Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis.

BACKGROUND: Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST). METHODS AND FINDINGS: The primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (-0.06; 95% UI: [-0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics. CONCLUSIONS: Compared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels.

A comparison of the performance of contemporary, historical, and cross-lab controls in QTc assessment in conscious nonhuman primates.

Cardiovascular safety pharmacology and toxicology studies include vehicle control animals in most studies. Electrocardiogram data on common vehicles is accumulated relatively quickly. In the interests of the 3Rs principles it may be useful to use this historical information to reduce the use of animals or to refine the sensitivity of studies. We used implanted telemetry data from a large nonhuman primate (NHP) cardiovascular study (n = 48) evaluating the effect of moxifloxacin. We extracted 24 animals to conduct a n = 3/sex/group analysis. The remaining 24 animals were used to generate 1000 unique combinations of 3 male and 3 female NHP to act as control groups for the three treated groups in the n = 3/sex/group analysis. The distribution of treatment effects, median minimum detectable difference (MDD) values were gathered from the 1000 studies. These represent contemporary controls. Data were available from 42 NHP from 3 other studies in the same laboratory using the same technology. These were used to generate 1000 unique combinations of 6, 12, 18, 24 and 36 NHP to act as historical control animals for the 18 animals in the treated groups of the moxifloxacin study. Data from an additional laboratory were also available for 20 NHP. The QT, RR and QT-RR data from the three sources were comparable. However, differences in the time course of QTc effect in the vehicle data from the two laboratories meant that it was not possible to use cross-lab controls. In the case of historical controls from the same laboratory, these could be used in place of the contemporary controls in determining a treatment's effect. There appeared to be an advantage in using larger (≥18) group sizes for historical controls. These data support the opportunity of using historical controls to reduce the number of animals used in new cardiovascular studies.

Intracameral antibiotics during cataract surgery: efficacy, safety, and cost-benefit considerations.

PURPOSE OF REVIEW: We summarize evidence-based considerations regarding the use of intracameral antibiotics during cataract surgery. RECENT FINDINGS: The use of intraoperative intracameral antibiotics reduced the incidence of postcataract surgery endophthalmitis 3.5-fold, with an odds ratio ranging from 0.14 to 0.19. A survey of the American Society of Cataract and Refractive Surgery showed usage of intracameral injections of antibiotics increased by 16% in the United States between 2014 and 2021. The frequency of vancomycin usage has sharply dropped to 6%, while moxifloxacin is now the dominant choice at 83% among respondents. One analysis showed that 2500 patients need to be treated with intracameral antibiotics to prevent one case of endophthalmitis. A 500 µg intracameral moxifloxacin at $22 dollars per dose is cost-effective, including for patients with posterior capsular rupture (PCR). SUMMARY: Studies substantiate the safety and efficacy of intracameral antibiotics for endophthalmitis prophylaxis. Intracameral moxifloxacin and cefuroxime are the most common choices. While vancomycin shows potential for efficacy, further studies evaluating clinical outcomes are needed. Adverse events are rare and commonly due to errors in preparation. Topical antibiotics do not provide additional prophylactic benefits to intracameral regimens. Intracameral antibiotics given alone are cost-effective.

Development and validation of synchronous spectrofluorimetric method for the simultaneous determination of duvelisib and moxifloxacin: greenness metric assessment and application to a pharmacokinetic study in rats.

Duvelisib (DUV) is a potent anticancer drug whereas Moxifloxacin (MOX) is an antimicrobial drug with anti-proliferative potency against cancerous cells, which is empirically administered in cancer treatment. DUV and MOX combination is commonly prescribed to combat infections in patients while they are under chemotherapy treatment. This study describes, for the first time, the development of a simple and green synchronous spectrofluorimetric (SSF) method for the simultaneous estimation of DUV and MOX in plasma. DUV and MOX were quantified at 273 and 362 nm, respectively without interference between each other at Δλof 120 nm. The experimental variables influencing fluorescence intensities were thoroughly investigated and the optimum conditions were established. At pH 3.5, the optimum synchronous fluorescence intensity (SFI) was achieved in water solvent by using sodium acetate buffer solution. Calibration curves for DUV and MOX, correlating the SFI with the corresponding drug concentration, were linear in the range of 50-1000 ng mL-1for both drugs, with good correlation coefficients. The method was extremely sensitive, with limits of detection of 24 and 22 ng mL-1, and limits of quantitation of 40 and 45 ngmL-1for DUV and MOX, respectively. The SSF method was validated according to the Food and Drug Administration (FDA) guidelines for validation of analytical procedures, and the validation parameters were acceptable. The proposed SSF method was applied to the pharmacokinetic and bioavailability studies in rats' plasma after single concurrent oral administration of both drugs. The results of the study revealed that caution should be taken with DUV dose when concurrently administered with MOX. The greenness of SSF method was assessed by three different metric tools namely Analytical Eco-scale, Green Analytical Procedure Index, and Analytical Greenness Calculator. The results confirmed that SSF method is an eco-friendly and green analytical approach. In conclusion, the proposed SSF method is a valuable tool for pharmacokinetic/bioavailability studies and therapeutic drug monitoring of simultaneously administered DUV and MOX.

