Susceptibility to respiratory infections increases with age. Diagnosing and treating tuberculosis in the elderly comes with the challenges of fewer specific symptoms and possibly more side effects of ...treatment. Much is unknown when it comes to tuberculosis in the elderly, especially in relation to inflammation, which may impact mortality. We, therefore, investigated a clinical cohort of elderly tuberculosis patients.
Patients aged ≥65 years, admitted to our tuberculosis reference center between 2005 and 2021, were retrospectively included in our cohort. Sociodemographic data, clinical characteristics, laboratory results, including inflammatory markers at baseline (monocyte, neutrophil, lymphocyte count, and CRP levels), and treatment outcomes were collected. They were compared to the National Dutch TB Registry and analyzed using descriptive statistics. Survival analysis was performed using univariate Cox regression analysis and a log-rank test. Results were visualized in Kaplan-Meier curves.
104 elderly tuberculosis patients, mostly European, with a mean age of 75 years, were included. None were HIV-infected. Miliary tuberculosis cases were overrepresented (14 %) compared to the National Dutch TB Registry (5 % in elderly, 2 % adults). Fever occurred in 77 % (57/74), and the duration of fever decreased with age. Innate immune markers, including monocyte/lymphocyte-ratio, moderately correlated with CRP. Overall mortality was 15 %, and highest (33 %) in patients with CRP levels >100 mg/mL.
In elderly tuberculosis patients in a low-incidence setting, mortality rates are higher in comparison to younger patients. The overrepresentation of miliary tuberculosis may suggest waning immunity, with a subset of patients exhibiting strong inflammation associated with increased mortality.
•Elderly TB patients in low-incidence areas face higher mortality than younger ones.•Miliary TB occurs more frequently in older patients than in younger patients.•Patients showing more inflammation are at a higher risk of mortality.
Treatment Outcomes in Multidrug-Resistant Tuberculosis Günther, Gunar; Lange, Christoph; Alexandru, Sofia ...
New England journal of medicine/The New England journal of medicine,
09/2016, Letnik:
375, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Multidrug-resistant tuberculosis is a major global challenge. This report examines the definition of treatment success and its effect on determining cure.
To the Editor:
Despite lengthy treatment ...with costly second-line drug regimens, curing multidrug-resistant (MDR) tuberculosis (bacillary resistance to at least isoniazid and rifampin) remains a challenge.
1
The World Health Organization (WHO) defines “cure” as “treatment completion” with at least three negative cultures after the intensive phase of therapy in the absence of “treatment failure.” The definition of “treatment failure” requires early termination of treatment or the need for permanent regimen change of at least two antituberculosis drugs. “Treatment success” is defined as the sum of cure and treatment completion.
2
We evaluated treatment outcomes according to WHO definitions in the TBNET . . .
Moxifloxacin has an important role in the treatment of tuberculosis (TB). Unfortunately, coadministration with the cornerstone TB drug rifampicin results in suboptimal plasma exposure. We aimed to ...gain insight into the moxifloxacin pharmacokinetics and the interaction with rifampicin. Moreover, we provided a mechanistic framework to understand moxifloxacin pharmacokinetics. We developed a physiologically based pharmacokinetic model in Simcyp version 19, with available and newly generated in vitro and in vivo data, to estimate pharmacokinetic parameters of moxifloxacin alone and when administered with rifampicin. By combining these strategies, we illustrate that the role of P‐glycoprotein in moxifloxacin transport is limited and implicate MRP2 as transporter of moxifloxacin‐glucuronide followed by rapid hydrolysis in the gut. Simulations of multiple dose area under the plasma concentration–time curve (AUC) of moxifloxacin (400 mg once daily) with and without rifampicin (600 mg once daily) were in accordance with clinically observed data (predicted/observed P/O ratio of 0.87 and 0.80, respectively). Importantly, increasing the moxifloxacin dose to 600 mg restored the plasma exposure both in actual patients with TB as well as in our simulations. Furthermore, we extrapolated the single dose model to pediatric populations (P/O AUC ratios, 1.04‐1.52) and the multiple dose model to children with TB (P/O AUC ratio, 1.51). In conclusion, our combined approach resulted in new insights into moxifloxacin pharmacokinetics and accurate simulations of moxifloxacin exposure with and without rifampicin. Finally, various knowledge gaps were identified, which may be considered as avenues for further physiologically based pharmacokinetic refinement.
