Key takeaways:
- New antibiotics offer a wide range of advantages including more convenient dosing and administration.
- Some novel antimicrobials offer oral options so you can switch patients from IV to oral sooner.
- Some novel antibiotics can combat multidrug-resistant bacteria that knock out older agents.
- Many novel agents come with a high cost and may need prior authorization.
In an update on antibiotic resistance that the CDC released in 2024, the agency noted that the incidence of antimicrobial resistance for six hospital-onset infections—carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Acinetobacter, C. auris, VRE, ESBL-producing Enterobacterales and multidrug-resistant Pseudomonas aeruginosa—had increased 20% over the course of the pandemic.
“We know that resistance thrives when we overuse antibiotics or don’t adhere to optimal dosing,” said Jose Mercado, MD, a hospitalist at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. Dr. Mercado moderated a recent session presented by the Society of Hospital Medicine on novel antimicrobials.
Other tactics to minimize resistance include shorter drug courses and oral options. “We want to challenge the status quo of prolonged IV therapy,” said Dr. Mercado. “That’s where novel agents can improve care.”
Central lines, of course, come with the risk of bloodstream infections, as well as logistical burdens and additional costs. The longer half-life of some new agents—think dalbavancin—can improve patient adherence and minimize resistance. And “having new oral agents allows us to switch to oral sooner.”
“We want to challenge the status quo of prolonged IV therapy. That’s where novel agents can improve care.”
Jose Mercado, MD
Dartmouth-Hitchcock Medical Center
A May 2024 study in The Lancet randomized patients with low-risk S. aureus bacteremia after five to seven days of IV therapy to either oral antibiotics or continued standard IV therapy. The primary endpoint was the occurrence of complications within 90 days.
The results: “Switching to early oral therapy showed no worse outcomes and was noninferior,” noted Dr. Mercado, who—along with his colleague, Julie Ann Justo, PharmD, MS, infectious diseases clinical pharmacist lead at Dartmouth Hitchcock Medical Center—discussed newer agents. “This challenges the belief that longer IV is always safer. Think about your last patient who was on six weeks of IV therapy. How could we have improved their experience and outcome?”
Dalbavancin
Dr. Mercado began the review of novel antibiotics with dalbavancin, a second generation lipoglycopeptide that the FDA approved in 2014.
“Its lipophilic tail significantly increases its protein binding and confers a much longer half-life than vancomycin: 14.4 days vs. 8 hours,” he pointed out. “A few other changes to its chemical structure improve its potency against gram-positive bacteria including MRSA and coagulase-negative staphylococci.”
While dalbavancin was approved to treat acute bacterial skin and skin structure infections (ABSSIs), “we are increasingly utilizing it off-label to treat bloodstream infections, osteomyelitis and infective endocarditis.” It is also, Dr. Mercado added, well-tolerated with less nephrotoxicity and ototoxicity than vancomycin.
In a study published by JAMA in August 2025, patients with complicated S. aureus bacteremia were randomized to either two doses of dalbavancin infused one week apart or daily infusions of standard IV antibiotics for four to eight weeks. Patients were excluded if they had uncomplicated bacteremia, CNS involvement, left-sided endocarditis, or retained infected prosthetic material, or were severely immune compromised.
“Some drugs address an unmet need in the market: the growing incidence of multidrug-resistant, gram-negative organisms that cause community-acquired urinary tract infections.”
Julie Ann Justo, PharmD, MS
Dartmouth Hitchcock Medical Center
As for the primary endpoint, which was a composite outcome at 70 days, dalbavancin demonstrated a similar risk-to-benefit profile as standard IV therapy. In terms of safety outcomes, results across both arms were also similar.
“Overall, this supports how dalbavancin could reduce the risk of long-term IV infusions and simplify treatment logistics, presumably offering a more favorable strategy from patients’ perspective,” Dr. Mercado said. “Would your patients rather have daily infusions or two visits?”
One specific patient population who may benefit from such a strategy is patients who inject drugs.
So far, Dr. Mercado pointed out, only small retrospective studies (not randomized trials) have provided evidence for better adherence with dalbavancin. Still, results suggest that dalbavancin improves compliance and utilizes fewer health care resources, with shorter hospital stays and more home discharges.
Tedizolid
Tedizolid was the next agent discussed, and it—like dalbavancin—was approved in 2014. It was approved for ABSSIs in both adult and pediatric patients, including infants and neonates, which is “particularly helpful,” Dr. Justo said.
It belongs to the oxazolidinone drug class, and doctors will be most familiar with an older oxazolidinone, linezolid.
“While linezolid is something you might consider as either an IV or oral option for serious gram-positive infections, including ABSSIs, patients won’t always tolerate it, particularly for longer durations of beyond 10 to 14 days,” said Dr. Justo. “This is often where tedizolid may come into play.”
Like linezolid, tedizolid inhibits bacterial protein synthesis. Its dosing is convenient, she added, with tedizolid given 200 mg IV or PO once daily for six days.
