1 Infection and Immunodeficiency Unit, Ward 42, East Block, 2 Pharmacy and 3 Orthopaedic Infection Unit, Ninewells Hospital and Medical School, Tayside University Hospitals NHS Trust (TUHT), Dundee, UK
Received 4 July 2002; returned 11 September 2002; revised 19 October 2002; accepted 27 October 2002
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Abstract |
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Keywords: teicoplanin, linezolid, bone and joint infection, therapeutic drug monitoring, cost minimization
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Introduction |
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The current standard of care, i.e. 4 weeks of high-dose intravenous therapy, is based on Waldvogel et al.s excellent series of articles.46 Although studies of children and diabetic adults have suggested a role for oral treatment,7,8 for many experts, parenteral therapy remains the standard of care. A recent systematic review of antibiotic therapy for bone and joint infections failed to recommend a preferred antimicrobial regimen based on the available evidence.9 In clinical practice, therefore, ß-lactams, flucloxacillin or clindamycin are generally used for methicillin-sensitive staphylococcal and streptococcal infections, whilst the glycopeptides are the antimicrobials of choice for methicillin-resistant staphylococci, a particular problem in PJI.10,11 To maximize tissue penetration and prevent the development of antimicrobial resistance, many clinicians use adjunctive oral rifampicin or fusidic acid therapy.12,13
Until relatively recently, bone and joint infections were common reasons for prolonged hospitalization to receive intravenous antibiotic therapy.14 The healthcare costs and patient inconvenience associated with this, however, have decreased for hospitals investing in the development of an outpatient and home parenteral antimicrobial therapy (OHPAT) programme, thus permitting the cost-effective management of large numbers of patients in the ambulatory environment. As many of these infections are either empirically managed or due to resistant species, glycopeptides are usually preferred. Although not available in the USA, teicoplanin is particularly attractive for the OHPAT setting, offering once-daily intravenous administration by bolus injection, minimal toxicity, infrequent therapeutic drug monitoring (TDM)15 and proven clinical efficacy.16 The intramuscular route provides an effective and alternative option but is not widely used. Furthermore, a number of centres have recently reported success with reduced frequency (alternate day or thrice weekly) teicoplanin regimens,17 which are likely to offer clinicians improved cost-effectiveness.18,19
The last 24 months has seen the advent of linezolid, the first oxazolidinone antibiotic, which has broad-spectrum activity against Gram-positive bacteria, including methicillin-sensitive and -resistant staphylococci.20 Its potential for use in bone and joint infections is theoretically high by virtue of the convenient twice-daily oral regimen, high (100%) bioavailability and excellent penetration into diseased tissues.21 In addition, there are early reports of clinical success in documented infections unresponsive to glycopeptides.22 The results of ongoing studies to assess the clinical effectiveness and long-term safety of linezolid in bone and joint infection, particularly with reference to myelo-suppression, are awaited with interest.
As oral therapy taken at home may potentially offer patients, hospital managers and clinicians cost advantages, we performed a cost-minimization analysis of patients treated with teicoplanin by an established OHPAT service, compared with traditional in-patient care and hypothetical outpatient oral linezolid therapy. In addition, as a secondary remit we audited our antibiotic management of these complex groups of patients with particular emphasis on the need for TDM of teicoplanin levels and with a view to producing a subsequent antibiotic management protocol that would be subject to further audit. We did not aim to evaluate the clinical impact of specific interventions in the management of these infections. Therefore, we are unable to provide information about the frequency of procedures such as surgical drainage or prosthesis and implant removal. We accept the importance of these interventions in relation to outcome but this is well beyond the remit of our study.
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Results |
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In the early period of our OHPAT programme, few patients underwent teicoplanin TDM. As our experience evolved and evidence became available, however, TDM was increasingly used with the aim of achieving a trough level 10 mg/L for bone and joint infections.24,25 All these patients had a trough level of >10 mg/L on at least one occasion. Although a mean of two assays per patient was calculated, wide inter-patient variation in the use of TDM (only 60% of patients had levels performed; see Table 1) and subsequent alteration of the maintenance regimen was evident. Our early programme experiences described above and the length of treatment did not always account for this suboptimal practice.
