Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis

Table 1 Characteristics of studies included in the meta-analysis

Author, yr	Region	Study design	Centers	Setting	Sample size, n	Mean age, yr	Identifiedconfounders	OR (95%CI)
Akhtar et al Shaheen[91], 2007	America	Case-control	Unicenter	Inpatient	1290		Adjusted for age, sex, comorbidities , antibiotics, chemotherapy	2.1 (1.6-2.7)
Al-Tureihi et al[19], 2005	America	Case-control	Unicenter	Inpatient	53		Adjusted for age, antibiotics	3.1 (1.0-9.7)
Aseeri et al[23], 2008	America	Case-control	Unicenter	Inpatient	188		Adjusted for admission date, sex, age group, antibiotic use, patient location, and room type	4.4 (2.3-8.2)
Bajaj et al[133], 2010	America	Case-control	Multicenter	Mixt	162		Adjusted for antibiotics, PPI	37.6 (6.2-227.6)
Barletta et al[92], 2014	Asia	Case-control	Unicenter	Inpatient	408		Adjusted for PPI exposure, antibiotics, immunosuppression	2.1 (1.2-3.8)
Baxter et al[93], 2008	America	Case-control	Multicenter	Inpatient	4493		Adjusted for antibiotics, age, hospital stay, other infections	1.2 (1.0-1.4)
Beaulieu et al[27], 2007		Cohort	Unicenter	Inpatient	827		Adjusted for age, sex, length of stay, comorbidities,	1.3 (0.9-2.0)
							APACHE score, NGT feeding, tracheal tube
							placement, antibiotics
Branch et al[94], 2007	America	Case-control	Unicenter	Inpatient	787	66.02	No	13.0 (7.5-22.7)
Buendgens et al[95], 2014	Europe	Case-control	Multicenter	Inpatient	3286		Adjusted for age, sex, antibiotics, comorbidities, other treatment	3.1 (1.1-8.7)
Campbell et al[38], 2013	America	Case-control	Unicenter	Inpatient	96		Adjusted for antibiotics, hospitalization	2.2 (0.6-8.0)
Cunningham et al[96], 2003	Europe	Case-control	Unicenter	Inpatient	320		Adjusted for antibiotics and chemotherapy	2.5 (1.5-4.1)
Dalton et al[22], 2009	America	Cohort	Multicenter	Inpatient	14719	74.7	Adjusted for number of medication groups,	1.9 (1.4-2.7)
							antibiotic days, age, length of stay, medical
							service, PPI days
Debast et al[116], 2009	Europe	Case-control	Unicenter	Inpatient	154		Adjusted for age, hospital stay, comorbidities, antibiotics	1.1 (0.5-2.4)
Dial et al[26], 2004 (case-control)	America	Case-control	Multicenter	Inpatient	188		Adjusted for age, antibiotics	2.6 (1.3-5.0)
Dial et al[26], 2004 (cohort)	America	Cohort	Multicenter	Inpatient	1187		Adjusted for age, antibiotics	2.1 (1.2-3.5)
Dial et al[98], 2005	Europe	Case-control	Multicenter	Outpatient	13563		Adjusted for age, sex, antibiotics	2.9 (2.4-3.5)
Dial et al[97], 2006	Europe	Case-control	Multicenter	Outpatient	3484		Adjusted for PPI and antibiotics	3.5 (2.3-5.3)
Dial et al[134], 2008	America	Case-control	Multicenter	Outpatient	9196	79.8	Adjusted for age, sex, antibiotics, comorbidities, physician visits, hospital admissions, length of stay	1.6 (1.3-1.9)
Dubberke et al[99], 2007	America	Cohort	Unicenter	Inpatient	36086		Adjusted for age, admissions, antibiotics, albumin level, leukemia/lymphoma, mechanical ventilation, antimotility agents	1.6 (1.3-2.1)
Elseviers et al[100], 2015	Europe	Case-control	Multicenter	Inpatient	743	71.9	Adjusted for age, co-morbidity, endoscopic procedures	1.9 (1.1-3.4)
Faleck et al[42], 2016	America	Cohort	Unicenter	Inpatient	11230	66	Adjusted for age, sex, antibiotics,	0.6 (0.4-0.8)
							comorbidities, length of stay
Garzotto et al[43], 2015	Europe	Case-control	Multicenter	Inpatient	225		No	0.4 (0.2-0.8)
Hebbard et al[135], 2017	Asia	Case-control	Unicenter	Inpatient	200	59.7	Adjusted for age, chemotherapy, abdominal surgery, antibiotics	2.4 (1.0-5.7)
Hensgens et al[117], 2011	Europe	Case-control	Unicenter	Inpatient	169		Adjusted for age, co-morbidity, antibiotics, ICU stay	1.1 (0.5-2.5)
Howell et al[136], 2010	America	Cohort	Unicenter	Inpatient	101796	65.4	Adjusted for age, comorbidities, antibiotics	1.7 (1.3-2.1)
Ingle et al[40], 2011	Asia	Cohort	Unicenter	Mixt	99	47	Adjusted for immunosuppression	1.8 (0.4-7.4)
Ingle et al[118], 2013	Asia	Case-control	Unicenter	Community	150	45.3	no	2.3 (0.6-9.2)
Jayatilaka et al[101], 2007	America	Case-control	Unicenter	Inpatient	366		Adjusted for PPI	2.7 (1.6-4.8)
Kazakova et al[102], 2006	America	Case-control	Unicenter	Mixt	195		Adjusted for antibiotics, PPI, length of stay,	5.0 (1.3-19.3)
							psychosis, depression
Khan et al[39], 2012	Asia	Cohort	Unicenter	Inpatient	123		Adjusted for surgery, PPI, antibiotics, hospitalization,	3.2 (1.2-8.5)
							Underlying debilitating conditions
Khanafer et al[119], 2013	Europe	Cohort	Unicenter	Inpatient	40			2.5 (0.6-9.6)
Kuntz et al[2], 2011	America	Case-control	Unicenter	Mixt	3344		no	2.3 (1.5-3.3)
Kurti et al[3], 2015	Europe	Case-control	Multicenter	Inpatient	979	72.4	Adjusted for antibiotics, PPI, length of stay,	1.6 (1.1-2.2)
Kutty et al[41], 2010	America	Case-control	Multicenter	Outpatient	144	62	No	1.7 (0.7-4.0)
Lewis et al[103], 2016	America	Cohort	Unicenter	Inpatient	41663		No	6.4 (3.6-11.5)
Lin et al[137], 2013	Asia	Case-control	Multicenter	Inpatient	86	59	Age, sex, unit,	10.1 (1.2-87.4)
							antibiotics,
							length of stay
Linney et al[24], 2010	America	Case-control	Unicenter	Inpatient	284		Age, sex, discharge date and hospital unit,	2.4 (1.4-4.3)
							antibiotics, diabetes mellitus, IBD, cancer,
							enteral feeding, length of stay
Loo et al[120], 2005	America	Case-control	Multicenter	Inpatient	474		no	1.0 (0.7-1.4)
Loo et al[138], 2011	America	Cohort	Multicenter	Inpatient	4143	67.4	Adjusted for age, PPI, antibiotics, chemotherapy	2.6 (1.7-4.0)
Lowe et al[121], 2006	America	Case-control	Multicenter	Inpatient	13692	78.7	Adjusted for antibiotics, other medications, and	0.9 (0.7-1.0)
							comorbidities
McFarland et al[122], 2007	America	Case-control	Multicenter	Mixt	368		No	0.8 (0.5-1.4)
Mizui et al[104], 2013	Asia	Case-control	Multicenter	Inpatient	2716	71.7	No	3.2 (1.4-7.3)
Modena et al[105], 2005	America	Case-control	Unicenter	Inpatient	250		Adjusted for macrolides, ICU, length of stay, infections	3.3 (1.6-6.8)
Mori et al[123], 2015	Asia	Case-control	Unicenter	Outpatient	78	58.2	No	0.4 (0.1-2.0)
Muto et al[106], 2005	America	Case-control	Multicenter	Inpatient	406		Adjusted for PPI, antibiotics, diabetes mellitus, organ transplantation	2.4 (1.3-4.4)
Pakyz et al[107], 2014	America	Case-control	Multicenter	Inpatient	14164		No	1.4 (1.3-1.5)
Peled et al[108], 2007	America	Cohort	Unicenter	Inpatient	217		Adjusted for PPI, low albumin level,	3.7 (1.5-9.3)
Pepin et al[11], 2005	America	Cohort	Unicenter	Inpatient	5619		Adjusted for age, length of stay, antibiotics	1.0 (0.7-1.2)
Ro et al[139], 2016	Asia	Cohort	Unicenter	Inpatient	1005	64.8	Adjusted for age, antibiotics, comorbidities	3.3 (1.5-7.2)
Roughead et al[109], 2016	Asia	Cohort	Multicenter	Mixt	54957		Adjusted for antibiotics, PPI, length of stay,	2.4 (1.9-3.1)
Shah et al[34], 2000	Europe	Case-control	Unicenter	Inpatient	252		No	0.8 (0.4-1.5)
Southern et al[110], 2010	Europe	Cohort	Multicenter	Inpatient	3904	65.5	No	2.3 (1.1-4.5)
Vesteinsdottir et al[111], 2012	Europe	Case-control	Multicenter	Mixt	333		No	1.6 (1.0-2.6)
Yang et al[112], 2011	Asia	Case-control	Multicenter	Inpatient	1420	67.12	No	1.9 (1.3-2.7)
Yearsley et al[25], 2006	Europe	Case-control	Unicenter	Inpatient	308	79.1	Adjusted for PPI, antibiotics, female sex	1.9 (1.1-3.2)
Yip et al[140], 2001	America	Case-control	Unicenter	Inpatient	54		No	3.0 (0.8-11.1)

