Association of indicators of extensive disease and rifampin-resistant tuberculosis treatment outcomes: an individual participant data meta-analysis.

BACKGROUND: Indicators of extensive disease-acid fast bacilli (AFB) smear positivity and lung cavitation-have been inconsistently associated with clinical rifampin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB) outcomes. We evaluated the association of these indicators with end-of-treatment outcomes. METHODS: We did an individual participant data meta-analysis of people treated for RR/MDR-TB with longer regimens with documented AFB smear and chest radiography findings. We compared people AFB smear-negative without cavities to people: (1) smear-negative with lung cavities; (2) smear-positive without lung cavities and (3) AFB smear-positive with lung cavities. Using multivariable logistic regression accounting for demographic, treatment and clinical factors, we calculated adjusted ORs (aOR) for any unfavourable outcome (death, lost to follow-up, failure/recurrence), and mortality and treatment failure/recurrence alone. RESULTS: We included 5596 participants; included participants significantly differed from excluded participants. Overall, 774 (13.8%) were AFB smear-negative without cavities, 647 (11.6%) only had cavities, 1424 (25.4%) were AFB smear-positive alone and 2751 (49.2%) were AFB smear-positive with cavities. The median age was 37 years (IQR: 28-47), 3580 (64%) were male and 686 (12.5%) had HIV. Compared with participants AFB smear-negative without cavities, aOR (95% CI) for any unfavourable outcome was 1.0 (0.8 to 1.4) for participants smear-negative with lung cavities, 1.2 (0.9 to 1.5) if smear-positive without cavities and 1.6 (1.3 to 2.0) if AFB smear-positive with lung cavities. Odds were only significantly increased for mortality (1.5, 95% CI 1.1 to 2.1) and failure/recurrence (2.2, 95% CI 1.5 to 3.3) among participants AFB smear-positive with lung cavities. CONCLUSION: Only the combination of AFB smear-positivity and lung cavitation was associated with unfavourable outcomes, suggesting they may benefit from stronger regimens.

Design, synthesis and evaluation of the antibacterial activity of new Linezolid dipeptide-type analogues.

Worldwide studies towards development of new drugs with a lower rate in emergence of bacterial resistance have been conducted. The molecular docking analysis gives a possibility to predict the activity of new compounds before to perform their synthesis. In this work, the molecular docking analysis of 64 Linezolid dipeptide-type analogues was performed to predict their activity. The most negative scores correspond to six Fmoc-protected analogues (9as, 9bs, 9bu, 10as, 10ax and 10ay) where Fmoc group interacts in PTC for Linezolid. Twenty-six different Fmoc-protected Linezolid dipeptide-type analogues 9(as-bz) and 10(as-bz) were synthesized and tested in antimicrobial experiments. Compounds 9as, 9ay, 9ax, 10as, 10ay and 9bu show significant activity against group A Streptococcus clinical isolated. Analogue 10ay also display high activity against ATCC 25923 Staphylococcus aureus strain and MRSA-3, MRSA-4 and MRSA-5 clinical isolates, with MIC values lower than Linezolid. The highest activity against multidrug-resistant clinical isolates of Mycobacterium tuberculosis was exhibited by 9bu. Finally, a cytotoxicity assay with ARPE-19 human cells revealed a non-cytotoxic effect of 9bu and 10ay at 50 and 25 µM, respectively.

Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report.

The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline, delamanid) and repurposed (i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1-2) and 57 (11.3%) as serious (grade 3-5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.

Coccidioidomycosis in Latin America.

