### Dosing CrCl > 80: 2.5 - 4.5 IV q 6 - 8 h. Probably best to dose q 8 with a 4-hour infusion. It decreases mortality. [^1] CrCl 80-50: 2.5 - 4.5 IV q 6 - 8 h. CrCl 50-10: ? CrCl < 10: ? Hemodialysis: Peritoneal dialysis: ### Important side effects It is like every other penicillin. ### Important drug interactions Methotrexate, probenecid, and vecuronium. When added to [[vancomycin]] it is associated with acute kidney injury. [^2] [^3] One article is entitled "*Increasing Evidence of the Nephrotoxicity of [[Piperacillin-tazobactam]] and [[Vancomycin]] Combination Therapy---What Is the Clinician to Do?*" [^4] How about not give that combination? Duh. How hard can it be to, oh, I don't know, think about the disease and give something else? Hard it appears. A meta-analysis suggests an odds ratio of 3 for AKI when combined with [[vancomycin]]. [^5] Although not all are convinced of the combined nephrotixicity: > "Studies necessary to determine the causality of V + PT for increased AKI have not yet been performed. Relying on potentially flawed surrogates of glomerular function (eg, SCr) can result in confounded and incorrect findings. In the absence of human data confirming causality and animal data suggesting that injury does not occur, we opine that the association observed may well be "fiction."". [^6] ### Rants and Screeds The use of this antibiotic in [[Sepsis and Bacteremia]] empirically is associated with increased mortality rates compared to other agents, especially if the MIC is in the high end of 'sensitive', greater than 2 ug/ml. Funny how we had a [[Piperacillin]] shortage (inexpensive) but plenty of pip/tazo (expensive). Wonder why? ### Pearls Beta-lactamase inhibitor combinations are problematic with some gram-negative rods, depending on the strain and the type of beta-lactamase. Clavulanate can be antagonistic for [[ticarcillin]] [^7] and other beta-lactam antibiotics. [^8] This is less of a problem with tazobactam, maybe occurring 1% of the time. [^9] > "Clinicians must remember that the addition of tazobactam **does not always increase the susceptibility of P. aeruginosa** and other Gram-negative bacilli expressing AmpC β-lactamases. However, tazobactam does extend [[Piperacillin]]'s activity against most β-lactamase producing strains of Enterobacteriaceae, H. influenzae, N. gonorrhoeae, and M. catarrhalis and has the potential to lower MICs against these strains expressing ESBLs." [^10] ### Treatment of choice In my opinion? Nothing. I do not believe I have ever used the drug. ### Use for Like all beta-lactamase inhibitor combination, I can't find a use for them. It is approved for appendicitis, [[cellulitis]], cutaneous abscesses, diabetic foot infection, diverticulosis/itis, endometritis, *[[Escherichia]]* *coli* infections, gynecologic infections, intraabdominal infections, neutropenic fever, PID, [[peritonitis]], and [[pneumonia]]. ### Don't use for ### Class Penicillin. ### Puswhisperers [Beta-lactam Side Effect - Sometimes an STD](http://www.pusware.com/PW2/BetaLactamSide.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop319.mp3) [Grumpy and Getting Worse with Age](http://www.pusware.com/PW7/Grumpy.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop837.mp3) ### Rationalizations [^1]: Rhodes NJ, Liu J, O'Donnell JN, Dulhunty JM, Abdul-Aziz MH, Berko PY, Nadler B, Lipman J, Roberts JA. Prolonged Infusion [[Piperacillin]]-Tazobactam Decreases Mortality and Improves Outcomes in Severely Ill Patients: Results of a Systematic Review and Meta-Analysis. Crit Care Med. 2018 Feb;46(2):236-243. doi: 10.1097/CCM.0000000000002836. PMID: 29116995. [^2]: Gomes DM, Smotherman C, Birch A, Dupree L, Della Vecchia BJ, Kraemer DF, Jankowski CA. Comparison of acute kidney injury during treatment with [[vancomycin]] in combination with [[Piperacillin]]-tazobactam or [[cefepime]]. Pharmacotherapy. 2014 Jul;34(7):662-9. doi: 10.1002/phar.1428. Epub 2014 Apr 18. PMID: 24753221. [^3]: Navalkele B, Pogue JM, Karino S, Nishan B, Salim M, Solanki S, Pervaiz A, Tashtoush N, Shaikh H, Koppula S, Koons J, Hussain T, Perry W, Evans R, Martin ET, Mynatt RP, Murray KP, Rybak MJ, Kaye KS. Risk of Acute Kidney Injury in Patients on Concomitant [[Vancomycin]] and [[Piperacillin]]-Tazobactam Compared to Those on [[Vancomycin]] and [[Cefepime]]. Clin Infect Dis. 2017 Jan 15;64(2):116-123. doi: 10.1093/cid/ciw709. Epub 2016 Oct 20. PMID: 27986669. [^4]: Watkins RR, Deresinski S. Increasing Evidence of the Nephrotoxicity of [[Piperacillin-tazobactam]] and [[Vancomycin]] Combination Therapy-What Is the Clinician to Do? Clin Infect Dis. 2017 Nov 29;65(12):2137-2143. doi: 10.1093/cid/cix675. PMID: 29020249. [^5]: Hammond DA, Smith MN, Li C, Hayes SM, Lusardi K, Bookstaver PB. Systematic Review and Meta-Analysis of Acute Kidney Injury Associated with Concomitant [[Vancomycin]] and [[Piperacillin-tazobactam]]. Clin Infect Dis. 2017 Mar 1;64(5):666-674. doi: 10.1093/cid/ciw811. Epub 2016 Dec 10. PMID: 27940946. [^6]: Kyle J Popovich, Evan S Snitkin, Chad Zawitz, Alla Aroutcheva, Darjai Payne, Stephanie N Thiede, Michael Schoeny, Stefan J Green, Mary K Hayden, Bala Hota, Robert A Weinstein, Frequent Methicillin-Resistant _Staphylococcus aureus_ Introductions Into an Inner-city Jail: Indications of Community Transmission Networks, _Clinical Infectious Diseases_, Volume 71, Issue 2, 15 July 2020, Pages 323–331, [https://doi.org/10.1093/cid/ciz818](https://doi.org/10.1093/cid/ciz818) [^7]: Lister PD, Gardner VM, Sanders CC. 1999. Clavulanate Induces Expression of the [[Pseudomonas]] aeruginosa AmpC Cephalosporinase at Physiologically Relevant Concentrations and Antagonizes the Antibacterial Activity of [[Ticarcillin]]. Antimicrob Agents Chemother 43:. https://doi.org/10.1128/aac.43.4.882 [^8]: Weber DA, Sanders CC. Diverse potential of beta-lactamase inhibitors to induce class I enzymes. Antimicrob Agents Chemother. 1990 Jan;34(1):156-8. doi: 10.1128/AAC.34.1.156. PMID: 2327752; PMCID: PMC171539. [^9]: https://www.medscape.com/s/viewarticle/565768_3 [^10]: Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev. 2010 Jan;23(1):160-201. doi: 10.1128/CMR.00037-09. PMID: 20065329; PMCID: PMC2806661.