Pharmacology

Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis

Russell R. Kempker, M. Tobias Heinrichs, Ketino Nikolaishvili, Irina Sabulua, Nino Bablishvili, Shota Gogishvili, Zaza Avaliani, Nestani Tukvadze, Brent Little, Adam Bernheim, Timothy D. Read, Jeannette Guarner, Hartmut Derendorf, Charles A. Peloquin, Henry M. Blumberg, Sergo Vashakidze
DOI: 10.1128/AAC.00226-17

Article Figures & Data

Figures

  • FIG 1
    FIG 1

    Serum concentrations of pyrazinamide versus time after dosing in 10 adults with drug-resistant pulmonary tuberculosis.

  • FIG 2
    FIG 2

    (A) Correlation between peak serum pyrazinamide concentration and dosages; (B) correlation between serum free pyrazinamide concentration and lung tissue pyrazinamide concentration. *, Pearson correlation coefficient.

  • FIG 3
    FIG 3

    Representative transverse CT views from the seven patients with films available for review. Three main lesions types were identified, including cavitary lesions (a), mass lesions (b), and a consolidation from one patient (c).

  • FIG 4
    FIG 4

    Representative photomicrographs of hematoxylin and eosin-stained specimens for each of the nine patients with tissue pyrazinamide concentrations (listed) available. (a) Cases were classified as severe necrosis when, in addition to what is presented in the photomicrograph, confluent necrosis was present in multiple fields in multiple blocks (two or three blocks). (b) Cases were classified as moderate necrosis when necrosis was confluent with one field. (c) Cases were classified as having rare necrosis when necrosis was scattered within a field. Magnifications, ×4.

Tables

  • TABLE 1

    Study population characteristics for 10 patients with drug-resistant pulmonary TB

    ParameterValue (n = 10)
    Demographic characteristics
        No. (%) of male patients8 (80)
        Median (range) age (yr)30.2 (15–54)
        No. (%) of patients with the following characteristics:
            Georgian ethnicitya7 (70)
            Diabetes mellitusb1 (10)
            Hepatitis C antibody positive1 (10)
            Hepatitis B surface antigen positive1 (10)
            Alcohol user0
            Tobacco user3 (30)
            Retreatment TB case3 (30)
        Median (range) wt (kg)53.0 (48–71)
        Median (range) body mass index (kg/m2)19.5 (15–22)
    Laboratory values
        Median (range) creatinine clearancec (ml/min)91.1 (52–155)
        Median (range) albumin level (g/dl)4.2 (3.5–4.9)
        Median (range) hemoglobin level (g/dl)13.7 (12.4–15.5)
        Median (range) alanine aminotransferase level (U/liter)18 (10–133)
    Tuberculosis characteristics and treatment
        No. (%) of patient isolates with the following drug susceptibility pattern:
            Isoniazid monoresistant1 (10)
            Isoniazid and ofloxacin resistant1 (10)
            MDR6 (60)
            XDR2 (20)
        No. (%) of patients receiving pyrazinamide at a daily dose ofd:10 (83)
            1,200 mg2 (20)
            1,600 mg8 (80)
        Median (range) pyrazinamide dose (mg/kg)24.7 (22.5–33.3)
        Median (range) no. of days prior to surgery that the patient had received pyrazinamide363 (120–504)
        No. (%) of patients with the following indication for surgical resection:
            Treatment failure and localized lesion1 (10)
            High risk of relapse and localized lesion9 (90)
        No. (%) of patients with the following type of surgery:
            Lobectomy5 (50)
            Segmentectomy5 (50)

    • ↵a One patient was Armenian, one was Azeri, and two were of other ethnicities.

    • ↵b The patient was receiving insulin.

    • ↵c Determined using the Cockcroft-Gault equation.

    • ↵d At the time of surgical resection.

  • TABLE 2

    Noncompartmental analysis of serum pyrazinamide concentrations

    ParameteraMedian (range) valueb
    k el (h−1)0.059 (0.039–0.13)
    t 1/2 (h)11.7 (5.3–17.6)
    T max (h)2.0 (1.7–4)
    C max (μg/ml)37.8 (27.1–54.7)
    AUClast (μg · h/ml)246.7 (69.6–353.1)
    AUC0–∞ (μg · h/ml)827.6 (208.5–1,139.7)
    CL/F (liters/h)1.9 (1.4–7.7)
    V/F (liters)36.4 (28.6–58.5)

    • ↵a k el, elimination rate constant; t1/2, half-life; Tmax, time to Cmax; Cmax, maximal serum concentration; AUClast, area under the serum concentration-versus-time curve at the time of the last concentration determination; AUC0–∞, area under the serum concentration-versus-time curve from time zero to infinity; CL, clearance; V, volume of distribution; F, bioavailability (which was assumed to be 1 for purposes of analysis).

    • ↵b Data are for 10 patients receiving pyrazinamide.

  • TABLE 3

    Comparison of free serum and lung tissue pyrazinamide concentrations among patients with drug-resistant pulmonary TB

    SubjectDose of pyrazinamide (mg/kg)Serum concn at time of resectiona (μg/ml)Tissue concn (μg/ml)Tissue concn/serum concn ratio
    133.3341.04NAbNA
    22428.0325.060.89
    32425.67c13.950.54
    430.7728.9119.780.68
    525.4025.4419.290.76
    63244.7140.170.90
    722.5334.1321.980.64
    829.6327.7225.760.93
    922.8626.9520.960.78
    1022.8623.0017.750.77
    Median (range) 27.8720.960.77 (0.54–0.93)

    • ↵a Free serum concentration = measured pyrazinamide concentration × 0.85 (29).

    • ↵b NA, no lung tissue concentration was available for subject 1 due to a low dialysate volume.

    • ↵c For this patient, the serum concentration at the time of surgical resection was estimated with a one-compartment pharmacokinetic model.

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KEYWORDS

antitubercular agents
pyrazinamide
Tuberculosis, Multidrug-Resistant
Tuberculosis, Pulmonary
tuberculosis
drug resistance
drug penetration
pyrazinamide
microdialysis
pharmacology

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