Efficacy of SPR720 in murine models of non-tuberculous mycobacterial pulmonary infection.

BACKGROUND: Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is increasing worldwide, with Mycobacterium avium complex (MAC) and Mycobacterium abscessus as the predominant pathogens. Current treatments are poorly tolerated and modestly effective, highlighting the need for new treatments. SPR719, the active moiety of the benzimidazole prodrug SPR720, inhibits the ATPase subunits of DNA gyrase B, a target not exploited by current antibiotics, and therefore, no cross-resistance is expected with standard-of-care (SOC) agents. OBJECTIVES: To evaluate the in vitro activity of SPR719 against MAC and M. abscessus clinical isolates, including those resistant to SOC agents, and in vivo efficacy of SPR720 in murine non-tuberculous mycobacteria (NTM) pulmonary infection models. METHODS: NTM isolates were tested for susceptibility to SPR719. Chronic C3HeB/FeJ and severe combined immunodeficient murine models of pulmonary infection were used to assess efficacy of SPR720 against MAC and M. abscessus, respectively. RESULTS: SPR719 was active against MAC (MIC90, 2 mg/L) and M. abscessus (MIC90, 4 mg/L) clinical isolates. Efficacy of SPR720 was demonstrated against MAC pulmonary infection, both as a monotherapy and in combination with SOC agents. SPR720 monotherapy exhibited dose-dependent reduction in bacterial burden, with the largest reduction observed when combined with clarithromycin and ethambutol. Efficacy of SPR720 was also demonstrated against M. abscessus pulmonary infection where monotherapy exhibited a dose-dependent reduction in bacterial burden with further reductions detected when combined with SOC agents. CONCLUSIONS: In vitro activity of SPR720 against common NTM pathogens and efficacy in murine infections warrant the continued clinical evaluation of SPR720 as a new oral option for the treatment of NTM-PD.

Serum Cell-Free DNA-based Detection of Mycobacterium avium Complex Infection.

Rationale: Mycobacterium avium complex (MAC) is the most common cause of nontuberculous mycobacterial (NTM) pulmonary disease (PD), which exhibits increasing global incidence. Current microbiologic methods routinely used in clinical practice lack sensitivity and have long latencies, leading to delays in diagnosis and treatment initiation and evaluation. A clustered regularly interspaced short palindromic repeats (CRISPR)-based assay that measures MAC cell-free DNA (cfDNA) concentrations in serum could provide a rapid means to detect MAC infection and monitor response to antimicrobial treatment. Objectives: To develop and optimize a CRISPR MAC assay for MAC infection detection and to evaluate its diagnostic and prognostic performance in two MAC disease cohorts. Methods: MAC cfDNA serum concentrations were measured in individuals with diagnoses of MAC disease or who had bronchiectasis or chronic obstructive pulmonary disease diagnoses without histories of NTM PD or NTM-positive sputum cultures. Diagnostic performance was analyzed using pretreatment serum from two cohorts. Serum MAC cfDNA changes during MAC PD treatment were evaluated in a subset of patients with MAC PD who received macrolide-based multidrug regimens. Measurements and Main Results: The CRISPR MAC assay detected MAC cfDNA in MAC PD with 97.6% (91.6-99.7%) sensitivity and 97.6% (91.5-99.7%) specificity overall. Serum MAC cfDNA concentrations markedly decreased after MAC-directed treatment initiation in patients with MAC PD who demonstrated MAC culture conversion. Conclusions: This study provides preliminary evidence for the utility of a serum-based CRISPR MAC assay to rapidly detect MAC infection and monitor the response to treatment.

A narrative review of nontuberculous mycobacterial pulmonary disease: microbiology, epidemiology, diagnosis, and management challenges.

