Cefixime

Limits on what this shows

• Negative or null findings: No respirometry, membrane potential or mitochondrial study with cefixime found.
• At-risk subgroups: Not defined.
• Counter-evidence on record: Beta-lactams as a class differ widely in structure and exposure; the study does not say which were tested.

Direction

Excess exposure toxicity at class level (drug toxicity, not a nutrient deficiency; Hard Rule 2).

Regulatory status

Not addressed in either label read [1][2].

Population evidence

CLASS EXTRAPOLATION, Tier C: Kalghatgi 2013 [23] (cell culture and mice; abstract read as a reconstructed OpenAlex record): quinolones, aminoglycosides and beta-lactams caused mitochondrial dysfunction and reactive oxygen species overproduction in mammalian cells. Cohort test: cefixime is not named in the abstract, keywords or record, and the full text was not opened, so cefixime is treated as not in the cohort. PubMed "cefixime mitochondria" returned 0 results on the HTML results page [29].

Mechanism

Class-level proposal: bactericidal antibiotic exposure of mitochondria. Not shown for cefixime.

Boundary

Class extrapolation only; no cefixime data. Shares its source with the oxidative stress entry (see the overlap map).

Counter-evidence held on record

No evidence that cefixime changes human mitochondrial function; no supplement is implied.

Limits on what this shows

• Negative or null findings: PubMed "cefixime oxidative stress" returned 3 records: Maliar 2024; a Salmonella macrophage paper in which cefixime was combined with a loxapine derivative and ROS was reported for the derivative, not for cefixime alone; and a vitamin E supplementation trial in women with urinary tract infection in which both groups received cefixime 400 mg per day for 3 days and no redox marker was reported [29].
• At-risk subgroups: Not defined.
• Counter-evidence on record: The two sources point in opposite directions and neither measures a biological redox marker after cefixime. Beta-lactams differ widely in structure; the class study does not say which were tested.

Direction

Reverse-direction (protective) in vitro chemistry for cefixime; excess oxidant load at class level (drug toxicity). Neither is an antioxidant nutrient deficiency (Hard Rule 2).

Regulatory status

Not addressed in either label read [1][2].

Population evidence

Tier B, Maliar 2024 [22] (cell-free chemical assay; text read through a summarizing fetch tool): 18 prescribed antibiotics tested in a modified DPPH/FRAP microplate method at 8 to 4096 micromolar; cefixime is one of six antibiotics (with doxycycline, tigecycline, rifampicin, tebipenem and cefuroxime) described as showing detectable antioxidant potential; no cefixime-specific DPPH50, FRAP50 or PABI value was in the readable text (the values are in Table 1, shown only as an image), and the authors note the assays do not fully mimic physiological conditions. CLASS EXTRAPOLATION, Tier C: Kalghatgi 2013 [23] (cell culture and mice; abstract read as a reconstructed OpenAlex record): quinolones, aminoglycosides and beta-lactams at clinically relevant doses caused mitochondrial dysfunction and excess reactive oxygen species in mammalian cells, with oxidative stress markers in treated mice reduced by N-acetyl-L-cysteine. Cohort test: only classes are named, cefixime is not named, so cefixime is treated as not in the cohort.

Mechanism

Chemical radical-scavenging reactivity in the cell-free assay; class-level reactive oxygen species generation in cells. Neither is shown for cefixime in a biological system.

Boundary

Mechanistic and class extrapolation only. The class source is shared with the mitochondrial burden entry (see the overlap map).

Counter-evidence held on record

No evidence that cefixime changes oxidative stress or antioxidant nutrient needs in people; no antioxidant supplement is supported.

Limits on what this shows

• Negative or null findings: PubMed "cefixime copper" returned 13 records, all seen (repair pass): the two complex papers above plus wastewater photocatalysis and nanoparticle chemistry, a copper corrosion paper, analytical chemistry and bacterial copper-nanoparticle microbiology; none concerned host copper status. "cefixime ceruloplasmin" and "cefixime serum copper" each returned 0 records [29]. Neither label has copper text [1][2].
• At-risk subgroups: Not defined.
• Counter-evidence on record: The two papers disagree on direction for antibacterial activity (lower with complexes in Arayne, higher in Umekar); both are solvent-phase synthesis, and Umekar's characterization has internal inconsistencies (differing spectral ranges and an unusual silver salt formula noted by the summarizer). Laboratory complexes made over a week in ethanol say little about the stomach or small intestine. The copper-complex yield, purity and identity were not independently checked here.

