Introduction
Antibiotic-resistant bacteria are a growing global threat, causing longer hospital stays, higher costs, and increased mortality. The rise of multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) bacteria—such as MRSA and carbapenem-resistant Klebsiella pneumoniae—has made many infections hard to treat. To address this, the WHO listed priority pathogens in 2017, emphasizing the urgent need for new antibiotics, particularly against Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterales.
Since then, several new antibiotics and combinations have been approved (2017–2025), mostly belonging to existing classes like fluoroquinolones, tetracyclines, β-lactams, and β-lactamase inhibitors. Key examples include cefiderocol, plazomicin, lefamulin, and pretomanid. While these drugs expand treatment options, none introduce a truly new mechanism of action. Responsible use, strict monitoring, and ongoing research remain essential to preserve their efficacy and combat the spread of resistant infections.
New Antibiotics Simultaneously Covering CR-E, CR-PA and CR-AB
Cefiderocol is a newly approved cephalosporin effective against all three top-priority multidrug-resistant Gram-negative bacteria — carbapenem-resistant Enterobacterales (CR-E), Pseudomonas aeruginosa (CR-PA), and Acinetobacter baumannii (CR-AB). These pathogens produce carbapenemases that destroy most β-lactam antibiotics, making treatment difficult.
Cefiderocol overcomes this resistance with a unique “Trojan Horse” mechanism — it binds to iron (via a siderophore group) and enters bacterial cells through iron transport channels, bypassing normal resistance barriers. It remains stable against all known β-lactamases and shows strong affinity for target PBPs, giving it broad activity against CR-E, CR-PA, and CR-AB.
Clinically, cefiderocol is approved for complicated urinary tract infections and hospital-acquired pneumonia. It’s administered intravenously and mainly causes mild gastrointestinal side effects.
New Antibiotics Simultaneously Covering CR-E, CR-PA and CR-AB
Cefiderocol is a newly approved cephalosporin effective against all three top-priority multidrug-resistant Gram-negative bacteria — carbapenem-resistant Enterobacterales (CR-E), Pseudomonas aeruginosa (CR-PA), and Acinetobacter baumannii (CR-AB). These pathogens produce carbapenemases that destroy most β-lactam antibiotics, making treatment difficult.
Cefiderocol overcomes this resistance with a unique “Trojan Horse” mechanism — it binds to iron (via a siderophore group) and enters bacterial cells through iron transport channels, bypassing normal resistance barriers. It remains stable against all known β-lactamases and shows strong affinity for target PBPs, giving it broad activity against CR-E, CR-PA, and CR-AB.
Clinically, cefiderocol is approved for complicated urinary tract infections and hospital-acquired pneumonia. It’s administered intravenously and mainly causes mild gastrointestinal side effects.
New Antibiotics for CR-E
Besides cefiderocol, several new drugs are effective against carbapenem-resistant Enterobacterales (CR-E), including eravacycline, plazomicin, meropenem/vaborbactam, imipenem/relebactam, aztreonam/avibactam, cefepime/enmetazobactam, and meropenem/nacubactam. Among these, plazomicin and aztreonam/avibactam stand out for their unique mechanisms and broad resistance coverage.
Plazomicin: A New Aminoglycoside
Plazomicin is a next-generation aminoglycoside that disrupts bacterial protein synthesis by binding to the 30S ribosomal subunit, causing faulty protein production and bacterial death. It resists most aminoglycoside-inactivating enzymes (15 of 17) but is ineffective against A. baumannii and P. aeruginosa due to efflux pumps.
Given intravenously, it is mainly used for complicated UTIs caused by CR-E. Dose adjustment is needed in renal impairment. Adverse effects include nephrotoxicity, ototoxicity (possible hearing loss), and rare neuromuscular paralysis.
Aztreonam/Avibactam: A Revolutionary Combination
This combination is effective against CR-E producing multiple carbapenemase types. Aztreonam resists class B carbapenemases, while avibactam inhibits class A and D enzymes, making the duo active against classes A, B, and D simultaneously.
Approved for complicated intra-abdominal and urinary infections, and hospital-acquired pneumonia in Europe, it is administered intravenously with renal dose adjustment. Common side effects include anemia, diarrhea, and elevated liver enzymes.
Other combinations—meropenem/vaborbactam, imipenem/relebactam, cefepime/enmetazobactam, and meropenem/nacubactam—offer narrower spectra, mainly targeting class A or D carbapenemase producers. Meropenem/nacubactam, still under review, shows dual β-lactamase inhibition and PBP2 targeting for enhanced activity.
New Antibiotics for MRSA
Several new antibiotics are available for treating multidrug-resistant Gram-positive infections, including MRSA. These include fluoroquinolones (delafloxacin, lascufloxacin, alalevonadifloxacin) and the tetracycline omadacycline. Omadacycline stands out due to its safety, excellent oral bioavailability, and once-daily dosing, allowing an easy switch from IV to oral therapy.
