Background. Preterm infants with very low birth weight are at increased risk of invasive fungal infections. Preventive strategies are needed to improve their clinical course and survival.

Objectives. To assess the efficacy and safety of antifungal agents as prophylaxis in controlling invasive fungal infection and mortality in very low birth weight (VLBW) and extremely low birth weight (ELBW) infants in neonatal intensive care units.

Methods. We searched MEDLINE (PubMed), Cochrane databases, Google Scholar, Trip database, Herdin, and ClinicalTrials.gov without language restriction and publications from January 1988 to May 2021. We included randomized controlled trials or controlled clinical trials that compared the effect of prophylactic oral or systemic antifungal agents versus placebo in preterm infants < 37 weeks age of gestation and with birth weight lower than 1500 grams. We conducted a meta-analysis using RevMan 5.4.1 and certainty of evidence rating using GRADEpro software.

Results. A total of 14 studies (including 3,001 preterm infants with VLBW) were included. We found that prophylactic use of nystatin significantly reduced the incidence of invasive fungal infections (IFI) (pooled RR 0.16; 95% CI 0.11, 0.23; 4 RCTs, N = 1295; P < 0.00001; moderate certainty evidence) in preterm infants compared to placebo but had no significant effect on the mortality (RR 0.87; 95% CI 0.62, 1.23; 4 RCTs, N = 1295; P = 0.43; low certainty evidence). Similarly, fluconazole decreased the incidence of IFI (RR 0.38; 95% CI 0.28, 0.53; P = 0.02) and showed statistically significant reduction in mortality (RR 0.78; 95% CI 0.61, 0.99; RCTs, N = 1484; P = 0.04; high certainty evidence). The comparison of the two antifungals showed a trend favoring fluconazole, however the difference was not statistically significant in decreasing IFI (RR 1.60; 95% CI 0.68, 3.77; P = 0.28) and mortality (RR 1.62; 95% CI 0.76, 3.45; P = 0.21).

Conclusion. Administration of antifungal prophylaxis proves to be beneficial and can probably decrease invasive fungal infection and mortality. The evidence showed that Fluconazole is superior as antifungal prophylaxis compared to placebo while there is no significant difference between fluconazole and nystatin in decreasing fungal infection and mortality among preterm neonates.

Nystatin ; Fluconazole ; Prophylaxis ; Infant, Very Low Birth Weight

PURPOSE: Lipid rafts are cholesterol enriched microdomains that colocalize signaling pathways involved in cell proliferation, metastasis, and angiogenesis. We examined the effect of methyl-β-cyclodextrin (MβCD)-mediated cholesterol extraction on the proliferation, adhesion, invasion, and angiogenesis of triple negative breast cancer (TNBC) cells. METHODS: We measured cholesterol and estimated cell toxicity. Detergent resistant membrane (DRM) and non-DRM fractions were separated using the OptiPrep gradient method. Cell cycles stages were analyzed by flow cytometry, apoptosis was assessed using the TdT-mediated dUTP nick end-labeling assay, and metastasis was determined using a Matrigel invasion assay. Neo-vessel pattern and levels of angiogenic modulators were determined using an in vitro angiogenesis assay and an angiogenesis array, respectively. RESULTS: The present study found that the cholesterol-depleting agent MβCD, efficiently depleted membrane cholesterol and caused concentration dependent (0.1–0.5 mM) cytotoxicity compared to nystatin and filipin III in TNBC cell lines, MDA-MB 231 and MDA-MB 468. A reduced proportion of caveolin-1 found in DRM fractions indicated a cholesterol extraction-induced disruption of lipid raft integrity. MβCD inhibited 52% of MDA-MB 231 cell adhesion on fibronectin and 56% of MDA-MB 468 cell adhesion on vitronectin, while invasiveness of these cells was decreased by 48% and 52% respectively, following MβCD treatment (48 hours). MβCD also caused cell cycle arrest at the G2M phase and apoptosis in MDA-MB 231 cells (25% and 58% cells, respectively) and in MDA-MB 468 cells (30% and 38% cells, respectively). We found that MβCD treated cells caused a 52% and 58% depletion of neovessel formation in both MDA-MB 231 and MDA-MB 468 cell lines, respectively. This study also demonstrated that MβCD treatment caused a respective 2.6- and 2.5-fold depletion of tyrosine protein kinase receptor (TEK) receptor tyrosine kinase levels in both TNBC cell lines. CONCLUSION: MβCD-induced cholesterol removal enhances alterations in lipid raft integrity, which reduces TNBC cell survival.
Apoptosis ; Caveolin 1 ; Cell Adhesion ; Cell Cycle ; Cell Cycle Checkpoints ; Cell Line ; Cell Proliferation ; Cell Survival ; Cholesterol ; Detergents ; Fibronectins ; Filipin ; Flow Cytometry ; In Vitro Techniques ; Membrane Microdomains ; Membranes ; Methods ; Neoplasm Metastasis ; Nystatin ; Protein-Tyrosine Kinases ; Triple Negative Breast Neoplasms* ; Vitronectin

