In recent years, the prevalence of moderate to severe acne refractory to standard therapy has increased. Resistance to systemic antibiotics is also increasing, and acne therapy becomes ineffective, while topical antibiotics remain a reliable treatment. Systemic retinoids are increasingly used in the treatment of moderate to severe acne. A flare phenomenon may occur during the first few months of therapy with systemic retinoids. In addition, further therapy with these drugs is associated with some adverse events and side effects (retinoid dermatitis, cheilitis, etc.), which may cause some patients to stop treatment permanently. Physicians should take care to minimize the risks associated with systemic retinoids. The use of topical antibiotics in the first phase of therapy and moisturizing agents throughout the retinoid therapy may be of benefit. The proposed approach of step-down doses of systemic isotretinoin combined with topical clindamycin solution and a moisturizing agent allows for high treatment adherence, achieving excellent clinical outcomes and long-term remission of acne. The addition of a topical antibiotic prevents the flare, and moisturizer agents minimize the dryness caused by systemic retinoids.