(Probiotici-sinbiotici-farmabiotici-postbiotici-probiotici tindalizzati….)

franco vicariotto IPA (international probiotics association)

Probiotici in ostetricia e ginecologia,facciamo chiarezza

MICROBIOMA

“The human body is colonized by a vast number of microbes,

collectively referred to as the human microbiota.

The link between these microbesand our health is the focus of a

growing number of researchinitiatives, and new insights are

emerging rapidly

da dove partiamo…………..

Il futuro della medicina personalizzata dipendera dagli studi sul microbiomae dalla lotta all’antibioticoresistenza

Il concetto di ologenoma dell’evoluzione postula che l’ OLOBIONTE(ospite di piu’ simbionti) con il suo OLOGENOMA (genoma ospite piu’ microbioma) sia un livello di selezione in evoluzione

Ogni animale e’ un OLOBIONTE costituito dall’ospite e da diversi microbi e virus simbiotici

“Favorisce l’equilibrio della flora intestinale”

2019 ITALIA 544,947 milioni crescita 5 %

restoring o ceppospecificita’

dove andiamo con i probiotici…….

la battaglia dei claims…e del mercato…

Integratori,nutraceutici o farmaci?

Function/ characteristic Probiotic Antibiotic/Antimicotic

Natural YES NO

Without side effects YES NO

Specific activity against pathogens YES YES (but it alters also commensal/positive bacteria)

Relapses prevention YES NO

Absence of possibile pathogen resistance development YES NO

Help to balance vaginal microflora YES NO

Probiotic vs common antibiotic

Composition of vaginal microbiome A healthy vaginal microbiota is dominant in 5 clusters CST (community state types) j ravel 2011

Lactobacilli produce

Function

Lactic acid Help to maintain vaginal pH, inhibiting the proliferation of pathogenic bacteria

Hydrogen peroxide

Toxic to anaerobic pathogens, directly destroy pathogenic anaerobic bacteria

Bacteriocins Proteins that inhibit the growth & reproductive success of competing pathogens

Biosurfactants Reduce surface tension and have the ability to disrupt and dislodge pathogenic biofilms

Function of Lactobacilli

The association between ethnicity and vaginal microbiota composition

Microbiome revolution: Clinical applications in OBGYN

probiotics and vaginitis

Clinical applications of probiotics as adjunct therapy as seen in Gastroenterology, Pediatrics and now more and more data is demonstrating the benefit in women’s health

Microbioma (and probiotics) in relation to Women Health

Pregnancy Gynec

Pro-inflammatory cytokinesSperm motility and viability

Preterm deliveryEczema-AllergyBreastfeeding

Fertilization Menopause

utiatrophy

dysbiosis

STDVaginitisVaginosis

Metabolicdisorders

QUANDO UNA TERAPIA CON PROBIOTICI?ORALI O VAGINALI? SOPRAVVIVONO IN VAGINA?

NUOVI CEPPI SPECIFICI DEDICATI?DA SOLI O IN ASS. A TERAPIA FARMA ?

EFFICACI SUI BIOFILMS?

open questions

Restoring della disbiosi o ceppospecificita’ antibatterica?

guidelines per prescrizioni responsabili e etiche

Il futuro (non troppo lontano…)

E il passato (troppo vicino…)

Il trapianto di microbiota vaginale potrebbe ripristinare il micro-ambiente locale e aiutare a trattare le recidive di un disturbo ginecologico molto comune come la vaginosi batterica. I risultati pubblicati su Nature Medicine, potrebbero infatti aprire la strada a un’opzione più semplice ed economica per affrontare la vaginosibatterica ricorrente.

Una settimana prima del trapianto di microbiota vaginale è stata prescritta una crema antibiotica per ridurre la concentrazione dei batteri vaginali.I ricercatori hanno quindi raccolto fluidi vaginali da tre donatrici con un microbiota vaginale sano e hanno effettuato un trapianto di microbiota vaginale nelle cinque partecipanti allo studio.

quattro delle cinque hanno mostrato una remissione a lungo termine della vaginosi batterica entro 21 mesi dal trapianto

due donne sono state sottoposte a solo un trapianto, per le restanti sono stati necessari tre trapianti ciascuna.

nella quinta partecipante è stato osservato solo un parziale miglioramento dopo due trapianti.

La grande scommessa dei probiotici

La gravidanza e i primi 1000 giorni di vita

• What triggers metabolic diseases during pregnancy?

