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Temporal trends, risk factors and outcomes of infections due to extended-spectrum β-lactamase producing Enterobacterales in Swiss solid organ transplant recipients between 2012 and 2018

Temporal trends, risk factors and outcomes of infections due to extended-spectrum β-lactamase... Background: The burden of antimicrobial resistance is high in solid organ transplant (SOT ) recipients. Among Swiss SOT recipients, we assessed temporal trends of ESBL-producing Enterobacterales (ESBL-E), identified risk factors for ESBL-E, and assessed the impact of resistance on patient outcome. Methods: Data from the Swiss Transplant Cohort Study (STCS), a nationwide prospective cohort of SOT-recipients, were analysed. Temporal trends were described for ESBL-detection among Escherichia coli and non-Escherichia coli. In a nested case–control study, cases with ESBL-E infection were 1:1 matched (by time since transplantation, organ transplant, pathogen) to controls infected with non-ESBL-E. Factors associated with resistance and with unfavourable 30-day outcome (death, infection relapse, graft loss) were assessed. Results: From 2012 to 2018, we identified 1′212 infection episodes caused by Enterobacterales in 1′074 patients, thereof 11.4% (138/1′212) caused by ESBL-E. The proportion of ESBL-production among Escherichia coli remained stable over time (p = 0.93) but increased for non-E. coli (p = 0.02) Enterobacterales. In the case–control study (n = 102), antibiotic pre-treatment was independently associated with ESBL-production (aOR = 2.6, 95%-CI: 1.0–6.8, p = 0.046). Unfavourable outcome occurred in 24/51 (47%) cases and 9/51 (18%) controls (p = 0.003). Appropriate empiric antibi- otic therapy was the only modifiable factor associated with unfavourable outcome. Conclusions: In Swiss SOT-recipients, proportion of infections with ESBL-producing non-E. coli Enterobacterales increased in recent years. Antibiotic pre-treatment represents a risk factor for ESBL-E. Improving appropriateness of empiric antibiotic treatment might be an important measure to reduce unfavourable outcome, which was observed in almost half of SOT-recipients with ESBL-E infections. *Correspondence: philipp.kohler@kssg.ch Philipp Kohler and Aline Wolfensberger contributed equally to this work Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Kohler et al. Antimicrob Resist Infect Control (2021) 10:50 Page 2 of 12 Keywords: Solid organ transplant, Renal transplant, Extended-spectrum beta-lactamase, Enterobacterales, Switzerland Introduction infectious diseases working group [10]. Six participating Antimicrobial resistance is a major threat to the achieve- transplantation centres (Basel, Bern, Geneva, Lausanne, ments of modern medicine. Solid organ transplant (SOT) St. Gallen and Zurich) undergo regular data monitoring recipients are at particular risk for acquisition of resistant and in-depth data quality audits. pathogens, most likely due to increased healthcare and antibiotic exposure [1]. Specifically in SOT-recipients, Study design and participants donor-derived infections due to resistant pathogens are We included SOT-recipients of heart, liver, kidney, and associated with significant burden of disease [2]. Over kidney-pancreas grafts aged 18 or older enrolled in the the last decade, Gram-negative bacteria have become STCS. Lung transplant recipients were excluded because the focus of attention regarding antibiotic resistance for of the particular challenge to distinguish colonisation both the general hospital population and SOT-recipients. from infection in this population. From August 2012 A recent systematic review reported that 20% of SOT- onwards, information about ESBL production has been recipients are colonized with ESBL-producing Escheri- available in the STCS database. For the analysis of tem- chia coli [3]. Colonization by ESBL-producing isolates poral trends, we thus retrieved all infection episodes is an important risk factor for subsequent infection [4]; diagnosed between August 2012 and December 2018. about one in 10 renal transplant recipients (RTR) colo- Participants contributed a maximum of one episode per nized by ESBL-producing bacteria experiences a urinary year. Those with episodes caused by resistant and suscep - tract infection (UTI) caused by these pathogens [5]. tible pathogens were counted as having had one resistant Compared to infections with non-resistant pathogens, episode and were not eligible as controls. Patients with those caused by resistant bacteria are associated with an episodes caused by ESBL-producing E. coli and non-E. increased risk for recurrent infection, allograft dysfunc- coli Enterobacterales in the same year were counted in tion and excess mortality [5, 6]. Case-fatality infection both groups. with resistant pathogens is high (up to 50% in the case A nested case–control study was performed to assess of bacteremia due to carbapenem-resistant Enterobacte- risk factors for infection by ESBL-E and its effect on rales) [7–9]. 90-day outcome afterwards. As opposed to the analy- Among Swiss SOT recipients, most infections in the sis for temporal trends (episode level) this analysis first year post-transplantation are caused by Entero - was performed on the patient-level (i.e. only one epi- bacterales. Among E. coli and Klebsiella pneumoniae, sode per patient considered). We included all patients ESBL-production was observed in 15%, whereas no with infections due to ESBL-producing (or MDR and carbapenemase-producing Enterobacterales (CPE) were extended-spectrum cephalosporine-resistant, see below) identified in our cohort [10]. Here, we aimed to assess Enterobacterales, diagnosed between August 2012 and temporal trends of ESBL-producing Enterobacterales December 2016. In case of multiple episodes caused by (ESBL-E), to identify risk factors for infections with a resistant pathogen, only the patients’ first episode after ESBL-E, and to assess the impact of ESBL-production on transplantation was considered. Cases were matched to patient outcome. controls in a 1:1 fashion, applying incidence density sam- pling according to time to first infectious episode after transplantation; type of transplanted organ and bacte- Methods rial pathogen were used as further matching criteria. Data source Controls with previous colonization by ESBL-E were The Swiss Transplant Cohort Study (STCS) is a nation - excluded. Detailed information about infections in cases wide, multi-centre, open, prospective cohort and has and controls were additionally collected via chart review enrolled all SOT-recipients in Switzerland since May and recorded in an electronic database (SecuTrial ). 2008 [11]. Clinical and laboratory data are prospec- These included administration of antibiotics within tively collected at the time of transplantation, at 6 and 30  days before infection (both therapeutic and prophy- 12  months, and annually thereafter. Infectious epi- lactic), travel history, urinary obstruction (only for RTR), sodes are identified by transplant infectious disease (ID) admission to acute or intensive care, involvement of ID physicians on a regular basis using electronic patient specialist, type, duration and effectiveness of empiric and records, according to definitions developed by the STCS definite antibiotic treatment, and 90-day outcome. Kohler  et al. Antimicrob Resist Infect Control (2021) 10:50 Page 3 of 12 Microbiology considered a key predictor. We used the change in esti- Pathogen identification and resistance testing was per - mate method as screening method for selection of co- formed on a routine basis in the microbiology labo- variables into the multivariable logistic regression model ratories serving the participating centres. Since 2012, (i.e. change of key predictor estimate > 10% after add- information about infections caused by ESBL-E is being ing the co-variable to the model) [13]. R software ver- recorded. Also, the presence of multidrug-resistance sion 3.6.1 was used for all statistical analyses; a p value (MDR) is recorded according to the European Centre for of < 0.05 was considered statistically significant. Disease Prevention and Control (ECDC) definitions [12]. For the analysis of temporal trends, the variable “ESBL- production” as reported in the database was used to Results classify resistant and susceptible pathogens. For the Temporal trends case–control study, this definition was extended to also Between 2012 and 2018, we registered 1′212 infec- include MDR pathogens with resistance to extended- tious episodes caused by Enterobacterales among 1′074 spectrum cephalosporins (ESC), i.e. 3rd or 4th genera- patients, mostly among RTR (784/1′074, 73%). Among tion cephalosporins. This approach was chosen because all isolates, ESBL-production was reported in 138/1′212 for some bacterial