Detail characteristics of 34 antibiotic (ATB) cohort included in the meta-analysis
| Author | Year | Country | Trial type | Median follow-up | Cancer type | N | Line of therapy | Antibiotics regimen in relation to ICI | Time frame | Immunotherapy | Antibiotic | References |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Derosa et al. | 2018 | France | Retrospective cohort | - | Advanced NSCLC | 239 | Mixed line | ≤30 days before ICI initiation; also ≤60 days explored | - | Anti-PD-(L)1 alone or anti-PD-(L)1 + anti-CTLA-4 | β-lactams most common; also quinolones and sulfonamides | 3 |
| Huemer et al. | 2018 | Austria | Retrospective single-center study | - | NSCLC | 30 | All were 2nd-line or above | 1 month before ICI to 1 month after ICI | 2015.5–2017.11 | Nivolumab (25), pembrolizumab (5) | Penicillins (64%), fluoroquinolones (36%), carbapenems (18%) | 4 |
| Zhao et al. | 2019 | China | Single-center retrospective study | - | Advanced NSCLC | 109 | Mixed lines; first line 28 (25.7%), ≥ second line 81 (74.3%) | Within 1 month before or after first ICI | 2016.1–2018.5 | Pembrolizumab, nivolumab, SHR-1210 (camrelizumab) | Most commonly β-lactam inhibitors and fluoroquinolones | 5 |
| Barrón et al. | 2019 | Multiple Latin American countries (Mexico, Colombia, Argentina, Peru, and Brazil) | Multicenter retrospective study | - | Advanced NSCLC | 140 | Mostly ≥2nd line | Within 30 days prior to ICI initiation | - | PD-1/PD-L1 | β-lactams, quinolones | 6 |
| Bagley et al. | 2019 | USA | Retrospective cohort study using Flatiron Health EHR-derived database | - | Advanced NSCLC | 1,960 | First-line | Primary analysis: ABX from −6 to +4 weeks around ICI start; secondary analyses: within 6 weeks pre-ICI and within 4 weeks post-ICI | - | ICI | - | 7 |
| Hakozaki et al. | 2019 | Japan | Retrospective single-center study | - | Advanced NSCLC | 90 | Second or later line | Antibiotics for ≥3 days within 30 days of nivolumab therapy | 2016.1–2017.4 | Nivolumab monotherapy | TMP/SMX, amoxicillin/clavulanate, ceftriaxone, meropenem, piperacillin/tazobactam, ampicillin/sulbactam, cefazolin, levofloxacin | 8 |
| Kim et al. | 2019 | Korea | Retrospective single-center study | - | Advanced NSCLC | 131 | Mixed-line | Antibiotics within 60 days before ICI initiation; subgroup analyses for within 30 days and 31–60 days before ICI | 2012.2–2018.5 | Nivolumab, pembrolizumab, and others (anti-PD-1/PD-L1/CTLA-4-based regimens) | Cephalosporins; fluoroquinolones; beta-lactam/beta-lactamase inhibitors; carbapenems; glycopeptides; macrolides | 9 |
| Pinato et al. | 2019 | UK | Prospective multicenter cohort study | 14.6 months | NSCLC subgroup from pan-cancer cohort | 119 | Mixed (mostly first-line metastatic) | Broad-spectrum antibiotics within 30 days prior to ICI initiation (pATB) or during ICI (cATB) | 2015.1–2018.4 | Anti-PD-1/PD-L1 ICIs | Mainly β-lactam based | 10 |
| Ouaknine Krief et al. | 2019 | France | Retrospective real-world cohort study | 500 days (IQR 401–599) | NSCLC | 72 | Nivolumab used as 2nd-line or later therapy | Early use of antibiotics (EUA) = 2 months before to 1 month after ICI initiation | 2014.7–2017.9 | Nivolumab | Oral or iv antibiotics, median duration 9.5 days, mainly β-lactams (36/51) and vancomycin | 11 |
| Mielgo Rubio et al. | 2019 | Spain | Retrospective multicenter study | 6.5 months | Advanced NSCLC, PD-L1 ≥50% | 121 | 1st-line | Antibiotics 2 months before to 1 month after ICI start | 2016.9–2019.3 | Pembrolizumab monotherapy | Quinolones (40.7%), penicillins/derivatives (35.2%); iv 65.5%, oral 34.5% | 12 |
| Schett et al. | 2020 | Switzerland (two tertiary centers) | Retrospective observational cohort | 5.5 months (95% CI 5–14) | Advanced NSCLC (EGFR WT, ALK–) | 218 | Across 1st–4th-lines (majority 2nd-line) | Within 2 months prior to ICI start | 2013.1–2017.12 | Nivolumab/pembrolizumab/atezolizumab | β-lactams, quinolones, macrolides (oral or iv) | 13 |
| Chalabi et al. | 2020 | Multiple countries (mainly Europe and America) | Pooled retrospective analysis of randomized Phase II/III trials (OAK + POPLAR) | 19.2 months | NSCLC | 1,512 | Mixed line | 30 days before ICI to 30 days after ICI (±30 days) | - | Atezolizumab | Quinolones, penicillins, cephalosporins | 14 |
