Tratamento clínico de zumbido primário em adultos e idosos: revisão sistemática / Clinical treatment of primary tinnitus in adults and in the elderly: systematic review

O zumbido no ouvido é definido como uma ilusão auditiva ou sensação sonora endógena, não relacionada a nenhuma fonte externa de estimulação. É um sintoma frequente na população idosa. Até hoje, vários autores argumentam que o desconhecimento da etiologia do zumbido, aliado à subjetividade desta manifestação, mais a sobreposição das enfermidades e dos sintomas que, geralmente, acometem os pacientes idosos, dificultam a obtenção de um bom resultado terapêutico. O objetivo desta revisão foi levantar quais os tratamentos clínicos mais utilizados na prática clínica no tratamento do zumbido primário em adultos e idosos. Procedeu-se à verificação do status dos últimos 5 anos de estudos em textos de acesso livre, no banco de dados eletrônicos da PubMed. Apresentaram tratamentos clínicos para o zumbido primário 25 artigos; aqueles com resultados satisfatórios foram quatro artigos sobre acupuntura, dois sobre neuromodulação de resenha coordenada acústica, um sobre uso combinado de amplificação e gerador de som, e um sobre psicoterapia corporal, que incluíam tanto adultos e idosos, tendo a idade média entre 51 a 54 anos. Não se pode afirmar que os tratamentos propostos são eficazes na cura dos sintomas de zumbido em adultos e idosos, mas sim que existem algumas terapêuticas de baixo custo que apresentam respostas relativamente satisfatórias. (AU)

Tinnitus is defined as a hearing illusion or endogenous auditory sensation that is not related to any external stimulation source. It is a frequent symptom among elderly people. To date, many authors have argued that the lack of knowledge about the tinnitus etiology, added to the subjectivity of this manifestation, and the overlap of other diseases and symptoms that often occur with aged patients make the obtainment of a good therapeutic result difficult. The objective of this review was to find the most used clinical treatment in clinical practice for primary tinnitus on adults and elderly. The status of the last five years of studies in free full texts on PubMed database was checked. Twenty-five articles showed clinical treatment for primary tinnitus, with four articles about acupuncture, two about acoustic coordinate reset neuromodulation, one about sound generator associated with conventional amplification, and one about body-psychotherapy which included adults and elderly with an average age between 51 to 54 years old showing satisfactory results. It is difficult to state that the proposed treatment is efficient on healing the tinnitus symptoms on adults and elderly but there are some low-cost therapies showing relatively satisfactory responses. (AU)

Efeito da d-cicloserina no tratamento do transtorno de estresse pós-traumático: uma revisão / The effect of d-cycloserine in the treatment of post-traumatic stress disorder: a review

Objetivo: Realizar uma revisão da literatura sobre o efeito da D-cicloserina (DCS) no tratamento do Transtorno de estresse pós-traumático (TEPT). Métodos: Foram revisados 14 ensaios clínicos, revisões sistemáticas e meta-análises selecionados na base de dados PubMed que correspondessem aos descritores D-cicloserina e Transtorno de estresse pós-traumático. Resultados: Os resultados mostram-se heterogêneos, incluindo resultados com e sem benefícios clínicos para o uso da DCS, provavelmente devido à diferença de métodos utilizados nos estudos realizados. Entretanto, a DCS apresenta efeito benéfico quando administrada em pacientes com quadros mais graves de TEPT e quando associada à terapia de exposição com realidade virtual. Conclusão: A DCS tem se mostrado uma opção terapêutica promissora quando associada à terapia de exposição; entretanto, mais estudos devem ser realizados para comprovar sua efetividade no tratamento do TEPT.

Aim: To review the literature about the effect of D-cycloserine (DCS) on the treatment of Post-traumatic stress disorder (PTSD). Methods: Were reviewed fourteen clinical trials, systematic reviews and meta-analyzes selected in the PubMed database that corresponded to the descriptors D-cycloserine and Post-traumatic stress disorder. Results: The results are heterogeneous, including results with and without clinical benefit for the use of DCS, probably due to the different methods used in the studies. However, DCS has a beneficial effect when administered to patients with severe PTSD and when associated with virtual reality exposure therapy. Conclusion: It has been shown that DCS is a promising therapeutic choice when associated with exposure therapy, however further studies should be performed to prove its effectiveness in the treatment of PTSD.

