Tuberculosis-HIV treatment with rifampicin or rifabutin: are the outcomes different?

BACKGROUND: Rifamycins are a group of antibiotics mainly used in the treatment of tuberculosis (TB), however they interact with antiretroviral therapy (ART). Rifabutin allows more regimens options for concomitant imunodeficiency virus (HIV) treatment compared to rifampicin. OBJECTIVE: Compare the outcomes of TB-HIV co-infected patients who used rifampicin or rifabutin. METHODS: We analysed data from a prospective cohort study at National Institute of Infectious Diseases Evandro Chagas, Rio de Janeiro (RJ), Brazil. Patients who were treated for TB and HIV with rifampicin or rifabutin, from February 2011 to September 2016 were included. FINDINGS: There were 130 TB-HIV patients, of whom 102 were treated with rifampicin and 28 with rifabutin. All patients in the rifabutin-treated group and 55% of the rifampicin-treated group patients were ART-experienced. Patients treated with rifampicin had similar abandon and cure rates, interruptions in treatment due to adverse reactions, immune reconstitution inflammatory syndrome and a similar mortality rate as those treated with rifabutin. However, rifampicin-treated patients had higher CD4 counts and more frequently undetectable HIV viral load by the end of treatment (67% versus 18%, p < 0.001) compared to rifabutin-treated patients, even when only ART-experienced patients were evaluated (66,6% versus 36,3%, p = 0.039). CONCLUSIONS: Patients who used rifabutin had worst immune and virological control. This group had more ART-experienced patients. New and simpler regimens are needed for patients who do not respond to previous antiretroviral therapies.

Hearing thresholds in patients with drug-resistant tuberculosis: baseline audiogram configurations and associations.

OBJECTIVE:: To use baseline audiogram parameters in order to ascertain whether drug-resistant tuberculosis (DR-TB) has effects on hearing, as well as to describe the configurations of the audiograms and to determine whether there are parameters that can be associated with those configurations. METHODS:: This was a prospective study involving patients diagnosed with DR-TB at a tuberculosis treatment center in the state of Ogun, in Nigeria. The patients included in the study were submitted to pure tone audiometry at baseline (within two weeks after treatment initiation). For comparative analyses, data regarding demographic and clinical characteristics were collected from the medical records of the patients. RESULTS:: The final sample comprised 132 patients. The mean age of the patients was 34.5 ± 12.6 years (range, 8-82 years), and the male:female ratio was 2:1. Of the 132 patients, 103 (78.0%) resided in neighboring states, 125 (94.7%) had previously experienced antituberculosis treatment failure, and 18 (13.6%) were retroviral-positive. Normal audiograms were found in 12 patients (9.1%), whereas sensorineural hearing loss was identified in 104 (78.8%), the two most common configurations being ascending, in 54 (40.9%), and sloping, in 26 (19.7%). Pure-tone averages at low frequencies (0.25-1.0 kHz) and high frequencies (2.0-8.0 kHz) were 33.0 dB and 40.0 dB, respectively. Regarding the degree of hearing loss in the better ear, 36 patients (27.3%) were classified as having normal hearing and 67 (50.8%) were classified as having mild hearing loss (26-40 dB), whereas 29 (21.9%) showed moderate or severe hearing loss. Among the variables studied (age, gender, retroviral status, previous treatment outcome, and weight at admission), only male gender was associated with audiometric configurations. CONCLUSIONS:: In this sample of patients with DR-TB, most presented with bilateral, mild, suboptimal sensorineural hearing loss, and ascending/sloping audiometric configurations were associated with male gender. OBJETIVO:: Utilizar parâmetros do audiograma basal para verificar se a tuberculose resistente (TB-R) tem efeitos na audição, descrever as configurações dos audiogramas e determinar se há parâmetros que possam ser associados a essas configurações. MÉTODOS:: Estudo prospectivo com pacientes diagnosticados com TB-R em um centro de tratamento de tuberculose no estado de Ogun, Nigéria. Os pacientes incluídos no estudo foram submetidos à audiometria de tons puros em até duas semanas após o início do tratamento (audiometria basal). Características demográficas e clínicas foram coletadas dos prontuários médicos dos pacientes para análises comparativas. RESULTADOS:: A amostra final envolveu 132 pacientes. A média de idade dos pacientes foi de 34,5 ± 12,6 anos (variação, 8-82 anos), e a razão homem:mulher foi de 2:1. A maioria dos pacientes (n = 103; 78,0%) residia nos estados vizinhos e tinha história de falha de tratamento antituberculose (n = 125; 94.7%); 18 (13.6%) apresentavam status retroviral positivo. Doze pacientes (9,1%) apresentaram audiogramas normais, e 104 (78,8%) apresentaram perda auditiva neurossensorial, sendo as configurações mais comuns do tipo ascendente, em 54 (40,9%), e descendente, em 26 (19,7%). As médias de tons puros em frequências baixas (0,25-1,0 kHz) e altas (2,0-8,0 kHz) foram de 33,0 dB e 40,0 dB, respectivamente. Quanto ao grau de perda auditiva no melhor ouvido, 36 pacientes (27,3%) apresentaram audição normal, e 67 (50,8%) apresentaram perda auditiva leve (26-40 dB), enquanto 29 (21,9%) mostraram perda auditiva moderada ou grave. Entre as variáveis estudadas (idade, gênero, status retroviral, desfecho de tratamento anterior e peso na admissão), somente o gênero masculino foi associado às configurações audiométricas. CONCLUSÕES:: Nesta amostra de pacientes com TB-R, a maioria apresentou perda auditiva neurossensorial leve e subótima bilateralmente, com configurações audiométricas ascendentes/descendentes associadas ao gênero masculino.

