Global Burden of Fungal Infections and Antifungal Resistance from 1961 to 2024: Findings and Future Implications

Background: Antifungal resistance (AFR) is a global public health problem with devastating effects, especially among immunocompromised individuals. Addressing AFR requires a One Health approach including Antifungal Stewardship (AFS). This study aimed to comprehensively review global studies published on fungal infections and AFR and to recommend solutions to address this growing problem. Materials and Methods: This was a narrative review that was conducted using published papers on fungal infections, AFR, and AFS between January 1961 and March 2024. The literature was searched using PubMed, Google Scholar, Web of Science, and EMBASE. Results: This found that there has been an increase in fungal infections globally, especially among immunocompromised patients. Due to this increase in fungal infections, there has been a proportionate increase in the use of antifungal agents to prevent and treat fungal infections. This increased use of antifungal agents has worsened the problem of AFR contributing to increased morbidity and mortality. Globally, fungal infections have contributed to 150 million infections annually and 1.7 million deaths per year. By the year 2023, over 3.8 million people died from fungal infections. Addressing AFR remains a challenge because the treatment of antifungal-resistant infections is difficult. Finally, the treatment of fungal infections is a global challenge exacerbated by the limited number of antifungal agents to treat invasive fungal infections. Conclusion: The results of this study indicated that fungal infections and AFR are prevalent across humans, animals, agriculture, and the environment. Addressing this problem requires the provision of solutions such as improving the awareness of AFR, conducting further research on the discovery of new antifungal agents, and implementing AFS programs. If this global problem is not addressed, the morbidity and mortality associated with AFR will continue to rise in the future.

Pathogen characteristics and its sensitivity against antimicrobial agents in fatal bacterial granuloma after eyelid trauma in vitro

AIM: To understand the pathogen characteristics and its sensitivity against antimicrobial agents in fatal bacterial granuloma after eyelid trauma (FBGT) in vitro, and to provide laboratory evidence for diagnosis. METHODS: The FBGT pathogens were isolaated and cultured with reformed rabbit-brain anaerobic enriched broth (RRAB), and identified by ATB/API 20A system. The minimum inhibiting concentration (MIC) was determined by anaerobic broth dilution method. RESULTS: A total of 22 strains of pathogen were separated from 21 patients with FBGT and identified as Propionibacterium acnes (PA) by ATB/API 20A system. The MIC of ciprofloxacin for 22 PA strains was 0.0625-0.5mg/L, the MIC of penicillin, ampicillin, ampicillin/sulbactam, cefoperazone, lincomycin, and imipenem/cilastatin were 0.125-0.5mg/L, the MIC of ticarcillin/clavulanic acid was 0.250-1.000mg/L, and the MIC of metronidazole was 64-256mg/L. The pathogen of FBGT was strictly anaerobic PA, which growed slowly and better in nutritious RRAB broth. All PA were resistant to metronidazole, but susceptive to other routine antimicrobial agents, such as penicillin, ampicillin and lincomycin. CONCLUSION: FBGT should not be treated with metronidazole. Clinicians should choose combined use of drugs or operation to treat FBGT according to patients' individual condition and the results of drug sensitivity test.

Evaluation of rational use of antimicrobial agents in a Brazilian intensive care unit

The present study sought to assess the rational use of antimicrobial agents in a Brazilian intensive care unit (ICU) and its association with antimicrobial resistance in elderly patients admitted to the unit. Results: Choice of empiric and sensitivity-guided therapy was inadequate in > 80% and 59% of cases respectively. Inadequate antimicrobial therapy, whether empiric or sensitivity-guided, was positively correlated with bacterial resistance (r = 0.316;p = 0.001). Sensitivity testing revealed a 46.5% resistance rate to eight out of the ten most commonly used antibiotics. Multiple drug-resistant organisms were found in 40.8% of patients. A significant increase was observed in the number of multidrug-resistant samples between 2006/2007 and 2008 (r = 0.41, p = 0.006), (r = 0.598, p = 0.001), (r = 0.688, p = 0.00). Conclusion: We found a high rate of antibiotic misuse in the study sample. Inadequate therapy was correlated with resistance to antimicrobial agents.