INTRODUCTION: Nontuberculous mycobacteria (NTM) are a diverse group of mycobacterial species that are ubiquitous in the environment. They are opportunistic pathogens that can cause a range of diseases, especially in individuals with underlying structural lung disease or compromised immune systems. AREAS COVERED: This paper provides an in-depth analysis of NTM infections, including microbiology, environmental sources and transmission pathways, risk factors for disease, epidemiology, clinical manifestations and diagnostic approaches, guideline-based treatment recommendations, drugs under development, and management challenges. EXPERT OPINION: Future approaches to the management of NTM pulmonary disease will require therapies that are well tolerated, can be taken for a shorter time period and perhaps less frequently, have few drug-drug interactions, and are active against the various strains of pathogens. As the numbers of infections increase, such therapies will be welcomed by clinicians and patients.

Nontuberculous mycobacterial pulmonary disease and the potential role of SPR720.

INTRODUCTION: Nontuberculous mycobacteria infect patients who have structural lung disease or those who are immunocompromised. Nontuberculous mycobacterial pulmonary disease (NTM-PD) is increasing in prevalence. Treatment guidelines for Mycobacterium avium complex (MAC) pulmonary disease involve a three-drug regimen with azithromycin, ethambutol, and rifampin, and those of Mycobacterium abscessus complex (MAB) pulmonary disease involve a combination of three or more antimicrobials including macrolides, amikacin, and a ß-lactam or imipenem. However, these regimens are poorly tolerated and generally ineffective. AREAS COVERED: SPR720 is a novel therapeutic agent that has demonstrated activity against a range of NTM species, including MAC and MAB. Encouraging in vitro and pre-clinical data demonstrate that SPR720 is active both alone and in combination with standard-of-care agents, with no evidence of cross-resistance to such agents. It is generally well tolerated with mainly gastrointestinal and headache adverse events of mild or moderate severity. EXPERT OPINION: Management of NTM-PD is challenging for many reasons including length of therapy, poor efficacy, drug intolerance, recurrence, and resistance development. The current antimicrobial management options for NTM-PD are limited in number and there exists a large unmet need for new treatments. SPR720 has encouraging data that warrant further study in the context of a multidrug regimen.

Safety and pharmacokinetics of SPR206 in subjects with varying degrees of renal impairment.

SPR206 is a novel polymyxin derivative with potent in vitro activity against susceptible and multidrug-resistant strains of Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter species. SPR206 is eliminated renally. The safety, tolerability, and pharmacokinetics (PK) of SPR206 were evaluated in healthy subjects with normal renal function (Cohort 1) and subjects with varying degrees of renal impairment (RI) (Cohorts 2-4) or end-stage renal disease (ESRD) on hemodialysis (HD) (Cohort 5). Subjects in Cohorts 1-4 received a 100-mg intravenous (IV) dose of SPR206. Subjects in Cohort 5 received a 100-mg IV dose within 2 h after HD on day 1 and 1 h before HD on day 5. Safety and PK analyses included 37 subjects. Mostly mild but no serious treatment-related adverse events were reported. Systemic exposure to SPR206 increased as renal function decreased, with mean area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last) values 39% to 239% greater in subjects with RI vs healthy subjects. Mean plasma clearance (CL) of SPR206 decreased with decreasing renal function (29% to 76% lower vs healthy subjects). In subjects with ESRD, AUC0-last decreased by 51%, and CL increased by 92% for dialyzed vs nondialyzed conditions. SPR206 was excreted in urine within 12 h in healthy subjects and subjects with mild RI (Cohort 2) but was prolonged in those with moderate and severe RI (Cohorts 3 and 4, respectively). In summary, SPR206 was generally safe and well tolerated, and the PK of SPR206 was well characterized in subjects with RI.

Ceftobiprole for Treatment of Complicated Staphylococcus aureus Bacteremia.

