Sometimes an article pops up addressing a question we have been mulling over for quite some time. It so happened with a recent publication which shed new light on penem dosing for ICU patients[1].
Conducted at a single Belgian centre (sic!), a standard dose of meropenem (1 g IV q8h infused over 30 min) was compared to prolonged 3 h administration of 1 and 2 g q8h, measuring not only plasma exposure but also ELF levels by micro-BAL. PK/PD analyses in this fairly large study of 25 and 30 patients per cohort suggested that we may be underdosing the drug for pneumonia patients. Here the main findings:
- Standard 1 g qh8 dosing achieves adequate attainment rates in plasma but not in ELF
- Not even 2 g IV q8h day infused over 3 hours achieved ELF levels sufficiently high to attain 40% T>MIC profile for pathogens with MIC of 2 mg/L.
In all scenarios, continuous infusion was superior to intermittent standard dosing, not a surprise given earlier work by Nicolau suggesting the same benefit [2]. Again it was noticed that many ICU patients (approx. 30%) had hypernormal Clcr rates of > 120 mL/kg x min; obviously, this subpopulation would really stand to benefit from higher dosing regimens, not just when P.aeruginosa is involved.
Meropenem is approved in Europe for pneumonia (community-acquired and nosocomial) [3]. Dosing recommendations specifically mention that for severely ill patients or infections with borderline susceptible pathogens a dose of 2g q8h should be considered. This is good advice and sound judgement now confirmed by the Frippiat trial. Meropenem is also approved for bacterial meningitis, cUTI, peri-partum infections and for cystic fibrosis patients because these infections are often caused by the same bacteria. In other words: EMA approval was not just indication-driven, but appropriately considered the overlapping pathogen spectrum seen with these infections.
Not so in the US where the indication list is very short: meropenem is only approved for cIAI (1 g q8h) and cSSSI (500 mg q8h or 1 g q8h for P. aeruginosa). Why this difference in labeling when both regulatory authorities certainly had access to the same data? This obvious lack of harmonization is the product of different regulatory philosophies; in contrast, bacteria have no problem achieving global MIC collaboration.
Given FDA’s tough new VAP/HAP standards[4] few companies will attempt to go after this indication. Tigecycline[5] tried and failed, and so did doripenem[6]. Ceftobiprole is in need of funding to run another pneumonia program[7]. HAP/VAP registration trials have become very expensive and no company will make this commitment lightly. But that’s not a concern for regulators.
Is imipenem at 1 g q8h still an acceptable comparator drug for a NI study? I am not sure but as the only penem with a “lower respiratory tract infection” label [8], it should be an acceptable comparator for registration studies although the approved dose seems very suboptimal.
From all we now know about the penems, meropenem at 2 g q8h infused over 3-4 hours could upstage imipenem and become the premier penem for this indication. There may be some concern that such a high-dose regimen may result in higher seizure rates. However, with prolonged dosing, high peak levels are avoided making previous safety concerns less relevant. Any bets?
References:
[1] F Frippiat. JAC 2015; 70:207
[2] Nicolau. CID 2008; 47: S32
[3] http://mri.medagencies.org/download/NL_H_1727_001_PAR.pdf
[4] Draft Guidances from 2010 and most recently 2014 – http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM234907.pdf
[5] http://www.medscape.org/viewarticle/812167
[6] http://www.fda.gov/Drugs/DrugSafety/ucm285883.htm
[7] http://www.basilea.com/chameleon/public/de7cde4b-8150-0816-4ebb-77bfe8cb1ef5/620981.pdfline
[8] http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/050587s076lbl.pdf
