Update on Novel Antimicrobials and Their Uses

Antimicrobials have been essential to treating infections since their initial use in the early 20th century. Approximately 236 million antibiotic prescriptions are dispensed each year in the US alone.¹ Shortly after the introduction of these medications more than 100 years ago, microorganisms began to develop resistance, and that process has continued to intensify ever since. The CDC reported that in 2019, 2.8 million people were affected by antibiotic-resistant infections, resulting in 35,000 deaths.¹ That same year, the World Health Organization reported 1.27 million deaths globally from antibiotic-resistant infections, which were directly associated with 4.95 million deaths.² The constant battle with resistance is a driving force behind the continued need to develop new antimicrobials. Since 2023, twelve antimicrobials have been approved for use by the FDA (Table).^3-15 Understanding these medications, what novel benefits they offer, and their unique characteristics, potential barriers to use, and where they fit in the overall approach to treatment of infectious disease is essential for their judicious and effective use.

Pivmecillinam (Pivya)

Pivmecillinam has been available as an antibiotic in other countries for many years but was approved by the FDA for use in the US in 2024.^5,16 The prodrug is an oral penicillin-class antibiotic available in tablet form. It is converted to mecillinam.¹⁷ Unlike other penicillins, which may target multiple penicillin-binding proteins (PBPs), pivmecillinam exclusively binds to PBP2 in the cell wall of gram-negative bacteria.³ In a study of 216 patients with uncomplicated cystitis, a 3-day course of pivmecillinam was noninferior to a 7-day course of cephalexin for clinical cure (95.0% vs 93.6%) and bacteriological cure (89.7% vs 81.7%).¹⁸ In a second study, bacteriologic cure after 3 days of pivmecillinam or norfloxacin in adult women with uncomplicated urinary tract infection (uUTI) was significantly higher with norfloxacin (75% vs 91%; P < .001), but there was no difference between the 2 antibiotics in clinical cure and symptom improvement at day 4 after therapy initiation (95% vs 96%; P = .39).¹⁹ A third study evaluating a 3-day regimen of either pivmecillinam or sulfamethoxazole showed no difference in symptom alleviation at days 7 through 10 (95.4% vs 92.6%; 95% CI, –4.5% to 10%), nor a difference in bacteriological cure (68.8% vs 77.9%; 95% CI, –9.2% to 6.3%).²⁰ Although not currently approved for use in men in the US, a retrospective study in Sweden evaluated pivmecillinam, nitrofurantoin, and trimethoprim in 171 adult men and found no significant difference in treatment failure or relapse within 3 months.²¹ A Danish retrospective study of 21,864 adult men and women (including pregnant women) showed that a 3-day course of pivmecillinam was sufficient to treat women younger than 50 years with uUTI, whereas a 5-day course was sufficient to treat both men and women older than 50 years with uUTI.²² Patients in the study with infections from extended-spectrum β-lactamase (ESBL)-producing pathogens required a 5-day course regardless of age.⁸ It should be acknowledged that many of the studies evaluating pivmecillinam were conducted more than 20 years ago, and changes in pathogen susceptibility may have occurred since. However, clinical use with the antibiotic in other countries appears to indicate that it remains effective, and despite not being approved for use in the US at the time, the latest version of the Infectious Diseases Society of America’s guidelines for acute uncomplicated cystitis and pyelonephritis in women listed pivmecillinam as 1 of 4 first-line oral options for uUTIs.²³ It is appropriate to consider pivmecillinam as a co–first-line option for adult women with any uUTI, but it would also be reasonable to reserve its use for patients with known or prior ESBL pathogens.

Gepotidacin (Blujepa)

