Nosocomial and Ventilator-associated Pneumonia

Abstract

Nosocomial pneumonia (NP), including its subtype ventilator-associated pneumonia (VAP), represents a major cause of morbidity, mortality, and increased healthcare utilization in hospitalized patients, particularly in intensive care settings. This comprehensive, question-and-answer formatted review synthesizes current evidence on the epidemiology, pathophysiology, and management of NP and VAP, with a focus on multidrug-resistant organisms (MDROs). Key distinctions between NP and VAP are explored in terms of microbiological profiles, diagnostic approaches, and therapeutic implications. The review provides a detailed analysis of risk factors for MDROs – including prolonged mechanical ventilation, prior antibiotic exposure, and host-related immunosuppression – emphasizing the importance of risk stratification in guiding empirical antibiotic selection. A critical appraisal of international guideline recommendations (IDSA/ATS, ERS, SEPAR) highlights areas of consensus and divergence, particularly regarding empirical treatment strategies and the role of narrow- versus broad-spectrum coverage. The integration of rapid molecular diagnostic tools, such as multiplex PCR, is discussed in depth, including their potential to improve diagnostic yield, facilitate early de-escalation, and enhance antimicrobial stewardship. Recent advances in antimicrobial development are reviewed, covering novel β-lactam/β-lactamase inhibitor combinations and siderophore cephalosporins with activity against ESBL−, KPC−, and carbapenemase-producing pathogens. Their appropriate use in critically ill patients is contextualized within the framework of pharmacokinetic/pharmacodynamic optimization. Finally, the review examines current evidence on treatment duration, supporting a 7–8 day course in most cases, with individualized extension in selected high-risk populations. The utility of procalcitonin as a biomarker to guide antibiotic discontinuation is also addressed. This review provides clinicians with a concise, evidence-based reference to inform the complex decision-making required in managing nosocomial pneumonia in the era of antimicrobial resistance.

Resumen

La neumonía nosocomial (NN), incluyendo su subtipo la neumonía asociada a ventilación mecánica (NAVM), constituye una de las principales causas de morbilidad, mortalidad y aumento de los costes sanitarios en pacientes hospitalizados, especialmente en unidades de cuidados intensivos. Esta revisión, presentada en un formato de preguntas y respuestas, sintetiza la evidencia actual sobre la epidemiología, fisiopatología y manejo de la NN y la NAVM, con especial atención a los patógenos multirresistentes (PMR). Se analizan las diferencias clave entre la NN y la NAVM en cuanto a perfil microbiológico, estrategias diagnósticas e implicaciones terapéuticas. Se detallan los principales factores de riesgo para infecciones por PMR—como la ventilación prolongada, la exposición previa a antibióticos y la inmunosupresión—, destacando la necesidad de una estratificación individualizada del riesgo para guiar el tratamiento empírico. Se revisan críticamente las recomendaciones de las principales guías internacionales (IDSA/ATS, ERS, SEPAR), resaltando coincidencias y discrepancias, especialmente en cuanto al uso de tratamientos empíricos de amplio o estrecho espectro. Asimismo, se discute el papel de las técnicas diagnósticas moleculares rápidas, como la PCR múltiple, en la mejora del rendimiento diagnóstico y la optimización del uso de antimicrobianos. Se incluye un análisis actualizado de los nuevos antibióticos disponibles frente a PMR, contextualizado en pacientes críticos, y se revisa la evidencia que respalda pautas abreviadas de 7-8 días en pacientes con buena evolución clínica. Finalmente, se aborda la utilidad de la procalcitonina como biomarcador para orientar la suspensión del tratamiento antibiótico.

What are the key differences between nosocomial pneumonia and ventilator-associated pneumonia?

Nosocomial pneumonia (NP), also known as hospital-acquired pneumonia, is defined as a pulmonary infection that occurs at least 48 h after hospital admission in patients who showed no signs of infection at the time of admission. Ventilator-associated pneumonia is a subtype of NP that develops in patients undergoing invasive mechanical ventilation for at least 48 h.¹ Both entities exhibit substantial differences in terms of pathogenesis, diagnosis, and therapeutic management.

NP is one of the most prevalent hospital-acquired infections¹ – and according to some recent reviews, possibly the most common.^2,3 Its incidence varies depending on clinical setting and patient characteristics. Recent data suggest that NP affects approximately 1 in every 100 hospitalized patients and occurs in up to 10% of patients admitted to intensive care units who require intubation.³ Both conditions are associated with substantially increased morbidity and mortality, with VAP-related mortality approaching 10%.^4,5 They are also linked to increased healthcare costs and prolonged hospital stays.^6,7

