Antithrombotic Prophylaxis with Rivaroxaban in Patients with Prehospital COVID-19: A Meta-analysis of Two Placebo-Controlled Trials.

BACKGROUND: We conducted a prespecified meta-analysis of two randomized, placebo-controlled trials of rivaroxaban 10 mg daily in prehospital patients with acute coronavirus disease 2019 (COVID-19). Individually, the trials had limited power to detect a treatment effect due to recruitment stopping ahead of plan. MATERIAL AND METHODS: The statistical analysis plan for the meta-analysis was finalized before unblinding of PREVENT-HD, the larger of the two trials. Pooled risk ratios and pooled risk differences along with the two-sided 95% confidence intervals were calculated using random-effect models. RESULTS: Rivaroxaban did not reduce the occurrence of either the primary prespecified endpoint, a composite of symptomatic arterial and venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, all-cause hospitalization, and all-cause mortality (risk difference: 0.0044; 95% confidence interval: -0.0263, 0.0175; p = 0.69 for pooled risk difference) or the secondary endpoint of all-cause hospitalization (p = 0.76). Although thrombotic events were infrequent, pooled analysis did reveal that rivaroxaban reduced arterial and venous thrombotic events (placebo 6 events, rivaroxaban 0 events; pooled risk difference: -0.0068; 95% confidence interval: -0.0132, -0.0006; p = 0.03). In the pooled studies, only one major bleeding event was observed in a rivaroxaban-allocated patient with no critical site or fatal bleeding events. CONCLUSION: Although this meta-analysis does not support antithrombotic prophylaxis with rivaroxaban in a broad prehospital population with acute COVID-19, the prevention of arterial and venous thrombotic events among rivaroxaban-allocated patients is consistent with the known thromboprophylactic effect of the drug in medically ill patients.

Sulopenem for the Treatment of Complicated Urinary Tract Infections Including Pyelonephritis: A Phase 3, Randomized Trial.

BACKGROUND: Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations will facilitate earlier hospital discharge. METHODS: Hospitalized adults with pyuria, bacteriuria, and signs and symptoms of complicated urinary tract infection (cUTI) were randomized to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid or 5 days of IV ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate, depending on uropathogen susceptibility. The primary end point was overall combined clinical and microbiologic response at the test-of-cure visit (day 21). RESULTS: Of 1392 treated patients, 444 and 440 treated with sulopenem and ertapenem, respectively, had a positive baseline urine culture and were eligible for the primary efficacy analyses. Extended-spectrum ß-lactamase-producing organisms were identified in 26.6% of patients and fluoroquinolone-nonsusceptible pathogens in 38.6%. For the primary end point, noninferiority of sulopenem to the comparator regimen was not demonstrated, 67.8% vs 73.9% (difference, -6.1%; 95% confidence interval, -12.0 to -.1%). The difference was driven by a lower rate of asymptomatic bacteriuria in the subgroup of ertapenem-treated patients who stepped down to ciprofloxacin. No substantial difference in overall response was observed at any other time point. Both IV and oral formulations of sulopenem were well-tolerated and compared favorably to the comparator. CONCLUSIONS: Sulopenem followed by oral sulopenem-etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down therapy for the treatment of cUTIs, driven by a lower rate of asymptomatic bacteriuria in those who received ciprofloxacin. Both formulations of sulopenem were well-tolerated. CLINICAL TRIAL REGISTRATION: NCT03357614.

Sulopenem or Ciprofloxacin for the Treatment of Uncomplicated Urinary Tract Infections in Women: A Phase 3, Randomized Trial.