BACKGROUND: Ceftobiprole is a cephalosporin that may be effective for treating complicated Staphylococcus aureus bacteremia, including methicillin-resistant S. aureus. METHODS: In this phase 3, double-blind, double-dummy, noninferiority trial, adults with complicated S. aureus bacteremia were randomly assigned in a 1:1 ratio to receive ceftobiprole at a dose of 500 mg intravenously every 6 hours for 8 days and every 8 hours thereafter, or daptomycin at a dose of 6 to 10 mg per kilogram of body weight intravenously every 24 hours plus optional aztreonam (at the discretion of the trial-site investigators). The primary outcome, overall treatment success 70 days after randomization (defined as survival, bacteremia clearance, symptom improvement, no new S. aureus bacteremia-related complications, and no receipt of other potentially effective antibiotics), with a noninferiority margin of 15%, was adjudicated by a data review committee whose members were unaware of the trial-group assignments. Safety was also assessed. RESULTS: Of 390 patients who underwent randomization, 387 (189 in the ceftobiprole group and 198 in the daptomycin group) had confirmed S. aureus bacteremia and received ceftobiprole or daptomycin (modified intention-to-treat population). A total of 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], -7.1 to 11.1). Findings appeared to be consistent between the ceftobiprole and daptomycin groups in key subgroups and with respect to secondary outcomes, including mortality (9.0% and 9.1%, respectively; 95% CI, -6.2 to 5.2) and the percentage of patients with microbiologic eradication (82.0% and 77.3%; 95% CI, -2.9 to 13.0). Adverse events were reported in 121 of 191 patients (63.4%) who received ceftobiprole and 117 of 198 patients (59.1%) who received daptomycin; serious adverse events were reported in 36 patients (18.8%) and 45 patients (22.7%), respectively. Gastrointestinal adverse events (primarily mild nausea) were more frequent with ceftobiprole. CONCLUSIONS: Ceftobiprole was noninferior to daptomycin with respect to overall treatment success in patients with complicated S. aureus bacteremia. (Funded by Basilea Pharmaceutica International and the U.S. Department of Health and Human Services; ERADICATE ClinicalTrials.gov number, NCT03138733.).

Impact of antibiotic pharmacokinetics in urine on recurrent bacteriuria following treatment of complicated urinary tract infections.

The clinical relevance of bacteriuria following antibiotic treatment of complicated urinary tract infections in clinical trials remains controversial. We evaluated the impact of urine pharmacokinetics on the timing of recurrent bacteriuria in a recently completed trial that compared oral tebipenem pivoxil hydrobromide to intravenous ertapenem. The urinary clearance and urine dwell time of ertapenem were prolonged relative to tebipenem and were associated with a temporal difference in the repopulation of bladder urine with bacteria following treatment, potentially confounding the assessment of efficacy.

Pharmacokinetics of SPR206 in Plasma, Pulmonary Epithelial Lining Fluid, and Alveolar Macrophages following Intravenous Administration to Healthy Adult Subjects.

SPR206 is a next-generation polymyxin being developed for the treatment of multidrug-resistant (MDR) Gram-negative infections. This Phase 1 bronchoalveolar lavage (BAL) study was conducted to evaluate SPR206's safety and pharmacokinetics in plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AM) in healthy volunteers. Subjects received a 100 mg intravenous (IV) dose of SPR206 infused over 1 h every 8 h for 3 consecutive doses. Each subject underwent 1 bronchoscopy with BAL at 2, 3, 4, 6, or 8 h after the start of the third IV infusion. SPR206 concentrations in plasma, BAL, and cell pellet were measured with a validated LC-MS/MS assay. Thirty-four subjects completed the study and 30 completed bronchoscopies. Mean SPR206 peak concentrations (Cmax) in plasma, ELF, and AM were 4395.0, 735.5, and 860.6 ng/mL, respectively. Mean area under the concentration-time curve (AUC0-8) for SPR206 in plasma, ELF, and AM was 20120.7, 4859.8, and 6026.4 ng*h/mL, respectively. The mean ELF to unbound plasma concentration ratio was 0.264, and mean AM to unbound plasma concentration ratio was 0.328. Mean SPR206 concentrations in ELF achieved lung exposures above the MIC for target Gram-negative pathogens for the entire 8-h dosing interval. Overall, SPR206 was well tolerated; 22 subjects (64.7%) reported at least 1 treatment-emergent adverse event (TEAE). Of the 40 reported TEAEs, 34 (85.0%) were reported as mild in severity. The most frequent TEAEs were oral paresthesia (10 subjects [29.4%]) and nausea (2 subjects [5.9%]). This study demonstrates pulmonary penetration of SPR206 and supports further development of SPR206 for the treatment of patients with serious infections caused by MDR Gram-negative pathogens.

