You will select one of the following study designs (scientific peer-reviewed articles) for review – experimental, cohort, or case-control. Once you have received approval for your selected article, yo

You will select one of the following study designs (scientific peer-reviewed articles) for review – experimental, cohort, or case-control. Once you have received approval for your selected article, yo
C lostridium species are obligate anaerobic, endo- spore-forming bacilli that usually colonize in the gastrointestinal tracts of humans. Of the >200 spe- cies of Clostridium, >30 are potential pathogens in humans, such as C. perfringens and Clostridioides diffi – cile. However, C. innocuum has rarely been described as associated with human disease. C. innocuum was fi rst identifi ed in the 1960s among 8 patients in the United States; the name, in- nocuum, described its lack of virulence (1 ,2 ). It was challenging to distinguish C. innocuum from other Clostridium species (especially C. ramosum and C. clostridioforme, together called the RIC group) be- cause of their similar phenotypes of atypical clos- tridial colonial morphology, rare spore-forming features, and fatty acid pattern (3 –5). Identifying C. innocuum has become faster and more accurate after the introduction of molecular techniques such as 16S RNA sequencing and matrix-associated laser desorption/ionization time-of-fl ight (MALDI-TOF) mass spectrometry (6 ). In 1995, Cutrona et al. reported the fi rst case of endocarditis caused by C. innocuum (7). Although the bacterium was considered less pathogenic and seldom caused infections previously, more and more clinical evidence has emerged since 2000s, suggesting C. innocuum might be a potential cause of antibiotic-associated diarrhea and of extraintesti- nal clostridial infection (EICI), such as bacteremia, intra-abdominal infection, and endocarditis (8 –10). However, we are not aware of a study of C. innocu- um infection with a large enough cohort of patients to describe its clinical characteristics. Precise diagnosis of C. innocuum is necessary because of its unique intrinsic resistance to vanco- mycin, presumably caused by the presence of 2 chro- mosomal genes that enable the synthesis of a pepti- doglycan precursor terminating in serine with low vancomycin affi nity (9 ,11). Although vancomycin is one of the recommended antimicrobial drugs to treat infections caused by Clostridium species, espe- cially C. diffi cile, intrinsic resistance to vancomycin in C. innocuum poses the risk for inappropriate treat- ment for patients who acquire C. innocuum infection ( 12). C. diffi cile is one of the most representative clos- tridial species to cause human disease and has been well investigated. In the United States, ≈500,000 in- fections were identifi ed annually, and 15,000–30,000 deaths were associated with C. diffi cile infection (CDI) (12– 14) In previous studies, we demonstrated C. innocu- um as a potential invasive pathogen causing severe colitis and EICI in a small case series and proved its cellular toxicity in vitro (8 ,9 ). Herein, we conducted a retrospective case–control study to describe and Case–Control Study of Clostridium innocuum Infection, Taiwan Yi-Ching Chen, 1 Yi-Chun Kuo, 1 Mi-Chi Chen, Young-Da Zhang, Chyi-Liang Chen, Puo-Hsien Le, Cheng-Hsun Chiu Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 28, No. 3, March 2022 599 Author affi liations: Chang Gung University, Taoyuan, Taiwan (Y.-C. Chen, Y.-C. Kuo, C.-H. Chiu); Chang Gung Memorial Hospital, Taoyuan (Y.-C. Chen, M.-C. Chen, Y.-D. Zhang, C.-L. Chen, P.-H. Le, C.-H. Chiu) DOI: https://doi.org/10.3201/eid2803.204421 1These authors contributed equally to this article. Vancomycin-resistant Clostridium innocuum was recently identifi ed as an etiologic agent for antibiotic-associated diarrhea in humans. We conducted a case–control study involving 152 C. innocuum-infected patients during 2014– 2019 in Taiwan, using 304 cases of Clostridioides diffi – cile infection (CDI) matched by diagnosis year, age (+2 years), and sex as controls. The baseline characteristics were similar between the 2 groups. C. innocuum–infected patients experienced more extraintestinal clostridial infec- tion and gastrointestinal tract–related complications than did patients with CDI. The 30-day mortality rate among C. innocuum –infected patients was 14.5%, and the over- all rate