The diagnosis is based on clinical criteria, supported by microbiological studies. In cases of VAP, it is essential to obtain representative respiratory samples using techniques that minimize upper airway contamination. In contrast, a less invasive diagnostic approach is typically adopted for NP, depending on the patient's clinical evolution. In both scenarios, imaging techniques and the use of biomarkers play a critical role, as their combined application facilitates early identification and appropriate management of the infectious process. A recent review⁸ assessed 29 potential biomarkers in respiratory samples for VAP, however, none demonstrated the >90% sensitivity and specificity required for routine clinical application.¹

From a microbiological standpoint, both NP and VAP may involve common pathogens⁹ such as Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter spp., as well as respiratory viruses and, in immunocompromised patients, opportunistic fungal pathogens. In cases of NP, the bacterial flora often resembles that found in community-acquired pneumonia, whereas VAP is more frequently associated with gram-negative bacilli, which tend to exhibit higher rates of antibiotic resistance.¹⁰

The type of pneumonia and the risk of infection with multidrug-resistant microorganisms are key determinants when selecting initial empirical antibiotic therapy, as inappropriate treatment has a direct impact on patient outcomes and survival.¹¹ In NP, initial therapy may be guided by local antibiotic resistance patterns and often allows for narrower-spectrum antibiotics. In contrast, VAP typically requires broader empirical coverage, which can then be adjusted on patient clinical characteristics and microbiological findings¹² – a topic that will be discussed in further detail in subsequent sections.

In summary, while NP and VAP share some overlapping features, they differ markedly in incidence, microbiological profile, and clinical consequences. These differences require tailored therapeutic strategies and prevention protocols, informed by the latest evidence, in order to mitigate associated healthcare costs and reduce patient morbidity and mortality.

What are the risk factors for nosocomial pneumonia caused by multidrug-resistant organisms?

NP, particularly VAP, remains a significant cause of morbidity and mortality among hospitalized patients, especially those in intensive care units (ICUs).¹² The emergence of multidrug-resistant organisms (MDROs) as causative agents complicates treatment strategies and worsens outcomes, due to limited therapeutic options and its association with prolonged hospital stays, increased healthcare costs, and elevated mortality rates.¹³ Understanding the risk factors associated with MDRO-related NP is crucial for both prevention and effective management.¹⁴

One of the most well-established risk factors for MDRO-associated NP is prolonged mechanical ventilation.¹⁵ VAP represents a common subtype of NP, with the risk increasing proportionally with the duration of intubation.¹⁶ Patients who require mechanical ventilation for more than seven days face a significantly higher risk of developing MDRO-related VAP.¹⁷ This risk increases with each additional day of ventilation, emphasizing the importance of timely weaning.¹⁵ Endotracheal tubes serve as a nidus for bacterial colonization and biofilm formation, facilitating infection by pathogens such as P. aeruginosa, Acinetobacter baumannii, and carbapenem-resistant Enterobacterales.¹⁸ The main risk factors for MDROs in VAP are summarised in Table 1.

Table 1.

Ventilator-associated pneumonia: risk factors for multidrug resistance in adults.

Risk factors for MDR pathogens (including Pseudomonas aeruginosa, other gram-negative bacilli, and MRSA):

- IV antibiotic use within the previous 90 days - Septic shock at the time of VAP - ARDS preceding VAP - ≥5 days of hospitalization prior to the occurrence of VAP - Acute renal replacement therapy prior to VAP onset

Risk factors for MDR Pseudomonas and other gram-negative bacilli:

- Treatment in an ICU in which >10% of gram-negative isolates are resistant to an agent being considered for monotherapy - Treatment in an ICU in which local antimicrobial susceptibility rates are not known - Colonization with or prior isolation of MDR Pseudomonas or other gram-negative bacilli on culture from anybody site.

Risk factors for MRSA:

- Treatment in an ICU in which >10–20% of Staphylococcus aureus isolates are methicillin resistant - Treatment in an ICU in which the prevalence of MRSA is not known - Colonization with or prior isolation of MRSA on culture from anybody site.

MDR: multidrug resistant; MRSA: methicillin-resistant Staphylococcus aureus; IV: intravenous; VAP: ventilator-associated pneumonia; ARDS: acute respiratory distress syndrome; ICU: intensive care unit.

Adapted from: Kalil et al.¹²

Another critical factor is the prior or extended use of broad-spectrum antibiotics in the preceding 90 days.¹⁹ While empiric antimicrobial therapy is often necessary in critically ill patients, it also disrupts the normal microbiota and creates selective pressure that favours the emergence of resistant strains.²⁰ Repeated or inappropriate antibiotic exposure significantly increases the likelihood of subsequent MDRO infection, highlighting the need for judicious antibiotic use and robust antimicrobial stewardship programmes.^21,22

Patient-specific factors also play a pivotal role. Comorbid conditions such as chronic obstructive pulmonary disease (COPD), diabetes mellitus, chronic kidney disease, hepatic dysfunction, and immunosuppression – whether due to corticosteroid use, chemotherapy, or human immunodeficiency virus (HIV) infection – are associated with increased susceptibility to nosocomial MDRO infections.^23,24 These conditions compromise host defences, facilitating colonization and infection by resistant organisms.²⁴