Gepotidacin is a first-in-class oral triazaacenaphthylene antibiotic that received FDA approval this year to treat uUTI.³ Gepotidacin works by disturbing the replication of bacterial DNA by inhibiting DNA gyrase topoisomerase II and topoisomerase IV. It differs from other antibiotics that have a similar mechanism of action (eg, fluoroquinolones) by specifically binding to the ParC subunit of bacterial topoisomerase IV and the GyrA subunit of bacterial DNA gyrase.²⁴ Though its FDA-approved indication is limited to certain uropathogens, the drug has shown in vitro activity against a much broader spectrum of pathogens, including ESBL-producing organisms (including fluoroquinolone-resistant pathogens), Streptococcus pneumoniae, Staphylococcus aureus, Moraxella catarrhalis, and other bacteria implicated in infections beyond UTIs.^3,24 Two phase 3 studies—EAGLE-2 (NCT04020341) and EAGLE-3 (NCT04187144)—demonstrated that gepotidacin was noninferior to nitrofurantoin in a total of 3136 adults and adolescent females with uUTI.²⁵ The EAGLE-3 study also showed that gepotidacin use resulted in significantly more therapeutic success (58% vs 44%; 95% CI, 6.8%-22.8%).²⁵ Although more than half of the subjects were older than 50 years, the study excluded patients with a creatinine clearance of less than 60 mL/min, patients in long-term care facilities, and certain patients with obesity. Gepotidacin offers a new oral treatment option for patients with uUTI, particularly those with infections caused by ESBL pathogens or those with β-lactam and sulfonamide allergies who are unable to be treated with nitrofurantoin. Gepotidacin utility should be limited to women without obesity and with good kidney function until it is studied in other patient populations. It should also be used cautiously in patients at risk for QTc prolongation.

Sulopenem Etzadroxil/Probenecid (Orlynvah)

Sulopenem etzadroxil with probenecid is the first oral penem antibiotic. It was approved in 2024 to treat adult women with uUTIs.⁴ Sulopenem is a part of the penem class, whereas probenecid reduces renal tubular excretion of sulopenem so that blood concentrations can be sufficient. Unlike carbapenems, sulopenem contains a methyl group that helps the antibiotic resist DHP-1-mediated degradation, along with a sulfur atom at the 1 position of its 5-membered ring.²⁶ Although the antibiotic has demonstrated a broad spectrum of activity against many gram-positive and gram-negative bacteria in vitro, that has not consistently translated into clinical success in trials. Its FDA approval stipulates a very narrow use, and product labeling explicitly indicates that it should not be used in a complicated UTI (cUTI)⁴; however, it does provide an alternative to treat infections in women with no other oral options, including those with indicated ESBL-producing pathogens. Caution or avoidance is advised in patients with blood dyscrasias, uric acid kidney stones, and gout because of its ability to exacerbate or worsen those conditions. Additionally, probenecid can decrease the clearance of ketorolac and ketoprofen, and concurrent use is contraindicated. If a patient needs an analgesic, a noninteracting medication such as acetaminophen should be used.

Minocycline Hydrochloride (Emrosi)

Minocycline hydrochloride is a low-dose modified-release formulation of minocycline.⁸ The new once-daily extended-release capsule formulation was approved in 2024 for the treatment of rosacea in adults. In 2 studies comparing its use with doxycycline and placebo, its use was associated with significantly more patients achieving greater Investigator Global Assessment treatment success at week 16 in both the MVOR-1 study (NCT05296629; 65.0% vs 46.1% vs 31.2%; 95% CI, 19.6-46.2) and the MVOR-2 study (NCT05343455; 60.1% vs 31.4% vs 26.8%; 95% CI, 21.3-46.8).²⁷ In both studies, the patients receiving minocycline also showed a greater reduction in inflammatory lesion counts when compared against placebo (MVOR-1: 79.6% vs 47.3%, P < .001; MVOR-2: 75.4% vs 46.3%, P < .001) and doxycycline (MVOR-1: 79.7% vs 63.9%, P < .001; MVOR-2: 76.1% vs 61.2%, P < .001). The antibiotic’s demonstrated efficacy and convenient once-daily dosing make it an attractive option, potentially as a first-line treatment. This specific formulation can release a low dose of minocycline over time, whereas a higher dose is released immediately. This allows for a constant amount of minocycline in the body, causing less inflammation and less resistance.²⁸ A savings program offered by the manufacturer may make it cost-effective, as well; however, this can be dependent on insurance coverage. In patients without insurance or where insurance does not cover the medication, it would be reasonable to reserve minocycline for situations where alternative therapy is ineffective.

Metronidazole (Likmez)

Metronidazole oral suspension was FDA approved in 2023 and is the only liquid formulation of an old antibiotic.¹¹ Its therapeutic use does not differ from other metronidazole formulations. Before its approval, any liquid formulation of metronidazole required compounding for patients who were unable to use other oral dosage forms. The oral suspension provides a standardized, commercially available alternative for patients who have difficulty swallowing pills, dysphagia, percutaneous endoscopic gastrostomy tubes, and other situations where liquid medication would be preferable. Metronidazole oral suspension is a strawberry-peppermint flavored oral suspension. It should be stored at room temperature and protected from light. Unlike other forms of metronidazole, it eliminates the need for compounding or crushing tablets for patients who cannot swallow pills; however, its taste may still be a limitation to some patients and could affect adherence.