was 23.0%. Chronic kidney disease, solid tumor, intensive care unit admission, and shock status were 4 independent risk factors for death. C. innocuum identifi ed from clinical specimens should be recognized as a patho- gen requiring treatment, and because of its intrinsic van- comycin resistance, precise identifi cation is necessary to guide appropriate and timely antimicrobial therapy. RESEARCH evaluate the clinical characteristics and outcomes of infections caused by C. innocuum. To this end, we se- lected case-patients with CDI as the control group. Institute Review Boards in Chang Gung Memo- rial Hospital (CGMH; Taoyuan, Taiwan) approved the study, allowing review of the medical data of the patients (IRB#201900906B0). A waiver of con- sent was granted given the retrospective nature of the project and anonymous analysis of the clinical information of patients. Methods Study Design, Clinical Setting, and Case Enrollment We conducted a retrospective case–control study at CGMH during 2014–2019. CGMH is a tertiary medi- cal center accommodating 3,700 patient beds. We selected C. difficile as the control to better illustrate the clinical features of C. innocuum infection. The case and control groups were assigned in a 1:2 ratio and matched in the diagnosed year, age +2 years, and sex. We identified cases with C. innocuum and C. difficile infections using the rapid ID 32A system (bioMérieux, https://www.biomerieux.com) and MALDI-TOF mass spectrometry Biotyper (Bruker Daltonik GmbH, https://www.bruker.com) (15– 17). MALDI-TOF mass spectrometry was introduced in 2009 in the clinical microbiology laboratory of CGMH, but C. innocuum was not reported routinely because it was considered a clinically insignificant microorganism. To trace the cases infected with C. innocuum, we reviewed the original reporting data- base from the MALDI-TOF mass spectrometry sys- tem directly and identified the samples reporting C. innocuum. Our definition of a microbiologically confirmed C. innocuum infection was that the origi- nal report from the MALDI-TOF mass spectrometry database revealed C. innocuum in the strongest 2 sig- nals and had signal scores >2.00. We defined C. dif- ficile infections by the same rationale. We reviewed baseline information of each pa- tient and enlisted all patients with C. innocuum in- fection in the study. We defined C. difficile infection as a positive PCR-based toxin assay with presence of clinical symptoms compatible with the infection, or a positive culture of C. difficile with compatible clinical symptoms (e.g., documented diarrhea or radiologic features of toxic megacolon). We ex- cluded cases with concomitant C. innocuum and C. difficile isolated from the same clinical sample from the study. For the case-control matching, 3 authors (Y.-C. Chen, Y.-C. Kuo, and M.-C. Chen) reviewed baseline information of all cases with C. innocuum and C. difficile infection. We randomly selected 2 controls for each case, matched by diagnostic year, age (+ 2 years), and sex of the index case. If no con- trols were eligible from these 3 matching variables, then we dropped the sex criterium, followed by the age criterium if necessary. After the matching pro- cess, we further reviewed the clinical information of these patients. Clinical Data Resources, Variables, and Definition We collected demographic data, clinical manifes- tations, laboratory testing results, images, and mi- crobiology reports through an electronic medical record system (EMR). Demographic data were age, sex, race, underlying systemic diseases, and acquisi- tion modality (community vs. hospital). We defined hospital-acquired infection as the symptoms that oc- curred >48 hours after admission, or <4 weeks af- ter discharge from a healthcare facility; otherwise, it was classified as a community-acquired infec- tion (18). We calculated the Charlson Comorbidity Index score for each patient to represent the base- line physiologic condition affected by underlying disease. The index is composed of 19 underlying conditions in 4 categories. Each category had a weighted score based on the risk for 1- and 10-year mortality rate (19). We recorded clinical symptoms such as diar- rhea, fever, bloody stool, abdominal pain, vomiting, and abdominal distension. We also reviewed dis- ease-related complications, including toxic megaco- lon, ileus, bowel perforation, and shock. Recurrent