Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients.

BACKGROUND: New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29. RESULTS: A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, -6.8 percentage points; 95% confidence interval [CI], -11.3 to -2.4; P = 0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, -3.0 percentage points; 95% CI, -5.9 to -0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group. CONCLUSIONS: Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.).

Impact of Molnupiravir Treatment on Patient-Reported COVID-19 Symptoms in the Phase 3 MOVe-OUT Trial: A Randomized, Placebo-Controlled Trial.

BACKGROUND: Molnupiravir is an orally administered antiviral authorized for COVID-19 treatment in adults at high risk of progression to severe disease. Here, we report secondary and post hoc analyses of participants' self-reported symptoms in the MOVe-OUT trial, which evaluated molnupiravir initiated within 5 days of symptom onset in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed COVID-19. METHODS: Eligible participants completed a 15-item symptom diary daily from day 1 (randomization) through day 29, rating symptom severity as "none," "mild," "moderate," or "severe"; loss of smell and loss of taste were rated as "yes" or "no." Time to sustained symptom resolution/improvement was defined as the number of days from randomization to the first of 3 consecutive days of reduced severity, without subsequent relapse. Time to symptom progression was defined as the number of days from randomization to the first of 2 consecutive days of worsening severity. The Kaplan-Meier method was used to estimate event rates at various time points. The Cox proportional hazards model was used to estimate the hazard ratio between molnupiravir and placebo. RESULTS: For most targeted COVID-19 symptoms, sustained resolution/improvement was more likely, and progression was less likely, in the molnupiravir versus placebo group through day 29. When evaluating 5 distinctive symptoms of COVID-19, molnupiravir participants had a shorter median time to first resolution (18 vs 20 d) and first alleviation (13 vs 15 d) of symptoms compared with placebo. CONCLUSIONS: Molnupiravir treatment in at-risk, unvaccinated patients resulted in improved clinical outcomes for most participant-reported COVID-19 symptoms compared with placebo. Clinical Trials Registration. ClinicalTrials.gov: NCT04575597.

Molnupiravir for the treatment of COVID-19 in immunocompromised participants: efficacy, safety, and virology results from the phase 3 randomized, placebo-controlled MOVe-OUT trial.

PURPOSE: Immunocompromised patients have a potentially increased risk for progression to severe COVID-19 and prolonged replication of SARS-CoV-2. This post hoc analysis examined outcomes among immunocompromised participants in the MOVe-OUT trial. METHODS: In phase 3 of MOVe-OUT, non-hospitalized at-risk adults with mild-to-moderate COVID-19 were randomized to receive molnupiravir 800 mg or placebo twice daily for 5 days. Immunocompromised participants were identified based on prior/concomitant medications and/or medical history. All-cause hospitalization/death, adverse events, SARS-CoV-2 titers, infectivity, and RNA sequences were compared between immunocompromised participants who received molnupiravir or placebo and with non-immunocompromised participants. RESULTS: Fifty-five of 1408 participants were considered immunocompromised. Compared to placebo, fewer molnupiravir-treated immunocompromised participants were hospitalized/died through Day 29 (22.6% [7/31] vs. 8.3% [2/24]), with fewer adverse events (45.2% [14/31] vs. 25.0% [6/24]). A larger mean change from baseline in SARS-CoV-2 RNA was observed with molnupiravir compared to placebo in non-immunocompromised participants (least squares mean [LSM] difference Day 5: - 0.31, 95% confidence interval [CI] - 0.47 to - 0.15), while the mean change was comparable between treatment groups in immunocompromised participants (LSM difference Day 5: 0.23, 95% CI - 0.71 to 1.17). Molnupiravir treatment was associated with increased clearance of infectious virus. Increased errors in viral nucleotide sequences in post-baseline samples compared to placebo support molnupiravir's mechanism of action and were not associated with observation of novel treatment-emergent amino acid substitutions in immunocompromised participants. CONCLUSION: Although the study population was small, these data suggest that molnupiravir treatment for mild-to-moderate COVID-19 in non-hospitalized immunocompromised adults is efficacious and safe and quickly reduces infectious SARS-CoV-2. GOV REGISTRATION NUMBER: NCT04575597.

