probiotics and infections and infections … · what about safety? • the evidence support that...

Probiotics and InfectionsPerspectives for pediatric conditions

Hans Hoekstra, M.D., Ph.D.Hieronimus Bosch Teaching Hospital‘s-Hertogenbosch, The Netherlands

Marrakech, SOMIPEV, April 7th 2018

PROBIOTICS

What are probiotics?

“Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.”

FAO/WHO 2002 Guidelines for the Evaluation of Probiotics in Food. ftp://ftp.fao.org/es/esn/food/wgreport2.pdf (accessed 26/1/2018)

Saccharomyces

Mechanisms of effects are strain specific

!"#$%#&%'()%*+,&%-%'.&%#,

/*+,&%-%'.&%#,)#-)&0+)(&".%,()-#")10+,#&21+).,*)3+,#&21+)

4+&0#*()$2)5+,6(7)81+'%+(7)9%,+.3+

!"#$%& '(")*"% '+,-*#

!"#$%&#'())('*+,-./,0.1'234'56.'789/+95,30'32':43;,35,<1',0'!33-='25>?$$25>=293=34@$.1$.10$233-$A@4.>345(=>-2 B9<<.11.-'(C$D$()EFG

!"#$%&"#'(()*+,-"./%*)*+55!"#$%&"#'(()*+,0)$0,'+:8;)<=>?@1"##-",%.2#0*+&%)(",3''+ABA;)/C=DE

Disturbing observations on probiotics concerning

• Quantities of viable cells in samples tested, with pill-to-pilland lot-to-lot variations• Mislabeling of incorporated strains• Contamination with potentially pathogenic genera• Decreased shelf lives as stated on package• Probiotic matrices• Transfer of antibiotic resistance

Probiotic yeast versus probiotic bacteria

!"#$

%&'"()*+&,

-.'"/"0'"1 !$.2"'"3"'4

5"26+07+'8).2("22"0.+07+9$.$'"1 ()'$8")*

:;-!< =-><;5?-

!"#$% !#$%

&'()*'( *'()+'(

,- ./0

,- ./0

!"#$%&'()*#+*(,-*.,/0#1+*23($0(&4,*53#$*677896:;8:8<8=

Map of the antibiotic susceptibility of probiotic strains (I)

Neut C et al. Med Mal Infect 2017; 47:477-83.

Map of the antibiotic susceptibility of probiotic strains (II)

Neut C et al. Med Mal Infect 2017; 47:477-83.

What About Safety?

• The evidence support that probiotics are generally safe for most populations

• There are reported cases of fungaemia in patients using Sb and bacteremia in patients taking LGG or L. casei

• Few cases of sepsis associated with Sb, LGG and B. subtilis have been reported

• Most cases occurred in an IC setting in the presence of a CVL; experts recommend the use of scrupulous hand hygiene when manipulating a CVL after handling probiotic preparations

• Sb is contraindicated in patients with a CVL, critically ill or immunocompromised patients

Doron S, Snydman DR. Risk and Safety of Probiotics. Clinical Infectious Diseases: 2015;60(Suppl 2):S129-S134. doi:10.1093/cid/civ085.

Severe Infections are Declining in Many Countries, …

But Antibiotics are the Most Commonly used Drugs in Western Countries

Global Consumption of Antibiotics

TP Van Boeckel, Lancet Infect Dis.2014 742–750,

Global Consumption of Antibiotics

TP Van Boeckel, Lancet Infect Dis.2014 742–750

Medical use of antibiotics increased 36% globally in a decade

Use of antibiotics age in low resource settings

First antibiotic useage <2 years

Rogawski ET et al. Bull World Health Organ 2017;95:49-61

Antibiotic prescription (age groups; 1000 individuals)

!"#$ #%&#&'())"* %+,-." +/&#*$(0(+$(. "12+%,-"

Consequences of Antibiotic (Mis)use

• Antibiotic resistance

• Adverse drug events

• Drug side effects

• Antibiotic associated diarrhea (AAD)

• Clostridium difficile infection

• Disruption to microbiome (dysbiosis)

Ohl CA, Luther VP. J. Hosp. Med. 2011;6:S4

After antibiotic exposure

Tight Junctions Disruption

Short ChainFatty Acids

Normal HGMDisruption HGM due to

antibiotic exposureDisturbed HGM and infection

(e.g., C difficile)

Luminal Osmosis

Inflammation

Antibiotic

AADBouhnik Y. Gut Microflora Digestive Physiology And Pathology. Paris; 2009:181-197.

