Management of ventilator-associated pneumonia (VAP) caused by resistant gram-negative bacteria: which is the best strategy to treat?

ABSTRACT

Introduction: Treatment of ventilator-associated pneumonia (VAP) is a major challenge. The increase in multi-drug resistant bacteria has not been accompanied by the validation of new drugs, or by any new antimicrobial strategies to exploit the available agents. VAP due to Gram-negative bacteria has increased mortality, both due to the resistant pathogens themselves and due to inappropriate treatment. Local epidemiology, patients’ characteristics and clinical responses provide the most important information for therapeutic decision-making. Moreover, data on VAP therapy due to resistant bacteria are lacking, and the choice of treatment is often based on clinical practice and individual experience.

Areas covered: This review summarizes the strategies available for treating the three most prevalent resistant Gram-negative organisms causing VAP: Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae. The review covers the results of a Pubmed search, clinical practice guidelines and reviews, and the authors’ experience.

Expert opinion: The existing evidence focuses on bloodstream infections or other sites rather than pneumonia and there are no recommendations for the treatment of VAP by multi-drug resistant Gram-negative bacteria, especially for combination regimens. The approval of new drugs is needed to provide effective and safe alternatives for treating carbapenemase-producing strains. Precision medicine and personalized approach are also fundamental in future research.

KEYWORDS:

• Ventilator-associated pneumonia (VAP)
• Acinetobacter baumannii
• Pseudomonas aeruginosa
• Enterobacteriaceae spp
• Klebsiella pneumoniae
• antimicrobial treatment
• multidrug resistant pathogens (MDR)
• extensively drug-resistant (XDR)
• pandrug-resistant (PDR)
• Gram-negative bacteria (GNB)

Article Highlights

• Empirical antimicrobial therapy should be rapidly administered in patients with suspected VAP.

• The choice of empirical strategy should be chosen according to the patient’s risk factors, such as previous colonization and the local epidemiology.

• If VAP due to MDR strains is suspected, combination therapy is recommended in order to achieve the broadest initial coverage until susceptibilities are known.

• Empirical prescription against P.aeruginosa and Klebsiella pneumonia should include adjunctive aminoglycosides within the first three days.

• When the local rate of XDR Gram-negative bacteria is high, the empirical use of colistin combination therapy may be justified.

• Once microbiological results are available, initial therapy must be adapted accordingly; the mechanisms of resistance should be considered in the choice of appropriate target therapy.

• Therapy with BL/BLI is suboptimal for patients with VAP caused by ESBL strains and is not recommended.

• Carbapenems with optimized dosage should be used as part of combination therapy for VAP due to carbapenem-resistant isolates, up to a MIC50 of 8 mg/L.

• Ceftazidime-avibactam is a valid alternative as specific therapy against some carbapenemase-producing strains, among them Klebsiella pneumoniae and Pseudomonas aeruginosa.

• Nebulized antibiotics added to standard therapy are not recommended due to the very weak evidence and the potential risk of respiratory and renal adverse events.

• In the presence of indicators of improvement, an 8 day antibiotic course is safe in VAP.

• Baseline severity and clinical response to empirical therapy should also be taken into consideration in order to adapt the type and length of treatment.

Acknowledgments

The authors thank Anabel Romero, BSc, PhD (Barcelona, Spain) for her critical review of this manuscript and Michael Maudsley for help with the English.

Declaration of interest

Jordi Rello received honoraria by participation in consultancies and speaker’s bureau from Anchoagen, Pfizer and Thermo Fisher. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers Disclosure

A reviewer on this manuscript has disclosed speaker’s honoraria from Pfizer, MSD and Angelini. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

Centro de investigation biomedica en red de enfermedades respiratorias, Instituto de  salud Carlos III (Ciberes).