MAGNA EST VERITAS ET PRAEVALEBIT Kunsthalle

MAGNA EST VERITAS ET PRAEVALEBIT
Body of the Dead Christ in the Tomb (Hans Holbein the Younger). Basler
Kunsthalle
 Experienced R & D teams and real scientists in Europe, US starting in 1950s:
bright ideas, although classical antibacterial classes increasingly researched
 Strong R& D efforts of Japanese firms, up to the present time
 Reliance on tried & tested in vitro and in vivo assays rather than fancy
screens with little in vivo correlation
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Unsatisfactory due diligence prior to testing in human; lack of Pharma
expertise (into EU-IMI)
Problems in clinical study arrangement and analysis
THE RAPID PROFIT MOTIVE
ANTIBACTERIAL R&D IS NOT A POOR RELATIVE, AND CANNOT BE
DONE ON THE CHEAP!
MICs Macrolide S Pneumo
MICs Macrolide R Pneumo
Pneumo time-kills
R selection pneumo
MICs Macrolide S GAS
MICs Macrolide R GAS
MICs H.influenzae
Free AUC/MIC
Toxicity
Telithromycin*
S
S
cidal; ermB static
+
S
ermB R
R (efflux)
>25 except ermB
+
Solithromycin
S
S
cidal; ermB static
+/S
0.03-1 (ermB)
R (efflux?)
1, but ↑ELF
-?
Pankuch et al (1998), AAC, 42: 624; Ibid., 42:, 3032; Nagai et al. (2002), AAC 46: 546; Jacobs et al (2003), JAC, 52: 809;
Azoulay-Dupuis et al (2006), AAC, 50: 3033; Mcghee et al (2010) AAC, 54: 230; Farrell et al (2010) IJAA, 35: 537.
Future of ketolides:
Paediatric indication for MDR pneumococcal otitis media; β-lactam allergy
WE BADLY NEED NEW PAEDIATRIC ANTIBACTERIALS (e.g. ketolides)
against R vaccine-selected serotypes
Tigecycline
Bacteriostatic
? Enterics and non-fermenters? Breakpoints?
GI toxicity at required dosages
Eravacycline (TP 434)
Spectrum and mechanism similar to tigecycline
Step-down IV to oral
Not active against P.aeruginosa (?efflux)
? Toxicity different from tigecycline?
A(O)madacycline
Rejected by three companies
Fyfe et al., ECCMID 2011; P-1149; Sutcliffe et al, ICAAC 2010, F1-2158
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Once daily, step-down IV to oral
Broader spectrum: linezolid-R staph, Haemophilus (Both NO)
↓toxicity (antimitochondrial bone marrow, neuropathy, etc.)
Renslo (2010) Exp. Rev. Anti Infect. Ther. 8: 565
HOWEVER: Compounds 33-35 had NOAEL values 10-fold > than
linezolid in real (AUC) terms., and seemed to almost completely
divorce antibacterial activity from mitochondrial toxicity. Compound
33 progressed into a Phase I trial but went no further. No further
information available.
Radezolid: Phase 2, 450 mg QD and BID; PK/PD, toxicity problems
 MICs for MRSA 0.25-0.5 mg/L
 Once daily 200 mg for six days for cSSSI, oral step-down
 Free AUC/MIC with an MIC of 0.25 mg/L = 22.4, at 200 mg (static); o.5 mg/L = 10
 Free AUC/MIC is c.20 for an organism with MIC 0.5 mg/L only after 400 mg (better)
 BUT: ↑ AE AT 300 AND 400 MG [Bien et al (2009), ECCMID P1089]
 At current doses linezolid provides a free AUC of 140, with AUC/MIC ratio 35-70.
 Free AUC/MIC NOT effective against linezolid-resistant strains
 QIDP from FDA
Yum et al (2010), AAC, 54: 5381; Capparelli et al (2012), ID Week, #1460; Bien et al (2008), ICAAC, F12063; Prokocimer et al (2008) ICAAC, F1-2064; Renslo (2010) Ext Op. Anti-infect. Ther. 8: 565;
Alexander et al (2013), AAC (In press); Betriu et al (2010), 54: 2212; Schaadt et al (2009), AAC, 53: 3236
NAB 739:
 MICs a few dilutions higher than those of polymyxin B
 Promising infection models
 Decreased toxicity
Neopolymyxin congeners
CAN NEWER AGENTS WITH A POLYMYXIN-LIKE ACTIVITY BE
SYNTHESIZED?