CI: Confidence interval; IBD: Inflammatory bowel disease; ICU: Intensive care unit; PPI: Proton pump inhibitor; NGT: Naso-gastric tube; OR: Odds ratio.

Table 2 Subgroup analysis

Subgroup analysis	No. of studies(n = 56)	ORs	95%CI	Heterogeneity, I2, %	Heterogeneity between groups, P value
Study design
Case-control	40	2	1.68-2.38	85.54	0.931
Cohort	16	1.98	1.51-2.59	85.99
Study type
Adjusted	38	1.95	1.67-2.27	85.02	0.856
Unadjusted	18	2.02	1.41-2.91	85.58
Centers
Unicentric	31	2.18	1.72-2.75	83.99	0.241
Multicentric	25	1.82	1.51-2.19	86.97
Type
Inpatient	43	1.95	1.67-2.29	84.99	0.868
Outpatient	6	2.1	1.36-3.24	84.84
Mixt	7	2.19	1.39-3.45	76.77
Region
Europe	14	1.78	1.35-2.34	74.33	0.231
America	31	2	1.67-2.40	88.58
Asia	11	2.31	1.96-2.72	89.18
Age
Age < 65 yr	6	2.06	1.11-3.81	35.39	0.86
Age ≥ 65 yr	13	1.93	1.40-2.68	92.11
NOS
NOS ≥ 7	26	1.88	1.55-2.28	87.65	0.441
NOS < 7	30	2.11	1.69-2.62	81.98

CI: Confidence interval; NOS: Newcastle-Ottawa Quality Assessment Scale; ORs: Odds ratio.