Treatment Of Multidrug-resistant Pathogens Research Articles

Antibacterial and in vitro anticancer activities of the antimicrobial peptide NRC-07 encapsulated in chitosan nanoparticles.

Antimicrobial peptides (AMPs) are promising alternatives to conventional antibiotics and chemotherapy in the treatment of multidrug-resistant pathogens and drug-resistant cancers. Clinical application of AMPs is limited due to low stability and inefficient transport. Encapsulation in nanocarriers may improve their therapeutic potential. Chitosan nanoparticles (CS-NPs) are efficient carriers for proteins and peptides, improving the treatment of microbial infections and targeted drug delivery. We examined toxicity against cancer cell lines and antibacterial activities of the pleurocidin-like AMP NRC-07 upon encapsulation in CS-NPs by ionotropic gelation. The biological activities of various formulations of free and encapsulated NRC-07 and free nanoparticles were evaluated against Pseudomonas aeruginosa and breast cancer cells, using assays for cell viability and lactate dehydrogenase cytolysis with non-cancer cell lines as controls. NRC-07-containing nanoparticles decreased the bacterial and cancer cell viability in a concentration-dependent manner. Activities of encapsulated peptide were >2-fold higher than those of free NRC-07 peptide. Unloaded CS-NPs and free peptide were not cytotoxic against control cells. Encapsulation of NRC-07 into CS-NPs enhanced the antibacterial and selective cytotoxicity of the peptide, possibly enhancing anticancer activities. Encapsulation presents a promising tool for the development of efficient drug delivery systems.

In Vitro Pharmacokinetics of LL-37 and Oncorhyncin II Combination Against Acinetobacter baumannii

Background: Multidrug-resistant (MDR) Acinetobacter baumannii is one of the most common nosocomial pathogens. Antimicrobial peptides (AMPs) have been introduced as a viable alternative to antibiotics in the treatment of MDR pathogens. Objectives: This study was designed to assess the in vitro pharmacokinetics of the combination of two potent AMPs, LL-37 and oncorhyncin II, against A. baumannii (ATCC19606). Methods: The synthesized genes of oncorhyncin II and LL-37 were introduced into Escherichia coli BL21 as the expression host. The minimum inhibitory concentration (MIC), time-kills, and growth kinetics of these peptides were used to evaluate their antimicrobial efficiencies against A. baumannii (ATCC19606). Results: LL-37 and oncorhyncin II recombinant peptides showed MIC of 30.6 and 95.87 µg/mL against A. baumannii, respectively. Additive action was confirmed by combining the generated AMPs at the checkerboard approach. The combination of LL-37 and oncorhyncin II at 2 × MIC resulted in a rapid drop in log10 CFU/mL of A. baumannii in the time-kill and growth kinetic findings studies. Conclusions: The combination of the produced LL-37 and oncorhyncin II synergizes the bioactivity of the individual peptides. Therefore, these peptides or their combinations might function as novel antibiotics and be used to develop and produce new antimicrobial drugs for the treatment of infections caused by A. baumannii.

Synergistic antibacterial effects of colistin in combination with aminoglycoside, carbapenems, cephalosporins, fluoroquinolones, tetracyclines, fosfomycin, and piperacillin on multidrug resistant Klebsiella pneumoniae isolates.

Multidrug resistant Enterobacterales have become a serious global health problem, with extended hospital stay and increased mortality. Antibiotic monotherapy has been reported ineffective against most drug resistant bacteria including Klebsiella pneumoniae, thus encouraging the use of multidrug therapies as an alternative antibacterial strategy. The present works assessed the antibacterial activity of colistin against K. pneumoniae isolates. Resistant isolates were tested against 16 conventional antibiotics alone and in combination with colistin. The results revealed that all colistin resistant isolates demonstrated multidrug resistance against the tested antibiotics except amikacin. At sub-inhibitory concentrations, combinations of colistin with amikacin, or fosfomycin showed synergism against 72.72% (8 of 11 isolates). Colistin with either of gentamicin, meropenem, cefoperazone, cefotaxime, ceftazidime, moxifloxacin, minocycline, or piperacillin exhibited synergism against 81.82% (9 of 11 isolates). Combinations of colistin with either of tobramycin or ciprofloxacin showed synergism against 45.45% (5 in 11 isolates), while combinations of colistin with imipenem or ceftolozane and tazobactam displayed 36.36% (4 of 11 isolates) and 63.64% (7 of 11 isolates) synergism. In addition, combinations of colistin with levofloxacin was synergistic against 90.91% (10 of 11 isolates). The results revealed that combinations of colistin with other antibiotics could effectively inhibit colistin resistant isolates of K. pneumoniae, and thus could be further explore for the treatment of multidrug resistant pathogens.

