Patient outcomes by baseline pathogen resistance phenotype and genotype in CERTAIN-1, a Phase 3 study of cefepime-taniborbactam versus meropenem in adults with complicated urinary tract infection.

CERTAIN-1 was a Phase 3, double-blind, randomized, parallel group study of the efficacy and safety of cefepime-taniborbactam versus meropenem in the treatment of adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. We determined susceptibility of Enterobacterales and Pseudomonas aeruginosa baseline pathogens to cefepime-taniborbactam and comparators and characterized ß-lactam resistance mechanisms. Microbiologic response and clinical response were assessed in patient subsets defined by baseline pathogens that were of cefepime-, multidrug-, or carbapenem-resistant phenotype or that carried ß-lactamase genes. Among Enterobacterales baseline pathogens, 26.8%, 4.1%, and 3.0% carried genes for extended-spectrum ß-lactamases (ESBLs), AmpC, and carbapenemases, respectively. Within each treatment group, while composite success rates at Test of Cure in resistant subsets by pathogen species were similar to those by pathogen overall, composite success rates in meropenem patients were numerically lower for cefepime-resistant Escherichia coli (9/19; 47.4%) and ESBL E. coli (13/25; 52.0%) compared with E. coli overall (62/100; 62.0%). Cefepime-taniborbactam achieved composite success in 7/8 (87.5%) patients with carbapenem-resistant Enterobacterales and 8/9 (88.9%) patients with Enterobacterales with a carbapenemase gene (5 OXA-48-group; 2 KPC-3; 2 NDM-1). Cefepime-taniborbactam also achieved composite success in 8/16 (50.0%) patients and clinical success in 13/16 (81.3%) patients with P. aeruginosa; corresponding rates were 4/7 (57.1%) and 6/7 (85.7%) for meropenem. Cefepime-taniborbactam demonstrated efficacy in adult cUTI patients with cefepime-, multidrug-, and carbapenem-resistant pathogens including pathogens with ESBL, AmpC, and carbapenemase genes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03840148.

Cefepime-Taniborbactam in Complicated Urinary Tract Infection.

BACKGROUND: Carbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime-taniborbactam is an investigational ß-lactam and ß-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-ß-lactamases. METHODS: In this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime-taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority. RESULTS: Of the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime-taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime-taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P = 0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime-taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime-taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups. CONCLUSIONS: Cefepime-taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.).

Examining the activity of cefepime-taniborbactam against Burkholderia cepacia complex and Burkholderia gladioli isolated from cystic fibrosis patients in the United States.

The novel clinical-stage ß-lactam-ß-lactamase inhibitor combination, cefepime-taniborbactam, demonstrates promising activity toward many Gram-negative bacteria producing class A, B, C, and/or D ß-lactamases. We tested this combination against a panel of 150 Burkholderia cepacia complex (Bcc) and Burkholderia gladioli strains. The addition of taniborbactam to cefepime shifted cefepime minimum inhibitory concentrations toward the provisionally susceptible range in 59% of the isolates tested. Therefore, cefepime-taniborbactam possessed similar activity as first-line agents, ceftazidime and trimethoprim-sulfamethoxazole, supporting further development.

In Vitro Activity of Cefepime-Taniborbactam and Comparators against Clinical Isolates of Gram-Negative Bacilli from 2018 to 2020: Results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program.

