Endoscopic therapy for Barrett's high grade dysplasia and intramucosal esophageal cancer is effective in community clinical practice by advanced endoscopists following multidisciplinary approach.

Barrett's esophagus with high-grade dysplasia (BEHGD) and intramucosal esophageal adenocarcinoma (IMC) can be treated by radiofrequency ablation (RFA) and endoscopic mucosal resection (EMR). Efficacy of RFA and EMR in academic medical centers has been demonstrated in previous studies. However, the clinical effectiveness of this approach in community clinical practice is not fully established.All patients with biopsy-proven BEHGD and IMC (T1a), who were treated endoscopically between 2007 and 2014, were prospectively enrolled. Treatment algorithms were determined by consensus opinion after presentation at gastrointestinal tumor board. Patients underwent EMR and/or RFA until eradication-of-dysplasia and complete remission of intestinal metaplasia (CRIM) was achieved. Patients were then enrolled in an endoscopic surveillance program.A total of 60 patients underwent endoscopic therapy for BEHGD (32) or IMC (28). Median length BE was 4 cm. Forty-six patients had EMR. Median treatment interval was nine months. Median follow-up was 33 months (Interquartile range: 16-50). Fifty-five (92%) patients achieved eradication-of-dysplasia and 52(87%) CRIM. One patient with BEHGD did not achieve any benefit six months into treatment. Nine (15%) patients relapsed after CRIM with nondysplastic-BE (6), BE with low-grade dysplasia (1), and BEHGD (2). After retreatment, eradication-of-intestinal metaplasia was achieved in five patients. BE length was a negative predictor for achieving CRIM (OR 0.81; P = 0.04). There were no procedure-related severe complications. Eleven patients with prior EMR developed symptomatic strictures, which were all successfully dilated.Endoscopic management of BEHGD and IMC can be safely and effectively performed in a community clinical practice similarly to high-volume academic medical centers when performed by advanced endoscopists following multidisciplinary approach.

Frequency and Distribution of Tuberculosis Resistance-Associated Mutations between Mumbai, Moldova, and Eastern Cape.

Molecular diagnostic assays, with their ability to rapidly detect resistance-associated mutations in bacterial genes, are promising technologies to control the spread of drug-resistant tuberculosis (DR-TB). Sequencing assays provide detailed information for specific gene regions and can help diagnostic assay developers prioritize mutations for inclusion in their assays. We performed pyrosequencing of seven Mycobacterium tuberculosis gene regions (katG, inhA, ahpC, rpoB, gyrA, rrs, and eis) for 1,128 clinical specimens from India, Moldova, and South Africa. We determined the frequencies of each mutation among drug-resistant and -susceptible specimens based on phenotypic drug susceptibility testing results and examined mutation distributions by country. The most common mutation among isoniazid-resistant (INH(r)) specimens was the katG 315ACC mutation (87%). However, in the Eastern Cape, INH(r) specimens had a lower frequency of katG mutations (44%) and higher frequencies of inhA (47%) and ahpC (10%) promoter mutations. The most common mutation among rifampin-resistant (RIF(r)) specimens was the rpoB 531TTG mutation (80%). The mutation was common in RIF(r) specimens in Mumbai (83%) and Moldova (84%) but not the Eastern Cape (17%), where the 516GTC mutation appeared more frequently (57%). The most common mutation among fluoroquinolone-resistant specimens was the gyrA 94GGC mutation (44%). The rrs 1401G mutation was found in 84%, 84%, and 50% of amikacin-resistant, capreomycin-resistant, and kanamycin (KAN)-resistant (KAN(r)) specimens, respectively. The eis promoter mutation -12T was found in 26% of KAN(r) and 4% of KAN-susceptible (KAN(s)) specimens. Inclusion of the ahpC and eis promoter gene regions was critical for optimal test sensitivity for the detection of INH resistance in the Eastern Cape and KAN resistance in Moldova. (This study has been registered at ClinicalTrials.gov under registration number NCT02170441.).

Pharmacokinetic profiles of meloxicam in turtles (Trachemys scripta scripta) after single oral, intracoelomic and intramuscular administrations.

