Ofloxacin population pharmacokinetics in patients with tuberculosis.

SETTING: Two tuberculosis hospitals in the United States. OBJECTIVE: To determine the population pharmacokinetic (PK) parameters of ofloxacin following multiple oral doses. DESIGN: A total of 73 patients with tuberculosis (TB) participated in the study. Subjects received multiple doses of ofloxacin as part of their treatment. They also received concurrent medications based on in vitro susceptibility data. Serum samples were collected over 10 h and assayed by a validated high performance liquid chromatography (HPLC) assay. Concentration-time data were analyzed using population methods. RESULTS: Ofloxacin concentrations increased linearly with increasing oral doses. Delayed absorption was seen at least once in 29% of patients. Ofloxacin elimination decreased with declining renal function and increasing age. Higher daily doses were well tolerated, and appeared to maximize the peak concentration to minimal inhibitory concentration ratio (Cmax:MIC). CONCLUSION: Ofloxacin PK parameters were comparable to those previously published for other patient populations. Higher daily doses may offer pharmacodynamic advantages for the treatment of TB.

Treatment experience of multidrug-resistant tuberculosis in Florida, 1994-1997.

OBJECTIVE: To study the clinical characteristics and results of patients with diagnoses of multidrug-resistant tuberculosis (MDR-TB) in the state of Florida. METHODS: Retrospective chart review of all patients (n = 81) with diagnoses of MDR-TB in Florida between January 1, 1994, and July 31, 1997. RESULTS: The average number of resistant drugs was 4.8 (range, 2 to 11). Of 81 patients, 46 patients (57%) completed adequate therapy, 26 patients (32%) died, and 9 patients (11%) never completed a satisfactory course of treatment. Patients who received at least part of their therapy at A. G. Holley State Hospital, a specialized tuberculosis (TB) treatment center, had significantly higher treatment completion rates (79%) than those treated as outpatients alone (48% treatment completion rate, p < 0.001), even after the exclusion of patients who were acutely ill and died within 2 months of diagnosis. CONCLUSION: In Florida, a specialized TB care program for MDR-TB, including at least partial inpatient therapy, yielded higher treatment completion rates compared to outpatient treatment alone.

Use of rifabutin with protease inhibitors for human immunodeficiency virus-infected patients with tuberculosis.

Drug interactions between rifamycins and highly active antiretroviral therapy (HAART) have raised concerns in the treatment of human immunodeficiency virus (HIV)-infected patients with tuberculosis. We conducted a study of this interaction by measuring serum drug levels of all HIV-infected patients with tuberculosis who were admitted to A. G. Holley State Tuberculosis Hospital (Florida) from October 1997 through December 1998, who were concomitantly treated with rifabutin and HAART. All 25 patients studied became culture-negative within 2 months of initiation of therapy for tuberculosis and remained negative for a median of 13 months follow-up after completion of therapy. HIV viral loads (mean+/-SEM) decreased significantly from 4.95+/-0.21 log10 copies/mL before initiation of HAART to 2.77+/-0.07 log10 copies/mL before discharge (P<.001); 20 of 25 patients achieved viral loads of <500copies/mL. In summary, the concomitant use of rifabutin and HAART can lead to successful treatment of HIV-infected patients with tuberculosis without increased side effects.

Pulmonary tuberculosis in AIDS patients: transient chest radiographic worsening after initiation of antiretroviral therapy.

OBJECTIVE: Immune function and inflammatory responses often increase in AIDS patients who receive antiretroviral therapy. We evaluated the occurrence and nature of transient worsening on chest radiographs in AIDS patients with tuberculosis after initiation of antiretroviral therapy and compared these findings with chest radiographs of patients undergoing antituberculous therapy alone. MATERIALS AND METHODS: A retrospective review of sequential chest radiographs was performed of 87 patients undergoing therapy for pulmonary tuberculosis: AIDS patients receiving antiretroviral therapy (n = 31), HIV-positive patients not receiving antiretroviral therapy (n = 26), and HIV-negative patients (n = 30). Pulmonary consolidations, thoracic lymphadenopathy, and pleural effusions were evaluated for worsening, stability, or improvement. Patients with concurrent pulmonary infections were excluded. RESULTS: Transient worsening on radiography was observed in 14 (45%) of 31 AIDS patients receiving antiretroviral therapy, including seven patients (23%) who showed severe worsening. Of 56 patients in the other two groups, 11 (20%) showed worsening (p = 0.023), two of whom showed severe worsening (p = 0.009). Worsening was first noted between 1 and 5 weeks after initiation of antiretroviral therapy, with improvement occurring between 2 weeks and 3 months later. Four patients with severe worsening converted their tuberculin purified protein derivative responses from anergic to positive after antiretroviral treatment. CONCLUSION: Transient worsening is frequently seen on chest radiography in AIDS patients with tuberculosis who subsequently undergo antiretroviral therapy. This phenomenon may be related to improved immune function.