Hearing thresholds in patients with drug-resistant tuberculosis: baseline audiogram configurations and associations / Limiares auditivos em pacientes com tuberculose resistente: configurações do audiograma basal e associações

ABSTRACT Objective: To use baseline audiogram parameters in order to ascertain whether drug-resistant tuberculosis (DR-TB) has effects on hearing, as well as to describe the configurations of the audiograms and to determine whether there are parameters that can be associated with those configurations. Methods: This was a prospective study involving patients diagnosed with DR-TB at a tuberculosis treatment center in the state of Ogun, in Nigeria. The patients included in the study were submitted to pure tone audiometry at baseline (within two weeks after treatment initiation). For comparative analyses, data regarding demographic and clinical characteristics were collected from the medical records of the patients. Results: The final sample comprised 132 patients. The mean age of the patients was 34.5 ± 12.6 years (range, 8-82 years), and the male:female ratio was 2:1. Of the 132 patients, 103 (78.0%) resided in neighboring states, 125 (94.7%) had previously experienced antituberculosis treatment failure, and 18 (13.6%) were retroviral-positive. Normal audiograms were found in 12 patients (9.1%), whereas sensorineural hearing loss was identified in 104 (78.8%), the two most common configurations being ascending, in 54 (40.9%), and sloping, in 26 (19.7%). Pure-tone averages at low frequencies (0.25-1.0 kHz) and high frequencies (2.0-8.0 kHz) were 33.0 dB and 40.0 dB, respectively. Regarding the degree of hearing loss in the better ear, 36 patients (27.3%) were classified as having normal hearing and 67 (50.8%) were classified as having mild hearing loss (26-40 dB), whereas 29 (21.9%) showed moderate or severe hearing loss. Among the variables studied (age, gender, retroviral status, previous treatment outcome, and weight at admission), only male gender was associated with audiometric configurations. Conclusions: In this sample of patients with DR-TB, most presented with bilateral, mild, suboptimal sensorineural hearing loss, and ascending/sloping audiometric configurations were associated with male gender.

