Fighting P. aeruginosa (Part I)

It has never been easy to cure Pseudomonas aeruginosa infections.  Few antibiotics nowadays have reliable activity against this problem pathogen that seems to have more built-in resistance features than most other Gram-negatives.  In the past, cephalosporins, aztreonam, penems, ciprofloxacin, and aminoglycosides were useful drugs with reliably cidal activity, especially when given in combination.  However, this hardy organism has become less susceptible over time, with efflux systems and OMP changes being major defenses.[i]  Despite toxicity concerns, colistin is being used more of late given the lack of better alternatives. 

Fortunately, there are a few antipseudomonal agents in the development pipeline:

• Ceftolozane (CXA-201), an antipseudomonal cephalosporin, has been developed by Cubist in combination with tazobactam.   Ceftolozane is a potent antipseudomonal agent in its own right and the combination covers some MDR  P. aeruginosa and strains resistant to carbapenems or piperacillin/tazobactam as well  [ii],[iii].  The NDA was submitted in April 2014.
• Plazomicin (ACH-490)  is a newer aminoglycoside in Phase 3 development at Achaogen with superior activity against many MDR K. pneumoniae and other CRE and ESBL producers.  It is less susceptible to aminoglycoside-modifying enzymes (AME) and may provide coverage where other aminoglycosides would fail.  However, anti-pseudomonal activity seems to be only en par with amikacin [iv].   In a large study of recent clinical isolates, the MIC90 was 32 μg/ml against for MDR  P. aeruginosa isolates [v].  It is an IV drug and comes with the usual toxicity profile of the class.
• Polyphor’s novel pseudomonas-specific drug, POL-7080 will be co-developed with Roche.  It acts on a novel outer membrane target called LptD / OstA.  It is a peptidomimetic for IV administration.  Early clinical tests showed an acceptable safety profile and a Phase 2a PK study was recently started in Europe.   A unique feature is narrow Pseudomonas-specific activity: it has no activity against other Gram-negatives.  This is a drug for which a companion diagnostic would seem very useful, both for the Phase 2/3 studies as well as later in the clinic.
• LpxC inhibitors block the production of endotoxin (lipid A), a major virulence factor of Gram-negatives without killing the bacteria.  This MoA is unique and drug activity cannot always be assessed by the traditional MIC or MBC tests.  Several companies (Chiron / Novartis and Achaogen) are testing compounds with rather narrow-spectrum activity for P. aeruginosa and E. coli.  There have been reports of cardiac toxicity in animals but the clinical significance of these effects are unclear [vi].  ACHN-975 is in Phase 1 testing which should address this open issue.

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