| Cortellini et al. | 2021 | Europe multicenter | Retrospective multicenter real-world cohort | 21.8 months | Metastatic NSCLC with PD-L1 ≥50% | 950 | First-line only | Systemic ATB within 30 days before first-line treatment initiation | 2017.1–2020.5 | Pembrolizumab monotherapy | - | 15 |
| Hamada et al. | 2021 | Japan | Single-center retrospective study | 251.5 days | Advanced NSCLC | 69 | Mixed lines (1L/2L/≥3L) | Within 21 days before or after first anti-PD-1 dose | 2016.1–2019.12 | Nivolumab or pembrolizumab | Levofloxacin, macrolides, cephems, TMP-SMX, carbapenems, tazobactam/piperacillin | 16 |
| Verschueren et al. | 2021 | Belgium | Single-country real-world cohort | - | Stage IV NSCLC | 442 | Mixed lines: 1L, 2L, and 3L | Antibiotic use within 30 days before and 30 days after treatment initiation | - | Nivolumab, pembrolizumab, atezolizumab | - | 17 |
| Ren et al. | 2021 | China | Pooled analysis of 5 tislelizumab monotherapy studies | - | NSCLC | - | - | Within 30 days of day 1 | - | Tislelizumab | - | 18 |
| Balado et al. | 2021 | Spain | Retrospective study | - | Advanced/metastatic NSCLC, PD-L1 ≥50% | 49 | 1st-line immunotherapy | ATB+: systemic antibiotics within ±30 days of pembrolizumab start | 2017.7–2020.1 | Pembrolizumab monotherapy | - | 19 |
| Castello et al. | 2021 | Italy | Prospective registration + retrospective analysis | 12.4 months (9.7–15.2) | NSCLC | 50 | Mixed-line | 12 patients received antibiotics 1 month before ICI initiation, and 11 patients received antibiotics within 1 month after ICI initiation (3 of whom received antibiotics in both time periods) | 2015.12–2019.5 | Nivolumab (62%), pembrolizumab (32%), nivolumab + ipilimumab (4%), atezolizumab (2%) | β-lactam ± inhibitor (8 cases), quinolone (8 cases), rifaximin (1 case), glycopeptide (1 case), 2 cases unspecified | 20 |
| Geum et al. | 2021 | South Korea | Retrospective single-center cohort study | - | Advanced/recurrent NSCLC, predominantly adenocarcinoma (70%) | 140 | ≥2nd-line | Any systemic antibiotic use from 30 days before nivolumab initiation until completion of nivolumab therapy | 2015.7–2018.6 | Nivolumab | Various systemic antibiotics, mainly broad-spectrum agents | 21 |
| Ochi et al. | 2021 | Japan (9 institutions) | Multicenter retrospective cohort study | - | Advanced/metastatic NSCLC | 531 | Any line of therapy | Within 2 months before or 1 month after starting ICI | 2015.12–2018.5 | PD-1/PD-L1 (nivolumab/pembrolizumab/atezolizumab) | β-lactams most common, other classes (e.g., quinolones, macrolides) used at lower frequencies, not further detailed in the original report | 22 |
| Lu et al. | 2021 | Taiwan, China | Retrospective cohort | - | NSCLC | 340 | 1st/2nd-line: 70%; ≥3rd-line: 30% | Systemic antibiotics within 30 days before ICI | 2016.1–2019.3 | ICI: ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab (96% PD-(L)1 monotherapy) | Broad-spectrum antibiotics: fluoroquinolones 39%, penicillins 38%, 1st/2nd-gen cephalosporins 33%, 3rd/4th-gen cephalosporins 30%, carbapenems 7%, macrolides 5% | 23 |
| Nyein et al. | 2022 | USA | Retrospective single-center study | - | NSCLC (Stage III/IV) | 256 | - | From 60 days before ICI to 30 days after ICI | 2011.1–2017.3 | PD-1/PD-L1/CTLA-4 (monotherapy or combined with chemotherapy/targeted therapy) | β-lactams, fluoroquinolones, macrolides, cephalosporins, tetracyclines; Most commonly used: levofloxacin (15), cefazolin (14), azithromycin (8) | 24 |
| Qiu et al. | 2022 | China | Retrospective study | - | NSCLC | 148 | 1st-line: 48.0%, 2nd-line: 37.8%, 3rd-line: 14.2% | ATB exposure was defined as use within 60 days before or after ICI initiation, and was further classified as 30–60 days before ICI, within 30 days before ICI, concurrent with ICI, within 30 days after ICI, and 30–60 days after ICI. | 2018.1–2021.6 | Camrelizumab, pembrolizumab, toripalimab, sintilimab, tislelizumab, nivolumab, durvalumab | β-lactams, quinolones, and their combination. Subclasses of β-lactams: Penicillins, cephalosporins, carbapenems | 25 |