Post-hoc analysis of the safety and efficacy of isavuconazole in older patients with invasive fungal disease from the VITAL and SECURE studies.

Isavuconazole is a triazole with broad-spectrum antifungal activity. In this post-hoc analysis of two prospective clinical trials (VITAL and SECURE), the safety and efficacy of isavuconazole in patients aged ≥ 65 years with invasive fungal diseases were evaluated. Patients were divided into two subgroups (≥ 65 and < 65 years). Adverse events (AEs); all-cause mortality; and overall, clinical, mycological, and radiological response were assessed. A total of 155 patients ≥ 65 years were enrolled in both trials. Most patients reported AEs. In the isavuconazole arm of both studies, serious AEs (SAEs) were greater in patients ≥ 65 versus < 65 years: 76.7% versus 56.9% (VITAL); 61.9% versus 49.0% (SECURE). In SECURE, SAE rates were similar in the ≥ 65 years subgroup of both treatment arms (61.9% vs 58.1%), while in the < 65 years subgroup the SAE rate was lower in the isavuconazole arm (49.0% vs 57.4%). In VITAL, all-cause mortality through day 42 (30.0% vs 13.8%) was higher, and overall response at end of treatment (27.6% vs 46.8%) was lower in patients ≥ 65 years versus < 65 years. In SECURE, all-cause mortality was similar between both subgroups, and isavuconazole (20.6% vs 17.9%) and voriconazole (22.6% vs 19.4%) treatment arms. The overall response was lower in the ≥ 65 years than the < 65 years subgroup in the isavuconazole (23.7% vs 39.0%) and voriconazole (32.0% vs 37.5%) arms. The safety and efficacy of isavuconazole were better in patients < 65 versus ≥ 65 years, and the safety profile was more favorable than that of voriconazole in both subgroups.Clinicaltrials.gov identifier NCT00634049 and NCT00412893.

Plain language summary: use of isavuconazole in Chinese patients with an invasive fungal disease.

WHAT IS THIS SUMMARY ABOUT?: Invasive aspergillosis (also known as IA) is a type of fungal infection, caused by a species of fungus called Aspergillus, that can be life threatening. Isavuconazole and voriconazole belong to a group of antifungal drugs called triazoles that are recommended for treating IA. In the USA and in Europe, isavuconazole is approved for treating patients with IA. In China, isavuconazole was recently being reviewed for approval for treating patients with IA. This study looked at whether isavuconazole works in the same way in healthy Chinese people as it does in healthy Western people. It also looked to see how well isavuconazole works and how many side effects it has compared with voriconazole in Chinese patients with IA. WHAT WERE THE RESULTS?: The results of this study showed that healthy Chinese people's bodies processed isavuconazole the same way as healthy Western people's bodies. The amount of drug in people's bodies did not change how well the drug worked or how many side effects there were. Isavuconazole worked as well as and had a similar number of side effects as voriconazole in treating Chinese patients with IA. WHAT DO THE RESULTS OF THE STUDY MEAN?: These findings show that isavuconazole may be a suitable treatment for Chinese patients with IA using the same dose that is used in Western patients.

Ceftobiprole activity against Gram-positive and Gram-negative pathogens causing bone and joint infections in the United States from 2016 to 2020.

