Francesco Menichetti (Pisa, Italy)

Choosing antibiotics in difficult to treat staphylococcal infections

New anti gram-positives antibiotics

ABSSSI CAP HAP VAP note

CeftarolineZinforo

Astra Zeneca X X No VAP600 mg bid

CeftobiproleMabelio

Basilea X X No VAP500 mg bid

Telavancina *Vibativ

Astellas X X X Once-daily10 mg/KgNo IR

DalbavancinXydalba

Angelini X Once-weeklyIV 1500mg

OritavancinOrbactiv

The MedicinesCompany

X IV Single dose1200 mg

TedizolidSivextro

MSD X 200 mg IV/OSX 6 days

* When alternative treatment is not suitable

Review of new antibiotics

• Drug profile

• Personal experience

• Place in therapy today & tomorrow

5th Generation Cephalosporins

Ceftobiprole

Broad-spectrum cephalosporin

Enhanced gram-positive spectrum

including MRSA, VISA, and EF

CAP, HAP

Bactericidal

IV with q8h – q12h dosing

t1/2 = 3 – 4 h

Elimination: renal

MIC range 0.5 – 2 mg/L

500 mg TID

Ceftaroline

Broad-spectrum cephalosporin

Enhanced gram-positive spectrum, including MRSA, VISA, and EF

CAP, ABSSSI

Bactericidal

IV with q8h – q12h dosing

t1/2 = 2 – 3 h

Elimination: renal

MIC range 0.5 – 2 mg/L

600 mg BID

Case 1: ceftaroline

• Male, 73 years-old

• HIV infection (2004), on Antiretroviral Therapy

• COPD (heavy smoker)

• Admitted for bilateral pneumonia

Chest X-Ray

Lung CT-scan

MRSA bilateral pneumonia

• MRSA isolated from sputum & BAL

• MDR strain: Fluoroquinolone R, Gentamicin-R, Cotrimoxazole-R; susceptible to glycopeptideantibiotics, doxicicline, tygecicline, rifampin

• Ceftaroline MIC: 1 mg/ml (E-test)

MRSA bilateral pneumonia

• Ceftaroline 600 mg bid x 14 days,

• Favorable response

• C. difficile relapse: fidaxomicin

• Pathogen-directed therapy of CAP

Case 2: ceftobiprole

• Male, 93-years-old

• E. faecalis aortic valve endocarditis

• Spondylodiscitis L1/L2

• Treated with ampi/sulbactam plus daptomycin

• Bilateral nosocomial pneumonia

• No sputum, no BAL

• Urinary antigens (SP, LP): negatives

Chest X-Ray

Lung CT-scan

CT-Pet

Case 2

• Ceftobiprole 500 mg tid x 21 days

• Patient improved, no toxicity

• Ceftobiprole combined with daptomycin wasthen continued for E. faecalis endocarditis

• Empiric therapy for nosocomial pneumonia

Case 3: ceftobiprole

• Male, 62 years-old

• Arterial hypertension, BPH

• Post surgical (removal of the nail) left foot ABSSSI

• Polimicrobial (MRSA+P.aeruginosa)

• MIC: MRSA 0.75 mg/l; P. aeruginosa: 2 mg/l

Case 3

• Previous antibiotic therapy

• Ceftobiprole 500 mg tid, 14 days

• No side effects

• Improved

Ceftobiprole monotherapy for nosocomial polimicrobial infection

(Off-label)

Ceftaroline/Ceftobiprole: overall personal impression

• Cephalosporins with anti-MRSA activity

• Ceftobiprole: activity against some gram-neg. rods(i.e.: P.aeruginosa)

• PK/PD, efficacy and safety of the class

• Good choice for CAP, HAP, ABSSSI with respect to combination antibiotic therapy

• Potentially useful, alone or in combo, for othersevere infections

Ceftaroline/Ceftobiprole: place in therapy today

Pneumonia

• CAP requiring hospitalization

• HAP (not VAP) ceftobiprole

ABSSSI

• ceftaroline

• Severe Infections (data required !!) due to MRSA, MSSA, (polimicrobial, ceftobiprole)

• Potentially useful for MRSA endocarditis, meningitis, bone infection, etc.

