Nicolette Theriault, MPH

A collection of 8 articles focusing on use of oritavancin (Orbactiv

) in daily clinical practice (real world) in patients with skin and skin structure and bone infections was recently 

, which was co-edited by Matteo Bassetti and Teena Chopra. The challenges of making formulary and clinical decisions based on regulatory studies are significant and the need for real world clinical experience is increasingly important.

The introductory article describes the importance of real-world evidence in the context of augmenting and filling in knowledge gaps; 4 articles reported on use of oritavancin in skin and soft tissue infections (SSTI) in order to avoid hospitalization, or expedite hospital discharge, and included evaluation of 2 dosing patterns, and the pharmacoeconomic potential of single dose oritavancin; 1 article modeled the pharmacokinetics of a new oritavancin dosing regimen; and 2 articles concerned oritavancin use in bone or other infections, evaluating once a week oritavancin for treatment of acute osteomyelitis, as well as a review of case studies of off -label use for osteomyelitis.

In a retrospective study of 2 cohorts evaluated oritavancin administered in skin and soft tissue infections in avoiding hospitalization or permitting early discharge from hospital.

 The 2 groups were recruited at multiple sites over a 2-year period. The group examining hospital avoidance enrolled 115 patients with the primary endpoint being hospital admission in 30 days. Of the 115 patients only 3 were admitted with gram-negative infections. Using 2013 HCUP data the mean cost of managing a skin infection in the out-patient setting was $3698 which is markedly less than the billed hospital costs for a SSTI $ 6823. The second cohort, 151 hospitalized patients with SSTI were treated with a range of IV antibiotics but given a single dose of oritavancin prior to hospital discharge were evaluated for re-admission at 30 days. All-cause re-admission was 6.6% while infection related readmissions were 2.6%. Of the 4 patients readmitted with re-infection 2 had gram-negative pathogens. Authors concluded that use of oritavancin within hospital protocols could provide savings and potentially improved care for patients with SSTI.  

 reported on 75 evaluable patients at a single academic medical center who were treated for a range of skin infections (n = 25), surgical wound infections (n = 12) and osteomyelitis or septic arthritis (n = 10). Clinical cure or improvement was achieved in 68 of 75 patients (93.2%). Five patients (6.8%) failed therapy. Responses of note included skin infection 95.8% success, osteomyelitis/septic arthritis 10 of 10 patients were cured or improved and surgical wound infections 11/12 (91.7%). Nine patients reported adverse events. Notably 57% of patients avoided at least one day in hospital resulting in avoided costs of $343,654. Additionally, use of single dose oritavancin avoided the need for long term IV line placement in 61.3% of patients which is required with other parenteral therapies. Other reasons for using oritavancin included social/insurance barriers (46.7%) and allergy or ADR to other antibiotics (10.7%).

Early directed oritavancin therapy given in the emergency department was studied by Helton et al

 over a 12-month period in 122 patients to evaluate the avoidance or reduction of hospitalization which would otherwise have occurred with standard regimen. Sixty-one patients received oritavancin while 61 received standard therapy over the same period. Those receiving oritavancin were associated with a significantly shorted length of stay than those who received vancomycin, 19.5 h vs 85.9h p<0.01. All cause 30-day readmission or return visits to the ED were the same for both groups.

 examined expedited discharge from hospital in patients with skin and soft tissue infections received oritavancin or oral step-down antibiotics following vancomycin therapy. Overall, 199 patients met the study criteria (oritavancin n =99 and oral stepdown antibiotics n=100). Groups were well matched at baseline. Patients who received oritavancin had a shorter LoS than those in the oral stepdown group (3.5 days vs 5.6 days). Additionally, patients who received oritavancin had a lower SSTI 30-day readmission rate and SSTI progression rates.

Although oritavancin has a long terminal half life it is approved only for a single dose of 1200mg.Certain infections may require longer courses of therapy, e.g. bone or joint infections. Rose and Hutson

 examined a 2-dose regimen of oritavancin in which a simulated 1200mg dose given over 3 hours was followed 7 days later by a simulated 800mg dose infused over 3 hours. Oritiavancin displayed predictable linear pharmacokinetic concentrations providing adequate therapeutic concentrations. The total and free concentrations stayed above the susceptible breakpoint of 0.12mg//L for 8 weeks and 4.6 weeks respectively with the 2-dose regimen. This achieved a significantly higher AUC:MIC ratio against organisms with MICs u to 0.25mg/L.

