title: Poor Penetration of Antibiotics Into Pericardium in Pericardial Tuberculosis.
abstract: Pericardial tuberculosis (TB) is associated with high therapy failure and high mortality rates. Antibiotics have to penetrate to site of infection at sufficient non-protein bound concentrations, and then enter bacteria to inhibit intracellular biochemical processes. The antibiotic concentrations achieved in pericardial fluid in TB pericarditis have never been measured before. We recruited two cohorts of patients with TB pericarditis, and left a pigtail catheter in-situ for serial drug concentration measurements over 24 h. Altogether, 704 drug concentrations were comodeled for pharmacokinetic analyses. The drug concentrations achieved in pericardial fluid were compared to the minimum inhibitory concentrations (MICs) of clinical Mycobacterium tuberculosis isolates. The total rifampicin concentration pericardial-to-serum ratios in 16 paired samples were 0.19 ± 0.33. The protein concentrations of the pericardial fluid in TB pericarditis were observed to be as high as in plasma. The non-protein bound rifampicin concentrations in pericardial fluid were 4-fold lower than rifampicin MICs in the pilot study, and the peak concentration was 0.125 versus 0.208 mg/L in the second (p = 0.001). The rifampicin clearance from pericardial fluid was 9.45 L/h versus 7.82 L/h in plasma (p = 0.002). Ethambutol peak concentrations had a pericardial-to-plasma ratio of 0.55 ± 0.22; free ethambutol peak concentrations were 2.30-lower than MICs (p < 0·001). The pericardial fluid pH was 7.34. The median pyrazinamide peak concentrations were 42.93 mg/L versus a median MIC of 800 mg/L at pH 7.34 (p < 0.0001). There was no significant difference between isoniazid pericardial fluid and plasma concentrations, and isoniazid peak concentrations were above MIC. This is the first study to measure anti-TB drug concentrations, pH and protein in the pericardial TB fluid. Pericardial concentrations of the key sterilizing drugs for TB were below MIC, which could contribute to poor outcomes. A new regimen that overcomes these limitations might need to be crafted.
authors: Divisions of Cardiology, Groote Schuur Hospital, University of Cape Town, Observatory, South Africa.
authors: Justin
authors: J
authors: Shenje
authors: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Dallas, TX, USA.
authors: F
authors: F
authors: Ifeoma Adimora-Nweke
authors: Endocrinology and Diabetes Medicine, Groote Schuur Hospital, University of Cape Town, Observatory, South Africa.
authors: Ian L
authors: IL
authors: Ross
authors: Divisions of Cardiology, Groote Schuur Hospital, University of Cape Town, Observatory, South Africa; Department of Medicine, Groote Schuur Hospital, University of Cape Town, Observatory, South Africa.
authors: Mpiko
authors: M
authors: Ntsekhe
authors: Clinical Pharmacology, Groote Schuur Hospital, University of Cape Town, Observatory, South Africa.
authors: Lubbe
authors: L
authors: Wiesner
authors: Divisions of Cardiology, Groote Schuur Hospital, University of Cape Town, Observatory, South Africa.
authors: Armin
authors: A
authors: Deffur
authors: Clinical Pharmacology, Groote Schuur Hospital, University of Cape Town, Observatory, South Africa.
authors: Helen M
authors: HM
authors: McIlleron
authors: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Dallas, TX, USA.
authors: Jotam
authors: J
authors: Pasipanodya
authors: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Dallas, TX, USA; Department of Medicine, Groote Schuur Hospital, University of Cape Town, Observatory, South Africa.
authors: Tawanda
authors: T
authors: Gumbo
authors: Divisions of Cardiology, Groote Schuur Hospital, University of Cape Town, Observatory, South Africa; Department of Medicine, Groote Schuur Hospital, University of Cape Town, Observatory, South Africa.
authors: Bongani M
authors: BM
authors: Mayosi
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015415:Biomarkers; D018791:CD4 Lymphocyte Count; D060085:Coinfection; D005260:Female; D015658:HIV Infections; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010490:Pericardial Effusion / Q000737:chemistry / Q000188:drug therapy / Q000382:microbiology; D010495:Pericarditis, Tuberculous / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D010496:Pericardium / Q000378:metabolism*; D010539:Permeability; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D015415:Biomarkers
keywords: Drug penetration; Ethambutol; Pericardium; Protein binding; Pyrazinamide; Rifampicin