Management of four pregnant women with multidrug-resistant tuberculosis.

This case series describes the medical management of four pregnant women with active multidrug-resistant tuberculosis. None of the four patients were infected with human immunodeficiency virus. Three patients had disease due to multidrug-resistant Mycobacterium tuberculosis, and one had disease due to multidrug-resistant Mycobacterium bovis. Only one patient (patient 3) began retreatment during pregnancy, because her organism was susceptible to three antituberculosis drugs that were considered nontoxic to the fetus. Despite concern over teratogenicity of the second-line antituberculosis medications, careful timing of treatment initiation resulted in clinical cure for the mothers, despite some complications due to chronic tuberculosis and/or therapy. All infants were born healthy and remain free of tuberculosis. Pregnancy and multidrug-resistant tuberculosis need not be a public health disaster, as both conditions can be managed concurrently and successfully.

Risk factors for rifampin mono-resistant tuberculosis.

Use of rifampin is required for short-course treatment regimens for tuberculosis. Tuberculosis caused by isolates of M. tuberculosis with resistance to rifampin and susceptibility to isoniazid is unusual, but it has been recognized through surveillance. Patients with tuberculosis (cases) with rifampin mono-resistance were compared with HIV-matched controls with tuberculosis caused by a drug-susceptible isolate. A total of 77 cases of rifampin mono-resistant tuberculosis were identified in this multicenter study. Three were determined to be laboratory contaminants, and 10 cases had an epidemiologic link to a case with rifampin mono-resistant tuberculosis, suggesting primary acquisition of rifampin-resistant isolates. Of the remaining 64 cases and 126 controls, there was no difference between cases and controls with regard to age, sex, race, foreign birth, homelessness, or history of incarceration. Cases were more likely to have a history of prior tuberculosis than were controls. Of the 38 cases and 74 controls with HIV infection, there was no difference between cases and controls with regard to age, sex, race, foreign birth, homelessness, history of incarceration, or prior tuberculosis. Cases were more likely to have histories of diarrhea, rifabutin use, or antifungal therapy. Laboratory analysis of available isolates showed that there was no evidence of spread of a single clone of M. tuberculosis. Further studies are needed to identify the causes of the development of rifampin resistance in HIV-infected persons with tuberculosis and to develop strategies to prevent its emergence.

Misdiagnosis of multidrug-resistant tuberculosis possibly due to laboratory-related errors.

OBJECTIVE: To describe 9 cases where a misdiagnosis of multidrug-resistant tuberculosis (MDR TB) was made, possibly due to laboratory-related errors. DESIGN: Case series. SETTING: Public and private hospitals, outpatient clinics, and mycobacteriology laboratories serving those institutions in Los Angeles County, Calif. PATIENTS: Consecutive sample of 70 patients diagnosed with MDR TB who were identified between August 1993 and August 1994 by the Multidrug-Resistant Unit within TB Control in Los Angeles County. OUTCOME MEASURE: Detection of laboratory-related diagnostic errors. RESULTS: Pulmonary MDR TB was misdiagnosed in 9 (13%) of 70 patients. Reasons why the diagnoses appeared to be erroneous are as follows: growth of MDR TB from an old tuberculous lesion in a patient who was never treated for TB and whose diagnosis predated anti-TB drugs (1 case), documented contamination with Mycobacterium avium complex (1 case), suspected cross-contamination (1 case), suspected specimen mislabeling (1 case), successful treatment using drugs to which the isolate was reportedly resistant (4 cases), discrepant susceptibility test results on additional sputum specimens submitted by the patient (2 cases), and no clinical evidence of TB (3 cases). CONCLUSIONS: These cases emphasize the diagnostic errors that can occur if mycobacterial susceptibility results are not correlated with all clinical data including other laboratory results for a given patient. We conclude that susceptibility results alone are not enough to dictate treatment, and that careful clinical correlation is necessary in making the diagnosis of MDR TB.

Low antituberculosis drug concentrations in patients with AIDS.

OBJECTIVE: To determine the frequency and magnitude of below normal apparent peak serum concentrations for antituberculosis drugs in patients with AIDS and CD4 cell counts less than 200 cells/mm3. We also explored the data for potential relationships between response variables and patient characteristics. DESIGN: Prospective study of consecutive patients seen in tuberculosis clinics. SETTING: Five urban tuberculosis clinics in four major metropolitan areas. PARTICIPANTS: Twenty-six patients diagnosed with HIV infection and receiving treatment for active tuberculosis were eligible. MAIN OUTCOME MEASURES: After 2 weeks or more of therapy, blood was collected 2 hours after observed doses of the antituberculosis drugs. Serum samples were frozen, shipped to National Jewish Center in Denver, and analyzed by HPLC or GC. Serum concentrations were compared with the proposed normal ranges. Data were analyzed to determine correlations between antituberculosis drug serum concentrations and patient characteristics. RESULTS: Low-2-hour serum concentrations were common for antituberculosis drugs, particularly rifampin and ethambutol. Absorption of isoniazid was generally high. Potential drug-drug interactions were found between rifampin and fluconazole (fluconazole appears to increase rifampin concentrations) and between pyrazinamide and zidovudine (zidovudine may lower pyrazinamide concentrations). Patients receiving pyrazinamide had lower rifampin concentrations than those not receiving pyrazinamide. CONCLUSIONS: Low antituberculosis drug serum concentrations occur frequently during the treatment of tuberculosis in patients with AIDS. Additional research is required for patients with drug-resistant tuberculosis, and to clarify the nature of the potential drug-drug interactions.

