The changing landscape of OPAT to COpAT
Outpatient parenteral antimicrobial therapy programs are common for conditions that traditionally require weeks or months of parenteral treatment.
These include bone and joint, skin and soft tissue infections; pulmonary, cardiac device and intra-abdominal infections; and infective endocarditis (IE).
Outpatient parenteral antimicrobial therapy (OPAT) has significant advantages, including reduced hospital stays and improved patient satisfaction. Despite its benefits, it still has limitations involving potential vascular access complications and secondary line infections, and is burdensome for patients or caregivers.
There is an increase in interest and research about OPAT, including randomized controlled trials (RCTs) of oral antimicrobial therapy instead of prolonged IV therapy in some disease states commonly treated with OPAT.
Increased interest in oral therapies
OVIVA and POET were noninferiority RCTs comparing IV with oral therapy for bone and joint infections and IE.
OVIVA compared 6 weeks of oral therapy (started within 1 week) vs. IV treatment for bone and joint infection. Treatment failure within 1 year occurred among 14.6% of participants in the IV group vs. 13.2% in the oral group, demonstrating noninferiority. The rate of serious adverse events was similar between the groups: 27.7% in the IV group compared with 26.2% in the oral group, with significantly fewer catheter complications. The most used oral therapies excluding rifampin were fluroquinolones (FQ; 37%) and combination therapy (17%).
POET compared partial oral therapy with IV therapy for IE with a composite primary outcome of all-cause mortality, unplanned cardiac surgery, embolic events or relapse of bacteremia within 6 months of antibiotic completion. Patients could be randomly assigned to oral therapy after 10 days of IV (the median was 17 days.)
The primary composite outcome occurred in 12% of participants in the IV group vs. 9% in the oral group, meeting noninferiority. The rates of adverse events from antibiotics were similar: 6% in the IV group vs. 5% in the oral group, the most common being allergy, bone marrow suppression and gastrointestinal effects, with no difference between the groups. Oral regimens had high or moderate bioavailability and consisted of two antibiotics. The most used oral antibiotics included amoxicillin, rifampin, linezolid and moxifloxacin.
In addition to noninferiority, clinical outcomes and similar safety outcomes, there was a decreased length of hospital stay and cost in the oral therapy groups in both trials.
Oral regimens for these serious infections require careful selection in addition to monitoring for adherence, adverse events and clinical improvement. This requires a multidisciplinary team, including an infectious diseases physician and an infectious diseases pharmacist, which fits existing OPAT models.
Oral antimicrobials used for prolonged periods of time or that require outpatient monitoring are best described as complex outpatient antibiotic therapy (COpAT).
Factors in selecting optimal COpAT oral therapy include:
- bioavailability;
- penetration to site of infection (ie, bone);
- drug interactions;
- patient compliance;
- gastrointestinal malabsorption; and
- toxicity monitoring.
Since the publications of OVIVA and POET, there has been an increased interest and use of oral therapies for serious infections and in using COpAT, but data on operationalizing it in a real-world setting are limited.
A hospital in the United Kingdom was one of the first to describe real-world implementation, comparing treatment for 1 year before and 1 year after the implementation of an OVIVA-based protocol. The cohort included 328 patients: 145 pre-implementation (all IV) and 183 post-implementation (121 oral and 62 IV). Both groups were evaluated by OPAT service with weekly telemedicine visits, multidisciplinary reviews and in-person evaluations at 6 and 12 weeks.
IV therapy was used in the post-implementation group due to multidrug resistance (48.4%), culture-negative infection (29%), allergies or intolerances (11.3%), adherence concerns (4.8%) and malabsorption (1.6%). The study found no significant difference in infection-free survival at 1 year, which was with 13.6% in the pre-implementation arm and 18.6% in the post-implementation group.
Adverse reactions were more common in the post-implementation group (36.2% vs. 23%), with more than double the rate of gastrointestinal intolerances (24% post vs. 9%).
Hospital length of stay was shorter (9 vs. 13 days) and cost of treatment was reduced by a median of around $3,500 per patient in the post-implementation group.
The most used pre-implementation therapy was IV cephalosporins (50.7%) and glycopeptides (35.6%), and post-implementation was oral FQs (33.9%) and penicillins (33.1%) with a similar rate (approximately 25%) of rifampin used both pre- and post-implementation.
A survey of U.K. OPAT patients found their preference was oral therapy with weekly clinical visits, followed by oral therapy with weekly telephone follow-up, or once-weekly antibiotic injections over traditional OPAT or continued hospitalization.