Taniborbactam is a novel cyclic boronate ß-lactamase inhibitor in clinical development in combination with cefepime. We assessed the in vitro activity of cefepime-taniborbactam and comparators against a 2018-2020 collection of Enterobacterales (n = 13,731) and Pseudomonas aeruginosa (n = 4,619) isolates cultured from infected patients attending hospitals in 56 countries. MICs were determined by CLSI broth microdilution. Taniborbactam was tested at a fixed concentration of 4 µg/mL. Isolates with cefepime-taniborbactam MICs of ≥16 µg/mL underwent whole-genome sequencing. ß-lactamase genes were identified in meropenem-resistant isolates by PCR/Sanger sequencing. Against Enterobacterales, taniborbactam reduced the cefepime MIC90 value by >64-fold (from >16 to 0.25 µg/mL). At ≤16 µg/mL, cefepime-taniborbactam inhibited 99.7% of all Enterobacterales isolates; >97% of isolates with multidrug-resistant (MDR) and ceftolozane-tazobactam-resistant phenotypes; ≥90% of isolates with meropenem-resistant, difficult-to-treat-resistant (DTR), meropenem-vaborbactam-resistant, and ceftazidime-avibactam-resistant phenotypes; 100% of VIM-positive, AmpC-positive, and KPC-positive isolates; 98.7% of extended-spectrum ß-lactamase (ESBL)-positive; 98.8% of OXA-48-like-positive; and 84.6% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC90 value by 4-fold (from 32 to 8 µg/mL). At ≤16 µg/mL, cefepime-taniborbactam inhibited 97.4% of all P. aeruginosa isolates; ≥85% of isolates with meropenem-resistant, MDR, and meropenem-vaborbactam-resistant phenotypes; >75% of isolates with DTR, ceftazidime-avibactam-resistant, and ceftolozane-tazobactam-resistant phenotypes; and 87.4% of VIM-positive isolates. Multiple potential mechanisms, including carriage of IMP, certain alterations in PBP3, permeability (porin) defects, and possibly, upregulation of efflux were present in most isolates with cefepime-taniborbactam MICs of ≥16 µg/mL. We conclude that cefepime-taniborbactam exhibited potent in vitro activity against Enterobacterales and P. aeruginosa and inhibited most carbapenem-resistant isolates, including those carrying serine carbapenemases or NDM/VIM metallo-ß-lactamases (MBLs).

Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-ß-Lactamase-Positive Clinical Isolates of Enterobacterales from a 2018-2020 Global Surveillance Collection.

Ceftibuten-ledaborbactam etzadroxil is a cephalosporin-boronate ß-lactamase inhibitor prodrug combination under development as an oral treatment for complicated urinary tract infections caused by multidrug-resistant (MDR) Enterobacterales producing serine ß-lactamases (Ambler class A, C, and D). In vivo, ledaborbactam etzadroxil (formerly VNRX-7145) is cleaved to the active inhibitor ledaborbactam (formerly VNRX-5236). To more completely define the breadth of ceftibuten-ledaborbactam's activity against important antimicrobial-resistant pathogens, we assessed its in vitro activity against phenotypic and genotypic subsets from a 2018-2020 global culture collection of 3,889 clinical isolates of Enterobacterales, including MDR organisms, extended-spectrum-ß-lactamase (ESBL)-positive organisms, and organisms that are nonsusceptible and resistant to other antimicrobials. MICs were determined by CLSI broth microdilution and interpreted using both CLSI and EUCAST breakpoints. Ledaborbactam was tested at a fixed concentration of 4 µg/mL. ß-Lactamase genes were characterized by PCR followed by Sanger sequencing or whole-genome sequencing for selected ß-lactam-resistant isolate subsets. At ≤1 µg/mL, ceftibuten-ledaborbactam (MIC90, 0.25 µg/mL) inhibited 89.7% of MDR isolates, 98.3% of isolates with a presumptive ESBL-positive phenotype, and 92.6% of trimethoprim-sulfamethoxazole-nonsusceptible, 91.7% of levofloxacin-nonsusceptible, 88.1% of amoxicillin-clavulanate-nonsusceptible, 85.7% of ceftibuten-resistant (MIC >1 µg/mL), and 54.1% of carbapenem-nonsusceptible isolates. Against specific ESBL genotype-positive isolates (AmpC negative, serine carbapenemase negative, and metallo-ß-lactamase negative), ceftibuten-ledaborbactam inhibited 96.3% of CTX-M-9 group (MIC90, 0.25 µg/mL), 91.5% of CTX-M-1 group (MIC90, 0.5 µg/mL), and 88.2% of SHV-positive (MIC90, 2 µg/mL) isolates at ≤1 µg/mL. Against specific serine carbapenemase genotype-positive isolates, ceftibuten-ledaborbactam inhibited 85.9% of KPC-positive (MIC90, 2 µg/mL) and 82.9% of OXA-48-group-positive (MIC90, 2 µg/mL) isolates at ≤1 µg/mL. Continued development of ceftibuten-ledaborbactam appears warranted.

Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable ß-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes.

