By Marie Rosenthal, MS
Antimicrobial resistance (AMR) is everyone’s problem, according to Robert A. Bonomo, MD, who spoke at MAD-ID 2024, in Orlando, Fla. By 2050, increases in AMR will be responsible for 300 million deaths globally, which is why a strong pipeline for antimicrobial medications is needed.
“We all know that AMR is not getting any better,” said Dr. Bonomo, MD, the senior associate dean and a distinguished university professor at Case Western Reserve University, as well as a clinical scientist investigator for Case VA Center for Antimicrobial Resistance and Epidemiology, in Cleveland.
One of the aspects of AMR that keeps him up at night is the increasing problem of beta-lactamase–mediated resistance. Out of six common forms of resistance, four are mediated by this enzyme: third-generation cephalosporin-resistant Escherichia coli, carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Klebsiella pneumoniae and E.coli, and multidrug-resistant Pseudomonas aeruginosa, he said.
“I'm worried about our society, I'm worried about our world when it comes to AMR,” Dr. Bonomo said. “The hard data show an estimated 5 million deaths associated with AMR in 2019. What worries me the most is that the highest resistance rate will emerge in sub-Sahara Africa, at 27.3 deaths per 100,000 people.”
He noted that these deaths are “a political, economic, medical and social statement.” It is important to recognize this is not just a problem for Africa. Since unusual infections and rare resistant isolates from other countries cross borders into the United States, so global issues become local concerns. AMR cannot be ignored, Dr. Bonomo said.
Resistant organisms dominate the major infections, including lower respiratory tract, bloodstream and intraabdominal. The six leading resistant pathogens associated with deaths are E. coli, K. pneumoniae, A. baumannii (as mentioned above), Staphylococcus aureus, Streptococcus pneumoniae and Pseudomonas aeruginosa. These organisms were responsible for 929,000 deaths attributed to AMR and 3.57 million deaths associated with AMR in 2019, according to Dr. Bonomo (Lancet Reg Health West Pac 2024;43:100972).
Despite the recent introduction of new antimicrobials, a good pipeline is also important because resistance will develop to all of them. The historical relationship has been that an antibiotic is introduced into clinical medicine, it gets used and organisms develop resistance to it.
Dr. Bonomo believes some mechanisms of resistance may be present early, but they are not recognized until society starts using the product (Clin Infect Dis 2024 Jan 30. ciad758, https://doi.org/10.1093/cid/ciad758).
If that proves to be the case, “we are going to have to change our paradigms,” Dr. Bonomo said.
“Why am I worried about current agents in the pipeline?” He asked, adding his concern also extends to newer approved antibiotics, including: ceftazidime-avibactam (Avycaz, Abbvie), imipenem-cilastatin-relebactam (Recarbrio, Merck), meropenem-vaborbactam (Vabomere, Melinta), ceftolozane-tazobactam (Zerbaxa, Merck) and cefiderocol (Fetroja, Shionogi).
“I'm worried because the old paradigm was you introduced the drug and then a couple of years later, you observed resistance in clinic,” he said. “It is only my opinion—the new time line is that drug resistance has emerged already. And when we introduced a new drug into the clinic, we are finding that resistance.”
Although they probably are not enough, some new beta-lactam beta-lactamase inhibitors have entered the pipeline or been recently approved, which Dr. Bonomo described as powerful drugs:
- cefepime-taniborbactam (VenatoRx Pharmaceuticals/Melinta Therapeutics);
- cefepime-zidebactam (Wockhardt);
- sulbactam-durlobactam (sul-dur; Xacduro, Innoviva);
- cefepime-enmetazobactam (Exbilifep, Allecra, Therapeutics); and
- xeruborbactam (Shionogi)
The combination of taniborbactam with cefepime looks very promising in laboratory studies and appears to have good tolerability and safety. In one phase 3 study among hospitalized adults with complicated urinary tract infections (cUTIs) who received IV cefepime-taniborbactam or meropenem every eight hours for seven days (with the possibility of extending to 14 days if needed), cefepime-taniborbactam was 70.6% effective in 207 of 293 patients, while meropenem was 58.0% effective in 83 of 143 patients.
Unfortunately, the FDA issued a complete response letter to VenatoRx and Melinta for their new drug application for cefepime-taniborbactam for cUTIs, but the companies have addressed the manufacturing issues that concerned the FDA, so the agency is reviewing the application again.
A novel product taking a similar approach is xeruborbactam, which when combined with ceftazidime, cefepime or meropenem, significantly decreased the minimum inhibitory values of many metallo-beta-lactamases, including strains producing NDM, VIM, IMP, GIM-1 and DIM-1 enzymes.
“Durlobactam plus sulbactam is also an interesting combination,” Dr. Bonomo said. Durlobactam protects sulbactam from degradation by enzymes that may be produced by A. baumannii, thereby inhibiting its ability to outwit the drug, he explained.
In 2023, the FDA approved sul-dur for hospital-acquired (HABP) and ventilator-associated bacterial pneumonia (VABP) caused by A. baumannii in adult patients.
In a multicenter, active-controlled, open-label (investigator-unblinded, assessor-blinded), noninferiority clinical trial in 177 hospitalized adults with pneumonia caused by carbapenem-resistant A. baumannii (CRAB), patients received either sul-dur or colistin for up to 14 days. Both treatment arms also received an additional antibiotic, imipenem/cilastatin, as background therapy for potential HABP/VABP pathogens other than A. baumannii−calcoaceticus complex. The primary measure of efficacy was all-cause mortality within 28 days of treatment in patients with a confirmed infection with CRAB. Of patients who received sul-dur, 19% (12/63) died, compared with 32% (20/62) who received colistin. This result demonstrated that sul-dur was noninferior to colistin.
Sul-dur is the preferred agent for CRAB, Dr. Bonomo said, but he noted that strain differences could occur among Acinetobacter, so it’s important to watch the data.
“Cefepime-enmetazobactam is a very recent addition,” he said. The FDA approved cefepime-enmetazobactam for the treatment of cUTIs in February. Approval was supported by clinical data demonstrating that cefepime-enmetazobactam was effective against extended-spectrum beta-lactamases (ESBLs) and AmpC. Results from the phase 3 ALLIUM trial showed that cefepime-enmetazobactam was noninferior and in some cases superior to piperacillin-tazobactam in clinical cure and microbiological eradication in patients with cUTIs.
“A novel inhibitor to watch is zidebactam,” Dr. Bonomo said. Zidebactam is a bicyclo-acyl hydrazide beta-lactam enhancer being developed for gram-negative infections. It appears highly active against Enterobacterales and P. aeruginosa, has good activity against Stenotrophomonas maltophilia and Burkholderia cepacia, and retains activity against carbapenem-resistant isolates of Acinetobacter species (J Antimicrob Chemother 2022;77[10]:2642-2649).
Another medication in the pipeline, gepotidacin (GlaxoSmithKline), is a first-in-class, triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by blocking two essential topoisomerase enzymes. This drug will have an advantage because mutations in both enzymes would likely be necessary for resistance to occur, Dr. Bonomo said, so developers hope this medication will maintain long-term effectiveness.
Lastly, a new and interesting drug to consider because of its activity against Acinetobacter is zosurabalpin (RG6006, Roche). This drug effectively treated highly drug-resistant contemporary isolates of CRAB both in vitro and in mouse models of infection, overcoming existing antibiotic resistance mechanisms. This novel class (tethered macrocyclic peptide) blocks the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane.
Dr. Bonomo has received research grants from Allecra, Merck and Wockhardt within the past three years.
