Cefadroxil

Limits on what this shows

• Negative or null findings: Cephalexin, the closest structural analog (cefadroxil differs by one para-hydroxyl group), produced no in vivo respiratory toxicity at the dose that was toxic for cephaloridine [24]. A broader antibiotic-mitochondria respirometry paper was not opened and is not used.
• At-risk subgroups: Not defined. Renal impairment raises cefadroxil exposure (label dosing table) but no mitochondrial consequence was studied. [1]
• Counter-evidence on record: The cephalexin in vivo null result is the nearest direct counter-evidence for a structurally similar agent.

Direction

Possible mitochondrial functional impairment (class level, animal). Not a nutrient deficiency; theoretical for cefadroxil.

Regulatory status

Not addressed in any label opened. [1][5]

Population evidence

CLASS EXTRAPOLATION. Cohort test: cefadroxil was not named in any of the six records returned by a PubMed listing for cephalosporin mitochondrial respiratory toxicity; the drugs studied were cephaloglycin, cephaloridine and cephalexin (and imipenem) [24]. In that literature cephaloglycin cut net succinate uptake by 70% after in vivo and in vitro exposure (JPET 1988), cephaloridine at 300 mg/kg intravenously reduced succinate uptake and respiration while the same dose of cephalexin had no effect (JPET 1990), and cephalexin inhibited succinate uptake only after in vitro exposure. These are abstract-level readings of listing records; the full papers were not opened. A direct PubMed query "cefadroxil mitochondrial" returned zero records. [24][25]

Mechanism

Named for the toxic cephalosporins: inhibition of mitochondrial uptake of anionic substrates such as succinate after renal tubular accumulation. Cefadroxil is a renal tubular secreted anion, so the route of exposure exists, but no study tested its mitochondrial effect. [24][7]

Counter-evidence held on record

Boundary High-dose rabbit studies of two toxic cephalosporins; cefadroxil was not tested. Shares the rabbit evidence with the oxidative stress entry. Framing caution Animal class data from other drugs; it does not describe human mitochondrial function on cefadroxil. Labeled class extrapolation and capped at yellow.

Limits on what this shows

• Negative or null findings: PubMed "cefadroxil oxidative stress" returned zero records and "cefadroxil glutathione" three, only one of which is relevant [25]. Class level (CLASS EXTRAPOLATION, Tier C): in rabbit kidney, cephaloridine and cephaloglycin raised oxidized glutathione (cephaloglycin about one-fifth of cephaloridine) while cephalexin, the closest structural analog tested, did not reduce respiration; cefadroxil was not studied [24].
• At-risk subgroups: Not defined.
• Counter-evidence on record: Cephalexin, the closest analog tested in rabbit kidney, showed no oxidative or respiratory toxicity in vivo [24]. Brain astroglia are not an oral-dosing target tissue.

Direction

Possible reduction of glutathione restoration by uptake competition, in vitro only. Not a nutrient deficiency and not shown in people. A competition effect on a peptide-based glutathione precursor is a transport observation, not an antioxidant-capacity measurement.

Regulatory status

Not addressed in any label opened. [1][5]

Population evidence

None in humans. Tier B: Dringen 1998 [18], rat astroglia-rich primary cultures; after 24 hours without glucose or amino acids, cysteinylglycine (CysGly) could replace cysteine plus glycine for glutathione restoration; captopril (a PepT1 substrate) had almost no effect, whereas alanylalanine and cefadroxil (PepT2 substrates) reduced restoration and high-concentration cefadroxil blocked CysGly utilization almost completely. Concentrations were not retrieved. Read as an OpenAlex abstract paraphrase; a PubMed listing summary of the same record said glutathione "increased", which conflicts with the OpenAlex text and with the study conclusion (PepT2-mediated CysGly uptake); the OpenAlex reading is used and the discrepancy is disclosed. The full paper was not opened.

