Efficacy of Plazomicin Reinforced by Additional Research

A new treatment against multidrug-resistant Enterobacteriaceae, including carbapenem-resistant Enterobacteriaceae (CRE), just received US Food and Drug Administration (FDA) approval. The safety and efficacy of the drug—plazomicin, a next-generation aminoglycoside antibiotic—was reinforced by additional research presented at the 2018 ASM Microbe Meeting, held June 7—11, 2018, in Atlanta, Georgia.

The results of the first study, in which investigators evaluated the activity of plazomicin against over 6400 clinical isolates from around the world, revealed the prowess of the plazomicin in inhibiting the growth of virtually all Enterobacteriaceae isolates, including CRE, and over 90% of isolates resistant to gentamicin and tobramycin.

For the study, investigators examined 6417 isolates from 90 international hospitals in 2017 as part of the Antimicrobial Longitudinal Evaluation and Resistance Trends program. A total of 5658 of the isolates were Enterobacteriaceae, 438 were gram-positive species, were 167 Pseudomonas aeruginosa, and 154 were Acinetobacter spp. The sources of infections were identified as bloodstream infections (BSI; 28.1% of cases), urinary tract infections (UTI; 22.3%), pneumonia in hospitalized patients (21.0%), skin and skin structure infections (16.4%), intra-abdominal infections (9.9%), and others (2.3%).

Plazomicin was shown to inhibit the growth of 96.7% and 99.0% of Enterobacteriaceae isolates at ≤2 and ≤4 µg/mL, respectively. Activity was similar across the most common species, including Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. At ≤4 µg/mL, plazomicin inhibited the growth of 90.2% (185/204) of CRE isolates.

A total of 94.8% (726/766) of gentamicin-resistant isolates and 94.9% (672/708) of tobramycin-resistant isolates were inhibited by plazomicin. The activities were similar regardless of geographic region. Impressive activities against P aeruginosa and coagulase-negative staphylococci were evident. Limited activity was seen against A baumannii, Enterococcus spp., and Streptococcus pneumoniae.

According to investigator Mariana Castanheira, PhD, from JMI Laboratories in North Liberty, Iowa, “These results corroborate previous reports from the literature that describe plazomicin as a potential agent for the treatment of serious infections caused by Enterobacteriaceae isolates, including CRE, in patients who have limited alternative treatment options.”

The pharmacokinetics of plazomicin activity was modeled in the second study, which used pooled data from phase 1, 2, and 3 studies. The results clarified the real-time activity of the antibiotics and showed that age, sex, race, or infection type do not influence decisions regarding dose.

Michael Trang, PharmD, Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, and colleagues examined the pharmacokinetics of plazomicin using pooled data from 4 phase 1 studies, 1 phase 2 study, and 2 phase 3 studies. The phase 3 Evaluating Plazomicin In cUTI (EPIC; NCT01970371) and the Combating Antibiotic Resistant Enterobacteriaceae (CARE; NCT01970371) trials compared plazomicin with colistin against CRE.

Pharmacokinetic modeling was based on a total of 4990 measurements of plasma levels of plazomicin in samples collected from 564 individuals (143 healthy subjects and 421 adult patients). The individuals were comparable in terms of body mass index, height and weight. Differences between the individuals included gender prevalence, race, and prevalence in the type of infection, which included complicated UTI (cUTI), BSI, acute pyelonephritis, and hospital-acquired bacterial pneumonia (HAVP) or ventilator-associated bacterial pneumonia (VABP).

The results of the model indicated that activity of plazomicin was influenced largely by the speed in which the drug moved from the blood to the site of the infection, as well as kidney function, assessed by the rate of the clearance of creatinine.

Dr. Trang spoke with MD Magazine^®’s sister publication, Contagion^®, about the results of the study, stating, “Based on the results, no dosage adjustment is required on the basis of age, sex, race, or infection type. The final population pharmacokinetics model for plazomicin was considered reliable for conducting simulations and for generating individual post-hoc estimates of exposure for use in subsequent pharmacokinetic-phamacodynamic analyses for safety and efficacy.”

The EPIC trial enrolled 609 adult patients with cUTIs or acute pyelonephritis. The patients were randomized to 4-7 days of treatment with plazomicin 15 mg/kg every 25 hours or to intravenous meropenem (IV) 1 g every 24 hours. Patients could then opt for oral levofloxacin 500 mg/day for several days. Plazomicin performed significantly better than meropenem in the primary endpoint of microbial eradication (87% vs.72%) and outperformed meropenem in patients with pyelonephritis as well as those complicated UTIs. The superiority of plazomicin was independent of oral levofloxacin.

The as-yet unpublished CARE trial involved 39 patients with BSI, HAVP, or VABP caused by CRE. They were randomized 1:1 to 7-14 days of plazomicin 15 mg/kg every 24 hours or colistin delivered in a 300-mg loading dose followed by daily infusions of 5 mg/kg. Meropenem or tigecycline could be used if necessary.

In the CARE trial, plazomicin was associated with significantly better overall outcomes than colistin concerning the 28-day all-cause mortality and significant disease-related complications, and 28-day all-cause mortality.

Based on the EPIC and CARE results, Achaogen, the developer of plazomicin, submitted a New Drug Application to the US Food and Drug Administration in October 2017. The application was accepted and approved on June 26, 2018, to treat cUTI. A submission to the European Medicines Agency is planned for later in 2018.

The study evaluating plazomicin activity against global insolates was funded by Achaogen, Inc.

The modeling study was publicly funded.

A version of this article was originally published by Contagion^® as “New Research Reinforces the Efficacy of Plazomicin.”DISCLOSURES

Mariana Castanheira, none

Michael Trang, none

PRESENTATIONS

SATURDAY-645 Activity of Plazomicin and Comparator Agents Tested against Contemporary Clin. Isolates Collected Worldwide. M. Castanheira, J. M. Streit, S. Arends, R. K. Flamm; JMI Lab., North Liberty, IA

SUNDAY-516 Population Pharmacokinetic Analyses for Plazomicin Using Pooled Data from Phase 1, 2 and 3 Studies. M. Trang¹, J. Seroogy², S. A. Van Wart¹, S. M. Bhavnani¹, A. Kim², P. G. Ambrose¹, C. M. Rubino¹; ¹ICPD, Schenectady, NY, ²Achaogen, Inc., South San Francisco, CA

Brian Hoyle, PhD, is a medical and science writer and editor from Halifax, Nova Scotia, Canada. He has been a full-time freelance writer/editor for over 15 years. Prior to that, he was a research microbiologist and lab manager of a provincial government water testing lab. He can be reached at hoyle@square-rainbow.com