Epidemiology of Nontuberculous Mycobacteria in Tuberculosis suspects, Southwest of China, 2017-2022.

Objectives: This study summarizes the epidemiological characteristics, species distribution, and drug sensitivity of clinical nontuberculous mycobacteria (NTM) isolates at the Public Health Clinical Center of Chengdu, China, from January 2017 to December 2022. Methods: We retrospectively analyzed data from patients with clinically isolated NTM strains. Chi-square analysis assessed the rate of Mycobacterium strain isolation over 6 years. Results: The number of samples tested for Mycobacterium tuberculosis (MTB) and/or NTM increased each year, while MTB detection decreased and NTM detection rose significantly each year (P=0.03). The average age of NTM patients was 51 ± 17.53 years, with a 14.1% HIV infection rate. The predominant isolates were Mycobacterium avium-intracellulare (MAC) and M. chelonae/M. abscessus, with 96.4% of cases being of Han ethnicity. Amikacin, moxifloxacin, and clarithromycin were effective against M. avium and M. intracellulare; linezolid, amikacin, and cefoxitin were effective against M. chelonae/M. abscessus. Over 90% of NTM cases originated from the respiratory tract. Conclusion: The NTM isolation rate in Southwest China has risen in recent years, primarily among elderly patients with a high HIV co-infection rate. The main NTM isolates were MAC and M. chelonae/M. abscessus. Amikacin, moxifloxacin, clarithromycin, and linezolid exhibited strong antibacterial activity against SGM, while amikacin and linezolid displayed relatively better antibacterial activity against RGM. The prevalence of NTM infection may be positively associated with regional economic development and health conditions.

Comparing the sensitivity of cross-over and parallel study designs for QTc assessment: An analysis based on a single large study of moxifloxacin in 48 nonhuman primates.

The cardiovascular safety pharmacology (SP) study conducted to satisfy ICH S7A and S7B has commonly used a cross-over study design where each animal receives all treatments. In an increasing number of cases, cross-over designs are not possible and parallel studies have to be used. These can seldom be as large as 8 animals/treatment to match an n = 8 cross-over. Animals in parallel designs receive only one treatment. Parallel studies will have a different sensitivity to detect changes. This sensitivity is a critical question in using nonclinical QTc evaluations to support an integrated proarrhythmic risk assessment under the newly released ICH E14/S7B Q&As. The current analysis used a study large enough (n = 48) to be analyzed both as a parallel and as a cross-over design to directly compare the performance of the two experimental designs coupled to different statistical models, while all other study conduct aspects were the same. A total of 48 nonhuman primates (NHP) received 2 different treatments twice: vehicle, moxifloxacin (80 mg/kg), vehicle, moxifloxacin (80 mg/kg). Post-dose QTc interval data were recorded for 48 h for each treatment. Data were analyzed using 12 animals randomly selected for each treatment in a parallel design or as an n = 48 animal cross-over study. Different statistical models were used. The primary endpoint was the residual deviation (sigma) from the models applied to hourly time intervals. The sigma was used to determine the minimal detectable difference (MDD) for the study design-statistical model combination. Two statistical models were applicable to either study design. They gave similar sigma and resulting MDD values. In cross-over designs, the individual animal identification (ID) can be used in the statistical model. This enabled the smallest MDD value. Simple statistical models for analysis were identified: Treatment + Baseline for parallel designs and Treatment + ID for cross-over designs. The statistical sensitivity of NHP parallel study designs is reasonable (MDD for n = 6 of 12.7 ms), and in combination with testing exposures higher than likely to be necessary in man could be used in an integrated risk assessment. Where sensitivity of the NHP in vivo QTc assessment is critical, the cross-over design enabled a higher sensitivity (MDD 12.2 ms for n = 4; 8 ms for n = 8).

Occurrence, distribution, and risk assessment of quinolone antibiotics in municipal sewage sludges throughout China.

A nationwide study of the occurrence, distribution, potential drivers, and ecological risks of 24 quinolone antibiotics (QNs) in 74 Chinese sludge samples from 48 wastewater treatment plants (WWTPs) was conducted. In domestic sludge, the ∑QNs concentrations were  3rd-generation QNs > 4th-generation QNs > 1st-generation QNs. Meanwhile, abundant veterinary and human/veterinary quinolones (

Synthesis, characterization and assessment of antioxidant and antibacterial potential of dihydroquinoline-3-carboxylic acid and their metal derivatives.

