# Short-Course Versus Prolonged-Course Antimicrobial Therapy in Adults With Catheter-Related Septic Thrombosis: A Propensity-Weighted Retrospective Study

Marine Stoldick, Margot Vannier, Mikael Verdalle-Cazes, Manuel Etienne, Kévin Alexandre

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Marine Stoldick, Margot Vannier, Mikael Verdalle-Cazes, Manuel Etienne, Kévin Alexandre. Short-Course Versus Prolonged-Course Antimicrobial Therapy in Adults With Catheter-Related Septic Thrombosis: A Propensity-Weighted Retrospective Study. Open Forum Infectious Diseases, 2023, 10 (11), 10.1093/ofid/ofad530. hal-04853526

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MAJOR ARTICLE

# Short-Course Versus Prolonged-Course Antimicrobial Therapy in Adults With Catheter-Related Septic Thrombosis: a Propensity-Weighted Retrospective Study

Marine Stoldick¹**, Margot Vannier², Mikael Verdalle-Cazes³, Manuel Etienne⁴, Kévin Alexandre⁴*

¹ CHU Rouen, Department of Infectious diseases, F-76000 Rouen, France; ² CHU Rouen, Department of Biostatistics, F-76000 Rouen, France; ³ CHU Rouen, Department of Radiology, F-76000 Rouen, France; ⁴ Univ Rouen Normandie, Inserm UMR 1311 DYNAMICURE, CHU Rouen, Department of Infectious diseases, F-76000 Rouen, France

**Background.** Optimal duration of antimicrobial therapy (AT) for catheter-related septic deep venous thrombosis (DVT) is unknown. We aimed to compare the outcomes of patients receiving short-course AT (≤21 days) versus prolonged-course AT (>21 days).

**Methods.** A monocentric retrospective study comparing adults with catheter-related septic DVT from 2015 to 2020 treated with short- or prolonged-course AT. A propensity score-weighted analysis was used to mitigate potential bias. The primary outcome was a composite of all-cause mortality or recurrent bloodstream infection 30 days after AT discontinuation.

**Results.** Of 172 catheter-related septic DVT patients included, 104 were treated with prolonged-course AT and 68 with short-course AT. In the propensity-score analysis, we found no significant difference in 30-day all-cause mortality or relapse between the two groups (wHR, 2.16; 95% CI, 0.68-6.88; p= .192). No difference in 90-day all-cause mortality and 90-day relapse were observed

*Corresponding author: Dr Kévin ALEXANDRE, CHU Rouen, Department of Infectious Diseases, 1 rue de Germont, 76031 Cedex. Tel: +33232880674, Fax: +33232880287, e-mail: kevin.alexandre@chu-rouen.fr

**Alternate corresponding author: Dr Marine STOLDICK, CHU Rouen, Department of Infectious Diseases, 1 rue de Germont, 76031 Cedex. Tel: +33232888990, Fax:+33232880287, e-mail: marine.stoldick@chu-rouen.fr

© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
between the treatment groups, (wHR, 1.01; 95% CI, 0.49-2.05; p= .987 and wHR, 1.13; 95% CI, 0.08-15.62; p= .928, respectively).

**Conclusions.** A 21-day AT could be an effective and safe option to treat catheter-related septic DVT. Further randomized studies are needed to establish the optimal duration of AT for patients with catheter-related septic DVT.

**Keywords:** catheter-related infection; septic thrombosis; duration; short-course therapy.

INTRODUCTION

Healthcare-associated (HA) primary bloodstream infections (BSI) result in increased morbidity, mortality and costs [1–3]. Indeed, every year in Europe the burden of HA primary BSI is estimated at 25,000 deaths and 145 disability-adjusted life years per 100,000 population [4]. Septic deep venous thrombosis (DVT) is a life-threatening infection complicating up to 70% of catheter-related bloodstream infections (CRBSIs) with an attributable mortality of approximately 20% [5,6].

The recommended antimicrobial treatment (AT) duration of catheter-related septic DVT usually exceeds 4 weeks [7]. Exposure to such prolonged AT is associated with an increased likelihood of adverse events [8], *Clostridioides difficile* infections (CDI) [9] and antibacterial resistance [10]. On the other hand, shorter AT durations allow a more rapid return to patient baseline activity [11], reduce antibiotic exposure, venous access complications and adverse events. Finding the optimal AT duration is challenging as shorter treatments may expose patients to relapse and death, particularly for pathogens such as *Staphylococcus aureus* and *Candida* spp. [12–14].

Several trials have demonstrated no significant difference in mortality between short-course and prolonged-course AT in the treatment of Gram-negative and Gram-positive uncomplicated bacteremia [11,15,16].

Infectious Diseases Society of America (IDSA) guidelines on septic DVT, based on expert opinion, recommend a prolonged AT of 3 to 6 weeks [7] for catheter-related septic DVT. In 2017, French experts proposed a unique treatment length of 3 weeks [17], relying on scarce data of such treatment reduction strategies.

