Authors: Montserrat Rodríguez-Aguirregabiria
Categories: Review, Hospital-acquired pneumonia, Ventilator-associated pneumonia, Antimicrobial therapy, Neumonía nosocomial, Tratamiento antibiótico, Neumonía asociada a ventilación mecánica
Source: Revista Española de Quimioterapia
Authors: Montserrat Rodríguez-Aguirregabiria
Nosocomial pneumonia is one of the most common nosocomial infections and is associated with significant clinical and economic burdens, such as long-term hospitalization, high medical costs, and increased morbidity and mortality. The increasing incidence of nosocomial pneumonia caused by multidrug-resistant bacteria is a challenge in certain clinical settings, as it often carries a higher risk of delays in initiating an appropriate treatment and, therefore, a worse prognosis. The aim of this article is to analyze some of the key aspects that should be taken into account when choosing an antibiotic treatment for a patient with a nosocomial pneumonia in a multidrug-resistant environment.
Nosocomial pneumonia (NN) is one of the most common nosocomial infections and is associated with significant clinical and economic burdens, such as long-term hospitalization, high medical costs, and increased morbidity and mortality [1]. NN Hospital-acquired pneumonia (HAP) that occurs 48 hours or more after hospital admission and does not appear to have been incubating at the time of admission, ventilator-associated pneumonia (VAP) occurs in intubated patients more than 48 hours after mechanical ventilation is initiated, and ventilated HAP (vHAP) refers to HAP that develops in hospitalized patients who ultimately require mechanical ventilation due to pneumonia [2]. vHAP has a worst prognosis than other types of NN. The overall mortality rate of VAP and vHAP ranges from 15% to 40%, but the attributable mortality is estimated at 10% to 13% [2–4].
Various factors have been associated with a worse prognosis of NN including the existence of comorbidities, the patient’s performance status, and the infection severity at the time of its development and the patient’s response to infection. On the other hand, early and appropriate antibiotic treatment is known to improve the outcomes [5]. Multidrug-resistant (MDR) bacteria have been identified to cause nosocomial pneumonia. Infections caused by MDR pathogens significantly increased the risk of inadequate empirical antibiotic treatment, and are associated with a delayed treatment, persistent or recurrent infection, prolonged hospital stay, and an increased morbidity and mortality [6].
In light of the above considerations, the present paper aims to offer a guide with the key aspects to take into account to select antimicrobial treatment in a patient with a NN from a Spanish perspective.
In the latest report of the Survey on the Prevalence of Healthcare-associated Infections and Antimicrobial Use in Acute Care Hospitals in Spain (EPINE-2024), Pseudomonas aeruginosa (15%) and Staphylococcus aureus (11.2%) were the main pathogens causing HAP, followed by Klebsiella pneumoniae (8.6%), Escherichia coli (5.1%) and Serratia marcescens (4.5%). Methicillin resistance was observed in 25% S. aureus strains in nosocomial infections. Roughly 20-40% of enterobacterales strains were resistance to third-generation cephalosporins, and additionally, 2-14.5% of isolates demonstrate resistance to carbapenems. P. aeruginosa stands out as the most frequent etiological pathogen, with 24% of isolates exhibiting resistance to carbapenems [7].
Recently, a total of 3,180 non-duplicated P. aeruginosa clinical isolates from two Spanish nationwide surveys were analyzed. A decrease in resistance to all tested antibiotics, including older and newer antimicrobials, was observed. The highest resistance rates were documented for ciprofloxacin, followed by imipenem and piperacillin/tazobactam. However, there was a significant increase in the proportion of carbapenemase production among carbapenem-resistant strains. Resistance rates were higher for all agents among the Intensive Care Units (ICU) isolates [8]
On the other hand, according to data from the National Surveillance Study of Nosocomial Infection in Intensive Medicine Services (ENVIN-HELICS 2024), VAP accounted for 36.6% of the infections acquired in the ICU. The most frequent bacterial pathogens were P. aeruginosa (15.8%), S. aureus (12.5%), and K. pneumoniae (8.9%), and followed by E. coli (7.1%), and S. marcescens (5.9%). Other non-glucose-fermenting Gram-negative bacilli (NGFGN) such as Stenotrophomonas maltophilia and Acinetobacter baumannii were particularly relevant causing 5.8% and 1.2% of VAP, respectively. Difficult-to-treat P. aeruginosa strains were found in the 30% of VAP. Enterobacterales as E. coli and K. pneumoniae were 25.6% and 28.8% resistance to third-generation cephalosporins, and 3.2% and 14.8% resistance to carbapenems, respectively [9]
In The CARBA-MAP study a total of 2,704 carbapenemase-producing microorganisms were included. Globally, the most frequent types of carbapenemase in enterobacterales and P. aeruginosa were OXA-48-like, alone or in combination with other enzymes (1,523 cases, 66.8%) and VIM (365 cases, 88.6%), respectively. Among enterobacterales, carbapenemase-producing K. pneumoniae was reported in 1,821 cases (79.9%), followed by E. cloacae complex in 334 cases (14.6%). KPC was mainly present in the South and South-East regions of Spain, and OXA-48-like in the rest of the country. Regarding P. aeruginosa, VIM was widely distributed all over the country [10].
