Table 1.
Incidence and prevalence of C. difficile, and risk factors associated with C. difficile infection reported in Japanese patient populations
| Reference | Study period | Study design | Patient population | C. diff diagnosis (n) | C. diff definition | Incidence | Prevalence | Risk factors for CDI |
|---|---|---|---|---|---|---|---|---|
| Akahoshi et al. [24] | November 2007–May 2014 |
Retrospective, single-center, chart review n = 308 |
HSCT (n = 102 autologous; n = 206 allogeneic) |
n = 30 Occurring median 7 days (range 0–36) after HSCT conditioning |
Diarrhea (≥ 3 loose stools/24 h) in first 100 days post HSCT Positive CD toxina or positive CD toxin plus GDHb |
Cumulative incidence 6.2% in HSCT population (9.2% allogeneic; 1.0% autologous) | – |
Allogeneic HSCT, total body irradiation, stem cell source, acute leukemia, duration of neutropenia – linked with increased risk for CDI Allogeneic HSCT: OR for CDI 18.6 (95% CI 2.48–139) p < 0.01; duration of neutropenia ≥ 17 days in first 30 days: OR for CDI 10.4 (95% CI 2.37–46 p < 0.01) |
| Daida et al. [31] | July 2003–September 2012 | Retrospective case–control study via medical record review from a single center |
Pediatric patients (aged 0–19 years) admitted to hospital with cancer (n = 51) Matching case controls were selected from patients without CDI admitted to hospital within 2 months (before/after) admission for patients with CDI (n = 94) |
n = 51 |
Test for C. diff toxins A/Ba Appearance of symptoms ≥ 3 days after admission |
51/189 = 26.98% | – | Multivariable analysis of risk factors for hospital-acquired CDI: younger age is a risk factor: age 0–3 years vs. age 4–6 years, OR 0.13 (95% CI 0.03–0.59); p = 0.008, and vs. age ≥ 7 years, OR 0.12 (95% CI 0.03–0.45); p = 0.002. Prolonged neutropenia is a risk factor: OR 1.11 (95% CI 1.03–1.20); p = 0.008. Use of ≥ 4 antibiotics in the 60 days from diagnosis or reference date: OR 3.55 (95% CI 1.40–9.04); p = 0.008 |
| Furuichi et al. [32] | August 2012–March 2013 |
Prospective, non-interventional cohort to assess rates of community-acquired C. diff colonization (single center) n = 346 children |
Healthy neonates (n = 95) and pediatric patients at hospital admission (n = 251) |
0 (0%) C. diff (asymptomatic) colonization in neonates Pediatric population without underlying disease: C. diff colonization 21.6% and 9% toxin positive colonization; vs. with underlying disease 30.8% and 23.1% (colonization and toxin-positive colonization) |
Cultured fecal samples positive for C. diff toxin A/Bb |
Asymptomatic CDI 9% toxin-positive colonization in pediatric patients with no underlying disease 23.1% toxin-positive colonization in pediatrics with underlying disease |
– | Risk factors for toxin-positive C. diff colonization: underlying disease (OR 4.17, 95% CI 1.15–15.04; p = 0.049); age 12–23 months (OR 4.19, 95% CI 1.52–11.52; p = 0.01); tube feeding (OR 24.28, 95% CI 4.70–125.34; p < 0.001); toxin-positive C. diff (OR 8.29, 95% CI 1.87–36.84; p = 0.005) |
| Hashimoto et al. [26] | January 1996–November 2004 |
Retrospective chart review (single center) n = 242 |
Living-donor liver transplant recipients (adult) | Diarrhea 76/242; C. diff diarrhea 11/242 | C. diff diarrhea: ≥ 3 loose stools on ≥ 2 consecutive days and positive stool culture and assays for toxin Ac and GDHd | 11/242 C. diff diarrhea = 4.5%e | – |
Male gender (OR 4.56; 95% CI 1.02–33.3, p = 0.05) and serum creatinine md/dL ≥ 1.5 (OR 16.0, 95% CI 3.85–68.3, p = 0.0003) predicted risk for C. diff diarrhea Intensity of antibiotic use did not predict for C. diff diarrhea |
| Hata et al. [62] | November 2007–December 2012 |
Phase 3, multicenter, open-label RCT (assessing antibiotic prophylaxis) n = 579 |
Colorectal surgery (colorectal cancer patients; elective laparoscopic) | Rate of C. diff infection: oral–IV prophylaxis group 1/289; IV prophylaxis 3/290 | Positive test for C. diff toxins in patients developing enteritis/colitis/diarrhea (assay not described) | Incidence rate C. diff toxins in oral–IV and IV groups 0.3% and 1.0%, respectively (p = NS between oral–IV and IV prophylaxis groups) | 5.2 cases/1000 patientse | – |
| Hikone et al. [20] | August 2011–September 2013 |