BACKGROUND: There are limited treatment options for uncomplicated urinary tract infection (uUTI) caused by resistant pathogens. Sulopenem etzadroxil/probenecid (sulopenem) is an oral thiopenem antibiotic active against multidrug-resistant pathogens that cause uUTIs. METHODS: Patients with uUTI were randomized to 5 days of sulopenem or 3 days of ciprofloxacin. The primary endpoint was overall success, defined as both clinical and microbiologic response at day 12. In patients with ciprofloxacin-nonsusceptible baseline pathogens, sulopenem was compared for superiority over ciprofloxacin; in patients with ciprofloxacin-susceptible pathogens, the agents were compared for noninferiority. Using prespecified hierarchical statistical testing, the primary endpoint was tested in the combined population if either superiority or noninferiority was declared in the nonsusceptible or susceptible population, respectively. RESULTS: In the nonsusceptible population, sulopenem was superior to ciprofloxacin, 62.6% vs 36.0% (difference, 26.6%; 95% confidence interval [CI], 15.1 to 7.4; P <.001). In the susceptible population, sulopenem was not noninferior to ciprofloxacin, 66.8% vs 78.6% (difference, -11.8%; 95% CI, -18.0 to 5.6). The difference was driven by a higher rate of asymptomatic bacteriuria (ASB) post-treatment in patients on sulopenem. In the combined analysis, sulopenem was noninferior to ciprofloxacin, 65.6% vs 67.9% (difference, -2.3%; 95% CI, -7.9 to 3.3). Diarrhea occurred more frequently with sulopenem (12.4% vs 2.5%). CONCLUSIONS: Sulopenem was noninferior to ciprofloxacin in the treatment of uUTIs. Sulopenem was superior to ciprofloxacin in patients with uUTIs due to ciprofloxacin-nonsusceptible pathogens. Sulopenem was not noninferior in patients with ciprofloxacin-susceptible pathogens, driven largely by a lower rate of ASB in those who received ciprofloxacin. CLINICAL TRIAL REGISTRATION: NCT03354598.

Increased rates of extended-spectrum beta-lactamase isolates in patients hospitalized with culture-positive urinary Enterobacterales in the United States: 2011 - 2020.

Antimicrobial resistance in Enterobacterales has made empiric therapy for hospitalized patients with urinary tract infections (UTIs) more challenging. We analyzed the antibiotic susceptibility of nonduplicate Enterobacterales isolates from urine cultures tested at US hospitals in the BD Insights Research Database (2011-2020). Multivariable generalized estimating equation models were used to assess resistance trends over time. A total of 322 US hospitals provided data on 876,507 urinary Enterobacterales isolates (62.4% Escherichia coli). Enterobacterales antibiotic resistance rates were 64.6%, 29.3%, 27.6%, and 26.3% for beta-lactams, fluoroquinolones, nitrofurantoin, and trimethoprim/sulfamethoxazole, respectively, and 12.4% had an extended-spectrum beta-lactamase (ESBL) phenotype. In multivariable models, rates of ESBL isolates and isolates resistant to ≥3 drug classes increased significantly between 2011 and 2020, while other categories of resistance generally decreased. We conclude that antimicrobial resistance is common in urinary Enterobacterales isolates. Management of UTIs should be guided by urine culture data and may benefit from new therapies.

Regional Differences in Antibiotic-resistant Enterobacterales Urine Isolates in the United States: 2018-2020.

Antimicrobial resistance (AMR) can complicate effective management of urinary tract infections. We conducted a retrospective study of AMR in Enterobacterales urine isolates from ambulatory and hospitalized adult patients from 2018-2020 (BD Insights Research Database) to evaluate regional differences in isolates with an extended-spectrum beta-lactamase-producing phenotype and those not susceptible to beta-lactams, fluoroquinolone (FQ), nitrofurantoin (NFT), trimethoprim/sulfamethoxazole (TMP/SMX), or multiple antibiotic classes (≥ 2 or ≥ 3). Our analyses included 349,741 Enterobacterales urine isolates from 321 inpatient facilities and 980,354 isolates from 338 ambulatory care facilities. In multivariable analyses, the highest rate of resistance was to beta-lactams (60.8% and 55.8% for inpatient and ambulatory settings, respectively), followed by FQ (27.5%), NFT (27.0%), and TMP/SMX (25.4%) for inpatients and by TMP/SMX (22.4%), FQ (21.6%), and NFT (21.6%) for ambulatory patients. Isolates with an extended-spectrum beta-lactamase-producing phenotype (13.2% and 8.6% for inpatient and ambulatory settings, respectively) and multidrug resistance (inpatient and ambulatory rates of 23.4% and 17.7% for ≥ 2 drugs; 9.9% and 6.4% for ≥ 3 drugs) were also prevalent. Statistically significant differences by geographic region (P ≤ 0.005) were observed for AMR classes in both inpatient and ambulatory settings, but the rates remained above the thresholds recommended for empiric urinary tract infection therapy across most regions.

A multicenter analysis of trends in resistance in urinary Enterobacterales isolates from ambulatory patients in the United States: 2011-2020.

