Evaluation of omadacycline regimens for community-acquired bacterial pneumonia patients infected with Staphylococcus Aureus by pharmacokinetic/pharmacodynamic analysis.

Omadacycline is an FDA-approved agent for community-acquired bacterial pneumonia (CABP). The purpose of this study is to evaluate the effectiveness of omadacycline for treating CABP patients infected with Staphylococcus aureus, including Methicillin-Resistant Staphylococcus aureus (MRSA) and Methicillin-Susceptible Staphylococcus aureus (MSSA), using pharmacokinetic/pharmacodynamic (PK/PD) analysis. Monte Carlo simulations (MCSs) were performed by utilizing omadacycline pharmacokinetic (PK) parameters, minimum inhibitory concentration (MIC) data, and in vivo PK/PD targets to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) values for different dose regimens against MRSA and MSSA in CABP patients. A dosage regimen with a PTA or CFR expectation value greater than 90% was considered optimal. For all recommended dose regimens, PTA values for MRSA MIC ≤1 and MSSA MIC ≤4 on days 1, 4, and 7 were greater than 90%. Based on the MIC distribution of Staphylococcus aureus, all dose regimens had CFR values greater than 90% for both MRSA and MSSA. CFR values for different bacterial strains were still greater than 90% within the range of PK/PD target values less than 40, although they gradually decreased with increasing PK/PD target values. PK/PD modeling demonstrated that all recommended dose regimens of omadacycline are highly effective against CABP patients infected with MRSA and MSSA. The study provides theoretical support for the efficacy of omadacycline in different dose regimens.

Socio-demographic and comorbid risk factors for poor prognosis in patients hospitalized with community-acquired bacterial pneumonia in southeastern US.

BACKGROUND: How socio-demographic characteristics and comorbidities affect bacterial community-acquired pneumonia (CAP) prognosis during/after hospitalization is important in disease management. OBJECTIVES: To identify predictors of medical intensive care unit (MICU) admission, length of hospital stay (LOS), in-hospital mortality, and bacterial CAP readmission in patients hospitalized with bacterial CAP. METHODS: ICD-9/10 codes were used to query electronic medical records to identify a cohort of patients hospitalized for bacterial CAP at a tertiary hospital in Southeastern US between 01/01/2013-12/31/2019. Adjusted accelerated failure time and modified Poisson regression models were used to examine predictors of MICU admission, LOS, in-hospital mortality, and 1-year readmission. RESULTS: There were 1956 adults hospitalized with bacterial CAP. Median (interquartile range) LOS was 11 days (6-23), and there were 26 % (513) MICU admission, 14 % (266) in-hospital mortality, and 6 % (117) 1-year readmission with recurrent CAP. MICU admission was associated with heart failure (RR 1.38; 95 % CI 1.17-1.62) and obesity (RR 1.26; 95 % CI 1.04-1.52). Longer LOS was associated with heart failure (adjusted time ratio[TR] 1.27;95 %CI 1.12-1.43), stroke (TR 1.90;95 %CI 1.54,2.35), type 2 diabetes (TR 1.20;95 %CI 1.07-1.36), obesity (TR 1.50;95 %CI 1.31-1.72), Black race (TR 1.17;95 %CI 1.04-1.31), and males (TR 1.24;95 %CI 1.10-1.39). In-hospital mortality was associated with stroke (RR 1.45;95 %CI 1.03-2.04) and age ≥65 years (RR 1.34;95 %CI 1.06-1.68). 1-year readmission was associated with COPD (RR 1.55;95 %CI 1.05-2.27) and underweight BMI (RR 1.74;95 %CI 1.04-2.90). CONCLUSIONS: Comorbidities and socio-demographic characteristics have varying impacts on bacterial CAP in-hospital prognosis and readmission. More studies are warranted to confirm these findings to develop comprehensive care plans and inform public health interventions.

The safety and efficacy of stem cells for the treatment of severe community-acquired bacterial pneumonia: A randomized clinical trial.