The management of osteomyelitis is a major clinical challenge with long courses of antibiotic therapy required. Current standard antibiotics require either prolonged hospitalization or outpatient parenteral therapy. Both are not without challenges. Van Hise et al

 undertook a 2-year real world assessment of the efficacy and safety of once weekly oritavancin in the treatment of gram-positive bone infections. Evaluations were undertaken as 7-10 days and 3 and 6 months. A total of 134 patients were treated with oritavancin across 20 different infectious disease clinics. Of the positive cultures 71.9% (98/128) were MRSA, nine of these had concomitant bacteremia. Oritiavancin was given an initial dose of 1200mg then 800 mg weekly thereafter for a total of four or five doses.118 patients of 134 achieved clinical success at day 7-10. One hundred and thirty of 134 were available for long term follow up and showed 13/134 (9.7%) reported a relapse or persistent infection. Nine of the 134 were admitted to hospital in the follow up period but none for osteomyelitis related issues. Adverse events were reported in five patients (3.7%) including 3 hypoglycemia-related symptoms, 1 tachycardia and 1 tachycardia with chest pain. None were hospitalized due to the adverse event and all patient completed their treatment. This is the largest real-world clinical study of patients with osteomyelitis treated with oritavancin. It showed a high rate of clinical success while avoiding prolonged hospital stay or use of OPAT facilities. The low incidence of adverse events and convenience of weekly single dose therapy provides an efficacious and well tolerated therapy for a difficult to manage infection in osteomyelitis.

 reviewed the literature of the real-world clinical care report use of oritavancin in osteomyelitis, encompassing 23 patients and demonstrated an overall clinical cure or improvement in 87% of patients with adverse events observed in only 2 patients. Clinical efficacy was 81.8% in MRSA, 71.4% in MSSA and 50% in vancomycin-resistant enterococcal infections.

Oritavancin is a single dose IV therapy, FDA approved for use in treatment of acute bacterial skin and skin structure infections (ABSSSI), complicated skin and soft tissue infections (cSSSI), osteomyelitis, and other disease entities caused by gram-positive bacteria. Oritavancin offers a more patient friendly treatment option as it can be administered intravenously (IV) once a week compared to daily IV or oral tablets, thereby reducing the impact on daily activities and potentially reducing the length of hospitalization or avoiding it altogether. Additionally, use of oritavancin can expedite an early discharge from hospital by avoiding the need for oral stepdown or OPAT alternative therapies. Each of these scenarios lead to cost savings while enhancing patient care.

GSTMicro LLC, Henrico VA. GST is a consultant to Ferring Inc, KBP Biosciences, Summit plc and Melinta Therapeutics. NT has nothing to declare.

1. Estrada S, Lodise TP, Tillotson GS, Delaportas D. The Real-World Economic and Clinical Management of Adult Patients with Skin and Soft Tissue Infections (SSTIs) with Oritavancin: Data from Two Multicenter Observational Cohort Studies. Drugs Real World Outcomes. 2020;7(Suppl 1):6-12. doi:10.1007/s40801-020-00199-3

2. Brownell LE, Adamsick ML, McCreary EK, et al. Clinical Outcomes and Economic Impact of Oritavancin for Gram-Positive Infections: A Single Academic Medical Center Health System Experience. Drugs Real World Outcomes. 2020;7(Suppl 1):13-19. doi:10.1007/s40801-020-00192-w

3. Helton B, MacWhinnie A, Minor SB, Lodise TP, Rafferty KD, Allison SL. Early Directed Oritavancin Therapy in the Emergency Department May Lead to Hospital Avoidance Compared to Standard Treatment for Acute Bacterial Skin and Skin Structure Infections: A Real-World Retrospective Analysis. Drugs Real World Outcomes. 2020;7(Suppl 1):20-29. doi:10.1007/s40801-020-00201-y

4. Whittaker C, Lodise TP, Nhan E, Reilly J. Expediting Discharge in Hospitalized, Adult Patients with Skin and Soft Tissue Infections Who Received Empiric Vancomycin Therapy with Oritavancin: Description of Findings from an Institutional Pathway. Drugs Real World Outcomes. 2020;7(Suppl 1):30-35. doi:10.1007/s40801-020-00196-6

