Nuovi scenari di gestione delleinfezioni da Gram+ con
antibioticoterapia long-actingRoma, 23 Maggio, 2018
Mario VendittiDepartment of Public Health and Infectious Diseases
Policlinico Umberto I,
“Sapienza” University of Rome
"Esperienze di pratica clinica nellagestione delle infezioni da GRAM+
con antibiotici long acting"
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 environmentexposure
“nuovi” e “vecchi” batteri Gram positiviAR & MDR
Vecchi BatteriMRSA & MRSE
HLGR/HLSR E faecalis & E faecium
E casseliflavus
Pediococcus & Leuconostoc
Erysipelothrix rusiopathiae
Lactobacillus spp
Clostridium difficile
Nuovi Batteri• MSSA borderline sensibile a
glico & Dapto
• VISA & VRSA &S. haemolyticus
• Lin R/MR ConsMRSA?
• VRE
• Corynebacterium striatum, C. jeikeium, C. urealyticum
• Clostridium innocuum
“nuovi” & “vecchi” farmaci vs patogeni +/- MDR
Vecchi farmaci
Rifampicina
Vanco, Teico & Dapto
Cefazolina
Linezolid
Minociclina
ac fusidico, cotrimossazolo,
fosfomicina
Nuovi farmaci
Orita/Telavancina
Dalbavancina
Ceftarolina & ceftiboprole
Tedizolid
Eravacycline, omadacycline
Iclaprim
Telavancin
0.06
0.06
0.06
0.03
0.12
0.03
In vitro activity of glico/lipopepdidesliterature 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/lipopepdidesliterature review from Crotty MP et al J Clin Microbiol 2016
dalbavancin
0.06
0.06
0.06
0.03
0.06
0.12
0.008S. pneumoniae
Comparative in vitro activities (μg/mL) of dalbavancin and seven other antimicrobial agents against consecutive
MSSA/MRSA isolates recovered from osteomyelitis specimensCitron D et al Diagn Microbiol Infect Dis, 2014
Outcome drivers
activity of the antibiotic vs offending pathogen
Hospital environmentexposure
Perilous Cycle
Resistant Pathogen colonization
Antimicrobial Resistance Antimicrobial Use
Infection
Unknown pathogen
Amoxaclav/glycopeptides
ESBL production…...
ESBL+ E. coli, K. pneumoniae
ESBL-producing bacteria
Carbapenems
Carbapenem resistance,
MDR-PDR K pneumoniae, Acinetobacter, P aeruginosa, MRSA & Co.
MDR/XDR/PDR
?????
Hospitalization for infection (i.e. ABSSSI)
C. difficile & Candida Relapsing CDAD +/-candidemia
Topical vancofidaxo & antifungal agents
Caso 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 vancocina ev)
• 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.........
K pneumoniae ESBL +
80sCeftriaxone
- Long half life ( 8h)- Once a day- Protein binding (85%)- Only IV ( IM)- Milestone of OPAT- Well tolerated- Many indications(SSTI, CAP, UTI, etc.)- Cost (at that times)
2016Dalbavancin
- Long half life ( 14 days)- Weekly drug- Protein binding (dalba93%)- Only IV- super-potential for OPAT- Well tolerated- Potential for manyindications- Cost
Revolutionary drugs!!!
90steicoplanin
- Long half life ( 40h)- Once a day->tris in wk- Protein binding (85%)- Only IV ( IM)- Milestone of OPAT- Well tolerated- Many indications(SSTI, bone, UTI, etc.)- Cost (still today)
ENDOCARDITE STREPTOCOCCICA:TRATTAMENTI
Terapia Durata
Standard*:
Penicillina (20 M/d) 4-6 settimane
Pen + genta 2 settimane
Ceftriaxone (2 g/d) 4-6 settimane
Possibili:
Cef + amino 2 settimane
Teico (6-10 mg/Kg/d) 4 settimane
* MIC di penicillina 0.1 mg/L
§: oggi: Ampicillina 2 gr ev ogni 4 ore
§
Dopo il paper di FrancioliJAMA, 1992……
Fino a metà degli anni 90!
4-WeekTreatment of Streptococcal Native Valve Endocarditis with High-Dose Teicoplanin
Venditti M, et al AAC, 1992
STIMA 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 +
netilmicina
48 124 (248)
Ceftriaxone 26 494
Experience with outpatient intravenousteicoplanin 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 troughserum 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 comparedwith the high hospitalization costs of inpatient treatment.
Oritavancin Phase III Clinical StudyRandomized double blind trial design with 60 day safety follow
Corey GR et al. 24th ECCMID Barcelona, Spain 10-13 May 2014. poster_113642Wilcox M et al. ICAAC 2013. Denver, Colorado. 10-13 September 2013. Poster L-202
E la dalba?
