Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
Records 1-30 (of 80 Records) |
Query Trace: Posey J[original query] |
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Tuberculosis in United States-bound follow-to-join asylees, 2014-2019
Liu Y , Posey DL , Weinberg MS , Phares CR . Am J Trop Med Hyg 2024 Persons may seek asylum in the United States or at a U.S. port of entry. Principal asylees are those who are granted asylum status. Their spouse and unmarried children under 21 years of age may be granted asylum if accompanying, or following to join, the principal asylees. U.S.-bound follow-to-join asylees must undergo an overseas medical examination that includes tuberculosis (TB) screening. Culture-based overseas TB screening in U.S.-bound follow-to-join asylees has not been evaluated. We evaluated data from overseas TB screening in 19,088 arrivals of follow-to-join asylees during 2014-2019 and assessed data from their postarrival evaluation, which is recommended for those at risk for TB. Of 19,088 arrivals of follow-to-join asylees, 29 (152 cases/100,000 persons) met criteria for class B0 TB (recent completion of TB treatment overseas) and 340 (1,781 cases/100,000 persons) met criteria for class B1 pulmonary TB (chest radiograph/clinical symptoms suggestive of TB but negative sputum cultures overseas). Of 6,847 persons aged 2 to 14 years from countries with a WHO-estimated TB incidence of ≥20 cases/100,000 population/year, 408 (6.0%) were classified as class B2 latent TB infection (LTBI). Postarrival evaluations were completed in 44.8%, 51.5%, and 40.4% of persons with class B0 TB, class B1 TB, and class B2 LTBI, respectively. In conclusion, culture-based overseas TB screening in U.S.-bound follow-to-join asylees is effective in identifying those with TB (class B0 TB) or those at risk for TB (class B1 TB and class B2 LTBI). Completion of postarrival evaluation for newly arrived follow-to-join asylees was less frequent than that reported for immigrants and refugees. |
Prediction of pyrazinamide resistance in Mycobacterium tuberculosis using structure-based machine-learning approaches
Carter JJ , Walker TM , Walker AS , Whitfield MG , Morlock GP , Lynch CI , Adlard D , Peto TEA , Posey JE , Crook DW , Fowler PW . JAC Antimicrob Resist 2024 6 (2) dlae037 BACKGROUND: Pyrazinamide is one of four first-line antibiotics used to treat tuberculosis; however, antibiotic susceptibility testing for pyrazinamide is challenging. Resistance to pyrazinamide is primarily driven by genetic variation in pncA, encoding an enzyme that converts pyrazinamide into its active form. METHODS: We curated a dataset of 664 non-redundant, missense amino acid mutations in PncA with associated high-confidence phenotypes from published studies and then trained three different machine-learning models to predict pyrazinamide resistance. All models had access to a range of protein structural-, chemical- and sequence-based features. RESULTS: The best model, a gradient-boosted decision tree, achieved a sensitivity of 80.2% and a specificity of 76.9% on the hold-out test dataset. The clinical performance of the models was then estimated by predicting the binary pyrazinamide resistance phenotype of 4027 samples harbouring 367 unique missense mutations in pncA derived from 24 231 clinical isolates. CONCLUSIONS: This work demonstrates how machine learning can enhance the sensitivity/specificity of pyrazinamide resistance prediction in genetics-based clinical microbiology workflows, highlights novel mutations for future biochemical investigation, and is a proof of concept for using this approach in other drugs. |
A standardised method for interpreting the association between mutations and phenotypic drug resistance in Mycobacterium tuberculosis.
Miotto P , Tessema B , Tagliani E , Chindelevitch L , Starks AM , Emerson C , Hanna D , Kim PS , Liwski R , Zignol M , Gilpin C , Niemann S , Denkinger CM , Fleming J , Warren RM , Crook D , Posey J , Gagneux S , Hoffner S , Rodrigues C , Comas I , Engelthaler DM , Murray M , Alland D , Rigouts L , Lange C , Dheda K , Hasan R , Ranganathan UDK , McNerney R , Ezewudo M , Cirillo DM , Schito M , Köser CU , Rodwell TC . Eur Respir J 2017 50 (6) A clear understanding of the genetic basis of antibiotic resistance in Mycobacterium tuberculosis is required to accelerate the development of rapid drug susceptibility testing methods based on genetic sequence.Raw genotype-phenotype correlation data were extracted as part of a comprehensive systematic review to develop a standardised analytical approach for interpreting resistance associated mutations for rifampicin, isoniazid, ofloxacin/levofloxacin, moxifloxacin, amikacin, kanamycin, capreomycin, streptomycin, ethionamide/prothionamide and pyrazinamide. Mutation frequencies in resistant and susceptible isolates were calculated, together with novel statistical measures to classify mutations as high, moderate, minimal or indeterminate confidence for predicting resistance.We identified 286 confidence-graded mutations associated with resistance. Compared to phenotypic methods, sensitivity (95% CI) for rifampicin was 90.3% (89.6-90.9%), while for isoniazid it was 78.2% (77.4-79.0%) and their specificities were 96.3% (95.7-96.8%) and 94.4% (93.1-95.5%), respectively. For second-line drugs, sensitivity varied from 67.4% (64.1-70.6%) for capreomycin to 88.2% (85.1-90.9%) for moxifloxacin, with specificity ranging from 90.0% (87.1-92.5%) for moxifloxacin to 99.5% (99.0-99.8%) for amikacin.This study provides a standardised and comprehensive approach for the interpretation of mutations as predictors of M. tuberculosis drug-resistant phenotypes. These data have implications for the clinical interpretation of molecular diagnostics and next-generation sequencing as well as efficient individualised therapy for patients with drug-resistant tuberculosis. |
COVID-19 testing of United States-bound agricultural workers in Mexico
Teleaga J , White ZA , Cervantes J , Assael R , Barrera G , Toney S , Marano N , Rodriguez Lainz A , Assael C , Ortega A , Chappelle CG , Bustamante N , Moser K , Posey DL . J Immigr Minor Health 2023 25 (6) 1295-1301 The COVID-19 pandemic presents global health, welfare, and economic concerns. The agricultural workforce has experienced adverse effects, placing the U.S. food supply at risk. Agricultural workers temporarily travel to the United States on H-2A visas to supplement the agricultural workforce. Approximately 300,000 agricultural workers enter the United States with H-2A visas each year; over 90.0% are from Mexico. During February-May 2021, a COVID-19 testing pilot was performed with Clínica Médica Internacional (CMI), a clinic that performs medical examinations for US-bound immigrants, to determine the SARS-CoV-2 infection status of H-2A agricultural workers in Mexico before entry to the US. The CerTest VIASURE Real Time PCR Detection Kit was used. Participants' demographic information, test results, and testing turnaround times were collected. Workers who tested positive for SARS-CoV-2 completed isolation before US entry. During the pilot, 1195 H-2A workers were tested; 15 (1.3%) tested positive. Average reporting time was 31 h after specimen collection. This pilot demonstrated there is interest from H-2A employers and agents in testing the H-2A community before US entry. Testing for SARS-CoV-2 can yield public health benefit, is feasible, and does not delay entry of temporary agricultural workers to the US. |