Coccidioidomycosis is a highly prevalent systemic mycosis in Latin America and has been reported (human and zoonotic cases) in México, Guatemala, Honduras, Colombia, Venezuela, Brazil, Paraguay, Bolivia, and Argentina. The incidence of coccidioidomycosis in Latin America is unknown due to lack of clinical awareness and limited access to laboratory diagnosis. Coccidioidomycosis is as prevalent in Mexico as in the endemic regions of the United States. The number of cases reported in Brazil and Argentina has progressively increased during the last decade, including areas that were not considered as endemic. Genetic studies have shown that the prevalent species in Latin America is Coccidioides posadasii. Coccidioides immitis has been reported sporadically in indigenous cases from Mexico and Colombia. Coccidioidomycosis and tuberculosis share some risk factors such as immunosuppression and residing in areas endemic for these conditions, so their coexistence in the same patient is not uncommon in Latin America. In most regions, clinical diagnosis of coccidioidomycosis is based on direct sputum examination and histopathology results from biopsies or autopsies. This would explain why primary coccidioidomycosis is rarely diagnosed, and most cases published are about chronic pulmonary or disseminated disease.

Clinical challenges in the era of multiple and extensively drug-resistant tuberculosis.

In 2014, there were 480 000 new cases of multidrug-resistant tuberculosis (MDR-TB) around the world, but only 25% of them were diagnosed and reported. Drug resistance in TB is necessarily a laboratory diagnosis. An urgent priority in everyday practice is to diagnose tuberculosis and rule out drug resistance as quickly and as accurately as possible. However, worldwide, only 12% of new bacteriologically confirmed TB cases and 58% of previously treated TB cases were tested for drug resistance in 2014. New tools for diagnosis of TB and drug-resistant TB have been introduced for clinical practice during the past decade. Those new tools can detect and identify drug resistance to antituberculosis drugs in less than 24 hours, and they should be urgently integrated into clinical practice, especially in high-burden regions. Ongoing transmission of TB generates new infections, and this infected population is the inexhaustible source of new TB cases. If we are really determined to stop the global TB epidemic, we need to treat active cases and also halt the transmission of the infection. The only strategy for preventing the development of active disease in individuals with subclinical infection is to give treatment for this latent infection. Global control of TB requires a huge investment of funds to address current detection and treatment gaps. We must reconsider our current strategy and combine social components with biomedical interventions. This will require the development of alliances between government and civil society, as well as leadership and true political commitment at the highest level of government.

En el 2014 se presentaron 480 000 nuevos casos de tuberculosis multirresistente, pero solo se diagnosticó y notificó 25% de ellos. La farmacorresistencia en la tuberculosis se diagnostica necesariamente por medio de pruebas de laboratorio. En la práctica clínica diaria resulta urgente y prioritario poder diagnosticar la tuberculosis y descartar la farmacorresistencia con la mayor rapidez y exactitud posibles. Sin embargo, en todo el mundo, apenas 12% de los nuevos casos de tuberculosis bacteriológicamente confirmados y 58% de los casos ya tratados se sometieron a prueba de farmacorresistencia en el 2014.En los diez últimos años se han dado a conocer nuevas herramientas para el diagnóstico de la tuberculosis y la tuberculosis farmacorresistente en la práctica clínica. Esas herramientas nuevas permiten detectar e identificar la resistencia a medicamentos antituberculosos en menos de 24 horas, por lo que deberían integrarse urgentemente a la práctica clínica, especialmente en las regiones con una carga de enfermedad alta.La persistencia de la transmisión de la tuberculosis genera nuevas infecciones, y la población infectada es una fuente inagotable de nuevos casos de esta enfermedad. Si estamos realmente decididos a poner fin a la epidemia mundial de la tuberculosis, tenemos que tratar los casos activos y también detener la transmisión de la infección. La única estrategia para prevenir la aparición de la enfermedad activa en personas con infección subclínica es administrar tratamiento contra esta infección latente.El control mundial de la tuberculosis requiere una enorme inversión de fondos para cerrar las brechas existentes en la detección y el tratamiento. Debemos reconsiderar nuestra estrategia actual y combinar los componentes sociales con las intervenciones biomédicas. Esto obliga a conformar alianzas entre el gobierno y la sociedad civil, y requiere del liderazgo y de un verdadero compromiso político de las más altas instancias gubernamentales.

