Discovery of pyridoquinoxaline-based new P-gp inhibitors as coadjutant against Multi Drug Resistance in cancer.

Multi-drug resistance (MDR) is a serious challenge in contemporary clinical practice and is mostly responsible for the failure of cancer medication therapies. Several experimental evidence links MDR to the overexpression of the drug efflux transporter P-gp, therefore, the discovery of novel P-glycoprotein inhibitors is required to treat or prevent MDR and to improve the absorption of chemotherapy drugs via the gastrointestinal system. In this work, we explored a series of novel pyridoquinoxaline-based derivatives designed from parental compounds, previously proved active in enhancing anticancer drugs in MDR nasopharyngeal carcinoma (KB). Among them, derivative 10d showed the most potent and selective inhibition of fluorescent dye efflux, if compared to reference compounds (MK-571, Novobiocin, Verapamil), and the highest MDR reversal activity when co-administered with the chemotherapeutic agents Vincristine and Etoposide, at non-cytotoxic concentrations. Molecular modelling predicted the two compound 10d binding mode in a ratio of 2:1 with the target protein. No cytotoxicity was observed in healthy microglia cells and off-target investigations showed the absence of CaV1.2 channel blockade. In summary, our findings indicated that 10d could potentially be a novel therapeutic coadjutant by inhibiting P-gp transport function in vitro, thereby reversing cancer multidrug resistance.

Exploring of spectrum beta lactamase producing multidrug-resistant Salmonella enterica serovars in goat meat markets of Bangladesh.

The emergence of Salmonella enterica serovars that produce extended-spectrum beta-lactamase and exhibit multi-drug resistance (MDR) poses a substantial global threat, contributing to widespread foodborne illnesses and presenting an alarming issue for public health. This study specifically concentrated on the isolation and identification of ESBL-resistant genes (bla TEM, bla SHV, bla CTX-M1, bla CTX-M2, bla CTX-M9, MultiCase ACC, MultiCase MOX, MultiCase DHA, bla OXA) and the antibiogram profiling of Salmonella enterica serovars found in goat meat samples procured from retail outlets in Bangladesh. During the research in the Sylhet district of Bangladesh, researchers gathered a total of 210 samples of goat meat from 13 different Upazilas. Primarily, cultural and biochemical methods were used for isolation of bacteria from the selected samples. Salmonella enterica serovars Typhimurium and Enteritidis, along with three ESBL-resistant genes, were identified through polymerase chain reactions (PCRs). The disk diffusion test was used to determine antimicrobial susceptibilities. Out of 210 samples analysed, Salmonella spp. was detected in 18.10 % (38 out of 210), with S. Enteritidis and S. Typhimurium found in 9.05 % (19 out of 210) and 5.24 % (11 out of 210) of the samples, respectively. A total of 72.73 % (8/11) of S. Enteritidis and 100 % (19/19) of S. Typhimurium isolates were positive by Multidrug-resistant patterns. The positive outcomes were found of S. Typhimurium tested 63.16 % (12 out of 19) for the bla TEM gene and 21.05 % (4/19) for the bla SHV, gene. The study proposes that the retail goat meat market channel could be a prominent transmission way of ESBL-producing MDR Salmonella enterica serovars, representing a significant public health hazard.

Analysis of mcr family of colistin resistance genes in Gram-negative isolates from a tertiary care hospital in India.