Validation of novel Mycobacterium tuberculosis isoniazid resistance mutations not detectable by common molecular tests (preprint)
Kandler JL , Mercante AD , Dalton TL , Ezewudo MN , Cowan LS , Burns SP , Metchock B , Cegielski P , Posey JE . bioRxiv 2018 322750 Resistance to the first-line anti-tuberculosis (TB) drug, isoniazid (INH), is widespread, and the mechanism of resistance is unknown in approximately 15% of INH-resistant (INH-R) strains. To improve molecular detection of INH-R TB, we used whole genome sequencing (WGS) to analyze 52 phenotypically INH-R Mycobacterium tuberculosis complex (MTBC) clinical isolates that lacked the common katG S315T or inhA promoter mutations. Approximately 94% (49/52) of strains had mutations at known INH-associated loci that were likely to confer INH resistance. All such mutations would be detectable by sequencing more DNA adjacent to existing target regions. Use of WGS minimized the chances of missing infrequent INH resistance mutations outside commonly targeted hotspots. We used recombineering to generate 12 observed clinical katG mutations in the pansusceptible H37Rv reference strain and determined their impact on INH resistance. Our functional genetic experiments have confirmed the role of seven suspected INH resistance mutations and discovered five novel INH resistance mutations. All recombineered katG mutations conferred resistance to INH at a minimum inhibitory concentration of ≥0.25 μg/mL and should be added to the list of INH resistance determinants targeted by molecular diagnostic assays. We conclude that WGS is a superior method for detection of INH-R MTBC compared to current targeted molecular testing methods and could provide earlier diagnosis of drug-resistant TB. |
The implementation of CDC COVID-19 recommendations for testing, isolation, quarantine and movement at emergency intake sites of unaccompanied children in the United States, April 1-May 31, 2021
Bustamante ND , Sauber-Schatz E , Lee D , Hailu K , Liu Y , Pezzi C , Yonkman J , Gonzalez J , Appelgate A , Marano N , Posey DL , Cetron M , Monterroso E . J Immigr Minor Health 2023 1-6 In March 2021, Emergency Intake Sites (EIS) were created to address capacity shortfalls during a surge of Unaccompanied Children at the Mexico-United States land border. The COVID-19 Zone Plan (ZP) was developed to decrease COVID-19 transmission. COVID-19 cumulative percent (%) positivity was analyzed to evaluate the impact of the ZP, venue type and bed capacity across EIS from April 1-May 31, 2021. Results: Of 11 EIS sites analyzed, 54% implemented the recommended ZP. The overall % positivity was 2.47% (95% CI 2.39-2.55). The % positivity at EIS with the ZP, 1.83% (95% CI 1.71-1.95), was lower than that at EIS without the ZP, 2.83%, ( 95% CI 2.72-2.93), and showed a lower 7-day moving average of % positivity. Conclusion: Results showed a possible effect of the ZP on % positivity when controlling for venue type and bed capacity in a specific EIS group comparison, indicating that all three variables could have had effect on % positivity. They also showed that smaller intake facilities may be recommendable during public health emergencies. |
Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment
Antimycobacterial Susceptibility Testing Group , Posey James E . Eur Respir J 2022 59 (4) Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance. https://bit.ly/3i43wb6 | Approximately 85 000 deaths globally in 2019 were due to drug-resistant tuberculosis (TB), which corresponds to 7% of global deaths attributable to bacterial antimicrobial resistance [1]. Yet concerns have been mounting that drug-resistant TB was being underestimated because the approaches to define susceptibility and resistance to anti-TB agents had not kept up with those used for other major bacterial pathogens [2–9]. Here, we outline the recent, evidence-based initiatives spearheaded by the World Health Organization (WHO) and others to update breakpoints (traditionally referred to as critical concentrations (CCs)) that are used for phenotypic antimicrobial susceptibility testing (AST), also called drug susceptibility testing in the TB literature. | eng |
Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.
Allix-Béguec C , Arandjelovic I , Bi L , Beckert P , Bonnet M , Bradley P , Cabibbe AM , Cancino-Muñoz I , Caulfield MJ , Chaiprasert A , Cirillo DM , Clifton DA , Comas I , Crook DW , De Filippo MR , de Neeling H , Diel R , Drobniewski FA , Faksri K , Farhat MR , Fleming J , Fowler P , Fowler TA , Gao Q , Gardy J , Gascoyne-Binzi D , Gibertoni-Cruz AL , Gil-Brusola A , Golubchik T , Gonzalo X , Grandjean L , He G , Guthrie JL , Hoosdally S , Hunt M , Iqbal Z , Ismail N , Johnston J , Khanzada FM , Khor CC , Kohl TA , Kong C , Lipworth S , Liu Q , Maphalala G , Martinez E , Mathys V , Merker M , Miotto P , Mistry N , Moore DAJ , Murray M , Niemann S , Omar SV , Ong RT , Peto TEA , Posey JE , Prammananan T , Pym A , Rodrigues C , Rodrigues M , Rodwell T , Rossolini GM , Sánchez Padilla E , Schito M , Shen X , Shendure J , Sintchenko V , Sloutsky A , Smith EG , Snyder M , Soetaert K , Starks AM , Supply P , Suriyapol P , Tahseen S , Tang P , Teo YY , Thuong TNT , Thwaites G , Tortoli E , van Soolingen D , Walker AS , Walker TM , Wilcox M , Wilson DJ , Wyllie D , Yang Y , Zhang H , Zhao Y , Zhu B . N Engl J Med 2018 379 (15) 1403-1415 BACKGROUND: The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear. METHODS: We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance. RESULTS: A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted. CONCLUSIONS: Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.). |
Discovery of substituted benzyloxy-benzylamine inhibitors of acetyltransferase Eis and their anti-mycobacterial activity
Pang AH , Green KD , Chandrika NT , Garzan A , Punetha A , Holbrook SYL , Willby MJ , Posey JE , Tsodikov OV , Garneau-Tsodikova S . Eur J Med Chem 2022 242 114698 A clinically significant mechanism of tuberculosis resistance to the aminoglycoside kanamycin (KAN) is its acetylation catalyzed by upregulated Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. In search for inhibitors of Eis, we discovered an inhibitor with a substituted benzyloxy-benzylamine scaffold. A structure-activity relationship study of 38 compounds in this structural family yielded highly potent (IC(50) 1M) Eis inhibitors, which did not inhibit other acetyltransferases. Crystal structures of Eis in complexes with three of the inhibitors showed that the inhibitors were bound in the aminoglycoside binding site of Eis, consistent with the competitive mode of inhibition, as established by kinetics measurements. When tested in Mtb cultures, two inhibitors (47 and 55) completely abolished resistance to KAN of the highly KAN-resistant strain Mtb mc(2) 6230 K204, likely due to Eis inhibition as a major mechanism. Thirteen of the compounds were toxic even in the absence of KAN to Mtb and other mycobacteria, but not to non-mycobacteria or to mammalian cells. This, yet unidentified mechanism of toxicity, distinct from Eis inhibition, will merit future studies along with further development of these molecules as anti-mycobacterial agents. |
Molecular surveillance for large outbreaks of tuberculosis in the United States, 2014-2018.
