Cost-minimization analysis and audit of antibiotic management of bone and joint infections with ambulatory teicoplanin, in-patient care or outpatient oral linezolid therapy

Dilip Nathwani1,*, Gavin D. Barlow1, Katherine Ajdukiewicz1, Kirsteen Gray2, John Morrison1, Ben Clift3, Anthony J. France1 and Peter Davey1

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


    Abstract
 Top
 Abstract
 Introduction
 Results
 Discussion
 References
 
Bone and joint infections are significant causes of morbidity, mortality and healthcare costs. The cost of treatment for such infections is driven primarily by the length of hospital stay. Many of these infections will require treatment with prolonged periods of parenteral antibiotic therapy. Clinicians and healthcare managers are being attracted increasingly by administering treatment in the ambulatory setting as this offers clinical, economic and quality of life advantages from both the hospital’s and patient’s perspective. Our retrospective audit of managing 55 treatment episodes of bone and joint infections with teicoplanin delivered in the outpatient or home setting revealed that the mean cost of care per episode of infection was less with treatment in the ambulatory setting (£1749.15) compared with the in-patient setting (£11 400) or compared with the hypothetical situation of treatment with oral linezolid in the home setting (£2546). Teicoplanin therapeutic drug monitoring appears to be valuable in establishing optimal serum levels, which appear to correlate with good clinical outcomes. The potential for alternative day or thrice weekly dosing with teicoplanin may offer further cost advantages whilst maintaining equivalent clinical effectiveness.

Keywords: teicoplanin, linezolid, bone and joint infection, therapeutic drug monitoring, cost minimization


    Introduction
 Top
 Abstract
 Introduction
 Results
 Discussion
 References
 
Osteomyelitis, primary septic arthritis and prosthetic joint infection (PJI) are significant causes of morbidity, mortality and fiscal costs.1,2 The cost of PJI in the USA, for example, is in excess of $50 000 per managed case.3 A combination of surgical and antimicrobial therapy is the mainstay of current management. The specific aim of antibiotic therapy is to penetrate bone and surrounding tissues and kill bacteria. For acute osteomyelitis and primary septic arthritis, with or without adjunctive surgery, treatment is often curative. In contrast, for chronic osteomyelitis and PJI, antibiotics are administered to either ‘sterilize’ the surgical site prior to operation or suppress infective exacerbations in conservatively managed patients.

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.


    Results
 Top
 Abstract
 Introduction
 Results
 Discussion
 References
 
Since April 1998, data have been recorded for all patients managed by our OHPAT service as part of an ongoing clinical research and quality assurance programme.23 Using a standardized data collection sheet to record patient-specific information from the above registry and the hospital’s laboratories results database, basic demographic, clinical, microbiological and pharmacological data were ascertained for each recorded bone or joint infection episode. We also collected length of in-patient hospital stay and time on OHPAT. The mean duration of treatment data presented here is only that spent in the home or outpatient setting. Indeed, a small number of patients were never hospitalized. In the cost-minimization analysis we have compared with this the hypothetical time that may have been spent as an in-patient or at home with oral linezolid. The clinical microbiology and management data are presented in Table 1; 71% of culture positive patients had an MRSA/MRSE infection sensitive to glycopeptides.


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Table 1. Clinical management of 55 episodes of bone or joint infection with teicoplanin delivered through an OHPAT programme
 
We identified 55 treatment episodes in 50 patients treated with either teicoplanin monotherapy or teicoplanin in combination with oral rifampicin. Four of these episodes were septic arthritis and the remainder were osteomyelitis (three acute and 48 chronic). Forty per cent of patients with chronic osteomyelitis had a prosthetic joint infection. All patients received intravenous loading doses of teicoplanin (6 mg/kg/12 h for three doses) followed by a maintenance regimen of 6 mg/kg/day. Three patients were managed with an alternate day regimen. Teicoplanin was administered either by daily visit to a specialist OHPAT nurse (25%) or by self/carer administration (75%), with weekly outpatient visits for monitoring purposes. We have assumed that medical outpatient follow-up would have been similar for all patients regardless of the exact treatment regimen.

