Nystatin

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C source was opened that supports even a yellow grade, and no circulating claim of nystatin mitochondrial damage was found to rebut. This is a disclosed gap, not a finding of safety. Re-check PubMed and Europe PMC when access is restored; the specific lead is mammalian-cell nystatin studies that measured mitochondrial membrane potential or respiration (label any such tool use as mechanism, not a clinical finding).

What was searched

Web search "nystatin mitochondrial membrane potential reactive oxygen species mammalian cells cytotoxicity in vitro" returned the Wikipedia nystatin page and figure pages for unrelated compounds (for example beta-sitosterol, statin hepatocyte papers) and no nystatin mitochondria record. A second phrasing ("nystatin mitochondrial toxicity OR mitochondrial respiration OR oxidative phosphorylation ...") was not performed because the shared web-search budget was exhausted. A PubMed listing for "nystatin mitochondria" returned 429 and the fetch tool asked not to retry. The Crossref title search returned 429 (same instruction). The OpenAlex search endpoint errored.

Repair search (2026-10-09)

WebSearch refused all three planned queries (mammalian ATP leakage and K+ efflux; nystatin-permeabilized cells in respiration assays; iron and copper in fungal context) because the shared search budget was used up. PubMed listings ("nystatin ATP potassium erythrocytes"; "nystatin mitochondria") returned 429 with a do-not-refetch instruction; the Europe PMC REST search returned 429 twice; OpenAlex search and filter endpoints errored; Semantic Scholar errored; Springer, MDPI and PLOS site searches and ScienceDirect topic pages are robots-disallowed. Crossref bibliographic searches worked intermittently: "nystatin mitochondria oxidative phosphorylation" returned only generic oxidative phosphorylation chapters and no nystatin record. The one Crossref hit on nystatin and mammalian cells that was opened, Fisher and Bryson 1977 [28], reports toxicity by chromium-51 release and cell survival, not mitochondrial endpoints. Nystatin used as a permeabilizing tool in respiration assays is a research method, not a clinical finding, and no such paper was located or opened.

Channel outcomes

Labels [1][2][3][4][5] and Wikipedia [20] have no mitochondrial content. DrugBank [21] gave mechanism only (the rest is behind sign-in). The PubChem toxicity summary [30] describes pore formation and leakage in fungal cells and no mitochondrial content. Tooling-limited plus a likely thin literature: the lack of results is not a reliable negative.

Limits on what this shows

• Null findings: None located for nystatin in humans. The class review itself reports a null for lipid peroxidation in one species [18].
• At-risk subgroups: None established. The label's renal insufficiency exposure caveat [2] is the only route to systemic exposure, and no redox data exist for it.

Regulatory status

No oxidative stress, antioxidant or lipid peroxidation statement in the labels read [1][2][3][4][5].

Population evidence

None in humans for nystatin. No malondialdehyde, glutathione, antioxidant enzyme or ROS measurement in nystatin users was retrieved. Class source [18]: Mesa-Arango et al., Frontiers in Microbiology 2012, review of amphotericin B. It states "AmB induces oxidative damage in the cells," also that "the role of oxidative damage in the antifungal effect of AmB is still unknown," that lipid peroxidation was not induced in Aspergillus terreus, and that AmB "can also act as an antioxidant." Circulating statement: Wikipedia says nystatin "impacts cell membrane potential and transport by lipid peroxidation" without a primary source that was opened [20].

Mechanism

Plausible only in the fungal cell membrane at the site of drug contact. No systemic mechanism, since the drug is not absorbed [1][2]. Direction: mechanism-only, neither depletion nor excess.

Class cohort test

CLASS EXTRAPOLATION, capped at yellow. Nystatin was NOT in the cohort of [18]; the review covers amphotericin B, with natamycin mentioned only for pore-independent action, and nystatin appears only in a reference title. It is Tier C for this drug. The extrapolation is defensible only as fungal-cell chemistry, not as human redox status.

Counter-evidence held on record

Counter-evidence and confounding Insignificant absorption [1][2] argues against any systemic oxidative effect. The class source is narrative, in fungi, and internally unsettled on whether the drug is pro- or anti-oxidant [18]. Framing caution Not a statement that nystatin lowers antioxidant capacity in people. No antioxidant supplement is implied or recommended.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C source for nystatin and copper, and no circulating copper claim for nystatin found. Kept independent of Iron (Hard Rule 7). Not a finding of safety.

What was searched

Web search "nystatin copper(II) complex OR iron chelation nystatin metal ions binding polyene" returned a polyene-complex patent (title only, not opened), a fluconazole copper/zinc complex paper (opened; nystatin not a test compound, mentioned only for synergy with an unrelated zinc complex) [26], and a kojic acid chelator paper (opened; no nystatin). A general nutrient-depletion search returned only generic depletion articles with no nystatin item. The Antidote Research nystatin page fetch errored. A zinc/nystatin interaction page reported no known interaction (Tier D) [23].