AIM: Colistin serves as the drug of last resort for combating numerous multidrug-resistant (MDR) Gram-negative infections. Its efficacy is hampered by the prevalent issue of colistin resistance, which severely limits treatment options for critically ill patients. Identifying resistance genes is crucial for controlling resistance spread, with horizontal gene transfer being the primary mechanism among bacteria. This study aimed to assess the prevalence of plasmid-mediated mcr genes associated with colistin resistance in Gram-negative bacteria, utilizing both genotypic and phenotypic tests. METHODS AND RESULTS: The clinical isolates (n=913) were obtained from a tertiary care center in Chennai, India. Colistin resistance was seen among Gram-negative isolates. These strains underwent screening for mcr-1, mcr-3, mcr-4, and mcr-5 genes via conventional PCR. Additionally, mcr-positive isolates were confirmed through Sanger sequencing and phenotypic testing. The bacterial isolates predominantly comprised Klebsiella pneumoniae (62.43%), Escherichia coli (19.71%), Pseudomonas aeruginosa (10.73%), Acinetobacter baumannii (4.81%), along with other species. All isolates exhibited multidrug resistance to three or more antibiotic classes. Colistin resistance, determined via broth microdilution (BMD) using CLSI guidelines, was observed in 13.08% of the isolates studied. Notably, mcr-5 was detected in K. pneumoniae in PCR, despite their absence in Sanger sequencing and phenotypic tests (including the combined-disk test, colistin MIC in the presence of EDTA, and Zeta potential assays). This finding underscores the importance of employing multiple diagnostic approaches to accurately identify colistin resistance mechanisms. CONCLUSION AND IMPACT: The study highlights a concerning prevalence of colistin resistance among Enterobacterales, especially those producing carbapenemase, thereby impacting mortality rates. Nonetheless, further investigations are warranted to elucidate common mechanisms of colistin resistance and to evaluate the efficacy of screening techniques in detecting isolates carrying mcr genes responsible for enzyme-mediated lipopolysaccharide (LPS) modification.

Cefiderocol heteroresistance associated with mutations in TonB-dependent receptor genes in Pseudomonas aeruginosa of clinical origin.

The siderophore-cephalosporin cefiderocol (FDC) presents a promising treatment option for carbapenem-resistant (CR) P. aeruginosa (PA). FDC circumvents traditional porin and efflux-mediated resistance by utilizing TonB-dependent receptors (TBDRs) to access the periplasmic space. Emerging FDC resistance has been associated with loss of function mutations within TBDR genes or the regulatory genes controlling TBDR expression. Further, difficulties with antimicrobial susceptibility testing (AST) and unexpected negative clinical treatment outcomes have prompted concerns for heteroresistance, where a single lineage isolate contains resistant subpopulations not detectable by standard AST. This study aimed to evaluate the prevalence of TBDR mutations among clinical isolates of P. aeruginosa and the phenotypic effect on FDC susceptibility and heteroresistance. We evaluated the sequence of pirR, pirS, pirA, piuA, or piuD from 498 unique isolates collected before the introduction of FDC from four clinical sites in Portland, OR (1), Houston, TX (2), and Santiago, Chile (1). At some clinical sites, TBDR mutations were seen in up to 25% of isolates, and insertion, deletion, or frameshift mutations were predicted to impair protein function were seen in 3% of all isolates (n = 15). Using population analysis profile testing, we found that P. aeruginosa with major TBDR mutations were enriched for a heteroresistant phenotype and undergo a shift in the susceptibility distribution of the population as compared to susceptible strains with wild-type TBDR genes. Our results indicate that mutations in TBDR genes predate the clinical introduction of FDC, and these mutations may predispose to the emergence of FDC resistance.

Phenotypic identification of different ß-Lactamases in intrinsic and acquired colistin resistant uropathogenic gram negative bacteria.

