SH: My dear Watson, did you read the news of the astonishing debacle that befell Mme Erava and made the headlines, creating anxiety of hitherto unknown proportions in Tetraland?
Dr.W.: A disaster of epic proportions, for sure, and a mystery, an explanation which will require some very expert investigation. There is talk of some supernatural reason for the calamity as all natural causes of failure have been eliminated, it seems.
SH: Well, of course, that is the general view of the uneducated classes. But, as we have seen in just so many cases, efforts to avoid responsibility and exposure are reactions to be reckoned with. These are self-serving attempts to obfuscate and shift blame. One must not forget that most disasters can be traced to some faulty design, trivial at times. Just think of the booster rocket O-ring….
Dr. W.: I am not sure I follow your reasoning as this IGNITE-2 problem has already stymied some of our best analytical minds. Certainly, the usual wise crackers and know-it-alls will now come forward with their pat answers, snickering and trying to look smart after the fact. Nobody can honestly claim to have foreseen that IGNITE-2 would auto-combust, wouldn’t you agree?
It doesn’t matter how beautiful your theory is, it doesn’t matter how smart you are. If it doesn’t agree with experiment, it’s wrong.
Richard Feynman
SH: Well, with the IGNITE studies we have not only fire and light but also a lot of smoke. When the cIAI data were published many weak points were glossed over. Watson, have you read Plato recently?
Dr. W.: What makes you think we need to go back 2000 years to unravel a 21st century riddle? Have you become a sophist, a cynic, a dialectic follower of Socrates? Are you asking because you believe his methods would be used profitably in this case?
SH: It has occurred to me that his way of challenging orthodoxy may be applicable to many of today’s problems. Dear Watson, do you believe in the power of tetracyclines to destroy bacteria?
Dr. W.: First, let me say that I intend to respond to any sophistic rhetoric with solid scientific arguments; I will also not stray away from the ethics laid down in the Hippocratic oath I swore.
SH: You will then kindly tell me whether you believe in the ‘ethical drug business’? Or do you think it is just another euphemism?
Dr. W.: There is a good deal of ‘framing’ going on in the drug business, no doubt.
SH: Do you believe that the ‘ethical business’ approach demands thorough investigation whether a drug works in a certain indication?
Dr. W.: Certainly this is a reasonable expectation.
SH: Would you be inclined to think that ethical drug development wants to clarify what dose is just barely adequate for efficacy, or do you believe they would rather test a dose which certainly works but may have toxicity?
Dr. W.: Neither suggestion is correct – in anti-infectives the goal is to find the ‘sweet spot’ right from the get-go, without any testing of the efficacy or safety limits…
SH: What, then, is the ‘sweet spot’ and how do you find this most appropriate dose when you are dealing with a population never tested before, with a PO dose never tested before, a dose regimen derived indirectly from markers, and …
Dr. W.: You are most unkind, Sherlock. The good folks in Tetraland have modeled exposure and attainment, making allowances for numerous factors, indeed all variables that one can humanly think of. Then they fed it all into their most powerful Cray computers.
SH: You argue convincingly that we should eliminate poor dose selection as a cause of clinical failure. Yet failure we saw. I ask you again: Do you believe in the power of tetracyclines?
Dr. W.: They are potent drugs, and we trust them for trivial and not-so trivial infections… of the respiratory kind, especially.
SH: When did you last use a tetracycline for UTI? Have you seen articles on cUTI and the efficacy of doxycycline or tigecycline?
Dr. W.: There are other drugs that have been used more often. Nonetheless, tetracyclines are still often tried for prostatitis which is a special case of UTI and a difficult one at that, wouldn’t you agree?
SH: You are making a good point, Watson, but we are not treating Chlamydia, or GC, or prostatitis here: I was strictly referring to efficacy data in cUTI patients. My Baker Street Irregulars have been unable to find any well-done comparative trials against a beta-lactam or fluoroquinolone. When you look for anecdotal reports, you will not be disappointed. But that is just about all you’ll find, and it is not much.
So, it should make us wonder why there are no studies of tetracyclines in cUTI. Without such precedents and clinical validation points as anchors, how do the PK modelers arrive at the ‘right dose’?
Dr. W.: We should not be too narrow in our thinking. Modelling is a powerful tool, and inferences can be made based on urinary levels and MIC data; in addition, much can be deduced from other drugs studied in cUTI.
SH: But of course! How could I neglect all the good PK/PD work done for fluoroquinolones and beta-lactams? In those cases, was a correlation with clinical outcomes available which validated the methodology?
Dr. W.: Yes, of course. It was with these drug classes that the science was established. It is now mature enough to be expanded to other drugs with other MoA and PK profiles.
SH: There is much truth in the concept you just expounded. Extrapolation to other antibiotic classes makes sense and is justified by logic. But where are the safeguards that the concept can be extended and applied to a new antibiotic class?
When you lean over a ledge, it helps to know your body’s point of gravity. Armed with such knowledge you might find it fun to explore the physics, but people have fallen from the balcony because the railing was not strong enough!
Dr. W.: Sometimes, people lean over the ledge because they have no fears. Or they think they know the risks and choose to ignore them. And some are just lucky and walk right up to the ledge without a problem. But when Mme. Erava steps out, the railing collapses. Call it bad luck, blame the gods of statistics…
SH: But it was not a railing that collapsed, my dear Watson, it was a case of auto-combustion…not a minor slip! We are dealing with a case of colossal structural failure: remember, that none of several carefully chosen efficacy endpoints were actually met.
Dr. W.: Yes, yes, and I was also surprised by the fact of how clean the adverse event profile supposedly was. So many unusual findings, all in a very sizeable and credible study. Do you think we will ever learn why there were so many atypical and strange and unforeseen outcomes?
SH: I think I just heard a knock at our front door. There is a gentleman pacing the sidewalk as you will have noticed, and he seems quite distraught. Please excuse me for a moment to check up on our new visitor. No, it is not our friend Lestrade but someone with a cart-load of papers, all figures and tables it seems…
<The next issue of this serialized story will appear after ICAAC – The Editors.>