Bone and joint infections (BJIs) present significant treatment challenges. Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus, is approved in many European and other countries for the treatment of adults with community- and hospital-acquired pneumonia, excluding ventilator-associated pneumonia. In this study, the in vitro activity of ceftobiprole and comparators was evaluated against clinical isolates collected from BJIs in the USA from 2016 to 2020. Gram-positive pathogens made up 70.6% of all BJI isolates and included S. aureus (47.4% of all isolates), ß-hemolytic streptococci, coagulase-negative staphylococci, and Enterococcus faecalis. Ceftobiprole was highly active against S. aureus (MIC50/90 values, 0.5/1 mg/L; 99.6% susceptible using the European Committee on Antimicrobial Susceptibility Testing susceptibility breakpoint of ≤2 mg/L for the treatment of pneumonia patients) and exhibited potent activity against the other Gram-positive cocci and the predominant BJI Gram-negative groups. These results support the further evaluation of ceftobiprole for this potential indication.

In vitro activity of ceftobiprole and comparator antibiotics against contemporary European isolates (2016-19).

Objectives: To evaluate the susceptibility to ceftobiprole of clinical bacterial isolates obtained from hospitalized patients in Europe. Methods: A total of 20 000 non-duplicate bacterial isolates were collected in 2016-19 from patients with documented infections at medical centres located in 17 countries in Europe. Bacterial identification was confirmed and susceptibility to ceftobiprole and comparator agents was tested using the EUCAST broth microdilution methodology and interpretive criteria by a central microbiology laboratory. Results: Of the 20 000 isolates, 10 007 (50.0%) were Gram-positive and 9993 (50.0%) were Gram-negative. The most common species was Staphylococcus aureus (35.0%), followed by Streptococcus pneumoniae (15.0%), Klebsiella pneumoniae (11.1%), Pseudomonas aeruginosa (11.0%), Escherichia coli (9.7%) and Haemophilus influenzae (3.0%). Overall, 99.7% (6981/7000) of S. aureus, including 99.5% (3483/3502) of MRSA, 97.8% (2941/3007) of S. pneumoniae, 100% (605/605) of H. influenzae and 76.3% (5492/7197) of Enterobacterales isolates were susceptible to ceftobiprole. Susceptibility to ceftobiprole was higher for isolates from northern and western Europe as compared with eastern and southern Europe. Conclusions: Ceftobiprole continues to exhibit potent and broad-spectrum activity against Gram-positive and Gram-negative clinical isolates from Europe, and as expected, with a slight north-to-south and west-to-east susceptibility gradient.

Pharmacokinetics and Safety of Ceftobiprole in Pediatric Patients.

BACKGROUND: Ceftobiprole, the active moiety of the prodrug ceftobiprole medocaril, is an advanced-generation, broad-spectrum, intravenous cephalosporin, which is currently approved for the treatment of adults with hospital-acquired or community-acquired pneumonia. METHODS: Noncompartmental pharmacokinetics and safety were analyzed from 2 recently completed pediatric studies, a single-dose, phase 1 study in neonates and infants up to 3 months of age (7.5 mg/kg) and a phase 3 study in patients 3 months to 17 years of age with pneumonia (10-20 mg/kg with a maximum of 500 mg per dose every 8 hours for up to 14 days). RESULTS: Total ceftobiprole plasma concentrations peaked at the end of infusion. Half life (median ranging from 1.9 to 2.9 hours) and overall exposure (median AUC ranging from 66.6 to 173 µg•h/mL) were similar to those in adults (mean ± SD, 3.3 ± 0.3 hours and 102 ± 11.9 µg•h/mL, respectively). Calculated free-ceftobiprole concentrations in the single-dose study remained above a minimum inhibitory concentration (MIC) of 4 mg/L (fT > MIC of 4 mg/L) for a mean of 5.29 hours after dosing. In the pneumonia study, mean fT > MIC of 4 mg/L was ≥5.28 hours in all dose groups. Ceftobiprole was well tolerated in both studies. CONCLUSIONS: Pharmacokinetic parameters of ceftobiprole characterized in the pediatric population were within the range of those observed in adults. In the pneumonia study, the lowest percentage of the dosing interval with fT > MIC of 4 mg/L was 50.8%, which suggests that pharmacokinetic-pharmacodynamic target attainment can be sufficient in pediatric patients. Ceftobiprole was well tolerated.

