New Antibiotics for Lower Respiratory Tract Infections

Abstract

Respiratory tract infections are frequently encountered in clinical practice. The growing incidence of antimicrobial resistance among the causative pathogens exerts sustained pressure on the existing therapeutic options. The emergence of antimicrobial resistance limits the treatment options and often leads to unfavorable patient outcomes. However, in the past few years, newly developed antibiotics have become available, providing viable choices for antibiotic-resistant infections. New β-lactam/β-lactamase combinations, such as ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/relebactam, are effective against carbapenem-resistant Enterobacterales. Several new drugs including ceftolozane/tazobactam are active against multi-drug-resistant Pseudomonas aeruginosa, while sulbactam/durlobactam and cefiderocol have potent activity against Acinetobacter baumannii. A number of new options, such as lefamulin, omadacycline, and delafloxacin, have also emerged for pathogens commonly associated with community acquired pneumonia. This article aims to review the characteristics of newly approved antibiotics for the treatment of respiratory tract infections, as well as to discuss some investigational agents that are currently under development.

1. Introduction

Lower respiratory tract infections (LRTIs) remain among the leading causes of mortality attributable to infectious diseases worldwide, causing approximately 2.6 million deaths annually [1]. In 2021 an estimated 2.18 million deaths occurred due to LRTIs with 0.66 million associated with Streptococcus pneumoniae, Haemophilus influenza, and influenza virus. LRTIs represent not only a severe disease, but also a huge economic burden. Immunization through vaccination is a determinant factor for the reduction of mortality associated with LRTIs [1]. While in general, significant progress has been made in reducing LRTI-related mortality through, for example increased access to healthcare facilities and vaccination programs, the burden of these infections remains high, especially in low- and middle-income countries [2].

LRTIs are classified into community-acquired pneumonia (CAP) and nosocomial pneumonia. Nosocomial pneumonia represents an umbrella term, which includes hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). CAP refers to an acute infection of the pulmonary parenchyma acquired outside of the hospital setting, while HAP refers to pneumonia acquired ≥48 h after hospital admission and VAP refers to pneumonia acquired ≥48 h after endotracheal intubation [3,4]. In CAP, S. pneumoniae is the most frequently identified bacterial cause. In contrast, HAP and VAP can be caused by a diverse range of microorganisms and may also involve multiple pathogens. Common pathogens implicated in HAP and VAP include methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and other aerobic Gram-negative bacilli, such as Klebsiella pneumoniae, Escherichia coli, and Acinetobacter baumannii [5].

LRTI classification and knowledge of the most common pathogens identified are crucial for the initial assessment following diagnosis, and for selecting appropriate empirical therapy. However, in the era of growing antimicrobial resistance, local endemicity and surveillance cultures, in combination with the host’s epidemiologic and clinical parameters, should further guide clinician’s choice of antimicrobial therapy. This literature review aims to give an overview of clinical evidence around the currently available antibiotic therapy for LRTIs.

2. Current Guidelines

The initial approach to treating CAP is typically empirical, but the selection of the appropriate antibiotic is guided by the comorbidities and risk factors of the individual. Furthermore, clinical prediction rules including the Pneumonia Severity Index (PSI) should be taken into consideration for selecting an inpatient or outpatient antibiotic regimen, while specific factors such as allergies and renal function should be evaluated for.

When treating healthy outpatient adults, in the absence of comorbidities or risk factors for antibiotic-resistant pathogens, the recommended options are amoxicillin, doxycycline, or macrolide (only in areas with pneumococcal resistance to macrolides < 25%) [6]. For outpatient adults with comorbidities including chronic heart, lung, liver, or renal disease, diabetes mellitus, alcoholism, malignancy, or asplenia, treatment recommendations differ. Notably, combination therapy including amoxicillin/clavulanate, or a cephalosporin (e.g., cefpodoxime) and macrolide (azithromycin or clarithromycin) or doxycycline is recommended in case of contraindications to both quinolones and macrolides [6]. Alternatively, there is the option of monotherapy with a respiratory fluoroquinolone such as levofloxacin, moxifloxacin, or gemifloxacin [6].

In hospitalized patients with CAP, the initial therapeutic strategy is guided by the severity of the disease and the risk of infection with drug-resistant pathogens. More specifically, for a CAP episode to be characterized as severe, at least one major or three minor criteria should be met. The major criteria include septic shock with need of vasopressors or respiratory failure requiring mechanical ventilation, while the minor criteria include respiratory rate ≥ 30 breaths/min, PaO₂/FiO₂ ratio ≤ 250, multilobar infiltrates, confusion/disorientation, uremia (blood urea nitrogen levels ≥ 20 mg/dL), leukopenia (white blood cell count < 4000 cells/μL), thrombocytopenia (platelet count < 100.000/μL), hypothermia (core temperature < 36 °C), and hypotension requiring aggressive fluid resuscitation. For an inpatient with non-severe pneumonia, a β-lactam (e.g., ampicillin/sulbactam, cefotaxime, ceftriaxone, or ceftaroline) combined with a macrolide (azithromycin or clarithromycin) or monotherapy with a respiratory fluoroquinolone (levofloxacin or moxifloxacin) is recommended [6]. If MRSA or P. aeruginosa were previously isolated from respiratory samples before the CAP episode, empiric coverage for these pathogens should be included. Additionally, cultures should be obtained to determine whether the continuation or discontinuation of the targeted therapy is warranted [6]. If the patient was recently hospitalized and received parenteral antibiotics while there were locally validated risk factors for MRSA or P. aeruginosa, then culture should be obtained, but add-on treatment for both of these pathogens is not recommended until the results of the cultures are available [6]. In cases where the criteria for an episode of severe pneumonia are met, a combination of a β-lactam with a macrolide is the preferred regimen or a combination of a β-lactam with a fluoroquinolone. However, the latest updates of the global recommendations refer to it as a second option or advise against the administration of fluoroquinolone [6,7]. While the guidelines for treating patients with a prior respiratory isolation of MRSA or P. aeruginosa remain the same for both CAP and severe CAP, in cases of recent hospitalization and parenteral antibiotic administration, the addition of coverage for MRSA or P. aeruginosa—based on locally validated risk factors—is required while awaiting culture results [6].

For HAP/VAP, current guidelines primarily stratify patients based on their risk of multidrug-resistant (MDR) pathogen infection and mortality, categorizing them as either low- or high-risk [8]. For patients at low risk of mortality (which is defined as a ≤15% chance of death, based on clinical assessments and validated scoring systems), the recommended empiric therapy includes ertapenem, ceftriaxone, cefotaxime, moxifloxacin, or levofloxacin [8]. These agents provide coverage against non-resistant Gram-negative bacteria, such as E. coli, K. pneumoniae, and Proteus species, as well as methicillin-sensitive S. aureus (MSSA). It is important to note that, while third-generation cephalosporins like ceftriaxone and cefotaxime are effective, their use is associated with an increased risk of Clostridioides difficile infection and the spread of MDR pathogens.

For high-risk patients who are not in septic shock, empiric therapy depends on local antibiotic resistance patterns. If treated in an intensive care unit (ICU), where a single broad-spectrum agent is active against more than 90% of likely Gram-negative pathogens, monotherapy with an antipseudomonal agent such as imipenem, meropenem, cefepime, piperacillin/tazobactam, levofloxacin, or ceftazidime can be used [8]. However, if more than 25% of S. aureus isolates in the ICU are MRSA, vancomycin or linezolid should be added. For patients in septic shock, initial therapy should include dual antipseudomonal coverage along with MRSA coverage if indicated. The dual regimen should include an antipseudomonal β-lactam, such as imipenem, meropenem, cefepime, piperacillin/tazobactam, ceftazidime, or aztreonam, plus a second agent like an aminoglycoside (gentamicin, tobramycin, or amikacin) or an antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin) [8]. In settings where A. baumannii is a concern, colistin may be required. If extended-spectrum β-lactamase (ESBL)-producing organisms are prevalent, carbapenems are preferred. However, cefepime or piperacillin/tazobactam may still be considered based on local susceptibility patterns [8].

3. Persisting Challenges

The management algorithm for LRTI is currently complicated by a number of issues. Antimicrobial resistance is a global concern driven by the overuse and misuse of antimicrobial agents, facilitating the emergence of MDR bacteria and underscoring the critical need for antibiotic surveillance, as well as the development of novel antibiotics [9]. The magnitude of the problem becomes evident when evaluating the results of a study from 2021, which reports that approximately 4.71 million deaths were attributed to infections caused by antibiotic-resistant bacteria [10]. Importantly, the phenomenon of antimicrobial resistance seems to have widely spread including pathogens isolated in CAP, as increased rates of antimicrobial resistance among community isolates have been noted [11]. This could be justified by a concerning trend of increasing antibiotic prescriptions, with a 25% rise in England between 2002 and 2010, despite a 19% decrease in LRTI consultations [12]. The widespread use of antibiotics has not only contributed to increased antibiotic resistance, but also to the emergence of opportunistic pathogens [13]. Associated mechanisms responsible for resistance include enzymatic inactivation, the use of efflux pumps, porin mutations, and modifications to target sites [14]. In order to direct research efforts toward the development of novel antibiotics, the World Health Organization (WHO) has published a list of bacterial pathogens of major public health concern. The ultimate goal is to prevent and control the growing global threat of antimicrobial resistance. The list includes Gram-negative bacterial pathogens such as carbapenem-resistant A. baumannii (CRAB), carbapenem-resistant Enterobacterales (CRE), and third-generation cephalosporin-resistant Enterobacterales (3GCRE), as well as MRSA, etc. [15].

Established treatment may not be beneficial for all patients, as shown by the diverse absence of improved clinical outcomes and the potential for adverse events in a meta-analysis of 2661 patients [16]. Combination therapy of beta-lactam and macrolide was not associated with decreased mortality rates, shorter length of stay (LOS), or reduced respiratory insufficiency compared to beta-lactam monotherapy in the treatment of community-acquired pneumonia. However, it was associated with increased clinical success rates. This comes in discordance with a large population study of 8872 patients showing that the addition of macrolides was not associated with improved clinical outcomes for CAP patients [17]. Although dosage regimens were mainly similar between these different studies, there were substantial differences in the definitions of primary endpoints and studied population. On this aspect, clinicians should think beyond antibiotics’ antibacterial action and take into consideration pleiotropic immunomodulating effects, commonly favoring outcomes [18].

Gastrointestinal disturbances are commonly observed with various antibiotics used to treat LRTIs [19]. Fluoroquinolones, in addition to these effects, are associated with neurological symptoms and serious adverse events such as QT prolongation and tendinitis, particularly in elderly patients or those with pre-existing cardiac conditions [19]. Macrolides pose a risk of elevated liver enzyme levels, especially in individuals with a history of liver disease. In contrast, cephalosporins and pleuromutilins are generally well tolerated, with fewer severe adverse effects reported [19]. On top of this, one can add the disruption of gut microbiota leading to C. difficile-associated diarrhea and colitis. Although nebulized antibiotics have been introduced in recent years to minimize systemic toxicity, their use has been discontinued in the latest treatment recommendations in the absence of favorable hard primary endpoints and contradictory results [20].

In terms of cost, it seems that RTIs represent a significant economic burden in healthcare systems globally. In China, a study revealed an average attributable cost of $2853.93 per patient in cases of HAP, whereas the median cost for ICU-acquired RTIs reaches $12,301.17 [21]. Another meta-analysis from 20 countries primarily in high-income regions like Europe, North America, and the Western Pacific, found an average inpatient cost of €17,803.9 per episode and €128.9 for outpatient care in older patients with acute respiratory infections. More importantly, mortality rates in RTIs remain persistently high with meta-analyses describing a rate of 10% in VAP [22].

These issues highlight the need for improved antibiotic stewardship, better diagnostic tools, and the development of new antimicrobial agents to address the growing challenges in LRTI management [23].

4. New Antibiotics for LRTIs

In recent years, significant progress has been achieved in the research and development of new antibiotics for the treatment of respiratory tract infections. To address the growing challenge of antimicrobial resistance, several novel drugs with valuable therapeutic characteristics have been approved for the treatment of pneumonia. (

Table 1. New antibiotics (mechanism of action, spectrum of activity, administration, pneumonia approval clinical trials, and major side effects).