PURPOSE: Evaluate the safety profile of expanded allogeneic adipose-derived mesenchymal stem cell (eASC) for the treatment of severe community-acquired bacterial pneumonia (CABP). MATERIALS AND METHODS: Randomized, multicenter, double-blind, placebo-controlled, phase 1b/2a trial. Patients with severe CABP were enrolled to receive intravenous infusions of Cx611 or placebo. The primary objective was safety including hypersensitivity reactions, thromboembolic events, and immunological responses to Cx611. The secondary endpoints included the clinical cure rate, ventilation-free days, and overall survival (Day 90). RESULTS: Eighty-three patients were randomized and received infusions (Cx611: n = 42]; placebo: n = 41]. The mean age was similar (Cx611: 61.1 [11.2] years; placebo: 63.4 [10.4] years). The number of AEs and treatment-emergent AEs were similar (243; 184 and 2; 1) in Cx611 and placebo respectively. Hypersensitivity reactions or thromboembolic events were similar (Cx611: n = 9; placebo: n = 12). Each study arm had similar anti-HLA antibody/DSA levels at Day 90. The clinical cure rate (Cx611: 86.7%; placebo: 93.8%), mean number of ventilator-free days (Cx611: 12.2 [10.29] days; placebo: 15.4 [10.75] days), and overall survival (Cx611: 71.5%; placebo: 77.0%) did not differ between study arms. CONCLUSION: Cx611 was well tolerated in severe CABP. These data provide insights for future stem cell clinical study designs, endpoints and sample size calculation. TRIAL REGISTRATION: NCT03158727 (retrospectively registered: May 09, 2017). Full study protocol: https://clinicaltrials.gov/ProvidedDocs/27/NCT03158727/Prot_000.pdf.

Omadacycline in the treatment of community-acquired bacterial pneumonia in patients with comorbidities: a post-hoc analysis of the phase 3 OPTIC trial.

Introduction: The 2019 American Thoracic Society/Infectious Disease Society of America guidelines recommend respiratory fluoroquinolones to treat community-acquired bacterial pneumonia (CABP) in adults with comorbidities. Fluoroquinolones are effective against both typical and atypical pathogens. However, fluoroquinolone treatment has a risk of adverse effects, and the Food and Drug Administration has issued black box safety warnings for their use. Inpatient use of fluoroquinolones has reduced as a result; however, most antibiotic courses are completed as outpatients and discharge prescriptions account for the majority of fluoroquinolone use. As such, a new treatment option is needed to replace fluoroquinolones. Omadacycline is an aminomethylcycline antibiotic with a broad spectrum of activity and is available as a once-daily intravenous or bioequivalent oral formulation. Methods: This study assessed the safety and clinical efficacy of omadacycline compared with moxifloxacin for the treatment of adult CABP patients with Pneumonia Severity Index (PSI) risk class II/III and ≥1 comorbidity through a post-hoc analysis of the phase 3 OPTIC study (NCT02531438). Results: In total, 239 omadacycline- and 222 moxifloxacin-treated patients were assessed. The median age was similar between groups (omadacycline: 57 years; moxifloxacin: 58 years), with 26.0% and 26.6%, respectively, ≥65 years of age. Early clinical response was 91.6% for patients with ≥1 comorbidity treated with omadacycline and 91.4% for those treated with moxifloxacin. Post-treatment evaluation results for overall response were 89.1% in the omadacycline group and 87.4% in the moxifloxacin group. Conclusion: Safety warnings have reduced inpatient use of fluoroquinolones; however, outpatient and discharge prescriptions account for the majority of fluoroquinolone use. Outpatients with comorbidities need an efficacious alternative to fluoroquinolones. Omadacycline maintains the similar efficacy and benefits of fluoroquinolones as a once-daily, monotherapy, bioequivalent oral option with potent in vitro activity against the most common CABP pathogens, including S. pneumoniae and atypical pathogens, but offers a materially different safety profile consistent with its tetracycline heritage. In conclusion, both omadacycline and moxifloxacin exhibited similar efficacy in patients with PSI risk class II/III and comorbidities. Omadacycline fulfills an unmet need as an oral monotherapy treatment option for adult patients with CABP, which will further reduce the use of fluoroquinolones. Clinical trial registration: https://www.clinicaltrials.gov/study/NCT02531438, identifer: NCT02531438; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004071-13, identifier: EudraCT #2013-004071-13.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses Evaluating Omadacycline Dosing Regimens for the Treatment of Patients with Community-Acquired Bacterial Pneumonia Arising from Streptococcus pneumoniae and Haemophilus influenzae.

