Update of the Treatment of Nosocomial Pneumonia in the ICU

Rafael Zaragoza; Pablo Vidal-Cortés; Gerardo Aguilar; Marcio Borges; Emili Diaz; Ricard Ferrer; Emilio Maseda; Mercedes Nieto; Francisco Xavier Nuvials; Paula Ramirez; Alejandro Rodriguez; Cruz Soriano; Javier Veganzones; Ignacio Martín-Loeches


Crit Care. 2020;24(383) 

In This Article

Current and Future Solutions

In the event of sepsis in a critically ill patient, there is an urgent need to commence an empirical antibiotic treatment that is suitable, appropriate and early[1,2] with the risk of resistance to multiple antibiotics, which hinders complying with the premises mentioned.

The future use of rapid diagnostics is promising and will undoubtedly change our approaches to diagnosis and treatment of NP optimizing empiric antibiotic treatment. New tests have been developed such as multiplex polymerase chain reaction (MPCR), exhalome analysis and chromogenic tests.[73]

MPCR has reported a sensitivity of 89.2% and a specificity of 97.1%, using BAL samples, and 71.8% sensitivity and 96.6% (range, 95.4–97.5%) using endotracheal aspirates (ETA).[74]

In the MAGIC-BULLET study, Filmarray® showed a sensitivity of 78.6%, an specificity of 98.1%, a positive predictive value of 78.6% and a negative predictive value of 96.6% in respiratory samples. Furthermore, Filmarray® provided results within only 1 h directly from respiratory samples with minimal sample processing times.[34]

A new score (CarbaSCORE) was recently published; its aim is to identify those critically ill patients who will need to be treated with a carbapenem with the intention of using these antibiotics more selectively.[75] This consideration is appropriate, however, ascertaining some of the variables necessary, such as the existence of bacteraemia or colonization by MDROs involves a delay, which cannot be assumed in the septic patient.

An algorithm that includes the priorities analysed to update empirical and targeted treatment in critically ill patients has been designed (Figure 2) after reviewing the major randomized, controlled clinical trials of antimicrobial agents actually available for NP in the last 10 years[76–84] (Table 3) and the considerations made before about epidemiology (Table 1), antimicrobial resistances (Table 2), rapid microbiological test and risk factors for HAP.

Figure 2.

PANNUCI algorithm. From empirical to targeted treatment on nosocomial pneumonia in ICU. After analyzing the onset, the previous use of antimicrobials or clinical condition (vHAP or VAP), empirical antimicrobial therapy is chosen based on risk factors, previous colonization, local flora and/or use of rapid techniques. Therefore, targeted therapy is selected depending on the type of microorganism isolated and the possible advantages of one antimicrobial over others. AT, antimicrobial therapy; vHAP, ventilated hospital-acquired pneumonia; VAP, ventilator-associated pneumonia; MDR, multidrug-resistant; PCR, polymerase chain reaction; CFT/TAZ, ceftolozane/tazobactam; CAZ/AVI, ceftazidime/avibactam; PIP/TAZ, piperacillin/tazobactam; AMG, aminoglycoside; AZT, aztreonam; EAT, empirical antimicrobial treatment; TAT, targeted antimicrobial treatment; OXA-48, OXA-48 carbapenemase; KPC, Klebsiella pneumoniae carbapenemase; R, resistance. *If Oxa-48 susceptible to CAZ/AVI

Some new antibiotics have been recommended over old ones based on their potential advantages shown in pivotal studies (Table 3), observational studies and in vitro data. However, the use of other families of antibiotics has been also warranted.

Various experts recommend using these new antibiotics according to the site of infection, clinical severity, existence of risk factors for MDRO acquisition, existence of comorbidities and existing MDROs in each unit/hospital as suggested in the algorithm.[4,5,85–87]

The onset of two antibiotics such as ceftolozane/tazobactam (CFT-TAZ) and ceftazidime/avibactam (CAZ/AVI) has broadened the treatment options for patients with suspected MDRO infection. Both antibiotics offer some advantages: apart from the demonstrated efficacy in clinical trials for approval, they present a better in vitro activity and less resistance and can also be used within the scope of an antibiotic policy aimed to reserve carbapenems.[4,5]

Because of its specific features, all authors included in this point of view manuscript coincided in the choice of CFT/TAZ to treat P. aeruginosa[85,86] infections and CAZ/AVI for infections caused by KPC-like carbapenemase-producing Enterobacteriaceae.[87] However, they acknowledged that both antibiotics have never been compared head to head.

