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ABSTRACT: Disease caused by nontuberculous mycobacteria (NTM) is increasing in frequency. The outcome of treatment for NTM lung disease is poor, particularly lung disease caused by Mycobacterium simiae and M. abscessus. Exploring synergy between active available drugs is a sensible way forward given the lack of new active drugs.We tested for synergy between amikacin and clofazimine in 564 consecutive clinical isolates identified as 21 species of rapidly growing mycobacteria, 16 clinical M. avium complex isolates and 10 M. simiae isolates, using standardized methods.Clofazimine and amikacin are active in vitro against NTM alone; 97% (n=548) of the rapid growers revealed MICs of clofazimine ≤1 μg/ml, 93% (n=524) proved susceptible to amikacin. The combination showed significant synergistic activity in 56 of 68 (82%) eligible M. abscessus isolates, 4 of 5 M. chelonae isolates and 1 M. fortuitum and 1 M. cosmeticum isolate, with 4-8 fold decreases in MICs to both drugs. Significant synergy could also be demonstrated against all M. avium complex and M. simiae isolates, with FICs <0.5.Clofazimine and amikacin show significant synergistic activity against both rapid and slow growing nontuberculous mycobacteria. The safety and tolerability of adding clofazimine to amikacin-containing regimens should be tested in clinical trials and the results of susceptibility tests to these two compounds and their combination merit clinical validation. Synergy between clofazimine and other antibiotics with intracellular targets should be explored.
Antimicrobial Agents and Chemotherapy 10/2012; · 4.84 Impact Factor
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Proceedings of the American Thoracic Society 10/2012; 9(4):204-9.
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Go-Eun Choi,
Sung Jae Shin,
Choul-Jae Won,
Ki-Nam Min,
Taegwon Oh,
Mi-Young Hahn,
Keehoon Lee,
Soo Hyun Lee, Charles L Daley,
Seonwoo Kim,
Byeong-Ho Jeong,
Kyeongman Jeon,
Won-Jung Koh
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ABSTRACT: RATIONALE: Macrolides, such as clarithromycin (CLR) and azithromycin (AZM), are frequently the only oral antibiotics that are active against Mycobacterium abscessus and Mycobacterium massiliense infections. Neither CLR nor AZM have previously been demonstrated to provide superior treatment efficacy for these infections. OBJECTIVES: We compared the treatment efficacies of CLR and AZM and determined the correlation between efficacy and induced erm(41) expression in experimental models of M. abscessus and M. massiliense infections. MEASUREMENTS AND MAIN RESULTS: In all tested M. abscessus isolates, a high level of inducible CLR resistance developed (minimal inhibitory concentration [MIC] on day 3 vs. day 14; P<0.001). Whereas the AZM MIC increased on day 14 (P<0.01 vs. day 3), the level was significantly lower than the CLR MIC on day 14 (P<0.001). However, the MICs of CLR and AZM for the M. massiliense isolates did not change. Compared to CLR, AZM presented greater antibiotic activity against M. abscessus in vitro, ex vivo, and in vivo (P<0.05), whereas both macrolides were comparably effective against M. massiliense. In M. abscessus infection, the level of erm(41) expression was higher following exposure to CLR than following exposure to AZM (P<0.001). Experiments using an erm(41)-knockout M. abscessus mutant and an M. massiliense transformant expressing M. abscessus erm(41) confirmed that erm(41) was responsible for inducible CLR resistance. CONCLUSIONS: CLR induces greater erm(41) expression and thus higher macrolide resistance than AZM in M. abscessus infection. AZM may be more effective against M. abscessus, whereas both macrolides appear to be equally effective against M. massiliense.