The costs of teicoplanin administration (including associated consumables), a specialist OHPAT nurse and in-patient care were obtained from reliable sources within NHS Tayside; Scottish Health Services Costs, Information and Statistics Division, NHS Scotland (see www.show.scot.nhs/isd); the British National Formulary (BNF); and previous publications.19 The actual time associated with PIC line insertion was not costed, but we estimate this to take our nurse practitioner 40 min at an approximate cost of £10. We have not included this in our analysis. The intangible cost to the patients in terms of inconvenience and discomfort in our experience is thought to be low and not worthy of consideration here (J. Morrison, personal communication). The cost of linezolid used in this paper is the UK hospital price, whereas a higher price of £445 for 10 tablets is quoted in the British National Formulary (community price). Linezolid in the UK is primarily prescribed by hospital pharmacies. For the purpose of the cost-minimization analysis (see Table 2), we did not correct for the three patients who received an alternate-day teicoplanin regimen, but assumed that all patients received once-daily therapy.
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Discussion |
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The value of TDM for teicoplanin has recently been reviewed.25 For patients with bacteraemia or osteomyelitis, there is clear evidence24 of a relationship between trough serum concentrations of 10 mg/L and favourable clinical outcome.17,24 Furthermore, tailoring the teicoplanin regimen according to serum concentrations may be a more cost-effective strategy compared with fixed dosing.29 Our own experience, and that of others, has revealed significant inter-individual variation in trough teicoplanin concentration25 and has highlighted the opportunity to maintain satisfactory levels with less frequent dosing. Alternate-day or thrice-weekly regimens, therefore, are likely to be used increasingly in the future17 and may lead to additional cost savings. Indeed, using this more targeted approach resulted in an estimated saving of £170 000 per annum in one study.25
Although the primary aim of this study was not to evaluate teicoplanin TDM, the analysis of our experience has revealed that we have consistently used loading doses (6 mg/kg/12 h for three doses) and have managed to achieve a serum trough concentration of at least 10 mg/L, on at least one occasion in all patients who had levels performed. Our mean duration of therapy was 38 days, which is in keeping with current management recommendations.46 Although all patients were deemed to be clinically improved or cured at the time of outpatient discharge (follow-up microbiological data were not available for most patients), we appear to be inconsistent regarding the use of adjunctive rifampicin (10%) and in the use of intravenousoral switch therapy (5%). In addition, we performed teicoplanin levels on a mean of two occasions, but often in situations where a level of 10 mg/L had already been established. The reasons for this are likely to be multifactorial and may reflect: repeated monitoring, albeit unnecessarily, to ensure adequate serum concentration; uncertainty about the exact role of teicoplanin TDM and our evolving experience with use of this regimen in real life practice; concerns about adherence in self-administering patients; or a rising serum creatinine level.
To date we have not had an OHPAT protocol for the use of teicoplanin in bone and joint infections. This evaluation stimulated a recent multidisciplinary audit meeting during which a protocol for future OHPAT teicoplanin use was developed (see Scheme 1A and 1B). This formalizes our once-daily regimen (Scheme 1A) and also thrice-weekly regimen (Scheme 1B), which is proving very attractive and valuable in older, less ambulant patients with chronic bone infection. Since its introduction 2 months ago our experience in all five patients (at the time of completing this paper) has been to obtain optimal levels with this regimen (D. Nathwani, personal observation). The protocol was based on the presented analysis, pertinent published literature17,24,25,29 and our current and previous teicoplanin experience. The new protocol will be subjected to a continuing audit and quality assurance programme and, when necessary, amended according to new published evidence and our ongoing experiences. We would value hearing from and sharing experience with others who have embarked upon similar or even alternative regimens.
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Footnotes |
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References |
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