Lipoglycopeptides, Outpatient Parenteral Antibiotic Therapy, and the Infectious Disease Doctor—Moving Forward

Outpatient parenteral antibiotic therapy (OPAT) was first described in 1974 for the treatment of children with cystic fibrosis. In 1978, Antoniskis et al1 reported 13 adult patients who self-administered parenteral antibiotics, primarily for osteomyelitis. Subsequently, several articles appeared in the literature showing the significant cost savings, efficacy, and safety of patients treated with parenteral antibiotics on an outpatient basis for a variety of infections, many of which involved bones and joints.2,3 The development of potent drugs with prolonged half-lives and long-term stability in solution, such as ceftriaxone, allowed for once daily dosing without sacrificing efficacy. Newer indwelling intravenous catheters also helped promote the use of outpatient intravenous therapy. Outpatient parenteral antibiotic therapy is now considered the standard of care for many infections, not only in the United States but also in many other countries.4 Over the past several years, newer antibiotics with prolonged half-lives, such as daptomycin, ertapenem, and more recently a group of newer lipoglycopeptides, have facilitated outpatient treatment for a variety of gram-positive and gram-negative infections. Some infections treated with OPAT can be accomplished with relatively short courses of therapy, whereas others often require prolonged treatment lasting for several weeks, such as osteomyelitis5 and infective endocarditis. The current standard recommendation for treating chronic osteomyelitis is 6 weeks of parenteral antibiotic therapy. In the case of methicillin-resistant Staphylococcus aureus (MRSA), the drug of choice has been vancomycin, even though it usually penetrates bone poorly and requires the insertion of an intravenous catheter with careful monitoring of drug levels and renal function.6,7 Suggested alternatives to vancomycin have been daptomycin, linezolid, and a lipopeptide. In this issue of IDCP, Ruggero et al8 describe the successful treatment of a patient with MRSA vertebral osteomyelitis using outpatient oritavancin, a lipoglycopeptide currently approved by the Food and Drug Administration for the treatment of acute bacterial skin infections caused by susceptible gram-positive organisms including MRSA. Because of the patient's history of drug abuse, other medical problems, and poor compliance, he was treated with oritavancin at a dosage of 1200 mg every 2 weeks for 4 doses, plus a fifth dose one month after the fourth dose. Although it is not known with certainty whether or not the infection was eventually cured, this case demonstrated the feasibility of treating a patient with osteomyelitis as an outpatient, using a long half-life lipoglycopeptide antibiotic. Guskey and Tsuji9 published a comparative review of the lipoglycopeptides: oritavancin, dalbavancin, and televancin.10 There have been other studies that demonstrate the efficacy of treating bone and joint infections using these drugs.11–13 Schroeder et al14 reported 286 bone and joint infections treated with once-daily telavancin at a dosage of 10 mg/kg per day (adjusted for renal function) with a positive clinical response rate of 70%. This was a retrospective analysis of the efficacy and safety of telavancin with the primary organism being MRSA. The median duration of televancin treatment was 21 days, with a range of 3 to 105 days. Televancin-associated adverse events occurred in 57%. Previous animal data suggested adequate bone penetration of telavancin, but because of its half-life, administration was required every 24 hours.15 Studies in rabbits that received oritavancin at a dosage of 20 mg/kg (equivalent to a 1200 mg dose in humans) showed oritavancin concentrations greater than 10 μg/mL in serum for greater than 24 hours after a single dose, with bone concentrations remaining above the minimum inhibitory concentration90 of S. aureus for greater than 16 hours after a single dose of 20 mg/kg.16 Dalbavancin is another lipoglycopeptide with a prolonged half-life that has been shown to obtain high concentrations in human bone and can be infused over 30 minutes using a peripheral intravenous (IV) catheter. A 2015 study17 published in Antimicrobial Agents and Chemotherapy using an S. aureus with an minimum inhibitory concentration90 of 0.06 μg/mL showed a cortical bone level 12 hours after infusion to be 6.3 μg/g and 2 weeks later, 4.1 μg/g. A not yet published study from a single center in the Ukraine reported on 59 patients who were administered dalbavancin as two 1500 mg IV infusions 1 week apart. All patients underwent debridement and bone cultures, with the most common site of infection being the foot or leg. At day 42, clinical cure was seen in all patients, and at 180 days, 93% were cured. Although these are preliminary studies, it appears that these newer lipoglycopeptides, particularly oritavancin and dalbavancin,18 have a future in the treatment of infections requiring prolonged therapy such as osteomyelitis and eventually possibly infective endocarditis. This therapy is particularly attractive to be given on an outpatient basis such as emergency rooms, office practice-based infusion centers, free-standing infusion centers, home infusion centers, and hospital outpatient departments. Although the cost of a single infusion of these drugs is quite expensive, eliminating the need for a venous catheter with its daily maintenance and decreased need for monitoring potential drug toxicities, plus the added convenience for patients, would make treatment for osteomyelitis and other infections requiring prolonged courses of treatment attractive for outpatient therapy. The usage of a peripheral IV rather than a venous catheter that can be removed after the infusion would be very appealing for both patients and medical personnel. Regardless of which antibiotic is used during OPAT, the ultimate responsibility rests upon the ordering and attending physician. As pointed out by Keller et al19 in a recent article published in Clinical Infectious Diseases, patients need to be monitored for adverse drug events including clinical assessment with laboratory monitoring, especially those receiving vancomycin. Because of the increasing use of outpatient therapies in patients with complex medical problems, the infectious disease physician trained in OPAT will be the natural leader to run these programs.