That six-day duration, Dr. Justo pointed out, is specifically for ABSSIs. “As an ID pharmacist, I have sometimes recommended longer durations of tedizolid beyond six days off-label for other serious infections, with close monitoring for effectiveness and toxicity.”
The drug has a similarly broad coverage for both gram-positive aerobes and anaerobes including MSSA, MRSA, streptococci and enterococci like VRE. But its shorter duration—six days vs. 10 days for linezolid—is an advantage that may offer decreased toxicity.
“Linezolid is known for hematologic toxicities that manifest in the form of cytopenias, particularly thrombocytopenia,” Dr. Justo pointed out. When linezolid is used longer-term, such as over months to treat mycobacterial infections, “linezolid is also well-known for causing neuropathies.”
With tedizolid dosing of 200 mg per day vs. linezolid’s 600 mg twice a day, tedizolid offers, in theory at least, “lower toxicities compared to linezolid.”
“In theory” only, Dr. Justo admitted, because published data on a wide variety of patients taking tedizolid beyond six days is relatively scant. But those data are emerging and preliminarily suggest that, “the incidence of side effects are potentially lower with tedizolid than linezolid.”
At the same time, tedizolid offers lower risk of serotonin syndrome than linezolid, again due to lower dosing. That’s important because of other medications patients might be taking, such as SSRIs.
So why aren’t doctors using this drug more regularly? “Tedizolid hasn’t overtaken linezolid’s market share in the U.S. because it’s still a branded product,” Dr. Justo said. “That means the cost is relatively high, and its use often requires prior authorization from an insurer.”
Omadacycline
As Dr. Justo noted, omadacycline was approved in 2018, offers both IV and oral options, and has a lot of benefits.
“I’m going to sing its praises,” she said, “but it’s still expensive and it requires prior authorization for most patients in the U.S., which is part of the reason why you don’t see it used that often.” However, the antimicrobial “might come in handy in certain patient cases.”
As a tetracycline, omadacycline was approved for two indications: community-acquired bacterial pneumonia and ABSSIs, particularly in adults, with doses varying by indication. Dosing also varies by whether the drug is given as IV or oral. After a loading dose, the maintenance dose is only once a day, which makes it excellent for patient adherence and simplicity of care.
Omadacycline also has what Dr. Justo called “a broad spectrum of activity” against gram-positives (MSSA, MRSA, VRE), gram-negatives, atypicals and anaerobes, but not P. aeruginosa nor Proteus species. It overcomes resistance from efflux pumps and ribosomal protection proteins that can render older tetracyclines inactive.
One important pearl: Patients on omadacycline need to fast for at least four hours before they take the drug. “They must take it on an empty stomach with water and then avoid dairy or polyvalent cations for four hours after to ensure appropriate absorption.” That longer fasting period before omadacycline administration, Dr. Justo added, is unique.
The drug also has an emerging role in treating nontuberculous mycobacterial infections. “We’re seeing more of these patients in our ID clinic, so this is a real lifesaver,” Dr. Justo said. “The main barrier remains its high cost, but it is worth the effort to obtain prior authorization, when needed.”
Oral agents for uncomplicated UTIs
Dr. Justo also discussed three novel agents that the FDA approved more recently to treat uncomplicated UTIs.
“These drugs address an unmet need in the market: the growing incidence of multidrug-resistant, gram-negative organisms that cause community-acquired urinary tract infections,” she noted. “We’re seeing an increase in the clinical scenario where patients have to be admitted just for IV antibiotics because we have no oral agents for multidrug-resistant organisms that cause uncomplicated UTIs.”
As Dr. Justo explained, all three agents target extended-spectrum beta-lactamase producing (ESBL) Enterobacterales like E. coli or Klebsiella species. But also on the rise in the U.S.—and much more prevalent internationally—are metallo-betalactamase producing Enterobacterales, such as New Delhi metallo-betalactamase (NDM).
“These bacteria are unfortunately increasing in incidence within the U.S. as well,” Dr. Justo said. “It’s important that these oral drugs can cover those too.”
• Pivmecillinam: This agent, which has been used for decades internationally, was FDA-approved in 2024 to treat adult females with uncomplicated UTIs caused by susceptible E. coli, Proteus mirabilis and S. saprophyticus. It is a prodrug that metabolizes to the active drug mecillinam, a penicillin antibiotic.
The dosing of pivmecillinam is 185 mg PO three times a day for three to seven days. Dr. Justo pointed out that dosing in Europe can be higher and that the drug is sometimes given in combination with probenecid to increase mecillinam blood concentrations.
The drug has a relatively narrow spectrum of activity that is, “really focused on the gram-negative side,” she noted. “It does retain activity against gram-negative bacteria that produce important beta-lactamases, such as ESBLs.” It does not, however, have activity against Pseudomonas aeruginosa, Serratia marcescens, E. faecalis or S. aureus.