Omadacycline, a novel aminomethylcycline with in vitro activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and Haemophilus influenzae, is approved in the United States to treat patients with community-acquired bacterial pneumonia (CABP). Using nonclinical pharmacokinetic-pharmacodynamic (PK-PD) targets for efficacy and in vitro surveillance data for omadacycline against S. pneumoniae and H. influenzae, and a population pharmacokinetic model, PK-PD target attainment analyses were undertaken using total-drug epithelial lining fluid (ELF) and free-drug plasma exposures to evaluate omadacycline 100 mg intravenously (i.v.) every 12 h or 200 mg i.v. every 24 h (q24h) on day 1, followed by 100 mg i.v. q24h on day 2 and 300 mg orally q24h on days 3 to 5 for patients with CABP. Percent probabilities of PK-PD target attainment on days 1 and 2 by MIC were assessed using the following four approaches for selecting PK-PD targets: (i) median, (ii) second highest, (iii) highest, and (iv) randomly assigned total-drug ELF and free-drug plasma ratio of the area under the concentration-time curve to the MIC (AUC/MIC ratio) targets associated with a 1-log10 CFU reduction from baseline. Percent probabilities of PK-PD target attainment based on total-drug ELF AUC/MIC ratio targets on days 1 and 2 were ≥91.1% for S. pneumoniae for all approaches but the highest target and ≥99.2% for H. influenzae for all approaches at MIC90s (0.12 and 1 µg/mL for S. pneumoniae and H. influenzae, respectively). Lower percent probabilities of PK-PD target attainment based on free-drug plasma AUC/MIC ratio targets were observed for randomly assigned and the highest free-drug plasma targets for S. pneumoniae and for all targets for H. influenzae. These data provided support for approved omadacycline dosing regimens to treat patients with CABP and decisions for the interpretive criteria for the in vitro susceptibility testing of omadacycline against these pathogens.

Omadacycline in treating community-based infections: a review and expert perspective.

INTRODUCTION: Omadacycline is approved for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and soft tissue infection (ABSSSI). The integration of newer agents into clinical use involves understanding the nuances of clinical decision-making. This review will provide an in-depth focus on omadacycline in clinical practice. AREAS COVERED: Literature review of omadacycline utilizing PubMed was performed to provide a comprehensive evaluation of omadacycline pharmacology, microbiology, registrational Phase 3 clinical trials, and post-marketing clinical studies. In addition, the immunomodulatory and other attributes of tetracycline class of antibiotics, of which omadacycline is a member, are reviewed, introducing the concept of antibiotic selection with attention to the bacterial pathogen and human host relationship. EXPERT OPINION: Omadacycline builds upon the favorable attributes of tetracycline antibiotics and provides very reliable empiric coverage for both Staphylococcus aureus and Streptococcus spp. Clinicians require a more robust understanding of antibiotics, including omadacycline, in order to optimize patient outcomes, streamline care, and reduce medical costs.

Seroprevalence of community-acquired atypical bacterial pneumonia among adult COVID-19 patients from a single center in Al Madinah Al Munawarah, Saudi Arabia: A retrospective cohort study.

OBJECTIVES: To investigate the seroprevalence of the community-acquired bacterial that causes atypical pneumonia among confirmed severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) patients. METHODS: In this cohort study, we retrospectively investigated the seroprevalence of Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila among randomly selected 189 confirmed COVID-19 patients at their time of hospital presentation via commercial immunoglobulin M (IgM) antibodies against these bacteria. We also carried out quantitative measurements of procalcitonin in patients' serum. RESULTS: The seropositivity for L. pneumophila was 12.6%, with significant distribution among patientsolder than 50 years (χ2 test, p=0.009), while those of M. pneumoniae was 6.3% and C. pneumoniae was 2.1%, indicating an overall co-infection rate of 21% among COVID-19 patients. No significant difference (χ2 test, p=0.628) in the distribution of bacterial co-infections existed between male and female patients. Procalcitonin positivity was confirmed amongst 5% of co-infected patients. CONCLUSION: Our study documented the seroprevalence of community-acquired bacteria co-infection among COVID-19 patients. In this study, procalcitonin was an inconclusive biomarker for non-severe bacterial co-infections among COVID-19 patients. Consideration and proper detection of community-acquired bacterial co-infection may minimize misdiagnosis during the current pandemic and positively reflect disease management and prognosis.