infection was defined if the patient had a repeated microbiological culture from the same specimen source within 8 weeks of initial documented symp- toms resolution (20, 21). Outcome assessment includ- ed 30-day, 90-day, and overall deaths after the in- fection. We reviewed previous antibiotic exposures according to each class: penicillins, cephalosporins, carbapenems, fluoroquinolones, aminoglycosides, macrolides, tetracyclines, glycopeptides, oxazolids, polymyxins, lincosamides, and metronidazole. We defined antibiotic exposure rates as the percentage of patients who received any drugs <30 days before C. innocuum or C. difficile infection and duration of antibiotic exposure as total days of any antimicro- bial drug use in a patient <30 days before the event of C. innocuum or C. difficile infection. Bacterial Isolation and Identification We performed anaerobic bacterial cultures in the clinical microbiology laboratory, as described 600 Emerging Infectious Diseases • www .cdc.gov/eid • Vol. 28, No. 3, March 2022 Clostridium innocuum Infection, Taiwan previously (9). We streaked all the anaerobic samples onto the selective agar plate, including CDC-ANA- BAP (anaerobic blood agar plate), CDC-ANA-PEA (anaerobic phenylethyl alcohol blood agar plate), and BBE/KVLB (Bacteroides bile esculin and laked kanamycin) bi-plate. We incubated agar plates in an- aerobic conditions (90% N 2/10% CO 2) at 37°C for 5 days. We grossly reviewed the growing colonies on Emerging Infectious Diseases • www .cdc.gov/eid • Vol. 28, No. 3, March 2022 601 Table 1. % D V H O L Q H F K D U D F W H U L V W L F V D Q G F O L Q L F D O G L D J Q R V H V L Q J U R X S V R I S D W L H Q W V E W K H L Q I H F W L Q J Clostridium V S H F L H V L Q F D V H – F R Q W U R O V W X G R I C. innocuum L Q I H F W L R Q 7 D L Z D Q 9 D U L D E O H 7 R W D O 1 C. innocuum Q Clostridioides difficile Q OR b & , f S Y D O X H $ J H P H D Q 6 ‘ f † f f f 1 $ 6 H [ 0 f f f ‒2.10) ) f f f (0.48‒1.06) + R V S L W D O L ] D W L R Q f f f ‒0.90) 1 R G D V P H G L D Q , 4 5 U D Q J H f ‡ 22 (36, 0‒492) 0‒492) 0‒409) 1 $ & K D U O V R Q & R P R U E L G L W , Q G H [ P H D Q 6 ‘ f † f f 1 $ ‘ L D E H W H V P H O O L W X V f f f ‒2.11) & K U R Q L F N L G Q H G L V H D V H f f f ‒0.81) & R Q J H V W L Y H K H D U W I D L O X U H f f f ‒1.40) $ , ‘ 6 f f f ‒6.44) 6 R O L G W X P R U f f f ‒1.2 ) , Q L W L D O , & 8 D G P L V V L R Q f f f ‒ .03) $ F T X L V L W L R Q R I L Q I H F W L R Q + R V S L W D O D F T X L U H G f f f ‒0.63) & R P P X Q L W D F T X L U H G f f f ‒3.93) & O L Q L F D O G L D J Q R V L V Clostridium – D V V R F L D W H G G L D U U K H D f f f ‒0.26) ( [ W U D L Q W H V W L Q D O F O R V W U L G L D O L Q I H F W L R Q f f f ‒11.01) % D F W H U H P L D f f f ‒120.00) , Q W U D – D E G R P L Q D O L Q I H F W L R Q f f f ‒10.23) % L O L D U W U D F W L Q I H F W L R Q f f f ‒ 9.1 ) 5 H F X U U H Q W L Q I H F W L R Q f f f 1 $ 1 $ 6 N L Q D Q G V R I W W L V V X H L Q I H F W L R Q f f f ‒8.13) * H Q L W D O W U D F W L Q I H F W L R Q f f f 1 $ 1 $ & R P S O L F D W L R Q , O H X V f f f ‒4.29) % R Z H O S H U I R U D W L R Q f f f ‒28. 0) + S R Y R O H P L F R U V H S W L F V K R F N f f f ‒4.30) 0 R U W D O L W – G D P R U W D O L W f f f ‒1.20) – G D P R U W D O L W f f f ‒0.99) 2 Y H U D O O P R U W D O L W f f f ‒1.21) 9 D O X H V D U H Q R b f H [ F H S W D V L Q G L F D W H G S Y D O X H R I 2 5 V Z D V D Q D O ] H G E X Q L Y D U L D W H O R J L V W L F U H J U H V V L R Q , & 8 L Q W H Q V L Y H F D U H X Q L W , 4 5 L Q W H U T X D U W L O H U D Q J H 1 $ Q R W D S S O L F D E O H I R U F R Q W L Q X R X V Y D U L D E O H V R U W R R I H Z H Y H Q W V f W R F D O F X O D W H D V W D E O H 2 5 2 5 R G G V U D W L R †By independent t test. ‡By Mann -Whitney test. §Two cases were diagnosed as pyospermia and bacterial vaginitis. = Table 2. Antibiotic exposure before Clostridium infection in case –control study of C. innocuum infection *= Antibiotic exposure = C. innocuum , n== 152 = Clostridioides difficile , n== 304 = Odds ratio (95% CI) = p value = Any antibiotic exposure = 121 (79.6) = 289 (95.1) = 0.20 (0.11 –0.39) = <0.001 = Mean duration of antibiotic exposure, d (SD) † 13.7 (8.6) = 15.6 (8.3) = NA = 0.039 = Antibiotic exposure rate by drug class = =Penicillins = 36 (23.7) = 107 (35.2) = 0.57 (0.37 –0.89) = 0.013 = =Cephalosporins = 81 (53.3) = 206 (67.8) = 0.54 (0.36 –0.81) = 0.003 = =Carbapenems = 36 (23.7) = 102 (33.6) = 0.62 (0.40 –0.96) = 0.031 = =Fluoroquinolones = 31 (20.4) = 108 (35.5) = 0.47 (0.29 –0.74) = 0.001 = =Aminoglycosides = 13 (8.6) = 20 (6.6) = 1.33 (0.64 –2.75) = 0.444 = =Macrolides = 3 (2.0) = 8 (2.6) = 0.75 (0.20 –2.85) = 0.667 = =Tetracyclines = 6 (3.9) = 5 (1.6) = 2.46 (0.74 –8.19) = 0.143 = =Glycopeptides = 52 (34.2) = 92 (30.3) = 1.20 (0.79 –1.81) = 0.393 = =Oxazolids = 0 (0) = 2 (0.7) = NA = NA = =Polymyxins = 6 (3.9) = 11 (3.6) = 1.10 (0.40 –3.02) = 0.861 = =Lincosamides = 6 (13.9) = 21 (6.9) = 0.55 (0.22 –1.40) = 0.213 = =Metronidazole = 16 (10.5) = 33 (10.9) = 0.97 (0.51 –1.81) = 0.915 = *Data are presented as no (%) unless otherwise indicated. NA, not applicable for continuous variables or too few events (<5) to calculate a stable odds ratio . = †By independent student t test. The =p=value =of odds ratio was analyzed by univariate logistic regression. = = RESEARCH plate and analyzed 1 representative colony for each agar plate by the rapid ID 32A system (bioMérieux) for identification of the microorganisms. Antimicrobial Susceptibility Testing We tested antimicrobial susceptibilities to clindamy- cin, metronidazole, penicillin, piperacillin, and am- picillin/sulbactam by the break-point agar dilution method according to Clinical and Laboratory Stan- dards Institute criteria (document M11-A8) for an- aerobic bacteria (22). We used interpretive criteria in document M100S to determine susceptibility (22). Statistical Analysis We performed statistical analysis by SPSS Statistics 24.0 (SPSS Inc., https://www.ibm.com/products/ spss-statistics). For continuous variables, we deter- mined significance by using the independent t test or Mann-Whitney U test as appropriate. If the con- tinuous variable had outliers and did not fit the nor- mal distribution, variables were shown as median (interquartile range, range). We analyzed the cat- egorical variables by χ 2 test and considered p<0.05 statistically significant. We obtained odds ratios (ORs) from cross-tabulation and analyzed the p val- ue of ORs by univariate logistic regression. We esti- mated mortality rate at 30 days and 90 days after the positive culture and analyzed by Kaplan-Meier sur- vival analysis using methods described previously ( 23). In addition, we examined risk factors associ- ated with 30- and 90-day mortality in both groups by logistic regression. Results Participants and Demographic Information By the MALDI-TOF mass spectrometry system, 180 samples yielded the growth of C. innocuum. We ex- cluded 22 of those from further analysis because of lack of access to clinical information and 6 because of concomitant isolation of C. innocuum and C. dif- ficile from the same sample (CI group). We matched the control group with C. innocuum samples in ac- cordance with the study criteria. From 1,134 C. dif- ficile cases during the study period, we enrolled 304 cases as controls (CD group). All control cases were 602 Emerging Infectious Diseases • www .cdc.gov/eid • Vol. 28, No. 3, March 2022 Table 3. & O L Q L F D O D Q G O D E R U D W R U F K D U D F W H U L V W L F V E W K H L Q I H F W L Q J Clostridium V S H F L H V L Q F D V H – F R Q W U R O V W X G R I C. innocuum L Q I H F W L R Q 7 D L Z D Q & K D U D F W H U L V W L F C. innocuum Q Clostridioides difficile Q S Y D O X H & O L Q L F D O V P S W R P V ‘ L D U U K H D f f ) H Y H U f f $ E G R P L Q D O S D L Q f f 9 R P L W L Q J f f $ E G R P L Q D O G L V W H Q V L R Q f f % O R R G W H V W L Q J Leukocytes, cells/μL † f f + H P R J O R E L Q J G / † f f Platelet count × 1,000/μL † f f & 5 3 P J / P H G L D Q , 4 5 f ‡ f f 6 W R R O U R X W L Q H Q R S R V L W L Y H W R W D O b f 2 F F X O W E O R R G f f 0 X F X V f f 3 X V F H O O V f f 6 D P S O H V L W H 6 W R R O f f % O R R G f f $ V F L W H V f f % L O H f f 3 X V D E V F H V V f f : R X Q G G H H S W L V V X H f f ( Q G R F H U Y L [ f 6 H P H Q f $ Q W L P L F U R E L D O V X V F H S W L E L O L W 0 H W U R Q L G D ] R O H f f & O L Q G D P F L Q f f 3 H Q L F L O O L Q f f $ P S L F L O O L Q V X O E D F W D P f f 9 D O X H V D U H Q R b f S D W L H Q W V H [ F H S W D V L Q G L F D W H G $ P R Q J S D W L H Q W V Z L W K C difficile & ‘ f – D V V R F L D W H G G L D U U K H D W K H & ‘ W R [ L Q D V V D S R V L W L Y H U D W H Z D V b χ W H V W V Z H U H X V H G W R F