Disruption Microbiome

!"#$%&'$(&)*+(,,)-,

+./0!""'*)(&-1/.)(,,2-(/

3+.!.4+.56

+.*'7)&)"

8"-91'$-$:,(;'9"*'7)&)"

!"#$%&'&()*+#%(%,)-+.%*)$/0'*+#+&

1%,2)3'*(+4,

!"#$%&'()*+)!"#$%&'(')*+(',,'-'".+,-+#$%,*-. %&3/*(%+&

!"#$%&'()*+#,-.,$/+,0%$,1"*&-'"-$(,2,34#'"-#"#,

!"#$%&!'#(#)* +,%&-.)/'01)#&2341540564,&72'889'#":;8)5&<"=.'#144&>?>!&+@ABC&5=DD"#*5&#)()0)#'*4"0 "E&*9)&40*)5*40'.&:48#"<4"*'&'E*)# 14'##9)48 1;5<4"545F'&#)G4)3>.4048'. '01&H/D)#4:)0*'. I'5*#")0*)#"."(;JJ&KLMJCNO&LPA

EUBIOSIS => “Normal" and "balanced" intestinal microbiota fulfills all the conditions for us to benefit from its health effects (metabolism, immunity, trophicity, barrier effect)

DYSBIOSIS => Intestinal dysbiosis can be defined as an unfavorable dysbalance of the intestinal microbiota.

vs

!"#$%&'%#()"*+'&(,$(-),'%'&(.$/0$#","$*($1(,2'(34,(/".%$5"$,-6(

! 74,%","$*8%')-,'&(&"#$%&'%#(9$5'#",:;(,:0'(<(&"-5','#(-*&(,2'(/',-5$)".(#:*&%$/'=(

! >*1)-//-,$%:(5$?')(&"#'-#'#(9@A(-*&(A!=

! A')"-.(&"#'-#'

! B*,"5"$,".8-##$."-,'&(&"-%%2'-;(%'.4%%'*,(&"-%%2'-(5:(AC(&"11".")'

! D4*.,"$*-)(5$?')(&"#$%&'%#

! A$)$8%'.,-)(.-*.'%

! A'%,-"*(-))'%3"'#

! A'%,-"*(/'*,-)(-*&(*'4%$8&'E')$0/'*,-)(.$*&","$*#;(#4.2(-#(-4,"#/(#0'.,%4/(&"#$%&'%#

!"#$%&'%#()"*+'&(,$(-),'%'&(.$/0$#","$*($1(,2'(34,(/".%$5"$,-6(

! 74,%","$*8%')-,'&(&"#$%&'%#(9$5'#",:;(,:0'(<(&"-5','#(-*&(,2'(/',-5$)".(#:*&%$/'=(

! >*1)-//-,$%:(5$?')(&"#'-#'#(9@A(-*&(A!=

! A')"-.(&"#'-#'

! B*,"5"$,".8-##$."-,'&(&"-%%2'-;(%'.4%%'*,(&"-%%2'-(5:(AC(&"11".")'

! D4*.,"$*-)(5$?')(&"#$%&'%#

! A$)$8%'.,-)(.-*.'%

! A'%,-"*(-))'%3"'#

! A'%,-"*(/'*,-)(-*&(*'4%$8&'E')$0/'*,-)(.$*&","$*#;(#4.2(-#(-4,"#/(#0'.,%4/(&"#$%&'%#

!"#$%&'()*&+,&-"..,$/')"01&2)'("#'&-/#*/')"03

4"&'(,*,&%)55,.,0-,*&6/'',.3

!/0&/07'()08&,$*,&,9:$/)0&'(,&.,*#$'*3

The course of life of a microbiota

!"#$%#&%'()*+"&%+,,-)*"./.0&)+0&%$%#&%')+((#'%+&.1)1-($%#(%(

!"!"