Direction

If anything, copper (a metal ion) binding the drug (Hard Rule 4), which is a drug-activity or timing question and not a copper loss. No depletion of copper is shown or implied. Not a copper deficiency.

Regulatory status

No copper, zinc or other mineral interaction text in either label read; iron oxide appears only as a capsule colorant [1][2].

Population evidence

Tier B, Arayne 2002 [30] (abstract only, read as an OpenAlex record through a summarizing fetch tool; numeric MICs not retrieved): cefixime copper, zinc and cadmium complexes were prepared and compared with free cefixime by serial-dilution MIC and disk-diffusion zones against Staphylococcus aureus, Escherichia coli, Klebsiella and Proteus; the authors concluded complex formation lowered antimicrobial activity (MIC values rose). Tier B, Umekar 2021 [31] (open-access article page read through a summarizing fetch tool): copper chloride (1 mmol) in hot absolute ethanol was mixed with cefixime (2 mmol) and stirred at room temperature for a week; the precipitate was characterized by UV, FTIR and proton NMR; the missing NMR singlet near 11 to 12 ppm offered as evidence of binding was reported for the palladium, silver and zinc complexes and was not reported for copper in the text relayed; no stoichiometry or stability constant was measured; the paper reports that the metal complexes inhibited bacteria more than cefixime did. Cohort test: both papers use cefixime itself as the ligand. Neither used a person, an animal, a cell line or a physiological fluid, and neither measured copper absorption, serum copper or ceruloplasmin.

Mechanism

Named, in outline only: coordination of copper(II) by the cefixime molecule (mechanism class A, absorption interference by chelation). Whether cefixime binds copper in gut fluid, competes with dietary ligands or changes copper absorption has not been tested in anything read.

Boundary and why not higher

Yellow because real Tier B mechanistic work on this drug and copper exists, and the skill rule bars ungraded when any Tier B source exists; it stays yellow because nothing was measured in a biological system. Orange would need a human or animal study of serum copper, ceruloplasmin or copper absorption with cefixime. Kept independent of Iron (Hard Rule 7); the Umekar metal list does not include iron.

Counter-evidence held on record

A laboratory chemistry signal, not a copper deficiency and not a reason to take copper. No copper supplement is recommended or implied; the label gives no mineral separation interval, so none is stated.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or Tier C evidence that cefixime changes iron status or absorption, or that iron changes cefixime exposure, and no circulating claim about cefixime and iron found. Two chemistry items were opened and judged not to be Tier B evidence for iron (an editor may revisit this call): the Umekar 2021 cefixime metal-complex paper [31] lists cadmium, silver, palladium, zinc, nickel and copper and does not include iron; and an analytical spectrophotometric method [32] in which cefixime reduces ferric chloride to ferrous iron at 70 degrees C in a bipyridyl reagent mixture (a reagent reaction without stoichiometry or physiological medium, and with internal inconsistencies in the paper, not a study of dietary iron or iron status). The beta-lactam iron effect in the literature involves other cephalosporins (the Wiesner Table 1 mineral-supplement entries are for cefalexin and cefdinir, not cefixime [21]) and does not transfer to cefixime. Iron oxide and ferrosoferric oxide appear in the labels only as capsule colorants. The class-level hemolytic anemia text and the case report are graded under oxygen delivery and are not iron evidence.

Direction

Not determined.