Objective: Identification of MBL, AmpC and ESBLs in colistin intrinsic and acquired resistant uropathogenic gram negative bacteria. Method: Urine samples were collected from Hayatabad Medical Complex, Peshawar during 17 January to 30 June 2019. Collected urine samples were aseptically transported microbiology lab of Health Research Institution (HRI), National Institute of Health (NIH), Khyber Medical College, Peshawar and streaked on different media. Positive growth was identified by API-10s. Antibiotic sensitivity profile was done by Modified Kirby Bauer disc diffusion method. Detection of metallo ßlactamases (MBL) production by Imipenem EDTA synergy test, Double Disc Synergy Test (DDST) for detection of ESBLs and D-test for the detection of inducible AmpC beta lactamases test was used. Colistin resistance was identified via broth micro dilution according to CLSI manual. Colistin resistant bacteria was divided in two categories; acquired and intrinsic resistant bacteria according to CLSI manual. Results: Out of 2000 urine samples, 281(14%) gram-negative bacteria were isolated. Among positive samples, acquired colistin resistant bacteria were 241 and intrinsic resistant bacteria were 40 isolates. MBL was produce by twenty one (11.7%) E.coli and seventeen (40.5%) Pseudomonas aeruginosa. E. coli, Pseudomonas aeruginosa, Klebsiella Pneumoniae, Serratia Oderifora and Proteus Marblis were ESBLs producing bacteria. AmpC production was prevalent in fourteen (7.8%) E. coli and twelve (28.6%) Pseudomonas aeruginosa. Fifty-five samples showed resistance to colistin out of 241 samples. In colistin resistant bacteria, two E.coli were MBL, ESBLs, while one E.coli was ESBLs, AmpC co-producing bacteria. The most prevalent extended drug resistant bacteria were Pseudomonas aeruginosa (28.6%) and Escherichia coli (6.1%), While 155(86.6%) Escherichia coli, 25 (59.5%) Pseudomonas aeruginosa and 22 (95.7%) Serratia Oderifora was multi drug resistant bacteria. Conclusion: Current study concluded that ESBL, MBL AmpC enzymes and their co-expression was observed with colistin resistance in E.coli and Pseudomonas aeruginosa.

Synergistic effects of silver nanoparticles in combination with ineffective antibiotics against multidrug resistant Salmonella typhi.

Objectives: To determine the antimicrobial activity of silver nano-particles(AgNPs) with tetracycline and ampicillin against multi-drug resistance (MDR) and extensively-drug resistance (XDR) Salmonella typhi. Methods: Cross sectional non-probability purposive study was conducted from September, 2021 to May, 2022 at Microbiology department PNS Shifa, Hospital Karachi. Blood cultures of patients suspicious of typhoid fever were collected and incubated in automated Bact/Alert system. Positive cultures were identified on blood and MacConkey and processed by API-10S, confirmed by serotyping (O9 antisera) (SSI Diagnostica's Salmonella). Antibiotic resistance was done by Kirby-Bauer disk diffusion (Sigma and Rich). MDR and XDR isolates were preserved in Brain Heart Infusion in a volume of 2ml in screw capped bottles at -70°C. Antimicrobial powders (ampicillin and tetracycline (Alfa Aesar) weighed by an electrical weighing balance (OHAUS) to take 1mg of antimicrobial drug. Absorbance spectra of serial concentrations of antibiotics (UV-Vis spectrophotometer (Mole-Qule-) AgNPs (10nm) (nanocomposix) + Antibiotic in (1:1 volume ratio). Conjugation of silver nanoparticles with tetracycline and ampicillin was done by FTIR (thermos scientificThermos ScientificNicolet 50). Results: Out of 77 isolates, 54 were resistant to ceftriaxone (XDR) and 23 sensitive to ceftriaxone (MDR). All isolates were susceptible to azithromycin and meropenem. Comparison of zone of inhibitions of ampicillin and Amp-AgNPsas and tetracycline with Tet-AgNPs was done. Minimal inhibitory concentration was also done to determine antimicrobial activity. Conclusion: Significant synergistic inhibitory effects against Salmonella Typhi isolates were obtained by combination of tetracycline with silver nano-particles even at low concentration.

Tocopherol-human serum albumin nanoparticles enhance lapatinib delivery and overcome doxorubicin resistance in breast cancer.

Introduction: HER2, a tyrosine kinase receptor, is amplified in HER2-positive breast cancer, driving cell signaling and growth. Aim: This study aimed to combat multidrug resistance in Dox-insensitive breast adenocarcinoma by creating a nanoformulation therapy with a tyrosine kinase inhibitor. Methodology: Human serum albumin (HSA) was conjugated with α-D-tocopherol succinate to form nanoaggregates loaded with lapatinib (Lapa). Results: The resulting Lapa@HSA(VE) NPs were 117.2 nm in size and demonstrated IC50 values of 10.25 µg/ml on MCF7 (S) and 8.02 µg/ml on MCF7 (R) cell lines. Conclusion: Lapa@HSA(VE) NPs showed no hepatotoxicity, unlike free Lapa, as seen in acute toxicity studies in rats.

