Association of Antibiotic Resistance With Antibiotic Use for Epidermal Growth Factor Receptor Inhibitor–Related Papulopustular Eruption | Dermatology | JAMA Dermatology | JAMA Network
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Table 1.  Demographic Characteristics of 71 Patients With Positive Bacterial Wound Culture Results From Papulopustular Eruptions Secondary to EGFR Inhibitor Therapya
Demographic Characteristics of 71 Patients With Positive Bacterial Wound Culture Results From Papulopustular Eruptions Secondary to EGFR Inhibitor Therapya
Table 2.  Positive Bacterial Wound Culture Results From 71 Patientsa
Positive Bacterial Wound Culture Results From 71 Patientsa
1.
Li  T, Perez-Soler  R.  Skin toxicities associated with epidermal growth factor receptor inhibitors.  Target Oncol. 2009;4(2):107-119. doi:10.1007/s11523-009-0114-0PubMedGoogle ScholarCrossref
2.
Lacouture  ME, Anadkat  MJ, Bensadoun  RJ,  et al; MASCC Skin Toxicity Study Group.  Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities.  Support Care Cancer. 2011;19(8):1079-1095. doi:10.1007/s00520-011-1197-6PubMedGoogle ScholarCrossref
3.
Eilers  RE  Jr, Gandhi  M, Patel  JD,  et al.  Dermatologic infections in cancer patients treated with epidermal growth factor receptor inhibitor therapy.  J Natl Cancer Inst. 2010;102(1):47-53. doi:10.1093/jnci/djp439PubMedGoogle ScholarCrossref
4.
Common Terminology Criteria for Adverse Events v5.0 (CTCAE). https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed July 4, 2018
5.
Cunliffe  WJ, Holland  KT, Bojar  R, Levy  SF.  A randomized, double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris.  Clin Ther. 2002;24(7):1117-1133. doi:10.1016/S0149-2918(02)80023-6PubMedGoogle ScholarCrossref
6.
Potthoff  K, Hofheinz  R, Hassel  JC,  et al.  Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion.  Ann Oncol. 2011;22(3):524-535. doi:10.1093/annonc/mdq387PubMedGoogle ScholarCrossref
Research Letter
April 24, 2019

Association of Antibiotic Resistance With Antibiotic Use for Epidermal Growth Factor Receptor Inhibitor–Related Papulopustular Eruption

Author Affiliations
  • 1Department of Dermatology, Stanford University School of Medicine, Stanford, California
  • 2Department of Infectious Diseases, Stanford University School of Medicine, Stanford, California
  • 3Department of Oncology, Stanford University School of Medicine, Stanford, California
JAMA Dermatol. 2019;155(7):848-850. doi:10.1001/jamadermatol.2019.0063

Papulopustular eruption (PPE) develops in up to 90% of patients with cancer treated with epidermal growth factor receptor (EGFR) inhibitors.1 Consensus recommendations for management include emolliation, sunscreen, topical corticosteroids, and topical and systemic antibiotics, which effectively decrease severity of EGFR inhibitor–related PPE.2 Although the initial EGFR inhibitor–related PPE is sterile, secondary infection increases the severity and duration of PPEs. Higher-grade, refractory cases may show antibiotic-resistant bacterial infection on wound culture.3 This study investigated whether use of topical clindamycin and/or oral tetracyclines during management of EGFR inhibitor–related PPE is associated with antibiotic-resistant bacterial infection.

Methods

We conducted a retrospective medical record review of the Stanford Cancer Institute Research Database. All patients were screened for inclusion and provided a waiver of consent. Patients included in the cohort were enrolled in the database from January 1, 2012, to July 31, 2016, diagnosed with at least grade 1 EGFR inhibitor–related PPE,4 and had a subsequent wound culture of the PPE that yielded bacterial organism. We collected dates of EGFR inhibitor therapy, time and duration of antibiotic exposure to topical clindamycin and/or oral tetracyclines, and bacterial wound culture results, including antibiotic susceptibility testing. Patients concurrently treated with antiseptics or with no antibiotic duration reported were excluded. The study was approved by the Stanford University Administrative Panel on Human Subjects in Medical Research under the extended approval process. All data were deidentified.

To compare patients whose wound culture yielded antibiotic-resistant bacteria with those whose wound culture did not, age was compared with an unpaired t test. Categorical variables were compared by χ2 or Fisher exact test as appropriate. Cox proportional hazards regression was performed to determine whether time from EGFR inhibitor therapy start to first positive wound culture result was associated with antibiotic exposure. Antibiotic exposures were treated as time-dependent variables. All tests were 2-sided, and P < .05 was considered to be statistically significant. All statistical analyses were conducted with SAS statistical software, version 9.4 (SAS Institute Inc).

Results

Among 71 patients (mean [SD] age, 62.4 [13.1] years; 46 [64.8%] male) with positive bacterial wound culture results, the incidence of clindamycin-resistant infection was highest among patients who received topical clindamycin therapy for greater than 4 weeks (n = 19 [63.3%]) vs no treatment (n = 8 [26.7%]) and treatment for less than 4 weeks (n = 3 [10.0%]). The incidence of tetracycline-resistant infection was highest among patients who received oral tetracycline therapy for greater than 4 weeks (n = 14 [46.7%]) vs no treatment (n = 12 [40.0%]) and treatment for less than 4 weeks (n = 4 [13.3%]) (Table 1 and Table 2). The risk of antibiotic-resistant bacterial infection was greater with increased treatment time for patients with history of oral tetracycline use (hazard ratio, 3.15; 95% CI, 1.45-6.85; P = .004) or prior topical clindamycin use (hazard ratio, 1.94; 95% CI, 0.83-4.50; P = .12).

