Infezioni da Gram+ con - con antibiotici long acting" - ICAR 2018
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Nuovi scenari
"Esperienze di gestione
di pratica clinicadelle
nella
infezioni
gestione delleda Gram+dacon
infezioni GRAM+
antibioticoterapia long-acting
con antibiotici long acting"
Roma, 23 Maggio, 2018
Mario Venditti
Department of Public Health and Infectious Diseases
Policlinico Umberto I,
“Sapienza” University of Rome
My disclousures Research grants - Pfizer, Novartis, MSD, Advisor/consultant • - Pfizer, MSD, Angelini, Gilead, Sanofi Speaker/chairman - Astra Zeneca, Astellas, Pfizer, MSD, Gilead, Novartis
premessa
Outcome drivers
activity of the antibiotic vs
offending pathogen
Hospital environment
exposure
“nuovi” e “vecchi” batteri Gram positivi
AR & MDR
Vecchi Batteri Nuovi Batteri
MRSA & MRSE • MSSA borderline sensibile a
HLGR/HLSR E faecalis & E glico & Dapto
faecium • VISA & VRSA &S. haemolyticus
E casseliflavus • Lin R/MR ConsMRSA?
Pediococcus & Leuconostoc • VRE
Erysipelothrix rusiopathiae • Corynebacterium striatum, C.
Lactobacillus spp jeikeium, C. urealyticum
Clostridium difficile • Clostridium innocuum
“nuovi” & “vecchi” farmaci
vs patogeni +/- MDR
Vecchi farmaci Nuovi farmaci
Rifampicina Orita/Telavancina
Vanco, Teico & Dapto Dalbavancina
Cefazolina Ceftarolina & ceftiboprole
Linezolid Tedizolid
Minociclina Eravacycline, omadacycline
ac fusidico, cotrimossazolo, Iclaprim
fosfomicina
In vitro activity of glico/lipopepdides
literature review from Crotty MP et al J Clin Microbiol 2016
Telavancin
0.06
0.06
0.06
0.03
0.12
0.03
In vitro activity of glico/lipopepdides
literature review from Crotty MP et al J Clin Microbiol 2016
dalbavancin Telavancin
0.06 0.06
0.06 0.06
0.06 0.06
0.03 0.03
0.06 0.12
0.12 0.03
S. pneumoniae 0.008
Comparative in vitro activities (μg/mL) of dalbavancin and
seven other antimicrobial agents against consecutive
MSSA/MRSA isolates recovered from osteomyelitis specimens
Citron D et al Diagn Microbiol Infect Dis, 2014
Outcome drivers
activity of the antibiotic vs
offending pathogen
Hospital environment
exposurePerilous Cycle
Hospitalization for infection (i.e. ABSSSI)
Resistant Pathogen colonization
Infection
ESBL+ E. coli, K. pneumoniae Unknown pathogen
MDR-PDR K pneumoniae, Acinetobacter,
ESBL-producing bacteria
P aeruginosa, MRSA & Co.
MDR/XDR/PDR
C. difficile & Candida Relapsing CDAD +/-candidemia
Antimicrobial Resistance Antimicrobial Use
Amoxaclav/glycopeptides
ESBL production…... Carbapenems
?????
Carbapenem resistance,
Topical vancofidaxo & antifungal agentsCaso clinico • Paziente di sesso femminile, 72 anni. • Ipertensione arteriosa essenziale. • Diabete tipo 2. • Obesa • Malattia del pavimento pelvico cistiti • Grave spondilodoscoartrosi e gonatrosi • Recente ricovero per TIA • Cellulite della natica sinistra in rapporto a iniezioni IM.
Caso clinico:
decorso in ospedale
• Ricovero in Chirurgia Generale: drenaggio pus con isolamento di MRSA (in IV giornata,
comunicato…..)
• ingresso cipro os per 10 giorni e vanco iv, aggiunta in empirico in III giornata
• VIII giornata: CDAD ….. vanco anche per os....CATUR...
• X giornata: cistopielite da BGN ….................. ceftrixone empirico poi…...
• XII giornata: meropenem (sospende
K pneumoniae ESBLev)
vancocina +
• XVI giornata: PICC
• XX giornata (notte): sindrome settica, rimuove PICC (CVC introdotto 48 ore dopo) ed inizia
linezolid ev (in bilico per andare in UTI…. Ma non c’erano posti letto) e migliora subito!