Tolerability of FQs
FQs were commonly used in the OVIVA trial, and it could be expected to see their use increase in bone and joint infections.
This led Vollmer and colleagues to review the tolerability of FQs in prosthetic joint infections managed by debridement, antibiotics and implant retention with 2 to 6 weeks of IV therapy, followed by oral therapy for 3 or 6 months total for total hip arthroplasty and total knee arthroplasty.
An FQ-based regimen was used in 57% (90/156) of patients, with unplanned discontinuation occurring more often at 36% in the FQ group compared with 3% in the non-FQ group. The most frequent reason for discontinuation was tendinopathy, followed by myalgia, arthralgia, and nausea. Early discontinuation of rifampin occurred in 14.7% of patients.
These data emphasized the need for management of these oral regimens by a specialized team through a COpAT model.
Oral therapy for IE
Three acute-care public hospitals in Los Angeles County implemented a new expected practice to define the scope of oral transitional therapy for IE.
A study comparing outcomes of IV-only vs. oral transitional antimicrobial therapy included 257 patents treated for IE — 46 transitioned to oral and 211 completing IV. The most common organism in both groups was Staphylococcus aureus, followed by Streptococcus species and Enterococcus faecalis. This differed from the POET trial, which saw mostly streptococci with minimal S. aureus and no MRSA.
There was no difference in primary outcomes of clinical success at 90 days, which occurred in 84.4% of patients in the IV group compared with 87% of patients in the oral group (P = .66). Although the IV group was older with more comorbidities, a multivariable regression did not demonstrate these to have a significant impact on the outcome.
There were significantly fewer adverse events in the oral group, 8.7% vs. 27.5% (P = .004) in the IV group, with the biggest differences being in acute kidney injury and line-related adverse effects. The length of stay and 90-day readmission rates were similar between the groups. The most common oral therapy was linezolid (65%), followed by high-dose penicillin.
Cost savings
A study assessed 100 patients treated with COpAT at West Virginia University Medicine from December 2020 to February 2022.
COpAT protocols were created for infection type and organism and used to evaluate IV-to-oral transition by an ID physician with follow-up by an ID physician-pharmacist outpatient team.
People who inject drugs accounted for 78% of patients, with the most common indication being bone and joint infection, followed by mixed bone and joint infection and IE, with S. aureus being the most isolated organism. Oral therapy was most common, with linezolid and FQ,s often in combination.
The median duration of therapy was 28 days for IV and 14 days for oral. This resulted in a savings of 1,425 days of IV therapy and 1,363 hospital days, and a cost avoidance of $42,684 and $2,794,150, respectively.
Patients reported high medication adherence and low readmission rates. In addition to described benefits, it has been hypothesized that COpAT would maintain or improve patient satisfaction.
OPAT/COpAT service
RCTs and real-world data show that early transition to oral therapy can result in comparable clinical outcomes while reducing hospital length of stay, line-related complications and cost, but it still requires a multidisciplinary team for selection and outpatient monitoring. This has led OPAT to encompass therapies beyond parenteral for long-term outpatient courses, better described now as an OPAT/COpAT service.
References:
- Azamgarhi T, et al. Clin Infect Dis. 2021;doi:10.1093/cid/ciaa985.
- Freli257ng S, et al. Clin Infect Dis. 2023;doi:10.1093/cid/ciad119.
- Iversen K, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1808312.
- Juskowich, JJ, et al. Open Forum Infect Dis. 2022;doi:10.1093/ofid/ofac492.843.
- Li HK, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1710926.
- Mahoney MV et al. Curr Infect Dis Rep. 2021;doi:10.1007/s11908-021-00766-x.
- Rawson TM, et al. JAC Antimicrob Resist. 2022;doi:10.1093/jacamr/dlac087.
- Rivera, CG, et al. J Am Coll Clin Pharm. 2021;doi:10.1002/jac5.1473.
- Rivera CG, et al. Open Forum Infect Dis. 2022;doi:10.1093/ofid/ofac242.
- Seaton RA, et al. J Antimicrob Chemother. 2019. doi: 10.1093/jac/dkz122.
- Vollmer NJ, et al. Clin Infect Dis. 2021;doi:10.1093/cid/ciab145.
For more information:
Kelly M. Percival, PharmD, BCPS AQ-ID, is a clinical pharmacy specialist in infectious diseases at University of Iowa Hospitals & Clinics. Percival can be reached at kelly-percival@uiowa.edu.
Disclosure: Percival reports no relevant financial disclosures.