Prolonged hospitalisation (≥2 days) in the past 90 days, particularly in ICUs, and high frequency of antibiotic resistance in the community or in the specific hospital unit are independent risk factors for MDRO colonization and infection.¹ Frequent use of invasive devices – including central venous catheters, urinary catheters, endotracheal tubes, and feeding tubes – further increases vulnerability.²⁵ These devices can serve as conduits for pathogen entry and biofilm development, highlighting the importance of strict aseptic techniques.²⁶ Additionally, recent surgical procedures, especially gastrointestinal surgeries, are recognised risk factors for MDRO-related VAP.²⁰ Surgical interventions may disrupt mucosal barriers and require postoperative mechanical ventilation, both of which contribute to infection risk.²⁰ Key risk factors for multidrug resistance and poor outcomes in non-ventilator nosocomial pneumonia are outlined in Table 2.

Table 2.

Non-ventilator nosocomial pneumonia: risk factors for MDR pathogens and/or increased mortality in adults.

Risk factors for increased mortality:

- Ventilator support for NP - Septic shock

Risk factors for MDR Pseudomonas aeruginosa, other gram-negative bacilli, and MRSA:

- IV antibiotic use within the previous 90 days

Risk factors for MDR Pseudomonas aeruginosa and gram-negative bacilli:

- Colonization with or prior isolation of MDR Pseudomonas or other gram-negative bacilli

Risk factors for MRSA:

- Treatment in an unit in which >20% of Staphylococcus aureus isolates are methicillin resistant - Treatment in unit in which the prevalence of MRSA is not known - Colonization with or prior isolation of MRSA

NP: nosocomial pneumonia; MDR: multidrug resistant; MRSA: methicillin-resistant Staphylococcus aureus; IV: intravenous.

Adapted from: Kalil et al.¹²

Environmental and institutional factors are equally important. Inadequate adherence to infection control protocols – especially poor hand hygiene, suboptimal disinfection of equipment, and overcrowded wards – can facilitate horizontal transmission of MDRO between patients.²⁷ High colonization pressure within healthcare facilities and lapses in antimicrobial stewardship also contribute to the spread of resistance.²⁸

In conclusion, MDRO-related NP results from a multifactorial interplay involving host-related vulnerabilities, clinical interventions, and healthcare system dynamics.²⁹ Early identification of high-risk patients, strict infection prevention, and prudent antimicrobial use are essential strategies to reduce the incidence and burden of this serious healthcare-associated infection.³⁰

Which antibiotics should be considered in the initial empirical treatment of nosocomial pneumonia with risk of MDROs?

The empirical treatment of NP should be tailored to local antimicrobial resistance patterns, individual patient history, and the presence of risk factors for infections caused by MDROs. Current guidelines from the Infectious Diseases Society of America and the American Thoracic Society (IDSA/ATS),¹² the European Respiratory Society (ERS)¹ and the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR)³¹ all emphasize the importance of individualized treatment, although they diverge on certain recommendations. An overview of the suggested empiric treatment options and doses is presented in Table 3.

Table 3.

Suggested empiric treatment options and doses.

Antibiotics with activity against gram-positives	Anti-pseudomonal β-lactam agents	Anti-pseudomonal non-β-lactam agents	Antibiotics active against carbapenem-resistant GNB
Oxazolidinones: Linezolid 600 mg every 12 h IV	Penicillins: Piperacillin–tazobactam 4.5 g every 6 h IV	Quinolones: Levofloxacin 750 mg every 24 h IV or POCiprofloxacin 400 mg every 8 h IV or 750 mg every 12 h PO	Ceftolozane–tazobactam 3 g every 8 h IV
Glycopeptides: Vancomycin 15–20 mg/kg every 8–12 h IV.Consider loading dose in critically ill patients	Carbapenems: Meropenem 1 g every 8 h IVImipenem 500 mg every 6 h IV	Aminoglycosides: Tobramycin 5–7 mg/kg every 24 h IVGentamicin 5–7 mg/kg every 24 h IVAmikacin 15–20 mg/kg every 24 h IV	Ceftazidime–avibactam 2.5 g every 8 h IV
	Cephalosporins: Cefepime 2 g every 8 h IVCeftazidime 2 g every 8 h IV	Polymyxins: Colistin 5 mg/kg IV (loading dose), then 2.5 mg every 12 h IV
	Monobactam: Aztreonam 2 g every 8 h IV

IV: intravenous, GNB: gram-negative bacilli, PO: peros.

