Reason for Hope: Promising Gram-Negative Infection Treatments in the Pipeline

Gram-negative bacteria are the world’s highest-priority pathogens because of their resistance to antibiotics, the speed with which they develop new resistance, and their ability to pass along genetic material that allows other bacteria to become drug-resistant as well.¹ A number of recent studies report on new innovative compounds that are effective and less prone to development of resistance for infections caused by tough-to-treat Gram-negative bacteria, including carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae (CRE), pathogens that the World Health Organization rank as “critical.”¹ New data presented at IDWeek 2017, held October 4 to 8 in San Diego, California, provides reason for hope in the ongoing effort to keep pace with emerging threats of antibiotic resistance.

Plazomicin for Complicated Urinary Tract Infection and Acute Pyelonephritis

Several IDWeek presentations described studies involving plazomicin, a next-generation aminoglycoside antibiotic derived from sisomicin.^2-4 The antibiotic has breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of recalcitrant bloodstream infections caused by Enterobacteriaceae and has been fast-tracked for regulatory review for treatment of CRE infections.^5-6

In the pivotal EPIC (Evaluating Plazomicin in Complicated Urinary Tract Infection; ClinicalTrials.gov identifier: NCT02486627) trial,² 388 adult patients hospitalized with complicated urinary tract infection (cUTI), including acute pyelonephritis (AP), were randomly assigned to intravenous (IV) plazomicin or IV meropenem. Clinical and microbiological responses, and the composite cure involving both, were evaluated. Plazomicin was noninferior to meropenem at day 5 of treatment for the composite cure. The clinical cure at that time favored plazomicin. At the final follow-up, the rates of composite cure and microbiologic cure were higher for the plazomicin group than the meropenem group. The clinical cure rates were comparable. The rates of clinical and microbiologic relapse favored plazomicin.

The CARE (Combating Antibiotic Resistant Enterobacteriaceae; ClinicalTrials.gov identifier: NCT01970371) randomized phase 3 trial compared plazomicin with colistin in the treatment of serious CRE bloodstream or ventilator-associated infections.⁷ At day 28, the rate of mortality or serious disease-related complications was 23.5% and 50% in the plazomicin and colistin groups, respectively. In patients with bloodstream infections, all-cause mortality or significant complications at day 28 were 14.3% and 53.3% in the respective groups. Through day 60, the rate of death in patients with bloodstream infections was 63% less in the plazomicin group.

The EPIC and CARE data met the approval benchmarks for the FDA and the European Medicines Agency. A New Drug Application (NDA) was submitted to the FDA in late October 2017, and a European Medicines Agency approval submission is anticipated in 2018.⁶

Meropenem/Vaborbactam

The combination of meropenem and vaborbactam demonstrated convincing success in the TANGO-2 phase 3 trial against CRE infections compared with best available therapy.^8-12 The trial was stopped early when an interim analysis indicated that randomization of patients to the comparator was not warranted. The results were bolstered by the concurrent demonstration of the efficacy of meropenem-vaborbactam against more than 14,000 Gram-negative clinical isolates.¹³ The drug recently was approved by the FDA for treatment of adults with cUTIs. Approval for treatment of CRE is anticipated.

Cefiderocol for cUTI or AP

Cefiderocol is a novel siderophore cephalosporin antibiotic being developed as a treatment for multidrug-resistant (MDR) Gram-negative infections. The APEKS-cUTI study¹⁴ reported the clinical efficacy of cefiderocol in the treatment of cUTI and uncomplicated AP. A total of 371 adult patients with cUTI or AP were randomly assigned to regular IV infusions of cefiderocol or imipenem/cilastatin. Cefiderocol was noninferior to imipenem/cilastatin in clinical and microbiologic responses, and was well-tolerated with comparable rates of adverse events (AEs) and serious AEs.

Ceftolozane/Tazobactam for MDR Pseudomonas aeruginosa

A retrospective study¹⁵ of outcomes of 30 patients with MDR Pseudomonas aeruginosa respiratory infections indicated the efficacy of the combination of the novel cephalosporin and the established β-lactamase inhibitor and provides evidence supporting the expanded use of ceftolozane/tazobactam. The combination is currently approved for complicated intra-abdominal infections (cIAIs) and cUTIs, and has been implicated as being useful for pneumonia caused by carbapenem-resistant P aeruginosa.¹⁶ Nearly 90% of the patients in the analysis harbored MDR P aeruginosa. The initial antibiotic therapy was unsuccessful in two-thirds of the patients. Ceftolozane/tazobactam was clinically successful in 80% of all patients, and 12 of 13 had documented eradication of the bacteria.

Ceftazidime-Avibactam for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia

The phase 3 randomized, double-blind, noninferiority REPROVE clinical trial (ClinicalTrials.gov identifier: NCT01808092) randomly assigned 870 patients with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) to IV ceftazidime plus avibactam or meropenem.¹⁷ The study groups were comparable for day 28 all-cause mortality (9.6% vs 8.3%) and for the rates of clinical cure in several assessed categories, including the intent-to-treat population (67.2% vs 69.1%). The treatments were comparably efficacious in subgroups including ventilated patients, patients with HABP or VABP, and patients with normal or impaired renal clearance. The trial was the first phase 3 HABP/VABP study to meet the 2014 FDA guidance benchmarks.