Linezolid for endocarditis: a case series of 14 patients

Sir, Linezolid is an antibiotic with bacteriostatic activity against Gram-positive microorganisms licensed for complicated skin and soft tissue infections and pneumonia, but not for bacteraemia with or without endocarditis. However, the most recent guidelines from the Infectious Diseases Society of America consider linezolid an alternative treatment for catheter-related bacteraemia caused by Gram-positive organisms.1 Twelve patients cared for at Cisanello Hospital in Pisa received linezolid for the treatment of native valve (n = 7), prosthetic valve (n = 1) or pacemaker (PM) endocarditis (n = 4) due to Gram-positive organisms: three methicillin-susceptible Staphylococcus aureus (MSSA); three methicillin-resistant S. aureus (MRSA); three methicillin-resistant Staphylococcus epidermidis (MRSE); one vancomycin-resistant Enterococcus faecium (VRE); and two polymicrobial (one Streptococcus bovis + MRSE and one E. faecium + Enterococcus durans). Linezolid was given for failure of previous therapy (seven), renal toxicity due to vancomycin and amikacin combined therapy (one) or oral maintenance therapy (four). Two further patients, with MSSA native (one) and prosthetic (one) aortic valve endocarditis, received linezolid as continuous infusion as primary therapy. The serum bactericidal test (SBT) of patients receiving linezolid was performed according to the usual methods.2 Table 1 summarizes the characteristics of patients and treatment regimens. Characteristics of patients with infective endocarditis treated with linezolid F, female; M, male; C, chemotherapy; DA, drug addict; HIV, human immunodeficiency virus; LC, lung cancer; RI, renal insufficiency; A, aortic; Mi, mitral; P, prosthetic; T, tricuspid; AMK, amikacin; SXT, co-trimoxazole; GEN, gentamicin; LVX, levofloxacin; MXF, moxifloxacin; OXA, oxacillin; TZP, piperacillin/tazobactam; RIF, rifampicin; TEC, teicoplanin; VAN, vancomycin; AMC, amoxicillin/clavulanate; MEM, meropenem; PM-R, PM removal and re-implantation. Characteristics of patients with infective endocarditis treated with linezolid F, female; M, male; C, chemotherapy; DA, drug addict; HIV, human immunodeficiency virus; LC, lung cancer; RI, renal insufficiency; A, aortic; Mi, mitral; P, prosthetic; T, tricuspid; AMK, amikacin; SXT, co-trimoxazole; GEN, gentamicin; LVX, levofloxacin; MXF, moxifloxacin; OXA, oxacillin; TZP, piperacillin/tazobactam; RIF, rifampicin; TEC, teicoplanin; VAN, vancomycin; AMC, amoxicillin/clavulanate; MEM, meropenem; PM-R, PM removal and re-implantation. Linezolid was administered at a dose of 1200 mg by continuous infusion over 24 h in two patients, 600 mg twice daily by the intravenous (iv) route in eight patients and by the oral route (as consolidation therapy or because there was no venous access) in four patients. Overall response to linezolid was 12/14 (86%), which is comparable to data reported previously.3 Two patients died: one was a drug addict with MSSA endocarditis and cerebral embolic lesions contraindicating surgery; and the other one had MRSA PM endocarditis, but the PM was not removed because the patient's condition was too severe. Six patients were cured with antibiotic therapy alone and six with antibiotics and surgery (three) or electrocatheter removal (three). Response of MRSA and MSSA endocarditis was 2/3 (67%) and 4/5 (80%), respectively. All other cases were cured: one VRE; three MRSE; and two cases of polymicrobial endocarditis. Response of native valve endocarditis was 7/8 (87.5%) and that of prosthetic valve endocarditis was 2/2 (100%). In three out of four patients with PM endocarditis (75%), the removal of the PM combined with antibiotic therapy, linezolid monotherapy in one case, was able to heal the infection. In these three patients, PM culture was still positive for the same S. epidermidis strain as isolated from the blood, probably due to the inactivity of linezolid against slime-producing bacteria.4 Therefore, for PM endocarditis, linezolid may be an option only if the entire device is removed. Patients were followed up for at least 6 months, and no relapses were recorded. Two patients received linezolid as primary therapy, administered by continuous iv infusion, combined with meropenem (Patients 13 and 14 in Table 1). Linezolid was first started as empirical therapy by intermittent infusion and continued after the diagnosis of endocarditis was made. In Patient 13, during intermittent administration, linezolid serum concentration was 9 mg/L at peak and 1.5 mg/L at trough and the SBT titre was 1:2 for both samples; during continuous infusion the linezolid serum concentration was 4 mg/L and the SBT titre was 1:16. In Patient 14, during intermittent administration, linezolid serum concentration was 7 mg/L at peak and 2 mg/L at trough and the SBT titre was 1:2 for both samples; during continuous infusion the linezolid serum concentration was 5 mg/L and the SBT titre was 1:8. In Patients 13 and 14, the MBC for MSSA was only 2 mg/L, within the range of susceptibility. This result may be important because linezolid is considered bacteriostatic or slowly bactericidal.5 The SBT titre of 1:16 in Patient 13 means that serum diluted 16 times was still bactericidal; the serum concentration of linezolid was 4 mg/L and the ratio between linezolid concentration and MBC (C/MBC) was only 2 and not 16. In Patient 14, the SBT titre was 1:8 with a linezolid concentration of 5 mg/L and the C/MBC was 2.5. Therefore, SBT titre might give a more accurate measure of bactericidal activity than the C/MBC. The high SBT titre in this case might be related to continuous infusion. Pistella et al.6 have reported that continuous infusion of linezolid may be an option for treating cerebritis complications of S. aureus endocarditis, as serum concentrations correlated with CSF levels. In Patient 13, a case of endocarditis complicated by cerebral embolism and meningitis, the high levels of linezolid achieved may explain the positive outcome. Linezolid may be useful in cases of right-sided endocarditis complicated by lung abscesses, where it may reach higher concentrations than glycopeptides or lipopeptides. Although the pharmacokinetics of linezolid in endocardial vegetations and around prosthetic cardiac devices are unknown, the good distribution of linezolid to many compartments might favour a good effect. Linezolid was generally well tolerated; one patient developed reversible thrombocytopenia (40 000 platelets/μL) requiring drug interruption. In conclusion, linezolid may be used as rescue therapy in severe and difficult-to-treat patients who have endocarditis. No specific financial support was provided for this study. C. T. and F. M. have each received a speaker honorarium from Pfizer. All other authors: none to declare.