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1.
Infectio ; 25(4): 207-211, oct.-dic. 2021. tab, graf
Artigo em Espanhol | LILACS, COLNAL | ID: biblio-1286715

RESUMO

Resumen Objetivo: Describir la proporción, características clínicas, demográficas y programáticas de casos fatales de coinfección TB/VIH de Cali-Colombia, en 2017. Material y Método: Estudio de corte transversal, con información de las bases de datos del programa de tuberculosis, las historias clínicas y unidades de análisis de mortalidad disponibles. Resultados: Se depuraron 257 casos fatales por TB, el 24,5% (63/257) falleció con coinfección TB/VIH. La mediana de edad fue 43 años (Rango Intercuartílico: 30-52), 73% (46/63) eran hombres, 76,2% (48/63) no pertenecían al régimen contributivo, 28,6% eran habitantes de calle. 81,2% (39/48) eran casos nuevos de TB, 76,6% (37/47), inició tratamiento; al 74,6% (47/63) se les realizó unidad de análisis de mortalidad. La presentación pulmonar fue frecuente (75,9%-44/58), en 60% de los registros se observó desnutrición (Índice de Masa Corporal <20), en 39,7% (25/63) dependencia al alcohol, tabaco o farmacodependencia. Conclusiones: La mortalidad asociada a TB/VIH es prevenible, pero en 2017 representó la cuarta parte de la mortalidad por TB en Cali. Hombres adultos con condiciones de vulnerabilidad social, diagnosticados en estados avanzados de enfermedad, fueron blanco de fatalidad. Mejorar los sistemas de información e integrar los programas de TB/VIH, deben ser estrategias prioritarias para la salud pública en Colombia.


Abstract Objective: To describe the proportion, clinical, demographic and programmatic characteristics of fatal cases of TB/HIV coinfection from Cali-Colombia, in 2017. Material and Method: Cross-sectional study, with information from the TB program databases, clinical records and mortality analysis units available. Results: 257 TB fatal cases were cleared in Cali in 2017, 24.5% (63/257) of these died with TB/HIV coinfection. The median age was 43 years (Interquartile Range: 30-52), 73% (46/63) were men, 76.2% (48/63) did not belong to the contributory health regimen, 28.6% were homeless. 81.2% (39/48) were new TB cases, 76.6% (37/47) started treatment; 74.6% (47/63) had mortality analysis register. Pulmonary presentation was frequent (75.9% -44 / 58), in 60% of the registries malnutrition was observed (Body Mass Index <20), in 39.7% (25/63), dependence on alcohol, tobacco or drug dependence was registered. Conclusions: Mortality associated with TB/HIV is preventable, but in 2017 it represented a quarter of the TB mortality in Cali. Adult men with conditions of social vulnerability, diagnosed in advanced stages of disease, were fatally targeted. Improving information systems and integrating TB/HIV programs should be priority strategies for public health in Colombia.


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Tuberculose , HIV , Índice de Massa Corporal , Infecções por HIV , Saúde Pública , Estudos Transversais , Mortalidade , Estratégias de Saúde , Colômbia , Vulnerabilidade Social , Desnutrição
2.
Rev Peru Med Exp Salud Publica ; 38(2): 318-325, 2021.
Artigo em Espanhol | MEDLINE | ID: mdl-34468583

RESUMO

Reports of infection and/or disease caused by non-tuberculous mycobacteria (NTM) are becoming increasingly frequent. This scope review describes the epidemiological and clinical trend of infection/disease caused by NTM in Latin America. OVID MEDLINE, Embase and LILACS databases were explored for relevant articles. After filtering, we included 44 articles, representing an overall population of 2,826 subjects diagnosed with NTM infection and disease; the majority of the publications included subjects from Brazil and Colombia (75%), cross-sectional studies were the most common (36.6%), most subjects were male (61.3%) and the median age of subjects was 40.1 years. Disease by NTM was reported in 37 publications, extrapulmonary presentation was the most frequent (54%), main comorbidities were other pulmonary diseases, HIV, cystic fibrosis, diabetes and malnutrition, as reported in 13 studies; tuberculosis diagnosis previous to NTM disease was reported in 15 articles. Aesthetic procedures were reported in 12 articles while clinical procedures were reported in 3 articles. Several NTM species were reported, being Mycobacterium avium (52%), M. abscessus (34%), M. chelonae (18%), M. fortuitum (16%) and M. kansasii (9.1%) the most frequent. Culture and molecular testing were the main methods for diagnosis and identification. Scientific literature on NTM from Latin American countries is scarce. There is an urgent need to conduct studies on the frequency and clinical impact of NTM infections, in order to accurately identify the current morbidity and mortality associated with NTM in Latin American. It is also important to strengthen the local diagnostic capacity and the existing networks focused on studying NTM.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Tuberculose , Adulto , Estudos Transversais , Humanos , América Latina/epidemiologia , Masculino , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Micobactérias não Tuberculosas , Tuberculose/diagnóstico , Tuberculose/epidemiologia
3.
Artigo em Inglês | MEDLINE | ID: mdl-34444201