Metal complexes of drug are used to inhibit growth of pathogenic microorganisms and reduces drug resistance. Moxifloxacin is a dihydroquinoline-3-carboxylic acid 4th generation fluoroquinolone antibiotic that has tendency to bind with metal ions. In current study four moxifloxacin-metal complexes i.e. Moxifloxacin-sliver (Moxi-Ag), Moxifloxacin-rhodium (Moxi-Rh), Moxifloxacin-titanium (Moxi-Ti) and Moxifloxacin-rubidium (Moxi-Rb) have been synthesized and evaluated for antibacterial activities against resistant microorganisms along with antioxidant effects. The structure elucidation was carried out using FTIR, 1H- NMR and UV-Vis spectroscopy. Agar well diffusion method and DPPH (1, 1- dipheny1-2-picrylhydrazyl) methods were used to study the antibacterial and antioxidant activity respectively. Both 1H NMR and FTIR spectra clearly showed that Moxi-metal complexes are formed due to change in their carboxyl stretching band in IR, H-2 and H-5 peak position in 1H NMR. All the Moxi-metal complexes showed distinguished antibacterial effects against both Gram-negative and Gram-positive bacteria as compared to drug which was found resistant against many microorganisms. Moxi-Rb and Moxi-Ag metal complexes showed higher antioxidant activity (IC50 values range from 8.26 - 9.19 µg/ml) than Moxi-Ti and Moxi-Rh metal complexes (IC50 range from 11.23 - 14.65 µg/ml).

Antibiotics and antimycotics in waste water treatment plants: Concentrations, removal efficiency, spatial and temporal variations, prediction, and ecological risk assessment.

For investigating the spatial, temporal variations and assessing ecological risk of 10 antibiotics and 6 antimycotics, influent sewage water and treated effluent were collected during three different seasons in 19 waste water treatment plants of Tianjin. High performance liquid chromatography tandem mass spectrometry was used to analyze 16 substances. The concentration range of influent samples was not detected (nd) -547.94 ng/L and the concentration range of effluent samples was nd-52.97 ng/L. By calculating the removal efficiency, it was found that Ciprofloxacin (CIP), Ofloxacin (OFL) and Clotrimazole (CTR) were effectively removed. There were significant spatial and temporal differences, the concentration in the dry season was evidently higher than that in the wet and normal seasons, and the northeast was lower than that in the northwest and southeast. By establishing a data set of influent and effluent, the priority features were extracted by feature engineering, which were temperature and NH3-N. Under the condition of ensuring the best performance of the models, the influent model with 9 features and the effluent model with 4 features were established, and the quantitative relationship between the above features and concentration was obtained through partial dependence analysis. Except for Moxifloxacin (MOX), Norfloxacin (NOR) and OFL in the influent samples, the RQ values for other antibiotics and antimycotics were less than 0.1. Among the effluent samples, only NOR had an RQ value greater than 0.1, and OFL, MOX, and Pefloxacin (PEF) had RQ values between 0.01 and 0.1. Comparing the observations and predictions individual RQ values, the predictions were ideal and matched the observations. This work effectively assessed environmental impact and provided a valuable reference for evaluating antibiotics and antimycotics ecological toxicity.

Economic Evaluation of Nemonoxacin, Moxifloxacin and Levofloxacin in the Treatment of Early Community-Acquired Pneumonia with Possible Pulmonary Tuberculosis.

The Chinese community-acquired pneumonia (CAP) Diagnosis and Treatment Guideline 2020 recommends quinolone antibiotics as the initial empirical treatment options for CAP. However, patients with pulmonary tuberculosis (PTB) are often misdiagnosed with CAP because of the similarity of symptoms. Moxifloxacin and levofloxacin have inhibitory effects on mycobacterium tuberculosis as compared with nemonoxacin, resulting in delayed diagnosis of PTB. Hence, the aim of this study is to compare the cost-effectiveness of nemonoxacin, moxifloxacin and levofloxacin in the treatment of CAP and to determine the value of these treatments in the differential diagnosis of PTB. Primary efficacy data were collected from phase II-III randomized, double-blind, multi-center clinical trials comparing nemonoxacin to moxifloxacin (CTR20130195) and nemonoxacin to levofloxacin (CTR20140439) for the treatment of Chinese CAP patients. A decision tree was constructed to compare the cost-utility among three groups under the perspective of healthcare system. The threshold for willingness to pay (WTP) is 1-3 times GDP per capita ($11,174-33,521). Scenarios including efficacy and cost for CAP patients with a total of 6% undifferentiated PTB. Sensitivity and scenario analyses were performed to test the robustness of basic analysis. The costs of nemonoxacin, moxifloxacin, and levofloxacin were $903.72, $1053.59, and $1212.06 and the outcomes were 188.7, 188.8, and 188.5 quality-adjusted life days (QALD), respectively. Nemonoxacin and moxifloxacin were dominant compared with levofloxacin, and the ICER of moxifloxacin compared with nemonoxacin was $551,643, which was much greater than WTP; therefore, nemonoxacin was the most cost-effective option. Regarding patients with PTB who were misdiagnosed with CAP, taking nemonoxacin could save $290.76 and $205.51 when compared with moxifloxacin and levofloxacin and resulted in a gain of 2.83 QALDs. Our findings demonstrate that nemonoxacin is the more economical compared with moxifloxacin and levofloxacin, and non-fluoroquinolone antibiotics are cost-saving and utility-increasing compared to fluoroquinolones in the differential diagnosis of PTB, which can help healthcare system in making optimal policies and help clinicians in the medication of patients.