A Clinical Extensively-Drug Resistant (XDR) Escherichia coli and Role of Its β-Lactamase Genes.

An extensively-drug resistant (XDR) Escherichia coli W60 was isolated from the urine sample of a patient. The genetic basis for its XDR phenotype was investigated, particularly the basis for its resistance toward β-lactam/BLI (β-Lactamase Inhibitor) combinations. Following determination of the XDR phenotype, third generation genomic sequencing was performed to identify genetic structures in E. coli W60. Further cloning analysis was performed to identify determinants of β-lactam/BLI combination resistance. It was found that E. coli W60 is resistant to nearly all of the tested antibiotics including all commonly used β-lactam/BLI combinations. Analysis of the genomic structures in E. coli W60 showed two novel transferable plasmids are responsible for the resistance phenotypes. Further genetic analysis showed blaNDM–5 leads to high resistance to β-lactam/BLI combinations, which was enhanced by co-expressing bleMBL. pECW602 harbors a truncated blaTEM that is not functional due to the loss of the N-terminal signal peptide coding region. Research performed in this work leads to several significant conclusions: the XDR phenotype of E. coli W60 can be attributed to the presence of transferable multidrug resistance plasmids; NDM-5 confers high resistance to β-lactam/BLI combinations; co-expression of bleMBL enhances resistance caused by NDM-5; the signal peptides of TEM type β-lactamases are essential for their secretion and function. Findings of this work show the danger of transferable multidrug resistance plasmids and metallo-β-lactamases, both of which should be given more attention in the analysis and treatment of multidrug resistant pathogens.

A novel method to determine antibiotic sensitivity in Bdellovibrio bacteriovorus reveals a DHFR-dependent natural trimethoprim resistance

Bdellovibrio bacteriovorus is a small Gram-negative bacterium and an obligate predator of other Gram-negative bacteria. Prey resistance to B. bacteriovorus attack is rare and transient. This consideration together with its safety and low immunogenicity makes B. bacteriovorus a valid alternative to antibiotics, especially in the treatment of multidrug resistant pathogens. In this study we developed a novel technique to estimate B. bacteriovorus sensitivity against antibiotics in order to make feasible the development and testing of co-therapies with antibiotics that would increase its antimicrobial efficacy and at the same time reduce the development of drug resistance. Results from tests performed with this technique show that among all tested antibiotics, trimethoprim has the lowest antimicrobial effect on B. bacteriovorus. Additional experiments revealed that the mechanism of trimethoprim resistance in B. bacteriovorus depends on the low affinity of this compound for the B. bacteriovorus dihydrofolate reductase (Bd DHFR).

Determination of colistin-related nephrotoxicity and risk factors in intensive care unit.

OBJECTIVE:Colistin is a cationic polypeptide antibiotic with a cyclic structure that belongs to the polymyxin group. It was banned from clinical use because of its significant renal side effects, such as nephrotoxicity. However, the administration of colistin has recently been initiated again in the treatment of multi-drug resistant pathogens, such as Acinetobacter baumannii and Pseudomonas aeruginosa. Nephrotoxicity and neurotoxicity are the main problems encountered in the clinical use of polymyxins. The aim of this study was to determine the frequency and risk factors of colistin-related nephrotoxicity in the adult intensive care unit (ICU).METHODS:In this study, a retrospective review of patients who were followed up between January 1 and December 31, 2016 and who received colistin treatment in the adult ICU was performed. Retrospective computer records of age, sex, site of infection and microorganism breeding, daily creatinine values, and additional diseases were recorded and examined. Nephrotoxicity was assessed using the Risk, Injury, Failure, Loss, and End-stage kidney disease criteria.RESULTS:A total of 48 patients were included in the study. Of these, 50% were male. The mean age of the patients with nephrotoxicity was 59.73±22.38 years, and the mean age of those without nephrotoxicity was 58.00±22.39 years. A. baumanni was observed to be the causative microorganism in all patients, and the most frequent infection was pneumonia. Nephrotoxicity was investigated in 54.2% (n=26) of the patients. In this study, when risk factors for nephrotoxicity were evaluated, it was found that the presence of nephrotoxicity was greater in cases with chronic obstructive pulmonary disease, malignancy, or abdominal surgery in patients older than 65 years. In addition, mortality was greater in those who developed nephrotoxicity, although it was not statistically significant.CONCLUSION:In this study, the rate of nephrotoxicity was 54.2% in patients who received colistin in the ICU. Therefore, patients in the adult ICU receiving colistin therapy should be carefully monitored for the development of nephrotoxicity as a side effect.