In this context, we aimed to compare the effectiveness of short-course versus prolonged-course AT for catheter-related septic DVT of the upper limb.
# METHODS

## Study setting and design

The study took place in a 2,500-bed teaching hospital (Rouen, France). This was a monocentric, retrospective study between 2015 and 2020. Patients were eligible for inclusion if they were adults (aged ≥18 years) with a catheter-related septic DVT of the upper limb. Patients meeting any of the following criteria were excluded: missing information about AT duration, microbiological documentation or susceptibility testing, secondary septic localization (endocarditis, osteomyelitis, arthritis and abscess), prolonged AT for another infection and early death (i.e. death within 21 days of the treatment initiation or on the day treatment ended). Patients for whom the catheter was not removed or with an infectious source different from the catheter (for example bacteremic urinary infection with secondary septic thrombosis) were not excluded as long as the definition of catheter related septic DVT was respected.

## Study definitions

Catheter-related septic DVT was defined as the combination of a DVT homolateral to the catheter and certain or possible CRBSI.

DVT was defined as demonstration of a thrombus by sonography in a deep vein of the upper limb (subclavian, jugular, axillary and humeral veins and the brachio-cephalic venous trunk) with no size threshold.

Bacteremia was defined as ≥ 1 positive peripheral drawn blood culture.

Certain CRBSI was defined as bacteremia or fungemia in a patient with an intravascular device with one of the following criteria: (i) the same microbial species isolated from a quantitative catheter culture (i.e. >10² colony forming units (CFU)/mL) and ≥ 1 peripheral blood culture; (ii) growth of a microorganism in a blood culture obtained through a catheter hub detected by an automated blood culture system at least 2 hours earlier than a simultaneous peripheral drawn blood culture of equal volume [7].

Possible CRBSI was defined as the positive result of quantitative catheter culture (i.e. > 10² CFU/mL) or growth in a culture of blood obtained through a catheter hub and systemic signs of infection (fever, chills, hypotension) with no other obvious source of infection [7,18].

Long-term central venous catheters (CVC) were defined as totally implanted access ports and tunneled catheters.

Short-term CVC were defined as catheters inserted in a central vein used in critically ill patients or during anesthesia for a predicted duration of less than 14 days.
Other catheters were defined as midlines, peripherally inserted central catheters, hemodialysis catheters or Swan-Ganz catheters.

## Data collection

We screened patients using the hospital's radiology software to identify every upper limb DVT over the study period. Then, we reviewed electronic and paper medical records to assess inclusion and exclusion criteria. The following data were collected: demographic data; underlying diseases (immunosuppression status (chemotherapy, immunotherapy, cirrhosis, transplantation, dialysis), Charlson comorbidity-weighted index (CCWI), presence of permanent foreign device (i.e. pacemaker, defibrillator, ventricular assist device, prosthetic heart valve, orthopedic device)); microbiological results (possible or certain CRBSI, presence and duration of bacteremia, microorganisms); biological data (maximal C-reactive protein level and renal function); clinical presentation (fever, sepsis or septic shock, intensive care unit admission); thrombus characteristics (total or partial, number of venous segments involved (one segment corresponding to one anatomic vein)); catheter characteristics (type, catheterization duration, indication); management (catheter removal, oral treatment, curative anticoagulation). A public national registry recording all deaths of French citizens ascertained that all fatalities were taken into account in our study. We ensured that patients were followed up in our hospital, with no mention of relapse in either their medical or microbiological records. When patients were followed up in another hospital, we contacted them to make sure of the absence of relapse.

## Classification and outcomes

Patients were classified as having received short-course or prolonged-course AT if they received ≤21 days or >21 days of AT, respectively. AT duration was defined as the duration of intravenous or oral AT between the first and the last day of appropriate AT (i.e. proven *in vitro* susceptibility according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints).

The primary outcome was a composite of 30-day post-treatment all-cause mortality or relapse, defined as positive blood culture(s) with the same species during the follow-up. Secondary outcomes were 90-day post-treatment all-cause mortality, relapse, CDI, a new infection or colonization with a more resistant or multidrug-resistant bacteria and the length of hospital stay. A more resistant bacteria was defined by the observation of a phenotypic resistance to an antibiotic to which the bacteria involved in the septic thrombosis was susceptible before exposure to AT. Systematic active surveillance for multidrug-resistant bacteria was not performed in our institution.

## Patient consent statement
According to French law, no patient consent was required to collect and analyze retrospective and pseudonymized data. This study was approved by the Grading Committee of Research Projects from Rouen University Hospital (number 879).

## Statistical analysis

Quantitative variables were described as mean and standard deviation (SD) or median and interquartile range (IQR). Categorical data were reported as numbers and percentages. The $\chi^2$ test or Fisher's exact test were used for qualitative variables and Student's t test or Mann-Whitney test were used for quantitative variables, as appropriate. A p value <0.05 was considered statistically significant. Confidence intervals were calculated at 95%.

Propensity-scores (PS) were calculated using a series of univariable Cox proportional hazard models to determine which patient characteristics were associated with the choice of treatment duration group. A covariate (patient characteristic) was included in the PS model if at least one of the following criteria was true for at least one of the outcomes: (i) the absolute value of the parameter estimate was at least 0.2 for at least one level of the covariate or (ii) the p value was less than 0.01 for at least one level of the covariate [19]. Applying these criteria, the following variables were included: age, gender, hospital ward, immunosuppression, CCWI, permanent foreign device, certain or possible CRBSI, presence of bacteremia, microorganism type, sepsis or septic shock, catheter type, time between the first microbiological documentation and catheter removal and initiation of effective AT and curative anticoagulation. We assessed the balance of the covariates between short and prolonged-course treatment groups using standardized differences and variance ratios. Standardized differences of <10% and variance ratios of <10% from 1.0 were considered negligible.

