Since it was first described in 1974 in children with cystic fibrosis,1 use of outpatient parenteral antimicrobial therapy (OPAT) has been shown to be safe, efficacious and cost effective.2–6 The benefits of receiving intravenous (IV) antimicrobial therapy at home or other ambulatory settings include improving quality of life while reducing length of hospitalization, healthcare costs and exposure to nosocomial pathogens. OPAT guidelines have been developed by the Infectious Diseases Society of America (IDSA)7 and the Good Practice Recommendations (GPR) Working Group.8 While it is estimated that >1 in 1000 American adults receive OPAT annually,7 it is not known how many children receive OPAT each year.
There are few studies on pediatric OPAT, and they may not be generalizable to current practice for a variety of reasons. Two of the largest studies were conducted over 10 years ago at a single center, before the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA), and before widespread use of peripherally inserted central catheters (PICCs) for OPAT administration.2,9 Indeed, more than half the patients in these earlier series received OPAT through central venous catheters.2,9 More recent studies about pediatric OPAT had small numbers of patients,10 or limited their analysis to patients with osteoarticular infections.11
Catheter- or antibiotic-associated complications are well described in children receiving OPAT,2,3,9–15 but interventions to improve the safety of pediatric OPAT have not been evaluated. Data from adults suggests that OPAT oversight by antimicrobial stewardship programs can reduce OPAT overuse and costs and improve patient safety and outcomes.16–18 To quantify the number of children receiving OPAT each year, evaluate associated clinical characteristics and outcomes and identify opportunities to improve the safety of pediatric OPAT, we reviewed all patients discharged with OPAT from our institution over a 17-month period.
We conducted a retrospective review of OPAT use at our institution between August 1, 2010 and December 31, 2011. Patients were included in the study if they were discharged from Mayo Clinic Children’s Hospital in Rochester, MN with IV antimicrobial therapy and received a minimum of 1 day of parenteral therapy as an outpatient. Study patients were identified using records of the pediatric discharge planning nurse specialist (who records patients discharged with all home healthcare needs, including OPAT). All pediatric hospitalists and consultants caring for children hospitalized at our institution are faculty at our medical school.
The decision to use OPAT was made by the primary attending physician and did not require pediatric infectious disease (ID) approval. Providers, together with nurses and pediatric discharge planning specialists, assessed stability of the home environment and ability of parents or guardians to administer medications before discharge with OPAT. If there were any concerns regarding patient compliance or suitability of the home environment for OPAT, OPAT was generally not used. The home healthcare nurse provided teaching of parents or guardians before hospital discharge or at the first home visit that generally occurred on the day of discharge. Catheter flushing instructions were dependent on home healthcare agency and catheter type. PICC lines were generally flushed with 10 mL of saline and 3 units of heparin after each infusion. Agents were usually infused through pushes, 24-hour pumps, or Intermate infusion systems. Catheter dressing changes were performed once weekly by the home healthcare nurse. Patients followed by the ID service were seen for follow-up in the outpatient pediatric ID clinic where potential for transition to oral agents was assessed. Primary care physicians were generally not involved in OPAT management. On rare occasions, if patients lived far from our center, primary care physicians might monitor weekly laboratories.
Demographic, clinical and laboratory data were abstracted by chart review. All patients were followed for a minimum of 3 months after discharge. Treatment failure was defined as failure to clear the infection while receiving OPAT, recurrence of infection with the same organism or clinical relapse within 3 months of discharge. Neutropenia was defined as absolute neutrophil count below or equal to 1.0 × 109/L. Leukopenia was defined as peripheral white blood count below 4.0 × 109/L. Eosinophilia was defined as eosinophil count above 0.5 × 109/L. Renal insufficiency was defined as ≥2-fold rise in baseline serum creatinine level attributed to the antimicrobial agent. Hepatitis was defined as any clinically significant rise in transaminases attributed to the antimicrobial agent. Differences between categorical variables were analyzed using Fisher exact test. This study was approved by our institutional review board.