American Journal of Respiratory and Critical Care Medicine 08/2012; · 11.08 Impact Factor
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ABSTRACT: Rationale: Currently recommended multidrug treatment regimens for Mycobacterium avium complex (MAC) lung disease yield limited cure rates. This results, in part, from incomplete understanding of the pharmacokinetics and pharmacodynamics of the drugs. Objectives: To study pharmacokinetics, pharmacodynamics, and drug interactions of multidrug treatment regimens in a large cohort of patients with MAC lung disease. Methods: We retrospectively collected pharmacokinetic data of all patients treated for MAC lung disease in the Adult Care Unit at National Jewish Health, Denver, Colorado, in the January 2006 to January 2010 period; we retrospectively calculated areas under the time-concentration curve (AUC). Minimum inhibitory concentrations (MIC) of their MAC isolates were retrieved for pharmacodynamic calculations. Measurements and Main Results: We included 531 pharmacokinetic analyses, performed for 481 patients (84% females; mean age, 63 yr; mean body mass index, 21.6). Peak serum concentrations (C(max)) below target range were frequent for ethambutol (48% of patients); clarithromycin (56%); and azithromycin (35%). Concurrent administration of rifampicin led to 68%, 23%, and 10% decreases in C(max) of clarithromycin, azithromycin, and moxifloxacin. C(max)/MIC or AUC/MIC ratios associated with bactericidal activity were seldom met; 57% of patients achieved target ratios for ethambutol, versus 42% for clarithromycin, 19% for amikacin, 18% for rifampicin, and 11% for moxifloxacin. Conclusions: Currently recommended regimens for MAC lung disease yield important pharmacologic interactions and low concentrations of key drugs including macrolides. Pharmacodynamic indices for rifampicin, clarithromycin, amikacin, and moxifloxacin are seldom met. This may partly explain the poor outcomes of currently recommended treatment regimens. Trials of new drugs and new dosing strategies are needed.
American Journal of Respiratory and Critical Care Medicine 06/2012; 186(6):559-65. · 11.08 Impact Factor
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ABSTRACT: The Mycobacterium simiae complex bacteria can cause opportunistic infections in humans. In the case of definite disease, there are no evidence-based treatment regimens and outcomes are very disappointing. To increase the evidence base underpinning treatment regimens for M. simiae complex disease, drug susceptibility patterns and rifampicin/ethambutol synergy were assessed retrospectively in 69 clinical M. simiae complex isolates from 60 patients (22 patients with M. simiae, 24 with Mycobacterium lentiflavum, 8 with Mycobacterium triplex, 5 with Mycobacterium parascrofulaceum and 1 with Mycobacterium stomatepiae) submitted to the mycobacteriology laboratory at National Jewish Health (Denver, CO). Quantitative drug susceptibility testing (DST) was performed using the radiometric BacTec 460 macrodilution method. Results were related to pharmacokinetic (PK) measurements, where available. All M. simiae complex species proved susceptible to clarithromycin and, to a lesser extent, rifabutin, clofazimine, streptomycin and moxifloxacin. Synergy or additive action between rifampicin and ethambutol was observed for all species except M. simiae. Mycobacterium simiae is poorly susceptible in vitro to rifampicin and ethambutol alone as well as in combination; PK measurements support the limited efficacy of these drugs against M. simiae. The triple-drug regimen of a rifamycin, ethambutol and a macrolide may be advised to treat disease caused by M. lentiflavum, M. triplex, M. parascrofulaceum and M. stomatepiae; for M. simiae, this regimen appears less active. These findings may partly explain the limited treatment results in M. simiae disease. A treatment regimen including a macrolide, moxifloxacin and one or two additional drugs based on DST results may be advisable; clofazimine and amikacin or streptomycin are potential candidates.
International journal of antimicrobial agents 11/2011; 39(2):173-6. · 3.03 Impact Factor
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ABSTRACT: Phylogenetic analyses on the basis of multiple house-keeping genes and whole genome sequences have offered new insights in the phylogeny of the genus Mycobacterium. This genus yields obligate pathogens, the M. tuberculosis complex and M. leprae, as well as opportunistic pathogens (e.g. M. avium, M. intracellulare, M. kansasii, M. marinum, M. malmoense) and saprophytes (e.g. M. phlei, M. sphagni, M. gordonae). The most virulent mycobacteria, the M. tuberculosis complex, M. leprae and the M. kansasii-M. szulgai-M. marinum-M. ulcerans group are phylogenetically related and infections by these organisms are better treatable than those caused by less virulent and phylogenetically more distantly related Mycobacterium species. The most virulent Mycobacterium species are also characterized by high levels of natural drug susceptibility. In this paper, we review studies of phylogeny, drug susceptibility, and clinical significance to support our hypothesis that drug susceptibility in mycobacteria is acquired and reflects the low level of competition in -and adaptation to- a closer-to-human (environmental) niche. In turn, mycobacteria that inhabit the most competitive environmental niches are the least adapted to humans, thus of low clinical significance, but most tolerant to antibiotics derived from microbes with which they share their habitat, lowering the chances of cure in case of infection.
Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 10/2011; 12(4):832-7. · 3.22 Impact Factor
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The Lancet Infectious Diseases 08/2011; 11(8):585. · 17.39 Impact Factor
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Won-Jung Koh,
Kyeongman Jeon,
Nam Yong Lee,
Bum-Joon Kim,
Yoon-Hoh Kook,
Seung-Heon Lee,
Young Kil Park,
Chang Ki Kim,
Sung Jae Shin,
Gwen A Huitt, Charles L Daley,
O Jung Kwon
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ABSTRACT: Mycobacterium massiliense has been recognized as a separate species from Mycobacterium abscessus; however, little is known regarding the clinical impact of this differentiation.
To compare clinical features and treatment outcomes between patients with M. abscessus lung disease and those with M. massiliense lung disease.
We performed molecular identification of stored clinical isolates of M. abscessus complex and compared clinical characteristics and treatment outcomes between 64 patients with M. abscessus lung disease and 81 patients with M. massiliense lung disease.
The clinical and radiographic manifestations of disease caused by each species were similar. Standardized combination antibiotic therapy, including a clarithromycin-containing regimen in combination with an initial 4-week course of cefoxitin and amikacin, was given to 57 patients (24 with M. abscessus and 33 with M. massiliense) for more than 12 months. The proportion of patients with sputum conversion and maintenance of negative sputum cultures was higher in patients with M. massiliense infection (88%) than in those with M. abscessus infection (25%; P < 0.001). Inducible resistance to clarithromycin (minimal inhibitory concentrations ≥ 32 μg/ml) was found in all tested M. abscessus isolates (n = 19), but in none of the M. massiliense isolates (n = 28).
Treatment response rates to combination antibiotic therapy including clarithromycin were much higher in patients with M. massiliense lung disease than in those with M. abscessus lung disease. The inducible resistance to clarithromycin could explain the lack of efficacy of clarithromycin-containing antibiotic therapy against M. abscessus lung disease.
American Journal of Respiratory and Critical Care Medicine 02/2011; 183(3):405-10. · 11.08 Impact Factor
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ABSTRACT: Tuberculosis is a leading cause of death worldwide, yet the determinants of death are not well understood. We sought to determine risk factors for mortality during treatment of drug-susceptible pulmonary tuberculosis under program settings.
Retrospective chart review of patients with drug-susceptible tuberculosis reported to the San Francisco Tuberculosis Control Program from 1990-2001.
Of 565 patients meeting eligibility criteria, 37 (6.6%) died during the study period. Of 37 deaths, 12 (32.4%) had tuberculosis listed as a contributing factor. In multivariate analysis controlling for follow-up time, four characteristics were independently associated with mortality: HIV co-infection (HR = 2.57, p = 0.02), older age at tuberculosis diagnosis (HR = 1.52 per 10 years, p = 0.001); initial sputum smear positive for acid fast bacilli (HR = 3.07, p = 0.004); and experiencing an interruption in tuberculosis therapy (HR = 3.15, p = 0.002). The association between treatment interruption and risk of death was due to non-adherence during the intensive phase of treatment (HR = 3.20, p = 0.001). The median duration of treatment interruption did not differ significantly in either intensive or continuation phases between those who died and survived (23 versus 18 days, and 37 versus 29 days, respectively). No deaths were directly attributed to adverse drug reactions.
In addition to advanced age, HIV and characteristics of advanced tuberculosis, experiencing an interruption in anti-tuberculosis therapy, primarily due to non-adherence, was also independently associated with increased risk of death. Improving adherence early during treatment for tuberculosis may both improve tuberculosis outcomes as well as decrease mortality.
