New Research Reinforces Efficacy of Plazomicin

Research presented at the 2018 ASM Microbe Meeting has reinforced the value of the just-approved next-generation aminoglycoside antibiotic, plazomicin, in treating multidrug-resistant Enterobacteriaceae, including carbapenem-resistant Enterobacteriaceae (CRE) in adults with complicated urinary tract infections (cUTI) including acute pyelonephritis, caused by certain Enterobacteriaceae, in patients with limited or no options for alternative treatment.

The first study, an evaluation of the activity of plazomicin against over 6400 clinical isolates gathered worldwide during 2017, revealed the prowess of the antibiotic in inhibiting the growth of virtually all Enterobacteriaceae isolates, including CRE, and over 90% of isolates resistant to gentamicin and tobramycin.

Mariana Castanheira, PhD, and colleagues at JMI Laboratories in North Liberty, Iowa, harnessed their extensive global database of clinical isolates to explore the efficacy of plazomicin. Investigators examined 6417 isolates gathered from 90 hospitals in 2017 as part of the Antimicrobial Longitudinal Evaluation and Resistance Trends program. The isolates included 5658 Enterobacteriaceae, 438 gram-positive species, 167 Pseudomonas aeruginosa, and 154 Acinetobacter spp. The sources of infections were 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 inhibited the growth of 96.7% and 99.0% of Enterobacteriaceae isolates at ≤2 and ≤4 µg/mL, respectively. The activity was similar for the most common species, including Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. When supplied at ≤4 µg/mL, plazomicin inhibited the growth of 90.2% (185/204) of CRE isolates.

Furthermore, plazomicin inhibited 94.8% (726/766) of gentamicin-resistant isolates and 94.9% (672/708) of tobramycin-resistant isolates. The activities were similar irrespective of geographic region. Impressive activities against P aeruginosa and coagulase-negative staphylococci were evident. Activities against A baumannii, Enterococcus spp, and Streptococcus pneumoniae were limited.

“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,” said Dr. Castanheira.

The other study modeled the pharmacokinetics of plazomcin activity using pooled data from phase 1, 2, and 3 studies has clarified the real-time activity of plazomicin and indicated that age, sex, race, or infection type do not influence decisions concerning dose.

For this study, 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 to colistin against CRE.

The pharmacokinetic modeling was based on 4990 measurements of plasma levels of plazomicin in samples collected from 564 individuals (143 healthy subjects and 421 adult patients). The people 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 modeling revealed that the activity of plazomicin was influenced mainly by the speed that the drug moves from the blood to the site of infection and kidney function assessed by the rate of the clearance of creatinine.

“Based on the results, no dosage adjustment is required on the basis of age, sex, race, or infection type,” said Dr. Trang during a poster discussion session attended by Contagion^®.

“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,” said Dr. Trang.

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 FDA-approval of the use of plazomicin to treat cUTI was granted on June 26, 2018. 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.

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.