Nominating Thiamphenicol for IDSA’s 10 x ’20 Campaign

If you were developing a new antibiotic with a novel MoA, one that covers most GPC, most GNR, most anaerobes and atypicals, including many MDR pathogens like MRSA, enterococci (both E. faecalis and E. faecium), and one that has also activity against rickettsiae and bioterrorism agents, you would consider it a sure blockbuster.  If it eventually were shown that this drug can cause aplastic anemia (in 1 of 30,000 cases) it would still be considered a useful antibiotic but relegated to back-up status.

Aplastic Anemia
Bone marrow in aplastic anemia

This is indeed how chloramphenicol is used abroad.  Not so in the US where a litigious environment enforces blind adherence to guidelines and labeling orthodoxy.  A patient dying from a MDR infection or ending up on dialysis post-colistin therapy is easier to defend than a case of aplastic anemia due to chloramphenicol requiring BMT.

Wait, what about serious anaphylactic reactions to penicillins?  Admittedly rare, they can end deadly [1].  Between 1 in 2000 to 1 in 10,000 patients exposed to penicillin will have a true Type 1 anaphylactic reaction from which 10% will die.

Why is dying from anaphylactic shock an acceptable outcome but BMT for aplastic anemia is not?  Why are we using the beta-lactam class of antibiotics without much concern but treat chloramphenicol like a leper?.

I am not trying to make the case for broader use of chloramphenicol (although one could certainly argue in favor of its revival).   Instead, I’d like to make a pitch for reintroducing thiamphenicol into clinical practice.  Thiamphenicol is almost as active as chloramphenicol, has a similarly broad antibacterial spectrum, and is certainly a lot safer than chloramphenicol.

The reactive nitroso group released from chloramphenicol is most likely the mutagenic trigger for aplastic anemia.  Whether correct or not, pharmaceutical chemists have heeded the warning and come up with thiamphenicol and florfenicol, two very similar drugs which no longer have a NO2 side chain on the molecule [2] [3] [4] [5]. Importantly, neither has been associated with aplastic anemia despite significant use in Europe and Asia.  So, why are we not introducing thiamphenicol into our antibiotic armamentarium?

You may think that there is no commercial interest because chloramphenicol and thiamphenicol are cheap old drugs without patent protection.  I would say: So what!  If after all these years generic amoxicillin can still generate hundreds of million dollars of revenue each year for generics companies like Sandoz, a business case can be made for thiamphenicol too.

Let’s nominate thiamphenicol for QIDP status and FDA fast-tracking.  It has a lot more going for it than most drugs currently in Phases 2 and 3 development.  Move over, ‘new’ quinolones, aminoglycosides, oxazolidinones and tetracyclines – there is an old but better player around.

 Abbreviations:

BMT          bone marrow transplantation
QIDP        qualified Infectious Diseases product
MoA          mechanism of action
GPC         Gram-positive cocci
GNR         Gram-negative rods
MDR         multi-drug resistant
MRSA       methicillin-resistant S. aureus

References: 

[1] R. Lin.  A perspective on penicillin allergy.  Arch Int Med 1992; 152: 930
[2] Mandell, Chapter 26: M. Moffa: Tetracyclines, Glycylcyclines, and Chloramphenicol.  Mandell’s PPID, 8th ed. 2014
[3] ttp://www.merckmanuals.com/vet/pharmacology/antibacterial_agents/chloramphenicol_and_congeners.html
[4] R. Root, ed. Tetracyclines and Chloramphenicol.  P. 301 in: Clinical Infectious Diseases – A Practical Approach, Oxford Univerity Press, 1999
[5] M. Wilcox.  Chapter 16: Chloramphenicol and Thiamphenicol.   In: R. Finch (ed).  Antibiotic and Chemotherapy.  Elsevier 2010

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