Antibiotic Clinical Trial Landscape

Roughly a quarter of all entries, at least 15 of the ~60 compounds listed,  target tuberculosis (TB). The WHO’s 2023 pipeline analysis found that the number of anti-tuberculosis drug candidates had more than doubled since the 2017 analysis, rising to 19. 

While now on a slight downturn, global TB case counts rose for three consecutive years after 2020, driven primarily by COVID-19 disruptions to diagnosis and treatment. However, the overall picture is more sobering. The global TB incidence rate has decreased by only about 8% since 2015, far short of the WHO End TB Strategy milestone of a 50% reduction by 2025. 

Additionally, drug resistance remains a serious problem among TB cases. An estimated 390,000 people developed multidrug-resistant or rifampicin-resistant TB in 2024, and only 42% of them accessed treatment.

Only six compounds are in Phase III trials: gepotidacin, zoliflodacin, nafithromycin, sulopenem, etzadroxil, and solithromycin. There are a significant number of early-phase candidates, but the small number in late-stage development reflects the Broken ARM market.

The WHO’s 2023 analysis found that 72% of pipeline agents belong to well-known antibiotic classes, including three new topoisomerase inhibitors with mechanisms that differ in part from those of older agents in the same class. Only six candidates (19%) are first-in-class compounds with distinct mechanisms of action.

The main change in the pipeline between 2017 and 2023 was a substantial shift toward agents active against gram-negative bacteria. Broad-spectrum antibiotics targeting two or more gram-negative pathogens increased from 6% to 44%. This table includes several polymyxin derivatives (MRX-8, QPX-9003), reflecting that developers are still attempting to rehabilitate one of the oldest, most nephrotoxic antibiotic classes because better options for carbapenem-resistant gram-negatives are in short supply. New polymyxin derivatives reportedly have improved safety profiles, but none appear to overcome colistin resistance, which is an ongoing limitation.

The proportion of oral antibiotics in the clinical pipeline decreased from 47% in 2017 to 37% in 2023. Most gram-negative candidates are administered intravenously, which limits their utility for outpatient step-down therapy and creates stewardship complications in under-resourced settings.

A notable subset of this pipeline is explicitly non-systemic: cannabidiol (topical, S. aureus), PLG0206 (topical), peceleganan (topical, wound infections), exeporfinium chloride (nasal decolonization), pravibismane (topical, diabetic foot/orthopedic implant), and murepavadin (inhalation). Topical strategies reflect a pragmatic strategy — bypassing the pharmacokinetic challenges of systemic delivery by targeting the site of infection directly. Nanoparticle-enabled and localized delivery is a promising strategy to enhance drug penetration into biofilms and intracellular niches, though key translational barriers remain, including scalability, target-site retention, and safety.