Lefamulin: a New Hope in the Field of Community-Acquired Bacterial Pneumonia.

Purpose of Review: Community-acquired bacterial pneumonia (CABP) continues to be a worldwide health concern since it is the major cause of mortality and hospitalisation worldwide. Increased macrolide resistance among Streptococcus pneumoniae and other infections has resulted in a significantly larger illness burden, which has been exacerbated by evolving demography and a higher prevalence of comorbid disorders. Owing to such circumstances, the creation of new antibiotic classes is critical. Recent Findings: Lefamulin, also referred to as BC-3781, is the primary pleuromutilin antibiotic which has been permitted for both intravenous and oral use in humans for the remedy of bacterial infections. It has shown activity against gram-positive bacteria including methicillin-resistant strains as well as atypical organisms which as often implicated in CABP. It has a completely unique mechanism of action that inhibits protein synthesis via way of means of stopping the binding of tRNA for peptide transfer. The C(14) side chain is responsible for its pharmacodynamic and antimicrobial properties, together with supporting in overcoming bacterial ribosomal resistance and mutations improvement amplifying the number of hydrogen bonds to the target site. Summary: This review aims to highlight the pre-existing treatment options and specific purposes to shed some light upon the development of a new drug lefamulin and its specifications and explore this novel drug's superior efficacy to already existing treatment strategies.

Pharmacokinetics, Safety and Pharmacokinetics/Pharmacodynamics Analysis of Omadacycline in Chinese Healthy Subjects.

Objective: Omadacycline is a new type of aminomethylcycline antibiotic, having a broad antibacterial spectrum. But the pharmacokinetic characteristics and safety profile of the Chinese population remain unknown. It is also unclear whether the US-approved treatment regimen is applicable for the Chinese population. Methods: In a randomized, double-blinded, placebo-controlled dose-escalated trial, the pharmacokinetics of omadacycline was evaluated by a non-compartmental and compartmental model. Monte Carlo simulations were performed using the pharmacokinetic data from the Chinese population to evaluate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of the US FDA-approved dose regimen. Results: The three-compartment model successfully described the rapid distribution and slow elimination of omadacycline after the intravenous infusion (i.v.). The double-peak concentration-time curve of the oral absorption (p.o.) was explained by the two-compartment model with two absorption compartments. The steady-state AUC of 100 mg omadacycline i.v. and 300 mg omadacycline p. o. were 12.1 and 19.4 mg h/L, respectively. Pharmacokinetics/pharmacodynamics (PK/PD) analysis showed that the omadacycline dosing regimen with a loading dose (200 mg i.v. q24 h, 100 mg i.v. q12 h, 450 mg p. o. q24 h × 2 days or 300 mg p. o. q12 h) and maintenance dose (100 mg i.v. q24 h or 300 mg p. o. q24 h) could cover the main pathogens of the indications acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP): Staphylococcus aureus and Streptococcus pneumoniae. Also, omadacycline had showed a good safety profile in the Chinese population. Conclusions: With the evidence provided, omadacycline could be a novel treatment option to Chinese patients with ABSSSI and CABP.

Pooled microbiological findings and efficacy outcomes by pathogen in adults with community-acquired bacterial pneumonia from the Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 phase 3 trials of lefamulin versus moxifloxacin.

OBJECTIVES: Lefamulin, a pleuromutilin antibiotic approved for community-acquired bacterial pneumonia (CABP), was evaluated for microbiological efficacy in a prespecified pooled analysis of LEAP 1 and 2 phase 3 clinical trial data in patients with CABP. METHODS: In LEAP 1, adults (PORT risk class III‒V) received intravenous (IV) lefamulin 150 mg every 12 h (q12h) for 5‒7 days or moxifloxacin 400 mg every 24 h (q24h) for 7 days, with optional IV-to-oral switch. In LEAP 2, adults (PORT II‒IV) received oral lefamulin 600 mg q12h for 5 days or moxifloxacin 400 mg q24h for 7 days. Primary outcomes were early clinical response (ECR) at 96 ± 24 h after treatment start and investigator assessment of clinical response (IACR) 5‒10 days after the last dose. Secondary outcomes included ECR and IACR in patients with a baseline CABP pathogen (detected via culture, urinary antigen testing, serology and/or real-time PCR). RESULTS: Baseline CABP pathogens were detected in 709/1289 patients (55.0%; microbiological intention-to-treat population). The most frequently identified pathogens were Streptococcus pneumoniae (61.9% of patients) and Haemophilus influenzae (29.9%); 25.1% had atypical pathogens and 33.1% had polymicrobial infections. Pathogens were identified most frequently by PCR from sputum, followed by culture from respiratory specimens. In patients with baseline CABP pathogens, ECR rates were 89.3% (lefamulin) and 93.0% (moxifloxacin); IACR success rates were 83.2% and 86.7%, respectively. Results were consistent across CABP pathogens, including drug-resistant isolates and polymicrobial infections. CONCLUSION: Lefamulin is a valuable IV and oral monotherapy option for empirical and directed CABP treatment in adults.

