Failure of Linezolid Treatment for Enterococcal Endocarditis

Linezolid is the first oxalidinone antibiotic approved for clinical use. It has activity against sensitive and resistant strains of Staphylococcus aureus and vancomycin-sensitive and vancomycin-resistant strains of E. faecalis and Enterococcus faecium, as well as against Streptococcus pneumoniae. It has good tissue penetration, with similar antimicrobial levels following an oral or intravenous dose [1–3]. Despite linezolid's promising profile against drug-resistant enterococcal species and efficacy in animal models of vancomycin-resistant E. faecium (VREF) endocarditis [4], the effectiveness of linezolid in patients with enterococcal bacteremia or endocarditis has not been formally studied. The approved clinical indications for linezolid use are pneumonia and skin and soft-tissue infections. We describe a case of linezolid failure in a dialysis patient with enterococcal endocarditis and severe allergies to both ampicillin and vancomycin.

Case report. A 40-year-old man with hepatitis C, hypertension, and end-stage renal disease was admitted to the hospital because of fevers and chills occurring during hemodialysis. Eight weeks prior to this admission, the patient had been treated at another hospital for group B streptococcal endocarditis of the aortic valve. After 2 weeks of therapy with ampicillin and gentamicin, he developed tongue swelling and shortness of breath that were attributed to the ampicillin. Treatment with ampicillin was changed to levofloxacin, and the patient completed a total of 6 weeks of therapy. Two weeks prior to admission to our hospital, follow-up blood cultures showed no growth.

Cultures of blood samples drawn through the patient's dialysis catheter and of peripheral blood obtained on admission to our hospital were positive for E. faecalis. The organism was susceptible to vancomycin, ampicillin, streptomycin, and linezolid, but it demonstrated resistance to levofloxacin and high-level resistance to gentamicin when tested by MicroScan (Dade MicroScan). Because of a history of erythema multiforme following vancomycin administration and because of the recent allergy to ampicillin, the patient was administered 600 mg of intravenous linezolid every 12 h. On days when the patient underwent hemodialysis, the second dose of linezolid was given after dialysis. The patient's dialysis catheter was removed and hemodialysis was performed through a temporary access catheter. Transesophageal echocardiography revealed aortic and mitral valve insufficiency and a tricuspid valve vegetation. The patient was initially hemodynamically stable but developed worsening congestive heart failure in the third week of his hospitalization. During 3 weeks of intravenous linezolid therapy, cultures of blood obtained on days 4, 7, and 15 remained positive for E. faecalis. MIC testing on the E. faecalis strain isolated after >2 weeks of linezolid therapy revealed continued sensitivity with an MIC of 2 μg/mL by the E-test (AB Biodisk).

Because of persistent bacteremia and worsening heart failure, the patient was desensitized to ampicillin and, beginning on day 18 of hospitalization, was treated with 2 g of ampicillin every 12 h and 1 g of streptomycin after each session of hemodialysis. The blood streptomycin level was determined on one occasion and was found to be therapeutic, at 20 μg/mL; however, this test is not performed routinely, because results are obtained from an outside laboratory and are not available in a timely fashion. The patient's bacteremia cleared within 24 h after starting ampicillin therapy.

On day 25 of hospitalization, the patient underwent mitral and aortic valve replacement and repair of the affected tricuspid valve leaflet. Grossly, the aortic and mitral valve leaflets were described as necrotic without discreet vegetations. A vegetation on the posterior leaflet of the tricuspid valve was excised. The patient tolerated the procedure well and had an uneventful postoperative course. Blood cultures continued to show no growth. Culture of valvular tissue from the aortic valve grew E. faecalis. Culture of mitral valve leaflet showed no growth, and the tricuspid vegetation was not cultured. The patient received 6 weeks of intravenous therapy with ampicillin and streptomycin after his surgery and was healthy 6 months after the operation.

Discussion. Linezolid is an oxalidinone antibiotic that inhibits protein synthesis by binding to the 50S ribosomal subunit near its interface with the 30S ribosomal subunit, interfering with the formation of the 70S initiation complex [1, 2]. Although this mechanism is unique among protein synthesis inhibitors, linezolid, like other antibiotics with this mechanism of action, is considered bacteriostatic; thus, its potential for the treatment of severe infections, such as bacteremia or endocarditis, may be limited [5]. The combination of linezolid with aminoglycosides has not been studied for the treatment of enterococcal infections; however, because both classes of agents inhibit protein synthesis by acting on the cell's ribosomal subunit, combination therapy is unlikely to be synergistic [6].

Several investigators have reported successful treatment of serious VREF infections, including bacteremia, endocarditis, and meningitis, with linezolid [7–9]. Gonzales et al. [10] described 5 patients with susceptible VREF infections who all developed linezolid-resistant VREF infections after first being treated with linezolid. Clinical isolates of vancomycin-resistant E. faecalis (VRE) and VREF studied by Prytowsky et al. [11] have developed resistance to linezolid after exposure to doubling concentrations of the drug. Interestingly, the VRE isolates developed in vitro resistance after 4–8 passes, while VREF isolates developed resistance after 11 passes, and some VREF isolates remained susceptible to linezolid through all 12 passes. Rao and White [12] describe a patient with ampicillin-susceptible E. faecalis prosthetic valve endocarditis whose infection was cured with 6 weeks of linezolid therapy. Their patient received 4 days of ampicillin therapy, however, prior to the change to linezolid.

To our knowledge, the case we describe is the first reported clinical failure of linezolid in a patient with a drug-susceptible E. faecalis infection. Linezolid therapy failed in our patient's case, not because of resistance, but presumably because of a combination of host factors and antibiotic failure related to the organisms sequestered within his valvular vegetation. The Enterococcus strain remained susceptible after 3 weeks, but linezolid therapy did not sterilize the blood cultures or the aortic valve, most likely because of the bacteriostatic nature of this single agent. Although linezolid is available as a treatment option for drug-resistant gram-positive bacterial infections, its efficacy in the treatment of serious infections such as endocarditis remains questionable. This case reminds us to exhaust all available means to treat patients with regimens that have proven efficacy for their clinical condition.

• Received December 2, 2002.
• Revision received September 3, 2003.

• © 2003 by the Infectious Diseases Society of America