R P S D U H D O O W K H F D W H J R U L F D O Y D U L D E O H V O L V W H G L Q W K H W D E O H H [ F H S W D V Q R W H G & 5 3 & -reactive protein; IQR, interquartile range. †By independent t test. ‡By Mann -Whitney test. §By Fisher exact test. #Data are expressed as susceptible isolate number/total isolate number (%). = Clostridium innocuum Infection, Taiwan matched precisely on diagnostic year and age (+ 2 years); 25 controls were not matched on sex. The mean patient age for the 456 cases was 66.7 years, and 58.3% of patients were male (Table 1). Both groups were similar regarding age, sex, and Charlson Co- morbidity Index score (5.7 + 3.2 for CI and 6.2 + 3.3 for CD). Subgroup analysis of each age group (<50, 50–60, 60–70, 70–80, and >80 years) also revealed no statistical difference. Overall, 8 pediatric patients were recruited, 3 in the CI group and 5 in the CD group. Regarding underlying systemic diseases, the CD group showed more patients with chronic kid- ney disease (18.4% vs. 30.9%; p = 0.005) (Table 1). Of note, more patients acquired the infection in the community in the CI group (33.6% vs. 16.8%; odds ratio [OR] 2.5, 95% CI 1.6–3.9; p<0.001) (Table 1). Disease Characteristics and Severity We observed notable differences in disease charac- teristics between the 2 groups. Those in the CI group had a 6.5 times higher risk of developing EICI, in- cluding bacteremia, intra-abdominal infection, bili- ary tract infection, skin and soft tissue infection, pyospermia, and bacterial vaginitis (36.8% for CI vs. 8.2% for CD; OR 6.5, 95% CI 3.9 –11.0; p<0.001) (Table 1). On the contrary, most disease manifesta- tion in the CD group was confined to the intestine and colon, mainly C. difficile–associated diarrhea. Most patient had antibiotic exposure 30 days be- fore the CI or CD infection event. CD group showed higher 30-day antibiotic exposure rate (95.1%) than CI group (79.6%; p<0.001) (Table 2) and longer dura- tion (mean 15.6 days, SD 8.3) than CI group (mean 13.7 days, SD 8.6; p<0.001). Patients in CD group re- ceived more penicillins, cephalosporins, carbapen- ems, and fluroquinolones (Table 2). Regarding disease severity, most of the patients in both groups required hospitalization (93.4% in the CI group and 97.7% in the CD group; p = 0.03) (Table 1). Although most patients in CD group had intestinal infections, gastrointestinal tract–related complications of ileus, bowel perforation, clinical sepsis, and shock occurred more frequently in the CI group (26.3%) than CD group (11.2%; OR 2.8, 95% CI 1.7–4.7; p<0.001). CI group also showed a higher rate of intensive care unit (ICU) admission (23.6% vs. 9.5%; OR 2.9, 95% CI 1.7–5.0; p<0.001) (Table 1). All the data indicated that the disease severity at the acute stage was more severe and invasive in the C. innocuum–infected patients. Fur- thermore, we saw no recurrence of infection in CI group but recurrence of infection in 4.9% of CD group (p = 0.005). We observed no statistically significant differ- ences in clinical presentations, but patients with C. innocuum infection had fewer diarrheal symptoms Emerging Infectious Diseases • www .cdc.gov/eid • Vol. 28, No. 3, March 2022 603 Figure. Kaplan-Meier curve of 30-day (A), 90-day (B), and overall (C) survival rates of patients with Clostridioides difficile and Clostridium innocuum , Taiwan. In the C. innocuum group, the 30-day survival rate was 85.5%, 90-day survival rate 84.2%, and overall survival rate 77.0%. The 90-day survival rate was slightly higher than the C. difficile group (p value of log rank test = 0.05), whereas the 30-day and overall survival rates did not show a significant difference between the 2 groups. RESEARCH and less fever. In the laboratory testing results, patients experienced anemia more commonly in the CD group than CI group; hemoglobin counts were 9.8 (2.0) g/dL in CD and 10.7 (2.4) g/dL in CI (p<0.001) (Table 3). We observed no difference in other systemic inflammatory markers. A limited number of patients received colonoscopy examina- tion, and we found no pseudomembranous colitis in the CI group. Outcome and Risk Factor for Mortality Rate The 30-day mortality rate in the CI group was 14.5%; the 90-day rate, 15.8%, and the overall rate, 23.0%. Although the 90-day mortality rate was slightly higher in the CD group with a significant difference (p value of log rank test = 0.05) in Kaplan-Meier