RESUMO

Nontuberculous mycobacteria (NTM) are ubiquitous microorganisms naturally resistant to antibiotics and disinfectants that can colonize drinking water supply systems. Information regarding the spread of NTM in specifically South America and Colombia is limited. We aimed to identify and characterize NTM present in tap water samples from Cali, Colombia. Drinking water samples and faucet biofilm swabs were collected in 18 places, including the city's three main water treatment plants (WTPs). Filter-trapped material and eluates (0.45 µm) from swab washes were plated in 7H11 agar plates. Suspected colonies were evaluated microscopically, and NTM species were identified based on the rpoB gene. Antibiotic susceptibility testing was also performed. Fifty percent (9/18) of sampling points were positive for NTM (including two WTPs), from which 16 different isolates were identified: Mycobacterium mucogenicum (8/16), M. phocaicum (3/16), M. chelonae (2/16), M. mageritense (2/16), and M. fortuitum (1/16), all rapidly growing mycobacteria. A susceptibility profile was obtained from 68.75% (11/16) of the isolates. M. chelonae was the most resistant species. All NTM isolated are potentially responsible for human diseases; our findings might provide a baseline for exploring NTM transmission dynamics and clinical characterization, as well as potential associations between NTM species found in drinking water and isolates from patients.


Assuntos
Água Potável , Infecções por Mycobacterium não Tuberculosas , Colômbia , Humanos , Mycobacteriaceae , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Micobactérias não Tuberculosas/genética
4.
Am J Trop Med Hyg ; 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33617470

RESUMO

Tuberculosis (TB) contact investigation facilitates earlier TB diagnosis and initiation of preventive therapy, but little data exist about the quality of its implementation. We conducted a retrospective cohort study to evaluate processes of TB contact investigation for index TB patients diagnosed in Cali, Colombia, in 2017, including dropout at each stage and overall yield. We constructed multivariable models to identify predictors of completing 1) the baseline household visit and 2) a follow-up clinic visit for TB evaluation among referred contacts. Sixty-eight percent (759/1,120) of registered TB patients were eligible for contact investigation; 77% (582/759) received a household visit. Odds of completing a household visit were significantly lower among men (adjusted odds ratio [aOR]: 0.6; 95% CI: 0.4-0.9; P = 0.009) and patients living in Cali's western zone (aOR: 0.5; 95% CI: 0.3-0.8; P = 0.008). Among 1880 screened contacts, 31% (n = 582) met the criteria for clinic referral, 47% (n = 271) completed a clinic visit, and 85% (231/271) completed testing. After adjusting for clustering by index patient, odds of completing referral were higher among contacts with cough (aOR: 22; 95% CI: 7.1-66; P < 0.001) and contacts living in the western zone (aOR: 4.1; 95% CI: 1.2-15; P = 0.03). The cumulative probability of a symptomatic contact from an eligible household completing TB evaluation was only 28%. The yield of active TB patients among contacts was only 0.3% (5/1880). Only 16% (17/103) of children aged < 5 years were included, and none of the eight persons were living with HIV-initiated preventive therapy. Routine monitoring of process indicators may facilitate quality improvement to close gaps in contact tracing and increase yield.

5.
PLoS One ; 15(4): e0224908, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32330146

RESUMO

Beijing strains of Mycobacterium tuberculosis (lineage 2) have been associated with drug-resistance and transmission of tuberculosis worldwide. Most of the Beijing strains identified in the Colombian Pacific coast have exhibited a multidrug resistant (MDR) phenotype. We sought to evaluate the clonality and sublineage of Beijing strains circulating in Southwestern Colombia. Thirty-seven Beijing strains were identified through spoligotyping out of 311 clinical isolates collected in 9 years from 2002-2010. Further analysis by MIRU-VNTR 24 loci was conducted for the Beijing strains. For sublineage classification, deletions of RD105, RD207, and RD131 and point mutations at fbpB, mutT2, and acs were evaluated. Drug-resistance associated mutations to first- and second-line anti-TB drugs were also evaluated. Additionally, two Beijing strains were Illumina-whole genome sequenced (one MDR and one drug-susceptible). Among the 37 Beijing strains characterized, 36 belonged to the SIT190 type from which 28 were MDR, four pre-extensively drug resistant (XDR) TB, and four XDR-TB. The remaining strain was SIT1 and drug susceptible. MIRU-VNTR analysis allowed the identification of three Beijing clusters and two unique strains. Beijing strains were confirmed as "modern" sublineage. The mutations rpoB S531L and katG S315T were the most common among MDR strains. Moreover, the two strains evaluated by whole genome sequencing (WGS) shared most of the genetic features with the sublineage 2.2.1 "modern" Beijing previously characterized from Asian strains. WGS analysis of the MDR strain revealed the presence of eight SNPs previously reported in other MDR "Beijing-like" strains from Colombia. The presence of "modern" Beijing strains in Southwestern Colombia, most of them with MDR phenotype, suggests a different origin of this M. tuberculosis sublineage compared to other Beijing strains found in neighboring South American countries. This work may serve as a genetic baseline to study the evolution and spread of M. tuberculosis Beijing strains in Colombia, which play an important role in the propagation of MDR-TB.