CFT/TAZ presents greater in vitro activity against P. aeruginosa, with less resistance than the remaining current anti-pseudomonal agents in global terms.[88] CFT/TAZ also exhibits the lowest mutant prevention concentration (MPC) against P. aeruginosa, as well as colistin and quinolones (2 mg/L).[85] The clinical trial ASPECT-NP[83] reveals a favourable result for patients who suffer from HAP that require invasive MV treated with CFT/TAZ (mortality at 28 days, 24.2% vs 37%) and also in those patients in whom initial antibiotic treatment failed (mortality at 28 days, 22.6% vs 45%). In patients with bacteraemia, a trend towards a higher rate of clinical cure (10.5% vs 36%), without statistical significance, was observed in CFT/TAZ-treated patients. In this clinical trial, higher levels of microbiological cure in pneumonia caused by P. aeruginosa were also observed in patients who received CFT/TAZ.

On the other hand, CAZ/AVI was associated with better survival rates in patients with bacteraemia who required rescue treatment in infections caused by KPC-producing Enterobacteriaceae.[89] In case of infection caused by a CAZ/AVI-susceptible OXA-48 strain, CAZ/AVI could be an option to treat it.[90] Data extracted from an in vitro study suggest that CAZ/AVI plus aztreonam could be an option to treat infections caused by metallo-β-lactamase-producing Enterobacteriaceae.[91]

The MERINO Trial[92] randomized patients hospitalized with bacteraemia caused by enterobacteria resistant to ceftriaxone to receive antibiotic treatment with meropenem or piperacillin/tazobactam. The clinical outcomes were unfavourable for the group of patients that received piperacillin/tazobactam, which cuts down the treatment options for these infections. In published clinical trials, both CFT/TAZ and CAZ/AVI[82,83] antibiotics demonstrated appropriate activity and clinical efficacy to ESBL-E, whereby they arise as a new alternative and may be included in carbapenem-spare regimens.

Cefiderocol recently received US Food and Drug Administration's (FDA) approval for the treatment of complicated urinary tract infections, including pyelonephritis, and is currently being evaluated in phase III trials for treating nosocomial pneumonia and infections caused by carbapenem-resistant Gram-negative pathogens including Acinetobacter spp..[93]

Colistin is really a non-effective drug to consider for HAP unless aerosolized. The Magic Bullet trial failed to demonstrate non-inferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but showed the greater nephrotoxicity of colistin.[84] However, sometimes, especially in VAP caused by MDR Acinetobacter baumannii, no other options are available. Other antimicrobials such as ceftobiprole or tigecycline have not been considered due to the failure to demonstrate non-inferiority in some of the trials reviewed (Table 3).

The use of aerosolized therapy for VAP is still controversial. Two recent multicenter, randomized, double-blinded, placebo-controlled trials of adjunctive nebulized antibiotics for VAP patients with suspected MDR Gram-negative pneumonia were negative to achieve their primary endpoints.[94,95] For this reason, their use as an adjunctive therapy cannot be supported. Rescue therapy for MDROs might be considered when systemic therapy failed.[96]

Antibiotic stewardship and duration of antibiotic therapy also deserve our attention. The clinical severity of a suspected VAP makes intensivists start as soon as possible broad-spectrum antimicrobial therapy when, in fact, many patients treated do not have NP. Clinical scores, such as Clinical Pulmonary Infection Score (CPIS), or non-specific biomarkers such procalcitonin (PCT) and C-reactive protein (CRP) must be applied to begin or to stop antibiotic treatment as previously discussed.[73]

Prolonged courses of antimicrobial therapy promote more resistance. European guidelines recommend antibiotic treatment for HAP no longer than 7 days.[2] However, the duration of therapy for MDROs is not clearly established. A new trial (iDIAPASON) is trying to demonstrate that a shorter therapy strategy in Pseudomonas aeruginosa-VAP treatment is safe and not associated with an increased mortality or recurrence rate.[97] This strategy could lead to decreased antibiotic exposure during hospitalization in the ICU and in turn reduce the acquisition and the spread of MDROs.