Weights were constructed as the inverse of the probability of being in the short-course group (1/p) among those actually in the short-course group, and as the inverse of the probability of being in the prolonged-course group (1/1-p) among those in the prolonged-course group.

We presented incidence of death or relapse 30 days and 90 days after treatment discontinuation on cumulative incidence curves with unweighting and inverse probability of treatment weighting (IPTW).

Cox proportional hazard models were used to compute hazard ratio (HR) and IPTW hazard ratio (wHR) with 95% confidence intervals (95% CIs). The Hosmer-Lemeshow test was used to assess the fit of regression models.

Sensitivity analysis was performed by including only patients with a certain CRBSI. The following variables were included in the propensity-score: age, gender, hospital ward, immunosuppression, CCWI, permanent foreign device, microorganism type, sepsis or septic shock, catheter type, time between the first microbiological documentation and catheter removal and initiation of effective AT and curative anticoagulation.
Data analysis was performed using SAS Enterprise Guide version 8.1 software.

# RESULTS

## Patient characteristics

Between January 2015 and December 2020, 3592 Doppler ultrasonography reports were reviewed, finding 750 DVT of the upper limb. After exclusion, data from 172 adult patients were analyzed: 68 in the short-course AT group and 104 in the prolonged-course AT group. Finally, 163 patients were analyzed with the PS as data were missing for 4 patients regarding the covariate "curative anticoagulation" and for 5 patients regarding the covariate "time between the first microbiological documentation and catheter removal" (Figure 1).

Patient characteristics are presented in Table 1. The median age was 63 (52.5-70) years old, 73 patients (42.4%) were female and the median overall CCWI was 5 (3-8). The median duration of AT was 16 (13-21) days in the short-course group and 30 (25.5-42) days in the prolonged-course group. As expected, the majority of short-course treatments were administered after 2017. Baseline characteristics displayed some significant differences: gender, hospital ward, immunosuppression, presence of permanent foreign device, possible or certain CRBSI, presence of bacteremia, type of catheter, time between the first microbiological documentation and catheter removal and initiation of effective AT and curative anticoagulation. Duration of curative anticoagulation was unavailable for 45 patients. Among the 98 other patients, 39% received 6 weeks or less curative anticoagulation, 37% received more than 6 weeks and 24% were under long-term anticoagulation.

The proportion of *S. aureus*, *Candida* spp. and non-fermenting Gram-negative bacilli (NFGNB) was higher in the prolonged-course group (43.3% versus 23.5%), with a clear imbalance concerning *S. aureus* infection (28.9% versus 13.2%). Overall, the most frequently isolated species were coagulase-negative staphylococci (CoNS): 35.5%, followed by *S. aureus*: 22.7%, Gram-negative bacilli 9.9%, *Candida* spp. 7.6% and NFGNB 5.2%. Among the 56 possible CRBSI, 33 (59%) presented clinical symptoms (purulence or inflammation) or the diagnosis was confirmed by an infectious diseases specialist.

## Primary outcome

In both unweighted and weighted analyses, we found no significant difference in terms of 30-day all-cause mortality or relapse between short and prolonged AT durations. In the unweighted analyses, by day 30 post-treatment, 4/68 (5.9%) and 15/104 (14.4%) patients died or experienced relapse in the short-course and prolonged-course groups, respectively (HR, 2.55; 95% CI, 0.85-7.69; p=.096) (Table 2, Figure 2A). After propensity weighting, on day 30 post-treatment, 4/66 (6.1%) and 14/97 (14.4%) patients died or experienced relapse in the short-course and prolonged-course groups, respectively (wHR, 2.16; 95% CI, 0.68-6.88; p=.192) (Table 2, Figure 2B). The c-statistic value of the propensity score model was 0.807.
In univariate analysis, short-course AT duration was not associated with 30-day all-cause mortality or relapse (p= .081) (Supplementary Table S1). Also, infections due to S. aureus, Candida spp. or NFGNB were not associated with a difference in the primary outcome (p= .619) (Supplementary Table S1). Palliative care, hospitalization in a medical ward, catheter type, indication for catheter placement and time between the first microbiological documentation and catheter removal were significantly associated with an increased risk of 30-day mortality or relapse (Table 3). In multivariate analysis, these associations were not significant (Table 3).

## Secondary outcomes

Using the propensity score, we found no significant difference between short and prolonged AT groups for 90-day all-cause mortality 11/66 (16.7%) versus 21/97 (21.6%) respectively (wHR, 1.01; 95% CI, 0.49-2.05; p= .987) and 90-day relapse 1/66 (1.5%) versus 2/97 (2.1%) respectively (wHR, 1.13; 95% CI, 0.08-15.62; p= .928) (Table 2, Supplementary Figure S1.B. and Supplementary Figure S3.B.). There were 2 (2.9%) CDI in the short-course AT group whereas none occurred in the prolonged-course AT group (not significant, p= .155) (Table 4). There were 2 (2.9%) reports of new colonization or infection with a more or multidrug-resistant organism in the short-course group and 5 (4.8%) in the prolonged-course group (not significant, p= .705) (Table 4). The length of hospital stay was not significantly different between the two groups, with a median of 33 days and 30 days in the short-course and the prolonged-course groups, respectively (p= .536) (Table 4).