A Case of Cycloserine-Induced Lichenoid Drug Eruption Supported by the Lymphocyte Transformation Test

Lichenoid drug eruption (LDE) is a rare form of delayed-type drug eruption. Among anti-tuberculosis (Tb) agents, cycloserine (CS) has been reported as a rare cause of LDE. Positive results on the lymphocyte transformation test (LTT) have not been reported in patients with LDE. In the present case, we performed LTT and a patch test, and successfully proved CS as the offending drug in this patient, who had been treated with multiple anti-Tb drugs. These observations suggest that CS should be considered a possible cause of LDE and that LTT can be an option for the diagnosis of LDE.

DRESS (drug reaction with eosinophilia and systemic symptom) syndrome caused by both first-line and second-line antitubercular medications: A case report with a brief literature review

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but potentially fatal drug-induced systemic hypersensitivity response characterized by erythematous eruption, fever, leukocytosis with eosinophilia, and internal organ involvement. Antitubercular agents are potential causative agents for DRESS syndrome but difficult to verify as a culprit drug, since antitubercular agents are coadministered as a combination regimen. A 42-year-old female with endobronchial tuberculosis was diagnosed with DRESS syndrome after 4-week treatment of isoniazid, rifampicin, ethambutol, and pyrazinamide with prednisolone 50 mg. All the antitubercular agents were stopped and replaced with levofloxacin, cycloserine, p-aminosalicylic acid, and kanamycin. However, severe exacerbation of DRESS syndrome compelled the patient to discontinue the administration of the second-line antitubercular agents. Two months later, the patient underwent a patch test for all the antitubercular agents which had been used, and the results showed positivity to isoniazid and cycloserine. We report a rare case of DRESS syndrome that reacted to cycloserine as well as isoniazid. Development of coreactivity to other drugs should be differentiated with a flare-up reaction in the management of DRESS syndrome.

A Case of Disseminated Multidrug-Resistant Tuberculosis involving the Brain

We report a case of a 23-year-old female immigrant from China who was diagnosed with multidrug-resistant tuberculosis affecting her lung and brain, resistant to the standard first-line therapeutics and streptomycin. She was treated with prothionamide, moxifloxacin, cycloserine, and kanamycin. However, her headache and brain lesion worsened. After the brain biopsy, the patient was confirmed with intracranial tuberculoma. Linezolid was added to intensify the treatment regimen, and steroid was added for the possibility of paradoxical response. Kanamycin was discontinued 6 months after initiation of the treatment; she was treated for 18 months with susceptible drugs and completely recovered. To our knowledge, this case is the first multidrug-resistant tuberculosis that disseminated to the brain in Korea.

Diagnosis and Treatment of Multidrug-Resistant Tuberculosis / 대한내과학회지

Despite global efforts to control tuberculosis (TB), multidrug-resistant TB (MDR-TB) is still a serious problem worldwide. The diagnosis of MDR-TB is based on mycobacterial culture followed by drug susceptibility testing, with results available in weeks to months. This requirement calls for rapid direct tests, especially genotypic tests, in which specimens are amplified directly for the detection of MDR-TB. The treatment of MDR-TB is challenging because of the high toxicity of second-line drugs and the longer treatment duration required compared to drug-susceptible TB. The selection of drugs in MDR-TB is based on the treatment history, drug susceptibility results, and TB drug resistance patterns in each region. Recent World Health Organization guidelines recommend the use of at least four second-line drugs (i.e., a newer fluoroquinolone, an injectable agent, prothionamide, and cycloserine or para-aminosalicylic acid) in addition to pyrazinamide. Kanamycin is the initial choice of an injectable drug, and newer fluoroquinolones include levofloxacin and moxifloxacin. For extensively drug-resistant TB, group 5 drugs such as linezolid and clofazimine need to be included. New drugs such as delamanid and bedaquiline have recently been approved for treating MDR-TB and other agents with novel mechanisms of action that can be given for shorter durations (6-12 months) for MDR-TB are under investigation.