Omadacycline: A New Generation Tetracycline
Omadacycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit, blocking tRNA attachment and halting protein formation. It is bacteriostatic but effective against MRSA and designed to evade most tetracycline resistance mechanisms, especially efflux pumps.
As an aminomethylcycline, omadacycline offers strong oral absorption and a long half-life, supporting once-daily dosing. It is approved for treating MRSA-related skin infections and community-acquired pneumonia.
Patients should take it on an empty stomach with water and avoid dairy or antacid products, which reduce absorption. Side effects are typical of tetracyclines—nausea, tooth discoloration, and reversible bone growth inhibition. It is contraindicated in pregnant women and children under 8 years.
New Antibiotics for Pre-XDR Mycobacterium tuberculosis
Pretomanid is a newly approved antibiotic vital for treating tuberculosis caused by pre-XDR strains of Mycobacterium tuberculosis. Pre-XDR TB is defined as resistance to rifampicin, isoniazid, and any fluoroquinolone. When combined with bedaquiline and linezolid, pretomanid forms a 6-month regimen—significantly shorter than traditional TB treatments.
Pretomanid
Developed in Pretoria, pretomanid is a nitroimidazole prodrug with a dual mechanism of action.
- In oxygen-rich environments: it inhibits mycolic acid synthesis, destroying bacterial cell walls.
- In low-oxygen environments: it releases reactive nitrogen species that disrupt bacterial respiration and energy production.
Pretomanid is effective only for pulmonary TB and offers the convenience of once-daily dosing due to its 16–20-hour half-life. The main side effect is reversible liver toxicity.
Some Comments on Other New Antibiotics
Several new antibiotics show promise due to improved safety, broader MDR activity, and favorable pharmacokinetics:
- Contezolid – A safer oxazolidinone for MRSA infections with fewer side effects than linezolid, particularly less myelosuppression and MAO inhibition. No dose adjustment needed in mild renal or hepatic impairment.
- Sulbactam/Durlobactam – Approved for HABP and VABP caused by MDR A. baumannii, including CR-AB. Durlobactam protects sulbactam from β-lactamase degradation. Requires dose adjustment in renal impairment.
- Lefamulin – First systemic pleuromutilin for humans, approved for CAP due to resistant S. pneumoniae or H. influenzae. Can be given orally or IV, with no renal dose adjustment needed.
New Antibiotics: Problems
While new antibiotics offer hope against MDR infections, key issues remain:
- Limited clinical trials for severe infections like endocarditis or meningitis.
- Lack of data in special populations (children, elderly, obese, critically ill).
- Belong to existing drug classes, increasing risk of rapid resistance.
- High cost limits accessibility.
Although these new antibiotics bring hope in combating MDR bacteria, several challenges persist. Most have not been evaluated for severe infections such as endocarditis, meningitis, or osteomyelitis, and clinical data for their use in children, the elderly, obese, and critically ill patients are limited. Furthermore, as many belong to existing antimicrobial classes, the risk of rapid resistance emergence remains high. Their high cost also limits widespread use. Hence, these agents must be used judiciously—guided by infection site, microbiological diagnosis, and antibiogram results. Knowledge of local and regional resistance patterns is crucial for informed empirical therapy decisions. Clinicians should review antibiotic therapy within 48–72 hours to assess patient response and make necessary adjustments while ensuring proper dosage, treatment duration, and administration route to preserve their long-term effectiveness.
New Therapeutic Strategies
Bacterial resistance cannot be completely eliminated, only slowed. Hence, in addition to new antibiotics, alternative non-antibiotic strategies are being explored to combat MDR infections. These include the use of antibodies, bacteriophages, phage-derived enzymes, and microbiome-modulating agents. Bezlotoxumab is one such example—an intravenous monoclonal antibody that binds to Clostridioides difficile toxin B, neutralizing its harmful effects on the intestinal lining. It is the only approved antibody for this indication, used alongside antibiotics. Another promising approach involves Direct Lytic Agents, proteins or peptides derived from bacteriophages that rapidly break down bacterial cell walls. Exebacase, a lysin-class enzyme currently in Phase III trials, targets S. aureus infections, including MRSA-related endocarditis. Further studies are expected to confirm its efficacy and clinical utility.
Conclusion
Since 2017, sixteen new antibiotics or combinations have been approved for treating MDR infections, but none introduce entirely new mechanisms of action. Data on their safety and efficacy in specific conditions remain limited, and few non-antibiotic strategies are available. Therefore, rational and targeted use of both current and future antibiotics is essential to delay the onset of the “post-antibiotic era.” Continued research, responsible prescribing, and collaboration among physicians and pharmacists are vital to protect public health.
Source: Machado, E.; Sousa, J.C. New Antibiotics for Treating Infections Caused by Multidrug-Resistant Bacteria. Antibiotics 2025, 14, 997. https://doi.org/10.3390/antibiotics14100997
