Comment on: The case for ‘conservative pharmacotherapy’

Sir,

We read with great interest the article by Jorgensen et al.¹ We agree with the need for evidence to support the use of new technologies. We would like to address some of the points raised in their article.

We agree that initial ‘therapeutic’ ranges for drugs such as gentamicin, tobramycin and amikacin were based on small, retrospective studies that could not establish cause and effect relationships. One could argue that such ‘toxic ranges’ set back the advancement of aminoglycoside therapy for two decades. It was not until the 1990s that high dose, once-daily doses replaced small, frequent doses. However, now we have a good understanding of the relationships between drug exposure and efficacy, and, in some cases, toxicity. Examples include vancomycin, the β-lactams, linezolid and the fluoroquinolones. Recent clinical trial designs have effectively incorporated preclinical pharmacokinetic/pharmacodynamic (PK/PD) data.² Such preclinical PK/PD data may now be submitted to regulatory agencies as part of the approval process. In this regard, the in vitro hollow fibre system model has been qualified by the EMA as a methodology for use in support of selection and development of anti-TB regimens.³

We also agree that PK/PD studies in humans are difficult and data interpretation is complex. This is precisely why a hollow fibre infection model, where you can isolate ‘bug versus drug’, provides such useful information. The consistency of PK/PD drivers from hollow fibre systems to animal models to humans is why the EMA made the decision above. It is also the reason why these preclinical PK/PD targets are used for developing dosing regimens during clinical drug development and setting breakpoints for antibiotics. Again, achieving these PK/PD targets does not guarantee efficacy or the avoidance of toxicity, but it is the best we can do at this time. We consider these changes to be important advancements that can be carried forward into the clinic.

Sometimes, clinicians set aside preclinical data and focus primarily on clinical trial data. Clinical trial data are important. However, depending on the sample size and outcome chosen, it may not be possible to demonstrate clear PK/PD relationships in humans. That does not mean that the relationships are absent. The targets generated by preclinical studies are reproducible and they can be highly predictive of what happens in vivo. Antimicrobials kill pathogens, but they cannot reverse tissue damage, immune dysfunction or end organ damage. Patients may die subsequent to an infection, but without live pathogens within them. In such cases, the antimicrobial did its job, but, if the outcome variable was 30 day mortality, then no effect can be shown.

We agree that drug exposure is only one factor, but it can be decisive and it is one of the few variables that we can control. Sometimes the pathogen cannot be identified. If identified, an MIC value is just one measure of susceptibility under static in vitro conditions. MICs are clearly limited, but they are currently one of the best available tools for testing the susceptibility of a pathogen to a drug. Typically, we can measure total and free drug in plasma and not at the actual site of infection. Still, these tools are better than no information at all. Consider drug penetration into the CSF for patients with meningitis; the drugs we consider to be the best for meningitis are precisely those with the greatest exposure. Similarly, exposure–response relationships were published for fluoroquinolones in the treatment of pneumonia decades ago.^4–6

Jorgensen et al.¹ stated that “Patients are frequently cured of their infection despite ‘subtherapeutic’ antimicrobial exposures”. This is true. All clinical tools have limitations, as do the clinicians employing them. However, that does not mean that we should stop using these tools. We need to learn to use them better. We interpret the PK/PD literature to indicate that you can optimize therapy and give the patient the best chance to overcome the infection. The goal of TDM, or ‘precision dosing’, is to maximize the favourable probabilities.⁷ This should never be misconstrued as a guarantee. Rather, you are taking your best shot with the tools that you have available. Bear in mind that no amount of any other diagnostic tool, be it a serum chemistry panel, blood culture or MRI scan, can cure the patient. TDM is yet another diagnostic tool. All of these tools allow clinicians to make informed decisions without cutting open their patients. Work will continue to refine and improve the tools available. We agree with the need for more studies evaluating the impact of TDM, especially in areas such as infectious disease due to the rise of antimicrobial resistance with limited new antibiotics coming to the market, leaving precision dosing one of the few areas we have to improve treatment.⁸

Transparency declarations

None to declare.

References