Model-Based Approach for Optimizing Ceftobiprole Dosage in Pediatric Patients.

Ceftobiprole is an advanced-generation cephalosporin for intravenous administration with activity against Gram-positive and Gram-negative organisms. A population pharmacokinetic (PK) model characterizing the disposition of ceftobiprole in plasma using data from patients in three pediatric studies was developed. Model-based simulations were subsequently performed to assist in dose optimization for the treatment of pediatric patients with hospital-acquired or community-acquired pneumonia. The population PK data set comprised 518 ceftobiprole plasma concentrations from 107 patients from 0 (birth) to 17 years of age. Ceftobiprole PK was well described by a three-compartment model with linear elimination. Ceftobiprole clearance was modeled as a function of glomerular filtration rate; other PK parameters were scaled to body weight. The final population PK model provided a robust and reliable description of the PK of ceftobiprole in the pediatric study population. Model-based simulations using the final model suggested that a ceftobiprole dose of 15 mg/kg of body weight infused over 2 h and administered every 12 h in neonates and infants <3 months of age or every 8 h in older pediatric patients would result in a ceftobiprole exposure consistent with that in adults and good pharmacokinetic-pharmacodynamic target attainment. The dose should be reduced to 10 mg/kg every 12 h in neonates and infants <3 months of age who weigh <4 kg to avoid high exposures. Extended intervals and reduced doses may be required for pediatric patients older than 3 months of age with renal impairment.

A post hoc analysis of two Phase III trials showing the efficacy and tolerability of ceftobiprole in East Asian patients.

Aim: To evaluate the efficacy and safety of ceftobiprole in patients from East Asia. Materials & methods: A post hoc analysis was conducted of two randomized, double-blind, Phase III studies in patients with community- or hospital-acquired pneumonia. Results: Findings for East Asian patients were consistent with the overall study populations. A trend toward higher microbiological eradication rates and numerically lower rates of all-cause mortality were reported for ceftobiprole versus comparators (all-cause mortality [intent-to-treat]: community-acquired pneumonia, 1.5 vs 2.8%; hospital-acquired pneumonia excluding ventilator-associated pneumonia, 5.9 vs 11.4%). The incidence of adverse events was similar between treatment groups. Conclusion: This post hoc analysis supports the efficacy and tolerability of ceftobiprole in East Asian patients. ClinicalTrials.gov trial identifiers: NCT00326287, NCT00210964, NCT00229008.

Lay abstract Pneumonia is a major cause of morbidity and mortality in East Asia and treatment is complicated by increasing rates of antibiotic resistance in this region. This study analyzed results from two clinical trials that assessed the benefits of the novel antibiotic ceftobiprole in patients from mainland China, Hong Kong, Taiwan and South Korea. In East Asian patients with either community- or hospital-acquired pneumonia, outcomes following ceftobiprole treatment were similar to those achieved with established antibiotics. There was also an indication that ceftobiprole may improve the rate at which causative bacteria were eradicated and may potentially reduce mortality rates compared with other antibiotics. Ceftobiprole was well tolerated in this population and will be a useful option for the treatment of pneumonia in East Asia.

Efficacy and safety of ceftobiprole in patients aged 65 years or older: a post hoc analysis of three Phase III studies.

Aim: To evaluate the efficacy and safety of ceftobiprole in patients aged ≥65 years. Materials & methods: We conducted a post hoc analysis of three randomized, double-blind, Phase III studies in patients with acute bacterial skin and skin structure infections, community-acquired pneumonia and hospital-acquired pneumonia. Results: Findings for patients aged ≥65 years (n = 633) were consistent with those for the overall study populations, although a trend toward improved outcomes was reported in some subgroups, for example, patients aged ≥75 years with community-acquired pneumonia were more likely to achieve an early clinical response with ceftobiprole than comparator (treatment difference 16.3% [95% CI:1.8-30.8]). The safety profile was similar between treatment groups in all studies. Conclusion: This analysis further supports the efficacy and safety of ceftobiprole in older patients with acute bacterial skin and skin structure infections or pneumonia. Clinicaltrials.gov trial identifiers: NCT03137173, NCT00326287, NCT00210964, NCT00229008.

