Post on 07-Feb-2021
4/6/2015
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ANTIBACTERIALS:
Recent Releases
&
Pipeline Promises
Idaho Society of Health-Systems Pharmacists
Gerry Barber, RPh, MPH
Department of Pharmacy Services
University of Colorado Hospital April 11, 2015
Disclosures
Commercial Grants:• Cubist C. difficile in solid organ Tx recipients
• Merck ESBL research (ertapenem) among pts with UTI
Speaker bureau: Cubist
4/6/2015
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Assessment Questions
1. A new ABX attains QIDP status giving it 10 years of
market exclusivity
True False
2. Both dalbavancin & oritavancin have T1/2 > 200 hrs
True False
3. Surotomycin is an orally-active cyclic lipopeptide
in Phase III studies for ABSSSI
True False
Probability of Market Entry,Costs
Adams CP, et. al. Health Affairs 2006; 25:420-428.
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New Drug Development
� Enormous Costs to Reach Approval
� $802 million per new entity1
� Others: $500 million + 2
� Vary by therapy (ie, RA vs. GU)
� Vary by regulatory policy
� Continuing Trend: for Chronic Diseases
� 70’s – 80’s: not a single new antibiotic class
� Resistant infxns, iatrogenic issues: new ABX
� 2012: GAIN Act – FDA QIDP designation 3
� Seems to bring ABX to market quicker, but…
� Are they innovative ABX???
1. DiMasi JA, et al. J Health Economics 2003;22:151-185.
2. Adams CP, et al. Health Affairs 2006; 25:420-428.
3. Keener AB. Nature 2014;20690-691.
Ceftolozane/tazobactam (ZerbaxaTM)
Merck
Indications:
� Complicated urinary tract infxns (cUTI),
including pyelonephritis
� Complicated intrabdominal infxns (cIAI), with
metronidazole
� Adult patients, designated susceptible
organisms
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Ceftolozane/tazobactam
Pharmacology / MOA:
� Inhibitor of cell wall synthesis
� Ceftolozane: anti-pseudomonal cephalosporin
� Tazobactam:
� Inhibits some beta-lactamases
� Little relevant anti-bacterial activity
Ceftolozane/tazobactam
Injectable, fixed dose combination product:
� Cephalosporin - ceftolozane SO4 1g
� β-lactamase inhibitor - tazobactam Na 0.5g
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Ceftolozane/tazobactam (Zerbaxa)
Phase 3, (n=806)
� Outcomes:
� Clinical Response: ZERB+METR non-inferior to Meropenem
� 83% vs. 87.3% ZERB+METR vs. Meropenem, respectively
� Common ADR > 3% : N/V/D, constipation, HA , pyrexia
Comp. IAI CR: Resolution S&S of IAI at TOC visit (24-32 days p 1st dose)
2014 Cubist. Lexington, MA
ZERB 1.5g + METR 500mg vs. Meropenem 1g: ivpb q8h x 4-14d
Ceftolozane/Tazobactam “Take homes”
� C/T 1.5g ivpb q8h (1-hr infusion for compl. IAI, UTI)
� Renal dose adjustments needed
� Anti-pseudomonal β-lactam , selective activity against g(-),
g(+) pathogens, ESBLs, and B. fragilis
� Not active against KPC & metallo beta-lactamases
� Caution in pcn or β-lactam allergy
� Pregnancy Category B
� Nearing end of Phase 3 VAP trials
Agent Dose Daily Cost
Ceftol/Tazo 1.5g q8h $251.00
Pip/Tazo 4.5g q8h $ 23.47
Meropenem 2g q8h $ 60.38
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Dalbavancin (DalvanceTM)
ActavisIndication:
� Treatment of ABSSSI caused by designated
susceptible gram + organisms
Pharmacology / MOA:
� 2nd gen. semisynthetic lipoglycopeptide:
- Disrupts cell membrane biosynthesis
- Anchors in lipophilic bacterial membrane, ‘ing
stability
- Bactericidal
- Long T1/2: Dosed ivpb 1g initially, then 0.5g on day 8
Dalbavancin IVPB
1g dose; then 0.5g on day 8
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Dalbavancin
Phase 3, Discover 1 & 2 Trials (n=1312)
� Outcomes:� Early CR: Dabavancin non-inferior to comparator
� 79.7% vs. 79.8% pooled analysis, DALB vs. comparator, respectively
� ADR > 2% : Nausea, ~4%; HA, ~ 3.5% both arms
� Serious TEAE: 1 anaphylaxis (dalbavancin)
Discover – 1 Early CR: no increase in baseline lesion at 48-72h; temp < 37.60 C among ITT subjects
SIRS criteria pts: 62%
Discover – 2 Early CR: same as aboveSIRS criteria pts: 43%
Boucher H, et al. NEJM. 2014;370:2169-2179.
