New antibiotics on the (near) horizon – a report from Josh Davis from recent USA ID Week

Guest posting: Assoc. Prof. Josh Davis, President, Australasian Society for Infectious Diseases. @Guru_JoshD

“ID week” is a large US infectious diseases conference; this year it was in San Francisco, and had over 8,000 delegates. The most talked about trial at this conference (mentioned in at least 5 different sessions) was the Australian-led MERINO trial, an RCT which showed that piperacillin/tazobactam is inferior to meropenem for treating bacteraemia due to ceftriaxone-resistant E. coli or Klebsiella species. This was yet another negative trial, the result of which does not help us in our quest to minimise carbapenem use.  Here is an instructive interview with the main MERINO investigator, Patrick Harris.

This led onto other presentations about how to treat multi-resistant bacteria, including new antibiotics. On the plus side, there are 7 new antibiotics which have been/will be approved by the US FDA in 2018/2019. On the downside, none of these are new drug classes/mechanisms of action. Note the FDA approval only applies to the US market, but once a drug is FDA approved, companies usually apply for TGA approval in Australia. The new antibiotics (with my opinions thrown in) are:

  • Cefiderocol – a “siderophore” antibiotic – uses iron uptake by bacteria to gain access to the cell (a “Trojan Horse” mechanism). Active against multi-drug resistant Pseudomonas, Acinetobacter and Klebsiella. This drug will be useful for highly resistant infections with limited treatment options.
  • Eravacycline – a halogenated tetracycline– recently FDA approved. Failed in 2 phase 3 RCTs of complicated urinary tract infection. This is likely because only 16% gets into the urine. But it has been shown to be non-inferior to carbepenems for intra-abdominal infections, so will be marketed for this indication. There is not much need for this in my view. Amp/gent/metronidazole is still a highly effective combination, with low levels of gentamicin resistant in enteric Gram negatives in Australia. We have other back up options where >72 hours of IV antibiotics are needed, including IV amoxycillin/clavulanate or piperacillin/tazobactam.
  • Omadacycline – from an aminomethylcycline subclass of tetracyclines-  FDA approval imminent. Q24h dosing. Non-inferior to moxifloxacin in community-acquired pneumonia and to linezolid in skin/soft tissue infections. I don’t see much role for this as yet. Pencillin plus doxycycline remains our first line treatment for CAP, and flucloxacillin for skin infections. We already have other good options for penicillin allergy and/or MRSA cover (e.g. clindamycin, cotrimoxazole)
  • Plazomycin – a next-generation aminoglycoside (“neoglycoside”).  Resistant Gram negatives (e.g. ESBL-producing E. coli or Klebsiella and carbapenem-producing Enterobacteriaceae (CPE)) are often resistant to aminoglycosides like gentamicin and tobramycin whereas plazomycin is often works against these. It is unaffected by 15 out of the 17 known aminoglycoside-modifying enzymes. The MIC90 for CPEs averages 1.0 mg/L, equating with susceptibility. This was approved by the FDA in June 2018 It was shown to be non-inferior to meropenem for UTIs, but has only been approved for patients with “limited treatment options” (i.e. highly resistant bacteria). This will be a useful agent in the rare situation of highly resistant Gram negatives.
  • Fosfomycin is available in Australia as an oral formulation for resistant UTIs. Intravenous fosfomycin in going to the FDA for UTI – note that susceptibility testing is not properly validated and gives conflicting results – labs need to use a complex method called agar dilution to reliably test for resistance. See also this posting.
  • Lefamulin – a “pleuromutilin” – binds to 50S bacterial ribosome and blocks protein production. It is active against respiratory pathogens, MRSA, VRE and M. genitalium. Has been shown to be non-inferior to moxifloxacin +/- linezolid in CAP.  Unclear yet whether this will have a useful role in Australia. Perhaps for M. genitalium (which is increasingly resistant to azitrhomycin and even moxifloxacin).
  • Iclaprim – derived from trimethoprim. It is twenty times more active against Staph. aureus than trimethoprim and has good Gram negative cover. FDA approval likely in 2019.

 

 

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