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.
Adult ; Aminosalicylic Acid ; Antitubercular Agents ; Cycloserine ; Drug Hypersensitivity Syndrome ; Eosinophilia* ; Ethambutol ; Female ; Fever ; Humans ; Hypersensitivity ; Isoniazid ; Kanamycin ; Leukocytosis ; Levofloxacin ; Patch Tests ; Prednisolone ; Pyrazinamide ; Rifampin ; Tuberculosis

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.
Cycloserine ; Diagnosis ; Drug Eruptions* ; Drug Hypersensitivity ; Humans ; Lichenoid Eruptions ; Lymphocyte Activation* ; Lymphocytes* ; Patch Tests

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.
Biopsy ; Brain* ; China ; Cycloserine ; Emigrants and Immigrants ; Female ; Headache ; Humans ; Kanamycin ; Korea ; Linezolid ; Lung ; Mycobacterium tuberculosis ; Prothionamide ; Streptomycin ; Tuberculoma, Intracranial ; Tuberculosis, Central Nervous System ; Tuberculosis, Multidrug-Resistant* ; Tuberculosis, Pulmonary ; Young Adult

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.
Adult ; Aged ; Antitubercular Agents/blood/*pharmacokinetics/therapeutic use ; Chromatography, High Pressure Liquid ; Cycloserine/blood/*pharmacokinetics/therapeutic use ; Fluoroquinolones/blood/*pharmacokinetics/therapeutic use ; Humans ; Medication Adherence ; Middle Aged ; Prothionamide/blood/*pharmacokinetics/therapeutic use ; Retrospective Studies ; Sputum/*microbiology ; Tandem Mass Spectrometry ; Tuberculosis, Multidrug-Resistant/blood/*drug therapy ; Young Adult

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.
Clofazimine ; Cycloserine ; Diagnosis* ; Drug Resistance ; Fluoroquinolones ; Kanamycin ; Levofloxacin ; Prothionamide ; Pyrazinamide ; Tuberculosis ; Tuberculosis, Multidrug-Resistant* ; World Health Organization

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.
Adult ; Aged ; Amikacin ; Aminosalicylic Acid ; Capreomycin ; Cohort Studies ; Cycloserine ; Drug Monitoring* ; Ethionamide ; Female ; Humans ; Pharmacokinetics ; Retrospective Studies ; Tuberculosis ; Tuberculosis, Meningeal ; Tuberculosis, Multidrug-Resistant* ; Virginia* ; Linezolid

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.
Aminosalicylic Acid ; Antitubercular Agents ; Cycloserine ; Desensitization, Immunologic ; Drug Hypersensitivity Syndrome* ; Hepatic Encephalopathy ; Humans ; Hypersensitivity ; Kanamycin ; Levofloxacin ; Male ; Methylprednisolone ; Middle Aged ; Patient Dropouts ; Pyrazinamide ; Streptomycin ; Tuberculosis ; Tuberculosis, Multidrug-Resistant

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.
Clofazimine ; Cycloserine ; Drug Resistance ; Extensively Drug-Resistant Tuberculosis ; Fluoroquinolones ; Kanamycin ; Levofloxacin ; Linezolid ; Prothionamide ; Pyrazinamide ; Tuberculosis ; Tuberculosis, Multidrug-Resistant* ; World Health Organization

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.
Academies and Institutes ; Agar ; Aminosalicylic Acid ; Culture Media ; Cycloserine ; Humans ; Isoniazid ; Mycobacterium tuberculosis ; Ofloxacin ; Prothionamide ; Quality Control ; Rifampin ; Sensitivity and Specificity ; Streptomycin

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.
Agar ; Cefoxitin ; Clostridium difficile* ; Clostridium* ; Cycloserine ; Diarrhea ; Fructose ; Genes, vif ; Immunoassay ; Immunoenzyme Techniques ; Korea ; Polymerase Chain Reaction ; Prevalence ; Sensitivity and Specificity ; Spores