A Randomized Clinical Trial of Single-Dose Versus WeeklyDalbavancin for Treatment of ABSSSI
Dunne et al Clin Infect Dis. 2016 Mar 1; 62(5): 545–551
Concentrations of dalbavancinin sternal and femoral bones in rats
Barnea Y et al J Antimicrob Chemother 2016; 71: 460–463
Comparative efficacy of dalba vs vancoin sternal osteomyelitis in rats
Barnea Y et alJ Antimicrob Chemother 2016; 71: 460–463
P=0.35
P=0.53
Dissemination: 5% with vanco or dalba33% with saline
Dalbavancin treatment in a deep sternal wound MRSA infectionafter coronary artery bypass surgery: a case report GUZEK et al. Journal of
Cardiothoracic Surgery (2018) 13:3
DALBAVANCIN BONE CONCENTRATIONSDunne MW, et al. Antimicrob Agents Chemother.2015 Apr;59(4):1849-1855.
Concentrations of dalba in bone after a single 1000 mg infusion
Sintesi della efficacia di dalbavancina in vari modelli animali di infezione
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 R
Murillo O et al Enferm Infecc Microbiol Clin. 2017;35(Supl 1):28-32
Activity of dalba, alone and in combo with rifa, againstMRSA in a foreign-body infection model
Baldoni D et al Intern J Antimicrob Agents, 2013
Cure rate of cage associated infections at day 12
Gram-positive BSI: DalbavancinA 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: similar
Date 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%2. acute bacterial skin &
skin structure infection: 21.7% 3. bone (17.4%) & joint (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).
2. Bacteremic infections: 24.6%
Bone & Joint +/-prothesis: approx 50%
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 experienceBouza E et al Int J Antimicrob Agents. 2017.
Dalba in the treatment of different Gram-positive infections: a real-life experienceBouza E et al Int J Antimicrob Agents. 2017.
The high clinical success rate was also confirmed in patientswho received Dalbavancin as rescue therapy
(clinical success higher than 75%)
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 Dalbavancinregimen and the inpatient regimen were calculated
for all patients included in the study. The overallcost of Dalbavancin and Standard therapy was
estimated at €1,083,637 and €1,295,118, respectively. Therefore, the overall cost reductionof301Dalbavancin treatment in these 69 patientswas estimated at €211,481 or €3,064 per patient.
Dalbavancin in the treatment of different Gram-positive infections: a real-life experience
Bouza E et al Int J Antimicrob Agents. 2017.
Cost savings
Dalba for endocarditis and/or BSIs by Gram-positive cocci Hidalgo Tenorio C et al,ECCMID 2018, abt P2017
Characteristics n=63
• Average length of stay was 26 days;
• main use: early discharge (OK in 82.5%);
• Follow up OK in 53/56 pts (KO for 1 death and 2 readmissions;
Dalba for endocarditis and/or BSIs by Gram-positive cocci Hidalgo Tenorio C et al,ECCMID 2018, abt P2017
• AE: 2 drug fevers;
• average patient Hospital day reduction: 14;
• total reduction: 877 days
Conclusions
• Dalbavancin could be effective in cardiovascular infections as a sequential
therapy in stable patients. • It could allow early discharge of patients
and important pharmacoeconomic benefits.
?
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 surgeryDunne 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, respectively
Telavancin
0.06
0.06
0.06
0.03
0.12
0.03
In vitro activity of glico/lipopepdidesliterature review from Crotty MP et al J Clin Microbiol 2016
dalbavancin
0.06
0.06
0.06
0.03
0.06
0.12
0.008S. pneumoniae
Simulated mean concentration timeprofile 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 osteomyelitisJandourek A et al ECCMID 2017
Study design
Dalbavancin for the treatment of osteomyelitis
Hospital stay & antibiotic treatment lenght (mITT population) and safety
Dalbavancin for the treatment of osteomyelitisin 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 Enterococcus
Dalbavancin for the treatment of osteomyelitis in adult patients
Rappo U et al ECCMID 2018
Dalbavancin & bone infection
Conclusions• The long half life of Dalba and its bone penetration after a short
treatmentregimen allows once-weekly dosing and mantain serumconcentration above the MIC90 for most grampositive pathogensover at least 42 days.
• Good dalba bone penetration after a short dosing regimen is relevantfor osteomyelitis
• The 2 dose, once weekly regimen may offer advantages to patientsand 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 thattreatment of adult osteomyelitis with a2-dose weekly regimen of dalba has a favourable and durable clinical benefit
Concludendo…….
?
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?