Lay abstract Infections are a common cause of severe disease and death in older patients. Antibiotic treatment may also be complicated by age-related changes within the body. The present study analyzed results from three large clinical trials that assessed the benefits of the novel antibiotic ceftobiprole in the older population. In patients aged over 65 years with skin infections or with pneumonia acquired either in the community or in a hospital setting, ceftobiprole offered similar benefits to established antibiotics. There was also some preliminary evidence that older patients may respond more quickly to ceftobiprole compared with the other antibiotics used in these studies. Overall, ceftobiprole was well tolerated and will be a useful treatment option for infections in older patients. Clinical trial registration: NCT03137173, NCT00326287, NCT00210964, NCT00229008 (Clinicaltrials.gov).

Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients.

Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to <6 [intravenous (i.v.) only], 6 to <12, and 12 to <18 years), receiving 10 mg/kg body weight (maximum, 372 mg) isavuconazonium sulfate either i.v. or orally. A population PK model using weight-based allometric scaling was constructed with the pediatric i.v. and oral data plus i.v. data from a phase 1 study in adults. The best model was a 3-compartment model with combined zero-order and first-order input, with linear elimination. Stepwise covariate modeling was performed in Perl-speaks-NONMEM version 4.7.0. None of the covariates examined, including age, sex, race, and body mass index, were statistically significant for any of the PK parameters. The area under the concentration-time curve at steady state (AUCSS) was predicted for pediatric patients using 1,000 Monte Carlo simulations per age cohort for each administration route. The probability of target attainment (AUCSS range, 60 to 233 µg · h/ml) was estimated; this target range was derived from plasma drug exposures in adults receiving the recommended clinical dose. Predicted plasma drug exposures were within the target range for >80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).

A Phase 3, Randomized, Investigator-blinded Trial Comparing Ceftobiprole With a Standard-of-care Cephalosporin, With or Without Vancomycin, for the Treatment of Pneumonia in Pediatric Patients.

BACKGROUND: The advanced-generation, broad-spectrum, intravenous (IV) cephalosporin, ceftobiprole, is an effective and well-tolerated treatment for adults with hospital-acquired pneumonia (HAP) or community-acquired pneumonia (CAP), but its effects in pediatric patients have not been established. METHODS: In this multicenter, investigator-blinded, active-controlled, phase 3 study, patients 3 months to <18 years old with HAP or CAP requiring hospitalization were randomized (2:1) to ceftobiprole versus standard-of-care (SoC) IV cephalosporin treatments (ceftazidime or ceftriaxone), with or without vancomycin. After at least 3 days' IV treatment, patients demonstrating clinical improvement could be switched to an oral antibiotic, to complete a minimum of 7 days' treatment. RESULTS: Overall, 138 patients were randomized to ceftobiprole (n = 94) or a SoC cephalosporin (n = 44). Median time to oral switch was 6.0 days in the ceftobiprole group and 8.0 days in the SoC cephalosporin group. While on IV therapy, adverse events and treatment-related adverse events were reported by 20.2% and 8.5% of ceftobiprole-treated patients and 18.2% and 0% of SoC cephalosporin-treated patients. Early clinical response rates at day 4 in the intention-to-treat population were 95.7% and 93.2% (between-group difference, 2.6%; 95% confidence interval, -5.5% to 14.7%) in the ceftobiprole and comparator groups, and clinical cure rates at the test-of-cure visit were 90.4% and 97.7% (between-group difference, -7.3%; 95% confidence interval, -15.7% to 3.6%), respectively. CONCLUSIONS: Ceftobiprole was well tolerated and, in this small phase 3 study, demonstrated similar efficacy to SoC cephalosporins in pediatric patients with HAP or CAP requiring hospitalization.