OBJECTIVES: The purpose of this ex vivo study was to compare the antifungal activity of a synthetic peptide consisting of 15 amino acids at the C-terminus of human β-defensin 3 (HBD3-C15) with calcium hydroxide (CH) and Nystatin (Nys) against Candida albicans (C. albicans) biofilm. MATERIALS AND METHODS: C. albicans were grown on cover glass bottom dishes or human dentin disks for 48 hr, and then treated with HBD3-C15 (0, 12.5, 25, 50, 100, 150, 200, and 300 µg/mL), CH (100 µg/mL), and Nys (20 µg/mL) for 7 days at 37℃. On cover glass, live and dead cells in the biomass were measured by the FilmTracer Biofilm viability assay, and observed by confocal laser scanning microscopy (CLSM). On dentin, normal, diminished and ruptured cells were observed by field-emission scanning electron microscopy (FE-SEM). The results were subjected to a two-tailed t-test, a one way analysis variance and a post hoc test at a significance level of p = 0.05. RESULTS: C. albicans survival on dentin was inhibited by HBD3-C15 in a dose-dependent manner. There were fewer aggregations of C. albicans in the groups of Nys and HBD3-C15 (≥ 100 µg/mL). CLSM showed C. albicans survival was reduced by HBD3-C15 in a dose dependent manner. Nys and HBD3-C15 (≥ 100 µg/mL) showed significant fungicidal activity compared to CH group (p < 0.05). CONCLUSIONS: Synthetic HBD3-C15 peptide (≥ 100 µg/mL) and Nys exhibited significantly higher antifungal activity than CH against C. albicans by inhibiting cell survival and biofilm.
Amino Acids ; Biofilms ; Biomass ; Calcium Hydroxide ; Candida albicans ; Cell Survival ; Dentin ; Glass ; Humans* ; Microscopy, Confocal ; Microscopy, Electron, Scanning ; Nystatin

Nystatin, a polyene antifungal antibiotic, is a cholesterol sequestering agent. The antifungal agent alters composition of the plasma membrane of eukaryotic cells, whereas its effects on cells are poorly investigated. In the current study, we investigated the question of whether nystatin was able to induce expression of macrophage inflammatory protein-1 (MIP-1). THP-1 cells rarely express MIP-1alpha and MIP-1beta, however, upon exposure to nystatin, significantly elevated expression of MIP-1alpha and MIP-1beta was observed in a dose-dependent fashion at the messenger and protein levels. Cellular factors activated by nystatin as well as involved in nystatin-induced expression of MIP-1 proteins were identified in order to understand the molecular mechanisms of action of the anti-fungal agent. Treatment with nystatin resulted in enhanced phosphorylation of Akt, ERK, p38 MAPK, and JNK. Abrogation or significant attenuation of nystatin-induced expression of MIP-1alpha and MIP-1beta was observed by treatment with Akt inhibitor IV, LY294002, and SP6001250. Inhibition of ERK or p38MAPK using U0126 and SB202190 did not lead to attenuation of MIP-1 expression. In addition, inhibitors of protein kinase C, such as GF109203X and Ro-318220, also attenuated expression of MIP-1. These results indicate that nystatin is able to activate multiple cellular kinases and, among them, Akt and JNK play primary roles in nystatin-induced expression of MIP-1 proteins.
Cell Membrane ; Chemokine CCL3 ; Chemokine CCL4 ; Cholesterol ; Eukaryotic Cells ; Macrophage Inflammatory Proteins* ; Macrophages* ; Nystatin* ; p38 Mitogen-Activated Protein Kinases ; Phosphorylation ; Phosphotransferases ; Protein Kinase C