Characteristics of OPAT
During the study period, there were 126 pediatric hospital discharges with OPAT, corresponding to 2.5% of all pediatric hospital discharges. One hundred nine unique patients received OPAT; among these, 13 (12%) patients received 2 or more OPAT courses. The mean patient age was 8.8 years (range: 1 month–20 years), and there was an equal distribution of males (n = 63, 50%) and females (n = 63, 50%).
OPAT was used to treat a variety of diagnoses, most commonly bone and joint infections (Table 1). Primary services most often discharging patients with OPAT were: General Pediatrics (n = 49, 38.9%), Orthopedic Surgery (n = 25, 19.8%) and Hematology/Oncology (n = 14, 11.1%). The pediatric ID service was consulted before discharge in 114 of 126 courses (90.5%) to help with coordinating OPAT administration, home healthcare, laboratory monitoring and follow-up. ID consultation was not mandatory before discharge with OPAT.
A pathogen was identified in 86 of 126 OPAT courses (68.3%; Table 2). Of the 40 courses without pathogens identified, 30 (75%) had negative cultures or serology tests and in 10 (25%) no cultures were sent. The most commonly used antimicrobial agents were ceftriaxone (n = 22, 17.5%), cefazolin (n = 20, 15.9%) and cefepime (n = 16, 12.7%), followed by vancomycin (n = 15, 11.9%), carbapenems (n = 15, 11.9%) and piperacillin/tazobactam (n = 8, 10.3%). Ten patients (7.9%) received a combination of 2 or more antimicrobial agents. Other agents were prescribed in 15 courses (11.9%) including ceftazidime (n = 3), amphotericin B (n = 3), clindamycin (n = 2), ciprofloxacin (n = 2), cefotaxime (n = 1), daptomycin (n = 1), amikacin (n = 1), ganciclovir (n = 1) and acyclovir (n = 1).
Duration of Treatment
The median duration of all 126 OPAT courses was 12 days (mode: 12 days, range: 1–51 days). Among the 107 courses where OPAT was used for 7 or more days, the median duration was 14 days (mode: 12 days, range: 7–51 days). The median duration of OPAT was longest for treatment of hardware infections (38 days), endovascular infections (31 days) and bone and joint infections (20.5 days). Shorter durations were used to treat intra-abdominal infections (14 days), skin and soft tissue infections (14 days), catheter-related bloodstream infection (12 days), urinary tract infection/pyelonephritis (12 days), complicated pneumonia (11.5 days) and cystic fibrosis exacerbations (10 days).
There was variability in laboratory monitoring of drug levels, complete blood counts and renal and liver function tests. Among 107 courses with a minimum duration of 7 days of therapy, laboratory monitoring was performed at least once weekly in 87 (81.3%) and not at all in 17 (15.9%). The frequency of laboratory monitoring was unknown in 3 (2.8%) courses where patients were lost to follow-up. Patients were more likely to have laboratory monitoring if OPAT was managed by the ID service versus other services (85/97, [87.6%] versus 2/10 [20.0%]; P < 0.001). The cure rate was not significantly higher among patients followed by ID compared with those not followed by ID (88/96 [91.7%] versus 8/10 [80.0%]; P = 0.2), although this analysis was limited by the small number of patients without ID involvement.
Complications developed during OPAT therapy in 36 of 123 (29.3%) courses and 35 of 109 (32.1%) individual patients (Table 3). Catheter-associated complications were less common (10/45, 22.2%) than drug-associated complications (35/45, 77.8%; Fig., Supplemental Digital Content 1, http://links.lww.com/INF/B421). Catheter-associated complications including infection, blockage, development of a deep venous thrombosis, dislocation and pain occurred exclusively in patients with PICC lines and those being treated for bone and joint, endovascular and skin and soft tissue infections (Table 3). Antimicrobial-associated complications occurred most frequently in patients with bone and joint infection, catheter-related bloodstream infection and intra-abdominal infections and in those receiving cefazolin, piperacillin/tazobactam and vancomycin. Among 35 patients with complications, 17 (48.6%) had 1 or more unscheduled visits to the emergency department or other healthcare providers, and 8 (22.8%) required rehospitalization.
