Pharmacokinetics of standard versus high-dose rifampin for tuberculosis preventive treatment: A sub-study of the 2R2 randomized controlled trial.

BACKGROUND: Pharmacokinetic data of rifampin, when used for tuberculosis preventive treatment (TPT) are not available. We aimed to describe the pharmacokinetics of rifampin used for TPT, at standard and higher doses, and to assess predictors of rifampin exposure. METHODS: A pharmacokinetic sub-study was performed in Bandung, Indonesia among participants in the 2R2 randomized trial, which compared TPT regimens of 2 months of high-dose rifampin at 20 mg/kg/day (2R20) and 30 mg/kg/day (2R30), with 4 months of standard-dose rifampin at 10 mg/kg/day (4R10) in adolescents and adults. Intensive pharmacokinetic sampling was performed after 2-8 weeks of treatment. Pharmacokinetic parameters were assessed non-compartmentally. Total exposure (AUC0-24) and peak concentration (Cmax) between arms were compared using one-way ANOVA and Tukey's post-hoc tests. Multivariable linear regression analyses were used to assess predictors of AUC0-24 and Cmax. RESULTS: We enrolled 51 participants in this study. In the 4R10, 2R20, and 2R30 arms, the geometric mean AUC0-24 was 68.0, 186.8, and 289.9 h⋅mg/L, and Cmax was 18.4, 36.7, and 54.4 mg/L, respectively; high interindividual variabilities were observed. Compared with the 4R10 arm, AUC0-24 and Cmax were significantly higher in the 2R20 and 2R30 arms (P < 0.001). Drug doses, body weight, and female sex were predictors of higher rifampin AUC0-24 and Cmax (P < 0.05). AUC0-24 and Cmax values were much higher than those previously reported in persons with TB disease. CONCLUSIONS: Doubling and tripling the rifampin dose led to three- and four-fold higher exposure compared to standard dose. Pharmacokinetic/pharmacodynamic modelling and simulations are warranted to support trials of shortening the duration of TPT regimens with high-dose rifampin.

High-dose rifamycins in the treatment of TB: a systematic review and meta-analysis.

BACKGROUND: There is growing interest in using high-dose rifamycin (HDR) regimens in TB treatment, but the safety and efficacy of HDR regimens remain uncertain. We performed a systematic review and meta-analysis comparing HDR to standard-dose rifamycin (SDR) regimens. METHODS: We searched MEDLINE, Embase, CENTRAL, Cochrane Database of Systematic Reviews and clinicaltrials.gov for prospective studies comparing daily therapy with HDRs to SDRs. Rifamycins included rifampicin, rifapentine and rifabutin. Our primary outcome was the rate of severe adverse events (SAEs), with secondary outcomes of death, all adverse events, SAE by organ and efficacy outcomes of 2-month culture conversion and relapse. This study was prospectively registered in the International Prospective Register of Systematic Reviews (CRD42020142519). RESULTS: We identified 9057 articles and included 13 studies with 6168 participants contributing 7930 person-years (PY) of follow-up (HDR: 3535 participants, 4387 PY; SDR: 2633 participants, 3543 PY). We found no significant difference in the pooled incidence rate ratio (IRR) of SAE between HDR and SDR (IRR 1.00, 95% CI 0.82 to 1.23, I 2=41%). There was no significant difference when analysis was limited to SAE possibly, probably or likely medication-related (IRR 1.07, 95% CI 0.82 to 1.41, I 2=0%); studies with low risk of bias (IRR 0.98, 95% CI 0.79 to 1.20, I 2=44%); or studies using rifampicin (IRR 1.00, 95% CI 0. 0.75-1.32, I 2=38%). No significant differences were noted in pooled outcomes of death, 2-month culture conversion and relapse. CONCLUSIONS: HDRs were not associated with a significant difference in SAEs, 2-month culture conversion or death. Further studies are required to identify specific groups who may benefit from HDR.

Active testing of groups at increased risk of acquiring SARS-CoV-2 in Canada: costs and human resource needs.

BACKGROUND: Testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely passive, which impedes epidemic control. We defined active testing strategies for SARS-CoV-2 using reverse transcription polymerase chain reaction (RT-PCR) for groups at increased risk of acquiring SARS-CoV-2 in all Canadian provinces. METHODS: We identified 5 groups who should be prioritized for active RT-PCR testing: contacts of people who are positive for SARS-CoV-2, and 4 at-risk populations - hospital employees, community health care workers and people in long-term care facilities, essential business employees, and schoolchildren and staff. We estimated costs, human resources and laboratory capacity required to test people in each group or to perform surveillance testing in random samples. RESULTS: During July 8-17, 2020, across all provinces in Canada, an average of 41 751 RT-PCR tests were performed daily; we estimated this required 5122 personnel and cost $2.4 million per day ($67.8 million per month). Systematic contact tracing and testing would increase personnel needs 1.2-fold and monthly costs to $78.9 million. Conducted over a month, testing all hospital employees would require 1823 additional personnel, costing $29.0 million; testing all community health care workers and persons in long-term care facilities would require 11 074 additional personnel and cost $124.8 million; and testing all essential employees would cost $321.7 million, requiring 25 965 added personnel. Testing the larger population within schools over 6 weeks would require 46 368 added personnel and cost $816.0 million. Interventions addressing inefficiencies, including saliva-based sampling and pooling samples, could reduce costs by 40% and personnel by 20%. Surveillance testing in population samples other than contacts would cost 5% of the cost of a universal approach to testing at-risk populations. INTERPRETATION: Active testing of groups at increased risk of acquiring SARS-CoV-2 appears feasible and would support the safe reopening of the economy and schools more broadly. This strategy also appears affordable compared with the $169.2 billion committed by the federal government as a response to the pandemic as of June 2020.

Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.

Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB.Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided.Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.

Assessment of humoral immunity to poliomyelitis, tetanus, hepatitis B, measles, rubella, and mumps in children after chemotherapy.

BACKGROUND: To evaluate the effect of chemotherapy on humoral immunity to vaccine-preventable disease, the authors investigated the persistence of protective antibody titers in a group of patients who were alive and well after they were treated for pediatric malignancies. METHODS: Serum antibody levels were evaluated for polio, tetanus, hepatitis B, rubella, mumps, and measles in 192 children. The terms lack of immunity and loss of immunity, respectively, were used to describe the absence of immunity in patients who were tested only after chemotherapy and in patients who were tested both before and after chemotherapy and determined to have immunity before chemotherapy. RESULTS: Overall, the absence of a protective serum antibody titer for hepatitis B, measles, mumps, rubella, tetanus, and polio was detected in 46%, 25%, 26%, 24%, 14%, and 7% of patients, respectively. On univariate analysis, loss of antibodies against rubella, mumps, and tetanus was associated significantly with younger age (P < 0.001, P = 0.02, and P = 0.001, respectively), and loss of antibodies against measles was significantly associated with younger age and female gender (P = 0.0003 and P = 0.008, respectively). The administration of 59 booster vaccinations to 51 patients who had lost > or = 1 protective antibody titer resulted in an overall response rate of 93%. CONCLUSIONS: Chemotherapy induced different rates of loss of protective antibody titers depending on the type of vaccination administered. This finding may be responsible for the failure of vaccination programs for patients who have undergone chemotherapy. The administration of a booster dose after the completion of chemotherapy is a simple and cost-effective way to restore humoral immunity against most vaccine-preventable diseases.