Pilot Study of Ampicillin-Ceftriaxone Combination for Treatment of Orthopedic Infections Due to Enterococcus faecalis

Serious Enterococcus faecalis infections usually require combination therapy to achieve a bactericidal effect. In orthopedic infections, the prognosis of enterococcal etiology is considered poor, and the use of aminoglycosides is questioned. The ampicillin-ceftriaxone combination has recently been accepted as alternative therapy for enterococcal endocarditis. After one of our patients with endocarditis and vertebral osteomyelitis was cured with ampicillin-ceftriaxone, we started a pilot study of orthopedic infections. Patients with infections due to E. faecalis (with two or more surgical samples or blood cultures) diagnosed during 2005 to 2008 were recruited. Polymicrobial infections with ampicillin- and ceftriaxone-resistant microorganisms were excluded. Patients received ampicillin (8 to 16 g/day)-ceftriaxone (2 to 4 g/day) and were followed up prospectively. Of 31 patients with E. faecalis infections, 10 received ampicillin-ceftriaxone. Including the first patient, 11 patients were treated with ampicillin-ceftriaxone: 3 with prosthetic joint infections, 3 with instrumented spine arthrodesis device infections, 2 with osteosynthesis device infections, 1 with foot osteomyelitis, and 2 with vertebral osteomyelitis and endocarditis. Six infections (55%) were polymicrobial. All cases except the vertebral osteomyelitis ones required surgery, with retention of foreign material in six cases. Ampicillin-ceftriaxone was given for 25 days (interquartile range, 15 to 34 days), followed by amoxicillin (amoxicilline) being given to seven patients (64%). One patient with endocarditis died within 2 weeks (hemorrhagic stroke) and was not evaluable. For one patient with prosthesis retention, the infection persisted; 9/10 patients (90%) were cured, but 1 patient was superinfected. Follow-up was for 21 months (interquartile range, 14 to 36 months). Ampicillin-ceftriaxone may be a reasonable synergistic combination to treat orthopedic infections due to E. faecalis. Our experience, though limited, shows good outcomes and tolerability and may provide a basis for further well-designed comparative studies.Enterococcus faecalis is a low-virulence microorganism that colonizes the human gastrointestinal tract (23) and produces a variety of infections, especially under antimicrobial pressure or in nosocomial settings, including urinary tract and intra- abdominal infections, bacteremia, endocarditis, meningitis, and orthopedic and foreign-body-related infections (20). In orthopedic infections, enterococci are relatively common etiologic agents (26, 27); however, it is often difficult to distinguish infection from colonization, as the bacteria may be isolated in samples of doubtful significance or in combination with other microorganisms.As is well known in clinical practice, some enterococcal infections are difficult to treat (21). Though susceptible at relatively low MICs, enterococci are characteristically resistant to the bactericidal effect of cell wall-active antibiotics (16). Most E. faecalis strains show the “paradoxical or Eagle effect,” in which penicillins are more bactericidal just above the MIC and less bactericidal as the drug concentration increases (6, 9). This phenomenon has been attributed by some authors to an intrinsic defect in the autolytic activity of the microorganism (14). As a result of these special features, in the absence of high-level aminoglycoside (AG) resistance, an ampicillin-AG combination is now the therapy of choice for deep-seated infections by E. faecalis where a bactericidal effect is desirable, such as for endocarditis or meningitis (20, 23).In orthopedic and foreign-body infections, in which biofilm formation occurs, the bactericidal effect is sought in order to eradicate infection and avoid relapses. For serious enterococcal orthopedic infections, most authors recommend a combination therapy with AG (26, 37). However, the role of AG in the treatment of orthopedic infections has often been questioned, as the local conditions in infected bone may reduce their efficacy against susceptible microorganisms (17), and they have serious side effects that may limit their use.The ampicillin-ceftriaxone (AMP-CRO) combination has recently been recommended (strength, IIbC) for endocarditis due to E. faecalis that is highly resistant to AG (2) after the studies of Gavaldà et al. (11-13). The basis for these reports was an in vitro study by Mainardi et al. which found a synergistic effect between amoxicillin (amoxicilline) and low levels of cefotaxime against several AG-susceptible and AG-resistant E. faecalis strains (18).Pyogenic vertebral osteomyelitis may present as a complication of infective endocarditis (22, 25, 32). We undertook this pilot study after one of our patients with enterococcal endocarditis and vertebral osteomyelitis was treated with AMP-CRO and cured at both infection sites. To our knowledge, this is the first study to evaluate a double β-lactam combination for the treatment of orthopedic infections caused by E. faecalis.(These data were partially reported at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2008 [8a].)