Emergence of Staphylococcus aureus (MRSA) with reduced susceptibility to teicoplanin during therapy

Michael Weinbren* and Keith Struthers

Public Health Laboratory, Coventry and Warwickshire Hospital, Stoney Stanton Road, Coventry CV1 4FH, UK

Sir,

We read with interest the letters from Hassan et al.1 and Elsaghier et al.2 describing the emergence of resistance to teicoplanin in four patients infected with methicillin-resistant Staphylococcus aureus. In two cases, infection arose following spinal surgery and required prolonged glycopeptide therapy for presumed deep-seated sepsis, with bone being a likely focus. Line-related bacteraemia was the initial focus of infection in the other two cases, with one patient going on to develop multiple splenic abscesses and the other endocarditis. Resistance was postulated to have arisen in all four cases during teicoplanin therapy, where a maintenance dose 400 mg daily was used (the dose was changed to 600 mg/day in one patient after >12 days of treatment and the MIC of the isolate was 16 mg/L by that time).

Hassan et al.1 cite a case report where a low dose of 200 mg daily was thought to have contributed to the development of resistance.3 This raises the question of what is the correct dose of teicoplanin? When it was first marketed, 200 mg/day was recommended, but this was changed to 6 mg/kg/day for serious infections, with 400 mg being the dose for the ‘average patient’. The trial data supporting the latter recommendation were highly variable, with some studies showing no demonstrable difference, whereas in others, the low-dose arm was terminated before statistical significance was reached. However, retrospective analysis of data for soft tissue infections showed that 3 mg/kg was significantly less effective as judged by cure or improvement. Further modifications to dosage are recommended, for example in septic arthritis (12 mg/kg/day), staphylococcal endocarditis (trough level >20 mg/L) and infections in drug addicts and some burn patients (the latter due to the rapid excretion of drug).

If a mere doubling of dose has a significant impact on outcome, does this not suggest that antibiotic levels are precarious/borderline, and that perhaps there may be a subset of patients who would benefit from even higher dosage? In addition, other factors, for example individual drug handling and MIC for an organism, could have a more profound effect than doubling of the dose. In a large study of bone infections reported by Le Frock et al.,4 the MIC of teicoplanin for 44 out of 45 S. aureus isolates was <0.4 mg/L (these authors found a 400 mg dose to be effective). In contrast, the MICs for the isolates described in the two letters were between 1 and 4 mg/L, up to a 10-fold difference.

Teicoplanin dosage has been reviewed for a variety of clinical conditions. In osteomyelitis it was concluded that no evidence exists for a beneficial effect with a dosage >6 mg/kg.5 However, in a systematic review and meta-analysis of antibiotic therapy for bone and joint infections (teicoplanin was not included), the authors concluded that: ‘There exists little high-quality evidence on antibiotic therapy for osteomyelitis and septic arthritis. The observed heterogeneity among patient populations and medical and surgical treatment concepts preclude reliable inferences from the available data.’6 Guidance should be evidence based, but can the resolving powers of studies be sufficient to ensure adequate dosage for every patient?

Laboratory resistance to teicoplanin can be selected by repeated passage in sub-MIC levels. In vivo subtherapeutic levels of antibiotic may occur when infection occurs at sites where antibiotic penetration is suboptimal (e.g. poorly vascularized areas of bone), but equally could result from inadequate dosing or a combination of both. No data were provided either on renal function, body weight or initial drug levels in the four cases described.

It is known that the standard dose of teicoplanin often produces serum trough levels of <10 mg/L.7 In a study of ‘primary S. aureus septicaemia’, successful treatment correlated with pre-dose serum concentrations, and a trough level of >10 mg/L was suggested.7 The authors could not rule out a beneficial effect from higher levels.

These case reports have raised a number of important issues, first, of dosage, and secondly, its relationship to the emergence of resistance during teicoplanin therapy. With regard to the former, despite the above evidence, the dosage recommendation in the data sheet for the therapy of S. aureus septicaemia remains inadequate. On theoretical grounds, dosage may also be insufficient for the therapy of osteomyelitis. Would it therefore not be prudent to give higher doses of teicoplanin in severe infections, including deep-seated sepsis (together with early surgical intervention where appropriate), particularly with organisms for which the MIC is close to the breakpoint. This might be combined with setting a target trough level, such as 20 mg/L.

With regard to the emergence of resistance and dosage, no conclusion should be drawn. Given the uncertainty over the teicoplanin regimens used, one cannot rule out the possibility that appropriate levels might have prevented the emergence of resistance.

MacGowan & Wise8 have suggested that the emergence of resistance in organisms close to the breakpoint needs to be taken into account when setting future MIC breakpoints. An alternative to adjusting the breakpoint would be to increase the dose of antibiotic, where this may be done safely.

Footnotes

* Corresponding author. Tel: +44-24-76844124; Fax: +44-24-76-220081; E-mail: michael.weinbren{at}wh-tr.wmids.nhs.uk Back

References

1 . Hassan, I. A., Chadwick, P. R. & Johnson, A. P. (2001). Clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to teicoplanin in Northwest England. Journal of Antimicrobial Chemotherapy 48, 454–5.[Free Full Text]

2 . Elsaghier, A. A., Aucken, H. M., Hamilton-Miller, J. M., Shaw, S. & Kibbler, C. C. (2002). Resistance to teicoplanin developing during treatment of methicillin-resistant Staphylococcus aureus infection. Journal of Antimicrobial Chemotherapy 49, 423–30.[Free Full Text]

3 . Fitch, L. & Johnson, A. P. (1998). Reduced susceptibility to teicoplanin in a methicillin-resistant strain of Staphylococcus aureus. Journal of Antimicrobial Chemotherapy 41, 578.[Free Full Text]

4 . Le Frock, J. L., Ristuccia, A. M., Ristuccia, P. A., Quenzer, R. W., Haggerty, P. G., Allen, J. E. et al. (1992). Teicoplanin in the treatment of bone and joint infections. European Journal of Surgery S567, 9–13.

5 . Wilson, A. P. R., Grüneberg, R. N. & Neu, H. (1993). Dosage recommendations for teicoplanin. Journal of Antimicrobial Chemotherapy 32, 792–6.[ISI][Medline]

6 . Stengel, D., Bauwens, J., Ekkernkamp, A. & Porzsolt, F. (2001). Systematic review and meta-analysis of antibiotic therapy for bone and joint infections. Lancet Infectious Diseases 1, 175–88.[Medline]

7 . Harding, I., MacGowan, A. P., White L. O., Darley, E. S. R. & Reed, V. (2000). Teicoplanin therapy for Staphylococcus aureus septicaemia: relationship between pre-dose serum concentrations and outcome. Journal of Antimicrobial Chemotherapy 45, 835–41.[Abstract/Free Full Text]

8 . MacGowan, A. P. & Wise, R. (2001). Establishing the interpretation of in vitro susceptibility tests. Journal of Antimicrobial Chemotherapy 48, Suppl. S1, 17–28.[Abstract/Free Full Text]