Meloxicam is an anti-inflammatory and analgesic drug used to treat many pathological conditions in turtles. With the aim to fill the lack of data about its pharmacokinetic in this species, eighteen turtles (Trachemys scripta scripta) were divided in three groups and treated with a single dose of meloxicam (0.2 mg/kg) by intramuscular, intracoelomic and oral route, respectively. At scheduled time points, blood samples were collected and meloxicam concentrations were determined by HPLC. Pharmacokinetic parameters were calculated from the obtained concentration-time curves. After intramuscular treatment, a plasma peak of meloxicam equal to 1590.03 ± 1845.32 ng/mL (mean ± SD) and a Tmax of 1.17 ± 0.45 h were reached, indicating a quick absorption of the drug. The intracoelomic administration brought to the largest AUC (12621.04 ± 6203.79 h*ng/mL) and to a Cmax and a Tmax equal to 1154.52 ± 662.78 ng/mL and 2.82 ± 1.39 h, respectively. Following oral treatment, the plasma concentrations of meloxicam were very low indicating a scarce absorption. Further studies are warranted to determine the effective plasma concentration of meloxicam in turtles and, consequently, the dosage regimen.

Intra-articular administration of lidocaine in anaesthetized dogs: pharmacokinetic profile and safety on cardiovascular and nervous systems.

The intra-articular administration of lidocaine is a frequent practice in human orthopaedic surgical procedures, but an eventual absorption of the drug into the bloodstream can lead to toxicity, mainly concerning the central nervous system and the cardiovascular systems. The purpose of this study was to determine the pharmacokinetic profile and the safety, in terms of cardiovascular and CNS toxicity, of lidocaine after intra-articular administration to anesthetized dogs undergoing arthroscopy. Lidocaine 2% was administered to eight dogs before surgery in differing amounts, depending on the volume of the joints involved, and blood samples were taken at predetermined time points. The maximum serum concentration of lidocaine ranged from 0.50 to 3.01 µg/mL (mean ± SD: 2.18 ± 0.91 µg/mL), and the time to reach it was 28.75 ± 15.74 min. No signs of cardiac toxicity were detected during the entire procedure, and possible signs of CNS toxicity were masked by the anaesthesia. However, concentrations reported in literature as responsible for neurotoxicity in dog were achieved in three of eight investigated subjects. Pending further studies, veterinarians should consider the possibility of side effects occurring following the intra-articular administration of local anaesthetics.

Highly nonlinear trion-polaritons in a monolayer semiconductor.

Highly nonlinear optical materials with strong effective photon-photon interactions are required for ultrafast and quantum optical signal processing circuitry. Here we report strong Kerr-like nonlinearities by employing efficient optical transitions of charged excitons (trions) observed in semiconducting transition metal dichalcogenides (TMDCs). By hybridising trions in monolayer MoSe2 at low electron densities with a microcavity mode, we realise trion-polaritons exhibiting significant energy shifts at small photon fluxes due to phase space filling. We find the ratio of trion- to neutral exciton-polariton interaction strength is in the range from 10 to 100 in TMDC materials and that trion-polariton nonlinearity is comparable to that in other polariton systems. The results are in good agreement with a theory accounting for the composite nature of excitons and trions and deviation of their statistics from that of ideal bosons and fermions. Our findings open a way to scalable quantum optics applications with TMDCs.

Clinical diagnosis of tuberculosis by specialists and non-specialists.

In resource-limited settings, tuberculosis (TB) is often diagnosed by non-physicians using the acid-fast bacilli (AFB) smear only. This study examines the diagnostic accuracy of various clinicians using patient-risk history, radiography and AFB smear. A total of 321 physicians, nurses and medical students evaluated 22 profiles of TB suspects and quantified their clinical suspicion (1-99%). Culture results determined diagnostic accuracy. Overall, high-level physician training may not be required; nurses working on TB, given radiograph readings, were as accurate as TB physicians and more accurate than other physicians and clinicians. By considering clinical findings with smear results, TB specialists were significantly more accurate than smear results alone.

