Cefpodoxime

Limits on what this shows

• Negative or null findings: No oral, intravenous or in vitro respirometry study with cefpodoxime 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 [19] (cell culture and mice; abstract read through a reconstructed OpenAlex record): quinolones, aminoglycosides and beta-lactams at clinically relevant doses caused mitochondrial dysfunction and reactive oxygen species overproduction in mammalian cells, and treated mice showed raised oxidative stress markers and tissue damage; N-acetyl-L-cysteine reduced the damage. Only drug classes are named in the abstract. Cohort test: cefpodoxime was not named and its inclusion could not be verified (full text not opened), so cefpodoxime is treated as not in the cohort. PubMed "cefpodoxime mitochondria" returned 0 records [24].

Mechanism

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

Boundary

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

Counter-evidence held on record

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

Limits on what this shows

• Negative or null findings: The rat study of cefpodoxime for 7 days measured glucose, total protein, AST, ALT and hemoglobin but no redox marker [15].
• At-risk subgroups: Not defined.
• Counter-evidence on record: None identified; the evidence is one class-level abstract.

Direction

Excess oxidant load at class level (drug toxicity). Not an antioxidant nutrient deficiency.

Regulatory status

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

Population evidence

CLASS EXTRAPOLATION, Tier C: Kalghatgi 2013 [19], as described in the mitochondrial entry; cefpodoxime not named, treated as not in the cohort. PubMed "cefpodoxime oxidative" returned 9 records, all formulation, analytical, sensor or interaction studies (cyclodextrin dissolution, rat absorption from an emulsion, an HPTLC assay, a cefditoren sensor, a luminol-copper chemiluminescence assay, particle preparation, an insulin binding study, a gold nanoparticle sensor, a solubility comparison); none measured oxidative stress in cells, animals or people exposed to cefpodoxime [24].

Mechanism

Class-level reactive oxygen species generation. Not shown for cefpodoxime.

Boundary

Class extrapolation only. Shares its source with the mitochondrial entry (see the overlap map).

Counter-evidence held on record

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

Limits on what this shows

• Why no grade: Dual condition met: (1) no Tier B or Tier C evidence that cefpodoxime changes copper status or absorption was found, and (2) no circulating claim about cefpodoxime and copper was found on the labels or consumer page read. A luminol-copper(II) chemiluminescence assay that determines thirteen cephalosporins appeared in a PubMed listing; it is an analytical method, was seen at title level only, and is not copper biology.

Direction

Not determined.

Channels tried

Crossref title search "cefpodoxime copper complex" (10 results: USP-NF monograph records, a cyclodextrin inclusion-complex paper and a handbook entry; none about copper status) [25]; PubMed listing "cefpodoxime copper" (first attempt blocked by a browser-check page; read successfully in the repair pass: 1 record, PMID 20925986, the luminol-copper(II) chemiluminescence assay, analytical only) and "cefpodoxime ceruloplasmin" (repair pass, 0 records, no results page) [24]; the "cefpodoxime oxidative" listing (the chemiluminescence assay above) [24]; both tablet labels (no copper text) [1][2]; the Drugs.com food-interaction page (no copper claim) [23]; Wikipedia (no claim) [4].

Genuine gap or tooling

Mostly a genuine gap. In the repair pass the PubMed "cefpodoxime copper" listing was read (1 record, an analytical chemiluminescence method that uses copper(II) as a reagent, PMID 20925986, abstract-level, not copper biology) and "cefpodoxime ceruloplasmin" returned 0 records [24]. WebSearch remained exhausted, and serum copper and copper-complex phrasings were not run (rate limiting), so a small tooling limitation remains.

Re-check

Run "cefpodoxime serum copper", "cefpodoxime Wilson" and a metal-complex phrasing when access allows; "cefpodoxime copper" and "cefpodoxime ceruloplasmin" are done.

Counter-evidence held on record

This is a disclosed gap, not a finding of no effect. Do not infer a need for copper.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or Tier C evidence that cefpodoxime changes iron status or absorption, and no circulating claim about cefpodoxime and iron found. The beta-lactam iron effect in the literature is cefdinir with iron salts, which runs from iron to a different drug and does not transfer to cefpodoxime; the sibling cefdinir dossier's iron timing entry was not used as evidence here. Iron oxide appears in the Aurobindo label only as an inactive ingredient of the 100 mg tablet. The hemoglobin and hematocrit decrease listed in the label is graded under oxygen delivery and is not iron evidence.

Direction

Not determined.