Mesothelial cells in tuberculous pleural effusions of HIV-infected patients.

The scarcity of mesothelial cells is a well-known characteristic of tuberculous pleural effusions. We report three HIV-infected patients with tuberculous pleural effusions, in which mesothelial cells were found in significant numbers in the pleural fluid. Clinicians should be aware that the altered immune responses that occur in HIV-infected patients may affect the cytologic profile of tuberculous pleural effusions, and they should be cautious not to exclude this diagnosis based solely on the presence of mesothelial cells in the fluid.

Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.

Transient worsening of tuberculous symptomatology and lesions following antituberculous therapy (paradoxical response) has previously been described as a rare occurrence. To determine the incidence of paradoxical responses in patients with AIDS and TB who are treated with antituberculous therapy and subsequently with combination antiretroviral therapy (ARV), we conducted a prospective study of 33 HIV-seropositive TB patients treated with anti-TB therapy and antiretroviral therapy (Group 1) compared with 55 HIV-seronegative TB patients treated with anti-TB therapy (Group 2) and 28 HIV-seropositive TB patients treated with anti-TB therapy but not on antiretrovirals (historical control; Group 3). In Group 1 patients, paradoxical responses were temporally more related to the initiation of ARV than to the initiation of anti-TB therapy (mean +/- SD: 15 +/- 11 d versus 109 +/- 72 d [p < 0.001]) and occurred much more frequently (12 of 33; 36%) compared with Group 2 (1 of 55; 2%) (p < 0.001) or with Group 3 (2 of 28; 7%) (p = 0.013). The majority of patients who experienced paradoxical responses and received tuberculin purified protein derivative (PPD) in Group 1 had their tuberculin skin tests convert from negative to strongly positive after ARV. These observations suggest that a paradoxical response associated with enhanced tuberculin skin reactivity may occur after the initiation of ARV in HIV-infected TB patients. Furthermore, the skin test conversion after the initiation of ARV may have important public health implications.

Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus.

Until recently it was thought that age greater than 35 yr was the main risk factor for the development of drug-induced hepatitis (DIH) in patients receiving antituberculosis therapy. We conducted a study to determine whether infection with either the hepatitis C virus or the human immunodeficiency virus (HIV) were significant risk factors for the development of DIH in patients receiving antituberculosis therapy. Our study consisted of two parts. In the first part, 134 consecutive patients admitted for the treatment of tuberculosis (TB) were followed for the development of DIH. All of these patients were also screened for the presence of hepatitis C and HIV. In the second part of the study, those patients who were hepatitis C positive and who developed DIH on repeated reintroduction of the anti-TB drugs were offered a liver biopsy. If active inflammation, which may be suggestive of hepatitis C infection, was present on the biopsy specimen, treatment with alpha-interferon was begun and the anti-TB drugs were subsequently reintroduced. During the 18 mo of the study, 22 patients developed DIH. The relative risk of developing DIH if the patient was hepatitis C or HIV positive was fivefold and fourfold, respectively (p < 0.05). If a patient was coinfected with both hepatitis C and HIV the relative risk of developing DIH was increased 14.4-fold (p < 0.002). In the treatment part, four patients were treated with alpha-interferon, and all were able to undergo the reintroduction of anti-TB therapy without reoccurrence of DIH. Infection with hepatitis C and HIV are independent and additive risk factors for the development of DIH during TB therapy. The treatment of hepatitis C with alpha-interferon may allow the reintroduction of anti-TB agents in those who previously developed DIH when exposed to these drugs.