Activity of 5-chloro-pyrazinamide in mice infected with Mycobacterium tuberculosis or Mycobacterium bovis.

Background & objectives: Pyrazinamide is an essential component of first line anti-tuberculosis regimen as well as most of the second line regimens. This drug has a unique sterilizing activity against Mycobacterium tuberculosis. Its unique role in tuberculosis treatment has lead to the search and development of its structural analogues. One such analogue is 5-chloro-pyrazinamide (5-Cl-PZA) that has been tested under in vitro conditions against M. tuberculosis. The present study was designed with an aim to assess the activity of 5-Cl-PZA, alone and in combination with first-line drugs, against murine tuberculosis. Methods: The minimum inhibitory concentration (MIC) of 5-Cl-PZA in Middlebrook 7H9 broth (neutral pH) and the inhibitory titre of serum from mice that received a 300 mg/kg oral dose of 5-Cl-PZA 30 min before cardiac puncture were determined. To test the tolerability of orally administered 5-Cl-PZA, uninfected mice received doses up to 300 mg/kg for 2 wk. Four weeks after low-dose aerosol infection either with M. tuberculosis or M. bovis, mice were treated 5 days/wk with 5-Cl-PZA, at doses ranging from 37.5 to 150 mg/kg, either alone or in combination with isoniazid and rifampicin. Antimicrobial activity was assessed by colony-forming unit counts in lungs after 4 and 8 wk of treatment. Results: The MIC of 5-Cl-PZA against M. tuberculosis was between 12.5 and 25 μg/ml and the serum inhibitory titre was 1:4. Under the same experimental conditions, the MIC of pyrazinamide was >100 μg/ml and mouse serum had no inhibitory activity after a 300 mg/kg dose; 5-Cl-PZA was well tolerated in uninfected and infected mice up to 300 and 150 mg/kg, respectively. While PZA alone and in combination exhibited its usual antimicrobial activity in mice infected with M. tuberculosis and no activity in mice infected with M. bovis, 5-Cl-PZA exhibited antimicrobial activity neither in mice infected with M. tuberculosis nor in mice infected with M. bovis. Interpretation & conclusion: Our findings showed that 5-Cl-PZA at doses up to 150 mg/kg was not active in chronic murine TB model. Further studies need to be done to understand the mechanism and mode of inactivation in murine model of tuberculosis.

Intestinal barrier function and serum concentrations of rifampin, isoniazid and pyrazinamide in patients with pulmonary tuberculosis

Intestinal barrier function and serum concentrations of rifampin, isoniazid and pyrazinamide were studied in healthy controls and patients with active pulmonary tuberculosis. A case-control study of 29 controls and 30 cases attending at the Health Center, July, 2004 to December, 2005 was conducted. The body mass index was significantly reduced in cases compared to controls (p < 0.001). The intestinal paracellular transport of lactulose was significantly (p = 0.019) reduced in cases compared to controls. The transcellular transport of mannitol and the lactulose:mannitol ratio were not significantly (p = 0.0698) reduced in cases compared to controls. Low serum concentrations of rifampin, isoniazid and pyrazinamide were observed in 81 percent (48/59), 92 percent (54/59) and 28 percent (12/59), respectively, in all individuals. The results demonstrated a marked decrease on intestinal paracellular transport in patients with active pulmonary tuberculosis and reduced serum concentrations of rifampin and isoniazid in both groups.

Pharmacokinetics of pyrazinamide in children with primary progressive disease of lungs.

BACKGROUND & OBJECTIVE: As the dosages recommended for children are based on weight, empirical and derived by extrapolation from the studies in adults, pyrazinamide (PZA) pharmacokinetics in children is likely to be different from adults. Limited information exists regarding the pharmacokinetics of PZA in paediatric patients of primary progressive disease (PPD) of lungs. This study aims to look at the changed pharmacokinetics of pyrazinamide in children with PPD of lungs by using reverse phase high-pressure liquid chromatography (HPLC). METHODS: A total of 40 children (age range 5 to 13 yr) of PPD were receiving pyrazinamide (30 mg/kg/day). On 11(th) day of short course antitubercular therapy, blood samples (two per day from 11(th) to 13(th) day) were collected at 0 h (pre-dose), 1, 2, 3, 4, 8 and 24 h after pyrazinamide administration and concentration of pyrazinamide was estimated by reverse phase high-pressure liquid chromatography. The mean peak serum concentration, the time to reach mean peak serum concentration, total clearance, concentration at time zero, volume of distribution, terminal elimination rate constant, elimination half-life, total area under serum concentration-time curve were measured. RESULTS: The mean serum concentrations of pyrazinamide were found higher than its minimum inhibitory concentration (20 microg/ml) required to inhibit the growth of tubercle bacilli from 1 to 8 h continuously. INTERPRETATION & CONCLUSION: Our results suggest that a dose of 30 mg/kg/day achieves much higher concentration of pyrazinamide as compared to its minimum inhibitory concentration (20 microg/ml). Therefore, lowering of pyrazinamide dosage is suggested in children for better patient compliance along with reduction in cost, side-effects and toxicity without compromising its efficacy.