BACKGROUND: Urinary tract infections (UTIs), which are usually caused by bacteria in the Enterobacterales family, are a common reason for outpatient visits. Appropriate empiric therapy for UTIs requires an understanding of antibiotic resistance in the community. In this nationwide study, we examined trends in antibiotic resistance in urinary Enterobacterales isolates from ambulatory patients in the United States (US). METHODS: We analyzed the antimicrobial susceptibility profiles (extended-spectrum beta-lactamase [ESBL]-producing phenotype and not susceptible [NS] to beta-lactams, trimethoprim/sulfamethoxazole [TMP/SMX], fluoroquinolones [FQ], or nitrofurantoin [NFT]) of 30-day non-duplicate Enterobacterales isolates from urine cultures tested at ambulatory centers in the BD Insights Research Database (2011-2020). The outcome of interest was the percentage of resistant isolates by pathogen and year. Multi-variable generalized estimating equation models were used to assess trends in resistance over time and by additional covariates. RESULTS: A total of 338 US facilities provided data for > 2.2 million urinary Enterobacterales isolates during the 10-year study. Almost three-quarters (72.8%) of Enterobacterales isolates were Escherichia coli. Overall unadjusted resistance rates in Enterobacterales isolates were 57.5%, 23.1%, 20.6%, and 20.2% for beta-lactams, TMP/SMX, FQ, and NFT, respectively, and 6.9% had an ESBL-producing phenotype. Resistance to two or more antibiotic classes occurred in 16.4% of isolates and 5.5% were resistant to three or more classes. Among isolates with an ESBL-producing phenotype, 70.1%, 59.9%, and 33.5% were NS to FQ, TMP/SMX, and NFT, respectively. In multivariable models, ESBL-producing and NFT NS Enterobacterales isolates increased significantly (both P < 0.001), while other categories of resistance decreased. High rates (≥ 50%) of beta-lactam and NFT resistance were observed in Klebsiella isolates and in non-E. coli, non-Klebsiella Enterobacterales isolates. CONCLUSIONS: Antimicrobial resistance was common in urinary Enterobacterales isolates. Isolates with an ESBL-producing phenotype increased by about 30% between 2011 and 2020, and significant increases were also observed in NFT NS Enterobacterales isolates. Resistance rates for all four antibiotic classes were higher than thresholds recommended for use as empiric therapy. Non-E. coli Enterobacterales isolates showed high levels of resistance to commonly used empiric antibiotics, including NFT. These data may help inform empiric therapy choices for outpatients with UTIs.

Impact of Empirical Antibiotic Therapy on Outcomes of Outpatient Urinary Tract Infection Due to Nonsusceptible Enterobacterales.

Resistance to oral antibiotics commonly used to treat outpatient urinary tract infections (UTIs) is increasing, but the implications of empirical treatment of resistant pathogens are not well described. Using an electronic records database, we reviewed the outcomes of patients >18 years of age who developed an outpatient UTI and had an outpatient urine culture result showing a member of the order Enterobacterales along with prescription data for an oral antibiotic filled on the day before, day of, or day after the culture was collected. Linear probability models were used to estimate partial effects of select clinical and demographic variables on the composite outcome. In all, 4,792 patients had 5,587 oral antibiotic prescriptions. Of 5,395 evaluable episodes, 22% of patients received an antibiotic to which the pathogen was resistant in vitro, and those patients were almost twice as likely to require a second prescription (34% versus 19%) or be hospitalized (15% versus 8%) within 28 days of the initial prescription fill compared to patients who received an antibiotic to which the pathogen was susceptible. Approximately 1% of Enterobacterales isolates were resistant to all commonly available classes of oral antibiotics. A greater risk of treatment failure was seen in patients over 60 years of age, patients with diabetes mellitus, men, and those treated with an antibiotic when prior culture identified an organism resistant to that class. The increasing resistance among members of Enterobacterales responsible for outpatient UTIs is limiting the effectiveness of empirical treatment with existing antibiotics, and consequently, outpatients with UTI are more likely to require additional courses of therapy or be hospitalized. IMPORTANCE Resistance rates for bacteria that cause urinary tract infections (UTIs) have increased dramatically. Regional rates of resistance to commonly prescribed antibiotics now exceed 20%, which is the threshold at which the Infectious Diseases Society of America recommends therapy be guided by culture. Our goals were to describe outcomes for outpatients with UTIs caused by bacteria resistant to empirically chosen antibiotics and to create a simple stratification schema for clinicians to identify UTI patients at increased risk of treatment failure due to antibiotic mismatch. These data are relevant to clinicians, given how common uncomplicated UTIs are, and highlight the need for clinicians to understand local resistance rates and the importance of culture-guided treatment, especially in vulnerable patients. These findings also showed that 1% of bacteria were resistant to all major classes of oral antibiotics, underscoring the need for new antibiotics to treat patients with UTIs due to resistant bacteria.

