Diagnosis and the treatment of Gram-negative bacilli pneumonia in the ICU

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Background

Ventilator-associated pneumonia (VAP) remains a major cause of morbidity and mortality in intensive care units (ICUs), accounting for 25% of infections in the ICU patients and being reported to affect 5-40% of patients receiving invasive mechanical ventilation, with large variations depending upon the country, ICU type and criteria used to identify VAP. VAP is associated with prolonged duration of mechanical ventilation and prolonged duration of ICU stay, whereas mortality seems mainly driven by patients’ underlying conditions and illness severity.
The available evidence supports a beneficial effect of prompt antibiotic administration on survival rates in sepsis. However, the clinical diagnosis of pneumonia is challenging in critically ill patients. Furthermore, collection of microbiological evidence for infection is slow, and previous antibiotic exposure may render results unreliable. Indeed, cultures remain negative in 30-80% of patients clinically considered infected. Biomarkers may help to identify or perhaps to rule out bacterial infections in this setting, thus limiting unnecessary antibiotic use. Novel molecular assays for rapid pathogen detection in clinical samples show good specificity yet poor sensitivity, thus providing a primarily rule-in method for infection. However, further investigations are warranted to fully appraise their potential impact on patient outcomes.
The organisms associated with VAP vary according to many factors including duration of mechanical ventilation, length of hospital and ICU stays before VAPs, timing and cumulative exposure to antimicrobials and the local ecology. However, Gram-negative bacilli (Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Acinetobacter species) are frequently involved in late-onset VAP (occurring after at least 5 days of hospitalization). These pathogens, especially P. aeruginosa, are associated with a high mortality rate and represent a therapeutic challenge with a recurrence rate of around 30%. Despite recent guidelines frame the treatment of VAP, several uncertainties remain, particularly for treating non-fermenting GNB pneumonia, such as the optimal duration of antibiotic therapy for PA-VAP, the use of a combination of antibiotics, the modalities of administration (continuous prolonged or intermittent administration of beta-lactams), the benefit of de-escalation or of Therapeutic Drug Monitoring (TDM). TDM could appear necessary to avoid under or overdosing, to minimize the risk of antibiotic toxicity and maximize drug efficacy through optimized pharmacokinetic, especially for aminoglycosides and glycopetides. However, the routine use of TDM for beta-lactams remains controversial.
Finally, extremely drug-resistant (XDR) Gra-negative bacteria, including carbapenem resistant A. baumanii, P. aeruginosa and K. pneumonia are frequently involved in late-onset VAP. Whereas polymyxins are still the cornerstone of therapy for these infections, some studies indicate that polymyxin B and colistin could be associated with less renal and neurological toxicity than previously reported. Several questions remains incompletely addressed, including the need and type of combinations therapies, optimal dosing regimen, ways to prevent the emergence of resistance and role of nebulized therapies. Drugs newly approved or in late development phase mainly include ceftolozane-tazobactam, ceftazidime-avibactam, aztreonam-avibactam, ceftaroline-avibactam, carbapenems combined with beta-lactamase inhibitors, cefiderocole or evaracycline. Limited data are currently available in ICU patients.

Therefore, the main goal of the proposed research theme is to focus on the modalities of diagnosis and of treatment of Gram-negative bacilli pneumonia in the ICU. We welcome submissions of all types of articles (Original Research, Methods, Opinion, Review, Mini-Review, Perspective, and Hypothesis & Theory) on the following subtopics:
• Epidemiology
• New diagnostic modalities
• Antibiotic treatment: choice of molecules, duration of antibiotic therapy, number of molecules
• Antibiotic stewardships program: de-escalation, Therapeutic Drug Monitoring
• Place of the new molecules or associations: ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, ceftolozane-tazobactam, cefiderocole, eravacycline, etc.
• New modalities of administration: nebulization

Keywords: bacteria, gram negative, VAP, Ventilator-Associated Pneumonia

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