Outcomes and Use of Therapeutic Drug Monitoring in Multidrug-Resistant Tuberculosis Patients Treated in Virginia, 2009-2014 / 결핵및호흡기질환

BACKGROUND: Reports of therapeutic drug monitoring (TDM) for second-line medications to treat multidrug-resistant tuberculosis (MDR-TB) remain limited. METHODS: A retrospective cohort from the Virginia state tuberculosis (TB) registry, 2009-2014, was analyzed for TDM usage in MDR-TB. Drug concentrations, measured at time of estimated peak (Cmax), were compared to expected ranges. RESULTS: Of 10 patients with MDR-TB, 8 (80%) had TDM for at least one drug (maximum 6 drugs). Second-line drugs tested were cycloserine in seven patients (mean C2hr, 16.6+/-10.2 microg/mL; 4 [57%] below expected range); moxifloxacin in five (mean C2hr, 3.2+/-1.5 microg/mL; 1 [20%] below); capreomycin in five (mean C2hr, 21.5+/-14.0 microg/mL; 3 [60%] below); para-aminosalicylic acid in five (mean C6hr, 65.0+/-29.1 microg/mL; all within or above); linezolid in three (mean C2hr, 11.4+/-4.1 microg/mL, 1 [33%] below); amikacin in two (mean C2hr, 35.3+/-3.7 microg/mL; 1 [50%] below); ethionamide in one (C2hr, 1.49 microg/mL, within expected). Two patients died: a 38-year-old woman with human immunodeficiency virus/acquired immune deficiency syndrome and TB meningitis without TDM, and a 76-year-old man with fluoroquinolone-resistant (pre-extensively drug-resistant) pulmonary TB and low linezolid and capreomycin concentrations. CONCLUSION: Individual pharmacokinetic variability was common. A more standardized approach to TDM for MDR-TB may limit over-testing and maximize therapeutic gain.

Successful readministration of second-line antituberculous agents in a patient with near-fatal drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome

For the treatment of multidrug-resistant (MDR) tuberculosis, maintenance of appropriate antituberculous agents is essential because of its low cure rate and high dropout rate. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe drug-induced systemic hypersensitivity response resulting in cessation of causative agents. In cases of second-line antituberculous agent-induced DRESS, it is extremely difficult to find other replacement medications to cure MDR tuberculosis. A 53-year-old male who had taken the second-line antituberculous agents (cycloserine, streptomycin, p-aminosalicylic acid, and prothionamide) as well as pyrazinamide for 5 weeks experienced DRESS syndrome accompanying hepatic coma. His symptoms improved with discontinuation of antituberculous agents and administration of high-dose methylprednisolone for 1 month. To resume the antituberculous medication, second-line antituberculous agents were administered one by one using a rapid desensitization protocol. While kanamycin, levofloxacin, and cycloserine were successfully readministered, p-aminosalicylic acid- and prothionamide-induced cutaneous hypersensitivity symptoms were relatively mild compared to previous reactions. Herein, we report a case of successfully treated MDR tuberculosis having a history of fatal DRESS syndrome to antituberculous agents using the rapid desensitization protocol.

Low Serum Concentrations of Moxifloxacin, Prothionamide, and Cycloserine on Sputum Conversion in Multi-Drug Resistant TB