Raz KM , Talarico S , Althomsons SP , Kammerer JS , Cowan LS , Haddad MB , McDaniel CJ , Wortham JM , France AM , Powell KM , Posey JE , Silk BJ . Tuberculosis (Edinb) 2022 136 102232 OBJECTIVE: This study describes characteristics of large tuberculosis (TB) outbreaks in the United States detected using novel molecular surveillance methods during 2014-2016 and followed for 2 years through 2018. METHODS: We developed 4 genotype-based detection algorithms to identify large TB outbreaks of ≥10 cases related by recent transmission during a 3-year period. We used whole-genome sequencing and epidemiologic data to assess evidence of recent transmission among cases. RESULTS: There were 24 large outbreaks involving 518 cases; patients were primarily U.S.-born (85.1%) racial/ethnic minorities (84.1%). Compared with all other TB patients, patients associated with large outbreaks were more likely to report substance use, homelessness, and having been diagnosed while incarcerated. Most large outbreaks primarily occurred within residences among families and nonfamilial social contacts. A source case with a prolonged infectious period and difficulties in eliciting contacts were commonly reported contributors to transmission. CONCLUSION: Large outbreak surveillance can inform targeted interventions to decrease outbreak-associated TB morbidity. |
The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis
Walker TM , Fowler PW , Knaggs J , Hunt M , Peto TE , Walker AS , Crook DW , Walker TM , Miotto P , Cirillo DM , Kser CU , Knaggs J , Iqbal Z , Hunt M , Chindelevitch L , Farhat MR , Comas I , Comas I , Posey J , Omar SV , Peto TE , Walker AS , Crook DW , Suresh A , Uplekar S , Laurent S , Colman RE , Rodwell TC , Nathanson CM , Zignol M , Ismail N , Rodwell TC , Walker AS , Steyn AJC , Lalvani A , Baulard A , Christoffels A , Mendoza-Ticona A , Trovato A , Skrahina A , Lachapelle AS , Brankin A , Piatek A , GibertoniCruz A , Koch A , Cabibbe AM , Spitaleri A , Brandao AP , Chaiprasert A , Suresh A , Barbova A , VanRie A , Ghodousi A , Bainomugisa A , Mandal A , Roohi A , Javid B , Zhu B , Letcher B , Rodrigues C , Nimmo C , Nathanson CM , Duncan C , Coulter C , Utpatel C , Liu C , Grazian C , Kong C , Kser CU , Wilson DJ , Cirillo DM , Matias D , Jorgensen D , Zimenkov D , Chetty D , Moore DA , Clifton DA , Crook DW , vanSoolingen D , Liu D , Kohlerschmidt D , Barreira D , Ngcamu D , SantosLazaro ED , Kelly E , Borroni E , Roycroft E , Andre E , Bttger EC , Robinson E , Menardo F , Mendes FF , Jamieson FB , Coll F , Gao GF , Kasule GW , Rossolini GM , Rodger G , Smith EG , Meintjes G , Thwaites G , Hoffmann H , Albert H , Cox H , Laurenson IF , Comas I , Arandjelovic I , Barilar I , Robledo J , Millard J , Johnston J , Posey J , Andrews JR , Knaggs J , Gardy J , Guthrie J , Taylor J , Werngren J , Metcalfe J , Coronel J , Shea J , Carter J , Pinhata JM , Kus JV , Todt K , Holt K , Nilgiriwala KS , Ghisi KT , Malone KM , Faksri K , Musser KA , Joseph L , Rigouts L , Chindelevitch L , Jarrett L , Grandjean L , Ferrazoli L , Rodrigues M , Farhat M , Schito M , Fitzgibbon MM , Loemb MM , Wijkander M , Ballif M , Rabodoarivelo MS , Mihalic M , Wilcox M , Hunt M , Zignol M , Merker M , Egger M , O'Donnell M , Caws M , Wu MH , Whitfield MG , Inouye M , Mansj M , DangThi MH , Joloba M , Kamal SM , Okozi N , Ismail N , Mistry N , Hoang NN , Rakotosamimanana N , Paton NI , Rancoita PMV , Miotto P , Lapierre P , Hall PJ , Tang P , Claxton P , Wintringer P , Keller PM , Thai PVK , Fowler PW , Supply P , Srilohasin P , Suriyaphol P , Rathod P , Kambli P , Groenheit R , Colman RE , Ong RTH , Warren RM , Wilkinson RJ , Diel R , Oliveira RS , Khot R , Jou R , Tahseen S , Laurent S , Gharbia S , Kouchaki S , Shah S , Plesnik S , Earle SG , Dunstan S , Hoosdally SJ , Mitarai S , Gagneux S , Omar SV , Yao SY , GrandjeanLapierre S , Battaglia S , Niemann S , Pandey S , Uplekar S , Halse TA , Cohen T , Cortes T , Prammananan T , Kohl TA , Thuong NTT , Teo TY , Peto TEA , Rodwell TC , William T , Walker TM , Rogers TR , Surve U , Mathys V , Furi V , Cook V , Vijay S , Escuyer V , Dreyer V , Sintchenko V , Saphonn V , Solano W , Lin WH , vanGemert W , He W , Yang Y , Zhao Y , Qin Y , Xiao YX , Hasan Z , Iqbal Z , Puyen ZM , CryPticConsortium theSeq , Treat Consortium . Lancet Microbe 2022 3 (4) e265-e273 Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (73%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (07%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (914%), moxifloxacin (916%) and ethambutol (933%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation. 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license |
Post-arrival evaluation of immigrant and refugee children in the USA with latent tuberculosis infection diagnosed overseas, 20072019
Wang Z , Posey DL , Brostrom RJ , Morris SB , Marano N , Phares CR . J Pediatr 2022 245 149-157 e1 OBJECTIVE: To assess outcomes from the U.S. post-arrival evaluation of newly arrived immigrant and refugee children aged 2-14 years who were diagnosed with latent tuberculosis infection (LTBI) during a required overseas medical examination. STUDY DESIGN: We compared overseas and U.S. interferon-γ release assay (IGRA)/tuberculin skin test (TST) results and LTBI diagnosis; assessed post-arrival LTBI treatment initiation and completion; and evaluated the impact of switching from TST to IGRA to detect Mycobacterium tuberculosis (Mtb) infection overseas. RESULTS: 73,014 children were diagnosed with LTBI overseas and arrived in the United States during 2007‒2019. In the United States, 45,939 (62.9%) completed, and 1,985 (2.7%) initiated but did not complete a post-arrival evaluation. Among these 47,924 children, 30,360 (63.4%) were retested for Mtb infection. For 17,996 children with a positive overseas TST, 73.8% were negative when retested by IGRA. For 1,051 children with a positive overseas IGRA, 58.0% were negative when retested by IGRA. Overall, among children who completed a post-arrival evaluation, 18,544 (40.4%) were evaluated as having no evidence of TB infection, and 25,919 (56.4%) had their overseas LTBI diagnosis confirmed. Among the latter, 17,229 (66.5%) initiated and 9,185 (35.4%) completed LTBI treatment. CONCLUSIONS: Requiring IGRA testing overseas could more effectively identify children who will benefit from LTBI treatment. However, IGRA reversions may occur, highlighting the need for individualized assessment for risk of infection, progression, and poor outcome when making diagnostic and treatment decisions. Strategies are needed to increase the proportions receiving a post-arrival evaluation and completing LTBI treatment. |
Mutation of Mycobacterium tuberculosis and Implications for Using Whole-Genome Sequencing for Investigating Recent Tuberculosis Transmission.