Channels tried

PubMed listing "cefpodoxime iron" (3 records, all shown: a German review of newer beta-lactams, the Wiesner beta-lactam bioavailability review whose snippet names cefdinir with iron salts as the largest drop, and a red panda E. coli isolate report; none measured iron in anyone given cefpodoxime) [24]; both tablet labels (no iron text apart from the inactive ingredient) [1][2]; PubMed listings "cefpodoxime ferritin" (0 records) and "cefpodoxime iron deficiency" (0 records) in the repair pass [24]; Wiesner Table 1 (no cefpodoxime iron row among its food and antacid entries) [13]; Drugs.com (no iron claim) [23].

Genuine gap or tooling

Mostly a genuine gap. In the repair pass "cefpodoxime ferritin" and "cefpodoxime iron deficiency" each returned 0 records (no results pages) and a longer boolean query (serum iron, iron absorption, transferrin, iron status, ferrous sulfate) returned a page with no result list, treated as unparsed and not counted [24]. WebSearch remained exhausted; the iron-supplement co-administration phrasing was only covered by that one unparsed boolean query.

Re-check

Run "cefpodoxime ferrous sulfate" and "cefpodoxime iron absorption" as single-term listings when access allows; "ferritin" and "iron deficiency" 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: Chachaty found faecal antibiotic activity in only one cefpodoxime volunteer [9]. A retrospective single-center comparison of levofloxacin versus cefpodoxime prophylaxis after allogeneic stem cell transplantation (71 per arm) reported similar C. difficile incidence between arms, with no counts in the abstract; because levofloxacin is itself a high-risk antibiotic, an equal rate neither supports nor contradicts a cefpodoxime effect [10]. The Northern California estimate is modest (1.58) because the comparator is other antibiotics [6]. A 2021 Reactions Weekly item is a single case of acute diarrhea from community-associated C. difficile superinfection after cefpodoxime (paywalled preview, metadata only) [11]. The best-known US outpatient cohort (Zhang 2022) does not report cefpodoxime at all [20], and the Utah hospital cohort (Webb 2020) does not either [21]; neither is counted.
• At-risk subgroups: Older adults, people with longer hospital stays, proton pump inhibitor use, prior gastrointestinal disease or recent infection raised C. difficile risk in the Northern California analysis [6]. The same Miller analysis adjusted for proton pump inhibitor receipt [5]. Infants under 2 months: safety and efficacy not established (label) [1]. No cefpodoxime-specific high-risk stratum estimate was found.
• Counter-evidence on record: Both case-control estimates are observational and confounded by indication and health care exposure (Hard Rule 6); the volunteer studies remove confounding by indication but are small, culture-based, abstract-level and mostly without a non-antibiotic control group except Chachaty [7][8][9]. Effect sizes for the flora studies are P values and descriptions in the abstracts, not numeric differences. The Orrhage and Brismar studies share a senior author (C. E. Nord) but use different volunteers, comparator arms and analyses [7][8].

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 tablet labels: "Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefpodoxime proxetil, and may range in severity from mild diarrhea to fatal colitis"; "Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile"; "prolonged use of cefpodoxime proxetil may result in overgrowth of non-susceptible organisms"; pseudomembranous colitis is listed in postmarketing experience; one label describes reports occurring more than two months after dosing [1]. Diarrhea 7% in multiple-dose tablet trials (N=4696), dose-related. [1][2]

Population evidence: Miller 2023 [5]

Matched case-control study in an insurance claims database (5 controls per case; the Methods name the Merative MarketScan Research Databases, Commercial and Medicare 2001 to 2021, Multi-State Medicaid 2014 to 2018; cases had no inpatient stay in the prior 12 weeks), exposure in the 30 days before the index date, community-associated C. difficile infection. Cefpodoxime (third-generation cephalosporin): 324 exposed cases versus 114 exposed controls, unadjusted OR 14.24, adjusted OR 9.17 (95% CI 6.99 to 12.04; the table caption calls the intervals credible intervals), adjusted by conditional logistic regression for other antibiotic exposures, Elixhauser comorbidities, proton pump inhibitor receipt within 90 days and number of health care visits in the prior 90 days, matched on age, sex, insurance type and enrollment period. For scale only (other drugs, not evidence for cefpodoxime): cefdinir 11.02, cefuroxime 9.59, cefixime 12.04, cephalexin 2.88 in the same table. Repair-pass check of the totals (OUP article page, summarizer-relayed, and the OpenAlex abstract record): both pairs of numbers appear in the paper. The abstract and the Results sentence give 159,404 cases and 797,020 controls (the study totals); the Table 2 column headers give n = 181,041 for cases and n = 905,205 for controls, and the paper does not explain the difference (905,205 is exactly 5 times 181,041; the Methods note that patients with more than one antibiotic received a separate indicator for each, which may mean the Table 2 headers count something other than patients, but the paper does not say so). Neither pair is used in any calculation here; the cefpodoxime row (324 exposed cases, 114 exposed controls, adjusted OR 9.17, 95% CI 6.99 to 12.04) was read again in the same table and is unchanged. The 159,404 and 797,020 figures are the study totals as stated by the authors in the abstract and Results. The 30 to 180 day sensitivity values for cefpodoxime are in a supplementary table that was not readable.

