For the pharmacokinetic analysis of isoniazid transfer into CSF, steady-state isoniazid concentrations of plasma and CSF were measured in eleven tuberculous meningitis patients confirmed with findings of CSF and neuroimazing. Peak plasma levels (4.17-21.5 micrograms/mL) were achieved at 0.25 to 3 hours after multiple isoniazid dose (600 mg/day). Terminal half-life, total clearance (CI/F) and volume of distribution (Vd/F) were 1.42 +/- 0.41 hr, 0.47 +/- 0.22 L/kg/hr and 0.93 +/- 0.48 L/kg, respectively. Isoniazid concentrations in CSF collected intermittently were highest at 3 hr (Mean, 4.18 micrograms/mL) and were 0.54 +/- 0.21 micrograms/mL at 12 hrs after the last dose of isoniazid 10 mg/kg/day. CSF/plasma partitioning of isoniazid and equilibration rate were estimated using modified pharmacokinetic/pharmacodynamic model. Disposition rate constant from CSF to plasma and CSF/plasma partitioning ratio of isoniazid were estimated to be 0.39 h-1 and 1.17, respectively.
Administration, Oral ; Humans ; Isoniazid/*cerebrospinal fluid ; Metabolic Clearance Rate ; Models, Biological ; Tuberculosis, Meningeal/*cerebrospinal fluid

Fifty nine patients of tuverculous menigiis who were admitted to the Pediatric department of Seoul Red Cross Hospital during the period from March, 1976 to December 1977 were treated with rifampin in addition to isoniazid and streptomycin injection, and Compaired with 135 cases of tuberculous meningitis who were admitted during the period from January, 1971 to December, 1975. The contrast group was composed of 21 cases who obtained as folows. 1) Out of 59 patients givern rifampin, only 5 patients died resulting in lower motality rate (8.5%) whereas 20 patients died out of 135 cases given PAS regimen showing 14.8% of motality rate. 2) Seven cases on each stage of PAS regimen group and 10 cases of stage I, 9 cases of stage II and III of rifampin group were reviewed for the respects of defeveration, durratio of disappearance of meningeal irritation signs, improvements of conciousness and neurological defects and self feeding ability. It was very hard to conclude the superiority on one group because of the similarity of days needed for the improvement. However, superior results with rifampin regimen could be mentioned among the patients with second and third stage of tuberculous meningitis for the clinical improvements. 3) Serial examination of cerebrospinal fluids of the cases in 3 stage revealed no direct relationship either for the clinical improvements or the for ultimate outcome of the patients themselves. C. S. F. improvements were observed in average within one to three weeks. 4) Side effects of fifampin ; the level of SGOT, SGPT and bilirubin at the time of of admission wrer all normal. Twenty-one cases out of 41 patients showed the impairment of liver function after the first to second week of treatment with the dosage of 15-20mg/kg/day. In 3 out of 21 cases, the drug had to be discontinued, owing to the futher elevation of SGOT and SGPT but in 18 out of 21 cases, liver function was gradually normalized within one to two weeks after the dosage of rifampin had been reduced down to 10mg/kg/day. There was no evidence of impairment of liver function on the follow-up evaluation from 4 to 10 months later. And there were no significant changes in Hb, Hct, platelet counts during the course of the therapy. The hepatitis, the well known side effects such as hemolytic anemia, skin rashes and G-I tract disturbance were not observed during the course of treatment. Bases on the above observations that rifampin reduced the motality and shortened the duration of clinical manifestation without the serious side effects except for transient hepatitis, rifampin plus isoniazid would seem to be preferred for the patients who are seen at the late stage of the disease. We know that the number of cases of this study is not enough to draw the definite conclusion of the superiority of rifampin, however, the of these prelininary observations seemed to cast a bright light for the futher trial and follow up observations.
Alanine Transaminase ; Anemia, Hemolytic ; Aspartate Aminotransferases ; Bilirubin ; Cerebrospinal Fluid ; Child* ; Exanthema ; Follow-Up Studies ; Hepatitis ; Humans ; Isoniazid ; Liver ; Platelet Count ; Red Cross ; Rifampin* ; Seoul ; Streptomycin ; Tuberculosis, Meningeal*

Pseudomembranous colitis (PMC) is known to be associated with the long-term administration of antibiotics, which alter normal gastrointestinal flora and allow overgrowth of Clostridium difficile. However, antituberculosis agents are rarely reported as a cause of this disease. Besides, most cases of antituberculosis agent-induced PMC have been observed in patients with pulmonary tuberculosis but not with tuberculous meningitis. This report presents a case of PMC associated with antituberculosis therapy in a patient with tuberculous meningitis. A 29-year-old female patient was admitted due to headaches and diplopia that had lasted for 2 weeks. She had not recently received antimicrobial therapy. She was diagnosed with tuberculous meningitis by cerebrospinal fluid findings and neurologic examination, including brain imaging study. She was treated with standard antituberculosis agents (HERZ regimen: isoniazid, ethambutol, rifampicin, and pyrazinamide). After 11 days of HERZ, she developed a fever, sudden widespread skin eruption, and elevation of liver enzymes. Considering adverse drug reactions, antituberculosis agents were stopped. One week later, her symptoms were relieved. Thus, antituberculosis agents were reintroduced one at a time after liver function returned to normal. However, she presented with frequent mucoid, jelly-like diarrhea, and lower abdominal pain. Sigmoidscopy revealed multiple yellowish plaques with edematous mucosa, which were compatible with PMC. She was treated with oral vancomycin considering drug interactions. Symptoms were relieved and did not recur when all antituberculosis agents except pyrazinamide were started again. Therefore, when a patient complains of abdominal pain or diarrhea after initiation of antituberculosis therapy, the physician should consider the possibility of antituberculosis agent-associated PMC.
Abdominal Pain ; Adult ; Anti-Bacterial Agents ; Cerebrospinal Fluid ; Clostridium difficile ; Diarrhea ; Diplopia ; Drug Interactions ; Drug-Related Side Effects and Adverse Reactions ; Enterocolitis, Pseudomembranous* ; Ethambutol ; Female ; Fever ; Headache ; Humans ; Isoniazid ; Liver ; Mucous Membrane ; Neuroimaging ; Neurologic Examination ; Pyrazinamide ; Rifampin ; Skin ; Tuberculosis, Meningeal* ; Tuberculosis, Pulmonary ; Vancomycin