Short-Course Therapy for Right-Side Endocarditis Due to Staphylococcus aureus in Drug Abusers: Cloxacillin versus Glycopeptides in Combination with Gentamicin

Right-side endocarditis caused by Staphylococcus aureus has a more favorable prognosis than does left-side endocarditis, particularly in the absence of metastatic disease. The results of 2 weeks of treatment with a combination of an isoxazolyl-penicillin and an aminoglycoside are satisfactory in >90% of patients [1]; therefore, an effective treatment for drug abusers who refuse prolonged hospitalization is feasible and convenient. Moreover, a recent study has confirmed similar results for patients who received 2 weeks of cloxacillin monotherapy, which indicates that adding an aminoglycoside may not be necessary because it does not provide any therapeutic advantage [2].

Glycopeptides (either vancomycin or teicoplanin) are the drug of choice for treatment of S. aureus endocarditis in patients who are allergic to β-lactams or who have infections caused by methicillin-resistant organisms. Although in vitro bacterial killing of S. aureus is slower with the glycopeptides [3], several authors have reported that vancomycin or teicoplanin are effective in the treatment of both right- and left-side S. aureus endocarditis when administered for 4–6 weeks [4, 5]. Because the rates of treatment failure and of relapse seem to be higher among patients who were treated with glycopeptides alone, and because a slower rate of achieving cultures negative for S. aureus among patients who are infected with that organism and who are treated with teicoplanin has been demonstrated [6, 7], a combination with aminoglycosides or rifampin is usually recommended in these situations. Increasing the dosage of teicoplanin above 12 mg/kg per day has been suggested as well [8, 9]. To our knowledge, no attempts to use short-course glycopeptide regimens to treat right-side S. aureus endocarditis have been reported.

We present the results of a prospective, open, randomized study in which the efficacy of a 14-day course of a glycopeptide in the treatment of right-side staphylococcal endocarditis was evaluated. To improve the efficacy of the therapy, a regimen that contained aminoglycoside was used.

Patients and methods. Parenteral drug abusers were included in the study if they were found to have fever, isolation of methicillin-susceptible S. aureus from ⩾2 cultures of blood samples, and any of the following: septic pulmonary embolization, tricuspid regurgitation murmur, and echocardiographic evidence of endocarditis. Echocardiographic evidence included presence of intracardiac mass on valve or supporting structures, abscess, or nodular tricuspid thickening.

Patients were excluded from enrollment if any of the following criteria were met: isolation of methicillin-resistant S. aureus from cultures of blood samples, allergy to the antibiotics used, extrapulmonary metastatic focus at enrollment or developed within the first 48 h of therapy, a serum creatinine level of >220 nmol/L (>2.5 mg/dL), left-side endocarditis observed on an echocardiogram, presence of nonbiological valvular prosthesis or long-term catheter, polymicrobial infections, pregnancy, or receipt of effective antimicrobial treatment during the 72 h prior to the study period.

Eligible patients were randomly allocated to 1 of 3 therapeutic groups. Patients in the cloxacillin group received iv cloxacillin (2 g, given every 4 h), patients in the vancomycin group received iv vancomycin (500 mg, given every 6 h), and patients in the teicoplanin group received iv teicoplanin (12 mg/kg, given every 24 h, with a loading dose of 24 mg/kg given on the first day). All patients in the 3 groups also received iv gentamicin (1.5 mg/kg given every 8 h).

For all patients, blood samples were obtained for culture 2–5 days and 2–4 weeks after the end of therapy and when clinically indicated. Blood cultures were processed by use of the BACTEC 860A system (Becton Dickinson). MICs of teicoplanin, vancomycin, and oxacillin were determined by use of standard microdilution methods with Mueller-Hinton broth with cationic supplement (Oxoid). Once a steady state was reached, samples were obtained to determine the antibiotic levels and serum bactericidal titer 20 min after the end of the infusion (peak) and just before the infusion (trough). Serum cloxacillin and teicoplanin levels were determined by use of an agar diffusion bioassay with S. aureus ATCC 25922 as the indicator strain [10]. Levels of vancomycin and gentamicin were determined by means of the fluorescence polarization immunoassay method (TDx; Abbott Laboratories). Serum bactericidal titers were determined by use of standard methods [11].

