Tuberculous Pericarditis is Multibacillary and Bacterial Burden Drives High Mortality

• The antibiotic concentrations achieved in TB pericarditis fluid have up to now been unknown
• The pH in pericardial fluid was alkaline, which would mean that pyrazinamide effect would be compromised.
• The protein content in pericardial fluid was high, which would lead to low non-protein bound drug concentrations
• The concentrations of rifampicin, ethambutol and pyrazinamide in pericardial were dramatically low and below their MICsTuberculous pericarditis kills many patients, even those receiving appropriate antibiotic treatment which consists of a cocktail of rifampicin, isoniazid, ethambutol and pyrazinamide. It is unknown if curative concentrations of these drugs are achieved at the site of tuberculous pericarditis. Therefore, we measured the concentrations of each of these antibiotics in pericardial fluid of patients with tuberculous pericarditis. There were dramatically low rifampicin, ethambutol, and pyrazinamide concentrations in pericardial fluid, compared to susceptibility of the infecting bacterium, Mycobacterium tuberculosis. Only isoniazid entered pericardial fluid at effective concentrations. This could explain the high rates of mortality and morbidity of current therapy. There might be a need to identify new drugs that can penetrate into pericardial fluid for treatment of tuberculosis pericarditis.

BackgroundTuberculous pericarditis is considered to be a paucibacillary process; the large pericardial fluid accumulation is attributed to an inflammatory response to tuberculoproteins. Mortality rates are high. We investigated the role of clinical and microbial factors predictive of tuberculous pericarditis mortality using the artificial intelligence algorithm termed classification and regression tree (CART) analysis.MethodsPatients were prospectively enrolled and followed in the Investigation of the Management of Pericarditis (IMPI) registry. Clinical and laboratory data of 70 patients with confirmed tuberculous pericarditis, including time-to-positive (TTP) cultures from pericardial fluid, were extracted and analyzed for mortality outcomes using CART. TTP was translated to log10 colony forming units (CFUs) per mL, and compared to that obtained from sputum in some of our patients.FindingsSeventy patients with proven tuberculous pericarditis were enrolled. The median patient age was 35 (range: 20–71) years. The median, follow up was for 11.97 (range: 0·03–74.73) months. The median TTP for pericardial fluid cultures was 22 (range: 4–58) days or 3.91(range: 0·5–8·96) log10CFU/mL, which overlapped with the range of 3.24–7.42 log10CFU/mL encountered in sputum, a multi-bacillary disease. The overall mortality rate was 1.43 per 100 person-months. CART identified follow-up duration of 5·23 months on directly observed therapy, a CD4 + count of ≤ 199.5/mL, and TTP ≤ 14 days (bacillary load ≥ 5.53 log10 CFU/mL) as predictive of mortality. TTP interacted with follow-up duration in a non-linear fashion.InterpretationPatients with culture confirmed tuberculous pericarditis have a high bacillary burden, and this bacterial burden drives mortality. Thus proven tuberculosis pericarditis is not a paucibacillary disease. Moreover, the severe immunosuppression suggests limited inflammation. There is a need for the design of a highly bactericidal regimen for this condition.