Channels tried

PubMed "cefixime iron" (11 records, all shown: photocatalysis and nanoparticle chemistry, two Ugandan sexually transmitted disease trials in which iron-folate was a control-arm treatment, a case report and a prescribing profile; none measured iron in anyone given cefixime) [29]; PubMed "cefixime anemia" (17 records, none about iron status) and "cefixime ferritin" (1 record, PMID 32745608, an anaphylaxis case in a COVID-19 patient indexed with ferritin and cefixime adverse effect tags; abstract not seen, not an iron-cefixime study) [29]; both labels (no iron interaction text) [1][2]; Wiesner 2024 Table 1 (no iron row for cefixime) [21]; Drugs.com food-interaction page (no known food or alcohol interactions) and interaction index (no iron or ferrous entry) [28]; Wikipedia (no claim) [4]. Repair pass 2026-10-10: PubMed "cefixime ferrous sulfate" (0 results), "cefixime serum iron" (0 results), "cefixime iron absorption" (2 records: a TiO2 photocatalysis paper and a Fe@Au nanoparticle biosensor, both chemistry) and "cefixime hemoglobin" (4 records: three bacterial-susceptibility papers and one mouse Salmonella study [33], none a person given cefixime with an iron or hemoglobin outcome) [29]; WebSearch phrasings on cefixime with iron, ferrous sulfate, bioavailability, serum iron, ferritin and children returned only cefdinir and cephalexin interaction pages, general iron bioavailability trials (ferrous sulfate formulations, one single-record check confirmed no cefixime mention) and Helicobacter pylori iron-deficiency trials with no cefixime text in the records opened; the Umekar and Pasha chemistry papers above [31][32].

Genuine gap or tooling

Genuine gap after the repair pass: five iron phrasings now return nothing about iron status or absorption with cefixime. Remaining limits: WebSearch was exhausted, PMC and Wiley full texts were not reachable, and the mouse study [33] was read at abstract and metadata level only.

Re-check

Open the full text of the mouse study [33] for a cefixime-only or uninfected cefixime group with hemoglobin, and search a drug-interaction database (Stockley or Micromedex) for a cefixime-iron entry when licensed access exists. "cefixime ferritin" (1 record, not relevant), "cefixime ferrous sulfate" and "cefixime serum iron" are done.

Counter-evidence held on record

A disclosed gap, not a finding of no effect and not a reason to take iron.

Limits on what this shows

• Null and weakening findings: No pseudomembranous colitis in 51 volunteers, shedding returned to 8% by day 50, and stool changes were not significantly linked to toxigenic C. difficile or fecal toxin A [10]. In a pediatric oncology cohort receiving a 5-day cefixime course to prevent irinotecan-associated diarrhea, 3 of 85 patients developed C. difficile infection (no non-cefixime comparison for that outcome in the abstract) [13]. The Miller odds ratio fell from 12.04 at 30 days to 5.01 at 90 days [5], and the posterior probability that cefixime carries a lower odds ratio than cefdinir was about 29% per the Figure 2 legend (so the ranking among later-generation cephalosporins is not firm) [5]. The Levy lower bound is 1.2 [6]. A FAERS descriptive analysis lists diarrhea and clostridium colitis as cefixime's most reported events (no counts in the abstract) [14].
• At-risk subgroups: Not defined for cefixime by the datasets read. Miller adjusted for proton pump inhibitor receipt and comorbidity [5]; label pediatric text says gastrointestinal reaction incidence with the suspension was comparable to adults [1]. Pediatric C. difficile data for cefixime exist only as the single oncology cohort above [13].
• Counter-evidence on record: Both patient datasets are observational and subject to confounding by indication and health care exposure (Hard Rule 6); the volunteer studies remove confounding by indication but are small, culture-based and abstract-level. Chachaty 1992 and 1993 are from one laboratory, and the 1993 paper says it confirms earlier preliminary findings, so the two are counted as one laboratory's contribution [9][10]. Finegold 1987 had an active comparator (cefaclor), not a placebo [7].

Direction

Disturbance and infection risk (an outcome entry with a direct composition arm). Not a nutrient deficiency. No probiotic or supplement is implied. The named mechanism is loss of colonization resistance from antibiotic exposure of the gut flora.

Regulatory status

Both labels: CDAD "has been reported with use of nearly all antibacterial agents, including cefixime, and may range in severity from mild diarrhea to fatal colitis"; one label adds "CDAD has been reported to occur over two months after the administration of antibacterial agents" [2]. Superinfection and colitis appear only in the cephalosporin-class adverse reaction list [1][2]. Adult tablet trials: diarrhea 16%, loose or frequent stools 6% [1].