survival analysis, the overall mortality rate did not show a statistically significant difference between the 2 groups (Figure). Using logistic regression, we identified chronic kidney disease (OR 8.6, 95% CI 2.6–28.4; p<0.001), solid tumor (OR 3.5, 95% CI 1.0–12.0; p = 0.051), ICU admission (OR 7.3, 95% CI 2.4–21.9; p<0.001), and shock status (odds ratio 8.0, 95% CI 2.4–27.2; p<0.001) as 4 independent risk fac- tors for both 30-day and overall mortality rates in the patients with C. innocuum infection. We identified 7 bacteremias caused by C. innocuum in this study. Two of those patients experienced septic shock, and 1 needed ICU hospitalization. The 30-day mortality rate for the 7 patients was 42.9% (3/7) and 90-day was 57.1% (4/7). Microbiologic Result and Antimicrobial Susceptibility Among the 152 C. innocuum isolates, we recovered 96 (63.2%) isolates from stool specimens; the rest were from the blood (7 ), ascites (13), pus/abscess (16), wound/deep tissue (16), bile juice (2 ), endo- cervix (1 ), and semen (1 ). We detected 18 polymi- crobial infections in the CI group, most of which were from ascites and pus/abscess samples. More C. innocuum isolates (36.8%) than C. difficile iso- lates (8.2%) were from extraintestinal specimens (p<0.001) (Table 3), which is compatible with our clinical observation. We performed antimicrobial susceptibility testing on limited isolates. In the C. innocuum isolates, we observed the highest sus- ceptibility rate for metronidazole (20/20, 100%) and ampicillin/sulbactam (21/21, 100%), followed by penicillin (35/44, 79.5%) and clindamycin 30/44 (68.2%). Discussion Genus Clostridium is large and heterogeneous; it in- cludes <200 species. Accurate species identification has been difficult. In recent years, several new spe- cies have been recognized and others reclassified using newer molecular diagnostic methods, such as 16S rRNA gene sequencing (24). Among the medi- cally important Clostridium spp., C. perfringens is the predominant species isolated from cases of bac- teremia. The severity of EICI varies; for bacteremia, the mortality rate was found to be 48%–52% by dif- ferent studies (25– 27). The risk factors for disease acquisition and death were related to an underly- ing immunocompromised condition such as hemo- dialysis, malignancy, immunosuppressant use, and Crohn’s disease (25). The main portal of entry is the hepatobiliary and gastrointestinal tract. We believe this is also the case in C. innocuum because stool was a common source for the C. innocuum isolates and gastrointestinal tract–related complications were not uncommon in C. innocuum–infected patients. 604 Emerging Infectious Diseases • www .cdc.gov/eid • Vol. 28, No. 3, March 2022 Table 4. 5 H S R U W H G F D V H V R I H [ W U D L Q W H V W L Q D O Clostridium innocuum L Q I H F W L R Q – 7 D L Z D Q & K D U D F W H U L V W L F & D V W L J O L R Q L H W D O 10 f & U X P – & L D Q I O R Q H H W D O 29 f + X Q J H W D O 30 f 0 X W R K H W D O 31 f $ U R F D – ) H U U L H W D O 32 f < H D U D Q G F R X Q W U 8 Q L W H G 6 W D W H V 8 Q L W H G 6 W D W H V 7 D L Z D Q – D S D Q 6 S D L Q $ J H V H [ ) 0 0 0 ) 8 Q G H U O L Q J F R Q G L W L R Q V & K U R Q L F + & 9 L Q W H U V W L W L D O Q H S K U L W L V D I W H U U H Q D O W U D Q V S O D Q W $ , ‘ 6 ‘ 0 Z L W K & ‘ $ ‘ D Q G & 0 9 F R O L W L V ALL = Takayasu arteritis, ESRD under PD Isolation site = Blood = Blood = Blood = Blood, BM = Peritoneal fluid = Vancomycin MIC = 16 μg/mL NA = >32 μg/mL 8 μg/mL 8 μg/mL Diagnosis = Bacteremia secondary to infectious hematoma Bacteremia = Bacteremia = Pelvic osteomyelitis complicated with iliac muscle abscess PD peritonitis complicated with sigmoid colon perforation 7 U H D W P H Q W , 9 7 = 3 , 9 & / , , 9 ‘ $ 3 3 2 0 7 = , 9 7 = 3 , 9 7 = 3 , 9 0 7 = , 9 & / , , 9 & 7 ; , 3 $ 0 3 , 3 & / , ‘ X U D W L R Q G D V D Q G V X U J H U 1 $ Z H H N V Z H H N V G D V 2 X W F R P H 5 H F R Y H U H G 5 H F R Y H U H G 5 H F R Y H U H G 5 H F R Y H U H G ‘ L H G $ / / D F X W H O P S K R E O D V W L F O H X N H P L D $ 0 3 D P S L F L O O L Q % 0 E R Q H P D U U R Z & ‘ $ ‘ C. difficile – D V V R F L D W H G G L D U U K H D & / , F O L Q G D P F L Q & 0 9 F W R P H J D O R Y L U X V & 7 ; F H I R W D [ L P H ‘ $ 3 G D S W R P F L Q ( 5 < H U W K U R P F L Q ( 6 5 ‘ H Q G V W D J H U H Q D O G L V H D V H + & 9 K H S D W L W L V & Y L U X V , 3 L Q