Em 2014, houve 480 mil novos casos de tuberculose (TB) resistente a múltiplos medicamentos, porém apenas 25% foram diagnosticados e notificados. A resistência aos medicamentos na TB requer necessariamente que seja feito um diagnóstico laboratorial. É prioridade na prática clínica diária diagnosticar a TB e descartar a resistência aos medicamentos o mais rápido e com maior precisão possível. Porém, em 2014, o teste da resistência aos medicamentos foi realizado mundialmente em apenas 12% dos novos casos de TB com confirmação bacteriológica e em 58% dos casos de TB com tratamento anterior.Novas ferramentas para o diagnóstico de TB e TB resistente a múltiplos a medicamentos foram introduzidas na prática clínica na última década. São ferramentas com capacidade de detectar e identificar a resistênciaaos medicamentos antituberculose em menos de 24 horas e, portanto, é imprescindível que sejam integradas à prática clínica, sobretudo em regiões de elevada carga da doença.A transmissão contínua da TB causa novas infecções, sendo a população infectada uma fonte inesgotável de novos casos da doença. Se estivermos realmente determinados a conter a epidemia global de TB, é preciso tratar os casos ativos e interromper a transmissão da infecção. A única estratégia para prevenir o surgimento de doença ativa em indivíduos com infecção subclínica é o tratamento da infecção latente.O controle global da TB requer um enorme investimento financeiro para sanar as falhas atuais de detecção e tratamento da doença. A estratégia atual deve ser reexaminada e combinar componentes sociais e intervenções biomédicas. Faz-se necessário forjar alianças entre o governo e a sociedade civil bem como assumir a liderança e o firme compromisso no mais alto nível político.

Performance of the G4 Xpert® MTB/RIF assay for the detection of Mycobacterium tuberculosis and rifampin resistance: a retrospective case-control study of analytical and clinical samples from high- and low-tuberculosis prevalence settings.

BACKGROUND: The Xpert® MTB/RIF (Xpert) assay is a rapid PCR-based assay for the detection of Mycobacterium tuberculosis complex DNA (MTBc) and mutations associated with rifampin resistance (RIF). An updated version introduced in 2011, the G4 Xpert, included modifications to probe B and updated analytic software. METHODS: An analytical study was performed to assess Xpert detection of mutations associated with rifampin resistance in rifampin-susceptible and -resistant isolates. A clinical study was performed in which specimens from US and non-US persons suspected of tuberculosis (TB) were tested to determine Xpert performance characteristics. All specimens underwent smear microscopy, mycobacterial culture, conventional drug-susceptibility testing and Xpert testing; DNA from isolates with discordant rifampin resistance results was sequenced. RESULTS: Among 191 laboratory-prepared isolates in the analytical study, Xpert sensitivity for detection of rifampin resistance associated mutations was 97.7% and specificity was 90.8%, which increased to 99.0% after DNA sequencing analysis of the discordant samples. Of the 1,096 subjects in the four clinical studies, 49% were from the US. Overall, Xpert detected MTBc in 439 of 468 culture-positive specimens for a sensitivity of 93.8% (95% confidence interval [CI]: 91.2%-95.7%) and did not detect MTBc in 620 of 628 culture-negative specimens for a specificity of 98.7% (95% CI: 97.5%-99.4%). Sensitivity was 99.7% among smear-positive cases, and 76.1% among smear-negative cases. Non-determinate MTBc detection and false-positive RIF resistance results were low (1.2 and 0.9%, respectively). CONCLUSIONS: The updated Xpert assay retained the high sensitivity and specificity of the previous assay versions and demonstrated low rates of non-determinate and RIF resistance false positive results.

Mutation at embB codon 306, a potential marker for the identification of multidrug resistance associated with ethambutol in Mycobacterium tuberculosis.

