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The New England Journal of Medicine May 2021Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis.
METHODS
In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months.
RESULTS
Among 2516 participants who had undergone randomization, 2343 had a culture positive for that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group.
CONCLUSIONS
The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).
Topics: Adolescent; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Child; Confidence Intervals; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Moxifloxacin; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Pulmonary; Young Adult
PubMed: 33951360
DOI: 10.1056/NEJMoa2033400 -
Clinical Microbiology and Infection :... Jan 2022Outcomes of treatment of tuberculosis patients with regimens including pretomanid have not yet been systematically reviewed. (Review)
Review
BACKGROUND
Outcomes of treatment of tuberculosis patients with regimens including pretomanid have not yet been systematically reviewed.
OBJECTIVES
To appraise existing evidence on efficacy and safety of pretomanid in tuberculosis.
DATA SOURCES
Pubmed, clinicaltrials.gov. and Cochrane library.
STUDY ELIGIBILITY CRITERIA
Quantitative studies presenting original data on clinical efficacy or safety of pretomanid.
PARTICIPANTS
Patients with tuberculosis.
INTERVENTIONS
Treatment with pretomanid or pretomanid-containing regimens in minimum one study group.
METHODS
Two authors independently extracted data and assessed risk of bias. Data on efficacy (early bactericidal activity, bactericidal activity, end-of-treatment outcomes and acquired resistance) and safety were summarized in tables. Mean differences in efficacy outcomes between regimens across studies were calculated.
RESULTS
Eight studies were included; four randomized controlled trials on 2-week early bactericidal activity in rifampicin-susceptible tuberculosis, three trials with randomized rifampicin-susceptible tuberculosis arms and a single rifampicin-resistant tuberculosis arm (two on 8-week bactericidal activity, one on end-of-treatment outcomes), one single-arm trial with end-of-treatment outcomes in highly resistant tuberculosis. Activity of pretomanid-moxifloxacin-pyrazinamide was superior to standard treatment on daily change in colony-forming units at days 0-2, 0-56 and 7-56 and time to culture conversion in rifampicin-susceptible tuberculosis (hazard ratio: 1.7; 95% CI 1.1-2.7), but not at end of treatment in one study. This study was stopped due to serious hepatotoxic adverse events, including three deaths, in 4% (95% CI 2-8) patients on pretomanid-moxifloxacin-pyrazinamide and none in controls. In patients with uncomplicated rifampicin-resistant tuberculosis on pretomanid-moxifloxacin-pyrazinamide treatment, 91% (95% CI 59-100) had favourable end-of-treatment outcomes. In patients with highly resistant tuberculosis, 90% (95% CI 83-95) on pretomanid-bedaquiline-linezolid had favourable outcomes six months after treatment, but linezolid-related toxicity was frequent. No acquired resistance to pretomanid was reported.
CONCLUSIONS
Evidence suggests an important role for pretomanid in rifampicin-resistant and highly resistant tuberculosis. Trials comparing pretomanid to existing core and companion drugs are needed to further define that role.
Topics: Antitubercular Agents; Humans; Linezolid; Moxifloxacin; Nitroimidazoles; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 34400340
DOI: 10.1016/j.cmi.2021.08.007 -
JAMA Jan 2021Antibiotics are an effective and safe alternative to appendectomy for managing uncomplicated acute appendicitis, but the optimal antibiotic regimen is not known. (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Antibiotics are an effective and safe alternative to appendectomy for managing uncomplicated acute appendicitis, but the optimal antibiotic regimen is not known.
OBJECTIVE
To compare oral antibiotics with combined intravenous followed by oral antibiotics in the management of computed tomography-confirmed uncomplicated acute appendicitis.
DESIGN, SETTING, AND PARTICIPANTS
The Appendicitis Acuta (APPAC) II multicenter, open-label, noninferiority randomized clinical trial was conducted from April 2017 until November 2018 in 9 Finnish hospitals. A total of 599 patients aged 18 to 60 years with computed tomography-confirmed uncomplicated acute appendicitis were enrolled in the trial. The last date of follow-up was November 29, 2019.