[Box: see text].

Direct prediction of antimicrobial resistance in Pseudomonas aeruginosa by metagenomic next-generation sequencing.

Objective: Pseudomonas aeruginosa has strong drug resistance and can tolerate a variety of antibiotics, which is a major problem in the management of antibiotic-resistant infections. Direct prediction of multi-drug resistance (MDR) resistance phenotypes of P. aeruginosa isolates and clinical samples by genotype is helpful for timely antibiotic treatment. Methods: In the study, whole genome sequencing (WGS) data of 494 P. aeruginosa isolates were used to screen key anti-microbial resistance (AMR)-associated genes related to imipenem (IPM), meropenem (MEM), piperacillin/tazobactam (TZP), and levofloxacin (LVFX) resistance in P. aeruginosa by comparing genes with copy number differences between resistance and sensitive strains. Subsequently, for the direct prediction of the resistance of P. aeruginosa to four antibiotics by the AMR-associated features screened, we collected 74 P. aeruginosa positive sputum samples to sequence by metagenomics next-generation sequencing (mNGS), of which 1 sample with low quality was eliminated. Then, we constructed the resistance prediction model. Results: We identified 93, 88, 80, 140 AMR-associated features for IPM, MEM, TZP, and LVFX resistance in P. aeruginosa. The relative abundance of AMR-associated genes was obtained by matching mNGS and WGS data. The top 20 features with importance degree for IPM, MEM, TZP, and LVFX resistance were used to model, respectively. Then, we used the random forest algorithm to construct resistance prediction models of P. aeruginosa, in which the areas under the curves of the IPM, MEM, TZP, and LVFX resistance prediction models were all greater than 0.8, suggesting these resistance prediction models had good performance. Conclusion: In summary, mNGS can predict the resistance of P. aeruginosa by directly detecting AMR-associated genes, which provides a reference for rapid clinical detection of drug resistance of pathogenic bacteria.

Glutathione-Sensitive Photosensitizer-Drug Conjugates Target the Mitochondria to Overcome Multi-Drug Resistance in Cancer.

Multi-drug resistance (MDR) is a major cause of cancer therapy failure. Photodynamic therapy (PDT) is a promising modality that can circumvent MDR and synergize with chemotherapies, based on the generation of reactive oxygen species (ROS) by photosensitizers. However, overproduction of glutathione (GSH) by cancer cells scavenges ROS and restricts the efficacy of PDT. Additionally, side effects on normal tissues are unavoidable after PDT treatment. Here, to develop organic systems that deliver effective anticancer PDT and chemotherapy simultaneously with very little side effects, three GSH-sensitive photosensitizer-drug conjugates (CyR-SS-L) are designed and synthesized. CyR-SS-L localized in the mitochondria then is cleaved into CyR-SG and SG-L parts by reacting with and consuming high levels of intracellular GSH. Notably, CyR-SG generates high levels of ROS in tumor cells instead of normal cells and be exploited for PDT and the SG-L part is used for chemotherapy. CyR-SS-L inhibits better MDR cancer tumor inhibitory activity than indocyanine green, a photosensitizer (PS) used for PDT in clinical applications. The results appear to be the first to show that CyR-SS-L may be used as an alternative PDT agent to be more effective against MDR cancers without obvious damaging normal cells by the combination of PDT, GSH depletion, and chemotherapy.

Newly isolated Drexlerviridae phage LAPAZ is physically robust and fosters eradication of Klebsiella pneumoniae in combination with meropenem.