Nelson KN , Talarico S , Poonja S , McDaniel CJ , Cilnis M , Chang AH , Raz K , Noboa WS , Cowan L , Shaw T , Posey J , Silk BJ . Front Public Health 2021 9 790544 Tuberculosis (TB) control programs use whole-genome sequencing (WGS) of Mycobacterium tuberculosis (Mtb) for detecting and investigating TB case clusters. Existence of few genomic differences between Mtb isolates might indicate TB cases are the result of recent transmission. However, the variable and sometimes long duration of latent infection, combined with uncertainty in the Mtb mutation rate during latency, can complicate interpretation of WGS results. To estimate the association between infection duration and single nucleotide polymorphism (SNP) accumulation in the Mtb genome, we first analyzed pairwise SNP differences among TB cases from Los Angeles County, California, with strong epidemiologic links. We found that SNP distance alone was insufficient for concluding that cases are linked through recent transmission. Second, we describe a well-characterized cluster of TB cases in California to illustrate the role of genomic data in conclusions regarding recent transmission. Longer presumed latent periods were inconsistently associated with larger SNP differences. Our analyses suggest that WGS alone cannot be used to definitively determine that a case is attributable to recent transmission. Methods for integrating clinical, epidemiologic, and genomic data can guide conclusions regarding the likelihood of recent transmission, providing local public health practitioners with better tools for monitoring and investigating TB transmission. |
Disease surveillance among U.S.-bound immigrants and refugees - Electronic Disease Notification System, United States, 2014-2019
Phares CR , Liu Y , Wang Z , Posey DL , Lee D , Jentes ES , Weinberg M , Mitchell T , Stauffer W , Self JL , Marano N . MMWR Surveill Summ 2022 71 (2) 1-21 PROBLEM/CONDITION: Each year, approximately 500,000 immigrants and tens of thousands of refugees (range: 12,000-85,000 during 2001-2020) move to the United States. While still abroad, immigrants, refugees, and others who apply for admission to live permanently in the United States must undergo a medical examination. This examination identifies persons with class A or B conditions. Applicants with class A conditions are inadmissible. Infectious conditions that cause an applicant to be inadmissible include infectious tuberculosis (TB) disease (class A TB), infectious syphilis, gonorrhea, and infectious Hansen's disease. Applicants with class B conditions are admissible but might require treatment or follow-up. Class B TB includes persons who completed successful treatment overseas for TB disease (class B0), those with signs or symptoms suggestive of TB but whose overseas laboratory tests and clinical examinations ruled out current infectious TB disease (class B1), those with a diagnosis of latent TB infection (LTBI) (class B2), and the close contacts of persons known to have TB disease (class B3). Voluntary public health interventions might also be offered during the overseas examination. After arriving in the United States, a follow-up TB examination is recommended for persons with class B TB. PERIOD COVERED: This report summarizes health information that was reported to CDC's Electronic Disease Notification (EDN) system for refugees, immigrants, and eligible others who arrived in the United States during 2014-2019. Eligible others are persons who although not classified as refugees (e.g., certain parolees, special immigrant visa holders, and follow-to-join asylees) are eligible for the same services and benefits as refugees. DESCRIPTION OF SYSTEM: The EDN system has both surveillance and programmatic components. The surveillance component is a centralized database that collects 1) health-related data from the overseas medical examination for immigrants with class A or B conditions and for all refugees and eligible others and 2) TB-related data from the postarrival TB examination. The programmatic component is a reporting system that sends arrival notifications to state and local health agencies in the jurisdiction where newly arriving persons have reported intending to live and provides state and local health agencies and other authorized users with medical data from overseas examinations. RESULTS: During 2014-2019, approximately 3.5 million persons moved to the United States from abroad, including 3.2 million immigrants, 313,890 refugees, and 95,993 eligible others. Among these, the overseas examination identified 139,683 persons (3,903 per 100,000 persons examined) with class B TB, 54 with primary or secondary syphilis (30 per 100,000 persons tested), 761 with latent syphilis (415 per 100,000 persons tested), and, after laboratory testing for gonorrhea was added in 2016, a total of 131 with gonorrhea (374 per 100,000 persons tested). Refugees were offered additional, voluntary interventions, including vaccinations and presumptive treatment for parasites. By 2019, first- and second-dose coverage with measles-containing vaccine were 96% and 80%, respectively. In refugee populations for whom presumptive treatment is recommended, up to 96% of refugees, depending on the specific regimen, were offered and accepted treatment. For the 139,683 persons identified overseas with class B TB, EDN sent arrival notifications and overseas medical data to the appropriate state or local health agency to facilitate postarrival TB examinations. Among 101,119 persons identified overseas as having class B0 TB (6,586) or class B1 TB (94,533), a total of 67,432 (67%) had a complete postarrival examination reported to EDN. Among 35,814 children aged 2-14 years identified overseas with class B2 TB, 20,758 (58%) had a complete postarrival examination reported to EDN. (Adults are not routinely tested for immune reactivity to Mycobacterium tuberculosis during the overseas medical examination.) Among those with a complete postarrival examination reported to EDN, the number with a diagnosis of culture-positive TB disease within the first year of arrival was 464 (688 cases per 100,000 persons examined) for those with class B0 or B1 TB and was 11 (53 cases per 100,000 persons examined) for children with class B2 TB. INTERPRETATION: During 2014-2019, the overseas medical examination system prevented importation of 6,586 cases of infectious TB, 815 cases of syphilis, and 131 cases of gonorrhea. When the examination is used to offer public health interventions, most refugees (up to 96%) accept the intervention. Postarrival follow-up examinations, which were completed for 88,190 persons and identified 475 cases of culture-positive TB, represent an important opportunity to further limit spread of TB disease in the United States by identifying and providing, if needed, preventive care for those with LTBI or treatment for those with disease. PUBLIC HEALTH ACTION: Federal, state, and local health departments and agencies should continue to use EDN data to monitor, evaluate, and improve health-related programs and policies aimed at U.S.