Evaluation of outpatient treatment with ertapenem in a double blind controlled clinical trial of complicated skin/skin structure infections

doi:10.1016/j.jinf.2003.10.001

Journal of Infection

Volume 48, Issue 1, January 2004, Pages 32-38

https://doi.org/10.1016/j.jinf.2003.10.001 Get rights and content

Abstract

Objectives. The patient characteristics and the efficacy and safety of ertapenem 1 g once daily vs. piperacillin-tazobactam 13.5 g divided Q6H were examined in patients who received outpatient parenteral antimicrobial therapy (OPAT) during a clinical trial of complicated skin/skin structure infections.

Methods. The population analyzed included 363 patients treated at US sites in a large randomized double-blind study.

Results. In this analysis, 146 (40%) patients at 19 (66%) sites were managed by OPAT. A lower proportion of treated patients who received OPAT had severe infection (12% vs. 20%, P=0.03). In evaluable patients managed by OPAT, 45 (83.3%) of 54 treated with ertapenem and 41 (82.0%) of 50 treated with piperacillin-tazobactam were cured at the test of cure assessment 10–21 days post-therapy (OR 1.2 (95% CI, 0.4–3.2), P=0.78). The safety profile of both drugs was generally similar; diarrhoea was the most common adverse event in both groups.

Conclusions. In this trial of complicated skin/skin structure infection, OPAT was commonly used by US investigators. Among patients who received OPAT, ertapenem 1 g daily was as effective as piperacillin-tazobactam 3.375 g Q6H.

Introduction

The use of outpatient parenteral antimicrobial therapy (OPAT), administered in a hospital-based outpatient clinic, a physician's office, an outpatient infusion center, or the patient's home, has grown considerably in the United States, where >250,000 patients are estimated to receive OPAT each year.¹ OPAT is also being used more commonly internationally, especially in China, South America, and Europe.² Registries of patients managed by OPAT, which provide information about the infections treated, responsible pathogens, antimicrobial agents used, site of administration, patient outcome, and patient satisfaction, now exist in the United States and internationally. Data from both registries show that with careful patient selection, OPAT is highly effective and associated with a low frequency (<5%) of adverse events.³ Additionally, OPAT has the advantages of decreased healthcare costs and increased convenience and comfort for the patient. The most common diagnosis managed by OPAT in the United States and Europe is skin/skin structure infection, followed by osteomyelitis and joint infections.³

Attributes of an antimicrobial agent to consider when assessing the feasibility of OPAT include spectrum of activity, dosage regimen, mode of administration, safety profile, drug stability, and cost. Ertapenem (Merck and Co., Inc.) is a once a day parenteral carbapenem antimicrobial that was licensed in the United States in November 2001 for treatment of several infectious disease indications, including complicated skin/skin structure infections, and in Europe in April 2002. Ertapenem has excellent in vitro activity against methicillin-susceptible Staphylococcus aureus, and most streptococci, Enterobacteriaceae, and anaerobes, but unlike the other carbapenems has limited activity against Pseudomonas aeruginosa, Acinetobacter spp., and enterococci, which are more prevalent in nosocomial infections, especially those acquired in an intensive care unit.4., 5.

In a large, double-blind clinical trial comparing ertapenem 1 g once a day (plus three placebo saline infusions each day) with four daily doses of piperacillin-tazobactam 3.375 g for treatment of complicated skin/skin structure infections, the overall cure rates were equivalent between the two agents.⁶ Given the widespread use of OPAT for management of skin/skin structure infections in the United States, allowance of OPAT was an important feature of this study, especially because oral therapy was not permitted in the study design. The purpose of the current analysis was two-fold: (1) examine the demographic and disease characteristics of patients who did or did not receive study therapy as an outpatient, and (2) compare the efficacy, safety and tolerability of ertapenem vs. piperacillin-tazobactam for treatment of skin/skin structure infection in patients who received outpatient antimicrobial therapy.