High prevalence of latent tuberculosis infection among injection drug users in Tijuana, Mexico.

BACKGROUND: We studied prevalence and correlates of latent tuberculosis infection (LTBI) among injection drug users (IDUs) in Tijuana, Mexico, where tuberculosis (TB) is endemic. METHODS: IDUs aged > or =18 years were recruited via respondent-driven sampling (RDS) and underwent standardized interviews, human immunodeficiency virus (HIV) antibody testing and LTBI screening using Quanti-FERON((R))-TB Gold In-Tube, a whole-blood interferon-gamma release assay (IGRA). LTBI prevalence was estimated and correlates were identified using RDS-weighted logistic regression. RESULTS: Of 1020 IDUs, 681 (67%) tested IGRA-positive and 44 (4%) tested HIV-positive. Mean age was 37 years, 88% were male and 98% were Mexican-born. IGRA positivity was associated with recruitment nearest the US border (aOR 1.64, 95%CI 1.09-2.48), increasing years of injection (aOR 1.20/5 years, 95%CI 1.07-1.34), and years lived in Tijuana (aOR 1.10/5 years, 95%CI 1.03-1.18). Speaking some English (aOR 0.38, 95%CI 0.25-0.57) and injecting most often at home in the past 6 months (aOR 0.68, 95%CI 0.45-0.99) were inversely associated with IGRA positivity. DISCUSSION: Increased LTBI prevalence among IDUs in Tijuana appears to be associated with greater drug involvement. Given the high risk for HIV infection among Tijuana's IDUs, interventions are urgently needed to prevent HIV infection and treat LTBI among IDUs before these epidemics collide.

Valley coherent exciton-polaritons in a monolayer semiconductor.

Two-dimensional transition metal dichalcogenides (TMDs) provide a unique possibility to generate and read-out excitonic valley coherence using linearly polarized light, opening the way to valley information transfer between distant systems. However, these excitons have short lifetimes (ps) and efficiently lose their valley coherence via the electron-hole exchange interaction. Here, we show that control of these processes can be gained by embedding a monolayer of WSe2 in an optical microcavity, forming part-light-part-matter exciton-polaritons. We demonstrate optical initialization of valley coherent polariton populations, exhibiting luminescence with a linear polarization degree up to 3 times higher than displayed by bare excitons. We utilize an external magnetic field alongside selective exciton-cavity-mode detuning to control the polariton valley pseudospin vector rotation, which reaches 45° at B = 8 T. This work provides unique insight into the decoherence mechanisms in TMDs and demonstrates the potential for engineering the valley pseudospin dynamics in monolayer semiconductors embedded in photonic structures.

Immunotherapy of coccidioidomycosis.

Transfer factor (TF) derived from donors with strong delayed hypersensitivity to coccidioidin (CDN) was administered to four patients with active disseminated or progressive pulmonary coccidioidomycosis. The clinical and immunologic response to TF was studied. Before the administration of TF, all four patients had defective thymus-derived lymphocyte (T-cell) function. In no case were lymphocytes in culture stimulated to incorporate [(3)H]thymidine when exposed to CDN. Cases 1 and 2 had no skin test response to CDN or other antigen, nor was antigen-induced migration inhibition factor (MIF) release detected. Cases 3 and 4 had skin reactivity to CDN as well as MIF release. Lymphocyte reactivity to phytohemagglutinin (PHA), as measured by the incorporation of [(3)H]thymidine, was low or absent in all. After the administration of TF, patients with negative skin tests became reactive to CDN, MIF release was present in all but case 1, and lymphocyte stimulation was present in response to CDN in all. Lymphocyte reactivity to PHA was also increased after the administration of TF in all cases. All responses to single doses of TF were transient, lasting no more than 10 days. Subsequent doses were less effective at restoring lymphocyte stimulation once it had waned. Multiple doses of TF administered at frequent intervals appear to be the most effective way to maintain lymphocyte reactivity. Clinical response to the administration of TF correlated closely with specific transfer as measured by response to CDN in skin test, lymphocyte stimulation, and MIF release. After TF administration, all patients mounted a more effective host response against the infecting fungus. In each patient, smears and cultures became negative. Fistulas, when present, diminished in extent or closed; and pulmonary infiltrates cleared. Nonspecific signs of infection such as fever, weight loss, and anorexia also improved. Clinical improvement paralleled immunologic improvement. When immunologic improvement was transient so was clinical improvement. Multiple doses of TF at frequent intervals may maintain transferred T-cell reactivity. TF may prove to be a useful adjunct in the management of patients with coccidioidomycosis. Whether TF from CDN-negative donors may have similar effects is not known and requires exploration.