-bound or recently arrived immigrants, refugees, and eligible others. Additional public health interventions that could be offered during the overseas medical examination should be considered (e.g., treatment for LTBI). Finally, for persons with class B TB, measures should be taken to identify and remove barriers to completing postarrival examinations to reduce risk for TB disease and community transmission, along with measures to encourage reporting of completed examinations for better data-driven decision-making. |
Multidrug-resistant tuberculosis in U.S.-bound immigrants and refugees
Liu Y , Posey DL , Yang Q , Weinberg MS , Maloney SA , Lambert LA , Ortega LS , Marano N , Cetron MS , Phares CR . Ann Am Thorac Soc 2021 19 (6) 943-951 RATIONALE: Approximately two-thirds of new cases of tuberculosis (TB) in the United States are among non-U.S.-born persons. Culture-based overseas TB screening in U.S.-bound immigrants and refugees has substantially reduced the importation of TB into the United States, but it is unclear to what extent this program prevents the importation of multidrug-resistant TB (MDR-TB). OBJECTIVES: To study the epidemiology of MDR-TB in U.S.-bound immigrants and refugees, and to evaluate effect of culture-based overseas TB screening in U.S.-bound immigrants and refugees on reducing the importation of MDR-TB into the United States. METHODS: We analyzed data of immigrants and refugees who completed overseas treatment for culture-positive TB during 2015-2019. We also compared mean annual number of MDR-TB cases in non-U.S.-born persons within 1 year of arrival in the United States between 1996-2006 (when overseas screening followed a smear-based algorithm) and 2014-2019 (after full implementation of a culture-based algorithm). RESULTS: Of 3,300 culture-positive TB cases prevented by culture-based overseas TB screening in immigrants and refugees during 2015-2019, 122 (3.7%, 95% confidence interval (CI) 3.1-4.1) had MDR-TB, 20 (0.6%, 95% CI 0.3-0.9) had rifampicin-resistant TB, 382 (11.6%, 95% CI 10.5-12.7) had isoniazid-resistant TB, and 2,776 (84.1%, 95% CI 82.9-85.4) had rifampicin- and isoniazid-susceptible TB. None were diagnosed with extensively drug-resistant TB (XDR-TB). Culture-based overseas TB screening in U.S.-bound immigrants and refugees prevented 24.4 MDR-TB cases per year from arriving in the United States, 18.2 cases more than smear-based overseas TB screening. Mean annual number of MDR-TB cases among non-U.S.-born persons within 1 year of arrival in the United States decreased from 34.6 cases in 1996-2006 to 19.5 cases in 2014-2019 (difference of 15.1, p<0.001). CONCLUSIONS: Culture-based overseas TB screening in U.S.-bound immigrants and refugees substantially reduced the importation of MDR-TB into the United States. |
Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis from Mycobacterium tuberculosis to overcome kanamycin resistance
Punetha A , Green KD , Garzan A , Thamban Chandrika N , Willby MJ , Pang AH , Hou C , Holbrook SYL , Krieger K , Posey JE , Parish T , Tsodikov OV , Garneau-Tsodikova S . RSC Med Chem 2021 12 (11) 1894-1909 Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a deadly bacterial disease. Drug-resistant strains of Mtb make eradication of TB a daunting task. Overexpression of the enhanced intracellular survival (Eis) protein by Mtb confers resistance to the second-line antibiotic kanamycin (KAN). Eis is an acetyltransferase that acetylates KAN, inactivating its antimicrobial function. Development of Eis inhibitors as KAN adjuvant therapeutics is an attractive path to forestall and overcome KAN resistance. We discovered that an antipsychotic drug, haloperidol (HPD, 1), was a potent Eis inhibitor with IC(50) = 0.39 ± 0.08 μM. We determined the crystal structure of the Eis-haloperidol (1) complex, which guided synthesis of 34 analogues. The structure-activity relationship study showed that in addition to haloperidol (1), eight analogues, some of which were smaller than 1, potently inhibited Eis (IC(50) ≤ 1 μM). Crystal structures of Eis in complexes with three potent analogues and droperidol (DPD), an antiemetic and antipsychotic, were determined. Three compounds partially restored KAN sensitivity of a KAN-resistant Mtb strain K204 overexpressing Eis. The Eis inhibitors generally did not exhibit cytotoxicity against mammalian cells. All tested compounds were modestly metabolically stable in human liver microsomes, exhibiting 30-60% metabolism over the course of the assay. While direct repurposing of haloperidol as an anti-TB agent is unlikely due to its neurotoxicity, this study reveals potential approaches to modifying this chemical scaffold to minimize toxicity and improve metabolic stability, while preserving potent Eis inhibition. |
Overseas gonorrhea screening among newly arrived refugees during 2018
Butler KR , Lee D , Hollberg M , Posey DL . J Immigr Minor Health 2021 23 (6) 1354-1358 We assessed the overseas gonorrhea results reported in the CDC's Electronic Disease Notification (EDN) system among refugees ≥ 15 years old who arrived in the United States during 2018. Of 18,720 refugees, 57 (0.4%) tested positive. Among those with a positive test, 31 (54.5%) were born in the Democratic Republic of the Congo, followed by 12 (21.1%) from Afghanistan. Thirty-three (57.9%) cases were female. Fifty-one cases (89.4%) were between 15 and 44 years of age; 25 (43.9%) were ages 15-24 and 26 (45.6%) were ages 25-44. Among the cases, 56 (98.2%) were treated overseas with the recommended therapy of ceftriaxone and azithromycin. Our findings suggest that the risk of gonorrhea in refugees is similar to that in the U.S. Given recent worldwide increases in gonorrhea, additional monitoring among refugees are necessary to assess the appropriateness of the gonorrhea screening requirement in the overseas medical examination. |
Logically Inferred Tuberculosis Transmission (LITT): A Data Integration Algorithm to Rank Potential Source Cases.