Fecal Microbiota Spores, Live-brpk (Vowst)

Vowst is an oral tablet regimen that received FDA approval in 2023 to prevent Clostridioides difficile infection (CDI).¹⁴ It contains a fecal microbiota spores agent, which is live purified Firmicutes spores that alter bile acid levels and replenish short-chain fatty acids, causing colonization resistance against C difficile, restoring the intestinal microbiome. In a randomized trial, a total of 182 patients with resolved CDI, all of whom had experienced the infection 3 separate times, were given fecal microbiota or placebo.²⁹ Recurrence of a CDI was significantly less, occurring in 12% of those treated with fecal microbiota compared with 40% in the placebo group (12% vs 40%; 95% CI, 0.18-0.58; P < .001).¹⁵ A significant benefit was seen in both younger and older adults. However, this study did not include patients who had received a monoclonal antibody or immunoglobulin therapy for C difficile within the past 3 months. These exclusions make it difficult to apply these data to patients who have recurrent CDIs (rCDIs) but have tried other treatment options. Fecal microbiota was well tolerated, with mainly mild gastrointestinal adverse effects comparable to placebo. Although fecal microbiota cannot treat CDI, it has shown clinical efficacy and can be a type of prophylaxis for patients who are unable to eliminate the pathogen entirely. For patients who are unwilling or unable to receive a fecal transplant, this is another viable option to improve their quality of life.

Aztreonam/Avibactam (Emblaveo)

Aztreonam with avibactam is a novel antibiotic that received FDA approval in 2025 and comprises a β-lactamase inhibitor that was first discovered in 1980.⁷ Aztreonam is a bactericidal monobactam antibiotic that has been available alone since 1986 and works by disrupting bacterial cell wall synthesis by targeting PBP3.³⁰ Although the chemical structure of aztreonam prevents hydrolysis by class B metallo-β-lactamases (MBLs), it can be degraded by other ESBLs and AmpC β-lactamases.³⁰ Avibactam is a next-generation β-lactamase inhibitor that was first approved in 2015 for use in combination with ceftazidime. It is not effective against MBLs, but it can protect against ESBLs and AmpC β-lactamases.³⁰ Aztreonam-avibactam’s use in the US is restricted to complicated intra-abdominal infections (cIAIs), only in combination with metronidazole and only in adults who have no other options for treatment. However, it has been evaluated in multiple infection types alone and in combination. In the open-label phase 3 REVISIT trial (NCT03329092), aztreonam-avibactam was compared with meropenem in patients with cIAIs or hospital-acquired pneumonia and ventilator-associated pneumonia (HAP-VAP).³¹ The adjudicated clinical cure rate was similar between antibiotics for both cIAIs (76.4% vs 74.0%; difference, 2.4%; 95% CI, –7.4% to 13.0%) and HAP-VAP (45.9% vs 41.7%; difference, 4.3%; 95% CI, –15.5% to 23.1%). Use of aztreonam-avibactam resulted in lower 28-day mortality (4% vs 7%). The combination was well tolerated, with no treatment-related serious adverse events reported. It is unclear whether additional indications or approval for use as monotherapy will be granted to aztreonam-avibactam in the future. Its use is also impacted by the need for dose adjustments and its high cost. Because of these factors, aztreonam-avibactam should be administered only when no other antibiotic can be used.

Ceftobiprole Medocaril Sodium (Zevtera)