Of 123 OPAT courses with follow-up, 109 (88.6%) resulted in cure, 13 (10.6%) were treatment failures and 1 (0.8%) resulted in OPAT discontinuation because the patient did not have an infection. Treatment failures occurred in patients with catheter-related bloodstream infections (n = 1), hardware infections (n = 2), intra-abdominal infections (n = 2), central nervous system infection (n = 1), complicated pneumonia (n = 1) and complicated pyelonephritis (n = 1).
We report one of the largest and most recent series of children receiving OPAT. At our children’s hospital, 2.5% of hospitalized patients were discharged with OPAT for a variety of indications, most commonly for treatment of bone and joint infections. In one-third of OPAT courses, children developed catheter- or antibiotic-associated complications that frequently resulted in unplanned healthcare visits or readmissions.
Our overall cure rate of 89% is slightly lower than previous reported rates between 96% and 99%.2,9,15,19 These differences may be explained by the fact that our study included lengthier follow-up time than an earlier study15 and included patients with heterogeneous syndromes including difficult to eradicate hardware-associated infections, unlike earlier studies that evaluated OPAT only for osteoarticular infections.2 Last, our study was conducted in the current era of widespread community-associated drug-resistant pathogens, including MRSA, which emerged after publication of the prior studies.2,9 In 2011, MRSA accounted for 28% of all S. aureus isolates at our institution. In our cohort, 11.5% of bone and joint infections were due to MRSA.
The proportion of OPAT courses with antibiotic- or catheter-associated complications was 29% in our study, comparable with previously published rates.9,15 As in other studies,2,9,15 rash and neutropenia were the most common antibiotic-associated complications we observed, although we also noted additional complications of nephrotoxicity and Clostridium difficile-associated colitis that were not seen in prior studies.2,9,15 These additional toxicities likely reflect the current reality of increasingly drug-resistant pathogens that require use of vancomycin or broad-spectrum agents. In this series, half of children with OPAT-related complications had unplanned healthcare visits and nearly a quarter of them were readmitted. This is also in the range of what has previously been reported.9,11,13,20 Despite ample literature describing OPAT- or PICC-line–associated complications,2,3,9,10,12–15,21–23 in our experience many providers initiating and managing OPAT underestimate the associated risks. There is a need to increase provider and patient education about risks associated with OPAT in children. The complications in children receiving OPAT also raise concern about the actual cost-effectiveness and caregiver satisfaction of OPAT in children, which deserves further study.
In this study and others, catheter-related complications were generally seen in children treated for more than 2–3 weeks,9,11,20,22 suggesting that shortening the duration of OPAT and converting to oral therapy sooner might reduce OPAT complication rates.24 In certain infectious syndromes, it is not clear that prolonged OPAT is superior to oral therapy or early conversion to oral antibiotics after an initial short IV phase. Observational studies have demonstrated similar outcomes with prolonged IV therapy or early conversion to oral antibiotics after an initial short IV phase in children with osteoarticular infections25–31 or perforated appendicitis.32 Randomized controlled trials support the use of oral therapy in children with urinary tract infection33 and pyelonephritis.34 A Cochrane Collaboration Systematic Review comparing oral and parenteral antibiotics in children with severe pneumonia found that oral antibiotics are effective and safe,35 although only 3 studies met the inclusion criteria. There is a need for prospective randomized trials of OPAT versus oral therapy of complicated infections in children. In particular, studies about pharmacokinetics/pharmacodynamics of antimicrobials in children, duration of OPAT therapy and timing of transition from IV to oral therapy could inform the development of pediatric-specific OPAT guidelines.
We found that laboratory monitoring of OPAT patients was more likely to occur once weekly, as recommended by IDSA guidelines,7 if patients were followed by the ID service, suggesting that an additional way to improve the safety of pediatric OPAT would be to increase involvement of ID or antimicrobial stewardship groups in OPAT initiation and management. Recent studies in adults demonstrate that ID oversight of OPAT increases safety and efficacy of OPAT16,18 and that mandatory ID consultation before discharge results in less unnecessary OPAT use for treatment of infections that can be effectively treated with oral antimicrobials. It is likely that pediatric antimicrobial stewardship programs can also reduce unnecessary OPAT use and improve the quality of care of children receiving OPAT, but it is unclear how many pediatric antimicrobial stewardship programs have the necessary resources and infrastructure to participate in OPAT oversight. Our ID service was frequently consulted to coordinate home care and follow-up of patients after decisions to use OPAT had been made. We are hoping to expand the role of the ID service to help determine whether OPAT should be initiated in the first place.