Vaara et al (2008), AAC, 52: 3229; Ali et al (2009), JAC, 64¨1067; Mingeot-Leclercq et al
(2012) Peptides, 35: 248; Vaara et al (2013), IJAA 41: 292; Vaara (2013) JAC, In press.
TD-1792:
 Heterodimer of vancomycin + ceftazidime-like β-lactam
 Bactericidal against MRSA, hVISA, VISA (c. 0.03 mg/L)
 No detectable resistance selection
 MIC several dilutions lower than telavancin for all
resistotypes
Blais et al (2012), AAC, 56: 1584; Appelbaum et al (unpublished)
WHY NOT DEVELOPED?
DIFFICULT PRECEDENT WITH TELAVANCIN?
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Excellent , rapidly cidal antistaphylococcal activity in soft tissue and
blood
Approximately 50% of VISA non-S at >1 mg/L
Selects staph R in vitro, in tissue when given for ↑ time
Cross- R with vancomycin, ? dalbavancin, oritavancin
In vitro synergy with gentamicin and plazomicin (plazomicin not
active against 16S rRNA methylases). NOT with rifampin
CAN THE BREAKPOINT BE RAISED BY DOSE ESCALATION?
Appelbaum (2007 and unpublished)), IJAA: 30: 398; Julian et al (2007), AAC, 51: 3445;
Credito et al (2007), AAC: 51: 1504; Lin et al (2010), AAC, 54: 2258; Bayer et al Ann. NY
Acad. Sci. (2013), 1277: 139.
 Good MRSA activity, including VISA, at <2 mg/L
 Very little R selection in vitro compared with dapto
 Excellent synergy with aminoglycosides
 ? Alternative therapy for pneumonia and
bacteremia/endocarditis
 ? Long-term safety issues
Kosowska-Shick et al (2009) AAC, 53: 4217; Lin et al (2010) AAC, 54: 2201.
DALBAVANCIN, ORITAVANCIN ?
Broad spectrum of activity
BUT: static/barely cidal against Gram Clinical R selection that probably could have been foretold by properly performed and interpreted in
vitro studies (unpublished)
R probably due to up regulation of efflux pump(s) and rapid selection of l-tRNA synthetase
mutations: R mutants were considered ‘unfit.’
Appelbaum (2012) JAC 67, 2062; Tomayko (2012 Gordon Conference)
THE PERFECT EXAMPLE OF LACK OF DUE DILIGENCE AND INSIGHT:
WHAT IS THE MEANING OF ‘FITNESS’ IN R MUTANTS?
THIS IS PROBABLY A PROPERTY OF THIS STRUCTURAL CLASS, BUT NOT
OF ALL BORON COMPOUNDS
 Broader spectrum than ciprofloxacin against
current MDR Gram-negatives
 Good antistaphylococcal activity against
MRSA/QRSA
 ? Improved activity against anaerobes
 ?Improved activity against QRSP
Delafloxacin, KPI-10 (same source, similar structure)
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Good all-round Gram +, – spectrum, anaerobes (but NOT against MDR
Gram-negatives)
Delafloxacin: free AUC/MIC too low at suggested dosage to treat QRSA
? GOOD AGAINST QRSP
Harnett et al (2004), JAC, 53: 783; Burak et al. (2009), ICAAC, A1-1941; Bhavani et al (2009) ICAAC, A1-1942;
Hoover et al (2012) ICAAC, A-1957; Deane et al (2012 ICAAC, F-2046, F-2047; Flamm et al (2012) ICAAC F-2051
Finafloxacin:
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Activity under acidic conditions
Helicobacter pylori, UTI, topical otitis media
Stubbings et al (2011) AAC, 55: 4394
CAN BROAD SPECTRUM NON-TOXIC QUINOLONES
BE SYNTHESIZED?
 Active against MRSA/QRSA
 Free AUC/MIC against QRSA >25 (the only
quinolone under development with this property)
 Phase II studies completed in India and promising
lack of toxicity. Oral prodrug WCK 2349 with good
tolerability and bio
 Phase 1 (US) and 2 (India) recently completed
 Lower activity against QR Gram-, anaerobes
Jacobs et al (2004) AAC: 48: 3338; Peric et al (2004) AAC 48: 3188; Patel et al (2004)
48: 4754
 Many tested, none have progressed
 EV-035 and pyrrolamide families:
More active against Gram-positive
than –negative
Heim et al (2012), ICAAC, F-2030; Nickelsen et al (2013), IJAA, 41: 28
Systemic Pleuromutilin:
BC 3781
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Oral and IV under development: SSSI and cRTI
Anti-Gram + and atypicals, but MIC90 2 mg/L against
H.influenzae?