isolates ESBL-production was not isolates (11.4%). ESBL rates for episodes of kidney, heart, tested or reported. and liver transplant patients were 13.2% (168/1271), 12.4% (11/89), and 13.6% (30/221), respectively; across the six participating centres, the proportion of ESBL- Definitions producing isolates ranged from 8.3 to 18.3%. The propor - In brief, proven infection was defined as the presence of tion of ESBL E. coli remained stable over time (p = 0.93) clinical signs or symptoms, detection of a bacterial path- whereas an increasing trend (p = 0.024) was observed for ogen, and given treatment [10]. Effectiveness of antibiotic non-E. coli Enterobacterales (Fig.  1). No temporal trend treatment was assessed according to locally performed was observed when ESBL E. coli and non-E. coli were susceptibility tests. Beta-lactam/beta-lactamase inhibitor combined (p = 0.36). combinations were considered inadequate against ESBL- E irrespective of the reported minimal inhibitory con- centration. Unfavourable outcome was defined as any of Case–control study: population and infection the following: microbiological relapse (i.e. infection with characteristics the same pathogen at same body site as the initial infec- Between 2012 and 2016, we identified 88 case patients tious episode), graft failure (defined as dialysis post renal which were matched to 88 controls. After chart review transplantation; or re-transplantation post heart or liver and revision of the original susceptibility test results, transplantation; or recurrence of insulin-dependence fol- 51 matching pairs remained for the analysis. For the 37 lowing pancreas transplant) or death, all within 90  days excluded patients, reasons for exclusion were mostly lim- after infection. ited or missing susceptibility testing (15/37) and revision of case status (14/37). Of the 51 cases and controls, 33 Statistical analysis (65%) were RTR, 4 (8%) kidney-pancreas, 9 (18%) liver A temporal trend analysis was performed to detect a or kidney-liver, and 5 (10%) heart transplant patients, pattern in occurrence of infectious episodes caused by respectively. The urinary tract was the most common site ESBL-producing E. coli and non-E. coli Enterobacte- of infection (75%). E. coli was the most frequent pathogen rales between 2012 and 2018, using Chi-squared test found in infections (75.5%), followed by K. pneumoniae for trends in proportion. In the matched subpopulation (15.7%) and other pathogens (8.8%). (including episodes which occurred between 2012 and Baseline characteristics of cases and controls were 2016), a descriptive analysis was done followed by uni- summarized in Table  1. Infections occurred a median variate and multivariable conditional logistic regression of 69  days after transplant (interquartile range [IQR]: to evaluate risk factors for infections caused by ESBL-E. 25–232), mostly (68%) within the first 6  months after Age and gender, as well as baseline characteristics associ- transplantation (Fig.  2). Patients were predominantly ated with ESBL-E infection in univariate analysis (p < 0.1) outpatients at time of diagnosis (63% for ESBL-E, 61% for were included in the multivariable model. Multicollinear- non-ESBL-E infections). ESBL-E and non-ESBL-E infec- ity was assessed calculating the variance inflation factor tions were evenly distributed among centres and years, as (cut-off > 10). were infection sites and comorbidities. Travel history was For the analysis regarding impact of resistance not available for most patients and therefore dropped on patient outcome, infection by ESBL-E itself was from further analyses. Kohler et al. Antimicrob Resist Infect Control (2021) 10:50 Page 4 of 12 Fig. 1 Proportion of patients with ESBL-producing Escherichia coli (left) and non-E. coli (right) among all patients infected with the corresponding pathogen in the Swiss Transplant Cohort Study between 2012 and 2018 Risk factors for ESBL infection (47%) patients with ESBL-E infections (p < 0.003). This Male gender (p = 0.04) and antibiotic treatment within difference was mainly due to relapse of infection (5/51 vs. 30  days prior to infection (p = 0.05) were significantly 20/51, p = 0.001), whereas graft loss (4/51 vs. 1/51) and associated with ESBL-E infection (Table  2). Antibiotic mortality (3/51 vs. 4/51) were similar in both groups. pre-treatment remained as independent risk factor for Evaluating the impact of resistance on unfavourable ESBL-E infection in multivariable analysis after correc- outcome, infection with ESBL-E was associated with tion for age, gender and underlying metabolic/endo- unfavourable (OR = 4.0, 95%-CI: 1.7–10.5, p = 0.003) and crinologic disease (adjusted OR = 2.6, 95% CI: 1.0–6.8, adequate empiric therapy (OR = 0.3, 95%-CI: 0.1–0.9, p = 0.046). p = 0.03) with favourable outcome in univariate analy- sis (Table  4). After adjusting for modifiable (adequate empiric therapy) and non-modifiable (gender and need for ICU stay after infection) factors, the effect of ESBL- Infection management and outcome E infection was still large, but not anymore signifi - Patients with susceptible and resistant pathogens were cantly associated with unfavourable outcome (adjusted similar in terms of proportion of hospital admission OR = 3.1, 95%-CI: 0.8–12.5, p = 0.10). (16/51 vs. 14/51), intensive care admission (9/51 vs. 8/51), or involvement of an ID physician for choice of treatment (22/51 vs. 27/51) (Table 3). Length of stay was longer for those with resistant (median 18  days, IQR 8.2–30  days) Discussion vs. those with susceptible pathogens (median 9, IQR In this study based on data from a prospective national 3–24  days), but did not reach statistical significance cohort representing all SOT-recipients in Switzerland, (p = 0.10). Patients with susceptible pathogens were more we show that ESBL-producing non-E. coli infections have likely to receive appropriate empiric antibiotic therapy been increasing over the last years and that antibiotic (36/51, 76%) vs. those with resistant pathogens (16/51, pre-treatment is independently associated with infection 36%) (p < 0.001). Inappropriate therapy was mostly due caused by ESBL-producing pathogens. Almost half of to late initiation (i.e. > 2 days after infection) of antibiotic patients with ESBL-E had a relapsing infection compared therapy (similar in both groups: 8/51 vs. 11/51, p = 0.44), to only 18% in those with non-ESBL E infections. Ade- or due to administration of beta-lactam/beta-lactamase quate empiric therapy, being less common among those inhibitors against resistant pathogens (1/51 vs. 10/51, with ESBL-E infection, was the only modifiable factor p = 0.004). associated with unfavourable outcome. The comprehen - Unfavourable outcome occurred in 9/51 (18%) con - sive dataset and the thorough revision of the original data trols with non-ESBL-E infections as compared to 24/51 are particular strengths of the study. Kohler  et al. Antimicrob Resist Infect Control (2021) 10:50 Page 5 of 12 Table 1 Baseline characteristics of patients infected without and with extended-spectrum beta-lactamase (ESBL)-Enterobacterales Cases (N = 51) Controls (N = 51) Male, N (%) 28 (54.9%) 17 (33.3%) Age at time of infection, mean (SD) 54.8 (12) 53.4 (14.8) Transplanted organ (matched variable) Kidney 33 (64.7%) 33 (64.7%) Kidney-pancreas 4 (7.8%) 4 (7.8%) Liver (incl kidney-liver) 9 (17.6%) 9 (17.6%) Heart 5 (9.8%) 5 (9.8%) BMI at transplantation, mean (SD) 25.5 (4.1) 25.1 (4.2) Caucasian ethnicity, N (%) 46 (90.2%) 49 (96.1%) Comorbidities, N (%) Cardiopulmonary disease 27 (52.9%) 25 (49%) Metabolic/endocrine disease 35 (68.6%) 43 (84.3%) Cancer 8 (15.7%) 6 (11.8%) Other 32 (62.7%) 31 (60.8%) Previously documented ESBL colonization 19 (37%) 0 (0%) Antibiotics (30 days before infection), N (%) 24 (47.1%) 14 (27.5%) BL/BLI 10 (37%) 6 (28.6%) Carbapenem 6 (22.2%) 3 (14.3%) Quinolone 10 (37%) 3 (14.3%) Cephalosporine 7 (25.9%) 0 (0%) Sulfamethoxazol/trimethoprim 7 (25.9%) 4 (19%) Hospital-onset, N (%) 20 (39.2%) 19 (37.3) Day of onset (median, IQR) 20 (9.5–60) 8 (6–42) Days from transplantation to infection, median (IQR) 67 (24–228) 71 (33–227) Year of 1st infection, N (%) 2012 6 (11.8%) 8 (15.7%) 2013 9 (17.6%) 13 (25.5%) 2014 14 (27.5%) 12 (23.5%) 2015 16 (31.4%) 10 (19.6%) 2016 6 (11.8%) 8 (15.7%) Infection site, N (%) Urinary tract 38 (74.5%) 39 (76.5%) With bacteremia 5 (13.2%) 10 (25.6%) Abdominal/liver 2 (3.9%) 3 (5.9%) Respiratory tract 3 (5.9%) 5 (9.8%) Surgical site 3 (5.9%) 4 (7.8%) Primary bacteremia 2 (3.9%) 1 (2.0%) Other 3 (5.9%) 1 (2.0%) If urinary tract infection, N (%) Obstruction 2/38 (5.3%) 5/39 (12.8%) Catheter 12/38 (31.6%) 17/39 (43.6%) ESBL extended-spectrum beta-lactamase, SD standard deviation, BMI body mass index, IQR interquartile range, BL/BLI beta-lactam/beta-lactamase-inhibitor Previously ESBL colonized participants were not