Before the study was initiated, the following criteria of efficacy were defined: “cure” was defined as microbiological eradication and satisfactory clinical response, “clinical failure” was defined as no response or worsening during treatment (persistence of fever on day 7, progression of infiltrates, new pulmonary embolisms, or some combination of these), “microbiological failure” was defined as a positive blood culture result achieved after day 5 of therapy, and “microbiological relapse” was defined as a positive blood culture result achieved after cessation of treatment. All chest radiographs were evaluated by a radiologist who was blinded to the therapy administered.

Results are presented as mean ± SD. Demographic and physiologic characteristics of the 3 groups were compared by use of Student's t test for continuous data (separate estimates of variance were used when variances differed significantly) and by use of the Mantel-Haenszel extended χ² test for categorical data. Fisher's exact test (2-tailed) was used when appropriate. Analysis was performed by use of the Epi Info software package (available through the Centers for Diseases Control Epidemiology Program Web site at http://www.cdc.gov/epo/epi/epiinfo.htm). The RRs and 95% CIs are given with χ² and P values to illustrate the amount of risk associated with some of the effects.

Results. During a 30 month-period, 34 patients who met the criteria for enrollment in the study were randomized. Of these patients, 3 could not be evaluated for efficacy because 2 patients (1 patient in the vancomycin group and 1 in the teicoplanin group) developed extrapulmonary foci within the first 48 h of therapy and 1 patient in the teicoplanin group withdrew voluntarily.

Of the 31 assessable patients, 11 received cloxacillin-gentamicin, 10 received vancomycin-gentamicin, and 10 received teicoplanin-gentamicin. All microorganism strains isolated were susceptible to oxacillin, vancomycin, teicoplanin, and gentamicin. Characteristics of the patients at enrollment were similar in the 3 groups (table 1), although patients in the teicoplanin group presented with pleural effusion less frequently than did patients in the other groups. All the patients had definite endocarditis according to the Duke criteria. No patients with prosthetic valves were included. All patients were followed for at least 12 weeks after completion of therapy.

Clinical and microbiological outcome are shown in table 2. No patients died. A total of 7 patients (22.6%) had clinical failure or microbiological relapse, with differences among groups. None of the 11 patients in the cloxacillin group had clinical failure, compared with 4 (40%) of 10 patients in the vancomycin group (RR, 1.67; 95% CI, 1.0–2.66; P = .03) and 3 (30%) of 10 patients in the teicoplanin group (RR, 1.43; 95% CI, 0.95–2.14; P = .09). Therapeutic success was significantly more frequent among patients who received cloxacillin than among those patients who received a glycopeptide (RR, 1.54; 95% CI, 1.12–2.12; P = .03).

No patient developed microbiological failure, but 3 patients experienced microbiological relapses. One patient who received treatment with vancomycin and another patient who received treatment with teicoplanin had positive blood culture results 4 and 6 days after completion of therapy, respectively. Both episodes of relapse were cured with cloxacillin and gentamicin administered during a 2-week treatment period. The other relapse occurred in a patient in the teicoplanin group who presented with fever and a femoral abscess caused by the same strain of S. aureus 40 days after the end of therapy. In patients who experienced microbiological relapse, the strains isolated from blood cultures displayed MICs that were identical to those of strains isolated during the first episode.

Duration of fever was significantly longer among patients in the teicoplanin group (mean duration, 8.2 days) than among patients in the cloxacillin (mean duration, 4.8 days) or the vancomycin (mean duration, 5.8 days) groups (P = .04; table 2). Four patients experienced clinical failure, 3 of whom were in the vancomycin group and 1 was in the teicoplanin group. Fever persisted in all these patients; the new infiltrates were present after 7 days of their respective therapies (table 2). Three of 4 patients were cured after they switched therapy to cloxacillin-gentamicin for 14 days. The other patient responded to prolonged therapy with teicoplanin-gentamicin.

