In this episode I’ll:
1. Discuss an article about using piperacillin-tazobactam in ESBL infection.
2. Answer the drug information question “Should adjunctive dexamethasone be given to adults with bacterial meningitis if they have already received at least 1 dose of antibiotics?”
3. Share a tip for responding to inpatient medical emergencies.
Lead author: Patrick Harris
Published in JAMA September 2018
Background
Extended-spectrum β-lactamases (ESBL) confer resistance to third-generation cephalosporins in bacteria such as Escherichia coli and Klebsiella pneumoniae. This leads to treatment with carbapenems, which in turn may select for carbapenem resistance. Some ESBL strains resistant to ceftriaxone will test as sensitive to piperacillin-tazobactam. Because of this, some clinicians have recommended using piperacillin-tazobactam to treat ESBL infections as a “carbapenem-sparing” strategy.
Methods
The authors of this study sought to determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae.
The study design was a noninferiority, parallel group, randomized clinical trial that included hospitalized patients enrolled from 26 sites in 9 countries. Eligibility criteria required adults with at least 1 positive blood culture with E coli or Klebsiella testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Nearly 400 patients were included in the study.
Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days. The total duration of antibiotics was determined by the treating clinician.
The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used.
Results
30-day Mortality was 12.3% in the piperacillin-tazobactam group compared to 3.7% in the meropenem group. Piperacillin-tazobactam did not meet the noninferiority margin set by the study. Non-fatal serious adverse events were not significantly different between groups.
Conclusion
The authors concluded:
Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting.
Discussion
This study clearly indicates that the carbapenem-sparing strategy using piperacillin-tazobactam over meropenem for patients with ESBL bacteremia should be abandoned. As I discussed back in episode 8, piperacillin-tazobactam may be a carbapenem sparing option in ESBL urinary tract infection but I would not use it as such in any severe infection or bacteremia.
Drug information question
Q: Should adjunctive dexamethasone be given to adults with bacterial meningitis if they have already received at least 1 dose of antibiotics?
A: No, according to the IDSA guidelines for bacterial meningitis.
The reason for the specific timing of dexamethasone in this patient population is because the studies that demonstrated benefit were the ones where dexamethasone was administered before the first antibiotic dose. The exact quote from the IDSA guidelines appears in the pediatric and adult sections and is:
Adjunctive dexamethasone should not be given to adult patients who have already received antimicrobial therapy, because administration of dexamethasone in this circumstance is unlikely to improve patient outcome.
Tip for responding to inpatient medical emergencies
At the beginning of any rapid response or emergent procedure such as rapid sequence intubation, make a note of your patient’s starting heart rate, rhythm, oxygen saturation, and blood pressure. Any significant change in these vital signs could signal clinical deterioration and can serve as a prompt for the pharmacist to obtain additional medications to serve the needs of the patient.
For example, new onset bradycardia and hypoxia during a difficult intubation may be a signal to obtain atropine or the code cart, while tachycardia and hypotension may be a signal to obtain vasopressors and IV fluids. Predicting pharmacotherapy needs in advance shortens the lag time from physician order to medication administration, which may be exactly what is needed to have a positive impact on the care of your patient.
Get my 6 tips for pharmacists responding to codes in my free download area at pharmacyjoe.com/free. It’s download #16.
If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.
Your review of the MERINO trial was too simplistic and misses some nuances of the results. Notably, zero deaths were attributed to infection! Also, the MERINO trial is just one of many studies evaluating the most appropriate therapy for ESBL bacteremia. A meta-analysis was published the week after MERINO which showed that carbapenems did not infer a survival benefit compared to non-carbapenem therapy, including BL/BLIs. Finally, the MERINO trial included only 2 patients from the US. The epidemiology of ESBL pathogens is heterogeneous and implying that SE Asian and Australian ESBLs are the same as the US extrapolates too much. . There remains value in prioritizing carbapenem use in specific patient populations, especially those patients with non-urosepsis, patients within the intensive care unit, or patients with an APACHE-II score of greater than 15. Piperacillin/tazobactam or alternative therapies may be sufficient for treatment of urinary tract infections or non-severe infections. Treatment decisions based on a single data point, such as the identification of ESBL genetic profile, does not account for patient acuity, pathogen minimum-inhibitory concentration, or risk of antibiotic resistance.
– Lucas Schulz, PharmD, BCIDP
Hi Lucas, thanks for writing about the additional details of the study.
It sounds like we both agree on the implications for practice: