Pulsed Azithromycin for the Treatment of Dacomitinib Induced Skin Toxicity in Patient with Tetracycline Intolerance – A Case Report

Pulsed Azithromycin for the Treatment of Dacomitinib Induced Skin Toxicity in Patient with Tetracycline Intolerance – A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pulsed Azithromycin for the Treatment of Dacomitinib Induced Skin Toxicity in Patient with Tetracycline Intolerance – A Case Report Wei Ho, Yi-Ming Chen, Mong-Wei Lin, Yu-Qing Liao, Shu-Wen Lin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4753337/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Skin toxicities such as paronychia and acneiform rash are common side-effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) and significantly altered the quality of life of patients. Consensus guidelines recommended tetracycline antibiotics as the first line choices for both prophylaxis and treatment for grade II-III acneiform rash and paronychia. While generally well-tolerated, a subset of patients experiences adverse effects such as nausea, vomiting, diarrhea, headache, and photosensitivity, leading to antibiotics intolerance and leaving EGFR TKI-induced skin toxicities unmanaged. Therefore, an alternative treatment is needed. Methods We present a case of stage IV EGFR-mutated non-small cell lung cancer (NSCLC) treated with the second-generation EGFR TKI, dacomitinib. The patient developed grade 3 skin toxicities and was subsequently treated with azithromycin after demonstrating intolerance to tetracycline antibiotics. Results Azithromycin was administered using various dosing strategies, and our findings indicated that 500 mg every other day might be the most effective regimen for treating EGFR-TKI-induced acneiform rash. However, this approach appeared to be less effective in managing paronychia. Conclusion This case highlights the potential efficacy of azithromycin 500mg once another day as an alternative to tetracycline antibiotics for managing EGFR TKI-related skin toxicities in NSCLC patients. EGFR TKI NSCLC azithromycin skin toxicity Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Gene mutation in epidermal growth factor receptors (EGFR) plays an important role in the oncogenesis of non-small lung cancer (NSCLC). These mutations could be found in 40–55% of East Asians and 15–25% of Caucasians with adenocarcinoma type NSCLC 1 and could be treated with EGFR tyrosine kinase inhibitors (TKI). Dacomitinib, a second generation of EGFR TKI, showed significant improvement of progression free survival in treating EGFR mutation NSCLC; however, 14% of patients experienced grade 3–4 dermatitis 2 . The presentation of EGFR-TKI-induced skin toxicity ranged from pruritus, paronychia, xeroderma to mucositis, stomatitis and hair changes. Such adverse reaction may have deleterious impact on quality of life and may also lead to TKI dose modification and even discontinuation in severe cases. Various pharmacological and non-pharmacological strategies were developed aiming at minimizing the impact of skin-related side effects. According to current expert consensus, systemic tetracycline antibiotics (doxycycline 100 mg once daily to twice daily, minocycline 100 mg once daily to twice daily, and tetracycline 250 or 500 mg twice daily) for 4–6 weeks were recommended for grade II-III skin toxicities such as acneiform rash and paronychia besides topical or oral immunomodulatory (i.e steroid, calcineurin inhibitor) 3 , 4 , 5 . However, in a double-blind trial using tetracycline to prevent EGFR-TKI-induced skin rashes, tetracycline-associated adverse events of any grades occurred in 4–41% patients, including nausea, vomiting, abdominal pain, fatigue, dyspepsia, and anorexia 6 . Therefore, there is a need for alternative effective and safe treatment for EGFR-TKI-induced skin toxicities. In this case report, we described a patient who was diagnosed with stage IV EGFR L858R mutated NSCLC experiencing dacomitinib-related acneiform rash and paronychia and successfully treated with azithromycin after intolerance to first line tetracycline antibiotics. Case report A 54-year-old woman, with a medical history notable for untreated hypertension and no smoking or alcohol use, was diagnosed with stage IV non-small cell lung cancer (NSCLC) harboring an EGFR L858R mutation in 2023. Consequently, she commenced oral dacomitinib (Vizimpro ® 45 mg/tab) at 45 mg daily. Within one week, she developed grade 1 diarrhea and mucositis and about 16 days later, she presented with skin eruption affecting the face, scalp, and trunk. Under the impression of grade 2 EGFR TKI-related skin toxicity, patient was initially treated with doxycycline 100 mg twice daily and topical steroids, resulting in partial improvement of the rash. However, she subsequently developed grade 2 nausea and vomiting. Despite these side effects from doxycycline, the patient continued the therapy. Three weeks later, her skin condition remained relatively stable, but diarrhea had escalated to grade 3, prompting a reduction in dacomitinib dosage to 30 mg daily. Additionally, doxycycline was switched to minocycline 100 mg twice daily. However, she experienced worsening nausea and vomiting after minocycline. Therefore, tetracycline 250 mg twice daily was then prescribed but acneiform rash persisted without improvement, and grade 2 nausea and vomiting presented. Two weeks after dacomitinib dose reduction, the patient’s diarrhea had improved to grade 1 while the skin eruption remained at grade 2, with xerosis appearing on the trunk and face. Oral antibiotics were ceased due to the side effects and lack of efficacy, and antihistamine ketotifen fumarate was added. Despite these interventions, her skin eruption progressed to involve the entire body except for the upper limbs, reaching grade 3 severity. Xerosis persisted at grade 2, and grade 1 paronychia developed over the toenails. Pulsed azithromycin with dose of 500 mg once daily for three consecutive days per week was initiated, resulting in improvement of the skin eruption to grade 2 severity within four days without reporting any discomfort. After two weeks, the severity of skin toxicity further decreased to grade 1. However, during the off time of azithromycin (on Friday to Sunday), the rash recurred, and grade 2 paronychia developed over the toenails. Therefore, azithromycin regimen was adjusted to three times a week on Tuesday, Thursday and Saturday. Acneiform rash and paronychia on toenails were improved; however, grade 1 paronychia developed over fingernails afterward. Under this regimen for about 2 months, the rash recurred during the off time of azithromycin (on Monday), and the severity of paronychia on fingernails increased to grade 2. The regimen was then shifted to azithromycin 250 mg six times a week (on Monday to Saturday), resulting in grade 1 acneiform rash recurrence after one week. Antibiotics were then switched to cephalexin 500 mg four times daily by another hospital, but after one week, due to the intolerance of cephalexin and lack of improvement in grade 1 acneiform rash and stable paronychia on toenails and fingernails, the regimen was shifted back to azithromycin 500 mg three times a week on Tuesday, Thursday and Saturday by the patient, which seemed to be the most proper regimen for her. Timeline and details are shown in Fig. 1 and Fig. 2 . Photos of acneiform rash and paronychia before and after azithromycin were in Fig. 3 and Fig. 4 . Discussion Skin toxicities are the most common side effects of EGFR-TKIs. Incidences of these side effects are frequent and range from 36% for mucositis to 80% for acneiform rash 7 . The mechanisms of EGFR TKI-induced skin toxicities include the inhibition of EGFR signaling by TKIs, disrupting the normal turnover of skin cells and leading to alteration of keratinocyte differentiation and proliferation 8 . Additionally, the inhibition of EGFR signaling can also lead to an increased production of pro-inflammatory cytokines and increased infiltration of inflammatory cells into the skin, resulting in inflammation and the development of skin rash 8 . Skin toxicities may cause significant physical and emotional discomfort, emphasizing the importance of the management, which encompasses both non-pharmacological and pharmacological strategies. Non-pharmacological approaches comprise the use of alcohol-free moisturizers, sun avoidance, and minimize hot water exposure. Pharmacologic approaches consist of the topical application and systematic usage of steroids, antihistamine and antibiotics. For EGFR TKI-induced grade II-III acneiform rash and paronychia, current expert consensus recommends the use of tetracycline antibiotics for a period of 4–6 weeks. Additionally, several studies also showed the potential of a long-term tetracycline use in preventing EGFR-TKI related skin toxicity 9 . Although the antibiotic regimen is generally well-tolerated, a double-blind trial using tetracycline to prevent EGFR-TKI-induced skin rashes reported adverse events of any grades occurred in 4–41% patients, involving nausea, vomiting, abdominal pain, fatigue, dyspepsia, and anorexia 6 . The patient presented in our case experienced similar side effects, including nausea, vomiting, and poor appetite, which led to the discontinuation of tetracycline antibiotic and making the management of skin toxicities a challenge. In previous studies, pulsed azithromycin of 500 mg daily for 3 consecutive days per week for at least two weeks has emerged as a potential alternative treatment of EGFR TKI-induced skin toxicities for patients who couldn’t tolerate tetracycline antibiotics 10 , 11 . The therapeutic effects of azithromycin were proposed to be attributed to its anti-inflammatory, immunomodulatory, and antimicrobial properties. First, azithromycin has been shown to possess anti-inflammatory properties by inhibiting the production of pro-inflammatory cytokines and reducing the infiltration of inflammatory cells into the skin 12 .Second, it modulates the immune response by reducing the activation and proliferation of T-lymphocytes and inhibiting the differentiation and activation of dendritic cells 13 .Third, its antimicrobial activity may contribute to reducing bacterial colonization and infection in the skin. Last, pulsed azithromycin therapy offers a convenient and well-tolerated treatment regimen, potentially improving patient compliance and adherence to treatment, leading to the improvement of clinical outcomes. Our case report further supported the efficacy and safety of pulsed azithromycin and provided a different dosing strategy in treating TKI-induced skin toxicity. The patient initially experienced severe side effects after taking tetracycline antibiotics for EGFR TKI induced skin toxicity. After shifting the antibiotics to pulsed azithromycin, her skin rash showed improvement without any antibiotics intolerance. After two months on this regimen, owing to recurrence of acneiform rash during off time of azithromycin, the patient attempted various antibiotic dosing strategy to minimize fluctuations in blood concentration. These included modifying the azithromycin schedule from three consecutive days (on Monday to Wednesday) to a more evenly distributed pattern (on Tuesday, Thursday, Saturday) and reducing to half dosage but six times weekly. Interestingly, during the triweekly dosage, acneiform rash recurred on the patient's face on the second day during off time of azithromycin. Additionally, while patient taking half dosage six times weekly, sustained acneiform rash was reported. Although no previous IC50 of azithromycin against EGFR TKI-induced skin toxicity, this observation seemed to be suggesting a daily intake of 500 mg every other day may be needed to achieve and maintain effective blood concentration. As for the symptoms of paronychia, azithromycin did not appear to be an effective management strategy, as indicated by increasing severity grades during its use. A similar trend was observed with tetracycline antibiotics. Previous studies indicated that tetracycline only marginally reduced the occurrence of EGFR TKI-induced paronychia 14 , 15 . While no studies have provided explicit explanations, we propose two potential reasons for this observation. First, it could be the different distribution of azithromycin within various skin layers. Acneiform rash commonly occurs in seborrheic areas, whereas inflammation of the nail bed epidermis may lead to paronychia 16 . Second, the higher severity of skin toxicity induced by EGFR-TKI might be accompanied by bacterial suprainfection, with common organisms often showing resistance to azithromycin according to previous antimicrobial resistance reports. Further research is required to confirm the efficacy of azithromycin in treating paronychia. It's important to consider the potential side effects for patients requiring long-term use of azithromycin. A meta-analysis suggests that extended use of azithromycin for chronic lung diseases, with dosages including 250 mg once daily for 1 year and 500 mg three times a week for 6 months, can lead to adverse effects. First, it may contribute to a 2.7-fold increase in bacterial resistance compared to control groups receiving a placebo. Second, it could potentially lead to a 1.17-fold rise in hearing impairments 17 . Therefore, long term use of azithromycin should be used carefully despite its effectiveness in treating acneiform rash. Despite the fact that our study seems to support the use of pulsed azithromycin treatment for EGFR TKI-induced acneiform rash, the patient in our case report received other topical agents including multiple steroids, antibiotics, and moisturizer concurrently with azithromycin, which could have potentially influenced the observed outcomes. However, the patient continuously using these topical agents from the onset of skin toxicity and stopped most of the agents while reinitiated azithromycin after cephalexin, the impact was small. The efficacy and safety of pulsed azithromycin in treating EGFR TKI-induced skin toxicities need to be confirmed in larger, randomized controlled trials. Conclusion Our case report highlights the potential of azithromycin 500mg once another day as an effective and well-tolerated alternative treatment for EGFR TKI-induced acneiform rash but less effective for paronychia. Declarations Consent to publish was obtained from the patient. No funding was received to assist with the preparation of this manuscript. Author Contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Wei, Ho and Yi-Ming Chen . The first draft of the manuscript was written by Wei, Ho and Yi-Ming Chen and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. References Yang CY, Yang JC, Yang PC. Precision Management of Advanced Non-Small Cell Lung Cancer. Annu Rev Med. 2020 Jan 27;71:117-136. doi: 10.1146/annurev-med-051718-013524. PMID: 31986082. Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Nadanaciva S, Sandin R, Mok TS. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1454-1466. doi: 10.1016/S1470-2045(17)30608-3. Epub 2017 Sep 25. PMID: 28958502. Chu, C. Y., Chen, K. Y., Chang, J. W. C., Wei, Y. F., Lee, C. H., & Wang, W. M. (2017). Taiwanese Dermatological Association consensus for the prevention and management of epidermal growth factor receptor tyrosine kinase inhibitor-related skin toxicities. Journal of the Formosan Medical Association, 116(6), 413-423. Lacouture, M. E., Sibaud, V., Gerber, P. A., Van den Hurk, C., Fernández-Peñas, P., Santini, D., ... & ESMO Guidelines Committee. (2021). Prevention and management of dermatological toxicities related to anticancer agents: ESMO Clinical Practice Guidelines☆. Annals of Oncology, 32(2), 157-170. Dsouza, P. C., & Kumar, S. (2017). Role of systemic antibiotics in preventing epidermal growth factor receptor: tyrosine kinase inhibitors-induced skin toxicities. Asia-Pacific Journal of Oncology Nursing, 4(4), 323-329. Jatoi, A., Rowland, K., Sloan, J. A., Gross, H. M., Fishkin, P. A., Kahanic, S. P., ... & Loprinzi, C. L. (2008). Tetracycline to prevent epidermal growth factor receptor inhibitor‐induced skin rashes: Results of a placebo‐controlled trial from the North Central Cancer Treatment Group (N03CB). Cancer: Interdisciplinary International Journal of the American Cancer Society, 113(4), 847-853. Lacouture, M. E., Anadkat, M. J., Bensadoun, R. J., Bryce, J., Chan, A., Epstein, J. B., ... & MASCC Skin Toxicity Study Group. (2011). Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Supportive Care in Cancer, 19, 1079-1095. Lacouture, M. E. (2006). Mechanisms of cutaneous toxicities to EGFR inhibitors. Nature Reviews Cancer, 6(10), 803-812. Arrieta, O., Carmona, A., de Jesus Vega, M. T., Lopez-Mejia, M., & Cardona, A. F. (2016). Skin communicates what we deeply feel: antibiotic prophylactic treatment to reduce epidermal growth factor receptor inhibitors induced rash in lung cancer (the Pan Canadian rash trial). Annals of Translational Medicine, 4(16). Nikolaou, V., Strimpakos, A. S., Stratigos, A., Katsambas, A., Antoniou, C., & Syrigos, K. N. (2012). Azithromycin pulses for the treatment of epidermal growth factor receptor inhibitor-related papulopustular eruption: An effective and convenient alternative to tetracyclines. Dermatology, 224(4), 315-319. Akoglu, G., Yavuz, S. O., & Metin, A. (2016). Erlotinib-induced purpuric papulopustular eruption treated with pulsed azithromycin. Indian Journal of Pharmacology, 48(3), 324-326. Pradhan, S., Madke, B., Kabra, P., & Singh, A. L. (2016). Anti-inflammatory and immunomodulatory effects of antibiotics and their use in dermatology. Indian journal of dermatology, 61(5), 469-481. Kanoh, S., & Rubin, B. K. (2010). Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clinical microbiology reviews, 23(3), 590-615. Shinohara, A., Ikeda, M., Okuyama, H., Kobayashi, M., Funazaki, H., Mitsunaga, S., ... & Saitoh, S. (2015). Efficacy of prophylactic minocycline treatment for skin toxicities induced by erlotinib plus gemcitabine in patients with advanced pancreatic cancer: A retrospective study. American journal of clinical dermatology, 16, 221-229. Arrieta, O., Vega-González, M. T., López-Macías, D., Martínez-Hernández, J. N., Bacon-Fonseca, L., Macedo-Pérez, E. O., ... & de la Garza-Salazar, J. (2015). Randomized, open-label trial evaluating the preventive effect of tetracycline on afatinib induced-skin toxicities in non-small cell lung cancer patients. Lung Cancer, 88(3), 282-288. Segaert, S., & Van Cutsem, E. (2005). Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Annals of oncology, 16(9), 1425-1433. Li, H., Liu, D. H., Chen, L. L., Zhao, Q., Yu, Y. Z., Ding, J. J., ... & Xie, C. M. (2014). Meta-analysis of the adverse effects of long-term azithromycin use in patients with chronic lung diseases. Antimicrobial agents and chemotherapy, 58(1), 511-517. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4753337","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":330956513,"identity":"34cda585-ca38-49fa-bb3d-6e1db6cc5c32","order_by":0,"name":"Wei 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13:41:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":208361,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTimeline of azithromycin dose regimen\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4753337/v1/812c716c9175052df08800d1.png"},{"id":63285820,"identity":"0a23cc14-751e-4c21-b6da-071265006882","added_by":"auto","created_at":"2024-08-26 13:41:59","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":485117,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGrade 3 acneiform rash before taking azithromycin on day 63\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGrade 1 acneiform rash after taking azithromycin on day 77\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4753337/v1/f57e98f6edb112e97f8dae6b.png"},{"id":63287220,"identity":"085870bd-8327-4c66-9c19-30e653a237ed","added_by":"auto","created_at":"2024-08-26 13:49:58","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":218800,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGrade 1 paronychia before taking azithromycin on day 63\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGrade 2 paronychia after taking azithromycin on day 133\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4753337/v1/ac10fb4ac8e2b614f0429a4d.png"},{"id":63911419,"identity":"3ee07577-6a86-4869-a6f2-6bec4bb91f3b","added_by":"auto","created_at":"2024-09-03 16:34:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1617474,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4753337/v1/e54a04d0-b096-477e-9e6a-21b83a82b9df.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pulsed Azithromycin for the Treatment of Dacomitinib Induced Skin Toxicity in Patient with Tetracycline Intolerance – A Case Report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGene mutation in epidermal growth factor receptors (EGFR) plays an important role in the oncogenesis of non-small lung cancer (NSCLC). These mutations could be found in 40\u0026ndash;55% of East Asians and 15\u0026ndash;25% of Caucasians with adenocarcinoma type NSCLC\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and could be treated with EGFR tyrosine kinase inhibitors (TKI). Dacomitinib, a second generation of EGFR TKI, showed significant improvement of progression free survival in treating EGFR mutation NSCLC; however, 14% of patients experienced grade 3\u0026ndash;4 dermatitis\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe presentation of EGFR-TKI-induced skin toxicity ranged from pruritus, paronychia, xeroderma to mucositis, stomatitis and hair changes. Such adverse reaction may have deleterious impact on quality of life and may also lead to TKI dose modification and even discontinuation in severe cases. Various pharmacological and non-pharmacological strategies were developed aiming at minimizing the impact of skin-related side effects. According to current expert consensus, systemic tetracycline antibiotics (doxycycline 100 mg once daily to twice daily, minocycline 100 mg once daily to twice daily, and tetracycline 250 or 500 mg twice daily) for 4\u0026ndash;6 weeks were recommended for grade II-III skin toxicities such as acneiform rash and paronychia besides topical or oral immunomodulatory (i.e steroid, calcineurin inhibitor) \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, in a double-blind trial using tetracycline to prevent EGFR-TKI-induced skin rashes, tetracycline-associated adverse events of any grades occurred in 4\u0026ndash;41% patients, including nausea, vomiting, abdominal pain, fatigue, dyspepsia, and anorexia\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Therefore, there is a need for alternative effective and safe treatment for EGFR-TKI-induced skin toxicities.\u003c/p\u003e \u003cp\u003eIn this case report, we described a patient who was diagnosed with stage IV EGFR L858R mutated NSCLC experiencing dacomitinib-related acneiform rash and paronychia and successfully treated with azithromycin after intolerance to first line tetracycline antibiotics.\u003c/p\u003e"},{"header":"Case report","content":"\u003cp\u003eA 54-year-old woman, with a medical history notable for untreated hypertension and no smoking or alcohol use, was diagnosed with stage IV non-small cell lung cancer (NSCLC) harboring an EGFR L858R mutation in 2023. Consequently, she commenced oral dacomitinib (Vizimpro\u003csup\u003e\u0026reg;\u003c/sup\u003e 45 mg/tab) at 45 mg daily. Within one week, she developed grade 1 diarrhea and mucositis and about 16 days later, she presented with skin eruption affecting the face, scalp, and trunk. Under the impression of grade 2 EGFR TKI-related skin toxicity, patient was initially treated with doxycycline 100 mg twice daily and topical steroids, resulting in partial improvement of the rash. However, she subsequently developed grade 2 nausea and vomiting. Despite these side effects from doxycycline, the patient continued the therapy. Three weeks later, her skin condition remained relatively stable, but diarrhea had escalated to grade 3, prompting a reduction in dacomitinib dosage to 30 mg daily. Additionally, doxycycline was switched to minocycline 100 mg twice daily. However, she experienced worsening nausea and vomiting after minocycline. Therefore, tetracycline 250 mg twice daily was then prescribed but acneiform rash persisted without improvement, and grade 2 nausea and vomiting presented.\u003c/p\u003e\n\u003cp\u003eTwo weeks after dacomitinib dose reduction, the patient\u0026rsquo;s diarrhea had improved to grade 1 while the skin eruption remained at grade 2, with xerosis appearing on the trunk and face. Oral antibiotics were ceased due to the side effects and lack of efficacy, and antihistamine ketotifen fumarate was added. Despite these interventions, her skin eruption progressed to involve the entire body except for the upper limbs, reaching grade 3 severity. Xerosis persisted at grade 2, and grade 1 paronychia developed over the toenails.\u003c/p\u003e\n\u003cp\u003ePulsed azithromycin with dose of 500 mg once daily for three consecutive days per week was initiated, resulting in improvement of the skin eruption to grade 2 severity within four days without reporting any discomfort. After two weeks, the severity of skin toxicity further decreased to grade 1. However, during the off time of azithromycin (on Friday to Sunday), the rash recurred, and grade 2 paronychia developed over the toenails. Therefore, azithromycin regimen was adjusted to three times a week on Tuesday, Thursday and Saturday. Acneiform rash and paronychia on toenails were improved; however, grade 1 paronychia developed over fingernails afterward. Under this regimen for about 2 months, the rash recurred during the off time of azithromycin (on Monday), and the severity of paronychia on fingernails increased to grade 2. The regimen was then shifted to azithromycin 250 mg six times a week (on Monday to Saturday), resulting in grade 1 acneiform rash recurrence after one week. Antibiotics were then switched to cephalexin 500 mg four times daily by another hospital, but after one week, due to the intolerance of cephalexin and lack of improvement in grade 1 acneiform rash and stable paronychia on toenails and fingernails, the regimen was shifted back to azithromycin 500 mg three times a week on Tuesday, Thursday and Saturday by the patient, which seemed to be the most proper regimen for her. Timeline and details are shown in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Photos of acneiform rash and paronychia before and after azithromycin were in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSkin toxicities are the most common side effects of EGFR-TKIs. Incidences of these side effects are frequent and range from 36% for mucositis to 80% for acneiform rash\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The mechanisms of EGFR TKI-induced skin toxicities include the inhibition of EGFR signaling by TKIs, disrupting the normal turnover of skin cells and leading to alteration of keratinocyte differentiation and proliferation\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Additionally, the inhibition of EGFR signaling can also lead to an increased production of pro-inflammatory cytokines and increased infiltration of inflammatory cells into the skin, resulting in inflammation and the development of skin rash\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSkin toxicities may cause significant physical and emotional discomfort, emphasizing the importance of the management, which encompasses both non-pharmacological and pharmacological strategies. Non-pharmacological approaches comprise the use of alcohol-free moisturizers, sun avoidance, and minimize hot water exposure. Pharmacologic approaches consist of the topical application and systematic usage of steroids, antihistamine and antibiotics. For EGFR TKI-induced grade II-III acneiform rash and paronychia, current expert consensus recommends the use of tetracycline antibiotics for a period of 4\u0026ndash;6 weeks. Additionally, several studies also showed the potential of a long-term tetracycline use in preventing EGFR-TKI related skin toxicity\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Although the antibiotic regimen is generally well-tolerated, a double-blind trial using tetracycline to prevent EGFR-TKI-induced skin rashes reported adverse events of any grades occurred in 4\u0026ndash;41% patients, involving nausea, vomiting, abdominal pain, fatigue, dyspepsia, and anorexia\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The patient presented in our case experienced similar side effects, including nausea, vomiting, and poor appetite, which led to the discontinuation of tetracycline antibiotic and making the management of skin toxicities a challenge.\u003c/p\u003e \u003cp\u003eIn previous studies, pulsed azithromycin of 500 mg daily for 3 consecutive days per week for at least two weeks has emerged as a potential alternative treatment of EGFR TKI-induced skin toxicities for patients who couldn\u0026rsquo;t tolerate tetracycline antibiotics\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. The therapeutic effects of azithromycin were proposed to be attributed to its anti-inflammatory, immunomodulatory, and antimicrobial properties. First, azithromycin has been shown to possess anti-inflammatory properties by inhibiting the production of pro-inflammatory cytokines and reducing the infiltration of inflammatory cells into the skin\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.Second, it modulates the immune response by reducing the activation and proliferation of T-lymphocytes and inhibiting the differentiation and activation of dendritic cells\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.Third, its antimicrobial activity may contribute to reducing bacterial colonization and infection in the skin. Last, pulsed azithromycin therapy offers a convenient and well-tolerated treatment regimen, potentially improving patient compliance and adherence to treatment, leading to the improvement of clinical outcomes. Our case report further supported the efficacy and safety of pulsed azithromycin and provided a different dosing strategy in treating TKI-induced skin toxicity.\u003c/p\u003e \u003cp\u003eThe patient initially experienced severe side effects after taking tetracycline antibiotics for EGFR TKI induced skin toxicity. After shifting the antibiotics to pulsed azithromycin, her skin rash showed improvement without any antibiotics intolerance. After two months on this regimen, owing to recurrence of acneiform rash during off time of azithromycin, the patient attempted various antibiotic dosing strategy to minimize fluctuations in blood concentration. These included modifying the azithromycin schedule from three consecutive days (on Monday to Wednesday) to a more evenly distributed pattern (on Tuesday, Thursday, Saturday) and reducing to half dosage but six times weekly. Interestingly, during the triweekly dosage, acneiform rash recurred on the patient's face on the second day during off time of azithromycin. Additionally, while patient taking half dosage six times weekly, sustained acneiform rash was reported. Although no previous IC50 of azithromycin against EGFR TKI-induced skin toxicity, this observation seemed to be suggesting a daily intake of 500 mg every other day may be needed to achieve and maintain effective blood concentration. As for the symptoms of paronychia, azithromycin did not appear to be an effective management strategy, as indicated by increasing severity grades during its use. A similar trend was observed with tetracycline antibiotics. Previous studies indicated that tetracycline only marginally reduced the occurrence of EGFR TKI-induced paronychia \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. While no studies have provided explicit explanations, we propose two potential reasons for this observation. First, it could be the different distribution of azithromycin within various skin layers. Acneiform rash commonly occurs in seborrheic areas, whereas inflammation of the nail bed epidermis may lead to paronychia\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Second, the higher severity of skin toxicity induced by EGFR-TKI might be accompanied by bacterial suprainfection, with common organisms often showing resistance to azithromycin according to previous antimicrobial resistance reports. Further research is required to confirm the efficacy of azithromycin in treating paronychia.\u003c/p\u003e \u003cp\u003eIt's important to consider the potential side effects for patients requiring long-term use of azithromycin. A meta-analysis suggests that extended use of azithromycin for chronic lung diseases, with dosages including 250 mg once daily for 1 year and 500 mg three times a week for 6 months, can lead to adverse effects. First, it may contribute to a 2.7-fold increase in bacterial resistance compared to control groups receiving a placebo. Second, it could potentially lead to a 1.17-fold rise in hearing impairments\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Therefore, long term use of azithromycin should be used carefully despite its effectiveness in treating acneiform rash.\u003c/p\u003e \u003cp\u003eDespite the fact that our study seems to support the use of pulsed azithromycin treatment for EGFR TKI-induced acneiform rash, the patient in our case report received other topical agents including multiple steroids, antibiotics, and moisturizer concurrently with azithromycin, which could have potentially influenced the observed outcomes. However, the patient continuously using these topical agents from the onset of skin toxicity and stopped most of the agents while reinitiated azithromycin after cephalexin, the impact was small. The efficacy and safety of pulsed azithromycin in treating EGFR TKI-induced skin toxicities need to be confirmed in larger, randomized controlled trials.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur case report highlights the potential of azithromycin 500mg once another day as an effective and well-tolerated alternative treatment for EGFR TKI-induced acneiform rash but less effective for paronychia.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eConsent to publish was obtained from the patient. No funding was received to assist with the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003eAuthor Contribution\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Wei, Ho and Yi-Ming Chen . The first draft of the manuscript was written by Wei, Ho and Yi-Ming Chen and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eYang CY, Yang JC, Yang PC. Precision Management of Advanced Non-Small Cell Lung Cancer. Annu Rev Med. 2020 Jan 27;71:117-136. doi: 10.1146/annurev-med-051718-013524. PMID: 31986082.\u003c/li\u003e\n \u003cli\u003eWu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Nadanaciva S, Sandin R, Mok TS. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1454-1466. doi: 10.1016/S1470-2045(17)30608-3. Epub 2017 Sep 25. PMID: 28958502.\u003c/li\u003e\n \u003cli\u003eChu, C. Y., Chen, K. Y., Chang, J. W. C., Wei, Y. F., Lee, C. H., \u0026amp; Wang, W. M. (2017). Taiwanese Dermatological Association consensus for the prevention and management of epidermal growth factor receptor tyrosine kinase inhibitor-related skin toxicities. Journal of the Formosan Medical Association, 116(6), 413-423.\u003c/li\u003e\n \u003cli\u003eLacouture, M. E., Sibaud, V., Gerber, P. A., Van den Hurk, C., Fern\u0026aacute;ndez-Pe\u0026ntilde;as, P., Santini, D., ... \u0026amp; ESMO Guidelines Committee. (2021). Prevention and management of dermatological toxicities related to anticancer agents: ESMO Clinical Practice Guidelines☆. Annals of Oncology, 32(2), 157-170.\u003c/li\u003e\n \u003cli\u003eDsouza, P. C., \u0026amp; Kumar, S. (2017). Role of systemic antibiotics in preventing epidermal growth factor receptor: tyrosine kinase inhibitors-induced skin toxicities. Asia-Pacific Journal of Oncology Nursing, 4(4), 323-329.\u003c/li\u003e\n \u003cli\u003eJatoi, A., Rowland, K., Sloan, J. A., Gross, H. M., Fishkin, P. A., Kahanic, S. P., ... \u0026amp; Loprinzi, C. L. (2008). Tetracycline to prevent epidermal growth factor receptor inhibitor‐induced skin rashes: Results of a placebo‐controlled trial from the North Central Cancer Treatment Group (N03CB). Cancer: Interdisciplinary International Journal of the American Cancer Society, 113(4), 847-853.\u003c/li\u003e\n \u003cli\u003eLacouture, M. E., Anadkat, M. J., Bensadoun, R. J., Bryce, J., Chan, A., Epstein, J. B., ... \u0026amp; MASCC Skin Toxicity Study Group. (2011). Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Supportive Care in Cancer, 19, 1079-1095.