Due to the spread of multidrug resistance there is a renewed interest in using bacteriophages (briefly: phages) for controlling bacterial pathogens. The objective of this study was the characterization of a newly isolated phage (i.e. phage LAPAZ, vB_KpnD-LAPAZ), its antimicrobial activity against multidrug resistant Klebsiella pneumoniae and potential synergistic interactions with antibiotics. LAPAZ belongs to the family Drexlerviridae (genus: Webervirus) and lysed 30 % of tested strains, whereby four distinct capsular types can be infected. The genome consists of 51,689 bp and encodes 84 ORFs. The latent period is 30 min with an average burst size of 27 PFU/cell. Long-term storage experiments show that LAPAZ is significantly more stable in wastewater compared to laboratory media. A phage titre of 90 % persists up to 30 min at 50 ˚C and entire phage loss was seen only at temperatures > 66 ˚C. Besides stability against UV-C, antibacterial activity in liquid culture medium was consistent at pH values ranging from 4 to 10. Unlike exposure to phage or antibiotic alone, synergistic interactions and a complete bacterial eradication was achieved when combining LAPAZ with meropenem. In addition, synergism with the co-presence of ciprofloxacin was observed and phage resistance emergence could be delayed. Without co-addition of the antibiotic, phage resistant mutants readily emerged and showed a mixed pattern of drug sensitivity alterations. Around 88 % became less sensitive towards ceftazidime, meropenem and gentamicin. Conversely, around 44 % showed decreased resistance levels against ciprofloxacin. Whole genome analysis of a phage-resistant mutant with a 16-fold increased sensitivity towards ciprofloxacin revealed one de novo frameshift mutation leading to a gene fusion affecting two transport proteins belonging to the major facilitator-superfamily (MFS). Apparently, this mutation compromises ciprofloxacin efflux efficiency and further studies are warranted to understand how the non-mutated protein might be involved in phage-host adsorption.

A retrospective study of uropathogen and its antibiotic resistance among children with urinary tract infection from a single center in China.

Urinary tract infection (UTI) is a well-known bacterial infection posing serious health problem in children. A retrospective study was conducted to explore the uropathogen and its antibiotic resistance in children with UTI. Data of urine culture and antimicrobial susceptibility test was collected. Consequently, 840 children were included. The overall culture-positive UTI was 458 (54.52 %) with Escherichia coli 166 (36.24 %), followed by Enterococcus faecalis 59 (12.88 %), Enterococcus faecium 70 (15.28 %) and others. They were highly resistant to the most commonly used antibiotics. In 694 children with complicated UTI, there were 8 children with fungal infection. Multiple drug resistance (MDR) was recorded in 315 (80.98 %). The overall proportion of Extended Spectrum ß-Lactamase (ESßL) production was 25 (6.43 %). In 146 children with simple UTI, MDR were also detected in 47 (77.05 %). There were 6 (9.84 %) positive for ESßL production. Our study found that complicated UTI was relatively common. Escherichia coli was the most prevalent isolate, followed by Enterococcus faecium and Enterococcus faecalis. These organisms were highly resistant to the most commonly used antibiotics. Relatively high prevalence of MDR and low ESßL-producing organisms were observed.

High Prevalence and Genetic Diversity of Multidrug Resistant and Extended Spectrum ß-Lactamase Producing Escherichia coli and Klebsiella pneumoniae in Mothers and Neonates in a Cameroonian Labour Ward.

BACKGROUND: Escherichia coli and Klebsiella pneumoniae rank among the primary bacterial culprits in neonatal infections and fatalities in sub-Saharan Africa. This study characterized the phenotypic and genotypic features of Escherichia coli and Klebsiella pneumoniae in a labour ward in Yaoundé, Cameroon. METHODS: A prospective and cross-sectional study spanning five months, from February 21 to June 30, 2022. Recto-vaginal swabs were obtained from expectant mothers, and nasopharyngeal swabs were collected from their babies. Hand swabs of healthcare workers and environmental samples were also collected. The samples were cultured on eosin methylene blue agar and isolates identified using the Enterosystem 18R kit. Extended-spectrum ß-lactamase (ESBL) production was assessed using CHROMAgar ESBL™ and the double disc synergy test. A Polymerase chain reaction (PCR) was employed to detect ß-lactamase genes. ERIC-PCR was used to assess the clonal relatedness of isolates. RESULTS: A total of 93 mothers and 90 neonate were collected. Two neonates with an engaged prognosis were referred to another hospital while one was stillborn. Likewise, 25 workers and 10 pools of environment were collected. Almost all pregnant women (90%) were colonized by one or more multi-drug resistant (MDR) isolates with 58% being concomitantly ESBL producers. Altogether, 14/22 (64%) neonates were colonized by MDR isolate while out of the five workers positive to Enterobacterales, all were colonized by MDR isolate. Escherichia coli predominated in pregnant women (55%) and neonates (73%) while K. pneumoniae (83%) predominated in healthcare workers. Finally, only one isolate of each species was detected in the environment. The blaCTX-M (75%) was the leading ß-lactamase gene detected. CONCLUSION: Our study suggests that drug-resistant E. coli and K. pneumoniae are circulating at high prevalence in labour ward in Yaoundé and emphasizes the necessity for effective infection prevention and control along with antimicrobial stewardship measures.