INTERVENTIONS
Patients randomized to receive oral monotherapy (n = 295) received oral moxifloxacin (400 mg/d) for 7 days. Patients randomized to receive intravenous antibiotics followed by oral antibiotics (n = 288) received intravenous ertapenem (1 g/d) for 2 days followed by oral levofloxacin (500 mg/d) and metronidazole (500 mg 3 times/d) for 5 days.
MAIN OUTCOMES AND MEASURES
The primary end point was treatment success (≥65%) for both groups, defined as discharge from hospital without surgery and no recurrent appendicitis during 1-year follow-up, and to determine whether oral antibiotics alone were noninferior to intravenous and oral antibiotics, with a margin of 6% for difference.
RESULTS
Among 599 patients who were randomized (mean [SD] age, 36 [12] years; 263 [44%] women), 581 (99.7%) were available for the 1-year follow-up. The treatment success rate at 1 year was 70.2% (1-sided 95% CI, 65.8% to ∞) for patients treated with oral antibiotics and 73.8% (1-sided 95% CI, 69.5% to ∞) for patients treated with intravenous followed by oral antibiotics. The difference was -3.6% ([1-sided 95% CI, -9.7% to ∞]; P = .26 for noninferiority), with the confidence limit exceeding the noninferiority margin.
CONCLUSION AND RELEVANCE
Among adults with uncomplicated acute appendicitis, treatment with 7 days of oral moxifloxacin compared with 2 days of intravenous ertapenem followed by 5 days of levofloxacin and metronidazole resulted in treatment success rates greater than 65% in both groups, but failed to demonstrate noninferiority for treatment success of oral antibiotics compared with intravenous followed by oral antibiotics.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03236961; EudraCT Identifier: 2015-003633-10.
Topics: Acute Disease; Administration, Intravenous; Administration, Oral; Adult; Anti-Bacterial Agents; Appendectomy; Appendicitis; Drug Therapy, Combination; Ertapenem; Female; Follow-Up Studies; Humans; Levofloxacin; Male; Metronidazole; Middle Aged; Moxifloxacin; Tomography, X-Ray Computed; Young Adult
PubMed: 33427870
DOI: 10.1001/jama.2020.23525 -
JAMA Network Open Oct 2022Although topical antibiotics are often prescribed for treating acute infective conjunctivitis in children, their efficacy is uncertain. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Although topical antibiotics are often prescribed for treating acute infective conjunctivitis in children, their efficacy is uncertain.
OBJECTIVE
To assess the efficacy of topical antibiotic therapy for acute infective conjunctivitis.
DESIGN, SETTING, AND PARTICIPANTS
A randomized clinical trial was conducted in primary health care in Oulu, Finland, from October 15, 2014, to February 7, 2020. Children aged 6 months to 7 years with acute infective conjunctivitis were eligible for enrollment. The participants were followed up for 14 days. A subsequent meta-analysis included the present trial and 3 previous randomized clinical trials enrolling pediatric patients aged 1 month to 18 years with acute infective conjunctivitis.
INTERVENTIONS
Participants in the present randomized clinical trial were randomized to moxifloxacin eye drops, placebo eye drops, or no intervention.
MAIN OUTCOMES AND MEASURES
The primary outcome in the present randomized clinical trial was time to clinical cure (in days); in the meta-analysis, the primary outcome was the proportion of participants with conjunctival symptoms on days 3 to 6.
RESULTS
The randomized clinical trial included 88 participants (46 [52%] girls), of whom 30 were randomized to moxifloxacin eye drops (mean [SD] age, 2.8 [1.6] years), 27 to placebo eye drops (mean [SD], age 3.0 [1.3] years), and 31 to no intervention (mean [SD] age, 3.2 [1.8] years). The time to clinical cure was significantly shorter in the moxifloxacin eye drop group than in the no intervention group (3.8 vs 5.7 days; difference, -1.9 days; 95% CI, -3.7 to -0.1 days; P = .04), while in the survival analysis both moxifloxacin and placebo eye drops significantly shortened the time to clinical cure relative to no intervention. In the meta-analysis, a total of 584 children were randomized (300 to topical antibiotics and 284 to a placebo), and the use of topical antibiotics was associated with a significant reduction in the proportion of children who had symptoms of conjunctivitis on days 3 to 6 compared with placebo eye drops (odds ratio, 0.59; 95% CI, 0.39 to 0.91).