Ethambutol inhibits arabinogalactan and lipoarabinomannan biosynthesis in mycobacteria. The occurrence of mutations in embB codon 306 in ethambutol-susceptible isolates and their absence in resistant isolates has raised questions regarding the utility of this codon as a potential marker for resistance against ethambutol. The characterization of mutations on embB 306 will contribute to a better understanding of the mechanisms of resistance to this drug; therefore, the purpose of this study was to investigate the association between embB 306 mutations and first-line drug resistance profiles in tuberculosis isolates. We sequenced the region surrounding the embB 306 codon in 175 tuberculosis clinical isolates, divided according to drug sensitivity, in three groups: 110 were resistant to at least one first-line drug, of which 61 were resistant to ethambutol (EMB(r)), 49 were sensitive to ethambutol (EMB(s)) but were resistant to another drug, and 65 were pansensitive isolates (P(s)). The associations between embB 306 mutations and phenotypic resistance to all first-line drugs were determined, and their validity and safety as a diagnostic marker were assessed. One of the P(s) isolates (1/65), one of the EMB(s) isolates (1/49), and 20 of the EMB(r) isolates (20/61) presented with an embB 306 mutation. Four different single-nucleotide polymorphisms (SNPs) at embB 306 were associated with simultaneous resistance to ethambutol, isoniazid, and rifampin (odds ratio [OR], 17.7; confidence interval [CI], 5.6 to 56.1) and showed a positive predictive value of 82%, with a specificity of 97% for diagnosing multidrug resistance associated with ethambutol, indicating its potential as a molecular marker for several drugs.

Primary drug resistance in a region with high burden of tuberculosis. A critical problem.

OBJECTIVE: To determine rates of drug resistance in new cases of pulmonary tuberculosis in a region with a high burden of the disease. MATERIALS AND METHODS: New case suspects were referred for drug susceptibility testing. RESULTS: 28.9% of new cases were resistant to at least one first line drug; 3.9% had a multidrug-resistant strain, 15.6% a monoresistant strain and 9.4% a polyresistant strain. CONCLUSION: Our rate of drug resistant tuberculosis in new cases is very high; this has important clinical implications, since even monoresistance can have a negative impact on the outcome of new cases treated empirically with a six month regimen.

Tuberculosis testing among populations with high HIV risk in Tijuana, Baja California, Mexico.

OBJECTIVE: To assess the prevalence of prior tuberculin skin testing (TST) among populations at risk for HIV infection in Tijuana, Mexico, and to identify factors associated with TST. METHODS: Sex workers, injection drug users, noninjecting drug users, and homeless persons > 18 years old were recruited by using targeted sampling for risk assessment interviews and serologic testing for HIV and Mycobacterium tuberculosis infection. Univariate and multivariate logistic regression were used to identify correlates of self-reported TST history. RESULTS: Of 502 participants, 38.0% reported prior TST, which was associated with previous incarceration in the United States of America [odds ratio (OR) = 13.38; 95% confidence interval (CI) = 7.37-24.33] and injection drug use (OR = 1.99; 95% CI = 1.27- 3.11). Positive results on serologic tests for M. tuberculosis infection (57%) and HIV (4.2%) were not associated with a prior TST. CONCLUSIONS: A history of TST was lower in HIV-positive participants even though TST is indicated for persons with HIV in Mexico. Fewer than half the individuals at high risk for HIV in this study had a history of TST; however, TST was fairly common among those individuals with a prior history of incarceration. Increased tuberculosis screening is needed for populations at risk of contracting HIV in Tijuana, particularly those outside of criminal justice settings.

SLCO1B1 and SLC10A1 polymorphism and plasma rifampin concentrations in patients with co-morbidity tuberculosis-diabetes mellitus in Baja California, Mexico.