Assessment of Antimicrobial Activity of Dehydrated Amniotic Membrane in Infectious Keratitis: A Small Retrospective Case Series and In Vitro Study.

PURPOSE: To describe a small case series of infectious keratitis with poor visual outcomes after amniotic membrane (AM) placement and to prospectively evaluate whether AM demonstrates antibacterial activity in vitro against pathogens commonly isolated from infectious corneal ulcers. METHODS: A retrospective case series and in vitro study of antibacterial activity of dehydrated AM using disk diffusion and measurement of inhibitory zones for bacterial assessment and inverted microscopy analysis for Acanthamoeba sp. growth. RESULTS: Three cases of known etiology infectious keratitis are described where the clinical presentation worsened after treatment with AM. In vitro analysis of dehydrated AM, with and without a soft contact lens, demonstrated no inhibition of growth against Pseudomonas aeruginosa or Streptococcus pneumoniae. There was minimal growth inhibition of Staphylococcus aureus, although these zones of inhibition were much smaller than that surrounding the positive control. For Acanthamoeba sp., solubilized, dehydrated AM did not alter cyst density. CONCLUSIONS: In an in vitro analysis, dehydrated AM did not provide evidence for a potentially clinically meaningful antibacterial effect against organisms commonly isolated from corneal ulcers.

Tailoring Terpesomes and Leciplex for the Effective Ocular Conveyance of Moxifloxacin Hydrochloride (Comparative Assessment): In-vitro, Ex-vivo, and In-vivo Evaluation.

AIM: To compare the ability of both terpesomes (TPs) and leciplex (LPs) loaded moxifloxacin hydrochloride (MOX) for enhancing ocular drug conveyance. METHODS: Two separate 21.31 full-factorial trials were established to determine the influence of multiple variables upon nanovesicles properties and select the optimized formulae using Design Expert® software. The thin-film hydration method was used to formulate TPs, while the single-step procedure was used for LPs. All formulae were characterized for their entrapment efficiency percent (EE%), particle size distribution (PS), polydispersity index (PDI), and zeta potential (ZP). Then, the optimized formulae were selected, evaluated, and compared for additional assessments. RESULTS: The optimized formulae TP4 and LP1 showed EE% of 84.14±0.21 and 78.47±0.17%, PS of 578.65±5.65 and 102.41±3.39 nm, PDI of 0.56±0.04 and 0.28±0.01, ZP of -12.50±0.30 and 32.50±0.50 mV, respectively. Further, LP1 showed enhanced corneal permeation across cow cornea compared to MOX solution and TP4. Besides, confocal laser scanning microscopy assessment viewed valuable infiltration from the fluoro-labeled LP through corneal layers compared to TP. LP1 showed spherical morphology and, its ability to adhere to mucus membranes was justified. Further, LP1 showed superiority over MOX solution in biofilm inhibition and eradication in addition to the treatment of infected mice with methicillin-resistant Staphylococcus aureus without any inflammatory response. Finally, the histopathological study verified the harmlessness and biocompatibility of the assembled LPs. CONCLUSION: The gained outcomes confirmed the capability of utilizing LPs as a successful nanovesicle for the ocular conveyance of MOX over TPs and MOX solution.

Clinical Benefits and Cost-Effectiveness of Moxifloxacin as Initial Treatment for Community-Acquired Pneumonia: A Meta-Analysis and Economic Evaluation.