RESUMO Objetivo: Utilizar parâmetros do audiograma basal para verificar se a tuberculose resistente (TB-R) tem efeitos na audição, descrever as configurações dos audiogramas e determinar se há parâmetros que possam ser associados a essas configurações. Métodos: Estudo prospectivo com pacientes diagnosticados com TB-R em um centro de tratamento de tuberculose no estado de Ogun, Nigéria. Os pacientes incluídos no estudo foram submetidos à audiometria de tons puros em até duas semanas após o início do tratamento (audiometria basal). Características demográficas e clínicas foram coletadas dos prontuários médicos dos pacientes para análises comparativas. Resultados: A amostra final envolveu 132 pacientes. A média de idade dos pacientes foi de 34,5 ± 12,6 anos (variação, 8-82 anos), e a razão homem:mulher foi de 2:1. A maioria dos pacientes (n = 103; 78,0%) residia nos estados vizinhos e tinha história de falha de tratamento antituberculose (n = 125; 94.7%); 18 (13.6%) apresentavam status retroviral positivo. Doze pacientes (9,1%) apresentaram audiogramas normais, e 104 (78,8%) apresentaram perda auditiva neurossensorial, sendo as configurações mais comuns do tipo ascendente, em 54 (40,9%), e descendente, em 26 (19,7%). As médias de tons puros em frequências baixas (0,25-1,0 kHz) e altas (2,0-8,0 kHz) foram de 33,0 dB e 40,0 dB, respectivamente. Quanto ao grau de perda auditiva no melhor ouvido, 36 pacientes (27,3%) apresentaram audição normal, e 67 (50,8%) apresentaram perda auditiva leve (26-40 dB), enquanto 29 (21,9%) mostraram perda auditiva moderada ou grave. Entre as variáveis estudadas (idade, gênero, status retroviral, desfecho de tratamento anterior e peso na admissão), somente o gênero masculino foi associado às configurações audiométricas. Conclusões: Nesta amostra de pacientes com TB-R, a maioria apresentou perda auditiva neurossensorial leve e subótima bilateralmente, com configurações audiométricas ascendentes/descendentes associadas ao gênero masculino.

Rifampicin-warfarin interaction leading to macroscopic hematuria: a case report and review of the literature.

BACKGROUND: Rifampicin remains one of the first-line drugs used in tuberculosis therapy. This drug's potential to induce the hepatic cytochrome P450 oxidative enzyme system increases the risk of drug-drug interactions. Thus, although the presence of comorbidities typically necessitates the use of multiple drugs, the co-administration of rifampicin and warfarin may lead to adverse drug events. We report a bleeding episode after termination of the co-administration of rifampicin and warfarin and detail the challenges related to international normalized ratio (INR) monitoring. CASE PRESENTATION: A 59-year-old Brazilian woman chronically treated with warfarin for atrial fibrillation (therapeutic INR range: 2.0-3.0) was referred to a multidisciplinary anticoagulation clinic at a university hospital. She showed anticoagulation resistance at the beginning of rifampicin therapy, as demonstrated by repeated subtherapeutic INR values. Three months of sequential increases in the warfarin dosage were necessary to reach a therapeutic INR, and frequent visits to the anticoagulation clinic were needed to educate the patient about her pharmacotherapy and to perform the warfarin dosage adjustments. The warfarin dosage also had to be doubled at the beginning of rifampicin therapy. However, four weeks after rifampicin discontinuation, an excessively high INR was observed (7.22), with three-day macroscopic hematuria and the need for an immediate reduction in the warfarin dosage. A therapeutic and stable INR was eventually attained at 50% of the warfarin dosage used by the patient during tuberculosis therapy. CONCLUSIONS: The present case exemplifies the influence of rifampicin therapy on warfarin dosage requirements and the increased risk of bleeding after rifampicin discontinuation. Additionally, this case highlights the need for warfarin weekly monitoring after stopping rifampicin until the maintenance dose of warfarin has decreased to the amount administered before rifampicin use. In particular, patients with cardiovascular diseases and active tuberculosis represent a group with a substantial risk of drug-drug interactions. Learning how to predict and monitor drug-drug interactions may help reduce the incidence of clinically significant adverse drug events.

Impact of treatment completion, intolerance and adverse events on health system costs in a randomised trial of 4 months rifampin or 9 months isoniazid for latent TB.

