| Abstract|| |
Outpatient parenteral antimicrobial therapy (OPAT) is a well-established method in medical specialties. Its use in renal transplant recipients has not been thoroughly explored. No guidelines within this patient subset exist. This study describes OPAT outcomes within a UK teaching hospital renal transplant population. Renal function, mapped by estimated glomerular filtration rate (eGFR), and clinical response to infection were collected retrospectively. A total of 635 antimicrobial episodes were administered to nine renal transplant patients over 12 discrete OPAT courses during the study period. Eleven of 12 OPAT courses (91.67%) produced a clinical improvement in infection. One course was terminated due to immunosuppressive-related neutropenia. No patient required admission due to failure of OPAT or adverse events. There was no significant change in graft function throughout the OPAT courses compared with baseline renal function (ANOVA, P = 0.06). One minor line infection was reported. This was treated conservatively and did not interrupt the OPAT. OPAT is safe and clinically effective in our renal transplant recipients with no significant deterioration in eGFR. The incidence of adverse events, specifically line complications, was lower in our population than those reported in the literature. Future work should develop OPAT guidelines designed for transplant recipients to outline the degree of monitoring required.
|How to cite this article:|
Harrison J, Hossain MA, Morsy M, Ghazanfar A. Outpatient parenteral antibiotic therapy in a renal transplant population: A single-center experience. Saudi J Kidney Dis Transpl 2015;26:1121-9
|How to cite this URL:|
Harrison J, Hossain MA, Morsy M, Ghazanfar A. Outpatient parenteral antibiotic therapy in a renal transplant population: A single-center experience. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2021 Dec 3];26:1121-9. Available from: https://www.sjkdt.org/text.asp?2015/26/6/1121/168560
| Introduction|| |
Outpatient parenteral antimicrobial therapy (OPAT) has gained a global fame over the last four decades following its initial success in patients with cystic fibrosis reported by Rucker and Harrison in 1974.  It has a well-reported application in orthopedics, oncology and pediatric specialities. ,, Its outcomes in immunosuppressed patients have been either studied in neutropenic patients in hematology and oncology settings , or in very few patients with acquired immunodeficiency syndrome (AIDS). , The availability of an OPAT service is therefore variable across UK centers.  The most frequent use is for the treatment of bone and soft tissue infections. ,, The use of OPAT within the renal transplant population is limited and has only been reported by a single center. 
Guidelines for the use of OPAT among immunosuppressed patients, such as renal transplant recipients, have yet to be established. It has been found that the clinical safety and outcomes of OPAT vary according to co-morbidities, social factors and frequency of followup.  The current guidelines are largely reported from oncological and hematological groups. , The absence of clinical guidelines for OPAT, within a solid organ transplant population, leaves clinicians without a supportive strategy for safety and follow-up.
OPAT facilitates early discharge from inpatient hospital stay and is thus cost-effective. , This trend has been demonstrated globally across different specialties. , Moreover, OPAT reduces the risk of nosocomial infection and is associated with high patient acceptability.  Delivery of a safe protocol for renal transplant recipients would help enable OPAT implementation among a larger population.
In this case series, outcomes of renal transplant recipients receiving OPAT in a single UK transplant center are reported. The subsequent impact on graft function and survival during the OPAT is also investigated.
| Methods|| |
A retrospective analysis of all completed OPAT courses in transplants recipients was identified from all transplants performed from 1 st January 1996 to 31 st December 2012. All patients with a functioning transplant that subsequently underwent OPAT were included in this study. For all accepted referrals to the OPAT team, patient variables including age, sex and nature of infection were retrieved using the departmental electronic database. Where necessary, case notes were used as an adjunct for data collection.
Consideration of OPAT after referral was performed via a trust-wide team of assessors, comprising a nurse specialist and a consultant microbiologist. Authorization by this team was recorded in the medical records and constituted commencement of the OPAT course. Initiation of the OPAT course was commenced if each patient satisfied the conditions outlined in [Table 1]. Each discrete antimicrobial dose administration during the OPAT course was defined as an OPAT episode. For each OPAT course, duration of the course, type of antimicrobial agent used along with cost of each course per day was investigated.
|Table 1: Local guidelines outlining the initial assessment criteria for OPAT referrals.|
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OPAT success was defined either by clinical cessation of sepsis leading to the end of the OPAT course or if sepsis had improved sufficiently to be managed with a suitable oral antimicrobial alternative. Cessation of infection was defined as an improvement in clinical parameters, including pain and vital signs in conjunction with white cell count (WCC) and biochemical markers and C-reactive protein (CRP). Readmission arising from a deteriorating sepsis, measured via vital signs and biochemical markers, or central venous catheter-related complication was termed an OPAT failure.