PURPOSE: Moxifloxacin and levofloxacin are currently recommended as empirical initial treatment options for community-acquired pneumonia (CAP) in China according to guidelines. Most studies that evaluated the efficacy and safety of moxifloxacin and levofloxacin in treating CAP as initial empirical treatment were single-centered trials assessing different clinical end points. In addition, there is limited research investigating moxifloxacin's clinical benefits in the context of health care resource utilization and reimbursement from the payer's perspective in China. Hence, this study was aimed at comparing the clinical efficacy of moxifloxacin and levofloxacin by conducting a meta-analysis and assessing their economic value from the China payer's perspective through a cost-utility analysis model. METHODS: For the meta-analysis, 6 bibliographic databases were searched for relevant publications from January 2000 to August 2020, and studies were assessed for eligibility under predetermined criteria. Meta-analysis was performed by using a random effects model when analyses included >2 trials. For the economic evaluation, a decision-tree model was constructed to investigate the cost-utility of moxifloxacin versus levofloxacin as initial regimens in the treatment of CAP inpatients. Parameter values were derived from meta-analysis, published literature, and clinician survey. The outcome was reported in the form of an incremental cost-effectiveness ratio. One-way sensitivity analysis and probabilistic sensitivity analysis were undertaken to assess the robustness of the model. FINDINGS: Twenty-seven randomized controlled trials were included in the meta-analysis. Results indicated that the clinical response rate at the test-of-cure visit with initial treatment of moxifloxacin was significantly higher than that of levofloxacin (3441 patients; random effects model; I2 = 49%; odds ratio, 3.35; 95% CI, 2.35-4.77; P < 0.001). In terms of the safety profile, total adverse events were not significantly different between the 2 groups (2770 patients; random effects model; I2 = 40%; odds ratio, 0.77; 95% CI, 0.56-1.06; P = 0.11). Output of the cost-utility model showed that under the willingness-to-pay threshold of one-time China gross domestic product per capita, moxifloxacin is dominant over levofloxacin, being less costly and more efficacious (0.002 quality-adjusted life year gained, CNY 844 [US$131] saved in total cost, negative incremental cost-effectiveness ratio). Sensitivity analyses indicated the robustness of the model as moxifloxacin remained dominant when model parameter values fluctuated. IMPLICATIONS: Moxifloxacin is more efficacious than levofloxacin as the initial empirical treatment for CAP. In addition, treatment of CAP with moxifloxacin instead of levofloxacin is expected to be cost-saving from the perspective of payers in China. However, for the cost-utility analysis, in the absence of a national representative database on costs for hospitalization in China, inputs in the cost-utility model could be underestimated or overestimated due to estimating errors applied to both treatment arms.

Decision Analysis: Omadacycline Relative to Moxifloxacin Among Hospitalized Community-Acquired Bacterial Pneumonia Patients at Risk of Clostridioides difficile Infection.

BACKGROUND AND OBJECTIVE: Omadacycline is an aminomethylcycline antibiotic approved in the USA as once-daily intravenous/oral monotherapy for adults with community-acquired bacterial pneumonia (CABP). Omadacycline demonstrated noninferiority to the fluoroquinolone moxifloxacin in a phase III CABP trial; adverse-event rates were similar between treatment groups except for Clostridioides difficile infection (CDI), which occurred in 2% of moxifloxacin-treated patients and 0% of patients on omadacycline. Conceptual healthcare-decision analytic models were developed to better understand the economic implications of antibiotic selection and CDI risk in acute-care facilities. METHODS: A conceptual healthcare-decision analytic model was created to estimate incremental costs associated with treating 100 hospitalized CABP patients with an initial 5-day inpatient regimen of omadacycline instead of moxifloxacin. The underlying model assumption was that treatment with omadacycline has the potential to reduce CDI events relative to moxifloxacin. The model included excess costs associated with each treatment group from admission through discharge. Attributable CDI cost per case in the moxifloxacin group varied from $15,000 to $45,000 (US$). Omadacycline acquisition cost was $300-600/day for 5 days. RESULTS: At a CDI attributable cost per case of $30,000 (base-case analyses), the incremental treatment cost (US$) per 100 patients ranged from $300,000 to $- 120,000 (cost savings). The excess CDI incidence in moxifloxacin-treated patients would need to be 5-10% for omadacycline to be cost-saving, assuming the attributable CDI cost is approximately $30,000. CONCLUSION: Targeted omadacycline use may reduce economic burden associated with hospitalized CABP patients treated with moxifloxacin if it can reduce excess cases of moxifloxacin-associated CDI.

Bedaquilina para pacientes com tuberculose resistentes à rifampicina, multirresistentes e extensivamente resistentes a medicamentos / Bedaquiline for tuberculosis-resistant patients rifampicin, multi-resistant and extensively resistant to medicines