Discussion

In this study, patients who received topical clindamycin or oral tetracycline for management of EGFR inhibitor–related PPEs had a higher incidence of secondary skin infection with antibiotic-resistant bacteria compared with patients without prior antibiotic exposure, a finding that reached statistical significance with exposure to oral tetracyclines. A greater incidence of resistant infections was seen in patients with greater than 4 weeks of exposure to either antibiotic, suggesting that longer duration of antibiotic use is associated with increased risk of developing antibiotic resistance.

Our findings are consistent with a previous study5 in acne vulgaris, which found that antibiotic use without concurrent antiseptic therapy was associated with development of antibiotic-resistant bacteria. Guidelines for EGFR inhibitor–related PPE management understandably recommend against using benzoyl peroxide because of potential exacerbation of EGFR inhibitor–related xerosis and skin irritation.3,6 Given the finding that patients with a history of antibiotic monotherapy for EGFR inhibitor–related PPE may develop antibiotic-resistant skin infections, we suggest consideration of concurrent antiseptic therapy (eg, benzoyl peroxide, dilute bleach baths, or chlorhexidine) during topical or oral antibiotic therapy for EGFR inhibitor–related PPE.

Limitations to this study include the sample size and single-center design. Lifetime exposure to antibiotics, which may result in permanent changes to skin flora, was not assessed. Patient adherence to antibiotic use may have been variable. The effect of concurrent antiseptic therapy on reducing the incidence of antibiotic-resistant bacterial infections has not yet been determined. The risk of xerosis and skin irritation with concurrent antiseptic therapy in this patient population has not yet been determined; however, in our institutional experience, antiseptic-related xerosis can be effectively managed with diligent emolliation. We look forward to future studies that investigate whether the addition of topical antiseptics during management of EGFR inhibitor–related PPE may lead to reduction of antibiotic resistance and, subsequently, improved outcome and quality of life in this susceptible patient population.

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Article Information

Accepted for Publication: March 29, 2019.

Corresponding Author: Bernice Y. Kwong, MD, Department of Dermatology, Stanford University School of Medicine, 780 Welch Rd, CJ220J, Palo Alto, CA 94304-5779 (bernicek@stanford.edu).

Published Online: April 24, 2019. doi:10.1001/jamadermatol.2019.0063

Author Contributions: Dr Hirotsu and Mr Dang are co–first authors. Dr Hirotsu and Mr Dang had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Hirotsu, Kwong.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Hirotsu, Dang, Li, Kwong.

Critical revision of the manuscript for important intellectual content: Dang, Li, Neal, Pugliese, Subramanian, Kwong.

Statistical analysis: Li.

Administrative, technical, or material support: Subramanian, Kwong.

Supervision: Neal, Pugliese, Kwong.

Conflict of Interest Disclosures: Dr Neal reported serving in a consulting or advisory role for ARIAD/Takeda, AstraZeneca, and Genentech/Roche and receiving research funding from Genentech/Roche, Merck & Co., Novartis, Boehringer Ingelheim, Exelixis, ARIAD/Takeda, and Nektar Therapeutics. Dr Kwong reported serving as a consultant to Genentech/Roche. No other disclosures were reported.

Funding/Support: This study was supported in part by Cancer Center Support Grant 5P30CA124435 from the National Cancer Institute and Clinical and Translational Science Award UL1 RR025744 from the Stanford National Institutes of Health/National Center for Research Resources.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Li  T, Perez-Soler  R.  Skin toxicities associated with epidermal growth factor receptor inhibitors.  Target Oncol. 2009;4(2):107-119. doi:10.1007/s11523-009-0114-0PubMedGoogle ScholarCrossref
2.
Lacouture  ME, Anadkat  MJ, Bensadoun  RJ,  et al; MASCC Skin Toxicity Study Group.  Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities.  Support Care Cancer. 2011;19(8):1079-1095. doi:10.1007/s00520-011-1197-6PubMedGoogle ScholarCrossref
3.
Eilers  RE  Jr, Gandhi  M, Patel  JD,  et al.  Dermatologic infections in cancer patients treated with epidermal growth factor receptor inhibitor therapy.  J Natl Cancer Inst. 2010;102(1):47-53. doi:10.1093/jnci/djp439PubMedGoogle ScholarCrossref
4.
Common Terminology Criteria for Adverse Events v5.0 (CTCAE). https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed July 4, 2018
5.
Cunliffe  WJ, Holland  KT, Bojar  R, Levy  SF.  A randomized, double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris.  Clin Ther. 2002;24(7):1117-1133. doi:10.1016/S0149-2918(02)80023-6PubMedGoogle ScholarCrossref
6.
Potthoff  K, Hofheinz  R, Hassel  JC,  et al.  Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion.  Ann Oncol. 2011;22(3):524-535. doi:10.1093/annonc/mdq387PubMedGoogle ScholarCrossref
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