DALB x 2 doses vs. fd Vanco > 3d, +/- LZD 600mg po q12h x total 10-14 d
Dalbavancin
Jones RN, et al. Diagn Microbiol Infect Dis. 2013:75;304-307
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Dalbavancin
STPN isolates US 2002 – 2010 (n=9503)
Jones RN, SENTRY database / Durata, Chicago, IL
Dalbavancin “Take homes”
� Dalbavancin 1g ivpb; day 8: 0.5g ivpb (ABSSSI)
� Renal: CrCl < 30 mL/min = 750mg x 1; 375mg day 8
� HD: no dose change; w/o regard to timing of HD
� Hepatic: mild – mod dysfxn: AUC ~30% (caution)
� Time, conc. dependent cidal activity
� IVPB lipoglycopeptide, g (+) activity
� MRSA, MSSA
� S. pyogenes, agalactiae, anginosus group
� Enterococcus (VSE only). Empirically: Not a good bet
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Dalbavancin “Take homes” (cont’d)
� Synergy w/ other ABX: not shown
� DDI, DLs: not reported; Preg Cat C
� Caution: pts w/ hx ADR, intolerance to glycopeptides
� Outpatient treatment of ABSSSIs
� Alternative option to vancomycin for ABSSSIs
� Allergy to vancomycin or alternative agents
� Limited resource patients ?
� Ongoing studies: Single 1.5g dose & CAP
Oritavancin (OrabactivTM)
The Medicines Co.
Indication:
� Treatment of ABSSSI caused by designated susceptible gram + organisms
Pharmacology / MOA:
� 2nd gen. semisynthetic lipoglycopeptide:
- Disrupts cell membrane biosynthesis
- Inhibits polymerization & transpeptidation of cell
wall biosynthesis
- Bactericidal
- Long T1/2 (245 h): Dosed ivpb 1200mg x single dose
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Comparative Properties
Dosing IVPB 1g once; 0.5g day 8 1200mg once
Diluent
Rate
D5W 100 - 500 mL
30 minutes
D5W 1000 mL
3 hours
T1/2 ~204 hours ~245 hours
Vd
Protein Binding
~9 L
93%
~87 L
85%
Renal Excretion ~33% ~5% (< 1% feces)
Cost ~ $4,500 ~ $2,400
Property Dalbavancin Oritavancin
Zhanel G 2012 CID 54 (S3): S214-S219.
Belley 2010 AAC 54:5369-5371.
2014 Durata, Chicago, IL
2014 The Medicines Company, Parsippany, NJ
.
Oritavancin
Phase 3, Solo 1 & 2 Trials (n=1963)
� Outcomes:� Early CE: ORIT non-inferior to vancomycin
� 82.3% vs. 78.9% and 80.1% vs. 82.9%, both ORIT vs. Vanc, respectively
� ADR > 2% : N/V/D, HA, dizziness , LFTs, ~ ORIT vs. Vanc
� Tachycardia & infusion site phleb, each > 3% & twice incidence w Vanc
Solo – 1 & 2 Early CE: no increase in baseline lesion at 48-72h; temp < 37.60 C among ITT subjects; >20%
decrease in baseline lesion at 48-72h . Also,
investigator-assessed PTE (7-14d p End of Tx)
Corey GR, et al. NEJM. 2014;370:2180-2190
Corey GR, et al. CID. 2015;60:254-262.