eligible for the control group Including prophylaxis The three last decades have witnessed a global dis - propelled by various factors. Important drivers of com- semination of ESBL-producing Enterobacterales into munity-acquisition (mostly ESBL-E. coli carrying the healthcare systems and healthy populations alike [14]. plasmid-encoded bla gene) are travel to/health- CTX-M From an epidemiological perspective, their emergence is care in endemic countries or household crowding [15, Kohler et al. Antimicrob Resist Infect Control (2021) 10:50 Page 6 of 12 our cohort of SOT-recipients, we found stable numbers or ESBL-E. coli, but an increase in ESBL-non E. coli over time, a worrisome finding which has also been observed in other European SOT cohorts [18–20]. We can only speculate as to the reason for this trend. Increased in- hospital transmission of these pathogens is one possi- ble explanation, given the substantial differences in the prevalence of ESBL-producing Enterobacterales among participating centres in our study and given the many reports of resistant K. pneumoniae (and particularly high-risk clones such as ST11 or ST147) as a cause of nosocomial outbreaks among transplant and non-trans- plant patients [21–24]. In both community and hospital settings, antibiotic treatment—mainly cephalosporins but also quinolo- nes—is associated with ESBL-colonization or infection, probably due to selection (or co-selection in the case of quinolones) of ESBL-E in the gut flora of colonized patients [15, 25]. Razazi et  al. found treatment with 3rd generation cephalosporins to be predictive of ESBL-E colonization in patients admitted to intensive care [26]. Fig. 2 Histogram showing the time from transplant to onset of In a Canadian cohort of RTR, antibiotic pre-treatment infection in days for 51 cases (above) and 51 controls (below) was the strongest risk factor for detection of resistant Gram-negative bacteria in the urine [27]; in a recent study on enterobacterial bloodstream infections among 16]. In contrast, ESBL-non E. coli (mostly Klebsiella spp.) SOT-recipients in the United States, antibiotic expo- are often hospital-acquired, mainly as a result of clonal sure to trimethoprim-sulfamethoxazole and again 3rd expansion due to person-to-person transmission [17]. In generation cephalosporins were strong risk factors for Table 2 Univariable and multivariable conditional logistic regression analysis regarding risk of infection with ESBL-producing pathogen (vs. non-ESBL) Univariate Multivariable OR [95%-CI] (p value) aOR [95%-CI] (p value) Male versus female 2.4 [1.0–5.4] (0.04) 2.3 [0.9–5.0] (0.08) Age (years) at time of infection 1.0 [0.9–1.0] (0.58) 0.9 [0.9–1.0] (0.99) BMI at transplantation 1.0 [0.9–1.1] (0.92) Caucasian versus others 0.4 [0.1–2.1] (0.27) Comorbidities (yes/no) Cardiopulmonary disease 1.1 [0.6–2.3] (0.72) Metabolic/endocrine disease 0.5 [0.2–1.1] (0.10) 0.4 [0.2–1.1] (0.09) Cancer 1.4 [0.4–4.4] (0.57) Other 1.1 [0.5–2.7] (0.82) Year of infection 2012 – 2013 1.2 [0.3–4.7] (0.83) 2014 1.6 [0.3–7.1] (0.57) 2015 2.5 [0.6–11.1] (0.23) 2016 0.9 [0.2–5.3] (0.94) Antibiotics (yes/no) before infection 2.4 [1.0–5.9] (0.048) 2.6 [1.0–6.8] (0.046) ESBL extended-spectrum beta-lactamase, (a)OR (adjusted) odds ratio, CI confidence interval, BMI body mass index Any therapeutic or prophylactic antibiotic treatment within 30 days prior to infection Kohler  et al. Antimicrob Resist Infect Control (2021) 10:50 Page 7 of 12 Table 3 Management and outcome of infections caused by non-extended-spectrum beta-lactamase (ESBL)- and ESBL-producing Enterobacterales Cases (N = 51) Controls (N = 51) p value Management Hospital admission if community onset, N (%) 14 (43.8%) 16 (50.0%) 0.99 Length of stay after infection (median, IQR) 18 (8.2–30) 9 (3–24) 0.10 On intensive care after infection onset, N (%) 8 (23.5%) 9 (25.7%) 1.00 Days on intensive care (median, IQR) 5.5 (4–16) 3 (2–11) 0.38 Infectious diseases consult, N (%) 27 (52.9%) 22 (43.1%) 0.43 Initially 21 (41.2%) 16 (31.4%) 0.41 Upon microbiology results 18 (35.3%) 19 (37.3%) 1.00 Antibiotics (30 days after infection), N (%) Adequate empiric therapy 16 (35.6%) 34 (75.6%) < 0.001 Inadequate BL/BLI 10 (22.7%) 1 (2.3%) 0.004 Inadequate ceftriaxone/ceftazidime 2 (4.5%) 0 (0%) 0.15 Inadequate ciprofloxacin 5 (11.4%) 1 (2.3%) 0.09 No therapy before day 2 11 (21.5%) 8 (18.2%) 0.44 Outcome Re-admission, N (%) 15 (29.4%) 14 (27.5%) 1.00 Due to infection 12 (23.5%) 8 (15.7%) 0.35 Unfavourable outcome within 90 days, N (%) 24 (47.1%) 9 (17.6%) 0.003 Relapse 20 (39.2%) 5 (9.8%) 0.001 Graft loss 1 (2.0%) 4 (7.8%) 0.36 Death 4 (7.8%) 3 (5.9%) 1.00 ESBL extended-spectrum beta-lactamase, IQR interquartile range, BL/BLI beta-lactam/beta-lactamase-inhibitor Chi-square or Fisher’s exact test for dichotomous variables, as appropriate; Mann–Whitney U for continuous variables Administered within two days after infection diagnosis Inadequate BL/BLI were all piperacillin/tazobactam except for one case who received amoxicillin/clavulanic acid infections with ESBL-producers [28]. We could confirm and a higher rate of hospitalization [27]. Other stud- this important finding in our cohort of SOT-recipients. ies have even reported higher case fatality rates in those Due to the small sample size of the subgroups in our with resistant bacterial infections [6, 7]. In our univari- cohort, it is difficult to tell which antibiotic substances able analysis, ESBL-production was strongly associated contributed mainly to this effect. It is important to note with unfavourable outcome, which was mostly recurrent that not only cephalosporins or quinolones, but also infection among RTR. Similarly, data from a systematic beta-lactam/beta-lactamase inhibitor combinations have review showed that UTI recurrence was clearly more been independently associated with ESBL-Klebsiella common among RTR infected with ESBL-E compared to spp., at least in hospitalized non-transplant patients [29]. non-ESBL-E [5]. There are different reasons which could Consequently, we think that antibiotic stewardship pro- explain the higher recurrence rate in those with ESBL-E grams aiming at reducing the overall antibiotic use in this infections. First, as shown above, ESBL-infection devel- population is key in lowering the selection pressure for ops more often in those with previous antibiotic treat- ESBL-E and other resistant pathogens. In this context it ment. This is probably the first step in a vicious circle, is important to note that—according to a recent survey as antibiotic treatment itself might increase the risk for among European transplant centres—a majority of trans- UTI recurrence which then again exposes the patient plant physicians uses antibiotics including quinolones to antibiotic treatment [32]. Breaking this circle could and cephalosporins for asymptomatic bacteriuria in RTR be achieved by a reduction of antibiotic use. At least for despite the uncertain benefit of this intervention [30, 31]. the prevention of UTIs with non-antibiotic substances In general, SOT-recipients infected with resistant studies have shown promising results for transplant and pathogens fare worse than those infected with suscepti- non-transplant patients [33, 34]. Second, there have ble bacteria. Delmas-Frenette et al. found resistance to be been suggestions that E. coli strains like ST131, a hyper- associated with a longer duration of antibiotic treatment endemic clone often associated with ESBL-production, Kohler et al. Antimicrob Resist Infect Control (2021) 10:50 Page 8 of 12 Table 4 Risk of unfavourable outcome after Enterobacterales infection in solid organ transplant recipients Favourable (N = 69) Unfavourable (N = 33) Univariate Multivariable OR [95%-CI] (p value) aOR [95%-CI] (p value) ESBL infection, N (%) 27 (37.9) 24 (74.3) 4.1 [1.7–10.7] (< 0.01) 3.1 [0.8–12.5] (0.10) Age, mean (SD) 54.2 (13.7) 53.8 (13.1) 1.0 [0.9–1.0] (0.89) Male , N (%) 32 (46.4) 13 (39.4) 0.8 [0.3–1.7] (0.51) 0.5 [0.1–1.5] (0.20) BMI at transplant (mean, 25.0 (3.8) 25.9 (4.8) 1.0 [0.9–1.2] (0.33) SD) Ethnicity: caucasian 66 (95.7) 29 (87.9) 0.3 [0.1–1.6] (0.16) Year of infection, N (%) 2012 8 (11.6) 6 (18.2) – 2013 17 (24.6) 7 (21.2) 0.6 [0.1–2.2] (0.39) 2014 18 (26.1) 6 (18.2) 0.4 [0.1–1.8] (0.26) 2015 17 (24.6) 9 (27.3) 0.7 [0.2–2.7] (0.61) 2016 9 (13.0) 5 (15.2) 0.7 [0.2–3.4] (0.70) Transplanted organ, N (%) Kidney 41 (59.4) 25 (75.8) – Non-Kidney 28 (40.6) 8 (24.2) 0.4 [0.2–1.1] (0.09) Comorbidities, N (%) Cardiopulmonary 9 (13.0) 5 (15.2) 1.2 [0.5–2.9] (0.62) disease Metabolic/endocrine 34 (49.3) 18 (54.5) 1.2 [0.5–3.5] (0.70) disease Cancer 52 (75.4) 26 (78.8) 1.2 [0.4–3.8] (0.77) Other 43 (62.3) 20 (60.6) 0.9 [0.4–2.2] (0.87) Causing pathogen, N (%) Escherichia coli 54 (78.3) 23 (69.7) – Klebsiella spp. 7 (10.1) 9 (27.3) 3.0 [1.0–9.4] (0.05) Other 8 (11.6) 1 (3.0) 0.3 [0.1–1.7] (0.26) Time