Assuntos
Farmacorresistência Bacteriana Múltipla , Mutação , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Adolescente , Adulto , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Pequim/epidemiologia , Criança , Pré-Escolar , Colômbia/epidemiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Filogenia , Mutação Puntual , Deleção de Sequência , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto Jovem
6.
Colomb. med ; 50(4): 261-274, Oct.-Dec. 2019. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1114719

RESUMO

Abstract Aim: To assess the risk of tuberculosis (infection and disease) in children less than 15 years' old who are household contacts of pulmonary tuberculosis patients in three Colombian cities (Medellín, Cali, and Popayán). Methods: A cohort of 1,040 children household contacts of 380 adults with smear-positive pulmonary tuberculosis was followed up for 24 months. Study period 2005-2009. Results: Tuberculin skin test was positive (≥10 mm) in 43.7% (95% CI: 39.2-48.2). Tuberculin skin test positivity was associated with age 10-14 years (Prevalence Ratio -PR= 1.43, 95% CI: 1.1-1.9), having a BCG vaccine scar (PR= 1.52, 95% CI: 1.1-2.1), underweight, closer proximity to the index case and exposure time >3 months. The annual risk of infection (tuberculin skin test induration increase of 6 mm or more per year) was 17% (95% CI: 11.8-22.2) and was associated with a bacillary load of the adult index case (Relative Risk -RR= 2.12, 95% CI: 1.0-4.3). The incidence rate of active tuberculosis was 12.4 cases per 1,000 persons-year. Children <5 years without BCG vaccine scar had a greater risk of developing active disease (Hazard Ratio -HR= 6.00, 95% CI: 1.3-28.3) than those with scar (HR= 1.33, 95% CI: 0.5-3.4). The risk of developing active tuberculosis augmented along with the increase from initial tuberculin skin test (tuberculin skin test 5-9 mm HR= 8.55, 95% CI: 2.5-29.2; tuberculin skin test ≥10 mm HR= 8.16, 95% CI: 2.0-32.9). Conclusions: There is a need for prompt interruption of adult-to-children tuberculosis transmission within households. Conducting proper contact investigation and offering chemoprophylaxis to infected children could reduce tuberculosis transmission.


Resumen Objetivo: Evaluar el riesgo de tuberculosis (infección y enfermedad) en niños menores de 15 años de edad convivientes de pacientes con tuberculosis pulmonar en tres ciudades colombianas (Medellín, Cali y Popayán). Métodos: Se siguió durante 24 meses una cohorte de 1,040 niños convivientes de 380 adultos con tuberculosis pulmonar bacilífera. Periodo de estudio 2005-2009. Resultados: La prueba de tuberculina fue positiva (≥10 mm) en el 43.7% (IC 95%: 39.2-48.2), y estuvo asociada con la edad de 10-14 años (Razón de Prevalencia-RP= 1.43, IC 95%: 1.1-1.9), tener cicatriz de la vacuna BCG (RP= 1.52, IC 95%: 1.1-2.1). El riesgo anual de infección (aumento de la induración en la prueba de tuberculina de 6 mm o más al año) fue 17% (IC 95%: 11.8-22.2), y estuvo asociado con mayor carga bacilar en el adulto con tuberculosis pulmonar (Riesgo Relativo-RR= 2.12, IC 95%: 1.0-4.3). La tasa de incidencia de tuberculosis activa fue de 12.4 casos por 1,000 años-persona de seguimiento. Los niños menores de 5 años sin cicatriz de vacuna BCG tuvieron un mayor riesgo de desarrollar tuberculosis activa (Razón de Peligro -HR= 6.00, IC 95%: 1.3-28.3), que quienes tenían cicatriz (HR= 1.33, IC 95%: 0.5-3.4). El riesgo de desarrollar tuberculosis activa aumentó conforme el aumento de la prueba de tuberculina inicial (prueba de tuberculina 5-9 mm HR= 8.55, IC 95%: 2.5-29.2; prueba de tuberculina ≥10 mm HR= 8.16, IC 95%: 2.0-32.9). Conclusión: Es necesario interrumpir rápidamente la transmisión de tuberculosis de adultos a niños en los hogares. Realizar investigaciones de contacto apropiadas y ofrecer quimioprofilaxis a los niños infectados podría reducir la transmisión de la tuberculosis.