INTRODUÇÃO: A tuberculose (TB), conhecida anteriormente como tísica, é uma doença que pode ser causada por sete espécies do gênero do complexo Mycobacterium sendo a mais importante, do ponto de vista de saúde pública, a M. tuberculosis. Globalmente cerca de 10 milhões de pessoas tiveram TB no ano de 2018. No Brasil, em 2018, foram diagnosticados 72.788 casos novos de TB o que representa uma incidência de 34,8 casos por 100 mil habitantes. A TB pode ser classificada como pulmonar e extrapulmonar, sendo a primeira forma mais prevalente. Além disso, a TB pode ser classificada conforme a resistência à medicamentos, tais como: RR-TB, MDR-TB e XDR-TB. PERGUNTA DE PESQUISA: A bedaquilina (BDQ) associada ao tratamento padrão para pacientes adultos com RR-TB, MDR-TB ou XDR-TB, é mais eficaz, efetiva e segura comparado ao tratamento padrão utilizado pelo SUS (levofloxacino, moxifloxacino, amicacina, capreomicina, etionamida, terizidona, linezolida, clofazimina, pirazinamida, etambutol, isoniazida, rifampicina e paraminossalicílico) ou placebo? TECNOLOGIA: Bedaquilina (Sirturo®). EVIDÊNCIAS CIENTÍFICAS: A revisão sistematizada recuperou nove estudos (uma revisão sistemática [RS] com meta-análise em rede [network meta-analysis - NMA], um ensaio clínico randomizado [ECR] com dois relatos e sete estudos de coorte [seis retrospectivas e uma prospectiva]). A RS, com NMA, avaliou a BDQ em comparação aos medicamentos delamanida, metronidazol, moxifloxacino e levofloxacino. A RS avaliou os desfechos conversão de cultura do escarro e aceitabilidade, e não foram verificados resultados estatisticamente significantes. Os estudos de coorte avaliaram a BDQ em comparação aos mais diversos tratamentos disponíveis para RR-TB, MDR-TB e XDR-TB. As coortes avaliaram os seguintes desfechos: sobrevida sucesso no tratamento, tratamento completo, cura, conversão da cultura do escarro e mortalidade. Os resultados não foram estatisticamente significantes na meta-análise de modelo de efeitos randomizados para todos os desfechos avaliados, porém os resultados dos efeitos fixos demostraram resultados estatisticamente significantes favorecendo o tratamento com BDQ em comparação ao tratamento sem BDQ. Vale salientar que foram realizadas análises de subgrupos com o ECR, TMC207, que avaliou eficácia e segurança da BDQ associado ao tratamento padrão em comparação ao grupo placebo associado ao tratamento padrão em até 120 semanas para os desfechos de conversão da cultura do escarro, cura e segurança (mortalidade), porém não mudaram a direção dos resultados nas duas modelagem da meta-análise. AVALIAÇÃO ECONÔMICA (AE): Os tratamentos com BDQ comparado aos tratamentos do SUS mostraram-se dominados na avaliação de custo-efetividade, para o desfecho paciente curado. Assim, os tratamentos do SUS para RR-TB, MDR-TB e XDR-TB dominaram todos os tratamentos com BDQ, ou seja, todos os tratamentos com BDQ foram menos efetivos e mais caros que os tratamentos do SUS para obter a cura dos indivíduos com RR-TB, MDR-TB e XDR-TB. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO (AIO): A AIO, para os pacientes com RR-TB, variou entre um custo incremental R$ 936 mil no caso base a uma economia de -R$ 1 milhão ao final do quinto ano no cenário alternativo; para MDR-TB variou entre uma economia de -R$44 mil no caso base a um gasto de R$ 110 mil ao final do quinto ano no cenário alternativo; e para XDR-TB variou entre um custo incremental de R$ 188 mil no caso base a R$ 4 mil no cenário alternativo ao final do quinto ano. MONITORAMENTO DO HORIZONTE TECNOLÓGICO (MHT): Cinco medicamentos foram detectados no MHT para pacientes com MDR-TB e XDR-TB (canamicina, cicloserina, sutezolida, pretomanide e protionamida). CONSIDERAÇÕES FINAIS: Há resultados conflitantes nas evidências encontradas no relatório. O ECR, analisado como de alto risco de viés (Risk of Bias 2.0) mostrou que a BDQ associada ao tratamento padrão é eficaz em comparação ao grupo de tratamento placebo associado ao tratamento padrão, porém com maior número de mortes e episódios de náusea em comparação ao grupo de tratamento sem a BDQ. Os resultados da RS, com NMA, de qualidade moderada, não demonstraram diferenças estatisticamente significantes entre as tecnologias avaliadas. Os resultados das meta-análises dos estudos de coorte de baixa qualidade metodológica (Newcastle-Ottawa Scale), em combinação com o ECR da BDQ, foram demonstrados em efeitos fixos e randomizados. Os desfechos sucesso no tratamento, tratamento completo, cura, conversão da cultura do escarro e mortalidade não foram estatisticamente significantes no modelo de efeito randomizados na meta-análise. No entanto, foram estatisticamente significantes no modelo de efeito fixos da metaanálise, e favoreceram o tratamento com BDQ em comparação aos pacientes não tratados sem BDQ. A AE demonstrou que os tratamentos com BDQ foram dominados em relação aos tratamentos disponibilizados no SUS sem BDQ, para o desfecho paciente tratado, sendo, portanto, mais custosos e menos efetivos. A AIO, para pacientes com RR-TB, variou entre R$ 936 mil no caso base a uma economia de -R$ 1 milhão no cenário alternativo ao final do quinto ano, para MDRTB variou entre uma economia de -R$44 mil no caso base a um custo de R$ 110 mil ao final do quinto ano no cenário alternativo e para XDR-TB variou entre um custo adicional de R$ 188 mil no caso base a um custo adicional de R$ 4 mil ao final do quinto ano no cenário alternativo. RECOMENDAÇÃO PRELIMINAR DA CONITEC: A Conitec, em sua 87ª reunião ordinária, realizada nos dias 03 e 04 de junho de 2020, deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à incorporação no SUS da bedaquilina para pacientes com tuberculose resistente à rifampicina (RR-TB), a tuberculose multirresistente (MDR-TB) e para tuberculose extensivamente resistente a medicamentos (XDR-TB), condicionada ao monitoramento e apresentação dos dados de vida real, efetividade e segurança, da utilização da bedaquilina pela população brasileira e conforme critérios estabelecidos em protocolo do Ministério da Saúde. CONSULTA PÚBLICA: A Consulta Pública nº 24/2020 foi realizada entre os dias 22/06/2020 a 13/07/2020. Foram recebidas 66 contribuições no total, das quais 19 (29%) foram pelo formulário para contribuições técnico-científicas e 47 (71%) pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Das 19 contribuições de cunho técnico-científico, 95% submeteram a contribuição com opinião concordando totalmente com a recomendação preliminar da comissão. Apenas uma contribuição discordou da recomendação preliminar da Conitec, mas foi uma contribuição equivocada e se tratava de outro tema de consulta pública, portanto, foi excluída da análise. Das 47 contribuições recebidas sobre experiência ou opinião, apenas 15 foram analisadas, pois 32 estavam em branco, se tratavam de outro tema ou foram preenchidas inadequadamente. As 15 contribuições remanescentes concordaram 100% com a decisão preliminar da comissão. Após a apreciação das contribuições encaminhadas na consulta pública nº 24/2020, o plenário da Conitec considerou que: I) Foi apresentado um novo preço de USD 340 da bedaquilina pela Johnson & Johnson, sendo proposto um desconto de 15% no preço utilizado no relatório de recomendação preliminar (USD 400); II) Foram enviadas novas estimativas de incidência para pacientes com tuberculose multirresistente, bem como evidência de possíveis limitações na análise de impacto orçamentário; III) A nova análise de impacto orçamentário, utilizando os novos parâmetros enviados na consulta pública, aponta para economia de recursos na população com tuberculose multirresistente e um custo incremental com tuberculose resistente à rifampicina e tuberculose extensivamente resistente no cenário sem taxa de difusão gradual da bedaquilina (100% no primeiro ano de incorporação). No entanto, ao adotarmos o cenário com taxa difusão gradual da bedaquilina, 30% no primeiro ano de incorporação a 70% no quinto ano, os resultados mudam e proporcionam economia de recursos para pacientes com tuberculose resistente à rifampicina e um custo incremental para pacientes com tuberculose multirresistente e tuberculose extensivamente resistente. RECOMENDAÇÃO FINAL DA CONITEC: Os membros da Conitec presentes na 89ª reunião ordinária, no dia 05 de agosto de 2020, deliberaram por unanimidade recomendar a incorporação da bedaquilina para pacientes com tuberculose resistentes à rifampicina, multirresistentes e extensivamente resistente a medicamentos, condicionado a apresentação de dados de vida real e conforme preconizado pelo Ministério da Saúde. Foi assinado o Registro de Deliberação nº 538/2020. DECISÃO: Incorporar a bedaquilina para pacientes com tuberculose resistentes à rifampicina, multirresistentes e extensivamente resistente a medicamentos, condicionado a apresentação de dados de vida real e conforme preconizado pelo Ministério da Saúde, no âmbito do Sistema Único de Saúde - SUS, conforme Portaria nº 36, publicada no Diário Oficial da União nº 168, seção 1, página 77, em 01 de setembro de 2020.