• XXIII giornata: Candida glabrata dalle emocolture e dal PICC..caspo; stop linezolid
• IXXX giornata: passa a fluconazolo per os (ma dopo tre giorni passa a vorico orale),
sospendendo caspo, vanco os e mero
• XXXII giornata: iniziale retinite da Candida vorico cronico sotto controllo dell’oculista
• XXXVI giornata dimessa!!!!
• Follow up: retinite guarita in tre mesi, ma a causa di un nuovo trattamento antibiotico con
chinolone per cistite va incontro a CDAD recidivanti.........Revolutionary drugs!!!
80s 90s 2016
Ceftriaxone teicoplanin Dalbavancin
- Long half life ( 8h) - Long half life ( 40h) - Long half life ( 14 days)
- Once a day - Once a day->tris in wk - Weekly drug
- Protein binding (85%) - Protein binding (85%) - Protein binding (dalba
- Only IV ( IM) - Only IV ( IM) 93%)
- Milestone of OPAT - Milestone of OPAT - Only IV
- Well tolerated - Well tolerated - super-potential for OPAT
- Many indications - Many indications - Well tolerated
(SSTI, CAP, UTI, etc.) (SSTI, bone, UTI, etc.) - Potential for many
- Cost (at that times) - Cost (still today) indications
- CostENDOCARDITE STREPTOCOCCICA:
TRATTAMENTI
* MIC di penicillina 0.1 mg/L
Terapia Durata
Standard*:
Penicillina (20 M/d) § 4-6 settimane
Pen + genta 2 settimane
Ceftriaxone (2 g/d) 4-6 settimane
Dopo
Fino a il paper
Possibili:
metà di
degliFrancioli
anni 90!
Cef + aminoJAMA, 1992…… 2 settimane
Teico (6-10 mg/Kg/d) 4 settimane
§: oggi: Ampicillina 2 gr ev ogni 4 ore4-WeekTreatment of Streptococcal Native Valve
Endocarditis with High-Dose Teicoplanin
Venditti M, et al AAC, 1992STIMA DELLE GIORNATE DI OSPEDALIZZAZIONE RISPARMIATE IN
PAZIENTI CON ENDOCARDITE STREPTOCOCCICA IN 5 STUDI
(aa ‘80 e ‘90)
Trattamento N° pazienti N° giornate
risparmiate
Ceftriaxone
amox x os 30 380
Ceftriaxone 55 200
Teicoplanina 16 65
Ceftriaxone + 48 124 (248)
netilmicina
Ceftriaxone 26 494Experience with outpatient intravenous
teicoplanin therapy for chronic osteomyelitis
Graninger W, et al. Eur J Clin Microbiol Infect Dis. 1995.
• 37 pts with acute exacerbations of chronic osteomyelitis caused by
MSSA(n = 13), MRSA(n = 12), MS-Cons (n = 9), MR-Cons (n = 1) and
enterococci (n = 2) were treated iv with teicoplanin.
• After a loading dose of 7 to 16 mg/kg (median 11 mg/kg) for 4 to 7
days, pts received 9 to 25 mg/kg (median 14 mg/kg) on Mondays,
Wednesdays and Fridays in an outpatient setting to reach trough
serum levels between 5 mg/l and 15 mg/l.
• The duration of treatment ranged from 28 to 150 days (median 60
days).
• Cure or improments was obtained in 31 (84%) pts.
• Adverse effects occurred in 6 pts, and caused discontinuation of
treatment in 3 pts.
• The financial savings exceeded US$60,000 per patient compared
with the high hospitalization costs of inpatient treatment.Oritavancin Phase III Clinical Study
Randomized double blind trial design with 60 day safety follow
Corey GR et al. 24th ECCMID Barcelona, Spain 10-13 May 2014. poster_113642
Wilcox M et al. ICAAC 2013. Denver, Colorado. 10-13 September 2013. Poster L-202E la dalba?
A Randomized Clinical Trial of Single-Dose Versus Weekly
Dalbavancin for Treatment of ABSSSI
Dunne et al Clin Infect Dis. 2016 Mar 1; 62(5): 545–551Concentrations of dalbavancin
in sternal and femoral bones in rats
Barnea Y et al J Antimicrob Chemother 2016; 71: 460–463Comparative efficacy of dalba vs vanco
in sternal osteomyelitis in rats
Barnea Y et alJ Antimicrob Chemother 2016; 71: 460–463
P=0.35
Dissemination: 5% with vanco or dalba
33% with saline P=0.53Dalbavancin treatment in a deep sternal wound MRSA infection
after coronary artery bypass surgery: a case report GUZEK et al. Journal of
Cardiothoracic Surgery (2018) 13:3DALBAVANCIN BONE CONCENTRATIONS
Dunne MW, et al. Antimicrob Agents Chemother.2015 Apr;59(4):1849-1855.