Randomized Study of Rivaroxaban vs Placebo on Disease Progression and Symptoms Resolution in High-Risk Adults With Mild Coronavirus Disease 2019.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 infection may be associated with a prothrombotic state, predisposing patients for a progressive disease course. We investigated whether rivaroxaban, a direct oral anticoagulant factor Xa inhibitor, would reduce coronavirus disease 2019 (COVID-19) progression. METHODS: Adults (N = 497) with mild COVID-19 symptoms and at high risk for COVID-19 progression based on age, body mass index, or comorbidity were randomized 1:1 to either daily oral rivaroxaban 10 mg (N = 246) or placebo equivalent (N = 251) for 21 days and followed to day 35. Primary end points were safety and progression. Absolute difference in progression risk was assessed using a stratified Miettinen and Nurminen method. RESULTS: The study was terminated after 497 of the target 600 participants were enrolled due to a prespecified interim analysis of the first 200 participants that crossed the futility boundary for the primary efficacy end point in the intent-to-treat population. Enrollees were 85% aged <65 years; 60% female; 27% Hispanic, Black, or other minorities; and 69% with ≥2 comorbidities. Rivaroxaban was well tolerated. Disease progression rates were 46 of 222 (20.7%) in rivaroxaban vs 44 of 222 (19.8%) in placebo groups, with a risk difference of -1.0 (95% confidence interval, -6.4 to 8.4; P = .78). CONCLUSIONS: We did not demonstrate an impact of rivaroxaban on disease progression in high-risk adults with mild COVID-19. There remains a critical public health gap in identifying scalable effective therapies for high-risk people in the outpatient setting to prevent COVID-19 progression.

Outcomes in Patients with Staphylococcus aureus Bacteremia Treated with Dalbavancin in Clinical Trials.

INTRODUCTION: Dalbavancin is a long-acting, bactericidal, lipoglycopeptide antibiotic approved by the US Food and Drug Administration and the European Medicines Agency for treatment of acute bacterial skin and skin structure infections in adults, with potent activity against Gram-positive pathogens, including methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Here we describe the clearance and clinical outcomes of patients with S. aureus bacteremia in five clinical trials of skin and skin structure infections or catheter-related bloodstream infections that evaluated the efficacy and safety of dalbavancin. METHODS: Patients with uncomplicated S. aureus bacteremia identified in blood cultures drawn at baseline (before study drug) with at least one follow-up blood culture are described from four phase 3 trials in skin and skin structure infections and one phase 2 catheter-related infection study. Dalbavancin was administered as a single-dose (1500 mg intravenous [IV]) or a two-dose regimen (1000 mg IV on day 1, 500 mg IV on day 8). Comparators included vancomycin IV or linezolid IV/oral for 10-14 days. RESULTS: All 39 patients (100%) who received dalbavancin, including 8 patients on the single-dose regimen, had clearance of bacteremia versus 19/20 patients (95%) treated with comparators (vancomycin or linezolid). At end of treatment, 33/36 dalbavancin-treated patients (92%) achieved clinical success versus 18/23 patients (78%) treated with comparators. CONCLUSIONS: All 39 patients with uncomplicated S. aureus bacteremia treated with dalbavancin (single- or two-dose regimen) and with follow-up blood cultures had clearance of their bloodstream infection. Clinical response rates were similar to daily comparator therapy for 10-14 days. TRIAL REGISTRATION: DISCOVER 1, NCT01339091; DISCOVER 2, NCT01431339; DUR001-303, NCT02127970; VER001-9; VER001-4, NCT00057369.

Safety of Dalbavancin in the Treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSI): Nephrotoxicity Rates Compared with Vancomycin: A Post Hoc Analysis of Three Clinical Trials.