Antimicrobial	Mechanism of Action	Spectrum of Activity	Administration	Pneumonia Approval Clinical Trials and Drug Comparator/Results	Major Side Effects
Antibiotic agents for community-acquired pneumonia
Lefamulin	Binds to the 50S bacterial ribosomal subunit in the PTC.	S. pneumoniae MSSA H. influenzae Legionella pneumophila Mycoplasma pneumoniae Chlamydophila pneumoniae	600 mg PO q12h or 150 mg IV q12h infused over 1 h	LEAP 1 clinical trial (NCT02559310)—A study to evaluate the efficacy and safety of IV-to-PO lefamulin VS moxifloxacin in patients with CABP. Result: Lefamulin was noninferior to moxifloxacin for early clinical response (87.3% vs. 90.2%) and investigator assessment of clinical response (mITT, 81.7% vs. 84.2%, respectively). LEAP 2 (NCT02813694)–A study to evaluate the efficacy and adverse events of a 5-day oral lefamulin regimen in patients with CABP. Result: Lefamulin and moxifloxacin showed similar early clinical response rates (90.8% for both). The rates of clinical response success were similar: 87.5% for lefamulin and 89.1% for moxifloxacin in the mITT population, and 89.7% for lefamulin and 93.6% for moxifloxacin in the clinically evaluable population.	QT prolongation Fetal loss Diarrhea Administration-site reactions Hepatic enzyme elevation Nausea Hypokalemia, insomnia Headache
Omadacycline	Binds to 30S ribosomal subunits in the mRNA translation complex of bacteria and inhibits the binding of aminoacyl–tRNA to the mRNA–ribosome complex.	S. pneumoniae MSSA H. influenzae L. pneumophila M. pneumoniae Ch. pneumoniae	IV and PO therapy Loading dose on day 1: 200 mg IV infusion over 1 h OR 100 mg IV over 30 min q12h OR 300 mg po q12h on day 1. Maintenance dose: 100 mg IV over 30 min q24h, or 300 mg p.o q24h for 7–14 days	OPTIC clinical trial—(NCT02531438)—A phase 3 randomized, double-blind, multi-center study to compare the safety and efficacy of omadacycline IV/PO to moxifloxacin IV/PO for treating adults with CAP. Result: Non inferiority for omadacycline compared to moxifloxacin. NCT04160260—A phase 1 multi-center study to measure the pharmacokinetics of oral omadacycline in adults with CABP. All participants received a LD of omadacycline (300 mg po q12h on day 1), followed by maintenance treatment of 300 mg po q24h) for a total treatment duration of 7–10 days. All study participants achieved clinical success for overall clinical response.	Nausea Vomiting Infusion-site reactions ↑ AST, ALT, γ-GT hypertension Headache Diarrhea Insomnia Constipation
Delafloxacin	Inhibits both bacterial DNA topoisomerase IV and DNA gyrase (topoisomerase II) With similar potency.	MSSA levofloxacin-resistant S. aureus and S. pneumoniae E. coli H. influenzae M. catarrhalis atypical species	300 mg IV q12h Or 450 mg PO q12h	DEFINE clinical trial—(NCT02679573)—A phase 3, multicenter, randomized, double-blind, comparator-controlled study to evaluate the safety and efficacy of IV to PO delafloxacin in adults with CABP. In the ITT population ITT, ECR rates were 88.9% in the delafloxacin and 89.0% in the moxifloxacin group Result: Noninferiority of delafloxacin compared with moxifloxacin.	Nausea Diarrhea Headache ↑ transaminase Vomiting
Ceftobiprole	The active moiety of ceftobiprole medocaril binds to essential PBPs and inhibits their transpeptidase activity.	Gram-positive and Gram-negative bacteria, e.g., antibiotic-resistant strains of S. aureus (MRSA and VRSA) penicillin-resistant S. pneumoniae (PRSP), Enterococcus faecalis, non-ESBL Enterobacteria P. aeruginosa	500 mg IV q8h	NCT00326287-A randomized, double-blind, multicenter study of ceftobiprole medocaril Versus placebo in the treatment of hospitalized patients with CAP. Result: Ceftobiprole was non-inferior to the comparator (ceftriaxone ± linezolid) in all clinical and microbiological analyses conducted. NCT00229008—A phase 3 randomized double-blind study of ceftobiprole medocaril versus linezolid plus ceftazidime in the treatment of nosocomial pneumonia. Result: Ceftobiprole monotherapy was as efficacious as ceftazidime/linezolid for clinical and microbiological cure and was noninferior to ceftazidime/linezolid in the subgroup of patients with HAP excluding VAP.	Nausea Vomiting
Antibiotic agents for nosocomial pneumonia
Cefiderocol	Inhibition of bacterial cell wall synthesis: Binds iron. Entry into the bacterial cell is accomplished via the siderophore pathway. Binds to PBPs (especially PBP3).	CRAB, Carbapenem resistant K. pneumoniae, P. aeruginosa, S. maltophilia	2 g IV q8h infused over 3 h	CREDIBLE-CR Trial (NCT02714595)—Evaluated cefiderocol in adult patients with Carbapenem-resistant pathogen infections, including nosocomial pneumonia. Results: Clinical cure rate of 50% for cefiderocol (compared to 53% for BAT). Findings: Comparable efficacy to best BAT, but higher deaths in A. baumannii infections treated with cefiderocol.	↑ liver function tests Hypokalemia Diarrhea Hypomagnesemia Atrial fibrillation
Ceftolozane/tazobactam	Ceftolozane: Inhibition of bacterial cell wall synthesis. Binds to PBPs (especially PBP1b, PBP1c, and PBP3) Tazobactam: Beta-lactamase inhibitor. Extends ceftolozane’s activity against ESBL-producing Enterobacterales.	P. aeruginosa (including MDR and XDR strains), ESBL-producing Enterobacteriales	3 g IV q8h infused over 3 h	ASPECT-NP Trial (NCT02105636): Compared ceftolozane/tazobactam (3 g q8h) to meropenem (1 g q8h) for nosocomial pneumonia (including VAP). Results: Ceftolozane/tazobactam non-inferior to meropenem with a 28-day all-cause mortality rate of 24% vs. 25.3%	↑ risk of C. difficile infection
Ceftazidime/Avibactam	Ceftazidime: inhibition of bacterial cell wall synthesis. Binds to PBPs (e.g., PBP3). Avibactam: inhibits a broad range of β-lactamases including class A (KPC and ESBL), Class C (AmpC), and some class D serine enzymes. Ineffective against metallo-β-lactamases.	P. aeruginosa (including MDR and Carbapenem-resistant strains), Enterobacteriaceae	2.5 g IV q8h (2 g ceftazidime and 0.5 g avibactam), infused over 3 h	REPROVE Trial (NCT02238083): ceftazidime/avibactam (2.5 g q8h) vs. meropenem (1 g q8h) for nosocomial pneumonia (including VAP). Results: Ceftazidime/avibactam non-inferior to meropenem. The clinical cure rate was 68.8% for ceftazidime/avibactam and 73.0% for meropenem (not statistically significant).	Diarrhea Nausea Headache Vomiting Fever
Meropenem/vaborbactam	Meropenem: inhibition of bacterial cell wall synthesis. Binds to PBPs. Vaborbactam: inhibits class A (e.g., KPC) and class C β-lactamases. Ineffective against class B (metallo-β-lactamases) or class D β-lactamases.	Meropenem-non-susceptible strains of Enterobacteriaceae, including KPC and ESBL-producing strains. CRE	2 g meropenem,2 g vaborbactam q8h, administered as a 3 h IV infusion	TANGO II Trial (NCT02644339): Clinical Cure Rates: End of Treatment: 65.6% for meropenem/vaborbactam vs. 33.3% for the BAT, (p = 0.03). Test of Cure: 59.4% for meropenem/vaborbactam vs. 26.7% for BAT, also showing a statistically significant difference (p = 0.02).	Diarrhea Anemia Hypokalemia
Imipenem/Cilastatin/Relebactam	Imipenem: inhibition of bacterial cell wall synthesis. Binds to PBPs (especially PBP2 and PBP1b). Cilastatin: renal dehydropeptidase inhibitor. Relebactam: potentiates imipenem’s activity by binding to the active site of serine β-lactamases of Ambler classes A and C.	ESBL- and KPC-producing Enterobacterales.	1.25 g IV q6h infused over 30 min	RESTORE-IMI 1 (NCT02111524): imipenem/cilastatin/relebactam vs. colistin plus imipenem for imipenem-non-susceptible infections, including HAP and VAP. Result: 87.5% (imipenem/cilastatin/relebactam) vs. 66.7% (colistin plus imipenem). RESTORE-IMI 2 (NCT02493764): imipenem/cilastatin/relebactam vs. piperacillin/tazobactam for HAP/VAP caused by Enterobacterales. Mortality rate: 15.9% (imipenem/cilastatin/relebactam) vs. 21.3% (piperacillin/tazobactam). Result: Non-inferior efficacy.	Diarrhea Nausea Vomiting
Sulbactam/Durlobactam	Sulbactam: Inhibition of bacterial cell wall synthesis. Binds to PBPs (especially PBPs1 and PBP3). Durlobactam: inhibits Amber Class A, C, and D serine β-lactamases but not class B metallo-β-lactamases.	A. baumannii–calcoaceticus complex (ABC)-CRAB	2 g (1 g sulbactam, 1 g durlobactam) IV q6h infused over 3 h	ATTACK clinical trial (NCT03894046)—A study to evaluate the efficacy and safety of IV sulbactam/durlobactam vs. colistin in the treatment of patients with infections caused by A. baumannii–calcoaceticus complex. Result: the 28-day all-cause mortality was lower in the sulbactam–durlobactam group (19%) compared to the colistin group (32%). Nephrotoxicity was significantly lower with sulbactam–durlobactam (13%) than colistin (38%).	Liver test abnormalities Diarrhea Anemia Hypokalemia
h
Cefepime/enmetazobactam	Cefepime: inhibition of bacterial cell wall synthesis. Binds to PBPs (especially PBP2 and PBP3). Enmetazobactam: inactivates Ambler Class A β-lactamases.	Broad-spectrum antimicrobial activity against a range of multidrug-resistant Enterobacteriaceae	2.5 g IV (2 g cefepime, 0.5 g enmetazobactam) q8h infused over 4 h	Twenty healthy volunteers were assed to study the intrapulmonary pharmacokinetics of a regimen of 2 g cefepime-1 g enmetazobactam q8h IV. Result: concentration-time profiles of both agents in plasma and ELF were similar.	↑ transaminases, ↑ bilirubin Headache Phlebitis/infusion site reactions
Aztreonam/avibactam	Aztreonam: Inhibition of bacterial cell wall synthesis. Binds to PBPs (Especially PBP3) Avibactam: β-lactamase inhibitor.	MBL-producing bacteria, that may co-produce SBLs–including ESBLs, AmpC and the carbapenemase enzymes, KPC, and OXA-48-like1–7, S. maltophilia	Loading dose: 2 g/0.67 g IV Maintenance dose: 1.5 g/0.5 g IV q6h infused over 3 h. * maintenance dose is adjusted based on renal function	REVISIT Study (NCT03329092): A phase 3, randomized, multicenter, open-label trial tested aztreonam/avibactam vs. meropenem for cIAI and HAP/VAP caused by Gram-negative, MDR, and MBL-producing bacteria. Result: Clinical cure rates were similar between groups, with aztreonam–avibactam showing lower 28-day all-cause mortality. Microbiological response was 75.7% for Aztreonam–avibactam vs. 73.9% for meropenem. The 28-day all-cause mortality for HAP/VAP was 10.8% for aztreonam–avibactam vs. 19.4% for meropenem. ASSEMBLE Study (NCT03580044): assessed aztreonam–avibactam vs. best available therapy for infections caused by MBL-producing bacteria. Aztreonam–avibactam showed a 41.7% clinical cure rate, compared to 0% for Best available therapy. 15 patients were included—the small sample size limits the study results.	↑ transaminases, hepatic function abnormalities

Abbreviations: PBPs; penicillin-biding proteins, CRAB; carbapenem-resistant Acinetobacter baumannii, S. pneumoniae; Streptococcus pneumoniae, K. pneumoniae; Klebsiella pneumoniae, P. aeruginosa; Pseudomonas aeruginosa, S. maltophilia, IV; intravenous, q8h; three times a day, MDR; multidrug-resistant, XDR; extensively drug-resistant, ESBL; extended Spectrum β-Lactamase, C. difficile; Clostridium difficile, KPC; Klebsiella pneumoniae carbapenemase, VAP; ventilator-associated pneumonia, CRE; carbapenem-resistant Enterobacteriaceae, BAT; best available therapy, q6h; four times a day, HAP; hospital-associated pneumonia, PTC; peptidyl transferase center, MSSA; methicillin-sensitive Staphylococcus aureus, q12h; two times a day, m RNA; messenger RNA, t RNA; transfer RNA, PO; per os, E. Coli; Escherichia coli, H. Influenzae; Haemophilus influenzae, M. catarrhalis; Moraxella catarrhalis, VRSA; vancomycin-resistant Staphylococcus aureus, CABP; community-acquired bacterial pneumonia, m ITT; modified intention to treat, CAP; community-acquired pneumonia, ELF; epithelial lining fluid, MBL; Metallo-β-lactamases, ESBL; extended spectrum β lactamases, SBL; serine ß-lactamases, OXA; oxacillinase, and cIAI; complicated intra-abdominal infection; * denotes cone of caution; ↑ denotes ‘increased’.

, Figure 1).

4.1. Antibiotic Agents for Community-Acquired Pneumonia

4.1.1. Lefamulin

Lefamulin is a newly developed pleuromutilin that exerts its antimicrobial activity by inhibiting bacterial protein synthesis. This is achieved through binding to the peptidyl transferase center within the bacterial 50S ribosomal subunit. The drug displays a broad-spectrum of activity against pathogens commonly associated with CAP, such as S. pneumoniae, and H. influenzae, as well as atypical bacteria like M. pneumoniae, Legionella Pneumophila, and Chlamydia pneumoniae [24]. Moreover, lefamulin exhibits activity against MDR S. pneumoniae (MIC_50/90 0.06/0.12 μg/mL) and MRSA (MIC_50/90 0.06/0.12 μg/mL) according to the SENTRY surveillance program [25].

LEAP 1 phase III trial assessed the efficacy and safety of lefamulin in comparison to moxifloxacin for the treatment of CAP. Participants were randomized to receive lefamulin 150 mg IV every 12 h (q12h) or moxifloxacin 400 mg IV every 24 h (q24h). In terms of early clinical response, lefamulin was non-inferior to moxifloxacin (87.3% vs. 90.2%, respectively), as well as for the European Medicines Agency’s (EMA) primary endpoint, the investigators assessment of clinical response (81.7% vs. 84.2%, respectively) [26]. LEAP 2 evaluated the efficacy and adverse events of oral lefamulin (600 mg q12h for 5 days) vs. oral moxifloxacin (400 mg q24h for 7 days) in patients with CAP. Early clinical response rate was 90.8% for both drugs, with rates of investigator assessment of clinical response success of 87.5% with lefamulin and 89.1% with moxifloxacin. The most frequently reported adverse effects were gastrointestinal disorders [27]. These data come in line with prior pharmacokinetic and pharmacodynamic studies that support the use of lefamulin in the treatment of CAP. Specifically, a study that used a three-compartment population pharmacokinetic model utilizing available data from Phase 1 clinical trials demonstrated that lefamulin rapidly distributes from plasma to epithelial lining fluid (ELF), achieving an approximate 5:1 ELF-to-plasma exposure ratio after both oral and intravenous administration [28,29]. Notably, studies showed that the AUC/MIC ratio is the primary PK/PD driver for efficacy [29].

