Individualized TB care for drug-susceptible pulmonary tuberculosis: clinical alternatives when HRZE is contraindicated or not tolerated

Introduction: While the standard HRZE regimen is the cornerstone of drug-susceptible tuberculosis (DS-TB) treatment, its success is frequently undermined by treatment-limiting adverse drug reactions (ADRs) and complex drug-drug interactions (DDIs). In clinical practice, managing those situations remains a critical challenge often overlooked by guidelines. Effective toxicity management is essential to prevent treatment interruption, loss-to-follow up, relapse, and escalating healthcare costs. Areas covered: We provided a clinical framework for identifying and mitigating toxicities associated with HRZE regimen. Reviewing current literature and international guidelines, we analyzed different ADRs, provided safety profiles and management strategies for each HRZE drug. The discussion includes structured protocols for sequential drug re-challenge, management of high-risk populations, and DDIs. Furthermore, we evaluate evidence-based alternative regimens for cases where the standard of care is untenable. Expert opinion: DS-TB therapy must evolve from rigid protocols toward a precision medicine framework prioritizing patient safety alongside efficacy. We advocate for a ‘shorter is better, less is more’ approach, emphasizing regimen simplification and better-tolerated agents. Clinical success often depends on proactive communication between clinicians and patients, as well as individualized therapeutic adjustments, rather than on novel compounds alone. Bridging the gap between standardized guidelines and nuanced clinical judgment is vital for optimizing real-world outcomes.