RATIONALE: Treatment for latent tuberculosis infection with isoniazid for 9 months (9INH) has poor completion and serious adverse events, while treatment for 4 months with daily rifampin (4RIF) has significantly higher completion and fewer adverse events. OBJECTIVES: To compare the health system costs of 4RIF and 9INH. METHODS: In a randomised trial conducted in five Canadian centres, one Brazilian and one Saudi Arabian centre, consenting subjects were randomised to receive 4RIF or 9INH. Health system costs were estimated from healthcare utilisation including scheduled and unscheduled visits, investigations and drugs. All activities for all subjects were evaluated using financial information from 2007 from the Montreal Chest Institute. Costs were expressed in Canadian dollars. RESULTS: Total health system cost per patient allocated to 4RIF was $854 compared with $970 for 9INH (p<0.0001). The average cost per patient for the 328 of 420 (78%) who completed 4RIF therapy was $1094 compared with $1625 for the 254 of 427 (60%) completing 9INH (p<0.0001). Costs were modestly increased in patients with minor intolerance and substantially increased if the treating physician stopped treatment because of possible adverse events. Total costs related to management of adverse events with 9INH were $48 142 compared with $25 684 for 4RIF (p=0.008). Using these data, incremental cost-effectiveness analyses showed that 4RIF would be cost saving and prevent more cases within 2 years if efficacy exceeded 74%, and cost saving if efficacy exceeded 65%. CONCLUSIONS: The 4RIF regimen was significantly cheaper per patient completing treatment because of better completion and fewer adverse events.

Análise do tratamento da tuberculose pulmonar em idosos de um hospital universitário do Rio de Janeiro, RJ, Brasil / Analysis of the treatment of pulmonary tuberculosis in elderly patients at a university hospital in Rio de Janeiro, Brazil

OBJETIVOS: Descrever os aspectos clínicos e terapêuticos da tuberculose pulmonar e comparar os efeitos adversos e resultados do tratamento entre idosos e não idosos. MÉTODOS: Foi realizado um estudo caso-controle com 117 indivíduos idosos (acima de 60 anos) e 464 não idosos (15-49 anos) portadores de tuberculose pulmonar atendidos no Instituto de Doenças do Tórax da Universidade Federal do Rio de Janeiro no período de 1980 a 1996. RESULTADOS: No grupo de idosos, houve associação entre diabetes mellitus (OR = 3,98; IC95 por cento = 2,07-7,65; p = 0,001), doenças pulmonares (OR = 7,24; IC95 por cento = 3,64-14,46; p = 0,001) e cardiovasculares (OR = 5,86; IC95 por cento = 2.88-11.95; p = 0,001). O tabagismo (OR = 2,07; IC95 por cento = 1,26-3,42; p = 0,002) e o etilismo (OR = 1,63; IC95 por cento = 1,01-2,68; p = 0,041) também foram mais freqüentes neste grupo. O tratamento levou a freqüentes reações adversas nos idosos (OR = 1,62; IC95 por cento = 1,04-2,54; p = 0,024), principalmente de origem gastrintestinal (OR = 1,64; IC95 por cento = 1,01-2,77; p = 0,047), e sua eficácia foi menor neste grupo: apenas 51 por cento de cura e 24 por cento de óbitos. O abandono do tratamento foi elevado nos dois grupos, em torno de 23 por cento. CONCLUSÕES: As reações adversas e o resultado do tratamento foram piores nos idosos, com maior freqüência de complicações e letalidade, devido a uma maior toxicidade farmacológica e a uma maior prevalência de doenças associadas neste grupo etário.