Effect of Molnupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19 : A Randomized, Placebo-Controlled Trial.

BACKGROUND: In the MOVe-OUT trial, molnupiravir showed a clinically meaningful reduction in the risk for hospitalization or death in adults with mild to moderate COVID-19 and risk factors for progression to severe disease. OBJECTIVE: To identify other potential clinical benefits of molnupiravir versus placebo. DESIGN: Secondary analysis of the randomized, double-blind, placebo-controlled phase 3 component of MOVe-OUT. (ClinicalTrials.gov: NCT04575597). SETTING: 107 sites globally. PARTICIPANTS: 1433 nonhospitalized adults aged 18 years or older with mild to moderate COVID-19. INTERVENTION: Molnupiravir, 800 mg, or placebo every 12 hours for 5 days. MEASUREMENTS: Changes from baseline in C-reactive protein (CRP) concentration and oxygen saturation (Spo 2), need for respiratory interventions (including invasive mechanical ventilation), and need for medical services in all randomly assigned participants through day 29, and need for respiratory interventions and time to discharge in the subgroup of participants who were hospitalized after randomization. RESULTS: Participants receiving molnupiravir showed faster normalization of CRP and Spo 2, with improvements observed on day 3 of therapy, compared with placebo. Molnupiravir-treated participants had a decreased need for respiratory interventions versus placebo-treated participants (relative risk reduction [RRR], 34.3% [95% CI, 4.3% to 54.9%]), with similar findings in participants who were hospitalized after randomization (RRR, 21.3% [CI, 0.2% to 38.0%]). Hospitalized participants who received molnupiravir were discharged a median of 3 days before those who received placebo. Acute care visits (7.2% vs. 10.6%; RRR, 32.1% [CI, 4.4% to 51.7%]) and COVID-19-related acute care visits (6.6% vs. 10.0%; RRR, 33.8% [CI, 5.6% to 53.6%]) were less frequent in molnupiravir- versus placebo-treated participants. LIMITATIONS: Some analyses were performed post hoc. Longer-term benefits of molnupiravir therapy were not evaluated. Participants were not immunized against SARS-CoV-2. CONCLUSION: The findings suggest there are additional important clinical benefits of molnupiravir beyond reduction in hospitalization or death. PRIMARY FUNDING SOURCE: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.

Exposure-Efficacy Analyses Support Optimal Dosing Regimens of Ceftolozane/Tazobactam in Participants with Hospital-Acquired/Ventilator-Associated Bacterial Pneumonia in ASPECT-NP.

An exposure-efficacy analysis of the phase 3 ASPECT-NP trial was performed to evaluate the relationship between plasma exposure of ceftolozane and tazobactam and efficacy endpoints (primary: 28-day all-cause mortality; key secondary: clinical cure at test-of-cure visit) in adult participants with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP). Participants (N = 231) from the ceftolozane/tazobactam treatment group in the intention-to-treat population who had pharmacokinetic data available and relevant baseline lower respiratory tract (LRT) pathogen(s) susceptibility data were included. Population pharmacokinetic models were used to predict individual ceftolozane and tazobactam plasma exposure measures (percentage of the interdose interval with free drug concentrations above the MIC [%ƒT>MIC] and %ƒT above a threshold [%ƒT>CT = 1 µg/mL], respectively) associated with the last dose using the highest ceftolozane/tazobactam MIC for the relevant baseline LRT pathogens. Efficacy measures were comparable between the baseline LRT pathogens and across MIC cutoffs (1-8 µg/mL). Most participants (82%) had 99% ƒT>MIC for ceftolozane; 9% (N = 21/231) had 0% ƒT>MIC due to high MICs of the LRT pathogen (64-256 µg/mL). The %ƒT>MIC for ceftolozane exceeded 73% for all participants with baseline LRT pathogen(s) MIC ≤4 µg/mL. All 231 participants achieved the tazobactam pharmacokinetic/pharmacodynamic target of >20% ƒT>CT where CT = 1 µg/mL. For either efficacy endpoint, median ceftolozane %ƒT>MIC was 99% in participants achieving efficacy. No exposure-efficacy trend was observed for ceftolozane or tazobactam. These results further support the recommended ceftolozane/tazobactam dosing regimens evaluated in ASPECT-NP for patients with HABP/VABP.