Ceftobiprole Compared With Vancomycin Plus Aztreonam in the Treatment of Acute Bacterial Skin and Skin Structure Infections: Results of a Phase 3, Randomized, Double-blind Trial (TARGET).

BACKGROUND: The development of novel broad-spectrum antibiotics, with efficacy against both gram-positive and gram-negative bacteria, has the potential to enhance treatment options for acute bacterial skin and skin structure infections (ABSSSIs). Ceftobiprole is an advanced-generation intravenous cephalosporin with broad in vitro activity against gram-positive (including methicillin-resistant Staphylococcus aureus) and gram-negative pathogens. METHODS: TARGET was a randomized, double-blind, active-controlled, parallel-group, multicenter, phase 3 noninferiority study that compared ceftobiprole with vancomycin plus aztreonam. The Food and Drug Administration-defined primary efficacy endpoint was early clinical response 48-72 hours after treatment initiation in the intent-to-treat (ITT) population and the European Medicines Agency-defined primary endpoint was investigator-assessed clinical success at the test-of-cure (TOC) visit. Noninferiority was defined as the lower limit of the 95% CI for the difference in success rates (ceftobiprole minus vancomycin/aztreonam) >-10%. Safety was assessed through adverse event and laboratory data collection. RESULTS: In total, 679 patients were randomized to ceftobiprole (n = 335) or vancomycin/aztreonam (n = 344). Early clinical success rates were 91.3% and 88.1% in the ceftobiprole and vancomycin/aztreonam groups, respectively, and noninferiority was demonstrated (adjusted difference: 3.3%; 95% CI: -1.2, 7.8). Investigator-assessed clinical success at the TOC visit was similar between the 2 groups, and noninferiority was demonstrated for both the ITT (90.1% vs 89.0%) and clinically evaluable (97.9% vs 95.2%) populations. Both treatment groups displayed similar microbiological success and safety profiles. CONCLUSIONS: TARGET demonstrated that ceftobiprole is noninferior to vancomycin/aztreonam in the treatment of ABSSSIs, in terms of early clinical response and investigator-assessed clinical success at the TOC visit. CLINICAL TRIALS REGISTRATION: NCT03137173.

Clinical experience with isavuconazole in healthy volunteers and patients with invasive aspergillosis in China, and the results from an exposure-response analysis.

BACKGROUND: Isavuconazole is a broad-spectrum triazole for the treatment of invasive fungal disease (IFD). OBJECTIVE: To investigate the clinical experience with isavuconazole in Chinese individuals. PATIENTS/METHODS: Participants were Chinese healthy volunteers from a Phase I pharmacokinetics (PK) and safety study of single/multiple doses of isavuconazole (n = 36) and Chinese patients from the global Phase III SECURE study that assessed safety and efficacy of isavuconazole vs voriconazole for IFD treatment (n = 26). RESULTS: No clinically relevant differences in PK were found between Chinese and Western participants, although exposure was increased in Chinese volunteers. Treatment-emergent adverse events (TEAEs) were reported in 75.0% of healthy volunteers, many of which were infusion-related. No serious AEs were reported. In SECURE, findings in Chinese patients (n = 26) were similar to the global population. For patients who received ≥1 dose of study drug, allcause mortality from first dose to Day 42 was 10.0% (1/10) with isavuconazole and 25.0% (4/16) with voriconazole (treatment difference [95% confidence interval, CI]: -15.0% [-43.2%, 13.2%]). Overall response at the end of treatment for patients with proven/probable IFD was 25.0% and 16.7% with isavuconazole and voriconazole, respectively (treatment difference [95% CI] -8.3% [-60.2%, 43.5%]). Isavuconazole was associated with lower incidence of hepatobiliary, eye, skin, subcutaneous tissue and psychiatric disorders compared with voriconazole and lower incidence of treatment-related TEAEs, serious TEAES or death overall. CONCLUSIONS: Although further research is required, this study demonstrated a favourable risk-benefit profile of isavuconazole in Chinese patients.