leucocyte count < 0.5 G/L ª the remaining patients had a 1′000 CFU growth on their removed catheter tips CoNS-CRBSI, 71% (130) were diagnosed with fever, 35% Index was 4, 34% (11) of patients had a malignancy, and (64) presented local signs and 42% (78) were severely 25% (8) had orthopedic hardware or intravascular pros- neutropenic. Ninety-two percent of catheters (170) were thetic material in situ on admission. Severe neutropenia short-term intravascular catheters, most of them CVCs was infrequently observed (1, 3%) in this group. (150, 82%). In general, the two groups presented similar baseline Figure 2 shows the distribution of treatment duration characteristics (Table 1). Similar percentages regarding in our study group. Eighty-three percent of patients the presence of prosthetic material and catheter charac- (152) received adequate antibiotic therapy (Additional teristics were observed in both groups. However, file 1: Table S1) and 76% (140) were treated according to CoNS-CRBSI in the “no treatment” group were less fre- the current IDSA guidelines (i.e., at least 5–7 days). The quently observed in the hemato-oncologic department median duration of treatment was 10 (IQR, 5–15) days. (6% vs 49% in the “treatment” group, p < 0.001), had less Vancomycin was the most frequently administered ad- often hematologic cancer (6% vs 53%, p < 0.001), were equate antibiotic agent (135, 73%). less severely neutropenic (3% vs 51%, p < 0.001), and presented both fewer local (9% vs 40%, p = 0.002) and Patients without antibiotic therapy and comparison with systemic signs (53% vs 76%, p = 0.015). patients who received treatment ≥5 days Two groups of patients were created, one that received Evaluation of outcomes adequate therapy for ≥5 days and the other without anti- The mean follow-up time was 234 (SD ±155.1) days biotic therapy. Among patients without antibiotic treat- (Table 2). Of the 184 patients with CoNS-CRBSI, a ment (32, 17%, “no treatment” group in Table 1), CRBSI non-resolved infection was observed in 30 patients were most frequently observed in internal medicine de- (16%), with septic thrombosis being the most frequently partments (12, 38%). The median Charlson Comorbidity observed complication (25, 14%). Recurrences were Fig. 2 Distribution of the duration of antibiotic therapy (n = 184) Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 6 of 8 Table 2 Outcomes by duration of treatment (≥5 days vs. no treatment) Characteristic All patients Treatment ≥5 days No treatment p-value (n = 184) (n = 140) (n = 32) Primary outcome Non-resolved infection 30 (16%) 29 (21%) 0 (0%) 0.010 Septic thrombosis 25 (14%) 24 (17%) 0 (0%) 0.025 Prolonged bacteremia 4 (2%) 4 (3%) 0 (0%) 0.751 Abscess 2 (1%) 2 (1%) 0 (0%) 1.000 Secondary oucomes Recurrence (bacteremia) 8 (4%) 8 (6%) 0 (0%) 0.358 ICU admission 18 (10%) 15 (11%) 1 (3%) 0.111 Days to discharge, 13 (7–21) 15 (8–21) 11.5 (5–32) 0.253 median (IQR) Hospital mortality 22 (12%) 12 (9%) 6 (19%) 0.169 Mortality during follow-up 38 (21%) 26 (19%) 8 (25%) 0.563 Side effects 3 (2%) 3 (2%) Days of follow-up, 234.2 (±155.1) 241.2 (±152.3) 232.4 (±161.2) mean (±SD) Abbreviations: ICU intensive care unit, IQR interquartile range, SD standard deviation All values expressed as no. (%), unless otherwise indicated. including all patients with ≥1 day treatment or no treatment infrequently detected (8, 4%; all bacteremias) and no in those who received treatment according to guide- prosthetic material infections with CoNS were observed lines, p = 0.01). The subgroup analysis utilized propen- during the entire follow-up. Focusing on raw group sity scores and nearest neighbor matching to compare proportion comparisons, none of the patients without groups of similar patients with and without antibiotic antibiotic therapy experienced a non-resolved infec- treatment. The rates of outcomes approached each tion (0% infections in the no-treatment group vs 22% other after propensity score matched adjustment in terms of the non-resolved infection (0% vs 16%, p =0.06; Table 3 and Additional file 1: Figures S1-S2). The majority of the Table 3 Group comparisons following the nearest neighbor 32 patients chosen for these analyses were non-neutropenic matching process (31, 96.9%). Characteristic Treatment ≥5 days No Treatment p-value (n = 32) (n = 32) On the basis of univariate analyses, the secondary outcomes were similar in the two comparison groups Age mean (±SD) 58.0 (±15.7) 57.3 (±11.5) 0.892 (Table 2). In particular, no recurrence was observed Sex (mean) 26 (81%) 24 (75) 0.762 in the “no treatment” group. Side effects due to anti- ICU 11 (34%) 10 (31%) 1.000 biotic therapy were observed in only three of 32 pa- Internal medicine 11 (34%) 12 (38%) 1.000 tients (2%). Malignancy 13 (41%) 11 (34%) 0.796 Hematologic cancer 3 (9%) 2 (6%) 1.000 Discussion Our findings indicate that patients not receiving antibi- Immunosuppression 5 (16%) 5 (16%) 1.000 otics for CoNS-CRBSI after catheter removal experience Renal failure 5 (16%) 7 (22%) 0.749 a similarly low rate of complications as patients receiv- CCI, mean 4.3 4.1 0.109 ing ≥5 days of antibiotic therapy. This conclusion may Any surgical treatment 21 (66%) 18 (56%) 0.608 probably only be applied to non-neutropenic patients Orthopedic hardware or 10 (31%) 8 (25%) 0.781 given our results, which are supported by a neighbor intravascular prosthetic analysis and a principal components analysis for the pri- material mary outcome. Fever (> 38.2 °C) 19 (59%) 17 (53%) 0.801 To date, there are no well-designed and adequately pow- Catheter type: short-term 29 (91%) 30 (94%) 1.000 ered trials to compare the role of antibiotic therapy in Primary endpoint 5 (16%) 0 (0%) 0.062 CoNS-CRBSI following catheter removal. Accordingly, (Non-resolved Infection) practice often relies on prescriber preference and individual Abbreviations: SD standard deviation, ICU intensive care unit, CCI Charlson experience. The current IDSA guideline on catheter-related Comorbidity Index All values expressed as no. (%), unless otherwise indicated infections suggests prescribing antibiotic therapy for at least Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 7 of 8 5 to 7 days after catheter removal [10]. Other guidelines or Our study has several limitations. This was a small, reviews support similar recommendations [3, 11, 12, 15]. retrospective, single-center study and the results may Alternatively, patients with CoNS-CRBSI can be followed not be applicable to patients with severe neutropenia. without antibiotic administration if the patients have nei- However, the population included in the nearest neigh- ther orthopedic hardware nor intravascular prosthetic ma- bor analysis also included very ill patients and therefore terial in place. This strategy is based on expert opinion our conclusions may be applied to a variety of patient [10] and current recommendations (2009) are not based settings. Moreover, patients receiving ≥5 days of on relevant clinical evidence. Unfortunately, little progress antibiotic therapy showed higher risk of complications. has been made since that time to improve the evidence Following matching, this difference was reduced, with- base regarding antibiotic administration for CoNS-CRBSI. out statistical significance at the 5% level. The remaining In a retrospective study, Raad et al. concluded that difference might be explained by the presence of un- prolonged antibiotic treatment was not associated with measured confounders. Furthermore, patients without better resolution of bacteremia or significantly lower rate significant growth of CoNS on the catheter tip as well as of recurrence. However, in Raad’s study patients without CoNS-CRBSI diagnosed by differential time-to-positivity antibiotics were not separately analyzed [17]. In an ob- (without tip culture), were not included, which may have servational case-control study including patients with led to an underestimation of the total burden of CoNS- and without CoNS bacteremia, Molina et al. found an CRBSI. On one hand, no molecular typing was per- association between mortality and delay of appropriate formed for recurrences, which can lead to overesti- antibiotic treatment. However, worse outcomes related mation of this specific outcome; on the other hand, to inappropriate empirical treatment were observed irre- patients were not on defined clinical and follow-up pro- spective of whether patients had CoNS-BSI or not. A tocols, which may have led to an increased number of sub-analysis performed in only those patients with CoNS lost-to-follow-up patients. bacteremia showed that appropriate empirical treatment or delay of appropriate treatment did not affect out- Conclusions comes [5]. Recently, Park et al. concluded that in- These limitations notwithstanding, our study clearly sug- appropriate empirical therapy does not lead to poor gests that managing CoNS-CRBSI in non-neutropenic outcomes in CoNS-CRBSI bacteremia [7]. The reten- patients without clinical evidence of local symptoms tion of an eradicable focus such as intravascular cath- solely with catheter removal appears to be an option eter, however, might adversely affect outcomes in with neither short-term complications nor long-term re- CoNS bacteremia. Moreover, that study population currences, even if orthopedic hardware or intravascular also included bacteremic patients without a CoNS- prosthetic material remain in place. To verify our find- CRBSI thus limiting the generalizability of their results ings and ensure patient safety, further investigations in to intravascular