Current evidence indicates that a subgroup of patients with early-onset VAP may have a low likelihood of infection with MDROs. However, there are insufficient data to confirm that clinicians can reliably identify these patients, as a significant number will be infected by resistant gram-negative bacteria or MRSA.⁷

The ERS advocates for narrow-spectrum empirical treatment (such as ertapenem, ceftriaxone, cefotaxime, levofloxacin, or moxifloxacin) in patients with early-onset pneumonia (within the first five days of hospitalization), provided there are no risk factors for MDROs and no high risk of mortality. Conversely, the IDSA does not distinguish between early- and late-onset NP and recommends initial coverage for methicillin-sensitive S. aureus (MSSA), P. aeruginosa, and other gram-negative bacilli (GNB) in all patients.

For GNB coverage, the IDSA recommends monotherapy in patients without MDR risk factors and in settings with low resistance rates (<10%). In contrast, in higher-risk settings – or when MDR risk factors or underlying structural lung disease are present- combination therapy with two anti-pseudomonal agents is recommended, one of which must be a beta-lactam-based agent.

SEPAR, for its part, also avoids the early/late-onset classification and aligns largely with ERS in recommending narrow-spectrum antibiotics agents for patients at low risk of MDR and mortality. In patients at higher risk, or in settings with high MDR prevalence (>25%), SEPAR suggests broad-spectrum monotherapy if >90% of local GNB are susceptible to the selected agent and the patient is not in septic shock. Otherwise, combination therapy targeting Pseudomonas spp.^1,31 is adviced. Notably aztreonam is not recommended as a monotherapy due to its lack of activity against MSSA.¹

In the presence of risk factors for methicillin-resistant S. aureus (MRSA), an additional agent with anti-MRSA activity should be included in the empirical regimen.^1,12,31

In specific clinical scenarios, such as prior infections with extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, carbapenems are considered the treatment of choice.³²

In patients with a history of infections caused by carbapenem-resistant GNB, combinations regimens including as ceftazidime–avibactam³³ or ceftolozane–tazobactam³⁴ should be considered.

During outbreaks or in patients colonized with A. baumannii, empirical combination therapy including polymyxins is recommended until susceptibility results are available.³²

In critically ill patients with hemodynamic instability or organ dysfunction, prolonged or continuous infusions of beta-lactams, guided by therapeutic drug monitoring, may help to optimize pharmacokinetic/pharmacodynamic target attainment.³⁵

In most cases, switching to targeted monotherapy after 3–5 days is appropriate, as long as the initial empirical treatment was effective and the patient shows clinical improvement.¹

The performance of the IDSA/ATS recommendations were evaluated in several ICUs. They found that guideline-concordant therapy resulted in adequate initial empirical treatment in 97% of patients, compared with 80% of those who received a non-concordant regimen.⁷

What do rapid microbiological diagnostic techniques contribute to the targeted treatment of nosocomial pneumonia?

Recent advances in rapid molecular diagnostic techniques have led to a paradigm shift in the management of NP. Among these tools, multiplex polymerase chain reaction (PCR) stands out, allowing the simultaneous detection of multiple respiratory pathogens and resistance genes in various types of respiratory samples. These methods offer high sensitivity and specificity, even in the setting of polymicrobial infections, and markedly reduce turnaround times compared to conventional microbiological techniques.³⁶Table 4 provides an overview of these tests and their key characteristics.

Table 4.

Main characteristics of rapid microbiological diagnostic techniques.

Type of technique	Example platform	Detected pathogens	Resistance genes	Time	Sample type	Clinical considerations
Automated multiplex PCR	Biofire FilmArray Pneumonia Panel	34 bacteria, viruses, and fungi	7	∼1 h	Sputum, tracheal aspirate, BAL	Useful for guiding empirical therapy in ICU; rapid detection of coinfections and resistance
	FilmArray Respiratory Panel	18 respiratory viruses and 4 bacteria	Not applicable	<1 h	Sputum, tracheal aspirate, BAL	Useful for differential diagnosis of viral infections; especially in emergency departments
	Curetis Unyvero System	29 bacteria + fungus	19	4–5 h	Sputum, tracheal aspirate, BAL	Good performance in BAL; less widely available; higher technical complexity
Real-time PCR	GeneXpert System	Varies by cartridge (e.g., MRSA, TB, influenza)	Yes, depending on cartridge	<2 h	Nasopharyngeal swab, sputum, BAL	Suitable for targeted diagnosis; ideal for specific infections with high clinical suspicion
Antigen test	Alere BinaxNOW, Sofia SARS Antigen FIA	Respiratory viruses, Legionella (serotype 1), S. pneumoniae	No	<30 min	Nasopharyngeal swab	Fast, low-cost, and simple; limited utility in hospitalized patients

BAL: bronchoalveolar lavage, ICU: intensive care unit, MRSA: methicillin-resistant Staphylococcus aureus, PCR: polymerase chain reaction, TB: tuberculosis.