PURPOSE: Low serum concentrations of drugs used to treat multi-drug resistant tuberculosis (MDR-TB) have occasionally been associated with treatment failure. We determined the frequencies of low serum concentrations of anti-MDR-TB drugs, and assessed the effects of these concentrations on 2-month sputum conversion. MATERIALS AND METHODS: The serum levels of moxifloxacin (MF), prothionamide (PTH), and cycloserine (CS) were determined for 89 serum samples by high-pressure liquid chromatography-tandem mass spectrometry. RESULTS: Low serum concentrations of MF, PTH, and CS below the minimal levels of the normal ranges were 83.3% (20/24), 59.2% (29/49), and 71.2% (47/66), respectively. There were no significant differences between the 2-month sputum conversion group (n=25) and the 2-month sputum non-conversion group (n=4) in median drug concentrations (microg/mL) of MF (1.46 vs. 1.60), PTH (0.91 vs. 0.70), and CS (14.90 vs. 14.90). However, a poor compliance rate was significantly greater in the 2-month sputum non-conversion group (75.0%, 3/4) than in the 2-month sputum conversion group (0%, 0/25) (p=0.001). CONCLUSION: The frequency of low serum concentrations of anti-MDR-TB drugs was substantial and might not affect the 2-month sputum conversion rate. Larger prospective studies with timely sampling are needed to investigate the role of therapeutic drug monitoring in MDR-TB.

Medical Treatment of Pulmonary Multidrug-Resistant Tuberculosis

Treatment of multidrug-resistant tuberculosis (MDR-TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration required compared with drug-susceptible TB. The efficacy of treatment for MDR-TB is poorer than that for drug-susceptible TB. The selection of drugs in MDR-TB is based on previous treatment history, drug susceptibility results, and TB drug resistance patterns in the each region. Recent World Health Organization guidelines recommend the use of least 4 second-line drugs (a newer fluoroquinolone, an injectable agent, prothionamide, and cycloserine or para-aminosalicylic acid) in addition to pyrazinamide. The kanamycin is the initial choice of injectable durgs, and newer fluoroquinolones include levofloxacin and moxifloxacin. For MDR-TB, especially cases that are extensively drug-resistant, group 5 drugs such as linezolid, clofazimine, and amoxicillin/clavulanate need to be included. New agents with novel mechanisms of action that can be given for shorter durations (9-12 months) for MDR-TB are under investigation.

XDR tuberculosis: a report from the New Delhi Tuberculosis centre, India

During the 6 years from 2001 to 2006, a total of 18,443 M. tuberculosis isolates were processed for drug sensitivity testing. Of those, 9614 [52.12%] were found to be multidrug resistant. A total of 86 [0.89%] cases met the criteria of XDR among the MDR-TB cases. Year-wise detection of these XDR cases is given in Table I. A consistent decline was observed in the incidence of reported cases of XDR over the years right from the year 2001. These 86 cases were reported from 7 states with the largest number from Delhi [49] followed by neighbouring Rajasthan [10], Haryana [9], Uttar Pradesh [8], Uttaranchal [5], Punjab [4] and Madhya Pradesh [1]. Of those 86 cases, only 5 patients were females and rest were males. A total of 53 out of 86 [61.6%] of the isolated resistant strains were resistant to more than 4 classes of drugs indicating severity of resistance

Terapia cognitivo-comportamental no transtorno de pânico / Cognitive-behavioral therapy in panic disorder

OBJETIVO: O transtorno de pânico é uma condição crônica e recorrente que prejudica a qualidade de vida e o funcionamento psicossocial dos portadores. Embora os medicamentos sejam efetivos na redução dos ataques de pânico, muitos pacientes não respondem adequadamente a essas intervenções. A terapia cognitivo-comportamental fornece um método alternativo eficaz para tratar transtorno de pânico e evitação agorafóbica. O objetivo do estudo é o de descrever o uso de técnicas cognitivo-comportamentais no tratamento do transtorno de pânico. MÉTODO: Revisão narrativa a partir dos bancos de dados do Medline, SciELO e PsycInfo e de livros-texto especializados. RESULTADOS: Foram descritos os fundamentos da terapia cognitivo-comportamental no tratamento do transtorno pânico e revisadas as evidências de eficácia em curto e longo prazos. O uso de medicação concomitante a terapia cognitivo-comportamental foi também discutido. CONCLUSÕES: A terapia cognitivo-comportamental individual ou em grupo é eficaz para pacientes com transtorno de pânico, seja como tratamento de primeira linha ou como um próximo passo para pacientes com resposta parcial a outros tratamentos.