Surgical Site Infection in Head and Neck Cancer Patients: Observations from A Tertiary Care Hospital.

Ramakrishna Pai JakribettuBackground Surgical site infections (SSIs) in head and neck cancer (HNC) patients can significantly affect the outcome of the surgery. Appropriate antimicrobial prophylaxis is needed for prevention of SSI. Aim To study the causative agents causing SSI among the HNC patients and their drug resistance pattern. Materials and Methods This was a retrospective study. The antibiotic suspectibility pattern of the aerobic bacteria isolated from the wound infection in the patients underwent surgery for head and neck cancer, admitted from January 2015 to December 2016 were added in the study. The demographic details of patients, pathogens isolated, and their antimicrobial susceptibility were collected, entered into Microsoft Excel, and statistical analysis was done as per percentage of isolates and drug resistance. Results A total of 130 culture-positive pus samples were included in the study. The majority of the samples were from males (71.5%), one-third of the patients belonged to the sixth decade of their life. Buccal mucosa and tongue were the common cancer in the head and neck region. The common gram-negative pathogens were Klebsiella sp. and Acinetobacter sp. and Staphylococcus aureus and Enterococcus sp. among the gram-positive bacteria. Methicillin-resistant S. aureus isolation rate was noted to be as high as 64.28%. High levels of resistance to aminopenicillins, third generation cephalosporins, co-trimoxazole and fluoroquinolones among the gram-negative pathogens. Anti-MRSA drugs such as vancomycin, linezolid, and teicoplanin resistance was not seen among S. aureus . Conclusion The resistance pattern among the pathogens isolated from SSI in HNC patients is alarming. So, implementation of strict infection control practices to prevent SSI rather than treating them with high end antimicrobials is the best option.

The prevalence of antimicrobial drug resistance of non-typhoidal Salmonella in human infections in sub-Saharan Africa: a systematic review and meta-analysis.

INTRODUCTION: Non-typhoidal Salmonella (NTS) bacteremia is common in sub-Saharan Africa. We examined the prevalence of antibiotic resistance to fluoroquinolones, third-generation cephalosporins, and multi-drug resistance (MDR) in NTS human isolates from sub-Saharan Africa. METHODS: A systematic review was conducted using a search in Ovid Medline, Embase, and African Index Medicus of publications between 2000 and 2021. A random-effects model meta-analysis was performed using data from 66 studies that included 29,039 NTS blood and 1,065 stool isolates. RESULTS: The pooled prevalence proportions of MDR were 0.685 (95% CI 0.574-0.778) and 0.214 (0.020-0.785) in blood vs. stool isolates. The corresponding estimates of fluoroquinolones resistance were 0.014 (0.008-0.025) vs. 0.021 (0.012-0.036) and third-generation cephalosporins resistance 0.019 (0.012-0.031) vs. 0.035 (0.006-0.185). Similar results were found for children and adults. Resistance prevalence to these antibiotics in blood isolates increased between 2000-2010 and 2011-2021. The guidelines employed to determine antimicrobial resistance and epidemiological characteristics (e.g. sample size, study duration) correlated with the resistance prevalence. CONCLUSIONS: The prevalence of MDR and resistance to fluoroquinolones and third-generation cephalosporins in NTS in sub-Saharan Africa is alarming. EXPERT OPINION: Standardized surveillance of antimicrobial drug resistance in NTS in sub-Saharan Africa is warranted to guide healthcare policymaking and antibiotic stewardship programs.