The clinical implementation of these techniques has significantly enhanced antimicrobial stewardship. Prospective studies have shown that their use increases microbiological diagnostic yield, shortens the duration of empirical treatments, facilitates de-escalation of broad-spectrum antibiotics, and accelerates the initiation of targeted treatment.^37,38 A recent real-world trial³⁹ demonstrated that the use of multiplex PCR in critically ill patients improved antibiotic appropriateness by 21% compared to standard management. Additionally, clinical predictors of positive bacterial detection have been identified, including prolonged hospitalization, high APACHE II scores, elevated C-reactive protein levels, septic shock, and recent hospital readmissions.⁴⁰

Despite these benefits, current international guidelines – such as those from the ERS and ATS/IDSA, do not yet provide specific recommendations for the routine use of these techniques in NP. A major challenge remains in the interpretation of results: detection of non-quantified bacterial DNA does not reliably distinguish between colonization and active infection, particularly in chronically colonized or carrier patients.³⁸

Another important limitation is the restricted coverage of commercial panels, which may not include all relevant pathogens, leading to potential false-negatives results. Consequently, these techniques should not replace conventional cultures, which remain essential for a comprehensive diagnosis and susceptibility testing. Moreover, the detection of resistance genes in vitro does not always correlate with clinical resistance phenotypes. This discrepancy is especially relevant in gram-negative bacteria, where resistance mechanisms such as AmpC production, reduced membrane permeability, or efflux pumps may not be detected.³⁸

Additionally, the lack of standardization in sample collection, processing, and analysis, across centers limits the generalizability of results. Importantly, current evidence does not conclusively demonstrate improvements in hard clinical outcomes -such as mortality or hospital length of stay-with the routine use of these techniques.⁴⁰

The high cost of these technologies further underscores the need for robust cost-effectiveness analysis to define the clinical scenarios in which their implementation provides a net clinical benefit.

Nonetheless, it has been proposed that multiplex PCR could be considered in all cases of suspected NP to expedite diagnostic and guide early treatment, always in conjunction with conventional cultures.⁴¹ Emerging technologies such as mass spectrometry (MALDI-TOF) and next-generation sequencing (NGS) may further enhance the diagnostic landscape in the near future, although their clinical application remains limited at present.⁴²

In immunocompromised patients, although bacteria (especially gram-negative) remain the leading cause of NP, clinicians should maintain a broad differential diagnosis, including viral and opportunistic infections. This is especially important in cases of clinical deterioration despite antibiotic therapy or when imaging findings are atypical for bacterial pneumonia. Non-infectious etiologies should also be considered. While chest computed tomography (CT) can provide valuable information, radiological patterns are often atypical in this population and bronchoalveolar lavage (BAL) remains the cornerstone diagnostic procedure.^18,43Table 5 summarizes the main pathogens to consider in immunocompromised hosts, along with their associated characteristics.

Table 5.

Main pathogens to consider in immunocompromised hosts.

Pathogen	Recommended sample	Diagnostic techniques	Considerations	Relevant clinical aspects
Aspergillus spp.^44	BAL, serum	PCR; galactomannan, β-d-glucan (BAL and serum); culture	Galactomannan in BAL: sensitivity >80% in critically ill patients. Galactomannan in serum: sensitivity <20% in non-neutropenic, ∼70% in neutropenic patients. β-d-Glucan: high negative predictive value.	Increased risk in prolonged mechanical ventilation, COPD, or corticosteroid use. Colonization is common, but high burden in BAL is associated with poor prognosis.
Pneumocystis jirovecii^45	BAL, induced sputum, serum, histology	PCR; direct immunofluorescence; β-d-glucan (BAL and serum); LDH	Serum β-d-glucan: ∼90% sensitivity, low specificity. LDH is non-specific but often elevated in infection.	Frequent clinical–radiological dissociation.
Cytomegalovirus (CMV)^46	BAL, plasma, histological specimen	PCR, viral load, serology, positive histology, antigenemia (pp65)	Viral load in BAL has greater sensitivity than plasma in lung transplant recipients. No standardized threshold to distinguish pneumonia from non-specific reactivation.	Reactivation is frequent in critically ill immunocompromised patients. High risk in transplant recipients and with prolonged corticosteroid use. May cause neutropenia → secondary bacterial infections. Can also cause GI involvement, retinitis, encephalitis, polyradiculopathy.
Herpes simplex virus (HSV)^46	BAL, blood	PCR; cytology (cytopathic effects)	Positive PCR does not confirm disease. A viral load >10^5 copies/million cells in BAL suggests herpetic pneumonia.	Frequent reactivation; consider if skin lesions, oral/genital ulcers, encephalitis, or esophagitis are present.

BAL: bronchoalveolar lavage, COPD: chronic obstructive pulmonary disease, GI: gastrointestinal, LDH: lactate dehydrogenase, PCR: polymerase chain reaction.

What do new antibiotics offer for nosocomial pneumonia?