Rifampicin is one of the most important drugs for the treatment of tuberculosis (TB). Polymorphisms in SLCO1B1 and SLC10A1 genes are associated with impaired transporter function of drug compounds such as rifampicin. The relationship between genetic variation, clinical comorbidities, and rifampicin exposures in TB patients has not been completely elucidated. The aim of this study was to investigate the prevalence of SLCO1A1 and SLCO1B1 polymorphisms in TB and TB-DM patients and to determine their relationship with rifampicin pharmacokinetics on patients from México. Blood samples were collected in two hospitals in Baja California, Mexico from February through December 2017. Sampling included 19 patients with TB, 11 with T2DM and 17 healthy individuals. Polymorphisms genotype rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs72559746,rs2291075 and rs4603354 of SLCO1B1 and rs4646285 and rs138880008 of SLC10A1 were analyzed by Sanger's sequencing. None of the SLCO1B1 and SLC10A1 variants were significantly associated with rifampicin Cmax. TB and T2DM patients with suboptimal Cmax rifampicin levels showed wild alleles in rs11045819 and rs2291075 in SLCO1B1 SLC10A1 and SLC10A1. This is the first study to analyze SLC10A1 and SLCO1B1 polymorphisms in TB and TB-T2DM patients and healthy individuals in Mexico. Further research to confirm and extend these findings is necessary.

Latent tuberculosis among persons at risk for infection with HIV, Tijuana, Mexico.

Because there is little routine tuberculosis (TB) screening in Mexico, the prevalence of latent TB infection (LTBI) is unknown. In the context of an increasing HIV epidemic in Tijuana, Mexico, understanding prevalence of LTBI to anticipate emergence of increased LTBI reactivation is critical. Therefore, we recruited injection drug users, noninjection drug users, female sex workers, and homeless persons for a study involving risk assessment, rapid HIV testing, and TB screening. Of 503 participants, the overall prevalences of TB infection, HIV infection, and TB/HIV co-infection were 57%, 4.2%, and 2.2%, respectively; no significant differences by risk group (p>0.05) were observed. Two participants had TB (prevalence 398/100,000). Incarceration in Mexico (odds ratio [OR] 2.28), age (OR 1.03 per year), and years lived in Tijuana (OR 1.02 per year) were independently associated with TB infection (p<0.05). Frequent LTBI in marginalized persons may lead to increases in TB as HIV spreads.

Clinical comparison of two Mexican coccidioidins.

Coccidioidin, an extract from the saprophytic mycelial form of Coccidioides spp., has been a very useful antigen preparation both for skin and serological tests for coccidioidomycosis. Unfortunately, coccidioidin is not currently available for skin testing in the United States. Coccidioidin has been produced commercially in Mexico by a vaccine and reagents laboratory of the Mexican Federal Government. It also has been produced at the Microbiology Laboratory of the Faculty of Medicine, Universidad Nacional Autónoma de México exclusively as an antigen for research projects. The objective of the study was to compare both coccidioidins in their reactivity and safety when applied in humans. One hundred and eighty-four volunteers were tested; median age was 33 (range 14-82). When the cutoff point is set in 5 mm, 88 subjects (47.8%) had a positive test for the commercial coccidioidin and 76 (41.3%; CI(95%) 0.50, 1.15; P = 0.20) were positive with the research antigen. Seventy-five subjects were positive for both antigens and 96 were negative for both. Fifty-nine subjects (31.3%) reported an adverse reaction after the application of the antigen; they were mostly very mild local reactions. Mexican research coccidioidin is a safe and reliable antigen that can be used for the detection of coccidioidomycosis infection in mammals.

Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis.