Winglee K , McDaniel CJ , Linde L , Kammerer S , Cilnis M , Raz KM , Noboa W , Knorr J , Cowan L , Reynolds S , Posey J , Sullivan Meissner J , Poonja S , Shaw T , Talarico S , Silk BJ . Front Public Health 2021 9 667337 Understanding tuberculosis (TB) transmission chains can help public health staff target their resources to prevent further transmission, but currently there are few tools to automate this process. We have developed the Logically Inferred Tuberculosis Transmission (LITT) algorithm to systematize the integration and analysis of whole-genome sequencing, clinical, and epidemiological data. Based on the work typically performed by hand during a cluster investigation, LITT identifies and ranks potential source cases for each case in a TB cluster. We evaluated LITT using a diverse dataset of 534 cases in 56 clusters (size range: 2-69 cases), which were investigated locally in three different U.S. jurisdictions. Investigators and LITT agreed on the most likely source case for 145 (80%) of 181 cases. By reviewing discrepancies, we found that many of the remaining differences resulted from errors in the dataset used for the LITT algorithm. In addition, we developed a graphical user interface, user's manual, and training resources to improve LITT accessibility for frontline staff. While LITT cannot replace thorough field investigation, the algorithm can help investigators systematically analyze and interpret complex data over the course of a TB cluster investigation. Code available at: https://github.com/CDCgov/TB_molecular_epidemiology/tree/1.0; https://zenodo.org/badge/latestdoi/166261171. |
Optimising pyrazinamide for the treatment of tuberculosis
Zhang N , Savic RM , Boeree MJ , Peloquin C , Weiner M , Heinrich N , Bliven-Sizemore E , Phillips PP , Hoelscher M , Whitworth W , Morlock G , Posey J , Stout JE , Mac Kenzie W , Aarnoutse R , Dooley KE . Eur Respir J 2021 58 (1) Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for tuberculosis. The dose of pyrazinamide that optimises efficacy while remaining safe is uncertain, as is its potential role in shortening treatment duration further.Pharmacokinetic data, sputum culture, and safety laboratory results were compiled from TBTC Studies 27 and 28 and PanACEA MAMS-TB, multi-center Phase 2 trials in which participants received rifampicin (range 10-35 mg·kg(-1)), pyrazinamide (range 20-30 mg·kg(-1)), plus two companion drugs. Pyrazinamide pharmacokinetic-pharmacodynamic (PK/PD) and PK-toxicity analyses were performed.In TBTC studies (n=77), higher pyrazinamide maximum concentration (Cmax) was associated with shorter time to culture conversion (TTCC) and higher probability of two-month culture conversion (p-value<0.001). Parametric survival analyses showed that relationships varied geographically, with steeper PK-PD relationships seen among non-African than African participants. In PanACEA MAMS-TB (n=363), TTCC decreased as pyrazinamide Cmax increased and varied by rifampicin Cmax (p-value<0.01). Modeling and simulation suggested that very high doses of pyrazinamide (>4500 mg) or increasing both pyrazinamide and rifampicin would be required to reach targets associated with treatment shortening. Combining all trials, liver toxicity was rare (3.9% with Grade 3 or higher liver function tests, LFT), and no relationship was seen between pyrazinamide Cmax and LFT levels.Pyrazinamide's microbiologic efficacy increases with increasing drug concentrations. Optimising pyrazinamide alone, though, is unlikely to be sufficient to allow tuberculosis treatment shortening; rather, rifampicin dose would need to be increased in parallel. |
Cost effectiveness analysis of implementing tuberculosis screening among applicants for non-immigrant U.S. work visas
Sayed BA , Posey DL , Maskery B , Wingate LT , Cetron MS . Pneumonia (Nathan) 2020 12 (1) 15 BACKGROUND: While persons who receive immigrant and refugee visas are screened for active tuberculosis before admission into the United States, nonimmigrant visa applicants (NIVs) are not routinely screened and may enter the United States with infectious tuberculosis. OBJECTIVES: We evaluated the costs and benefits of expanding pre-departure tuberculosis screening requirements to a subset of NIVs who arrive from a moderate (Mexico) or high (India) incidence tuberculosis country with temporary work visas. METHODS: We developed a decision tree model to evaluate the program costs and estimate the numbers of active tuberculosis cases that may be diagnosed in the United States in two scenarios: 1) "Screening": screening and treatment for tuberculosis among NIVs in their home country with recommended U.S. follow-up for NIVs at elevated risk of active tuberculosis; and, 2) "No Screening" in their home country so that cases would be diagnosed passively and treatment occurs after entry into the United States. Costs were assessed from multiple perspectives, including multinational and U.S.-only perspectives. RESULTS: Under "Screening" versus "No Screening", an estimated 179 active tuberculosis cases and 119 hospitalizations would be averted in the United States annually via predeparture treatment. From the U.S.-only perspective, this program would result in annual net cost savings of about $3.75 million. However, rom the multinational perspective, the screening program would cost $151,388 per U.S. case averted for Indian NIVs and $221,088 per U.S. case averted for Mexican NIVs. CONCLUSION: From the U.S.-only perspective, the screening program would result in substantial cost savings in the form of reduced treatment and hospitalization costs. NIVs would incur increased pre-departure screening and treatment costs. |
Tuberculosis among newly arrived immigrants and refugees in the United States
Liu Y , Phares CR , Posey DL , Maloney SA , Cain KP , Weinberg MS , Schmit KM , Marano N , Cetron MS . Ann Am Thorac Soc 2020 17 (11) 1401-1412 Rationale: U.S. health departments routinely conduct post-arrival evaluation of immigrants and refugees at risk for tuberculosis (TB), but this important intervention has not been thoroughly studied.Objectives: To assess outcomes of the post-arrival evaluation intervention.Methods: We categorized at-risk immigrants and refugees as having had recent completion of treatment for pulmonary TB disease overseas (including in Mexico and Canada); as having suspected TB disease (chest radiograph/clinical symptoms suggestive of TB) but negative culture results overseas; or as having latent TB infection (LTBI) diagnosed overseas. Among 2.1 million U.S.-bound immigrants and refugees screened for TB overseas during 2013-2016, 90,737 were identified as at risk for TB. We analyzed a national data set of these at-risk immigrants and refugees and calculated rates of TB disease for those who completed post-arrival evaluation.Results: Among 4,225 persons with recent completion of treatment for pulmonary TB disease overseas, 3,005 (71.1%) completed post-arrival evaluation within 1 year of arrival; of these, TB disease was diagnosed in 22 (732 cases/100,000 persons), including 4 sputum culture-positive cases (133 cases/100,000 persons), 13 sputum culture-negative cases (433 cases/100,000 persons), and 5 cases with no reported sputum-culture results (166 cases/100,000 persons). Among 55,938 with suspected TB disease but negative culture results overseas, 37,089 (66.3%) completed post-arrival evaluation; of these, TB disease was diagnosed in 597 (1,610 cases/100,000 persons), including 262 sputum culture-positive cases (706 cases/100,000 persons), 281 sputum culture-negative cases (758 cases/100,000 persons), and 54 cases with no reported sputum-culture results (146 cases/100,000 persons). Among 30,574 with LTBI diagnosed overseas, 18,466 (60.4%) completed post-arrival evaluation; of these, TB disease was diagnosed in 48 (260 cases/100,000 persons), including 11 sputum culture-positive cases (60 cases/100,000 persons), 22 sputum culture-negative cases (119 cases/100,000 persons), and 15 cases with no reported sputum-culture results (81 cases/100,000 persons). Of 21,714 persons for whom treatment for LTBI was recommended at post-arrival evaluation, 14,977 (69.0%) initiated treatment and 8,695 (40.0%) completed treatment.Conclusions: Post-arrival evaluation of at-risk immigrants and refugees can be highly effective. To optimize the yield and impact of this intervention, strategies are needed to improve completion rates of post-arrival evaluation and treatment for LTBI. |
Molecular evaluation of fluoroquinolone resistance in serial Mycobacterium tuberculosis isolates from individuals diagnosed with multidrug-resistant tuberculosis.
