Preventing pediatric antibiotic-associated diarrhea and Clostridium difficile infections with probiotics: A meta-analysis

Table 1 Excluded studies from pediatric antibiotic-associated diarrhea and Clostridium difficile infections by year of publication and reason

Probiotic strain	Outcome	Reason for exclusion	Ref.
C. butyricum	AAD	Open, dose ranging study	Kurata et al[62], 1988
L. acidophilus + Bifido bifidum	Prevent AAD	Outcome measured by days of diarrhea. No data on AAD incidence	Contardi et al[50], 1991
Bifido bifidum _ Strept thermo	Prevention of nosocomial diarrhea	Unclear how many were exposed to antibiotics	Saavedra et al[58], 1994
L. acidophilus + L. bulgaricus	Prevent GI effects	No data on AAD, just “any GI effects”	Witsell et al[51], 1995
L. rhamnosus GG	Prevention of nosocomial diarrhea	Unclear how many were exposed to antibiotics	Szajewska et al[59], 2001
L. acidophilus + Bifido infantis + FOS	Increase in body weight for children on antibiotics	No data on diarrhea provided	Schrezenmeir et al[56], 2004
L. casei	Eradicate H. pylori in children given triple therapy	No data on diarrhea provided	Sýkora et al[57], 2005
L. reuteri	Reduce side effects of triple therapy for pediatric H. pylori infections	No data on diarrhea provided, only “disorders of defecation”, mixed diarrhea and upper GI	Lionetti et al[52], 2006
L. acidophilus + L. rhamnosus	Eradicate H. pylori in children given triple therapy	No data on diarrhea provided	Plewinska et al[55], 2006
Bifido animalis + L. casei	Eradication of H. pylori in children	Side effects (diarrhea) not documented	Goldman et al[53], 2006
S. boulardii	Eradication of H. pylori in children	No data on diarrhea provided	Hurduc et al[54], 2009
L. rhamnosus GG	Prevention of nosocomial pediatric respiratory or GI infections	None were exposed to antibiotics	Hojsak et al[60], 2010
L. reuteri DSM 17938	Prevent nosocomial diarrhea in children	Unclear how many were exposed to antibiotics	Wanke et al[61], 2012
Mix of 9 bacterial strains and inulin and lactoferrin	Improve H. pylori eradication and reduce AAD in children	Poorly described product (unknown concentrations of inulin and lactoferrin)	Tolone et al[63], 2012

S. boulardii: Saccharomyces boulardii; L. rhamnosus: Lactobacillus rhamnosus; H. pylori: Helicobacter pylori; AAD: Antibiotic-associated diarrhea; CDI: Clostridium difficile infection; GI: Gastrointestinal.

Table 2 Characteristics of enrolled pediatric population and probiotic therapies for 22 clinical trials of pediatric antibiotic-associated diarrhea and Clostridium difficile infections

