Transcript New Antimicrobials What the Internist Needs to Know

New Antimicrobials Agents
Michael J. Tan, MD, FACP, FIDSA
Associate Professor of Internal Medicine,
Northeast Ohio Medical University
Summa Health System, Akron, OH
Disclosures
 Speaker Bureaus
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Cubist
Pfizer
Actavis
The Medicines Company
Theravance
 Research
 Cubist
 Merck
Which of the following is an approved
indication for ceftolozane-tazobactam?
A. Acute bacterial skin and skin structure infection
B. Complicated intraabdominal infections
C. Bacteremia due to methicillin-resistant
Staphylococcus aureus
D. Hospital acquired pneumonia due to resistant
pseudomonas
E. All of the above
Objectives
 Review antimicrobials
 New antimicrobials
Select New Antibacterial Agents
Approved Since 1998
Antibacterial
Year
Novel
Rifapentine
1998
No
Quinupristin/dalfopristin
1999
No
Moxifloxacin
1999
No
Gatifloxacin*
1999
No
Linezolid
2000
Yes
Cefditoran pivoxil
2001
No
Ertapenem
2001
No
Gemifloxacin
2003
No
Daptomycin
2003
Yes
Telithromycin*
2004
No
Tigecycline
2005
No
Doripenem
2007
No
Telavancin
2009
No
Ceftaroline
2010
No
Fidaxomicin
2011
Yes
Tedizolid
2014
No
Dalbavancin
2014
No
Oritavancin
2014
No
Ceftolozane/Tazobactam
2014
No
2015
No
Ceftazidime/Avibactam
Spellberg CID 2004, modified
Pneumococcal conjugate vaccine
(PCV13)
 CAPiTA trial
 Looking at difference with vaccine containing serotype pneumococcal
pneumonia
• 1st episode confirmed vaccine type-CAP, 49 vs 90 (PCV13 vs. placebo)
• 1st episode confirmed NB/NI/VT-CAP, 33 vs. 60
• 1st episode of VT-IPD, 7 vs 28.
 ACIP/CDC
 Over 65: Give PCV13, follow with PPSV 23 (8wk)
 Immunecompromised: Give PCV 13, follow with PPSV23.
 Previous PPSV23: Give PCV13 (at least 1y if known), follow with PPSV
23 (at least 5 yr after previous PPSV23 and 8 wks after PCV13)
 May have decreased efficacy with inactivated influenza vaccination
 Officially: PPSV23 should follow PCV 13 by 12 mos (based on
reimbursement, immunecompromised, min 8 weeks)
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Pipeline
 Gram positive agents:
 Dalbavancin, oritavancin, tedizolid (all three approved 2014)
 CDI agents
 monoclonal antibody, non-toxigenic C diff, oxazolidinone with FQ
moiety, Lipoglycopeptide
 HCV
 Multiple agents (new approvals 2014, 2015)
 Gram negative agents:
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Ceftolozane/tazobactam (CXA 201) (Approved December 2014)
Ceftazidime/avibactam (NXL104) (Approved February 2015)
Ceftaroline-avibactam
Imipenem/MK-7655
Plazomicin (Aminoglycoside)
Ervacycline (Fluorocycline)
Brilacidin (Peptide defense protein mimetic) Novel
Telavancin (Vibativ™)
 Approved September 2009
 Lipoglycopeptide, built on vancomycin
 Cell wall and cell membrane active
 Indications:
 Complicated skin and skin structure infection due to certain Gram
positives including MRSA
 NEW 6/13: HABP/VABP caused by susceptible isolates of S aureus
(including MRSA) when alternative treatments are not suitable
 Dosing
 10mg/kg IV q24h
 Renal dosing necessary
 Dialysis dosing not yet established
AEs
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Teratogenic (but preg cat c!) in some animals
Nephrotoxicity
QTc prolongation (looks less than FQ)
Interference with INR, PT, PTT, without bleeding risk
Nausea/vomitting, taste disturbance, foamy urine
No increase in Red Man
Patients with pre-existing moderate-severe renal
impairment (Crt Cl <=50), treated for HABP/VABP had
higher mortality compared with vancomycin.