## Sensitivity analysis

Data from 116 adult patients with certain CRBSI were analyzed: 35 in the short-course AT group and 81 in the prolonged-course AT group. Finally, 113 patients were analyzed with the PS as data were missing for 1 patient regarding the covariate “curative anticoagulation” and for 2 patients regarding the covariate “time between the first microbiological documentation and catheter removal”. Patient characteristics are presented in Supplementary Table S2.

Performing our analyses including only patients with certain CRBSI had no effect on the findings of the study. In both unweighted and weighted analyses, we found no significant difference in terms of 30-day all-cause mortality or relapse between short and prolonged AT durations. In the unweighted analyses, by day 30 post-treatment, 3/35 (8.6%) and 13/81 (16.0%) patients died or experienced relapse in the short-course and prolonged-course groups, respectively (HR, 1.92; 95% CI, 0.55-6.72; p= .310) (Table 2, Figure 3A). After propensity weighting, on day 30 post-treatment, 3/34 (8.8%) and 13/79 (16.5%) patients died or experienced relapse in the short-course and prolonged-course groups, respectively (wHR, 2.10; 95% CI, 0.54-8.20; p= .286) (Table 2, Figure 3B). The c-statistic value of the propensity score model was 0.778.

In univariate analysis, short-course AT duration was not associated with 30-day all-cause mortality or relapse (p= .385) (Supplementary Table S3). Also, infections due to S. aureus, Candida spp. or NFGNB were not associated with a difference in the primary outcome (p= .663) (Supplementary
Table S3). Palliative care, hospitalization in a medical ward, catheter type, indication for catheter placement and time between the first microbiological documentation and catheter removal were significantly associated with an increased risk of 30-day mortality or relapse (Table 3). In multivariate analysis, these associations were not significant (Table 3).

Using the propensity score, we found no significant difference between short and prolonged AT groups for 90-day all-cause mortality 6/34 (17.6%) versus 16/79 (20.3%) respectively (wHR, 1.12; 95% CI, 0.43-2.89; p= .819) and 90-day relapse 1/34 (2.9%) versus 2/79 (2.5%) respectively (wHR, 1.14; 95% CI, 0.07-18.81; p= .928) (Table 2, Supplementary Figure S2.B. and Supplementary Figure S4.B.). There was 1 (2.9%) CDI in the short-course AT group whereas none occurred in the prolonged-course AT group (not significant, p= .302) (Table 4). There was 1 (2.9%) reports of new colonization or infection with a more or multidrug-resistant organism in the short-course group and 5 (6.2%) in the prolonged-course group (not significant, p= .666)(Table 4). The length of hospital stay was not significantly different between the two groups, with a median of 36 days and 30 days in the short-course and the prolonged-course groups, respectively (p= .359) (Table 4).

DISCUSSION

In this monocentric propensity-weighted retrospective study, we found that patients receiving 21
days or less AT for catheter-related septic DVT have a similar risk of death and relapse within 30
days after treatment discontinuation as patients receiving prolonged-course AT.

Current IDSA guidelines for catheter-related septic DVT suggest prescribing AT for a total length of 3 to 6 weeks, based on a low quality of evidence due to scarcity of studies on this subject [7]. Some experts suggest a unique treatment duration as long as 3 weeks [17]. The microbiological epidemiology in our study was in accordance with previous studies [6,20] and the PS allowed us to reduce the effects of some assessed confounding factors and to balance out the differences between the two groups, in particular the higher proportion of *S. aureus* and NFGNB infection in the prolonged-course group. Nevertheless, we were not able to analyze the outcomes according to microorganisms due to the size of study. Furthermore, some data suggest that treatment duration reduction should not be done in specific populations or for particular microbial species. Indeed, shorter-course AT (14 days) for *S. aureus* uncomplicated CRBSI is not recommended for immunosuppressed patients due to an increased risk of death [7]. Wilson et al. found that overall mortality rate was significantly lower for patients receiving 28 days or more of AT for catheter-related *S. aureus* DVT than patients receiving less than 28 days of AT [13]. In *Candida* septic thrombosis, AT duration in survivors is always prolonged (more than 4 weeks) whereas fatal cases have received shorter-course AT as described by Strinden in 8 reported cases [14]. In our study, only 13 patients suffered from catheter-related septic DVT due to *Candida* spp.. Therefore, shortening AT duration for fungal and *S. aureus* infections should be done with caution
considering these limited data. Additionally, oncohematologic patients were underrepresented because of our monocentric design, excluding hematologic patients treated in a different hospital.

