Role of outpatient parenteral antibiotic therapy in the treatment of community acquired skin and soft tissue infections in Singapore

Outpatient parenteral antibiotic therapy (OPAT) is the provision of at least two doses of intravenous (IV) antibiotics without intervening hospital stay. Since 1974, when OPAT was first reported for the treatment of pediatric patients with cystic fibrosis [1], the practice has been adopted worldwide [2–4]. Outpatient parenteral antibiotic therapy is a safe and cost-effective means of avoiding or reducing length of hospital stay for patients who require IV antibiotics but are otherwise medically stable.

Skin and soft tissue infections (SSTIs) are common indications for OPAT treatment in North America, United Kingdom and Australasia [2–4]. A significant proportion of OPAT courses administered in these countries, for example, up to 52% in a 10 year retrospective OPAT cohort in Glasgow UK, is for the treatment of SSTIs [5].

Outpatient parenteral antibiotic therapy was first introduced to Singapore in 2002 and is now a well accepted practice within the healthcare system [6]. Despite this experience, use of OPAT for the treatment of SSTIs in Singapore remains infrequent. Based on literature regarding the success, safety and cost-effectiveness of OPAT for the treatment of SSTIs, a clinical protocol was developed enabling patients diagnosed with SSTIs in the Emergency Department (ED) of a Singapore university hospital to be referred directly to OPAT, thus avoiding potential hospital admission. In this report, we describe the characteristics, treatment and outcomes of patients treated by this management protocol since 2012.

Tan Tock Seng Hospital (TTSH) is a 1500-bed university teaching hospital and the second largest acute general hospital in Singapore. The hospital’s OPAT service was established in 2002, providing care for approximately 350 patients per year and saving an estimated 5000 bed days per year. The majority of OPAT referrals are from the hospital’s inpatient wards. After assessment by the OPAT nurse and physician, enrolled patients receive antimicrobials by either daily bolus infusion or elastomeric infusors in the hospital’s OPAT clinic (76% of episodes) or in the patient’s home by trained carers (17%) or outreach nurses (7%) [6]. The hospital’s OPAT clinic comprises four recliner chairs and one bed for infusion therapy and three consultation rooms. Both the hospital’s OPAT clinic and outreach nurses provide OPAT services daily – during office hours on weekdays and until noon on weekends and public holidays. The service is managed by a multidisciplinary team of five full time OPAT nurses, Infectious Diseases physicians and supported by the hospital pharmacy.

Clinical evaluation at baseline included patient demographics, underlying co-morbidities, potential predisposing factors, and physical examination including extent of affected area. Laboratory tests done at ED included full blood count, renal function, random glucose and C-reactive protein. Radiographic imaging of the affected limb to exclude the presence of a foreign body, gas in the soft tissue, or osteomyelitis was performed where clinically indicated.

Patients referred by ED were further evaluated by the OPAT physician and counseled by experienced OPAT nurses. Information leaflets and emergency contact numbers were provided and at least one dose of IV antibiotic was administered in ED before discharge. Daily IV antibiotics were then administered via peripheral cannula in the hospital OPAT clinic from the following day. From February 2012 to November 2012, IV ceftriaxone 2 g was administered, this was subsequently switched to IV cefazolin 2 g with oral probenecid 1 g [7] from December 2012 onwards to narrow the spectrum of antimicrobial activity. Daily temperature, pulse rate, blood pressure, patient symptoms and extent of cellulitis were monitored at each visit. After approximately three days of IV antibiotics in the OPAT clinic, patients with satisfactory response to treatment, as defined by the resolution of fever, receding erythema and reduction in swelling and pain, were switched to oral antibiotics, usually cloxacillin or clindamycin for a week [8]. The duration of intravenous or oral antibiotics could be shortened or extended by the OPAT physician depending on patient response. An outpatient review was arranged after seven days of oral antibiotics, with additional follow-up arranged until completion of oral therapy if this was extended. Concomitant tinea pedis or eczema was treated with appropriate topical antifungal cream or emollients respectively. Patients not responding to IV antibiotics, with local or systemic deterioration, were alerted to the OPAT physician and appropriate management such as drainage of abscess or hospital admission was arranged. The collection and publication of these data was approved by the institutional ethics review board.

Of 120 patients that were treated in OPAT, clinical improvement occurred in 90%. Twelve patients (10%) required hospital admission. Seven had worsening cellulitis requiring further course of IV antibiotics. Four patients admitted required surgical incision and drainage of abscess under general anesthetic. Intra-operative cultures were positive for methicillin sensitive Staphylococcus aureus (MSSA) and Klebsiella pneumoniae in one patient each. Both organisms were susceptible to cefazolin and ceftriaxone. One patient was admitted for acute renal impairment following administration of five days of ceftriaxone, one week of oral amoxicillin-clavulanic acid then one week of oral cloxacillin. The renal impairment was attributed to antibiotic related interstitial nephritis and resolved after cessation of antibiotics. Two patients required outpatient surgical drainage of abscess under local anesthetic in the ED but both did not require hospital admission and recovered after an additional course of oral antibiotics. The total number of hospital beds days saved, calculated as the number of days for which IV antibiotics was administered in the hospital’s OPAT clinic, was 318 days in total, with median of 6 days (4–8 days) saved per month.

Patients requiring hospital re-admission were more likely to have a diagnosis of tinea pedis compared to those who completed treatment (33.3% vs. 3.7%, p < 0.01), however, these patients had a diagnosis of concomitant trauma or diabetes which may have additionally contributed to the readmission. A trend towards higher median CRP at baseline was noted in patients readmitted compared to those who completed treatment (74 vs. 21.8, p = 0.17), but did not reach statistical significance. Other characteristics including age, co-morbidities, duration of symptoms were not significantly different between the two groups.