A major antimicrobial resistance mechanism in Gram-negative bacteria is the production of ß-lactamase enzymes. The increasing emergence of ß-lactamase-producing multi-drug-resistant "superbugs" has resulted in increases in costly hospital Emergency Department (ED) visits and hospitalizations due to the requirement for parenteral antibiotic therapy for infections caused by these difficult-to-treat bacteria. To address the lack of outpatient treatment, we initiated an iterative program combining medicinal chemistry, biochemical testing, microbiological profiling, and evaluation of oral pharmacokinetics. Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing ß-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum ß-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.

VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-ß-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa.

As shifts in the epidemiology of ß-lactamase-mediated resistance continue, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are the most urgent threats. Although approved ß-lactam (BL)-ß-lactamase inhibitor (BLI) combinations address widespread serine ß-lactamases (SBLs), such as CTX-M-15, none provide broad coverage against either clinically important serine-ß-lactamases (KPC, OXA-48) or clinically important metallo-ß-lactamases (MBLs; e.g., NDM-1). VNRX-5133 (taniborbactam) is a new cyclic boronate BLI that is in clinical development combined with cefepime for the treatment of infections caused by ß-lactamase-producing CRE and CRPA. Taniborbactam is the first BLI with direct inhibitory activity against Ambler class A, B, C, and D enzymes. From biochemical and structural analyses, taniborbactam exploits substrate mimicry while employing distinct mechanisms to inhibit both SBLs and MBLs. It is a reversible covalent inhibitor of SBLs with slow dissociation and a prolonged active-site residence time (half-life, 30 to 105 min), while in MBLs, it behaves as a competitive inhibitor, with inhibitor constant (Ki ) values ranging from 0.019 to 0.081 µM. Inhibition is achieved by mimicking the transition state structure and exploiting interactions with highly conserved active-site residues. In microbiological testing, taniborbactam restored cefepime activity in 33/34 engineered Escherichia coli strains overproducing individual enzymes covering Ambler classes A, B, C, and D, providing up to a 1,024-fold shift in the MIC. Addition of taniborbactam restored the antibacterial activity of cefepime against all 102 Enterobacterales clinical isolates tested and 38/41 P. aeruginosa clinical isolates tested with MIC90s of 1 and 4 µg/ml, respectively, representing ≥256- and ≥32-fold improvements, respectively, in antibacterial activity over that of cefepime alone. The data demonstrate the potent, broad-spectrum rescue of cefepime activity by taniborbactam against clinical isolates of CRE and CRPA.

A Real-world Patient Registry for Oritavancin Demonstrates Efficacy and Safety Consistent With the Phase 3 SOLO Program.

BACKGROUND: Oritavancin is a lipoglycopeptide used in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in adults. To characterize its use in patients in the postapproval setting, a patient registry was developed. METHODS: Data collected in an ongoing retrospective observational registry are used to evaluate the utilization, outcomes, and adverse events (AEs) associated with oritavancin for the treatment of infections presumed or confirmed to be caused by gram-positive (GP) bacteria in clinical practice. RESULTS: Data for 112 patients from 8 sites were collected. All patients received a single 1200-mg dose of oritavancin mostly in an infusion center. Infection type included cellulitis (67.0%), cutaneous abscess (21.4%), and wound (4.5%). Most patients (72.3%) received 1 or more antimicrobial agents for the index GP infection within 28 days prior to oritavancin treatment. Of positive cultures obtained prior to oritavancin administration, methicillin-resistant Staphylococcus aureus was the predominant pathogen (78.4%). A positive clinical response was observed in 92.8% of patients, and microbial eradication was observed in 90.0% of patients with post-therapy cultures. Within 28 days following oritavancin administration, 4 (3.6%) patients were hospitalized for failure of treatment of the index infection. Five (4.5%) patients experienced 1 or more possible drug-related AEs, which were consistent with types previously reported. There were no drug-related serious AEs reported. CONCLUSIONS: Clinical and microbiologic outcomes and safety of single-dose oritavancin 1200 mg were similar in this older patient population with multiple comorbid conditions to those observed in the phase 3 SOLO trials.

Single Intravenous Dose of Oritavancin for Treatment of Acute Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: Summary of Safety Analysis from the Phase 3 SOLO Studies.