The Role of Delafloxacin in Patients with Community-Acquired Bacterial Pneumonia in the Outpatient Setting: A Budget Impact Model.

BACKGROUND AND OBJECTIVE: Community-acquired bacterial pneumonia (CABP) affects millions of people each year in the USA. The majority of patients with CABP are treated in the community setting with empirical antimicrobial therapy. Delafloxacin is an anionic fluoroquinolone approved for the treatment of adult patients with CABP. This de novo analysis sought to estimate the budget impact of delafloxacin in the treatment of adult patients with CABP in the outpatient setting from the payer's perspective. METHODS: A budget impact model (BIM) was developed from the perspective of a US third-party payer to estimate the cost of introducing delafloxacin for the outpatient treatment of CABP over a 1-year time horizon. Population, clinical, and cost inputs were based on the available literature, clinical trial data, and real-world evidence studies. Scenario analyses were conducted to evaluate the potential budget impact among COPD/asthma patients based on the findings from the phase III trial of delafloxacin for CABP, which indicated that patients with COPD or asthma may experience improved effectiveness with delafloxacin compared to moxifloxacin. RESULTS: In the base-case analysis, with a hypothetical plan of 1,000,000 members, the model estimated that adding delafloxacin to the formulary resulted in a total budget impact of $58,987. This increase was mainly attributed to treatment acquisition costs. In the scenario analysis that was restricted to COPD/asthma patients, adding delafloxacin to the formulary was estimated to result in a total budget impact of $5,042. CONCLUSION: The results of the budget impact analyses provide conservative estimates of the impact of adding delafloxacin to outpatient formularies in substitution of moxifloxacin.