Probiotic strain	Age range	Country	Setting (inpatient or outpatient)	Type of inciting infection	Type of antibiotic (s)	Diarrhea defined1	Ref.
S. boulardii lyo	1-5 yr	France	Out	Resp	Mixed: amox (19%), ceph (11%)	> 3	Benhamou et al[30], 1999
S. boulardii lyo	1-15 yr	Turkey	Out	Nr	Sulbactam-ampicillin only	> 2	Erdeve et al[34], 2004
S. boulardii lyo	1-15 yr	Turkey	Out	Nr	Azithromycin only	> 2	Erdeve et al[34], 2004
S. boulardii lyo	6 mo-14 yr	Poland	In and Out	OM, Resp	Mixed: ceph (41%), amox (29%)	> 3/2 d	Kotowska et al[36], 2005
S. boulardii lyo	6 mo-14 yr	China	In	Resp	IV only: ceph (52%), amox (26%)	> 3/2 d	Shan et al[43], 2014
L. rhamnosus GG	5 mo-11 yr	Finland	Out	OM	Amox only	"by parents"	Vaisanen et al[47], 1998
L. rhamnosus GG	2 wk-12.8 yr	Finland	Out	Resp	Mixed: amox (66%)	> 3/2 d	Arvola et al[29], 1999
L. rhamnosus GG	6 mo-10 yr	United States	Out	Resp, UTI, skin	Mixed: amox (52%)	> 2	Vanderhoof et al[48], 1999
L. rhamnosus GG	5-17 yr	Poland	In	H. pylori +	Amox and clarithromycin only	> 3/2 d	Szajewska et al[44], 2009
L. sporogenes (aka Bacilllus sporogenes) + FOS	4 mo-15 yr	Italy	Out	Resp	Mixed: ceph (41%), amox (30%)	> 2	La Rosa et al[37], 2003
C. butyricum MIYAIRI	1 mo-15 yr	Japan	Nr	Resp, GI	Mixed: ceph (48%)	> 3	Seki et al[42], 2003
L. acidophilus	1 mo-18 yr	Bulgaria	In	Resp, Pyel	Mixed: b-lactams, clinda, amino	Nr	Pancheva-dimitrova et al[39], 2004
B. clausii	6 mo-12 yr	Philippines	In and Out	Resp, GU, Skin	Mixed beta-lactams: pen (47%), ceph (35%)	"otherwise unexplained"	Destura et al[33], 2008
Mixes
L. acidophilus +L. bulgaricus	5 mo-6 yr	United States	Out	OM, pharyn, etc.	Amox only	> 1	Tankanow et al[46], 1990
L. acidophilus + Bifido infantis	1-36 mo	Thailand	In	Sepsis or meningitis	Mixed: cefotaxime (89%)	Nr	Jirapinyo et al[35], 2002
Bifido lactis + Strept thermophilus	6-36 mo	Brazil	In	Nr	Mixed: amp (76%), amox (58%)	> 3/2 d	Corrêa et al[32], 2005
Bifido longum PL03 + L. rhamnosus KL53A + L. plantarum PL02	5 mo-16 yr	Poland	In and Out	Resp, OM, UTI	Mixed: amox (43%), ceph (26%)	> 3/2 d	Szymański et al[45], 2008
L. rhamnosus (3 strains) E/N, Pen and Oxy	3 mo-14 yr	Poland	In and Out	Resp, OM, UTI, skin	Mixed: amp or pen (50%), ceph (37%)	> 3/2 d	Ruszczyński et al[40], 2008
Kefir (mix of 9 strains)1	1-5 yr	United States	Out	Resp	Nr	Nr	Merenstein et al[38], 2009
C. butyricum + Bifido. infantis	3 mo-3 yr	China	In	Pneumonia	Mixed: ceph (46%)	> 2	Investigating Group for Prevention of AAD in Children with Pneumonia by Clostridium Butyricum and Bifidobacterium[49], 2012
Bifido animalis +L. acidophilus +Strept thermophilus	1-17 yr	United Kingdom	Out	Resp, skin, UTI	Mixed: pen (71%)	> 3/2 d	Conway et al[31], 2007
L. casei + L. acidophilus + L. reuteri + L. bulgaricus + Strept. cremoris + Bifido. bifidum + Bifido. infantis + FOS	4-14 yr	Iran	Out	H. pylori +	Amox and clarithromycin only	> 3/2 d	Saneeyan et al[41], 2011
L. casei + L. rhamnosus + L. bulgaricus + L. acidophilus + Strept. thermophilus + Bifido. breve + Bifido. infantis	3-14 yr	Iran	Out	H. pylori +	Amox and furazolidone only	> 3/2 d	Ahmad et al[28], 2013

Diarrhea defined as > 3/2 d: indicates 3 or more loose/watery stools for at least 2 consecutive days; > 3: 3 or more loose or watery stools/day; > 2: 2 or more watery stools/day; "by parents": Defined by parents; "otherwise unexplained": Diarrhea with no other explanation associated with antibiotic use. Amino: Aminoglycosides; Amp: Ampicillin; Amox: Amoxicillin +/- clavulanic acid; Ceph: Cephalosporins; Clinda: Clindamycin; GU: Genito-urinary; FOS: Fructooligosaccharide (990 mg/d); H. pylori: Helicobacter pylori; In: Inpatient; Nr: Not reported; OM: Otitis media; Out: Outpatient; Pharyn: Pharyngitis; Pyel: Pyelonephritis; Resp: Upper or lower respiratory tract infection; UTI: Urinary tract infection.

¹Kefir contains: Lactococcus plantarum, L. rhamnosus, L. acidophilus, L. casei, L. lactis subspecies diacetylactis, Leuconostoc cremoris, Bifido. longum, Bifido. breve, Saccharomyces florentinus.