• Empiric monotherapy for pts with sepsis or febrileneutropenia (risk factors for MRSA)

• Not (alone) for ESBL-producers or carbapenemasegram-negative bugs

Ceftaroline/Ceftobiprole: place in therapy tomorrow

Why I consider/decide touse ceftaroline/ceftobiprole

• Monotherapy (in place of combo) for registeredindications (hospitalized CAP, HAP, ABSSI) especially(but not exclusively) for pts with MRSA risk factors

• Empiric, broad-spectrum, antibiotic therapy in ptswith sepsis syndrome (monotherapy or combo according to local epidemiology)

• Selected severe infections caused by susceptiblepathogens when a betalactam may be the preferredchoice

POTENTIAL COMPETITORS: LINEZOLID, DAPTOMYCIN,

TEICOPLANIN, VANCOMYCIN

Dalbavancin: a long-acting anti-gram-positive antibiotic for the treatment

of ABSSSI (and other severe infections)

Dalbavancin (Angelini)

• Activity vs most G+

• bactericidal

• Good PK profile (high concentrations, long half-life, low potential for interactions)

– 63% in bone similar to linezolid (60%)

• Good safety proflie

FDA approves Dalvance to treat skin infections QIDP; May 23, 2014

Comparative Activity vsStaphylococci

MIC90 (mg/L)

2221Vancomycin

4441Teicoplanin

0.120.060.060.06Dalbavancin

(1129)(353)(1119)(2834)(N)

Antibiotic

MR CoNSMS CoNSMRSAMSSAOrganism

Jones. ICAAC 2004. Abstract E-2009.

Personal experience

• Recurrent cellulitis (strepto, staphylo) in pts with post-surgical chronic arm lymphedema (i.e. mastectomy)

• Dalbavancin 1500 mg IV every 2/3 weeks for preventing recurrence

• A costly alternative to montly benzatin-penicillin

• Maximum-dose-limit ?

• Potential for decreasing the risk of recurrence i.e:. after 4-6 doses ??

• Prosthetic joint infections in place of chronicsuppressive oral/parenteral antibiotic therapy(linezolid, teicoplanin etc.)

• Need for defined etiology (MSSA/MRSA)

• Less pressure on gastrointestinal flora ?

• Less toxicity ?

• Chronic osteomyelitis: in place of daptomycin

Personal experience

De-escalation, step-down therapy

• Shifting from a glycopeptide/daptomycinantibiotic to complete/continue prolongedantibiotic course

• Selected case of MSSA/MRSA endocarditis, vascular prosthetic infection, vertebralosteomyelitis for an earlier discharge from hospital

Personal experience

Case report - 1

Male, 51 years-old

Vertebral osteomyelitis L1-L2, Staphylococcus hominis MS

oxacillin 4 gr/day for 7 d., then ceftriaxone 2 gr/day for 14 d.

Case report - 1

• Need to discharge from hospital

• Need to complete 6 weeks of antibiotic therapy

• No vein acces (drug abuser)

• Dalbavancin 1500 mg every 15 d., three doses

• EOT: WBC 17300 6530/mmc; PCR 9,92 0,87 mg/dl

• No more pain, no more analgesic drugs

NMR during… NMR 4 months FU

Case report- 1

Male, 77 years-old

May 2016: low-grade fever, low-back pain

Aorto-bisiliac vascular prosthesis

Mild dementia, vascular enecephalophaty

September 2016 admitted to Vascular Surgery Unit

Mild increase of inflammation index

TTE: negative

Abdominal US: negative

Spine NMR …

Case report - 2

Spine NMR

Tonelli, GiuseppeTonelli, Giuseppe

E778F3DC-2B30-424B-9A95-AF0ADA399C7BE778F3DC-2B30-424B-9A95-AF0ADA399C7B

14/08/193914/08/1939

77 YEAR77 YEAR

MM

Page: 3 of 3Page: 3 of 3

Ospedale di Livorno Ospedale di Livorno

Scintigrafia globale corporea con cellule autologhe marcateScintigrafia globale corporea con cellule autologhe marcate

TC/SPET FUSIONTC/SPET FUSION

02/09/2016 15.00.0099FA247B-E58E-49E2-B650-D16D6843191399FA247B-E58E-49E2-B650-D16D68431913

------

------

------

IM: 0IM: 0

T: 256T: 256B: 0B: 0

Z: 0,62Z: 0,62

WBC scintigraphy

Case report 2

• Blood culture: MSSA

• Paravertebral needle aspirate: MSSA

• Vascular prosthesis MSSA infection with vertebral (L3-L4, L4-L5) and paravertebral tissue involvement

• High-risk for surgery: no prosthesis removal

• Long.term suppressive antibiotic therapy• Daptomycin + ceftaroline for 25 d.• Need to discharge, need to continue ATBT• Dalbavancin 1500 mg every 15 days for three doses…….