Susceptibility of Mixed Infection of Ureaplasma Urealyticum and Mycoplasma Hominis to Seven Antimicrobial Agents and Comparison with that of Ureaplasma Urealyticum Infection

In order to investigate the susceptibility of mixed infection of Ureaplasma Urealyticum (UU) and Mycoplasma Hominis (MH) to 7 kinds of antimicrobial agents and comparison with that of UU infection in NGU patients, the in vitro susceptibility was determined by using microdilution method. The positive results were analyzed. The results showed that the sequence of susceptibility to 7 kinds of antimicrobial agents for both UU infection group and UU-MH mixed infection group was almost the same from the highest susceptibility to the lowest accordingly: Josamycin, Doxycycline, Minocycline, Sparfloxacin, Roxithromycin, Ofloxacin and Azithromycin. The total drug resistance rate for UU-MH mixed infection group (97. 67 %) was significantly higher than that for UU infection group (44. 67 %, P<.0. 01). The highest drug resistance rate in UU group and UU-MH mixed infection group was 31. 33 % (Ofloxacin) and 90. 48 % (Azithromycin) respectively. UU-MH mixed infection showed an increased drug resistance and changes of drug resistance spectrum.

In vitro drug resistance of clinical isolated Brucella against antimicrobial agents

Objective:To explore the antibiotic resistance of Brucella melitensis and instruct rational use of antimicrobial agents in clinical treatment of Brucella infection.Methods:Bacteria were cultured and identified by BACTEC9120 and VTTEK Ⅱ automicrobic system.E-test was used to detect the minimal inhibitory concentration(MIC) of antimicrobial agents in the drug susceptivity experiment.Results:A total of 19 brucella strains(all Brucella melitensis) were isolated from 19 patients,who had fever between January 2010 and June 2012,and 17 samples were blood,one was bone marrow,the other sample was cerebrospinal fluid.The MIC range of ceftazidime was 2.0-8.0 mg/L,rifampicin was 0.06-2.0 mg/L,amikacin was 4.0-12.0 mg/L,levofloxacin was 2.0-8.0 mg/ L,doxycycline was 8.0-32.0 mg/L,sulfamethoxazole-trimethoprim was 4.0-16.0 mg/L,ampicillin was 1.5-2.0 mg/L and gentamicin was 0.50-0.75 mg/L.Conclusions:The drugs used in this experiment cover common drugs for treating Brcella.Meanwhile,the results are consistent with clinical efficacy.It is suggested personalized regimen according to patients' status in treatment of Brucella.

Effects of various antimicrobial agents on multi-directional differentiation potential of bone marrow-derived mesenchymal stem cells

Antimicrobial drugs of several classes play an important role in the treatment of bone and joint infections. In addition to fighting pathogenic microorganisms, the effects of drugs on local tissues and cells are also related to the course and prognosis of bone and joint infections. The multi-directional differentiation potential of bone marrow-derived mesenchymal stem cells (MSCs) is essential for tissue repair after local injury, which is directly related to the recovery of bone, cartilage, and medullary adipose tissue. Our previous studies and the literature indicate that certain antimicrobial agents can regulate the differentiation potential of bone marrow-derived MSCs. Here, in order to systematically analyze the effects of various antimicrobial drugs on local tissue regeneration, we comprehensively review the studies on the effects of these drugs on MSC differentiation, and classify them according to the three differentiation directions (osteogenesis, chondrogenesis, and adipogenesis). Our review demonstrates the specific effects of different antimicrobial agents on bone marrow-derived MSCs and the range of concentrations at which they work, and provides a basis for drug selection at different sites of infection.

