Concurrent Silicosis and Pulmonary Mycosis at Death

To examine risk for mycosis among persons with silicosis, we examined US mortality data for 1979–2004. Persons with silicosis were more likely to die with pulmonary mycosis than were those without pneumoconiosis or those with more common pneumoconioses. Health professionals should consider enhanced risk for mycosis for silica-exposed patients

Serial counts of Mycobacterium tuberculosis in sputum as surrogate markers of the sterilising activity of rifampicin and pyrazinamide in treating pulmonary tuberculosis

BACKGROUND: Since the sterilising activity of new antituberculosis drugs is difficult to assess by conventional phase III studies, surrogate methods related to eventual relapse rates are required. METHODS: A suitable method is suggested by a retrospective analysis of viable counts of Mycobacterium tuberculosis in 12-hr sputum collections from 122 newly diagnosed patients with pulmonary tuberculosis in Nairobi, done pretreatment and at 2, 7, 14 and 28 days. Treatment was with isoniazid and streptomycin, supplemented with either thiacetazone (SHT) or rifampicin + pyrazinamide (SHRZ). RESULTS: During days 0–2, a large kill due to isoniazid occurred, unrelated to treatment or HIV status; thereafter it decreased exponentially. SHRZ appeared to have greater sterilising activity than SHT during days 2–7 (p = 0.044), due to rifampicin, and during days 14–28, probably due mainly to pyrazinamide. The greatest discrimination between SHRZ and SHT treatments was found between regression estimates of kill over days 2–28 (p = 0.0005) in patients who remained positive up to 28 days with homogeneous kill rates. No associations were found between regression estimates and the age, sex, and extent of disease or cavitation. An increased kill in HIV seropositive patients, unrelated to the treatment effect, was evident during days 2–28 (p = 0.007), mainly during days 2–7. CONCLUSIONS: Surrogate marker studies should either be in small groups treated with monotherapy during days 2 to about 7 or as add-ons or replacements in isoniazid-containing standard regimens from days 2 to 28 in large groups

Selective Inactivity of Pyrazinamide against Tuberculosis in C3HeB/FeJ Mice Is Best Explained by Neutral pH of Caseum

Pyrazinamide (PZA) is one of only two sterilizing drugs in the first-line antituberculosis regimen. Its activity is strongly pH dependent; the MIC changes by several orders of magnitude over a range of pH values that may be encountered in various in vivo compartments. We recently reported selective inactivity of PZA in a subset of C3HeB/FeJ mice with large caseous lung lesions. In the present study, we evaluated whether such inactivity was explained by poor penetration of PZA into such lesions or selection of drug-resistant mutants. Despite demonstrating similar dose-proportional PZA exposures in plasma, epithelial lining fluid, and lung lesions, no dose response was observed in a subset of C3HeB/FeJ mice with the highest CFU burden. Although PZA-resistant mutants eventually replaced the susceptible bacilli in BALB/c mice and in C3HeB/FeJ mice with low total CFU burdens, they never exceeded 1% of the total population in nonresponding C3HeB/FeJ mice. The selective inactivity of PZA in large caseous lesions of C3HeB/FeJ mice is best explained by the neutral pH of liquefying caseum

Factors associated with default from treatment among tuberculosis patients in nairobi province, Kenya: A case control study