The primary outcome was graft function stability, defined as <10% variation in renal function at OPAT completion compared with OPAT commencement. Estimated glomerular filtration rate (eGFR) and serum creatinine (SCr) measured at OPAT initiation, during the first two weeks of therapy and at OPAT course completion were used as markers of graft function. Observed clinical improvement in sepsis and inflammatory response (CRP and WCC) were additional outcomes. Secondary outcome measurements included number of days for each OPAT course and the subsequent cost. All complications during each OPAT course were recorded. Analysis of variance was used to compare graft function (eGFR and SCr) during each OPAT period at date of commencement, first and second week function and at the end. Graphpad v5.0 for Mac (Graphpad Inc, San Diego, CA, USA) was used for the analysis.
| Results|| |
Between 1996 and 2012, 1147 renal transplants were performed. Of this cohort, nine patients [eight donations after brain death (DBD) and one live related donor] were included in the study after referral to OPAT. All grafts were functioning at the time of referral. Of these patients, 55.5% (n = 5) were immunosuppressed with tacrolimus and mycophenolate mofetil (MMF), 22.2% (n = 2) were maintained with tacrolimus and prednisolone and 22% (n = 2) had triple-agent immunosuppression of tacrolimus, MMF and prednisolone. These nine patients (four females, mean age 47.5 years, range 24-64 years, mean weight 76.2 ± 4.9 kg) were referred to OPAT and received 12 discrete courses of therapy over the study period [Table 2]. Mean time from transplant to OPAT commencing was 4.6 years (median 0.62, range 0.1-16.2 years).
|Table 2: Clinical demographics for renal transplant recipients who underwent the OPAT program.|
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The 12 courses equated to 320 home antimicrobial days, during which 635 OPAT episodes were self-administered to renal transplant recipients at home via a peripherally inserted central catheter (PICC). The mean duration of each OPAT course was 26.67 days (median 25, range 9-51 days).
Dual-agent therapy (teicoplanin and meropenem) was required in one course, with this patient presenting with macropapular rash, rigors, mouth ulceration and cervical lymphadenopathy. Thus, six weeks of high-dose intravenous antibiotic were commenced while the source of infection was located, which the improved symptoms. An aneurysm of the external iliac artery and graft patch was identified with CT angiography. In the absence of positive microbiological cultures, possibly owing to the preoperative course of systemic high-dose antibiotics, two intravenous antibiotics were commenced to cover gram positive and gram negative organisms, followed by lifelong oral ciprofloxacin. Eleven OPAT courses out of 12 (91.67%) delivered broad-spectrum antibiotics to patients, with antiviral medication being delivered in the remaining one OPAT course [Table 3]. Positive microbiological growth was recorded in 10 (83.33%) OPAT courses, and was not seen in one case of a persistent psoas abscess and an aneurysm of the transplant renal artery [Table 4]. Both these cases required surgical intervention to treat the primary pathology.
|Table 4: Diagnosis and organism growth frequency during the OPAT courses.|
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No patients required renal replacement therapy during or post OPAT. All patients had functioning transplants at the time of follow-up, mean follow-up 84.7 ± 21.1 months. Collectively, there was no significant deterioration in graft function during the OPAT period (Kruskal- Wallis ANOVA, P = 0.06) [Figure 1]. An overall improvement in mean graft function was observed, but the overall change from initiation of OPAT to end of the course was not observed. In one case (OPAT course A), there was a 23% reduction in graft function recorded between Week 2 and completion of OPAT. This reduced renal function was transient and returned to baseline within two weeks of completion of therapy. The cause for this fluctuation is not certain, but the patient remained systemically well and did not require intervention.
|Figure 1. Serum creatinine (left) and eGFR demonstrated no significant change over the OPAT period for all courses (ANOVA, P > 0.05).|
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With respect to inflammatory marker response (serum leukocyte and CRP), one case developed profound unretractable neutropenia, of which MMF was thought to be the contributing factor. Following a reduction in MMF dosage and administration of a granulocyte colony stimulating factor (GCSF), the neutropenia improved and the graft function remained stable. Despite an initial adequate clinical response to OPAT-delivered ertapenem, this neutropenia prompted a switch to oral ciprofloxacin and doxycycline.
There was one reported minor line complication that was treated conservatively. There were no hospital admissions in relation to the central venous catheters, nor did any line have to be removed or replaced during any of the 635 OPAT episodes. No patients were declared unsuitable for OPAT due to difficultly obtaining or maintaining venous access.
No OPAT failures were recorded. Improvements in clinical symptoms of infection were observed in 11 OPAT courses (91.67%). Complete resolution of infection was observed in ten OPAT courses (83.33%), with the two remaining cases requiring surgical intervention. Digital amputation was indicated for one patient (Patient A) presenting with recurrent chronic osteomyelitis. Surgical drainage of a fistulous connection between the appendix and a chronic psoas abscess was indicated for the remaining patient (Patient G). However, the aim of OPAT in this case was to reduce the infectious load prior to appendectomy, which was achieved. This same patient then commenced a second OPAT course for the treatment of a cold residual abscess. The patient's graft function remained stable throughout both OPAT courses.
