Treatment Of Multidrug-resistant Infections Research Articles

A hope for ineffective antibiotics to return to treatment: investigating the anti-biofilm potential of melittin alone and in combination with penicillin and oxacillin against multidrug resistant-MRSA and -VRSA.

The emergence and rapid spread of multi-drug resistant (MDR) bacterial strains, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), have posed a significant challenge to the medical community due to their ability to form biofilm and develop resistance to common antibiotics. Traditional antibiotics that were once effective in treating bacterial infections are now becoming increasingly ineffective, leading to severe consequences for patient outcomes. This concerning situation has called for urgent research to explore alternative treatment strategies. Recent studies have shown that antimicrobial peptides (AMPs) hold promise as effective agents against biofilm-associated drug-resistant infections as well as to enhance the efficacy of conventional antibiotics. Accordingly, we aimed to investigate the antimicrobial and antibiofilm effects of melittin AMP, both alone and in combination with penicillin and oxacillin, against biofilm-forming MDR-MRSA and -VRSA. In this study, we investigated the kinetics of biofilm formation and assessed various parameters related to the antimicrobial and antibiofilm efficacy of melittin and antibiotics, both alone and in combination, against MDR-MRSA and -VRSA. The antimicrobial parameters included the Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), Fractional Inhibitory Concentration Index (FICi), Fractional Bactericidal Concentration Index (FBCi), and the antibiofilm activity of melittin and antibiotics indicated by the Minimum Biofilm Inhibitory Concentration (MBIC), Minimal Biofilm Eradication Concentration (MBEC), Fractional Biofilm Inhibitory Concentration Index (FBICi), and Fractional Biofilm Eradication Concentration Index (FBECi). The MIC results showed that all S. aureus isolates were resistant to penicillin (≥0.25 μg/mL), and 66% of isolates were resistant to oxacillin. The geometric means of the MIC values for penicillin, oxacillin, and melittin were 19.02, 16, and 1.62 μg/ml, respectively, and the geometric means of the MBC values for penicillin, oxacillin, and melittin were 107.63, 49.35, and 5.45 μg/ml, respectively. The study revealed that the combination indexes of melittin-penicillin and melittin-oxacillin, as determined by FIC values against all isolates, were 0.37 and 0.03, respectively. Additionally, melittin-penicillin and melittin-oxacillin exhibited combination indexes based on FBC values against all isolates at 1.145 and 0.711, respectively. Besides, melittin inhibited the biofilm formation of all S. aureus isolates, with MBIC values ranging from 10 to 1.25 μg/mL, and MBEC values ranging from 40 to 10 μg/mL. Generally, the combination indexes of melittin-penicillin and melittin-oxacillin, determined using FBIC values against all isolates, were 0.23 and 0.177, respectively. Moreover, melittin-penicillin and melittin-oxacillin typically had combination indexes based on FBEC values against all isolates at 5 and 2.97, respectively. In conclusion, our study provides evidence that melittin is effective against both planktonik and biofilm forms of MRSA and VRSA and exhibits significant synergistic effects when combined with antibiotics. These results suggest that melittin and antibiotics could be a potential candidate for further investigation for in vivo infections caused by MDR S. aureus. Furthermore, melittin has the potential to restore the efficacy of penicillin and oxacillin antibiotics in the treatment of MDR infections. Applying AMPs, like melittin, to revive beta-lactam antibiotics against MRSA and VRSA is an innovative approach against antibiotic-resistant bacteria. Further research is needed to optimize dosage and understand melittin mechanism and interactions with beta-lactam antibiotics for successful clinical applications.

