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.

Keywords: Gram-negative bacteria; antimicrobial resistance; combination therapy; glucose-non-fermenting; mechanisms of resistance; nosocomial infections; precision medicine.

Figure 1.

Proposed algorithm for the interpretation of antimicrobial susceptibility testing and treatment of Pseudomonas aeruginosa

Figure 2.

Forest plot comparing mortality for combination therapy versus monotherapy in major cohort studies of Acinetobacter baumannii infections (both retrospective and prospective)[,–,–193]

Figure 3.

Proposed algorithm for the interpretation of antimicrobial susceptibility testing and treatment of Acinetobacter baumannii UTI Urinary Tract Infection; BSI Bloodstream Infection; CNS Central Nervous System; IAI Intraabdominal Infection; OM Osteomyelitis

Figure 4.

Proposed algorithm for the interpretation of antimicrobial susceptibility testing and treatment of Stenotrophomonas maltophilia TMP-SMX Trimethoprim Sulfamethoxazole; BSI Bloodstream Infection; IAI Intraabdominal Infection; SSI Skin and Soft Tissue Infection; OM Osteomyelitis

Figure 5.

Proposed algorithm for the interpretation of antimicrobial susceptibility testing and treatment of Burkholderia cepacia complex