Telavancin
 Unique aspects
 Based on vancomycin, but varied mechanism
• Cell Wall and Cell membrane active
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Another option for MRSA activity, some VRE
IV only
No need to check levels
Looks to be more effective than vanc in skin, but results not
statistically significant.
 Had issues with marketing and supply line
 Now has 2 year supply available
Ceftaroline (Teflaro), Forest
Pharmaceuticals
 Cephalosporin ? Generation
 Approved 10/29/2010
 Indications:
 Acute bacterial skin and skin structure infections (ABSSSI)
• MRSA, MSSA, Strep, E coli, K pneumo, K oxy.
 Community-acquired bacterial pneumonia (CABP)
• MSSA, Pneumococcus (+/- bacteremia), H infl, K pneumo, K oxy, E
coli
 Dosing
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600mg IV q12h over 1hr Crt Cl >50
400mg IV q12h over 1hr Crt Cl >30-<=50
300mg IV q12h over 1hr Crt Cl >=15, <=30
200mg IV q12h over 1hr ESRD, including HD.
Teflaro PI
Ceftaroline
Teflaro PI
Ceftaroline
 Binds PBP2a, PBP2x
 AEs
 Well tolerated, no specific AE >5%
 Nausea, diarrhea, rash, most common
 No significant difference between ceftaroline and comparators,
Vanc/Aztreonam, Ceftriaxone.
 Pregnancy B
 Minimal interactions with P450 drugs
 Excretion: Primarily kidneys, 64% in urine unchanged.
Teflaro PI
Ceftaroline-Unique Aspects
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IV Only
No hepatic adjustment
Dose have renal dosing recommendations
Indicated for ABSSSI, CABP
In vitro activity vs. MRSA
Marginal at best for Enterococcus fecaelis, Minimal if
any for E faecium.
Ceftolozane/Tazobactam (Zerbaxa)
 Cubist, approved December 2014
 Cephalosporin + B-lactamase inhibitor
 Extended gram negative, P aeruginosa, ESBL activity
 Indications (due to susceptible bacteria):
 Complicated intraabdominal infection (CIAI) + metronidazole
• E cloacae, E coli, K pneumo, K oxytoca, P mirabilis, P aeruginosa, B
fragilis, S anginosus, S constellatus, S salivarius
 Complicated urinary tract infection
• E coli, K pneumo, P mirabilis, P aeruginosa
 Dosages
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Crt cl > 50
Crt cl 30-50
Crt cl 15-29
Crt cl <15
1.5g (1g/0.5) IV q8h
750mg (500mg/250mg) IV q8h
375mg (250mg/125mg) IV q8h
750mg (500mg/250mg) IV x1, 150mg (100/50) q8h
Ceftolozane/Tazobactam (Zerbaxa)
 Unique aspects
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IV Only
Similar AE profile to other cephalosporins
Pregnancy Cat B
*Anaerobic activity, but studies done with metro
Increased ESBL activity
No KPC or metallo beta-lactamase activity
Retains activity against most resistant Pseudmonas
 Geriatrics, renal impairment
 In cIAI vs. meropenem, cure rate lower in 65 and older
• Not seen in cUTI
 In cIAI vs. meropenem, cure rate lower in crt cl 30-50
• Similar trend seen in cUTI vs. levoflox in crt cl 30-50
Ceftazidime/avibactam (Avycaz)
 Actavis (now Allergan), approved February 2015
 Cephalosporin (3rd gen) with new B-lactamase inhibitor
 Avibactam
• Inhibits AmpC, KPC, but NOT ESBL or NDM-1
 Indications (due to susceptible bacteria), 18 and older
 Complicated intra-abdominal infection, in combination with
metronidazole (E coli, K pneumo, P mirabilis, Providencia stuartii, E
cloacae, K oxytoca, P aeruginosa)
 Complicated urinary tract infection, including pyelonephritis (E coli, K
pneumo, Citrobacter koseri, Citrobacter, freundii, Proteus spp, E
cloacae, E aerogenes, P aeruginosa
 Dosages
 2.5g (2g/0.5g) over 2h q8h
Ceftazidime/avibactam (Avycaz)
 Dosages
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>50mL/min
31-50
16-30
6-15
2.5g (2g/0.5g) over 2h q8h
1.25g (1g/0.25g) over 2h q8h
0.94g (0.75g/0.19g) over 2h q12h
