Clinical Characteristics, Treatment, and Prognosis of Amoxicillin-Induced AGEP/ALEP

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Introduction
Acute generalized exanthematous pustulosis (AGEP) is a rare and serious skin adverse reaction with a morbidity of only 1 to 5 in 1,000,000 [1].AGEP is characterized by nonfollicular sterile pustules on an erythematous base and fever and can be induced by drugs, infection, foods, and xenobiotics [2].More than 90% of patients with AGEP are related to drug intake [3,4].
Penicillin is often associated with allergic reactions, with the most common adverse skin reactions being hives and rashes [5].AGEP is a rare cutaneous adverse reaction to amoxicillin.What is known about amoxicillin-induced AGEP comes mainly from case reports.Te clinical characteristics of amoxicillin-induced AGEP are unclear.Te purpose of this study was to investigate the clinical characteristics of amoxicillin-induced AGEP and to provide evidence for the prevention and treatment of amoxicillininduced AGEP by collecting related cases.

Inclusion and Exclusion
Criteria.Case reports and case series were included, and reviews, mechanism studies, and duplicate reports were excluded.

Discussion
Several drugs have been reported in association with AGEP, such as pristinamycin, quinolones, hydroxychloroquine, sulfonamides, terbinafne, diltiazem, ketoconazole, and fuconazole [6].Te clinical characteristics of AGEP induced by diferent drugs may be diferent.AGEP can occur at any age and seems to be more common in women [1].Amoxicillin-induced AGEP appeared in both male and female patients with no gender diference.Te mean duration of drug-induced AGEP depends on the drug class.
AGEP can be triggered 1 day after a burst of antibiotics and an average of 11 days after exposure to other nonantibiotic drugs.6 Diltiazem-induced AGEP ranged from 1 day to 3 weeks, whereas terbinafne-induced AGEP ranged from 1 day to 77 days [7,8].Amoxicillin-induced AGEP ranged from 6 h to 28 d after administration.Tis may suggest that the pathogenesis of AGEP is diferent for diferent druginduced AGEP.Te severity, laboratory tests, and prognosis of AGEP caused by diferent drugs may vary.Laboratories for AGEP caused by other drugs found hypocalcemia in some cases and eosinophilia in 30% of cases [9].In rare cases, AGEP may also be associated with life-threatening systemic  4 Dermatologic Terapy symptoms, including cholestasis, nephritis, and lung and bone marrow involvement, with mortality rates as high as 5% [2].ALEP is a rare variant of AGEP in which lesions are usually confned to the face, neck, or chest [10,11].Amoxicillin-clavulanic acid and amoxicillin are the most commonly reported causes of ALEP cases compared to other drugs [12].About 20% of patients have amoxicillin-induced ALEP.Most current studies on diferent drug-induced AGEP have been limited to observational or case reports with small sample sizes.Future multicenter, large-sample studies are needed to clarify the clinical characteristics of AGEP induced by diferent drugs.Te possibility of other drugs inducing AGEP cannot be ruled out, as 26% of patients were taking multiple drugs simultaneously.Clavulanic acid can also induce acute systemic erythematous impetigo [13].Other drugs have been reported to be associated with AGEP, such as acetylsalicylic acid, ibuprofen, gliclazide, acarbose, and prednisolone [14][15][16][17][18]. Te determination of amoxicillin as the primary cause of AGEP is based on the timing of the onset of AGEP and the sequence of medications taken, as well as the improvement of symptoms after withdrawal.
Te diagnosis of AGEP is confrmed by clinical presentation, histopathological examination, and patch test [1].Amoxicillin-induced AGEP is characterized by an acute and extensive pustular exanthema composed of numerous small, mostly nonfollicular, sterile pustules on erythematous skin, while erythroderma is common but not widespread in AGEP.Te rash is distributed on the extremities, trunk, and face.AGEP patients are often accompanied by fever, with body temperature generally above 38 °C, and only a few patients have mucosal damage.Patients with amoxicillininduced AGEP fever had a temperature of up to 40 °C.Mucous membranes were involved in about 22% of patients.Systemic involvement occurs in about 20% of patients, mostly involving liver, kidney, and lung function.Severe AGEP patients may experience multiple organ dysfunction and even death [19].Liver, kidney, and lung involvement occurred in 22% of amoxicillin-induced AGEP patients.Leukocytosis and elevated neutrophil count (>7500/mm 3 ) are another important characteristic of AGEP [1].Te neutrophil count exceeded 7500/mm 3 in all patients with amoxicillin-induced AGEP.