Retrospective chart review of in- and outpatient samples (single center) n = 2193 samples tested for C. diff toxin |
In- and outpatient samples tested for C. diff |
107 specimens positive for C. diff toxin; 76 cases of healthcare-facility onset CDI |
Positive C. diff toxin testb |
Incidence rate 0.8 cases/10,000 patient-days 30-day and 90-day mortality rates: 7.9% and 14.5%, respectively |
– | Risk factors for recurrent CDI: malignant disease (OR 7.98; 95% CI 1.22–52.2; p = 0.03); history of ICU hospitalization (OR 49.9; 95% CI 1.01–2470; p = 0.049) |
| Honda et al. [18] | September 2010–August 2012 |
Retrospective chart review (single tertiary care center) n = 22,863 adult patients; and 1537 C. diff tests in 851 patients |
Cases of CDI in a non-outbreak setting | 126 cases diagnosed with CDI (86.5% were healthcare-facility onset CDI) |
Diarrhea and positive toxin assayb or presence of pseudomembranous colitisf Healthcare-facility onset CDI: symptom onset > 3 days from admission Community-onset CDI: symptom onset prior to or within 3 days of admission |
Healthcare-facility onset CDI: 3.11 cases/10,000 patient-days Community-onset CDI: 0.2 cases/10,000 patient-days for CDI attributable to the study hospital 30-day all-cause mortality in CDI cohort: 15.1% |
126/22,863 = 5.5 cases/1000 patientse | – |
| Hosokawa et al. [25] | January 2007–December 2008 |
Retrospective cohort (single center) n = 201 patients |
Allogeneic HSCT patients (135 unrelated cord blood; 39 unrelated bone marrow and 27 related peripheral blood stem cell) |
167/201 patients tested for C. diff 17/201 diagnosed C. diff diarrhea C. diff diarrhea in: 11/135 (9%) unrelated cord blood recipients; 2/39 (6%) unrelated BMT recipients; 4/27 (16%) related PBST recipients |
C. diff diarrhea: > 3 loose stools/24 h for 2 consecutive days and positive ELISA for C. diff toxin A | Cumulative incidence of C. diff diarrhea 9% at post-transplant day 100 | – |
Total body irradiation associated with reduced risk of C. diff diarrhea C. diff diarrhea was not a cause of any death; no recurrence of C. diff diarrhea after treatment |
| Iwamoto et al. [27] | Two periods: March 2004–February 2006 and April 2008–December 2008 |
Prospective observational cohort (single center) n = 1226 |
Rheumatology inpatients | 54 cases of healthcare associated infection of which 2 were C. diff infection (1 patient in each study period) | Healthcare-associated infection: developing > 3 days after admission | 2/1226 in rheumatology patients (0.16%)e | – | – |
| Iwashima et al. [44] | April 2005–March 2008 |
Retrospective cohort study assessing genotypic features of isolates and clinical characteristics of CDI (single center) n = 610 submitted specimens |
Patients with stools found positive for C. diff culture (n = 106; of which 35 excluded as asymptomatic carriers and n = 14 excluded for non-toxigenic strains) | 71 C. diff infection cases assessed |
PCR assessment of toxin A and B; ribotyping CDI: diarrhea or colitis with positive test for C. diff toxin B and no other enteropathogenic microorganisms Recurrent CDI: recurring within 2 months of previous episode |
Incidence of CDIs with binary toxin-positive strains 5.6% (noted in patients with non-severe CDI) | Prevalence < 5 CDI cases/month | – |
| Kaneko et al. [30] | January 2006–April 2009 |
Retrospective cohort investigating for CDI during active phase of inflammatory bowel disease (single center) n = 137 |
Active ulcerative colitis | 55/137 (40.1%) tested samples were CDI positive | Presence of toxin A antigeng in gut lavage | 40.1% in a sample tested for possible CDI | – | – |
| Kobayashi et al. [21] | April 2012–September 2013 | Retrospective cohort study based on chart review at four teaching hospitals in Japan | Patients aged ≥ 14 years with hospital-onset CDI | n = 160 with hospital-onset CDI | According to SHEA/IDSA 2010 guidelines, based on positive CD toxin EIA.b Hospital-onset CDI: hospitalized for condition other than CDI for ≥ 2 days | 1.04 cases per 10,000 patient-days; 1.61 cases per 1000 admissions | – | – |
| Komatsu et al. [22] | June 2008–December 2013 |
Single-center RCT n = 379 Looking at efficacy of perioperative synbiotics to prevent infectious complications (particularly surgical site infection) |