Section snippets

Study design

A prospective, double-blind (with sponsor blinding), multicenter study was conducted at sites in the United States and Latin America from April 1998 through November 1999, in accord with guidelines published by the Infectious Disease Society of America.⁷ Written informed consent was obtained from all patients, and the institutional review board at each participating site approved the protocol and consent form. Patients were randomized to ertapenem or piperacillin-tazobactam in a 1:1 ratio using

Results

The distribution of patients is shown in Fig. 1. Of the 363 treated patients in the United States, 146 (40%) at 19 (66%) of the 29 sites received some portion of their study therapy as an outpatient. Investigators at 10 sites enrolled from 1 to 44 patients but did not manage any with OPAT. Baseline demographic and disease characteristics of treated patients who did or did not receive OPAT were generally similar, with the following exceptions. The proportions of Hispanic patients (5 of 146 (3%)

Discussion

OPAT was commonly prescribed by US investigators in this study, despite the inherent difficulties of the double-blind design of the trial, which required infusions of study drug every 6 h. This likely reflects the current trend for OPAT use in the United States. OPAT has become a particularly important modality in the management of skin/skin structure infections, where patients with serious infections are commonly managed with parenteral therapy at home or in the outpatient clinic. Reportedly,

Acknowledgements

Financial support: funding was provided by Merck and Co., Inc.