to infection, median 70 (31–256) 61 (14–203) 1.0 [1.0–1.0] (0.24) (IQR) Type of infection, N (%) Urinary tract (vs. other) 50 (72.5) 27 (81.8) 1.7 [0.6–5.2] (0.31) Bacteremia 19 (27.5) 8 (24.2) 0.8 [0.3–2.1] (0.72) Hospital-onset, N (%) 26 (38.2) 13 (39.4) 1.1 [0.4–2.5] (0.91) LOS after infection , 14 (4–26) 16 (7.2–33) 0.9 [0.9–1.0] (0.58) median (IQR) On ICU after infection , 10 (21.3) 7 (31.8) 1.7 [0.5–5.4] (0.35) 2.3 [0.6–8.1] (0.20) N (%) Kohler  et al. Antimicrob Resist Infect Control (2021) 10:50 Page 9 of 12 Table 4 (continued) Favourable (N = 69) Unfavourable (N = 33) Univariate Multivariable OR [95%-CI] (p value) aOR [95%-CI] (p value) Antibiotic therapy , N (%) 60 (87.0) 28 (84.8) 0.8 [0.3–2.9] (0.77) Treatment with carbap- 23 (33.3) 17 (51.5) 2.1 [0.9–5.0] (0.08) enems Treatment duration, 13 (7–19) 13 (7–18) 1.0 [0.9–1.0] (0.95) median (IQR) Adequate empiric 39 (65.0) 11 (39.3) 0.3 [0.1–0.9] (0.03) 0.5 [0.1–1.7] (0.27) a,d therapy , N (%) Infectious diseases con- 36 (52.2) 13 (39.4) 0.6 [0.3–1.4] (0.23) sult, N (%) Initially 27 (39.1) 10 (30.3) 0.7 [0.3–1.6] (0.39) Upon microbiology 27 (39.1) 10 (30.3) 0.7 [0.3–1.6] (0.39) results BMI body mass index, ESBL extended-spectrum beta-lactamase, (a)OR (adjusted) odds ratio, CI confidence interval, IQR interquartile range, LOS length of stay, ICU Intensive Care Unit Included in multivariable analysis based on individual impact on key predictor variable "ESBL infection"[13] Variable dropped from final model because of parsimony reasons; inclusion does not alter results Within 30 days after diagnosis Within 2 days after diagnosis Kohler et al. Antimicrob Resist Infect Control (2021) 10:50 Page 10 of 12 come along with increased virulence compared to sus- the occurrence of ESBL-producing pathogens in our ceptible pathogens [35]. However, in a study among study was antibiotic pre-treatment, calling for action healthy young women ST131 was not associated with to strengthen antibiotic stewardship programs in this recurrence [36]. Third, patients with resistant infections setting. Also, improving appropriateness of empiric are less likely to receive appropriate empiric antibiotic antibiotic treatment might be an important measure therapy, as shown in our results and by others [7]. In a to reduce unfavourable outcome, which occurred in recent study on community-acquired UTI among non- almost half of SOT-recipients with ESBL-E infections. transplant patients, the higher recurrence rate among ESBL-E infections was primarily driven by inappropri- Abbreviations ate antibiotic treatment [37]. This is in line with results CI: Confidence interval; CPE: Carbapenemase-producing Enterobacterales; from our multivariable analysis, showing a reduction of ECDC: European Centre for Disease Prevention and Control; ESBL: Extended- spectrum beta-lactamase; ESBL-E: ESBL-producing Enterobacterales; ESC: the association between ESBL and unfavourable outcome Extended-spectrum cephalosporin; ICU: Intensive Care Unit; ID: Infectious after adjusting for inappropriate empiric therapy. Improv- diseases; IQR: Interquartile range; MDR: Multidrug-resistance; RTR: R enal ing appropriateness of empiric therapy in this population transplant recipient; OR: Odds ratio; SOT: Solid organ transplant; STCS: Swiss Transplant Cohort Study; UTI: Urinary tract infection. without universally administering carbapenems repre- sents a challenge. However, using clinical prediction tools Acknowledgements which identify patients at high risk for ESBL-E infection None. The members of the Swiss Transplant Cohort Study are: Patrizia Amico, could be an option [38]. Also, shortening the turnaround Andres Axel, John-David Aubert, Vanessa Banz, Beckmann Sonja, Guido Beldi, time of resistance results might mitigate the deleterious Christian Benden, Christoph Berger, Isabelle Binet, Pierre-Yves Bochud, Sanda effect of inappropriate empiric therapy. Branca, Heiner Bucher, Thierry Carrel, Emmanuelle Catana, Yves Chalandon, Sabina de Geest, Olivier de Rougemont, Michael Dickenmann, Joëlle Lynn Limitations of our study are the retrospective design Dreifuss, Michel Duchosal, Thomas Fehr, Sylvie Ferrari-Lacraz, Christian Garzoni, and the lack of travel history, which in the healthy popula- Paola Gasche Soccal, Christophe Gaudet, Emiliano Giostra, Déla Golshayan, tion is among the most important risk factors for ESBL-E Karine Hadaya, Jörg Halter, Dimitri Hauri, Dominik Heim, Christoph Hess, Sven Hillinger, Hans Hirsch, Patricia Hirt, Günther Hofbauer, Uyen Huynh-Do, Franz colonization and infection. However, travel is unlikely to Immer, Michael Koller (Head of the data center), Bettina Laesser, Brian Lang, have a major impact in this particular patient population. Roger Lehmann, Alexander Leichtle, Christian Lovis, Oriol Manuel, Hans-Peter Because most of our study participants were RTR, the Marti, Pierre Yves Martin, Michele Martinelli, Katell Mellac, Aurélia Merçay, Karin Mettler, Pascal Meylan, Nicolas Mueller (Chairman Scientific Committee), Anto - results might not be applicable to other SOT recipients. nia Müller, Thomas Müller, Ulrike Müller-Arndt, Beat Müllhaupt, Mirjam Nägeli, The sample size for the analysis of unfavourable outcome Manuel Pascual (Executive office), Klara Posfay-Barbe, Juliane Rick, Anne Ros- might have been too small to draw valid conclusions. In selet, Simona Rossi, Silvia Rothlin, Frank Ruschitzka, Urs Schanz, Stefan Schaub, Aurelia Schnyder, Macé Schuurmans, Federico Simonetta, Katharina Staufer, particular, our study might have been underpowered to Susanne Stampf, Jürg Steiger (Head, Excecutive office), Guido Stirniman, evaluate the impact of being a RTR (compared to other Christian Toso, Christian Van Delden (Executive office), Jean-Pierre Venetz, Jean SOT recipients), of infections with K. pneumoniae (vs. Villard, Madeleine Wick (STCS coordinator), Markus Wilhelm, Patrick Yerly E. coli), or of treatment with carbapenems, which were Authors’ contributions all marginally associated with unfavourable outcome Participated in research design (PK, AW, CvD, SK, OM, PS, NM); Participated in in univariate analysis. Also, molecular analysis of caus- the writing of the paper (all authors); Participated in the performance of the research (data collection: PK, AW, AB, KB, MF, CH, OM, DN, SR, LW ); Participated ing pathogens, which could shed light on the molecular in data analysis (PK, AW, SS, AB, NM). All authors read and approved the final epidemiology of ESBL-E in our geographic area includ- manuscript. ing the presence of E. coli ST131 or healthcare-associ- Funding ated K. pneumoniae clones, was not performed. Further, The Swiss Transplant Cohort Study is supported by the Swiss National Science using ESC-resistance as a proxy for ESBL-production is Foundation (SNSF, http://www.snf.ch), Unimedsuisse (https ://www.unime debatable. However, in the antibiotic resistance report of dsuis se.ch) and the participating Transplant Centers. PK received an Ambi- zione Career Grant from the SNSF (Grant Number 179919). PWS is supported the ECDC from 2016, 89% of ESC-resistant E. coli were by the academic career program “Filling the Gap” of the Medical Faculty of the ESBL-producers [39]. Last, appropriateness of antibiotic University of Zurich. therapy was defined in a rather conservative way, catego - Availability of data and materials rizing treatment with piperacillin/tazobactam as inap- The datasets generated during and/or analysed during the current study are propriate also in non-bacteremic urinary tract infections. not publicly available but are available from the corresponding author on reasonable request. Conclusions Declarations To conclude, ESBL-production among non-E. coli Ethics approval and consent to participate Enterobacterales has steadily been increasing among Written informed consent was obtained from all patients; ethics approval was Swiss SOT-recipients in recent years. The role of resist - obtained in all participating centres. ant high-risk clones in this worrisome trend remains unknown. The only modifiable factor associated with Kohler  et al. Antimicrob Resist Infect Control (2021) 10:50 Page 11 of 12 Consent for publication 13. Mickey RM, Greenland S. The impact of confounder selection criteria on Not applicable. effect estimation. Am J Epidemiol. 1989;129:125–37. 14. Pitout JDD, Laupland KB. Extended-spectrum beta-lactamase-producing Competing interests Enterobacteriaceae: an emerging public-health concern. Lancet Infect All authors declare that they have no competing interests. Dis. 2008;8:159–66. 15. Karanika S, Karantanos T, Arvanitis M, Grigoras C, Mylonakis E. Fecal colo- Author details nization with extended-spectrum beta-lactamase-producing Enterobac- Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital teriaceae and risk factors among healthy individuals: a systematic review St. Gallen, St. Gallen, Switzerland. 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A randomised, double-blind, placebo- 39. ECDC Surveillance Report. Surveillance of antimicrobial resistance in controlled trial of a herbal medicinal product containing Tropaeoli majoris Europe. https ://ecdc.europ a.eu/sites /porta l/files /docum ents/AMR-surve herba (Nasturtium) and Armoraciae rusticanae radix (Horseradish) for illan ce-Europ e-2016.pdf. Last accessed 17 Dec 2020. the prophylactic treatment of patients with chronically recurrent lower urinary tract infections. Curr Med Res Opin. 2007;23:2415–22. Publisher’s Note 35. Nicolas-Chanoine M-H, Bertrand X, Madec J-Y. Escherichia coli ST131, an Springer Nature remains neutral with regard to jurisdictional claims in pub- intriguing clonal group. Clin Microbiol Rev. 2014;27:543–74. lished maps and institutional affiliations. 36. Ismail MD, Ali I, Hatt S, Salzman EA, Cronenwett AW, Marrs CF, et al. 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Temporal trends, risk factors and outcomes of infections due to extended-spectrum β-lactamase producing Enterobacterales in Swiss solid organ transplant recipients between 2012 and 2018