OBJECTIVE: To describe the clinical and therapeutic aspects of pulmonary tuberculosis and compare the adverse effects of the treatment and its outcome in elderly and nonelderly patients. METHODS: This was a case-control study of 117 elderly individuals (over the age of 60 years) and 464 nonelderly individuals (aged 15-49 years). All subjects presented pulmonary tuberculosis that had been diagnosed and treated at the Thoracic Diseases Institute of the Federal University of Rio de Janeiro between 1980 and 1996. RESULTS: In the elderly group, pulmonary tuberculosis was found to be correlated with diabetes (OR = 3.98; 95 percent CI = 2.07-7.65; p = 0.001), lung disease (OR = 7.24; 95 percent CI = 3.64-14.46; p = 0.001) and heart disease (OR = 5.86; 95 percent CI = 2.88-11.95; p = 0.001). Smoking (OR = 2.07; 95 percent CI = 1.26-3.42; p = 0.002) and alcohol abuse (OR = 1.63; 95 percent CI = 1.01-2.68; p = 0.041) were also more common in the elderly group. In the elderly group, the treatment more frequently resulted in adverse reactions (OR = 1.62; 95 percent CI = 1.04-2.54; p = 0.024), especially gastrointestinal reactions (OR = 1.64; 95 percent CI = 1.01-2.77; p = 0.047), and treatment efficacy was lower: cure rate, 51 percent; mortality rate, 24 percent. Treatment adherence was low (approximately 77 percent) in both groups. CONCLUSIONS: In the elderly group, adverse reactions were more common, treatment outcomes were less favorable, there was a greater frequency of clinical complications and deaths related to drug toxicity, and the prevalence of concomitant diseases was higher.

[Analysis of the treatment of pulmonary tuberculosis in elderly patients at a university hospital in Rio de Janeiro, Brazil]. / Análise do tratamento da tuberculose pulmonar em idosos de um hospital universitário do Rio de Janeiro, RJ, Brasil.

OBJECTIVE: To describe the clinical and therapeutic aspects of pulmonary tuberculosis and compare the adverse effects of the treatment and its outcome in elderly and nonelderly patients. METHODS: This was a case-control study of 117 elderly individuals (over the age of 60 years) and 464 nonelderly individuals (aged 15-49 years). All subjects presented pulmonary tuberculosis that had been diagnosed and treated at the Thoracic Diseases Institute of the Federal University of Rio de Janeiro between 1980 and 1996. RESULTS: In the elderly group, pulmonary tuberculosis was found to be correlated with diabetes (OR = 3.98; 95% CI = 2.07-7.65; p = 0.001), lung disease (OR = 7.24; 95% CI = 3.64-14.46; p = 0.001) and heart disease (OR = 5.86; 95% CI = 2.88-11.95; p = 0.001). Smoking (OR = 2.07; 95% CI = 1.26-3.42; p = 0.002) and alcohol abuse (OR = 1.63; 95% CI = 1.01-2.68; p = 0.041) were also more common in the elderly group. In the elderly group, the treatment more frequently resulted in adverse reactions (OR = 1.62; 95% CI = 1.04-2.54; p = 0.024), especially gastrointestinal reactions (OR = 1.64; 95% CI = 1.01-2.77; p = 0.047), and treatment efficacy was lower: cure rate, 51%; mortality rate, 24%. Treatment adherence was low (approximately 77%) in both groups. CONCLUSIONS: In the elderly group, adverse reactions were more common, treatment outcomes were less favorable, there was a greater frequency of clinical complications and deaths related to drug toxicity, and the prevalence of concomitant diseases was higher.

Safety, efficacy and pharmacokinetics of ritonavir 400mg/saquinavir 400mg twice daily plus rifampicin combined therapy in HIV patients with tuberculosis.