Based on the LEAP 1 and LEAP 2 studies, an analysis specifically focused on elderly patients, including those aged 65 and older, demonstrated that the clinical efficacy of lefamulin was comparable to that observed in the general population. In patients aged 65–74 years, the early clinical response rate was 91.0% for lefamulin, while for those aged 75 and older, the response rate was 86.7%. At the test-of-cure (TOC), the clinical response rate was 88.8% for those aged 65–74 years, and 83.5% for those aged 75 and older, suggesting that lefamulin is an effective treatment option for elderly patients aged 65 and older with community acquired bacterial pneumonia (CABP) [30]. It is particularly interesting that lefamulin can be safely used without dose adjustment in special populations such as patients with cystic fibrosis [31], while pharmacokinetic studies have also shown that no dosage adjustment is needed in patients with renal impairment, including those undergoing hemodialysis [32]. Similarly, in individuals with moderate and severe hepatic impairment, intravenous lefamulin was well-tolerated may not require significant dose adjustment [33]. However, animal studies suggested that lefamulin may cause fetal harm when used during gestation or lactation with low fetal body weight, malformations, and fetal loss being potential adverse effects [24].

Except for its antibacterial activity against a wide spectrum of pathogens, a recent in vivo study showed a potential immune-modulatory activity of lefamulin. More specifically, the study conducted by Paukner S, et al. compared the immune modulatory activity of lefamulin to that of azithromycin, an antimicrobial with known anti-inflammatory activity, and of the antiviral oseltamivir in the influenza A/H1N1 acute respiratory distress syndrome (ARDS) in mice. Results showed that lefamulin significantly decreased the total immune cell infiltration, specifically the neutrophils, inflammatory monocytes, CD4+ and CD8+ T-cells, natural killer (NK) cells, and B-cells into the lung by day 6, contrary to azithromycin and oseltamivir. Future clinical trials need to investigate the potential anti-inflammatory and immune modulatory action of lefamulin highlighted in this study, which may be beneficial for CAP and prevention of acute lung injury and ARDS [34].

Although lefamulin is a promising alternative in treating hospital-acquired bacterial pneumonia (HABP) caused by common pathogens and MDR strains, economic issues pose a significant burden to its wide use [24,25,35]. Specifically, the average wholesale price for IV use is $205 daily, and the oral formulation costs $275 daily, while older antibiotic agents, such as moxifloxacin, are available at a significantly lower cost [35,36]. Therefore, when considering using lefamulin, its economic burden should be carefully weighed against its benefits.

Given its broad spectrum of activity and high bacterial susceptibility rates, lefamulin is considered a valuable treatment option for CAP and has already been granted approval from both the U.S. Food and Drug Administration (FDA) and EMA.

4.1.2. Omadacycline

Omadacycline, a minocycline derivative, is a novel first-in-class aminomethyciline antibiotic. Like tetracyclines, omadacycline inhibits bacterial protein synthesis by binding to the primary tetracycline binding site on the 30S bacterial ribosomal subunit. Due to two structural modifications at the C-7 and C-9 positions of the tetracycline D-ring, the drug is able to overcome common tetracycline resistance mechanisms. Susceptible to omadacycline microorganisms isolated in the community-acquired bacterial pneumonia (CABP) studies included S. pneumoniae, S. aureus (MSSA), H. influenzae, Haemophilus parainfluenzae, K. pneumoniae, L. pneumophila, Mycoplasma pneumoniae, and C. pneumoniae [37]. It has also shown in vitro activity against atypical and anaerobic pathogens [38].

The OPTIC phase III, randomized, double-blind clinical trial compared the safety and efficacy of omadacycline to moxifloxacin for the treatment of CAP. Participants were randomly assigned to omadacycline (100 mg q12h for two doses, then 100 mg i.v. q24h), or moxifloxacin (400 mg i.v.q24h). After 3 days, patients could be switched to oral omadacycline (300 mg q24h) or moxifloxacin (400 mg q24h), respectively. Omadacycline was non-inferior to moxifloxacin for early clinical response, defined as survival with improvement of symptoms (81.1% and 82.7%, respectively). In addition, omadacycline demonstrated noninferiority to the comparator for the investigator-assessed clinical response at the post-treatment evaluation (87.6% and 85.1%, respectively) [39].

Important data that was derived from PK and PD studies also supported the evaluation of omadacycline in treating CAP. A study that used a three-compartment population pharmacokinetic model evaluated data from phase 1 and phase 3 clinical trials, so both healthy and infected individuals were included, found that the total-drug ELF/free drug plasma penetration ratio for omadacycline based on day 4 AUC from time zero to 24 h was 2.06, indicating an effective drug penetration to the lung tissue [40]. In addition, another study utilized non-clinical PK/PD targets and in vitro surveillance data for omadacycline, including MIC, and a population PK model to assess the effective doses of the regimen. The study found that there was an increased probability of reaching the PK/PD targets in the ELF for both S. pneumoniae (91.1%) and H. influenzae (99.2%), supporting approved dosing regimens. Lower target attainment was observed for some free-drug plasma targets, especially for H. influenzae [41]. All in all, omadacycline exhibits a higher epithelial lining fluid (ELF) concentration compared to the majority of tetracyclines, with a ratio of 1.47 for ELF to total plasma omadacycline, based on mean AUC_{24 lining f} values [42]. Overall, the drug has a similar safety profile to other tetracyclines. Notably, when compared to moxifloxacin, a lower incidence of diarrhea was observed, and importantly no cases of C. difficile infection were reported [39].

It is worth noting the oral-only pharmacokinetic study of omadacycline in patients with CABP (ClinicialTrials.gov identifier NCT04160260) that supported the FDA’s approval of oral-only omadacycline therapy for CABP. This study included 18 participants who received omadacycline; 14 were included in the pharmacokinetic population after excluding two patients with emesis and two with outlying pharmacokinetic values. All participants received a loading dose of omadacycline (300 mg po q12h on Day 1), followed by maintenance treatment of 300 mg orally q24h, for a total treatment duration of 7–10 days. All study participants achieved clinical success for overall clinical response [43].

Clinical data revealed a potent efficacy of omadacycline against Mycobacterium abscessus infections, as shown in a multicenter retrospective study conducted across five major nontuberculous mycobacterial (NTM) disease clinics in the United States, where 117 patients were treated with omadacycline as part of multidrug regimens. The study demonstrated favorable long-term safety and tolerability, with a median treatment duration of 8 months, and showed microbiological response in pulmonary disease patients—46% achieving at least one negative culture and 18% achieving culture conversion [44]. Retrospective observational studies reported the potent efficacy of early initiation of omadacycline in critically ill patients with severe Chlamydia psittaci pneumonia complicated by ARDS. Timely initiation of treatment with omadacycline alongside mechanical ventilation (when required) resulted in increased cure rate with clinical and laboratory improvement [45].Although clinical evidence remains limited, case studies have demonstrated that omadacycline can be effective in the treatment of severe L. pneumophila pneumonia, particularly in patients unresponsive to initial empirical therapy [46].

Of interest, omadocycline may also exhibit an anti-inflammatory activity. More specifically, treatment of a murine model of ALI with omadacycline in vitro resulted in significant, dose-dependent reductions in Interleukin 6 (IL-6), CXC motif chemokine ligand 1-(CXCL-1), and Matrix metalloproteinase-9 (MMP-9) expression and inhibition of IL-8-induced neutrophil chemotaxis [47]. Furthermore in vivo, omadacycline yielded protective and therapeutic effects by reducing the production of proinflammatory cytokines and chemokines and neutrophil infiltration into the lungs, along with modestly improving lung injury severity after intranasal lipopolysaccharide challenge [47].

Omadacycline appears to be equally effective for high-risk populations, including patients with CABP or acute bacterial skin and skin structure infections who have mild-to-moderate renal impairment, with comparable clinical success rates and safety profiles across renal function groups [48]. When assessing the systematic exposure to the drug between young individuals (33–43 years old) and elderly (65–73 years old), no significant difference was observed. The study also examined if it is necessary to adjust the dose of the antibiotic in individuals with mild, moderate, and severe hepatic impairment, to conclude that no significant changes in the dose should be made [49].

Omadacycline is a potentially cost-effective therapeutic option for patients with CAP despite the higher acquisition cost compared to older antibiotics [50]. A budget impact analysis took place in the United States of America, and the objective was to evaluate the economic impact of utilizing omadacycline as a treatment option among patients with CAP. While the base-case analysis indicated a mild cost increase of $20,643 over a three-year period, mainly due to acquisition costs, the scenario analysis indicated significant cost savings due to the reduction of the hospitalization length, as omadacycline allows a switch to oral treatment [50].

The drug has been granted approval from the FDA for the treatment of CABP and acute bacterial skin and skin structure infections (ABSSSI) in adults [51]. Studies demonstrate that omadacycline treatment does not require dose adjustment for any patient population while preclinical and clinical data support both indications for i.v.-to-oral or oral-only dosing regimens [43]. However, it is not approved for use in Europe for this particular indication.

4.1.3. Delafloxacin

Delafloxacin is an anionic fluoroquinolone, that differs from other quinolones because of its ability to inhibit both bacterial topoisomerase IV and DNA gyrase with similar potency [52]. The ability to target both enzymes makes it more difficult for bacteria to develop resistance. Delafloxacin demonstrates a broad spectrum of activity against Gram-positive bacteria including MSSA (MIC₉₀ 0.004–0.12 mg/L), MRSA (MIC₉₀ 0.5–4 mg/L), levofloxacin-resistant S. aureus, and S. pneumoniae (MIC₉₀ 0.012–0.03 mg/L), Gram-negative pathogens such as E. coli (MIC₉₀ 4 mg/L), H. influenzae (MIC₉₀ 0.002–0.00 mf/L), and Moraxella catarrhalis (M. catarrhalis) (MIC₉₀ 0.004–0.008 mg/L), and atypical species (MIC₉₀ 0.5 mg/L) [53]. The drug is approved for use in Europe and the United States for the treatment of CAP [54].

The DEFINE-CABP phase III study compared the efficacy and safety of delafloxacin 300 mg q12h to moxifloxacin 400 mg q24h in adults with CAP. The primary endpoint was early clinical response (ECR) defined as improvement at 96 (±24) h after the first dose of study drug. Response rates were 88.9% in the delafloxacin group and 89.0% in the moxifloxacin group. When combined with improvement in vital signs, significantly favorable response rates were observed with delafloxacin (52.7% versus 43%) especially in a subgroup of patients with chronic obstructive pulmonary disease (COPD) or asthma (93.4% in delafloxacin versus 76.8% in comparator arm). Overall, delafloxacin demonstrated noninferiority to moxifloxacin and appeared to be safe and well tolerated. Commonly reported adverse effects were diarrhea, transaminases elevation, and headache [55]. At both therapeutic and supratherapeutic doses, delafloxacin showed a lack of effect on the prolongation of the QTc interval [56], as well as high lung penetration [57]. In patients with renal impairment, the total drug exposure increased as renal function worsened, leading to a dose reduction recommendation for individuals with severe renal impairment when delafloxacin is administered intravenously. However, it is highlighted that no dose adjustment is necessary for oral delafloxacin, even in cases of severe renal impairment [58].

In immunocompromised individuals, delafloxacin may have equally favorable results to conventional fluoroquinolones, even in cases of MDR bacterial infections. This is exemplified by a recent case of an 86-year-old male with severe COVID-19 pneumonia complicated by the development of a lung abscess caused by ciprofloxacin-resistant P. aeruginosa. Microbiological analysis confirmed P. aeruginosa resistant to several key antimicrobials, including ciprofloxacin, meropenem, and aminoglycosides. Initial intravenous therapy with piperacillin/tazobactam led to marked clinical improvement. Notably, the switch to oral delafloxacin allowed continuation of effective antimicrobial therapy in an outpatient setting, despite the resistance profile of the isolate and with clinical recovery without relapse [59].

Delafloxacin is an important antibiotic agent, considering its broad spectrum of activity, as well as the results from the DEFINE-CABP clinical trial. However, its economic profile restricts its wide use. A budget-impact model, developed in the United States of America, aimed to evaluate the overall cost of adding delafloxacin for outpatient CABP treatment. In the hypothetical scenario of adding delafloxacin to the therapeutic plan for a health plan population of 1,000,000 members, the overall budget would increase by $58,987, primarily due to drug acquisition costs. However, in a targeted population scenario, including COPD and asthma patients, the budget impact was significantly lower, at $5042, highlighting that delafloxacin may not be economically viable for broad use but may be cost-effective in certain high-risk groups [60].

4.1.4. Ceftobiprole

Ceftobiprole is a fifth-generation parenteral extended spectrum cephalosporin approved by EMA in 2013 and by FDA on April 2024 with a standard dosage of iv 500 mg every 8 h (q8h). It is indicated for the management of CAP and non-ventilator associated HAP, with low/medium MDR risk, in frail patients that are admitted to common wards and who may be at high risk of adverse events with anti-MRSA options (like oxazolidinones and glycopeptides) including anemia, renal failure, or thrombocytopenia. It represents a reasonable carbapenem sparing option [61]. Mean ELF penetration of ceftobiprole has been reported at approximately 25.5% of free plasma concentration in healthy volunteers, while linezolid reaches up to 100% [62]. In general, ceftobiprole’s antibacterial efficacy is time-dependent, and greater exposure to the drug is important for microbiological eradication and clinical cure. A time above the MIC (T > MIC) exceeding 51% of the dosing interval is associated with favorable clinical outcomes, whereas achieving T > MIC > 62.2% is necessary to ensure microbiological eradication [63].

Its unique antibiotic spectrum, which for the first time combines activity against both MRSA and vancomycin-resistant S. aureus (VRSA), penicillin-resistant S. pneumoniae (PRSP), Enterococcus faecalis, non-ESBL Enterobacteriaceae, and P. aeruginosa, makes it a very attractive and advantageous monotherapy option [64]. However, it is degraded by both ESBLs and serine and metallo-carbapenemases [65].