Regulatory fine-tuning of mcr-1 increases bacterial fitness and stabilises antibiotic resistance in agricultural settings

Antibiotic resistance tends to carry fitness costs, making it difficult to understand how resistance can be maintained in the absence of continual antibiotic exposure. Here we investigate this problem in the context of mcr-1, a globally disseminated gene that confers resistance to colistin, an agricultural antibiotic that is used as a last resort for the treatment of multi-drug resistant infections. Here we show that regulatory evolution has fine-tuned the expression of mcr-1, allowing E. coli to reduce the fitness cost of mcr-1 while simultaneously increasing colistin resistance. Conjugative plasmids have transferred low-cost/high-resistance mcr-1 alleles across an incredible diversity of E. coli strains, further stabilising mcr-1 at the species level. Regulatory mutations were associated with increased mcr-1 stability in pig farms following a ban on the use of colistin as a growth promoter that decreased colistin consumption by 90%. Our study shows how regulatory evolution and plasmid transfer can combine to stabilise resistance and limit the impact of reducing antibiotic consumption.

Antimicrobial Peptides Demonstrate Activity against Resistant Bacterial Pathogens.

The antimicrobial resistance crisis is an ongoing major threat to public health safety. Low- and middle-income countries are particularly susceptible to higher fatality rates and the economic impact of antimicrobial resistance (AMR). As an increasing number of pathogens emerge with multi- and pan-drug resistance to last-resort antibiotics, there is an urgent need to provide alternative antibacterial options to mitigate disease transmission, morbidity, and mortality. As identified by the World Health Organization (WHO), critically important pathogens such as Klebsiella and Pseudomonas species are becoming resistant to last-resort antibiotics including colistin while being frequently isolated from clinical cases of infection. Antimicrobial peptides are potent amino acid sequences produced by many life forms from prokaryotic, fungal, plant, to animal species. These peptides have many advantages, including their multi-hit mode of action, potency, and rapid onset of action with low levels of resistance being evident. These innate defense mechanisms also have an immune-stimulating action among other activities in vivo, thus making them ideal therapeutic options. Large-scale production and formulation issues (pharmacokinetics, pharmacodynamics), high cost, and protease instability hinder their mass production and limit their clinical application. This review outlines the potential of these peptides to act as therapeutic agents in the treatment of multidrug-resistant infections considering the mode of action, resistance, and formulation aspects. Clinically relevant Gram-positive and Gram-negative pathogens are highlighted according to the WHO priority pathogen list.

Retrospective Evaluation of Intravenous Fosfomycin in Multi-drug Resistant Infections at A Tertiary Care Hospital in İstanbul

Introduction: Fosfomycin has started to be used again as a possible therapeutic alternative in cases injected with resistant bacterial pathogens. Its primary mechanism of action is inhibition of the first step of cell wall synthesis; This mechanism is effective against both Gram-positive and Gram- negative bacterial groups. However, its clinical efficacy against bacteria that develop multidrug resistance is largely unknown. Therefore, we aimed to evaluate the clinical and microbiological efficacy of intravenous Fosfomycin in a tertiary care center. Methods: The group of adult patients aged 18 years and over who applied to the hospital between January 2018 and December 2022 and were given intravenous fosfomycin therapy for at least 24 hours due to any infection were retrospectively analyzed. Results: 71 patients were included in our study. The female/male ratio of these patients was 35/36, and the mean age was 61.5±17.0 (18-84). The avarage time to treatment was 10.6 days (11.3-+11.4). 22 patients (31%) from Intensive Care Unit and 49 (69%) patients from other clinics were included in the study. 18 bacteremia (26%), 15 pneumonia (21%), 14 wound infections (19%), 13 ventilator-associated pneumonia (18%), 5 urinary tract infections (UTI) (8%), 4 abdominal infections (6%) and 2 endocarditis (3%). Detected causative microorganisms were 18 carbapenem susceptible Klebsiella pneumoniae (44%), pandrug resistan Klebsiella pneumoniae (17.5%), 5 MRSA (12.5%), 5 pandrug resistan Pseudomonas aerinosa (12%) ,4 Escherichia coli (10%), 1 Acinetobacterbaumanii (2.5%) and 1 Enterobacter spp. (2.5%). Looking at the underlying diseases, one of our patients had diabetes mellitus and another patient had chronic renal failure. Mean procalcitonin (PCT) and C reaktive protein (CRP) (cutoff value0.5 ng/mL) values were 2.53±1.2 ng/ml and 89.7±21.9 mg/dl, respectively. Median sodium (Na), potassium (K), AST, ALT, and creatinine values of the patients before and after fosfomycin IV treatment were calculated and there was no statistically significant difference. Clinics combined with fosfomycin IV were as follows: 31 meropenem (44%), 15 colistin (26%), 18 tigecycline (26%), 3 vancomycin (4%), 3 amikacin (4%) and 1 daptomycin (1%). Conclusions: According to the results of our study, it was seen that Fosfomycin is a safe and effective option in the treatment of multidrug-resistant infections. Accordingly, our results are compatible with the literature.

