ABSTRACT
Hospital-acquired pneumonia (HAP) is associated with high mortality and costs, and frequently caused by multidrug-resistant (MDR) bacteria. Although prior antimicrobial therapy is a major risk factor for HAP, the underlying mechanism remains incompletely understood. Here, we demonstrate that antibiotic therapy in hospitalized patients is associated with decreased diversity of the gut microbiome and depletion of short-chain fatty acid (SCFA) producers. Infection experiments with mice transplanted with patient fecal material reveal that these antibiotic-induced microbiota perturbations impair pulmonary defense against MDR Klebsiella pneumoniae. This is dependent on inflammatory monocytes (IMs), whose fatty acid receptor (FFAR)2/3-controlled and phagolysosome-dependent antibacterial activity is compromized in mice transplanted with antibiotic-associated patient microbiota. Collectively, we characterize how clinically relevant antibiotics affect antimicrobial defense in the context of human microbiota, and reveal a critical impairment of IM´s antimicrobial activity. Our study provides additional arguments for the rational use of antibiotics and offers mechanistic insights for the development of novel prophylactic strategies to protect high-risk patients from HAP.
Subject(s)
Anti-Bacterial Agents , Anti-Infective Agents , Humans , Mice , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Monocytes , Anti-Infective Agents/pharmacology , Klebsiella pneumoniae , LungABSTRACT
In 2020, an estimated total of 155 million people had survived tuberculosis. Among this number, a sizable proportion have considerable post-tuberculosis morbidity, as shown for the adult population. This systematic review aims to identify the spectrum and prevalence of post-tuberculosis sequelae in children and adolescents. Four databases were systematically searched from database inception to Feb 7, 2022, for literature on post-treatment outcomes of tuberculosis acquired during childhood. Of the 4613 identified publications, 71 studies were included in this systematic review. Studies on cohorts with comparably rare (most of which were extrapulmonary) tuberculosis presentations, such as spinal tuberculosis and tuberculous meningitis were over-represented; however, no study assessed long-term sequelae in a cohort with an average childhood tuberculosis spectrum. The descriptive analysis includes long-term outcomes of 3529 paediatric patients 1 month to 36 years after confirmed (47%) or clinical (53%) tuberculosis. In a considerable proportion of children, a broad spectrum of post-tuberculosis sequelae were identified, ranging from radiological residua after pulmonary tuberculosis, to disabling deformities after musculoskeletal and cutaneous tuberculosis, to somatic and psychosocial impairment after tuberculous meningitis. A better understanding and comprehensive assessment of post-tuberculosis sequelae in children are needed to improve tuberculosis care beyond antituberculous treatment.
