Clostridioides difficile infection after cardiac surgery: Assessment of prevalence, risk factors and clinical outcomes—retrospective study

Patients

Between January 2014 and December 2016, a total of 6,198 adult patients underwent cardiac surgery in our hospital. Seventy of the patients were diagnosed with CDI. The control group was comprised of 73 patients for whom CDI had been excluded and this group was matched to the group of CDI patients by the date of surgery.

Demographics, comorbidities, type and timing of cardiac surgery, operative characteristics, perioperative antibiotic use, exposure to known risk factors for CDI and in-hospital mortality were collected retrospectively. Additionally, length of hospitalization until the onset of diarrhea, severity and recurrence of the disease, methods of treatment and seasonal distribution of CDI were obtained.

CDI was suspected in each patient who experienced diarrhea (defined as the passage of three or more unformed stools per day). CDI was defined as a combination of symptoms and signs of the disease and confirmed by microbiological evidence of toxin-producing CD in the patients’ stools (Debast, Bauer & Kuijper, 2014). Stool samples were analyzed using the rapid enzyme immunoassays test, C. Diff Quik Chek Complete test (Techlab, Orlando, USA).

Non-severe CDI was defined by a white blood cell (WBC) count of ≤ 15,000 cells/mL and a serum creatinine level < 1.5 mg/dL. Severe CDI was specified by a WBC count of ≥ 15,000 cells/mL or a serum creatinine level >1.5 mg/dL. Criteria for fulminant CDI included occurrence of hypotension or shock, ileus or megacolon (McDonald et al., 2018).

The treatment of CDI was consistent with the 2010 recommendations (Cohen et al., 2010). Metronidazole was the drug of choice for an initial episode of non-severe CDI and vancomycin was the drug of choice for an initial episode of severe CDI. Combination therapy with oral or rectal vancomycin and intravenously administered metronidazole was the regimen of choice for the treatment of severe, complicated or fulminant CDI.

Recurrence of the disease was identified as a relapse within 8 weeks after the onset of a previous episode (Debast, Bauer & Kuijper, 2014). Stress hyperglycemia was defined as one or more blood sugar measurements > 180 mg/dL during the first postoperative 24 h (Gelijns et al., 2014). In-hospital mortality was specified as death occurring during the same hospitalization stay as the cardiac surgery.

Each patient received periprocedural antimicrobial prophylaxis (most often the first generation of cephalosporin). Routine laboratory variables were determined using standard laboratory techniques. Study protocol was approved by the local Research Ethics Committee (Andrzej Frycz Modrzewski Krakow University, Krakow, Poland 10/2019). Verbal consent of patients was acquired.

Statistical analysis

Descriptive statistics were described as numbers and percentages for categorical variables. Continuous variables were presented as mean (± standard deviation) or median and quartiles, as appropriate. Normality was assessed using the Shapiro–Wilk test. Equality of variances was assessed using Levene’s test. Differences between groups were compared using the Student’s or Welch’s t-test depending on the equality of variances for normal distributed variables. The Mann–Whitney U test was used for non-normal distributed continuous variables. Nominal variables were compared by the Pearson’s chi-square test or Fisher’s exact test if 20% of cells had an expected count of less than 5. Significance was accepted at P ≤ 0.05. Statistical analyses were performed with JMP®, Version 14.2.0 (SAS Institute INC., Cary, NC, USA) and using R, Version 3.4.1 (R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing. Vienna, Austria, 2017. https://www.r-project.org/).

Baseline characteristics

Of the 6,198 patients, 70 (1.1%) developed CDI. Patients with CDI were significantly older in comparison to the control group (median age 73.0 vs 67.0, P = 0.005). There was no correlation between gender and incidence of CDI (P = 0.595). The European System for Cardiac Operative Risk Evaluation (EuroSCORE) values were higher in patients with CDI (P < 0.001). Patients with CDI more often received PPI, statins, β-blockers and acetylsalicylic acid before surgery (P = 0.008, P = 0.012, P = 0.004, and P = 0.001, respectively). In addition, the presence of atherosclerosis, coronary disease, and history of malignant neoplasms correlated positively with the development of CDI (P = 0.012, P = 0.036 and P = 0.05, respectively). Patients in the CDI group were hospitalized more often during the six months prior to the surgery (P = 0.001). Mean preoperative hospitalization time in the cardiac surgery ward was 1.5 ± 0.2 days. Other baseline variables were comparable among groups (Table 1).

Perioperative characteristics

The most common surgical procedures performed before CDI were valvular heart surgery and coronary artery bypass grafting (41.4% and 35.7%, respectively). There were no differences between the studied groups as far as the type or timing of surgery, aortic cross-clamp and cardiopulmonary bypass time, volume of postoperative drainage, administration of blood products, value of postoperative ejection fraction and frequency of reoperations. Patients with CDI more frequently received additional antibiotics (P = 0.014). During the early postoperative course patients with CDI had a significantly higher glucose level and were exposed more frequently to stress hyperglycemia (P < 0.001 for both comparisons). During the preoperative period, as well as after surgery, patients with CDI had a significantly lower WBC count (P = 0.007 for both comparisons). Other intra- and postoperative variables were similar in both groups (Table 2).

Course of Clostridioides difficile infection

The type of antibiotic therapy used before the first episode of CDI, median times of the disease diagnosis and severity of the infection are shown in Table 3. Five patients in whom fulminant CDI developed, underwent emergency laparotomy and two patients died due to extensive multiple organ failure.

All patients with CDI were treated with oral metronidazole, oral vancomycin or both (intravenous metronidazole with oral vancomycin). Fidaxomicin was not used in our department during the study period (Table 3). Two patients underwent a fecal microbiota transplant during recurrence of the disease.

Although baseline and early postoperative WBC count were significantly lower in patients with CDI, during the course of the disease, WBC count was similar among analyzed groups (P = 0.139). In contrast, C-reactive protein (CRP) was higher in the CDI group during this period (P < 0.001).

There were no differences in the incidence rate of CDI between the analyzed years although a seasonal pattern was observed. Most cases occurred in March (n = 14, 20%) and the least number of cases were found in January (n = 2, 3%), (P = 0.038 between March and rest of the months) (Fig. 1).

In 9 patients (12.9%) CDI recurred during hospitalization. Mean time of relapse was 27.7 ± 11.8 days after the first episode of the disease. Recurrent CDI was more common in overweight patients having high plasma glucose just after surgery or a higher CRP level during the first episode of the disease as well as for those with a history of coronary disease or diabetes mellitus (P = 0.005, P = 0.030, P = 0.009, P = 0.049, and P = 0.025, respectively), (Table 4).

Fifteen patients (21.4%) died from the CDI group and 7 (9.6%) from the control group (P = 0.050). The median number of days between CDI diagnosis and death was 14.0 [4.0; 25.0]. Emergent procedures, prolonged stay in the intensive care unit, longer mechanical ventilation and high WBC count during the diarrhea were associated with higher mortality in patients with CDI (P = 0.05, P = 0.041, P = 0.004 and P = 0.007, respectively), (Table 4).

Limitations

This study has several limitations. It was a retrospective study based on available data obtained during patients’ cardiac procedure hospital stay. Therefore, the true incidence of CDI could be higher due to a lack of information regarding potential post-discharge diagnosis of the disease. The size of the study group was limited and patients were very heterogeneous. It is probable that analysis of patients with one type of cardiac surgery may provide different results.