Non-typhoidal Salmonella (NTS) usually causes diarrheal disease, but some patients might develop bloodstream infection. The occurrence and case fatality of bloodstream infections caused by NTS are high in sub-Saharan Africa. However, the information on antibiotic resistance of these bacteria in this region is scarce. We performed a systematic review and meta-analysis to examine the prevalence of multi-drug resistance (MDR) and resistance to antibiotics used to treat NTS bloodstream infection: fluoroquinolones and third-generation cephalosporins in NTS isolates from patients from sub-Saharan Africa.We used data from 66 studies. In NTS blood isolates, the combined prevalence was 1.4% for fluoroquinolones resistance, 1.9% for resistance to third-generation cephalosporins, and 68.5% for MDR. These estimates were 2.1%, 3.5%, and 21.4% in stool isolates. The prevalence of resistance to fluoroquinolones and third-generation cephalosporins in blood isolates has increased in the past 2 decades. The guidelines employed to determine antimicrobial resistance and the study epidemiological characteristics were related to the resistance prevalence.The high prevalence of MDR in NTS raises concerns, and the emergence of resistance to fluoroquinolones and third-generation cephalosporins is worrisome. Strengthening the monitoring of antimicrobial drug resistance in NTS is essential to guide patients' care and policymaking in sub-Saharan Africa.

Potential antifungal applications of heterometallic silica nanohybrids: A synergistic activity.

An estimated 1.7 million fatalities and 150 million cases worldwide are attributed to fungal infections annually, that are in rise due to immunocompromised patient population. The challenges posed by traditional treatments can be addressed with the help of nanotechnology advancements. In this study, Co, Cu, and Ag-were doped into silica nanoparticles. Then the synthesized monometallic silica nanohybrids were combined to formulate heterometallic silica nanohybrids, characterized structurally and morphologically, compared, and evaluated for antifungal activity based on their individual and synergistic activity. The antifungal assays were conducted by using ATCC cultures of Candida albicans and QC samples of Trichophyton rubrum, Microsporum gypseum, and Aspergillus niger. The MIC (ranging from 49.00 to 1560.00 µg/mL), MFC (ranging from 197.00 to 3125.00 µg/mL), IC50 values (ranging from 31.10 to 400.80 µg/mL), and FICI of nanohybrids were determined and compared. Moreover, well diffusion assay was performed. ABTS assay and DPPH assay were conducted to investigate the radical scavenging activity (RSA) of nanohybrids. SEM analysis clearly evidenced the structural deformations of each fungal cells and spores due to the treatment with trimetallic nanohybrid. According to the results, the trimetallic silica nanohybrids exhibited the most powerful synergistic RSA and the most effective antifungal activity, compared to the bimetallic silica nanohybrids.

Mechanism of antibacterial phytoconstituents: an updated review.

The increase of multiple drug resistance bacteria significantly diminishes the effectiveness of antibiotic armory and subsequently exaggerates the level of therapeutic failure. Phytoconstituents are exceptional substitutes for resistance-modifying vehicles. The plants appear to be a deep well for the discovery of novel antibacterial compounds. This is owing to the numerous enticing characteristics of plants, they are easily accessible and inexpensive, extracts or chemicals derived from plants typically have significant levels of action against infections, and they rarely cause serious adverse effects. The enormous selection of phytochemicals offers very distinct chemical structures that may provide both novel mechanisms of antimicrobial activity and deliver us with different targets in the interior of the bacterial cell. They can directly affect bacteria or act together with the crucial events of pathogenicity, in this manner decreasing the aptitude of bacteria to create resistance. Abundant phytoconstituents demonstrate various mechanisms of action toward multi drug resistance bacteria. Overall, this comprehensive review will provide insights into the potential of phytoconstituents as alternative treatments for bacterial infections, particularly those caused by multi drug resistance strains. By examining the current state of research in this area, the review will shed light on potential future directions for the development of new antimicrobial therapies.

Antibiotic Stewardship in the Management of Infected Diabetic Foot Ulcer Disease in Less Developed Countries.