Repair search (2026-10-09)

The planned WebSearch for iron and copper in a fungal context was refused (search budget used up). Crossref bibliographic searches for "nystatin iron copper ferritin serum" and "nystatin Candida iron uptake copper" returned a fetch error and then 429 with a do-not-refetch instruction, so no result list was obtained. The PubChem toxicity summary [30] contains no copper content. No ceruloplasmin or serum copper study in nystatin users was located.

Channel outcomes

Labels read list no copper or mineral interaction. PubMed, Europe PMC, Crossref and PMC were blocked, rate-limited or bot-challenged. Tooling-limited for database searching, with a clean zero on the open-web results actually read.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C evidence and no circulating iron claim found. Any hemoglobin effect would also belong to the Oxygen delivery entry, which is kept separate (see Overlap map). Anemia is an outcome, not a nutrient (Hard Rule 2). Not a finding of safety.

What was searched

Web search "nystatin anemia hemoglobin adverse effect oral nystatin hematologic OR iron deficiency candida gastrointestinal" returned label mirrors and drug-guide pages; the label sections read list no hematologic reaction [1][2][4]. The shared copper/iron chelation search above returned nothing on nystatin and iron. Drugs.com interaction checker [22] and HelloPharmacist [23][24] list no iron interaction. Candida-related GI disease can itself affect nutrition, but no source on that was retrieved.

Repair search (2026-10-09)

Same refused or rate-limited channels as Copper; no ferritin, serum iron or iron absorption study in nystatin users was located. The IVAN nystatin arm [8] was re-opened for the full text: nature.com still shows only the abstract and figure captions behind a subscription preview, and the page lists supplementary tables (clinical characteristics, sequencing, metabolomics, bacterial abundance) that were not accessible and are not stated to report iron indices. The only nystatin and red-cell source opened is the in vitro hemolysis poster [19] already graded under Oxygen delivery/utilization; the 1973 Nature New Biology paper on nystatin-treated human red cells [27] is a research-tool ion-equilibration method and says nothing about iron.

Channel outcomes

Same blocks as Copper. Tooling-limited for database searching; web results read contain nothing on nystatin and iron.

Limits on what this shows

• Null findings: IVAN nystatin arm: no reduction of intestinal Candida and no microbiome remodeling reported [8]. Oral rinse: bacterial alpha diversity stable, "overall, salivary and plaque microbiomes remained stable" [13]. Vaginal: lactobacilli co-occur with yeast in most women before treatment [15].
• At-risk subgroups: Not established. The IVAN nystatin arm was IBD patients and the rinse studies were oral-cavity only, so no subgroup conclusion is drawn for swallowed nystatin.

Regulatory status

Labels list no microbiome statement. Clinical pharmacology: nystatin has "no appreciable activity against bacteria, protozoa, or viruses" [2]. Gastrointestinal adverse reactions listed are diarrhea, nausea, vomiting and GI upset; "well tolerated even with prolonged therapy" [1][4]. Overdosage text: above five million units daily causes nausea and GI upset, with no reports of serious toxic effects or superinfections [4].

Population evidence

IVAN, Pan et al., Nature Medicine 2026 [8]: prospective observational study, 53 patients with mild to moderate Crohn's disease or ulcerative colitis and oral thrush; nystatin (swish-and-spit) n = 18, fluconazole n = 35; 2 weeks of treatment, 8 weeks of follow-up; not randomized. Abstract: "fluconazole, but not nystatin, effectively reduced intestinal Candida burden"; figure titles state fluconazole "but not oral nystatin" was associated with improved disease activity. No nystatin-arm diversity values or p-values were retrievable (abstract page only; full text and supplementary tables paywalled). Press coverage [10][11][12] repeats the same finding and adds nothing independent. Oral rinse study, Zhang et al. [13]: single-arm, 19 of 20 completed, nystatin 600,000 IU four times daily for 7 days, not swallowed; salivary and plaque Shannon diversity unchanged (p = 0.39 and 0.76 at 1 week; 0.87 at 3 months for responders); 16 species differed across visits by ANCOM-BC. Danna et al., Lancet 1991 [14]: 24 elderly inpatients with antibiotic-associated diarrhoea; the 5 with Candida overgrowth who received oral nystatin improved within 7 days with fecal Candida under 10^4 cfu/mL (intended antifungal effect; bacterial composition not reported in the summary read). Vaginal: Drake et al. [15], 93 women randomized to nystatin or miconazole; lactobacilli abundant in 78 of 86 (91%) before treatment, no post-treatment flora comparison by drug in the abstract. Preterm infant RCT [17]: oral nystatin lowered fungal colonization (29.8% vs 56.3%, RR 0.56, 95% CI 0.36 to 0.90); microbiome outcomes not reported.

Mechanism

Present for fungi, absent for bacteria. Direction: reduction of luminal Candida is the drug's intended pharmacologic effect (Hard Rule 2), not a nutrient deficiency. A bacterial effect has no named mechanism because the label records no antibacterial activity [2]. Any effect on the sterol-dependent fungal community could in principle alter cross-kingdom interactions, which is exactly what [8] reports for fluconazole but not for nystatin.