OBJECTIVE: To assess the drug concentrations, efficacy and safety of concomitant use of rifampicin and regimens containing ritonavir/saquinavir (400mg/400mg twice daily) in tuberculosis-HIV treatment-naive patients. DESIGN AND METHODS: This was an open-label, non-randomised, multiple-dose study. On study day (D)1, tuberculosis treatment (rifampicin 600mg/isoniazid 400mg per day fasting plus pyrazinamide 2 g/day) was introduced in 30 patients. On D31, highly active antiretroviral therapy (HAART) consisting of two nucleoside analogues plus ritonavir/saquinavir 400mg/400mg twice daily was initiated (n = 20). The pharmacokinetics were assayed with a validated reversed-phase HPLC method before the introduction of HAART on D30 (for rifampicin), after 30 days of HAART at D60 (for rifampicin plus ritonavir/saquinavir), and at the end of the study (without rifampicin) on D210 (for ritonavir/saquinavir). Clinical evaluations were performed on a monthly basis. CD4 counts and viral load were collected on D30, D60 and D180. Genotyping test for HIV was collected at baseline and at D180. Primary endpoints were drug concentration and viral load at D180 (<80 copies/mL). Secondary endpoints were presence of grade 3 and serious adverse events, clinical improvement, CD4 count and genotypic resistance to ritonavir/saquinavir. RESULTS: Ten patients dropped out of the study during tuberculosis therapy alone. Mean (+/- SD) baseline CD4 count (on D30) was 151.89 (+/- 146.77) cells/mm(3) and viral load was 5.34 (+/- 0.4) log. During the antiretroviral therapy, 15 patients dropped out, 14 because of adverse events. One patient (of five) presented a viral load of <80 copies/mL at D180. All but one patient increased CD4 counts from baseline. No genotypic resistance was detected. Clinical improvement was evident in all five patients who tolerated the therapy. Serum concentrations of ritonavir/saquinavir and rifampicin remained within the therapeutic range. CONCLUSIONS: Therapeutic concentrations of the studied drugs and reduction of viral load were achieved; adverse events are the main limitation of use of a ritonavir/saquinavir regimen in treatment-naive patients, but its clinical benefits were evident.

Psychiatric issues in the management of patients with multidrug-resistant tuberculosis.

INTRODUCTION: Psychiatric issues present a challenge in the treatment of patients with multidrug-resistant tuberculosis (MDR-TB). Both baseline psychiatric disorders and development of psychiatric complications related to anti-tuberculosis drugs and psychosocial factors require aggressive management. SETTING: A community-based non-governmental health organization in Lima, Peru. OBJECTIVE: To review the literature for psychiatric complications associated with anti-tuberculosis medications, to describe the incidence and prevalence of depression, anxiety and psychosis among individuals receiving MDR-TB therapy, and to detail the management approach used in this cohort. METHODS: A retrospective case series was performed among the first 75 patients to receive individualized MDR-TB therapy in Lima, Peru, between 1996 and 1999. RESULTS: Baseline depression and baseline anxiety were observed in respectively 52.2% and 8.7% of this cohort. Most individuals with baseline depression experienced improvement of depressive symptoms during the course of TB therapy. The incidence of depression, anxiety and psychosis during MDR-TB treatment was 13.3%, 12.0% and 12.0%, respectively. While the majority of individuals with depression, anxiety and psychosis required psychiatric pharmacotherapy, cycloserine was successfully continued in all but one case. CONCLUSION: Psychiatric comorbidities are not a contra-indication to MDR-TB therapy. Management of psychiatric complications is possible without compromising anti-tuberculosis treatment.

Tuberculosis prevention in Mexican immigrants: limitations of short-course therapy.

BACKGROUND: Two months of rifampin and pyrazinamide (RIF/PZA) for tuberculosis prevention has been advocated as a way to improve adherence in mobile populations, such as recent immigrants. However, RIF/PZA requires intensive patient and laboratory monitoring for hepatotoxicity. OBJECTIVES: To describe the feasibility and outcomes of using RIF/PZA for TB prevention during a tuberculosis outbreak in a Mexican immigrant community, where 23 adults and 11 children were treated with RIF/PZA between August 2001 and October 2001. METHODS: Retrospective chart review and interviews with health department employees were conducted to assess completion rates, hepatotoxicity, cost, and feasibility of monitoring. RESULTS: Ten (91%) children and 13 (57%) adults completed RIF/PZA. One child (9%) and four adults (17%) developed drug-induced hepatitis. Cultural barriers affected care. The adults resisted the biweekly blood draw, believing it would "drain them of energy." RIF/PZA, plus monitoring, was twice as costly as 4 months of rifampin. CONCLUSIONS: RIF/PZA was associated with significant hepatotoxicity, poor completion, and cultural barriers to monitoring, and was more costly than standard therapy. Tuberculosis prevention must address potential clinical, cultural, and economic barriers to completion and monitoring of short-course therapy in immigrants.

