さまよう薬剤師のブログ

学位を持っても、センスのない、感染制御専門薬剤師のブログ.  I have Ph.D. but less sense a ID pharmacist. Another face is an investor.

Plazomicin

先日FDAに承認された、Plazomicin。

 

感想

  • 新しく承認されたアミグリコシド
  • CREとESBL産生菌に期待できる
  • 尿路以外で、アミグリコシド単剤での治療は、困難かもしれないが、武器が増えることは嬉しい。
  • 副作用は、腎毒性、毒性、神経炎、胎児麻痺。TDM対象薬

 

 

About ZEMDRI


ZEMDRI is an aminoglycoside with once-daily dosing that has activity against certain Enterobacteriaceae, including CRE and ESBL- producing Enterobacteriaceae. Achaogen's EPIC clinical trial successfully evaluated the safety and efficacy of ZEMDRI in adult patients with cUTI, including pyelonephritis. ZEMDRI was engineered to overcome aminoglycoside-modifying enzymes, the most common aminoglycoside-resistance mechanism in Enterobacteriaceae, and has in vitroactivity against ESBL- producing, aminoglycoside- resistant, and carbapenem- resistant isolates. The Centers for Disease Control and Prevention (CDC) has characterized ESBL- producing Enterobacteriaceae as a "serious threat" and CRE as "nightmare bacteria", which is an immediate public health threat that requires urgent and aggressive action. 

 

ZEMDRI Phase 3 Clinical Results
The approval of ZEMDRI is supported in part by data from the EPIC (Evaluating Plazomicin In cUTI) clinical trial, which was the first randomized controlled study of once-daily aminoglycoside therapy for the treatment of cUTI, including pyelonephritis.

In the Phase 3 EPIC cUTI trial, ZEMDRI demonstrated non-inferiority to meropenem for the co-primary efficacy endpoints of composite cure (clinical cure and microbiological eradication) in the microbiological modified intent-to-treat (mMITT; N=388) population at Day 5 and test-of-cure (TOC) visit (Day 17 + 2). Composite cure rates at Day 5 were 88.0% (168/191) for ZEMDRI vs 91.4% (180/197) for meropenem (difference -3.4%, 95% CI, -10.0 to 3.1). Composite cure rates at TOC were 81.7% (156/191) for ZEMDRI vs 70.1% (138/197) for meropenem (difference 11.6%, 95% CI, 2.7 to 20.3). Composite cure at the TOC visit in patients with concomitant bacteremia at baseline was achieved in 72.0% (18/25) of patients in the ZEMDRI group and 56.5% (13/23) of patients in the meropenem group. The most common side effects (≥1% of patients treated with ZEMDRI) were decreased kidney function, diarrhea, hypertension, headache, nausea, vomiting, and hypotension.1

The FDA approved a breakpoint of <= 2 mcg/mL; greater than 99% of Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae in U.S. surveillance are susceptible to Zemdri when applying this breakpoint.2

Important Safety Information

BOXED WARNINGS: NEPHROTOXICITY, OTOTOXICITY, NEUROMUSCULAR BLOCKADE AND FETAL HARM

  • Nephrotoxicity has been reported with ZEMDRI. The risk of nephrotoxicity is greater in patients with impaired renal function, the elderly, and in those receiving concomitant nephrotoxic medications. Assess creatinine clearance in all patients prior to initiating therapy and daily during therapy. Therapeutic Drug Monitoring (TDM) is recommended for complicated urinary tract infection (cUTI) patients with CLcr less than 90 mL/min to avoid potentially toxic levels.
     
  • Ototoxicity, manifested as hearing loss, tinnitus, and/or vertigo, has been reported with ZEMDRI.Symptoms of aminoglycoside-associated ototoxicity may be irreversible and may not become evident until after completion of therapy. Aminoglycoside-associated ototoxicity has been observed primarily in patients with a family history of hearing loss, patients with renal impairment, and in patients receiving higher doses and/or longer durations of therapy than recommended.
     
  • Aminoglycosides have been associated with neuromuscular blockade. During therapy with ZEMDRI, monitor for adverse reactions associated with neuromuscular blockade particularly in high-risk patients, such as patients with underlying neuromuscular disorders (including myasthenia gravis) or in patients concomitantly receiving neuromuscular blocking agents.
  • Aminoglycosides, including ZEMDRI, can cause fetal harm when administered to a pregnant woman.

 

 

www.ncbi.nlm.nih.gov

 

increasing antimicrobial resistance among uropathogens limits treatment options for patients with complicated urinary tract infection (cUTI). Plazomicin, a new aminoglycoside, has in vitro activity against multidrug-resistant Enterobacteriaceae, including isolates resistant to currently available aminoglycosides, as well as extended-spectrum β-lactamase-producing and carbapenem-resistant Enterobacteriaceae We evaluated the efficacy and safety of plazomicin in a double-blind, comparator-controlled, phase 2 study in adults with cUTI or acute pyelonephritis. Patients were randomized 1:1:1 to receive intravenous plazomicin (10 or 15 mg/kg of body weight) or intravenous levofloxacin (750 mg) once daily for 5 days. Coprimary efficacy endpoints were microbiological eradication at the test of cure (TOC; 5 to 12 days after the last dose) in the modified intent-to-treat (MITT) and microbiologically evaluable (ME) populations. Overall, 145 patients were randomized to treatment. In the groups receiving plazomicin at 10 mg/kg, plazomicin at 15 mg/kg, and levofloxacin, microbiological eradication rates were, respectively, 50.0% (6 patients with microbiological eradication at TOC/12 patients treated [95% confidence interval {CI}, 21.1 to 78.9%]), 60.8% (31/51 [95% CI, 46.1 to 74.2%]), and 58.6% (17/29 [95% CI, 38.9 to 76.5%]) in the MITT population and 85.7% (6/7 [95% CI, 42.1 to 99.6%]), 88.6% (31/35 [95% CI, 73.3 to 96.8%]), and 81.0% (17/21 [95% CI, 58.1 to 94.6%]) in the ME population. In the MITT population, 66.7% (95% CI, 34.9 to 90.1%), 70.6% (95% CI, 56.2 to 82.5%), and 65.5% (95% CI, 45.7 to 82.1%) of the patients in the three groups, respectively, were assessed by the investigator to be clinically cured at TOC. Adverse events were reported in 31.8%, 35.1%, and 47.7% of the patients in the three groups, respectively. Serum creatinine values were generally stable over the course of the study. No plazomicin-treated patients with evaluable audiometry data had postbaseline sensorineural, conductive, or mixed hearing loss. In summary, plazomicin demonstrated microbiological and clinical success and an overall safety profile supportive of further clinical development. (This study has been registered at ClinicalTrials.gov under identifier NCT01096849.).