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial and systematic review and meta-analysis, topical antibiotics were associated with significantly shorter durations of conjunctival symptoms in children with acute infective conjunctivitis.
TRIAL REGISTRATION
ClinicalTrialsRegister.eu Identifier: 2013-005623-16.
Topics: Acute Disease; Anti-Bacterial Agents; Child; Child, Preschool; Conjunctivitis; Female; Humans; Male; Moxifloxacin; Ophthalmic Solutions; Randomized Controlled Trials as Topic
PubMed: 36194412
DOI: 10.1001/jamanetworkopen.2022.34459 -
Cellular and Molecular Life Sciences :... Jul 2022Spinal muscular atrophy (SMA) is a genetic disease resulting in the loss of α-motoneurons followed by muscle atrophy. It is caused by knock-out mutations in the...
Spinal muscular atrophy (SMA) is a genetic disease resulting in the loss of α-motoneurons followed by muscle atrophy. It is caused by knock-out mutations in the survival of motor neuron 1 (SMN1) gene, which has an unaffected, but due to preferential exon 7 skipping, only partially functional human-specific SMN2 copy. We previously described a Drosophila-based screening of FDA-approved drugs that led us to discover moxifloxacin. We showed its positive effect on the SMN2 exon 7 splicing in SMA patient-derived skin cells and its ability to increase the SMN protein level. Here, we focus on moxifloxacin's therapeutic potential in additional SMA cellular and animal models. We demonstrate that moxifloxacin rescues the SMA-related molecular and phenotypical defects in muscle cells and motoneurons by improving the SMN2 splicing. The consequent increase of SMN levels was higher than in case of risdiplam, a potent exon 7 splicing modifier, and exceeded the threshold necessary for a survival improvement. We also demonstrate that daily subcutaneous injections of moxifloxacin in a severe SMA murine model reduces its characteristic neuroinflammation and increases the SMN levels in various tissues, leading to improved motor skills and extended lifespan. We show that moxifloxacin, originally used as an antibiotic, can be potentially repositioned for the SMA treatment.
Topics: Animals; Disease Models, Animal; Exons; Humans; Mice; Moxifloxacin; Muscular Atrophy, Spinal; Phenotype; Survival of Motor Neuron 1 Protein
PubMed: 35864358
DOI: 10.1007/s00018-022-04450-8 -
Clinical Infectious Diseases : An... Feb 2023Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH).
METHODS
PWH and CD4+ counts ≥100 cells/μL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months after randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% noninferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV status. PWH were enrolled in a staged fashion to support cautious evaluation of drug-drug interactions between rifapentine and efavirenz.
RESULTS
A total of 2516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4+ count was 344 cells/μL (interquartile range: 223-455). The rifapentine-moxifloxacin regimen was noninferior to control (absolute difference in unfavorable outcomes -7.4%; 95% confidence interval [CI] -20.8% to 6.0%); the rifapentine regimen was not noninferior to control (+7.5% [95% CI, -7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%).
CONCLUSIONS
In people with HIV-associated DS-PTB with CD4+ counts ≥100 cells/μL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was noninferior to the 6-month control regimen and was safe.
CLINICAL TRIALS REGISTRATION
NCT02410772.
Topics: Humans; Rifampin; Moxifloxacin; Antitubercular Agents; HIV; Isoniazid; Drug Therapy, Combination; Tuberculosis, Pulmonary; Tuberculosis; HIV Infections
PubMed: 36041016
DOI: 10.1093/cid/ciac707 -
Der Ophthalmologe : Zeitschrift Der... Jun 2021A 53-year-old female patient presented with increased light sensitivity 3 weeks after oral intake of moxifloxacin tablets for an upper respiratory tract infection. The...