7.
Colomb Med (Cali) ; 50(4): 261-274, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32476692

RESUMO

Aim: To assess the risk of tuberculosis (infection and disease) in children less than 15 years' old who are household contacts of pulmonary tuberculosis patients in three Colombian cities (Medellín, Cali, and Popayán). Methods: A cohort of 1,040 children household contacts of 380 adults with smear-positive pulmonary tuberculosis was followed up for 24 months. Study period 2005-2009. Results: Tuberculin skin test was positive (≥10 mm) in 43.7% (95% CI: 39.2-48.2). Tuberculin skin test positivity was associated with age 10-14 years (Prevalence Ratio -PR= 1.43, 95% CI: 1.1-1.9), having a BCG vaccine scar (PR= 1.52, 95% CI: 1.1-2.1), underweight, closer proximity to the index case and exposure time >3 months. The annual risk of infection (tuberculin skin test induration increase of 6 mm or more per year) was 17% (95% CI: 11.8-22.2) and was associated with a bacillary load of the adult index case (Relative Risk -RR= 2.12, 95% CI: 1.0-4.3). The incidence rate of active tuberculosis was 12.4 cases per 1,000 persons-year. Children <5 years without BCG vaccine scar had a greater risk of developing active disease (Hazard Ratio -HR= 6.00, 95% CI: 1.3-28.3) than those with scar (HR= 1.33, 95% CI: 0.5-3.4). The risk of developing active tuberculosis augmented along with the increase from initial tuberculin skin test (tuberculin skin test 5-9 mm HR= 8.55, 95% CI: 2.5-29.2; tuberculin skin test ≥10 mm HR= 8.16, 95% CI: 2.0-32.9). Conclusions: There is a need for prompt interruption of adult-to-children tuberculosis transmission within households. Conducting proper contact investigation and offering chemoprophylaxis to infected children could reduce tuberculosis transmission.


Assuntos
Vacina BCG/administração & dosagem , Tuberculose Pulmonar/epidemiologia , Tuberculose/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Colômbia/epidemiologia , Busca de Comunicante , Progressão da Doença , Feminino , Humanos , Incidência , Lactente , Masculino , Prevalência , Teste Tuberculínico , Tuberculose/prevenção & controle , Tuberculose/transmissão , Tuberculose Pulmonar/prevenção & controle , Tuberculose Pulmonar/transmissão
8.
Diagn Microbiol Infect Dis ; 92(4): 305-308, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30025972

RESUMO

The emergence of drug-resistant tuberculosis and disease caused by nontuberculous mycobacteria has increased the need for accurate drug susceptibility testing of mycobacteria. The stability of the tested drugs in relevant test media have been understudied. We assessed the stability of isoniazid, rifampicin, clarithromycin, linezolid and amikacin in Middlebrook 7H9 medium and that of clarithromycin, amikacin and cefoxitin in the cation-adjusted Mueller Hinton broth. We used ultra-performance liquid chromatography (UPLC) methods for rifampicin and isoniazid and a microbiological assay for rifampicin, clarithromycin, amikacin, cefoxitin and linezolid. Rifampicin and isoniazid concentrations in Middlebrook 7H9 medium had decreased by 92% and 54% after 7 days. The microbiological assay revealed decreases in drug concentration of ≥75% (rifampicin, clarithromycin, cefoxitin) and 60% (linezolid) after 14 days. With the exception of amikacin, all antimycobacterial drugs were unstable during 14 days of incubation in the preferred media for DST. Drug stability may influence minimum inhibitory concentration measurements.


