- Is it true that the FDA ‘focuses on bugs instead of patients’ when they approve new antibiotics?
- Is it true that the call for ‘new MRSA drugs’ is misguided because the real problem lies with the failure of existing drugs that do not work although they should based on susceptibility testing?
- Is it true that the FDA is focused on getting ‘more antibiotics to market’ using ‘smaller and shorter’ studies with ‘less evidence’?
- Is the FDA neglecting non-antibiotic microbiome therapy for infectious diseases?
- Should the FDA demand that new antibiotics show on evidence that they ‘save lives’?
It’s not clear whether or not Zuckerman and Powers just want to be provocative or actually believe what they write.[1] Let’s start by stating the obvious:
- There is no other field in medicine that has a better, more solid, scientifically defined biomarker of outcome. It is the infecting organism that drives the pathology.
- No regulatory ‘breaks’ have been given for the few antibiotics approved in the last 15-25 years.
Truth be told, we are lucky to have a good number of antibiotics that still work well for most patients, esp. in outpatient care. It is rare to run into an infection caused by more resistant organisms that is not treatable with the existing armamentarium, and that’s a good thing. Thanks to research in academia and industry, we have antibiotics that can even handle many MDR pathogens. This situation may not last forever.
Big Pharma has lost interest in developing antibacterials. The change in attitude was also prompted by some misguided policies at the FDA in the early 2000s, when guidances were drawn up that ran counter to medical practice, resulting in regulatory uncertainty for almost a decade, creating FDA standards not harmonized with other agencies, and pushing the concept of placebo-controlled superiority studies. Overall result: Pharma drifted away from antimicrobials to oncology and other fields. This happened at a time when FDA regulatory zealots were in charge, driving a highly controversial agenda of ‘Guidance reform’.
Once the FDA finally approves an antibiotic, it has undergone rigorous testing for safety and efficacy. Phase 3 studies are large and indication-specific. The outcome of the new drug is invariably compared to another already approved antibiotic best suited for the indication; the days of ‘biocreep’ are over and done with. The design of studies is codified in numerous guidances, which are updated every 10 years or so. For almost all indications, antibiotic efficacy is evaluated clinically rather than microbiologically. The FDA still adheres to the ‘feel, function, survive’ logic for efficacy evaluation, although we have much better predictors of response, namely microbiologic eradication of the causative organism.
Contrarians feel a need to publish simplistic answers to complex problems. They see themselves as heroes cutting the Gordian knot with a single stroke. Zuckerman is entitled to her opinion, but the accusations don’t resonate for those of us who have followed the field.[1]
We believe it is too simplistic for them to state the following:
- There is no need for new antibiotics addressing MDR pathogens, as most patients die from infections treatable with existing antibiotics
- Microbial ‘test tube results’ are not relevant for clinical outcome assessment
- ‘Microbiome therapy’ is or can be better than antibiotics
- Steroid use in ICU pneumonia is life-saving
- Immune weakness calls for concomitant steroid therapy in ‘other infections’ as well
- Deaths and SAEs caused by antibiotics outweigh their benefits
- Clinical testing of antibiotics should center on improved survival
We’ve been there, heard it before. How can one ignore the role of microbiology or be ignorant of numerous failed studies on concomitant steroid use in bacterial pneumonia?
We also would have expected a better grasp of the regulatory history concerning clinical trial conduct and approval which the authors certainly knew but chose to ignore.
In the 90s, FDA vehemently defended the concept of new HIV therapeutics that had to show either (1) improved survival, or (2) a reduction in opportunistic infections. This may have seemed reasonable at first glance, but for clinical studies such endpoints were entirely misconceived: it would have taken 8-10 years of therapy to get a read-out. In the meantime, patients were left to die. Then VL reduction became a gold standard marker of efficacy replacing survival and AIDS-related infections.
We are glad that companies like Shionogi are still interested in the development of antibiotics like cefiderocol / Fetroja, a novel cephalosporin with dual MoA. The FDA knows about the mortality differences in VAP studies, an imbalance which was thoroughly investigated but remained unexplained. It is mentioned prominently in the label though. Similar things have happened before (tigecycline!).
Clinical outcomes, including deaths, are multifactorial and not solely a result of antibiotic efficacy. Clinical outcomes are influenced by comorbidities, supportive care and immune status of the individual, plus several other factors. To evaluate antibiotic efficacy we should primarily care about micro results, tissue penetration, and PK/PD. In our opinion, antibiotics primarily affect pathogens and secondarily the disease caused by pathogens. The ‘Feel-function-survival’ mantra are downstream events of antibiotic action and quite insensitive for outcome evaluations.
Antibiotics cure diseases by killing bugs. That’s all they do: kill bugs. Antibiotics don’t determine clinical outcomes alone. We don’t need to judge antibiotics on their effect on pain relief, reduction of inflammation, QoL, days of hospitalization or normalization of labs. In antiinfectives, we have the best of biomarkers for the occasion: microbial eradication and VL reduction.
Zuckerman and Powers seem to enjoy the limelight feeling good in the role of provocateurs. They have never developed a single antibiotic but see themselves as enlightened judges and gatekeepers. Let’s find them a soap box, a megaphone and a corner at Hyde Park!
ABBREVIATIONS
VAP ventilator-associated pneumonia
MDR multi-drug resistant
QoL quality-of-life
VL viral load
REFERENCE
[1] Zuckerman D. The FDA’s misguided thinking on antibiotics. STAT – First Opinion. Feb 10, 2025