BMC Infectious Diseases 01/2011; 11:1. · 3.12 Impact Factor
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Kathryn L Kellar,
Jennifer Gehrke,
Stephen E Weis,
Aida Mahmutovic-Mayhew,
Blachy Davila,
Margan J Zajdowicz,
Robin Scarborough,
Philip A LoBue,
Alfred A Lardizabal, Charles L Daley,
Randall R Reves,
John Bernardo,
Brandon H Campbell,
William C Whitworth,
Gerald H Mazurek
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ABSTRACT: Mycobacterium tuberculosis (Mtb) infection may cause overt disease or remain latent. Interferon gamma release assays (IGRAs) detect Mtb infection, both latent infection and infection manifesting as overt disease, by measuring whole-blood interferon gamma (IFN-γ) responses to Mtb antigens such as early secreted antigenic target-6 (ESAT-6), culture filtrate protein 10 (CFP-10), and TB7.7. Due to a lack of adequate diagnostic standards for confirming latent Mtb infection, IGRA sensitivity for detecting Mtb infection has been estimated using patients with culture-confirmed tuberculosis (CCTB) for whom recovery of Mtb confirms the infection. In this study, cytokines in addition to IFN-γ were assessed for potential to provide robust measures of Mtb infection.
Cytokine responses to ESAT-6, CFP-10, TB7.7, or combinations of these Mtb antigens, for patients with CCTB were compared with responses for subjects at low risk for Mtb infection (controls). Three different multiplexed immunoassays were used to measure concentrations of 9 to 20 different cytokines. Responses were calculated by subtracting background cytokine concentrations from cytokine concentrations in plasma from blood stimulated with Mtb antigens.
Two assays demonstrated that ESAT-6, CFP-10, ESAT-6+CFP-10, and ESAT-6+CFP-10+TB7.7 stimulated the release of significantly greater amounts of IFN-γ, IL-2, IL-8, MCP-1 and MIP-1β for CCTB patients than for controls. Responses to combination antigens were, or tended to be, greater than responses to individual antigens. A third assay, using whole blood stimulation with ESAT-6+CFP-10+TB7.7, revealed significantly greater IFN-γ, IL-2, IL-6, IL-8, IP-10, MCP-1, MIP-1β, and TNF-α responses among patients compared with controls. One CCTB patient with a falsely negative IFN-γ response had elevated responses with other cytokines.
Multiple cytokines are released when whole blood from patients with CCTB is stimulated with Mtb antigens. Measurement of multiple cytokine responses may improve diagnostic sensitivity for Mtb infection compared with assessment of IFN-γ alone.
PLoS ONE 01/2011; 6(11):e26545. · 4.09 Impact Factor
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Jerry A Nick,
Cathy S Chacon,
Sara J Brayshaw,
Marion C Jones,
Christine M Barboa,
Connie G St Clair,
Robert L Young,
David P Nichols,
Jennifer S Janssen,
Gwen A Huitt,
Michael D Iseman, Charles L Daley,
Jennifer L Taylor-Cousar,
Frank J Accurso,
Milene T Saavedra,
Marci K Sontag
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ABSTRACT: Long-term survivors of cystic fibrosis (CF) (age > 40 yr) are a growing population comprising both patients diagnosed with classic manifestations in childhood, and nonclassic phenotypes typically diagnosed as adults. Little is known concerning disease progression and outcomes in these cohorts.
Examine effects of age at diagnosis and gender on disease progression, setting of care, response to treatment, and mortality in long-term survivors of CF.
Retrospective analysis of the Colorado CF Database (1992-2008), CF Foundation Registry (1992-2007), and Multiple Cause of Death Index (1992-2005).
Patients with CF diagnosed in childhood and who survive to age 40 years have more severe CFTR genotypes and phenotypes compared with adult-diagnosed patients. However, past the age of 40 years the rate of FEV(1) decline and death from respiratory complications were not different between these cohorts. Compared with males, childhood-diagnosed females were less likely to reach age 40 years, experienced faster FEV(1) declines, and no survival advantage. Females comprised the majority of adult-diagnosed patients, and demonstrated equal FEV(1) decline and longer survival than males, despite a later age at diagnosis. Most adult-diagnosed patients were not followed at CF centers, and with increasing age a smaller percentage of CF deaths appeared in the Cystic Fibrosis Foundation Registry. However, newly diagnosed adults demonstrated sustained FEV(1) improvement in response to CF center care.
For patients with CF older than 40 years, the adult diagnosis correlates with delayed but equally severe pulmonary disease. A gender-associated disadvantage remains for females diagnosed in childhood, but is not present for adult-diagnosed females.