Population evidence: Baxter 2007 [6]

Retrospective case-control study in an integrated health system in Northern California, 1999 to 2005: 1,142 patients with hospital-acquired C. difficile-associated diarrhea and 3,351 controls matched on facility, calendar quarter, diagnosis-related group and length of stay; all cases and controls had received an antibiotic in the 60 days before the index date, so the comparison is against other antibiotic users. Adjusted for other antibiotics, demographics, selected health conditions and health care services. Cefpodoxime adjusted OR 1.58 (listed among agents with increased risk: imipenem-cilastatin 2.77, clindamycin 2.31, cefuroxime 2.16, moxifloxacin 1.88, ceftazidime 1.82, ceftizoxime 1.57, ceftriaxone 1.49; metronidazole 0.67 and doxycycline 0.41 lower). The 95% interval and exposed counts were not available in the abstract-level records read (three independent abstract-level records agreed on the point estimates: OpenAlex, the Cambridge abstract page and the PubMed record). Repair-pass retrieval attempts for the interval all failed: the Cambridge full-text article page and its PDF link (abstract only, paywall), JSTOR (JavaScript challenge page) and Semantic Scholar (closed access, abstract field empty); the interval and exposed counts remain not retrieved.

Population evidence: stool flora in volunteers [7][8][9]

Orrhage 2000 [7]: 30 healthy volunteers in three groups on oral cefpodoxime proxetil twice daily for 7 days (probiotic-plus-oligofructose, oligofructose only, or placebo). In all groups a marked decrease in aerobes with rapid, almost complete disappearance of Escherichia coli and then overgrowth of enterococci (P under 0.05); yeasts rose significantly in two groups; anaerobes fell sharply by day 4, mainly through loss of bifidobacteria (P under 0.05); lactobacilli fell; C. difficile was found in 1 person in the probiotic group and in 6 each in the other two groups. Brismar 1993 [8]: 10 volunteers on cefpodoxime proxetil 200 mg every 12 hours for 7 days (10 others on amoxicillin): faecal streptococci, Enterobacteriaceae and clostridia strongly reduced, with overgrowth of enterococci, yeasts and C. difficile; amoxicillin changes were somewhat smaller; oral flora changed only minimally. Chachaty 1992 [9]: randomized placebo-controlled study of 18 healthy adults, 3 groups of 6 (cefpodoxime proxetil, cefixime or placebo, 400 mg per day for 10 days); no C. difficile before treatment; the reconstructed abstract indicates C. difficile was detected afterward in all 6 cefpodoxime volunteers and 5 of 6 cefixime volunteers (reconstruction not fully certain); strains differed between volunteers; antibiotic activity was found in the stool of only 1 cefpodoxime volunteer; stool consistency changed in 3 of 12 treated volunteers; toxin A in one.

Mechanism

Named: suppression of susceptible aerobes and anaerobes with overgrowth of resistant enterococci, yeasts and, in vulnerable hosts, C. difficile. About half of an oral dose is not absorbed systemically [1], and in one volunteer study measurable drug was found in the stool of only 1 of 6 cefpodoxime volunteers, with an inverse relation to faecal beta-lactamase activity [9], so the exact colonic exposure route (unabsorbed drug versus biliary excretion) is not established by these abstracts.

Why red

Five Tier A sources with cefpodoxime in the cohort: two independent case-control datasets (an insurance claims database and a Northern California health system, different settings, years and case definitions) and three volunteer stool studies (two share a senior author but used different volunteers; the third is a separate randomized placebo-controlled study by different authors), consistent direction, a named mechanism, an effect large enough to matter (adjusted OR 9.17 with a lower bound of 6.99 in the claims data) and no Tier A source pointing the other way. 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 to the infection and flora-disturbance findings in the datasets named (30-day claims window; hospital stay with antibiotic exposure in the prior 60 days; 7 to 10 day courses in volunteers). Advance to only after an editor opens the full texts to confirm the Baxter confidence interval, the Chachaty counts and the Orrhage and Brismar numeric results (the Miller cefpodoxime row was confirmed on the publisher page in the repair pass). 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, and one volunteer study arm that included a probiotic is reported only as a finding. Diarrhea after antibiotic use should be evaluated for C. difficile by a clinician.