Assuntos
Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium/efeitos dos fármacos , Claritromicina/farmacologia , Meios de Cultivo Condicionados , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana , Estabilidade de Medicamentos , Humanos , Testes de Sensibilidade Microbiana/métodos , Rifampina/farmacologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-28807911

RESUMO

In pharmacokinetic/pharmacodynamic models of pulmonary Mycobacterium abscessus complex, the recommended macrolide-containing combination therapy has poor kill rates. However, clinical outcomes are unknown. We searched the literature for studies published between 1990 and 2017 that reported microbial outcomes in patients treated for pulmonary M. abscessus disease. A good outcome was defined as sustained sputum culture conversion (SSCC) without relapse. Random effects models were used to pool studies and estimate proportions of patients with good outcomes. Odds ratios (OR) and 95% confidence intervals (CI) were computed. Sensitivity analyses and metaregression were used to assess the robustness of findings. In 19 studies of 1,533 patients, combination therapy was administered to 508 patients with M. abscessus subsp. abscessus, 204 with M. abscessus subsp. massiliense, and 301 with M. abscessus with no subspecies specified. Macrolide-containing regimens achieved SSCC in only 77/233 (34%) new M. abscessus subsp. abscessus patients versus 117/141 (54%) M. abscessus subsp. massiliense patients (OR, 0.108 [95% CI, 0.066 to 0.181]). In refractory disease, SSCC was achieved in 20% (95% CI, 7 to 36%) of patients, which was not significantly different across subspecies. The estimated recurrent rates per month were 1.835% (range, 1.667 to 3.196%) for M. abscessus subsp. abscessus versus 0.683% (range, 0.229 to 1.136%) for M. abscessus subsp. massiliense (OR, 6.189 [95% CI, 2.896 to 13.650]). The proportion of patients with good outcomes was 52/223 (23%) with M. abscessus subsp. abscessus versus 118/141 (84%) with M. abscessus subsp. massiliense disease (OR, 0.059 [95% CI, 0.034 to 0.101]). M. abscessus subsp. abscessus pulmonary disease outcomes with the currently recommended regimens are atrocious, with outcomes similar to those for extensively drug-resistant tuberculosis. Therapeutically, the concept of nontuberculous mycobacteria is misguided. There is an urgent need to craft entirely new treatment regimens.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Mycobacterium abscessus/patogenicidade , Humanos , Infecções por Mycobacterium não Tuberculosas/mortalidade , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/mortalidade , Escarro/microbiologia , Resultado do Tratamento
10.
Antimicrob Agents Chemother ; 60(10): 6374-6, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27458221

RESUMO

In a hollow-fiber model, we mimicked the drug exposures achieved in the lungs of humans treated with standard amikacin, clarithromycin, and cefoxitin combination therapy for Mycobacterium abscessus infection. At optimal dosing, a kill rate of -0.09 (95% confidence interval, -0.04 to 0.03) log10 CFU per ml/day was achieved over the first 14 days, after which there was regrowth due to acquired drug resistance. Thus, the standard regimen quickly failed. A new regimen is needed.


Assuntos
Amicacina/farmacologia , Cefoxitina/farmacologia , Claritromicina/farmacologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Micobactérias não Tuberculosas/patogenicidade , Antibacterianos/farmacologia , Quimioterapia Combinada , Humanos , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas/crescimento & desenvolvimento , Falha de Tratamento
11.
Antimicrob Agents Chemother ; 60(6): 3779-85, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27067317

RESUMO

Current regimens used to treat pulmonary Mycobacterium abscessus disease have limited efficacy. There is an urgent need for new drugs and optimized combinations and doses. We performed hollow-fiber-system studies in which M. abscessus was exposed to moxifloxacin lung concentration-time profiles similar to human doses of between 0 and 800 mg/day. The minimum bactericidal concentration and MIC were 8 and 2 mg/liter, respectively, in our M. abscessus strain, suggesting bactericidal activity. Measurement of the moxifloxacin concentrations in each hollow-fiber system revealed an elimination rate constant (kel) of 0.11 ± 0.05 h(-1) (mean ± standard deviation) (half-life of 9.8 h). Inhibitory sigmoid maximal effect (Emax) modeling revealed that the highest Emax was 3.15 ± 1.84 log10 CFU/ml on day 3, and the exposure mediating 50% of Emax (EC50) was a 0- to 24-h area under the concentration time curve (AUC0-24)-to-MIC ratio of 41.99 ± 31.78 (r(2) = 0.99). The EC80 was an AUC0-24/MIC ratio of 102.11. However, no moxifloxacin concentration killed the bacteria to burdens below the starting inoculum. There was regrowth beyond day 3 in all doses, with replacement by a resistant subpopulation that had an MIC of >32 mg/liter by the end of the experiment. A quadratic function best described the relationship between the AUC0-24/MIC ratio and the moxifloxacin-resistant subpopulation. Monte Carlo simulations of 10,000 patients revealed that the 400- to 800-mg/day doses would achieve or exceed the EC80 in ≤12.5% of patients. The moxifloxacin susceptibility breakpoint was 0.25 mg/liter, which means that almost all M. abscessus clinical strains are moxifloxacin resistant by these criteria. While moxifloxacin's efficacy against M. abscessus was poor, formal combination therapy studies with moxifloxacin are still recommended.