Ceftobiprole’s efficacy and safety have already been demonstrated through two phase III trials conducted in 2012 and 2014 [66,67]. In a non-inferiority, double-blinded, multicenter, randomized trial of 706 patients with severe enough CAP to require hospitalization, ceftobiprole was compared to ceftriaxone with optional addition of linezolid. Non-inferiority of ceftobiprole was confirmed compared to the linezolid combination therapies [67], showing cure rates of 86.6% vs. 87.4% for ceftobiprole and comparator, respectively. In the intention-to-treat (ITT) analysis, cure rates were 76.4% vs. 79.3%, respectively. The overall incidence of treatment-related adverse events was higher in the ceftobiprole group, primarily owing to self-limited nausea (7% vs. 2%) and vomiting (5% vs. 2%) [67]. In 2014, a double-blinded, multicenter, and randomized study compared ceftobiprole medocaril (500 mg q8h) and ceftazidime combined with linezolid for 781 patients with HAP, including 210 with VAP [66]. The study showed that overall cure rates for ceftobiprole vs. ceftazidime/linezolid were 49.9% vs. 52.8% and 69.3% vs. 71.3%. Cure rates in HAP (excluding VAP) patients were 59.6% vs. 58.8% (ITT, 95% CI, −7.3 to 8.8), and 77.8% vs. 76.2% (Clinically Evaluable, CE). Cure rates in VAP patients were 23.1% vs. 36.8% (ITT) and 37.7% vs. 55.9% (CE). The result was non-inferiority of ceftobiprole against ceftazidime plus linezolid, except in patients with VAP [66]. This comes in agreement with a recent single-center retrospective study from Italy, where 159 patients with CAP or HAP hospitalized in common wards with an immune-depressing factor in 46%, a median age of 70 years and a median Charlson Comorbidity Index (CCI) of 5 were studied. Out of 159 cases, CAP accounted for 66% and HAP for 34%, with ceftobiprole being given either as a combination therapy mainly with levofloxacin or azithromycin in 77% of the cases or as a carbapenem sparing strategy in 44% of the cases. Interestingly, there were five cases of necrotizing pneumonia, three of them being community-acquired, which were all treated with ceftobiprole as a fist-line therapy, reaching a 100% survival rate. No statistically significant differences for mortality amongst ceftobiprole use as first-line (HR 1.00, p = 0.989) therapy compared to ceftobiprole use as second-line therapy (either after a carbapenem or anti-MRSA agent (HR 1.34, p = 0.52) or a second-line with other combination treatment (HR 0.53, p = 0.364)) were reported. Moreover, no statistically significant differences were reported when comparing <7 vs. >7 days of treatment (HR 1.02, p = 0.93). Of note, first-line treatment with ceftobiprole was associated with better survival than escalation or targeted second-line regimens, although there were no significant differences in the primary outcome. This new finding compared to other real-life studies, underlined the potential use of ceftobiprole as a carbapenem-sparing strategy achieving with favorable results [65].

Real-world evidence from ICU units shows that ceftobiprole treatment in critically ill patients with severe, polymicrobial infections led to a clinical cure in nearly 80% of cases. Despite a 32% in-hospital mortality rate, new MDR bacterial carriage was rare, and monitoring ceftobiprole concentrations was highlighted as essential [68]. Similarly, experience of multicenter trials presents ceftobiprole as a safe alternative regimen for HAP, achieving a clinical success rate up to 79% [69], and also as an empirical or rescue therapy in severe infections among individuals with multiple comorbidities [70].

A recent study in Canada suggests that ceftobiprole is primarily utilized as directed therapy for severe infections caused by MRSA, particularly in patients who have failed prior antimicrobial treatments. It is often administered in combination with daptomycin and/or vancomycin, demonstrating high microbiological and clinical cure rates [71]. It is also reported to be used empirically in select patients with CABP, as well as HABP similar to previous studies [71]. MRSA, MSSA, and methicillin-susceptible coagulase-negative Staphylococcus (MSCNS) display ceftobiprole sensitivity rates of >95%, comparable to the rates for linezolid, daptomycin, and vancomycin [72]. For ESBL-negative Enterobacterales, excluding Klebsiella oxytoca (K. oxytoca), the sensitivity is comparable to that of ceftazidime, ceftriaxone, and cefepime. Ceftobiprole has excellent activity against ESBL-negative Enterobacterales and P. aeruginosa but not for ESBL-positive Enterobacterales and A. baumannii [72].

Two studies of ceftobiprole in a pediatric population—a phase 1 single-dose trial in neonates and infants and a phase 3 study in children between 3 months to 17 years old—concluded that the pharmacokinetic profile of the drug shows no significant difference between adults and children. Peak plasma concentrations occurred at the end of infusion while half time and overall exposure remained the same between adults and children. Free ceftobiprole concentrations remained above the MIC (4 mg/L) for over 5 h in both studies, supporting adequate pharmacodynamic target reached, while ceftobiprole was well tolerated across all age groups [73]. Ceftobiprole constitutes an alternative regimen for the treatment of LRTIs, as supported by case series involving predominantly elderly, frail patients with multiple co-morbidities. These real-life experiences consistently show favorable clinical outcomes, suggesting its suitability in complex, high-risk populations commonly encountered in clinical practice [74].

In terms of cost, ceftobiprole is a cost-saving or at least cost-neutral alternative to linezolid/ceftazidime for the treatment of hospitalized patients with nosocomial pneumonia and community-acquired pneumonia [75].

4.2. Antibiotic Agents for Nosocomial Pneumonia

4.2.1. Cefiderocol

Cefiderocol is a novel, injectable, siderophore cephalosporin characterized by a cephalosporin core and side chains resembling those of ceftazidime and cefepime. Due to its unique mechanism of action, cefiderocol exhibits a broad spectrum of activity against numerous MDR Gram-negative bacteria. Microorganisms require iron for critical cellular processes, which they obtain either through heme uptake or by producing specific molecules called siderophores. Siderophores bind extracellular ferric iron and facilitate its transport into the bacterial cell through iron transporter channels [76]. Cefiderocol leverages this siderophore pathway to enter bacterial cells, employing a mechanism often referred to as the “Trojan horse” strategy [76,77]. Unlike conventional antibiotics that rely solely on passive diffusion through membrane porins, cefiderocol enters bacterial cells both passively and actively via its siderophore moiety. Once inside the bacterial cell, cefiderocol dissociates from iron and binds to penicillin-binding proteins (PBPs), particularly PBP3. This binding inhibits peptidoglycan synthesis, thereby disrupting bacterial cell wall synthesis. The unique chemical structure and mechanism of action of cefiderocol confers several advantages, including high intracellular penetration into the periplasmic space and enhanced stability against various beta-lactamases [76]. Cefiderocol, has potent in vitro activity against a broad range of Gram-negative bacteria, including CRAB, and carbapenem-resistant strains of K. pneumoniae, P. aeruginosa, and Stenotrophomonas maltophilia; however, it exhibits limited efficacy against Gram-positive and anaerobic microorganisms [77]. Cefiderocol is currently recommended for i.v. administration at a dose of 2 g q8h, delivered via a 3 h infusion. As kidney function significantly influences the pharmacokinetics of cefiderocol, dosage adjustments are necessary for patients with renal dysfunction. Reduced doses are required for patients with moderate-to-severe kidney impairment, kidney failure, or those undergoing hemodialysis. Conversely, patients with augmented kidney function should receive higher doses of cefiderocol [20]. Cefiderocol is generally well-tolerated, with the most frequently observed adverse events in patients with nosocomial pneumonia being elevated in liver function tests, hypokalemia, diarrhea, hypomagnesemia, and atrial fibrillation [78].

As for pharmacokinetics, cefiderocol penetrates ELF and has similar lung tissue concertation compared to ceftazidime. According to studies of healthy objects, the ELF concentration appears to be parallel to the total plasma concentration, indicating that cefiderocol distributes rapidly from plasma to ELF [79]. It is important to note that cefiderocol’s antimicrobial activity is time-related, with efficacy driven mainly by the duration that free drug concentrations remain above the MIC. The suggested regimen’s dosage of 2 g q8h delivered via 3 h infusion was selected based on PK and PD modeling to ensure effective drug levels against pathogens with MICs ≤4 µg/Ml are achieved [79].

In the pathogen-specific CREDIBLE-CR trial, adult patients with carbapenem-resistant pathogen infections, including nosocomial pneumonia, were randomly assigned to receive either 3 h infusions of cefiderocol (2 g q8h) or the best available therapy (BAT) for 7–14 days. In the cefiderocol arm, a clinical cure rate of 50% was achieved, compared to 53% in the BAT arm. Cefiderocol demonstrated clinical and microbiological efficacy comparable to BAT; however, an increased number of deaths were observed in patients with A. baumannii infections treated with cefiderocol [80]. However, the latter study suffered major design flaws including among others unevenly distributed populations in terms of disease severity. Recently, a retrospective observational study evaluated cefiderocol for the treatment of CRAB infections, particularly in comparison to colistin-containing regimens [81]. The all-cause mortality rate at day 30 was higher among patients treated with colistin (55.8% versus 34%, p = 0.018), although this difference was not observed in patients with VAP. Additionally, nephrotoxicity was reported in greatest rate in the colistin group [81]. Another randomized, phase III, double-blind study (APEKS-NP) compared cefiderocol to meropenem for the treatment of Gram-negative HAP and VAP. The primary endpoint, all-cause mortality at day 14, was 12.4% for cefiderocol and 11.6% for meropenem (adjusted difference 0.8%, p = 0.002). Cefiderocol was found to be non-inferior to high-dose, extended-infusion meropenem [82].

Real-world evidence among critically ill COVID-19 patients with VAP underscored the efficacy of cefiderocol in CRAB infections. Patients were assigned to receiving cefiderocol vs. a non-cefiderocol-containing antibiotic scheme [83]. The primary end point was 28-day-all cause mortality, which was significantly higher in the non-cefiderocol treatment group (44% vs. 67% p = 0.011) [83]. In line with this evidence, another real-world, retrospective observational cohort study evaluated cefiderocol as a treatment option for critically ill patients with CRAB infections (the majority of whom were respiratory infections) and limited treatment options due to previous intake of antibiotics against Gram-negative pathogens [84]. Notably, a high incidence of septic shock and COVID-19 was observed among patients; however, an overall clinical success rate of 53% was still achieved [84]. When compared with colistin as a treatment regimen, cefiderocol exhibited comparable results in terms of outcome and safety in patients with CRAB infections including RTIs [85,86,87], while it also seemed to be an independent factor of 30-day survival [87] or lower mortality risk [86]. More importantly, a cohort study which included 90 patients with monomicrobial CRAB VAP showed lower clinical failure rates with cefiderocol in contrast to colistin (25% and 48%, respectively) [88].

Another key aspect to cefiderocol is its potent use in treating Metallo-β-Lactamase (MBL)-producing CRE infections including pneumonias, by achieving clinical cure up to 72.2%, as observed in cohort studies [89]. In fact, when administered as a therapeutic regimen among novel β-lactam antibiotics for treating severe infections by New-Delhi MBL-producing Enterobacterales, it achieved 48% infection-free survival at day 90 [90]. Cefiderocol has also been tested for its efficacy in treating difficult-to-treat (DTR) P. aeruginosa either as monotherapy or as combination with other regimens. In this setting, it achieved efficacy rates up to 76.5% in patients with infection due to an extensively drug-resistant (XDR)/DTR P. aeruginosa who failed on previous regimens [91].

The newest data from the PERSEUS study demonstrate that cefiderocol is a valuable option for the treatment of serious Gram-negative bacterial infections, particularly those caused by P. aeruginosa. In this retrospective, multicenter study conducted in Spain between 2018 and 2022, 261 hospitalized patients (excluding Acinetobacter spp.) were treated with cefiderocol for at least 72 h. The overall clinical cure rate was 80.5%, with a 28-day mortality rate of 21.5%. Among patients with P. aeruginosa infections, the cure rate was even higher at 84.5%, and mortality was lower at 17.2%. Although cefiderocol was generally well tolerated, adverse drug reactions occurred in a small number of cases, including one fatal event. Importantly, mechanical ventilation and prior antibiotic use >7 days were associated with lower cure rates [92].

Based on the available evidence, the Infectious Diseases Society of America (IDSA) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) advise that cefiderocol should be prescribed for the treatment of CRAB infections with caution and as part of a combination therapy [20,93]. This approach aims to ensure that at least one active agent is included in the treatment regimen. Furthermore, the panel recommends reserving cefiderocol for CRAB infections only after alternative treatment options have been fully utilized [20,93]. For infections caused by S. maltophilia, the IDSA and ESCMID recommend utilizing cefiderocol as part of a combination therapy, at least until significant clinical improvement is achieved [20,93], because even though according to surveillance studies its susceptibility to cefiderocol approaches 100%, the available data are limited [94,95].

In conclusion, cefiderocol is currently approved by the EMA for the treatment of Gram-negative bacterial infections in patients with limited treatment options. Additionally, it is approved by the FDA for the treatment of HAP and VAP caused by susceptible Gram-negative microorganisms, such as K. pneumoniae and P. aeruginosa [96,97].

4.2.2. Ceftolozane/Tazobactam

Ceftolozane/tazobactam (C/T) is a novel fifth-generation injectable cephalosporin/beta-lactamase inhibitor combination approved, among others, for the treatment of HAP and VAP [98]. Ceftolozane, as a β-lactam, inhibits bacterial cell wall synthesis by binding to PBPs, particularly PBP1b, PBP1c, and PBP3. It exhibits enhanced outer membrane permeability, increased resistance to efflux pumps, and greater stability against chromosomal Ambler class C (AmpC) β-lactamases, thereby demonstrating potent in vitro activity against P. aeruginosa, including MDR and XDR strains [99]. Combined with tazobactam, ceftolozane provides extended activity against ESBL-producing Enterobacterales, but IDSA suggests it should be reserved for treating carbapenem-resistant organisms or polymicrobial infections [20,100]. However, it is important to note that the C/T combination is ineffective against carbapenemase-producing strains [98]. Ceftolozane is generally well-tolerated; however, the risk of C. difficile is increased [20]. It is important to note that ceftolozane effectively penetrates lung tissue [101]. According to a population pharmacokinetic (PK) model the drug has an adequate lung penetration with a plasma-to-ELF ratio of approximately 50%. The optimal dosing regimen for the treatment of nosocomial pneumonia to achieve antibacterial effect in the lungs is 3 g q8h, delivered via a 3 h infusion (a double of the approved dose for urinary tract and intrabdominal infections) [102].