NP, including VAP, remains a major cause of morbidity and mortality among hospitalized patients. The rising prevalence of MDR bacteria has prompted the development of novel antimicrobial agents, particularly those targeting extended-spectrum β-lactamases (ESBL), class A carbapenemases such as K. pneumoniae carbapenemase (KPC), class D enzymes like OXA-48, and metallo-β-lactamases (MBL).^18,47,48

In this context, several new antibiotics have been developed and approved by the Spanish Agency of Medicines and Medical Devices (AEMPS), expanding the therapeutic arsenal against MDR pathogens. Below, we summarize the most recently approved agents in Spain for the treatment of NP.

Ceftazidime–avibactam combines a third-generation cephalosporin with a β-lactamase inhibitor active against ESBL, KPC, and OXA-48 enzymes, although it lacks activity against MBL. The REPROVE trial³³ demonstrated its non-inferiority to meropenem in patients with NP, supporting its use as a carbapenem-sparing alternative.

Imipenem–relebactam, evaluated in the RESTORE-IMI 1 and 2 trials,^49,50 is active against ESBL, KPC, and certain resistant strains of P. aeruginosa. RESTORE-IMI 1⁴⁹ reported lower nephrotoxicity compared to colistin plus imipenem, while RESTORE-IMI 2⁵⁰ confirmed its non-inferiority to piperacillin–tazobactam.

Meropenem–vaborbactam, assessed in the TANGO II trial,⁵¹ showed superiority over the best available therapy (BAT) for infections caused by KPC-producing Enterobacterales. This agent combines a carbapenem with a non-β-lactam β-lactamase inhibitor active against class A (ESBL, KPC) and class C (AmpC) enzymes, but not against MBL or OXA-48. It provides potent inhibition of KPC without undergoing hydrolysis, in contrast to ceftazidime–avibactam, and binds reversibly to the enzyme.⁵²

Ceftolozane–tazobactam is notable for its activity against MDR P. aeruginosa, although it lacks efficacy against carbapenemase-producing strains.⁵³ In the ASPECT-NP⁵⁴ trial, it demonstrated higher microbiological eradication rates than meropenem, particularly in patients with concomitant respiratory and cardiovascular failure.

Cefiderocol was shown to be non-inferior to meropenem in the APEKS-NP trial⁵⁵ and exhibits activity against a broad range of MDR pathogens, including ESBL, KPC, OXA-48, MBL, and Acinetobacter spp.

Ceftobiprole, approved for the treatment of nosocomial pneumonia (excluding ventilator – VAP), provides coverage against MRSA, Streptococcus pneumoniae, and certain Pseudomonas strains.⁵⁶

Tables 6–8 provide a comprehensive overview of the pharmacological profiles, supporting clinical trial data, and antimicrobial spectra of the recently approved agents indicated for the treatment of NP.

Table 6.

New antibiotics for the treatment of nosocomial and ventilator-associated pneumonia.

Antibiotics	Spectrum	Approved dosage for the treatment of NP/VAP
Ceftazidime–avibactam	BLEE, KPC, AmpC, and some OXA (e.g. OXA 48), MDR P. aeruginosa	2 g of ceftazidime and 0.5 g of avibactam every 8 h by IV infusion over 2 h
Imipenem–relebactam–cilastatin	BLEE, KPC, AmpC, MDR P. aeruginosa, Streptococcus spp., MSSA	500 mg of imipenem; 500 mg of cilastatin, and 250 mg of relebactam administered by IV infusion every 6 h over 30 min
Meropenem–vaborbactam	BLEE, KPC, AmpC, non- MDR P. aeruginosa, Streptococcus spp., MSSA	2 g of meropenem and 2 g of vaborbactam every 8 h by IV infusion over 3 h
Ceftolozane–tazobactam	BLEE, MDR P. aeruginosa, some anaerobes, Streptococcus spp., MSSA	2 g of ceftolozane and 1 g of tazobactam every 8 h by IV infusion over 1 h
Cefiderocol	BLEE, KPC, MBL, OXA-48, MDR P. aeruginosa, S. maltophilia, A. baumannii, Streptoccus spp.	2 g every 8 h by IV infusion over 3 h
Aztreonam–avibactam	BLEE, KPC, MBL, OXA-48Proteus, Providencia, Serratia, Morganella; moderate activity against P. aeruginosa	Initial loading dose of 2 g/0.67 g infused over 3 h, followed by maintenance doses of 1.5 g/0.5 g every 6 h, each infused over 3 h, starting 3 h after completion of the loading dose.
Cefepime–enmetazobactam	BLEE, AmpC, P. aeruginosa, OXA-48	2 g/0.5 g IV every 8 h (2-h infusion)
Ceftobiprole*	Non extended spectrum β-lactamase, non-AmpC and non-carbapenemases-producing Enterobacterales, P. aeruginosa, MRSA.	500 mg every 8 h by IV infusion over 2 h

NP, nosocomial pneumonia; IV, intravenous; MBL, metallo-βlactamase; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; OXA, oxacillinase; VAP, ventilator-associated pneumonia. BLEE, extended-spectrum β-lactamase; KPC: Klebsiella pneumoniae carbapenemase; AmpC, class C β-lactamase; MDR: multidrug-resistant.

