Table 3.

Incidence of, and risk factors associated with, C. difficile infection recurrence in Japanese patient populations

Reference	Patient population	Treatment of initial CDI	Definition of recurrence	Recurrence	Recurrence risk factors
Akahoshi et al. [24]	HSCT (n = 102 autologous; n = 206 allogeneic); n = 30 with CDI	Oral metronidazole (500 mg three-times daily, 10–14 days)	New episode of diarrhea and positive toxin EIA within 365 days after first episode of CDI	1/30 (3.3%) within 100 days after HSCT	NR
Daida et al. [31]	Pediatric patients (aged 0–19 years) admitted to hospital with cancer	Oral metronidazole (30 mg/kg) for > 10 days until resolution of symptoms and neutrophil recovery to > 500/μL	Presence of CDI 2 weeks after resolution of primary CDI symptoms	13/51 (26%)	Statistical tests not performed. Recurrence more common in younger age (0–3 years; 9/13, 69%) than older children (19/38, 50%)
Hashimoto et al. [26]	Retrospective chart review (single center) of 242 living donor liver transplant recipients (adults) n = 11 with C. diff diarrhea	Oral vancomycin (n = 8; dose not given) or conservative management (no detail given)	No definition given, but patients assessed from hospital admission to 3 months after transplant	3/11 (27.3%); 2/8 (25%) in patients who received vancomycin	NR
Hikone et al. [20]	In- and outpatient samples tested for C. diff (n = 2193 samples) n = 76 with healthcare-associated CDI	Oral metronidazole or vancomycin (doses not given) for median 14 days (range 6–52 days)	New episode of CDI within 8 weeks from the previous episode; diagnosis based on presence of diarrhea and positive toxin EIA	14/76 (18.4%)	Univariate analysis: no risk factors identified Multivariate analysis: malignant disease (OR 7.98; 95% CI 1.22–52.2; p = 0.03) and ICU hospitalization (OR 49.9; 95% CI 1.01–2470; p = 0.049)
Honda et al. [18]	CDI cases in a non-outbreak setting n = 126 with CDI (86.5% were healthcare-facility onset CDI)	Oral metronidazole (500 mg three-times daily), oral vancomycin (125 mg or 500 mg four-times daily), combination oral metronidazole (500 mg three-times daily) plus vancomycin (125 mg or 500 mg four-times daily), combination oral metronidazole plus rectal vancomycin, combination oral and rectal vancomycin, or no treatment (stop unnecessary antimicrobials)	New episode of diarrhea and positive toxin assay within 30 days since last date of completing therapy for first CDI episode	8/126 (6%)	NR
Hosokawa et al. [25]	Allogeneic HSCT patients (135 unrelated CBT; 39 unrelated BMT and 27 related PBSCT) n = 17 with C. diff diarrhea	Oral metronidazole or oral vancomycin (dosage and duration not given)	New episode of diarrhea and positive toxin test within 8 weeks after improvement of first properly treated episode	0	NR
Iwashima et al. [44]	CDI cases in a hospital setting n = 71 consecutive patients with CDI	No formal regimens specified; 3 patients received treatment prior to recurrent CDI. Vancomycin mentioned (total dose range 6–12 g given for range of 1–28 days)	New CDI episode within 2 months after recovery from previous CDI episode	9/71 (12.7%)	NR
Kobayashi et al. [21]	Patients aged ≥ 14 years with hospital-onset CDI, n = 160	Metronidazole (n = 88, 55%), vancomycin (n = 52, 33%), metronidazole + vancomycin (n = 10, 6.3%), no antimicrobial (n = 10, 6.3%). Doses and duration of therapy not specified	According to SHEA/IDSA 2010 guidelines [69] – re-emergence of CDI symptoms, according to infectious disease physician judgment, ≤ 4 weeks after completion of treatment for initial CDI episode	23/160 (14%)	Recurrence did not differ according to severe/non-severe CDI or according to whether treatment adhered/did not adhere to clinical guidelines
Mori et al. [42]	Stool culture database n = 58 cases with CDI	Vancomycin or metronidazole (dosage and duration not given)	No definition given, but recurrence recorded within 60 days following symptom onset	3/58 (5.2%)	NR
Oshima et al. [40]	Adults and pediatric (≤ 18 years) patients receiving PPI who developed acute-onset diarrhea (n = 17,217). Also, control group (n = 286,018) Recurrent CDI (reported in 9 studies) occurred in n = 1279; n = 5459 in the control group	–	Not given in this systematic review and meta-analysis of published studies, but based on recurrence, as reported in published studies. CDI presence based on laboratory confirmation of C. diff or clinical definition	–	PPI use increased risk for recurrent CDI (pooled OR 1.73, 95% CI 1.39–2.15; p = 0.02)
Shimizu et al. 2015 [41]	Patients in a hospital setting with diarrhea (n = 334 fecal samples) n = 28 patients with severe CDI	Metronidazole, vancomycin (dosage and duration not given) or no treatment	No definition given and duration of assessment not detailed	Overall: 7/28 (25%); 5/16 (31.3%) in patients with GDH-positive/EIA toxin-positive test and 2/12 (16.7%) in patients with initial GDH-positive/EIA toxin-negative test, but who had confirmed positive toxigenic culture	No difference in incidence of recurrence between the two groups (p = 0.662)
Takahashi et al. [39]	National Hospital Organization cohort Assessed for newly diagnosed CDI (n = 878 patients) and matched controls (no CDI)	Metronidazole, vancomycin (dosage and duration not given) or no treatment	No definition given, but recurrence assessed and recorded within 30 days of initial CDI episode	34/714 (4.8%) among patients treated for CDI	NR

BMT bone marrow transplantation, CBT cord blood transplantation, CI confidence interval, EIA enzyme immunoassays, HSCT hematopoietic stem cell transplantation, ICU intensive care unit, NR not recorded, OR odds ratio, PBSCT peripheral blood stem cell transplant, PPI proton pump inhibitor, SHEA/IDSA Society for Healthcare Epidemiology of America and Infectious Disease Society of America