Efficacy and safety of tedizolid for the treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia in Japanese patients: Results from a subgroup analysis of a phase 3, randomized, double-blind study comparing tedizolid and linezolid.

INTRODUCTION: The results from the phase 3 study that evaluated the efficacy and safety of tedizolid phosphate, an oxazolidinone drug, for the treatment of gram-positive ventilated hospital-acquired bacterial pneumonia (vHABP)/ventilator-associated bacterial pneumonia (VABP) compared with linezolid (VITAL study), have been previously reported. We conducted a subgroup analysis to report the data obtained from Japanese patients enrolled in this study. METHODS: Patients aged ≥18 years with vHABP/VABP likely to be caused by gram-positive cocci were randomized 1:1 to tedizolid phosphate 200 mg once daily for 7 days or linezolid 600 mg twice daily for 10 days. In both treatment groups, patients with concurrent gram-positive bacteremia were treated for 14 days. Primary efficacy endpoints were day 28 all-cause mortality (ACM) and investigator-assessed clinical response at test-of-cure (TOC) in the intention-to-treat population. Safety outcomes included assessment of treatment-emergent adverse events. RESULTS: Fifty-three Japanese patients were randomized at received study drug (tedizolid, n = 28; linezolid, n = 25). Demographics and characteristics were generally similar between treatment groups. Rates of day 28 ACM were 10.7% and 20.0% with tedizolid and linezolid, respectively (difference, 9.3%; 95% CI, -10.1 to 28.7). Rates of investigator-assessed clinical cure at TOC were 78.6% and 72.0% with tedizolid and linezolid, respectively (difference, 6.6%; 95% CI, -16.7 to 29.8). Tedizolid phosphate was generally well tolerated and no new safety concerns were observed in the Japanese subgroup. CONCLUSION: The results from this subgroup analysis suggest generally favorable efficacy and safety of tedizolid in adult Japanese patients with vHABP/VABP. (ClinicalTrials.gov identifier: NCT02019420).

A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate and Linezolid for Treatment of Ventilated Gram-Positive Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia.

BACKGROUND: Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are associated with high mortality rates. We evaluated the efficacy and safety of tedizolid (administered as tedizolid phosphate) for treatment of gram-positive ventilated HABP/VABP. METHODS: In this randomized, noninferiority, double-blind, double-dummy, global phase 3 trial, patients were randomized 1:1 to receive intravenous tedizolid phosphate 200 mg once daily for 7 days or intravenous linezolid 600 mg every 12 hours for 10 days. Treatment was 14 days in patients with concurrent gram-positive bacteremia. The primary efficacy end points were day 28 all-cause mortality (ACM; noninferiority margin, 10%) and investigator-assessed clinical response at test of cure (TOC; noninferiority margin, 12.5%) in the intention-to-treat population. RESULTS: Overall, 726 patients were randomized (tedizolid, n = 366; linezolid, n = 360). Baseline characteristics, including incidence of methicillin-resistant Staphylococcus aureus (31.3% overall), were well balanced. Tedizolid was noninferior to linezolid for day 28 ACM rate: 28.1% and 26.4%, respectively (difference, -1.8%; 95% confidence interval [CI]: -8.2 to 4.7). Noninferiority of tedizolid was not demonstrated for investigator-assessed clinical cure at TOC (tedizolid, 56.3% vs linezolid, 63.9%; difference, -7.6%; 97.5% CI: -15.7 to 0.5). In post hoc analyses, no single factor accounted for the difference in clinical response between treatment groups. Drug-related adverse events occurred in 8.1% and 11.9% of patients who received tedizolid and linezolid, respectively. CONCLUSIONS: Tedizolid was noninferior to linezolid for day 28 ACM in the treatment of gram-positive ventilated HABP/VABP. Noninferiority of tedizolid for investigator-assessed clinical response at TOC was not demonstrated. Both drugs were well tolerated. CLINICAL TRIALS REGISTRATION: NCT02019420.