W U D S H U L W R Q H D O U R X W H , 9 L Q W U D Y H Q R X V U R X W H 0 , & P L Q L P X P L Q K L E L W R U F R Q F H Q W U D W L R Q 0 7 = P H W U R Q L G D ] R O H 1 $ Q R W D Y D L O D E O H 3 ‘ S H U L W R Q H D O G L D O V L V 3 2 R U D O U R X W H 7 = 3 S L S H U D F L O O L Q W D ] R E D F W D P Clostridium innocuum Infection, Taiwan A recent study by Ha et al. (28) also found that C. innocuum is one of the most common bacteria that could translocate from intestine to mesenteric tissue in patients with Crohn’s disease and further induce adipogenesis and local fibrosis, known to- gether as creeping fat. We found that among anaerobic clostridial spe- cies, C. innocuum has long been overlooked as a hu- man pathogen. Our study is to date the most com- prehensive observational study to depict the clinical manifestations and outcome of C. innocuum infection; not only it is more invasive than most Clostridium spe- cies, but it can cause more gastrointestinal tract com- plications following intestinal infection. Case reports of EICI related to C. innocuum infection have been published from the United States, Spain, Japan, and Taiwan (10,29–32) (Table 4). Bacteremia and intra- abdominal infection were the most common manifes- tations, which is compatible with our observations. All the infections occurred in patients with underly- ing conditions; prolonged antimicrobial therapy was required to treat these patients, whose mortality rate (20%) was similar to that observed in our study (23%). Compared to C. difficile, which is known to be a noso- comial pathogen, nearly one third of the C. innocuum infections occurred in the community. This observa- tion indicates that C. innocuum could be more virulent and competitive than C. difficile. Among the EICI, bacteremia is the most severe form of infection. In a recent study by Morel et al. ( 33), non–C. difficile Clostridium bacteremia requiring ICU hospitalization showed an aggressive clinical course and was usually life-threatening. The 28-day mortality rate was 55% and the 90-day mortality rate was 71% (33). This report is compatible with our findings of 30-day (42.9%) and 90-day (57.1%) mor- tality rates in the CI bacteremic patients. Identifying C. innocuum infection is important because the microorganism expresses intrinsic re- sistance to vancomycin, because of the synthesis of peptidoglycan precursors with low affinity for van- comycin (MIC 4–16 mg/L) (8 ,26). Moreover, highly vancomycin-resistant strains (MIC >16 mg/L) could develop if the bacteria were previously exposed to vancomycin (34). Because oral vancomycin has been recommended as the first-line therapy for C. difficile infection, distinguishing C. innocuum from other clostridial species becomes essential to avoid treat- ment failure caused by inappropriate antimicrobial use. Metronidazole and clindamycin appear to be appropriate choices for treating C. innocuum infec- tion, according to our antimicrobial susceptibility testing results. The main limitation of our study is the retro- spective study design and the inevitable miss- ing data. The lack of standardized medical record format prevented us from precisely defining ev- ery case-patient’s diagnosis, especially antibiot- ic-associated diarrhea and acute colitis, which have similar clinical descriptions in the medi- cal records. Some objective data were not avail- able, which may potentially compromise the ac- curacy of the estimated rates of presentations and diagnoses among the patients. However, the pro- portion of missing data appeared small and should not significantly affect the results of the study. Second, not all the C. innocuum isolates from the enrolled patients were tested for antimicrobial susceptibility, and that testing did not include van- comycin. Third, the study does not advance our understanding on virulence mechanism of C. in- nocuum. It is possible that C. innocuum possesses a unique virulence mechanism to cause gastrointesti- nal as well as extraintestinal infections, such as the lipopolysaccharide-like structure we described in our previous study (9 ). C. difficile also contains sur- face lipocarbohydrate, which has a similar biologic activity to the lipopolysaccharide in gram-negative bacteria (35); this hypothesis needs further experi- mental verification. In conclusion, C. innocuum should be consid- ered an important Clostridium species