American Journal of Respiratory and Critical Care Medicine 05/2010; 182(5):614-26. · 11.08 Impact Factor
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James D Heffelfinger,
Pragna Patel,
John T Brooks,
Helene Calvet, Charles L Daley,
Hazel D Dean,
Brian R Edlin,
Kathleen F Gensheimer,
John Jereb,
Charlotte K Kent,
Jeffrey L Lennox,
Janice K Louie,
Ruth Lynfield,
Philip J Peters,
Lauretta Pinckney,
Philip Spradling,
Andrew C Voetsch,
Anthony Fiore
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ABSTRACT: Among vulnerable populations during an influenza pandemic are persons with or at risk for HIV infection, tuberculosis, or chronic viral hepatitis. HIV-infected persons have higher rates of hospitalization, prolonged illness, and increased mortality from influenza compared with the general population. Persons with tuberculosis and chronic viral hepatitis may also be at increased risk of morbidity and mortality from influenza because of altered immunity and chronic illness. These populations also face social and structural barriers that will be exacerbated by a pandemic. Existing infrastructure should be expanded and pandemic planning should include preparations to reduce the risks for these populations.
American Journal of Public Health 10/2009; 99 Suppl 2:S333-9. · 3.93 Impact Factor
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ABSTRACT: IL-24 is a newly described member of the IL-10 family. We previously demonstrated that PBMC from TB patients exhibited low levels of IL-24 and IFN-gamma compared to subjects with latent tuberculosis infection (LTBI). In order to investigate the role of IL-24 in IFN-gamma expression in TB patients, we stimulated PBMC from individuals with LTBI or TB patients with the Mtb-specific antigen, early secretory antigenic target-6 (ESAT-6) and measured cytokine expression using quantitative real-time PCR (qPCR). Exogenous IL-24 increased IFN-gamma expression in PBMC obtained from TB patients while neutralization of IL-24 reduced IFN-gamma expression in PBMC from subjects with LTBI. Exogenous IL-24 enhanced IFN-gamma expression by increasing expression of IL-12 family cytokines, including IL-12alpha, IL-12beta, IL-23alpha and IL-27, and by reducing FOXP3 expression in PBMC from TB patients. This is the first demonstration that IL-24 may play an important role in IFN-gamma expression following infection with Mtb.
Immunology Letters 05/2008; 117(1):57-62. · 2.53 Impact Factor
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ABSTRACT: Published criteria for the diagnosis of Mycobacterium kansasii lung disease require the presence of clinical symptoms, positive microbiologic results, and radiographic abnormalities. In patients with HIV infection, the radiographic findings of M kansasii lung disease are not well described.
Medical records and chest radiographs of all patients with HIV infection and at least one respiratory specimen culture positive for M kansasii at San Francisco General Hospital between December 1989 and July 2002 were reviewed.
Chest radiographic results were abnormal in 75 of 83 patients (90%) included in the study. Radiographic abnormalities were diverse, with consolidation (66%) and nodules (42%) as the most frequent findings. The mid or lower lung zones were involved in 89% of patients. The pattern of radiographic abnormalities did not differ based on acid-fast bacilli smear status, the presence or absence of coexisting pulmonary infections, or CD4+ T-lymphocyte count. In multivariate Cox regression analysis, cavitation was the only radiographic abnormality independently associated with mortality (hazard ratio, 4.8; 95% confidence interval, 1.2 to 19.6).
Patients with HIV infection and M kansasii lung disease present with diverse radiographic patterns, most commonly consolidation and nodules predominantly located in the mid and lower lung zones. This finding is in contrast to the upper-lobe cavitary presentation described in patients without HIV infection. Although rare, the presence of cavitary disease in patients with HIV infection and M kansasii independently predicts worse outcome. The diversity in the radiographic presentation of M kansasii lung disease implies that clinicians should obtain sputum mycobacterial culture samples from any patient with HIV infection and an abnormal chest radiograph finding.