Population Pharmacokinetics, Exposure-Response, and Probability of Target Attainment Analyses for Tedizolid in Adolescent Patients with Acute Bacterial Skin and Skin Structure Infections.

Tedizolid phosphate is an oxazolidinone antibacterial agent approved for the treatment of Gram-positive acute bacterial skin and skin structure infections (ABSSSIs) in patients aged ≥12 years. To support the use of tedizolid phosphate in adolescents with ABSSSIs, a population pharmacokinetic (PK) model, developed using adult and pediatric data, was updated to include PK data from a phase 3 clinical trial (PN012) that evaluated the safety and efficacy of once-daily oral or intravenous 200-mg tedizolid phosphate treatment in adolescents (12 to <18 years) with ABSSSIs, along with emerging data from a phase 1 trial (PN013) in children (2 to <12 years). Updated PK parameter estimates remained similar to those of the previous model. Body weight was a statistically significant covariate on clearance and volume parameters, with no clinically meaningful effects on exposure in adolescents. Tedizolid exposures in adolescents from PN012 were slightly higher with largely overlapped area under the concentration-time curve distribution compared with adults from previous phase 2 and 3 trials. The probability of PK/pharmacodynamic target attainment at the MIC susceptibility breakpoint of 0.5 µg/ml for Staphylococcus and Streptococcus sp. was 100%. As most participants from the PN012 trial were cured, no significant exposure-efficacy relationship was identified. Tedizolid exposures were similar between participants with and without a safety event from PN012; no clear relationship was detected between exposure and safety. Despite lower body weight and higher exposures in adolescents, safety profiles in adolescents were similar those in adults. These results support the 200-mg, once-daily intravenous or oral dose of tedizolid phosphate in adolescents with ABSSSIs.

A multicenter analysis of the clinical microbiology and antimicrobial usage in hospitalized patients in the US with or without COVID-19.

BACKGROUND: Past respiratory viral epidemics suggest that bacterial infections impact clinical outcomes. There is minimal information on potential co-pathogens in patients with coronavirus disease-2019 (COVID-19) in the US. We analyzed pathogens, antimicrobial use, and healthcare utilization in hospitalized US patients with and without severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). METHODS: This multicenter retrospective study included patients with > 1 day of inpatient admission and discharge/death between March 1 and May 31, 2020 at 241 US acute care hospitals in the BD Insights Research Database. We assessed microbiological testing data, antimicrobial utilization in admitted patients with ≥24 h of antimicrobial therapy, and length of stay (LOS). RESULTS: A total of 141,621 patients were tested for SARS-CoV-2 (17,003 [12.0%] positive) and 449,339 patients were not tested. Most (> 90%) patients tested for SARS-CoV-2 had additional microbiologic testing performed compared with 41.9% of SARS-CoV-2-untested patients. Non-SARS-CoV-2 pathogen rates were 20.9% for SARS-CoV-2-positive patients compared with 21.3 and 27.9% for SARS-CoV-2-negative and -untested patients, respectively. Gram-negative bacteria were the most common pathogens (45.5, 44.1, and 43.5% for SARS-CoV-2-positive, -negative, and -untested patients). SARS-CoV-2-positive patients had higher rates of hospital-onset (versus admission-onset) non-SARS-CoV-2 pathogens compared with SARS-CoV-2-negative or -untested patients (42.4, 22.2, and 19.5%, respectively), more antimicrobial usage (68.0, 45.2, and 25.1% of patients), and longer hospital LOS (mean [standard deviation (SD)] of 8.6 [11.4], 5.1 [8.9], and 4.2 [8.0] days) and intensive care unit (ICU) LOS (mean [SD] of 7.8 [8.5], 3.6 [6.2], and 3.6 [5.9] days). For all groups, the presence of a non-SARS-CoV-2 pathogen was associated with increased hospital LOS (mean [SD] days for patients with versus without a non-SARS-CoV-2 pathogen: 13.7 [15.7] vs 7.3 [9.6] days for SARS-CoV-2-positive patients, 8.2 [11.5] vs 4.3 [7.9] days for SARS-CoV-2-negative patients, and 7.1 [11.0] vs 3.9 [7.4] days for SARS-CoV-2-untested patients). CONCLUSIONS: Despite similar rates of non-SARS-CoV-2 pathogens in SARS-CoV-2-positive, -negative, and -untested patients, SARS-CoV-2 was associated with higher rates of hospital-onset infections, greater antimicrobial usage, and extended hospital and ICU LOS. This finding highlights the heavy burden of the COVID-19 pandemic on healthcare systems and suggests possible opportunities for diagnostic and antimicrobial stewardship.