In a recent European surveillance study, C/T demonstrated overall susceptibility rates of 94% in Western Europe and 81% in Eastern Europe against P. aeruginosa isolates, and 95% in Western Europe compared to 79% in Eastern Europe for Enterobacterales [103]. Similar susceptibility patterns were observed in studies conducted in the United States [104]. Multiple studies have investigated the safety and efficacy of the drug. In the ASPECT-NP study, a controlled, randomized, double-blind trial, patients with nosocomial pneumonia (including VAP and ventilated hospital-acquired pneumonia) were randomized to receive C/T 3 g q8h versus meropenem 1 g q8h. Regarding the primary endpoints, the 28-day all-cause mortality rate was 24% in the C/T subgroup and 25.3% in the meropenem subgroup. C/T was non-inferior to the comparator, and no safety issues were observed with the 3 g dose regimen [105].

Of note, data derived from real world experience align with the findings observed in clinical trials including clinical success and mortality rates [106,107]. Real-world experience from France and Canada underlines the efficacy of C/T in treating severely ill patients with HAP and VAP caused by MDR P. aeruginosa strains along with an excellent safety profile [108]. When compared to aminoglycoside- or polymyxin-based regimens as treatment of drug-resistant P. aeruginosa infections, C/T indicated higher cure rates and decreased incidence of acute kidney injury, highlighting C/T’s safety and efficacy [109]. In a retrospective matched cohort study, among patients with pneumonia of DTR/MDR P. aeruginosa, C/T treatment led to higher clinical success rates than treatment with ceftazidime/avibactam (CAZ/AVI). The absolute difference between the two arms was 11.4% with an adjusted OR of 2.17. However, there was no difference in time to improved oxygenation, recurrent infection, hemodynamic stability, defervescence, or normalization of leukocytosis between the two arms, while subgroup analysis among immunocompromised showed no significant difference in clinical success rates [110].

C/T has received approval from both EMA and FDA for the treatment of HAP and VAP caused by Gram-negative pathogens, particularly MDR P. aeruginosa, also utilized as a carbapenem sparing strategy [20,111].

4.2.3. Ceftazidime/Avibactam

CAZ-AVI is an injectable third-generation cephalosporin combination with a non-β-lactam/β-lactamase inhibitor. Ceftazidime, a β-lactam antibiotic, exerts its antibacterial effect by inhibiting bacterial cell wall synthesis through binding to PBPs. As a broad-spectrum cephalosporin, it is effective against a wide range of Gram-negative bacteria, including P. aeruginosa and Enterobacteriaceae, such as E. coli and K. pneumoniae. Avibactam enhances ceftazidime’s bactericidal activity in presence of a wide range of β-lactamases, including Ambler class A (KPC and ESBL type enzymes), AmpC, and some class D serine enzymes, but is not effective against metallo-β-lactamases. Thus, the combination lacks activity against A. baumannii and S. maltophilia [112,113]. CAZ-AVI is recommended to be administrated i.v. at a dose of 2.5 g q8h, delivered via a 3 h infusion [20]. CAZ-AVI is generally well tolerated by patients; the most commonly reported adverse events include diarrhea, nausea, headache, vomiting, and fever [113]. Pharmacokinetics studies indicate that CAZ-AVI demonstrates effective penetration into the lungs, specifically into the ELF. The ELF-to-plasma penetration ratios are 52% for ceftazidime and 42% for avibactam, indicating that a significant portion of the drugs reaches the critical area of the lungs, where the infection occurs. These drug levels in the ELF exceed the concentrations needed to effectively kill bacteria, supporting the use of ceftazidime/avibactam in treating lung infections [114].

A pivotal phase III, randomized, double-blind clinical trial (REPROVE) was conducted to evaluate the safety and efficacy of CAZ-AVI in patients with nosocomial pneumonia. Patients were randomly assigned to receive either CAZ-AVI (2 g/500 mg q8h) or meropenem (1 g q8h) for 7–14 days. The primary endpoint was the proportion of patients clinically cured at the TOC visit in the co-primary clinically modified intention-to-treat (cMITT) and CE populations. In the cMITT population, 68.8% of patients in the CAZ-AVI group were clinically cured at the TOC visit, compared with 73.0% in the meropenem group. In the CE population, 77.4% of patients in the CAZ-AVI group achieved clinical cure, compared with 78.1% in the meropenem group. CAZ-AVI was determined to be non-inferior to meropenem in both co-primary analysis populations [115].

Robust real-world evidence supports the use of CAZ-AVI, including its use in RTIs, as demonstrated in more than 45 studies involving nearly 5000 patients [116,117,118,119,120]. An observational retrospective study which took place in India, assessed the efficacy of CAZ-AVI in managing Gram-negative HAP and VAP, with a focus on infections caused by carbapenem-resistant K. pneumoniae [116]. Out of 116 patients included in the study, 78.45% achieved a clinical cure, while 69.23% showed a microbiological cure. Initiating CAZ-AVI treatment within 72 h of diagnosis resulted in higher clinical cure rates, reaching 84.85%. The findings indicate that CAZ-AVI is an effective therapeutic option for treating carbapenem-resistant K. pneumoniae in nosocomial pneumonia and VAP cases [116]. Similarly, the CAVICOR study, a multicenter retrospective observational study, examined 339 patients with CRE infections (among which, pneumonia cases were also enlisted) and in which 189 individuals were treated with CAZ-AVI. CAZ-AVI achieved 21-day clinical cure rate in 89.4% of cases and 52.9% microbiological response, thus supporting its use in carbapenemase-producing bacteria [117]. It can also serve as an alternative regimen to colistin when treating infections with CRE achieving lower 30-day mortality rates (9% and 32%, respectively) as confirmed in a cohort study consisting of 38 patients with blood stream infection (BSI) and RTI [118]. Its efficacy has also been tested in critically ill patients with RTIs caused by Gram-negative bacteria and it has shown non-inferiority as monotherapy compared to combination therapy [119].

Apart from CRE, the efficacy of CAZ-AVI was also evaluated in RTIs caused by P. aeruginosa and ESBL Enterobacterales. Specifically, data from a multicenter study in Italian hospitals reported clinical success at the end of the follow up period up to 90.5% when using CAZ-AVI in patients with gram-negative bacteria infections (with nosocomial pneumonia being the most common infection), especially P. aeruginosa and ESBL Enterobacterales [120]. Additionally, a retrospective analysis of 195 U.S. hospitals compared the effectiveness of CAZ-AVI and C/T compared to BAT when treating infections caused by DTR P. aeruginosa (with RTIs being one of the most common infections) and concluded that CAZ-AVI was associated with lower mortality risk when compared to C/T [121].

In a real-world EZTEAM study, CAZ-AVI was evaluated to treat, among others, patients with RTIs. K. pneumoniae was the most common pathogen identified in the latest microbiological evaluation, before starting the treatment. Notably, 2/3 of the isolated pathogens were found to be MDR, of which 89.3% were carbapenem-resistant. Only a small percentage of the isolated K. pneumoniae bacteria were resistant to CAZ-AVI, while treatment success was achieved in 77.3% overall. Also, CAZ-AVI maintained a very good safety profile emphasizing its potent role in the treatment of MDR bacteria, including MDR K. pneumoniae [122].

To conclude, CAZ-AVI is approved by both EMA and FDA for the treatment of nosocomial pneumonia, including VAP. Despite the drug being on the market for only few years, global surveillance studies are already reporting resistance against CAZ-AVI. Nonetheless, according to these reports, the resistance rates of most Enterobacterales against CAZ-AVI remain low (<4%) and are mostly attributed to MBL species. Mutations in class A β-lactamase, especially KPC-3 and KPC-2 mutations, have been extensively reported and seem to contribute to the emergence of resistance [123]. Higher rates are observed in P. aeruginosa strains, particularly in XDR or CR isolates [123].

4.2.4. Meropenem/Vaborbactam

Meropenem/vaborbactam (MVB) is a combination of meropenem and vaborbactam, a novel non-β-lactam β-lactamase inhibitor derived from boric acid. Vaborbactam enhances the activity of meropenem by inhibiting class A (e.g., KPC) and class C β-lactamases, protecting meropenem from degradation. However, vaborbactam does not inhibit class B (metallo-β-lactamases) or class D β-lactamases. This combination significantly improves the activity of meropenem against meropenem-non-susceptible strains of β-lactamase-producing Enterobacteriaceae, including those with ESBLs, KPC carbapenemases, and other carbapenemases, as well as MDR Enterobacteriaceae, such as CRE. However, vaborbactam adds little benefit to meropenem’s activity against A. baumannii, S. maltophilia, or P. aeruginosa [124].

Pharmacokinetic studies of MVB demonstrated adequate lung penetration with the 2 g–2 g, three-dose regimen. The ELF penetration rates were 65% for meropenem and 79% for vaborbactam, calculated as the ratio of the area under the curve (AUC) in ELF to the free AUC in plasma. These findings highlight the ability of the drug combination to reach therapeutic concentrations at the site of respiratory infections [124].

The TANGO II was a phase III randomized trial that evaluated the safety and efficacy of MVB compared to the BAT in adults with severe infections caused by CRE, including HAP and VAP. Patients received either 7–14 days of monotherapy with MVB or 7–14 days of BAT. MVB was associated with higher clinical cure rates than BAT, at both the end of treatment (65.6% vs. 33.3%) and the TOC (59.4% vs. 26.7%). Importantly, MVB exhibited a lower incidence of nephrotoxicity, with diarrhea, anemia, and hypokalemia being the most frequently reported adverse effects [125]. Regarding special populations, such as immunocompromised patients, MVB demonstrated superior outcomes compared to the ΒAΤ [125]. In pediatric population, an open-label phase 1 trial (TANGOKIDS) aims to evaluate the dosage, pharmacokinetics, safety, and tolerability of a single “dose infusion” of MVB in pediatric patients, from birth to <18 years of age with serious bacterial infections; hence there are no available results yet [126].

Real-world evidence from individuals with gram negative infections, primarily including CRE, reported that early treatment with MVB is associated with high clinical success rates (82%), and low 30-day mortality and recurrence [127]. Studies have compared MVB to CAZ-AVI primarily as monotherapy for treatment of KPC-producing CRE infections. The two agents demonstrated comparable results (69% and 62%, respectively) regarding clinical success [128], although in a recent cohort study of 2775 patients with serious infections (the most frequent being pneumonia) from CRE, MVB was associated with (marginally significant) lower adjusted hospital mortality (20.6% vs. 17%, respectively) [129]. Even in CAZ-AVI-resistant infections—which comprised 59.5% of cases in the cohort—MVB achieved a clinical cure in 75.6% of patients, with microbiological eradication confirmed in all 25 cases where follow-up cultures were available; notably, outcomes were not affected by CAZ-AVI resistance, highlighting MVB effectiveness even in difficult-to-treat, MDR KPC-producing K. pneumoniae infections. Data received from another multi-center study regarding individuals with serious Gram-negative infections treated with MVB suggests a 70% clinical success rate, with lower success observed in nosocomial infections, delayed initiation (>72 h), and combination therapy. Mortality at 30, 60, and 90 days was 7.5%, 15%, and 22.5%, respectively. MVB was generally well tolerated, with one case of suspected Stevens–Johnson syndrome, and no observed C. difficile infections or acute kidney injury. In the study, 60% of patients had diabetes, 37.5% had chronic kidney disease, and 27.5% had heart failure, indicating a high burden of comorbidities among the patient population [130]. In Tiseo et al.’s observational study, individuals with infections due to KPC- and NDM-producing CRE (including pneumonia) received MVB either as monotherapy or in combination with tigecycline, fosfomycin, or aztreonam, achieving a clinical success rate of 77% and a 30-day mortality rate of 15.4% [131].

Cost-effectiveness analyses on the use of MVB report that, although it increases treatment-related costs due to higher drug acquisition and extended survival requiring long-term care, it also significantly improves clinical outcomes—resulting in increased life years and quality-adjusted life years (QALYs) [132,133].

The drug has been granted approval by the EMA for the treatment of HAP/VAP Nevertheless, MVB has not yet received approval from the FDA for this particular indication [134,135]. IDSA notes that MVB is reserved for treating infections caused by organisms exhibiting carbapenem resistance [20].

4.2.5. Imipenem/Cilastatin/Relebactam

Imipenem/cilastatin/relebactam (IMI/REL) is a novel β-lactam/β-lactamase inhibitor combination. Imipenem has antimicrobial activity through the inhibition of bacterial cell wall synthesis, while relebactam potentiates imipenem’s activity by binding to the active site of serine β-lactamases of Ambler classes A and ampC. Specifically, the addition of relebactam reestablishes imipenem’s activity against imipenem non-susceptible P. aeruginosa isolates. Moreover, the combination also demonstrates activity against ESBL- and KPC-producing Enterobacterales, although it lacks activity against A. baumannii and S. maltophilia [124].The optimal dosing for IMI/REL according to IDSA is 1.25 g iv every 6 h (q6h) in 30 min infusions [20]. Dose reduction is necessary for patients with renal dysfunction. The most reported adverse effects included diarrhea, nausea, and vomiting [136].

IM/REL has a dual PD profile, with imipenem demonstrating time-dependent antibacterial activity and relebactam acting as a concentration-dependent β-lactamase inhibitor. The efficacy of imipenem is best described by the percentage of the dosing interval during which free regimens concentrations exceed the MIC (fT > MIC), with a target of ≥30–40% required for bacterial stasis and killing. On the other hand, relebactam’s activity correlates with the free area under the concentration–time curve-to-MIC ratio (fAUC/MIC), with effective bactericidal activity observed at fAUC/MIC values between 8 and 18 [137]. It is noteworthy that both agents show comparable penetration into the ELF, a critical site for pulmonary infections, with ELF/plasma AUC ratios of approximately 54% for relebactam and 55% for imipenem after protein binding adjustment [138].