Class cohort test

No class extrapolation is used. All cited human data include nystatin itself, but only as mouthwash [8][13], oral therapy in 5 patients [14], vaginal pessary [15] or neonatal oral suspension [17]. None is a swallowed-tablet microbiome study.

Counter-evidence held on record

Counter-evidence and confounding Confounding by indication is presumed: patients with candidiasis, IBD, antibiotic exposure or prematurity have altered microbiota independent of any antifungal. The IVAN design was non-randomized with unequal arms (18 vs 35), the nystatin arm was a comparator rather than an untreated control, and a mouthwash that is spat out is not equivalent to swallowed tablets. A single-arm unpublished Thai study claims lower urinary indican on nystatin but measured no bacteria [25] (see Fails verification). Framing caution This is a context flag, not a depletion claim. Lower fungal load is the intended effect. Do not infer bacterial dysbiosis or any nutrient loss, and do not recommend a probiotic from this entry.

Limits on what this shows

• Null findings: No hematologic adverse reaction in the label sections read [1][2][4]. The neonatal RCT [17] reported no nystatin-related adverse drug reactions, but its definition covered only vomiting, diarrhea and allergy, and it measured no hemoglobin.
• At-risk subgroups: Hypothetically, patients with renal insufficiency on oral forms [2]. Not evidenced.

Regulatory status

Adverse reactions in the labels read are oral irritation, sensitization, GI effects, rash, urticaria, very rarely Stevens-Johnson syndrome, and rarely tachycardia, bronchospasm, facial swelling and myalgia. No anemia, hemolysis or other hematologic reaction is listed [1][2][4].

Population evidence

None in humans. Tier B in vitro source [19]: Knopik-Skrocka et al., poster abstract, 2007. Nystatin, "a known hemolytic agent," was tested on human, pig and horse erythrocytes; in isotonic KCl the cells were about 30 times more resistant to nystatin than to amphotericin B, and disaccharide media raised resistance to nystatin about 3-fold. Concentrations, species-level results and sample sizes were not in the page read.

Mechanism

Present in vitro: polyene pore formation in cholesterol-containing membranes. Absent in practice for oral or topical dosing, since nystatin is not absorbed [1][5]. The label's renal insufficiency statement [2] is the only route to measurable plasma levels, and no hemolysis data exist for it. Direction: potential cell-membrane toxicity, not a nutrient shortfall. Hard Rule 2: neither anemia nor hemolysis is filed as an oxygen-delivery deficiency here, and neither has been reported for nystatin in the sources read.

Class cohort test

Nystatin is the drug tested in [19]; no class extrapolation is used. The amphotericin B comparison in [19] is a comparator only.

Counter-evidence held on record

Counter-evidence and confounding The source is a meeting poster abstract, not a peer-reviewed paper, and in vitro hemolysis requires direct exposure of red cells. Oral dosing does not provide that. Framing caution Do not read this as a risk of anemia or low oxygen-carrying capacity from oral or topical nystatin. It is a mechanistic note kept for completeness.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C evidence opened and no circulating ATP claim found. This is a disclosed gap, not a finding of safety, and a priority for a re-check with working database access. Kept independent of Mitochondrial burden and Oxygen delivery/utilization (Hard Rule 7).

What was searched

Web search "nystatin ATP intracellular levels depletion cells nystatin treatment ATP content" was not performed because the shared web-search budget was exhausted. The erythrocyte poster [19] was checked and does not mention ATP. Labels, Wikipedia and DrugBank mechanism text have no ATP content. PubMed listing 429 (no retry per fetch tool).

Repair search (2026-10-09)

WebSearch for nystatin ATP leakage and K+ efflux in mammalian and erythrocyte membranes was refused (search budget used up). Crossref bibliographic searches "nystatin ATP depletion mammalian cells" and "nystatin red cells sodium potassium ATP" returned lists with no nystatin ATP study: the nystatin items were Fisher and Bryson 1977 [28] (toxicity by chromium-51 release and survival; ATP and potassium not discussed on the page read) and Aszalos 1975 [29] (nystatin acts synergistically with other antibiotics on Candida but not on CHO or 3T3 cells, measured as DNA synthesis; the abstract page has no ATP or potassium data and the full text was not opened). The 1973 paper on equilibrium dialysis of ions in nystatin-treated human red cells [27] is a research-tool method for altering intracellular ionic strength; its abstract (the only part opened) does not mention ATP, and it is a method, not a clinical finding. PubMed and Europe PMC listings returned 429 with do-not-refetch instructions. The PubChem toxicity summary [30] says potassium and cellular constituents leak from pores in fungal cells and does not address mammalian ATP.

Channel outcomes

Mostly tooling-limited: database discovery was rate-limited, and the mammalian membrane papers that were reachable measured viability, DNA synthesis or chromium release rather than ATP. Mechanistically, pore-mediated leakage in mammalian membranes at high concentrations could in principle lower cellular ATP, but no opened source shows it, so no yellow grade is assigned on inference. No circulating "low energy" claim for nystatin was seen in any page read.