Ceftolozane/tazobactam probability of target attainment and outcomes in participants with augmented renal clearance from the randomized phase 3 ASPECT-NP trial.

BACKGROUND: The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function. METHODS: Baseline renal function was categorized as normal renal function (creatinine clearance 80-130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit. RESULTS: A > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [- 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; - 2.6 [- 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; - 2.1 [- 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [- 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [- 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [- 8.7 to 19.0]). CONCLUSIONS: C/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC. Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.

Early Clinical Response as a Predictor of Late Treatment Success in Patients With Acute Bacterial Skin and Skin Structure Infections: Retrospective Analysis of 2 Randomized Controlled Trials.

In the treatment of acute bacterial skin and skin structure infections, pooled data from 2 clinical trials (N = 1333 patients) showed that programmatic and investigator-assessed early treatment success both had a high positive predictive value (94.3%-100.0%) for late clinical cure, including among hospitalized patients. The negative predictive value of programmatic early success was <20%. These exploratory findings require prospective real-world evaluation. CLINICAL TRIALS REGISTRATION: NCT01170221; NCT01421511.

Clinical Response of Tedizolid versus Linezolid in Acute Bacterial Skin and Skin Structure Infections by Severity Measure Using a Pooled Analysis from Two Phase 3 Double-Blind Trials.

Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI). In a pooled analysis of 1,333 ABSSSI patients from the ESTABLISH clinical trials, treatment with tedizolid or linezolid demonstrated similar early and posttherapy clinical responses in nonsevere and severe disease, irrespective of the parameters used to measure ABSSSI severity. Shorter 6-day treatment of ABSSSI, including those that were severe, with tedizolid phosphate demonstrated efficacy comparable to that of 10-day treatment with linezolid. (The ESTABLISH studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01170221 and NCT01421511.).

Analysis of the phase 3 ESTABLISH trials of tedizolid versus linezolid in acute bacterial skin and skin structure infections.

Tedizolid, a novel oxazolidinone with activity against a wide range of Gram-positive pathogens, was evaluated in two noninferiority phase 3 acute bacterial skin and skin structure infection trials. The data from individual trials showed its noninferior efficacy compared to that of linezolid and a favorable tolerability profile. To evaluate potential differences, the pooled data were analyzed. The patients received 200 mg of tedizolid once daily for 6 days or 600 mg of linezolid twice daily for 10 days. Efficacy was evaluated at 48 to 72 h (primary endpoint), on days 11 to 13 (end of therapy [EOT]), and 7 to 14 days after the EOT (posttherapy evaluation). Treatment-emergent adverse events and hematologic and clinical laboratory parameters were collected. The baseline characteristics were comparable between the treatment groups: 852/1,333 (64%) patients were from North America, and the majority of infections were caused by Staphylococcus aureus. Tedizolid was noninferior to linezolid (early clinical responses, 81.6% versus 79.4%, respectively). The early responses remained relatively consistent across various host/disease factors and severity measures. Nausea was the most frequently reported adverse event (tedizolid, 8.2%; linezolid, 12.2%; P=0.02), with onset occurring primarily during the first 6 days. Fewer tedizolid than linezolid patients had platelet counts of <150,000 cells/mm3 at the EOT (tedizolid, 4.9%; linezolid, 10.8%; P=0.0003) and during the postbaseline period through the last day of active drug visit (tedizolid, 6.4%; linezolid, 12.6%; P=0.0016). Efficacy was achieved with a 6-day once-daily course of therapy with the option of an intravenous/oral regimen, and fewer low platelet counts and gastrointestinal side effects were reported with tedizolid than with linezolid, all of which aligns well with antimicrobial stewardship principles. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01170221 and NCT01421511.).