Finally, it should be noted that S. maltophilia and A. baumannii ranked second and third among the NGFGN leading to HAP and VAP after P. aeruginosa [7,9]. S. maltophilia is intrinsically resistant to a wide range of antibiotics. Antimicrobials with in vitro susceptibility, such as TMP/SMX, quinolones, and tetracyclines derivatives (minocycline and tigecycline), are not commonly prescribed initially in patients with NN leading to inappropriate empirical treatment [11]. A. baumannii mainly responsible for nosocomial infections, have become especially difficult to treat when it is carbapenem resistant, owing to the paucity of therapeutic options [12]. Between 40-50% of nosocomial infections associated with A. baumannii were resistant to carbapenems in the EPINE and ENVIN reports [7,9].
MDR P. aeruginosa, ESBL-producing enterobacteria, methicillin-resistant S. aureus (MRSA), carbapenem-resistant A. baumannii (CRAB), and carbapenemase producing Enterobacteriaceae (CPE) are MDR bacteria commonly involved in HAP. The rate of resistant pathogens varies widely across different countries, settings and hospitals. Risk factors are, in general, common to all MDR pathogens [5]. European guidelines pointed out as high-risk of HAP/VAP caused for MDR bacteria patients who present and either septic shock and/or the following risk hospital settings with high rates of MDR pathogens, previous antibiotic use, recent prolonged hospital stay (>5 days of hospitalization), and previous colonization or infection with MDR pathogens [13]. They are also common in the elderly population, those with underlying pulmonary diseases (such as chronic obstructive pulmonary disease and bronchiectasis), diabetes mellitus, immunosuppressive conditions (like HIV and malignancies), chronic alcoholism, liver cirrhosis, and digestive surgery in the last year [14,15]. As well as, in patients admitted from long-term facilities, travel from high endemic area or in the event of a nosocomial outbreak [16].
The importance of colonization as a risk factor for suffering pneumonia by the same microorganism varies according to the type of MDR pathogen and location of the colonization. A recent meta-analyses reported a wide range in the incidence of infection for ESBL-producing enterobacteria following colonization, ranged from 5% in the general adult population to as high as 45% in solid organ transplant recipients. The pooled incidence of infection following colonization for CRE was 22%, and the risk ratio for infection following colonization with Enterobacterales was 15.83 compared with those without colonization (95% CI, 8.30–30.19) [17]. In a multicenter retrospective study HAP caused by MRSA or MDR P. aeruginosa was more common in the MDR bacteria colonization group (24.4% vs. 8.1%, P = 0.006 or 20.0% vs. 5.4%, P = 0.013). Correlation between MDR colonization and infection was evaluated among patients. The phi coefficient was 0.609 for SAMR, 0.311 for MDR Enterobacteriaceae, 0.516 for MDR P. aeruginosa, and 0.389 for MDR Acinetobacter species [18]. An observational cohort study performed in patient admitted to one medical ICU found that CRE colonization compared to non-colonization was associated with a 10.8-fold increased odds of CRE infection at 30 days (95% CI 2.8±41.9, p =0.0006). Only two non-colonized CRE developed and invasive infection by CRE [19]. These data suggest that BMR carrier status should be a factor influencing the choice of empirical treatment in a patient with NN. On the other hand, we must be aware of the relevance of infection control interventions among high-risk patients across the continuum of care.
Therapy should be individualized in accordance with the source and severity of infection and the susceptibility profile of the bacteria. Because of important differences in local epidemiology, rules about when empirical therapy against specific resistant bacteria should be started cannot be generalized [20]. Early initiation of empirical antibiotic therapy in severe infections is an essential criterion to qualify the treatment as adequate. But in addition, antibiotic therapy must be appropriate; that means, it must be effective against the microorganism causing the infection in each particular patient. Effective but late is associated with worse clinical outcomes [21]. Optimal treatment requires, the timely administration of appropriate antimicrobials, and also refers to strategies that achieve therapeutic drug concentrations at the infection site, ensuring both clinical and microbiological effectiveness while minimizing the risk of antibiotic-related toxicity [22].
The management of MDR Gram-negative infections has relied on old antimicrobials, including colistin, aminoglycosides, fosfomycin, and tigecycline. However, the clinical effectiveness of these agents is frequently limited by toxicity profiles, suboptimal pharmacokinetics, and rising resistance rates, which complicate therapeutic decision-making and negatively impact patient outcomes [23].