Dalbavancin: overall personal impression

• A lipo-glycopeptide with anti-MRSA activity

• PK/PD, efficacy and safety of the class

• Good choice for single shot therapy of ABSSSI with respect to prolonged treatment

• Advantage in terms of adherence, compliance, lenght of hospital stay

• Potentially useful, alone or in combo, for othersevere infections

Dalbavancin: overall personal impression

• A lipo-glycopeptide with anti-MRSA activity

• PK/PD, efficacy and safety of the class

• Good choice for single shot therapy of ABSSSI with respect to prolonged treatment

• Advantage in terms of adherence, compliance, long of hospital stay

• Potentially useful, alone or in combo, for othersevere infections

Dalbavancin: place in therapy today

ABSSSI

• Cellulitis

• Diabetic foot infection due to staphylococci

De-escalation, step-down therapy

• Shifting from a glycopeptide/daptomycin antibiotic to complete/continue prolonged antibiotic course

Situations warranting consideration for use of dalbavancin to treat ABSSSIs

• Pts necessitating IV therapy who are not candidates for indwelling intravenous catheters or with a history of intravenous catheter-related complications;

• Pts in whom deferment of hospital admission is planned;

• Pts requiring continuation of therapy at or after hospital discharge;

• Pts who are candidates for OPAT where home health or frequent infusion center visits are not feasible;

• Pts with a history or risk for non-compliance with oral therapy.

• Severe Infections (data required !!) due to MRSA, MSSA, other gram-positives

• Potentially useful for MRSA endocarditis, bacteremia, bone infection, etc.

• Empiric combo therapy for pts with sepsis or febrileneutropenia (risk factors for MRSA/streptococci)

Dalbavancin: place in therapy tomorrow

Type of infections

• ABSSSI: one-two shots!

– Erysipelas, cellulitis, abscess, skin ulces, nosocomial cellulitis

• CBSIs: empiric and targeted use

– One shot could be enough for CNS MR

• Bone and joint infections

• Endocarditis

Why I consider/decide to use Dalbavancin

• Monotherapy, for registered indications

• Empiric, broad-spectrum, antibiotic therapy in ptswith sepsis syndrome when an anti-gram-positive agent is required (combo according to localepidemiology)

• Selected severe infections caused by susceptiblepathogens when glycopeptide antibiotic or daptomycin may be the preferred choice

Tedizolid 200 mg OD 6 days vs linezolid 600 mg BID 10 days

Prokocimer P et al. JAMA. 2013;309(6):559-569

Tedizolid is a promising antibiotic for the treatment of ABSSSIs. Once daily dosing (IV/OS) and shorter duration of therapy compared to linezolid and other traditional antibiotics are attractive.Tedizolid has several potential benefits over linezolid:• it may be more potent than linezolid; • it may be less prone to developing resistance; • less likely to cause thrombocytopenia &

neuropathy.• it may be less likely to cause serotonin syndrome;• it may be less likely to interact with MAO inhibitors; Tedizolid has one drawback: it is expensive (??)

Tedizolid vs. Linezolid

Leading determinantsof antimicrobial resistance (AMR)

Determinants/criticity * Goal Instruments

ABs selective pressure reduction Antimicrobial Stewardship

Patient-to-patienttransmission of R bugs

reduction Infection Control

Paucity of new ABs* Implement PI research

New rules, fast-track, incentives

Paucity of validatedtherapeutic strategies *

New scientificevidence

Funds fo indipendentresearch

The knowledge of new antibiotics:a clinician must !

• …..and a chance for the pts…….

• Curiosity, not indolent drug prescription !

• Evidence from registration RCT: insufficient

• Potential usefullness of personal experience

• Need to consider off-label use

• More independent clinical research