Hospital-acquired pneumonia (non COVID-19) - Emerging treatments

Aerosolized antibiotic therapy

Aerosolized antibiotics have been found to be associated with higher rates of clinical recovery and microbial eradication than intravenous antibiotics in patients with ventilator-associated pneumonia (VAP), without an increase in mortality or nephrotoxicity.[120] One prospective, randomized, double-blind, placebo-controlled trial found reduced signs of respiratory infection with the use of aerosolized antibiotics.[121] A review published by the Society of Infectious Diseases Pharmacists provides evidence-based recommendations, including dosing, for several antibiotics for HAP.[122] They state that the best candidates are those who are not responding to intravenous antibiotics, have recurrent HAP, or have HAP due to an multidrug-resistant (MDR) organism. The 2016 Infectious Diseases Society of America guidelines for HAP/VAP recommend inhaled antimicrobials for patients infected with a pathogen only susceptible to aminoglycosides or polymyxins.[1] Negative studies in this population exist. One prospective, randomized, double blind, placebo-controlled study showed no difference in survival rates between patients with VAP who received aerosolized amikacin and those who received placebo.[123]

New antibiotics

Ceftobiprole, a fifth-generation cephalosporin, is approved in Europe for the treatment of HAP and community-acquired pneumonia (CAP), but it is not approved in the US. It covers MRSA and gram-negative bacteria, including Pseudomonas aeruginosa. Another fifth-generation cephalosporin, ceftaroline (which includes coverage against MRSA), is approved for CAP in Europe and the US, but not HAP, although there are data supporting its use for HAP.[124] Meropenem/vaborbactam, a carbapenem/beta-lactamase inhibitor combination, is approved in Europe for the treatment of HAP and VAP, but is not approved in the US for this indication as yet. Plazomicin is a new generation of aminoglycoside in phase III studies for HAP. It covers gram-negative organisms, such as Escherichia coli, Klebsiella pneumoniae, Enterobacter species, and Acinetobacter baumannii, without the ototoxicity or nephrotoxicity of older aminoglycosides.[125] Sulbactam/durlobactam, a coformulation of sulbactam (a beta-lactam antibiotic) and durlobactam (a beta-lactamase inhibitor), is approved in the US for the treatment of HAP and VAP caused by susceptible strains of Acinetobacter baumannii-calcoaceticus complex (ABC) in adults. One phase 3 study found sulbactam/durlobactam to be noninferior to colistin in patients with infections caused by carbapenem-resistant ABC.[126] Use of prophylactic antibiotics is controversial. One study has shown that patients who received intravenous prophylactic antibiotics had a lower rate of HAP;[127] other studies showed that patients became colonized with MDR pathogens that subsequently led to infections.[128][129]

Monoclonal antibodies

There are two monoclonal antibodies to treat pneumonia that have also been granted fast-track status by the Food and Drug Administration for development. The first is a broadly reactive monoclonal antibody (immunoglobulin G) against P aeruginosa. A phase 1 study evaluated three different doses of the drug for 84 days.[130] It found no serious adverse events, and low-grade adverse events that were not drug-related. The second monoclonal antibody is AR-301, an immunoglobulin G1 against the toxin of Staphylococcus aureus, including MRSA. AR-301 is in phase 3 clinical development. The European Union has granted orphan drug designation to AR-301. Other monoclonal antibodies under investigation include a lipopolysaccharide against P aeruginosa, another against Acinetobacter species, and yet another against respiratory syncytial virus.

Silver-coated endotracheal tubes

Endotracheal tubes with silver impregnation kill pathogens coating the tube. The largest study of silver-coated tubes showed that fewer ventilated patients acquired pneumonia with a silver-coated tube than without.[40] Although 1509 patients were enrolled, the study was not powered to detect a difference in length of stay or mortality. [ ]

Early tracheotomy

Early versus late tracheotomy has been studied in mechanically ventilated patients to determine if there is a benefit in outcomes or decrease in VAP. Varying conclusions have been found.[131][132][133] One meta-analysis found that early tracheotomy (≤7 days) was associated with lower VAP rates and shorter durations of mechanical ventilation and length of intensive care unit (ICU) stay than late tracheotomy, but did not reduce short-term, all-cause mortality.[134]

Sterile mechanical intubation

An emerging area of study is the role of sterility during endotracheal intubation. It seems intuitive that patients intubated in the field or the emergency department have a higher risk for VAP, but there is a paucity of data to support a policy requiring that patients be reintubated if they were not initially intubated in a clean, controlled environment.[135]

Osteopathic manipulation and respiratory therapy

In one randomized, double-blind, controlled trial from the US, patients admitted to the hospital who received 2 daily 15-minute osteopathic manipulative treatments (e.g., thoracic inlet myofascial release) had statistically significant reductions in length of stay, intravenous antibiotic duration, and respiratory failure or death among the per-protocol populations, but not among the intention-to-treat populations.[136] One systematic review showed that respiratory physical therapy reduced mortality in intubated patients undergoing mechanical ventilation who were admitted to ICU, but whether respiratory physical therapy prevented VAP or reduced length of stay in ICU was unclear.[137]

Probiotics

Multiple meta-analyses have reported a possible association between probiotics and lower rates of VAP.[45][46][47] However, these analyses included unblinded studies that were at high risk of bias. Restricting meta-analyses to double-blinded studies only shows no association between probiotics and VAP.[48] This lack of association has also been demonstrated in a large, rigorous, multicenter, randomized trial conducted after the most recent meta-analysis.[49]

Macrolides

Clarithromycin adjunctive therapy has been studied in patients with VAP to determine if it is associated with improved outcomes. When given for three days, mortality was significantly less in those who received clarithromycin (60% in placebo arm vs. 43% with clarithromycin; P=0.023). Clarithromycin was also associated with decreased hospitalization cost.[138]

Continuous lateral rotational therapy

Continuous lateral rotational therapy is occasionally used in ICU patients. A meta-analysis in trauma patients showed that it reduced the level of nosocomial pneumonia, but had no effect on mortality.[139]