Ampliação de uso dos medicamentos doxiciclina, estreptomicina e rifampicina para o tratamento da brucelose humana / Extension of use of the drugs doxycycline, streptomycin and rifampicin for the treatment of human brucellosis

CONTEXTO: No período de 2013 a 2016 foram registrados no Sistema de Informação de Agravos de Notificação (SINAN), 1.493 notificações de brucelose humana e observou-se que a partir de 2015, houve um aumento considerável no número de notificações. Esse comportamento crescente reforça a necessidade de implementação de ações específicas, incluindo a implantação de um sistema de vigilância e a garantia de acesso a diagnóstico e tratamento adequados e oportunos. Considerando que o Ministério da Saúde já adquire doxiciclina, rifampicina e estreptomicina para atender à demanda de outros programas (tuberculose e hanseníase, por exemplo), este relatório visa avaliar a ampliação de uso dos referidos medicamentos no SUS, para tratamento da brucelose humana. TECNOLOGIAS: Doxiciclina 100mg comprimido; sulfato de estreptomicina 1g pó para solução injetável; rifampicina 300mg cápsula; e rifampicina 20mg/mL suspensão oral. INDICAÇÃO: Brucelose humana. PERGUNTA: O uso da doxiciclina, rifampicina e estreptomicina é eficaz e seguro para o tratamento de pacientes com brucelose humana? EVIDÊNCIAS CIENTÍFICAS: Foram selecionadas três revisões sistemáticas que embasaram a recomendação de ampliação de uso dos medicamentos avaliados e, em geral, os resultados demonstraram que, na comparação de doxiciclina+rifampicina versus doxiciclina+estreptomicina, para os desfechos avaliados, não houve diferença entre os grupos. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário da ampliação de uso dos tratamentos analisados para a brucelose humana será entre R$ 26.046,72 e R$ 31.473,12 por ano, dependendo da percentagem de pacientes que seguirá cada um dos esquemas de tratamento analisados. Estes valores representam um aumento de 2,9% a 3,5% nos valores gastos na última compra feita pelo Ministério da Saúde. CONSIDERAÇÕES FINAIS: Com base nos resultados das revisões sistemáticas apresentadas, sugere-se que inicialmente seja recomendada a ampliação de uso dos seguintes medicamentos que já estão incluídos na Rename, para tratamento da brucelose humana: (i) doxiciclina 100mg comprimido; (ii) sulfato de estreptomicina 1g pó para solução injetável; (iii) rifampicina 300mg cápsula; e (iv) rifampicina 20mg/mL suspensão oral. RECOMENDAÇÃO DA CONITEC: os membros da CONITEC, presentes na 52ª reunião ordinária, realizada nos dias 1e 2 de fevereiro de 2017, deliberaram por unanimidade recomendar a ampliação de uso dos medicamentos doxiciclina, estreptomicina e rifampicina para tratamento de brucelose humana. DECISÃO: Ampliar o uso dos medicamentos doxiciclina, estreptomicina e rifampicina para tratamento da brucelose humana, no âmbito do Sistema Único de Saúde - SUS. A decisão foi dada pela Portaria SCTIE-MS nº 13 publicada no Diário Oficial da União (DOU) nº 50, de 14 de março de 2017, pág. 53.(AU)

Ampliação de uso dos medicamentos doxiciclina, estreptomicina e rifampicina para o tratamento da brucelose humana / Expansion of use of the drugs doxycycline, streptomycin and rifampicin for the treatment of human brucellosis