ORIT 1200mg ivpb once vs. Vanco 1g or 15mg/kg ivpb q12h x 7-10d
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Enterocococcal BSI Isolates: Oritavancin & other g(+) Agent Activity
Arias CA, et al: CID. 2012;54 (Suppl 3);S233-S238.
n = 884 isolates. Subset of SENTRY 2010, US Hospitals
Oritavancin “Take homes”
� Oritavancin 1200mg ivpb over 3 hours once (ABSSSI)
� No renal or hepatic dose adjustments
� Non-dialyzable; no dosing recs for severe renal or hepatic
dysfxn
� Conc. dependent bactericidal activity
� Synergy: oxacillin
� IVPB lipoglycopeptide, g (+) activity
� MRSA, MSSA
� S. pyogenes, agalactiae, dysagalactiae, anginosus group
� Enterococcus faecalis (VSE only)
� In-vitro: seemingly good VSE & VRE activity
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Oritavancin “Take homes” (cont’d)
� Contraindication
� Heparin x 48h post- ORIT dose as PTT falsely elevated
� Inhibits CYP450
� AUC of warfarin (~31%)
� Drug-Lab: artificially prolong PT/INR up to 24h
� Pregnancy Category C
� Caution: pts w/ hx ADR, intolerance to glycopeptides
� Elderly (?) small sample subjects > 65 yo
� Tachycardia
� Infusion-related events – slow rate, or interrupt
� Ongoing studies: -------
Tedizolid (SivextroTM)
Trius Merck
Indication:
� Treatment of ABSSSI caused by designated
susceptible gram + organisms
Pharmacology / MOA:
� Oxazolidinone:
- Prodrug tedizolid PO4 tedizolid (active moiety)
- Binds to 50S ribosomal subunit, inhibits protein
synthesis
- Bacteriostatic
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Oxazolidinone structures
Rybak JM, et al. Pharmacotherapy. 2014:34;1199.
Comparative Properties
Dosing IV or PO 200mg daily x 6 d 600mg q12h x 10 d
T1/2 9-11 hours 4-5 hours
Bioavailability >90% >90%
Vd
Protein Binding
~80 L
87%
~50 L
31%
ELF / AM to plasma ~40 / 20 fold ~4 / 0.13 fold
Renal Excretion ~18% ~30%
Price ($ IV / PO) $235 / $235 $140 / $260*
Property Tedizolid Linezolid
Bien P, et al. ICAAC 2010.
Prokocimer P, et al. AAC 2011;55:583-592.
Swaney SM, et al. AAC 1998;42:3251-3255.
Conte Jr JE, et al. AAC. 2002;46;1475-1480.
Housman ST, et al. AAC. 2012;56:2627-2634.
* Generic 2015
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Comparative Properties
Dosing IV or PO 200mg daily x 6 d 600mg q12h x 10 d
T1/2 9-11 hours 4-5 hours
Bioavailability >90% >90%
Vd
Protein Binding
~80 L
87%
~50 L
31%
ELF / AM to plasma ~40 / 20 fold ~4 / 0.13 fold
Renal Excretion ~18% ~30%
Price ($ IV / PO) $235 / $235 $140 / $260*
Property Tedizolid Linezolid
Bien P, et al. ICAAC 2010.
Prokocimer P, et al. AAC 2011;55:583-592.
Swaney SM, et al. AAC 1998;42:3251-3255.
Conte Jr JE, et al. AAC. 2002;46;1475-1480.
Housman ST, et al. AAC. 2012;56:2627-2634.