A 53-year-old female patient presented with increased light sensitivity 3 weeks after oral intake of moxifloxacin tablets for an upper respiratory tract infection. The symptoms were anisocoria and the pupils did not react to light or accommodation. The examination of the anterior segment of the eye revealed extensive bilateral iris transillumination defects (ITD). We diagnosed a bilateral acute iris transillumination (BAIT) syndrome. The BAIT syndrome is a rare disorder associated with massive depigmentation of the iris and atrophy of the iris musculature. A risk factor for BAIT syndrome seems to be the oral intake of antibiotics, in particular moxifloxacin after an upper respiratory tract infection but cases of spontaneous occurrence have also been described. Middle-aged women are particularly affected. The exact cause of BAIT syndrome is so far unknown but a potential mechanism involves the concentration of the antibiotic in the vitreous body. Differential diagnoses include other causes for ITD, such as albinism, intraocular inflammation, pseudoexfoliation syndrome and pigment dispersion syndrome. To date there is no specific treatment for BAIT syndrome. Possible complications include increased light sensitivity and post-BAIT glaucoma. Knowledge of the rare BAIT syndrome can be useful in the clinical routine for the differential diagnostic classification of an anisocoria and can possibly contribute to avoidance of unnecessary diagnostic steps.
Topics: Anisocoria; Female; Glaucoma, Open-Angle; Humans; Iris; Iris Diseases; Middle Aged; Moxifloxacin
PubMed: 32588124
DOI: 10.1007/s00347-020-01153-y -
Journal of Cataract and Refractive... Oct 2019To test the effect of injection volume and concentration on dosing and residence time of moxifloxacin in the anterior chamber (AC).
PURPOSE
To test the effect of injection volume and concentration on dosing and residence time of moxifloxacin in the anterior chamber (AC).
SETTING
Kaiser Permanente, Walnut Creek, California, USA.
DESIGN
Experimental study.
METHODS
Moxifloxacin 0.5%/0.05 mL, moxifloxacin 0.5%/0.10 mL, and moxifloxacin 0.15%/0.50 mL were drawn into 5 1.0 mL syringes each, injected into tared vials, and weighed. The doses delivered were calculated. The AC concentrations and elimination rates of the drug for two AC volumes were modeled for each dosing method.
RESULTS
The 0.05 mL injection volume resulted in the greatest range (35 μg) of delivered dose compared with larger injection volumes (≤25 μg). The mathematical model predicted that variation in dosing in each group would result in differences of 12 minutes or less for the presence of the drug in the AC. Injection of 0.5%/0.1 mL produced AC concentrations above 500 μg/mL for 1.9 to 3.0 hours and above 64 μg/mL for 5.5 to 6.5 hours, depending on the AC volume; however, flushing with a 0.15% concentration sustained AC levels for 1.9 hours and 5.5 hours, respectively, for the two AC volumes.
CONCLUSIONS
Smaller injection volumes of a higher concentration moxifloxacin resulted in less accuracy and less precision in the delivered dose (0.05 mL, P = .005; 0.10 mL, P = .03); however, the clinical significance of this might vary. Injection of 0.5%/0.1 mL and flushing with 0.15%/0.5 mL of moxifloxacin would provide similar drug AC residence times according to the model. Flushing provided more consistent AC concentrations with differing AC volumes.
Topics: Anterior Chamber; Anti-Bacterial Agents; Antibiotic Prophylaxis; Humans; Injections, Intraocular; Models, Theoretical; Moxifloxacin; Ophthalmic Solutions
PubMed: 31444079
DOI: 10.1016/j.jcrs.2019.04.020 -
Clinical Microbiology and Infection :... Jun 2023For non-tuberculous mycobacteria (NTM), minimum inhibitory concentration (MIC) distributions of wild-type isolates have not been systematically evaluated despite their...
Towards clinical breakpoints for non-tuberculous mycobacteria - Determination of epidemiological cut off values for the Mycobacterium avium complex and Mycobacterium abscessus using broth microdilution.