• Hormonal changes

• Metabolic stress

• Lifestyle changes

• Predisposition / risk factors

Gestational Diabetes Mellitus (GDM)

Maternal obesity / overweight

Gestational dyslipidaemia(high triglycerides /

cholesterol)

Pregnancy-induced hypertension

Metabolic diseases during pregnancy

Probiotics & Pregnancy - Why is it so important? What should the future look like?Metabolic diseases during pregnancy

Il microbioma materno in gravidanza puo’ essere responsabile di patologie materno-fetali e neonatali

POSITION PAPER PROBIOTCI IN OSTETRICIA

Parto pretermine e antibiotici compromettono il microbiota dei neonatiUn intervento mirato basato sulla manipolazione del microbiota alterato nei nati prematuri già dalle prime settimane di vita potrebbe perciò essere una strategia utile nella prevenzione di disturbi correlati ma che andranno a manifestarsi solo in seguito.

probiotici come farmaci……

la somministrazione di probiotici in gravidanza e durante

l’allattamento è stata descritta come una strategia sicura

ed efficace per potenziare

le proprietà immuno-protettive del latte materno e

prevenire la dermatite atopica nei neonati

l’abbondanza relativa di alcune specie di Lactobacilli, quali ilL. iners, L. crispatus e L. gasseri distingueva la flora vaginale delle donne infertili sine causa dalle donne infertili con causa nota e dalle donne fertili.

Questo profilo microbico sembra aumentare la suscettibilità all’invasione e colonizzazione di batteri quali Atopobium, Prevotella, ,Ureaplasma ed Escherichiache mimano un microambiente simile a quanto osservato nelle donne con vaginosi, con caratteristiche associate a complicanze durante il periodo del concepimento

La conoscenza approfondita del profilo microbico con tecniche di ultima generazione sembra rappresentare un elemento importante nella determinazione della precisa causa dell’infertilità femminile senza ricadere nella vaga nozione di “infertilità idiopatica” e apre la strada per interventi terapeutici personalizzati atti al ripristino di un habitat vaginale ottimale.”

Subclinical alteration of the cervical–vaginal microbiome in women with idiopathic

infertility

Authors Giuseppe Ricci Francesco De Seta, Manola Comar. First published: 16 February

2017

PROBIOTCI MICROBIOMA VAGINALE E INFERTILITA?

LA TERAPIA…..

PARTIAMO DALLE BASI….LA COLONIZZAZIONE GUT AND VAGINAL

PROBIOTICI VAGINALI

addio al medical device…dal 2020 solo farmaci in vagina

PROBIOTICI ORALIcosa fanno ? e come?

PROBIOTICI ORALI monoceppo o policeppo ?

Il nuovo regolamento sui dispositivi medici, MedicalDevice Regulation (EU) 2017/745, abroga leprecedenti direttive europee. Il nuovo regolamentosancisce chiaramente che i prodotti contenentiorganismi viventi non rientrano più nell’ambito deidispositivi medici (Art.1, pt. 6).

Probiotico orale(Il lungo viaggio)

cavita’ orale

stomaco

intestino

colonizzazione fecale

colonizzazione vaginale

per contiguita’ o forse via linfatica..?

Lo accompagnano nel viaggio ceppi gastro intestinali?o altri booster?

Oral availability

Morelli L et al. (2004) Utilization of the Intestinal Tract as a Delivery System for Urogenital Probiotics J Clin Gastroenterology. 38:S107–S110.

Probiotic strains like GR-1/RC-14 that have been clinically tested for their efficacy in supporting urogenital and also their oral availability

The first study to

document the ascension

of GR-1 and/or RC-14

recovered either one or

both lactobacilli from the

vagina of all ten women

studied.

All ten women had a

history of urogenital

dysbiosis and were given

twice daily oral treatment

for 14 days.

After one week, one or

both strains were found

and identified via

molecular typing

Augmentation of antimicrobial metronidazoletherapy of bacterial vaginosis with oral probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14: randomized, double-blind, placebo controlled trial. Anukam KC et al . (2006) Microbes and Infection , 8: 1450-1454.

Treatment in Combination with AntibioticsFollowing BV infection, combination treatment using GR-1/RC-14 (1 capsule, 10 billion CFUs, twice daily) with metronidazole (500 mg, twice daily) more than doubled (88%) the effectiveness of metronidazole alone (40%) in returning the vaginal microbiota to a healthy state. Vaginal colonisation

Trials probiotici orali

Does multi strain probiotic supplement reduce recurrence of bacterial vaginosis?

• A prospective study with:• 75 patients • aged 18-50 over 12-month period of observation,• recurrent BV

(Visit III) the recurrence rate of BV after treatment 16%, compared to 40% in the control group

• A statistically significant difference (p < 0.001) was evidenced by comparing these values with those reported in the medical literature

about recurrences rate data (40-60%)

• The comparative analysis of Amsel criteria confirmed uniform improvement of all the examined parameters.