Mechanism

Named: competitive PepT2 substrate occupancy; PepT2 mRNA was detected in these cultures and cefadroxil is a high-affinity PepT2 substrate (about 100% inhibition of glycylsarcosine uptake in a separate cell study) [18][17].

Counter-evidence held on record

Boundary and overlap Listing-level and abstract-level data only; shares the PepT2 transport observation with the transporter fact in the pharmacokinetic basis and the rabbit class data with the mitochondrial entry (see the overlap map). Framing caution Cell-culture transport competition; it does not describe glutathione status or antioxidant needs in people taking cefadroxil.

Limits on what this shows

• Negative or null findings: The PubMed combined mineral listing (16 records) returned no study of copper status, ceruloplasmin or absorption with cefadroxil. [25]
• At-risk subgroups: Not defined.
• Counter-evidence on record: None; the evidence is chemistry only.

Direction

Metal affects the drug in vitro. There is no evidence for the drug lowering or raising body copper.

Regulatory status

Copper is not mentioned in any label opened. [1][5]

Population evidence

None in humans or animals. Tier B in vitro: Zayed and Abdallah 2004 [20] prepared and characterized cefadroxil complexes with Fe, Co, Ni, Cu and Zn (stability constants about 1.5 x 10^7 to 5 x 10^13, 1:1 and 1:2 metal to ligand; listing-level summary, OpenAlex abstract empty); Sultana and Arayne 2007 [19] tested ten metal chlorides including copper at drug:salt 1:1 against cefadroxil, cephalexin, cefatrizine and cefpirome, reporting antagonism (higher MIC) in many cases without metal-by-drug detail in the abstract.

Mechanism

Chelation chemistry in vitro; physiological relevance not studied.

Counter-evidence held on record

Boundary and overlap Tier B chemistry kept distinct from iron. The same two in vitro papers support the zinc, copper and iron entries and are cross-listed in the overlap map. Framing caution No evidence that cefadroxil changes copper status. Do not infer a need for copper supplementation.

Limits on what this shows

• Negative or null findings: No cefadroxil study of ferritin, hemoglobin response, hepcidin or iron absorption was found in the combined PubMed mineral listing. [25]
• At-risk subgroups: Not defined.
• Counter-evidence on record: None; chemistry only.

Direction

Metal affects the drug in vitro. There is no evidence for the drug lowering or raising body iron. Anemia from immune hemolysis (see oxygen delivery) is a separate adverse outcome and is not iron deficiency.

Regulatory status

Iron appears in the labels only as the colorant ferric oxide in one capsule shell; no iron interaction is stated. [4][5]

Population evidence

None in humans or animals. Tier B in vitro: cefadroxil complexes of Fe (reported as Fe(II) in the OpenAlex keywords) and other d-block metals [20]; ferric iron was one of ten chlorides in the MIC study [19]. The beta-lactam dietary-intervention review [23] was read for cefadroxil mineral rows and listed cefadroxil only in food and beverage studies; the cefdinir-with-iron effect in the cephalexin dossier concerns a third-generation agent and is not used.

Mechanism

Chelation chemistry in vitro; physiological relevance not studied.

Counter-evidence held on record

Boundary and overlap Tier B chemistry only; cross-listed with copper and zinc in the overlap map. Framing caution No evidence that cefadroxil changes iron status. Do not infer a need for iron supplementation, and do not read a low hemoglobin after cefadroxil as iron deficiency.

