Dear Professor Whitty,
I wanted to write to you to highlight some interesting points raised by some senior colleagues in recent days. I imagine you are well aware of most of these but given the large burden of work you have been undertaking and the massive amount of information that is accumulating I was keen to ensure that their messages were getting through.
I was particularly keen to point out to you reports about the potential efficacy of co-trimoxazole in patients who had been admitted to ICU but who were not responding to regular therapy. One consultant reported that in patients with severe symptoms and elevated inflammatory markers despite usual antibiotics (penicillin and clarithromycin) and who were thought to be progressing to ARDS and ventilation, they made rapid progress on oral co-trimoxazole at a dose of 960 mg 12 hourly.
Interestingly, a large retrospective Japanese study on patients with idiopathic pulmonary fibrosis (IPF) who had required ventilation showed that co-trimoxazole and macrolides were a good addition to high dose corticosteroids. In this study, the dosage of co-trimoxazole significantly correlated with survival. I enclose a copy of the paper https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898301/.
Similar effects have also been reported in patients with pulmonary sarcoidosis and the acute respiratory distress syndrome (ARDS) who were treated with co-trimoxazole and corticosteroids. Again, I enclose one of the papers https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748620/.
The mechanism suggested is the ability to block the formyl peptide receptors (FPR) on neutrophils that are responsible for both intracellular and extracellular release of ROS. Blocking of the FPR can reduce endothelial damage, lipid peroxidation and apoptosis. IPF, as you will know, is associated with increased oxidative stress and mitochondrial dysfunction leading to increased ROS levels. It is thought that co-trimoxazole may have similar effects to dapsone due to its identical sulphonamide ring. Dapsone is known to have anti-inflammatory and immunosuppressive properties and as long ago as 1991 was shown to block FPR and to block neutrophil myeloperoxidase (PMA) in a dose-dependent way again reducing endothelial damage and apoptosis. It is postulated that co-trimoxazole may have similar immune effects to dapsone due to its identical sulphonamide ring.
I was keen to pass this information on to you as, if an inexpensive drug such as co-trimoxazole were found to have a significant effect on patients with Covid-19 related ARDS, it would be tragic if it were not widely shared and evaluated. I know that individual consultants would be very happy to speak to you or your staff personally.
One other point. Apparently, Pneumocystis carinii superinfection is very common in ARDS and co-trimoxazole confers benefits by reducing lung infiltrates and increasing PO2. The link is https://www.ncbi.nlm.nih.gov/pubmed/1873409. Hence the beneficial effects of co-trimoxazole might be by targeting undiagnosed fungal overgrowth in Covid-19 compromised patients because the majority of antibiotics do not target fungi. Fungal infections are also difficult to find unless you look for them because they may not show up in the usual cultures.
I hope that you find this useful. Please let me know when you have seen this as I intend to post it on my website so that it might be more widely disseminated.
I hope you are fully recovering despite the difficult task you have.
Keep safe and well.
Best wishes,
Liam Fox.