\u003c/li\u003e\n \u003cli\u003eLacouture, M. E. (2006). Mechanisms of cutaneous toxicities to EGFR inhibitors. Nature Reviews Cancer, 6(10), 803-812.\u003c/li\u003e\n \u003cli\u003eArrieta, O., Carmona, A., de Jesus Vega, M. T., Lopez-Mejia, M., \u0026amp; Cardona, A. F. (2016). Skin communicates what we deeply feel: antibiotic prophylactic treatment to reduce epidermal growth factor receptor inhibitors induced rash in lung cancer (the Pan Canadian rash trial). Annals of Translational Medicine, 4(16).\u003c/li\u003e\n \u003cli\u003eNikolaou, V., Strimpakos, A. S., Stratigos, A., Katsambas, A., Antoniou, C., \u0026amp; Syrigos, K. N. (2012). Azithromycin pulses for the treatment of epidermal growth factor receptor inhibitor-related papulopustular eruption: An effective and convenient alternative to tetracyclines. Dermatology, 224(4), 315-319.\u003c/li\u003e\n \u003cli\u003eAkoglu, G., Yavuz, S. O., \u0026amp; Metin, A. (2016). Erlotinib-induced purpuric papulopustular eruption treated with pulsed azithromycin. Indian Journal of Pharmacology, 48(3), 324-326.\u003c/li\u003e\n \u003cli\u003ePradhan, S., Madke, B., Kabra, P., \u0026amp; Singh, A. L. (2016). Anti-inflammatory and immunomodulatory effects of antibiotics and their use in dermatology. Indian journal of dermatology, 61(5), 469-481.\u003c/li\u003e\n \u003cli\u003eKanoh, S., \u0026amp; Rubin, B. K. (2010). Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clinical microbiology reviews, 23(3), 590-615.\u003c/li\u003e\n \u003cli\u003eShinohara, A., Ikeda, M., Okuyama, H., Kobayashi, M., Funazaki, H., Mitsunaga, S., ... \u0026amp; Saitoh, S. (2015). Efficacy of prophylactic minocycline treatment for skin toxicities induced by erlotinib plus gemcitabine in patients with advanced pancreatic cancer: A retrospective study. American journal of clinical dermatology, 16, 221-229.\u003c/li\u003e\n \u003cli\u003eArrieta, O., Vega-Gonz\u0026aacute;lez, M. T., L\u0026oacute;pez-Mac\u0026iacute;as, D., Mart\u0026iacute;nez-Hern\u0026aacute;ndez, J. N., Bacon-Fonseca, L., Macedo-P\u0026eacute;rez, E. O., ... \u0026amp; de la Garza-Salazar, J. (2015). Randomized, open-label trial evaluating the preventive effect of tetracycline on afatinib induced-skin toxicities in non-small cell lung cancer patients. Lung Cancer, 88(3), 282-288.\u003c/li\u003e\n \u003cli\u003eSegaert, S., \u0026amp; Van Cutsem, E. (2005). Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Annals of oncology, 16(9), 1425-1433.\u003c/li\u003e\n \u003cli\u003eLi, H., Liu, D. H., Chen, L. L., Zhao, Q., Yu, Y. Z., Ding, J. J., ... \u0026amp; Xie, C. M. (2014). Meta-analysis of the adverse effects of long-term azithromycin use in patients with chronic lung diseases. Antimicrobial agents and chemotherapy, 58(1), 511-517.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"EGFR TKI, NSCLC, azithromycin, skin toxicity","lastPublishedDoi":"10.21203/rs.3.rs-4753337/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4753337/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSkin toxicities such as paronychia and acneiform rash are common side-effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) and significantly altered the quality of life of patients. Consensus guidelines recommended tetracycline antibiotics as the first line choices for both prophylaxis and treatment for grade II-III acneiform rash and paronychia. While generally well-tolerated, a subset of patients experiences adverse effects such as nausea, vomiting, diarrhea, headache, and photosensitivity, leading to antibiotics intolerance and leaving EGFR TKI-induced skin toxicities unmanaged. Therefore, an alternative treatment is needed.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe present a case of stage IV EGFR-mutated non-small cell lung cancer (NSCLC) treated with the second-generation EGFR TKI, dacomitinib. The patient developed grade 3 skin toxicities and was subsequently treated with azithromycin after demonstrating intolerance to tetracycline antibiotics.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAzithromycin was administered using various dosing strategies, and our findings indicated that 500 mg every other day might be the most effective regimen for treating EGFR-TKI-induced acneiform rash. However, this approach appeared to be less effective in managing paronychia.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis case highlights the potential efficacy of azithromycin 500mg once another day as an alternative to tetracycline antibiotics for managing EGFR TKI-related skin toxicities in NSCLC patients.\u003c/p\u003e","manuscriptTitle":"Pulsed Azithromycin for the Treatment of Dacomitinib Induced Skin Toxicity in Patient with Tetracycline Intolerance – A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-26 13:41:53","doi":"10.21203/rs.3.rs-4753337/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"89ea65a5-3535-4313-a366-a5cee7729f78","owner":[],"postedDate":"August 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-09T04:38:41+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-26 13:41:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4753337","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4753337","identity":"rs-4753337","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}