* Generic 2015
Tedizolid
Phase 3, Establish 1 & 2 Trials (n=1415)
� Outcomes:� Early CR: TDZ non-inferior to LZD
� 79.5% vs. 79.4% and 85% vs. 83%, both TDZ vs. LZD, respectively
� ADR > 2% : N/V/D, HA, dizziness : same TDZ vs. LZD
� PLT < 112 x 103
/mm3
: TZD 2.3% vs. LZD 4.9%
Establish – 1 Early CR: no increase in baseline lesion at 48-72h; temp < 37.60 C among ITT subjects
Establish – 2 Early CR: >20% decrease in baseline lesion at 48-72h among ITT subjects
Prokocimer P, et al. JAMA. 2013;309:559-569.
Moran GJ, et al. Lancet ID. 2014;14:696-705.
TDZ 200mg q day x 6 d vs. LZD 600mg ivpb/po q12h x 10d
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Tedizolid “Take homes”
� Tedizolid 200 mg daily, ivpb/po x 6 d (ABSSSI)
� No renal or hepatic dosing adjustments
� Oxazolidinone, g (+) activity
� MRSA, MSSA
� S. pyogenes, agalactiae, anginosus group
� E. faecalis
� Not a good bet: UTI
� Synergy w/ other ABX: not shown
� Serotonergic DIs, myelosuppression warnings presently
absent… Caution warranted
� Pulm penetration, STPN activity Rx off-label lung infxns
On the horizon…
� Cadazolid
� Surotomycin
� Plazomicin
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Cadazolid (ACT 179811)Actelion
� Novel oral-active chimeric quinolonyl-
oxazolidinone
� Potent inhibitor of protein synthesis
� Weakly inhibits DNA replication
� Target: C. difficile infection
� Feb 2014: QIDP status
� Q4 2013: 2 x Phase III studies “IMPACT”
� To accrue ~ 1300 subjects
� CDZ 250mg po BID vs. Vanco 125mg po QID
Cadazolid
� Phase II dose-escalation trials (Sweden)
� 250mg, 500mg, 1g po BID vs. Vanco 125mg po QID
� Clin cure rates, all doses = non-inferiority, similar TEAE
� Sust. clin cure 4 weeks p last dose favor CDZ 250mg (as effective as 1g dosing)
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Cadazolid
Test of Resistance Development
Locher HH, et al. AAC. 2014;58:892-900.
Surotomycin (CBT 813315)Merck
Pharmacology / MOA
� Oral cyclic lipopeptide
� Disrupts membrane potential; binds / depolarizes
Mascio CT, et al. AAC. 2012;56:5023-5030.
Daptomycin
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SurotomycinActivity Spectrum� C. difficile (n=556), other intestinal anaerobes (n=445), Enterobacteriaceae (n=56)
� Resistance is rare and likely of low clinical significance given high fecal concs.
Citron DM, et al. AAC.2012;56:1613-1615.
Surotomycin
� QIDP status, currently Phase III
� Phase II dose-finding trial, CDAD:
Drug/Dose (PO) Recurrence Global Cure
SUR 125mg BID 17/61 (27.9%) 44/66 (66.7%)
SUR 250mg BID 10/58 (17.2%) 47/67 (70.1%)
VAN 125mg QID 21/59 (35.9%) 37/56 (56.1%)
GC = clinical cure & no recurrence 4 weeks p last dose
Patino H, et al. 51st ICAAC 2011: poster K205a
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Plazomicin (ACHN 490)
Achaogen� Semisynthetic aminoglycoside “neoglycoside”
� Q1 2014: Phase III superiority trial for CRE
� Phase II PLZ 15mg/kg qd vs LEVO 750mg IV qd
� cUTI + pyelonephritis: Similar MBE & TOC rates
� In vitro ACBA & PSAE isolates, 16 NYC hospitals
� Better w AGME isolates than permeability/efflux
� Synergy: β-lactams
� BARDA funding $100+ million
� Biowarfare, Y. pestis, F. tularensisRiddle V, et al. 52nd ICAAC 2012.