PURPOSE: Transient hypoxia is an initial event that accentuates ischemia/reperfusion (I/R) injury in the liver. Hepatic ischemia/reperfusion (I/R) injury is largely related to innate immunity via Toll-like receptor 4 (TLR4) signaling. However, the mechanism by which hypoxia could lead to activate TLR4 signaling remains unclear. Therefore, the aim of this experimental study investigates how TLR4 signalling is activated by hypoxia. METHODS: Hepatocytes were isolated from male wild-type (C57BL/6) mice (8~12 weeks old) by an in situ collagenase (Type IV, Sigma-Aldrich) perfusion technique. In this study, using primary mouse hepatocytes in culture to 1% oxygen, detection of TLR4 translocation to the lipid rafts on the cell membrane by immunofluorescence staining and immunoblotting was saught. RESULTS: Hypoxia caused TLR4/MD2 and beta2-Integrin (CD11b/CD18) translocation to lipid rafts associated with CD14 in hepatocytes. The cholesterol sequestering agent, Nystatin and Filipin prevented hypoxia-induced TLR4/MD2 translocation to lipid rafts. Consistent with a role for oxidative stress in this effect, in vitro H2O2 treatment of hepatocytes similarly caused TLR4/MD2 translocation to lipid rafts. In addition, translocation of hypoxia-induced TLR4 complex was inhibited by N-acetylcysteine (NAC) demonstrating that the activation of TLR4 signaling is dependent on ROS. Further, the cholesterol sequestering agent, nystatin, prevented hypoxia-induced high mobility group box 1 (HMGB1) release in hepatocytes. CONCLUSION: These results suggest that ROS dependent TLR4 signaling is achieved following receptor translocation to the lipid raft in hepatocytes. We hypothesized that this mechanism is required for the release of HMGB1, an early mediator of injury and inflammation in hepatic I/R injury.
Acetylcysteine ; Animals ; Anoxia* ; Cell Membrane ; Cholesterol ; Cluster Analysis* ; Collagenases ; Filipin ; Fluorescent Antibody Technique ; Hepatocytes* ; HMGB1 Protein ; Humans ; Immunity, Innate ; Immunoblotting ; Inflammation ; Liver ; Male ; Mice* ; Nystatin ; Oxidative Stress ; Oxygen ; Perfusion ; Sequestering Agents ; Toll-Like Receptor 4*

OBJECTIVEGastric cancer cells are insensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). To sensitize gastric cancer cells to TRAIL, we treated gastric cancer MGC803 cells with TRAIL and cisplatin.

METHODSCell proliferation was measured using MTT assay. Cell apoptosis was determined by flow cytometry. Expression of proteins was analyzed by Western blot. The distribution of lipid rafts and death receptors was analyzed by immunofluorescence microscopy. MGC803 cells were pretreated with 50 mg/L nystatin for 1 h, and followed by the treatment of cisplatin and TRAIL.