Recent evidence suggests that higher rifampicin doses may improve tuberculosis (TB) treatment outcome.
In this observational cohort study we evaluated all TB patients who were treated with high-dose ...rifampicin (> 10 mg/kg daily) in our reference centre, from January 2008 to May 2018. Indications, achieved plasma rifampicin exposures, safety and tolerability were evaluated.
Eighty-eight patients were included. The main indications were low plasma concentrations (64.7%) and severe illness (29.5%), including central nervous system TB. Adjusted rifampicin dosages ranged from 900 mg to a maximum of 2400 mg (corresponding to 32 mg/kg) per day. Patients with severe illness received high-dose rifampicin immediately, the others had a higher dosage guided by therapeutic drug monitoring. Four patients developed hepatotoxicity, of which two were proven due to isoniazid. Re-introduction of high-dose rifampicin was successful in all four. Eighty-seven patients tolerated high-dose rifampicin well throughout treatment. Only one patient required a dose reduction due to gastro-intestinal disturbance.
High-dose rifampicin, used in specific groups of patients in our clinical setting, is safe and well-tolerated for the whole treatment duration. Measurement of drug exposures could be used as a tool/guide to increase rifampicin dosage if a reduced medication absorption or a poor treatment outcome is suspected. We suggest to administer high-dose rifampicin to patients with severe manifestations of TB or low rifampicin exposure to improve treatment outcome.
The ongoing HIV epidemic and the increasing number of patients with drug-resistant tuberculosis (TB) are seriously hampering global TB-control activities, including those in the World Health ...Organization (WHO) Region Europe. Overall, the prevalence of HIV co-infection in TB patients increased from 3.4% in 2008 to 8% in 2014 in the region 1. The prevalence of multidrug-resistant (MDR)-TB (drug resistance against at least isoniazid and rifampicin) reported for Europe – 15% in newly diagnosed TB patients and 48% in previously treated TB patients – is the highest in the world 1.
The incidence of non-tuberculous mycobacterial pulmonary disease (NTM-PD) has increased in the Netherlands. The fibro-cavitary disease manifestation predominates, as elsewhere in Europe. We studied ...treatment and outcome of this disease manifestation, as such data are scarce.
We conducted a retrospective study of all patients diagnosed with NTM-PD according to the American Thoracic Society statement between 2008 and 2013 in a reference clinic.
Sixty-three patients were included. Thirty-two (51%) were females and mean age was 60.8 years. Most patients had underlying COPD (73%). M. avium complex pulmonary disease (MAC-PD) was most frequent (n = 38, 60.3%), followed by M. malmoense (n = 7) and M. kansasii (n = 6). Twenty-two patients had fibro-cavitary MAC-PD, 14 had nodular-bronchiectatic MAC-PD and 2 had other manifestations. Thirty-two (94%) patients treated for MAC-PD received a rifamycin-ethambutol-macrolide based regimen. Microbiological cure rates were lower for fibro-cavitary (52.4%) than for nodular bronchiectatic MAC-PD (100%; p = 0.03). Sixty-nine percent of treated patients experienced adverse events, most frequently gastrointestinal discomforts (71%), tinnitus (18%), hearing impairment (16%) and hepatotoxicity (18%).
Fibro-cavitary NTM-PD remains predominant, but is now diagnosed more frequently in women. Fibro-cavitary disease is harder to cure than nodular-bronchiectatic disease. Adverse events are frequent and can necessitate cessation of treatment.