Lefamulin in Patients with Community-Acquired Bacterial Pneumonia Caused by Atypical Respiratory Pathogens: Pooled Results from Two Phase 3 Trials.

Lefamulin was the first systemic pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia based on two phase 3 trials (Lefamulin Evaluation Against Pneumonia [LEAP]-1 and LEAP-2). This pooled analysis evaluated lefamulin efficacy and safety in adults with community-acquired bacterial pneumonia caused by atypical pathogens (Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae). In LEAP-1, participants received intravenous lefamulin 150 mg every 12 h for 5-7 days or moxifloxacin 400 mg every 24 h for 7 days, with optional intravenous-to-oral switch. In LEAP-2, participants received oral lefamulin 600 mg every 12 h for 5 days or moxifloxacin 400 mg every 24 h for 7 days. Primary outcomes were early clinical response at 96 ± 24 h after first dose and investigator assessment of clinical response at test of cure (5-10 days after last dose). Atypical pathogens were identified in 25.0% (91/364) of lefamulin-treated patients and 25.2% (87/345) of moxifloxacin-treated patients; most were identified by ≥1 standard diagnostic modality (M. pneumoniae 71.2% [52/73]; L. pneumophila 96.9% [63/65]; C. pneumoniae 79.3% [46/58]); the most common standard diagnostic modality was serology. In terms of disease severity, more than 90% of patients had CURB-65 (confusion of new onset, blood urea nitrogen > 19 mg/dL, respiratory rate ≥ 30 breaths/min, blood pressure <90 mm Hg systolic or ≤60 mm Hg diastolic, and age ≥ 65 years) scores of 0-2; approximately 50% of patients had PORT (Pneumonia Outcomes Research Team) risk class of III, and the remaining patients were more likely to have PORT risk class of II or IV versus V. In patients with atypical pathogens, early clinical response (lefamulin 84.4-96.6%; moxifloxacin 90.3-96.8%) and investigator assessment of clinical response at test of cure (lefamulin 74.1-89.7%; moxifloxacin 74.2-97.1%) were high and similar between arms. Treatment-emergent adverse event rates were similar in the lefamulin (34.1% [31/91]) and moxifloxacin (32.2% [28/87]) groups. Limitations to this analysis include its post hoc nature, the small numbers of patients infected with atypical pathogens, the possibility of PCR-based diagnostic methods to identify non-etiologically relevant pathogens, and the possibility that these findings may not be generalizable to all patients. Lefamulin as short-course empiric monotherapy, including 5-day oral therapy, was well tolerated in adults with community-acquired bacterial pneumonia and demonstrated high clinical response rates against atypical pathogens.

Efficacy of Omadacycline Versus Moxifloxacin in the Treatment of Community-Acquired Bacterial Pneumonia by Disease Severity: Results From the OPTIC Study.