Tigecycline Immunodetection Using Developed Group-Specific and Selective Antibodies for Drug Monitoring Purposes.

Tigecycline (TGC), a third-generation tetracycline, is characterized by a more potent and broad antibacterial activity, and the ability to overcome different mechanisms of tetracycline resistance. TGC has proven to be of value in treatment of multidrug-resistant infections, but therapy can be complicated by multiple dangerous side effects, including direct drug toxicity. Given that, a TGC immunodetection method has been developed for therapeutic drug monitoring to improve the safety and efficacy of therapy. The developed indirect competitive ELISA utilized TGC selective antibodies and group-specific antibodies interacting with selected coating TGC conjugates. Both assay systems showed high sensitivity (IC50) of 0.23 and 1.59 ng/mL, and LOD of 0.02 and 0.05 ng/mL, respectively. Satisfactory TGC recovery from the spiked blood serum of healthy volunteers was obtained in both assays and laid in the range of 81-102%. TGC concentrations measured in sera from COVID-19 patients with secondary bacterial infections were mutually confirmed by ELISA based on the other antibody-antigen interaction and showed good agreement (R2 = 0.966). A TGC pharmacokinetic (PK) study conducted in three critically ill patients proved the suitability of the test to analyze the therapeutic concentrations of TGC. Significant inter-individual PK variability revealed in this limited group supports therapeutic monitoring of TGC in individual patients and application of the test for population pharmacokinetic modelling.

Ephedra foeminea as a Novel Source of Antimicrobial and Anti-Biofilm Compounds to Fight Multidrug Resistance Phenotype.

Plants are considered a wealthy resource of novel natural drugs effective in the treatment of multidrug-resistant infections. Here, a bioguided purification of Ephedra foeminea extracts was performed to identify bioactive compounds. The determination of antimicrobial properties was achieved by broth microdilution assays to evaluate minimal inhibitory concentration (MIC) values and by crystal violet staining and confocal laser scanning microscopy analyses (CLSM) to investigate the antibiofilm capacity of the isolated compounds. Assays were performed on a panel of three gram-positive and three gram-negative bacterial strains. Six compounds were isolated from E. foeminea extracts for the first time. They were identified by nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) analyses as the well-known monoterpenoid phenols carvacrol and thymol and as four acylated kaempferol glycosides. Among them, the compound kaempferol-3-O-α-L-(2″,4″-di-E-p-coumaroyl)-rhamnopyranoside was found to be endowed with strong antibacterial properties and significant antibiofilm activity against S. aureus bacterial strains. Moreover, molecular docking studies on this compound suggested that the antibacterial activity of the tested ligand against S. aureus strains might be correlated to the inhibition of Sortase A and/or of tyrosyl tRNA synthase. Collectively, the results achieved open interesting perspectives to kaempferol-3-O-α-L-(2″,4″-di-E-p-coumaroyl)-rhamnopyranoside applicability in different fields, such as biomedical applications and biotechnological purposes such as food preservation and active packaging.

Doxycycline for Multidrug-Resistant Gram-Negative Bacterial Infection Treatment: A Scoping Review.