0.94g (0.75g/0.19g) over 2h q24h
 Contraindications
 Hypersensitivity to ceftaz/avi, ceftaz, cephs
 Warnings
 cIAI, cure rates lower in CrtCl 30-50 vs. >50. Dose in this subgroup
was 33% less than what is recommended
ceftazidime
avibactam
Ceftazidime/avibactam (Avycaz)
 Unique aspects
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IV Only
Similar AE profile to other cephalosporins
Pregnancy Cat B
Minimal anaerobic activity, need metro
Increased KPC/CRE activity
No ESBL or metallo beta-lactamase activity
Anti-Pseudmonal
 EXPENSIVE
Tedizolid (Sivextro)
 Approval for Acute bacterial skin and skin structure
infection caused by susceptible bacteria
 Gram positive and resistant GPC, including MRSA
 2nd of the oxazolidinone class
 Once daily option
 200 mg IV/PO q24h x6 days
 HAP/VAP in development
 Cat C
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Tedizolid (Sivextro)
 Unique aspects and potential concerns
 Based on mouse studies, patients with neutropenia may have
inadequate response to therapy
 AE profile similar to linezolid
 MIGHT:
• Have less hematologic side effects (duration dependent effect seen, but
studies only for 6 days)
• Have similar peripheral and optic neuropathy issues
• Have less interaction with pressors
• Have less interaction with SSRI/MAO (SSRI/MAO patients excluded
from study)
• Not be as good as linezolid for strep (by raw numbers)
 Cost currently on par with linezolid, but oral linezolid went generic
early 2015.
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Dalbavancin (Dalvance)
 Indication for acute bacterial skin and skin structure
infections caused susceptible strains of Gram positive
microorganisms (including MRSA)
 Non-inf compared with vanc/linezolid
 Lipoglycopeptide
 Effective half life of 8.5d (204 hrs)
 1000mg IV over 30min x1 followed by 500mg IV over
30min x1 (7d later)
 Renal impairment (<30mL/min not on scheduled HD)
 750mg IV over 30 min x1 followed by 375mg IV over 30 min x1 (7d
later) No recommendations for HD patients.
 May dialyze with high permeability membranes
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Dalbavancin (Dalvance)
 Unique aspects
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LONG half-life
Two doses for ABSSSI, but will two doses get done?
How do you deal with drug reactions and drug interaction issues?
Redman can happen with rapid infusion
Category C
 Currently one indication, potential for abuse?
 Quite expensive
 At least $1500/500mg vial
 May reduce cost by reducing hospitalization
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Oritavancin (Orbactiv)
 Indication for acute bacterial skin and skin structure
infections caused susceptible strains of Gram positive
microorganisms (including MRSA)
 Non-inf compared with vancomycin
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Lipoglycopeptide
Terminal half life of 245h, clearance 0.445L/h
1200mg IV over 3h x1 (reconstitute from 400mg vials)
Renal impairment >30mL/min, no dose adjustment
required. <30mL/min no recommendation
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Oritavancin (Orbactiv)
 Unique aspects
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LONG half-life, SINGLE dose for ABSSSI
How do you deal with drug reactions and drug interaction issues?
Redman can happen with rapid infusion
More cases of osteomyelitis reported in oritavancin arm as compared
with vancomycin arm.
 Artificially prolonged aPTT for 48h and PT/INR for up to 24h.
 Category C
 Currently one indication, potential for abuse?
 Expected to be expensive
 May reduce cost by reducing hospitalization
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