Acne is a ca-limited skin disease associated with youthful development, mainly on the face, chest, and back with white and blackhead acne, papules, pustules, nodules, and cysts. Rational drug treatment can control the progression of the disease, shorten the natural course of acne, prevent serious complications such as scarring, and relieve patients of the psychological stress caused by acne. At present, with the introduction of a large number of systemic drugs and topical drugs, especially retinoids, acne is now being treated. Acne has made great progress in treatment, but there are still some acne cases that are resistant to conventional medication, called refractory acne. The reasons for their formation are complex. How to analyze and treat refractory acne is a difficult problem. 1. Definition of refractory acne Refractory acne mainly refers to acne that does not improve or fades slowly after more than one month of continuous conventional drug treatment, or acne that recurs soon after stopping the drug. This type of acne does not respond to normal doses of antibiotic treatment, and some patients even continue to progress in the course of treatment, forming disfiguring scars. 2. Analysis of the etiology of refractory acne The formation of refractory acne is related to a variety of factors, including the patient’s own lack of compliance with treatment, as well as the doctor’s diagnosis, treatment is not reasonable and other reasons. Through a review of the literature and the author’s own experience, the causes of refractory acne are summarized below. 2.1 Diagnostic errors When encountering patients with refractory acne, the first thing to rule out is whether there is a diagnostic error. For example, sebaceous hyperplasia, rosacea, eosinophilic folliculitis, Staphylococcus aureus folliculitis, and gram-negative folliculitis. These diseases are sometimes difficult to distinguish from acne, and their treatment methods are very different from acne, so careful clinical observation is needed, and bacterial culture and histopathological examination should be performed if necessary to exclude them. 2.2 Improper objective evaluation of patient lesions Acne treatment requires frequent objective evaluation of the efficacy of acne. Poor efficacy may sometimes be a result of inconsistent or inappropriate selection of acne evaluation methods. Objective evaluation of acne lesion changes requires attention to two aspects: (1) the accuracy of the acne grading evaluation index; and (2) the uniformity of acne efficacy evaluation criteria. There are many methods for evaluating the efficacy of acne, from which dermatologists need to choose an evaluation method with which they are familiar. Carefully observe the type, distribution and number of lesions before starting medication, and evaluate them several times during or after treatment using the same evaluation method. The evaluation should be as objective and accurate as possible to eliminate misjudgment of efficacy due to unskilled evaluation methods. 2.3 Ignore the impact of psychological factors on acne patients Acne can cause psychological disorders in patients. Objective evaluation of the impact of acne on the patient’s psychology is very important to the treatment of acne. Measuring the degree of psychological impact of acne on patients requires the design of a uniform psychological impact scale. Physicians can rate and judge the psychological impact of acne according to the Acne Psychological Impact Scale designed by Cardiff. It is important to note that the Cardiff scale has a maximum score of 144. A score of 80 or higher indicates that acne is having a serious impact on the patient’s life and work. This should be taken seriously by the doctor. In general, patients with higher psychological scores also tend to have clinical manifestations that are inconsistent with the degree of psychological impact. These patients have high expectations for the treatment of the disease and hope to completely control their condition within a short period of time. This is the only way to achieve satisfactory results. Treating the lesions alone often has little effect. 2.4 Inadequate patient compliance with treatment Acne is a chronic disease, and its treatment is usually not a one-time event. Adherence to treatment for a period of time after the symptoms will gradually improve, and show good results. If patients lack such understanding in the treatment, they often stop using or change to other drugs without authorization and lead to poor results. To prevent the occurrence of similar situations, the doctor needs to do the necessary explanation to the patient before treatment. To prevent similar cases, it is necessary for the doctor to do the necessary explanation to the patient before the treatment. The patient should have a preliminary understanding of the possible adverse reactions and the expected therapeutic effect of the drugs currently used. Doctors should require patients to strictly implement medical advice, regular follow-up, and timely observation of changes in the condition after the use of drugs. 