BACKGROUND: Severity/mortality risk scores and disease characteristics may assist in deciding whether patients with community-acquired bacterial pneumonia (CABP) require outpatient treatment or hospitalization. The phase 3 OPTIC (Omadacycline for Pneumonia Treatment In the Community) study enrolled patients with Pneumonia Outcomes Research Team (PORT) risk class II-IV. Omadacycline demonstrated noninferiority to moxifloxacin in adults with CABP, at early clinical response (ECR) and posttreatment evaluation (PTE). We assessed efficacy of omadacycline versus moxifloxacin in these patients based on disease severity. METHODS: Patients were randomized 1:1 to receive intravenous (IV) omadacycline (100 mg every 12 hours for 2 doses followed by 100 mg daily [q24h], with optional transition to omadacycline 300 mg orally q24h after 3 days of IV treatment) or moxifloxacin IV 400 mg q24h (with optional transition to 400 mg orally q24h after 3 days of IV treatment). Total treatment duration was 7-14 days. We compared rates of early clinical success (72-120 hours after first dose) and investigator-assessed clinical success at PTE (5-10 days after last dose) in subgroups based (1) on severity/mortality risk scores (PORT, CURB-65, systemic inflammatory response syndrome, quick Sequential [Sepsis-related] Organ Failure Assessment, modified ATS, SMART-COP) and (2) on presence of baseline radiographic characteristics, chronic obstructive pulmonary disease (COPD)/asthma, or bacteremia. RESULTS: Altogether, 774 patients (omadacycline, n = 386; moxifloxacin, n = 388) were randomized. Clinical success rates (ECR/PTE) were similar between treatment groups (across all subgroups). Efficacy across treatment groups was similar in patients with baseline radiographic characteristics or COPD/asthma, but moxifloxacin had higher clinical success rates in patients with bacteremia. CONCLUSIONS: Efficacy of omadacycline was similar to that of moxifloxacin, regardless of disease severity/mortality risk and disease characteristics.

Oral 5-Day Lefamulin for Outpatient Management of Community-Acquired Bacterial Pneumonia: Post-hoc Analysis of the Lefamulin Evaluation Against Pneumonia (LEAP) 2 Trial.

BACKGROUND: Safe and effective oral antibiotics are needed for outpatient management of moderate to severe community-acquired bacterial pneumonia (CABP). OBJECTIVE: We describe a post-hoc analysis of adults with CABP managed as outpatients from the Lefamulin Evaluation Against Pneumonia (LEAP) 2 double-blind, noninferiority, phase 3 clinical trial. METHODS: LEAP 2 compared the efficacy and safety of oral lefamulin 600 mg every 12 h (5 days) vs. oral moxifloxacin 400 mg every 24 h (7 days) in adults (inpatients and outpatients) with Pneumonia Outcomes Research Team (PORT) risk classes II‒IV. RESULTS: Overall, 41% (151 of 368) of patients receiving lefamulin and 43% (159 of 368) of patients receiving moxifloxacin started treatment as outpatients-44% and 40%, respectively, were PORT risk class III/IV, and 21% in both groups had CURB-65 scores of 2‒3. Early clinical response (at 96 ± 24 h) and investigator assessment of clinical response success rates at test of cure (5‒10 days after last study drug dose) were high and similar in both groups among all (lefamulin, 91% vs. moxifloxacin, 89‒90%), PORT risk class III/IV (89‒91% vs. 88‒91%), and CURB-65 score 2‒3 (87‒90% vs. 82‒88%) outpatients. Few outpatients (lefamulin, 2.6%; moxifloxacin, 2.5%) discontinued the study drug because of treatment-emergent adverse events (TEAEs). No outpatient in the lefamulin group was hospitalized for a TEAE, compared with 5 patients (3%), including two deaths, in the moxifloxacin group. CONCLUSIONS: These data suggest that 5 days of oral lefamulin can be given in lieu of fluoroquinolones for outpatient treatment of adults with CABP and PORT risk class III/IV or CURB-65 scores of 2‒3.

Omadacycline vs moxifloxacin in adults with community-acquired bacterial pneumonia.