Sader et al (2012) JAC, 67: 1170.
RX-04
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Pyrrolocytosines, broad spectrum cidal activity (anti-ribosomal)
MICs <8 mg/L against most MDR P.aeruginosa, A.baumannii
Active at MICs <2 mg/L against MDR Enterobacteriaceae
MRSA: 0.5-2 mg/L
Devito et al (2011), ICAAC, F1-1850; Jacobs et al (2012) ICAAC, F-2059; Remy et Al (2012),
ICAAC, F-1521
Probably not, on their own, against the MBLs such as NDM-1
Doripenem : no FDA approval in paediatrics or for CNS infections
Current combinations under development add KPC but do not improve OMP-R
Imipenem/cilastatin + MK-7655 (structural analogue of avibactam):
Active primarily against class A including KPC, secondarily against AmpC
?Activity against class D
No activity against MBLs
Livermore et al (2012) ICAAC, E-192
Biapenem (RPX2003) + RPX 7009 (Carbavance)
Biapenem alone is effective against ESBL (<meropenem)
Combination active against KPC and other Class As
Combination not active against class B, D carbapenemases, but less
consistently R to biapenem
Nakamura & Komatsu (2005), 58: 1-10; King et al (2012), ICAAC, F-850; Livermore et al (2012), ICAAC, F855.
Ceftobiprole
AN OBJECT LESSON ON HOW TO MISMANAGE AND POTENTIALLY
BURY A GOOD ANTIBACTERIAL
Ceftaroline
First FDA-approved anti-MRSA cephalosporin, approved for cSSSI and CAP.
Active (alone) against most MRSA, pneumococci, H.influenzae
CLSI/EUCAST staph breakpoint 1 mg/L (phase 3 study 600 mg tds in progress)
EUCAST H.influenzae breakpoint: 0.03 mg/L
Avibactam does not significantly improve activity against β-lac + H.influenzae
↓Anti-anaerobic activity, even with avibactam
? Indications for combination: CRTI caused by ESBL enterics
Saravolatz et al (2010), AAC, 54: 3027; Jones et al (2011) JAC, SUPPL. 3, iii69; Appelbaum et al
(unpublished); Sader et al (2011) IDSA, 587.
Ceftazidime + avibactam (cefepime might have been
preferable because of broader Gram + spectrum)
Active against ESBLs, KPCs, AmpC
What is CAZ 104 activity against KPC clone ST 258?
Active against non-MBL resistant P.aeruginosa
? Activity against OXAs
Not active against MBLs
↓Anti-anaerobic activity
Livermore et al (2011) AAC, 55: 390; Levasseur et al (2012) AAC, 56: 1606; Bell et al (2011), ICAAC C21251; Dubreuil et al (2009), E-188; Lucast et al (2011 ECCMID, P1532.
Possibly cephalosporin with best anti-pseudomonal
activity
Active against all R P.aeruginosa resistotypes except
for MBLs
Some activity against AmpC, not comparable to
cefepime
Inactive against KPC, OXA, MBL producers
↓Anti-anaerobic activity
Addition of tazobactam (CXA 201) adds little
significant synergy
Juan et al (2010) AAC, 54: 846; Bulik et al (2010) AAC, 54: 557; Sader et L (2011) AAC 55:
2390
Aztreonam + avibactam
 against MBL Enterobacteriaceae, but probably not MBL
Pseudomonas nor class D OXAs.
Livermore et al (2011), 55: 390
BAL 30072 (siderophore)
 Not active against strains producing large amounts of AmpC
or certain ESBLs
 Combination + carbapenem enhances activity
 Very active against Burkholderia spp (orphan indication for
melioidosis)
 Active against only some MDR P.aeruginosa, Acinetobacter
 Rapid endogenous R development for a β-lactam
Vaara et al (2010) Curr Op Microbiol 13: 574; Page et al (2010) AAC, 54: 2291; Higgins et al
(2012) JAC, 67: 1167.
Unique mechanism of activity: novel
concept
Broad activity against Gram-negatives
including Pseudomonas and Acinetobacter
Flexibility
 AGENTS AGAINST MDR GRAM-NEGATIVE
ENTERICS AND NON-FERMENTERS (>1)
 CIDAL AGENTS AGAINST SYSTEMIC
MRSA/VISA
 ORAL STAPH SUPPRESSION THERAPY
 PAEDIATRICS!!! NEED NEW ANTIBACTERIAL
AGENTS (+ VACCINES) IN OTITIS MEDIA,
ETC.
 GONORRHOEA