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Abstract

Background: The burden of antimicrobial resistance is high in solid organ transplant (SOT ) recipients. Among Swiss SOT recipients, we assessed temporal trends of ESBL-producing Enterobacterales (ESBL-E), identified risk factors for ESBL-E, and assessed the impact of resistance on patient outcome. Methods: Data from the Swiss Transplant Cohort Study (STCS), a nationwide prospective cohort of SOT-recipients, were analysed. Temporal trends were described for ESBL-detection among Escherichia coli and non-Escherichia coli. In a nested case–control study, cases with ESBL-E infection were 1:1 matched (by time since transplantation, organ transplant, pathogen) to controls infected with non-ESBL-E. Factors associated with resistance and with unfavourable 30-day outcome (death, infection relapse, graft loss) were assessed. Results: From 2012 to 2018, we identified 1′212 infection episodes caused by Enterobacterales in 1′074 patients, thereof 11.4% (138/1′212) caused by ESBL-E. The proportion of ESBL-production among Escherichia coli remained stable over time (p = 0.93) but increased for non-E. coli (p = 0.02) Enterobacterales. In the case–control study (n = 102), antibiotic pre-treatment was independently associated with ESBL-production (aOR = 2.6, 95%-CI: 1.0–6.8, p = 0.046). Unfavourable outcome occurred in 24/51 (47%) cases and 9/51 (18%) controls (p = 0.003). Appropriate empiric antibi- otic therapy was the only modifiable factor associated with unfavourable outcome. Conclusions: In Swiss SOT-recipients, proportion of infections with ESBL-producing non-E. coli Enterobacterales increased in recent years. Antibiotic pre-treatment represents a risk factor for ESBL-E. Improving appropriateness of empiric antibiotic treatment might be an important measure to reduce unfavourable outcome, which was observed in almost half of SOT-recipients with ESBL-E infections. *Correspondence: philipp.kohler@kssg.ch Philipp Kohler and Aline Wolfensberger contributed equally to this work Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Kohler et al. Antimicrob Resist Infect Control (2021) 10:50 Page 2 of 12 Keywords: Solid organ transplant, Renal transplant, Extended-spectrum beta-lactamase, Enterobacterales, Switzerland Introduction infectious diseases working group [10]. Six participating Antimicrobial resistance is a major threat to the achieve- transplantation centres (Basel, Bern, Geneva, Lausanne, ments of modern medicine. Solid organ transplant (SOT) St. Gallen and Zurich) undergo regular data monitoring recipients are at particular risk for acquisition of resistant and in-depth data quality audits. pathogens, most likely due to increased healthcare and antibiotic exposure [1]. Specifically in SOT-recipients, Study design and participants donor-derived infections due to resistant pathogens are We included SOT-recipients of heart, liver, kidney, and associated with significant burden of disease [2]. Over kidney-pancreas grafts aged 18 or older enrolled in the the last decade, Gram-negative bacteria have become STCS. Lung transplant recipients were excluded because the focus of attention regarding antibiotic resistance for of the particular challenge to distinguish colonisation both the general hospital population and SOT-recipients. from infection in this population. From August 2012 A recent systematic review reported that 20% of SOT- onwards, information about ESBL production has been recipients are colonized with ESBL-producing Escheri- available in the STCS database. For the analysis of tem- chia coli [3]. Colonization by ESBL-producing isolates poral trends, we thus retrieved all infection episodes is an important risk factor for subsequent infection [4]; diagnosed between August 2012 and December 2018. about one in 10 renal transplant recipients (RTR) colo- Participants contributed a maximum of one episode per nized by ESBL-producing bacteria experiences a urinary year. Those with episodes caused by resistant and suscep - tract infection (UTI) caused by these pathogens [5]. tible pathogens were counted as having had one resistant Compared to infections with non-resistant pathogens, episode and were not eligible as controls. Patients with those caused by resistant bacteria are associated with an episodes caused by ESBL-producing E. coli and non-E. increased risk for recurrent infection, allograft dysfunc- coli Enterobacterales in the same year were counted in tion and excess mortality [5, 6]. Case-fatality infection both groups. with resistant pathogens is high (up to 50% in the case A nested case–control study was performed to assess of bacteremia due to carbapenem-resistant Enterobacte- risk factors for infection by ESBL-E and its effect on rales) [7–9]. 90-day outcome afterwards. As opposed to the analy- Among Swiss SOT recipients, most infections in the sis for temporal trends (episode level) this analysis first year post-transplantation are caused by Entero - was performed on the patient-level (i.e. only one epi- bacterales. Among E. coli and Klebsiella pneumoniae, sode per patient considered). We included all patients ESBL-production was observed in 15%, whereas no with infections due to ESBL-producing (or MDR and carbapenemase-producing Enterobacterales (CPE) were extended-spectrum cephalosporine-resistant, see below) identified in our cohort [10]. Here, we aimed to assess Enterobacterales, diagnosed between August 2012 and temporal trends of ESBL-producing Enterobacterales December 2016. In case of multiple episodes caused by (ESBL-E), to identify risk factors for infections with a resistant pathogen, only the patients’ first episode after ESBL-E, and to assess the impact of ESBL-production on transplantation was considered. Cases were matched to patient outcome. controls in a 1:1 fashion, applying incidence density sam- pling according to time to first infectious episode after transplantation; type of transplanted organ and bacte- Methods rial pathogen were used as further matching criteria. Data source Controls with previous colonization by ESBL-E were The Swiss Transplant Cohort Study (STCS) is a nation - excluded. Detailed information about infections in cases wide, multi-centre, open, prospective cohort and has and controls were additionally collected via chart review enrolled all SOT-recipients in Switzerland since May and recorded in an electronic database (SecuTrial ). 