Table 3 Description of the interventions for 22 clinical trials of pediatric antibiotic-associated diarrhea and Clostridium difficile

Probiotic strain	Random-ized	Blinding	Type of controls	Formulation	Daily dose(cfu/d)	Duration treatment	Follow-up po-st-treatment	Ref.
S. boulardii lyo	Yes	Double	Active (diosmectite)	Capsules	4.5 × 109	6-10 d	None	Benhamou et al[30], 1999
S. boulardii lyo	Yes	Open	No treatment	Sachet	5 × 109	duration	2 wk	Erdeve et al[34], 2004
S. boulardii lyo	Yes	Open	No treatment	Sachet	5 × 109	duration	2 wk	Erdeve et al[34], 2004
S. boulardii lyo	Yes	Double	Placebo	Wafers	1 × 1010	5-7 d	2 wk	Kotowska et al[36], 2005
S. boulardii lyo	Yes	Open	No treatment	Powder	1 × 1010	2 wk	2 wk	Shan et al[43], 2014
L. rhamnosus GG	Yes	Double	Milk control	Whey drink	8 × 1010	7 d	None	Vaisanen et al[47], 1998
L. rhamnosus GG	Yes	Double	Placebo	Capsules	4 × 1010	7-10 d	3 mo	Arvola et al[29], 1999
L. rhamnosus GG	Yes	Double	Placebo	Capsules	1-2 × 1010	10 d	None	Vanderhoof et al[48], 1999
L. rhamnosus GG	Yes	Double	Placebo	Capsules	2 × 109	7 d	6 wk	Szajewska et al[44], 2009
L. sporogenes [aka Bacilllus sporogenes] + FOS	Yes	Double	Placebo	Capsules	5.5 × 108	10 d	None	La Rosa et al[37], 2003
C. butyricum MIYAIRI	Nr	Open	No treatment	Capsules	1-4 × 107	6 d	None	Seki et al[42], 2003
L. acidophilus	Nr	Open	No treatment	Nr	2 × 109	duration	None	Pancheva-Dimitrova et al[39], 2004
B. clausii	Yes	Open	No treatment	Powder	4 × 109	7-21 d	6 wk	Destura et al[33], 2008
Mixes
L. acidophilus +L. bulgaricus	Yes	Double	Placebo	Sachets	2 × 109	10 d	None	Tankanow et al[46], 1990
L. acidophilus + Bifido infantis	Yes	Double	Placebo	Capsules	6 × 109	7 d	None	Jirapinyo et al[35], 2002
Bifido lactis + Strept thermophilus	Yes	Double	Placebo	Formula	4 × 108	15 d	15 d	Corrêa et al[32], 2005
Bifido longum PL03 + L. rhamnosus KL53A + L. plantarum PL02	Yes	Double	Placebo	Capsules	2 × 108	3-14 d	2 wk	Szymański et al[45], 2008
L. rhamnosus (3 strains) E/N, Pen and Oxy	Yes	Double	Placebo	Capsules	4 × 1010	3-30 d	2 wk	Ruszczyński et al[40], 2008
Kefir (mix of 9 strains)	Yes	Double	Heat-killed drink	Drink	7-10 × 109	10 d	4 d	Merenstein et al[38], 2009
C. butyricum + Bifido. infantis	Yes	Open	No treatment	Sachet	5 × 109	7 d	None	Investigating Group for Prevention of AAD in Children with Pneumonia by Clostridium Butyricum and Bifidobacterium[49], 2012
Bifido animalis + L. acidophilus + Strept thermophilus	Yes	Double, open	Control yogurt and no treatment groups	Yogurt	1 × 109	12 d	None	Conway et al[31], 2007
L. casei + L. acidophilus + L. reuteri + L. bulgaricus + Strept. cremoris + Bifido. bifidum + Bifido. infantis + FOS	Yes	Single	Placebo	Sachet	1 × 109	14 d	2 wk	Saneeyan et al[41], 2011
L. casei + L. rhamnosus + L. bulgaricus + L. acidophilus + Strept. thermophilus + Bifido. breve + Bifido. infantis	Yes	Double	Placebo	Sachet	1 × 109	28 d	4-8 wk	Ahmad et al[28], 2013

cfu/d: Colony-forming units/day; Diosmectite: An anti-spasmotic; Duration: Treatment given for the duration of the antibiotic; Nr: Not reported; S. boulardii: Saccharomyces boulardii; L. rhamnosus: Lactobacillus rhamnosus.

Table 4 Outcomes for 22 clinical trials of pediatric antibiotic-associated diarrhea and Clostridium difficile infections trials (total 23 treatment arms)