Currently, novel antibiotics are available for the treatment of nosocomial pneumonia caused by MDR Gram-negative pathogens including ceftolozane–tazobactam (CFT/TAZ), ceftazidime avibactam (CAZ/AVI), meropenem–vaborbactam (MER/VAB), imipenem–cilastatin–relebactam (IMI/REL), cefiderocol (CFD), and aztreonam-avibactam (ATM/AVI) [24,25].
CFD is a siderophore cephalosporin that has shown excellent antibacterial activity against a variety of β-lactamases-producing Gram negatives as Ambler A,B,C, and D β-lactamases, namely KPC and ESBLs from class A, AmpC, the carbapenemase OXA-48 from class D serine-β-lactamases, and the metallo-β-lactamases NDM, VIM, and IMP. CFD has demonstrated activity against members of the Enterobacteriaceae family, such as E. coli and K. pneumoniae, and non-fermenter bacilli P. aeruginosa, S. maltophilia and A. baumannii [26]. CFD resistant prevalence was low overall but varied by species (S. maltophilia 0.4% [95% CI 0.2-0.7%], Enterobacterales 3.0% [95% CI 1.5-6.0%], P. aeruginosa 1.4% [95% CI 0.5-4.0%]), and was highest for A. baumannii (8.8%, 95% CI 4.9-15.2%) and enterobacterales New Delhi metallo-β-lactamase-producing strains [27]. The effectiveness and safety of CFD in patients with Gram-negative bacterial infections, excluding Acinetobacter spp. was recently assessed in the PERSEUS study. Overall, the clinical cure rate was 80.5% (210/261) and the 28-day mortality rate was 21.5% (56/261). In patients with P. aeruginosa infection (66.7% [n = 174], including 73 [42%] with metallo-β lactamases), the clinical cure rate was 84.5%, and the 28-day mortality was 17.2%. These results suggest that CFD is a valuable option in the treatment of serious Gram-negative bacterial infections, particularly for those caused by P. aeruginosa [28]. Regarding the efficacy of CFD against carbapenem-resistant A. baumannii infections is important to highlight that an updating meta-analysis showed that CFD was associated with a significantly lower risk of mortality compared to non-cefiderocol-based regimens [29, 30,31].
Ceftazidime is a 3rd generation cephalosporin active against P. aeruginosa. Avibactam is an inhibitor of class A β-lactamases, including TEM, SHV, CTX-M, KPC, GES, PER, SME; chromosomal class C (AmpC) and plasmid class C; and some class D such as OXA-48 from K. pneumoniae [32]. The pivotal study for the comparison of CAZ-AVI versus meropenem in nosocomial pneumonia was the REPROVE. Similar clinical cure rates (67.2% vs. 69.1%; ITT difference −1.9; 95%CI −8.1, 4.3) and mortality (9.6% vs. 8.3%; ITT difference 1.5; 95% CI-2.4, 5.3) were observed demonstrating CAZ/AVI non-inferiority in the treatment of nosocomial pneumonia [33]. In a recent meta-analysis, lower all-cause mortality for patients with bacteremia (OR = 0.30, 95% CI 0.19–0.46) and improved rates of clinical cure for patients with bacteremia (OR = 4.90, 95% CI 2.60–9.23) and nosocomial pneumonia (OR = 3.20, 95% CI 1.55–6.60) was observed in the CAZ-AVI group [34]. Effectiveness of CAZ/AVI versus CFT/TAZ for MDR P. aeruginosa infections has been evaluated in CACTUS study. Treatment with CFT/TAZ resulted in higher rates of clinical success compared with CAZ-AVI for invasive infections due to multidrug-resistant P aeruginosa. There were no significant differences between study groups with respect to all-cause mortality, and treatment-emergent resistance was common with both agents [35]. In an additional comparative study, rates of 30-day survival, microbiologic failure, and recurrent infections did not vary between groups, but authors found those treated with CAZ/AVI were more likely to develop resistance (defined as ≥4-fold increased MIC) than those treated with CFT/TAZ (40% vs 10%; P = .002) [36].
MER/VAB is a combination of a group 2 carbapenem with a novel cyclic boronic acid-based β-lactamase inhibitor. Vaborbactam was shown to inhibit various class A carbapenemases (e. g. KPC-2, KPC-3, KPC-4, BKC-1, FRI-1, and SME-2), class A ESBLs, and class C cephalosporinases [37]. TANGO II trial showed reduced all-cause mortality, accompanied by a statistically significant increase in cure rates, associated with treatment with MER/VAB in patients with HAP/VAP or bacteremia caused by CRE versus best available therapy. This increased cure rate was demonstrated even in immunocompromised patients, a group typically excluded from clinical trials [38]. The comparative efficacy of CAZ/AVI and MER/VAB for treatment of CRE infections has also been evaluated, and no significant differences in clinical success or mortality was found, but development of resistance was more common with CAZ/AVI monotherapy [39]. MERVAR is a recent and promising option for the treatment of KPC-producing K. pneumoniae infections, including those resistant to CAZ/AVI. Real-world data from a cohort of 342 adults with bloodstream infections was recently published. 30-day mortality was independently associated with septic shock at infection onset, Charlson comorbidity index ≥ 3, dialysis, concomitant COVID-19, and INCREMENT score ≥ 8. However, the administration of MER/VAB within 48 hours from infection onset was a negative predictor of mortality [40].