Our study has several limitations. It is a retrospective, single center study over a short time frame. There were few OPAT patients not followed by the ID service, limiting our ability to discern differences in outcomes between patients with and without ID involvement. Finally, definitions of some of our complications were somewhat subjective (eg, hepatitis), and may not have prompted all providers to make modifications to antimicrobial therapy. Despite these limitations, our study is among the first to quantify the number of children discharged with OPAT for any indication from a children’s hospital and adds to the limited literature on pediatric OPAT.
In conclusion, our data suggest there has been little change over the past decade in the diagnoses and outcomes associated with pediatric OPAT. OPAT-related complication rates in children remain high, a fact that is likely underrecognized by many OPAT prescribers. Opportunities to increase involvement of pediatric ID or antimicrobial stewardship groups in OPAT initiation and management should be explored.
The authors thank Onalee Finseth, RN whose records assisted in identification of patients discharged on OPAT during the study period.
1. Rucker RW, Harrison GM. Outpatient intravenous medications in the management of cystic fibrosis. Pediatrics. 1974;54:358–360
2. Maraqa NF, Gomez MM, Rathore MH. Outpatient parenteral antimicrobial therapy in osteoarticular infections in children. J Pediatr Orthop. 2002;22:506–510
3. Bradley JS, Behrendt CE, Arrieta AC, et al. Convalescent phase outpatient parenteral antiinfective therapy for children with complicated appendicitis. Pediatr Infect Dis J. 2001;20:19–24
4. Wiernikowski JT, Rothney M, Dawson S, et al. Evaluation of a home intravenous antibiotic program in pediatric oncology. Am J Pediatr Hematol Oncol. 1991;13:144–147
5. Bradley JS. Outpatient parenteral antibiotic therapy. Management of serious infections. Part I: Medical, socioeconomic, and legal issues. Pediatric considerations. Hosp Pract (Off Ed). 1993;28(suppl 1):28–32
6. Goldenberg RI, Poretz DM, Eron LJ, et al. Intravenous antibiotic therapy in ambulatory pediatric patients. Pediatr Infect Dis. 1984;3:514–517
7. Tice AD, Rehm SJ, Dalovisio JR, et al.IDSA. Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines. Clin Infect Dis. 2004;38:1651–1672
8. Chapman AL, Seaton RA, Cooper MA, et al.BSAC/BIA OPAT Project Good Practice Recommendations Working Group. Good practice recommendations for outpatient parenteral antimicrobial therapy (OPAT) in adults in the UK: a consensus statement. J Antimicrob Chemother. 2012;67:1053–1062
9. Gomez M, Maraqa N, Alvarez A, et al. Complications of outpatient parenteral antibiotic therapy in childhood. Pediatr Infect Dis J. 2001;20:541–543
10. Van Winkle P, Whiffen T, Liu IL. Experience using peripherally inserted central venous catheters for outpatient parenteral antibiotic therapy in children at a community hospital. Pediatr Infect Dis J. 2008;27:1069–1072
11. Ruebner R, Keren R, Coffin S, et al. Complications of central venous catheters used for the treatment of acute hematogenous osteomyelitis. Pediatrics. 2006;117:1210–1215
12. Faden D, Faden HS. The high rate of adverse drug events in children receiving prolonged outpatient parenteral antibiotic therapy for osteomyelitis. Pediatr Infect Dis J. 2009;28:539–541
13. Hussain S, Gomez MM, Wludyka P, et al. Survival times and complications of catheters used for outpatient parenteral antibiotic therapy in children. Clin Pediatr (Phila). 2007;46:247–251
14. Barrier A, Williams DJ, Connelly M, et al. Frequency of peripherally inserted central catheter complications in children. Pediatr Infect Dis J. 2012;31:519–521
15. Le J, San Agustin M, Hernandez EA, et al. Complications associated with outpatient parenteral antibiotic therapy in children. Clin Pediatr (Phila). 2010;49:1038–1043