Population evidence: Miller 2023 [5]

Matched case-control study in the Merative MarketScan claims databases (Commercial, Medicare, Multi-State Medicaid), 159,404 community-associated CDI cases and 797,020 controls (5 per case), exposure in the 30 days before the index date, conditional logistic regression adjusted for other antibiotics, Elixhauser comorbidities, proton pump inhibitor receipt within 90 days and health care visits in the prior 90 days. Cefixime (a third-generation cephalosporin): 243 exposed cases versus 79 exposed controls, unadjusted OR 15.4, adjusted OR 12.04 (95% CI 8.84 to 16.38; the table caption says credible intervals). The 90-day window gave 5.01 (95% CI 4.03 to 6.22) [5]. For scale only (other drugs, not evidence for cefixime): cefdinir 11.02, cefuroxime 9.59, cefpodoxime 9.17, cephalexin 2.88 in the same table. The cefixime row was read on the publisher article page in two separate fetches (both through a summarizing tool) and agreed; the supplementary tables were not read. The Table 2 column headers (181,041 cases, 905,205 controls) are exposure counts per the summarizer and differ from the study totals; neither pair enters any calculation here.

Population evidence: Levy 2000 [6]

Retrospective cohort with a nested case-control analysis in four UnitedHealth Group-affiliated health plans, 1 January 1992 to 31 December 1994; 358,389 ambulatory enrollees, C. difficile diarrhea prevalence 12 per 100,000 person-years; cases confirmed on medical-record review; eligibility limited to people tested for C. difficile and exposed to one antibiotic. After controlling for other risk factors, only two antibiotics were associated with C. difficile diarrhea: cephalexin (OR 7.5, 95% CI 1.8 to 34.7) and cefixime (OR 6.4, 95% CI 1.2 to 39.0). The exposed counts are not in the abstract (record read once, through a summarizing tool; a second record had no abstract text). The authors note testing was more common with high-risk antibiotics and that the disease may be underdiagnosed.

Population evidence: volunteer stool studies [7][8][9][10]

Chachaty 1993 [10]: 51 healthy volunteers, cefixime 200 mg twice daily for 8 days; Enterobacteriaceae fell from 6.9 to 3.9 log CFU/g (P under 0.01), enterococci rose from 7.0 to 9.0 log CFU/g (P under 0.01), both recovered by day 50; C. difficile shedding rose from 6% before treatment to 57% at the end (P under 0.01) and was 8% at 50 days; no pseudomembranous colitis; stool changes in 13 (25%) during treatment; read on two records (PubMed and the ASM page, both through summarizing tools) that agreed. Chachaty 1992 [9]: randomized placebo-controlled, 3 groups of 6 healthy adults (cefixime, cefpodoxime proxetil or placebo, 400 mg per day for 10 days); C. difficile detected in 5 of 6 cefixime volunteers and never in placebo; antibiotic activity in the feces of four cefixime volunteers. Finegold 1987 [7]: 12 healthy young men, 6 on cefixime 400 mg once daily for 2 weeks (6 on cefaclor); in the cefixime arm Enterobacteriaceae usually decreased (E. coli decrease significant), clostridia and sometimes bifidobacteria decreased, group D streptococci rose 3 logs or more in 4 subjects, and C. difficile newly appeared in 4 subjects. Nord 1988 [8]: 10 healthy volunteers, cefixime 200 mg twice daily for 7 days; streptococci and E. coli decreased, enterococci increased, anaerobic cocci, clostridia and bacteroides were suppressed, C. difficile was isolated in 5 on day 7 (cytotoxin in 1), and the flora normalized within 2 weeks (summary of a truncated abstract).

Cohort test

Cefixime is named in Miller 2023 (table row) and Levy 2000 (abstract) among patient datasets, and is the studied drug in [7][8][10] and one of two active drugs in [9]. It is not named in Baxter 2007 [25] (abstract lists cefuroxime, cefpodoxime, ceftriaxone and others), Webb 2020 [26] (tables name cefazolin, cefdinir, cefepime, cefoxitin, ceftriaxone, cefuroxime, cephalexin; supplement not seen) or Zhang 2022 [27] (cefdinir, cefuroxime, cephalexin). Those three are excluded cohorts for cefixime and are not used as evidence.