Possible CRBSIs were included despite the risk of lower specificity of this definition, as for half of these infections, we found additional arguments to enhance diagnostic performance (clinical symptoms or confirmed diagnosis by an infectious diseases specialist). Fewer patients with certain CRBSI-DVT diagnoses were noticed in the short-course AT group and therefore possibly more non-septic thromboses were treated in this group, leading to the lack of difference observed in the study. However, we have taken these limitations into account by performing a sensitivity analysis based only on certain CRBSIs. Nevertheless, confirming the septic nature of a thrombus is challenging as its microbiological culture is almost never realized. Some authors suggest using PET/CT (positron emission tomography combined with computed tomography) in order to confirm septic thrombosis in case of bacteremia associated with catheter-related DVT. In a retrospective study, Gompelman et al. found that 90-day all-cause mortality or relapse were not significantly different in patients with non-remarkable [¹⁸F]FDG (2-[¹⁸F]fluoro-2-deoxy-D-glucose)-PET/CT uptake receiving 14-day AT or oral switch therapy, compared to patient treated with prolonged-course intravenous AT for *S. aureus* catheter-related DVT [21]. Nevertheless, due to prevalence of catheter-related DVT, cost and accessibility of PET such [¹⁸F]FDG-PET/CT-guided AT duration should be prospectively evaluated.

Reduction of AT duration is a keystone of antimicrobial stewardship, considering the potential risks of excessive AT duration: CDI, new resistance and longer hospital stays [9, 22, 23]. Due to low incidence of CDI and multidrug resistance bacteria, our study did not provide sufficient evidence of improvement of these metrics with shorter-course compared to prolonged-course AT. The similar length of hospital stay in both groups could have been explained by a more detailed analysis of the reasons for hospitalization to assess the proportion of hospital stay attributable to septic thrombosis and its treatment and the one attributable to other conditions in this oncologic population. Moreover, outpatient parenteral antimicrobial therapy could have reduced the length of hospital stay, despite a longer duration of antibiotic therapy.

The major limitation of our study is its retrospective design. Potential selection biases in that some prognostic factors may have influenced treatment decision, as clinical severity, that we could not accurately characterize with a scoring. We tried to overcome these biases with the use of a propensity score-weighted analysis and groups were well-balanced in IPTW analysis. However, we cannot exclude the possibility of additional, unmeasured confounding factors that could impact the association between AT duration and mortality or relapse. Thanks to available death records from the national registry, we had no missing data concerning all-cause mortality and we made sure that there was a regular hospital follow-up, to monitor the absence of relapse.

Future fields of study could focus on the development of better diagnostic methods of septic thrombosis using nuclear imaging methods. Moreover, wide variability in AT duration suggests a
need to produce high-quality evidence to identify optimal AT duration according to etiology
microorganism. Further prospective and randomized trials are needed to validate our findings.

In conclusion, our study provides interesting data regarding optimal treatment duration of catheter-related septic DVT. A 21-day AT for such infections appears as safe as longer-course AT. Nevertheless, pending additional studies, consideration should be given to prolonged treatment durations in patients with *Candida* spp. septic DVT and in oncohematologic patients.