OBJECTIVE: Panic disorder is a chronic and recurrent condition that impairs an individual's psychosocial functioning and quality of life. Despite the efficacy of psychopharmacological treatment in reducing panic attacks, many patients fail to respond adequately to these interventions. Cognitive behavioral therapy provides an alternative and efficacious method for treating panic disorder and agoraphobic avoidance. The objective of the study is to describe the use of cognitive behavioral therapy for panic disorder. METHOD: Narrative review of data collected from Medline, SciELO and PsycInfo and specialized textbooks. RESULTS: We describe the cognitive-behavioral model for the treatment of panic disorder, and review both short and long-term efficacy findings. We also discuss the role of combined treatment (cognitive behavioral therapy and psychopharmacology). CONCLUSIONS: Cognitive behavioral therapy, either individual or in group, can be used as first-line therapy for panic disorder. This treatment modality can also be indicated as a next step for patients failing to respond to other treatments.

Outcome of multi-drug resistant tuberculosis cases treated by individualized regimens at a tertiary level clinic.

AIM: To determine the clinical, radiological and drug resistance profile as well as the factors associated with treatment outcome of Multi-Drug Resistant Tuberculosis (MDR-TB). MATERIAL AND METHODS: All newly diagnosed patients with pulmonary MDR-TB from August 2002 to December 2004 enrolled at New Delhi Tuberculosis Centre, were included in the study. They were followed up clinically, radiologically and bacteriologically by sputum smear, culture and Drug Susceptibility Testing (DST) at regular intervals. According to their DST pattern and previous history of Anti-Tubercular Treatment (ATT), individualized treatment regimens were tailored for each patient. RESULTS: Out of total 27 bacteriologically proven cases of MDR-TB included in this study, 19 were males (mean age and weight 38.5 years and 52.6 kgs, respectively) and eight females (mean age and weight 34.3 years and 40.7 kgs, respectively). A majority (18) were residents of Delhi and the rest hailed from different parts of North India. All of them had a history of previous treatment ranging from six to 34 months. Cavity on chest X-rays was seen in 81%, while 44% showed extensive involvement. The patients received at least four "second line drugs" during their treatment with a mean of 6.2 anti-tubercular drugs during their intensive phase. Of the 27 patients, 13 were cured, 10 defaulted, one died, one is still on treatment and two were referred for surgery. Radiological improvement was observed in two third of cases and chest X-ray of two patients showed a complete resolution. Six predictors were identified for successful outcome of MDR-TB. They include weight gain at six months, culture conversion, radiological improvement during treatment, disease with M. tuberculosis strains exhibiting resistance to less than or up to three anti-tubercular drugs, use of less than or up to three second line drugs in treatment and no change of regimen during treatment. CONCLUSION: Default from treatment was observed to be a major challenge in the treatment of MDR-TB due to long duration and expense of ATT.

Comparison of Anti-mycobacterial Drug Susceptibility Test Results by Institutes and Methods / 대한임상미생물학회지

BACKGROUND: The purposes of the current study were to evaluate the concordant rates of anti-mycobacterial drug susceptibility test (DST) results in different solid media performed in different institutes, and to determine reliable susceptible testing methods. METHODS: One hundred and twenty two Mycobacterium tuberculosis strains were isolated from patients in A Hospital in 2005. DSTs were performed by the absolute concentration method using L?wenstein Jensen medium in both A Hospital (method A-1) and B Institute (method B-1) and by the proportion method using Middlebrook 7H10 agar in B Institute (method B-2). Nine drugs were used including isoniazid and rifampin. Sensitivity and specificity of each method were estimated by using the acceptable standard of 90% for isoniazid and rifampin and 80% for other drugs. The therapeutic outcomes of quinolone-administered patients were evaluated according to ofloxacin susceptibility results. RESULTS: Method B-1 showed sensitivity and specificity levels over the acceptable standard levels for all drugs. Method B-2 showed specificity lower than the acceptable levels for rifampin and cycloserine. Method A-1 showed specificity lower than the acceptable levels for isoniazid, streptomycin, p-aminosalicylic acid, and ofloxacin and sensitivity lower than the acceptable levels for prothionamide and cycloserine. The concordance rates of therapeutic outcomes with method B-1, method B-2, and method A-1 were 77%, 74%, and 65%, respectively. CONCLUSION: The drug susceptibility results for some drugs were discordant between the testing laboratories and media, requiring an urgent application of quality control programs to raise the reliability of anti-mycobacterial DST.