Natural killer cells from human immunodeficiency virus (HIV)-infected individuals are an important source of CC-chemokines and suppress HIV-1 entry and replication in vitro.

Macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation, normal T cell expressed and secreted), which are the natural ligands of the CC-chemokine receptor CCR5, inhibit replication of MT-2- negative strains of HIV-1 by interfering with the ability of these strains to utilize CCR5 as a coreceptor for entry in CD4(+) cells. The present study investigates the capacity of natural killer (NK) cells isolated from HIV-infected individuals to produce CC-chemokines and to suppress HIV replication in autologous, endogenously infected cells as well as to block entry of MT-2-negative HIV into the CD4(+) T cell line PM-1. NK cells freshly isolated from HIV-infected individuals had a high number of mRNA copies for MIP-1alpha and RANTES. NK cells produced significant amounts of RANTES, MIP-1alpha, and MIP-1beta constitutively, in response to stimulation with IL-2 alone and when they were performing their characteristic lytic activity (K562 killing). After CD16 cross-linking and stimulation with IL-2 or IL-15 NK cells produced CC-chemokines to levels comparable to those produced by anti-CD3-stimulated CD8(+) T cells. Furthermore, CD16 cross-linked NK cells suppressed (49-97%) viral replication in cocultures of autologous CD8/NK-depleted PBMC to a degree similar to that of PHA or anti-CD3-stimulated CD8(+) T cells. In 50% of patients tested, NK-mediated HIV suppression could be abrogated by neutralizing antibodies to MIP-1alpha, MIP-1beta and RANTES; in contrast, CD8(+) T cell-mediated suppression was not significantly overcome upon neutralization of CC-chemokines. Supernatants derived from cultures of CD16 cross-linked NK cells stimulated with IL-2 or IL-15 dramatically inhibited entry of a MT-2-negative strain of HIV, BaL, in the CD4(+)CCR5(+) PM-1 T cell line. These data suggest that activated NK cells may be an important source of CC-chemokines in vivo and may suppress HIV replication by CC-chemokine-mediated mechanisms in addition to classic NK-mediated lytic mechanisms.

The National Tuberculosis Curriculum Consortium: a model of multi-disciplinary educational collaboration.

The National Tuberculosis Curriculum Consortium (NTCC) seeks to instill knowledge, skills, and appropriate attitudes in the management and control of tuberculosis (TB) among students in the health professions. Unlike other organizations that have produced quality educational materials aimed at practicing clinicians, public health workers, and the general public, the NTCC is primarily focused on undergraduate and graduate education. The NTCC includes geographically disparate faculty from schools of medicine, nursing, pharmacy, public health, respiratory therapy, clinical laboratory sciences, and physician assistant who are experts in the areas of TB, curriculum development, and educational computing. Collaboration occurs through meetings, phone conferences and an innovative web portal that provides a work zone used to develop, organize, and archive products and resources. A critical accomplishment of the Consortium has been the development of core competencies for TB education for graduates in each of the health care disciplines. Those for medical schools are presented in this article. Current NTCC efforts are directed at developing interactive materials for TB education that can be accessed by multi-disciplinary faculty, nationally and abroad. The collaborative effort of the NTCC serves as a model for future endeavors to strengthen curricula, particularly pertaining to health concerns that are best served by multi-disciplinary approaches.

A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis.