Assuntos
Antibacterianos/farmacocinética , Fluoroquinolonas/farmacocinética , Modelos Estatísticos , Micobactérias não Tuberculosas/efeitos dos fármacos , Antibacterianos/farmacologia , Área Sob a Curva , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Fluoroquinolonas/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Moxifloxacina , Micobactérias não Tuberculosas/crescimento & desenvolvimento , Pneumonia/tratamento farmacológico , Pneumonia/microbiologia
12.
Antimicrob Agents Chemother ; 60(5): 2895-900, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26926649

RESUMO

Mycobacterium abscessus causes chronic pulmonary infections that are extremely difficult to cure. The currently recommended combination therapy is associated with high failure rates and relapse. Tigecycline has been explored in salvage regimens, with a response rate of 43% in those who received at least a month of therapy. We performed a dose-response study in a hollow-fiber system model of pulmonary M. abscessus infection in which we recapitulated tigecycline human pulmonary concentration-time profiles of 8 different doses for 21 days. We identified the maximal kill or efficacy in CFU per milliliter and the ratio of the 0- to 24-h area under the concentration-time curve to MIC (AUC/MIC) associated with 80% efficacy (EC80). The tigecycline efficacy was 5.38 ± 2.35 log10 CFU/ml, and the drug achieved the unprecedented feat of a bacterial level of 1.0 log10 CFU/ml below the pretreatment inoculum (1-log kill) of M. abscessus in the hollow-fiber system. The EC80 AUC/MIC ratio was 36.65, while that for a 1-log kill was 44.6. Monte Carlo experiments with 10,000 patients were used to identify the clinical dose best able to achieve the EC80 or 1-log kill. The standard dose of 100 mg/day had a cumulative fraction of response of 51% for the EC80 and 46% for 1-log kill. For both the EC80 target and 1-log kill, the optimal tigecycline clinical dose was identified as 200 mg/day. The susceptibility breakpoint was ≤0.5 mg/liter. Tigecycline is the most active single agent evaluated to date, and we propose that 200 mg/day be examined as the backbone of new combination therapy regimens to replace current treatment.


Assuntos
Antibacterianos/farmacologia , Pneumopatias/microbiologia , Minociclina/análogos & derivados , Mycobacterium/efeitos dos fármacos , Antibacterianos/farmacocinética , Área Sob a Curva , Humanos , Pneumopatias/metabolismo , Testes de Sensibilidade Microbiana , Minociclina/farmacocinética , Minociclina/farmacologia , Método de Monte Carlo , Tigeciclina
13.
Antimicrob Agents Chemother ; 60(2): 1097-105, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26643335

RESUMO

Multidrug therapy is a standard practice when treating infections by nontuberculous mycobacteria (NTM), but few treatment options exist. We conducted this study to define the drug-drug interaction between clofazimine and both amikacin and clarithromycin and its contribution to NTM treatment. Mycobacterium abscessus and Mycobacterium avium type strains were used. Time-kill assays for clofazimine alone and combined with amikacin or clarithromycin were performed at concentrations of 0.25× to 2× MIC. Pharmacodynamic interactions were assessed by response surface model of Bliss independence (RSBI) and isobolographic analysis of Loewe additivity (ISLA), calculating the percentage of statistically significant Bliss interactions and interaction indices (I), respectively. Monte Carlo simulations with predicted human lung concentrations were used to calculate target attainment rates for combination and monotherapy regimens. Clofazimine alone was bacteriostatic for both NTM. Clofazimine-amikacin was synergistic against M. abscessus (I = 0.41; 95% confidence interval [CI], 0.29 to 0.55) and M. avium (I = 0.027; 95% CI, 0.007 to 0.048). Based on RSBI analysis, synergistic interactions of 28.4 to 29.0% and 23.2 to 56.7% were observed at 1× to 2× MIC and 0.25× to 2× MIC for M. abscessus and M. avium, respectively. Clofazimine-clarithromycin was also synergistic against M. abscessus (I = 0.53; 95% CI, 0.35 to 0.72) and M. avium (I = 0.16; 95% CI, 0.04 to 0.35), RSBI analysis showed 23.5% and 23.3 to 53.3% at 2× MIC and 0.25× to 0.5× MIC for M. abscessus and M. avium, respectively. Clofazimine prevented the regrowth observed with amikacin or clarithromycin alone. Target attainment rates of combination regimens were >60% higher than those of monotherapy regimens for M. abscessus and M. avium. The combination of clofazimine with amikacin or clarithromycin was synergistic in vitro. This suggests a potential role for clofazimine in treatment regimens that warrants further evaluation.