In this report, we describe the successful outcomes of OPAT treatment in patients with SSTIs referred directly from ED to OPAT for continuation of IV antibiotics, without intervening hospital admission in a Singapore university hospital. Although a common source of OPAT referrals in US, UK and Australasia, there is a lack of published data from Asia regarding the use of OPAT in treating SSTIs.

Prior to the implementation of the referral workflow, approximately 9 patients with SSTIs were treated each year in our OPAT clinic. In contrast, 120 patients were treated in the 3 years since implementation, saving 318 hospital bed days. In our study, overall success was 90% with hospital admission in 10%. These outcomes compare favorably with published literature. Of 963 patients with cellulitis treated in Glasgow, UK, success rate was 87%, hospital admission occurred in 6%, adverse events in 7% with progression of infection in 2.8% [9]. In Alberta, Canada, a five-centre ED retrospective study of 416 patients, 11% required change in antibiotic therapy and 7% were hospitalized [10]. A randomized controlled trial in Christchurch, New Zealand comparing cellulitis treatment at home or in the hospital had 11.8% readmission rate for 101 patients on home treatment [11].

There are no standard criteria for when IV antibiotics are necessitated versus oral antibiotics for cellulitis, with studies having differing thresholds of severity. However, 56% of our patients had previously failed oral antibiotics prior to ED attendance, comparable to 51% to 71% of patients reported in other studies [11, 12] and indicates our threshold for giving IV antibiotics was appropriate.

Similarly, no validated objective measures exist of when patients can be switched from parenteral to oral antibiotics. Practice guidelines from the USA advocate once or twice weekly patient review by physician whilst undergoing OPAT but do not specify frequency of review for patients with cellulitis [13]. More recent UK guidelines suggest daily review in OPAT treatment of SSTIs to allow rapid switch from IV to oral therapy as soon as clinically indicated [2]. In UK, IV antibiotics were administered in OPAT for a median duration of 3 days in Glasgow, mean of 5.3 days in Dundee and 6.3 days in Sheffield [9, 14, 15]. Elsewhere, duration of IV antibiotics ranged from 6.24 days to 7 days in Australia [12, 16] to median 4 days in Canadian emergency rooms [10]. The median duration of antibiotics in our study was 3 days, which compares favorably with these studies and consistent with expert recommendations suggesting patients with uncomplicated infections should be switched after 3 to 4 days of IV therapy [8].

Previous studies have investigated factors associated with OPAT failure. In a retrospective cohort, female sex, diabetes and treatment with teicoplanin were independently associated with OPAT failure [9]. Longer duration of IV therapy was associated with methicillin-resistant Staphylococcus aureus (MRSA), older age, vascular disease, diagnosis of bursitis, treatment with teicoplanin in one cohort [9] and male sex, high baseline CRP and prolonged duration of symptoms prior to OPAT in another cohort [15]. Due to the small numbers in this report, we did not detect any significant difference in these risk factors for our cohort.

Most cases of community-acquired cellulitis are caused by Staphylococcus aureus and β-hemolytic streptococci. However, microbiologic isolation of pathogen is usually not possible in the majority. Consequently, cellulitis is generally treated empirically, with therapy usually directed towards these common pathogens unless otherwise indicated [17]. Of the 2 patients with positive cultures obtained from drained abscesses, MSSA and Klebsiella pneumoniae were isolated, confirming that cefazolin or ceftriaxone was appropriate in our management protocol for empirical treatment of community-acquired SSTI in Singapore. No cases of MRSA was isolated in keeping with the low prevalence of community acquired MRSA in Singapore [18].

Although our study was not designed to compare outcomes between ceftriaxone and cefazolin treated patients, no significant differences in outcome were noted between the two groups. A randomized double-blind controlled trial of once daily cefazolin 2 g with probenecid 1 g compared to once daily ceftriaxone 1 g for moderate to severe cellulitis found no difference in clinical cure at end of treatment (86% vs. 96%, p = 0.11) and at 1 month follow-up (96% vs. 91%, p = 0.55) [7]. In a retrospective study of 122 patients with documented MSSA infections treated in OPAT, 64% patient had cefazolin and 36% received ceftriaxone in OPAT. Favorable clinical outcomes were similar between cefazolin and ceftriaxone (67.9% vs. 79.8%, p = 0.17) with a similar incidence of adverse events and complications (5.1% vs. 2.3%, p = 0.65 and 26.9 vs. 18.2% p = 0.38) [19].

Our study has several limitations. Firstly, the lack of a standard severity scale for assessment of SSTIs may lead to a potential variance in the need for IV antibiotics and duration of antibiotics required. Reassuringly, the data from our study is broadly similar to findings of other outpatient cohorts of SSTIs treated with IV antibiotics. Secondly, as patients were managed as part of a clinical protocol, follow-up blood tests and microbiological investigations were not mandated for all patients resulting in incomplete data particularly on follow-up. Treatment related side effects were also not systematically recorded. However, aside from one patient with antibiotic related interstitial nephritis, none of the remaining patients developed significant adverse reactions necessitating a change in antibiotic therapy.

In conclusion, our report supports that OPAT treatment of community acquired SSTIs in a selected patient population has good outcomes in Singapore. Treatment was successful in the majority with low readmission rates comparable to other studies internationally.