**Financial support.** This work was not supported by any relevant funding sources.

**Potential conflicts of interest.** The authors report no conflict of interest.

**Acknowledgments.** The authors are grateful to Anaïs Lesourd for her support in editing the manuscript.

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TABLES
<table><caption>Table 1. Baseline characteristics of adults with catheter-related septic deep venous thrombosis receiving short- or prolonged-course AT.</caption><thead><tr><th></th><th>Total<br>n=172</th><th>Short-course<br>n=68</th><th>Prolonged-course<br>n=104</th><th>p value</th></tr></thead><tbody><tr><td><strong>Patient general status</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Age, years, median (IQR)</td><td>63 (52.5-70)</td><td>65 (53-70.5)</td><td>63 (51.5-69)</td><td>.499</td></tr><tr><td>Female sex</td><td>73 (42.4)</td><td>22 (32.3)</td><td>51 (49.0)</td><td>.030</td></tr><tr><td>BMI (n=169), kg/m², mean (SD)</td><td>24.8 (6.2)</td><td>25.1 (5.4)</td><td>24.6 (6.7)</td><td>.586</td></tr><tr><td>Surgical ward</td><td>67 (39.2)</td><td>36 (52.9)</td><td>31 (30.1)</td><td>.003</td></tr><tr><td>Medical ward</td><td>104 (60.8)</td><td>32 (47.1)</td><td>72 (69.9)</td><td></td></tr><tr><td>Period</td><td></td><td></td><td></td><td></td></tr><tr><td>2014-2017</td><td>66 (38.4)</td><td>20 (29.4)</td><td>46 (44.2)</td><td>.050</td></tr><tr><td>2018-2020</td><td>106 (61.6)</td><td>48 (70.6)</td><td>58 (55.8)</td><td></td></tr><tr><td><strong>Underlying conditions</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Solid tumor</td><td>93 (54.1)</td><td>40 (58.8)</td><td>53 (51.0)</td><td>.312</td></tr><tr><td>Hematologic malignancy</td><td>6 (3.5)</td><td>3 (4.4)</td><td>3 (2.9)</td><td>.682</td></tr><tr><td>Immunocompromised</td><td>67 (39.0)</td><td>20 (29.4)</td><td>47 (45.2)</td><td>.038</td></tr><tr><td>Palliative care</td><td>11 (6.4)</td><td>3 (4.4)</td><td>8 (7.7)</td><td>.530</td></tr><tr><td>CCWI, median (IQR)</td><td>5 (3-8)</td><td>6 (3-8)</td><td>5 (2-8)</td><td>.592</td></tr><tr><td>Permanent foreign device</td><td>20 (11.6)</td><td>13 (19.1)</td><td>7 (6.7)</td><td>.013</td></tr><tr><td><strong>Microbiological data</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Certain CRBSI</td><td>116 (67.4)</td><td>35 (51.5)</td><td>81 (77.9)</td><td>.0003</td></tr><tr><td>Bacteremia</td><td>128 (74.4)</td><td>40 (58.8)</td><td>88 (84.6)</td><td>.0003</td></tr><tr><td>Bacteremia duration (n=120), days, median (IQR)</td><td>4 (2-6)</td><td>4 (2-5)</td><td>4 (2-6)</td><td>.377</td></tr><tr><td>CoNS</td><td>61 (35.5)</td><td>27 (39.7)</td><td>34 (32.7)</td><td>/</td></tr><tr><td>S. aureus</td><td>39 (22.7)</td><td>9 (13.2)</td><td>30 (28.9)</td><td></td></tr><tr><td>GNB</td><td>17 (9.9)</td><td>6 (8.8)</td><td>11 (10.6)</td><td></td></tr><tr><td>Candida spp.</td><td>13 (7.6)</td><td>5 (7.4)</td><td>8 (7.7)</td><td></td></tr><tr><td>NFGNB</td><td>9 (5.2)</td><td>2 (2.9)</td><td>7 (6.7)</td><td></td></tr><tr><td>Others</td><td>33 (19.2)</td><td>19 (27.9)</td><td>14 (13.5)</td><td></td></tr><tr><td><strong>Biological data</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Creatinin, µmol/L, median (IQR)</td><td>67 (49-95.5)</td><td>67 (46-89)</td><td>70 (50-99)</td><td>.180</td></tr><tr><td>Maximal CRP (n=166), mg/L, median (IQR)</td><td>109.5 (55-192)</td><td>93.5 (51.5-190.5)</td><td>113 (57-192)</td><td>.701</td></tr><tr><td><strong>Clinical data</strong></td><td></td><td></td><td></td><td></td></tr></tbody></table>
<table><caption>Table 1. (continued)</caption><tr><td>Fever (n=152)</td><td>147 (96.7)</td><td>62 (98.4)</td><td>85 (95.5)</td><td>.404</td></tr><tr><td>Sepsis or septic shock</td><td>28 (16.3)</td><td>8 (11.8)</td><td>20 (19.2)</td><td>.195</td></tr><tr><td>ICU admission</td><td>26 (15.1)</td><td>10 (14.7)</td><td>16 (15.4)</td><td>.903</td></tr></table>

<table><tbody><tr><td colspan="5"><strong>Thrombosis</strong></td></tr><tr><td>Total thrombosis (n=153)</td><td>14 (10.0)</td><td>5 (8.5)</td><td>9 (11.1)</td><td>.608</td></tr><tr><td>&gt;1 venous segment</td><td>24 (14.0)</td><td>8 (11.8)</td><td>16 (15.4)</td><td>.503</td></tr><tr><td colspan="5"><strong>Catheter</strong></td></tr><tr><td>Type</td><td></td><td></td><td></td><td></td></tr><tr><td>Short-term CVC</td><td>63 (36.6)</td><td>36 (52.9)</td><td>27 (26.0)</td><td>.001</td></tr><tr><td>Long-term CVC</td><td>53 (30.8)</td><td>13 (19.1)</td><td>40 (38.4)</td><td></td></tr><tr><td>Other catheters</td><td>56 (32.6)</td><td>19 (28.0)</td><td>37 (35.6)</td><td></td></tr><tr><td>Duration (n=145), days, median (IQR)</td><td>15 (8-28)</td><td>15.5 (8-26)</td><td>14 (7-31)</td><td>.968</td></tr><tr><td>Indication</td><td></td><td></td><td></td><td></td></tr><tr><td>Parenteral nutrition</td><td>34 (20.7)</td><td>14 (21.5)</td><td>20 (20.2)</td><td>.248</td></tr><tr><td>Chemotherapy</td><td>47 (28.7)</td><td>14 (21.5)</td><td>33 (33.3)</td><td></td></tr><tr><td>Other</td><td>83 (50.6)</td><td>37 (57.0)</td><td>46 (46.5)</td><td></td></tr><tr><td colspan="5"><strong>Management</strong></td></tr><tr><td>Catheter removal</td><td>167 (97.1)</td><td>67 (98.5)</td><td>100 (96.2)</td><td>/</td></tr><tr><td>AT duration, days, median (IQR)</td><td>24.5 (19-31)</td><td>16 (13-21)</td><td>30 (25.5-42)</td><td>&lt;.0001</td></tr><tr><td>AT duration &gt; 14 days</td><td>147 (85.5)</td><td>43 (63.2)</td><td>104 (100)</td><td>/</td></tr><tr><td>Exclusive oral treatment</td><td>4 (2.3)</td><td>3 (4.4)</td><td>1 (1.0)</td><td>.302</td></tr><tr><td>Oral switch</td><td>17 (9.9)</td><td>7 (10.3)</td><td>10 (9.6)</td><td>.884</td></tr><tr><td>Curative anticoagulation (n=168)</td><td>143 (85.1)</td><td>52 (77.6)</td><td>91 (90.1)</td><td>.026</td></tr><tr><td>Anticoagulation duration (n=143)</td><td></td><td></td><td></td><td>.063</td></tr><tr><td>&le; 6 weeks</td><td>38 (26.6)</td><td>8 (15.4)</td><td>30 (33.0)</td><td></td></tr><tr><td>&gt; 6 weeks</td><td>36 (25.2)</td><td>14 (26.9)</td><td>22 (24.2)</td><td></td></tr><tr><td>Long-term anticoagulation</td><td>24 (16.8)</td><td>13 (25)</td><td>11 (12.1)</td><td></td></tr><tr><td>Unknown</td><td>45 (31.5)</td><td>17 (32.7)</td><td>28 (30.8)</td><td></td></tr></tbody></table>

