Hospital for Infectious and Tropical Diseases, Clinical Center of Serbia in Belgrade is the biggest infectious diseases facility in Serbia. Over 2700 patients with CDI were treated in this institution from 2008–2018. The overall number of CDI patients treated annually decreased notably from 494 patients treated in 2015, to 391 patients in 2016, 322 patients in 2017, and 275 patients in 2018.
In spite of huge number of treated patients, number of isolated and characterized strains presented in this study is much lower. There are several reasons for this discrepancy: samples were cultured and strains were collected only in four months’ period and not during the whole year. Diagnosis was based on typical endoscopic presentation in some patients, so no microbiological testing was required. Furthermore, stool cultures were negative for C.difficile in some patients, although they had positive GDH and toxin A/B tests. In addition, some of stored C. difficile strains could not be recultivated for typing.
The vast majority of patients in this study had been infected with the hypervirulent NAP1/BI/027 strain. During the period 2014/2015 the rate of patients infected with this ribotype was as high as 95.6%, suggesting that NAP1/BI/027 was causative strain in the outbreak of CDI in Serbia. The high rate of ribotype 027 infection was also observed in Romania (82.6%) and Poland (82.4%) during 2013/14 (13,14). Study data reflecting the predominance of NAP1/BI/027 infection are in concordance with previously reported prevalence of this ribotype in Serbia and neighboring Bosnia and Herzegovina (4). The other most prevalent strains in the region were 176, 001/072 and 014/020 which is consistent with presented study (4). Davies et al. demonstrated the same distribution of dominant C. difficile strains (027, 001/072 and 014/020) in European countries, although with lower rates compared to those recorded in Serbia (15).
An important observation of the study is that, although ribotype 027 remained the most prevalent strain, a significant decrease in the rate of patients infected with this ribotype was noted during the three-year period. Compared to 95.6% in 2014/2015, this strain was isolated in 52.6% of cases in 2017/2018, accompanied with decrease of overall number of patients treated for CDI. A similar trend in the prevalence of ribotype 027 was first observed by authors from Netherlands in 2009 due to responsible use of antibiotics and other preventive measures (16). Although international comparisons are difficult, decline in number of CDI caused by 027 ribotype was reported by other countries, such as Belgium and Great Britain. (17,18,19). As opposed to these results, Italy and Germany reported the increase in the rate of patients with ribotype 027 infection reaching 38% and 30%, respectively (20,21).
The decline in the prevalence of ribotype 027 infections, and CDI in general in Great Britain was the result of antibiotic stewardship with fluoroquinolone prescribing (19). Namely, one of the explanations for the spread of this ribotype in the epidemic era is the overuse of this class of antibiotics, considering that NAP1/BI/027 strain is resistant to fluoroquinolones. Presented patients infected with ribotype 027 were more often pretreated with fluoroquinolones comparing to other patients. Furthermore, study demonstrated a significant decrease in the rate of patients treated with fluoroquinolones (mainly ciprofloxacin) between the two periods. It might be one of the explanations for the decrease in the rate of ribotype 027 infection and overall number of CDI patients, along with other preventive measures.
Ribotype 027 infection caused severe form of CDI more often than other ribotypes, but it did not affect mortality and recurrence rates. There are controversial reports concerning the influence of ribotype 027 on the severity, recurrence and mortality rates in CDI. It was assumed that patients infected with NAP1/BI/ 027 strain develop more severe CDI forms and have greater risk of experiencing relapse, complications, and death (22–25). The Canada-wide CDI study analyzed the role of infecting strain type and patient age on the severity of CDI: a severe outcome, defined as CDI requiring intensive care unit care, colectomy, or causing death within 30 days after diagnosis, was detected in 12.5% of patients with ribotype 027 and 5.9% of patients with other ribotypes (25). Thirteen (24.5%) patients with ribotype 027 infection and two (18.8%) patients with non-027 ribotype infection experienced severe outcome in presented study. Portuguese authors demonstrated that lethal outcome was related to older age, leukocytosis and renal failure, and fatal comorbidities according to McCabe score (26). This study data also indicate higher mortality rate in patients with leukocytosis, renal failure and higher CRP. According to Michel and Gardner, all cause mortality at 30 days varied from 9–38%, and inhospital mortality ranged from 8–37.2% in patients with CDI infection (27). All cause mortality at 30 days was 18.75% in analyzed patients, regardless of the ribotype. However, the epidemiology of C. difficile is changing rapidly, and a number of studies suggest that strain type, including NAP1/BI/ 027, is not associated with more severe form of disease (28–29).
The results presented in the study have to be seen in light of some limitations. The small sample size is a main limitation in given results, so findings addressing the association of ribotype 027 with disease severity, mortality and recurrence rates needs further investigation. On the other hand, authors consider that although the sample is small, the declining trend of ribotype 027 infection rate and its association with lower fluoroquinolone utilization is undoubted.