Multidrug-resistant bacterial infections limit available therapeutic options. Doxycycline is an old antibiotic from the tetracycline class that exhibits a wide antibacterial action, including Gram-negative bacteria (GNB), and could be an alternative for the treatment of multidrug-resistant (MDR) Enterobacteriaceae. The study aimed to systematically identify, evaluate, and summarize the results of studies related to outcomes of treatments for MDR-GNB infections in patients treated with doxycycline. This review was conducted in four databases during weeks 41-52 of 2022: PubMed, Medline, Scopus, and Web of Science, from the earliest year available on each database to December 2022. Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines were followed in conducting this study, and PICO was used for the research question of this review. This scoping review found 8 retrospective studies that included 59 patients. Of these, 69% were treated for ventilator-associated pneumonia (VAP), 27% for urinary tract infections, 2% for bloodstream infections, and 2% for wound infections, both of which were associated with VAP. The usual dosage of doxycycline was 100 mg intravenously or orally. Clinical and microbiologic improvements were achieved in 81.3% and 87% of all patients, respectively. The mortality rate was 17.3% and was exclusively due to VAP. Doxycycline showed promising results in this review; however, randomized clinical trials or prospective cohorts are recommended to demonstrate the efficacy of doxycycline in the treatment of MDR infections with GNB.

Alginate chitosan microbeads and thermos-responsive hyaluronic acid hydrogel for phage delivery

Bacteriophages are potential alternatives to conventional antibiotics in the treatment of multidrug resistant infections. However, optimal treatment administration protocols are not established. The direct application of bacteriophages in local biomaterials-based carriers offers solutions to many of the limitations of current modalities. In this study, thermo-responsive hyaluronic acid-poly(N-isopropylacrylamide) (HA-pNIPAM) hydrogels and alginate-chitosan microbeads have been developed as bioresorbable local bacteriophage delivery systems designed to enable rapid and delayed phage release, respectively. The long-tailed Staphylococcus aureus phage ISP and the short-tailed Pseudomonas aeruginosa phage LUZ19 were selected as structurally diverse phages to load within both biomaterials. HA-pNIPAM hydrogels were synthesized and their thermo-responsive crosslinking was confirmed after rheological assessment. Alginate microbeads where prepared by ionic-gelation and chitosan surface deposition was confirmed by amine sensitive assays. After embedding phages, their antimicrobial potential was retained when stored at 4 °C. Release of both phages from HA-pNIPAM hydrogels was gradual and consistent over 21 days, whereby, continuous release of the short-tailed LUZ19 was observed for 21 days from the microbeads, while release of the long-tailed ISP portrayed burst-like release during early timepoints, with gradually reducing phage release thereafter. These findings suggest that the release kinetics of phage from biomaterials are impacted by both the biomaterial and the phages themselves. These results highlight the potential of HA-pNIPAM hydrogel and alginate-chitosan microbeads for local delivery of ISP and LUZ19 bacteriophages for both rapid burst release and controlled, extended release.

Phenotypic whole-cell screening identifies a protective carbohydrate epitope on Klebsiella pneumoniae

The increasing occurrence of recalcitrant multi-drug resistant (MDR) Klebsiella pneumoniae infections coupled with a diminishing pipeline of new antibioticswarrants the investigation of alternative antimicrobial therapies. We employed a target-agnostic phage display approach using live K. pneumoniaebacteria with the aim of isolating therapeutic monoclonal antibodies (mAbs) targetingconserved epitopes among clinically relevant strains. mAb targets were explored using ELISA and biolayer interferometry, and a high-throughput opsonophagocytic killing assay was developed to determine functional activity. Fluorescence-activated cell sorting was used to screen a global panel of clinical isolates, and high-content imaging further explored binding and functional activity. One mAb was tested in vivousing a lethal murine model of pneumonia. mAbs binding to carbohydrate epitopes were isolated in phage display selections enriched on wild-type and capsule-deficient strains. mAbs binding O1 lipopolysaccharide (LPS) and cross-binding O1/O2 LPS were identified. mAbs were shown to promote opsonophagocytic killing by human monocyte-derived macrophages, and clearance of macrophage-associated bacteria. One mAb, named B39, protected mice against MDR O1 and O2 strains when dosed therapeutically in a murine pneumonia model. Binding to a panel of O1 and O2 clinical isolates suggests B39 binds to both d-galactan-I and d-galactan-II of the LPS. With the rise of antimicrobial resistance among enteric pathogens, the discovery of a novel therapeutic mAb targeting the most prevalent K. pneumoniaeserotypes demonstrates a significant advancement in the field, and showcases the potential of alternative antimicrobial therapies for the treatment of MDR infections.