catheter infections [7]. Of note, all prospective randomized trials are needed. these studies included patients with catheter retention and none compared patient characteristics between the different groups in the setting of catheter removal Additional file as we did here. Our study clearly supports the option Additional file 1: Figure S1 Distribution of propensity scores post of following patients with CoNS-CRBSI without ad- matching process. Figure S2. Plot of the first two principal components ministering antibiotic treatment by providing the first with the full data set to determine the appropriateness of the matches direct comparison with the standard approach, anti- from the nearest neighbor process. Table S1. Characteristics and outcome of patients with antibiotic treatment (≥1 day) vs. patients biotic treatment. Interestingly, the presence of foreign without antibiotic treatment. (PDF 332 kb) bodies (e.g., orthopedic hardware or intravascular prosthetic material) did not influence the rate of late recurrences. To our knowledge, only one study has Abbreviations CCI: Charlson Comorbidity Index; CoNS: Coagulase-negative staphylococci; ever assessed the occurrence of recurrent CRBSI: Catheter-related bloodstream infections; ICU: Intensive Care Unit; CoNS-CRBSI [17], revealing that patients with cath- IDSA: Infectious Diseases Society of America eter retention were more likely to suffer from infec- tion recurrence. However, 1) only bacteremias were Acknowledgements reviewed without considering other metastatic foci, We thank Antoine Buetti, Paolo Mombelli and Elia Lo Priore for their editorial support. We thank Sara Droz (IFIK) for providing microbiological data. and 2) the role of antibiotics was not assessed in a Part of this work was presented at the ECCMID 2018 conference in sub-analysis. Reducing antibiotic use, in particular Madrid, Spain. vancomycin, may be effective in decreasing both sev- eral adverse effects in the short term [18, 19]and anti- Funding biotic resistance in the long term [20, 21]. No external founding was received. Hebeisen et al. Antimicrobial Resistance and Infection Control (2019) 8:21 Page 8 of 8 Availability of data and materials 12. Timsit JF, Dubois Y, Minet C, et al. New challenges in the diagnosis, The datasets used and/or analyzed during the current study are available management, and prevention of central venous catheter-related infections. from the corresponding author on reasonable request. Semin Respir Crit Care Med. 2011;32:139–50. 13. Brun-Buisson C, Abrouk F, Legrand P, Huet Y, Larabi S, Rapin M. Diagnosis of Authors’ contributions central venous catheter-related sepsis. Critical level of quantitative tip NB, UH, JM conceived and designed the study. NB, UH, AA analyzed the cultures. Arch Intern Med. 1987;147:873–7. data. NB, UH, JM, AA wrote the manuscript. All authors contributed to the 14. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying discussion and reviewed the manuscript. All authors commented and prognostic comorbidity in longitudinal studies: development and validation. approved the final version of the paper. J Chronic Dis. 1987;40:373–83. 15. Timsit JF, Rupp M, Bouza E, et al. A state of the art review on optimal practices Ethics approval and consent to participate to prevent, recognize, and manage complications associated with intravascular The study was approved by the regional (Canton of Bern) ethics committee devices in the critically ill. Intensive Care Med. 2018;44(6):742–59. (project number 2017–01827). 16. Harris PNA, McNamara JF, Lye DC, et al. Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in Consent for publication adults: a consensus definition. Clin Microbiol Infect. 2017;23:533–41. Not applicable (no individual person’s data). 17. Raad I, Kassar R, Ghannam D, Chaftari AM, Hachem R, Jiang Y. Management of the catheter in documented catheter-related coagulase-negative Competing interests staphylococcal bacteremia: remove or retain? Clin Infect Dis. 2009;49:1187–94. The authors declare that they have no competing interests. 18. Hanrahan TP, Harlow G, Hutchinson J, et al. Vancomycin-associated nephrotoxicity in the critically ill: a retrospective multivariate regression analysis*. Crit Care Med. 2014;42:2527–36. Publisher’sNote 19. Forouzesh A, Moise PA, Sakoulas G. Vancomycin ototoxicity: a reevaluation Springer Nature remains neutral with regard to jurisdictional claims in in an era of increasing doses. Antimicrob Agents Chemother. 2009;53:483–6. published maps and institutional affiliations. 20. Barlam TF, Cosgrove SE, Abbo LM, et al. 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Journal

Antimicrobial Resistance & Infection Control – Springer Journals

Published: Jan 29, 2019

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