Informe diário de evidências COVID-19: busca realizada em 19 de junho de 2020 / COVID-19 daily evidence report: search conducted on June 19, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 9 artigos e 6 protocolos.

Prediction of treatment outcomes for multidrug-resistant tuberculosis by whole-genome sequencing.

BACKGROUND: Whole-genome sequencing (WGS) has been proposed to be a powerful tool to predict drug resistance for antitubercular drugs. However, the feasibility of WGS in predicting final treatment outcomes for multidrug-resistant tuberculosis (MDR-TB) patients remains unclear PATIENTS AND METHODS: In this prospective observational study conducted from January 2014 to September 2016, MDR-TB patients were enrolled consecutively. Genotypic drug sensitivity testing was performed via WGS using culture isolates. Patients were followed for two years to determine the treatment outcomes. Multivariate analysis was used to identify the association between information provided by WGS and the final treatment outcomes RESULTS: A total of 123 patients with MDR-TB were included in this study. The overall favorable treatment outcome rate was 60.2%. Multivariate analysis showed that independent risk factors associated with unfavorable treatment outcome including high-level moxifloxacin phenotypic resistance (OR, 4.362; 95%CI, 1.364-13.950; p=0.013), cycloserine phenotypic resistance (OR, 7.457; 95%CI, 1.644-33.819; p=0.009), mutations causing high-level fluoroquinolones resistance (OR, 3.947; 95%CI, 1.195-13.034; p=0.024), and ethA mutation (OR, 3.817; 95% CI, 1.154-12.823; p=0.028). WGS costs for each patient are ¥450 ($63), and the average turnaround time was one week CONCLUSIONS: In summary, WGS showed promising feasibility in predicting treatment outcomes for MDR-TB patients within a clinically relevant time frame.

Intracellular Pharmacodynamic Modeling Is Predictive of the Clinical Activity of Fluoroquinolones against Tuberculosis.

Clinical studies of new antitubercular drugs are costly and time-consuming. Owing to the extensive tuberculosis (TB) treatment periods, the ability to identify drug candidates based on their predicted clinical efficacy is vital to accelerate the pipeline of new therapies. Recent failures of preclinical models in predicting the activity of fluoroquinolones underline the importance of developing new and more robust predictive tools that will optimize the design of future trials. Here, we used high-content imaging screening and pharmacodynamic intracellular (PDi) modeling to identify and prioritize fluoroquinolones for TB treatment. In a set of studies designed to validate this approach, we show moxifloxacin to be the most effective fluoroquinolone, and PDi modeling-based Monte Carlo simulations accurately predict negative culture conversion (sputum sterilization) rates compared to eight independent clinical trials. In addition, PDi-based simulations were used to predict the risk of relapse. Our analyses show that the duration of treatment following culture conversion can be used to predict the relapse rate. These data further support that PDi-based modeling offers a much-needed decision-making tool for the TB drug development pipeline.

Fluoroquinolone Antibiotic Prophylaxis to Prevent Post-Traumatic Bacterial Infectious Endophthalmitis: Using Monte Carlo Simulation to Evaluate the Probability of Success.

Purpose: Patients with open globe injuries routinely receive fluoroquinolone (FQ) prophylaxis to prevent bacterial infectious endophthalmitis. Owing to the rarity of this infection, there is an absence of clinical trials evaluating optimal prophylactic FQ dosing. To address this knowledge gap, we conducted a Monte Carlo simulation (MCS)-based study to identify the FQ dosing option(s) that optimize pharmacokinetic-pharmacodynamic FQ target attainment against common bacterial pathogens implicated in post-traumatic bacterial infectious endophthalmitis (PTBIE). Methods: Weighted mean pharmacokinetic parameters and standard deviations for ciprofloxacin, levofloxacin, and moxifloxacin were calculated from published studies in healthy volunteers. The incidence and FQ susceptibility profiles for the most common bacteria causing PTBIE were extracted from the literature. MCS was used to determine the cumulative fraction of response (CFR) for 5 FQ dosing options to determine the probability of attaining pathogen-specific target 24-hour area under the curve to minimum inhibitory concentration ratios in the vitreous humor of the eye against the 4 most common causative bacteria seen in PTBIE. Results: Moxifloxacin 400 mg po daily (M400) achieved the highest CFR (72%). Levofloxacin dosing options achieved CFRs between 54% and 63%. Ciprofloxacin dosing options achieved CFRs between 28% and 35%. Conclusion: M400 optimized the likelihood of prophylactic success in the prevention of PTBIE, and based on the study findings, M400 is predicted to optimize the probability of success compared with ciprofloxacin and levofloxacin dosing options currently endorsed by expert opinion.