Structural and functional insights into colicin: a new paradigm in drug discovery.

Colicins are agents of allelopathic interactions produced by certain enterobacteria which give them a competitive advantage in the environment. These protein molecules are mostly encoded by plasmids. The colicin operon consists of the activity, immunity and the lysis genes. The activity protein is responsible for the killing activity, the immunity protein protects the producer cell from the lethal action of colicin and the lysis protein facilitates its release. Colicins are primarily composed of three domains, namely the receptor-binding domain, the translocation domain and the cytotoxic domain. The protein molecule binds to its cognate receptor on the target cell via the receptor-binding domain and undergoes translocation into the cell either via the Tol system or the Ton system. After gaining entry into the target cell, there are various mechanisms by which colicins exert their lethality. These comprise DNase activity, RNase activity and pore formation in the target cell membrane or peptidoglycan synthesis inhibition. This review gives a detailed insight into the structural and functional aspect of colicins and their mode of action. This knowledge is of immense significance because colicins are being considered as very useful alternatives to conventional antibiotics in the treatment of multidrug-resistant infections. Besides, they also have a negligible harmful impact on the commensals. Thus, before tapping their therapeutic potential, it is imperative to know their structure and mechanism of action in detail.

172. Inpatient Antibiotic Prescribing Patterns Using the WHO Access Watch and Reserve (AWaRe) Classification in Okinawa, Japan: A Point Prevalence Survey

BackgroundFew studies have been done on inpatient antibiotic use in Japan and antibiotic stewardship programs with dedicated full-time equivalents are rare. We sought to better understand inpatient antibiotic use in Okinawa, Japan. We applied the World Health Organization (WHO) Access, Watch and Reserve (AWaRe) Classification to compare our findings to international literature. Access antibiotics are common front-line antibiotics, Watch antibiotics are high-priority antibiotics with toxicity or resistance concerns, and Reserve antibiotics are last-line treatments for multi-drug resistant infections.MethodsA point prevalence study was conducted in five hospitals in Okinawa, Japan on Oct 1, 2020. Physicians conducted chart reviews of all patients receiving intravenous antibiotics. Type of antibiotic, reason for use, duration, and microbiologic data was collected. The primary aim was to evaluate the proportion of patients who received antibiotics on the assessment date; secondary aims were to categorize antibiotics according to indication, class and AWaRe classification. Descriptive statistics were used to derive the distribution of AWaRe Classifications and drug class.Results1,728 unique patients were included and 504 (29%) received ≥1 antibiotic on the assessment date. A total of 559 antibiotics were used for 504 patients and 22.0% (n=123) were for prophylaxis. Of those receiving antibiotics for treatment (N=436), 385 (88.3%) patients had a documented infection source. The most common indications for antibiotic use were pneumonia (24.2% n=93), urinary tract infection (19.7% n=76), and intraabdominal (17.9% n=69). Overall, 43.1% (n=241) of the antibiotics were categorized Access and 54.4% (n=304) Watch [Figure 1]. Cephalosporins were the most common antibiotic class (56% n=313), followed by β-lactam inhibitors (18% n=106) and narrow penicillins (8.2% n=46) [Figure 2].Conclusion29% of inpatients in these 5 Okinawan hospitals were prescribed an antibiotic on the survey date. A majority of antibiotics used fall under the WHO AWaRe Watch classification which are antibiotics that may be more likely to cause resistance. Understanding appropriateness of antibiotics used in this population could inform antibiotic stewardship strategies and reduce antibiotic resistance.Figure 1. Antibiotic Distribution According to World Health Organization (WHO) Access, Watch and Reserve (AWaRe) Classification Figure 2. Antibiotic Distribution by Class in Okinawan Hospitals Disclosures All Authors: No reported disclosures

Risk of Bacteriophage Therapeutics to Transfer Genetic Material and Contain Contaminants Beyond Endotoxins with Clinically Relevant Mitigation Strategies.

