Polymyxin combination therapy for multidrug-resistant, extensively-drug resistant, and difficult-to-treat drug-resistant gram-negative infections: is it superior to polymyxin monotherapy?

INTRODUCTION: The increasing prevalence of infections with multidrug-resistant (MDR), extensively-drug resistant (XDR) or difficult-to-treat drug resistant (DTR) Gram-negative bacilli (GNB), including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter species, and Escherichia coli poses a severe challenge. AREAS COVERED: The rapid growing of multi-resistant GNB as well as the considerable deceleration in development of new anti-infective agents have made polymyxins (e.g. polymyxin B and colistin) a mainstay in clinical practices as either monotherapy or combination therapy. However, whether the polymyxin-based combinations lead to better outcomes remains unknown. This review mainly focuses on the effect of polymyxin combination therapy versus monotherapy on treating GNB-related infections. We also provide several factors in designing studies and their impact on optimizing polymyxin combinations. EXPERT OPINION: An abundance of recent in vitro and preclinical in vivo data suggest clinical benefit for polymyxin-drug combination therapies, especially colistin plus meropenem and colistin plus rifampicin, with synergistic killing against MDR, XDR, and DTR P. aeruginosa, K. pneumoniae and A. baumannii. The beneficial effects of polymyxin-drug combinations (e.g. colistin or polymyxin B + carbapenem against carbapenem-resistant K. pneumoniae and carbapenem-resistant A. baumannii, polymyxin B + carbapenem + rifampin against carbapenem-resistant K. pneumoniae, and colistin + ceftolozan/tazobactam + rifampin against PDR-P. aeruginosa) have often been shown in clinical setting by retrospective studies. However, high-certainty evidence from large randomized controlled trials is necessary. These clinical trials should incorporate careful attention to patient's sample size, characteristics of patient's groups, PK/PD relationships and dosing, rapid detection of resistance, MIC determinations, and therapeutic drug monitoring.

Antimicrobial resistance, virulence factors, and genotypes of Pseudomonas aeruginosa clinical isolates from Gorgan, northern Iran.

Pseudomonas aeruginosa is an important nosocomial pathogen with a capacity of resistance to multiple antibiotics and production of various extracellular and cell-associated virulence factors that clearly contribute to its pathogenicity. The objective of this study was to investigate the antibiotic susceptibility, virulence factors, and clonal relationship among clinical isolates of P. aeruginosa. Different clinical specimens from hospitalized patients were investigated for P. aeruginosa. Susceptibility of the isolates was evaluated by disc diffusion and broth microdilution methods, as described by the Clinical and Laboratory Standards Institute (CLSI) guideline. A total of 97 P. aeruginosa isolates were recovered from clinical specimens. The percentage of isolates resistant to antimicrobials was imipenem 25.77%, meropenem 15.46%, gentamicin 16.49%, tobramycin 15.46%, amikacin 16.49%, ciprofloxacin 20.61%, levofloxacin 24.74, ceftazidime 20.61%, piperacillin 15.46%, piperacillin/tazobactam 12.37%, colistin 9.27%, and polymyxin B 11.34%. Of isolates, 87.62% possessed ß-hemolytic activity, 78.35% lecithinase, 59.8% elastase, 37.11% DNase, and 28.86% twitching motility. The frequency of virulence genes in isolates was lasB 82.47%, plcH 82.47%, exoA 58.76%, exoS 56.7%, and pilA 10.3%. ERIC-PCR typing clustered P. aeruginosa isolates to 19 common types (CT1-CT19) containing isolates from different hospitals and 43 single types (ST1-ST43). Colistin and polymyxin B were the most effective agents against the majority of P. aeruginosa isolates, emphasizing the effort to maintain their antibacterial activity as last-line therapy. The frequency of some virulence factors and genes was noticeably high, which is alarming. In addition, more effective strategies and surveillance are necessary to confine and prevent the inter-hospital and/or intra-hospital dissemination of P. aeruginosa between therapeutic centers.

In vitro activities of cellulase and ceftazidime, alone and in combination against Pseudomonas aeruginosa biofilms.

BACKGROUND: Biofilms are a main pathogenicity feature of Pseudomonas aeruginosa and has a significant role in antibiotic resistance and persistent infections in humans. We investigated the in vitro activities of antibiotic ceftazidime and enzyme cellulase, either alone or in combination against biofilms of P. aeruginosa. RESULTS: Both ceftazidime and cellulase significantly decreased biofilm formation in all strains in a dose-dependent manner. Combination of enzyme at concentrations of 1.25, 2.5, 5, and 10 U/mL tested with 1/16× MIC of antibiotic led to a significant reduction in biofilm biomass. Cellulase showed a significant detachment effect on biofilms at three concentrations of 10 U/mL, 5 U/mL, and 2.5 U/mL. The MIC, MBC, and MBEC values of ceftazidime were 2 to 4 µg/mL, 4 to 8 µg/mL, and 2048 to 8192 µg/mL. When combined with cellulase, the MBECs of antibiotic showed a significant decrease from 32- to 128-fold. CONCLUSIONS: Combination of the ceftazidime and the cellulase had significant anti-biofilm effects, including inhibition of biofilm formation and biofilm eradication in P. aeruginosa. These data suggest that glycoside hydrolase therapy as a novel strategy has the potential to enhance the efficacy of antibiotics and helps to resolve biofilm-associated wound infections caused by this pathogen.

Antiviral Therapeutic Potential of Curcumin: An Update.

The treatment of viral disease has become a medical challenge because of the increasing incidence and prevalence of human viral pathogens, as well as the lack of viable treatment alternatives, including plant-derived strategies. This review attempts to investigate the trends of research on in vitro antiviral effects of curcumin against different classes of human viral pathogens worldwide. Various electronic databases, including PubMed, Scopus, Web of Science, and Google Scholar were searched for published English articles evaluating the anti-viral activity of curcumin. Data were then extracted and analyzed. The forty-three studies (published from 1993 to 2020) that were identified contain data for 24 different viruses. The 50% cytotoxic concentration (CC50), 50% effective/inhibitory concentration (EC50/IC50), and stimulation index (SI) parameters showed that curcumin had antiviral activity against viruses causing diseases in humans. Data presented in this review highlight the potential antiviral applications of curcumin and open new avenues for further experiments on the clinical applications of curcumin and its derivatives.