OBJECTIVE: Community-acquired bacterial pneumonia (CABP) is a major clinical burden worldwide. In the phase III OPTIC study (NCT02531438) in CABP, omadacycline was found to be non-inferior to moxifloxacin for investigator-assessed clinical response (IACR) at post-treatment evaluation (PTE, 5-10 days after last dose). This article reports the efficacy findings, as specified in the European Medicines Agency (EMA) guidance. METHODS: Patients were randomized 1:1 to omadacycline 100 mg intravenously (every 12 h for two doses, then every 24 h) with optional transition to 300 mg orally after 3 days, or moxifloxacin 400 mg intravenously (every 24 h) with optional transition to 400 mg orally after 3 days. The total treatment duration was 7-14 days. The primary endpoint for EMA efficacy analysis was IACR at PTE in patients with Pneumonia Patient Outcomes Research Team (PORT) risk class III and IV. RESULTS: In total, 660 patients were randomized as PORT risk class III and IV. Omadacycline was non-inferior to moxifloxacin at PTE. The clinical success rates were 88.4% and 85.2%, respectively [intent-to-treat population; difference 3.3; 97.5% confidence interval (CI) -2.7 to 9.3], and 92.5% and 90.5%, respectively (clinically evaluable population; difference 2.0; 97.5% CI 3.2-7.4). Clinical success rates with omadacycline and moxifloxacin were similar against identified pathogens and across key subgroups. CONCLUSIONS: Omadacycline was non-inferior to moxifloxacin for IACR at PTE, with high clinical success across pathogen types and patient subgroups.

Concordance of Early and Late End Points for Community-acquired Bacterial Pneumonia Trials.

BACKGROUND: While there are ongoing regulatory convergence efforts, differences remain in primary end points recommended for community-acquired bacterial pneumonia (CABP) trials. The US Food and Drug Administration (FDA) recommends assessing CABP symptom resolution at an early time point (3-5 days after randomization). Other regulatory agencies recommend assessing overall clinical response at a later time point (5-10 days after therapy ends). METHODS: We analyzed participant-level data from 6 recent CABP trials submitted to the FDA (n = 4645 participants) to evaluate concordance between early and late end-point outcomes. We used multivariate logistic regression to identify factors associated with discordance. RESULTS: Early and late end-point outcomes were concordant for 85.6% of participants. The proportions of early end-point responders that ultimately failed and early end-point nonresponders that ultimately succeeded were similar (6.0% vs 8.4%, respectively). Early end-point response was highly predictive of late end-point success (positive predictive value, 92.9%). Multivariate logistic regression identified early end-point responders/late end-point failures as less likely to be obese and more likely to be infected with Chlamydophila pneumoniae or Staphylococcus aureus, have received antibacterial drug therapy prior to randomization, and have severe chest pain at baseline. The most common investigator-provided reasons for failure among early end-point responders/late end-point failures were receipt of nonstudy antibacterial drug therapy and loss to follow-up. CONCLUSIONS: Early and late end-point outcomes were highly concordant. These data may be useful in the continuing efforts to reach international regulatory convergence on CABP clinical trial design recommendations.

Safety and efficacy of omadacycline for treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections in patients with mild-to-moderate renal impairment.

BACKGROUND: Many antibiotics require dosage adjustments in patients with renal impairment. In Phase III studies, omadacycline was non-inferior to moxifloxacin and linezolid in adults with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI), respectively. This analysis evaluated efficacy and safety measures from three omadacycline studies by patient renal function. METHODS: Patients were stratified as having normal renal function (creatinine clearance >89 mL/min), mild renal impairment (creatinine clearance 60-89 mL/min) or moderate renal impairment (creatinine clearance <60 mL/min); creatine clearance ≤30 mL/min (severe renal impairment) was an exclusion criterion. Efficacy endpoints were clinical success at the early clinical response (ECR) and post-treatment evaluation (PTE) time-points. Safety was evaluated as treatment-emergent adverse events (TEAEs) and laboratory measures. RESULTS: This subgroup analysis included 773 patients with CABP and 1339 patients with ABSSSI in intent-to-treat (ITT) and modified ITT populations, respectively. Clinical success rates were high at ECR and PTE across the studies (CABP 75-90%; ABSSSI 74-95%), and broadly similar between treatments, irrespective of renal function. Rates of TEAEs in patients with ABSSSI ranged from 33% to 52%, and were similar across renal function groups. In patients with CABP, higher rates were observed in patients with moderate renal impairment (56-61%) compared with patients with normal renal function or mild renal impairment (35-49%). The most common TEAEs were nausea and vomiting. CONCLUSIONS: Clinical success was similar across renal function groups, indicating no notable difference in the efficacy of omadacycline in patients with mild or moderate renal impairment. Omadacycline and comparators displayed similar safety profiles. CLINICALTRIALS. GOV REGISTRY: OPTIC (NCT02531438); OASIS-1 (NCT02378480); OASIS-2 (NCT02877927).