*

NP excluding VAP.

Adapted from: Bassetti et al.⁴⁷

Table 7.

Key clinical trials of new antibiotics in nosocomial pneumonia.

Author (year)	Trial	Antibiotic and regimen	Treatment setting and pathogens	Initial randomized sample size	Efficacy outcome
Torres (2018)^33	REPROVE TrialMultinational, phase 3, double-blind, non-inferiority trial	IV 2 g/500 mg CEF-AVI q 8 h versus IV 1 g MERO q 8 h for 7–14 days.	Hospitalized adults (18–90 years), with nosocomial pneumonia including VAP and non-VAP (all patients with nosocomial pneumonia who did not have VAP).Pathogen: Gram-negative (monomicrobial and polymicrobial).	n = 879 randomized (of which 62 were excluded, leaving n = 817):CEF-AVI: n = 409 (50%)MERO: n = 408 (50%)	CEFT-TAZ was non-inferior to MERO in terms of 28-day all-cause mortality and clinical cure at test-of-cure.
Motsch (2020)^49	RESTORE-IMI 1 Trial:Phase 3, randomized, double-blind study	IV 500/250 mg IMI/REL q 6 h versus colistin (IV loading dose, followed by maintenance doses q 12 h), plus IMI (500 mg q 6 h), 5–21days.	Hospitalized adult (>18) patients with imipenem non-susceptible (but colistin-and IMI/REL-susceptible) Gram-negative bacterial infections, including NP and VAPPathogen: Gram-negative pathogens including P. aeruginosa, K. pneumoniae spp., C. freundii, and other Enterobacteriaceae.	n = 47 randomized, of which IMI/REL, n = 31 (66%)Colistin–imipenem, n = 16 (34%)	Imipenem relebactam is an efficacious and well-tolerated treatment option for carbapenem non-susceptible infections.
Titov (2021)^50	RESTORE-IMI 2 Trial:Phase 3, randomized, double-blind, non inferiority trial	IV 500/500/250 mg IMI/REL at q 6 h for 7–14 days versus IV4 g/500 mgPIP/TAZ q 6 h for 7–14 days.	Hospitalized adult (>18) patients with nonventilated NBP, ventilated NBP, or VABP.Pathogen: Gram-negative pathogens (K. pneumoniae, P. aeruginosa, Acinetobacter calcoaceticus–baumannii complex, E. coli).	n = 537 randomized, of which IMI/REL, n = 268 (49.9%)PIP/TAZ, n = 269 (50.1%)	IMI/REL is an appropriate treatment option for Gram-negative NBP/VABP, including critically ill, high-risk patients.
Martin-Loeches I (2023)^54	ASPECT-NP (2019, subanalysis 2023)double-blind, non-inferiority trial	Ceftolozane–tazobactam 3 g/8 h vs meropenem 1 g/8 h	vNBP/VABP, R-SOFA ≥2, CV-SOFA ≥2, gram-negative MDR	726 (312/321 R-SOFA ≥2; 84/99 CV-SOFA ≥2)	Higher microbiological eradication with ceftolozane–tazobactam in patients with respiratory and cardiovascular dysfunction (CV-SOFA and combined R+CV-SOFA).
Wunderick (2021)^55	APEKS-NP Trial:Phase 3 randomized, controlled, double-blind, parallel-group non-inferiority trial	IV 2 g cefiderocol versus IV 2 g MERO q 8 h for 7–14 days	Hospitalized adult (>18 y) patients with acute bacterial pneumonia in the form of NP, VAP, or healthcare-associated gram-negative pneumonia (HCAP).Pathogen: Gram-negative pathogens including K. pneumoniae, P.aeruginosa, Acinetobacter baumannii, E. coli, E. cloacae, and others	n = 300 randomized, of which CEF, n = 148 (49%) MERO, n = 152 (51%)	Cefiderocol was non-inferior to high-dose meropenem in terms of all-cause mortality on day 14 in patients with gram-negative nosocomial pneumonia
Wunderink (2018)^51	TANGO II Trial:Phase 3, multinational, open-label, randomized controlled trial	IV 2 g/2 g MERO-VAB q 8 h for 7–14 days versus BAT	Hospitalized adults (>18) with confirmed or suspected CRE infections including,NBP/VABP, and CRE bacteremia.Pathogen: Gram-negative CREs including K. pneumoniae, E. coli, E. cloacae sp., P. mirabilis, and S. marcescens	n = 77 randomized, of which MERO-VAB, n = 52 (67.5%) BAT, n = 25 (32.5%)	MERO-VAB monotherapy for CRE infection was associated with increased clinical cure, decreased mortality, and reduced nephrotoxicity compared with BAT.

