Multidrug-resistant (MDR) Gram-negative organisms are a major health concern due to lack of effective therapy. Emergence of resistance to newer agents like ceftazidime-avibactam (CZA) further magnifies the problem. In this context, combination therapy of CZA with other antimicrobials may have potential in treating these pathogens. Unfortunately, there are limited data regarding these combinations. Therefore, the objective of this study was to evaluate CZA in combination with amikacin (AMK), aztreonam (AZT), colistin (COL), fosfomycin (FOS), and meropenem (MEM) against 21 carbapenem-resistant Klebsiella pneumoniae and 21 MDR Pseudomonas aeruginosa strains. The potential for synergy was evaluated via MIC combination evaluation and time-kill assays. All strains were further characterized by whole-genome sequencing, quantitative real-time PCR, and SDS-PAGE analysis to determine potential mechanisms of resistance. Compared to CZA alone, we observed a 4-fold decrease in CZA MICs for a majority of K. pneumoniae strains and at least a 2-fold decrease for most P. aeruginosa isolates in the majority of combinations tested. In both P. aeruginosa and K. pneumoniae strains, CZA in combination with AMK or AZT was synergistic (≥2.15-log₁₀ CFU/ml decrease). CZA-MEM was effective against P. aeruginosa and CZA-FOS was effective against K. pneumoniae. Time-kill analysis also revealed that the synergy of CZA with MEM or AZT may be due to the previously reported restoration of MEM or AZT activity against these organisms. Our findings show that CZA in combination with these antibiotics has potential for therapeutic options in difficult to treat pathogens. Further evaluation of these combinations is warranted.

Multidrug‐resistant organisms have caused a marked depletion of effective antimicrobials, and the narrow pipeline of antibiotics has demanded the need to find novel therapeutic alternatives including nonantibiotic agents. Bacteriophages (phages) are viruses that use the bacterial machinery to infect, replicate, and kill bacterial cells. Although a marked decline in their use was driven by the discovery of antibiotics, the era of antibiotic resistance has led to a resurgence of phage therapy into clinical practice. The term phage‐antibiotic synergy (PAS) was coined just over a decade ago and described that sublethal concentrations of antibiotics could stimulate phage production by bacterial cells. Recent literature has described PAS and other encouraging interactions with various phage and antibiotic combinations against a variety of bacterial strains. The primary objective of this review is to discuss the positive interactions between phage and antibiotic combinations, with an emphasis on PAS, reductions in bacterial growth or minimum inhibitory concentrations, enhanced biofilm eradication, and alterations in the emergence of bacterial resistance. A peer‐reviewed literature search was conducted (1890–2019) using the PubMed, Medline, and Google Scholar databases. Although more investigation is certainly needed, the combination of bacteriophages with antibiotics is a promising strategy to target organisms with limited or no therapeutic options. This approach may also foster the ability to lower the antibiotic dose and may reduce the potential for antibiotic resistance emergence during therapy.

Staphylococcus aureus is a major cause of nosocomial and community‐acquired infections and contributes to significant increase in morbidity and mortality especially when associated with medical devices and in biofilm form. Biofilm structure provides a pathway for the enrichment of resistant and persistent phenotypes of S. aureus leading to relapse and recurrence of infection. Minimal diffusion of antibiotics inside biofilm structure leads to heterogeneity and distinct physiological activity. Additionally, horizontal gene transfer between cells in proximity adds to the challenges associated with eradication of biofilms. This narrative review focuses on biofilm‐associated infections caused by S. aureus, the impact of environmental conditions on biofilm formation, interactions inside biofilm communities, and the clinical challenges that they present. Conclusively, potential solutions, novel treatment strategies, combination therapies, and reported alternatives are discussed.

Biofilm-associated multidrug-resistant infections pose significant challenges for antibiotic therapy. The extracellular polymeric matrix of biofilms presents an impediment for antibiotic diffusion, facilitating the emergence of multidrug-resistant populations.

Enterococcus faecium that harbor LiaFSR substitutions but are phenotypically susceptible to daptomycin (DAP) by current breakpoints are problematic since predisposition to resistance may lead to therapeutic failure. Using a simulated endocardial vegetation (SEV) PK/PD model, we investigated DAP regimens (6, 8 and 10 mg/kg/day) as monotherapy and in combination with ampicillin (AMP), ceftaroline (CPT) or ertapenem (ERT) against E. faecium HOU503, a DAP-susceptible strain that harbors common LiaS and LiaR substitutions found in clinical isolates (T120S and W73C, respectively). Of interest, the efficacy of DAP monotherapy, at any dose regimen, was dependent on the size of the inoculum. At an inoculum of ∼10⁹ CFU/g, DAP doses of 6-8 mg/kg/d were not effective and led to significant regrowth with emergence of resistant derivatives. In contrast, at an inoculum of ∼10⁷, marked reductions in bacterial counts were observed with DAP 6 mg/kg/d with no resistance. The inoculum effect was confirmed in a rat model using humanized DAP exposures. Combinations of DAP with AMP, CPT or ERT demonstrated enhanced eradication and reduced potential for resistance allowing for de-escalation of the DAP dose. Persistence of the LiaRS substitutions were identified in DAP-resistant isolates recovered from the SEV model and in DAP-resistant derivatives of an initially DAP-susceptible clinical isolate of E. faecium (HOU668) harboring LiaSR substitutions and recovered from a patient with a recurrent bloodstream infection. Our results provide novel data for the use of DAP monotherapy and combinations for recalcitrant E. faecium infections and paves the way for testing these approaches in humans.

Acinetobacter baumannii is currently classified as one of six pathogens that contribute to increased patient mortality. Thus, exploratory studies navigating alternative treatment strategies are of supreme interest. Herein, we completed minimum inhibitory concentration (MIC) testing, and time-kill analyses (TKA) on 50 carbapenem-resistant Acinetobacterbaumannii isolates including 28 colistin-resistant isolates. Upon testing of MEM or TGC in the presence of sub-inhibitory COL against the 50 isolates, there was a median 2-fold reduction in MEM and TGC MICs. In the TKAs, the COL+MEM combination was synergistic in 45 (90%) isolates and bactericidal in 43 (86%) isolates at 24 hours, whereas the COL+TGC combination TKAs demonstrated synergy in 32 (64%) isolates and bactericidal activity was shown in 28 (56%) isolates. Additionally, sulbactam (SUL) and TGC were added to the COL+MEM dual therapy regimen to assess the possible utility of a triple therapy regimen against five non-responsive isolates. The COL+MEM+SUL and COL+MEM+TGC regimens effectively restored synergy in (5/5) 100% of the isolates. The results of this study demonstrate the potential utility of COL combinations in the treatment of carbapenem-resistant isolates.