Assuntos
Amicacina/farmacologia , Antibacterianos/farmacologia , Claritromicina/farmacologia , Clofazimina/farmacologia , Mycobacterium avium/efeitos dos fármacos , Micobactérias não Tuberculosas/efeitos dos fármacos , Interações Medicamentosas , Sinergismo Farmacológico , Quimioterapia Combinada , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Mutação , Mycobacterium avium/genética , Mycobacterium avium/crescimento & desenvolvimento , Micobactérias não Tuberculosas/genética , Micobactérias não Tuberculosas/crescimento & desenvolvimento
14.
Antimicrob Agents Chemother ; 60(3): 1242-8, 2015 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-26643339

RESUMO

The treatment of pulmonary Mycobacterium abscessus disease is associated with very high failure rates and easily acquired drug resistance. Amikacin is the key drug in treatment regimens, but the optimal doses are unknown. No good preclinical model exists to perform formal pharmacokinetics/pharmacodynamics experiments to determine these optimal doses. We developed a hollow-fiber system model of M. abscessus disease and studied amikacin exposure effects and dose scheduling. We mimicked amikacin human pulmonary pharmacokinetics. Both amikacin microbial kill and acquired drug resistance were linked to the peak concentration-to-MIC ratios; the peak/MIC ratio associated with 80% of maximal kill (EC80) was 3.20. However, on the day of the most extensive microbial kill, the bacillary burden did not fall below the starting inoculum. We performed Monte Carlo simulations of 10,000 patients with pulmonary M. abscessus infection and examined the probability that patients treated with one of 6 doses from 750 mg to 4,000 mg would achieve or exceed the EC80. We also examined these doses for the ability to achieve a cumulative area under the concentration-time curve of 82,232 mg · h/liter × days, which is associated with ototoxicity. The standard amikacin doses of 750 to 1,500 mg a day achieved the EC80 in ≤ 21% of the patients, while a dose of 4 g/day achieved this in 70% of the patients but at the cost of high rates of ototoxicity within a month or two. The susceptibility breakpoint was an MIC of 8 to 16 mg/liter. Thus, amikacin, as currently dosed, has limited efficacy against M. abscessus. It is urgent that different antibiotics be tested using our preclinical model and new regimens developed.


Assuntos
Amicacina/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Testes de Sensibilidade Microbiana/métodos , Micobactérias não Tuberculosas/efeitos dos fármacos , Amicacina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana/instrumentação , Modelos Biológicos , Método de Monte Carlo , Taxa de Mutação , Micobactérias não Tuberculosas/genética , Micobactérias não Tuberculosas/patogenicidade
15.
J Antimicrob Chemother ; 70(10): 2838-43, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26142475

RESUMO

OBJECTIVES: This study aimed to provide basic pharmacodynamic information for key antibiotics used to treat Mycobacterium avium and Mycobacterium xenopi pulmonary disease. METHODS: M. avium subspecies hominissuis IWGMT49 and M. xenopi ATCC 19250 type strains were used; the MICs of clarithromycin, amikacin and moxifloxacin were determined by broth microdilution. Time-kill assays were performed, exposing bacteria to 2-fold concentrations from 0.062× to 32× the MIC at 37°C for 240 h for M. avium or 42 days for M. xenopi. The sigmoid maximum effect (Emax) model was fitted to the time-kill curve data. RESULTS: Maximum killing of M. avium by amikacin was obtained between 24 and 120 h (0.0180 h(-1)) and was faster and higher than with clarithromycin (0.0109 h(-1)); however, regrowth and amikacin-resistant mutants were observed. Killing rates for M. xenopi were higher, 0.1533 h(-1) for clarithromycin and 0.1385 h(-1) for moxifloxacin, yet required 42 days. There were no significant differences between the Hill's slopes determined for all of the antibiotics tested against M. avium or M. xenopi (P = 0.9663 and P = 0.0844, respectively). CONCLUSIONS: The killing effect of amikacin and clarithromycin on M. avium subspecies hominissuis was low, although amikacin activity was higher than that of clarithromycin, supporting its role in a combined therapy. Clarithromycin and moxifloxacin may have similar activity within treatment regimens for M. xenopi disease. Future studies of in vitro and in vivo pharmacokinetic/pharmacodynamic interactions are needed to improve the current regimens to treat these two important slowly growing mycobacteria in pulmonary disease.