Aim of the study

• Assess on healthy volunteers the effects on the gut microbiota of:

Ø Amoxicillin – Clavulanate (AC)

Ø Saccharomyces boulardii CNCM I-745 (Sb)

Ø AC in combination with Sb

• Assess the effects on gastro-intestinal symptoms, and especially antibiotic-associated

diarrhea (AAD)

Prospective randomized controlled study on the effects of Saccharomyces boulardii CNCM I-745 and

amoxicillin-clavulanate or the combination on the gut microbiota of healthy volunteers

!"#$%&#'( )*+,-*.'"/0)1+/&

Biplot of Redundancy Analysis

!"0$2&+1/'13'&4"'0.#5+1#+#'+/'&4"'6*1$)'78'9':5';"*#$#'78'-%1/"

Urge to restrain unnecessary antibiotic prescription

Recommendations for the use of probiotics in pediatric gastroenterology are now available

for most continents

!"#$%&'()*%"#$+,"(+-.%#%-%)#+/%*0+1("2%"*%-+$*()%#$+%#+)-3*'+4)$*("'#*'(%*%$

! !"#$%&'()*+%,%+ #*-.+"%/& %&0"1* -.#$"%/& /,0-%$##1*$ 23 $2/." /&* -$3! 4."+/5*05*$(.#*(60)/(%"%7*0,/#0-.#$"%/&0/,0-%$##1*$809*$:*#0,/#0)#*7*&"%/&0/,0-*13-#$"%/&80&**-0/,01/()%"$;0$-5%((%/&80-.#$"%/&0/,01/()%"$;%<$"%/&80=.$;%"30/,0;%,*! >/.&"#3'23'+/.&"#30$&-09%"1%&0+/.&"#30-%,,*#*&+*(! !/+%/'*+/&/5%+0%5)$+"07*#307$#%$2;*! ?/((%2;*0+1$&@*(09%"10%&+#*$(%&@0ABC0%55.&%<$"%/&0#$"*(

!"#$%&'()*+#(,-#./0#(1.")(#$-("./2(.-$3,./#%"&()-++/'-

Considerations for clinician with probiotic strains in antibiotic-associated diarrhea (AAD) and

C. difficile-associated diarrhea (CDAD)

Physicians should evaluate the risk factors by:• Class of antibiotics (AAD reduction up to 60%) • Duration of antibiotic treatment• Need for hospitalization• Age• Co-morbidities• Previous episodes of AAD or CDAD

Europe USA Latin America World APAC

(Cameron et al. 2017)c

Acute

gastroenteritis

T L. rhamnosus GG,

S. boulardii,

L reuteri

L. rhamnosus GG,

S. boulardii

L. rhamnosus GG,

S. boulardii,

L. reuteri

S. boulardii,

L. rhamnosus GG,

Indian Dahi

S. boulardii,

L. rhamnosus GG,

L reuteri

AAD P L. rhamnosus GG,

S. boulardii

L. rhamnosus GG,

S. boulardii

L. rhamnosus GG,

S. boulardii

S. boulardii;

L. rhamnosus GG,

B. lactis Bb12 + S.

thermophilus,

L. rhamnosus strains

E/N, Oxy and Pen

L rhamnosus GG

S.boulardii,

CDAD P S. boulardii S. boulardii

Recommendations for use of probiotics in childhood intestinal diseases by geographic region

One size may not fit all

• Countries, climate, culture, politics• Conditions and diseases, indications• Socioeconomic status• Nutrition, diet• Microbiomes, pathogens• Antibiotic exposure• Vaccination

• Antibiotic use in children could lead to long term disruption of the

microbiome with unknown, and possibly harmful, health effects

• Safe medical therapies (probiotics) are available for AGE/AAD/CDAD

• Positive evidence with probiotic drugs in these conditions mainly comes

from L. rhamnosus GG and S. boulardii CNCM I-745 strains

• Many other probiotics strains cannot be recommended because of

insufficient data or insufficient data on quality

• We need more good RCTs

Take home messages

Thank you!