INTRODUCTION: Dalbavancin is a lipoglycopeptide antibiotic approved as a single- and two-dose regimen for adults with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible gram-positive organisms. We present nephrotoxicity rates for patients with ABSSSI who received dalbavancin in three pivotal clinical trials and compare the rates with vancomycin. METHODS: In a phase 3b clinical trial (DUR001-303), patients were randomized to dalbavancin single-dose (1500 mg intravenous [IV]) or two-dose regimen (1000 mg IV on day 1, 500 mg IV on day 8). In two phase 3 clinical trials (DISCOVER 1 and DISCOVER 2), patients were randomized to dalbavancin (two-dose regimen) or vancomycin 1 g (or 15 mg/kg) IV every 12 h for at least 3 days with an option to switch to orally administered linezolid 600 mg every 12 h for 10-14 days. Patients on dalbavancin with a creatinine clearance below 30 mL/min not on regular dialysis received a reduced dose of 1000 mg (single-dose arm) or 750 mg IV on day 1, 375 mg IV on day 8 (two-dose arm). Nephrotoxicity was defined as a 50% increase from baseline serum creatinine (SCr) or an absolute increase in SCr of 0.5 mg/dL at any time point. P values were obtained using the Cochran-Mantel-Haenszel test. RESULTS: In dalbavancin-treated patients, rates of nephrotoxicity were low. The safety population with available creatinine values included 1325/1347 patients on any regimen of dalbavancin, and 54/651 patients who received vancomycin intravenously for at least 10 days and were not switched to orally administered linezolid. Patients on any regimen of dalbavancin had a lower rate of nephrotoxicity compared with patients receiving vancomycin intravenously for at least 10 days (3.7% vs 9.3%, respectively; P = 0.039). CONCLUSIONS: Nephrotoxicity rates were lower in patients on dalbavancin relative to vancomycin for at least 10 days. On the basis of this experience, dalbavancin may be less nephrotoxic than intravenously administered vancomycin.

Necrotizing Fasciitis Within 72 hours After Presentation with Skin and Skin Structure Infection.

INTRODUCTION: A small percentage of patients with skin infections later develop necrotizing fasciitis (NF). Diagnostic testing is needed to identify patients with skin infections at low risk of NF who could be discharged from the emergency department (ED) after antibiotic initiation. Elevated lactate has been associated with NF; existing estimates of the frequency of NF are based on retrospective reviews, and cases often lack testing for lactate. We present the incidence of patients with skin infections who developed NF and their baseline lactates. METHODS: In four phase-3 trials, 2883 adults with complicated or acute bacterial skin and skin structure infections were randomized to dalbavancin or comparator, with early and late follow-up visits through Day 28. We prospectively collected baseline plasma lactates in one trial to assess an association with NF. RESULTS: NF was diagnosed in 3/2883 patients (0.1%); all three survived. In the study with prospectively collected baseline lactates (n = 622), 15/622 (2.4%) had a lactate ≥4 millimoles per liter (mmol/L), including 3/622 (0.5%) with a lactate ≥7 mmol/L. NF was not seen in patients with a lactate <4 mmol/L; NF was seen in 1/15 (6.7%) with a lactate ≥4 mmol/L, including 1/3 (33.3%) with lactate ≥7 mmol/L. CONCLUSIONS: NF incidence within 72 hours of antibiotic initiation in patients with complicated or acute bacterial skin and skin structure infections was extremely low (0.1%) and occurred in 6.7% with a lactate ≥4 mmol/L. Lactate <4 mmol/L can be used to identify patients at low risk of NF who could be safely discharged from the ED after antibiotic initiation.

Epithelial Lining Fluid and Plasma Concentrations of Dalbavancin in Healthy Adults after a Single 1,500-Milligram Infusion.

Dalbavancin is a lipoglycopeptide antibiotic with a prolonged half-life. A phase 1 study assessed dalbavancin levels in epithelial lining fluid (ELF) in 35 healthy adults using ELF bronchial microsampling up to 168 h after administration of 1,500 mg dalbavancin. The penetration of dalbavancin into ELF was 36%. ELF levels of dalbavancin exceeded the MIC90s of Streptococcus pneumoniae and Staphylococcus aureus for ≥7 days.

Single-dose dalbavancin and patient satisfaction in an outpatient setting in the treatment of acute bacterial skin and skin structure infections.