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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Table 2. Cost-minimization analysis of bone and joint infections treated with teicoplanin (OHPAT) compared with in-patient care and outpatient oral linezolida
 

    Discussion
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 Abstract
 Introduction
 Results
 Discussion
 References
 
This study clearly shows that parenteral teicoplanin, delivered by a specialist outpatient service, is associated with lower financial costs compared with either ‘traditional’ in-patient care or hypothetical oral linezolid therapy. The cost-minimization analysis is most sensitive to the length of in-patient stay and to the cost of the antimicrobial therapy. The cost of delivering alternate-day or thrice-weekly teicoplanin through the ambulatory service would also further reduce total costs. Although outpatient oral linezolid therapy has notably lower costs than in-patient care, it is more expensive than once-daily ambulatory teicoplanin. We estimate that a 32% reduction in the acquistion cost of linezolid, from £67 to £46 per day, would be required to achieve cost-equivalence. We have assumed that medical outpatient follow-up, including haematological and biochemical monitoring, would have been the same for both ambulatory groups. Indeed, the emerging experience of adverse events with long-term linezolid treatment does suggest the need to observe for thrombocytopenia by regular weekly full blood count monitoring.26,27 This is essential in PJIs, which require protracted periods of antibiotic therapy. The analysis does not account for differing patient travel costs, indirect costs (e.g. the number of work days lost) and intangible costs (e.g. the inconvenience to the patient). Nevertheless, it is unlikely that any differences for these costs would outweigh the financial cost differential between ambulatory teicoplanin and outpatient linezolid therapy. In addition, we have previously shown that management by our OHPAT service is associated with high patient satisfaction28 and good clinical outcomes.23

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 intravenous–oral 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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Scheme 1a. Protocol for once daily teicoplanin treatment of joint/skin/soft tissue infection

 


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Scheme 1b. Protocol for three times a week teicoplanin Treatment of joint/skin/soft tissue infection

 
In the absence of a definitive evidence-based antimicrobial strategy for managing bone and joint infections, we have assumed each regimen to be equally clinically effective. We have not taken into account the undoubted significant impact of other interventions, such as surgical drainage or debridement, on the outcome of these complex infections. Prolonged in-patient care for parenteral antibiotic administration, however, would seem undesirable for clinical, fiscal and quality of life reasons. We have shown that teicoplanin therapy delivered by an established OPHAT service has clear cost advantages over both ‘traditional’ in-patient care and outpatient oral linezolid therapy. The safety, cost-effectiveness and patient-acceptability of this approach are now well established.15,16,27 Undoubtedly, oral linezolid is an attractive and overdue therapeutic option. There is currently a lack of high-quality data, however, about its safety and clinical efficacy for bone and joint infections. An appropriately powered randomized controlled trial could, potentially, answer these important outstanding questions. Until these data are available we would recommend that more established cost-effective therapies, such as teicoplanin delivered through OHPAT, should continue to be used, and urge caution and close monitoring if linezolid is to be used for prolonged periods.30


    Footnotes
 
* Corresponding author. Tel: +44-1382-660111; Fax: +44-1382-496547; E-mail: dilip.nathwani{at}tuht.scot.nhs.uk Back


    References
 Top
 Abstract
 Introduction
 Results
 Discussion
 References
 
1 . Lew, D. P. & Waldvogel, F. A. (1997). Osteomyelitis. New England Journal of Medicine 336, 999–1007.[Free Full Text]

2 . Virk, A. & Osman, D. R. (2001). Prosthetic joint infection. Current Treatment Options in Infectious Diseases 3, 287–300.

3 . Sculco, T. P. (1993). The economic impact of infected total joint arthroplasty. Instructional Course Lectures 42, 349–51.[Medline]

4 . Waldvogel, F. A., Medoff, G. & Swartz, M. (1970). Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects (part 1). New England Journal of Medicine 282, 198–206.[ISI][Medline]

5 . Waldvogel, F. A., Medoff, G. & Swartz, M. N. (1970). Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects (part 2). New England Journal of Medicine 282, 260–6.[ISI][Medline]

6 . Waldvogel, F. A., Medoff, G. & Swartz, M. N. (1970). Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects (part 3). New England Journal of Medicine 282, 316–22.[ISI][Medline]

7 . Dich, V. Q., Nelson, J. D. & Haltalin, K. C. (1975) Osteomyelitis in infants and children. American Journal of Diseases of Children 129, 1273–8.[Abstract]

8 . Bamberger, D. M., Daus, G. P. & Gerding ,D. N. (1987). Osteomyelitis in the feet of diabetic patients. Long-term results, prognostic factors, and the role of antimicrobial and surgical therapy. American Journal of Medicine 83, 653–60.[ISI][Medline]

9 . Stengel, D., Bauwens, K., Sehouli, J., Ekkernkamp, A. & Porzsolt, F. (2001). Systematic review and meta-analysis of antibiotic therapy of bone and joint infections. Lancet Infectious Diseases 1, 175.[Medline]

10 . Inman, R. D., Gallegos, K. V., Brause, B. D., Redecha, P. B. & Christian, C. L. (1984). Clinical and microbial features of prosthetic joint infection. American Journal of Medicine 77, 47–53.