Pyrazinamide (PZA) is an important first-line drug in all existing and new tuberculosis (TB) treatment regimens. PZA-resistance in M. tuberculosis is increasing, especially among M/XDR cases. Noted issues with PZA Drug Susceptibility Testing (DST) have driven the search for alternative tests. This study provides a comprehensive assessment of PZA molecular diagnostics in M/XDR TB cases. A set of 296, mostly XDR, clinical M. tuberculosis isolates from four countries were subjected to DST for eight drugs, confirmatory Wayne's assay, and whole-genome sequencing. Three genes implicated in PZA resistance, pncA, rpsA, and panD were investigated. Assuming all non-synonymous mutations cause resistance, we report 90% sensitivity and 65% specificity for a pncA-based molecular test. The addition of rpsA and panD potentially provides 2% increase in sensitivity. Molecular heterogeneity in pncA was associated with resistance and should be evaluated as a diagnostic tool. Mutations near the N-terminus and C-terminus of PZase were associated with East-Asian and Euro-American lineages, respectively. Finally, Euro-American isolates are most likely to have a wild-type PZase and escape molecular detection. Overall, the 8-10% resistance without markers may point to alternative mechanisms of resistance. Confirmatory mutagenesis may improve the disconcertingly low specificity but reduce sensitivity since not all mutations may cause resistance.

A performance evaluation of MTBDRplus version 2 for the diagnosis of multidrug-resistant tuberculosis.

OBJECTIVE: To evaluate the performance of a recently updated rapid molecular diagnostic test, GenoType® MTBDRplus version 2, designed to detect drug resistance in both acid-fast bacilli (AFB) smear-negative and -positive specimens. DESIGN: Sputum samples from 1128 patients at risk for multidrug-resistant tuberculosis (MDR-TB) were tested using MTBDRplus v2 and compared with reference standard MGIT™ 960™ drug susceptibility testing. The relationship of participant human immunodeficiency virus (HIV) status, diabetic status, previous treatment, and smear gradation to the likelihood of obtaining an interpretable result was assessed using logistic regression. RESULTS: The sensitivity and specificity of MTBDRplus v2 for detecting MDR-TB, when compared to a reference standard, were respectively 96.0% (95%CI 93.5-97.6) and 99.2% (95%CI 97.0-99.9) in AFB smear-positive specimens and 82.8% (95%CI 63.5-93.5) and 98.3% (95%CI 89.9-99.9) in AFB smear-negative specimens. A dose-response relationship was observed between the proportion of interpretable test results and AFB smear bacterial load after adjusting for age, sex, body mass index, HIV status, previous treatment and diabetic status. CONCLUSION: While MTBDRplus v2 performs well among both AFB smear-positive and -negative specimens, smear gradation appears to influence both the probability of obtaining an interpretable result and test sensitivity, indicating a significant association between bacillary load and test performance.

Redefining MTBDRplus test results: what do indeterminate results actually mean?

BACKGROUND: Although line-probe assays (LPAs) are promising, little research has been conducted to elucidate the true nature of indeterminate LPA results or assess the ability of these assays to perform on a wide range of clinical samples. OBJECTIVE: To evaluate the performance of the commercially available GenoType(®) MTBDRplus LPA against conventional BACTEC™ MGIT™ 960 culture and drug susceptibility testing (DST) among 308 pulmonary tuberculosis (PTB) and 32 extra-pulmonary TB samples. RESULTS: Invalid LPA results (defined as those with a missing Mycobacterium tuberculosis identification band) were obtained for 18 PTB samples, which were excluded from further analysis. The sensitivity and specificity of the MTBDRplus assay for multidrug-resistant TB, based upon the results obtained for the remaining 322 samples, was respectively 95.2% and 95.1%. Of 290 PTB samples, 40 (13.7%) were indeterminate on LPA (defined as the absence of both wild-type and corresponding mutation bands) for isoniazid (INH) and/or rifampicin (RMP), and were further evaluated by pyrosequencing (PSQ). Contrary to standard LPA interpretation, INH and RMP susceptibility were confirmed by both DST and PSQ in respectively 7.5% (3/40) and 27.5% (11/40) of indeterminate samples. CONCLUSION: PSQ was found to be a valuable and rapid technique to resolve discrepancies in LPA test results that were not interpretable.