Mechanism

Named: suppression of susceptible aerobes and anaerobes with overgrowth of resistant enterococci and, in vulnerable hosts, C. difficile. Only 40% to 50% of an oral dose is absorbed [1], and cefixime was detected in stool in 8 of 10 volunteers on day 7 [8] and antibiotic activity in the feces of 4 of 6 cefixime volunteers [9]; fecal antibiotic activity was linked to stool changes (8 of 18 with activity versus 5 of 33 without, P under 0.05) and inversely to fecal beta-lactamase [9][10]. The review of oral antibiotics for urinary tract infection notes that oral cephalosporins, cefixime among them, reduce Enterobacteriaceae and increase enterococci with C. difficile colonization [11] (narrative review, Tier C, context only). Two mouse studies of cefixime-induced gut microbiota change exist [12] (titles and keywords only; abstracts not retrieved).

Why red

Six Tier A sources with cefixime in the cohort: two independent patient datasets (different decades, health systems and case definitions) and four volunteer stool studies from three laboratories (Finegold, Nord, and Chachaty with two reports), consistent direction, a named mechanism, an effect large enough to matter (adjusted OR 12.04 with a lower bound of 8.84 in claims data; shedding 6% to 57% in 51 volunteers) and no Tier A source pointing the other way (excluded cohorts do not name cefixime and do not contradict). The category (gut flora) is measured directly in the volunteer studies, not inferred from an outcome. The grade attributes a disturbance and infection risk to the drug; it is not a deficiency claim.

Boundary and next step

Applies to adults and healthy volunteers and to the infection and flora-disturbance findings in the datasets named (30-day claims window, with the estimate falling at 90 days; 7 to 14 day volunteer courses). Advance to only after an editor opens the full texts to confirm the Levy exposed counts, the Miller supplementary windows, and the Nord 1988 and Finegold 1987 numeric results. customerVisible is never assigned here.

Counter-evidence held on record

This is an infection and disturbance risk, not a nutrient deficiency. No probiotic, prebiotic or supplement recommendation is made or implied. Diarrhea during or after antibiotic use, including weeks later, should be evaluated for C. difficile by a clinician.

Limits on what this shows

• Negative or null findings: PubMed "cefixime anemia" returned 17 records: one cefixime hemolysis case (Kaya), four case reports in which anemia was present but not attributed to cefixime, two cohorts of sickle cell disease patients on cefixime with no hemoglobin outcome, and laboratory or microbiology papers [29]. No cefixime cohort or trial reports a hemoglobin change. Repair pass: PubMed "cefixime hemoglobin" returned 4 records, none a person given cefixime with a hemoglobin outcome (bacterial susceptibility testing in three; one mouse Salmonella study [33] in which cefixime was a comparator treatment and the reported hemoglobin decrease was tied to the untreated infected group, not to cefixime; full text not opened) [29].
• At-risk subgroups: Not defined by the evidence beyond the single pediatric case; renal impairment prolongs half-life (label) [1].
• Counter-evidence on record: One case cannot give an incidence; the label list is class-wide without cefixime denominators; the case report was not read beyond metadata.

Direction

Adverse drug reaction (immune red-cell destruction in the case). Not a nutrient deficiency, not iron deficiency, not B12 and not a drug-intended effect (Hard Rule 2).

Regulatory status

Section 6.2, "Adverse Reactions Reported for Cephalosporin-class Drugs": "Allergic reactions, superinfection, renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, and colitis," with no cefixime-specific incidence; cefixime hemic and lymphatic reactions listed are transient thrombocytopenia, leukopenia, neutropenia, prolongation in prothrombin time, elevated LDH, pancytopenia, agranulocytosis and eosinophilia. Decreased hemoglobin and hematocrit were not found in the label text as relayed by the summaries. Section 7.3: "A false positive direct Coombs test has been reported during treatment with other cephalosporins" [1][2].