Concentrations of dalba in bone after a single 1000 mg infusionSintesi della efficacia di dalbavancina in vari modelli
animali di infezione
Murillo O et al Enferm Infecc Microbiol Clin. 2017;35(Supl 1):28-32
Patogeno modello di infezione agente di confronto efficacia
MSSA/MRSE batteriemia vanco/teico OK
MRSA/MRSE endocardite vanco/teico OK
MRSA, GISA endocardite nessuno OK & KO
MRSA inf. su corpo estraneo rifa & combo OK & KO
S pneumoniae* polmonite penicillina G OK
S pneumoniae batteriemia vanco/teico OK
E. faecalis batteriemia vanco/teico OK
B. Antracis carbonchio ciprofloxacina
* Sia Pen S che Pen RActivity of dalba, alone and in combo with rifa, against
MRSA in a foreign-body infection model
Baldoni D et al Intern J Antimicrob Agents, 2013
Cure rate of cage associated infections at day 12Gram-positive BSI: Dalbavancin
A phase 2, open-label, randomized, controlled, multicenter study
Raad. I. Clin Infect Dis. 2005
Dalba Vanco
- Overall success
at EOT 21/23 (91.3%) 18/28 (64.3%)
- Clinical success 20/23 (87%) 14/28 (50%)
- Micro. success 22/23 (95.7%) 22/28 (78.6%)
Adverse events: similarDate queste premesse, nella vita reale,
Dalba in che % viene usata per
ABSSSIs?
Bone & Joint infections?
Prosthetic joint infections?
endocarditis?
Other endovascular & cvc related infections?Dalbavancin in the treatment of different Gram-positive
infections: a real-life experience
Bouza E et al Int J Antimicrob Agents. 2017.
Dalbavancin was used for the following infections:
1. prosthetic joint infections : 29.0%
Bone & Joint +/-
2. acute bacterial skin &
skin structure infection: 21.7%
prothesis: approx 50%
3.2. bone
Bacteremic infections:
(17.4%) & joint 24.6%
(1.6%) infection: 19%
4. endocarditis (10.1%) & endovascular infections (2.9%): 13%
5. catheter-related bacteraemia: 11.6%
A total of 69 patients received Dalbavancin between 2016 and 2017 in 29 institutions in Spain (58% male,
median age 63.5 years).Dalbavancin in the treatment of different Gram-positive
infections: a real-life experience
Bouza E et al Int J Antimicrob Agents. 2017.VABBE’ ma, nella vita reale, Dalba in che
precentuale risulta efficace
ABSSSIs?
Bone & Joint infections?
Prosthetic joint infections?
endocarditis?
Other endovascular & cvc related infections?Dalba in the treatment of different Gram-positive infections: a real-life experience
Bouza E et al Int J Antimicrob Agents. 2017.Dalba in the treatment of different Gram-positive infections: a real-life experience
Bouza E et al Int J Antimicrob Agents. 2017.
The high clinical success rate was also confirmed in patients
who received Dalbavancin as rescue therapy
(clinical success higher than 75%)Dalbavancin in the treatment of different Gram-
positive infections: a real-life experience
Bouza E et al Int J Antimicrob Agents. 2017.
Cost savings
Overall, Dalbavancin reduced days of hospital stay
by 1160 days. Although dalbavancin permitted to
potentially treat in an outpatient setting 50 out of
the 69 patients, cost data for the Dalbavancin
regimen and the inpatient regimen were calculated
for all patients included in the study. The overall
cost of Dalbavancin and Standard therapy was
estimated at €1,083,637 and €1,295,118,
respectively. Therefore, the overall cost reduction
of301Dalbavancin treatment in these 69 patients
was estimated at €211,481 or €3,064 per patient.Dalba for endocarditis and/or BSIs by Gram-positive cocci
Hidalgo Tenorio C et al,ECCMID 2018, abt P2017
Characteristics n=63Dalba for endocarditis and/or BSIs by Gram-positive cocci
Hidalgo Tenorio C et al,ECCMID 2018, abt P2017
Conclusions
• Dalbavancin could be effective in
cardiovascular infections as a sequential
therapy in stable patients.