Data are presented as numbers (%) unless otherwise indicated.

Abbreviations: AT: antimicrobial therapy; IQR: Interquartile range; BMI: body mass index; SD: standard deviation; CCWI: Charlson comorbidity weighted-index; CRBSI: catheter-related bloodstream infection; CoNS: coagulase-negative staphylococci; GNB: Gram-negative bacilli; NFGNB: non-fermenting Gram-negative bacilli; CRP: C-reactive protein; ICU: intensive care unit; CVC: central venous catheter; AT: antimicrobial therapy.
<table><caption>Table 2. Hazard ratios of 30-day all-cause mortality or relapse, 90-day all-cause mortality and 90-day relapse in patients treated with short- and prolonged-course AT, before and after propensity score weighting according to CRBSI diagnosis.</caption><thead><tr><th rowspan="2"></th><th colspan="4">Total population<br>(possible and certain CRBSIs)</th><th colspan="4">Sensitivity analysis<br>(certain CRBSIs)</th></tr><tr><th>HR<br>(95% CI)<br>n=172</th><th>p value</th><th>wHR<br>(95% CI)<br>n=163</th><th>p value</th><th>HR<br>(95% CI)<br>n=116</th><th>p value</th><th>wHR<br>(95% CI)<br>n=113</th><th>p value</th></tr></thead><tbody><tr><td>30-day all-cause<br>mortality or relapse</td><td>2.55<br>(0.85-7.69)</td><td>.096</td><td>2.16<br>(0.68-6.88)</td><td>.192</td><td>1.92<br>(0.55-6.72)</td><td>.310</td><td>2.10<br>(0.54-8.20)</td><td>.286</td></tr><tr><td>90-day all-cause<br>mortality</td><td>1.52<br>(0.74-3.09)</td><td>.253</td><td>1.01<br>(0.49-2.05)</td><td>.987</td><td>1.28<br>(0.50-3.24)</td><td>.604</td><td>1.12<br>(0.43-2.89)</td><td>.819</td></tr><tr><td>90-day relapse</td><td>0.68<br>(0.10-4.86)</td><td>.705</td><td>1.13<br>(0.08-15.62)</td><td>.928</td><td>0.45<br>(0.06-3.18)</td><td>.423</td><td>1.14<br>(0.07-18.81)</td><td>.928</td></tr></tbody></table>

Abbreviations: AT: antimicrobial therapy; CRBSI: catheter-related bloodstream infection; HR: hazard ratio; wHR: inverse probability of treatment weighted hazard ratio; CI: confidence interval.