Optimization of four types of antimicrobial agents to increase the inhibitory ability of marine Arthrobacter oxydans KQ 11 dextranase mouthwash

We adopted the response surface methodology using single factor and orthogonal experiments to optimize four types of antimicrobial agents that could inhibit biofilm formation by Streptococcus mutans, which is commonly found in the human oral cavity and causes tooth decay. The objective was to improve the function of marine Arthrobacter oxydans KQ11 dextranase mouthwash(designed and developed by our laboratory). The experiment was conducted in a three-level, four-variable central composite design to determine the best combination of Zn SO_4, lysozyme, citric acid and chitosan. The optimized antibacterial agents were 2.16 g/L Zn SO_4, 14 g/L lysozyme, 4.5 g/L citric acid and 5 g/L chitosan. The biofilm formation inhibition reached 84.49%. In addition, microscopic observation of the biofilm was performed using scanning electron microscopy and confocal laser scanning microscopy. The optimized formula was tested in marine dextranase Arthrobacter oxydans KQ11 mouthwash and enhanced the inhibition of S. mutans. This work may be promoted for the design and development of future marine dextranase oral care products.

Synthesis of Pyridazinonethiadiazoles as Possible Antifungal Agents

Several 5-[1-aryl-1,4-dihydro-6-methylpyridazin-4-one-3-yl]-2-arylamino-1,3,4-thia diazoles were synthesized. The preliminary bio-active test shows that these compounds exhibit high antifungal activity.

Increasing Incidence of Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae (ESBL) and the Relation to Consumption of Broad-Spectrum Antimicrobial Agents 2003-2011 in a Large Area of Copenhagen, Denmark

Purpose: To investigate 1) the development in the incidence of ESBL-producing bacteria in hospitals and primary health care, 2) the contribution of primary health care to the incidence of ESBL-producing bacteria, and 3) the development in resistance patterns for all Escherichia coli and Klebsiella pneumoniae isolates in relation to antimicrobial consumption in hospitals and primary health care. Methods: ESBL-data were retrospectively collected from bacterial isolates from all specimens received at the Department of Clinical Microbiology from 2003 to 2011 together with the corresponding patient data. ESBL-production was detected in isolates from 1067 of 59,373 patients (1.8%) with an E. coli infection and in 263 of 8660 patients (3.0%) with a K. pneumoniae infection. Results: From 2003 to 2009, an increase in patients with an ESBL-producing isolate occurred in both hospitals and primary health care at the same time as an increased consumption of broad-spectrum antimicrobial agents was seen. Interventions to reduce prescription of cephalosporins and ciprofloxacin at the hospitals from 2010 resulted in a remarkable decrease in patients with ESBL-producing K. pneumoniae whereas a continuing increase was seen in patients with ESBL-producing E. coli both at hospitals and in primary health care. The proportion of patients with community-acquired ESBL-producing E. coli was stable with an increase of only 1.4% from 2007 to 2011. Conclusions: Reduction in prescription of broad-spectrum antimicrobial agents at the hospital level had an important impact on the incidence of ESBL-producing K. pneumoniae, but not on ESBL-producing E. coli.

Synthesis of New Fluorinated Fused Heteropolycyclic Nitrogen Systems Containing a Pyrazolotriazine Moiety as Antimicrobial Agents Part I

A simple route to synthesize novel fluorinated fused hetero-polycyclic nitrogen systems containing a pyrazolotriazine moiety (5,8,11) have been deduced from cyclization of 2-aminothiocarbonyl-5-arylidene-3-phenyl-1,2,4-triazin-6(1H)one (2) with diethoxy-phosphine, diethyl carbonate and/or diethyl oxalate in boil THF followed by cyclo condensation with aryl sulfonic acid hydrazide in EtOH/piperidine and finally fluorination with trifluoroethyl acetate. Structures of the products have been established from their elemental analysis and spectral measurements. The antimicrobial activity of the targets has also been evaluated.