Colorectal surgery (laparoscopic) |
0/168 cases C. diff infection in synbiotics group and 1/194 in control group Author reports use of synbiotics suppressed increases in potentially pathogenic C. diff (detected in 4% before surgery both groups; detected in 4% 7 days after surgery in synbiotic group vs. 13% control; p = 0.05 vs. day before surgery |
Gut microbiota assessed by YIF-SCAN and PCR analyses | 1/379 colorectal surgery patients (0.3%)e | – | – |
| Mizui et al. [37] | February 2010– February 2011 |
Retrospective study of risk factors for C. diff diarrhea (single center) n = 2716 patients given an injectable antibiotic Study also assessed impact of probiotics |
Inpatients given antibiotics |
29 had C. diff diarrhea (2687 had non-C. diff diarrhea) Risk factors investigated between groups re: use of antibiotics ≥ 8 days; enteral nutrition; IV hyperalimentation; fasting, proton pump inhibitors H2 blockers; serum albumin ≤ 2.9 g/dL |
C. diff diarrhea; tests not defined | – | – | Risk factors for C. diff diarrhea were: antibiotic use ≥ 8 days (OR 4.071; 95% CICI 1.333–12.430; p = 0.014), IV hyperalimentation (OR 3.414; 95% CI 1.469–7.934; p = 0.004), PPIs (OR 3.224; 95% CI 1.421–7.315; p = 0.005), H2 blockers (OR 2.376; 95% CI 1.047–5.391; p = 0.039) |
| Mori and Aoki [19] | January 2010– December 2014 | Retrospective case–control, epidemiological, single-center study assessing risk factors for CDI |
Outpatients (1,914,011 patient-years examined) CDI cases Age- and sex-matched controls (C. diff toxin- and culture-negative) |
26 patients had community-acquired CDI | Community-acquired CDI: outpatient presentation with diarrhea, stool culture positive C. diff toxin assaya,h | Incidence for community-acquired CDI 1.4/100,000 patient-years | – |
84.6% of patients with community acquired CDI had prior exposure to antibiotics Patients with community-acquired CDI more likely to have had prior antibiotics (OR 8.12; 95% CI 2.43—26.98) |
| Ogami et al. [38] | 4-year period (dates not given) |
Single-center, retrospective hospital cohort n = 463 |
Inpatients with antimicrobial associated diarrhea | 95/463 cases (20.5%) were CDI | CDI manifesting as antimicrobial-associated diarrhea (≥ 3 stools/day > 48 h after-ward admission) and stool toxin positive (A and/or B)a | – | – | Increased ward use of antimicrobials clindamycin (OR 1.739; 95% CI 1.050–2.881; p = 0.032) and piperacillin (OR 1.598; 95% CI 1.006–2.539; p = 0.047) increased risk of CDI |
| Oshima et al. [40] | Published studies 1990–2016 | Systematic review and meta-analysis of 67 published studies | Adults and pediatric (≤ 18 years) patients receiving PPI who developed acute-onset diarrhea. Also, control group |
n = 17,217 in the test group; n = 286,018 in the control group Recurrent CDI occurred in n = 1279; n = 5459 in the control group |
Laboratory confirmation of C. diff or clinical definition. No further detail provided | – | – |
PPI use increased risk for initial CDI episode (random effects model, overall OR 2.34, 95% CI 1.94–2.82; p < 0.00001) Age-stratified subgroup analyses: significant associations between PPI use and initial CDI episode in adults (OR 2.30, 95% CI 1.89–2.80; p < 0.00001) and pediatrics (OR 3.00, 95% CI 1.44–6.23; p < 0.00001) |
| Roughead et al. [36] |
2008–2013 (insurance database) 1996–2014 (hospital dataset) |
Retrospective data from worker insurance database and a hospital in-/outpatient dataset from a single center 1.2 million patient records examined and sequence symmetry analysis used to assess PPI use as risk factor for CDI |
n = 310 patients received PPIs and oral vancomycin (proxy indicator for CDI) | – | – | – | – | Positive association between PPI use and CDI (adjusted sequence ratio for insurance dataset 5.40; 95% CI 2.73–8.75 and for hospital dataset 3.21; 95% CI 2.12–4.55) |
| Sadahiro et al. [63] | May 2008–October 2011 |
Prospective, single-center RCT comparing oral antibiotics and probiotics pre surgery to prevent infection n = 310 |
Colon cancer | No change in detection of C. diff toxin across three treatment groups (probiotics; antibiotics; control (no probiotics or antibiotics)) | Assessment of C. diff toxin (A and B) in stool samples by RIDASCREEN | Rates of CDI increased post-operatively in all groups (probiotic group, from 2.0% to 7.0%; antibiotic group, 5.1% to 9.1%; control group, 2.1% to 10.5%) | – | – |