Willby M , Chopra P , Lemmer D , Klein K , Dalton TL , Engelthaler DM , Cegielski P , Posey JE . Antimicrob Agents Chemother 2020 65 (1) Fluoroquinolones (FQ) are crucial components of multidrug-resistant tuberculosis (MDR TB) treatment. Varying levels of resistance are associated with specific mutations within the Quinolone Resistance Determining Region (QRDR) of gyrA We sequenced the QRDR from serial isolates of MDR TB patients in the Preserving Effective TB Treatment Study (PETTS) with baseline (FQ(R)) or acquired FQ resistance (FQ(ACQR)) using the IonTorrent™ Personal Genome Machine to a depth of 10,000x and reported single nucleotide polymorphisms in ≥1% of reads. FQ(R) isolates harbored 15 distinct alleles with 1.3 (max=6) on average per isolate. Eighteen alleles were identified in FQ(ACQR) isolates with an average of 1.6 (max=9) per isolate. Isolates from 78% of FQ(ACQR) individuals had mutant alleles identified within 6 months of treatment initiation. Asp94Gly followed by Ala90Val were the predominant alleles in initial FQ-resistant isolates. Seventy-seven percent (36/47) of FQ(ACQR) group patients had isolates with FQ resistance alleles prior to changes to the FQ component of their treatment. Unlike individuals treated initially with other FQs, none of the 21 individuals treated initially with levofloxacin developed genotypic or phenotypic FQ resistance, although, country of residence is likely a contributing factor since 69% of these individuals were from a single country. Initial detection of phenotypic and genotypic resistance occurred simultaneously for most; however, phenotypic resistance occurred earlier in isolates harboring mixtures of very low-abundance (<1% of reads) alleles while genotypic resistance often occurred earlier for low-level resistance-associated alleles. Understanding factors influencing acquisition and evolution of FQ resistance could reveal strategies for improved treatment success. |
Structure-guided optimization of inhibitors of acetyltransferase Eis from Mycobacterium tuberculosis
Punetha A , Ngo HX , Holbrook SYL , Green KD , Willby MJ , Bonnett SA , Krieger K , Dennis EK , Posey JE , Parish T , Tsodikov OV , Garneau-Tsodikova S . ACS Chem Biol 2020 15 (6) 1581-1594 The enhanced intracellular survival (Eis) protein of Mycobacterium tuberculosis (Mtb) is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of Mtb, we designed and optimized structurally unique thieno[2,3-d]pyrimidine Eis inhibitors toward effective kanamycin adjuvant combination therapy. We obtained 12 crystal structures of enzyme-inhibitor complexes, which guided our rational structure-based design of 72 thieno[2,3-d]pyrimidine analogues divided into three families. We evaluated the potency of these inhibitors in vitro as well as their ability to restore the activity of kanamycin in a resistant strain of Mtb, in which Eis was upregulated. Furthermore, we evaluated the metabolic stability of 11 compounds in vitro. This study showcases how structural information can guide Eis inhibitor design. |
Isoniazid- and Rifampin-Resistance Mutations Associated with Resistance to Second-line Drugs and with Sputum Culture Conversion.
Click ES , Kurbatova E , Alexander H , Dalton TL , Chen MP , Posey JE , Ershova JJ , Cegielski P . J Infect Dis 2020 221 (12) 2072-2082 BACKGROUND: Mutations in the genes inhA, katG and rpoB confer resistance to anti-tuberculosis (TB) drugs isoniazid and rifampin. We questioned whether specific mutations in these genes were associated with different clinical and microbiological characteristics. METHODS: In a multi-country prospective cohort study of MDR-TB, we identified inhA, katG and rpoB mutations in sputum isolates using the Hain MTBDRplus line probe assay. For specific mutations, we performed bivariate analysis to determine relative risk of baseline or acquired resistance to other TB drugs. We compared time-to-sputum-culture-conversion (TSCC) using Kaplan-Meier curves and stratified Cox regression. RESULTS: In total, 447 participants enrolled January 2005-December 2008 from seven countries were included. Relative to rpoB S531L, isolates with rpoB D516V had less cross-resistance to rifabutin, increased baseline resistance to other drugs, and increased acquired fluoroquinolone resistance.Relative to mutation of katG only, mutation of inhA promoter and katG was associated with increased acquired fluoroquinolone resistance and slower TSCC (125.5 vs. 89.0 days). CONCLUSIONS: Specific mutations in inhA and katG are associated with differences in resistance to other drugs and TSCC. Molecular testing may make it possible to tailor treatment and assess additional drug resistance risk according to specific mutation profile. |
A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic.
Klopper M , Heupink TH , Hill-Cawthorne G , Streicher EM , Dippenaar A , de Vos M , Abdallah AM , Limberis J , Merker M , Burns S , Niemann S , Dheda K , Posey J , Pain A , Warren RM . BMC Med 2020 18 (1) 24 BACKGROUND: Atypical Beijing genotype Mycobacterium tuberculosis strains are widespread in South Africa and have acquired resistance to up to 13 drugs on multiple occasions. It is puzzling that these strains have retained fitness and transmissibility despite the potential fitness cost associated with drug resistance mutations. METHODS: We conducted Illumina sequencing of 211 Beijing genotype M. tuberculosis isolates to facilitate the detection of genomic features that may promote acquisition of drug resistance and restore fitness in highly resistant atypical Beijing forms. Phylogenetic and comparative genomic analysis was done to determine changes that are unique to the resistant strains that also transmit well. Minimum inhibitory concentration (MIC) determination for streptomycin and bedaquiline was done for a limited number of isolates to demonstrate a difference in MIC between isolates with and without certain variants. RESULTS: Phylogenetic analysis confirmed that two clades of atypical Beijing strains have independently developed resistance to virtually all the potent drugs included in standard (pre-bedaquiline) drug-resistant TB treatment regimens. We show that undetected drug resistance in a progenitor strain was likely instrumental in this resistance acquisition. In this cohort, ethionamide (ethA A381P) resistance would be missed in first-line drug-susceptible isolates, and streptomycin (gidB L79S) resistance may be missed due to an MIC close to the critical concentration. Subsequent inadequate treatment historically led to amplification of resistance and facilitated spread of the strains. Bedaquiline resistance was found in a small number of isolates, despite lack of exposure to the drug. The highly resistant clades also carry inhA promoter mutations, which arose after ethA and katG mutations. In these isolates, inhA promoter mutations do not alter drug resistance, suggesting a possible alternative role. CONCLUSION: The presence of the ethA mutation in otherwise susceptible isolates from ethionamide-naive patients demonstrates that known exposure is not an adequate indicator of drug susceptibility. Similarly, it is demonstrated that bedaquiline resistance can occur without exposure to the drug. Inappropriate treatment regimens, due to missed resistance, leads to amplification of resistance, and transmission. We put these results into the context of current WHO treatment regimens, underscoring the risks of treatment without knowledge of the full drug resistance profile. |
Pathogen Genomics in Public Health.