Oritavancin is a lipoglycopeptide with bactericidal activity against Gram-positive organisms. Its rapid concentration-dependent bactericidal activity and long elimination half-life allow single-dose treatment of acute bacterial skin and skin structure infections (ABSSSI). SOLO I and SOLO II were randomized, double-blind studies evaluating the efficacy and safety of a single 1,200-mg intravenous (i.v.) dose of oritavancin versus twice-daily i.v. vancomycin for 7 to 10 days in ABSSSI patients. Safety data from both studies were pooled for safety analysis. The database comprised pooled safety data for 976 oritavancin-treated patients and 983 vancomycin-treated patients. The incidences of adverse events, serious adverse events, and discontinuations due to adverse events were similar for oritavancin (55.3, 5.8, and 3.7%, respectively) and vancomycin (56.9, 5.9, and 4.2%, respectively). The median time to onset (3.8 days versus 3.1 days, respectively) and the duration (3.0 days for both groups) of adverse events were also similar between the two groups. The most frequently reported events were nausea, headache, and vomiting. Greater than 90% of all events were mild or moderate in severity. There were slightly more infections and infestations, abscesses or cellulitis, and hepatic and cardiac adverse events in the oritavancin group; however, more than 80% of these events were mild or moderate. Subgroup analyses did not identify clinically meaningful differences in the incidence of adverse events attributed to oritavancin. A single 1,200-mg dose of oritavancin was well tolerated and had a safety profile similar to that of twice-daily vancomycin. The long elimination half-life of oritavancin compared to that of vancomycin did not result in a clinically meaningful delay to the onset or prolongation of adverse events. (This study has been registered at ClinicalTrials.gov under registration no. NCT01252719 and NCT01252732.).

Evaluation of Oritavancin Dosing Strategies against Vancomycin-Resistant Enterococcus faecium Isolates with or without Reduced Susceptibility to Daptomycin in an In Vitro Pharmacokinetic/Pharmacodynamic Model.

The clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitro activity against VREfm, although its safety and efficacy for treating clinical VREfm infections have not been established. In this study, novel dosing regimens of daptomycin and oritavancin were assessed against both VREfm and daptomycin-nonsusceptible VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model.

Comparative Pharmacodynamics of Single-Dose Oritavancin and Daily High-Dose Daptomycin Regimens against Vancomycin-Resistant Enterococcus faecium Isolates in an In Vitro Pharmacokinetic/Pharmacodynamic Model of Infection.

There are limited therapeutic options to treat infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The lipoglycopeptide oritavancin exhibits in vitro activity against this pathogen, although its utility against infections caused by VREfm has not been clinically established. In this study, the pharmacodynamic activity of free-drug levels associated with 12 mg/kg/day of daptomycin and a single 1,200-mg dose of oritavancin were determined against three VanA VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model.

Effects of Oritavancin on Coagulation Tests in the Clinical Laboratory.

Previous studies have shown that some lipoglycopeptide and lipopeptide antimicrobial agents may cause falsely elevated values for some phospholipid-dependent coagulation tests. The effect of oritavancin, a lipoglycopeptide antibiotic, on coagulation test results was explored using pooled human plasma samples spiked with drug and in a clinical study after an infusion of a single 1,200-mg intravenous dose of oritavancin in normal healthy volunteers. Pooled plasma with oritavancin added ex vivo showed concentration-dependent prolongation of prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and dilute Russell viper venom time (DRVVT) test results. In contrast, oritavancin had no effect on the activated protein C resistance assay, chromogenic anti-factor Xa assay (anti-FXa), thrombin time, and an immunoassay for the laboratory diagnosis of heparin-induced thrombocytopenia. In participants that received a single dose of oritavancin, elevations in PT/INR result, aPTT, DRVVT, activated clotting time, and silica clotting time occurred, with the maximum times to resolution of test interference determined to be 12, 120, 72, 24, and 18 h, respectively. The anti-FXa assay was unaffected, whereas transient elevations in D dimer levels were observed in 30% of participants, with a maximum time to resolution of 72 h. Although oritavancin has no impact on the coagulation system in vivo, a single dose of oritavancin can produce falsely elevated values of some coagulation tests used to monitor hemostasis. The interference of oritavancin on affected tests is transient, and the test results revert to normal ranges within specified times after dosing.

