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.

Keywords: Drug penetration; Ethambutol; Pericardium; Protein binding; Pyrazinamide; Rifampicin.

Figures

Fig. 1

Rifampin concentrations in plasma and pericardium in pilot study. A. The figure shows that at all time points the total rifampicin pericardial concentrations were dramatically lower than in the paired plasma. Derived free drug concentrations were even lower. B. When all the concentrations at any time point were compared to the MICs, virtually all were below the MICs. Thus, no non-protein bound concentration was higher than MIC in pericardial space.

Fig. 2

Rifampicin concentrations in the blood and pericardial fluid. The p-values shown throughout are for the Mann–Whitney test, and compared the total drug concentrations in plasma versus pericardial fluid, and not the free drug. A. The concentration–time profiles of rifampicin in pericardium and in the blood over a 24 h dosing interval. The time to maximum concentration was longer in pericardial fluid, while the peak concentrations were blunted. B. Clearance of rifampicin from pericardial fluid (PF) and plasma for each patient. The median clearance from the blood was 7.82 (range: 7.79–7.84) L/h while that in pericardial fluid was 9.49 (range: 6.30–13.14) L/h. C. The 0–24 h AUC for total drug concentrations was lower in pericardial fluid than in plasma; the free drug concentrations were even lower. D. Total rifampicin peak concentrations achieved in pericardial fluid are lower than in plasma; free concentrations are substantially lower. E.  Comparison of free rifampicin peak concentrations to MICs demonstrates that the maximum concentrations achieved in pericardial fluid are lower than MICs. Thus, as the concentrations are cleared from the pericardium the gap between drug concentration and MIC rapidly widens.

Fig. 3

Ethambutol concentrations in plasma and pericardial fluid (PF). The concentration time profiles of ethambutol total concentration over 24 h demonstrate reduced penetration of ethambutol. Clearance from pericardium was slightly lower than plasma (15.91 versus 14.77 L/h). Despite the lower clearance from pericardial fluid, the median AUC0–24 in pericardial fluid was 17.83 mg ∗ h/L compared to 29.51 mg ∗ h/L in plasma, a 40% reduction. The median total ethambutol peak concentration was 0.87 mg/L in pericardial fluid compared to 1.84 mg/L in plasma, and was thus 53% lower. Since ethambutol is 30% protein bound, this means the free peak concentration in pericardium is a median of 0.61 mg/L. The non-protein bound peak ethambutol concentrations were lower than MICs for most patients.

Fig. 4

Isoniazid concentrations in plasma and pericardial fluid (PF). The concentration time profiles of total concentration over 24 h demonstrate matching concentration. Clearance from pericardium was similar between plasma and pericardial fluid. The median pericardial fluid AUC0–24 in pericardial fluid was 19.78 mg ∗ h/L compared to 18.75 mg ∗ h/L in plasma. The median total pericardial peak concentration was 2.12 mg/L in pericardial fluid and 2.44 mg/L in plasma, virtually the same. Isoniazid penetrated well into pericardial fluid and achieved concentrations of at least 64-fold higher than MICs.

Fig. 5

Pyrazinamide concentrations in plasma and pericardial fluid. While pericardial fluid pyrazinamide peak concentration was somewhat delayed, it nevertheless reached the same level as in plasma. Pyrazinamide clearance from the pericardium was similar to that from plasma. The median pericardial fluid AUC0–24 in pericardial fluid was 815.6 mg ∗ h/L compared to 687.90 mg ∗ h/L in plasma. The median total pericardial peak concentration was 38.45 mg/L in pericardial fluid and 40.59 mg/L in plasma.

Fig. 6

The pH of pericardial fluid and pyrazinamide MICs. A.  The pH in pericardial fluid in each patient was measured 8 times in triplicate; shown are the mean values and standard deviation. The D'Agostino and Pearson omnibus normality test p-value was 0.991, which means that the pH values in the pericardial fluid were normally distributed. All the pH values were greater than 7.0, and indeed were similar to the pH of 7.365 in the blood, which is slightly alkaline. B.  Pyrazinamide MICs measured at pH 5.9 were used calculate the actual MICs at physiological pH based on the relationship between the active moiety pyrazinoic acid (POA; anion POA−) and HPOA in the Handersen–Hasselbach equation (POA pKa = 2.9), as demonstrated by Zhang et al. (2002). At pH 5.90 the % of the HPOA is 0.1% compared to 0.00363% at pH 7.34, a 27.54-fold change, which is the factor used to calculate the MIC value at pH 7.34 based on that identified at pH 5.9. This leads to an MIC with a median 18.6-fold higher than the median peak concentrations; indeed the highest pyrazinamide peak concentration was 4-fold lower than the lowest MIC.