A high aminoglycoside regimen associated with renal replacement therapy for the treatment of multi-drug resistant pathogens

Infections caused by multi-drug resistant (MDR) Gram-negative (GN) organisms in critically ill patients are a therapeutic challenge. Few therapeutical options are available.

Applications and implications of mammalian antimicrobial peptides-a review

Antimicrobial peptides are host defense peptides that are present in members of both Kingdoms Plantae vis-a-vis Animalia. These comprise of a number of structurally diverse peptides which are upto 100 amino acid in length. These antimicrobial peptides are part of the inherent innate immune system of the host and are responsible for carrying out diverse activities ranging from killings the invading pathogens, modifying and regulating the immune system in executing these processes. In the immune system they have diverse functions such as acting as chemotaxis, modulation of inflammation, regulation of expression of inflammatory cytokines preventing hypersensitivity. Antimicrobial peptides are presently under trials for development of novel antibiotics which can be used for treatment of multidrug resistant pathogens. Currently different antimicrobial peptides are used as food preservatives and for prevention of microbes, like methicillin resistant S. aureus among others.

Incidence of and Risk Factors for Colistin-Associated Nephrotoxicity in a Large Academic Health System

Colistin, originally abandoned due to high rates of nephrotoxicity, has been recently reintroduced due to activity against carbapenem-resistant Gram-negative organisms. Recent literature, largely obtained from outside the United States, suggests a lower rate of nephrotoxicity than historically reported. A retrospective cohort of all patients who received colistin for ≥ 48 hours at the Detroit Medical Center over a 5-year period was performed to determine the rate of colistin-associated nephrotoxicity as defined by the RIFLE criteria. Fifty-four (43%) patients in the cohort developed nephrotoxicity. Patients who experienced nephrotoxicity after colistin administration were in the Risk (13%), Injury (17%), or Failure (13%) categories per RIFLE criteria. Patients who developed nephrotoxicity received significantly higher mean doses than those who did not (5.48 mg/kg per day vs 3.95 mg/kg per day; P < .001), and the toxicity occurred in a dose-dependent fashion. Independent predictors for nephrotoxicity were a colistin dose of ≥ 5.0 mg/kg per day of ideal body weight (odds ratio [OR], 23.41; 95% confidence interval [CI], 5.3-103.55), receipt of concomitant rifampin (OR, 3.81; 95% CI, 1.42-10.2), and coadministration of ≥ 3 concomitant nephrotoxins (OR, 6.80; 95% CI, 1.42-32.49). In this retrospective cohort, nephrotoxicity (as defined by RIFLE criteria) occurred among 43% of treated patients in a dose-dependent manner. Higher colistin doses, similar to those commonly used in the United States, led to a relatively high rate of nephrotoxicity. These data raise important questions regarding the safe use of colistin in the treatment of multidrug-resistant pathogens.

C60-containing nanostructured polymeric materials with potential biomedical applications

Star-shaped polymers with a fullerene (C60) core and an unexpanded structure were successfully prepared by reaction of C60 with amino end-capped polyesters HxC60(NHPCLn)x and polyethers HxC60(NHPEGn)x, respectively. Upon irradiation of these C60-derivatives, a large amount of singlet oxygen was released. Compared to previously synthesized star-shaped azafulleroids with an expanded structure, the photosensitivity of HxC60(NHPCLn)x is higher as assessed by a higher production of singlet oxygen. The cytotoxicity of the photoactive water-soluble HxC60(NHPEGn)x derivatives was tested against THP-1 cells and expressed in terms of cell viability. Moreover, they were processed as micro-/nanosized fibers by electrospinning, which however required the addition of poly(ɛ-caprolactone) (PCL). The diameter distribution of the fibers was trimodal, where the fraction with the 270nm average diameter was the major population. Because of their photoactivity, the herein reported star-shaped C60-derivatives are promising candidates for photodynamic cancer therapy and treatment of multidrug resistant pathogens.