Background
As a successful nosocomial pathogen, toxin-producing
C. difficile has caused approximately 10–30% healthcare-associated infections [
1,
2]. Increased incidence and severity of
Clostridium difficile infection (CDI) have been witnessed in Europe and North America in recent decades [
3,
4]. However, in developing countries, due to the poor awareness of healthcare workers and limited capacity of laboratory diagnosis, the potential public threat of CDI has not been fully recognized. A recent random-effects study including 37,663 patients reported a similar incidence rate of CDI in Asia in comparison with North America and Europe. Significant regional variation has been revealed and when compared with the Middle East and South Asia, East Asia was exposed to the highest CDI prevalence of 19.5% [
5], which necessitated good awareness and surveillance of CDI in this area.
However, unlike the rest of East Asia, limited data have focused on the burden of CDI in China. Although few regional studies alarmed that the hyper-virulent
C. difficile strain ST-1 (BI/NAP1/027), an epidemic strain in Europe and North America, has emerged in Chinese hospital settings, recent reports revealed that ST35, ST37 and ST3 were the most prevalent genotypes in mainland China [
6,
7]. Moreover, in consideration of the complex personnel mobility in medical institutions, the majority of CDI is hospital-acquired, and nosocomial transmission of
C. difficile contributes greatly to the spread of different genotypes. Recently, whole genome sequencing (WGS) identified the dissemination and spread of
C. difficile ribotype 027 (RT027) and sequence type 081 (ST081) in two Chinese hospitals [
8,
9]. Therefore, a better understanding of regional epidemiology is helpful to guide priorities for the management of hospital-acquired
Clostridium difficile infection (HA-CDI). Although many studies have explored the CDI situation in China, the lack of epidemiological data in blind areas impedes a full understanding of CDI in this country. To the best of our knowledge, this is the first study of HA-CDI in Chongqing, a provincial administrative unit in Southwest China [
6]. Our study was initiated to investigate the impact of HA-CDI by identifying its prevalence, determine the risk factors for the acquisition of this dilemma in patients with antibiotic-associated diarrhea (AAD), reveal the mortality of HA-CDI in this teaching hospital and inquire into the molecular epidemiology and antimicrobial resistance of
C.difficile isolates found in this study.
Discussion
Enhanced molecular diagnostic and antibiotic treatment strategies promote the continuous evolution of the knowledge of CDI epidemiology. Geographical heterogeneity and transcontinental dissemination have aroused more concerns about regional CDI surveillance. In China, although the state of dilemma introduced by CDI has been documented before [
6,
7], data are lacking in the central and western regions. To fill gaps in the epidemiological territory of CDI in China, the results in this study presented basic knowledge of the prevalence and mortality of HA-CDI, and helped to improve the recognition of patients at high risk for HA-CDI acquisition and to guide antibiotic stewardship initiatives of HA-CDI in this tertiary teaching hospital in Southwest China.
A survey focusing on antibiotic consumption in specialized public hospitals in 30 provinces in mainland China showed a decrease in the percentage of antibiotic use in inpatients in Chongqing, from 78.84 to 54.93% [
19]. The present study found the ratio of antibiotic use in inpatients was 43.4%. Despite being relatively low and comparable to the previous data reported by Zhou et al. [
20], this percentage, to a large extent, surpassed the recommendation of 30% by World Health Organization (WHO). Previous studies have reported varied frequencies of AAD from 0.57 to 14.9% in different populations [
21,
22]. The correlation between antibiotic use and the prevalence of AAD in Chongqing was previously unknown. The present study witnessed a moderate prevalence of AAD in 0.13% (a much lower rate) of antibiotic-treated inpatients. One possible explanation is that a majority of the patients in this cohort were from surgical wards and received antibiotics simply for perioperative prophylaxis.
In this investigation, HA-CDI accounted for 31.1% of AAD, which was consistent with previous reports [
20,
23]. The high prevalence of CDI among AAD is always a major concern worldwide [
24]. To prevent CDI from AAD, external interventions and internal defense mechanisms should work cooperatively. Our previous study has shown that interleukin-27 (IL-27)/IL-27 receptor signaling provides protection against
C. difficile-induced colitis in AAD patients [
25]. A recent systematic review and meta-analysis reported an incidence of 0.32 cases of CDI per 1000 patient admissions in Asia [
5] and a similar result was verified in a 7-year retrospective study in a large university hospital in Eastern China [
26]. This study reported a relatively low incidence of 0.18 per 1000 patient admissions, probably due to inadequate awareness of CDI among clinicians, low sensitivity of stool anaerobic culture for
C. difficile detection, and low testing frequency [
27]. Another possible reason is the missing information of a proportion of inpatients who might develop CDI after discharge.