OBJECTIVES: Treatment of acute bacterial skin and skin structure infections (ABSSSIs) in the outpatient setting has potential advantages. We performed a subanalysis of outcomes for patients treated as outpatients versus inpatients with dalbavancin, a long-acting lipoglycopeptide, in a phase 3 clinical trial of ABSSSI. METHODS: The study was a double-blind trial of patients with ABSSSI randomised to receive dalbavancin 1500 mg intravenously as a single dose or two doses (1000 mg followed by 500 mg a week later). The primary endpoint was ≥20% reduction in erythema at 48-72 h after the start of therapy. Patient satisfaction and preference for antibiotic treatment and care setting were measured using the 10-item Skin and Soft Tissue Infection (SSTI) questionnaire at Day 14. RESULTS: A total of 698 patients were randomised (386 treated as outpatients and 312 as inpatients). Outpatients were more likely to be younger and to have major abscess or traumatic wound infection; inpatients were more likely to have cellulitis as the type of ABSSSI, to meet SIRS criteria and to have elevated plasma lactate at baseline. Efficacy and safety outcomes at 48-72 h, Days 14 and 28 were similar between patients treated in the outpatient and inpatient setting with either the single-dose or two-dose regimen. Outpatients reported significantly greater convenience and satisfaction with antibiotic treatment and care setting compared with inpatients (P < 0.001). CONCLUSION: Single-dose dalbavancin is an effective treatment option for outpatients with ABSSSI and is associated with a high degree of patient treatment satisfaction and convenience.

Dalbavancin for the Treatment of Osteomyelitis in Adult Patients: A Randomized Clinical Trial of Efficacy and Safety.

BACKGROUND: Osteomyelitis is a challenging infection that can involve 4-6 weeks of intravenous (IV) antibiotics. Dalbavancin, approved for acute bacterial skin and skin structure infections, has potent activity against gram-positive pathogens. This study assessed the efficacy and safety of dalbavancin as a 2-dose regimen for osteomyelitis. METHODS: This study was a randomized, open-label, comparator-controlled trial in adults with a first episode of osteomyelitis defined by clinical symptoms, radiologic findings, and elevated C-reactive protein. Patients were randomized 7:1 to dalbavancin (1500 mg IV on days 1 and 8) or standard of care (SOC) for osteomyelitis (oral or IV) per investigator judgment for 4-6 weeks. The primary endpoint was clinical response at day 42, defined as recovery without need for additional antibiotics in the clinically evaluable (CE) population. Clinical response was also assessed at day 21, 6 months, and 1 year. RESULTS: Eighty patients were randomized to dalbavancin (n = 70) or SOC (n = 10). All had baseline debridement; Staphylococcus aureus was the most common pathogen (60% of patients). Clinical cure at day 42 was seen in 65/67 (97%) and 7/8 (88%) patients in the dalbavancin group and SOC group in the CE population, respectively. Clinical response was similar in the dalbavancin group at day 21 (94%), 6 months, and 1 year (96%). Treatment-emergent adverse events occurred in 10 patients in the dalbavancin group; no patient discontinued treatment due to an adverse event. CONCLUSIONS: A 2-dose regimen of weekly dalbavancin is effective and well tolerated for the treatment of osteomyelitis in adults. CLINICAL TRIALS REGISTRATION: NCT02685033.

In Vitro Activity of Sulopenem, an Oral Penem, against Urinary Isolates of Escherichia coli.

The in vitro activity of sulopenem was assessed against a collection from 2014 to 2016 of 539 urinary isolates of Escherichia coli from Canadian patients by using CLSI-defined broth microdilution methodology. A concentration of sulopenem 0.03 µg/ml inhibited both 50% (MIC50) and 90% (MIC90) of isolates tested; sulopenem MICs ranged from 0.015 to 0.25 µg/ml. The in vitro activity of sulopenem was unaffected by nonsusceptibility to trimethoprim-sulfamethoxazole and/or ciprofloxacin, multidrug-resistant phenotypes, extended-spectrum ß-lactamases, or AmpC ß-lactamases.

Treatment of acute bacterial skin and skin structure infection with single-dose dalbavancin in persons who inject drugs.