Comparative in vitro activity of oritavancin and other agents against methicillin-susceptible and methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) infections constitute a threat to the public health due to their prevalence and associated mortality and morbidity. Several agents have been recently approved to treat MRSA skin infections including lipoglycopeptides (dalbavancin, oritavancin, and telavancin), ceftaroline, and tedizolid. This study compared the MIC, minimum bactericidal concentration (MBC), and time-kill of these agents alongside daptomycin, linezolid, and vancomycin against MRSA (n=15); meropenem, cefazolin, and nafcillin were also included against methicillin-susceptible S. aureus (MSSA [n=12]). MIC and MBC testing was conducted in accordance with Clinical and Laboratory Standards Institute guidelines, and time-kills were evaluated at multiples of the MIC and the free-drug maximum plasma concentration (fCmax) at both standard and high inoculum densities for a subset of MRSA (n=2) and MSSA (n=2). MRSA and MSSA were highly susceptible to all agents, with the lipoglycopeptides having the most potent activity by MIC50/90. All agents excluding tedizolid and linezolid were bactericidal by MBC for MRSA and MSSA, though dalbavancin and telavancin exhibited strain-specific bactericidal activity for MRSA. All agents excluding tedizolid and linezolid were bactericidal by time-kill at their respective fCmax against MRSA and MSSA at standard inoculum density, though oritavancin exhibited the most rapid bactericidal activity. Oritavancin and daptomycin at their respective fCmax maintained similar kill curves at high inoculum density. In contrast, the killing observed with other agents was typically reduced or slowed at high inoculum density. These data demonstrate the rapid bactericidal activity of oritavancin and daptomycin against S. aureus relative to other MRSA agents regardless of bacterial burden.

Pooled analysis of single-dose oritavancin in the treatment of acute bacterial skin and skin-structure infections caused by Gram-positive pathogens, including a large patient subset with methicillin-resistant Staphylococcus aureus.

Oritavancin is a lipoglycopeptide antibiotic with bactericidal activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The phase 3 studies SOLO I and SOLO II demonstrated comparable efficacy and safety of a single dose of oritavancin compared with 7-10 days of twice-daily vancomycin in adults with acute bacterial skin and skin-structure infections (ABSSSIs). The present analysis assessed clinical responses by pathogen at 48-72 h and at study days 14-24 in SOLO patients within the pooled data set. Of the 1959 patients in the pooled SOLO studies, 1067 had at least one baseline Gram-positive pathogen and 405 had MRSA. Clinical response rates were similar for oritavancin- and vancomycin-treated patients by pathogen, including Staphylococcus aureus with or without the Panton-Valentine leukocidin (pvl) gene and from different clonal complexes, and were similar for pathogens within each treatment group. Oritavancin exhibited potent in vitro activity against all baseline pathogens, with MIC90 values (minimum inhibitory concentration required to inhibit 90% of the isolates) of 0.12 µg/mL for Staphylococcus aureus, 0.25 µg/mL for Streptococcus pyogenes and 0.06 µg/mL for Enterococcus faecalis. Whereas both oritavancin and vancomycin achieved similarly high rates of clinical response by pathogen, including methicillin-susceptible and -resistant Staphylococcus aureus, oritavancin provides a single-dose alternative to 7-10 days of twice-daily vancomycin to treat ABSSSIs.

Comparative In Vitro Activities of Oritavancin, Dalbavancin, and Vancomycin against Methicillin-Resistant Staphylococcus aureus Isolates in a Nondividing State.

Antibacterial agents that kill nondividing bacteria may be of utility in treating persistent infections. Oritavancin and dalbavancin are bactericidal lipoglycopeptides that are approved for acute bacterial skin and skin structure infections in adults caused by susceptible Gram-positive pathogens. Using time-kill methodology, we demonstrate that oritavancin exerts bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) isolates that are maintained in a nondividing state in vitro, whereas dalbavancin and the glycopeptide vancomycin do not.

Results from Oritavancin Resistance Surveillance Programs (2011 to 2014): Clarification for Using Vancomycin as a Surrogate To Infer Oritavancin Susceptibility.