16. Heintz BH, Halilovic J, Christensen CL. Impact of a multidisciplinary team review of potential outpatient parenteral antimicrobial therapy prior to discharge from an academic medical center. Ann Pharmacother. 2011;45:1329–1337
17. Gordon SM, Shrestha NK, Rehm SJ. Transitioning antimicrobial stewardship beyond the hospital: the Cleveland Clinic’s community-based parenteral anti-infective therapy (CoPAT) program. J Hosp Med. 2011;6(suppl 1):S24–S30
18. Shrestha NK, Bhaskaran A, Scalera NM, et al. Contribution of infectious disease consultation toward the care of inpatients being considered for community-based parenteral anti-infective therapy. J Hosp Med. 2012;7:365–369
19. Dagan R, Einhorn M. A program of outpatient parenteral antibiotic therapy for serious pediatric bacterial infections. Rev Infect Dis. 1991;13(suppl 2):S152–S155
20. Maraqa NF, Rathore MH. Pediatric outpatient parenteral antimicrobial therapy: an update. Adv Pediatr. 2010;57:219–245
21. Levy I, Bendet M, Samra Z, et al. Infectious complications of peripherally inserted central venous catheters in children. Pediatr Infect Dis J. 2010;29:426–429
22. Advani S, Reich NG, Sengupta A, et al. Central line-associated bloodstream infection in hospitalized children with peripherally inserted central venous catheters: extending risk analyses outside the intensive care unit. Clin Infect Dis. 2011;52:1108–1115
23. Tolomeo C, Mackey W. Peripherally inserted central catheters (PICCs) in the CF population: one center’s experience. Pediatr Nurs. 2003;29:355–359
24. Wheeler AM, Heizer HR, Todd JK. Influence of culture results onmanagement and outcome of pediatric osteomyelitis and/or septic arthritis. J Ped Infect Dis. 2012;1:152–156
25. Le Saux N, Howard A, Barrowman NJ, et al. Shorter courses of parenteral antibiotic therapy do not appear to influence response rates for children with acute hematogenous osteomyelitis: a systematic review. BMC Infect Dis. 2002;2:16
26. Zaoutis T, Localio AR, Leckerman K, et al. Prolonged intravenous therapy versus early transition to oral antimicrobial therapy for acute osteomyelitis in children. Pediatrics. 2009;123:636–642
27. Bachur R, Pagon Z. Success of short-course parenteral antibiotic therapy for acute osteomyelitis of childhood. Clin Pediatr (Phila). 2007;46:30–35
28. Jagodzinski NA, Kanwar R, Graham K, et al. Prospective evaluation of a shortened regimen of treatment for acute osteomyelitis and septic arthritis in children. J Pediatr Orthop. 2009;29:518–525
29. Ballock RT, Newton PO, Evans SJ, et al. A comparison of early versus late conversion from intravenous to oral therapy in the treatment of septic arthritis. J Pediatr Orthop. 2009;29:636–642
30. Peltola H, Pääkkönen M, Kallio P, et al.Osteomyelitis-Septic Arthritis Study Group. Short- versus long-term antimicrobial treatment for acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culture-positive cases. Pediatr Infect Dis J. 2010;29:1123–1128
31. Howard-Jones AR, Isaacs D. Systematic review of systemic antibiotic treatment for children with chronic and sub-acute pyogenic osteomyelitis. J Paediatr Child Health. 2010;46:736–741
32. Rice HE, Brown RL, Gollin G, et al. Results of a pilot trial comparing prolonged intravenous antibiotics with sequential intravenous/oral antibiotics for children with perforated appendicitis. Arch Surg. 2001;136:1391–1395
33. Hoberman A, Wald ER, Hickey RW, et al. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics. 1999;104(1 Pt 1):79–86
34. Bocquet N, Sergent Alaoui A, Jais JP, et al. Randomized trial of oral versus sequential IV/oral antibiotic for acute pyelonephritis in children. Pediatrics. 2012;129:e269–e275
35. Rojas MX, Granados C.. Oral antibiotics versus parenteral antibiotics for severe pneumonia in children. Cochrane Database Syst Rev. 2006:CD004979