Long‐Term Treatment With Systemic Rifampicin and Clindamycin for Epidermal Growth Factor Receptor Inhibitor‐Related Acneiform and Mucocutaneous Rash: A Valid Therapeutic Option

Epidermal growth factor receptor inhibitors (EGFRi) are increasingly used across solid tumors, and acneiform and mucocutaneous eruptions are the most frequent skin toxicities, often compromising quality of life and treatment adherence. Current guidance supports structured prevention and stepwise management, typically centred on oral tetracyclines, topical anti-inflammatories and emollients, but evidence for rescue strategies when tetracyclines fail or are contraindicated (e.g., for documented allergy, gastrointestinal intolerance, or concomitant conditions/medications) remains limited [1, 2]. Early data in patients on next-generation regimens, including amivantamab-based combinations, emphasize the value of proactive dermatological care to maintain dose intensity [3]. We conducted an Italian multicentre, retrospective cohort across four dermatology units to evaluate oral rifampicin plus clindamycin in EGFRi-related eruptions that were intolerant or unresponsive to standard care. Adults on EGFRi for solid malignancies who received rifampicin–clindamycin for cutaneous toxicity were included. Demographics, tumor type, EGFRi agent, eruption severity and distribution, prior dermatological therapies and outcomes were recorded. Most patients had already received topical regimens and a course of systemic tetracyclines without clinical control. Swabs were obtained where superinfection was suspected. The prescribed regimen was rifampicin 600 mg daily plus clindamycin 600 mg daily, with dose reductions to 300 mg daily for each drug in case of intolerance. Ethics approval and written informed consent were obtained. Twenty patients were included in the analysis, with a mean age of 67.1 years. A concise table of cohort features and outcomes and a single clinical figure can summarize applicability for routine care (see Table 1 and Figure 1). Mean follow-up was 44.1 weeks. G3 MC, DC, AZ Topical clinda Rifa 600 mg/Clinda 600 mga Rifa 300 mg/Clinda 300 mga Topical clinda 1% G2 MC, DC, topical clinda Rifa 600 mg/Clinda 600 mg Topical dapsone 7.5% gel G2 MC, DC, steroidsc, CI Rifa 600 mg/Clinda 600 mg Topical dapsone 7.5% G2 MC, DC, topical clinda Rifa 600 mg/Clinda 300 mg Topical clinda 1% G2 Topical clinda and hydrocortisone acetate 0.5% Rifa 600 mg/Clinda 600 mg Topical dapsone 7.5% G2 DC, combination of topical clinda and tretinoin Rifa 600 mg/Clinda 600 mg Topical clinda 1% G2 DC, combination of topical clinda and tretinoin Rifa 600 mg/Clinda 600 mg Topical clinda 1% G2 DC, Combination of topical clinda and tretinoin Rifa 600 mg/Clinda 600 mg Topical clinda 1% G2 DC, MC, combination of topical clinda and tretinoin Rifa 600 mg/Clinda 600 mg Topical clinda 1% G2 DC, Combination of topical clinda and tretinoin Rifa 600 mg/Clinda 600 mg Topical clinda 1% G2 DC, combination of topical clinda and tretinoin Rifa 600 mg/Clinda 600 mg Topical fusidic acid + Betamethasone valerate (scalp) G2 MC, DC, topical Clinda Rifa 600 mg/Clinda 300 mg Topical Clinda 1% G2 DC, combination of topical clinda and tretinoin Rifa 600 mg/Clinda 600 mg Topical clinda 1% G2 DC, MC, topical Clinda Rifa 600 mg/Clinda 600 mg Topical Clinda 1% G2 DC, combination of topical clinda and tretinoin Rifa 600 mg/Clinda 600 mg Topical clinda 1% G3 MC, DC, AZ Rifa 600 mg/Clinda 600 mg Topical clinda 1% G2 DC, Combination of topical Clinda and Tretinoin Rifa 600 mg/Clinda 600 mg Topical Dapsone 7.5% gel G2 DC, topical clinda and tretinoin Rifa 600 mg/Clinda 600 mg Topical clinda 1% G2 DC, combination of topical clinda and tretinoin Rifa 600 mg/Clinda 600 mg Topical clinda 1% G2 DC, combination of topical clinda and tretinoin Rifa 600 mg/Clinda 600 mg Topical Clinda 1% Clinical improvement occurred in nearly all cases. Eighteen out of 20 patients achieved complete resolution, one had partial improvement, and one had minimal residual scalp lesions at final review. No patient required permanent EGFRi discontinuation for skin toxicity after starting antibiotics. Adverse events were mild and self-limited: abdominal pain and nausea respectively in three patients, managed conservatively or with dose reduction. There were no cases of hepatotoxicity, severe infection or Clostridium difficile infection. One patient required temporary interruption and dose reduction due to abdominal pain. Concomitant topical therapy (most commonly clindamycin 1% or dapsone gel 7.5%) was used according to lesion site and severity. These findings suggest that rifampicin-clindamycin (a known combination typically employed for the management of other cutaneous diseases, such as hidradenitis suppurativa) can serve as an effective, well-tolerated rescue option for moderate to severe EGFRi-related eruptions when tetracyclines are inadequate or unsuitable. The benefit likely reflects anti-inflammatory rather than antimicrobial effects: rifampicin down-regulates key cytokines and, together with clindamycin, inhibits neutrophil chemotaxis [4]. Concerns about community-acquired C. difficile and long-term safety of the combination are valid, yet reported incidence appears low and manageable, and dermatology experience in hidradenitis suppurativa supports cautious use with appropriate monitoring [4]. Drug–drug interactions require attention, especially with rifampicin, but no clinically meaningful interactions with EGFRi were observed in this cohort. Limitations include the small sample size, retrospective design, absence of a comparator and reliance on CTCAE (Common Terminology Criteria for Adverse Events) grading without a rash-specific severity index. Nevertheless, in a real-world setting that included next-generation agents such as amivantamab, outcomes were favorable and adherence to oncological therapy was preserved. In conclusion, bearing in mind that prevention remains essential to reduce mucocutaneous reactions during EGFRi therapy [5], rifampicin-clindamycin may be considered within onco-dermatology algorithms as a second-line or rescue therapy for EGFRi-associated acneiform and mucocutaneous eruptions. A pragmatic prospective study comparing tetracycline-centred care with protocols that incorporate rifampicin–clindamycin would help define positioning, dose and duration. This study was conducted retrospectively using data from standard clinical practice. As no experimental interventions were involved, ethical approval was not required. The patients in this manuscript have given written informed consent to the publication of their case details. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.