Susceptibility tests to second line drugs and re-treatment of tuberculosis: revisiting early experiences / Las pruebas de sensibilidad a drogas de segunda línea y el re-tratamiento de la tuberculosis: visión retrospectiva de tres estudios

The value of susceptibility tests in guiding antituberculous therapy with second-line drugs remains controversial. We reanalyzed three reports regarding the relationship between in vitro susceptibility of Mycobacterium tuberculosis and the clinical outcome of in-patients treated with these drugs at the Muñiz Hospital, Buenos Aires, during the sixties. These patients had been irregularly treated with a standard regimen consisting of isoniazid, streptomycin and PAS; they developed resistance to at least the first two drugs and persisted culture-positive. Susceptibility testing to ethionamide, cycloserine and kanamycin were performed by the proportion method on Löwenstein Jensen medium. Some level of resistance was detected among isolates from patients not previously treated with these drugs, that could be due to cross resistance with previously administered first line structural analogs. However, the studies evidenced significant association between resistance to ethionamide and cycloserine and prior treatment with these drugs. Increased resistance to all three drugs was detected within the first three months of treatment. In vitro resistance to ethionamide emerged earlier and was the most frequent followed by resistance to cycloserine and kanamycin. The low frequency of resistance to kanamycin could be related to the low dosage of this drug used at that time. Simultaneous resistance to the three agents, but not to two or one drug, appeared to be a marker of treatment failure. An apparent reversion of drug resistance was observed in near 6% of patients, for whom susceptibility tests were repeated on subsequent isolates, indicating this percentage of inconsistency in reproducibility of test results.

La correlación entre resultados de pruebas de sensibilidad a drogas antituberculosas de segunda línea y evolución de los pacientes en tratamiento, aún es discutida. Se reanalizan aquí tres estudios realizados en la década del 60, sobre la relación entre resultados de pruebas de sensibilidad y tratamiento con estas drogas, en pacientes crónicos, internados en el hospital Muñiz, Buenos Aires, que habían sido tratados con el entonces régimen estándar, integrado por isoniacida, estreptomicina y PAS; se habían hecho resistentes al menos a dos de estas drogas y continuaban con cultivo positivo. La prueba de sensibilidad a etionamida, cicloserina y kanamicina se efectuó por el método de las proporciones en medio Löwenstein Jensen. Entre 4 y 13% de los pacientes previamente no tratados con estas drogas presentó cierto nivel de resistencia, fenómeno atribuido a la administración previa de drogas de primera línea con moléculas análogas. Se halló asociación significativa entre resistencia a etionamida y cicloserina, y tratamiento previo con estas drogas. La resistencia a las tres drogas fue detectada en los primeros tres meses de tratamiento, siendo la resistencia a etionamida la más frecuente, y la primera en emerger, seguida por cicloserina y kanamicina, cuya baja frecuencia en alcanzar resistencia estaría relacionada con las bajas dosis administradas. La resistencia simultánea a las tres drogas, pero no a una o dos, resultó marcadora de fracaso terapéutico. Se observó en cerca del 6% de los pacientes aparente reversión de la resistencia, en pruebas hechas en aislamientos sucesivos, interpretada como falla en la reproducibilidad de resultados.

Efficacy and safety of kanamycin, ethionamide, PAS and cycloserine in multidrug-resistant pulmonary tuberculosis patients.

