New Treatment Options for XDR Acinetobacter
In my mind, multi drug resistant Acinetobacter is the greatest unmet need in antibiotic therapy
today. The new β-lactam/β-lactamase inhibitor combinations such
as ceftazidime/avibactam and meropenem/vaborbactam do not offer good options
against MDR Acinetobacter. Plazomicin,
the new aminoglycosides, also does not offer anything as a treatment for Acinetobacter. Here is a brief review of
some of the options under development for carbapenem resistant Acinetobacter.
Cefiderocol
The one new drug close to availability which does have anti-Acinetobacter activity is cefiderocol. Cefiderocol,
a siderophore cephalosporin, has been used successfully for UTI but we have no
reports yet of its clinical use against Acinetobacter. However, in vitro, it
appears to be highly active. In a poster at ID Week 2017, cefiderocol was
active against 89% of a set of well characterised strains from the CDC. Not
perfect, but certainly an advance on our current armamentarium. It is currently
in phase 3 development.
ETX-2514 in
combination with sulbactam
ETX-2514 is novel diazabicyclooctane inhibitor which inhibits OXA β-lactamases
as well as having high affinity to PBPs. When combined with sulbactam, the
MIC90 was a 2 mg/L or less in strains from the Bonomo lab. It
is currently in phase 1 development.
AAI101 in combination
with cefepime
This new beta-lactamase inhibitor combined with cefepime has
activity against meropenem susceptible Acinetobacter. Unfortunately it had
little useful activity against OXA-23 or OXA-24 producing carbapenem-resistant Acinetobacter.
Monoclonal Antibodies
C8 is a monoclonal antibody developed by immunising mice
with sublethal concentrations of hypervirulent XDR Acinetobacter. In mouse
models, C8 was synergistic with colistin, improving survival compared to
monotherapy. A humanized variant of C8 has been developed but human trials have
not yet commenced.
Phage Therapy
Schooley and colleagues have recently published successful
treatment of MDR Acinetobacter with a
bacteriophage cocktail. The patient who was 68 years old and diabetic developed
gallstone pancreatitis. A pancreatic pseudocyst developed from which Candida albicans and Acinetobacter resistant to meropenem,
amikacin, trimethoprim/sulfamethoxazole, tetracycline, ciprofloxacin and
colistin was isolated. The patient had received courses of meropenem, colistin
and tigecycline with no avail and then, on the basis of synergy testing,
colistin and azithromycin. Despite this, the MDR Acinetobacter strain continued to be isolated and the patient
continued to deteriorate clinically.
Further synergy testing showed that rifampin
may have provided added synergy and therefore it was added. Despite this, the
patient continued to deteriorate and drain fluid, peritoneal fluid and respiratory
secretions continued to grow MDR Acinetobacter.
At a time when the patient was on multiple vasopressors and had developed renal
failure an application was submitted to the FDA requesting authorisation to use
phage therapy.
The phage cocktail had been developed by the US Navy’s
medical research centre and work at the Centre for Phage Technology at Texas
A&M. The phages were administered to the patient initially via percutaneous
catheters into the pseudocyst cavity, the gall bladder and a third intra-abdominal
cavity. After 36 hours bacteriophage therapy was given intravenously.
Eventually it was given at 2-hourly intervals. Coinciding with the combination
of intracavitary and intravenous bacteriophage therapy the patient clinically
improved and intravenous antibiotics were discontinued.
This is a fascinating case report of the use of
bacteriophage therapy for a MDR Acinetobacter
isolate. During the course of treatment the patient clearly improved coinciding
with this therapy. The therapy was not without its own issues as one isolate
grown 8 days after initiation of phage therapy was found to be resistant to the
initially used phage cocktail. This strain was used to select for new bacteriophages
with activity against this Acinetobacter
isolate. This was achieved within 72 hours and demonstrates an important use of
this therapy. Another interesting issue which arose is that minocycline was
added to the phage therapy 5 days after the phage therapy was initiated. The
researchers were able to demonstrate additive in vitro activity between the
phages and sub- inhibitory concentrations of minocycline.
Phage therapy is potentially an option in therapy of serious
XDR or PDR infections however many issues such as dose optimisation,
pharmacokinetics/pharmacodynamics, modes of administration, and the impact of
phage therapy on the microbiome remain to be answered. At the present time it
appears that phage therapy is very much a niche option but it is certainly
something to consider when all other options have been exhausted.
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