Armstrong GL , MacCannell DR , Taylor J , Carleton HA , Neuhaus EB , Bradbury RS , Posey JE , Gwinn M . N Engl J Med 2019 381 (26) 2569-2580 Rapid advances in DNA sequencing technology ("next-generation sequencing") have inspired optimism about the potential of human genomics for "precision medicine." Meanwhile, pathogen genomics is already delivering "precision public health" through more effective investigations of outbreaks of foodborne illnesses, better-targeted tuberculosis control, and more timely and granular influenza surveillance to inform the selection of vaccine strains. In this article, we describe how public health agencies have been adopting pathogen genomics to improve their effectiveness in almost all domains of infectious disease. This momentum is likely to continue, given the ongoing development in sequencing and sequencing-related technologies. |
Tuberculosis vaccine development: Progress in clinical evaluation
Sable SB , Posey JE , Scriba TJ . Clin Microbiol Rev 2019 33 (1) Tuberculosis (TB) is the leading killer among all infectious diseases worldwide despite extensive use of the Mycobacterium bovis bacille Calmette-Guerin (BCG) vaccine. A safer and more effective vaccine than BCG is urgently required. More than a dozen TB vaccine candidates are under active evaluation in clinical trials aimed to prevent infection, disease, and recurrence. After decades of extensive research, renewed promise of an effective vaccine against this ancient airborne disease has recently emerged. In two innovative phase 2b vaccine clinical trials, one for the prevention of Mycobacterium tuberculosis infection in healthy adolescents and another for the prevention of TB disease in M. tuberculosis-infected adults, efficacy signals were observed. These breakthroughs, based on the greatly expanded knowledge of the M. tuberculosis infection spectrum, immunology of TB, and vaccine platforms, have reinvigorated the TB vaccine field. Here, we review our current understanding of natural immunity to TB, limitations in BCG immunity that are guiding vaccinologists to design novel TB vaccine candidates and concepts, and the desired attributes of a modern TB vaccine. We provide an overview of the progress of TB vaccine candidates in clinical evaluation, perspectives on the challenges faced by current vaccine concepts, and potential avenues to build on recent successes and accelerate the TB vaccine research-and-development trajectory. |
Tuberculosis Regional Training and Medical Consultation Centers in the United States: Characteristics, outcomes, and quality of medical consultations, June 1, 2010 - May 31, 2014
Mase SR , Samron R , Ashkin D , Castro KG , Ryan S , Seaworth B , Chen L , Lardizabal A , Tuckey D , Khan A , Posey DL , Chappelle C , Temesgen Z . J Clin Tuberc Other Mycobact Dis 2019 17 100114 Background: Tuberculosis (TB) Regional Training and Medical Consultation Centers (RTMCCs) were established in 2005 for TB medical consultation, training and education in the United States. A medical consultation database (MCD) captured all consultations provided by RTMCCs; we report on those provided from June 1, 2010 to May 31, 2014. Method(s): All MCD consultations during 2010-2014 were categorized into: provider type, setting, consultation topic, and patient age. We analyzed data frequencies and performed subgroup analyses by RTMCC, by TB incidence for the geographical area, and by year of consultation. End-user satisfaction was assessed by a 2016 telephone evaluation of RTMCC services. Result(s): A total of 11,074 consultations were delivered, with 10,754 (97.1%) in the U.S. and its current or former territories. Of these, 6018 (56%) were for high, 2443 (22.7%) for medium, and 2293 (21.3%) for low TB incidence settings. Most were for adults (81.3%) and answered within 24 h (96.2%). Nearly 2/3 consultations originated from health departments; providers included mostly physicians (44.3%) or nurses (37.6%). Common consult categories included TB disease (47.7%), case management (29.8%), latent TB infection (19.3%), diagnosis (16.1%), pharmacology (14.7%) and adverse side effects (14.3%). Among adverse side effects, hepatotoxicity was most common (39.6%). Volume and nature of consult requests remained relatively stable over the four-year period. Feedback from a 2016 CDC evaluation indicated overall satisfaction with RTMCC medical consultation services. Conclusion(s): RTMCCS were an important source of TB medical consultation over the time-frame of this assessment and provided quality expert consultation within 24 h. RMTCCs represent a reservoir of TB subject-matter expertise in the United States. |
Bedaquiline Microheteroresistance after Cessation of Tuberculosis Treatment.
de Vos M , Ley SD , Wiggins KB , Derendinger B , Dippenaar A , Grobbelaar M , Reuter A , Dolby T , Burns S , Schito M , Engelthaler DM , Metcalfe J , Theron G , van Rie A , Posey J , Warren R , Cox H . N Engl J Med 2019 380 (22) 2178-2180 Bedaquiline improves survival among persons with multidrug-resistant tuberculosis (MDR-TB).1 We report the case of a 65-year-old South African man who was negative for human immunodeficiency virus and in whom MDR-TB was diagnosed in 2013 (resistant to rifampin and isoniazid; phenotypically susceptible to a fluoroquinolone and amikacin). A baseline radiograph showed changes consistent with bilateral tuberculosis with left apex cavitation. He started standardized treatment that included moxifloxacin, pyrazinamide, kanamycin, ethionamide, isoniazid, and terizidone. After initial sputum culture conversion (at month 3) and clinical improvement, the patient again became culture-positive, and bilateral cavitation developed. After detection of phenotypic resistance to fluoroquinolones (at month 6), his treatment was revised (at month 8) to include high-dose isoniazid, ethambutol, pyrazinamide, terizidone, linezolid, paraaminosalicylic acid, and kanamycin (Figure 1 and the Supplementary Appendix, available with the full text of this letter at NEJM.org). Bedaquiline was added 22 days later and was administered for 6 months.2 The patient remained culture-positive (treatment failure), and treatment was stopped 15 months after revision of the regimen. The patient died 7 months later. |
Immigrant and refugee health: A Centers for Disease Control and Prevention perspective on protecting the health and health security of individuals and communities during planned migrations
Mitchell T , Weinberg M , Posey DL , Cetron M . Pediatr Clin North Am 2019 66 (3) 549-560 Migration and forced displacement are at record levels in today's geopolitical environment; ensuring the health of migrating populations and the health security of asylum and receiving countries is critically important. Overseas screening, treatment, and vaccination during planned migration to the United States represents one successful model. These strategies have improved tuberculosis detection and treatment, reducing rates in the United States; decreased transmission and importation of vaccine-preventable diseases; prevented morbidity and mortality from parasitic diseases among refugees; and saved health costs. We describe the work of CDC's Division of Global Migration and Quarantine and partners in developing and implementing these strategies. |
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