Disseminated oxacillin-resistant Staphylococcus aureus infection responsive to vancomycin and quinupristin–dalfopristin combination therapy

Munshi Moyenuddin1, Christopher A. Ohl1, John C. Williamson2 and James E. Peacock1,*

1 Section on Infectious Diseases, Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157; 2 Department of Pharmacy, Wake Forest University Baptist Medical Center, Winston-Salem, NC, USA

Keywords: disseminated, oxacillin-resistant Staphylococcus aureus

Sir,

We describe a case with oxacillin-resistant Staphylococcus aureus (ORSA) bacteraemia with associated polyarticular septic arthritis, soft-tissue abscesses, vertebral osteitis and discitis. Although the ORSA isolates were susceptible to vancomycin (VAN), bacteraemia, fever and leucocytosis persisted while on treatment with VAN, rifampicin and gentamicin but resolved with combination treatment of VAN and quinupristin–dalfopristin (Q-D).

In April 2002, a 67-year-old female with a history of gout presented to the emergency department (ED) with pain and swelling of the right great toe with accompanying fever (unmeasured) for 5 days. She was treated with rofecoxib and colchicine. She returned to the ED 1 week later with spread of pain and swelling to her right ankle, right knee, right wrist, left wrist and left elbow with continued fever. She was admitted to the hospital with a temperature of 38.6°C, white blood cell count of 19.8 x 109 cells/L (normal range 4.8–10.8 x 109 cells/L), erythrocyte sedimentation rate (ESR) of 89 mm/h (normal range 0–30) and C-reactive protein (CRP) of 2710 µg/L (normal range 0.0–100). Blood, soft-tissue abscess drainage and debrided tissues from multiple joints were cultured. All of the specimens grew ORSA, susceptible to VAN and rifampicin (Table 1) as tested by the broth microdilution method.1 She was treated with VAN (15 mg/kg intravenous every 12 h) and rifampicin (10 mg/kg by mouth once a day). A transoesophageal echocardiogram (TEE) was negative for vegetations. The patient required numerous joint debridements for persistent inflammation. Repeated blood and joint fluid cultures remained positive for ORSA despite 3 weeks of treatment with VAN and rifampicin. During that 3 week period, vancomycin levels were therapeutic, with a mean trough value of 10.2 mg/L (range 6.2–13.9 mg/L). TEE was repeated, but did not demonstrate vegetations or abscess. The patient subsequently developed back pain. Magnetic resonance imaging (MRI) showed T1–T5 vertebral osteitis and L4–S1 discitis with an associated paraspinous abscess. Gentamicin (1 mg/kg intravenous every 8 h) was added to the treatment regimen. Nevertheless, the patient remained febrile (temperature 37.8–38.3°C) with persistent leucocytosis (white blood cell count of 11.9–16.8 x 109 cells/L). ORSA was again isolated from blood culture despite 4 weeks of treatment with VAN and rifampicin and 1 week of gentamicin. Chest X-ray, CT scans of the head, chest and abdomen, and CSF studies were normal. Q-D (7.5 mg/kg intravenous every 8 h) was added to VAN; rifampicin was discontinued due to increased liver enzymes (>three times normal) and gentamicin was discontinued after a week of treatment. After 7 days of the combination treatment (VAN and Q-D), fever, back pain and leucocytosis had resolved; repeat blood cultures drawn 72 h after addition of Q-D were negative. VAN and Q-D were continued for three more weeks, and, during that period, three blood cultures and one joint aspiration fluid culture were negative. Joint pain and swelling resolved. VAN subsequently had to be discontinued after a total of 8 weeks of therapy due to the development of worsening rash. Q-D was continued as monotherapy for a total of 8 weeks. Repeat ESR and CRP decreased to 47 mm/h and 220 µg/L, respectively, and repeat MRI was negative for any paraspinous abscess, with evidence of stable osteitis and discitis at the previous vertebral sites at the completion of 8 weeks of Q-D treatment. The patient remained afebrile with no joint pain or swelling.


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Table 1.  MICsa (mg/L) for ORSA isolates
 
ORSA strains have become endemic in hospitals worldwide and the frequency of their isolation has increased.2 Glycopeptides such as VAN are the therapeutic drugs of choice for ORSA infections.3 Although ORSA isolates from our patient were susceptible to VAN and rifampicin, neither 4 weeks of VAN plus rifampicin nor 1 week of VAN plus rifampicin and gentamicin sterilized her blood. However, combination therapy of Q-D and VAN sterilized blood within 3 days. Our observations are concordant with the results of a recent study that described two patients with ORSA bacteraemia who remained culture-positive on VAN rifampicin and Q-D rifampicin but subsequently became culture-negative when treated with the combination of VAN and Q-D.4 An in vitro study of ORSA endocarditis in rabbits showed that Q-D and VAN in combination were significantly more active than either drug as monotherapy as determined by time to negative cultures and by rate of decrease in cfu.5 A recent in vitro study using one ORSA strain demonstrated that the combination of Q-D with either VAN or linezolid achieved synergic killing (>2 log10 decrease in cfu).6 Although the combination of Q-D and VAN has not been investigated clinically, the response of our patient and the results of one similar study and two in vitro studies46 may indicate improved potency of the combination therapy (VAN plus Q-D) against ORSA. Further studies with larger numbers of ORSA strains and clinical trials using the combination treatment will be required to determine whether such a combination is therapeutically superior to VAN alone.

Footnotes

* Corresponding author. Tel: +1-336-716-4507; Fax: +1-336-716-3825; E-mail: jpeacock{at}wfubmc.edu Back

References

1 . National Committee for Clinical Laboratory Standards. (1997). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Fourth Edition: Approved Standard M7-A4. NCCLS, Wayne, PA, USA.

2 . Livermore, D. M. (2000). Antibiotic resistance in staphylococci. International Journal of Antimicrobial Agents 16, S3–10.[ISI][Medline]

3 . Paradisi, F., Corti, G. & Messeri, D. (2001). Antistaphylococcal (MSSA, MRSA, MSSE, MRSE) antibiotics. Medical Clinics of North America 85, 1–17.[ISI][Medline]

4 . Gugliotta, J. J., Critchley, I. A., Draghi, D. C., Karginova, E., Karlowsky, J. A. & Sahm, D. F. (2001). Synergistic killing of oxacillin-resistant S. aureus by quinupristin–dalfopristin and vancomycin. In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA, 2001. Abstract E-328, p. 169. American Society for Microbiology, Washington, DC, USA.

5 . Pavie, J., Zarrouk, V., Lefort, A., Garry, L., Leclercq, R., Carbon, C. et al. (2000). Activity of combination of quinupristin–dalfopristin (Q-D) and vancomycin (Vm) in vitro and in experimental endocarditis due to Staphylococcus aureus susceptible or resistant to quinupristin. In Program and Abstracts of the Fortieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 2000. Abstract 1006, p. 57. American Society for Microbiology, Washington, DC, USA.

6 . Allen, G. P., Cha, R. & Rybak, M. J. (2002). In vitro activities of quinupristin–dalfopristin and cefepime, alone and in combination with various antimicrobials, against multidrug-resistant staphylococci and enterococci in an in vitro pharmacodynamic model. Antimicrobial Agents and Chemotherapy 46, 2606–12.[Abstract/Free Full Text]