Therapies for multidrug resistant and extensively drug-resistant non-fermenting gram-negative bacteria causing nosocomial infections: a perilous journey toward ‘molecularly targeted’ therapy

Abstract

Non-fermenting Gram-negative bacilli are at the center of the antimicrobial resistance epidemic. Acinetobacter baumannii and Pseudomonas aeruginosa are both designated with a threat level to human health of 'serious' by the Centers for Disease Control and Prevention. Two other major non-fermenting Gram-negative bacilli, Stenotrophomonas maltophilia and Burkholderia cepacia complex, while not as prevalent, have devastating effects on vulnerable populations, such as those with cystic fibrosis, as well as immunosuppressed or hospitalized patients. Areas covered: In this review, we summarize the clinical impact, presentations, and mechanisms of resistance of these four major groups of non-fermenting Gram-negative bacilli. We also describe available and promising novel therapeutic options and strategies, particularly combination antibiotic strategies, with a focus on multidrug resistant variants. Expert commentary: We finally advocate for a therapeutic approach that incorporates in vitro antibiotic susceptibility testing with molecular and genotypic characterization of mechanisms of resistance, as well as pharmacokinetics and pharmacodynamics (PK/PD) parameters. The goal is to begin to formulate a precision medicine approach to antimicrobial therapy: a clinical-decision making model that integrates bacterial phenotype, genotype and patient's PK/PD to arrive at rationally-optimized combination antibiotic chemotherapy regimens tailored to individual clinical scenarios.

Epidemiology, Treatment, and Prevention of Nosocomial Bacterial Pneumonia

“…S. maltophilia S. maltophilia is capable of surviving on moist surfaces and producing biofilms, thus it is very difficult to treat. The main MDR mechanisms of S. maltophilia include the development of β-lactamase(s), aminoglycoside-modifying enzymes, efflux pumps, and mobile genes exhibiting resistance to trimethoprim-sulfamethoxazole (TMP-SMX) on integrons or plasmids [49]. It has been listed as one of the important MDR pathogens in major hospitals by the World Health Organisation.…”

“…With respect to S. maltophilia, it is usually susceptible in vitro to TMP-SMX, levofloxacin, moxifloxacin, and tigecycline [49]. These antibiotics are thus good options in the treatment of S. maltophilia-related HAP/VAP.…”

Constructing and deconstructing the bacterial cell wall

“…An outstanding example of the latter process is the recruitment by enteroaggregative E. coli of the MltE LT in order to excavate its peptidoglycan in order to allow the insertion of a macromolecular Type VI secretion system . The Gram‐negative bacterium Pseudomonas aeruginosa is a significant cause of morbidity and mortality as a result of infection of wounds and lungs, and β‐lactams are critical components of its chemotherapy . P. aeruginosa recycles its peptidoglycan during growth using LTs to excise peptidoglycan segments (these are called “muropeptides”).…”

“…Gram-negative bacteria use their second membrane as a barrier to antibiotic permeation, and to populate their periplasmic "moat" with both plasmid-encoded resistance enzymes and multiprotein motility and virulence complexes. 37,208,209 Given our long-standing interest in the β-lactamases as a pre-eminent Gram-negative defense against β-lactams 210 our focus turned several years ago to the relationship between β-lactamase expression and the peculiar mechanism used by Gram-negative bacteria to expand (grow) their peptidoglycan polymer. Extensive portions of the Gramnegative peptidoglycan are removed, degraded, and recycled during peptidoglycan growth.…”

Current trends in targeted therapy for drug-resistant infections

“…Based on recent reports, up to 2 million people every year are infected by resistant infections with minimum of 23,000 and 33,000 deaths per year in the USA and European Union, respectively (Cassini et al 2019., El Chakhtoura et al 2018. In this respect, it is estimated that near to 10 million deaths will be occurred by multi drug-resistant bacteria by 2050 year (Sierra et al 2017).…”