Crude cost analysis
The cost of an OPAT course was calculated according to the cost of antimicrobial with delivery per dose, with or without nursing administration. One patient was unable to self-administer and therefore a nurse provided daily home visits, which was charged at £70 per day. All other patients successfully self-administered. The total cost of all 635 OPAT episodes over 320 outpatient days equated to £35,070, whereas the equivalent cost of an inpatient stay, calculated at £264 per day,  was £84,480. The overall saving of £49,410 is a crude estimation and does not include the individual cost of antibiotics as an inpatient.
| Discussion|| |
We report the outcomes of 635 OPAT episodes administered to renal transplant recipients over a 12-year period. The clinical outcomes of OPAT in renal transplant recipients were previously limited to a solitary letter to the editor regarding a North American cohort, who found that the overall complication rates of OPAT in transplant recipients were comparable to the general population. However, analysis of renal-specific complications demonstrated that 10% of patients developed nephrotoxicity, half of which required renal biopsy. Overall, 3.3% of allografts failed during OPAT. We add to this limited data by demonstrating among a UK renal transplant population that OPAT can be offered as a cheap and effective alternative for patients requiring parenteral antibiotic treatment while maintaining a stable graft function. We have also shown that OPAT in renal transplant recipients can potentially save over £4000 per course of antimicrobial therapy when compared with an inpatient stay of the same duration. This financial benefit is of greater consequence when associated with a reduced risk and the subsequent cost of acquiring hospital-acquired infections is considered. Numerous specialties, such as orthopedics, implement OPAT to alleviate inpatient bed pressures. We demonstrate the same advantage among transplant recipients, given that hospital readmission secondary to OPAT complications did not occur and facilitated patient discharge up to seven weeks earlier.
This clinical and financial viability has led to an increase in UK OPAT practice; however, it is not without risk.  Within a generalized OPAT population, line complications and adverse drug reactions are the most frequently adverse events. , The solitary report of OPAT use among renal transplant recipients reported a complication rate of 23%, which was comparable to a generalized OPAT population.  There was no adverse effect recorded directly as a result of OPAT. Generally, a complication rate of 16.7% (n = 2) was recorded with one episode of neutropenia secondary to MMF and one temporary alteration in renal function secondary to auto-transplantation because of mycotic aneurysm on transplant renal artery.
Careful patient selection has been attributed as one key factor in ameliorating OPAT-derived risk,  especially in those who self-administer.  Despite the paucity of guidelines on selection criteria for transplant recipients and OPAT, our trust has implemented generalized contraindications to OPAT [Table 1]. The majority of the OPAT courses in the present study were self-administered. Benefits of self-administration include patient eligibility for anti-microbial regimes that require multiple daily administrations as well as reducing the nursing provision cost. In the one OPAT course that did not self-administer antimicrobials, the patient was the oldest of the group, aged 64 years, and had three hospital admissions with recurrent urosepsis and wound infection within a two-month period. This could indicate that older graft recipients may require more support at home while on OPAT and that close assessment with the referral team is required in patients over the age of 60 years. Furthermore, the referring clinician and OPAT team must acknowledge other comorbidities that could limit self-administration and the ability to comply with a multiple-dosing regimen.
Non-clinical factors, including a suitable home environment and willingness to attend follow-up appointments, have been identified as imperative to OPAT safety. , In all our OPAT courses, graft surveillance, clinical response to therapy and detection of adverse events was delivered in partnership by the nephrology and OPAT personnel. All patients received a minimum of twice-weekly contact in accordance with national and international guidelines. ,
Our study had several limitations; data were collected from a single tertiary transplant unit and subsequently only a limited number of cases were identified for inclusion. Moreover, as OPAT courses were delivered from a tertiary care renal unit, the safety of OPAT within transplant recipients may not be comparable to the wider healthcare system if OPAT was commenced without the availability of specialist multi-specialty teams. Being a retrospective study, the pre-OPAT stability of the patients had to be postulated given that they were deemed fit for outpatient therapy in conjunction with biochemical and microbiology reports rather than direct clinical observations. Additionally, the calculated cost comparison was a crude analysis, with the calculated in-patient cost limited to that of an overnight stay without provision of antimicrobial therapy or blood testing.
Future work is required to expand the knowledge surrounding the clinical effectiveness of OPAT in renal transplant recipients, with a specific focus on the renal function throughout treatment. Monitoring leukocyte response with relation to graft function is mandatory, along with the therapeutic index of immunosuppressives used. Following this, formal OPAT treatment guidelines for renal transplant recipients should be generated. Issues that need to be clarified include the type and frequency of renal function monitoring as well as what degree of change in renal function is deemed significant. Potential interactions of commonly used home intravenous antimicrobials with immunosuppressive regimens require a deeper understanding. A multidisciplinary approach involving the renal transplant team and OPAT team should be paramount in monitoring therapeutic response. Development of these guidelines will enable valuable OPAT services to be delivered to an increased number of immunosuppressed renal transplant patients more safely. Patient satisfaction data were not reported here given the retrospective study design, although this would be an area for future exploration.
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Department of Renal Transplantation, St. George's Hospital NHS Trust, Blackshaw Road, Tooting, London
[Table 1], [Table 2], [Table 3], [Table 4]