Integration of microscopy and serodiagnostic tests to screen for active tuberculosis.

SETTING: University of California San Diego Medical Center, USA. OBJECTIVE: To create a simple screening strategy for tuberculosis (TB) that includes antibody detection assays to improve the accuracy of microscopic examination of sputum for acid-fast bacilli (AFB smear). METHODS: Serum samples were obtained from 190 patients suspected of having active TB. TB diagnosis was established by Mycobacterium tuberculosis culture. HIV status was determined by commercial serologic tests. IgG antibody levels were measured by ELISA using purified M. tuberculosis antigens. Data from 130 randomly selected patients were used to develop a screening strategy; data from the remaining 60 patients were used for validation. RESULTS: AFB smear had 70% sensitivity and 88% specificity. In algorithms integrating single or multi-antigen ELISA with AFB smear and HIV results, the sensitivity improved over each test alone. The algorithm that included a four-antigen ELISA (38 kDa antigen, lipoarabinomannan, MPT-64 and glutamine synthase) had a sensitivity of 93% and a specificity of 76%. Compared to AFB smear, the sensitivity of the algorithm was significantly higher, while the specificity was not statistically different. CONCLUSION: This study demonstrates that a screening strategy can be created by integrating multi-antigen ELISA with AFB smear and HIV testing.

Transfer factor therapy for histoplasmosis in a patient with Hodgkin's disease.

A patient with recurrent chronic histoplasmosis was diagnosed also as having Hodgkin's disease. Studies of cell-mediated immunity (CMI) demonstrated no reaction to histoplasmin by skin test, lymphocyte transformation (LT), or leukocyte inhibition factor (LIF) assay. Clinical and immunologic studies were performed during treatment with 19 doses of dialyzable transfer factor (TF) prepared from a normal donor with strong CMI against histoplasmin. Transfer of CMI to the patient was demonstrated by all three tests. All tests reverted to nonreactive during the period of observation. Repeated doses of dialyzable TF were followed by reconversion of skin tests. The LIF assay was most reactive. Reactivation of histoplasmosis occurred during antimetabolic therapy for Hodgkin's disease; however, the lesions cleared rapidly when TF was added to amphotericin B. Amphotericin B was administered at a dosage of 25 mg three times each week during the entire study.

Determination of MICs of levofloxacin for Mycobacterium tuberculosis with gyrA mutations.

The purpose of the present study was to correlate gyrA mutations found in Mycobacterium tuberculosis isolates using the GenoType(®) MTBDRsl assay with minimum inhibitory concentrations of the fluoroquinolone levofloxacin (LVX). Of 123 archived clinical M. tuberculosis isolates evaluated, 93 isolates had an Ala90Val, Ser91Pro, Asp94Ala, Asn/Tyr, Gly or His mutation and 30 were wild-type. Phenotypically, gyrA mutations Ala90Val, Ser91Pro or Asp94Ala showed a low level of resistance to LVX, while Asp94Asn/Tyr, Asp94Gly or Asp94His mutations had high-level resistance.

Predicting differential rifamycin resistance in clinical Mycobacterium tuberculosis isolates by specific rpoB mutations.