Chest 05/2008; 133(4):875-80. · 5.25 Impact Factor
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ABSTRACT: Although a defective Th1 response has been demonstrated in patients infected with Mycobacterium tuberculosis (Mtb), the mechanisms leading to this defect are not well understood. To study the immune response to Mtb infection, we stimulated PBMC from individuals with latent tuberculosis infection (LTBI) or patients with tuberculosis (TB) with the Mtb specific antigen early secretory antigenic target-6 (ESAT-6). mRNAs for a panel of cytokines were measured using quantitative real-time PCR (qPCR). PBMC from TB patients exhibited low levels of IFN-gamma, IL-12alpha, IL-12beta, and IL-23 mRNA but high levels of IL-9 mRNA. Sera from TB patients blocked the differentiation and function of dendritic cells from TST negative (TST-) donors. Exogenous IL-9 reduced IFN-gamma mRNA expression in PBMC from LTBI by 30% (n=4) and neutralization of IL-9 restored the IFN-gamma mRNA expression in PBMC from TB patients by 66% (n=8). Thus, increased expression of IL-9 may contribute to the development of TB.
Clinical Immunology 03/2008; 126(2):202-10. · 4.05 Impact Factor
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ABSTRACT: Streptococcus pneumoniae is the leading cause of bacterial pneumonia and associated bacteremia during HIV infection. Rapid diagnostic assays may limit inappropriate therapy.
Clinical signs and symptoms and sera and urine were collected prospectively from 70 adults with pneumococcal pneumonia, including 47 with HIV co-infection. Pneumococcal C-polysaccharide antigen was detected in urine using the Binax immunochromatographic test (ICT). A systematic review of 24 published studies was conducted.
Clinical symptoms, signs, and laboratory parameters except leukocytosis, were similar in HIV-infected and HIV-seronegative pneumonia. The performance of the urine antigen ICT was independent of HIV-status (sensitivity 81%, specificity 98%, positive (PPV) and negative predictive values (NPV) 98%, and 82%, respectively). The sensitivity of sputum Gram's stain was 58% (34/59) with sputum unable to be provided by 16%. The CRP response was identical in HIV-infected (mean+/-SD) 133+/-88 vs. seronegative 135+/-104 mg/L (p=0.9). In the systematic review, the ICT performance revealed 74% sensitivity (95% CI 72-77%) and 94% specificity (95% CI 93-95%). Urine antigen testing increases etiologic diagnosis by 23% (range: 10-59%) when testing adults with community acquired pneumonia of unknown etiology.
Urinary antigen detection provides a credible rapid diagnostic test for pneumococcal pneumonia regardless of HIV-status. CRP response to acute infection is similar in HIV co-infection and increases diagnostic certainty.
The Journal of infection 11/2007; 55(4):300-9. · 4.13 Impact Factor
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ABSTRACT: Human immunodeficiency virus (HIV) infection has a major but unquantified impact on the risk of tuberculosis.
To quantify the impact of HIV infection on the number of tuberculosis cases in San Francisco.
We studied all patients reported with tuberculosis in San Francisco from 1991 to 2002. The initial isolates of Mycobacterium tuberculosis were genotyped using IS6110 restriction fragment-length polymorphism genotyping as the primary method, and clustered cases (identical genotype patterns) were identified.
We determined the case number, case rate, and the fraction of tuberculosis attributable to HIV infection. Of 2,991 reported tuberculosis cases, 2,193 (73.3%) had a genotype pattern of M. tuberculosis available. Genotypic clusters with at least one HIV-positive person were larger, lasted longer, and had a shorter time between successive cases relative to clusters with only HIV-uninfected persons (P < 0.00005, P = 0.0009, P = 0.018, respectively). Overall, 13.7% of the tuberculosis cases were attributable to HIV infection and an estimated 405 excess tuberculosis cases occurred.
During a period encompassing the resurgence and decline of tuberculosis in San Francisco, a substantial number of the tuberculosis cases were attributable to HIV infection. Coinfection with HIV amplified the local tuberculosis epidemic.
American Journal of Respiratory and Critical Care Medicine 11/2007; 176(9):936-44. · 11.08 Impact Factor
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ABSTRACT: Interferon-gamma release assays (IGRAs) are attractive alternatives to the tuberculin skin test (TST) for detecting Mycobacterium tuberculosis infection. However, the inability to definitively confirm the presence of most M. tuberculosis infections hampers assessment of IGRA accuracy. Although IGRAs are primarily indicated for the detection of latent tuberculosis infection, we sought to determine the sensitivity of the TST and 2 whole-blood IGRAs (QuantiFERON-TB assay [QFT] and QuantiFERON-TB Gold assay [QFT-G]) in situations in which infection is confirmed by recovery of M. tuberculosis by culture.