Antibiotics: IV, intravenous; q 6 h/8 h, every 6/8 h; CEF-AVI, ceftazidime–avibactam; MERO, meropenem; IMI-REL, imipenem–cilastatin–relebactam; PIP/TAZ, piperacillin–tazobactam; MERO-VAB, meropenem–varborbactam; BAT, best available therapy. VA(B)P, ventilator associated(bacterial) pneumonia; N(B)P, nosocomial(bacterial) pneumonia; CRE, carbapenem-resistant.

Adapted from: Bassetti et al.⁴⁷ and Almyroudi et al.⁴⁸

Table 8.

Activity profile against key resistance mechanisms and pathogens.

Antibiotic	ESBL	Amp C	KPC (Class A)	MBL (Class B)	OXA-48-like (Class D)	P. aeruginosa(VIM, IMP)	MRSA
Piperacillin–tazobactam
Cefepime–enmetazobactam
Ceftolozane–tazobactam
Ceftazidime–avibactam
Meropenem–vaborbactam
Imipenem–relebactam
Cefiderocol
Aztreonam–avibactam
Ceftobiprole

: active;

: not active;

: limited or variable activity.

ESBL: extended-spectrum β-lactamase; KPC: Klebsiella pneumoniae carbapenemase; MBL: metallo-β-lactamase; AmpC: class C β-lactamase; OXA-48: oxacillinase-48; VIM: verona integron-encoded metallo-β-lactamase; IMP: Imipenemase metallo-β-lactamase; MRSA: methicillin-resistant Staphylococcus aureus.

In conclusion, the introduction of novel antimicrobial agents has significantly broadened the therapeutic landscape for NP caused by MDR pathogens. Optimal antibiotic selection should be informed by local epidemiological data and individual patient risk factors, with the dual aim of improving clinical outcomes and limiting the emergence of further resistance. These agents constitute a critical component in the management of severe infections, particularly among critically ill patients. Their prudent, evidence-based use is imperative to ensure sustained efficacy and to safeguard therapeutic options for the future.

Can the duration of antimicrobial therapy be shortened in certain populations without increasing rates of relapsing infections or decreasing clinical cure?

Historically, the recommended duration of antibiotic therapy for NP extended to 14 days or more.^1,57 The primary goal of antibiotic therapy is to eradicate the infection; therefore, the duration must be sufficient to achieve clinical cure. However, excessively prolonged therapy can lead to adverse effects, disruption of the patient's microbiota, and the emergence of MDR.⁵⁸

Recent guidelines recommend a 7–8 day course of antibiotic therapy in patients showing a favorable clinical response. Multiple studies have demonstrated no significant differences between short (7–8 days) and long (14 days) antibiotic courses in terms of mortality, duration of mechanical ventilation, or length of ICU stay.^1,31 Moreover, short-course therapy was associated with a higher number of antibiotic-free days and a lower incidence of MDR pathogens compared to longer regimens.⁵⁹ However, it is important to note that most of the available data are derived from studies in patients with VAP, with limited evidence in those with NP. Regarding relapse rates, no significant differences were observed between short and long courses overall. Nonetheless, in patients with VAP caused by non-fermenting gram-negative bacteria, the shorter course was linked to a higher risk of relapse.⁶⁰ This association was not observed in VAP caused by other pathogens.

The 7–8 day course recommendation does not apply to certain high-risk groups, including patients with immunodeficiency, cystic fibrosis, empyema, lung abscess, cavitary lesions, or necrotising pneumonia. These patients may require longer treatment durations. Similarly, individuals who received inappropriate initial empiric therapy or those with specific bacteriological findings – such as MDR pathogens, MRSA, or bacteraemia – should individualized treatment, guided by clinical response and, when appropriate, serial biomarker measurements.

The utility of biomarkers in guiding the duration of the antibiotic therapy has been explored in recent years, with serum procalcitonin (PCT) being the most extensively studied. In patients with NP who do not present risk factors necessitating prolonged treatment, the expected duration remains 7–8 days. In these cases, routine serial measurement of serum PCT levels is not recommended, as it provides minimal or no added benefit and may unnecessarily increase healthcare costs.^1,7 In contrast, for patients with severe immunosuppression, initially inappropriate therapy, or infection due to MDR pathogens, antibiotic courses often extend beyond 8 days and should be tailored to the individual. In such cases, combining PCT daily monitoring with clinical assessment may support decisions regarding treatment duration.¹ When PCT level is less than 80% of the first peak concentration, or if it reaches an absolute concentration of less than 0.5 ng/mL, antibiotic could be stopped.⁶¹ Multiple meta-analyses have also supported a beneficial role for the use of serial PCT to decrease the duration of antibiotic therapy and potentially improve antibiotic stewardship which were associated with decreased antibiotic duration, mortality, costs and side affects.^62–64

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