And pivmecillinam has still not been distributed in the U.S., although “we’re hoping it can make it to market by the fourth quarter of 2025,” Dr. Justo said. Pricing is not yet available.
• Sulopenem etzadroxil/probenecid: When the FDA approved this drug in fall 2024, Dr. Justo said a common tagline was that it was the first oral carbapenem to come to market.
“But it’s not actually a carbapenem. Its chemical structure is slightly different, making it a penem antibiotic, specifically a thiopenem,” she noted. Sulopenem etzadroxil is a prodrug converted to sulopenem in the human body; it is combined with probenecid as a booster to maintain adequate concentrations of sulopenem. Dosing is 500 mg of sulopenem etzadroxil and 500 mg of probenecid PO twice a day for five days.
“Despite its slightly different chemical structure, sulopenem’s coverage is similar to an IV carbapenem in that it retains activity against gram-negative Enterobacterales producing beta-lactamases like ESBLs and NDM,” she noted. “Importantly, this agent lacks activity against Pseudomonas aeruginosa, enterococci or MRSA.”
The FDA required the drug company to include on the label that this drug is not indicated for complicated UTIs or complicated intraabdominal infection,” Dr. Justo noted. “This drug failed to demonstrate sufficient clinical effectiveness in patients with these more complicated infections when compared to standard antibiotic therapies.”
That’s a key point, she added. “If you look at the drug development trajectory for new antibiotics over the last decade, uncomplicated UTI was the first step to get a drug to market,” said Dr. Justo. Clinicians would then be eager to use that agent off-label for more serious indications. But “the FDA went out of its way to state that this drug won’t get you there for those more serious indications.”
One potential advantage of this new drug: It does not interact with valproic acid. That has always been one drawback of an IV carbapenem such as meropenem in a patient on valproic acid.
However, sulopenem etzadrozil/probenecid comes with sticker shock. “The average wholesale price for a five-day course was recently released at $3,570,” Dr. Justo said. She noted that her health system’s pharmacy and therapeutics committee (which both she and Dr. Mercado serve on) will be discussing that potential cost to the health system and to patients in-depth.
It is also still unclear whether the drug will be available at community pharmacies or only through a specialty pharmacy, which may be more likely
• Gepotidacin: The final agent that Dr. Justo discussed is “the newest of the bunch,” she said, and was approved earlier this year. Gepotidacin is indicated for uncomplicated UTIs caused by susceptible E. coli, Klebsiella pneumoniae, Citrobacter freundii complex, S. saprophyticus, or E. faecalis in adult females—and in pediatric patients at least 12 years of age who weigh at least 40 kg.
“It is really great to see this drug come out of the gate with that pediatric indication,” said Dr. Justo.
Gepotidacin is a triazaacenaphthylene, a new chemical class that has a similar mechanism of action as fluoroquinolones, but with a unique binding site. Its spectrum of activity is also similar to fluoroquinolones, and it retains activity against gram-negative bacteria producing beta-lactamases like ESBLs.
As for adverse drug events, “gepotidacin has a slightly higher rate of GI intolerance, so the manufacturer suggests patients take it after a meal,” Dr. Justo said. It also has other side effects, such as the risk of QTc prolongation, acetylcholinesterase inhibition, and/or increased risk of C. diff infection.
Also, “when considering use of gepotidacin,” she noted, “you have to check for CYP34A interactions, as gepotidacin itself is a CYP3A4 substrate.”
Probably the most exciting news about this compound is not its use against uncomplicated UTIs, but its activity against Neisseria gonorrhoeae.
“If you come across a case of this that is resistant to ceftriaxone, it’s terrifying,” Dr. Justo said. “Multidrug-resistant Neisseria gonorrhoeae is an urgent public health threat.” The FDA is now considering whether to approve gepotidacin to treat uncomplicated urogenital gonorrhea, she added, “so keep an eye out for more information there in the coming months.”
How these three agents—when available—will be rolled out in hospitals remains an open question, said Dr. Justo.
“We will look at pricing, access and logistics before we make final determinations,” she explained. “For instance, the estimated pricing of sulopenem etzadrozil/probenecid is on par with other high-cost oral antimicrobials that currently require additional steps, such as consultation with infectious diseases and/or antimicrobial stewardship, to ensure patients can reliably access and afford them.”
Phyllis Maguire has been Executive Editor of Today’s Hospitalist since 2006. Based in Bucks County, Pa., her health care interests are hospital medicine and long-term care options. She also likes zydeco, hiking, and reading memoirs and romances.
More on novel antimicrobials
WANT TO HEAR more about the new antibiotics coming to market? Earlier this year, hospitalist Jose Mercado, MD, and his colleague, Julie Ann Justo, PharmD, MS, infectious diseases lead clinical pharmacist, both at Dartmouth Hitchcock Medical Center in Lebanon, N.H., discussed novel agents in “The bug stops here: novel antimicrobials” part 1 and part 2 on Dartmouth Health’s podcast The Cure.