2.5 Adverse drug reactions affect the use of drugs Topical or oral medications for acne may have some adverse reactions, which are tolerated by some patients, but not by others, and patients who cannot tolerate them often discontinue their medications. Therefore, clinicians need to explain to patients the possible adverse reactions to medications before treatment and instruct them to inform their doctors when they encounter such phenomena. The doctor will take effective measures to minimize the degree of adverse reactions and ensure the continued use of the drug. 2.6 Resistance to Propionibacterium acnes (P. acnes) There is increasing evidence that. Propionibacterium acnes plays an important role in the inflammatory response to acne. In the early 1980s, P. acnes was rarely drug-resistant, but in recent years, the widespread use of antibiotics in acne treatment has led to an increase in the number of drug-resistant strains of P. acnes. A multinational, multicenter study conducted by Ross et al. in Europe in 2003 showed that among 662 acne patients, drug-resistant strains were detected in 515 lesions, with the lowest detection rate of 51% and the highest detection rate of 91% for strains resistant to one antibiotic, and the highest detection rate of 92% for strains resistant to both clindamycin and erythromycin. The highest detection rate was 92%. Tetracycline-resistant strains were generally lower, with an average of about 27%. Ross concluded that the difference in detection rates of resistant strains of Propionibacterium acnes was closely related to the antibiotic use habits of local physicians. Antibiotics that are used more frequently and for longer periods of time also have more resistant strains to them. Bacterial drug resistance is a common problem worldwide, and China is no exception, although there are no reports on this aspect in China. However, a large number of clinical data show that the problem of drug resistance in Propionibacterium acnes already exists. In clinical practice, the following phenomena contribute to the determination of drug resistance: ① ineffective treatment with antibiotics effective for others; ② patients treated with long-term oral erythromycin; ⑧ patients treated with multiple oral or topical antibiotics; ④ no effect of antibiotic treatment within 1 month; Ross believes that the combination of benzoyl peroxide and antibiotics can reduce the development of drug resistance in P. acnes. It was clinically shown that the combination of 5% benzoyl peroxide and 3% erythromycin topically significantly improved the efficacy of both and reduced the drug resistance of Propionibacterium acnes. In order to reduce the drug resistance of Propionibacterium acnes. The author believes that clinicians should: (1) minimize the frequency of antibiotic replacement; (2) avoid using multiple different oral or topical antibiotics at the same time; (3) combine topical antibiotics with benzoyl peroxide as much as possible; (4) alternate topical azelaic acid or zinc sulfate with antibiotic ointment; (5) topical retinoids combined with oral or topical antibiotic treatment can significantly reduce the development of resistance. For strains that have developed resistance can be switched to another antibiotic or other drug therapy (such as spironolactone, isotretinoin, etc.). 2.7 Inappropriate use of isotretinoin Isotretinoin is highly effective in the treatment of acne. Systematic application of isotretinoin is effective for many severe acne. Oral isotretinoin is considered the most effective drug for the treatment of acne, but it is often not used as a first-line drug due to its more serious adverse effects, such as H-dryness, desquamation, and teratogenicity. Oral isotretinoin is generally indicated for moderate to severe acne, and is particularly suitable for the treatment of cystic and nodular acne. It is generally not recommended for common acne of less than moderate severity. If the indications are not properly grasped, the condition is often delayed and treatment is delayed or unnecessary pain is caused to the patient. In addition, some studies have shown that the recurrence rate of isotretinoin is as high as 82% if the cumulative dose is <120 mg, kg. The cumulative dose should be increased to reduce the recurrence rate. 2.8 Special types of rare severe acne With all of the above possibilities ruled out, these patients are likely to belong to a few special types of severe acne, such as fulminant acne, aggregated acne, and cystic sinusoidal acne. Most of these types of acne are less effective with first-line acne medications and require oral isotretinoin treatment. For nodular and cystic lesions, Kligman recommends the following treatment options: (1) topical glucocorticoid ointment can be applied 3 times daily for 5-7 d; (2) intra-lesion glucocorticoid injections 2-3 times over 3-4 weeks; (3) if the lesions do not subside after 3-4 weeks, liquid nitrogen cryotherapy can be considered, lasting 10-20s each time and repeated once every 2 weeks. 20s, repeated once in 2 weeks. For cystic lesions can be applied: ① local or intradermal glucocorticoid injection in the acute inflammatory phase; ② liquid nitrogen freezing treatment can be used in the non-acute phase. Treatment of sinusoidal lesions is the most difficult, and in addition to treatment with conventional antibiotics and isotretinoin I=1 administration, topical topical and intradermal glucocorticoid injections can be used appropriately. If the pus is large, surgical drainage can be performed. 