Limits on what this shows

• Negative or null findings: Adamsson 1997 [14]: 20 healthy volunteers, cefadroxil 500 mg twice daily for 10 days versus phenoxymethylpenicillin 1 g twice daily for 10 days; cefadroxil significantly suppressed aerobic oropharyngeal flora but not anaerobes, faecal aerobic and anaerobic changes were minor, and flora was back to normal about 2 weeks after stopping (abstract only; log counts, C. difficile and resistance data were not visible). The large cohorts that reported CDI for first-generation cephalosporins did not report cefadroxil: Brown 2026 [10] and Zhang 2022 [11] report only cephalexin, and a 506,068-admission Intermountain cohort [12] reports cefazolin (OR 2.3) and cephalexin (OR 2.1) but not cefadroxil; they are Tier C for cefadroxil and were not used for the grade.
• At-risk subgroups: Not stratified for cefadroxil. The labels name no subgroup beyond "all patients" with post-antibiotic diarrhea; the single case report involved prolonged postoperative prophylaxis. Infants aged 1 to 3 months are the only age group with direct flora data. [1][13][15]
• Counter-evidence on record: The faecal result in healthy adults was minor [14]. Confounding by indication and healthcare exposure is presumed in claims data; the Miller authors compare many agents within one framework but the 30-day window estimate is sensitive to the window chosen [9].

Direction

Disturbance and infection risk (an outcome entry). It is not a nutrient deficiency and implies no supplementation or probiotic. Loss of colonization resistance is the named mechanism; the human flora data on cefadroxil itself are sparse.

Regulatory status

US labels: C. difficile-associated diarrhea "has been reported with use of nearly all antibacterial agents", "may range in severity from mild diarrhea to fatal colitis", and "has been reported to occur over two months after the administration of antibacterial agents"; it "must be considered in all patients who present with diarrhea following antibiotic use"; "prolonged use of cefadroxil may result in the overgrowth of nonsusceptible organisms". Diarrhea is listed without a frequency. UK SmPC: diarrhoea is common (1/100 to under 1/10); candidiasis uncommon; for severe and persistent diarrhoea consider pseudomembranous colitis. [1][2][3][5]

Population evidence

Miller 2023 [9]: matched case-control (5 controls per case by age, sex, insurance type and enrollment period) in the MarketScan claims database, 159,404 community-associated CDI cases and 797,020 controls; exposure in the 30 days before diagnosis. Cefadroxil: exposed in 253 cases and 308 controls; unadjusted OR 4.11; adjusted OR 2.84 (95% CI 2.27 to 3.54). For scale in the same table: cefixime 12.04 (8.84 to 16.38); cefadroxil and cephalexin were grouped as first-generation agents with adjusted ORs between 2.15 and 3.58. Read as full text through a summarizing fetch tool. The authors report that estimates shifted with exposure windows of 30 to 180 days. Bennet 2002 [13]: infants aged 1 to 3 months treated with one of eight oral antibiotics (phenoxymethylpenicillin, amoxicillin, pivampicillin, cefaclor, cefadroxil, loracarbef, erythromycin, co-trimoxazole). E. coli increased with penicillins or cephalosporins; enterococci persisted or increased with cephalosporins; Bacteroides, bifidobacteria and lactobacilli were suppressed to undetectable levels in most infants on all agents except phenoxymethylpenicillin and loracarbef. Cefadroxil is not reported separately in the abstract, and group sizes were not retrievable (paywalled). Angerett 2022 [15]: case report (n = 1), C. difficile colitis after extended oral cefadroxil prophylaxis following total knee arthroplasty, followed by multidrug-resistant E. coli bacteremia and periprosthetic joint infection requiring repeated debridement.

Mechanism

Named: suppression of anaerobic colonic flora (Bacteroides, bifidobacteria, lactobacilli) with outgrowth of E. coli, enterococci and, in susceptible people, toxin-producing C. difficile [13]. Not shown for cefadroxil by sequencing.