Ceftobiprole medocaril sodium is a fifth-generation cephalosporin administered intravenously and was approved in 2024 for the treatment of skin and skin structure infections, S aureus bacteremia, and S aureus right-sided infective endocarditis in adults, as well as for community-acquired pneumonia (CAP) in patients older than 3 months.⁹ It has a broad spectrum of activity against gram-positive and gram-negative bacteria and is one of the only antibiotics available with coverage against both methicillin-resistant S aureus (MRSA) and Pseudomonas aeruginosa.^9,32 The prodrug has also shown in vitro activity against MRSA strains resistant to vancomycin, linezolid, and daptomycin.³² Its broad spectrum is further enhanced by tight bonds to proteins responsible for β-lactam resistance in S pneumoniae, including strains resistant to ceftriaxone and penicillin.³² Its clinical utility has been evaluated in multiple studies. In the ERADICATE study (NCT03138733), ceftobiprole was noninferior to daptomycin for overall treatment success in patients with complicated S aureus bacteremia (69.8% vs 68.7%; adjusted difference, 2%; 95% CI, –7.1 to 11.1), and mortality was similar between the 2 groups (9.0% vs 9.1%).³³ It is worth noting that most patients in the daptomycin group received a dose of 6 mg/kg, which is lower than doses currently recommended for bacteremia. It is possible that ceftobiprole may not be noninferior to higher doses of daptomycin. The TARGET trial (NCT03137173) evaluated ceftobiprole’s use in SSTIs and found that its early clinical success rate was noninferior to the combination therapy of vancomycin and aztreonam (91.3% vs 88.1%; adjusted difference, 3.3%; 95% CI, –1.2 to 7.8); microbiologic success and safety were similar.³⁴ In a study of patients with CAP requiring hospitalization, cure rates were noninferior to a combined regimen of ceftriaxone and linezolid (86.6% vs 87.4%; 95% CI, –6.9% to 5.3%).³⁵ However, ceftobiprole use was associated with higher rates of self-limited nausea (7% vs 2%) and vomiting (5% vs 2%). Ceftobiprole should not be used in HAP-VAP due to an observed mortality in clinical studies.³² Ceftobiprole’s greatest benefit appears to be related to adverse effects rather than bacterial coverage. Despite slightly more nausea and vomiting, extended use of comparator regimens often presents concerns for more significant issues, such as nephrotoxicity or hematologic effects. In such situations, ceftobiprole offers a reasonable alternative.

Sulbactam/Durlobactam (Xacduro)

Sulbactam with durlobactam is a parenteral approved for HAP-VAP caused by carbapenem-resistant Acinetobacter baumannii (CRAB).¹⁰ The antibiotic is unique in that both components are β-lactamase inhibitors.^10,26 Specifically, sulbactam binds PBP1 and PBP3 to inhibit bacterial wall synthesis, whereas durlobactam helps mitigate the deterioration of sulbactam against CRAB. In the phase 3 ATTACK study (NCT03894046), adults with CRAB and all receiving imipenem/cilastatin were randomly assigned to sulbactam/durlobactam or colistin.³⁶ Twenty eight–day mortality with sulbactam/durlobactam was noninferior (19.0% vs 32.3%; difference, –13.2%; 95% CI, –3.0 to 3.5), and clinical cure rates were similar (62% vs 40%; 95% CI, 2.9-40.3). Nephrotoxicity was significantly lower with sulbactam/durlobactam (13% vs 38%; P < .001). Although its treatment range appears limited, A baumannii infections are highly resistant, and treatment options are often associated with adverse effects such as nephrotoxicity. Therefore, sulbactam/durlobactam offers a potentially safer treatment option for this very niche patient population.

Cefepime/Enmetazobactam (Exblifep)

Cefepime with enmetazobactam combines the only fourth-generation cephalosporin with a novel β-lactamase inhibitor. Cefepime with enmetazobactam was approved by the FDA in 2024 for the treatment of cUTIs.⁶ Enmetazobactam is a penicillin acid sulfone β-lactamase inhibitor that primarily targets ESBLs.³⁷ Unlike its parent drug tazobactam, enmetazobactam has activity against class A β-lactamases and carbapenemases. Additionally, unlike avibactam, it is not active against class B, C, and most D β-lactamases, nor does it work against the class D oxacillinase OXA-1.³⁷ Compared with piperacillin and tazobactam, significantly more patients with a cUTI or acute pyelonephritis caused by gram-negative bacteria who received cefepime and enmetazobactam experienced treatment success (combined clinical cure and microbiological eradication) by day 14 (79.1% vs 58.9%; treatment difference, 21.2; 95% CI, 14.3-27.9).³⁸ The difference appears to have been driven by the difference in microbiological eradication (92.5% vs 88.9%; 95% CI, −1.0% to 8.0%), as no significant difference was seen in clinical cure. It is worth noting that there was no difference between groups at the end of treatment. Subanalyses indicated that cefepime with enmetazobactam was favorable across all age groups (including older adults) and genders, but that no difference may exist in patients with a baseline estimated glomerular filtration rate of less than 30 mL/min/1.73 m². Although a difference was seen in patients from Eastern Europe and other countries, it was not noted among study patients in the Americas, which could impact the practical use in the US. However, cefepime with enmetazobactam was more favorable in patients with ESBLs. This suggests that the antibiotic’s value may be in conserving carbapenem use for these multidrug-resistant infections. Although not currently FDA approved for pneumonia, a phase 1 study in 20 healthy volunteers showed that a regimen of cefepime 2 g with enmetazobactam 1 g administered intravenously every 8 hours resulted in intrapulmonary levels sufficient to treat Enterobacteriaceae, and suggests that studies evaluating a role in pulmonary infections may be conducted in the future.³⁹ Although there are benefits to using this new antibacterial, cefepime with enmetazobactam can cause neurotoxicity and increase prothrombin time.