Limits on what this shows

• Negative or null findings: No cohort or trial quantifying hemoglobin change or hemolysis incidence with cefpodoxime against a comparator was found. PubMed listings: "cefpodoxime anemia" 4 records (the FAERS paper, the Yilmaz case, a ceftriaxone hemolysis report and a Russian pediatric efficacy trial); "cefpodoxime hemoglobin" 2 records (the rat study and a susceptibility survey) [24]. A French pharmacovigilance and cohort analysis of drug-induced immune hemolytic anemia did not name cefpodoxime in its abstract [22].
• At-risk subgroups: Not defined by the evidence beyond the single adult case; renal impairment prolongs half-life (label) [1].
• Counter-evidence on record: The label figures have no denominators; one case report cannot give an incidence; the rat study is in a different species, its dose equivalence to humans is not stated, and it is abstract-level only.

Direction

Adverse drug reaction and laboratory change (immune red-cell destruction in the case; cause of a hemoglobin decrease otherwise not stated). Not a nutrient deficiency, not iron deficiency, not B12 and not a drug-intended effect (Hard Rule 2).

Regulatory status

Tablet labels, laboratory changes (Hematologic): "decreased hemoglobin, decreased hematocrit" and "positive Coombs' test, and prolonged PT, and PTT", with no incidence rates; hemolytic anemia appears in a cephalosporin-class adverse reaction list; "Cephalosporins, including cefpodoxime proxetil, are known to occasionally induce a positive direct Coombs' test." [1][2]

Population evidence

Tier B case report, Yilmaz 2013 [14]: an adult (indexed as female) with acute interstitial nephritis (biopsy-confirmed) and immune hemolytic anemia (peripheral smear and positive Coombs test) after cefpodoxime proxetil; recovered after dialysis, intravenous methylprednisolone 500 mg per day for 2 days and oral prednisolone 60 mg per day tapered over 3 weeks; hemoglobin values and antibody type were not in the reconstructed abstract. Tier B rat study, Mujeeb 2011 [15]: 12 male Wistar rats (6 per group), cefpodoxime proxetil 20 mg/kg orally twice daily for 7 days; hemoglobin decreased significantly versus control while glucose, total protein, AST and ALT did not change; sperm counts also fell; no numeric values in the abstract. A FAERS description of third-generation cephalosporins names pyrexia, pruritus and diarrhea as the most common cefpodoxime events and mentions hemolytic anemia only generically [16].

Mechanism

Named in outline for the case: drug-induced immune hemolysis with a positive Coombs test. The mechanism of the rat hemoglobin decrease and of the label-listed hemoglobin decrease is not given.

Boundary and why not higher

Orange would need a hemoglobin or hemolysis incidence for cefpodoxime 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 cefpodoxime was opened, and no circulating claim about cefpodoxime and energy was found. The class mitochondrial study [19] reports mitochondrial dysfunction in general terms and does not name cefpodoxime; it is graded under mitochondrial burden and kept separate from ATP production (Hard Rule 7).

Direction

Not determined.

Channels tried

PubMed listings "cefpodoxime ATP" (0 records; the page noted the search ran without automatic term mapping, and a zero count of this kind may undercount) and "cefpodoxime mitochondria" (0 records) [24]; the "cefpodoxime oxidative" listing (9 records, none about cellular energy) [24]; the repair-pass "cefpodoxime bioenergetics" listing (2 records, neither an ATP or respiration measurement) [24]; Quan 2020 [27], an in vitro paper in which cefpodoxime proxetil at 5 micromolar was tested in NMDA-injured SH-SY5Y cells with an MTT viability assay (an MTT readout is not an ATP measurement, the abstract names no ATP, ROS or membrane potential endpoint, and the work is a neuroprotection finding, so it is not ATP evidence and is not graded); both labels (no energy text) [1][2]; Drugs.com and Wikipedia (no claim) [23][4].

Genuine gap or tooling

Probable genuine gap. In the repair pass "cefpodoxime bioenergetics" returned 2 records, neither measuring energy output (a virtual-screening and in vitro neuroprotection paper, PMID 32448083 [27], and a CTX-M docking paper, PMID 35934203, title only); a boolean query combining respiration, bioenergetics, mitochondrial, membrane potential and oxidative phosphorylation returned a page with no result list (treated as unparsed, not counted); single-term "respiration" and "mitochondrial" listings were refused or errored. The full text of Kalghatgi 2013 (PMC3760005) was not readable (browser-check page), so which beta-lactams it tested is still unknown. WebSearch remained exhausted.

Re-check

Run single-term "cefpodoxime respiration" and "cefpodoxime mitochondrial" listings and open the full text of Kalghatgi 2013 (PMC3760005) to see which beta-lactams were tested; "bioenergetics" is done.

Counter-evidence held on record

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