2008 [11]. Clinical and laboratory data are prospec- These included administration of antibiotics within tively collected at the time of transplantation, at 6 and 30  days before infection (both therapeutic and prophy- 12  months, and annually thereafter. Infectious epi- lactic), travel history, urinary obstruction (only for RTR), sodes are identified by transplant infectious disease (ID) admission to acute or intensive care, involvement of ID physicians on a regular basis using electronic patient specialist, type, duration and effectiveness of empiric and records, according to definitions developed by the STCS definite antibiotic treatment, and 90-day outcome. Kohler  et al. Antimicrob Resist Infect Control (2021) 10:50 Page 3 of 12 Microbiology considered a key predictor. We used the change in esti- Pathogen identification and resistance testing was per - mate method as screening method for selection of co- formed on a routine basis in the microbiology labo- variables into the multivariable logistic regression model ratories serving the participating centres. Since 2012, (i.e. change of key predictor estimate > 10% after add- information about infections caused by ESBL-E is being ing the co-variable to the model) [13]. R software ver- recorded. Also, the presence of multidrug-resistance sion 3.6.1 was used for all statistical analyses; a p value (MDR) is recorded according to the European Centre for of < 0.05 was considered statistically significant. Disease Prevention and Control (ECDC) definitions [12]. For the analysis of temporal trends, the variable “ESBL- production” as reported in the database was used to Results classify resistant and susceptible pathogens. For the Temporal trends case–control study, this definition was extended to also Between 2012 and 2018, we registered 1′212 infec- include MDR pathogens with resistance to extended- tious episodes caused by Enterobacterales among 1′074 spectrum cephalosporins (ESC), i.e. 3rd or 4th genera- patients, mostly among RTR (784/1′074, 73%). Among tion cephalosporins. This approach was chosen because all isolates, ESBL-production was reported in 138/1′212 for some bacterial isolates ESBL-production was not isolates (11.4%). ESBL rates for episodes of kidney, heart, tested or reported. and liver transplant patients were 13.2% (168/1271), 12.4% (11/89), and 13.6% (30/221), respectively; across the six participating centres, the proportion of ESBL- Definitions producing isolates ranged from 8.3 to 18.3%. The propor - In brief, proven infection was defined as the presence of tion of ESBL E. coli remained stable over time (p = 0.93) clinical signs or symptoms, detection of a bacterial path- whereas an increasing trend (p = 0.024) was observed for ogen, and given treatment [10]. Effectiveness of antibiotic non-E. coli Enterobacterales (Fig.  1). No temporal trend treatment was assessed according to locally performed was observed when ESBL E. coli and non-E. coli were susceptibility tests. Beta-lactam/beta-lactamase inhibitor combined (p = 0.36). combinations were considered inadequate against ESBL- E irrespective of the reported minimal inhibitory con- centration. Unfavourable outcome was defined as any of Case–control study: population and infection the following: microbiological relapse (i.e. infection with characteristics the same pathogen at same body site as the initial infec- Between 2012 and 2016, we identified 88 case patients tious episode), graft failure (defined as dialysis post renal which were matched to 88 controls. After chart review transplantation; or re-transplantation post heart or liver and revision of the original susceptibility test results, transplantation; or recurrence of insulin-dependence fol- 51 matching pairs remained for the analysis. For the 37 lowing pancreas transplant) or death, all within 90  days excluded patients, reasons for exclusion were mostly lim- after infection. ited or missing susceptibility testing (15/37) and revision of case status (14/37). Of the 51 cases and controls, 33 Statistical analysis (65%) were RTR, 4 (8%) kidney-pancreas, 9 (18%) liver A temporal trend analysis was performed to detect a or kidney-liver, and 5 (10%) heart transplant patients, pattern in occurrence of infectious episodes caused by respectively. The urinary tract was the most common site ESBL-producing E. coli and non-E. coli Enterobacte- of infection (75%). E. coli was the most frequent pathogen rales between 2012 and 2018, using Chi-squared test found in infections (75.5%), followed by K. pneumoniae for trends in proportion. In the matched subpopulation (15.7%) and other pathogens (8.8%). (including episodes which occurred between 2012 and Baseline characteristics of cases and controls were 2016), a descriptive analysis was done followed by uni- summarized in Table  1. Infections occurred a median variate and multivariable conditional logistic regression of 69  days after transplant (interquartile range [IQR]: to evaluate risk factors for infections caused by ESBL-E. 25–232), mostly (68%) within the first 6  months after Age and gender, as well as baseline characteristics associ- transplantation (Fig.  2). Patients were predominantly ated with ESBL-E infection in univariate analysis (p < 0.1) outpatients at time of diagnosis (63% for ESBL-E, 61% for were included in the multivariable model. Multicollinear- non-ESBL-E infections). ESBL-E and non-ESBL-E infec- ity was assessed calculating the variance inflation factor tions were evenly distributed among centres and years, as (cut-off > 10). were infection sites and comorbidities. Travel history was For the analysis regarding impact of resistance not available for most patients and therefore dropped on patient outcome, infection by ESBL-E itself was from further analyses. Kohler et al. Antimicrob Resist Infect Control (2021) 10:50 Page 4 of 12 Fig. 1 Proportion of patients with ESBL-producing Escherichia coli (left) and non-E. coli (right) among all patients infected with the corresponding pathogen in the Swiss Transplant Cohort Study between 2012 and 2018 Risk factors for ESBL infection (47%) patients with ESBL-E infections (p < 0.003). This Male gender (p = 0.04) and antibiotic treatment within difference was mainly due to relapse of infection (5/51 vs. 30  days prior to infection (p = 0.05) were significantly 20/51, p = 0.001), whereas graft loss (4/51 vs. 1/51) and associated with ESBL-E infection (Table  2). Antibiotic mortality (3/51 vs. 4/51) were similar in both groups. pre-treatment remained as independent risk factor for Evaluating the impact of resistance on unfavourable ESBL-E infection in multivariable analysis after correc- outcome, infection with ESBL-E was associated with tion for age, gender and underlying metabolic/endo- unfavourable (OR = 4.0, 95%-CI: 1.7–10.5, p = 0.003) and crinologic disease (adjusted OR = 2.6, 95% CI: 1.0–6.8, adequate empiric therapy (OR = 0.3, 95%-CI: 0.1–0.9, p = 0.046). p = 0.03) with favourable outcome in univariate analy- sis (Table  4). After adjusting for modifiable (adequate empiric therapy) and non-modifiable (gender and need for ICU stay after infection) factors, the effect of ESBL- Infection management and outcome E infection was still large, but not anymore signifi - Patients with susceptible and resistant pathogens were cantly associated with unfavourable outcome (adjusted similar in terms of proportion of hospital admission OR = 3.1, 95%-CI: 0.8–12.5, p = 0.10). (16/51 vs. 14/51), intensive care admission (9/51 vs. 8/51), or involvement of an ID physician for choice of treatment (22/51 vs. 27/51) (Table 3). Length of stay was longer for those with resistant (median 18  days, IQR 8.2–30  days) Discussion vs. those with susceptible pathogens (median 9, IQR In this study based on data from a prospective national 3–24  days), but did not reach statistical significance cohort representing all SOT-recipients in Switzerland, (p = 0.10). Patients with susceptible pathogens were more we show that ESBL-producing non-E. coli infections have likely to receive appropriate empiric antibiotic therapy been increasing over the last years and that antibiotic (36/51, 76%) vs. those with resistant pathogens (16/51, pre-treatment is independently associated with infection 36%) (p < 0.001). Inappropriate therapy was mostly due caused by ESBL-producing pathogens. Almost half of to late initiation (i.e. > 2 days after infection) of antibiotic patients with ESBL-E had a relapsing infection compared therapy (similar in both groups: 8/51 vs. 11/51, p = 0.44), to only 18% in those with non-ESBL E infections. Ade- or due to administration of beta-lactam/beta-lactamase quate empiric therapy, being less common among those inhibitors against resistant pathogens (1/51 vs. 10/51, with ESBL-E infection, was the only modifiable factor p = 0.004). associated with unfavourable outcome. The comprehen - Unfavourable outcome occurred in 9/51 (18%) con - sive dataset and the thorough revision of the original data trols with non-ESBL-E infections as compared to 24/51 are particular strengths of the study. Kohler  et al. Antimicrob Resist Infect Control (2021) 10:50 Page 5 of 12 Table 1 Baseline characteristics of patients infected without and with extended-spectrum beta-lactamase (ESBL)-Enterobacterales Cases (N = 51) Controls (N = 51) Male, N (%) 28 (54.9%) 17 (33.3%) Age at time of infection, mean (SD) 54.8 (12) 53.4 (14.8) Transplanted organ (matched variable) Kidney 33 (64.7%) 33 (64.7%) Kidney-pancreas 4 (7.8%) 4 (7.8%) Liver (incl kidney-liver) 9 (17.6%) 9 (17.6%) Heart 5 (9.8%) 5 (9.8%) BMI at transplantation, mean (SD) 25.5 (4.1) 25.1 (4.2) Caucasian ethnicity, N (%) 46 (90.2%) 49 (96.1%) Comorbidities, N (%) Cardiopulmonary disease 27 (52.9%) 25 (49%) Metabolic/endocrine disease 35 (68.6%) 43 (84.3%) Cancer 8 (15.7%) 6 (11.8%) Other 32 (62.7%) 31 (60.8%) Previously documented ESBL colonization 19 (37%) 0 (0%) Antibiotics (30 days before infection), N (%) 24 (47.1%) 14 (27.5%) BL/BLI 10 (37%) 6 (28.6%) Carbapenem 6 (22.2%) 3 (14.3%) Quinolone 10 (37%) 3 (14.3%) Cephalosporine 7 (25.9%) 0 (0%) Sulfamethoxazol/trimethoprim 7 (25.9%) 