The efficacy and safety of IMI/REL have been investigated in two pivotal trials. The RESTORE-IMI 1 study compared IMI/REL monotherapy with colistin plus imipenem in patients with imipenem-non-susceptible bacterial infections, including nosocomial pneumonia. A favorable overall response was achieved in most patients, with rates of 71% for IMI/REL versus 70% for colistin plus imipenem. Among patients with HAP or VAP, clinical response rates were higher in the IMI/REL group (87.5%) compared to the colistin plus imipenem group (66.7%). The RESTORE-IMI 2 trial evaluated patients with HAP or VAP primarily caused by Enterobacterales. Participants were randomized to receive either IMI/REL or piperacillin/tazobactam for 7–14 days. The study demonstrated that IMI/REL was non-inferior to the comparator for the primary endpoint of day 28 all-cause mortality, with rates of 15.9% for IMI/REL and 21.3% for piperacillin/tazobactam. The results of both studies underscored that IMI/REL is a viable treatment option for Gram-negative nosocomial pneumonia [139].

Consistent with the clinical trials results, a study where real world data was collected, assessed the efficacy of IMI/REL in the treatment of HAP and VAP, especially when caused by drug resistant P. aeruginosa [140]. However, the study also found higher mortality rates in COVID-19 patients, suggesting that the treatment’s effectiveness may be affected by underlying conditions [140]. Due to the fact that treatment options for DTR P. aeruginosa are limited, evidence encourages the use of IMI/REL in severe cases as a salvage therapy, showing favorable results with a clinical efficacy and microbiological cure up to 64.3% [141]. In a multicenter retrospective study across 24 medical centers in the United States, evaluating the real-world use of IMI/REL in 151 adult patients with suspected or confirmed MDR Gram-negative infections, including LRTI from P. aeruginosa, clinical success was achieved in 70.2% of cases. However, factors such as heart failure, recent antibiotic use, ICU admission, and DTR P. aeruginosa were associated with lower odds of success [142]. Its safety and efficacy have also been evaluated in immunocompromised cancer patients, demonstrating favorable clinical outcomes, when used as empirical therapy. In a study involving 100 patients with febrile neutropenia, IMI/REL achieved a higher clinical success rate at the end of iv therapy compared to standard-of-care treatment (90% vs. 74%) [143]. Currently, IMI/REL has obtained approval from both the FDA and EMA for the treatment of HAP/VAP caused by resistant Gram-negative ESBL- or KPC-producing pathogens.

IMI/REL is generally considered to be a cost-effective therapeutic option. When compared to piperacillin/tazobactam as an empiric therapy against causative pathogens of HAP and VAP, it is more effective, as due to antimicrobial resistance, therapy with piperacillin/tazobactam is ineffective for 14% of the patients. Additionally, another analysis proved the cost-effectiveness of IMI/REL versus colistin plus imipenem, as for the patients treated with IMI/REL, higher cure rates, lower mortality, and reduced nephrotoxicity were achieved, and patients gained 3.7 QALYs, leading to savings of $11,015 per patient due to shorter hospital stays and lower adverse event-related costs. Therefore, it is a viable option despite its higher acquisition costs [144,145].

4.2.6. Sulbactam/Durlobactam

Sulbactam is a widely acknowledged old β lactamase inhibitor derived from penicillin with an intrinsic antibacterial activity against Acinetobacter spp. by inhibiting PBPs 1 and 3 but is prone to hydrolysis by β-lactamases since it has a small range of activity against a subset of Amber class A serine β-lactamases. On the other hand, contrary to the already available β-lactamase inhibitors such as avibactam, vaborbactam or relebactam, durlobactam is a novel non-β-lactam diazabicyclooctane (DBO) β-lactamase inhibitor, that protects sulbactam from degradation. It inhibits Amber Class A, C, and D serine β-lactamases, but not class B MBLs. While having some intrinsic activity against several genera of Enterobacterales such as E. coli, Enterobacter cloacae (E. cloacae) and K. pneumoniae by inhibiting PBP2, it has no activity on its own against Acinetobacter [146]. Combined as an i.v. β-lactam/β-lactamase inhibitor they act against class A, C, and D β-lactamase-producing A. baumannii strains [147]. A recent study that evaluated the in vitro activity of sulbactam/durlobactam (SUL/DUR) against clinical A. baumannii–calcoaceticus complex (ABC) species found SUL/DUR MIC values of ≤ 4 μg/mL which was the preliminary MIC breakpoint of susceptibility, for 98.3% of all ABC isolates. In summary SUL/DUR showed a potent antibacterial activity against a collection of geographically diverse clinical isolates ranging including carbapenem non susceptible and MDR isolates [148].

The efficacy and safety of SUL/DUR were assessed in a multinational, phase III trial (ATTACK). Patients with confirmed ABC infections, including HAP/VAP, were randomized to SUL/DUR or colistin, while all participants received IMI/REL as background therapy. SUL/DUR was non inferior to the comparator with 28-day all-cause mortality rates of 19% and 32%, respectively. The primary safety endpoint was the incidence of nephrotoxicity, which was significantly lower with SUL/DUR (13%) than colistin (32%) [149]. In a subset analysis of this phase 3 trial clinical and microbiological outcomes as TOC were compared for both mono and polymicrobial CRAB infections [150]. When tested in vitro, durlobactam restored imipenem susceptibility to the majority of coinfecting Gram-negative pathogens, such as carbapenem-resistant K. pneumoniae and P. aeruginosa, but no favorable effect was seen for S. maltophilia and P. mirabilis. This data suggested that the use of SUL/DUR plus a carbapenem could be an effective approach against polymicrobial infections that include CRAB, even though further research is required [150]. Taking into consideration the narrow spectrum of SUL/DUR and the need for coadministration of other antimicrobial agents to cover coinfecting pathogens, a study was designed to assess the in vitro antibacterial activity of SUL/DUR in combination with other seventeen antimicrobial agents (common Gram-negative, Gram-positive, and an antifungal agent such as CAZ-AVI, amikacin, imipenem, cefepime, minocycline, meropenem, rifampicin, etc.) [151]. Most combinations ended up in additivity indifference; however what was of outmost importance was the fact that no case of antagonism was seen, suggesting the safety of coadministration of SUL/DUR with other antimicrobial agents [151]. Furthermore, SUL/DUR showed sufficient intrapulmonary concentrations, with ELF-to-total plasma ratios of 55% for sulbactam and 37% for durlobactam [152].

Reports have highlighted favorable outcomes in combination regimens with cefiderocol, meropenem, or tigecycline, without reporting any safety issues [153,154]. Given that CRAB infections pose significant challenges in clinical practice, sulbactam–durlobactam may be a valuable component of combination therapy for serious and complicated pneumonia caused by CRAB, particularly when other treatment options such as cefiderocol prove ineffective [155]. A prospective, observational study that was conducted from 2017 to 2019, with a total of 87 unique colistin-resistant and/or cefiderocol-non-susceptible CRAB isolates from hospitals across U.S. [156] assessed the in vitro activity of SUL/DUR alone and SUL/DUR plus imipenem against CRAB isolates [156]. The results showed that 89% and 97% were susceptible to SUL/DUR and imipenem plus SUL/DUR, with MIC50/MIC90 values of 2 µg/mL/8 µg/mL and 1 µg/mL/4 µg/mL, respectively, indicating that the addition of imipenem lowered the median MIC by twofold to fourfold [156]. Of note, considering that resistant Acinetobacter strains emerge, including those resistant to newer drugs such as cefiderocol, certain case reports indicate that SUL/DUR combinations with other antibiotics can successfully treat carbapenem-resistant A. baumannii infections in cases where cefiderocol resistance has emerged. However, further research is warranted to evaluate this issue [153].

Despite its potential efficacy, a systematic review reported a higher cost associated with SUL/DUR, compared to ampicillin/sulbactam, which could be an important consideration, particularly for low- and middle-income countries [157].

SUL/DUR received FDA approval in May 2023 for the treatment of HABP and VABP caused by susceptible A. baumannii Complex (ABC) organisms for patients > 18 years old. Despite the combination’s narrow spectrum of activity, its effectiveness against ABC renders is a valuable option for these challenging infections with over 70% of CRAB isolates proving susceptible [147]. Approval for use in Europe is not granted yet.

4.2.7. Cefipime/Enmetazobactam

Cefepime/Enmetazobactam is an intravenous antibacterial fixed-dose combination of a 4th generation cephalosporin and an ESBL inhibitor, recently approved in January 2024 by EMA for treatment of HAP, including VAP [89]. More specifically, enmetazobactam has potent activity against ESBLs and cefepime is stable against hydrolysis by OXA-48 and AmpC β-lactamases. Together, this combination has demonstrated potent activity against Enterobacteriaceae expressing ESBLs, OXA-48, and/or AmpC. Thus, the combination has a broad-spectrum antimicrobial activity against a range of MDR Enterobacteriaceae [158]. The potential use of this combination for pulmonary infections was based on the study of Das et al., where 20 healthy volunteers were used to study the intrapulmonary pharmacokinetics of a regimen of 2 g cefepime-1 g enmetazobactam q8h i.v. Concentrations of the drug were calculated in blood and ELF, with the concentration–time profiles of both agents in plasma and ELF being similar. The mean ± standard deviation percentage of partitioning of total drug concentrations of cefepime and enmetazobactam between plasma and ELF was 60.59% ± 28.62% and 53.03% ± 21.05%, respectively [158]. Earlier, a 2020 study of the pharmacokinetics–pharmacodynamics (PK-PD) of cefepime–enmetazobactam against ESBL-producing K. pneumoniae showed that cefepime, given as 100 mg/kg of body weight q8h i.v., had a minimal antimicrobial effect, in a neutropenic murine pneumonia model. However, when this background regimen of cefepime was combined with enmetazobactam, a half-maximal effect was induced with enmetazobactam at 4.71 mg/kg q8h i.v. [159] These data and analyses provided evidence for the potential use and administration of this regimen in nosocomial pneumonia.

A more recent study was performed to investigate the activity of cefepime/enmetazobactam against recently circulating Enterobacterales isolates from Europe from 2019 to 2021 [160]. A total of 2627 isolates were collected, and antimicrobial susceptibility was determined according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. Isolates with phenotypic resistance to ceftriaxone and ceftazidime (but susceptible to meropenem) and isolates non-susceptible to meropenem were screened for the presence of ß-lactamases. Overall, susceptibility to third-generation cephalosporins was 77%, and 97.3% were susceptible to meropenem. Cefepime/enmetazobactam susceptibility was 97.9%, compared with 80.0% susceptibility to piperacillin/tazobactam and 99.4% to ceftazidime/avibactam. Most meropenem non-susceptible isolates carried a KPC (68%), which were not inhibited by cefepime/enmetazobactam, but were inhibited by ceftazidime/avibactam, while most meropenem non-susceptible isolates carrying OXA-48 (9/12 isolates) were susceptible to cefepime/enmetazobactam. Cefepime/enmetazobactam was proven highly active against Enterobacterales isolates, especially those resistant to third-generation cephalosporins, suggesting that it could be used as a carbapenem-sparing agent, even used to replace piperacillin/tazobactam [160]. We have to note that this regimen has been approved in Europe against HAP and VAP in 2024, and so far, the use of it is based on experience with cefepime alone and pharmacokinetic/pharmacodynamic analyses for cefepime–enmetazobactam.

4.2.8. Aztreonam/Avibactam

Aztreonam (ATM) is a monobactam that inhibits bacterial cell wall synthesis by binding to PBP3 leading to bacterial cell lysis and death. Unlike other β-lactams, ATM exhibits activity exclusively against Gram-negative bacteria, with no effect on Gram-positive bacteria or anaerobes. A key advantage of ATM is that it is not hydrolyzed by MBLs; however, is susceptible to degradation by other β-lactamases commonly co-produced by such resistant isolates, including AmpC cephalosporinases, ESBLs, and class A carbapenemases such as KPC, all of which can hydrolyze ATM [161]. Aztreonam/Avivactam (ATM/AVI) is the first β-lactam/β-lactamase inhibitor combination specifically designed to act against MBL-producing bacteria that may co-produce serine β-lactamases (SBLs)–including ESBLs, AmpC and the carbapenemase enzymes, KPC, and OXA-48-like1–7, as well as S. maltophilia [162,163].

ATM/AVI demonstrated strong in vitro activity against 8787 Enterobacterales isolates collected from 64 medical centers across Western Europe, Eastern Europe, the Asia-Pacific region, and Latin America [164]. It effectively inhibited 99.9% of tested isolates at a MIC of ≤8 mg/L, including 99.7% of CRE and MDR strains. The highest MIC value observed among MBL-producers was 2 mg/L, demonstrating potent activity against these pathogens [164]. ATM/AVI retained in vitro activity against 28 clinical isolates of S. maltophilia [165]. Interestingly, ATM/AVI fully restored ATM susceptibility in 82% (23/28) of isolates and reduced MICs to intermediate levels in an additional 3/5 of the remaining isolates. Given that S. maltophilia is intrinsically resistant to most β-lactams due to its L1 metallo-β-lactamase and L2 cephalosporinase, the study confirmed that avibactam effectively inhibits L2, while aztreonam remains unaffected by L1. Importantly, the study also revealed that ATM/AVI does not induce β-lactamase expression. These findings support the potential clinical use of ATM/AVI, as an alternative treatment for MDR S. maltophilia infections [165].