5. Rose WE, Hutson PR. A Two-Dose Oritavancin Regimen Using Pharmacokinetic Estimation Analysis. Drugs Real World Outcomes. 2020;7(Suppl 1):36-40. doi:10.1007/s40801-020-00188-6

6. Van Hise NW, Chundi V, Didwania V, et al. Treatment of Acute Osteomyelitis with Once-Weekly Oritavancin: A Two-Year, Multicenter, Retrospective Study. Drugs Real World Outcomes. 2020;7(Suppl 1):41-45. doi:10.1007/s40801-020-00195-7

7. Scoble PJ, Reilly J, Tillotson GS. Real-World Use of Oritavancin for the Treatment of Osteomyelitis. Drugs Real World Outcomes. 2020;7(Suppl 1):46-54. doi:10.1007/s40801-020-00194-8

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The challenges of making formulary and clinical decisions based on regulatory studies are significant and the need for real-world clinical experience is increasingly important.

Examining Real-World Evidence for Oritavancin Use in Gram-Positive Infections

The global emergence of antimicrobial resistance among gram-negative (GN) species is a major public health concern. This year the US Centers for Disease Control and Prevention 

 originating from a bariatric surgery clinic in Tijuana, Mexico, prompting the agency to issue travel warnings. Organisms were isolated from 10 patients across 2 states, and effective therapeutic options were very limited. As pan-resistant infections have become a reality, clinicians face an increasing dilemma with how to treat multidrug-resistant strains.

The first US case of pan-resistant bacteria was reported by 

 strain isolated from a urine culture in which both 

 were present on a novel IncF plasmid, resulting in resistance to both colistin and β-lactamase.

was documented in the US in a woman who had recently arrived from India and was admitted to a Nevada hospital with SIRS. A 

 strain isolated from her hip abscess was shown to be resistant to all 26 antimicrobials tested, including B-lactams, colistin, and aminoglycosides (

). Tigecycline demonstrated intermediate activity against this strain, but the patient died from septic shock within 1 month.

 and 3 plasmids belonging to multi-locus sequence strain (ST)15, and 4 β-lactamase genes: 2 chromosomal extended-spectrum β-lactamase (ESBL) (bla 

) and 2 plasmid borne elements (the carbapenemase bla 

). Genetically conferring resistance to all 

tested β-lactams and β-lactamase inhibitors

 colistin resistance, has spread globally and resulted in the high prevalence of 

. Although this strain was colistin-resistant, it lacked the 

 genes. These plasmids also contained elements similar to GN bacteria isolated from China, Nepal, India, the United States, and Kenya. However, not all recently approved or developmental agents were tested.

 isolated from a urine culture of a US patient recently treated in India. Genetic characterization showed a combination of bla 

ESBL gene was previously found in a Middle East isolate. None of these resistance mechanisms was plasmid borne; all were found on a 7.1mB Mb chromosome pair. Interestingly, colistin resistance was not due to 

-2; the mechanism is currently unknown. A range of approved and developmental agents were tested, however the only antibiotic with a minimum inhibitory concentrations (MIC) not considered resistant was cefiderocol, MIC 8 ug/ml (intermediate based on tentative CLSI breakpoints). The 

As pan-resistant bacteria emerge globally, in order to prevent inappropriate therapy being instituted, susceptibility testing methods need to be current and able to detect these strains. Additionally, rapid genomic analysis is needed to identify resistance mechanisms, with reporting and surveillance of these strains imperative to monitoring resistance patterns.

Nicolette graduated from the University of Liverpool with an MPH in International Public Health. Currently a research consultant at GST Micro, she is interested in antimicrobial resistance, particularly how it affects patient quality of life, as well as health care policy, and women's health.

Glenn has worked in infectious disease with a special interest in antibiotic resistance for over 30 years. Formerly of Bayer, Oscient and ,most recently, Cempra he has recently been consulting with several companies on developing new antibiotics. He is also a member of the Contagion® Editorial Advisory Board.

The global emergence of antimicrobial resistance among gram-negative species is a major public health concern.

Nicolette Theriault, MPH

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