| Joshi et al. | 2022 | USA | Prospective real-world cohort study | - | NSCLC | 136 | First-line only | 1 month before ICI | 2014.1–2019.5 | Pembrolizumab (1st-line, monotherapy or combined with chemotherapy) | β-lactams, fluoroquinolones, macrolides, cephalosporins, tetracyclines | 26 |
| Stokes et al. | 2022 | USA | Nested cohort study | NSCLC | 3,634 | pAbx (prior antibiotics): antibiotic exposure within 30 days before initiation of ICI | 2010–2018 | Nivolumab 59.1%, pembrolizumab 35.1% (total >94%) | The most common were β-lactams (30.1%); other ATBs were not subdivided | 27 | ||
| Stokes et al. | 2022 | USA | Nested cohort study | - | NSCLC | 3,634 | - | cAbx (concurrent antibiotics): antibiotic exposure within 60 days after initiation of ICI | 2010–2018 | Nivolumab 59.1%, pembrolizumab 35.1% (total >94%) | The most common were β-lactams (30.1%); other ATBs were not subdivided | 27 |
| Şen et al. | 2023 | Turkey | Retrospective cohort | - | NSCLC (Stage IV) | 90 | 81.1% 1st-line, 18.9% 2nd-line | Within 12 weeks after ICI initiation (primary analysis), the first 4/8 weeks were also analyzed | - | PD-1/PD-L1 | Outpatient: moxifloxacin, clarithromycin, amoxicillin-clavulanate; Inpatient: piperacillin-tazobactam, meropenem, vancomycin, colistin, TMP-SMX | 28 |
| Deng et al. | 2024 | China | Retrospective cohort study | 25.2 months (95% CI 22.99–27.34) | NSCLC, locally advanced or metastatic (Stage Ⅲ–Ⅳ) | 316 | 1st-line 238/316 (75.3%), ≥2nd-line 78/316 (24.7%); ATB group: 1st-line 108/134 (80.6%), ≥2nd-line 26/134 (19.4%); N-ATB group: 1st-line 130/182 (71.4%), ≥2nd-line 52/182 (28.6%) | Within 30 days before ICI initiation (p-ATB) or during ICI treatment | 2018.01–2023.10 | PD-1/PD-L1 inhibitors: tislelizumab (138 cases), camrelizumab (85 cases), sintilimab (61 cases), pembrolizumab (14 cases), and other ICIs (18 cases). | β-lactams (68 cases, 50.7%), quinolones (31 cases, 23.1%), quinolones + β-lactams (32 cases, 23.9%), macrolides (3 cases, 2.3%; β-lactams were further divided into BLBLI (β-lactam/β-lactamase inhibitor combinations, 54 cases, 40.3%) and non-BLBLI; common BLBLI included cefoperazone-sulbactam, mezlocillin-sulbactam, piperacillin-tazobactam, and amoxicillin-clavulanate. | 29 |
| Tamura et al. | 2024 | Japan | Retrospective study [propensity score matching (PSM)] | ABx: 45.9 months vs. Non-ABx: 47.2 months | NSCLC | 201 | First-line only | 30 days before ICI | 2018.12–2020.12 | Pembrolizumab or atezolizumab | β-lactam/β-lactamase inhibitor combinations [AMPC/CVA 63.6%, PIPC/TAZ 15.2%, ABPC/SBT 9.1%], fluoroquinolones [LVFX, MFLX], sulfonamide/trimethoprim, macrolide [CAM], penicillin [AMPC], cephalosporin [CEZ], and glycopeptide [VCM] | 30 |
| Luo et al. | 2024 | China | Prospective cohort study | - | EGFR+ advanced NSCLC | 74 | Mixed line | 2 months before and after ICI | 2019.3–2022.9 | PD-1/PD-L1 inhibitors | - | 31 |
| Xie et al. | 2024 | China West China Hospital of Sichuan University | Retrospective cohort study | - | NSCLC accounted for 74.8% (≈472/631) | 472 | - | Use of antibiotics within 3 months before initiation of ICI therapy | 2018.12–2023.6 | ICI | Cephalosporins | 32 |
| Rousseau et al. | 2025 | France | Retrospective cohort + target trial emulation | - | Advanced/metastatic NSCLC | 41,529 | 1st-line therapy | ≥2 prescriptions of ATC J01 antibiotics, with prescription dates falling between 60 days prior to and 42 days after pembrolizumab initiation | 2015.1–2022.12 | Pembrolizumab monotherapy or pembrolizumab combined with chemotherapy (1st-line) | Macrolides, penicillins, penicillins plus penicillinase inhibitors, β-lactams other than penicillin, sulfonamides, fluoroquinolones, and combinations of several antibiotic types | 33 |
| Ochi et al. | 2025 | Japan | Multicenter retrospective study | 17.0 months (95% CI 15.8–18.2) | NSCLC | - | 1st-line therapy | 2 months before therapy to 1 month after therapy | 2018.12–2020.12 | Anti–PD-1, anti–PD-L1 | - | 34 |
| Hu et al. | 2025 | China | Single-center retrospective | 33.79 months | mNSCLC (Stage IV) | 199 | - | ±30 days before and after ICI | 2017.12–2021.10 | PD-1/PD-L1 | β-lactams 83.3% (penicillins ± β-lactamase inhibitors, cephalosporins, carbapenems), quinolones 57.8%, aminoglycosides, glycopeptides, and macrolides | 35 |