2.9 Insufficient concentration of effective drugs in the sebaceous glands of hair follicles To some extent, insufficient effective concentration of drugs in the sebaceous glands of hair follicles is often associated with the development of drug resistance in Propionibacterium acnes. Most antibiotics effective in the treatment of acne have corresponding sites of action in the follicular sebaceous gland, and administration of high doses should generally show better clinical efficacy. However, in some non-P. acnes resistant patients, there is tolerance to antibiotic therapy. eady et al. found that sebaceous gland secretion function was increased in these patients compared to patients with normal acne, and that high levels of sebum secretion rates were directly associated with reduced effective drug concentrations in the local follicular sebaceous ducts. They suggested that the reduced effective drug concentration may be due to increased sebaceous secretion, which dilutes the drug concentration in the local hair follicle ducts. The effective drug concentration that does not reach the minimum inhibitory concentration decreases the inhibition rate of Propionibacterium acnes, which further affects the therapeutic effect of acne. If you encounter acne patients who are resistant to conventional doses of antibiotic therapy in the clinical setting, in addition to first considering the issue of bacterial resistance, you should also consider whether the problem is one of insufficient local effective drug concentration in the sebaceous glands of the hair follicles. If necessary, a culture of Propionibacterium acnes and a drug sensitivity test can be performed to differentiate. There are three ways to solve the problem of ineffective antibiotic treatment due to insufficient concentration of effective drugs in the sebaceous glands of hair follicles: ① Increase the dose of El antibiotics: ② Female patients can be treated with a combination of anti-androgenic drugs, such as Daing 35 and spironolactone: ③ Oral treatment with isotretinoin if necessary. 2.10 Neglecting the treatment of the causes of acne There are two main causes of acne: internal and external. The endogenous causes mainly refer to factors related to high androgen secretion within the body, such as adrenal tumors, polycystic ovary syndrome, congenital adrenal hypertrophy, Cushing's syndrome, etc., as well as hereditary factors such as synovitis, acne, pustulosis, bone hypertrophy, osteomyelitis syndrome, and acral syndrome. Clinically, for female patients with sudden onset of severe acne, especially individuals with no previous history of acne: acne with hirsutism, irregular menstrual cycle, voice changes, insulin resistance, and androgenetic alopecia, etc. should undergo endocrinological examination to determine whether the body has endocrine abnormalities. When patients with high androgen secretion are ineffective with conventional treatment, systemic application of anti-androgen drugs or glucocorticoid drugs is required. External causes mainly refer to exposure to substances that induce the occurrence of acne (mineral oil, cosmetic agents, detergents, decorative agents, etc.), intake of various acne-causing drugs (glucocorticoids, iodine, bromine, cod liver oil, thioredoxin, isoniazid, para-aminosalicylic acid, thiourea, phenytoin hydrated chloral, etc.), hot or humid seasons (tropical acne, summer acne), and local mechanical friction. These acne patients need to be treated for the cause and the corresponding cause removed, acne lesions will naturally subside, otherwise they show resistance to conventional acne treatment drugs. 3. General treatment principles for refractory acne When treating refractory acne, the author advocates first analyzing the cause of the disease according to the patient's specific situation, and then taking appropriate treatment measures for different causes. If the patient is not compliant with the treatment. Patients need to be convinced to follow medical advice and fully mobilize their motivation for treatment: patients who are resistant to Propionibacterium acnes need to be switched to other sensitive antibiotics or other therapeutic drugs. If it is difficult to find a clear cause, systematic application of anti-androgen drugs, isotretinoin or glucocorticoids can be considered. Refractory acne is not uncommon in clinical practice, and treatment requires specific and detailed analysis of different patients to rule out each of the above possible causes and finally reach a correct conclusion. Based on the results of the analysis, effective measures should be taken to treat acne in a timely manner. In the premise of minimizing the adverse effects, the condition can be effectively controlled as soon as possible. With the continuous improvement of the disease, the patient's anxiety, depression and other adverse psychological states can be effectively relieved. This is more conducive to the further treatment of the disease, thus forming a virtuous cycle of acne treatment. Do not blindly use drugs with strong effects but heavy adverse reactions, such as isotretinoin and Dainichi 35, to avoid delaying treatment or bringing unnecessary negative effects to patients.