11 . Tice, A. (2001). The use of outpatient parenteral antimicrobial therapy in the management of osteomyelitis: data from the outpatient parenteral antimicrobial therapy outcomes registries. Chemotherapy 47, Suppl., 5–16.[CrossRef][ISI][Medline]

12 . Norden, C. W., Bryant, R., Palmer, D., Montgomerie, J. Z. & Wheat, J. (1986). Chronic osteomyelitis caused by Staphylococcus aureus: controlled clinical trial of nafcillin therapy and nafcillin–rifampin therapy. Southern Medical Journal 79, 947–51.[ISI][Medline]

13 . Zimmerli, W., Widmer, A. F., Blatter, M., Frei, R. & Oshsner, P. E. (1998). Role of rifampicin for implant related staphylococcal infections. Journal of the American Association 279, 1537–41.[CrossRef]

14 . Tice, A. D. (2000). Outpatient parenteral antibiotic therapy (OPAT) in the United States: delivery models and indications for use. Canadian Journal of Infectious Disease 1, Suppl. A, 17–21.

15 . Wilson, A. P. R. & Gruneberg, R. N. (1994). Use of teicoplanin in community medicine. European Journal of Clinical Microbiology and Infectious Disease 13, 701–10.

16 . Nathwani, D. (1998). Non-inpatient use of teicoplanin. International Journal of Clinical Practice 52, 577–81.[ISI][Medline]

17 . Graninger, W., Presterl, E., Wenisch, C., Schwameis, E., Breyer, S. & Vukovich, T. (1997). Management of serious staphylococcal infections in the outpatient setting. Drugs 54, Suppl. 6, 21–8.[ISI][Medline]

18 . Spencer, C. M. & Bryson, H. M. (1995). Teicoplanin: a pharmacoeconomic evaluation of its use in the treatment of Gram-positive infections. Pharmacoeconomics 7, 275–374.[ISI][Medline]

19 . Davey, P. G., South, R. & Malek, M. (1996). Impact of glycopeptide therapy after hospital discharge on inpatient costs: a comparision of teicoplanin and vancomycin. Journal of Antimicrobial Chemotherapy 37, 623–34.[Abstract]

20 . Clemett, D. & Markham, A. (2000). Linezolid. Drugs 59, 815–27.[ISI][Medline]

21 . Rana, B., Butcher, I., Grigoris, P., Murnaghan, C., Seaton, R. A. & Tobin, C. M. (2002). Linezolid penetration into osteo-articular tissues. Journal of Antimicrobial Chemotherapy 50, 747–50.[Abstract/Free Full Text]

22 . Bassetti, M., Biagio, A. D., Cenderello, G., Del Bono, V., Palermo, A., Cruciani, M. et al. (2001). Linezolid treatment of prosthetic hip infections due to methicillin-resistant Staphylococcus aureus (MRSA). Journal of Infection 43, 148–57.[CrossRef][ISI][Medline]

23 . Nathwani, D. & Tice, A. D. (2002). Ambulatory antimicrobial use: the value of an outcomes registry. Journal of Antimicrobial Chemotherapy 49, 149–54.[Abstract/Free Full Text]

24 . Harding, I., McGowan, A. P., White, L. O., Darley, E. S. & Reed, V. (2000). Teicoplanin therapy for Staphylococcus aureus septicaemia: relationship between pre-dose serum concentration and outcome. Journal of Antimicrobial Chemotherapy 45, 835–41.

25 . Darley, E. S. R. (2001). The clinical value of teicoplanin therapeutic drug monitoring. CPD Infection 2, 93–7.

26 . Green, S. L., Maddox, J. C. & Huttenbach, E. D. (2001). Linezolid and reversible myelosuppression. Journal of the American Association 285, 1291.[CrossRef]

27 . Attassi, K., Hershberger, E., Alam, R. & Zervos, M. J. (2002). Thrombocytopenia associated with linezolid therapy. Clinical Infectious Diseases 34, 695–8.[CrossRef][ISI][Medline]

28 . Nathwani, D., Morrison, J., Seaton, R. A., France, A. J., Davey, P. & Gray, K. (1999). Outpatient and home parenteral antibiotic therapy (OHPAT): evaluation of the impact of one year’s experience in Tayside. Health Bulletin 57, 332–7.[Medline]

29 . Wilson, A. P. R. (2000). Clinical pharmacokinetics of teicoplanin. Clinical Pharmacokinetics 39, 167–83.[ISI][Medline]

30 . Zyvox (linezolid) [package insert]. (2002). Pharmacia and Upjohn Company, Kalamazoo, MI, USA.