OBJECTIVE
For non-tuberculous mycobacteria (NTM), minimum inhibitory concentration (MIC) distributions of wild-type isolates have not been systematically evaluated despite their importance for establishing antimicrobial susceptibility testing (AST) breakpoints.
METHODS
We gathered MIC distributions for drugs used against the Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) obtained by commercial broth microdilution (SLOMYCOI and RAPMYCOI) from 12 laboratories. Epidemiological cut-off values (ECOFFs) and tentative ECOFFs (TECOFFs) were determined by EUCAST methodology including quality control (QC) strains.
RESULTS
The clarithromycin ECOFF was 16 mg/L for M. avium (n = 1271) whereas TECOFFs were 8 mg/L for M. intracellulare (n = 415) and 1 mg/L for MAB (n = 1014) confirmed by analysing MAB subspecies without inducible macrolide resistance (n = 235). For amikacin, the ECOFFs were 64 mg/L for MAC and MAB. For moxifloxacin, the WT spanned >8 mg/L for both MAC and MAB. For linezolid, the ECOFF and TECOFF were 64 mg/L for M. avium and M. intracellulare, respectively. Current CLSI breakpoints for amikacin (16 mg/L), moxifloxacin (1 mg/L) and linezolid (8 mg/L) divided the corresponding WT distributions. For QC M. avium and M. peregrinum, ≥95% of MIC values were well within recommended QC ranges.
CONCLUSION
As a first step towards clinical breakpoints for NTM, (T)ECOFFs were defined for several antimicrobials against MAC and MAB. Broad wild-type MIC distributions indicate a need for further method refinement which is now under development within the EUCAST subcommittee for anti-mycobacterial drug susceptibility testing. In addition, we showed that several CLSI NTM breakpoints are not consistent in relation to the (T)ECOFFs.
Topics: Humans; Mycobacterium avium Complex; Anti-Bacterial Agents; Nontuberculous Mycobacteria; Amikacin; Mycobacterium abscessus; Moxifloxacin; Linezolid; Mycobacterium avium-intracellulare Infection; Microbial Sensitivity Tests; Drug Resistance, Bacterial; Macrolides; Mycobacterium tuberculosis; Mycobacterium Infections, Nontuberculous; Mycobacterium avium
PubMed: 36813087
DOI: 10.1016/j.cmi.2023.02.007 -
Paediatric Drugs Mar 2022Moxifloxacin is a fluoroquinolone that is commonly used in adults, but not children. Certain clinical situations compel pediatric clinicians to use moxifloxacin, despite...
BACKGROUND/OBJECTIVE
Moxifloxacin is a fluoroquinolone that is commonly used in adults, but not children. Certain clinical situations compel pediatric clinicians to use moxifloxacin, despite its potential for toxicity and limited pharmacokinetics (PK) data. Our objective was to further characterize the pharmacokinetics of moxifloxacin in children.
METHODS
We performed an opportunistic, open-label population PK study of moxifloxacin in children < 18 years of age who received moxifloxacin as part of standard care. A set of structural PK models and residual error models were explored using nonlinear mixed-effects modeling. Covariates with known biological relationships were investigated for their influence on PK parameters.
RESULTS
We obtained 43 moxifloxacin concentrations from 14 participants who received moxifloxacin intravenously (n = 8) or orally (n = 6). The dose of moxifloxacin was 10 mg/kg daily in participants ≤ 40 kg and 400 mg daily in participants > 40 kg. The population mean clearance and mean volume of distribution were 18.2 L/h and 167 L, respectively. The oral absorption was described by a first-order process. The estimated extent of oral bioavailability was highly variable (range 20-91%). Total body weight was identified as a covariate on clearance and volume of distribution, and substantially reduced the random unexplained inter-individual variability for both parameters. No participants experienced suspected serious adverse reactions related to moxifloxacin.
CONCLUSION
These data add to the existing literature to support use of moxifloxacin in children in certain situations; however, further prospective studies on the safety and efficacy of moxifloxacin are needed.
Topics: Adult; Child; Humans; Moxifloxacin; Prospective Studies
PubMed: 35284983
DOI: 10.1007/s40272-022-00493-3