Assuntos
Antibacterianos/farmacologia , Mycobacterium avium/efeitos dos fármacos , Mycobacterium xenopi/efeitos dos fármacos , Amicacina/farmacologia , Claritromicina/farmacologia , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana , Mutação , Taxa de Mutação , Mycobacterium avium/genética , Fatores de Tempo
16.
J Antimicrob Chemother ; 70(3): 811-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25344808

RESUMO

OBJECTIVES: This study was conducted to generate basic pharmacodynamic information on the relationship between antibiotic concentrations and the growth of rapidly growing mycobacteria (RGM), and thereby contribute to a better understanding of current and future drug regimens for diseases caused by RGM. METHODS: Type strains of Mycobacterium abscessus and Mycobacterium fortuitum were used; the MICs of cefoxitin, amikacin, moxifloxacin, linezolid and clarithromycin were determined by broth microdilution. Time-kill assays were performed, exposing the bacteria to 2-fold concentrations from 0.25 to 32 times the MIC at 30°C for 120 h. The sigmoid maximum effect (Emax) model was fitted to the time-kill curves data. RESULTS: The highest killing of M. abscessus was observed between 24 and 72 h; amikacin had the highest Emax (0.0427 h(-1)), followed by clarithromycin (0.0231 h(-1)) and cefoxitin (0.0142 h(-1)). For M. fortuitum, between 3 and 24 h, amikacin also showed the highest Emax (0.1933 h(-1)). There were no significant differences between the Hill's slopes determined for all the antibiotics tested against M. abscessus or M. fortuitum (P = 0.2213 and P = 0.2696, respectively). CONCLUSIONS: The total effect observed for all antibiotics was low and primarily determined by the Emax and not by the Hill's slope. The limited activity detected fits well with the poor outcome of antibiotic treatment for disease caused by RGM, particularly for M. abscessus. An evaluation of drug combinations will be the next step in understanding and improving current treatment standards.


Assuntos
Antibacterianos/farmacologia , Viabilidade Microbiana/efeitos dos fármacos , Micobactérias não Tuberculosas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Estatísticos , Micobactérias não Tuberculosas/fisiologia , Fatores de Tempo
17.
Expert Rev Anti Infect Ther ; 11(10): 1065-77, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24124798

RESUMO

Pulmonary disease (PD) caused by nontuberculous mycobacteria is an emerging infection mainly in countries where the incidence of tuberculosis is in decline. It affects an elderly population, often with underlying chronic lung diseases, but its epidemiology shows significant regional variation. Guidelines and recommendations for treatment of these infections exist, but build strongly on expert opinion, as very few good quality clinical trials have been performed in this field. Only for the most frequent causative agents, the Mycobacterium avium complex, Mycobacterium kansasii and Mycobacterium abscessus, a reasonable number of trials and case series is now available. For the less frequent causative agents of pulmonary nontuberculous mycobacterial (NTM) disease (Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium fortuitum, Mycobacterium chelonae) data is mostly limited to a few very small case series. Within this review, we have collected and combined evidence from all available trials and case series. From the data of these trials and case series, we reconstruct a more evidence-based overview of possible drug treatment regimens and their outcomes.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Micobactérias não Tuberculosas/efeitos dos fármacos , Idoso , Antibacterianos/farmacocinética , Ensaios Clínicos como Assunto , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Medicina Baseada em Evidências , Humanos , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas/classificação , Micobactérias não Tuberculosas/fisiologia , Análise de Sobrevida , Resultado do Tratamento
18.
J Clin Microbiol ; 51(7): 2220-4, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23658272

RESUMO

Previous evaluations of the molecular GenoType tests have promoted their use to detect resistance to first- and second-line antituberculosis drugs in different geographical regions. However, there are known geographic variations in the mutations associated with drug resistance in Mycobacterium tuberculosis, and especially in South America, there is a paucity of information regarding the frequencies and types of mutations associated with resistance to first- and second-line antituberculosis drugs. We therefore evaluated the performance of the GenoType kits in this region by testing 228 M. tuberculosis isolates in Colombia, including 134 resistant and 94 pansusceptible strains. Overall, the sensitivity and specificity of the GenoType MTBDRplus test ranged from 92 to 96% and 97 to 100%, respectively; the agreement index was optimal (Cohen's kappa, >0.8). The sensitivity of the GenoType MTBDRsl test ranged from 84 to 100% and the specificity from 88 to 100%. The most common mutations were katG S315T1, rpoB S531L, embB M306V, gyrA D94G, and rrs A1401G. Our results reflect the utility of the GenoType tests in Colombia; however, as some discordance still exists between the conventional and molecular approaches in resistance testing, we adhere to the recommendation that the GenoType tests serve as early guides for therapy, followed by phenotypic drug susceptibility testing for all cases.


Assuntos
Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana/métodos , Técnicas de Diagnóstico Molecular/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Tuberculose/microbiologia , Antituberculosos/farmacologia , Colômbia , Humanos , Mycobacterium tuberculosis/isolamento & purificação , Valor Preditivo dos Testes , Sensibilidade e Especificidade
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