Developing a new antibiotic for extensively drug-resistant pathogens: the case of plazomicin

Abstract

After a long void in the development of new antibiotics against Gram-negative pathogens, five new antibiotics have been approved over the last 4 years. All five antibioticsdceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, plazomicin and eravacyclinedare improved derivatives of well-known antibiotic classes and address class-specific resistance mechanisms. The recent approval of plazomicin prompted us to discuss the clinical development process of these antibiotics and the challenges involved in generating clinical evidence on their efficacy and safety in patients with infections caused by extensively drug-resistant (XDR) or pan-drugeresistant (PDR) Gram-negative bacteria.Plazomicin, a new aminoglycoside related to sisomycin, has been designed to withstand the most common aminoglycosidemodifying enzymes in Enterobacteriaceae, thus providing a new treatment option for carbapenem-resistant Enterobacteriaceae (CRE), which are more likely than others to possess aminoglycoside-modifying enzymes [1]. Its activity against CRE is unrelated to the carbapenem resistance mechanism (unlike the new b-lactam/b-lactamase inhibitor combinations), inhibiting 99% of 97 patient-unique clinical CRE isolates at an MIC of 4 mg/mL, most of which were Klebsiella pneumoniae carbapenemase producers, in a recent survey [2]. However, CRE producing New Delhi metallo-b-lactamase (NDM) are most likely to co-carry the genes for 16S rRNA methylases which affect all aminoglycosides including plazomicin and thus are resistant to these drugs [3]. Plazomicin has less or insufficient activity against Pseudomonas aeruginosa or Acinetobacter baumannii (Castanheira MS et al., 'Activity of plazomicin and comparator agents tested against recent clinical isolates collected in Asia-Pacific, Europe and Latin America,' paper presented at the 27th European Congress of Clinical Microbiology and Infectious Diseases, 2017).Plazomicin was recently approved by the US Food and Drug Administration (FDA) for complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). Approval was based on a single phase 3 randomized controlled trial (RCT), which was a 1:1 noninferiority RCT comparing plazomicin to meropenem, both followed by oral levofloxacin if needed (EPIC study) [4,5]. Plazomicin (306 patients randomized, 191 evaluated) was noninferior to meropenem (303 randomized, 197 evaluated) with respect to a coeprimary outcome of clinical and microbiologic cure at a 15% noninferiority margin. A phase 2 RCT was also completed, recruiting 98 patients with cUTI or AP to different doses of plazomicin (63 evaluated) vs. 47 patients to intravenous levofloxacin (29 evaluated). The high dose of plazomicin (51 patients) resulted in comparable efficacy to levofloxacin. Thus, approval for cUTI and AP was based on these two studies [5].However, the indication of bloodstream infections (BSI) caused by documented or presumed CRE was rejected by the FDA after the failure of the RCT to complete the planned enrolment (CARE study; ClinicalTrials.gov NCT019703...

Non-inferiority versus superiority trial design for new antibiotics in an era of high antimicrobial resistance: the case for post-marketing, adaptive randomised controlled trials

“…NI-RCTs appear to have departed from their primary field of application and are being used to empirically inform new SoC for MDR pathogens. The case for CAZ-AVI is made here, but similar conclusions can be drawn for other antimicrobials effective against MDR GNBs including plazomicin (approved on the ground of a single NI-RCT against meropenem) [79][80] or meropenem-varbobactam (approved on the ground of a single NI-RCT against piperacillin-tazobactam). [80][81][82] The choice of developing these drugs using NI-RCTs, instead of superiority RCTs, is primarily a matter of convenience.…”

“…The case for CAZ-AVI is made here, but similar conclusions can be drawn for other antimicrobials effective against MDR GNBs including plazomicin (approved on the ground of a single NI-RCT against meropenem) [79][80] or meropenem-varbobactam (approved on the ground of a single NI-RCT against piperacillin-tazobactam). [80][81][82] The choice of developing these drugs using NI-RCTs, instead of superiority RCTs, is primarily a matter of convenience. 40 In terms of logistics, a superiority RCT would have required to select only CR infections within a longer study time and higher costs for testing.…”

Difficult-to-Treat Antibiotic-Resistant Gram-Negative Pathogens in the Intensive Care Unit: Epidemiology, Outcomes, and Treatment

“…In vitro studies suggest that plazomicin has activity against most CREs including those isolates that produce KPC and VIM enzymes; however, there is concern that some NDM-producing isolates co-expresse16S rRNA methylase which inactivate the aminoglycoside-binding site in the ribosome inactivating nearly all aminoglycosides including plazomicin. 103,104 In addition to the complicated urinary tract infection indication, FDA approval for bloodstream infections caused by documented or presumed CRE was also sought but was denied because the RCT did not meet its predefined enrollment. 105,106 In this study 39 patients underwent randomization with 18 receiving plazomicin and 21 receiving a colistin-based regimen with an overall microbiological modified intention to treat population of 37 patients with confirmed CRE.…”

The global preclinical antibacterial pipeline

“…The basis of this Review was five databases or programmes with information about antibacterial preclinical research and development projects: the Center for anti-Infective agents (CeFaIa; 1235 data), CaRB-X funding proposals (804), RePaIR Impact Fund funding proposals (80), eNaBle (10 projects with data provided by project owners) and the Joint Programming Initiative on antimicrobial Resistance (JPIamR; 20 projects). No projects from JPIamR could be included because they did not meet the inclusion criteria.…”

“…A noticeable trend towards narrow-spectrum or even pathogen-specific drugs points to the future need of a highly developed diagnostic infrastructure that will be able to provide meaningful and rapid diagnostic results that impact the therapy decision. The challenges of the clinical development and commercialization of a narrow-spectrum or pathogen-specific drug are great as recently exemplified by the new aminoglycoside plazomicin, which was tested in patients with infections with carbapenem-resistant Enterobacteriaceae (mainly K. pneumoniae) 80 . It was extremely difficult to enrol patients with the specified resistant pathogens despite a large number of patients being screened.…”