| Sasabuchi et al. [28] | July 2010–March 2013 |
Retrospective cohort study using the Japanese Diagnosis Procedure Combination database (multicenter) n = 15,651 receiving prophylaxis n = 15,651 controls |
Severe sepsis and receiving stress ulcer prophylaxis within 2 days of hospital admission; propensity-matched controls did not receive prophylaxis | In propensity-matched cohort, 215 and 204 cases of CDI in the stress ulcer prophylaxis and control groups, respectively | Not specified, but ICD-10 codes used for other definitions. CDI coded as ‘complication’ in medical records during hospitalization | 1.4% in stress ulcer prophylaxis group and 1.3% in control (p = 0.588) | – | – |
| Suzuki et al. [23] | April 2010–March 2012 |
Single-center prospective cohort pre and post intensive infection control measures n = 80 |
Hospitalized patients | – |
Based on medical records and healthcare resource use New-onset nosocomial C. diff-associated disease |
C. diff-associated disease reduced from 0.47 cases/1000 inpatient days to 0.11 (p < 0.001) after intensive infection control team interventions | – | – |
| Takahashi et al. [39] | November 2010– October 2011 |
Multicenter case–control and cohort study n = 1026 CDI n = 878 controls |
National Hospital Organization cohort Assessed for newly diagnosed CDI and matched controls (no CDI) |
93.9% of CDI cases developed within 48 h of hospital admission | GI symptoms, clinical suspicion of CDI and positive C. diff toxinsa,h,i from stool or C. diff isolation from stool cultures, or both | – | – |
Risk factors for CDI development: disruption of feeding/parenteral and enteral feeding; first- and second-generation cephem antibiotics (OR 1.44; 95% CI 1.10–1.87), third- and fourth-generation cephem antibiotics (OR 1.86; 95% CI 1.48–2.33), carbapenem antibiotics (OR 1.87; 95% CI 1.44–2.42) Comorbidities more common in patients with CDI Analysis of 924 cases noted 11% mortality within 30 days of CDI onset Use of vancomycin reduce mortality (OR 0.43; 95% CI 0.25–0.75) PPIs and penicillin did not increase risk for CDI |
| Watanabe et al. [64] | January–June 2005 |
Multicenter, retrospective cohort n = 294 fecal samples submitted for C. diff testing |
Hospitalized patients | 79/294 (5.5 cases/1000 beds monthly) were C. diff toxin A+ | C. diff toxin testc | 5.5 cases/1000 beds monthly, assessed for C. diff were found to be C. diff toxin A+ | – | – |
| Yasunaga et al. [29] | 2007–2010 |
Retrospective database review: analysis of factors affecting C. diff- associated disease and outcomes of C. diff diarrhea after GI surgery Japanese Diagnosis Procedure Combination inpatient database (multicenter) n = 143,652 |
Inpatients/GI surgical patients |
409 cases of C. diff diarrhea (0.28%) Higher rates in colorectal surgery (0.37%) vs. gastrectomy (0.21%) and esophagectomy (0.25%) (p < 0.001) |
CD enterocolitic ICD-10 code |
Rate 0.28% Risk factors included: older age; higher Charlson comorbidity index; longer pre-operative LOS; non-academic center care In-hospital mortality higher in C. diff diarrhea than in non-C. diff diarrhea (3.4% vs. 1.6%: OR 1.83; 95% CI 1.07–3.13, p = 0.027) |
409/143,652 = 2.8/1000 patientse |
Risk factors included: older age; higher Charlson comorbidity index; longer pre-operative LOS; non-academic center care In-hospital mortality higher in C. diff diarrhea (3.4% vs. 1.6% in non-C. diff diarrhea: OR 1.83; 95% CI 1.07–3.13; p = 0.027) LOS attributable to post-operative C. diff diarrhea 12.4 days (95% CI 9.7–15.0; p < 0.001) |
BMT bone marrow transplantation; CI confidence interval; GDH glutamate dehydrogenase; GI gastrointestinal; HSCT hematopoietic stem cell transplantation; IV intravenous; LOS length of stay; OR odds ratio; PPI proton pump inhibitor; RCT randomized clinical trial; YIF-SCAN Yakuly Intestinal Flora-SCAN system
aTOX A/B QUIK CHEK®
bC DIFF QUIK CHEK COMPLETE®
cUNIQUICK
dCD CHECK
eCalculated from data available in the publication and not stated in the publication
fXPECT C. DIFF toxin A/B
gC. diff Toxin A test, Oxoid
hImmunoCard CD toxin A&B
iX/pect Toxin A/B