New perspectives on difficult-to-treat tuberculosis based on old therapeutic approaches.

Tuberculosis (TB) is an important clinical and public health issue worldwide. Despite improved treatment success rates following the introduction of antibiotics in daily clinical practice, the expected decline in incidence has been hampered by HIV epidemics and multi- and extensively drug-resistant TB. During the pre-antibiotic era, TB therapies were mainly based on improving hygiene conditions, strengthening the immune system, and targeting the rest of the affected lungs with invasive techniques. Detailed knowledge of old non-pharmacological therapies might support physicians and researchers in the identification of new solutions for difficult-to-treat patients. We performed a narrative literature review on the main old therapeutic options prescribed for patients with TB. The main recommendations and contraindications of sanatorium therapies (i.e., bed rest, fresh air, sunlight) and pulmonary collapse techniques are reviewed, evaluating their physiological basis and their impact on patient outcomes. We report studies describing new interventional pulmonary and surgical techniques and assess new perspectives based on old medical and surgical treatments, whose potential implementation could help complicated patients.

Regimens to treat multidrug-resistant tuberculosis: past, present and future perspectives.

Over the past few decades, treatment of multidrug-resistant (MDR)/extensively drug-resistant (XDR) tuberculosis (TB) has been challenging because of its prolonged duration (up to 20-24 months), toxicity, costs and sub-optimal outcomes.After over 40 years of neglect, two new drugs (bedaquiline and delamanid) have been made available to manage difficult-to-treat MDR-/XDR-TB cases. World Health Organization (WHO) guidelines published in March 2019 endorsed the possibility of treating MDR-TB patients with a full oral regimen, following previous guidelines published in 2016 which launched a shorter regimen lasting 9-10 months.The objectives of this article are to review the main achievements in MDR-TB treatment through the description of the existing WHO strategies, to discuss the main ongoing trials and to shed light on potential future scenarios and revised definitions necessary to manage drug-resistant TB.

Drug-resistant tuberculosis in Zhejiang Province, China: an updated analysis of time trends, 1999-2013.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) hinder the progress of TB control. OBJECTIVE: To track the trend of drug-resistant tuberculosis (DR-TB) prevalence in Zhejiang Province from 1999 to 2013, and identify risk factors of resistance to second-line drugs among MDR-TB patients. DESIGN: Four DR-TB surveys had been done in Zhejiang Province in 1999, 2004, 2008 and 2013 through questionnaires, in which demographic and epidemiological items were included. After questionnaires, drug susceptibility testing (DST) targeted at four first-line drugs was done for all TB patients and DST targeted at six second-line drugs (only in 2008 and 2013) for MDR-TB patients. The drug resistance trend over time was analyzed using the Cochran-Armitage test. The factors associated with resistance to second-line drugs among MDR-TB patients were examined by a multivariate logistic regression model. RESULTS: Of 936 patients enrolled, 27 (3.21%) and 20 (21.28%) MDR-TB cases were registered as new and previously treated cases, respectively. MDR-TB showed a decreasing trend (Z = -3.31, p < 0.01) while resistance to any first-line drugs showed an increasing trend (Z = 5.22, p < 0.001), from 1999 to 2013. The highest resistance rate was shown to ofloxacin among MDR-TB patients both in 2008 (28.8%) and in 2013 (27.7%), while resistance to para-aminosalicylate decreased significantly (Z = -2.06, p = 0.04) between 2008 and 2013. MDR-TB patients aged 45-65 years (OR = 5.00, p = 0.02) were more likely to be resistant to any second-line drugs. CONCLUSIONS: DR-TB including MDR-TB remains a major public health problem in Zhejiang Province. Further efforts on MDR-TB control should be conducted to hinder drug resistance, including critical clinical use of anti-TB antibiotics and preventing transmission.

Preliminary Favorable Outcome for Medically and Surgically Managed Extensively Drug-Resistant Tuberculosis, France, 2009-2014.

We report 20 cases of extensively drug-resistant tuberculosis managed in France. Treatment was individualized and included bedaquiline and linezolid for most patients and surgery in 8 patients. At last follow-up (22 months), 19 patients had achieved conversion from positive to negative on culture testing. These promising results of comprehensive management obtained in a small series deserve confirmation.

Treatment practices, outcomes, and costs of multidrug-resistant and extensively drug-resistant tuberculosis, United States, 2005-2007.

To describe factors associated with multidrug-resistant (MDR), including extensively-drug-resistant (XDR), tuberculosis (TB) in the United States, we abstracted inpatient, laboratory, and public health clinic records of a sample of MDR TB patients reported to the Centers for Disease Control and Prevention from California, New York City, and Texas during 2005-2007. At initial diagnosis, MDR TB was detected in 94% of 130 MDR TB patients and XDR TB in 80% of 5 XDR TB patients. Mutually exclusive resistance was 4% XDR, 17% pre-XDR, 24% total first-line resistance, 43% isoniazid/rifampin/rifabutin-plus-other resistance, and 13% isoniazid/rifampin/rifabutin-only resistance. Nearly three-quarters of patients were hospitalized, 78% completed treatment, and 9% died during treatment. Direct costs, mostly covered by the public sector, averaged $134,000 per MDR TB and $430,000 per XDR TB patient; in comparison, estimated cost per non-MDR TB patient is $17,000. Drug resistance was extensive, care was complex, treatment completion rates were high, and treatment was expensive.

The chemotherapy of tuberculosis: past, present and future.

The history of the development of modern chemotherapy for tuberculosis (TB), largely due to the British Medical Research Council, is first described. There is a current need to shorten the duration of treatment and to prevent and cure drug-resistant disease. These aims will only be achieved if the way in which multidrug treatment prevents resistance from emerging and the reasons for the very slow response to chemotherapy are understood. Consideration of mutation rates to resistance and the size of bacterial populations in lesions makes it very unlikely that resistance would emerge spontaneously, leaving irregularity in drug taking and inadequate dosage as the main reasons for its occurrence. Slow response to treatment seems due to the presence of persister populations whose natural history is only partly known. In the future, we need to explore the persister state in patients and in experimental murine TB, and to take it into account in the design of future mouse experiments. The activity of rifamycins and pyrazinamide is being increased by a rise in rifamycin dosage and the inhalation of pyrazinoic acid. New drugs are gradually being brought into use, initially TMC207 and the nitroimadazoles, PA824 and OPC67683. They will need to be tested in new combination regimens for drug-susceptible and multi- and extensively drug-resistant disease.