A phase Ib/IIa, randomised, double-blind, multicentre trial to assess the safety and efficacy of expanded Cx611 allogeneic adipose-derived stem cells (eASCs) for the treatment of patients with community-acquired bacterial pneumonia admitted to the intensive care unit.

BACKGROUND: Community-acquired bacterial pneumonia (CABP) can lead to sepsis and is associated with high mortality rates in patients presenting with shock and/or respiratory failure and who require mechanical ventilation and admission to intensive care units, thus reflecting the limited effectiveness of current therapy. Preclinical studies support the efficacy of expanded allogeneic adipose-derived mesenchymal stem cells (eASCs) in the treatment of sepsis. In this study, we aim to test the safety, tolerability and efficacy of eASCs as adjunctive therapy in patients with severe CABP (sCABP). METHODS: In addition to standard of care according to local guidelines, we will administer eASCs (Cx611) or placebo intravenously as adjunctive therapy to patients with sCABP. Enrolment is planned for approximately 180 patients who will be randomised to treatment groups in a 1:1 ratio according to a pre-defined randomization list. An equal number of patients is planned for allocation to each group. Cx611 will be administered on Day 1 and on Day 3 at a dose of 160 million cells (2 million cells / mL, total volume 80 mL) through a 20-30 min (240 mL/hr) intravenous (IV) central line infusion after dilution with Ringer Lactate solution. Placebo (Ringer Lactate) will also be administered through a 20-30 min (240 mL/hr) IV central line infusion at the same quantity (total volume of 80 mL) and following the same schedule as the active treatment. The study was initiated in January 2017 and approved by competent authorities and ethics committees in Belgium, Spain, Lithuania, Italy, Norway and France; monitoring will be performed at regular intervals. Funding is from the European Union's Horizon 2020 Research and Innovation Program. DISCUSSION: SEPCELL is the first trial to assess the effects of eASCs in sCABP. The data generated will advance understanding of the mode of action of Cx611 and will provide evidence on the safety, tolerability and efficacy of Cx611 in patients with sCABP. These data will be critical for the design of future confirmatory clinical investigations and will assist in defining endpoints, key biomarkers of interest and sample size determination. TRIAL REGISTRATION: NCT03158727 , retrospectively registered on 9 May 2017.

In vitro Activity of Lefamulin Against the Common Respiratory Pathogens Isolated From Mainland China During 2017-2019.

PURPOSE: Lefamulin is a novel antibiotic approved by the U.S. Food and Drug Administration in 2019 for the treatment of community-acquired bacterial pneumonia (CABP). In this study we evaluated the in vitro antimicrobial activity of lefamulin in order to better understand its antibiogram. METHODS: The test strains were isolated from patients across China during the period from 2017 to 2019, including 634 strains of respiratory pathogens. The minimum inhibitory concentrations (MICs) of lefamulin and comparators were determined by broth microdilution method. RESULTS: Lefamulin showed potent activity against Streptococcus pneumoniae and Staphylococcus evidenced by 100% inhibition at 0.25 mg/L, and favorable MIC50/90 (0.125/0.125 mg/L) against S. pneumoniae (penicillin MIC ≥ 2 mg/L), MIC50/90 (≤0.015/0.125 mg/L) against methicillin-resistant S. aureus, and MIC50/90 (≤0.015/0.06 mg/L) against methicillin-resistant S. epidermidis. Lefamulin also had good activity against Streptococcus pyogenes and Streptococcus agalactia (MIC50/90: ≤0.015/≤0.015 mg/L), ß-lactamase-producing Haemophilus influenzae (MIC50/90: 0.5/1 mg/L), ß-lactamase-negative H. influenzae (MIC50/90: 1/1 mg/L), Moraxella catarrhalis (MIC50/90: 0.25/0.25 mg/L), and Mycoplasma pneumoniae (MIC50/90: 0.03/0.03 mg/L) regardless of resistance to azithromycin. Lefamulin was generally more active than the comparators against the test strains. CONCLUSION: In summary, lefamulin has good and broad-spectrum coverage of respiratory pathogens (methicillin-sensitive and -resistant Staphylococcus, S. pneumoniae, ß-hemolytic Streptococcus, H. influenzae, M. catarrhalis and M. pneumoniae). In vitro activity supports the use of lefamulin in the treatment of CABP in China.