Rifampicin as an antivirulence adjunct in hypervirulent/hypermucoviscous Klebsiella pneumoniae infections: a scoping review.

backgroundHypervirulent/Hypermucoviscous Klebsiella pneumoniae (HvKp/HmKp) is associated with invasive community-acquired infections and metastatic complications, with reports of clinical failure despite in vitro susceptibility to standard antibiotics. Rifampicin has been described in experimental settings to modulate virulence by suppressing the hypermucoviscous phenotype through RNA polymerase-dependent regulation of capsule-associated genes. This scoping review aimed to systematically map the available evidence evaluating rifampicin as a potential antivirulence adjunct in HvKp/HmKp infections.

methodsThis scoping review was conducted in accordance with the Joanna Briggs Institute methodology and reported following the PRISMA-ScR guidelines. A structured search of PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library was performed from database inception to May 2026 using predefined terms related to hypervirulence, Klebsiella pneumoniae, and rifampicin/rifampin. The search was supplemented by grey literature and reference list screening. Studies evaluating rifampicin in phenotypically, genotypically, or syndromically defined HvKp were eligible, including experimental and clinical reports describing rifampicin as adjunctive or salvage therapy. Data were charted and synthesized narratively to map study characteristics, proposed mechanisms, and reported outcomes.

resultsOf 1,361 records identified, 11 studies met the inclusion criteria, comprising four experimental/mechanistic studies, five full-text clinical case reports, and two conference abstracts. Experimental studies suggested that rifampicin may reduce hypermucoviscosity by suppressing capsule-associated pathways, particularly through the RpoB-rmpA axis, leading to reduced capsule thickness and downregulation of virulence-related genes. Additional preclinical studies showed enhanced activity when rifampicin was used in combination with zidovudine or the outer membrane-disrupting peptide SLAP-S25, with improved bacterial killing and survival in murine infection models. Clinical evidence was limited to case reports and conference abstracts in which rifampicin was used only as part of combination therapy for severe, disseminated, persistent, or difficult-to-treat HvKp/HmKp infections. Reported clinical outcomes were variable, and the independent contribution of rifampicin could not be determined.

conclusionCurrent evidence suggests that rifampicin has biologically plausible antivirulence activity against HvKp/HmKp, mainly through suppression of capsule-associated hypermucoviscosity, and may have potential as an adjunct in selected severe or persistent infections. However, the available clinical evidence is sparse, uncontrolled, and heterogeneous. Rifampicin should therefore be considered hypothesis-generating rather than established therapy. Further mechanistic, pharmacokinetic, and prospective clinical studies are required to define its role, optimal combinations, dosing, safety, and clinical effectiveness in HvKp/HmKp infections.