Multidrug-resistant gram-negative infections (MDRGNIs) are an emerging and deadly threat worldwide. Some of these infections are now resistant to nearly all antibiotics, and very few treatment options exist. Some of the remaining antibiotics for these MDRGNIs can cause acute kidney injury and have other toxic effects and can worsen antibiotic resistance. When deciding which drugs to use, clinicians need to juggle the possible lethality of the infection with the dangers of its treatment.
Samuel Windham, MD, and Marin H. Kollef, MD, authors of a recent article in Current Opinion in Infectious Diseases, express this urgency. They offer recommendations based on current guidelines and recently published research for treating MDRGNIs with some of the newer antibiotics.
Dr. Kollef, professor of pulmonary and critical care medicine at Washington University in St. Louis, said in an email, “Our recommendations differ in that they offer an approach that is based on disease severity, local resistance prevalence in MDRGNIs, and patient risk factors for infection with MDRGNIs. For patients with severe infection and risk factors for infection with MDRGNIs, we suggest empiric coverage for MDRGNIs until susceptibility data are available or based on rapid molecular testing. Selection of antibiotic therapy would be based on which MDRGNIs predominate locally.”
In their article, the authors discuss how to best utilize the newer antibiotics of ceftazidime-avibactam (CZA), cefiderocol, ceftolozane-tazobactam (C/T), meropenem-vaborbactam (MVB), imipenem-relebactam (I-R), aztreonam-avibactam (ATM-AVI), eravacycline, and plazomicin.
The scope of the problem
Bacterial infections are deadly and are becoming less treatable. The Centers for Disease Control and Prevention reported in 2022 that the COVID-19 pandemic has reversed years of decreases in health care–associated infections. Much of the increase has been caused by multidrug-resistant organisms.
In November 2022, authors of an article published in The Lancet estimated worldwide deaths from 33 bacterial genera across 11 infectious syndromes. They found that these infections were the second leading cause of death worldwide in 2019 (ischemic heart disease was the first). Furthermore, they discovered that 54.9% of these deaths were attributable to just five pathogens – Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Three of those five bacterial species – E. coli, K. pneumoniae, and P. aeruginosa – are gram-negative and are highly prone to drug resistance.
The CDC classified each of those three pathogens as an “urgent threat” in its 2019 Antibiotic Resistance Threats in the United States report. Of particular concern are gram-negative infections that have become resistant to carbapenems, a heavy-hitting class of antibiotics.
Regarding organisms that cause MDRGNIs, known as serine-beta-lactamases (OXA, KPC, and CTX-M) and metallo-beta-lactamases (NDM, VIM, and IMP). Carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumanii also produce carbapenemases, rendering them invulnerable to carbapenem antibiotics.
Traditionally, a common alternative used for carbapenem-resistant infections has been colistin, an older and very toxic antibiotic. The authors cite recent research demonstrating that CZA yields significantly better outcomes with regard to patient mortality and acute kidney injury than colistin and that CZA plus aztreonam can even decrease mortality and length of hospital stay for patients who have bloodstream infections with metallo-beta-lactamase-producing Enterobacterales, which are some of the hardest infections to treat.
“CZA has been demonstrated to have excellent activity against MDR Pseudomonas aeruginosa and KPC Enterobacterales. It should be the preferred agent for use, compared with colistin, for the treatment of carbapenem-resistant gram-negative bacteria susceptible to CZA. Moreover, CZA combined with aztreonam has been shown to be an effective treatment for metallo-beta-lactamase MDRGNIs,” Dr. Kollef said.