RESULTS100 µg/L TRAIL resulted in (8.51 ± 3.45)% inhibition of cell proliferation and caused (3.26 ± 0.89)% cell apoptosis in MGC803 cells. Compared with the treatment with cisplatin alone, treatment with TRAIL (100 µg/L) and cisplatin (8.49 mg/L, IC(50) dose of 24 h) led to a dramatic increase in both inhibition of cell proliferation [(52.58 ± 4.57)% vs. (76.43 ± 5.35)%, P < 0.05] and cell apoptosis [(23.10 ± 3.41)% vs. (42.56 ± 4.11)%, P < 0.05]. Moreover, cleavage of caspase-8 and caspase-3 was detected. TRAIL (100 µg/L) did not induce obvious lipid rafts aggregation and death receptor 4 (DR4) clustering, while cisplatin (8.49 mg/L) significantly promoted the localization of DR4 in aggregated lipid rafts. Pretreatment with 50 mg/L nystatin, a cholesterol-sequestering agent, triggered (3.66 ± 0.52)% cell apoptosis after 24 h. Pretreatment with nystatin for 1 h before the addition of 8.49 mg/L cisplatin for 24 h caused a decreased tendency to cell apoptosis [(25.74 ± 3.28)% vs. (22.76 ± 2.97)%]. While, pretreatment with nystatin before the addition of cisplatin and TRAIL, the proportion of apoptotic cells decreased from (43.16 ± 4.26)% to (31.52 ± 3.99)% (P < 0.05).

CONCLUSIONCisplatin enhances TRAIL-induced apoptosis in gastric cancer MGC803 cells through clustering death receptors into lipid rafts.

Antineoplastic Agents ; administration & dosage ; pharmacology ; Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Caspase 8 ; metabolism ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cisplatin ; administration & dosage ; pharmacology ; Dose-Response Relationship, Drug ; Humans ; Membrane Microdomains ; metabolism ; Nystatin ; pharmacology ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; metabolism ; Stomach Neoplasms ; metabolism ; pathology ; TNF-Related Apoptosis-Inducing Ligand ; pharmacology

Plasma cell cheilitis is a rare, idiopathic, benign inflammatory disease of lips, characterized by dense plasma cell infiltrates in the upper dermis. It presents as erythematous patches with erosion usually on the lower lip of elderly people. Although, various therapeutic options, including topical steroids, intralesional injection of glucocorticoids, oral nystatin and topical antibiotics have been tried, none of them is promising. A 68-year-old woman presented with a 4-month history of erosive patches with crusts on her lower lip, which was resistant to topical corticosteroids. A histopathologic examination revealed dense inflammatory cell infiltration mainly consisting of plasma cells in the dermis, consistent with plasma cell cheilitis. She was treated with topical pimecrolimus and after 2 weeks of application, the lesion started to get better. After 7 weeks it had almost disappeared. Herein, we present a case of plasma cell cheilitis treated with topical application of pimecrolimus.
Adrenal Cortex Hormones ; Aged ; Anti-Bacterial Agents ; Cheilitis ; Dermis ; Female ; Glucocorticoids ; Humans ; Injections, Intralesional ; Lip ; Nystatin ; Plasma ; Plasma Cells ; Steroids ; Tacrolimus

The antibacterial and antifungal activities of three schiff bases were evaluated against some pathogenic bacteria and fungi. Parallel experiments were also carried out with standard drugs (Kanamycin for bacteria and Nystatin for fungi). Two compounds [N-(1-phenyl-2-hydroxy-2phenylethylidine)-2',4' dinitrophenyl hydrazine, abbreviated as PDH and N-(2-hydroxy benzylidine)-2'-hydroxy imine, abbreviated as HHP] showed significant antimicrobial activities. The rest one [N-(1-phenyl 2-hydroxy-2 phenyl ethylidine) 2'-hydroxy phenyl imine, abbreviated as PHP] showed moderate activity. All these three compounds were found to possess pronounced cytotoxic effect. These compounds can be considered as potent antimicrobial agents.
Aldehydes ; Anti-Infective Agents ; Bacteria ; Benzoin ; Fungi ; Hydrazines ; Nystatin ; Schiff Bases

OBJECTIVETo understand whether there were any differences of sensitivity to antifungals between the species of Saccharomyces (Candidas) isolated from oral cavity in the patients with oral candidosis and healthy volunteers. Observing the effect of nystatin topically used and discussing preliminarily the relationship between MIC and clinical effect in order to offer reference for clinical treatment.