Contexto: No período de 2013 a 2016 foram registrados no Sistema de Informação de Agravos de Notificação (SINAN), 1.493 notificações de brucelose humana e observou-se que a partir de 2015, houve um aumento considerável no número de notificações. Esse comportamento crescente reforça a necessidade de implementação de ações específicas, incluindo a implantação de um sistema de vigilância e a garantia de acesso a diagnóstico e tratamento adequados e oportunos. Considerando que o Ministério da Saúde já adquire doxiciclina, rifampicina e estreptomicina para atender à demanda de outros programas (tuberculose e hanseníase, por exemplo), este relatório visa avaliar a ampliação de uso dos referidos medicamentos no SUS, para tratamento da brucelose humana. Pergunta: O uso da doxiciclina, rifampicina e estreptomicina é eficaz e seguro para o tratamento de pacientes com brucelose humana? Evidências científicas: Foram selecionadas três revisões sistemáticas que embasaram a recomendação de ampliação de uso dos medicamentos avaliados e, em geral, os resultados demonstraram que, na comparação de doxiciclina+rifampicina versus doxiciclina+estreptomicina, para os desfechos avaliados, não houve diferença entre os grupos. Avaliação de Impacto Orçamentário: O impacto orçamentário da ampliação de uso dos tratamentos analisados para a brucelose humana será entre R$ 26.046,72 e R$ 31.473,12 por ano, dependendo da percentagem de pacientes que seguirá cada um dos esquemas de tratamento analisados. Estes valores representam um aumento de 2,9% a 3,5% nos valores gastos na última compra feita pelo Ministério da Saúde. Considerações finais: Com base nos resultados das revisões sistemáticas apresentadas, sugere-se que inicialmente seja recomendada a ampliação de uso dos seguintes medicamentos que já estão incluídos na Rename, para tratamento da brucelose humana: (i) doxiciclina 100mg comprimido; (ii) sulfato de estreptomicina 1g pó para solução injetável; (iii) rifampicina 300mg cápsula; e (iv) rifampicina 20mg/mL suspensão oral. Recomendação da Conitec: os membros da CONITEC, presentes na 52ª reunião ordinária, realizada nos dias 1 e 2 de fevereiro de 2017, deliberaram por unanimidade recomendar a ampliação de uso dos medicamentos doxiciclina, estreptomicina e rifampicina para tratamento de brucelose humana. Decisão: Ampliar o uso dos medicamentos doxiciclina, estreptomicina e rifampicina para tratamento da brucelose humana, no âmbito do Sistema Único de Saúde - SUS. A decisão foi dada pela Portaria SCTIE - MS nº 13 publicada no Diário Oficial da União (DOU) nº 50, de 14 de março de 2017.

High mortality associated with retreatment of tuberculosis in a clinic in Kampala, Uganda: a retrospective study.

The World Health Organization recommends for tuberculosis retreatment a regimen of isoniazid (H), rifampicin (R), ethambutol (E), pyrazinamide (Z), and streptomycin (S) for 2 months, followed by H, R, E, and Z for 1 month and H, R, and E for 5 months. Using data from the National Tuberculosis and Leprosy Program registry, this study determined the long-term outcome under programmatic conditions of patients who were prescribed the retreatment regimen in Kampala, Uganda, between 1997 and 2003. Patients were traced to determine their vital status; 62% (234/377) patients were found dead. Having ≤ 2 treatment courses and not completing retreatment were associated with mortality in adjusted analyses.

Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial.

BACKGROUND: Surgical debridement was the standard treatment for Mycobacterium ulcerans infection (Buruli ulcer disease) until WHO issued provisional guidelines in 2004 recommending treatment with antimicrobial drugs (streptomycin and rifampicin) in addition to surgery. These recommendations were based on observational studies and a small pilot study with microbiological endpoints. We investigated the efficacy of two regimens of antimicrobial treatment in early-stage M ulcerans infection. METHODS: In this parallel, open-label, randomised trial undertaken in two sites in Ghana, patients were eligible for enrolment if they were aged 5 years or older and had early (duration <6 months), limited (cross-sectional diameter <10 cm), M ulcerans infection confirmed by dry-reagent-based PCR. Eligible patients were randomly assigned to receive intramuscular streptomycin (15 mg/kg once daily) and oral rifampicin (10 mg/kg once daily) for 8 weeks (8-week streptomycin group; n=76) or streptomycin and rifampicin for 4 weeks followed by rifampicin and clarithromycin (7.5 mg/kg once daily), both orally, for 4 weeks (4-week streptomycin plus 4-week clarithromycin group; n=75). Randomisation was done by computer-generated minimisation for study site and type of lesion (ulceration or no ulceration). The randomly assigned allocation was sent from a central site by cell-phone text message to the study coordinator. The primary endpoint was lesion healing at 1 year after the start of treatment without lesion recurrence or extensive surgical debridement. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00321178. FINDINGS: Four patients were lost to follow-up (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, three). Since these four participants had healed lesions at their last assessment, they were included in the analysis for the primary endpoint. 73 (96%) participants in the 8-week streptomycin group and 68 (91%) in the 4-week streptomycin plus 4-week clarithromycin group had healed lesions at 1 year (odds ratio 2.49, 95% CI 0.66 to infinity; p=0.16, one-sided Fisher's exact test). No participants had lesion recurrence at 1 year. Three participants had vestibulotoxic events (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, two). One participant developed an injection abscess and two participants developed an abscess close to the initial lesion, which was incised and drained (all three participants were in the 4-week streptomycin plus 4-week clarithromycin group). INTERPRETATION: Antimycobacterial treatment for M ulcerans infection is effective in early, limited disease. 4 weeks of streptomycin and rifampicin followed by 4 weeks of rifampicin and clarithromycin has similar efficacy to 8 weeks of streptomycin and rifampicin; however, the number of injections of streptomycin can be reduced by switching to oral clarithromycin after 4 weeks. FUNDING: European Union (EU FP6 2003-INCO-Dev2-015476) and Buruli Ulcer Groningen Foundation.