BACKGROUND: Treatment of multidrug-resistant tuberculosis requires long-term therapy with a combination of multiple second-line drugs. These drugs are associated with numerous adverse events that can cause severe morbidity, such as deafness, and in some instances can lead to death. Our aim was to estimate the absolute and relative frequency of adverse events associated with different tuberculosis drugs to provide useful information for clinicians and tuberculosis programmes in selecting optimal treatment regimens. METHODS: We did a meta-analysis using individual-level patient data that were obtained from studies that reported adverse events that resulted in permanent discontinuation of anti-tuberculosis medications. We used a database created for our previous meta-analysis of multidrug-resistant tuberculosis treatment and outcomes, for which we did a systematic review of literature published between Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual patient-level information from authors. We also considered for this analysis studies contributing patient-level data in response to a public call made by WHO in 2018. Meta-analysis for proportions and arm-based network meta-analysis were done to estimate the incidence of adverse events for each tuberculosis drug. FINDINGS: 58 studies were identified, including 50 studies from the updated individual patient data meta-analysis for multidrug-resistant tuberculosis treatment. 35 of these studies, with 9178 patients, were included in our analysis. Using meta-analysis of proportions, drugs with low risks of adverse event occurrence leading to permanent discontinuation included levofloxacin (1·3% [95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]), and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2% [6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1% [9·9-19·6]). Risk of bias in selection of studies was judged to be low because there were no important differences between included and excluded studies. Variability between studies was significant for most outcomes analysed. INTERPRETATION: Fluoroquinolones, clofazimine, and bedaquiline had the lowest incidence of adverse events leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence. These results suggest that close monitoring of adverse events is important for patients being treated for multidrug-resistant tuberculosis. Our results also underscore the urgent need for safer and better-tolerated drugs to reduce morbidity from treatment itself for patients with multidrug-resistant tuberculosis. FUNDING: Canadian Institutes of Health Research, Centers for Disease Control and Prevention (USA), American Thoracic Society, European Respiratory Society, and Infectious Diseases Society of America.

Amphotericin B: side effects and toxicity.

Amphotericin B (AmB) is a crucial agent in the management of serious systemic fungal infections. In spite of its proven track record, its well-known side effects and toxicity will sometimes require discontinuation of therapy despite a life-threatening systemic fungal infection. The mechanism of action of AmB is based on the binding of the AmB molecule to the fungal cell membrane ergosterol, producing an aggregate that creates a transmembrane channel, allowing the cytoplasmic contents to leak out, leading to cell death. Most of the efforts at improving AmB have been focused on the preparation of AmB with a lipid conjugate. AmB administration is limited by infusion-related toxicity, an effect postulated to result from proinflammatory cytokine production. The principal acute toxicity of AmB deoxycholate includes nausea, vomiting, rigors, fever, hypertension or hypotension, and hypoxia. Its principal chronic adverse effect is nephrotoxicity. AmB probably produces renal injury by a variety of mechanisms. Risk factors for AmB nephrotoxicity include male gender, higher average daily dose of AmB (> or = 35 mg/day), diuretic use, body weight > or = 90 kg, concomitant use of nephrotoxic drugs, and abnormal baseline renal function. Clinical manifestations of AmB nephrotoxicity include renal insufficiency, hypokalemia, hypomagnesemia, metabolic academia, and polyuria due to nephrogenic diabetes insipidus. Human studies show convincingly that sodium loading in excess of the usual dietary intake notably reduces the incidence and severity of AmB-induced nephrotoxicity.

Surveillance of adverse events in the treatment of drug-resistant tuberculosis: A global feasibility study.

The World Health Organization launched a global initiative, known as aDSM (active TB drug safety monitoring and management) to better describe the safety profile of new treatment regimens for drug-resistant tuberculosis (TB) in real-world settings. However, comprehensive surveillance is difficult to implement in several countries. The aim of the aDSM project is to demonstrate the feasibility of implementing national aDSM registers and to describe the type and the frequency of adverse events (AEs) associated with exposure to the new anti-TB drugs. Following a pilot study carried out in 2016, official involvement of TB reference centres/countries into the project was sought and cases treated with bedaquiline- and/or delamanid-containing regimens were consecutively recruited. AEs were prospectively collected ensuring potential attribution of the AE to a specific drug based on its known safety profile. A total of 309 cases were fully reported from 41 centres in 27 countries (65% males; 268 treated with bedaquiline, 20 with delamanid, and 21 with both drugs) out of an estimated 781 cases the participating countries had committed to report by the first quarter of 2019.