<i>In Vitro</i>Antibacterial, Antifungal and Other Medical Properties of Endangered Medicinal Plant Seeds

The risk created by infectious microorganisms to humans attracted the development of common medicine. To find an alternative source, medicinal plants with diverse metabolites play an important role in curing the diseases and human disorders caused by microbial pathogens. Medicinal plants namely, Citrullus colocynthis, Hyoscyamus muticus, Ocimum basilicum, Amaranthus lividus, Salvia aegyptiaca and Ruta chalepensis are commonly used as a traditional medicine in Gulf countries. The present study aimed to investigate the antibacterial, antifungal and antioxidant potential of the organic crude extracts obtained from the seeds. Besides, the possible antimicrobial mechanisms of the extracts were evaluated by determining the enzyme activities. The antibacterial and antifungal activities of the crude extracts were evaluated by the broth micro dilution method and the effect of the extracts on the pathogens were determined by quantifying the alkaline phosphatase (ALP), lactate dehydrogenase (LDH) enzymes and intracellular protein leakage. Besides, the antioxidant properties were determined using hydroxyl radical scavenging assay, DPPH radical scavenging assay, reducing power assay and superoxide radical scavenging assay. Results indicated that the extracts of C. colocynthis showed promising activity against all the tested pathogens, especially the MIC values were ranged from 100 to 150 μg/ml for Gram positive bacteria and 100 to 250 μg/ml for Gram negative bacteria respectively. The MIC values of H. muticus, O. basilicum and R. chalepensis against the fungal pathogens were ranged from 100 to 500 μg/mL respectively. The ALP activity was higher in extract treated Klebsiella pneumoniae compared with control, whereas the LDH and protein concentrations for Escherichia coli and Staphylococcus aureus were comparatively higher. Furthermore, all the studied seed extract showed good antioxidant activities. In conclusion, the studied plant seed extracts documented good antimicrobial and antioxidant activities. Therefore, the medicinal plants would be the excellent source for natural antioxidant and antibacterial agents for medical and applications.

Design,synthesis and biological evaluation of novel non-azole derivatives as potential antifungal agents

A series of 3-substituted quinazolinones,2-substituted quinoxalines and 2-substituted benzopyrans were synthesized and evaluated for their antifungal activity in vitro.The new compounds revealed excellent in vitro antifungal activity with broad spectrum.The structure-activity relationships（SARs） of the derivatives were analyzed.Compound 9A2 exhibits better antifungal activity against 5 tested fungi in vitro than fluconazole,especially against Trichophyton rubrum and Microsporum gypseum.This study provides a series of novel lead compounds for the development of non-azole antifungal agents.

Structure-Activity Relationship, Cytotoxicity and Mode of Action of 2-Ester-substituted 1,5-Benzothiazepines as Potent Antifungal Agents

Our studies examined the structural features responsible for the antifungal activity of 2-ethoxycarbonyl-1,5- benzothiazepine （7a）. Three series of 1,5-benzothiazepine derivatives were synthesized and screened for their antifungal activity. The results suggested that the ethoxycarbonyl group at the 2 position and the imine moiety on the seven-membered ring are essential for activity. The most potent of the synthesized analogues （7a, 7b） were further studied by evaluating their cytotoxicity and mode of action （for 7a）. The results showed that compounds 7a and 7b were relatively safe for BV2 cells, but compound 7a interfered with Cryptococcus neoformans cell wall integrity by increasing the chitinase activity. Therefore, compound 7a was considered safe as an antifungal agent for animal cells.

A series of naphthalimide azoles: Design, synthesis and bioactive evaluation as potential antimicrobial agents

A series of naphthalimide azoles as potential antibacterial and antifungal agents were conveniently and efficiently synthesized starting from commercially available 6-bromobenzo[de]isochromene-1,3-dione. All the new compounds were characterized by NMR, IR, MS and HRMS spectra. Their antimicrobial activities were evaluated against four Gram-positive bacteria, four Gram-negative bacteria and two fungi using two-fold serial dilution technique. The biological assay indicated that most of the prepared compounds exhibited inhibition to the tested strains. In particular, the triazolium derivatives not only gave higher efficacy than their corresponding precursory azoles, but also demonstrated comparable or even better potency than the reference drugs Chloromycin, Orbifloxacin and Fluconazole. Some factors including structural fragments, pH and ClogP values of the target molecules were also preliminarily discussed.

