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.

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.

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.

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.