Bacteriophage therapy is a promising adjuvant therapeutic in the treatment of multidrug-resistant infections and chronic biofilm infections. However, there is limited knowledge about how to best utilize these agents in vivo, leading to a wide range of treatment protocols. Moreover, while bacteriophages are similar to antibiotics in their antimicrobial effects, these are active viruses and are very different from conventional antibiotics. One main difference that clinicians should be cognizant about is the potential ability of these therapeutics to horizontally transfer genetic material, and the clinical ramifications of such events. In addition, while bacteriophage therapeutics are readily tested for sterility and endotoxins, clinicians should also be aware of other contaminants, such as exotoxins, pathogenicity islands and prophages, that can contaminate bacteriophage therapeutics, and their clinical ramifications. While the perception may be that these are only theoretical issues, regulatory agencies are starting to recommend their evaluation when using bacteriophage therapy and subsequently these topics are discussed herein, as are ways to test for and mitigate the adverse effects of these issues.

Structural elucidation, mechanism of action, antibacterial proficiency and synergistic forte of purified Euphorbia hirta whole plant extract against multi-drug resistant otitis media infection

This study investigated the antibacterial potential of Euphorbia hirta whole plant extracts, honey and conventional antibiotics and their synergistic effects against selected multidrug resistant and typed bacterial strains associated with otitis media. E. hirta whole plant extract was purified using column chromatography technique. The antibacterial assays of extracts were done using standard microbiological procedures. Protein, sodium and potassium ion leakage of the synergistic mixtures was determined using flame-photometry. At 100 mg/ml, acetone extracts presented highest inhibition against S. aureus (NCTC 6571) with 32 ± 0.83 mm zone of inhibition. The fractional inhibitory concentration indices displayed higher synergism in combination of plant extract, honey and ciprofloxacin against P. mirabilis at 0.02 compared to drug combination synergy standard (≤ 0.5). This work revealed augmentation of ciprofloxacin potency when combined with purified E. hirta acetone extract and honey and implies their high potential in the treatment of multidrug resistant infection of otitis media.

Molecular characterization of carbapenemase producing Klebsiella pneumoniae strains by multiplex PCR and PFGE methods: The first K.pneumoniae isolates co-producing OXA-48/KPC and KPC/NDM in Turkey

IntroductionCarbapenems are frequently used in the treatment of multidrug-resistant infections caused by Klebsiella pneumoniae. The aim of the study is to definition and incidence of transferable carbapenemase genes of carbapenem resistant K. pneumoniae (CRKP) and to determine clonal relatedness of these strains in tertiary care hospital in Turkey. MethodsIdentification of all 100 K. pneumoniae isolates and low sensitivity to any of the carbapenem group antibiotics were determined by Vitek-2 (BioMérieux, France). The frequency of carbapenemase genes (blaOXA-48, blaNDM, blaKPC, blaVIM,blaIMP) and extended spectrum beta-lactamase (ESBL) genes (blaCTX-M, blaSHV, blaTEM) which frequently detected in Turkey, have been investigated by multiplex polymerase chain reaction (PCR). Clonal relatedness was determined using Pulsed-field gel electrophoresis(PFGE). ResultsNinety five isolates carried at least one of the carbapenemase genes (81.05% blaOXA-48, 38.9% blaNDM, 9.47% blaKPC,1.05% blaVIM). One isolate was carried the blaOXA-48+KPC and the two isolates were carried the blaKPC+NDM. PFGE demonstrated the presence of 24 pulse types and 63.09% of the isolates were in four main pulse types. ConclusionsThis study demonstrated the incidence of blaNDM is beginning to reach endemic levels, in addition to blaOXA-48 found endemic in Turkey. To our knowledge, this is the first report of the co-production of these two genes (blaKPC + NDM and blaOXA-48 + KPC) in CRKP isolates.