A loading dose improves the probability of achieving both avibactam and ATM target exposures in the first dosing interval, whereas a loading dose plus 3 h maintenance infusions in a 3:1 fixed four times per day (q6h) optimizes joint for probability of target attainment (PTA) [166]. While AVI prevented ATM degradation, the primary driver of bactericidal activity was its enhancement of ATM’s effect within clinically relevant concentrations (ATM: 5–125 mg/L, AVI: 0.9–22.5 mg/L) [167]. For adults with an estimated creatinine clearance (CrCL) greater than 50 mL/min, the recommended intravenous dose of ATM/AVI includes a loading dose of 2 g/0.67 g, followed by a maintenance dose of 1.5 g/0.5 g q6h, infused over three hours. In patients with CrCL 30–50 mL/min, the maintenance dose is reduced to 0.75 g/0.25 g q6h, while those with CrCL 15–30 mL/min receive 0.675 g/0.225 g q8h. For patients with CrCL ≤ 15 mL/min on intermittent haemodialysis, the maintenance dose is 0.675 g/0.225 g q12h, administered after dialysis. There are insufficient data to make dosing adjustment recommendations for patients undergoing renal replacement therapy other than haemodialysis (e.g., continuous veno-venous hemofiltration or peritoneal dialysis).

The efficacy and safety of ATM/AVI was tested in the REVISIT study (NCT03329092). In this phase 3, prospective, randomized, multicenter, open-label trial regarding complicated intra-abdominal infections (cIAI) and HAP/VAP caused by Gram-negative bacteria, including MDR and MBL-producing pathogens, patients were randomized to receive ATM-AVI or meropenem ± colistin for 7–14 days (for HAP/VAP). The primary endpoint was clinical cure at TOC in both the ITT and CE populations. Secondary endpoints included microbiological response, 28-day mortality, and safety outcomes. Clinical cure rates at TOC were comparable between groups. Favorable microbiological response was 75.7% for ATM/AVI ± MTZ and 73.9% for MER ± COL. The 28-day all-cause mortality for cIAI was 1.9% (ATM/AVI) vs. 2.9% (meropenem), while for HAP/VAP, it was 10.8% (ATM/AVI) vs. 19.4% (meropenem). ATM/AVI was generally well tolerated, with no treatment-related serious adverse events (AEs) reported [168].

In the ASSEMBLE study (NCT03580044), 15 patients with cIAI, nosocomial pneumonia, complicated urinary tract infections (cUTI), or BSI caused by MBL-producing Gram-negative bacteria were included to evaluate the efficacy, safety, and tolerability of ATM/AVI versus BAT. In a preliminary analysis, ATM/AVI achieved a 41.7% clinical cure rate (5/12), compared to 0% (0/3) for BAT, highlighting its potential against MBL-producing MDR infections, though the small sample limits generalizability [169].

ATM/AVI was approved by EMA on April 22, 2024, for the treatment of cIAI, HAP including VAP, cUTI, and infections caused by aerobic Gram-negative organisms in patients with limited treatment options. [170].

Table 2. Pharmacokinetic profiles, ELF-to-plasma ratio, and target attainment of antibiotics for LRTI.

Antibiotic	PK Characteristics	ELF/Plasma Ratio	Probability of Achieving Target Attainment
Lefamulin [171]	T1/2 13.2 h rapid oral absorption with 2 peaks 25% oral bioavalability (comparable variability in PK parameters following oral and IV administration) Administration with food delays drug absorption	Penetration in the ELF of the lung (measured by AUC0–24) is comparable following iv and oral administration in both fed and fasted states	>98% in the plasma and ELF for oral administration on the first day of dosing in both fed and fasted states
Omadacycline [42]	T1/2 13.5–13.8 h Linear PK Oral bioavailability (fasted) 34.5%-decreased with high-fat meals Low protein-binding Mostly biliary excretion	ELF and alveovar macrophage concentrations exceed plasma (ELF/plasma AUC ratio 1.47)	Concentration-dependent activity (AUC/MIC) Good lung penetration (especially with IV administration) PTA > 90% for S. pneumoniae at MIC ≤ 0.25 mg/L
Delafloxacin [53,172]	T1/2 ranges from 10–14 h (IV or oral administration, respectively) Oral bioavailability 59% High protein binding Primarily renal excretion	Higher concentrations in the ELF than those in plasma	≥99.5% for S. pneumoniae at MIC 1 mg/L ≥96.3% for S. aureus at MIC 0.5 mg/L
Ceftobiprole [173]	T1/2 3.1–3.3 h Prodrug rapidly hydrolyzed to active agent Linear PK, time independent (125–1000 mg) Low protein binding (16%) Renal elimination (80–90%)	ELF concentrations lower than plasma (mean ELF penetration 25.5%)	Observed target attainment of higher than 90% for %fT > MIC of up to 70% in patients with HAP for MIC values up to 4 mg/L
Meropenem/Vaborbactam [134,174]	T1/2 1.36 ± 0.07 and 1.47 ± 0.14 h for meropenem and vaborbactam, respectively Low plasma protein binding Renal excretion 25% hepatic metabolism of meropenem	63% for meropenem 53% for vaborbactam	High percent probabilities of PK-PD target attainment at or above the upper margins of meropenem–vaborbactam MIC distributions for ENT, KPC-producing ENT, and P. aeruginosa
Imipenem/Cilastatin/Relebactam [136,138]	T1/2 1.2 h for relebactam and 1.0 for imipenem Dose adjustment is required based on renal function High renal excretion for relebactam (94.7–100%)	Exposures in ELF versus plasma are 54% for relebactam and 55% for imipenem	High PTA across a wide range of MICs for HAP/VAP maintained across different levels of renal impairment
Sulbactam/Durlobactam [175]	T1/2 2.15 ± 1.16 h for sulbactam and 2.52 ± 0.77 h for durlobactam 38% and 10% plasma protein binding for sulbactam and relebactam, respectively Renal elimination Dose-proportional PK—stable between single and multiple doses	0.36 for durlobactam	High PTA across in vivo/in vitro models
Cefepime/Enmetazobactam [158,176]	T1/2 2.7 h for cefepime and 2.6 h for enmetazobactam 16.2–19% protein binding for cefepime Renal excretion	0.61 for cefepeme 0.53 for enmetazobactam	PTA ≥90% for Enterobacteriaceae with cefepime-enmetazobactam MICs of ≤8 mg/liter
Aztreonam/Avibactam [177,178]	T1/2 2.8 h for aztreonam and 2.2 h for avibactam Protein binding of 38% and 8%, respectively 70% and 97% renal elimination	The average ratio of aztreonam concentration in ELF to plasma concentration ranges from 21% to 60%. Avibactam’s concentration in ELF is 30% of the plasma concentration	High joint PTA across renal function groups
Ceftolozane/Tazobactam [102,179]	T1/2 2.6 h Linear PK up to 2 g (single dose) Renal excretion (100% unchanged in urine within 24 h) Addition of tazobactam causes no significant change for ceftolozane’s PK parameters	Approximately 50% plasma-to-ELF penetration ratio	For nosocomial pneumoniae PTA for ceftolozane is 98.4% against pathogens with an MIC up to 8 mg/L in ELF (at 3 g-dose scheme)
Ceftazidime/Avibactam [114,180,181]	T1/2 ~2.7 h Linear PK Low protein binding (21% for ceftazidime and 8% for avibactam) Renally excreted (>80% ceftazidime, >97% avibactam unchanged) Dose adjustment needed in renal impairment	Ceftazidime (52%) and avibactam (42%) in healthy volunteers	>96% joint PTA across different renal function categories in patients with nosocomial pneumonia
Cefiderocol [182,183]	T1/2 ~2.0–2.8 h linear PK moderate protein binding (~58%) Primarily renally excreted unchanged (~90% in urine). Low metabolism Low drug–drug interaction potential	ELF/plasma AUC ratio 0.09–0.12	PTA ≥ 90% for MIC values up to 4 mg/L

Abbreviations: T_1/2 half-life; PK pharmacokinetic; ELF epithelial lining fluid; PTA possibility of target achievement; IV intravenous; AUC area under curve; MIC minimal inhibitory concentration; HAP hospital-acquired pneumonia; VAP ventilator-associated pneumonia; KPC klebsiella pneumoniae carbapenemase; ENT Enterobacteriaceae.

provides information about the PK characteristics, ELF-to-plasma ratio), and the PTA

5. Antibiotics Awaiting Approval

Several promising antibiotics are currently in the pipeline, awaiting approval. These antibiotics aim to offer solutions to the increasing threat of antimicrobial resistance. Their approval could provide critical new options for treatment. In that aspect, further research as well as clinical trials are required a address the safety and efficacy of these newly developed antibiotic agents (

Table 3. Approval status of novel antimicrobials agents.

Antimicrobials	Ongoing Pneumonia Clinical Trials	Status of Trial
TEDIZOLID	NCT05534750—Evaluation of the Early Bactericidal Activity of Tedizolid and Linezolide Against Mycobacterium Tuberculosis (TEDITUB)	NCT05534750—RECRUITING
ERAVACYCLINE	NCT06282835—The Effectiveness and Safety Study of Eravacycline Combination Therapy for Multidrug-Resistant A. Baumannii Pneumonia NCT06670872—A Study on the Combination Therapy of Eravacycline for Treating CRAB Pneumonia NCT06666998—Real-World Pharmacokinetic/Pharmacodynamic Study of Eravacycline in Critically III Patients NCT06440304—Therapeutic Options for CRAB (TheraCRAB) NCT05568654—Reducing Antimicrobial Overuse Through Targeted Therapy for Patients With CAP	NCT06282835—RECRUITING NCT06670872—NOT YET RECRUITING. NCT06666998—NOT YET RECRUITING. NCT06440304—NOT YET RECRUITING NCT05568654—RECRUITING
MUREPAVADIN	NO ONGOING CLINICAL TRIALS	-
ZOSURABALPIN	NO ONGOING CLINICAL TRIALS	-
ZABOFLOXACIN	NO ONGOING CLINICAL TRIALS	-
IMIPENEM/CILASTATIN/FUNOBACTAM	NCT05204563—Comparison of the Efficacy and Safety of Imipenem/Cilastatin–Funobactam vs. Imipenem/Cilastatin/Relebactam in adult patients with HAP or VAP	NCT05204563—Completed

Abbreviations: A. baumannii; Acinetobacter baumanni, CRAB; carbapenem-resistant Acinetobacter baumanni, CAP; community-acquired pneumonia.

).

5.1. Tedizolid

Tedizolid (TDZ) is an oxazolidinone, like linezolid, prodrug which inhibits bacterial protein synthesis when converted in vivo by endogenous phosphatases into its active moiety. It has broad spectrum activity against Gram-positive pathogens including methicillin, vancomycin, and certain linezolid-resistant S. aureus isolates [184]. Initially, it was indicated for the treatment of ABSSSIs caused by susceptible Gram-positive bacteria, including MRSA, exhibiting a lower incidence of gastrointestinal and hematologic side effects compared to linezolid [185]. A study performed in Japan, that tested the in vitro activity of TDZ and linezolid against 286 isolates, including 236 clinical isolates of Nocardia species, showed that TDZ had four- to eight-fold higher activity than linezolid in 96.1 (275/286) Nocardia isolates, with (MIC)50 and (MIC)90 values of 0.25 and 0.5 μg/mL for TDZ and 2 and 2 μg/mL for linezolid, respectively [186]. Also, the drug demonstrates excellent pulmonary penetration with ELF concentrations approximately 40-fold higher than those of free plasma [187]. In a phase III trial, TDZ was compared to linezolid for the treatment of Gram-positive ventilated HAP or VAP. Participants received either i.v. TDZ 200 mg q24h for 7 days or linezolid 600 mg q12h for 10 days. TDZ was non-inferior to the comparator for all-cause mortality at day 28 (28.1% versus 26.4%, respectively,) but failed to demonstrate non-inferiority for investigator-assessed clinical cure at TOC. Both drugs were well-tolerated [184]. As far as side effects are concerned, thrombocytopenia is a possible but less frequently seen side effect in comparison to linezolid, but could occur regardless of its serum concentration, necessitating monitoring for platelet count [188]. Also, there was a case of severe optic neuropathy after a long-term therapy of 18 months, although this has not been the case for therapy regimens up to 6 months [189]. The drug is not approved by FDA or EMA for the treatment of pneumonia yet.

5.2. Eravacycline

Eravacycline (ERV) is an intravenous and oral synthetic fluorocycline structurally similar to tigecycline. Like other tetracyclines, the drug inhibits bacterial protein synthesis through binding to the 30s ribosomal subunit. ERV demonstrates a broad spectrum of activity against Gram-positive, Gram-negative aerobes, carbapenem-non-susceptible organisms, and anaerobic pathogens, such as MDR A. baumannii strains, MRSA, VRE, and CRE [190,191], but it is not active against P. aeruginosa. In addition, intrapulmonary penetration into the ELF is approximately 6 times greater than in plasma [192]. A retrospective trial that investigated the role of ERV in A. baumannii pneumonia associated the drug with higher 30-day mortality (33% vs. 15%, p = 0.048), lower microbiologic cure (17% vs. 59%, p = 0.004), and longer duration of mechanical ventilation (10.5 vs. 6.5 days, p = 0.0016) in comparison with the BAT. Patients in the ERV arm had more A. baumanni bacteremia and coinfection with SARS-CoV-2 though, and upon the exclusion of these patients, no differences were observed between the two arm’s outcomes [101,193]. A two-year study performed in China investigated the mutations and expression levels of genes responsible for heteroresistance among CRAB clinical isolates using PCR and q(RT-PCR). Twenty-five ERV heteroresistant isolates (17.36%) were detected among 144 CRAB isolates with ERV MIC values ≤4 mg/L, while no heteroresistant strains were detected in the carbapenem-susceptible (CSAB) group, indicating that CRAB isolates are more likely to develop ERV heteroresistance than CSAB. All of the heteroresistant strains contained OXA-23 carbapenemase and the predominant multilocus sequence typing was ST208 (72%). Of note, in the resistant subpopulation, cross-resistance was observed between ERV, tigecycline, and levofloxacin. As far as the mechanism of resistance is concerned, the addition of efflux pump inhibitors not only reduced significantly the ERV MIC in resistant subpopulations but also weakened the formation of heteroresistance in the first place. More specifically, the expression levels of adeABC and its regulator gene, adeRS, were much higher in the resistant population than in in heteroresistant parental strains (p < 0.05) with no significant differences in the expression of other efflux pump genes. An ISAba1 insertion in the adeS gene was identified in 40% (10/25) of the resistant subpopulations. Furthermore, a decrease in the expression of adeABC or adeRS by antisense RNA silencing inhibited eravacycline heteroresistance, confirming that high expression of adeABC and adeRS led to the formation of heteroresistant strains in CRAB isolates [194]. Another in vitro study conducted between 2018 and 2022 by Zhang et al. investigated the ERV heteroresistance prevalence among 280 common clinical isolates especially in carbapenem-resistant K. pneumoniae (CRKP). It indicated an overall ERV heteroresistance prevalence of 0.7% (2/280) for CRKP isolates and showed that heteroresistance led to a reduced bactericidal effect in CRKP following ERV exposure, in a time-dependent manner. Interestingly a dual treatment regimen of ERV with polymyxin B (PMB), against CRKP3 subgroup effectively inhibited the total CFU, while simultaneously reducing the required PMB concentration [195]. Common adverse events of ERV reported in phase I-III studies included infusion-site reactions and gastrointestinal effects such as nausea, vomiting, and diarrhea, and it may cause the same adverse events as other tetracyclines [194]. However, additional research will be required to determine the role of ERV in pneumonia treatment.