Ceftolozane has greater activity against P. aeruginosa compared with other anti-pseudomonal β-lactams. This is due to the stability of ceftolozane against AmpC β-lactamases that are intrinsically produced by P. aeruginosa. In combination with the β-lactamase inhibitor tazobactam, ceftolozane retains activity against the majority of resistance mechanisms commonly observed in P. aeruginosa and ESBL-producing Enterobacterales [41]. ASPECT-NP was phase 3, non-inferiority trial comparing CFT/TAZ with meropenem for treating NN. In a subset analysis focusing in vHAP after adjusting for clinically relevant factors the mortality risk in participants with vHAP was over twice as high when treated with meropenem compared with CEF/TAZ. CEF/TAZ may confer a survival advantage over meropenem in the high-risk subpopulation of participants with Gram negative vHAP, but this requires confirmation in an adequately powered trial [42]. The experience of CFT/TAZ on extremely immunosuppressed patients is scarce. A multicenter matched-cohort study of P. aeruginosa bloodstream infections episodes in neutropenic hematologic patients found that the use of CFT/TAZ was significantly associated with improved outcomes, and, in addition, it was found to be an independent risk factor associated with increased survival [43].
IMI/REL is active against Ambler class A (ESBLs, KPCs) and class C (AmpC)-lactamases. It also shows activity against carbapenem-resistant P. aeruginosa, inhibiting Pseudomonas-derived cephalosporinases [6]. A multicenter observational study included 151 patients treated with IMI/REL, and was predominantly prescribed for lower respiratory tract infections, accounting for 52.3% of cases. The 85.4% of the pathogens were carbapenem-non-susceptible, with P. aeruginosa being the most frequently targeted organism.
Clinical success was achieved in a significant proportion of cases (70%), indicating the potential effectiveness of IMI-REL in managing severe infections caused by resistant pathogens [44].
Aztreonam/avibactam (ATM/AVI) recently emerged as a promising option, which restores the monobactam effectiveness against specific β-lactamases. ATM shows marked stability against MBL and AVI inhibits a wide range of β-lactamases, including class A, class C, and some class D enzymes, but it is ineffective against MBL [45]. The ASSEMBLE study focused on infections caused by MBL-producing gram-negatives included only 15 adult patients. Clinical cure at the test-of-cure was 41.7 % (5/12), compared with 0% (0/3) for the best available therapy [46]. Aztreonam plus CAZ/AVI has been used as an alternative to ATM/AVI in the past due to lack of other therapeutic options [47]. In a recent report on 343 patients with MBL–producing Enterobacterales infections, the 30-day mortality rate was 29.7%. Sensitivity analysis showed that ATM plus CAZ/AVI, compared with colistin, was independently associated with a reduced 30-day mortality rate [48]. ATM/AVI combination has been evaluated in pharmacokinetics–pharmacodynamics studies and dose regimens seems to achieve higher joint probability of target attainment compare with proposed CAZ/AVI plus AZT dose regimens. However, additional clinical data are needed to fully elucidate the role CAZ/AVI-ATM versus ATM/AVI for these challenging infections [49,50].
Readapting the European guidelines to a new scenario, an initial empiric combination therapy of HAP/VAP caused for MDRB should cover Gram-negative bacteria and include antibiotic treatment for MRSA in those patients at risk. The authors found reasonable a single empiric Gram-negative agent, if it is effective against >90% Gram-negative bacteria, according to the local antibiotic susceptibility test [13]. Based on all these data we suggest the following empirical and targeted antibiotic treatment approach focus in MDR Gram-negative bacteria (Table 1).
Early appropriate antibiotic therapy in NN represent a major challenge in daily clinical practice in institutions with a higher incidence of MDR bacteria. In this short review, we highlight the most important key factors to consider when choosing antimicrobial therapy. Local epidemiology, the presence of risk factors for NN caused by MDR bacteria, and the spectrum of new available antibiotics must be considered. The management of infections caused by MDR bacteria should be approached from a comprehensive institutional perspective and requires a multidisciplinary team to design a prevention strategy, an early microbiological diagnosis, and empirical and targeted treatment based on current evidence and guidelines documents as core functions of an antimicrobial stewardship program.