Population evidence

Tier B case report, Kaya 2018 [18]: autoimmune hemolytic anemia, erythrophagocytosis and liver dysfunction after cefixime for a urinary tract infection in a child (correspondence in the Indian Journal of Hematology and Blood Transfusion; keywords include cold agglutinin disease and fresh frozen plasma infusion; parental consent noted). Only metadata and keywords were seen; the age, hemoglobin values, antibody findings and outcome are behind a paywall and are not claimed here. A FAERS analysis of third-generation cephalosporins lists diarrhea and clostridium colitis as cefixime's most reported events and mentions drug-induced immune hemolytic anemia only for the class [14].

Mechanism

Named in outline for the case: drug-induced immune hemolysis. No mechanism for a hemoglobin change with cefixime is given in anything read.

Boundary and why not higher

Orange would need a hemoglobin or hemolysis incidence for cefixime against a comparator. Oxygen delivery is kept independent of ATP production and of iron (Hard Rule 7).

Counter-evidence held on record

A laboratory and allergic-type adverse reaction flag for clinicians. It says nothing about iron, B12 or intake, and no supplement is indicated.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or Tier C source measuring ATP, respiration or energy output with cefixime was opened, and no circulating claim about cefixime and energy was found. The class mitochondrial study [23] reports mitochondrial dysfunction in general terms and does not name cefixime; it is graded under mitochondrial burden and kept separate from ATP production (Hard Rule 7).

Direction

Not determined.

Channels tried

PubMed "cefixime ATP" (2 records: a Haemophilus influenzae genome and susceptibility paper, and a rat study of neural modulation of cephalexin and cefixime intestinal absorption; neither measured ATP or energy output after cefixime) "cefixime respiration" (2 records, both bacterial: an E. coli biofilm metabolism paper and an electrochemical bacterial respiration assay for susceptibility testing; no human, animal or mammalian cell respiration) and "cefixime mitochondria" (0 results on the HTML page) [29]; "cefixime mitochondrial" in the export format failed twice with a fetch error (the same behavior seen for the confirmed zero-result "mitochondria" query, so probably zero, not confirmed) [29]; the "cefixime oxidative stress" listing (3 records, none about cellular energy) [29]; both labels (no energy text) [1][2]; Drugs.com and Wikipedia (no claim) [28][4]. Repair pass 2026-10-10: PubMed "cefixime bioenergetics" (10 records, all read at title and snippet level: a quantum-dot fluorescence sensor, gonococcal resistance and proteomics papers, wastewater and photocatalysis chemistry, a mouse dysbiosis study with tea polyphenols after cefixime, Caco-2 and bovine serum albumin binding studies, and a 1992 E. coli filamentation paper; none measured ATP, respiration or mitochondrial function after cefixime), "cefixime membrane potential" (18 results; the 10 on page 1 were drug-delivery, effluent-treatment, rat intestinal and renal brush-border transport, and bacterial combination papers, none mammalian mitochondrial membrane potential; 8 not seen) and "cefixime reactive oxygen species" (7 records, all bacterial, environmental or neutrophil-killing papers) [29]; WebSearch phrasings on cefixime with mitochondrial function, ATP levels, oxidative phosphorylation, hepatocytes and rats returned sepsis-mitochondria papers and other cephalosporins (cefepime in infected rats, cephaloridine, cephalothin, cefotiam and cefotaxime in rats), none with cefixime, so none was used.

Genuine gap or tooling

Probable genuine gap. Repair pass 2026-10-10 ran "cefixime bioenergetics", "cefixime membrane potential" and "cefixime reactive oxygen species" (details under Channels tried). Remaining limits: the Kalghatgi 2013 full text was not opened to see which beta-lactams were tested (three PMC attempts returned browser-check pages), "cefixime oxidative phosphorylation" returned a browser-check page, "cefixime mitochondrial" in the export format errored again, page 2 of "cefixime membrane potential" was not seen, and WebSearch was exhausted.

Re-check

Open the Kalghatgi 2013 full text or supplement; re-run "cefixime oxidative phosphorylation" and page 2 of "cefixime membrane potential" when access allows.

Counter-evidence held on record

A disclosed gap, not a finding of no effect. The claim that antibiotics lower energy has no cefixime-specific support.