5.3. Murepavadin

Murepavadin represents the first member of outer membrane protein targeting antibiotics. It exerts a novel mechanism of action by binding to lipopolysaccharide transport protein D, inhibiting its function, disrupting outer membrane assembly and causing cell death. Murepavadin has shown promising efficacy against MDR P. aeruginosa. However, intravenous murepavadin for pneumonia treatment has been withdrawn in phase III trials (NCT03409679 and NCT03582007) due to the significant incidence of nephrotoxicity. At present, clinical trials are focused on an inhaled formulation of murepavadin that aims to reduce systematic toxicity [196].

5.4. Zosurabalpin

Zosurabalpin (RG6006) is a clinical candidate awaiting approval, belonging to a new class of antibiotics, identified as a tethered Macrocyclic Peptide (MCP). It works by blocking the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane, through inhibition of the LptB2FGC complex leading to the accumulation of this endotoxin in the cell, ultimately resulting in the death of the bacteria. It has already been effective treating highly drug-resistant contemporary isolates of CRAB both in vitro and in multiple mouse infection models, including sepsis, thigh, and lung infection induced by CRAB strains, overcoming existing antibiotic resistance mechanisms with favorable non-clinical pharmacokinetic and safety profiles [197]. Its preclinical success suggests a substantial shift in treating antibiotic resistance, pending clinical trials to validate its effectiveness, pharmacokinetics, and resistance management.

5.5. Zabofloxacin

Zabofloxacin is an orally administered broad-spectrum fluoroquinolone (fluoronaphthyridone) that targets both DNA gyrase and topoisomerase IV enzymes but lacks potency against major nosocomial Gram-negative pathogens, namely P. aeruginosa and A. baumannii. It was first approved in South Korea to treat acute bacterial exacerbation of chronic obstructive pulmonary disease, while it is also approved in the Middle-East, and North-African countries [52]. The efficacy of oral zabofloxacin (367 mg q24h for 5 days) was compared with moxifloxacin (400 mg q24h for 7 days) in a phase three, multicenter, double-blinded, randomized non-inferiority clinical trial. A total of 345 COPD patients with moderate exacerbations were enrolled. The overall clinical cure rates were 88.2% for zabofloxacin and 89.1% for moxifloxacin, with no statistically significant difference (p = 0.89) detected [198].

5.6. Imipenem/Cilastatin/Funobactam

Imipenem/Cilastatin/Funobactam is a β-lactam/β-lactamase inhibitor active against serine carbapenemase-producing A. baumannii, P. aeruginosa, and Enterobacterales. It protects against hydrolysis by Ambler Class A, C, and D β-lactamases, including OXA-23 and OXA-24 found in A. baumannii [199]. The REITAB-2 (XNW4107-302) study is a phase 3, multicenter, randomized, double-blind clinical trial designed to compare the efficacy and safety of Imipenem/Cilastatin-XNW4107 (alternatively funobactam) (IMI-XNW4107) versus Imipenem/Cilastatin/Relebactam (IMI/REL) in adult patients with HAP or VAP. The study’s primary goal is to assess whether IMI-XNW4107 is non-inferior to IMI/REL in terms of all-cause mortality [200].

6. Limitations

Although clinical trials regarding new antibiotics provide valuable data, several limitations have a strong impact on the generalizability and interpretation of their findings. Many trials enrolled a narrow patient population, often excluding individuals with severe disease (e.g., PSI/Pneumonia Patient Outcomes Research Team (PORT) risk class V), immunocompromised status, or comorbid conditions such as cystic fibrosis or advanced COPD. This exclusion limits applicability to real-world, high-risk populations. Geographic representation was also restricted in some studies, which included few patients from major regions. Small sample sizes, non-uniform comparator therapies, and reliance on nonculture diagnostic methods, which may compromise microbiological precision, seem also to be limitations under consideration. Trials also raised concerns about protocol designs not fully reflecting routine clinical practice, such as fixed duration treatment and extensive exclusion criteria.

Table 4. Limitations of trials.

Antibiotic	Trial	Limitations
Lefamulin	LEAP 1 (NCT02559310)	Low number of PORT risk class V Patients. Few patients enrolled from North America, Western Europe, and Latin America. Planned sensitivity analyses by geographic region could not be performed. A total of 47.8% and 39.3% of patients were aged ≥65 years in the lefamulin and moxifloxacin groups, respectively.
Lefamulin	LEAP 2 (NCT02813694)	Extensive list of exclusion criteria may have limited generalizability. Many baseline pathogens were identified using nonculture methods, limiting the collection of MIC data. Samples were not tested for viral co-pathogens. Patients with suspected methicillin-resistant S aureus were excluded per protocol (3 patients enrolled). Race/ethnicity designation may have been misclassified, given that the methods of collection may not have been consistent across sites.
Omadacyclin	OPTIC (NCT02531438)	Patients with PSI risk class I or II were excluded or had limited enrollment. Also patients with the most severe community-acquired bacterial pneumonia (i.e., PSI risk class V) and immunocompromised were excluded, which limits the generalizability of the results to these important subpopulations of patients.
Delafloxacin	DEFINE (NCT02679573)	Patients with history of bronchiectasis or GOLD Stage 4 COPD or history of post obstructive pneumonia or severely immunocompromised were excluded.
Ceftobiprole	NCT00326287	Small number of patients within some of the risk strata (additional need for research in high risk). Registration study with a highly controlled patient population.
Ceftobiprole	NCT00229008	The subgroup of VAP patients was relatively small.
Cefiderocol	CREDIBLE-CR Trial (NCT02714595)	Pathogen-focused trial (carbapenem-resistant Gram-negative pathogen). Best-available therapy was not a uniform, protocol-defined single agent or combination regimen. Small sample size and heterogeneous patient population may have led to imbalances in baseline factors and might have contributed to the difference in all-cause mortality. Use of only APACHE II score as a stratification factor.
Ceftolozane/tazobactam	ASPECT-NP Trial (NCT02105636)	Immunosuppressed patients, patients with cystic fibrosis, and patients receiving dialysis were excluded.
Ceftazidime/Avibactam	REPROVE Trial (NCT02238083)	The duration of study treatment of 7–14 days might not be representative of clinical practice and guidelines, which typically involve antibiotic de-escalation. Small numbers of patients with bacteraemia.
Meropenem/vaborbactam	TANGO II Trial (NCT02644339)	Small sample size
Imipenem/Cilastatin/Relebactam	RESTORE-IMI 1 (NCT02111524)	Small sample size
Sulbactam/Durlobactam	ATTACK (NCT03894046)	Relatively small sample size
Aztreonam/avibactam		Small number of patients with carbapenemase (serine and metallo-β-lactamase)-producing pathogens

Abbreviations: PORT: Pneumonia Patient Outcomes Research Team; PSI: Pneumonia Severity Index; APACHE II: Acute Physiology and Chronic Health Evaluation II; GOLD: Global Initiative for Chronic Obstructive Lung Disease; VAP: Ventilator-Associated Pneumonia; MIC: Minimum Inhibitory Concentration; MRSA: Methicillin-Resistant Staphylococcus aureus; and COPD: Chronic Obstructive Pulmonary Disease.

summarizes the limitations of the conducted trials. These limitations should be taken into account when evaluating the efficacy, safety, and generalizability of new antibiotic therapies.

7. Antimicrobial Resistance to Newer Antibiotics

Despite their novelty, emerging resistance rates seem to be of concern. A common mechanism of resistance involves the overexpression of certain genes, such as the bla KPC gene, which encode for KPC carbapenemases. Even when a strain initially shows susceptibility to an antibiotic such as CAZ-AVI, the overexpression of this gene can lead to resistance, a phenomenon known as heteroresistance which can be found in CRKP [201]. In the same way, the production of other β-lactamases especially metallo-β-lactamases further contribute to resistance in CRE and CRAB [202,203]. Other mechanisms which are also linked to cephalosporin resistance include mutations in genes encoding PBPs, such as PBP3 which impair the antibiotic’s ability to bind to its target, thereby reducing its effectiveness [204]. Clinical isolates of E. coli harboring such mechanisms noted resistance to combination of antibiotics such as ATM-AVI, thus enhancing concerns [205]. Interestingly, a different approach for developing resistance is mutations in the cirA gene which encodes a catecholate siderophore receptor responsible for iron uptake, leading to the deficiency of the receptor. Since cefiderocol relies on the iron transport system to enter the bacterial cell, the absence of functional CirA disables the drug’s ability to enter the cell, thereby contributing to resistance [206]. This mechanism has been observed in various pathogen isolates including CRKP and CRE which developed resistance to cefiderocol [202,207]. For specific pathogens such as P. aeruginosa, resistance can involve mechanisms beyond β-lactamase production, such as the upregulation of efflux pumps like MexAB-OprM, which may confer resistance to certain antibiotics (e.g., CAZ-AVI) while retaining susceptibility to others (e.g., C/T) [208], whereas certain antibiotic modifying enzymes such as aminoglycosides-modyfing enzymes can also be found in CRAB [209]. It is of utmost importance for clinicians to identify the potential resistance mechanisms, as different mechanisms can significantly affect the bacterium’s susceptibility to various antibiotics [209] in addition to the fact that resistance to one β-lactam/β-lactamase inhibitor combination does not necessarily imply resistance to another [210].

Overall, the rapid and complex evolution of bacterial resistance mechanisms leaves us vulnerable, even to newer antibiotics. It is therefore essential to embed newer, structured, and strict antimicrobial stewardship strategies into clinical practice to help prevent the further spread of resistance. Thus, an approach centered on the appropriate and evidence-based use of antibiotics is of vital importance [211]. Following that, diagnostic stewardship includes selecting the appropriate diagnostic test to be performed for the right patient, timely, to avoid unreasonable antibiotic use. The test provider should also be trained to optimize the sample collection. More specifically, for instance, in RTIs, the test provider should swab both nostrils and the pharynx to increase the yield of nasopharyngeal sampling or should instruct the patient to provide an eligible sputum sample. Furthermore, in difficult cases, distal sampling should also be considered. If the patient suffers from CAP, a urine sample should be tested for S. pneumoniae and L. pneumophila antigens. When identifying the microorganism, narrowing the spectrum of the selected antibiotic agent, if applicable, is very important. Moreover, switching from IV to PO treatment, if possible, as well as de-hospitalizing the patient as soon as possible, leads to decreased antibiotic use by avoiding new emerging health care associated infections [211].

Biomarkers like procalcitonin (PCT) can serve as valuable tools in guiding clinical decisions and reducing unnecessary antimicrobial exposure, particularly when integrated into stewardship strategies for RTIs [212]. Such biomarkers may reflect both specific pathogens and the host response, and when used appropriately, they can further support clinical decision-making and strengthen antimicrobial stewardship initiatives [213] by promoting de-escalation and shorter antibiotic duration [214].

Research is shifting toward shorter-duration antibiotic treatments to minimize adverse outcomes while achieving results comparable to longer courses [215,216,217]. In this context, local antibiotic administration, i.e., through nebulization instead of systemic exposure has been examined as an option, especially in high MDR settings. The use of inhaled antibiotics could be a viable step-down alternative, ensuring shorter iv administration; hence the emergence of antibiotic resistance in the presence of data highlighting favorable outcomes [218]. In line with this, the implementation of antimicrobial stewardship programs can further reduce antibiotic exposure in other treatment settings, such as outpatient parenteral antimicrobial therapy (OPAT) [219,220]. However, further data are needed to support these strategies and ensure their safety and effectiveness.

These strategies should accompany the novel antibiotic agents in order to achieve optimal therapeutic outcomes while minimizing the risk of resistance development.

8. Conclusions

In the last decade, a significant number of drugs were approved for the treatment of respiratory tract infections. The characteristics of these agents effectively address the unmet needs arising from the increasing incidence of antimicrobial resistance, treatment failures, adverse events, and unprecedented costs. Even though extensive progress has been made in the development of antibiotics that are active against multi-drug-resistant Gram-negative bacteria, and hopefully will improve the outcomes of patients with nosocomial infections, strict antibiotic stewardship policies should be implemented to limit emerging resistance to these agents. Of note, resistance to one β-lactam/β-lactamase inhibitor does not necessarily preclude resistance to all, hence separate sensitivity tests should be aimed for. In view of this experience, several antimicrobial strategies, mainly based on synergistic antibiotic combinations with older regimens, have been developed to address this escalating issue [123], although the former far exceeds the scope of this review. Existing trials suffer limited numbers of diverse critically ill patients, commonly unevenly distributed, and salvage therapy managed, thus not allowing solid conclusions to be drawn. Larger randomized clinical trials and more real-world experience are pivotal to identify ideal settings for new regimens, hence ensuring the best outcomes for our patients.