4 (19%) Hospital-onset, N (%) 20 (39.2%) 19 (37.3) Day of onset (median, IQR) 20 (9.5–60) 8 (6–42) Days from transplantation to infection, median (IQR) 67 (24–228) 71 (33–227) Year of 1st infection, N (%) 2012 6 (11.8%) 8 (15.7%) 2013 9 (17.6%) 13 (25.5%) 2014 14 (27.5%) 12 (23.5%) 2015 16 (31.4%) 10 (19.6%) 2016 6 (11.8%) 8 (15.7%) Infection site, N (%) Urinary tract 38 (74.5%) 39 (76.5%) With bacteremia 5 (13.2%) 10 (25.6%) Abdominal/liver 2 (3.9%) 3 (5.9%) Respiratory tract 3 (5.9%) 5 (9.8%) Surgical site 3 (5.9%) 4 (7.8%) Primary bacteremia 2 (3.9%) 1 (2.0%) Other 3 (5.9%) 1 (2.0%) If urinary tract infection, N (%) Obstruction 2/38 (5.3%) 5/39 (12.8%) Catheter 12/38 (31.6%) 17/39 (43.6%) ESBL extended-spectrum beta-lactamase, SD standard deviation, BMI body mass index, IQR interquartile range, BL/BLI beta-lactam/beta-lactamase-inhibitor Previously ESBL colonized participants were not eligible for the control group Including prophylaxis The three last decades have witnessed a global dis - propelled by various factors. Important drivers of com- semination of ESBL-producing Enterobacterales into munity-acquisition (mostly ESBL-E. coli carrying the healthcare systems and healthy populations alike [14]. plasmid-encoded bla gene) are travel to/health- CTX-M From an epidemiological perspective, their emergence is care in endemic countries or household crowding [15, Kohler et al. Antimicrob Resist Infect Control (2021) 10:50 Page 6 of 12 our cohort of SOT-recipients, we found stable numbers or ESBL-E. coli, but an increase in ESBL-non E. coli over time, a worrisome finding which has also been observed in other European SOT cohorts [18–20]. We can only speculate as to the reason for this trend. Increased in- hospital transmission of these pathogens is one possi- ble explanation, given the substantial differences in the prevalence of ESBL-producing Enterobacterales among participating centres in our study and given the many reports of resistant K. pneumoniae (and particularly high-risk clones such as ST11 or ST147) as a cause of nosocomial outbreaks among transplant and non-trans- plant patients [21–24]. In both community and hospital settings, antibiotic treatment—mainly cephalosporins but also quinolo- nes—is associated with ESBL-colonization or infection, probably due to selection (or co-selection in the case of quinolones) of ESBL-E in the gut flora of colonized patients [15, 25]. Razazi et  al. found treatment with 3rd generation cephalosporins to be predictive of ESBL-E colonization in patients admitted to intensive care [26]. Fig. 2 Histogram showing the time from transplant to onset of In a Canadian cohort of RTR, antibiotic pre-treatment infection in days for 51 cases (above) and 51 controls (below) was the strongest risk factor for detection of resistant Gram-negative bacteria in the urine [27]; in a recent study on enterobacterial bloodstream infections among 16]. In contrast, ESBL-non E. coli (mostly Klebsiella spp.) SOT-recipients in the United States, antibiotic expo- are often hospital-acquired, mainly as a result of clonal sure to trimethoprim-sulfamethoxazole and again 3rd expansion due to person-to-person transmission [17]. In generation cephalosporins were strong risk factors for Table 2 Univariable and multivariable conditional logistic regression analysis regarding risk of infection with ESBL-producing pathogen (vs. non-ESBL) Univariate Multivariable OR [95%-CI] (p value) aOR [95%-CI] (p value) Male versus female 2.4 [1.0–5.4] (0.04) 2.3 [0.9–5.0] (0.08) Age (years) at time of infection 1.0 [0.9–1.0] (0.58) 0.9 [0.9–1.0] (0.99) BMI at transplantation 1.0 [0.9–1.1] (0.92) Caucasian versus others 0.4 [0.1–2.1] (0.27) Comorbidities (yes/no) Cardiopulmonary disease 1.1 [0.6–2.3] (0.72) Metabolic/endocrine disease 0.5 [0.2–1.1] (0.10) 0.4 [0.2–1.1] (0.09) Cancer 1.4 [0.4–4.4] (0.57) Other 1.1 [0.5–2.7] (0.82) Year of infection 2012 – 2013 1.2 [0.3–4.7] (0.83) 2014 1.6 [0.3–7.1] (0.57) 2015 2.5 [0.6–11.1] (0.23) 2016 0.9 [0.2–5.3] (0.94) Antibiotics (yes/no) before infection 2.4 [1.0–5.9] (0.048) 2.6 [1.0–6.8] (0.046) ESBL extended-spectrum beta-lactamase, (a)OR (adjusted) odds ratio, CI confidence interval, BMI body mass index Any therapeutic or prophylactic antibiotic treatment within 30 days prior to infection Kohler  et al. Antimicrob Resist Infect Control (2021) 10:50 Page 7 of 12 Table 3 Management and outcome of infections caused by non-extended-spectrum beta-lactamase (ESBL)- and ESBL-producing Enterobacterales Cases (N = 51) Controls (N = 51) p value Management Hospital admission if community onset, N (%) 14 (43.8%) 16 (50.0%) 0.99 Length of stay after infection (median, IQR) 18 (8.2–30) 9 (3–24) 0.10 On intensive care after infection onset, N (%) 8 (23.5%) 9 (25.7%) 1.00 Days on intensive care (median, IQR) 5.5 (4–16) 3 (2–11) 0.38 Infectious diseases consult, N (%) 27 (52.9%) 22 (43.1%) 0.43 Initially 21 (41.2%) 16 (31.4%) 0.41 Upon microbiology results 18 (35.3%) 19 (37.3%) 1.00 Antibiotics (30 days after infection), N (%) Adequate empiric therapy 16 (35.6%) 34 (75.6%) < 0.001 Inadequate BL/BLI 10 (22.7%) 1 (2.3%) 0.004 Inadequate ceftriaxone/ceftazidime 2 (4.5%) 0 (0%) 0.15 Inadequate ciprofloxacin 5 (11.4%) 1 (2.3%) 0.09 No therapy before day 2 11 (21.5%) 8 (18.2%) 0.44 Outcome Re-admission, N (%) 15 (29.4%) 14 (27.5%) 1.00 Due to infection 12 (23.5%) 8 (15.7%) 0.35 Unfavourable outcome within 90 days, N (%) 24 (47.1%) 9 (17.6%) 0.003 Relapse 20 (39.2%) 5 (9.8%) 0.001 Graft loss 1 (2.0%) 4 (7.8%) 0.36 Death 4 (7.8%) 3 (5.9%) 1.00 ESBL extended-spectrum beta-lactamase, IQR interquartile range, BL/BLI beta-lactam/beta-lactamase-inhibitor Chi-square or Fisher’s exact test for dichotomous variables, as appropriate; Mann–Whitney U for continuous variables Administered within two days after infection diagnosis Inadequate BL/BLI were all piperacillin/tazobactam except for one case who received amoxicillin/clavulanic acid infections with ESBL-producers [28]. We could confirm and a higher rate of hospitalization [27]. Other stud- this important finding in our cohort of SOT-recipients. ies have even reported higher case fatality rates in those Due to the small sample size of the subgroups in our with resistant bacterial infections [6, 7]. In our univari- cohort, it is difficult to tell which antibiotic substances able analysis, ESBL-production was strongly associated contributed mainly to this effect. It is important to note with unfavourable outcome, which was mostly recurrent that not only cephalosporins or quinolones, but also infection among RTR. Similarly, data from a systematic beta-lactam/beta-lactamase inhibitor combinations have review showed that UTI recurrence was clearly more been independently associated with ESBL-Klebsiella common among RTR infected with ESBL-E compared to spp., at least in hospitalized non-transplant patients [29]. non-ESBL-E [5]. There are different reasons which could Consequently, we think that antibiotic stewardship pro- explain the higher recurrence rate in those with ESBL-E grams aiming at reducing the overall antibiotic use in this infections. First, as shown above, ESBL-infection devel- population is key in lowering the selection pressure for ops more often in those with previous antibiotic treat- ESBL-E and other resistant pathogens. In this context it ment. This is probably the first step in a vicious circle, is important to note that—according to a recent survey as antibiotic treatment itself might increase the risk for among European transplant centres—a majority of trans- UTI recurrence which then again exposes the patient plant physicians uses antibiotics including quinolones to antibiotic treatment [32]. Breaking this circle could and cephalosporins for asymptomatic bacteriuria in RTR be achieved by a reduction of antibiotic use. At least for despite the uncertain benefit of this intervention [30, 31]. the prevention of UTIs with non-antibiotic substances In general, SOT-recipients infected with resistant studies have shown promising results for transplant and pathogens fare worse than those infected with suscepti- non-transplant patients [33, 34]. Second, there have ble bacteria. Delmas-Frenette et al. found resistance to be been suggestions that E. coli strains like ST131, a hyper- associated with a longer duration of antibiotic treatment endemic clone often associated with ESBL-production, Kohler et al. Antimicrob Resist Infect Control (2021) 10:50 Page 8 of 12 Table 4 Risk of unfavourable outcome after Enterobacterales infection in solid organ transplant recipients Favourable (N = 69) Unfavourable (N = 33) Univariate Multivariable OR [95%-CI] (p value) aOR [95%-CI] (p value) ESBL infection, N (%) 27 (37.9) 24 (74.3) 4.1 [1.7–10.7] (< 0.01) 3.1 [0.8–12.5] (0.10) Age, mean (SD) 54.2 (13.7) 53.8 (13.1) 1.0 [0.9–1.0] (0.89) Male , N (%) 32 (46.4) 13 (39.4) 0.8 [0.3–1.7] (0.51) 