SETTING: Rifampin (RMP) resistant Mycobacterium tuberculosis is usually assumed to be resistant to all rifamycins. Increasing evidence indicates, however, that some rpoB mutations, detectable by rapid molecular diagnostics, confer resistance to RMP but not to rifabutin (RBT), suggesting that RBT may be effective for the treatment of M. tuberculosis with these mutations. OBJECTIVE: To determine if specific rpoB mutations reliably predict differential phenotypic resistance to RMP and RBT. DESIGN: We selected 60 clinical M. tuberculosis isolates from a repository of multinational multidrug-resistant tuberculosis isolates and stratified them into two groups: 1) those with rpoB mutations suspected to confer differential resistance to RMP and RBT, and 2) those expected to be cross-resistant to RMP and RBT. These assumptions were tested by comparing the phenotypic susceptibilities of RMP/RBT with those predicted by mutations in the rpoB gene. RESULTS: Of 20 suspected RMP-resistant/RBT-susceptible isolates, 15 were RMP-resistant but RBT-susceptible, 3 were RMP- and RBT-susceptible, and 2 were cross-resistant to both RMP and RBT. In comparison, 40 of 40 suspected cross-resistant isolates were both RMP- and RBT-resistant. CONCLUSION: Our data support the association between specific rpoB mutations and differential resistance of M. tuberculosis to RMP and RBT. Clinical studies are required to investigate the efficacy of RBT in the treatment of M. tuberculosis harboring these mutations.

Phenotypic and genotypic diversity in a multinational sample of drug-resistant Mycobacterium tuberculosis isolates.

OBJECTIVE: To develop and evaluate rapid, molecular-based drug susceptibility testing (DST) for extensively drug-resistant tuberculosis (XDR-TB), we assembled a phenotypically and genotypically diverse collection of Mycobacterium tuberculosis isolates from patients evaluated for drug resistance in four high-burden countries. METHODS: M. tuberculosis isolates from India (n = 111), Moldova (n = 90), the Philippines (n = 96), and South Africa (n = 103) were selected from existing regional and national repositories to maximize phenotypic diversity for resistance to isoniazid, rifampin (RMP), moxifloxacin, ofloxacin, amikacin, kanamycin, and capreomycin. MGIT™ 960 was performed on viable isolates in one laboratory using standardized procedures and drug concentrations. Genetic diversity within drug resistance phenotypes was assessed. RESULTS: Nineteen distinct phenotypes were observed among 400 isolates with complete DST results. Diversity was greatest in the Philippines (14 phenotypes), and least in South Africa (9 phenotypes). Nearly all phenotypes included multiple genotypes. All sites provided isolates resistant to injectables but susceptible to fluoroquinolones. Many patients were taking drugs to which their disease was resistant. DISCUSSION: Diverse phenotypes for XDR-TB-defining drugs, including resistance to fluoroquinolones and/or injectable drugs in RMP-susceptible isolates, indicate that RMP susceptibility does not ensure effectiveness of a standard four-drug regimen. Rapid, low-cost DST assays for first- and second-line drugs are thus needed.

Fluconazole in the treatment of chronic pulmonary and nonmeningeal disseminated coccidioidomycosis. NIAID Mycoses Study Group.

PURPOSE: To determine the efficacy and safety of fluconazole as treatment for coccidioidomycosis. PATIENTS AND METHODS: This was a multicenter, open-label, single-arm study. Of 78 patients enrolled, 22 had soft-tissue, 42 had chronic pulmonary, and 14 had skeletal coccidioidomycosis. Forty-nine had at least one concomitant disease, 7 of whom had HIV infection. Patients were given oral fluconazole 200 mg/d. Nonresponders were increased to 400 mg/d. Treatment courses were long: a mean of 323 +/- 230 days at 200 mg and 433 +/- 178 days at 400 mg. Predefined assessment of disease-related abnormalities was performed at the time of enrollment and repeated at least every 4 months. A satisfactory response was defined as any reduction of baseline abnormality by month 4 and at least 51% reduction by month 8. RESULTS: Among 75 evaluable patients, a satisfactory response was observed in 12 (86%) of the 14 patients with skeletal, 22 (55%) of the 40 patients with chronic pulmonary, and 16 (76%) of the 21 patients with soft-tissue disease. Five patients (7%) required modification of treatment due to toxicity. Forty-one patients who responded were followed off drug. Fifteen (37%) of them experienced reactivation of infection. CONCLUSION: Fluconazole 200 or 400 mg/d is well tolerated and a moderately effective treatment for chronic pulmonary or nonmeningeal disseminated coccidioidomycosis. The relapse rate following therapy is high. Treatment trials with higher doses appear warranted. The relative efficacy of fluconazole versus other azoles or amphotericin B remains unknown.