We conducted a prospective, multicenter, cross-sectional comparison study in which 148 persons suspected to have tuberculosis were tested simultaneously with the TST, QFT, and QFT-G.
M. tuberculosis was cultured from samples from 69 (47%) of 148 persons suspected to have tuberculosis; the TST induration was > or = 5 mm for 51 (73.9%) of the 69 subjects (95% confidence interval [CI], 62.5%-82.8%). The QFT indicated tuberculosis infection for 48 (69.6%) of the 69 subjects (95% CI, 57.9%-79.2%) and was indeterminate for 7 (10.1%). The QFT-G yielded positive results for 46 (66.7%) of the 69 subjects (95% CI, 54.9%-76.7%) and indeterminate results for 9 subjects (13.0%). If subjects with indeterminate QFT-G results were excluded, 46 (76.7%) of 60 subjects (95% CI, 64.6%-85.6%) had positive TST results, and the same number of subjects had positive QFT-G results. HIV infection was associated with false-negative TST results but not with false-negative QFT-G results.
The TST, QFT, and QFT-G have similar sensitivity in persons with culture-confirmed infection. As with the TST, negative QFT and QFT-G results should not be used to exclude the diagnosis of tuberculosis in persons with suggestive signs or symptoms.
Clinical Infectious Diseases 10/2007; 45(7):837-45. · 9.15 Impact Factor
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ABSTRACT: The optimal length of tuberculosis treatment in patients coinfected with HIV is unknown.
To evaluate treatment outcomes for HIV-infected patients stratified by duration of rifamycin-based tuberculosis therapy.
We retrospectively reviewed data on all patients with tuberculosis reported to the San Francisco Tuberculosis Control Program from 1990 through 2001. Patients were followed for up to 12 months after treatment completion.
Of 700 patients, 264 (38%) were HIV infected, 315 (45%) were not infected, and 121 (17%) were not tested. Mean duration of treatment was extended to 10.2 months for HIV-infected patients versus 8.4 months for uninfected/unknown patients (p < 0.001). Seventeen percent of the HIV-infected and 37% of the HIV uninfected/unknown patients received 6 months of rifamycin-based therapy. The relapse rate among HIV-infected was 9.3 per 100 person-years versus 1.0 in HIV-uninfected/unknown patients (p < 0.001). HIV-infected individuals who received a standard 6-month rifamycin-based regimen were more likely to relapse than those treated longer (adjusted hazard ratio, 4.33; p = 0.02). HIV-infected individuals who received intermittent therapy were also more likely to relapse than those treated on daily basis (adjusted hazard ratio, 4.12; p = 0.04). The use of highly active antiretroviral therapy was associated with more rapid conversion of smears and cultures and with improved survival.
HIV-infected patients who received a 6-month rifamycin-based course of tuberculosis treatment or who received intermittent therapy had a higher relapse rate than HIV-infected subjects who received longer therapy or daily therapy, respectively. Standard 6-month therapy may be insufficient to prevent relapse in patients with HIV.
American Journal of Respiratory and Critical Care Medicine 07/2007; 175(11):1199-206. · 11.08 Impact Factor
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ABSTRACT: Differentiation of active from latent tuberculosis (TB) is a major challenge in the control of TB. In this study, PBMC from latent TB-infected subjects, TB patients, and tuberculin skin test-negative donors stimulated with the Mycobacterium tuberculosis (Mtb)-specific Ag, early secretory antigenic target 6, and mRNA for 45 immune-related genes was measured by quantitative real-time PCR. Univariate analysis showed significant differences in the expression of 10 genes (IFN-gamma, FOXP3, IL-1alpha, IL-1beta, IL-2, IL-6, IL-8, IL-12alpha, IL-12beta, and IL-24) in PBMC from TB patients vs latent TB-infected subjects (p < 0.01). Multivariate logistic regression and classification and regression tree analyses revealed that expression of three genes, IL-8, FOXP3, and IL-12beta, is predictive for TB vs latent Mtb infection. Thus, measurement of Ag-specific expression of these three genes may offer a specific and noninvasive means of differentiating between latent Mtb infection and TB.
The Journal of Immunology 03/2007; 178(6):3688-94. · 5.79 Impact Factor
