New Antibiotic Combination IMI/REL Can Treat Resistant Infection With Less Kidney Toxicity Interview with:

Michelle Hoffman Brown Associate Principal Scientist at Merck Merck

Michelle Brown

Michelle Hoffman Brown
Associate Principal Scientist
Merck What is the background for this study? What are the kidney risks of using colistin to treat carbapenem-resistant bacterial infections?

Response: Gram-negative pathogens are responsible for half of all healthcare-associated infections and their ability to resist traditional antibiotics makes them more dangerous for seriously ill patients in a healthcare setting. The need for new approaches to treat these pathogens is essential and this trial aimed to evaluate the efficacy and safety of imipenem/relebactam (IMI/REL) for the treatment of these challenging infections.

Nephrotoxicity is a common complication of colistin-based therapy and is the potential adverse experience of greatest concern to prescribing clinicians, limiting its use to treat carbapenem-resistant bacterial infections. Relebactam is a novel β-lactamase inhibitor that restores imipenem activity against many imipenem-non-susceptible strains of Gram-negative pathogens. In the Phase 3 RESTORE-IMI 1 study (NCT02452047), IMI/REL was shown to be as effective as, but better tolerated than, colistin plus imipenem, including as demonstrated by a lower incidence of treatment-emergent nephrotoxicity (prespecified secondary endpoint). This analysis looked at additional renal safety data from the RESTORE-IMI 1 trial. What are the main findings? How does Relebactam differ from bacterial inhibitors?

Response: A total of 47 patients were randomized, treated (31 IMI/REL, 16 colistin + IMI), and included in this analysis. Overall, the study showed that IMI/REL was efficacious in the treatment of MDR infections and was better tolerated than treatment with colistin.

The analyses of nephrotoxicity described in the IDWeek poster demonstrated that a significantly smaller percentage of patients in the IMI/REL than the colistin + IMI group experienced protocol-defined nephrotoxicity (% difference: -45.9 [95% CI: -69.1, -18.4]; P=.002) during study treatment and the 14-day follow-up period. These results were confirmed by applying KDIGO (Kidney Disease: Improving Global Outcomes) and RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) acute kidney injury (AKI) criteria, with no patients in the IMI/REL group in stage 3 AKI or failure compared with 31.3% and 25.0%, respectively, in the colistin + IMI group. Fewer renal adverse events, including discontinuations due to renal events, were observed in the IMI/REL group.

The magnitude of difference in nephrotoxicity observed between the treatment groups in this carefully controlled clinical study was a remarkable finding. While colistin’s association with nephrotoxicity is well established, clinical data from blinded, randomized trials describing the scope of potential renal injury due to colistin are limited. This trial was unique in its double-blind design and use of a defined colistin regimen based on current literature and rigorous PK/PD modeling that balanced drug exposure in terms of both safety and efficacy. Despite the controlled dose of colistin, with dose adjustment for decreased renal function, the double-blind design to minimize bias in categorization of adverse events, and pre-specified objective protocol criteria for defining nephrotoxicity, a significant difference was noted in renal safety in several analyses of AKI.

The development of resistance to β-lactamase antibacterials through the production of β-lactamases is

an important resistance mechanism among Gram-negative bacteria. β-lactamases inactivate β-lactamase antibiotics by hydrolysing the β-lactam amide bond to produce a ring-opened structure that no longer has antibacterial activity. Relebactam is a non-β-lactam, small molecule diazabicyclooctane (DABCO) β-lactamase inhibitor with activity against class A carbapenemases (such as KPC), ESBLs, and class C cephalosporinases (including AmpC). In combination with imipenem, relebactam has shown potentiation of imipenem’s antibacterial activity by inactivating β-lactamases. Neither imipenem nor relebactam are subject to efflux pumps in Pseudomonas aeruginosa, enabling the activity of the IMI/REL combination in organisms with this resistance mechanism. What should readers take away from your report?

Response: The bottom line is that IMI/REL demonstrated a more favorable renal safety profile compared with colistin-based therapy, a commonly used treatment regimen for carbapenem-resistant pathogens, as demonstrated by a lower incidence of treatment-emergent nephrotoxicity and AKI with IMI/REL across several different analyses.

Patients who have acquired a serious infection caused by multidrug-resistant (MDR) Gram-negative bacteria generally are at greater risk for adverse outcomes, have increased hospital length of stays, and have increased healthcare costs. There are few options available for these difficult-to-treat infections, and physicians have turned to older antibacterials such as colistin. This study demonstrated that IMI/REL was efficacious in the treatment of MDR infections and was better tolerated than treatment with colistin. These findings suggest that IMI/REL could provide a new treatment option for serious, hard-to-treat Gram-negative bacterial infections, with a lower likelihood of renal toxicity than this commonly used standard-of-care treatment regimen. What recommendations do you have for future research as a result of this work?

Response: The completed Phase 3 trial in resistant infections will be the basis of the initial US filing. IMI/REL was previously granted QIDP/Fast Track status by the FDA given its potential in an area of unmet medical need. Merck is conducting a second pivotal Phase 3 clinical study, RESTORE-IMI 2, comparing treatment with IMI/REL versus piperacillin/tazobactam in patients with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). Is there anything else you would like to add?

Response: According to the CDC, more than 23,000 people in the United States die each year from infections caused by resistant organisms, which are difficult to treat due to limited available treatment options and to toxicity associated with some treatments.

Effective, safe treatments are needed for patients with these infections. Findings from this trial suggest that IMI/REL could provide a new treatment option for such patients.


ID Week18 abstract:

Nephrotoxicity associated with imipenem/cilastatin/relebactam (IMI/REL) versus imipenem/cilastatin plus colistin (IMI+CST) in patients with imipenem-nonsusceptible (NS) bacterial infections

Oct 6, 2018 @ 7:45 pm 

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