0.5 [0.1–1.5] (0.20) BMI at transplant (mean, 25.0 (3.8) 25.9 (4.8) 1.0 [0.9–1.2] (0.33) SD) Ethnicity: caucasian 66 (95.7) 29 (87.9) 0.3 [0.1–1.6] (0.16) Year of infection, N (%) 2012 8 (11.6) 6 (18.2) – 2013 17 (24.6) 7 (21.2) 0.6 [0.1–2.2] (0.39) 2014 18 (26.1) 6 (18.2) 0.4 [0.1–1.8] (0.26) 2015 17 (24.6) 9 (27.3) 0.7 [0.2–2.7] (0.61) 2016 9 (13.0) 5 (15.2) 0.7 [0.2–3.4] (0.70) Transplanted organ, N (%) Kidney 41 (59.4) 25 (75.8) – Non-Kidney 28 (40.6) 8 (24.2) 0.4 [0.2–1.1] (0.09) Comorbidities, N (%) Cardiopulmonary 9 (13.0) 5 (15.2) 1.2 [0.5–2.9] (0.62) disease Metabolic/endocrine 34 (49.3) 18 (54.5) 1.2 [0.5–3.5] (0.70) disease Cancer 52 (75.4) 26 (78.8) 1.2 [0.4–3.8] (0.77) Other 43 (62.3) 20 (60.6) 0.9 [0.4–2.2] (0.87) Causing pathogen, N (%) Escherichia coli 54 (78.3) 23 (69.7) – Klebsiella spp. 7 (10.1) 9 (27.3) 3.0 [1.0–9.4] (0.05) Other 8 (11.6) 1 (3.0) 0.3 [0.1–1.7] (0.26) Time to infection, median 70 (31–256) 61 (14–203) 1.0 [1.0–1.0] (0.24) (IQR) Type of infection, N (%) Urinary tract (vs. other) 50 (72.5) 27 (81.8) 1.7 [0.6–5.2] (0.31) Bacteremia 19 (27.5) 8 (24.2) 0.8 [0.3–2.1] (0.72) Hospital-onset, N (%) 26 (38.2) 13 (39.4) 1.1 [0.4–2.5] (0.91) LOS after infection , 14 (4–26) 16 (7.2–33) 0.9 [0.9–1.0] (0.58) median (IQR) On ICU after infection , 10 (21.3) 7 (31.8) 1.7 [0.5–5.4] (0.35) 2.3 [0.6–8.1] (0.20) N (%) Kohler  et al. Antimicrob Resist Infect Control (2021) 10:50 Page 9 of 12 Table 4 (continued) Favourable (N = 69) Unfavourable (N = 33) Univariate Multivariable OR [95%-CI] (p value) aOR [95%-CI] (p value) Antibiotic therapy , N (%) 60 (87.0) 28 (84.8) 0.8 [0.3–2.9] (0.77) Treatment with carbap- 23 (33.3) 17 (51.5) 2.1 [0.9–5.0] (0.08) enems Treatment duration, 13 (7–19) 13 (7–18) 1.0 [0.9–1.0] (0.95) median (IQR) Adequate empiric 39 (65.0) 11 (39.3) 0.3 [0.1–0.9] (0.03) 0.5 [0.1–1.7] (0.27) a,d therapy , N (%) Infectious diseases con- 36 (52.2) 13 (39.4) 0.6 [0.3–1.4] (0.23) sult, N (%) Initially 27 (39.1) 10 (30.3) 0.7 [0.3–1.6] (0.39) Upon microbiology 27 (39.1) 10 (30.3) 0.7 [0.3–1.6] (0.39) results BMI body mass index, ESBL extended-spectrum beta-lactamase, (a)OR (adjusted) odds ratio, CI confidence interval, IQR interquartile range, LOS length of stay, ICU Intensive Care Unit Included in multivariable analysis based on individual impact on key predictor variable "ESBL infection"[13] Variable dropped from final model because of parsimony reasons; inclusion does not alter results Within 30 days after diagnosis Within 2 days after diagnosis Kohler et al. Antimicrob Resist Infect Control (2021) 10:50 Page 10 of 12 come along with increased virulence compared to sus- the occurrence of ESBL-producing pathogens in our ceptible pathogens [35]. However, in a study among study was antibiotic pre-treatment, calling for action healthy young women ST131 was not associated with to strengthen antibiotic stewardship programs in this recurrence [36]. Third, patients with resistant infections setting. Also, improving appropriateness of empiric are less likely to receive appropriate empiric antibiotic antibiotic treatment might be an important measure therapy, as shown in our results and by others [7]. In a to reduce unfavourable outcome, which occurred in recent study on community-acquired UTI among non- almost half of SOT-recipients with ESBL-E infections. transplant patients, the higher recurrence rate among ESBL-E infections was primarily driven by inappropri- Abbreviations ate antibiotic treatment [37]. This is in line with results CI: Confidence interval; CPE: Carbapenemase-producing Enterobacterales; from our multivariable analysis, showing a reduction of ECDC: European Centre for Disease Prevention and Control; ESBL: Extended- spectrum beta-lactamase; ESBL-E: ESBL-producing Enterobacterales; ESC: the association between ESBL and unfavourable outcome Extended-spectrum cephalosporin; ICU: Intensive Care Unit; ID: Infectious after adjusting for inappropriate empiric therapy. Improv- diseases; IQR: Interquartile range; MDR: Multidrug-resistance; RTR: R enal ing appropriateness of empiric therapy in this population transplant recipient; OR: Odds ratio; SOT: Solid organ transplant; STCS: Swiss Transplant Cohort Study; UTI: Urinary tract infection. without universally administering carbapenems repre- sents a challenge. However, using clinical prediction tools Acknowledgements which identify patients at high risk for ESBL-E infection None. The members of the Swiss Transplant Cohort Study are: Patrizia Amico, could be an option [38]. Also, shortening the turnaround Andres Axel, John-David Aubert, Vanessa Banz, Beckmann Sonja, Guido Beldi, time of resistance results might mitigate the deleterious Christian Benden, Christoph Berger, Isabelle Binet, Pierre-Yves Bochud, Sanda effect of inappropriate empiric therapy. Branca, Heiner Bucher, Thierry Carrel, Emmanuelle Catana, Yves Chalandon, Sabina de Geest, Olivier de Rougemont, Michael Dickenmann, Joëlle Lynn Limitations of our study are the retrospective design Dreifuss, Michel Duchosal, Thomas Fehr, Sylvie Ferrari-Lacraz, Christian Garzoni, and the lack of travel history, which in the healthy popula- Paola Gasche Soccal, Christophe Gaudet, Emiliano Giostra, Déla Golshayan, tion is among the most important risk factors for ESBL-E Karine Hadaya, Jörg Halter, Dimitri Hauri, Dominik Heim, Christoph Hess, Sven Hillinger, Hans Hirsch, Patricia Hirt, Günther Hofbauer, Uyen Huynh-Do, Franz colonization and infection. However, travel is unlikely to Immer, Michael Koller (Head of the data center), Bettina Laesser, Brian Lang, have a major impact in this particular patient population. Roger Lehmann, Alexander Leichtle, Christian Lovis, Oriol Manuel, Hans-Peter Because most of our study participants were RTR, the Marti, Pierre Yves Martin, Michele Martinelli, Katell Mellac, Aurélia Merçay, Karin Mettler, Pascal Meylan, Nicolas Mueller (Chairman Scientific Committee), Anto - results might not be applicable to other SOT recipients. nia Müller, Thomas Müller, Ulrike Müller-Arndt, Beat Müllhaupt, Mirjam Nägeli, The sample size for the analysis of unfavourable outcome Manuel Pascual (Executive office), Klara Posfay-Barbe, Juliane Rick, Anne Ros- might have been too small to draw valid conclusions. In selet, Simona Rossi, Silvia Rothlin, Frank Ruschitzka, Urs Schanz, Stefan Schaub, Aurelia Schnyder, Macé Schuurmans, Federico Simonetta, Katharina Staufer, particular, our study might have been underpowered to Susanne Stampf, Jürg Steiger (Head, Excecutive office), Guido Stirniman, evaluate the impact of being a RTR (compared to other Christian Toso, Christian Van Delden (Executive office), Jean-Pierre Venetz, Jean SOT recipients), of infections with K. pneumoniae (vs. Villard, Madeleine Wick (STCS coordinator), Markus Wilhelm, Patrick Yerly E. coli), or of treatment with carbapenems, which were Authors’ contributions all marginally associated with unfavourable outcome Participated in research design (PK, AW, CvD, SK, OM, PS, NM); Participated in in univariate analysis. Also, molecular analysis of caus- the writing of the paper (all authors); Participated in the performance of the research (data collection: PK, AW, AB, KB, MF, CH, OM, DN, SR, LW ); Participated ing pathogens, which could shed light on the molecular in data analysis (PK, AW, SS, AB, NM). All authors read and approved the final epidemiology of ESBL-E in our geographic area includ- manuscript. ing the presence of E. coli ST131 or healthcare-associ- Funding ated K. pneumoniae clones, was not performed. Further, The Swiss Transplant Cohort Study is supported by the Swiss National Science using ESC-resistance as a proxy for ESBL-production is Foundation (SNSF, http://www.snf.ch), Unimedsuisse (https ://www.unime debatable. However, in the antibiotic resistance report of dsuis se.ch) and the participating Transplant Centers. PK received an Ambi- zione Career Grant from the SNSF (Grant Number 179919). PWS is supported the ECDC from 2016, 89% of ESC-resistant E. coli were by the academic career program “Filling the Gap” of the Medical Faculty of the ESBL-producers [39]. Last, appropriateness of antibiotic University of Zurich. therapy was defined in a rather conservative way, catego - Availability of data and materials rizing treatment with piperacillin/tazobactam as inap- The datasets generated during and/or analysed during the current study are propriate also in non-bacteremic urinary tract infections. not publicly available but are available from the corresponding author on reasonable request. Conclusions Declarations To conclude, ESBL-production among non-E. coli Ethics approval and consent to participate Enterobacterales has steadily been increasing among Written informed consent was obtained from all patients; ethics approval was Swiss SOT-recipients in recent years. 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