Retrospective evaluation of intravenous fosfomycin in multi-drug resistant infections at a tertiary care hospital in Lebanon.

Fosfomycin has re-emerged as a possible therapeutic alternative for the treatment of resistant bacterial pathogens. Its main mechanism of action is the inhibition of the initial step of cell wall synthesis and is active against both Gram-positive and Gram-negative bacteria. However, its clinical effectiveness against multidrug resistant bacteria remains largely unknown. Therefore, we aim to evaluate the clinical and microbiological effectiveness of intravenous fosfomycin as well as its safety in a tertiary care teaching hospital in Lebanon. This is a retrospective chart review of adult patients who had presented to the hospital and were treated with intravenous fosfomycin for at least 24 hours for any type of infection between 2014 and 2019. Among 31 episodes treated with intravenous fosfomycin, 68% had an overall favorable clinical response. In 84% of the episodes, fosfomycin was administered in combination with other antibiotics, commonly tigecycline. Of those with available cultures at end of therapy, 73% achieved microbiological success. No relapse was documented within 30 days of completion of therapy. In the episodes secondary to resistant pathogens, the rates of favorable clinical outcome and microbiological success at the end of therapy were 71% and 73%, respectively. Fosfomycin resistance developed in two cases and mild adverse events occurred in 65% of the episodes during the course of treatment. Fosfomycin is a safe and effective option in the treatment of multi-drug resistant infections. Nevertheless, careful stewardship is important to maintain its efficacy and to reduce the risk of selection of antimicrobial resistance.

Green Strategy–Based Synthesis of Silver Nanoparticles for Antibacterial Applications

Antibiotics have been the nucleus of chemotherapy since their discovery and introduction into the healthcare system in the 1940s. They are routinely used to treat bacterial infections and to prevent infections in patients with compromised immune systems and enhancing growth in livestock. However, resistance to last-resort antibiotics used in the treatment of multidrug-resistant infections has been reported worldwide. Therefore, this study aimed to evaluate green synthesized nanomaterials such as silver nanoparticles (AgNPs) as alternatives to antibiotics. UV-vis spectroscopy surface plasmon resonance peaks for AgNPs were obtained between 417 and 475 nm. An X-ray diffraction analysis generated four peaks for bothPrunus africanaextract (PAE) andCamellia sinensisextract (CSE) biosynthesized AgNPs positioned at 2θ angles of 38.2°, 44.4°, 64.5°, and 77.4° corresponding to crystal planes (111), (200), (220), and (311), respectively. A dynamic light-scattering analysis registered the mean zeta potential of +6.3 mV and +0.9 mV for PAE and CSE biosynthesized nanoparticles, respectively. Fourier transform infrared spectroscopy spectra exhibited bands corresponding to different organic functional groups confirming the capping of AgNPs by PAE and CSE phytochemicals. Field emission scanning electron microscopy imaging showed that AgNPs were spherical with average size distribution ranging from 10 to 19 nm. Biosynthesized AgNPs exhibited maximum growth inhibitory zones of 21 mm with minimum inhibitory concentration and minimum bactericidal concentration of 125 and 250 μg/ml, respectively, against carbapenem-resistant bacteria.

A retrospective review of colistin utilisation at a tertiary care academic hospital in South Africa.

BackgroundThe use of the antibiotic colistin was increasing as a treatment option for multidrug-resistant (MDR) infections. Standardisation of colistin dosing and more appropriate record-keeping practices were required to fully assess the optimal usage of colistin. The aim of this study was to determine how and why colistin was used in the treatment of MDR infections in a tertiary care public hospital in South Africa (SA).MethodsThis cross-sectional retrospective record review described adult and paediatric patients who received colistin intravenously from 01 May 2016 to 31 April 2017. Information from patient records were captured on a data collection tool and analysed using descriptive statistics. Ethical approval was obtained from the Human Research Ethics Committee of the University of the Witwatersrand.ResultsA total of 43 patient records were reviewed. Acinetobacter baumannii was the most common organism isolated (85.2% adults and 62.5% paediatrics). Colistin was mostly prescribed for sepsis (18 adults and 15 paediatrics). Most adults (66.7%) received loading doses as recommended; however, there was a great variation in maintenance doses. Paediatric patients reviewed also showed varying dosing according to weight. The mean duration of colistin therapy was 10 days. Carbapenems were most commonly co-administered with colistin (58%).ConclusionThe findings suggested that although colistin usage was restricted in the hospital, it was not adequately monitored or controlled. Doses prescribed were made at the discretion of prescribing doctors and differed to currently accepted guidelines. Improved record-keeping practices related to the monitoring of colistin use were required.