Tedizolid phosphate for the management of acute bacterial skin and skin structure infections: efficacy summary.

The novel oxazolidinone tedizolid phosphate is in late-stage development for acute bacterial skin and skin structure infections (ABSSSIs). Preclinical and phase 1 trials have shown that 200-mg once-daily tedizolid phosphate dosing achieves the appropriate pharmacokinetic goals for optimal antimicrobial effect, and a randomized phase 2 dose-ranging trial confirmed that tedizolid phosphate may be an option for the treatment of ABSSSIs at the 200-mg dose, the lowest effective dose, over a mean of 6.4 days of therapy. In the first of two phase 3 trials, 6 days of 200-mg once-daily oral tedizolid phosphate (plus 4 days of placebo) was noninferior to 10 days of 600-mg twice-daily oral linezolid when evaluated at both the early (48- to 72-hour assessment) and test-of-cure (7-14 days after the last dose of active or placebo agent was given) time points. Initial results from the second phase 3 trial (intravenous to oral therapy design) confirm the study met all primary and secondary endpoints and continues to add insight into the clinical utility of tedizolid phosphate.

Molnupiravir: Mechanism of action, clinical, and translational science.

Molnupiravir is an oral prodrug of the broadly active, antiviral ribonucleoside analog N-hydroxycytidine (NHC). The primary circulating metabolite NHC is taken up into cells and phosphorylated to NHC-triphosphate (NHC-TP). NHC-TP serves as a competitive substrate for viral RNA-dependent RNA polymerase (RdRp), which results in an accumulation of errors in the viral genome, rendering virus replication incompetent. Molnupiravir has demonstrated activity against SARS-CoV-2 both clinically and preclinically and has a high barrier to development of viral resistance. Little to no molnupiravir is observed in plasma due to rapid hydrolysis to NHC. Maximum concentrations of NHC are reached at 1.5 h following administration in a fasted state. The effective half-life of NHC is 3.3 h, reflecting minimal accumulation in the plasma following twice-daily (Q12H) dosing. The terminal half-life of NHC is 20.6 h. NHC-TP exhibits a flatter profile with a lower peak-to-trough ratio compared with NHC, which supports Q12H dosing. Renal and hepatic pathways are not major routes of elimination, as NHC is primarily cleared by metabolism to uridine and cytidine, which then mix with the endogenous nucleotide pools. In a phase III study of nonhospitalized patients with COVID-19 (MOVe-OUT), 5 days of treatment with 800 mg molnupiravir Q12H significantly reduced the incidence of hospitalization or death compared with placebo. Patients treated with molnupiravir also had a greater reduction in SARS-CoV-2 viral load and improved clinical outcomes, compared with those receiving placebo. The clinical effectiveness of molnupiravir has been further demonstrated in several real-world evidence studies. Molnupiravir is currently authorized or approved in more than 25 countries.

Respiratory virus coinfections during the COVID-19 pandemic: epidemiologic analysis and clinical outcomes from the Phase 2/3 molnupiravir trial (MOVe-OUT).

This exploratory post hoc analysis assessed the incidence of respiratory viral coinfections and their impact on clinical outcomes in non-hospitalized adults with mild-to-moderate coronavirus disease-2019 (COVID-19) treated with molnupiravir versus placebo for 5 days in the Phase 2/3 MOVe-OUT trial (NCT04575597), which took place in October 2020 to January 2021 (Phase 2, n = 302) and May 2021 to October 2021 (Phase 3, n = 1,433). Among 1,735 total randomized participants, 1,674 had a baseline respiratory pathogen panel (NxTAG Respiratory Pathogen Panel for the Luminex MAGPIX instrument) performed and 69 (4.1%) were coinfected with at least one additional respiratory viral pathogen. Human rhinovirus/enterovirus (39/69, 56.5%) was the most common coinfection detected at baseline. In the modified intention-to-treat population, two participants with coinfecting respiratory RNA viruses were hospitalized and received respiratory interventions through Day 29, and none died; one participant in the molnupiravir group was coinfected with human rhinovirus/enterovirus, and one participant in the placebo group was coinfected with human metapneumovirus. Hospitalization or death occurred in 6.2% and 9.0% of non-coinfected participants in the molnupiravir versus placebo group, respectively, and over 90% did not require respiratory interventions. Most coinfecting respiratory RNA viruses detected at baseline were not detected at the end of therapy in both the molnupiravir and placebo groups. In summary, participants coinfected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and another respiratory RNA virus were not more likely to be hospitalized or die, or require respiratory interventions, compared to participants who were not coinfected with another respiratory RNA virus at baseline in both groups. IMPORTANCE: Respiratory viral coinfections are known to occur with coronavirus disease-2019 (COVID-19). In a cohort of non-hospitalized adults with mild-to-moderate COVID-19 treated with molnupiravir versus placebo in the MOVe-OUT trial during October 2020 to October 2021, 4.1% of participants had a documented viral coinfection; human rhinovirus/enterovirus was the most common pathogen detected with the NxTAG Respiratory Pathogen Panel assay. Participants who had a coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and another respiratory RNA virus were not more likely to have worse clinical outcomes compared to those participants without a viral coinfection, and many coinfecting respiratory RNA viruses were no longer detected at the end of the 5-day treatment period in both groups.

Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial.

IMPORTANCE: Acute bacterial skin and skin structure infections (ABSSSIs), including cellulitis or erysipelas, major cutaneous abscesses, and wound infections, can be life-threatening and may require surgery and hospitalization. Increasingly, ABSSSIs are associated with drug-resistant pathogens, and many antimicrobial agents have adverse effects restricting their use. Tedizolid phosphate is a novel oxazolidinone in development for the treatment of ABSSSIs. OBJECTIVES: To establish the noninferiority of tedizolid phosphate vs linezolid in treating ABSSSIs and compare the safety of the 2 agents. DESIGN, SETTING, AND PATIENTS: The Efficacy and Safety of 6-day Oral Tedizolid in Acute Bacterial Skin and Skin Structure Infections vs 10-day Oral Linezolid Therapy (ESTABLISH-1) was a phase 3, randomized, double-blind, noninferiority trial that was conducted from August 2010 through September 2011 at 81 study centers in North America, Latin America, and Europe. The intent-to-treat analysis set consisted of data from 667 adults aged 18 years or older with ABSSSIs treated with tedizolid phosphate (n = 332) or linezolid (n = 335). INTERVENTIONS: A 200 mg once daily dose of oral tedizolid phosphate for 6 days or 600 mg of oral linezolid every 12 hours for 10 days. MAIN OUTCOME MEASURES: The primary efficacy outcome was early clinical response at the 48- to 72-hour assessment (no increase in lesion surface area from baseline and oral temperature of ≤37.6°C, confirmed by a second temperature measurement within 24 hours). A 10% noninferiority margin was predefined. RESULTS: In the intent-to-treat analysis set, the early clinical treatment response rates were 79.5% (95% CI, 74.8% to 83.7%) of 332 patients in the tedizolid phosphate group and 79.4% (95% CI, 74.7% to 83.6%) of 335 patients in the linezolid group (a treatment difference of 0.1% [95% CI, -6.1% to 6.2%]). The sustained clinical treatment response rates at the end of treatment (day 11) were 69.3% (95% CI, 64.0% to 74.2%) in the tedizolid phosphate group and 71.9% (95% CI, 66.8% to 76.7%) in the linezolid group (a treatment difference of -2.6% [95% CI, -9.6% to 4.2%]). Results of investigator-assessed clinical treatment success rates at a posttherapy evaluation visit (1-2 weeks after the end-of-treatment visit) were 85.5% (95% CI, 81.3% to 89.1%) in the tedizolid phosphate group and 86.0% (95% CI, 81.8% to 89.5%) in the linezolid group (a treatment difference of -0.5% [95% CI, -5.8% to 4.9%), and were similar for 178 patients with methicillin-resistant Staphylococcus aureus isolated from the primary lesion. CONCLUSIONS AND RELEVANCE: Tedizolid phosphate was a statistically noninferior treatment to linezolid in early clinical response at 48 to 72 hours after initiating therapy for an ABSSSI. Tedizolid phosphate may be a reasonable alternative to linezolid for treating ABSSSI. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01170221.