BACKGROUND: Diabetic foot ulcers in developing countries often become infected. The healthcare systems are often not equipped to conduct the culture and the sensitivity tests required for prescribing a targeted antibiotic treatment for diabetic foot infection (DFI). METHODS: We evaluate antibiotic stewardship programmes for DFIs, at every level of health care, with an emphasis on resource-poor settings such as in Africa. RESULTS: The management of DFI very often is adapted to the financial and practical realities of the resource-poor regions. The application of the point-of-care Gram stain of deep tissue samples is efficient, rapid, low cost and ubiquitously available. Upon the identification of the predominant pathogen in the Gram stain, a semi-quantitative preemptive antibiotic treatment can be started in accordance with the World Health Organization Aware, Watch and Restrict Essential Medicine List. This list is catered to every country and is a powerful tool. However, some basic knowledge of the local microbiological epidemiology is necessary to choose the most appropriate agent. We report our experience on using the rapidly available Gram stain for narrowing the preemptive choice of listed antibiotic agents, as an economic tool for antibiotic stewardship in DFIs. CONCLUSIONS: In the practical and resource-saving management of DFI, the 'therapeutic' use of Gram stains is not common in resource-rich countries but should be added to the arsenal of the general efforts for antibiotic stewardship.

Active screening cultures to reduce infections caused by carbapenem-resistant Acinetobacter baumannii: a systematic review and meta-analysis.

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a significant healthcare-associated infection carrying substantial mortality. We aimed to assess the clinical impact of active screening cultures for CRAB. METHODS: A systematic review and meta-analysis, aiming to answer two questions: 1. Does screening vs no screening improve clinical outcomes? 2. Does positive screening ("CRAB carrier") predict CRAB infections? We searched MEDLINE, Cochrane library, Web of Science, and conferences, until January 2024, comparative studies reporting clinical outcomes (mortality, invasive CRAB infections). RESULTS: Of 5,407 screened publications, 9 studies (10,865 individuals) were included for study question #2. Invasive CRAB infection rate was significantly higher among CRAB carriers (odds ratio [OR] 11.14, 95% confidence interval [CI] 4.95-25.05, with substantial heterogeneity stemming from size rather than direction of the effect). Negative predictive value (NPV) of non-carriage for invasive infection was 97%. CRAB bloodstream infections rate was significantly higher among carriers (OR 16.23, 95% CI 2.9-110.08). No significant difference was demonstrated between the two groups CRAB ventilator-associated pneumonia, length of stay, and mortality. Only one study reported outcomes for the screening vs no screening (study question #1). CONCLUSIONS: Data to support active CRAB screening are scarce regarding its clinical benefit for patients. Positively screened patients are at significantly higher risk for invasive CRAB infections, with high NPV for non-carriage. This did not translate to reduced mortality.

Drug repurposing for fungal infections.

The rise of multidrug-resistant bacteria is a well-recognized threat to world health, necessitating the implementation of effective treatments. This issue has been identified as a top priority on the global agenda by the World Health Organization. Certain strains, such as Candida glabrata, Candida krusei, Candida lusitaniae, Candida auris, select cryptococcal species, and opportunistic Aspergillus or Fusarium species, have significant intrinsic resistance to numerous antifungal medicines. This inherent resistance and subsequent suboptimal clinical outcomes underscore the critical imperative for enhanced therapeutic alternatives and management protocols. The challenge of effectively treating fungal infections, compounded by the protracted timelines involved in developing novel drugs, underscores the pressing need to explore alternative therapeutic avenues. Among these, drug repurposing emerges as a particularly promising and expeditious solution, providing cost-effective solutions and safety benefits. In the fight against life-threatening resistant fungal infections, the idea of repurposing existing medications has encouraged research into both established and new compounds as a last-resort therapy. This chapter seeks to provide a comprehensive overview of contemporary antifungal drugs, as well as their key resistance mechanisms. Additionally, it seeks to provide insight into the antimicrobial properties of non-traditional drugs, thereby offering a holistic perspective on the evolving landscape of antifungal therapeutics.