<p>Abstract</p> <p>Background</p> <p>Successful treatment of tuberculosis (TB) involves taking anti-tuberculosis drugs for at least six months. Poor adherence to treatment means patients remain infectious for longer, are more likely to relapse or succumb to tuberculosis and could result in treatment failure as well as foster emergence of drug resistant tuberculosis. Kenya is among countries with high tuberculosis burden globally. The purpose of this study was to determine the duration tuberculosis patients stay in treatment before defaulting and factors associated with default in Nairobi.</p> <p>Methods</p> <p>A Case-Control study; Cases were those who defaulted from treatment and Controls those who completed treatment course between January 2006 and March 2008. All (945) defaulters and 1033 randomly selected controls from among 5659 patients who completed treatment course in 30 high volume sites were enrolled. Secondary data was collected using a facility questionnaire. From among the enrolled, 120 cases and 154 controls were randomly selected and interviewed to obtain primary data not routinely collected. Data was analyzed using SPSS and Epi Info statistical software. Univariate and multivariate logistic regression analysis to determine association and Kaplan-Meier method to determine probability of staying in treatment over time were applied.</p> <p>Results</p> <p>Of 945 defaulters, 22.7% (215) and 20.4% (193) abandoned treatment within first and second months (intensive phase) of treatment respectively. Among 120 defaulters interviewed, 16.7% (20) attributed their default to ignorance, 12.5% (15) to traveling away from treatment site, 11.7% (14) to feeling better and 10.8% (13) to side-effects. On multivariate analysis, inadequate knowledge on tuberculosis (OR 8.67; 95% CI 1.47-51.3), herbal medication use (OR 5.7; 95% CI 1.37-23.7), low income (OR 5.57, CI 1.07-30.0), alcohol abuse (OR 4.97; 95% CI 1.56-15.9), previous default (OR 2.33; 95% CI 1.16-4.68), co-infection with Human immune-deficient Virus (HIV) (OR 1.56; 95% CI 1.25-1.94) and male gender (OR 1.43; 95% CI 1.15-1.78) were independently associated with default.</p> <p>Conclusion</p> <p>The rate of defaulting was highest during initial two months, the intensive phase of treatment. Multiple factors were attributed by defaulting patients as cause for abandoning treatment whereas several were independently associated with default. Enhanced patient pre-treatment counseling and education about TB is recommended.</p

Relapse Associated with Active Disease Caused by Beijing Strain of Mycobacterium tuberculosis1

Risk for relapse was higher among persons of Asian–Pacific Islander descent

Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020.

Comprehensive guidelines for treatment of latent tuberculosis infection (LTBI) among persons living in the United States were last published in 2000 (American Thoracic Society. CDC targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221-47). Since then, several new regimens have been evaluated in clinical trials. To update previous guidelines, the National Tuberculosis Controllers Association (NTCA) and CDC convened a committee to conduct a systematic literature review and make new recommendations for the most effective and least toxic regimens for treatment of LTBI among persons who live in the United States.The systematic literature review included clinical trials of regimens to treat LTBI. Quality of evidence (high, moderate, low, or very low) from clinical trial comparisons was appraised using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. In addition, a network meta-analysis evaluated regimens that had not been compared directly in clinical trials. The effectiveness outcome was tuberculosis disease; the toxicity outcome was hepatotoxicity. Strong GRADE recommendations required at least moderate evidence of effectiveness and that the desirable consequences outweighed the undesirable consequences in the majority of patients. Conditional GRADE recommendations were made when determination of whether desirable consequences outweighed undesirable consequences was uncertain (e.g., with low-quality evidence).These updated 2020 LTBI treatment guidelines include the NTCA- and CDC-recommended treatment regimens that comprise three preferred rifamycin-based regimens and two alternative monotherapy regimens with daily isoniazid. All recommended treatment regimens are intended for persons infected with Mycobacterium tuberculosis that is presumed to be susceptible to isoniazid or rifampin. These updated guidelines do not apply when evidence is available that the infecting M. tuberculosis strain is resistant to both isoniazid and rifampin; recommendations for treating contacts exposed to multidrug-resistant tuberculosis were published in 2019 (Nahid P, Mase SR Migliori GB, et al. Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit Care Med 2019;200:e93-e142). The three rifamycin-based preferred regimens are 3 months of once-weekly isoniazid plus rifapentine, 4 months of daily rifampin, or 3 months of daily isoniazid plus rifampin. Prescribing providers or pharmacists who are unfamiliar with rifampin and rifapentine might confuse the two drugs. They are not interchangeable, and caution should be taken to ensure that patients receive the correct medication for the intended regimen. Preference for these rifamycin-based regimens was made on the basis of effectiveness, safety, and high treatment completion rates. The two alternative treatment regimens are daily isoniazid for 6 or 9 months; isoniazid monotherapy is efficacious but has higher toxicity risk and lower treatment completion rates than shorter rifamycin-based regimens.In summary, short-course (3- to 4-month) rifamycin-based treatment regimens are preferred over longer-course (6-9 month) isoniazid monotherapy for treatment of LTBI. These updated guidelines can be used by clinicians, public health officials, policymakers, health care organizations, and other state and local stakeholders who might need to adapt them to fit individual clinical circumstances

A double-blind placebo-controlled clinical trial of 3 anti-tuberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong

A double-blind placebo-controlled trial of antituberculosis chemoprophylaxis was undertaken in silicotic subjects In Hong Kong where there is a high prevalence of both silicosis and tuberculosis. During 1981 to 1997, 679 Chinese men with silicosis, with no history of previous antituberculosis chemotherapy and no evidence of active tuberculosis, were admitted to the trial and have been studied for between 2 and 5 yr. They were allocated at random to four series–rifampin for 12 wk (R3), isoniazid and rifampin for 12 wk (HR3), isoniazid alone for 24 wk (H6), or placebo (PI)-in a double-blind design with matching placebos for isoniazld and rifampin as appropriate. Active pulmonary tuberculosis developed more frequently during the 5 yr in the placebo series than in the three chemoprophylaxis series (p < 0.01, log-rank test), but there were no significant differences between the chemoprophylaxis series. The estimated proportions of patients with active pulmonary disease in the placebo series were 9% at 2 yr, 15% at 3 yr, 20% at 4 yr, and 27% at 5 yr. In contrast, in the three chemoprophylaxis series combined they were 5, 8, 10, and 13% respectively. Thus, although chemoprophylaxis halved the proportion of patients in whom tuberculosis developed, this proportion was still substantial. There was no evidence that chemoprophylaxis led to the selection of drug-resistant strains of bacilli. Adverse effects were reported with a similar frequency in all four series, suggesting that few were drug related. During the first 12 wk, hepatic toxicity was reported in 8 (1%) patients (3 HR3, 3 H6, and 2 PI), but only 1 (H6) had symptomatic hepatitis. The serum alanine aminotransferase concentrations during chemoprophylaxis were higher in the HR3 and H6 series than in the R3 series (p < 0.001); there was no significant difference between the R3 and PI series. In conclusion, more effective antituberculosis chemoprophylaxis regimens for silicotic subjects are needed; rifampin on Its own probably carries a very low risk of hepatic toxicity

A controlled clinical comparison of 6 and 8 months of antituberculosis chemotherapy in the treatment of patients with silicotuberculosis in Hong kong. American Review of Respiratory Diseases

Patients with silicotuberculosis have been reported to respond poorly to antituberculosis chemotherapy. Therefore, in a study in Hong Kong, 240 Chinese male patients with both silicosis and pulmonary tuberculosis were all prescribed treatment three times weekly with streptomycin, lsoniazid, rifampln, and pyrazinamide, allocated at random to be given for a total duration of either 6 (M6 reglmen) or 6 months (M8 regimen) In a concurrent comparison. Those with a history of previous antituberculosls chemotherapy received ethambutol as well for the first 3 months. The intake in the M6 regimen was terminated when preliminary results showed that It was Inadequate, and a further 63 patients were assigned to the M8 series. Of 91 assessable patients In the concurrent comparison with susceptible strains pretreatment, 44% were culture negative at 1 month, 80% at 2 months, and 98% at 3 months, and 1 had an unfavorable bacteriologic response during chemotherapy. Durlng 3 yr of assessment, bacteriologic relapse after chemotherapy occurred in 22% of the M6 compared wlth 7% of the M8 patients (p < 0.025, log-rank test). Inadequate chemotherapy was received by 12% of the 240 patients in the concurrent comparison because of default and by 22% because of adverse effects, but by 3 yr 92% of patients with susceptible strains pretreatment in each series had a favorable status followlng retreatment for relapse or for initially inadequate chemotherapy when required. The results show that patlents with silicosis require at least 8 months of treatment

A study of the characteristics and course of sputum smear-negative pulmonary tuberculosis

A total of 302 Chinese patients were diagnosed on clinical and radiographic grounds by chest physicians from the Hong Kong Chest Service as having radiographically active pulmonary tuberculosis, but had sputum negative for acid-fast bacilli on 5 recent microscopical examinations. They were not given antituberculosis chemotherapy until active disease had been confirmed by positive bacteriological findings, or by radiographic or clinical deterioration during close observation. Of the 283 patients assessed up to 30 months, 200 (71 %) had active disease confirmed and had chemotherapy started during the 30 months. A further 42 (15 %) had evidence of changing lesions on serial chest radiography, and hence of recently active disease. A number of characteristics of the patients and of their bacteriological and radiographic status were tested singly and in combination for association with the presence of active disease confirmed on admission or at any time during the 30 months. Patients with radiographic lesions which were larger and classified as “active” on independent radiological assessment, and with a history of blood-streaked sputum or frank haemoptysis were more likely to have unquestionably active disease on admission or at some time during the 30 months, than patients without these characteristics