Modified short-course chemotherapy of pulmonary tuberculosis in Ibadan, Nigeria--a preliminary report.

Over a 3 year period 3rd of April 1995 and 6th of April 1998 a controlled clinical trial of the modified short-course chemotherapy (SSC) in newly diagnosed cases of pulmonary tuberculosis in Nigeria was carried out. Between The SCC used was the one adopted from World Health Organisation/International Union Against Tuberculosis and Lung Diseases for developing countries by the Nigerian National Tuberculosis and Leprosy Control Programme (NTLCP). The regimen used consisted of streptomycin (S), isoniazid (H), Rifampicin (R) and pyrazinamide (Z) in the initial or intensive phase of 2 months. Ethambutol (E) was sometimes substituted for streptomycin. The continuation phase was 6 months of thiacetazone, (T) and isoniazid (H), i.e., 2SHRZ/6TH or 2EHRZ/6TH. Sputum conversion was 90% at the second month of treatment and there was no bacteriological relapse after 18 months of follow-up. Side effects were few and consisted mainly of acne vulgaris which occurred in twenty (20.6%) of 97 patients during the continuation phase. It is concluded that the 8-month chemotherapy regimen adopted by NTLCP is efficacious in treatment of smearpositive pulmonary tuberculosis (PTB).

Tuberculosis chemotherapy and sputum conversion among HIV-seropositive and HIV-seronegative patients in south-eastern Uganda.

OBJECTIVE: To investigate if there is a difference in response to tuberculosis treatment between HIV seronegative and HIV seropositive patients following two months of intensive phase tuberculosis treatment. DESIGN: Prospective cohort study. SETTING: St. Francis Leprosy Centre, south-east Uganda. SUBJECTS: Four hundred fifty seven patients with never previously treated sputum smear-positive tuberculosis admitted during a two-year period in 1991/1993. INTERVENTION: Intensive phase treatment with streptomycin, isoniazid, rifampicin and pyrazinamide. MAIN OUTCOME MEASURES: Sputum conversion from a positive to a negative smear at eight weeks of treatment. RESULTS: HIV seropositivity prevalence was 28%. Among HIV seronegative patients, conversion to a negative smear status occurred in 76% persons compared to 78% in HIV seropositive patients. This difference was not statistically significant (OR = 0.9; 95% CI, 0.6-1.5). HIV seropositive patients, however, were more likely to die (p = 0.017). A high prevalence of resistance to isoniazid and streptomycin was found. Isoniazid resistance was more likely in HIV seronegative patients with M. tuberculosis strains compared to HIV seropositive persons (p < 0.005). Initial resistance to antituberculosis drugs did not have a significant effect on smear conversion. CONCLUSION: This study demonstrates that HIV-seropositive status is not a principal factor in delaying sputum conversion among patients receiving intensive phase tuberculosis treatment.

PIP: A prospective cohort study was undertaken to investigate the response of HIV-seropositive and -seronegative patients at St. Francis Leprosy Center, southeastern Uganda, to tuberculosis chemotherapy. The study population included 457 patients without a history of prior tuberculosis therapy between 1991 and 1993. The subjects were exposed to an intensive phase therapy of rifampicin, streptomycin, isoniazid, and pyrazinamide. After the treatment, sputum culture and sensitivity tests were conducted. Findings showed that 77% of the patients who never received tuberculosis treatment in the past converted to a negative smear status after the 8-week treatment. There was no significant difference in sputum conversion rates between HIV-seropositive and -seronegative patients. The study also revealed that HIV seropositivity prevalence was 28%. Among HIV-seronegative patients, conversion to a negative smear status occurred in 76% compared to 78% HIV-seropositive patients. Moreover, a significant number of HIV-seronegative patients died during the initial course of the therapy. Also, a high prevalence of isoniazid and streptomycin resistance was noted; however, this result never affected the conversions of smears. In conclusion, the study clearly demonstrates that other factors outside the seropositive status may be the principal causes of the delay in sputum conversion among patients receiving intensive tuberculosis chemotherapy.