METHODSThe experiment was carried on 61 patients with candidosis in experimental group and 43 healthy volunteers in control group and isolates of Saccharomyces were obtained by the oral rinse technical method. To isolate and identify Saccharomyces in oral cavity by CHROMagar Saccharomyces culture medium and test the MIC of several antifungal agents such as nystatin, ketoconazole and fluconazole against Saccharomyces by NCCLSM27-A microdilution assay. 31 patients in experimental group were administered with nystatin, observing the clinical effect a week later and comparing the results with the MIC.

RESULTS(1) The incidence of Saccharomyces was 78.69% and 30.23% in experimental group and control group respectively. The proportion of Saccharomyces albicans was 80.70% (experimental group) and 92.31% (control group). (2) There was no significant difference between the susceptibility of Saccharomyces albicans to fluconazole and ketoconazole (P > 0.05), but the MIC data of azole antifungals were lower than nystatin. (3) The susceptibility of Saccharomyces albicans to fluconazole, ketoconazole and nystatin was 95.65%, 80.43%, and 89.13%, and a few isolates were resistent to antifungal agents. (4) The effectiveness of nystatin was 87.10%, and there were a few cases which MIC differs from the clinical effect.

CONCLUSIONAt present, the resistance of Saccharomyces in patients with oral fungal infection is not significant, most Saccharomyces albicans are sensitive to fluconazole, ketoconazole and nystatin. The MIC of fluconazole and ketoconazole are lower than nystatin, implying when the clinical effect of nystain is poor, to use an azole antifungal is optional. The MIC is relative to therapeutic effect to some degree, but it is not consistent completely.

Antifungal Agents ; Candida albicans ; Candidiasis, Oral ; Fluconazole ; Humans ; Ketoconazole ; Nystatin ; Saccharomyces

BACKGROUND: We wanted to investigate the effect of infectious complications on the outcome of patients who received allogeneic hematopoietic stem cell transplantation (HSCT), and we determined the risk factors for predicting infectious complication and the mortality in allogeneic HSCT recipients. METHODS: We enrolled all the patients who underwent allogeneic HSCT at Samsung Medical Center from February 1996 to October 2003. RESULTS: A total of 139 patients were enrolled. A total of 450 infectious episodes were observed in 131 allogeneic recipients (90.8%). Infectious complications occurred in the allogeneic recipients [3.243.00 episodes/patient]. Microbiologically documented infection (MDI), clinically documented infection (CDI), and unknown fever (UF) accounted for 41.6%, 34.0% and 24.4%, respectively, of the total infections. Pneumonia (15.1%) was the most common infection. Among the 187 MDIs, bacterial infection, viral infection and fungal infection accounted for 50.3%, 39.6%, and 7.5%, respectively. Twelve of 24 deaths in the late post-transplantation period were related with infection. The statistically significant risk factors for infection related to mortality, by multivariate analysis, were the underlying disease risk, the duration of neutropenia, the failure of stem cell engraftment, acute GVHD, MDI, UF, the number of infectious episodes, bacteremia, fungemia, pneumonia, genitourinary tract infections, S. aureus, E. coli, Pseudomonas spp., Aspergillus spp., Non-albicans candida and CMV diseases. CONCLUSIONS: The incidence of fungal infections was still low in our institute, even though prophylaxis for fungal infections was not applied, except for gargling with nystatin. In addition, most of them were non-albican Candida and Aspergillus species. Therefore, routine fluconazole prophylaxis may not be needed in our institute.
Aspergillus ; Bacteremia ; Bacterial Infections ; Candida ; Fever ; Fluconazole ; Fungemia ; Hematopoietic Stem Cell Transplantation* ; Hematopoietic Stem Cells* ; Humans ; Incidence ; Mortality ; Multivariate Analysis ; Neutropenia ; Nystatin ; Pneumonia ; Pseudomonas ; Risk Factors ; Stem Cells