<table><caption>Table 3. Significant risk factors of 30-day all-cause mortality or relapse in univariate and multivariate analysis according to CRBSI diagnosis.</caption><thead><tr><th rowspan="2"></th><th colspan="4">Total population<br>(possible and certain CRBSIs)<br>n=172</th><th colspan="4">Sensitivity analysis<br>(certain CRBSIs)<br>n=116</th></tr><tr><th colspan="2">Univariate analysis</th><th colspan="2">Multivariate analysis</th><th colspan="2">Univariate analysis</th><th colspan="2">Multivariate analysis</th></tr><tr><th></th><th>OR<br>(95% CI)</th><th>p value</th><th>OR<br>(95% CI)</th><th>p value</th><th>OR<br>(95% CI)</th><th>p value</th><th>OR<br>(95% CI)</th><th>p value</th></tr></thead><tbody><tr><td>Hospital ward</td><td>n=171</td><td></td><td>n=171</td><td></td><td>n=116</td><td></td><td>n=116</td><td></td></tr><tr><td>- Surgical</td><td>Reference</td><td></td><td>Reference</td><td></td><td>Reference</td><td></td><td>Reference</td><td></td></tr><tr><td>- Medical</td><td>6.35<br>(1.42-28.46)</td><td>.016</td><td>2.20<br>(0.39-12.40)</td><td>.373</td><td>4.67<br>(1.01-21.65)</td><td>.049</td><td>1.58<br>(0.23-10.79)</td><td>.638</td></tr><tr><td>Palliative care</td><td>n=172</td><td></td><td>n=172</td><td></td><td>n=116</td><td></td><td>n=116</td><td></td></tr><tr><td>-No</td><td>Reference</td><td></td><td>Reference</td><td></td><td>Reference</td><td></td><td>Reference</td><td></td></tr><tr><td>-Yes</td><td>8.75<br>(2.37-32.35)</td><td>.001</td><td>4.51<br>(0.95-21.34)</td><td>.057</td><td>16.33<br>(2.70-98.82)</td><td>.002</td><td>6.49<br>(0.63-66.29)</td><td>.115</td></tr><tr><td>Catheter type</td><td>n=172</td><td></td><td>n=172</td><td></td><td>n=116</td><td></td><td>n=116</td><td></td></tr><tr><td>- Short-term CVC</td><td>Reference</td><td></td><td>Reference</td><td></td><td>Reference</td><td></td><td>Reference</td><td></td></tr></tbody></table>
<table><tbody><tr><td>- Long-term CVC</td><td>12.68<br>(1.55-103.75)</td><td><strong>.018</strong></td><td>3.20<br>(0.21-48.59)</td><td>.401</td><td>10.85<br>(1.28-91.78)</td><td><strong>.029</strong></td><td>1.36<br>(0.06-31.43)</td><td>.849</td></tr><tr><td>- Other catheters</td><td>11.87<br>(1.45-96.99)</td><td><strong>.021</strong></td><td>5.06<br>(0.41-61.85)</td><td>.204</td><td>7.82<br>(0.91-66.83)</td><td>.060</td><td>1.88<br>(0.11-32.97)</td><td>.666</td></tr><tr><td><strong>Catheter indication</strong></td><td>n=164</td><td></td><td>n=164</td><td></td><td>n=111</td><td></td><td>n=111</td><td></td></tr><tr><td>- Chemotherapy</td><td>Reference</td><td></td><td>Reference</td><td></td><td>Reference</td><td></td><td>Reference</td><td></td></tr><tr><td>- Parenteral nutrition</td><td>0.56<br>(0.16-2.00)</td><td>.376</td><td>0.61<br>(0.13-2.77)</td><td>.519</td><td>0.36<br>(0.09-1.53)</td><td>.169</td><td>0.40<br>(0.07-2.22)</td><td>.298</td></tr><tr><td>- Other</td><td>0.21<br>(0.06-0.74)</td><td><strong>.015</strong></td><td>0.61<br>(0.13-2.83)</td><td>.532</td><td>0.10<br>(0.02-0.48)</td><td><strong>.004</strong></td><td>0.20<br>(0.02-1.98)</td><td>.170</td></tr><tr><td><strong>Time between the first microbiological documentation and catheter removal</strong></td><td>n=167</td><td></td><td>n=167</td><td></td><td>n=114</td><td></td><td>n=114</td><td></td></tr><tr><td></td><td>1.12<br>(1.01-1.25)</td><td><strong>.032</strong></td><td>1.06<br>(0.91-1.22)</td><td>.462</td><td>1.14<br>(1.01-1.30)</td><td><strong>.041</strong></td><td>1.05<br>(0.86-1.29)</td><td>.609</td></tr></tbody></table>

Abbreviations: CRBSI: catheter-related bloodstream infection; OR: Odds ratio; CI: confidence interval; CVC: central venous catheter.

<table><caption>Table 4. Proportion of 90-day CDI and 90-day colonization or infection with a more or multidrug-resistant organism and length of hospital stay in patients treated with short- and prolonged-course AT according to CRBSI diagnosis.</caption><thead><tr><th rowspan="2"></th><th colspan="3">Total population<br>(possible and certain CRBSIs)<br>n=172</th><th colspan="3">Sensitivity analysis<br>(certain CRBSIs)<br>n=116</th></tr><tr><th>Short-course<br>n=68</th><th>Prolonged-<br>course<br>n=104</th><th>p value</th><th>Short-course<br>n=68</th><th>Prolonged-<br>course<br>n=104</th><th>p value</th></tr></thead><tbody><tr><td>90-day CDI</td><td>2 (2.9%)</td><td>0 (0.0%)</td><td>.155</td><td>1 (2.9%)</td><td>0 (0.0%)</td><td>.302</td></tr><tr><td>90-day colonization or infection<br>with a more or multidrug-resistant<br>organism</td><td>2 (2.9%)</td><td>5 (4.8%)</td><td>.705</td><td>1 (2.9%)</td><td>5 (6.2%)</td><td>.666</td></tr><tr><td>Length of hospital stay (n=170),<br>days, median (IQR)</td><td>33.0<br>(17-58.0)</td><td>30.0<br>(19.0-48.0)</td><td>.536</td><td>36.0<br>(17-79.0)</td><td>30.0<br>(19.0-49.0)</td><td>.359</td></tr></tbody></table>

Abbreviations: AT: antimicrobial therapy; CRBSI: catheter-related bloodstream infection; CDI: Clostridioides difficile infection; IQR: interquartile range.

## FIGURES

**Figure 1.** Study flowchart.
<figure><img src="image_2.png" /><figcaption>**Figure 2.** Cumulative event curves for 30-day all-cause mortality or relapse in the unweighted (A) and inverse probability of treatment weighted (B) samples in total population.</figcaption></figure>
A.

<figure><img src="image_3.png" /></figure>

B.

<figure><img src="image_4.png" /></figure>
<figure><img src="image_5.png" /><figcaption>**Figure 3.** Cumulative event curves for 30-day all-cause mortality or relapse in the unweighted (A) and inverse probability of treatment weighted (B) samples in patients with certain catheter-related bloodstream infection.</figcaption></figure>