Pharmacokinetic evaluation of thiacetazone.

STUDY OBJECTIVE: To investigate the steady-state pharmacokinetics of thiacetazone (TB-1), which is active in vitro against Mycobacterium avium complex (MAC). DESIGN: Open-label phase I study. SETTING: Specialized referral hospital. PATIENTS: Twelve healthy men and women. INTERVENTIONS: Oral TB-1 150 mg/day was administered for 7 days, followed by blood and urine collection over 48 hours. MEASUREMENTS AND MAIN RESULTS: The serum concentration versus time curves of TB-1 showed sustained concentrations, with maximum values of 1.59 +/- 0.47 micrograms/ml, time to maximum 3.30 +/- 1.18 hours, and serum half-life of 15-16 hours. Less than 25% of TB-1 was recovered unchanged in the urine over 48 hours. Rashes occurred in two subjects at the end of the 7-day dosing period and resolved without progression or sequelae. CONCLUSIONS: Based on these data, we initiated a phase II study of TB-I in patients with pulmonary MAC infection who do not have the acquired immunodeficiency syndrome.

Pharmacokinetic evaluation of para-aminosalicylic acid granules.

STUDY OBJECTIVE: To determine the bioavailability and renal elimination of para-aminosalicylic acid (PAS) and its inactive metabolite acetyl-para-aminosalicylic acid (AcPAS) from a new PAS formulation. DESIGN: (a) Single-dose pharmacokinetic study in healthy volunteers; (b) Day-1 and day-8 pharmacokinetic comparison in patients with multidrug-resistant tuberculosis (MDR-TB). SETTING: Referral hospital that specializes in the treatment of mycobacterial infections. PATIENTS: (a) Twelve healthy male and female volunteers recruited by the investigators. Eleven subjects (92%) completed the study; one subject could not maintain venous access and was removed from the study. (b) Six sequential male and female patients receiving multidrug treatment for advanced MDR-TB. All patients completed the study. INTERVENTIONS: (a) Volunteers received a single 4-g dose of enteric-coated PAS granules administered with food. Blood and urine samples were collected over 24 hours after the dose. (b) Patients received 4-g doses of enteric-coated PAS granules every 8 hours for 7 days as part of their treatment regimen. Blood samples were obtained at approximately 2, 4, and 8 hours after the first dose on day 1 and the twenty-second dose on day 8. MEASUREMENTS AND MAIN RESULTS: Concentrations of PAS and AcPAS were determined using high-performance liquid chromatography. The serum concentration-time curves from volunteers and patients showed sustained PAS concentrations, in contrast to immediate-release sodium PAS tablets. In the six patients with tuberculosis, day 8 concentrations were considerably higher than those on day 1, and all were sustained well above the PAS minimal inhibitory concentration for Mycobacterium tuberculosis. CONCLUSIONS: Para-aminosalicylic acid granules produce adequate serum concentrations and appear to be safe.

Ten-year experience with artificial pneumoperitoneum for end-stage, drug-resistant pulmonary tuberculosis.

Artificial pneumoperitoneum is a form of collapse therapy that was used in the treatment of cavitary pulmonary tuberculosis before the availability of antimycobacterial chemotherapy. We report a series of cases of far-advanced pulmonary disease due to multiple-drug-resistant Mycobacterium tuberculosis, wherein artificial pneumoperitoneum with or without subsequent surgical extirpation was used as an adjunct to chemotherapy. Overall, among these desperate cases, therapeutic pneumoperitoneum provided no clear benefit.

Disseminated meningococcal infection in HIV-seropositive patients.

OBJECTIVE: Although increasing numbers of infections due to various bacterial pathogens have been described in HIV-infected individuals, there have been few reports to date of disseminated Neisseria meningitidis infections in such individuals. We describe here the presentation and clinical course of systemic meningococcal infection in two HIV-1-seropositive men and the response to meningococcal vaccine in one. DESIGN AND METHODS: Retrospective analysis of case reports of two patients identified in a municipal hospital in Denver, Colorado, USA, and evaluation by enzyme-linked immunosorbent assay of antibody response to quadrivalent (A, C, Y, W-135) meningococcal vaccine. RESULTS: A 27-year-old HIV-seropositive man with bacteremic group Y meningococcal pneumonia and a 45-year-old man with AIDS and group B meningococcal arthritis both responded to short-term antibiotic therapy without recurrence. The second patient responded to meningococcal vaccination with seroconversion to all four serogroups. CONCLUSIONS: Disseminated meningococcal infection, although rare in HIV-infected individuals, may present with a variety of clinical manifestations and responds well to antibiotic therapy. Meningococcal vaccine appears to be immunogenic in such individuals.