Measurement of vancomycin susceptibility has been shown to be highly predictive as a surrogate measure of oritavancin susceptibility among clinically indicated Gram-positive species. Results of studying over 30,000 pathogens (from 2011 to 2014) by cross-susceptibility analysis and determining the poor reproducibility of oritavancin-nonsusceptible results showed nearly perfect surrogate testing accuracy (99.86 to 99.94%). Any isolate of an indicated organism species with locally reproducible oritavancin-nonsusceptible results (extremely rare) should be referred to a reference laboratory for confirmation of the results and determination of the resistance mechanism.

Use of in vitro vancomycin testing results to predict susceptibility to oritavancin, a new long-acting lipoglycopeptide.

Oritavancin is a recently approved lipoglycopeptide antimicrobial agent with activity against Gram-positive pathogens. Its extended serum elimination half-life and concentration-dependent killing enable single-dose treatment of acute bacterial skin and skin structure infections. At the time of regulatory approval, new agents, including oritavancin, are not offered in the most widely used susceptibility testing devices and therefore may require application of surrogate testing using a related antimicrobial to infer susceptibility. To evaluate vancomycin as a predictive susceptibility marker for oritavancin, 26,993 recent Gram-positive organisms from U.S. and European hospitals were tested using reference MIC methods. Organisms included Staphylococcus aureus, coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci (BHS), viridans group streptococci (VGS), and enterococci (ENT). These five major pathogen groups were analyzed by comparing results with FDA-approved susceptible breakpoints for both drugs, as well as those suggested by epidemiological cutoff values and supported by pharmacokinetic/pharmacodynamic analyses. Vancomycin susceptibility was highly accurate (98.1 to 100.0%) as a surrogate for oritavancin susceptibility among the indicated pathogen species. Furthermore, direct MIC comparisons showed high oritavancin potencies, with vancomycin/oritavancin MIC90 results of 1/0.06, 2/0.06, 0.5/0.12,1/0.06, and >16/0.06 µg/ml for S. aureus, CoNS, BHS, VGS, and ENT, respectively. In conclusion, vancomycin demonstrated acceptable accuracy as a surrogate marker for predicting oritavancin susceptibility when tested against the indicated pathogens. In contrast, 93.3% of vancomycin-nonsusceptible enterococci had oritavancin MIC values of ≤0.12 µg/ml, indicating a poor predictive value of vancomycin for oritavancin resistance against these organisms. Until commercial oritavancin susceptibility testing devices are readily available, isolates that when tested show vancomycin susceptibility can be inferred to be susceptible to oritavancin by using FDA-approved breakpoints.

Single-dose oritavancin versus 7-10 days of vancomycin in the treatment of gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.

BACKGROUND: Oritavancin is a lipoglycopeptide antibiotic with rapid bactericidal activity against gram-positive bacteria. Its concentration-dependent activity and long half-life allow for single-dose treatment. METHODS: In a randomized, double-blind trial, adults with acute bacterial skin and skin structure infections (ABSSSIs) received either a single intravenous 1200-mg dose of oritavancin or 7-10 days of twice-daily vancomycin. Three efficacy endpoints were tested for noninferiority: (1) primary composite endpoint at 48-72 hours (cessation of spreading or reduction in lesion size, absence of fever, and no rescue antibiotic); (2) investigator-assessed clinical cure 7-14 days after end of treatment; and (3) ≥20% reduction in lesion area at 48-72 hours. RESULTS: A total of 503 and 502 patients comprised the modified intent-to-treat population for oritavancin and vancomycin, respectively. All 3 efficacy endpoints met the 10% noninferiority margin: the primary composite endpoint (80.1% vs 82.9%; 95% confidence interval [CI], -7.5 to 2.0), investigator-assessed clinical cure (82.7% vs 80.5%; 95% CI, -2.6 to 7.0), and proportion of patients attaining ≥20% reduction in lesion area (85.9% vs 85.3%; 95% CI, -3.7 to 5.0) for oritavancin vs vancomycin, respectively. Efficacy outcomes by pathogen, including methicillin-resistant Staphylococcus aureus and the frequency of adverse events, were similar between treatment groups. CONCLUSIONS: A single 1200-mg dose of oritavancin was noninferior to 7-10 days of vancomycin in treating ABSSSIs caused by gram-positive pathogens, and was well tolerated. Oritavancin provides a single-dose alternative to multidose therapies for the treatment of ABSSSIs. Clinical Trials Registration. NCT01252732.