Body of the Dead Christ in the Tomb (Hans Holbein the Younger). Basler

Kunsthalle

MAGNA EST VERITAS ET PRAEVALEBIT

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

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!

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

Telithromycin* Solithromycin

MICs Macrolide S Pneumo S S

MICs Macrolide R Pneumo S S

Pneumo time-kills cidal; ermB static cidal; ermB static

R selection pneumo + +/-

MICs Macrolide S GAS S S

MICs Macrolide R GAS ermB R 0.03-1 (ermB)

MICs H.influenzae R (efflux) R (efflux?)

Free AUC/MIC >25 except ermB 1, but ↑ELF

Toxicity + -? 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.

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

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, F1-2063; 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?

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) 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: 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 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

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, F-855.

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 C2-1251; 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