Landman D, et al. JAC. 2010;doi:10.1093/jac/dkq278
Plazomicin
� Pharmacokinetics (15 mg/kg dosing)
� Linear
� Protein binding ~16%
� Cmin ~ 0.4 (24h, mcg/mL)
� Cmax ~144 (24h, mcg/mL)
� AUC0-24 ~230 (h . mg/L)
� Half-life ~ 3.5 hours
� Renal Elim ~90%
� Urine collection ~805 mg/L (0-4 h)
Cass RT, et al. Antimicrob Agents Chemother. 2011;55:5784-5880.
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So, Which are Keepers?
� Consider all PK/PD characteristics & clinical scenario
� Likely broader off-label indications
� Application / receipt of new indications
� Outcomes
� ADRs
� Drug interactions
� User friendliness
� Patent application strategies
Time Will Tell…
ABT-773 / cethromycin
(originally Abbott, Taisho, then
Advanced Life Sciences)
III (moderate – severe
community-acquired
bacterial pneumonia)
Ketolide. Reversibly binds
to the 50S subunit of the
bacterial ribosome, blocking
protein synthesis, preventing
bacterial growth and
reproduction. Binds at 2
sites of bacterial ribosome
compared with current
macrolide agents binding at
1 site. (Note: solithromycin,
a fluoroketolide, binds at 3
sites and has iv and po
formulations).
Potent pneumococcal and
atypical respiratory organism
activity, including macrolide-
resistant strains. Oral
formulation; wide distribution
into pulmonary
compartments including
epithelial lining fluid. Like
solithromycin, additional side
chain structures /
modifications appear to
ameliorate CNS adverse
effects of telithromycin (lacks
telithromycin’s pyridine-
imidazole side chain) and
necessitate additional
bacteria mutations to effect
resistance. Has FDA
orphan-drug-status for
prophylaxis in patients
exposed to inhalational B.
anthracis (anthrax),
tularemia and plague.
Agent Number Study Phase MOA Comments Chemical Name(Company)
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ACHN-975 (Achaogen) I (safety, dose-
escalation trial)
Novel, LpxC-
inhibitor. LpxC-1 is
an inhibitor of LpxC,
a deacetylase
enzyme present in
many Gram-negative
bacteria [73].
Subcutaneous
injection in murine
models infected with
MDR-Acinetobacter
baumannii do not
actively kill or stunt
bacterial growth, but
stunt endotoxin
production and the
subsequent ability of
the bacteria to
activate the sepsis
cascade.
Development to
target MDRO-gram-
negatives including
MDR-Pseudomonas
aeruginosa.
Agent Number Study Phase MOA CommentsChemical Name(Company)
BC-3881 (Nabriva Therapeutics) II (Acute Bacterial Skin
and Skin Structure
Infections)
Novel pleuromutilin
antimicrobial; inhibits bacterial
protein synthesis by interaction
with 23S rRNA of the 50S
bacterial ribosome subunit.
Potent in vitro activity against
common Gram-positive skin
organisms including S. aureus
(MSSA and MRSA),
coagulase-negative
Staphylococcus spp.
Streptococcus agalactiae, and
S. pyogenes. Also exhibits in
vitro activity against a broad
spectrum of Gram-positive and
gram-negative community
respiratory pathogens including
S. pneumoniae, including
Moraxella catarrhalis and
Haemophilis influenza as well
as atypical bacteria, Legionella
pneumophila, Chlamydia
pneumoniae, and Mycoplasma
pneumonia
Intravenous formulation dosed
q12h in first human ABSSSI
trial (duration 5 – 14 days).
Previously utilized in veterinary
medicine or topical use in
humans (retapamulin, Altargo®,
Altabax® Glaxo-Smith Kline)
due to toxicity. In ABSSSI
demonstrated comparable
clinical success to vancomycin.
Relatively well-tolerated among
141 subjects, most frequent
AEs were headache, nausea,
and infusion site phlebitis.
Expected to move to Phase III
trials.
Agent Number Study Phase MOA CommentsChemical Name(Company)