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Economic Impact of Oritavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infections in the Emergency Department or Observation Setting: Cost Savings Associated with Avoidable Hospitalizations
2016, Clinical Therapeutics
Citation Excerpt :
Acute bacterial skin and skin structure infections (ABSSSIs) are among the most common infections observed in the emergency department (ED).1,2 Although patients with ABSSSIs have historically received care in the hospital, which often includes multiday regimens of intravenous antibiotics, data suggest that many of these patients can be managed effectively in the outpatient setting.3–5 Because most patients with ABSSSIs present to the ED, clinicians in the ED essentially serve as ”gatekeepers” to hospital admission.
Data indicate that acute bacterial skin and skin structure infection (ABSSSI) patients without major comorbidities can be managed effectively in the outpatient setting. Because most patients with ABSSSIs present to the emergency department, it is essential that clinicians identify candidates for outpatient treatment given the substantially higher costs associated with inpatient care. We examined the potential cost avoidance associated with shifting care from inpatient treatment with vancomycin to outpatient treatment with oritavancin for ABSSSI patients without major complications or comorbidities.
A decision analytic, cost-minimization model was developed to compare costs of inpatient vancomycin versus outpatient oritavancin treatment of ABSSSI patients with few or no comorbidities (Charlson Comorbidity Index score ≤1) and no life-threatening conditions presenting to emergency department. Hospital discharge data from the Premier Research Database was used to determine the costs associated with inpatient vancomycin treatment.
Mean costs for inpatient treatment with vancomycin ranged from $5973 to $9885, depending on Charlson Comorbidity Index score and presence of systemic symptoms. Switching an individual patient from inpatient vancomycin treatment to outpatient oritavancin treatment was estimated to save $1752.46 to $6475.87 per patient, depending on Charlson Comorbidity Index score, presence of systemic symptoms, and use of observation status. Assuming some patients may be admitted to the hospital after treatment with oritavancin, it is estimated that up to 38.12% of patients could be admitted while maintaining budget neutrality.
This cost-minimization model indicates that use of oritavancin in the emergency department or observation setting is associated with substantial cost savings compared with inpatient treatment with vancomycin.
Outcomes from global adult outpatient parenteral antimicrobial therapy programmes: A review of the last decade
2014, International Journal of Antimicrobial Agents
Citation Excerpt :
SSTIs are commonly encountered by OPAT services that receive community referrals. This group of conditions has been studied using a variety of study designs over the last decade [11,14,36,47–50]. Whilst outcomes are generally favourable, a marked variation in methodology and outcome reporting hampers direct comparison.
Outpatient parenteral antimicrobial therapy (OPAT) has become a global treatment modality since its advent in 1974. The multicentre outcome registries that were employed at the turn of the century to demonstrate the benefits and challenges in this treatment setting have been discontinued. In the intervening years, trends in clinical, patient satisfaction, programmatic and economic outcomes have been shown in sporadic cohort analyses from around the globe. These outcomes are generally reassuring and compare well with previous registry data. However, meaningful comparison of a range of key outcomes is hampered by a lack of uniformity to outcome reporting. In addition to ‘whole programme’ outcome reports, several studies have detailed real-world outcomes in OPAT pertaining to specific conditions and populations. This work has shown how prospective data collection in the OPAT setting can yield valuable insights into the effectiveness and safety of the management of many conditions, such as osteoarticular infection and endocarditis, in a diverse range of populations and increasingly from different countries. Enhanced and perhaps more uniform outcome surveillance in this fashion now constitutes good practice and will enable the benefits and risks of this treatment modality to be shared both in novel and established OPAT arenas.
Outpatient parenteral antibiotic therapy: Principles and practice
2013, European Journal of Internal Medicine
Citation Excerpt :
How frequently physician review is required is determined by the type and complexity of infection and the competencies within the team. It is recommended as a minimum however that a virtual review or inter-disciplinary meeting takes place weekly to discuss all patients within the OPAT programme and that there is a facility for ad hoc physician and other specialist review [20]. The majority of patients managed through OPAT are selected to successfully complete therapy and therefore treatment failure should be observed less frequently than in patients treated exclusively in hospital.
Outpatient parenteral antimicrobial therapy (OPAT) refers to the administration of a parenteral antimicrobial in a non inpatient or ambulatory setting with the explicit aim of facilitating admission avoidance or early discharge. Whilst OPAT has predominantly been the domain of the infection specialist, the internal medicine specialist has a key role in service development and delivery as a component of broader ambulatory care initiatives such as “hospital at home”. Main drivers for OPAT are patient welfare, reduction of risk of health care associated infection and cost-effective use of hospital resources. The safe practice of OPAT is dependent on a team approach with careful patient selection and antimicrobial management with programmed and adaptable clinical monitoring and assessment of outcome. Gram-positive infections, including cellulitis, bone and joint infection, bacteraemia and endocarditis are key infections potentially amenable to OPAT whilst resistant Gram-negative infections are of increasing importance. Ceftriaxone, teicoplanin, daptomycin and ertapenem lend themselves well to OPAT due to daily (or less frequent) bolus administration, although any antimicrobial may be administered if the patient is trained to administer and/or an appropriate infusion device is employed. Clinical experience from NHS Greater Glasgow and Clyde is presented to illustrate the key principles of OPAT as practised in the UK. Increasingly complex patients with multiple medical needs, the relative scarcity of inpatient resources and the broader challenge of ambulatory care and “hospital at home” will ensure the internal medicine specialist will have a key role in the future development of OPAT.