Little is known about cross-reactivity in beta-lactaminduced AGEP.For pinpointing the culprit drug, cutaneous patch testing can prove helpful in contrast to other adverse drug eruptions and should be performed earliest 6 weeks after complete resolution.Te sensitivity of patch testing is reported to be around 50-58% [20].In addition, LTT, intradermal tests, and skin prick tests are also helpful in fnding sensitizing drugs [21].Te LTT may be more sensitive than the patch test, especially in cases caused by beta-lactam antibiotics, and can help identify the culprit drug [22].Patch tests help to identify multiple positive reactions to penicillin, aminopenicillin, and cephalosporin and provide specifc avoidance indications.Mysore et al. reported one case of AGEP relapsing in a patient using piperacillin, ceftazidime, and meropenem [23].Some patients showed only positive for penicillin antibiotics and negative for cephalosporins.20 Although the patch test was negative for cephalosporins, we advise patients to use them with caution.
AGEP may be confused with other diseases, leading to misdiagnoses, such as generalized pustular psoriasis (GPP), Stevens-Johnson syndrome, toxic epidermal necrolysis, subcorneal pustular dermatosis, bullous impetigo, and hypersensitivity syndrome reaction [19].AGEP is clinically similar to GPP of the von Zumbusch type, and it is difcult to distinguish between the two.However, a history of psoriasis, prolonged fever, diferentiated histopathological picture, and no history of drug exposure contributed to the diagnosis of GPP [6].
Te exact pathogenesis of AGEP remains a mystery.AGEP is a T-lymphocyte-mediated delayed-type hypersensitivity response confrmed by patch tests and in vitro tests [24].Pathogenic agents (mainly drugs) come into contact with the body and activate specifc CD4+ and CD8 + T lymphocytes via antigen-presenting cells.Te activated lymphocytes enter the dermis and epidermis and release large amounts of the neutrophil chemotactic factor interleukin 8 (IL-8) to further neutrophil chemotactic into the blister and eventually form sterile pustules [25].IL-36RN mutations have been associated with a variety of aseptic impetigo, such as GPP and impetigo herpetiformis [26,27].In recent years, IL-36RN gene mutation has been found to be associated with some AGEP patients.IL-36RN is responsible for encoding the IL-36 receptor antagonist (IL-36Ra).IL-36RN is responsible for encoding the high expression of the IL-36 receptor antagonist (IL-36Ra) in Dermatologic Terapy the epithelial tissues of the skin.Structural changes in IL-36Ra lead to uncontrolled IL-36 signaling when IL-36RN is mutated, activating downstream proinfammatory signaling pathways that lead to impetigo eruptions [1,28].Patients with IL-36RN variants were more likely to have mucosal involvement [29,30].Conversely, oral mucosal involvement may be a clinical clue to potential mutations in IL-36RN.More studies are needed to confrm whether IL-36RN mutation is the molecular genetic basis of AGEP.Te optimal treatment plan for AGEP is still not determined, and discontinuation of suspect drugs is the most important means.Topical disinfection and wetting dressings as well as topical corticosteroids may be an efective means, and topical corticosteroids may also be efective for severe itching [19].Systemic glucocorticoids need to be used in severe cases, and skin lesions usually subside within a few days.Tere is a lack of high-quality evidence on the dose and duration of systemic glucocorticoid therapy.Diferent drug-induced AGEP resolution times difer, which may be related to the half-life of the drug.For example, the 40-50 days half-life of hydroxychloroquine results in AGEP resolution times ranging from 7 to 81 days [31].Amoxicillin-induced AGEP symptoms usually resolve spontaneously within 2-42 days.Although there is a lack of clinical evidence for the use of immunosuppressants, cyclosporine and etanercept are often administered in common practice with signifcant clinical results [32,33].IL-36 receptor antagonists may play an important role in the treatment of AGEP.Spesolimab is an IL-36 receptor antagonist approved for the treatment of GPP fares in adults [34].AGEP is self-limited and has a good prognosis.However, reexposure to the same trigger may also lead to another episode of AGEP [35][36][37].

Conclusion
AGEP is a very rare complication of amoxicillin and difers from other acute episodes of GPP.Clinicians should promptly discontinue and avoid readministering amoxicillin once patients develop AGEP.AGEP is self-limiting, and topical corticosteroids reduce the duration of hospitalization.Te evidence for systemic corticosteroid therapy in the treatment of AGEP is unclear.

Table 1 :
Basic characteristics of the 46 patients included.

Table 2 :
Clinical characteristics of the 46 patients included.
a Te number of patients out of 46 about whom information regarding this particular parameter was provided.

Table 3 :
Laboratory and histological examination of 46 patients included.
a Te number of patients out of 46 about whom information regarding this particular parameter was provided.b Median (minimum-maximum).

Table 4 :
Treatment and prognosis of the 46 patients included.