Why not red

One cefadroxil-specific CDI cohort, one grouped infant flora study without cefadroxil-specific figures, and one small adult volunteer study with minor faecal change. The two flora datasets disagree in size and neither reports C. difficile. Repair pass (attempt to firm the orange with cefadroxil-specific counts): Bennet 2002 was re-read on the Springer page (abstract only; no per-antibiotic infant numbers, no table, full text paywalled), the OpenAlex PMID record was opened again (no abstract; cefadroxil appears only as a keyword) and the PubMed record returned a bot-check page; Adamsson 1997 was located again by Crossref (DOI 10.1007/bf02113603) but its full text is paywalled, so no log counts were retrievable. PubMed "cefadroxil dysbiosis" returned 0 records. The grade is therefore unchanged: orange rests on one cefadroxil-specific CDI case-control estimate, the flora studies add only context. [13][14][28]

Counter-evidence held on record

Boundary in the title The orange grade covers C. difficile infection in a US insured community cohort within 30 days of exposure, not a proven change in the adult gut community and not a nutrient shortfall. The label directs that diarrhea after antibiotic use be evaluated for C. difficile. Framing caution This is an infection and disturbance risk, not a nutrient deficiency. No probiotic or supplement recommendation is made or implied.

Limits on what this shows

• Why no grade: Dual condition met. (1) No Tier B or C source ties cefadroxil or the cephalosporin class to a B-vitamin level; the vitamin-related PubMed records were rat pharmacokinetic work with active vitamin D3 (results not retrieved), a transporter comparator experiment in which folate slightly inhibited uptake of another cephalosporin in vesicles (ceftibuten, 1989; the direction is nutrient to drug and cefadroxil was only a competing substrate), and an unrelated case report. The repair-pass folate query returned two records, both drug-transport work (a 2021 human jejunum Ussing chamber study using cefadroxil as a PEPT1 probe alongside methotrexate, and the 1989 ceftibuten vesicle study); neither measured a folate, B12 or biotin level. (2) No circulating claim about cefadroxil and a named B vitamin was found: Drugs.com lists vitamin B12 among "frequently checked" interactions with no explanatory text, which is not a depletion claim. The infant and adult flora studies [13][14] did not measure vitamins.

Direction

Not determined.

Channels tried

PubMed "cefadroxil vitamin" (6 records, none measuring a vitamin level in people); PubMed "cefadroxil AND (carnitine OR OCTN2 OR pivalate OR pivampicillin)" (4 records); five labels (no B-vitamin text); Drugs.com mtm and interactions pages and RxList. Repair pass: PubMed "cefadroxil folate" (2 records, drug-transport work, see above), PubMed "cefadroxil B12" (0 records), PubMed "cefadroxil biotin" (0 records), and a Crossref bibliographic search for cefadroxil with vitamin B12, folate, biotin and status (20 returned records were general B-vitamin literature, none about cefadroxil). The NIH folate and biotin fact sheets were not opened in this review. [25][26][28]

Genuine gap or tooling

Genuine gap for human data. The separate biotin, folate and B12 PubMed queries that were previously not run have now been run (0, 2 non-nutrient, 0 records). Remaining tooling limits: a cobalamin-only PubMed query was not run, the rat vitamin D3 paper abstract was not retrievable, and PubMed was rate limited throughout.

Counter-evidence held on record

Re-check Any study measuring serum B12, folate or biotin before and after a cefadroxil course, or stool metabolomics of vitamin synthesis. Framing caution A disclosed gap, not a finding of no effect and not reassurance. The vitamin K pathway through gut flora is handled in its own yellow entry.

Limits on what this shows

• Negative or null findings: PubMed "cefadroxil hemolytic anemia" returned a single record. Absence of other cases in that listing is a limit of the search, not evidence that hemoglobin is unaffected in routine courses. [25]
• At-risk subgroups: Not defined by the evidence.
• Counter-evidence on record: None identified; the limitation is the absence of incidence data and a co-suspect drug in the only case.

Direction

Adverse drug reaction (immune-mediated red-cell destruction). It is not a nutrient deficiency, not iron deficiency and not a drug-intended effect.