Unexpected Pregnancy during Treatment of Multidrug-resistant Tuberculosis.

Several drugs used in the treatment of multidrug-resistant tuberculosis (MDR-TB) have been reported as teratogenic. Treatment of such cases during gestation is disputable. Some experts favor the termination of pregnancy, whereas others suggest reducing the dose of teratogenic drugs or even suspending the regimen during pregnancy. There have been no clinical trials on the subject, but case reports and case series show excellent outcomes for children exposed during pregnancy to second-line agents, indicating that aggressive management of gestational MDR-TB may benefit not only the mother but also the fetus. We present a case of pregnancy in a teenager while she was under treatment for MDR-TB and continued with full treatment and nevertheless delivered a healthy child.

Expanding understanding of epidemiology of coccidioidomycosis in the Western hemisphere.

Coccidioidomycosis is a disease of both national and worldwide importance that is most often diagnosed in nonendemic regions. The endemic region for Coccidioides spp. lies exclusively in the Western Hemisphere. Coccidioides spp. has long been identified in semiarid areas of the United States and Mexico, and endemic foci have been described in areas of Central and South America. Infection is usually the result of activities that cause the fungus to become airborne and inhaled by a susceptible host. Underlying medical diseases that affect T cell function are known to increase the risk of disseminated disease and include human immunodeficiency virus, cancer, and disease processes requiring transplantation and its subsequent immunosuppressive agents. In recent years the incidence of the coccidioidomycosis has increased in California and Arizona, which may be partially due to the massive migration of Americans to the Sunbelt states. To date the highest number of cases reported in Arizona was in 2004, when a total of 3,665 cases of coccidioidomycosis was reported, representing a 281% increase since 1997. Statistics on the prevalence and incidence of coccidioidomycosis in Latin America either are fragmentary or simply are not available.

Coccidioidomycosis and other endemic mycoses in Mexico.

The endemic mycoses traditionally include coccidioidomycosis, histoplasmosis, blastomycosis and paracoccidioidomycosis. Although sporotrichosis and chromomycosis are technically not included among the endemic mycoses, they are frequently diagnosed in Mexico. Most systemic endemic mycoses are a consequence of inhaling the fungi, while subcutaneous mycoses are acquired through the inoculation of vegetable matter or soil containing the organism. Coccidioidomycosis is caused by Coccidioides spp., a dimorphic pathogenic fungus. Approximately 60% of exposures result in asymptomatic infection; in the rest there are protean manifestations that range from a benign syndrome also known as "Valley Fever" to progressive pulmonary or extrapulmonary disease. Histoplasmosis, caused by the dimorphic fungus Histoplasma capsulatum, is endemic to the Americas. Pulmonary histoplasmosis manifestations are protean, ranging from a brief period of malaise to a severe, prolonged illness. The spectrum of illness in disseminated histoplasmosis ranges from a chronic, intermittent course to an acute and rapidly fatal infection. Paracoccidioidomycosis is a chronic, granulomatous systemic disease caused by Paracoccidioides brasiliensis that characteristically produces a primary pulmonary infection, often asymptomatic, and then disseminates to form ulcerative granulomata of the oral, nasal and occasionally the gastrointestinal mucosa. Sporotrichosis, caused by Sporothrix schenckii, has diverse clinical manifestations; the most frequent is the lymphocutaneous form. Generally, infection results from inoculation of the fungus through thorns, splinters, scratches and small traumas. Chromomycosis (Chromoblastomycosis) is a slowly progressive cutaneous and subcutaneous mycosis attributed to various saprophyte Hypomycetes fungi. The primary lesion is also thought to develop as a result of percutaneous traumatic inoculation.