In vivo synergy of daptomycin plus a penicillin agent for MRSA?

Marc Scheetz1,*, Pavani Reddy2, Michael Postelnick1 and John Flaherty2

1 Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL; 2 Division of Infectious Diseases, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA


* Corresponding author. Tel: +1-312-926-2546; Fax: +1-312-926-7956; Email: mscheetz{at}nmh.org

Keywords: methicillin-resistant Staphylococcus aureus , therapy , lipopeptide

Sir,

We describe a refractory case of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia treated with daptomycin plus a penicillin agent. A 64-year-old male with a history of end-stage renal disease on haemodialysis, diabetes and right leg osteomyelitis status post below the knee amputation presented to the emergency room with fevers of 2 days duration. On admission, his temperature was 38.5°C. Examination revealed a clean, dry right subclavian vascular catheter, a grade III/VI holosystolic murmur and a 6 cm grade II ulcer at the healed site of the right lower extremity amputation. His WBC count was 17 400 cells/mm3.

The patient was started on empirical intravenous vancomycin and piperacillin/tazobactam. Blood cultures from admission later yielded MRSA.

Over the next 6 days, blood cultures continued to grow MRSA. The patient's dialysis catheter was removed on day 6 and the tip grew > 1000 cfu of MRSA. However, despite continued vancomycin use, blood cultures were persistently positive. On hospital day 9, intravenous gentamicin was added; rifampicin therapy was initiated on day 12.

On day 14, the patient's blood cultures were negative for growth for the first time since admission. Blood cultures remained negative on days 16, 17 and 18 while on vancomycin, gentamicin and rifampicin, but once again grew MRSA on day 19.

When cultures remained positive on day 20, the three-drug antibiotic regimen was discontinued and daptomycin 400 mg (~4 mg/kg) intravenous (iv) every 48 h and oxacillin 1.0 g iv every 4 h was initiated. On day 22, the patient had respiratory distress and presumed aspiration pneumonia; as a result, piperacillin/tazobactam was substituted for oxacillin.

Daily blood cultures grew MRSA on days 23, 25 and 27. However, on day 28, or day 9 of combined daptomycin and penicillin agents, MRSA bacteraemia ceased. Kirby-Bauer disc diffusion showed the isolate to be susceptible to daptomycin, and blood cultures then remained negative until discharge (day 50).

Historically, it has been more difficult to eradicate MRSA compared with methicillin-susceptible S. aureus (MSSA) bloodstream infections, and vancomycin is clearly less efficacious than oxacillin in the treatment of MSSA.1 Traditional treatment options for MRSA include vancomycin plus or minus other antibiotics for synergy. In patients with persistently positive cultures for MRSA, either gentamicin or rifampicin may be added in an attempt to improve outcomes.1 The recent availability of quinupristin/dalfopristin, daptomycin and linezolid has expanded our treatment options for MRSA infection. However, the role of these newer agents remains undefined, and there is a need to classify better the efficacy of these new agents individually as well as in combination with traditional therapy. The course of therapy is particularly unclear when microbiological tests identify an MRSA patient with reduced susceptibility to vancomycin, and the patient fails to eradicate the organism.

Linezolid remains an option among previously mentioned therapies secondary to a favourable pharmacokinetic distribution, a low incidence of adverse effects, oral bioavailability and an FDA indication for MRSA; however, linezolid alone has not demonstrated superiority to vancomycin.2 Synergy studies for linezolid have not been fruitful to date, and response to the single agent may represent the best achievable clinical outcomes.3 There is both in vitro and in vivo data to support quinupristin/dalfopristin synergy, but utilization is limited by significant toxicity, administration issues, drug interactions and indifference when combined with most agents other than rifampicin.4 Clinical experience with daptomycin is lacking; however, trials are in progress for the treatment of Gram-positive bacteraemia and endocarditis.5

In vitro data on the activity of daptomycin against MRSA have been interesting. Time–kill curves suggest that daptomycin may have increased bactericidal activity against MRSA as compared with vancomycin, quinupristin/dalfopristin and linezolid.6 A recent article by Rand & Houck7 explored the combination of daptomycin and oxacillin against MRSA in an in vitro model. The investigators found that the combination of daptomycin and oxacillin was synergically bactericidal against MRSA as measured by time–kill studies.7 This report is particularly intriguing as phenotypic resistance to oxacillin was documented, and each agent was given at subtherapeutic concentrations. It was hypothesized that peptidoglycan precursors may have been minimized or the expression of mecA suppressed by daptomycin.

The outcome in this case may represent either the slow clearance of bacteraemia that would have occurred without the addition of daptomycin, the activity of daptomycin alone, or the in vivo synergy of daptomycin plus a penicillin agent. The apparent failure of traditional therapy dictated our extrapolation of in vitro studies, resulting in the trial of combination therapy. Future trials of patients with MRSA refractory to vancomycin alone will be needed to better define the role of new agents alone or in combination with vancomycin or ß-lactams.

References

1 . Karchmer, A. W. (1991). Staphylococcus aureus and vancomycin: the sequel. Annals of Internal Medicine 115, 739–41.[ISI][Medline]

2 . Stevens, D. L., Herr, D., Lampiris, H. et al. (2002). Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clinical Infectious Diseases 34, 1481–90.[CrossRef][ISI][Medline]

3 . Grohs, P., Kitzis, M. D. & Gutmann, L. (2003). In vitro bactericidal activities of linezolid in combination with vancomycin, gentamicin, ciprofloxacin, fusidic acid, and rifampin against Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 47, 418–20.[Abstract/Free Full Text]

4 . Brown, J. & Freeman, B. B., III (2004). Combining quinupristin/dalfopristin with other agents for resistant infections. Annals of Pharmacotherapy 38, 677–85.[Abstract/Free Full Text]

5 . Tally, F. P., Oleson, F. B., Berman, C. L. et al. (2000). Daptomycin treatment of serious gram-positive infections. In Abstracts of the Tenth European Congress of Clinical Microbiology and Infectious Diseases, Stockholm, Sweden, 2000. Abstract WeP233:8/1. European Society of Clinical Microbiology and Infectious Diseases, Basel, Switzerland.

6 . Fuchs, P. C., Barry, A. L. & Brown, S. D. (2002). In vitro bactericidal activity of daptomycin against staphylococci. Journal of Antimicrobial Chemotherapy 49, 467–70.[Abstract/Free Full Text]

7 . Rand, K. H. & Houck, H. J. (2004). Synergy of daptomycin with oxacillin and other ß-lactams against methicillin-resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 48, 2871–5.[Abstract/Free Full Text]





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