Regulatory status

UK SmPC 4.8: "Haemolytic anemia of immunologic origin" is very rare (under 1 in 10,000); 4.4: the Coombs test "can be transiently positive during or after treatment". US labels: positive direct Coombs tests are listed under Drug/Laboratory Test Interactions; hemolytic anemia and prolonged prothrombin time appear in the cephalosporin-class adverse reaction list, not in a cefadroxil-only list, with no frequencies. [1][2][5]

Population evidence

Tier B case report [16]: a 27-year-old woman, hemoglobin 4.9 g/dL on admission, 6 units of red cells, with hemolysis attributed by the authors to cefadroxil by an immune-complex mechanism and agranulocytosis attributed to cefadroxil and a co-ingested cold remedy (salicylamide, acetaminophen, caffeine, promethazine); recovery with prednisolone and G-CSF. The direct antiglobulin result was not in the abstract. Listing-level summary of a Japanese-language article; a second record could not be retrieved. No cohort, incidence or hemoglobin-change study with cefadroxil was found.

Mechanism

Named in outline: drug-dependent antibody binding to red cells (immune complex mechanism in the case report). Not studied beyond the report. [16]

Counter-evidence held on record

Boundary and why not higher Orange would need a cohort incidence figure or a measured hemoglobin change in cefadroxil users; neither was found. A label frequency category is a regulatory estimate, not a measured effect. Anemia is an outcome here and is never filed as a nutrient finding. Framing caution Hemolysis is an uncommon allergic-type reaction to a drug. It says nothing about iron, B12 or any nutrient intake, and no supplement is indicated.

Limits on what this shows

• Why no grade: Dual condition met. (1) No Tier B or C source measuring ATP production, ATP content or cellular energy output with cefadroxil or with any cephalosporin was found; the rabbit respiration and succinate-uptake data for other cephalosporins are recorded under mitochondrial burden as class extrapolation, and they did not measure ATP. (2) No circulating claim about cefadroxil and ATP or "low energy" was found on the consumer pages opened (Drugs.com, RxList).

Direction

Not determined.

Channels tried

PubMed "cefadroxil ATP" (3 records: renal disposition in LPS-treated mice, ABCC3/ABCC4 and cefadroxil oral availability in mice, rat Oatp2 hepatic uptake of beta-lactams; none measured ATP, respiration or membrane potential); PubMed "cefadroxil mitochondrial" (0 records); PubMed cephalosporin mitochondrial respiratory toxicity listing (6 records, cefadroxil absent); PubMed "cefadroxil oxidative stress" (0); five labels (no text); Drugs.com and RxList pages (no claim). Repair pass: PubMed "cefadroxil oxidative phosphorylation" (0 records); PubMed "cefadroxil respiration" (3 records, all about whole-animal breathing or acute toxicity in 1979 to 1983 Japanese and Italian papers: general pharmacology in dogs and rats, an acute toxicity study, and a respiratory-tract infection trial; none measured cellular respiration, ATP or membrane potential); a Crossref bibliographic search for cefadroxil with mitochondria, ATP, renal tubular transport and PEPT2 (titles only: PEPT2 knockout pharmacokinetics in mice, a PEPT2 cryo-EM structure with cefadroxil, species differences in PEPT2 transport; none about ATP or mitochondria, none opened). A further "cefadroxil mitochondria" PubMed query was rate limited (HTTP 429) and not read. [25][24][26][28]

Genuine gap or tooling

Mostly a genuine gap. Queries naming oxidative phosphorylation and respiration with cefadroxil have now been run and returned nothing relevant. Tooling-limited in part: PubMed and Crossref were heavily rate limited, only listing summaries and titles were read, a "cefadroxil mitochondria" query and a "membrane potential" query were not completed, and no OAT or PEPT2 mitochondrial-effect paper could be searched by full text.

Counter-evidence held on record

Re-check A study of cefadroxil on cellular respiration or ATP in human or animal tissue, or a stool-free metabolic study. Framing caution A disclosed gap, not a finding of no effect and not reassurance.