Outpatient parenteral antimicrobial therapy (OPAT) in a teaching hospital-based practice: A retrospective cohort study describing experience and evolution over 10 years
2012, International Journal of Antimicrobial Agents
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OPAT practice is mainly supported by this published experience as well as national guidance [12]. The formal evidence base is limited to two randomised controlled trials (RCTs) (both in soft tissue infection) [13,14], a Cochrane review of home care [15] and subset analyses of RCTs where participants have received OPAT [16,17]. The main drivers for OPAT service development are patient welfare, reduction of risk of healthcare-associated infections, and cost-effective use of hospital resources.
Use of outpatient parenteral antimicrobial therapy (OPAT) is increasing in settings with advanced healthcare systems internationally. This study describes a large OPAT service cohort developed in the west of Scotland and includes trends over a 10-year period of this service. Data were retrieved from a prospectively maintained electronic case database. Patient and logistic variables were collated for all OPAT episodes (n = 2638, resulting in 39 035 days of patient care over 10 years). Skin and soft-tissue infections and bone and joint infections accounted for 77% of OPAT cases, but a wide range of other conditions have been treated in this cohort. Outcome variables were evaluated for all first OPAT attendances (n = 2233), amongst which a successful outcome (cure or improvement) was found for 2063 (92.4%). Unplanned admission was observed in 9.1% of patients (6.3 events per 1000 OPAT patient days). Healthcare-associated infection rates were low: amongst first OPAT attendances, 14 intravenous line infections were observed (0.4 per 1000 OPAT patient days). Statistically significant trends over time included: a decrease in OPAT treatment time; increased referrals from non-local and secondary care sources; increased rate of co-morbidity of OPAT referrals; and increased self/carer administration of antimicrobials. Outcome proportions (success and adverse events) did not vary over time. This cohort study adds to the increasing observational data suggesting that OPAT is safe, effective and acceptable for treating a wide variety of infections. Observed trends over a 10-year period suggest that this model of infection management is adaptable and sustainable.
The Appropriate Use of Antibiotics in Surgery: A Review of Surgical Infections
2007, Current Problems in Surgery
Domiciliary parenteral antibiotic therapy
2006, Seminarios de la Fundacion Espanola de Reumatologia
Habitualmente, los tratamientos antibióticos intravenosos han sido procedimientos que se han llevado a cabo en el hospital; esta tendencia ha ido cambiando a partir de que Rucker, en 1994, describiera el tratamiento de infecciones respiratorias, en niños con fibrosis quística, fuera del hospital. En nuestro país, fue Antelo el primero en describir estos tratamientos, también en infecciones respiratorias.
El continuo crecimiento de los tratamientos antibióticos parenterales ambulatorios (TAPA) se ha debido a varios factores, entre ellos su probada eficacia, seguridad, ahorro de costes y preferencias de los pacientes.
En la actualidad, con un equipo sanitario preparado, una buena selección del paciente y modelo de tratamiento y un adecuado seguimiento es posible utilizar los TAPA en un gran número de infecciones. Con ello, los TAPA son una opción terapéutica que evita días de hospitalización y mejora la calidad de vida del paciente con un menor coste económico.
Intravenous antibiotic therapy was developed in hospital and was considered a hospital procedure until 1974, when the outpatient treatment of respiratory infections in children with cystic fibrosis was reported. In our country, Antelo was who did it in respiratory infections too.
The continuous growth of outpatient parenteral antimicrobial therapy (OPAT) has been largely attributable to several factors: it has proved effective, safe, cost saving and patients prefer it.
Nowadays, with an accurate health care team, patient and model of delivery selection and monitoring, the list of diseases amenable to OPAT is long. Thus, OPAT is seen as a potential treatment option to avoid hospitalisation, improves quality-of-life with less economic cost.

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^☆: These data were presented in part at the 40th Annual Meeting of the Infectious Diseases Society of America, Chicago, October 2002.

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Evaluation of outpatient treatment with ertapenem in a double blind controlled clinical trial of complicated skin/skin structure infections☆

Abstract

Introduction

Section snippets

Study design

Results

Discussion

Acknowledgements

Clin Microbiol Infect Dis

Home infusion therapy industry: an overview

Ambulatory antimicrobial use: the value of an outcomes registry

J Antimicrob Chemother

In vitro activities of ertapenem (MK-0826) against clinical bacterial isolates from 11 North American medical centers

Antimicrob Agents Chemother

In vitro activities of ertapenem (MK-0826) against recent clinical bacteria collected in Europe and Australia

Antimicrob Agents Chemother

Ertapenem once daily vs. piperacillin-tazobactam 4 times per day for treatment of complicated skin and skin-structure infections in adults: results of a prospective, randomized, double-blind multicenter study

Clin Infect Dis

General guidelines for the clinical evaluation of anti-infective drug products

Clin Infect Dis