BACKGROUND: We carried out this study to determine the efficacy and safety of a regimen containing kanamycin, ethionamide, isoniazid, para-aminosalicylic acid (PAS) and cycloserine in the treatment of multidrug-resistant tuberculosis (MDR-TB). METHODS: A prospective, uncontrolled study of 39 pulmonary tuberculosis patients, who had received adequate first-line antituberculosis treatment including supervised category II retreatment regimen, and were still sputum smear positive for acid-fast bacilli (AFB) in whom sputum culture revealed isolates of M. tuberculosis resistant to rifampicin and isoniazid with and without resistance to other antituberculosis drugs. They received kanamycin (initial 4-6 months), ethionamide, isoniazid, PAS and cycloserine for a minimum period of two years. RESULTS: Out of 39 patients, 29 (74.3%) achieved sputum conversion within six months and remained so at the end of two years. Two (5.1%) patients died, six (20.6%) patients were lost to follow up, and two (5.1%) patients remained sputum smear-positive for AFB through out the period of study. Twenty-nine patients, declared cured, were followed for an average period of 16 months (3-48 months), during which two (6.9%) patients relapsed, four (13.8%) patients were lost to follow-up and remaining 23 remained sputum smear-negative. Eight (21.1%) patients developed major side effects which required stoppage/change of drugs. CONCLUSION: In MDR-TB patients, regimen consisting of ethionamide, isoniazid, PAS and cycloserine and kanamycin appears to be effective and safe.

Comparison of Two Enzyme Immunoassays for Clostridium difficile Toxin A / 대한진단검사의학회지

BACKGROUND: Clostridium difficile is one of the most important pathogens responsible for nosocomial diarrhea. The disease is mediated by two toxins, designated as A and B; therefore, identification of the toxins is important for diagnosis. However, culture or cytotoxin assay are not easily done because of tedious procedures. Instead, toxin A immunoassay is widely used. We evaluated two different enzyme immunoassays (EIA) for C. difficile toxin A and compared them with culture and PCR results. METHODS: A total of 65 stool specimens were examined for toxin A using enzyme linked fluorescent immunoassay (ELFA, VIDAS CD II, Bio-Merieux, France) and enzyme linked immunosolvent assay (ELISA, C.DIFFICILE TOX A II, TECHLAB, USA ) and were also cultured for C. difficile using cycloserine cefoxitine fructose agar. We amplified toxin A and B genes using primers NK9-NK 11 and NK104-NK105, respectively, in 23 C. difficile isolates. RESULTS: The concordance rate between ELFA and ELISA was 76.9%. The sensitivity and specificity of the ELFA and ELISA based on the culture and PCR results for toxin A gene were 84.6%/98.1% and 84.6%/67.3%. Positive and negative predictive values were 91%/96.2% in VIDAS and 78.0%/ 94.6% in TECHLAB. The positive rates of toxin B genes were 100%, 83.3% and 50% in toxin A positive, variant and negative strains, respectively. CONCLUSIONS: The sensitivities of the ELFA and ELISA for toxin A were the same, but specificity and positive predictive value of the ELFA were higher than those of the ELISA. PCR or EIA method detecting both toxin A and toxin B is strongly recommended, because the variant strains (toxin A negative and toxin B positive) of C. difficile may be more prevalent than were anticipated in Korea.

Characterization of a Toxin A-Negative, Toxin B-Positive Variant Strain of Clostridium difficile / 대한진단검사의학회지

BACKGROUND: Clostridium difficile is one of the most important pathogens responsible for nosocomial diarrhea. Recently, we have frequently experienced culture positive, toxin A enzyme immunoassay negative strains. Therefore, we evaluated the strains with several PCR primer sets to characterize them. METHODS: A total of 351 stool specimens were examined for toxin A using enzyme linked fluorescent immunoassay (ELFA) and also cultured for C. difficile using cycloserine cefoxitine fructose agar incubated under anaerobic conditions. Spore stain and Vitek ANA identification card (BioMerieux, France) were used for identification of C. difficile. We amplified toxin A and toxin B genes in 81 isolates using primers NK1- NK2, NK3-NK2, NK9- NK11, and NK104-NK105. RESULTS: The concordance rate between ELFA and culture was 65.2% (229/351). PCR for the toxin A gene using NK1-NK2, NK3-NK2 and for the toxin B gene using NK104-NK105 showed almost the same results. However, toxin A gene PCR using NK9-NK11 showed that 45.7% (37/81) of the evaluated strains were toxin A (-)/ toxin B(+) variant strains; thus, the corrected sensitivity and specificity of the ELFA based on the PCR results for toxin A and B genes were 65.6% and 100%, respectively. CONCLUSIONS: The low sensitivity of the ELFA results for toxin A was due to the toxin A(-)/toxin B(+) variants of C. difficile, suggesting that the prevalence of the variant strains could be higher in Korea than was expected.

Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients

FTY720 is a new and effective immunosuppressive agent, which produces peripheral blood lymphopenia through a lymphocyte homing effect. We investigated the relationship between the dose of FTY720 or blood concentration (pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23 kidney transplant recipients randomized to receive FTY720 (0.25-2.5 mg/day) or mofetil mycophenolate (2 mg/day) in combination with cyclosporine and steroids. FTY720 dose, blood concentrations and lymphocyte counts were determined weekly before and 4 to 12 weeks after transplantation. The effect of PD was calculated as the absolute lymphocyte count or its reductions. PK/PD modeling was used to find the best-fit model. Mean FTY720 concentrations were 0.36 ± 0.05 (0.25 mg), 0.73 ± 0.12 (0.5 mg), 3.26 ± 0.51 (1 mg), and 7.15 ± 1.41 ng/ml (2.5 mg) between 4 and 12 weeks after transplantation. FTY720 PK was linear with dose (r² = 0.98) and showed low inter- and intra-individual variability. FTY720 produced a dose-dependent increase in mean percent reduction of peripheral lymphocyte counts (38 vs 42 vs 56 vs 77, P < 0.01, respectively). The simple Emax model [E = (Emax * C)/(C + EC50)] was the best-fit PK/PD modeling for FTY720 dose (Emax = 87.8 ± 5.3 percent and ED50 = 0.48 ± 0.08 mg, r² = 0.94) or concentration (Emax = 78.3 ± 2.9 percent and EC50 = 0.59 ± 0.09 ng/ml, r² = 0.89) vs effect ( percent reduction in peripheral lymphocytes). FTY720 PK/PD is dose dependent and follows an Emax model (EC50 = 0.5 mg or 0.6 ng/ml). Using lymphopenia as an FTY720 PD surrogate marker, high percent reductions ( about 80 percent) in peripheral lymphocytes are required to achieve best efficacy to prevent acute allograft rejection.

Comparison of Toxin A Enzyme Linked Fluorescence Assay and Latex Agglutination based on Clostridium difficile culture and Toxin A and B PCR assay / 대한임상미생물학회지

BACKGROUND: Clostidium difficile is one of the most important pathogens responsible for nosocomial diarrhea; therefore, we compared the efficacy of laboratory tests for diagnosing C. difficile diarrhea. METHODS: We evaluated 107 stool specimens using a latex agglutination test (LA) (BD CDT, Culturette CDT, Becton, Dickison and Company, USA) and an enzyme linked fluorescent immunoassay (ELFA) (VIDAS C. difficile Toxin A II, Bio-Merieux sa, Marcy-l'Etoile, France). Stool specimens were cultured using cycloserine cefoxitine fructose agar in anaerobic condition. For identification of C. difficile, spore stain and Vitek ANA identification card (Bio-Merieux sa) were used. Toxin A and toxin B genes were analysed by PCRs using primers NK3-NK2 and NK104N-K105 respectively. RESULTS: The concordance rate between LA and ELFA was 68.2%. Based on the culture results, the sensitivity/specificity of LA and ELFA were 54.8%/100% and 17.8%/100%, respectively. The positive rates of toxin A and B genes were both 90.4%(66/73). Based on the results of PCR assays for toxin A and B genes, the sensitivity/specificity of LA and ELFA were 37.9%/85.7% and 19.7%/100%, respectively. CONCLUSION: Based on C. difficile culture and toxin A and B gene PCR results, the sensitivity of LA was apparently higher than that of ELFA. However, it should not be simply estimated that ELFA has lower capability for detecting toxin A of C. difficile because the possibility of emerging variant strains of C. difficile could not be ruled out. The prevalence of toxigenic strains of C. difficile including variant strains should be studied in Korea.