causing EICI and gastrointestinal infection that has a risk for severe complications and a high mortality rate in immunocompromised patients; physicians should recognize it as a pathogen to treat clinically. More studies are needed to understand the virulence mechanism of C. innocuum. Precise identification of C. innocuum will guide appropriate and timely antimicrobial therapy for patients because of its in- trinsic vancomycin resistance. The study was financially supported by grants (CIR- PG3H0031-2 and CIRPG3H0041-2) from Chang Gung Memorial Hospital, Taiwan, and the Maintenance Project of the Center for Big Data Analytics and Statistics at Chang Gung Memorial Hospital (grant CLRPG3D0048) for statistical consultation and data analysis. About the Author Dr. Chen is an infectious disease specialist at Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. Her research interests are epidemiol- ogy, pathogenesis, and resistance mechanisms of enteric bacterial infection. Emerging Infectious Diseases • www .cdc.gov/eid • Vol. 28, No. 3, March 2022 605 RESEARCH References 1. Smith LD, King E. Clostridium innocuum, sp. n., a sporeforming anaerobe isolated from human infections. J Bacteriol. 1962;83:938–9. https://doi.org/10.1128/ jb.83.4.938-939.1962 2. Alexander CJ, Citron DM, Brazier JS, Goldstein EJ. 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J Med Microbiol. 2008;57:739–44. https://doi.org/ 10.1099/jmm.0.47678-0 Address for correspondence: Cheng-Hsun Chiu, Chang Gung Children’s Hospital—Department of Pediatrics, 5 Fu-Hsin St, Kweishan Taoyuan County 333, Taiwan; email: [email protected] Emerging Infectious Diseases • www .cdc.gov/eid • Vol. 28, No. 3, March 2022 607 ® Bacterial Infections To revisit the October 2020 issue, go to: https://wwwnc.cdc.gov/eid/articles/issue/26/10/table-of-contents • Operating Protocols of a Community Treatment Center for Isolation of Patients with Coronavirus Disease, South Korea • Communit y Treatment Centers for Isolation of Asymptomatic and Mildly Symptomatic Patients with Coronavirus Disease, South Korea • Clinical Course of Asymptomatic and Mildly S ymptomatic Patients with Coronavirus Disease Admitted to Community Treatment Centers, • Nation wide External Quality Assessment of SARS-CoV-2 Molecular Testing, South Korea • Impact of Social Distancing Measures on Corona virus Disease Healthcare Demand, Central Texas, USA • Multicenter Prev alence Study Comparing Molecular and Toxin Assays for Clostridioides difficile Surveillance, Switzerland • Effectiv eness of 23-Valent Pneumococcal Polysaccharide Vaccine against Invasive Pneumococcal Disease in Adults, Japan, 2013–2017 • Sequential Acquisition of Human P apillomavirus Infection at Genital and Anal Sites, Liuzhou, China • Drug R esistance Spread in 6 Metropolitan Regions, Germany, 2001–2018 • Silent Circulation of Rift V alley Fever in Humans, Botswana, 2013–2014 • Association between Shiga T oxin– Producing Escherichia coli O157:H7 stx Gene Subtype and Disease Severity, England, 2009–2019 • Effect of Nonpharmaceutical Interv entions on Transmission of Severe Acute Respiratory Syndrome Coronavirus 2, South Korea, 2020 • Main R outes of Entry and Genomic Diversity of SARS-CoV-2, Uganda • High Proportion of Asymptomatic S ARS-CoV-2 Infections in 9 Long-Term Care Facilities, Pasadena, California, USA, April 2020 • Tickborne R elapsing Fever, Jerusalem, Israel, 2004–2018 • Sea water-Associated Highly Pathogenic Francisella hispaniensis Infections Causing Multiple Organ Failure • Basic R eproduction Number of Chikungunya Virus Transmitted by Aedes Mosquitoes • Deaths Associated with Pneumonic Plague, 1946–2017 • Human Adeno virus B7–Associated Urethritis after Suspected Sexual Transmission, Japan • P olyester Vascular Graft Material and Risk for Intracavitary Thoracic Vascular Graft Infection • R apid, Sensitive, Full-Genome Sequencing of Severe Acute Respiratory Syndrome Coronavirus 2 • Limitations of Ribot yping as Genotyping Method for Corynebacterium ulcerans • Seoul Orthohanta virus in Wild Black Rats, Senegal, 2012–2013 • Contact T racing during Coronavirus Disease Outbreak, South Korea, 2020 • P ooling Upper Respiratory Specimens for Rapid Mass Screening of COVID-19 by Real-Time RT-PCR • Corona virus Disease among Persons with Sickle Cell Disease, United States, March 20–May 21, 2020 October 2020 This content isin the Public Domain.