• It could allow early
• Average length of stay was 26
discharge of patients
• AE: 2 drug fevers;
and important pharmacoeconomic
days; benefits.
• average patient Hospital
• main use: early discharge (OK day reduction: 14;
in 82.5%); • total reduction: 877 days
• Follow up OK in 53/56 pts (KO
for 1 death and 2 readmissions;?
DH Malattie Infettive X • Casi di osteomielite trattati 13 • Schema terapeutico: 1000 mg ev prima dose, 500 mg il giorno 8, poi 1000 mg al giorno 32 e 500 mg il giorno 40 • Piena soddisfazione: un paziente ha sofferto un evento di eritema pruriginoso contenuto con antistaminico. • …..meno usato per ABSSSI…….
DH Malattie Infettive Y
• Casi di osteomielite trattati 12 (compreso 1 caso di
spondilodiscite+endocardite)
• Schema terapeutico:
- fase 1: 2 sett. ev (dapto+/-altro); 4 sett nel caso con EI.
- fase 2: 1000 mg ev gg 1 e 28, 500mg gg 7 e 21, oppure
1000 mg gg 1, 500 mg gg7, 1500mg gg 21.
• Piena soddisfazione: un paziente ha sofferto un evento
di eritema pruriginoso contenuto con antistaminico
associato a lieve pancitopenia transitoria
• …..0 casi di terapia per ABSSSI…….!?
Phase 1 bone penetration study the PK of dalba in bone &
articular tissue in 30 healthy volunteers who received 1000 mg
iv dalba up to 14 days before elective orthopedic surgery
Dunne et al AAC 2015
Mean ± SD plasma concentrations in 31 patients at 772 h (1 month)and 1080 h (53 gg)
were 6.2 ± 2.4 and 3.4 ± 1.7, respectivelyIn vitro activity of glico/lipopepdides
literature review from Crotty MP et al J Clin Microbiol 2016
dalbavancin Telavancin
0.06 0.06
0.06 0.06
0.06 0.06
0.03 0.03
0.06 0.12
0.12 0.03
S. pneumoniae 0.008Simulated mean concentration time
profile in bone with 1,5 g IV on days 1 and 8
Dunne MW, et al. Antimicrob Agents Chemother.2015 Apr;59(4):1849-1855.Dalbavancin for the treatment of osteomyelitis
Jandourek A et al ECCMID 2017
Study designDalbavancin for the treatment of osteomyelitis Hospital stay & antibiotic treatment lenght (mITT population) and safety
Dalbavancin for the treatment of osteomyelitis
in adult patients
Jandourek A et al ECCMID 2017
• Patients were randomised (7:1) to dalbavancin 1500 mg IV over
30 minutes on Day 1 and Day 8 or standard of care (SOC)
antibiotic for 4–6 weeks based on investigator choice.
• 80 patients planned for enrollment
DALBA SOC
n: 59 n:9
clinical improvement at:
- day 21 48/48 6/9
- day 42 46/46 6/6
Microbiology in pts
evaluted at day 27 MSSA, 2 MRSA, 2 MSSA, 1 MRSA
8 EnterococcusDalbavancin for the treatment of osteomyelitis in
adult patients
Rappo U et al ECCMID 2018Dalbavancin & bone infection
Conclusions
• The long half life of Dalba and its bone penetration after a short
treatmentregimen allows once-weekly dosing and mantain serum
concentration above the MIC90 for most grampositive pathogens
over at least 42 days.
• Good dalba bone penetration after a short dosing regimen is relevant
for osteomyelitis
• The 2 dose, once weekly regimen may offer advantages to patients
and physicians
- eliminates the need for prolonged iv access
- optimizes adherences for infectionrequiring treatment duration of
4-6 wks
• Dalbawas well tolerated in this adult population
• Final outcomes at 6 weeks, 6 months and 1 year suggest that
treatment of adult osteomyelitis with a2-dose weekly regimen of
dalba has a favourable and durable clinical benefitConcludendo…….
?Fra 5 anni quali percentuali di impiego vi aspettate
per dalbavancina o oritavancina o analoghi?
ABSSSIs?
Bone & Joint infections?
Prosthetic joint infections?
endocarditis?
Other endovascular & cvc related infections?….. Ma soprattutto fra 5 anni…. •Avremo schedule di impiego terapeutico comuni? •…O ognuno avrà il suo schema?
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