Rezafungin (Rezzayo)

Rezafungin is a novel echinocandin antifungal agent that was FDA approved in 2023.¹³ Rezafungin’s mechanism of action involves concentration-dependent inhibition of (1,3)-β-D-glucan synthase, resulting in reduced production of (1,3)-β-D-glucan, a critical structural polysaccharide of the fungal cell wall (including Candida species) that is absent in mammalian cells.⁴⁰ The loss of glucan leads to osmotic instability and subsequent fungal cell lysis. Rezafungin exhibits activity against Candida and Aspergillus species, with clinical trials evaluating its efficacy for invasive candidiasis and candidemia. In a phase 3 study, rezafungin global cure rates at day 14 were noninferior to those achieved with caspofungin at day 14 (59% vs 61%; 95% CI, –14.9 to 12.7), 30-day all-cause mortality was similar (24% vs 21%; 95% CI, –9.7% to 14.4%), and treatment-emergent adverse events were experienced by the majority of patients in both groups. These included pyrexia, hypokalemia, pneumonia, septic shock, and anemia, but no new safety concerns were identified. This study did not include patients with candidiasis due to osteomyelitis, endocarditis, myocarditis, or meningitis, and rezafungin’s role in these more severe infections requires more research. The biggest benefit of rezafungin over other echinocandins is that it has a long half-life, which allows for once-weekly dosing. This advantage could potentially be applied to reduce hospital stays or to simplify regimen logistics for patients requiring longer durations of therapy.

Fecal Microbiota (Rebyota)

Rebyota was approved in 2022 for the prevention of CDI recurrence.¹⁵ Its mechanism of action is not fully understood, but it is thought to help restore the intestinal eubiosis and reintroduce new normal flora into the gastrointestinal tract. It is currently the only single-dose treatment to prevent CDI after its first recurrence. In the PUNCH CD3-OLS study (NCT03931941), the rectal suspension was administered within 24 to 72 hours after antibiotic completion for rCDI.⁴¹ At week 8, a total of 73.8% of patients experienced treatment success. Therapeutic success rates were higher in older patients at week 8 (77.9%; 95% CI, 1.09-2.18) and at 6 months (91.0%; 95% CI, 0.51-1.75). PUNCH CD3-OLS excluded patients who had received multiple treatments for CDI and those with a history of refractory CDI. Therefore, the oral tablet fecal microbiota may be better suited for patients with multiple recurrences of CDI, with the rectal suspension used earlier to prevent future recurrences. Although this agent does provide the advantage of “one-and-done” dosing without bowel preparation or laxatives before use, it must be administered rectally by a health care professional, which may place a logistical barrier to use for some patients.

Taurolidine/Heparin (DefenCath)

Taurolidine with heparin is an antibiotic/anticoagulation combination catheter lock cleaning solution that was approved in 2023.¹² Taurolidine is a thiadiazine antimicrobial derived from taurine, an amino acid that was previously been used to treat catheter-related infections. It prevents the adhesion of microorganisms to biological surfaces and injury to microbial cell walls. In LOCK IT-100 (NCT02651428), catheter solutions with either taurolidine and heparin or heparin alone were put into the hemodialysis catheter between hemodialysis sessions.⁴² The risk of developing a catheter-related bloodstream infection was reduced by 71% in patients who received taurolidine/heparin compared with heparin alone (HR 0.28; 95% CI, 0.11-0.7), and no adverse effects were similar. The addition of taurolidine to the heparin catheter lock solution appears to be a reasonable approach to prevent a potentially deadly infection in particularly vulnerable patients with chronic venous access.

Antibiotics have been the backbone of treatment for infections for the past several decades. Due to the virulence of bacteria and fungi, researchers continue to explore new tools to combat these infections. The development of these new antimicrobials provides hope that there are options out there to cover against resistant organisms or for new formulations that are palatable to patients with difficult situations. Thousands lose their lives to antibiotic-resistant infections, and even more are affected. Although these resistant infections get stronger, these novel antibiotics help mitigate the detrimental effects they have. The cycle of resistance isn’t going away, so there will always be an opportunity to create new drugs that could save lives. Whether it’s new mechanisms or new formulations, medications can provide a sense of safety while also improving patient outcomes and quality of life.

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