BACKGROUND: Persons who inject drugs (PWID) are at increased risk of acute bacterial skin and skin structure infections (ABSSSIs), a growing healthcare concern. Multiple medical, social, and economic issues, including adherence and comorbidities, complicate the medical care of the PWID population, adversely affecting patient outcomes. METHODS: We assessed demographics and outcomes for the PWID population in a double-blind trial of 698 patients randomized to dalbavancin 1500 mg as a single intravenous (IV) infusion or as a 2-dose regimen (1000 mg IV on day 1; 500 mg IV on day 8) for ABSSSI. The primary endpoint was ≥20% reduction in erythema at 48-72 hours in the intent-to-treat population; clinical status was also assessed at days 14 and 28. RESULTS: There were 212/698 (30.4%) patients with a history of injection drug use in this clinical trial. Dalbavancin efficacy was similar between the single- and 2-dose therapy groups in the PWID and non-PWID populations at all timepoints. Dalbavancin was well tolerated in the PWID population, with similar rates of adverse events as the non-PWID population. CONCLUSION: Dalbavancin as a single-dose or 2-dose regimen had similar efficacy for the treatment of ABSSSI at all timepoints in the PWID and non-PWID populations. A single 30-minute IV infusion would eliminate the need for indwelling IV access. The convenience of a single dose supervised in a health setting may also optimize treatment adherence in the PWID population.

Dalbavancin Pharmacokinetics and Safety in Children 3 Months to 11 Years of Age.

BACKGROUND: Dalbavancin is a novel lipoglycopeptide antibiotic that has potent in vitro activity against Gram-positive microorganisms. METHODS: We performed a phase 1, open-label, multicenter study to investigate the pharmacokinetics (PK) and safety of a single dose of intravenous dalbavancin in hospitalized pediatric subjects 3 months to 11 years of age. We combined these data with previously collected adolescent PK data and performed a population PK analysis. RESULTS: Model development was performed using 311 dalbavancin plasma concentrations from 43 subjects. The median age was 5.9 years (range: 0.3-16.9). A 3-compartment, linear PK model was developed. Based on simulations, the following age-dependent dosing regimen was found to achieve similar dalbavancin exposure to that in adults administered a 2-dose regimen: children 6 to <18 years of age, 12 mg/kg (1000 mg maximum) on day 1 and 6 mg/kg (500 mg maximum) on day 8 and children 3 months to <6 years of age, 15 mg/kg (1000 mg maximum) on day 1 and 7.5 mg/kg (500 mg maximum) on day 8. Similarly, the following age-dependent regimen was found to match adult exposure after a single-dose (1500 mg): 6 to <18 years of age, 18 mg/kg (1500 mg maximum) on day 1 and 3 months to <6 years of age, 22.5 mg/kg (1500 mg maximum) on day 1. Nineteen subjects experienced 36 treatment-emergent adverse events. Five of 36 adverse events were assessed as possibly or probably related to treatment. CONCLUSIONS: Dalbavancin pediatric dosing that matched adult exposure was identified. Overall, dalbavancin was well tolerated in our study population.

Efficacy of dalbavancin in the treatment of MRSA rat sternal osteomyelitis with mediastinitis.

OBJECTIVES: Dalbavancin, a semi-synthetic lipoglycopeptide, is characterized by a long plasma half-life, which allows weekly dosing. Dalbavancin may be a good treatment option for patients with deep sternal wound infections owing to its improved pharmacokinetic profile and antibacterial activity compared with currently used antibiotics. Here we evaluated the efficacy of 7 or 14 days of treatment with dalbavancin, compared with vancomycin and with saline, in reducing sternal bone MRSA counts in a rat Staphylococcus aureus deep sternal wound infection model. METHODS: A mid-sternal wound was surgically induced in anaesthetized rats. A clinical strain of MRSA was injected into the sternum to establish infection. Rats were treated intraperitoneally for 7 or 14 days with dalbavancin, vancomycin or saline. The number of cfu per gram of sternum or spleen tissue was determined using viable counts. The antibacterial efficacy was determined by the reduction in bacterial counts per gram of sternum or spleen tissue in each treatment group. RESULTS: Treatment with dalbavancin was superior to treatment with saline for 7 days (0.75 log reduction in bone cfu) or 14 days (>3 log reduction in bone cfu) and similar to treatment with vancomycin. Additionally, dalbavancin was also effective in reducing systemic dissemination of MRSA. CONCLUSIONS: Dalbavancin is effective in the treatment of MRSA rat sternal osteomyelitis.