Re-establishing the utility of tetracycline-class antibiotics for current challenges with antibiotic resistance

The progressive increase in antibiotic resistance in recent decades calls for urgent development of new antibiotics and antibiotic stewardship programs to help select appropriate treatments with the goal of minimising further emergence of resistance and to optimise clinical outcomes. Three new tetracycline-class antibiotics, eravacycline, omadacycline, and tigecycline, have been approved within the past 15 years, and represent a new era in the use of tetracyclines. These drugs overcome the two main mechanisms of acquired tetracycline-class resistance and exhibit a broad spectrum of in vitro activity against gram-positive, gram-negative, anaerobic, and atypical pathogens, including many drug-resistant strains. We provide an overview of the three generations of tetracycline-class drugs, focussing on the efficacy, safety, and clinical utility of these three new third-generation tetracycline-class drugs. We also consider various scenarios of unmet clinical needs where patients might benefit from re-engagement with tetracycline-class antibiotics including outpatient treatment options, patients with known beta-lactam antibiotic allergy, reducing the risk of Clostridioides difficile infection, and their potential as monotherapy in polymicrobial infections while minimising the risk of any potential drug-drug interaction. KEY MESSAGES The long-standing safety profile and broad spectrum of activity of tetracycline-class antibiotics made them a popular choice for treatment of various bacterial infections; unfortunately, antimicrobial resistance has limited the utility of the early-generation tetracycline agents. The latest generation of tetracycline-class antibiotics, including eravacycline, tigecycline, and omadacycline, overcomes the most common acquired tetracycline resistance mechanisms. Based on in vitro characteristics and clinical data, these newer tetracycline agents provide an effective antibiotic option in the treatment of approved indications in patients with unmet clinical needs - including patients with severe penicillin allergy, with renal or hepatic insufficiency, recent Clostridioides difficile infection, or polymicrobial infections, and those at risk of drug-drug interactions.