As is well known, the use of antibiotics may cause CDI [
28], but the case-control design focusing on the difference between antibiotic group and non-antibiotic group may have the trends to overestimate the impact of antibiotic exposure on the acquisition of HA-CDI. To explore the specific reasons leading to CDI, this study set up a comparison between the HA-CDI group and the non-
C. difficile AAD group in AAD patients to identify which antibiotics or predictors were associated with a high risk for HA-CDI. Although many risk factors were revealed in univariate analysis, only two independent risk factors, cephalosporin use prior to the onset of diarrhea and chronic kidney diseases were identified for patients with HA-CDI when compared to non-
C.difficile AAD, which is consistent with previous reports [
29‐
31] and not difficult to explain. In addition to the cephalosporins known to all [
32], chronic renal disease may cause poor excretion of antibiotic agents, high concentration in blood and finally, the imbalance of bacterial flora in the gut.
Age over 65 years was not associated with an increased risk for HA-CDI. Suffering from HA-CDI in younger age was observed in this study. Similar results have been reported in several previous studies in mainland China and France [
23,
29,
33]. Therefore, it is necessary to consider the age threshold in the recognition of inpatients at high risk for HA-CDI in different settings. Massive consumption of antibiotics by university students has been reported nationwide in China [
34]. Accumulative effects of antibiotic consumption may contribute partly to the acquisition of CDI in younger age, which deserves more attention. Moreover, ageing is accompanied by changes in the gut microbiome [
35], and it is speculated that it is not the age threshold, but the gut microbial structure that truly participates in the priming of HA-CDI.
To reveal the epidemiology of CDI in mainland China, in this non-outbreak situation, specific genotypes of toxigenic
C. difficile strains were observed. ST2 was the most predominant genotype, while recent studies reported that ST54, ST3 and ST37 were the most prevalent genotypes in mainland China [
6,
33,
36‐
38]. Noteworthily, in addition to ST54 and ST3, ST35 also emerged both in this work and another inspection in Yunnan [
39], a province bordering Chongqing, witnessing the spread of this toxin genotype over provinces in China. Toxigenic RT449 with a high prevalence in this work was not reported previously, and its predominant proportion may indicate an upcoming outbreak. One
C. difficile isolate was positive for binary toxin and belonged to ST5/RT498 in clade 3. Although the CDT+ strain appeared less frequently in Asia, this was not the first report of this toxin genotype in China. ST5 accounted for 83.7% of binary toxin gene-positive strains in a survey conducted by Chen et al. [
40] in 2018. Data on
C. difficile strains in clade 3 with binary toxins are not well documented in mainland China. WGS of three clade 3
C. difficile strains carrying binary toxin genes in a university hospital found that clade 3 has unusual clade-specific
PaLoc characteristic of Tn
6218 insertion, which may be the main feature to distinguish clade 3 from other
C. difficile [
41]. The identification of seven novel RTs indicated the diversity of
C. difficile strains in this hospital.
Despite the fact that clinical
C. difficile strains with hetero-resistance or high-level resistance to metronidazole were reported in China [
20,
33], the present study failed to identify strains resistant to metronidazole, vancomycin or tigecycline, indicating that these three antibiotic agents still seem to be appropriate for empirical treatment of HA-CDI. In addition, toxin types were associated with antibiotic resistance phenotypes. A-B- strains were more resistant than A + B+ strains, while the latest data from two hospitals in Shangdong illustrated that non-toxigenic strains were more sensitive [
42].
Our study has some limitations. First, these results were derived from a single-center. Widely recommended detection schemes, two-step and three-step methods for the diagnosis of CDI, were implemented in many laboratories in China, but anaerobic culture was not the choice for the final confirmation. This may be one of the causes for the lack of epidemiological data in this country. To obtain surveillance data for CDI, a network of reference or central laboratories such as that found in Europe is needed [
43]. Second, this study failed to track clinical treatments of HA-CDI, but most patients recovered from diarrhea after the discontinuation of antibiotic therapy. Third, highly sensitive tests, such as the nucleic acid amplification test (NAAT) or the glutamate dehydrogenase (GDH) screening test, were not performed in this study.
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