Probiotic strain	Attrit-ion	ITT orAPP	Incidence A-AD probiotic	Incidence AADcontrols	P value(% power)	IncidenceCDIprobiotic	Incidence CDIcontrols	P value(% power)	Ref.
S. boulardii lyo	21%	APP	25/327 (7.6%)	16/289 (5.5%)	0.29	--	--	--	Benhamou et al[30], 1999
					14%
S. boulardii lyo + SAM	29%	APP	7/117 (5.7%)	30/117 (25.6%)	< 0.001	--	--	--	Erdeve et al[34], 2004
					98%
S. boulardii lyo + AZT	29%	APP	7/127 (5.5%)	12/105 (11.4%)	0.15	--	--	--	Erdeve[34], 2004
					29%
S. boulardii lyo	8.60%	APP	9/119 (8.0%)	29/127 (23.0%)	0.001	3/119 (2.5)	10/127 (7.9%)	0.09	Kotowska et al[36], 2005
					87%			36%
S. boulardii lyo	15%	APP	6/139 (4.3%)	28/144 (19.4%)	< 0.001	1/139 (0.7%)	8/144 (5.6%)	0.04	Shan et al[43], 2014
					96%			42%
L. rhamnosus GG	0%	ITT	6/23 (26%)	8/36 (22%)	0.76	--	--	--	Vaisanen et al[47], 1998
					3%
L. rhamnosus GG	28.70%	APP	3/61 (5%)	9/58 (16%)	0.07	1/61 (1.6%)	1/58 (1.7%)	1	Arvola et al[29], 1999
					38%			10%
L. rhamnosus GG	6.90%	APP	7/93 (7.5%)	25/95 (26%)	0.001	--	--	--	Vanderhoof et al[48], 1999
					90%
L. rhamnosus GG	20%	ITT	2/34 (6%)	6/30 (20%)	0.13	--	--	--	Szajewska[44], 2009
					26%
L. sporogenes [Bac. sporogenes] + FOS	18%	ITT	14/48 (29%)	31/50 (62%)	0.001	--	--	--	La Rosa et al[37], 2003
					88%
C. butyricum MIYAIRI	Nr	Nr	6/86 (7%)	16/27 (59%)	< 0.001	0/86	0/27	--	Seki et al[42], 2003
					99%
L. acidophilus	Nr	Nr	10/215 (4.6%)	30/139 (21.6%)	< 0.001	--	--	--	Pancheva-Dimitrova et al[39], 2004
					99%
B. clausii	0%	ITT	3/162 (1.8%)	7/161 (4.3%)	0.22	0/162 (0%)	1/161 (0.6%)	0.5	Destura et al[33], 2008
					16%			3%
Mixes
L. acidophilus +L. bulgaricus	37%	APP	10/15 (66%)	16/23 (69.5%)	1	--	--	--	Tankanow et al[46], 1990
					3%
L. acidophilus +Bifido infantis	0%	ITT	3/8 (37.5%)	8/10 (80%)	0.14	--	--	--	Jirapinyo et al[35], 2002
					25%
Bifido lactis + Strept thermophilus	7.10%	APP	13/80 (16%)	24/77 (31.2%)	0.04	--	--	--	Corrêa et al[32], 2005
					54%
Bifido longum PL03 + L. rhamnosus KL53A + L. plantarum PL02	0%	ITT	1/40 (2.5%)	2/38 (5.3%)	0.61	--	--	--	Szymański et al[45], 2008
					3%
L. rhamnosus (3 strains) E/N, Pen and Oxy	1.20%	ITT	9/120 (7.5%)	20/120 (17%)	0.046	3/120 (2.5%)	7/120 (5.8%)	0.33	Ruszczyński et al[40], 2008
					53%			16%
Kefir (mix of 9 strains)	6.40%	ITT	11/61 (18%)	14/64 (21.9%)	0.66	--	--	--	Merenstein et al[38], 2009
					5%
C. butyricum +Bifido. infantis	2.10%	APP	15/193 (7.8%)	30/179 (16.8%)	0.01	--	--	--	Investigating Group for Prevention of AAD in Children with Pneumonia by Clostridium Butyricum and Bifidobacterium[49], 2012
					70%
Bifido animalis +L. acidophilus + Strept thermophilus	12%	ITT	2/48 (4%)	3/34 ( 9%)	0.64	--	--	--	Conway et al[31], 2007
					8%
L. casei + L. acidophilus + L. reuteri + L. bulgaricus + Strept. cremoris + Bifido. bifidum + Bifido. infantis + FOS	0%	ITT	3/25 (12%)	13/25 (52%)	0.005	--	--	--	Saneeyan et al[41], 2011
					80%
L. casei + L. rhamnosus + L. bulgaricus + L. acidophilus + Strept. thermophilus + Bifido. breve + Bifido. infantis	0%	ITT	2/33 (6.1%)	8/33 (24.2%)	0.04	--	--	--	Ahmad et al[28], 2013
					40%

AAD: Antibiotic-associated diarrhea; CDI: Clostridium difficile disease; S. boulardii: Saccharomyces boulardii; L. rhamnosus: Lactobacillus rhamnosus; Nr: Not reported.