Crescentic glomerulonephritis due to rifampin treatment in a patient with pulmonary atypical mycobacteriosis.

A 64-year-old male was treated continuously with rifampin, isoniazid and streptomycin for pulmonary atypical mycobacteriosis, Mycobacterium kansasii. Five weeks after beginning the treatment, the patient suddenly developed acute renal failure. A renal biopsy showed crescentic lesions characteristic of rapidly progressive glomerulonephritis with moderate interstitial changes. Serum antirifampin antibody was detected, and the cessation of rifampin treatment was followed by a rapid spontaneous recovery of the patient's renal function. This is, to our knowledge, the first case of rapidly progressive crescentic glomerulonephritis associated with rifampin treatment where circulating antirifampin antibody is demonstrated and the renal function spontaneously improved after discontinuing rifampin treatment.

Relapse rates in patients treated with dapsone monotherapy and combinations of dapsone and thiambutosine, thiacetazone, isoniazid and streptomycin in the pre-MDT era.

Relapse rates were studied in patients from northern Thailand who were started on dapsone monotherapy between 1949 and 1976. Included are a group of patients who, for various reasons, also received combinations of dapsone and thiambutosine, thiacetazone, isoniazid and streptomycin. The overall relapse rate in paucibacillary patients on dapsone monotherapy only was 2.7 per 1000 person-years at risk (PYR) (average observation period 13.9 years). In the multibacillary patients who received dapsone monotherapy only, the relapse rate was 10.5 per 1000 PYR (average observation period 12.4 years). In both groups it was found that 50% of the relapses occurred after the seventh year of follow up. The overall relapse rate in those patients whose treatment included thiambutosine, thiacetazone, isoniazid and/or streptomycin for at least 3 months was 17.9 per 1000 PYR (average observation period 11.9 years). The difference with the multibacillary patients treated with dapsone monotherapy only is not significant. It is concluded that alternative antileprosy drugs included in therapy regimens with dapsone in the pre-MDT era did not result in relapses occurring less often.

Detection of rifampicin-induced nephrotoxicity by N-acetyl-3-D-glucosaminidase activity.

The objective of the present study was to assess renal damage, if any, by non-invasive technique, viz NAG activity in urine and GFR in patients on continuous and intermittent rifampicin therapy. Eighty-four tuberculosis patients for cross-sectional study and six subjects for longitudinal study on antitubercular therapy and ten patients on withdrawal of rifampicin participated in the investigation; 13 leprosy patients intermittently treated with rifampicin were also included. Twenty-seven normal subjects served as controls. Rifampicin on continuous use resulted in a progressive increase in enzymuria with no change in GFR. An additive toxic effect was obvious in patients receiving streptomycin; when the treatment was withdrawn the urinary NAG activity stabilized within 15-21 days. However, patients receiving rifampicin intermittently did not show any evidence of renal damage. The results suggest that there is a need for monitoring renal damage, particularly on antitubercular therapy, when nephrotoxic agents are administered together.

Further studies of the killing of M. leprae by aminoglycosides: reduced dosage and frequency of administration.

The bactericidal activity of the aminoglycoside antibiotics streptomycin and kanamycin for Mycobacterium leprae in mice was assessed, both alone and in combination with rifampin, utilizing various dosage schedules. As in previous studies, 100 mg/kg five times weekly of streptomycin and kanamycin resulted, respectively, in 96% +/- 2% and 89% +/- 6% bactericide. Reducing the dosage of streptomycin to 50 mg/kg, 25 mg/kg, and even 12.5 mg/kg resulted in less but significant bactericidal activity. Such a reduction of kanamycin dosage resulted in no significant bactericidal activity. Reducing the frequency of administration of streptomycin (100 mg/kg) to twice weekly and once weekly resulted in a decreased but still significant killing of M. leprae; for kanamycin such a reduction in frequency of administration resulted in loss of bactericidal activity. Streptomycin when combined with rifampin was found more bactericidal than either drug alone, even when each was administered only once monthly.

Long-spacing collagen in skin biopsies from patients with lepromatous leprosy.

In the course fo evaluating the effect of different drugs on the morphology of Mycobacterium leprae (Edwards, Draper & Draper, 1972) and on the phagocytic cells containing these organisms (Edwards, 1973), an unusual feature was observed in the dermal connective tissue of skin biopsies obtained from some of the patients. Variable amounts of an extracellular, cross-striated osmiophilic material were present in the dermis. The purpose of this communication is to describe the banded substance observed in the extracellular space of the lepromatous skin and to compare it briefly with similar substances and structures reported to occur elsewhere.