•Predominantly fibrocavitary NTM pulmonary disease.•Increasing prevalence of nodular-bronchiectatic MAC-PD.•Lower Cure rates in fibro-cavitary vs. nodular bronchiectatic MAC-PD.•Toxicity is problematic and can necessitate cessation of therapy.
An electronic nose (eNose) device has shown a high specificity and sensitivity to diagnose or rule out tuberculosis (TB) in the past. The aim of this study was to evaluate its performance in patients ...referred to INERAM.
Patients aged ≥15 years were included. A history, physical examination, chest radiography (CRX) and microbiological evaluation of a sputum sample were performed in all participants, as well as a 5-minute breath test with the eNose. TB diagnosis was preferably established by the gold standard and compared to the eNose predictions. Univariate and multivariate logistic regression analyses were performed to assess potential risk factors for erroneous classification results by the eNose.
107 participants with signs and symptoms of TB were enrolled of which 91 (85.0%) were diagnosed with TB. The blind eNose predictions resulted in an accuracy of 50%; a sensitivity of 52.3% (CI 95%: 39.6-64.7%) and a specificity of 36.4% (CI 95%: 12.4-68.4%). Risk factors for erroneous classifications by the eNose were older age (multivariate analysis: OR 1.55, 95% CI 1.10-2.18, p = 0.012) and antibiotic use (multivariate analysis: OR 3.19, 95% CI 1.06-9.66, p = 0.040).
In this study, the accuracy of the eNose to diagnose TB in a tertiary referral hospital was only 50%. The use of antibiotics and older age represent important factors negatively influencing the diagnostic accuracy of the eNose. Therefore, its use should probably be restricted to screening in high-risk communities in less complex healthcare settings.
In the Netherlands, 1.4% of tuberculosis (TB) cases are caused by Mycobacterium bovis. After we admitted 3 patients with M. bovis infections to our reference hospital, we conducted a retrospective ...analysis of all M. bovis disease in the Netherlands during 1993-2007. We analyzed data from 231 patients for clinical, demographic, treatment, and outcome characteristics and for risk factors. Most patients were native Dutch (n = 138; 59.7%) or Moroccan (n = 54; 23.4%). Disease was mainly extrapulmonary (n = 136; 58.9%). Although 95 patients had pulmonary disease, person-to-person transmission did not occur, as shown by structural DNA fingerprinting analysis. Lymph node TB was more likely to develop in women (p<0.0001), whereas pulmonary M. bovis disease developed more frequently in men (p<0.0001). Diagnosis was accurate but delayed and led to inadequate treatment in 26% of the cases. Proportion of deaths from M. bovis disease was higher than that for M. tuberculosis disease.
Multidrug- and extensively drug-resistant tuberculosis have emerged as grave threats to public health worldwide. Very few active drugs are available or likely to become available soon. To address ...these problems we revisited a classical observation, the applicability of phenothiazines as antimicrobial drugs. Within this pharmacological class we selected thioridazine, which is most efficacious and least toxic, when used as an antipsychotic drug. We tested thioridazine monotherapy in the Balb/c mouse model for its activity to treat both susceptible and multidrug-resistant tuberculosis by a two months daily oral administration of 32 and 70 mg/kg. In addition, we tested its additive value when combined with a standard first-line regimen for susceptible tuberculosis. Thioridazine treatment resulted in a significant reduction of colony-forming-units of the susceptible (-4.4 log CFU, p<0.05) and multidrug-resistant tuberculosis bacilli (-2.4 log CFU, p<0.009) in the lung both at one and two months after infection, compared to controls. Moreover, when thioridazine was added to a regimen containing rifampicin, isoniazid and pyrazinamide for susceptible tuberculosis, a significant synergistic effect was achieved (-6.2 vs -5.9 log CFU, p<0.01). Thioridazine may represent an effective compound for treatment of susceptible and multidrug-resistant tuberculosis. The phenothiazines and their targets represent interesting novel opportunities in the search for antituberculosis drugs.
PDF