In vitro activities of five antifungal agents against pathogenic Exophiala species

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The Antimicrobial Activity of Wool Fabrics Treated with Crosslinking Agents and Polyhexamethylene Biguanide

In this study,we used citric acid(CA)as a crosslinking agent,mixed with polyhexamethylene biguanide,to perform a pad-dry-cure treatment on wool fabrics to study its antimicrobial effects and physical properties.

Antimicrobial activities of Acacia genus:A review

More than 1 300 species of the vast genus Acacia are found in tropical habitats. They are crucial economic plants since they produce traditional medicines, timber, and gum. The pharmacological uses of the Acacia genus include anti-diarrheal, anti-malarial, chronic pain relief, wound healing, anti-cancer, anti-rheumatism, and antidiabetes activities. It is also used for treating various illnesses such as gastroenteritis, allergies, Alzheimer’s disease, cough, and cardiovascular disease. The present review aims to summarize the antimicrobial activities including the antibacterial and antifungal activity of the Acacia genus. The literature was searched in books and online databases including SciFinder, Google Scholar, Scopus, Pub Med, and scientific journals using the most relevant keywords: Acacia+antimicrobial, Acacia+antibacterial, and Acacia+antifungal.

Controlling antifungal activity with light:Optical regulation of fungal ergosterol biosynthetic pathway with photo-responsive CYP51 inhibitors

Invasive fungal infections(IFIs)have been associated with high mortality,highlighting the urgent need for developing novel antifungal strategies.Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14a-demethylase(CYP51)inhibitors.The photocaged triazoles completely shielded the CYP51inhibition.The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4%and 83.7%,respectively.Importantly,the shielded antifungal activity(MIC80≥64μg/m L)could be efficiently recovered(MIC80=0.5—8μg/m L)by light irradiation.The new chemical tools enable optical control of fungal growth arrest,morphological conversion and biofilm formation.The ability for highprecision antifungal treatment was validated by in vivo models.The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model.Overall,this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.

2015-2021年CHINET临床分离沙雷菌属细菌耐药性变迁

目的了解国内主要地区临床分离沙雷菌属细菌对常用抗菌药物的耐药率及变迁。方法由CHINET中国细菌耐药性监测网参与成员单位将临床分离菌采用纸片扩散法或自动化商业药敏测试系统按CHINET统一技术方案进行仪器法药物敏感性试验。结果2015年1月—2021年12月从我国不同地区53所医院临床分离到的沙雷菌属17226株。分离的菌株数从2015年959株上升到2021年3588株,自门急诊患者中分离到的沙雷菌占7.3%(1265/17226),住院患者菌株占92.7%(15961/17226)。17226株沙雷菌属细菌中呼吸道标本占比最高(57.5%±2.5%),其次为血液标本(11.5%±1.5%)。7年连续监测发现除氨苄西林、头孢唑林及呋喃妥因外其他抗菌药物细菌耐药率均有所下降,亚胺培南和美罗培南虽然耐药率数值有所反复,但仍从8.1%和8.3%降到5.3%和5.2%。成年患者来源的菌株对头孢哌酮-舒巴坦、头孢他啶-阿维巴坦、头孢噻肟、亚胺培南、呋喃妥因和替加环素耐药率三级医院高于二级医院,其他抗菌药物耐药率均低于二级医院。分离自儿童患者的沙雷菌对头孢哌酮-舒巴坦、哌拉西林-他唑巴坦、阿米卡星、甲氧苄啶-磺胺甲唑和替加环素的耐药率低于5%。分离自ICU的菌株对抗菌药物的耐药率普遍高于其他监测科室。7年监测碳青霉烯类耐药肠杆菌目菌株检出率为8.2%。结论7年中沙雷菌属细菌耐药率呈缓慢下降趋势,继续加强标本及时送检及合理使用抗菌药物对细菌耐药率下降起着尤为重要的作用,落实医院感染控制可有效降低耐药细菌的发生。