Efectos adversos de consecuencia fatal por tratamiento con fármacos antituberculosos / Fatal adverse effects secundary to antituberculous therapy

We report the case of a patient with several adverse effects, of fatal consequence, associated with drugs used in the treatment for Tuberculosis. Patient was hospitalized at the Hospital Nacional Arzobispo Loayza of Lima, Peru, since May until July 2001. We identified the presence of several adverse effects associated with antituberculosis drugs (dermatitis, nausea, vomit, interstitial nephritis, hepatitis for drug and thrombocytopenia, associated with Intracraneal hemorrhage, of fatal consequence). This study reports a case very infrequent in the world (including Peru), in relation with the presence of several adverse effects of antituberculosis drugs, in the same patient, who died because of these effects. We want to inform the potential risks associated with antituberculosis drugs (of great use in Peru for the high prevalence of Tubersulosis), that must have a regimen and adequate control to avoid severe consequences.

Safety and bactericidal activity of rifalazil in patients with pulmonary tuberculosis.

Rifalazil, also known as KRM-1648 or benzoxazinorifamycin, is a new semisynthetic rifamycin with a long half-life of approximately 60 h. Rifalazil has potent bactericidal activity against Mycobacterium tuberculosis in vitro and in animal models of tuberculosis (TB). Prior studies in healthy volunteers showed that once-weekly doses of 25 to 50 mg of rifalazil were well tolerated. In this randomized, open-label, active-controlled phase II clinical trial, 65 subjects with sputum smear-positive pulmonary TB received one of the following regimens for the first 2 weeks of therapy: 16 subjects received isoniazid (INH) (5 mg/kg of body weight) daily; 16 received INH (5 mg/kg) and rifampin (10 mg/kg) daily; 17 received INH (5 mg/kg) daily plus 10 mg of rifalazil once weekly; and 16 received INH (5 mg/kg) daily and 25 mg of rifalazil once weekly. All subjects were then put on 6 months of standard TB therapy. Pretreatment and day 15 sputum CFU of M. tuberculosis were measured to assess the bactericidal activity of each regimen. The number of drug-related adverse experiences was low and not significantly different among treatment arms. A transient decrease in absolute neutrophil count to less than 2,000 cells/mm(3) was detected in 10 to 20% of patients in the rifalazil- and rifampin-containing treatment arms without clinical consequences. Decreases in CFU counts were comparable among the four treatment arms; however, the CFU results were statistically inconclusive due to the variability in the control arms. Acquired drug resistance did not occur in any patient. Studies focused on determining a maximum tolerated dose will help elucidate the full anti-TB effect of rifalazil.

Glycoprotein Ib/IX complex is the target in rifampicin-induced immune thrombocytopenia.

Thrombocytopenia is a major adverse effect of several drug treatments. Rifampicin has been recognized as a cause of immune thrombocytopenia during intermittent high-dose therapy. We characterized the antibody of a patient who presented with purpura and thrombocytopenia during treatment of tuberculosis with rifampicin. Drug-dependent binding of the antibody to platelets was demonstrated by flow cytometry. In a glycoprotein-specific immunoassay, the binding epitope of the IgG antibody was found in the glycoprotein Ib/IX complex, using four different monoclonal antibodies (mAbs) against various epitopes on the GPIb/IX complex, as well as mAbs against GPIIb/IIIa, GPIa/IIa and GPIV. By immunoprecipitation of biotin-labelled platelets, reactivity of the antibody with GPIb/IX was found only in the presence of the drug. These findings clearly demonstrate that rifampicin induces the formation of drug-dependent antibodies capable of causing thrombocytopenia. The binding site of the rifampicin-dependent antibody, located in the GPIb/IX complex, seems to be a favoured target for antibodies induced by different drugs.

Treatment of nontuberculous mycobacterial lymphadenitis with clarithromycin plus rifabutin.

Treatment with clarithromycin plus rifabutin in children with nontuberculous mycobacterial lymphadenitis was associated with resolution of chronic sinus formation and discharge after incomplete excision in five of five cases, and involution of the enlarged lymph nodes in two of three cases treated without surgery.