Rapid Screening of Essential Oils as Substances Which Enhance Antibiotic Activity Using a Modified Well Diffusion Method.

Antimicrobial resistance is recognized as one of the major global health challenges of the 21st century. Synergistic combinations for antimicrobial therapies can be a good strategy for the treatment of multidrug resistant infections. We examined the ability of a group of 29 plant essential oils as substances which enhance the antibiotic activity. We used a modified well diffusion method to establish a high-throughput screening method for easy and rapid identification of high-level enhancement combinations against bacteria. We found that 25 essential oils possessed antibacterial activity against Escherichia Coli ATCC 25922 and methicillin-resistant Staphylococcus aureus (MRSA) 43300 with MICs that ranged from 0.01% to 2.5% v/v. We examined 319 (11 × 29) combinations in a checkerboard assay with E. Coli ATCC 25922 and MRSA 43300, and the result showed that high-level enhancement combinations were 48 and 44, low-level enhancement combinations were 214 and 211, and no effects combinations were 57 and 64, respectively. For further verification we randomly chose six combinations that included orange and Petitgrain essential oils in a standard time-killing assay. The results are in great agreement with those of the well diffusion assays. Therefore, the modified diffusion method was a rapid and effective method to screen high-level enhancement combinations of antibiotics and essential oils.

Sonoactivated Nanoantimicrobials: A Potent Armament in the Postantibiotic Era.

Recent research on antibiotic-free therapies has demonstrated remarkable effectiveness in preventing and controlling multi-drug-resistant (MDR) bacterial infection. Antimicrobial sonodynamic therapy (aSDT) developed from photodynamic therapy (PDT) is of particular interest to researchers and clinicians as it is a promising noninvasive treatment of less accessible infections. However, several aSDT-related challenges need to be addressed. These involve companion imaging and diagnosis of aSDT in vivo, insufficient efficacy of aSDT due to the limited oxygen level in the site of infection, infection in the immunocompromised host, and the synergetic approaches for enhanced ROS-mediated antimicrobial activity. This Spotlight on Applications presents the recent approaches in the development of sonoactivated nanoantimicrobials. These developed strategies including bacterial enzyme-responsive sonotheranostics, the ultrasound-switchable nanoenzyme-augmented aSDT, sono-immunomodulating therapy, and sonoactivated chemodynamic therapy (CDT) have shown positive outcomes in the treatment of MDR infections. However, despite the promising results of these approaches, a deeper understanding of the nanoantimicrobial SDT mechanisms in the more precise preclinical model is essential for future optimization regarding efficacy and safety.

Target-Based Design of Promysalin Analogues Identifies a New Putative Binding Cleft in Succinate Dehydrogenase.

Promysalin is a small-molecule natural product that specifically inhibits growth of the Gram-negative pathogen Pseudomonas aeruginosa (PA). This activity holds promise in the treatment of multidrug resistant infections found in immunocompromised patients with chronic illnesses, such as cystic fibrosis. In 2015, our lab completed the first total synthesis; subsequent analogue design and SAR investigation enabled identification of succinate dehydrogenase (Sdh) as the biological target in PA. Herein, we report the target-guided design of new promysalin analogues with varying alkyl chains, one of which is on par with our most potent analogue to date. Computational docking revealed that some analogues have a different orientation in the Sdh binding pocket, placing the terminal carbon proximal to a tryptophan residue. This inspired the design of an extended side chain analogue bearing a terminal phenyl moiety, providing a basis for the design of future analogues.