[This article was first published on r on Everyday Is A School Day, and kindly contributed to R-bloggers]. (You can report issue about the content on this page here)Want to share your content on R-bloggers? click here if you have a blog, or here if you don't.Exploring pip/tazo PTA for Pseudomonas using popPK simulation. Key finds: 30-min infusions fall short of 90% PTA at MIC 16; prolonged infusion helps, but neutropenic fever population sees the biggest drop in PTA. ~46% of susceptible PsA isolates carry blaOXA-2 — tazobactam matters more than I thoughtMotivations We’ve learnt a bit of PK/PD last time, here. Let’s apply that on Pip/tazo and Pseudomonas. An FDA statement Feb 2024 detailed that for susceptible dose dependent (SDD) breakpoint of 16 mcg/mL, we should utilize 4.5 g q6h over 3-hour infusion because the standard dosing of 4.5g IV every 6 hours over 0.5 hours do not adequate achieve > 90% PTA. There is also a mention on the limitation where the fT > mic of 50% was used to calculate PTA, which was not adequately validated for PsA. This is a great opportunity for us to take a look at this, now that we have a better understanding of what PTA and fT>mic mean from a data structure standpoint!First, we’ll obtain the population PK parameters, make a model, and then perform the simulation, and visualize the PTA. We’ll be exploring A Pooled Pharmacokinetic Analysis for Piperacillin/Tazobactam Across Different Patient Populations: From Premature Infants to the Elderly. This model is more sophisticated than the previous one as it’s a pooled popPK model. We’ll then compare the PTA of the recommended dosing and infusion time, compared to standard dosing of 30 mins. And then look at some maximum amount of fT>mic used in the literature, and then explore the PTA given the threshold of fT>mic. Also, a curious question is, why do we need tazobactam for pseudomonas when piperacillin itself has activity against it? Could it be because of co-resistance of beta lactamase? Let’s take a look at all pseudomonas isolate that is pip/tazo susceptible and check for proportion of these beta lactamase genes in NCBI.Disclaimer: This is purely for educational purposes. Not a medical advice. If you find something wrong, please let me know so I can correct and continue to learn.Objectives: Piptazo modelProbability of Target AttaintmentProportion of PsA in NCBI that would benefit from tazobactamFinal thoughtOppotunities For ImprovementLessons LearntPiptazo Model LLM codelibrary(mrgsolve)library(tidyverse)mod mic used in the literature According to some literature that ft> mic 50% is not suitable for PsA, though there is no consensus on what the optimal threshold should be. I found some papers that used 70% or even 100%. Let’s look at the PTA if we use these thresholds.OK, we are seeing the PTA drops quite a bit if fT>mic is 100%. This is when the critically ill population parameter might come in handy. Some even said that this population may need fT>4xmic 100% to achieve optimal outcome. So let’s look at that as well.fT > mic 100% fT > 4 x mic 100% Wow… ‍When looking at the original paper, the number look quite similar to ours for extended infusion for both fT>mic 100% and fT>4xmic 100%.Proportion of PsA in NCBI that would benefit from tazobactam How are we going to do this? It might not be 100% but we tried filtering PsA of piptazo susceptible and the overlap it with piperacillin resistant, but there were zero overlap. What if we grab all PsA piptazo susceptible and check for beta lactamase genes with exact match?Over here we search for allele:(blaTEM-1 blaTEM-2 blaTEM-3 blaTEM-4 blaTEM-5 blaTEM-6 blaTEM-7 blaTEM-8 blaTEM-9 blaTEM-10 blaTEM-12 blaTEM-26 blaSHV-1 blaSHV-2 blaSHV-5 blaSHV-12 blaCTX-M-1 blaCTX-M-2 blaCTX-M-3 blaCTX-M-9 blaCTX-M-14 blaCTX-M-15 blaCTX-M-27 blaPER-1 blaPER-2 blaVEB-1 blaVEB-9 blaGES-1 blaOXA-2 blaOXA-10 blaOXA-15 blaPSE-4) .Then run through the same script as before. Let’s see what we find!There were 212 isolates of PsA susceptible to piptazo, but only 124 isolates with assemblies. Of the 124 isolates we were able to grab the assemblies, we detected 46% (n=57) with blaOXA-2. Which means, there is a good chance that piperacillin would be hydrolyzed without the tazobactam!Final Thought Wow, these population PK and PK/PD studies are mathematically intense! High respect to those who were able to tease the signal out of the noise from all these studies. Definitely lots to learn! Now, I think I have a better understanding why CLSI and FDA had issued statements about mic 16 and piptazo dosing etc. This makes so much more sense now. Opportunities For Improvement get more literature on clinical outcomes and fT > mic of different thresholds, and same with PTAdoes tazobactam mic matter in this setting?does albumin matter much here?what about cefepime PTA?Lessons learnt created an actual PTA plot of all the micslearnt to recreate model based on popPK study, thank goodness they provide equations on the paper!got a bit more comfortable with the model parameters in mrgsolveIf you like this article:please feel free to send me a comment or visit my other blogsplease feel free to follow me on BlueSky, twitter, GitHub or Mastodonif you would like collaborate please feel free to contact meTo leave a comment for the author, please follow the link and comment on their blog: r on Everyday Is A School Day.R-bloggers.com offers daily e-mail updates about R news and tutorials about learning R and many other topics. Click here if you're looking to post or find an R/data-science job.Want to share your content on R-bloggers? click here if you have a blog, or here if you don't.Continue reading: Exploring Piperacillin/Tazobactam Probability of Target Attainment (PTA) in Pseudomonas