• Abnormal vaginal microbiota decreased at subsequent visits, but the incidence of microbiologically confirmed was significantly higher in the

probiotic group at the end of treatment.

total CFU 109 Capsule• Lactobacillus plantarum PBS067, • Lactobacillus rhamnosus LRH020• Bifidobacterium animalis lactis BL050

Evaluation of an orally administered multi strain probiotic supplement in reducing recurrence of bacterial vaginosis : A clinical and microbiologically study (Vicariotto & Murina 2019 )

The study was conducted as follows:-Visit I: enrollment of BV diagnosed women (n=75) and metronidazole treatment as above descripted -Visit II: verification of antibiotic therapy success and allocation to active group (Intimique® Femme) of 50 women and control group of 25 women without any further therapy.-Reintegration period: supplementation with Intimique® Femme 1 dose/day for 14 consecutive days in the active group-Observation and Maintaining period: supplementation of Intimique® Femme 1 dose/day for 7 days per month from the subsequent month, after menstrual period, lasting 4 months. -Visit III: scheduled at the end of the study, or occurring during intervention period if the subject show BV symptoms.

Randomised Double Blind PlaceboControlled 423 pregnant women

Better GDM-related outcomes in probiotic (vs. placebo) groups

• Incidence of gestational diabetes in the probiotic group was significantly lower by 68% (2.1% vs. 6.5%; p = 0.03)

• The probiotic significantly decreased the incidence of gestational diabetes in women aged 35 or older (69% reduction; p < 0.01) and in women with a history of gestational diabetes (p = 0.004), but had no significant effect in women without these characteristics.

L. rhamnosus HN001• 6x109 CFU( n=212)• Placebo (n=211)• Daily for 12 wks (@14-16 weeks)• History of atopic disease

Early pregnancy probiotic supplementation with Lactobacillus rhamnosus HN001

may reduce the prevalence of gestational diabetes mellitus (GDM): A randomised controlled trial. Wickens et al. 2017 Br J Nutr 117:804-813

Oral Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 to reduce Group B Streptococcus colonization in pregnant women: A randomized controlled trial.(MingHo et al Taiwan J Obstet Gynecol. 2016 Aug;55 (4):515-8).2016.06.003.

RCT110 pregnant women aged 35-37

Oral probiotic could reduce the vaginal and rectal GBS colonization in women vs. placebo

GBS from positive to negative in 21 probiotic group (42.9%) and in 9 placebo (18.0%)

L. rhamnosus GR-1 & L. reuteri RC-14

109

(42.9%)

(18.0%)

144/159 (90.6%) in the placebo, 134/157 (85.4%) in the HN001, 144/158 (91.1%) in the HN019 group

Reduction in Risk of eczema

Early supplementation with Lactobacillus rhamnosus HN001 reduces eczema prevalence to 6 years: does it also reduce atopic sensitization? Wickens et al Clin Exp Allergy 2013;43:1048-1057

L. rhamnosus HN001• 6x109 CFU( n=212)• Placebo (n=211)• Daily for 12 wks (@14-16 weeks)• History of atopic disease

In a high-risk birth cohort, maternal supplementation from 35 weeks gestation until 6 months if breastfeeding and infant supplementation from birth until 2 years withLactobacillus rhamnosus HN001 6 billion CFU a day (6x109 CFU/day) halved the cumulative prevalence of eczema at 2 and 4 years.

Double-blind randomized placebo-controlled trial

Treatment of infectious mastitis during lactation: antibiotics versus oral administration of Lactobacilli isolated from breast milk (Arroyo R, et al Breastfeed Med 2015;10:425-439)

352 women randomly assigned into 3 treatment groups

Relieve or reduce pain associated with mastitis (as an adjunct to existing antibiotic therapy)

L. Fermentum CECT5716• 3x109 CFU• 6x109 CFU• 9x109 CFU• Control

L. fermentum CECT 5716, at a level(3x109 CFU/day) was shown to be effective and sufficient to produce a decrease in Staphylococcal load in breastmilk leading to improvement in pain symptoms in women suffering from breast pain associated with Staphylococcus in the breastmilk.

Randomized controlled trial

DiscussionThe aim of this trail was to compare the effects on the vaginal microbiota of oral probiotic capsules containing L. rhamnosus GR‐1 and L. reuteri RC‐14 versus placebo taken orally from early pregnancy until delivery. The biological effects were measured by Nugent scoring and culture of vaginal samples collected at three time points during pregnancy.

ConclusionOur study did not show evidence of an effect of oral probiotics on the vaginal microbiota in pregnancy.

Un trial serio e negativo!

PROBIOTICI VAGINALI? (attivi sui biofilms)

Io ci credevo…addio al medical device….

USA e CANADA

Opportuna una APP ,una guida clinica…..

Informazione sui probiotici?

CRITERI DI SELEZIONE E CONSIGLIO RAZIONALE

DEI PROBIOTICI IN FARMACIA

grazie