Thread by @edenhelmi

New drugs against GNB by Ursula Theuretzbacher #ECCMID2023

In Malaysia, we only have Cefta-avi for resistant GNB infections!
We hope @SHIONOGI_JP will include Malaysia in the list of countries for generic cefiderocol- a project by @gardp_amr

@KKMPutrajaya @DrZalihaMustafa

These are the drugs that are recently approved and we have none of these locally
We can only use Fe-troja(n)/Cefiderocol by @SHIONOGI_JP under the compassionate use program, and the drug is flown all the way from Europe

The cost is huge and our patients can rarely afford it

Again, the same table:
The red ones are called DBO/Diazabicyclooctanes. They have an added PBP activity in addition to BLI activity
Boronates have extended BLI activity (MBL)
The green one is the Tazobactam analogue

Here is an excellent podcast on these: asm.org/Podcasts/Edito…

This is the spectrum of activity of the new BLBLIs

And of these, only Sulbactam/durlobactam has activity against CRAB

Durlobactam is the next gen-DBO with an extended activity against the class D enzymes - which are the primary R mechanisms by Acinetobacter baumannii

And the coverage of NDM enzyme by some of the new agents is quite spotty, as shown here in the red bracket

Therefore, their performance against NDM-producing organisms in clinical practice needs further evaluation

The ability of these new BLBLI to inhibit the beta-lactamases depends on several factors, as shown below

And for Acinetobacter and Pseudomonas, their resistance is not only enzymes-based, making it difficult to develop agents that are active against them

Besides, different regions will have different prevalences of beta-lactamase enzymes

And in the Southeast Asia region, we have the highest burden of NDM, again highlighting the urgent need for agents that are active against it
Cefiderocol is one such agent

Again, in our region, the burden of NDM or MBL is very high, and Cefiderocol is the best agent currently against it

Susceptible rates by
CLSI: 88.1%
EUCAST: 66.3%
US FDA: 88.1%

What about Pseudomonas?
Are the new BLBLIs good against it?

The major issue with PA is that carbapenem resistance is driven not only by carbapenemases but by:
- PBP3 change
- Reduced uptake
- Change in outer membrane protein
- ampC overexpression

Again, the distribution of carbapenemases in Pseudomonas varies depending on the geographical location

How about CRAB?
There are 2 agents:
1) Sulbactam/Durlobactam
This is the new combo whereby Sulbactam, an old drug, can attack the Acinetobacter PBPs

However, it can be destroyed by the OXA enzymes, which is where the Durlobactam comes in - it protects it against the OXA enzymes

2) IV Rifabutin
It is an old drug
It has a very specific uptake mechanism into Acinetobacter

However, it cannot be taken alone for CRAB, as this will cause the emergence of resistance

And these are new oral BLBLIs that can be used to treat MDR GNB infections esp in UTI

For these agents, the accompanying agent plays a role in its (BLI) activity against the bug
Example: cumulative activity is the best for Ledaborbactam when it is combined with Ceftibuten

What is in the pipeline now?

And why is it so difficult to find new candidates/novel agents against GNB?

And the last slide...