Echocardiograms were not obtained for 5 patients (table 1); all of these patients responded satisfactorily to the treatments. In patients who experienced clinical failure or microbiological relapse, an echocardiogram was repeated, and no evidence of left-side endocarditis was present in any patient. No transesophagic echocardiograms were performed for any patient.

Mild to moderate side effects developed in 5 patients (2 patients who received treatment with vancomycin and 3 who received treatment with teicoplanin), but no patient discontinued therapy (table 2). The most common side effect was rash, which occurred in 1 patient who received treatment with vancomycin and in 3 patients who received treatment with teicoplanin. In addition, 1 patient who was treated with vancomycin developed a moderate increase in serum creatinine level at the end of therapy that resolved within 1 week after withdrawal of vancomycin and the aminoglycoside.

Response to therapy was not related to serum antibiotic levels or to serum bactericidal titers. All of the patients had antibiotic levels that were well above the MICs of the respective strains (table 3). Serum bactericidal titers were similar in the 3 groups. In no patient were titers below 1/8 in peak level, and most patients presented titers above 1/32.

Discussion. This open, randomized clinical trial confirms that a 14-day course of cloxacillin plus gentamicin is effective in the treatment of right-side endocarditis due to S. aureus in drug abusers; no failure was observed among the 11 patients who received this combination therapy. In contrast, therapy with either vancomycin or teicoplanin plus gentamicin was associated with an unacceptable rate of clinical or microbiological failure. Despite the small number of patients included in the groups, the risk of failure associated with either glycopeptide was demonstrated to be significantly higher than that associated with cloxacillin. In fact, enrollment in the trial had to be prematurely discontinued because of the risk of failure.

Previous studies have suggested that the glycopeptides could be a valid alternative for treatment of S. aureus endocarditis. Vancomycin, administered for 4–6 weeks, reached a rate of efficacy of 85% in several series that studied S. aureus endocarditis [4, 5]. On a similar note, a retrospective study examined the outcome, efficacy, and safety of teicoplanin administered for >4 weeks as monotherapy or combined with an aminoglycoside for treatment of 115 cases of S. aureus endocarditis [12]; this study confirmed that teicoplanin was useful for treatment of native and prosthetic valve endocarditis, although combination therapy was more successful than monotherapy.

However, other studies have noted worse results among patients with endocarditis who received treatment with vancomycin or teicoplanin. Levine et al. [13] found a mean duration of bacteremia of 9 days in a series of 42 consecutive patients with methicillin-resistant S. aureus endocarditis. Small and Chambers [3] found suboptimal outcomes in 5 of 13 injection drug users with endocarditis who received treatment with vancomycin. In other series, a 2-week course of vancomycin-tobramycin cured only 1 of 3 drug addicts who had methicillin-resistant S. aureus endocarditis, whereas 47 of 50 patients with methicillin-susceptible isolates were cured with a 2-week course of nafcillin-tobramycin therapy [1].

Most of the series that have compared vancomycin and teicoplanin as treatments for staphylococcal infections other than endocarditis have shown comparable results for both drugs [14–17]. However, in patients with endocarditis, teicoplanin dosages of 6 mg/kg per day have resulted in higher rates of failure to respond to therapy than was observed among patients who received vancomycin [18]. It is generally acknowledged that teicoplanin serum levels must be at least 10-fold higher than the MIC when used to treat S. aureus endocarditis [19]. Wilson et al. [9] recommend reaching serum levels >20 µg/mL, and other authors recommend serum levels of up to 40–60 µg/mL.

Our group recently confirmed a high rate of microbiological failure among patients who received teicoplanin monotherapy [8]. In this study, the patients were treated for the first week with 12 mg/kg per day (after a loading dose of 20 mg/kg that was administered during the first 3 days), and in the second week, the dosage was tapered to 7 mg/kg per day. The high rate of failure to respond to therapy was attributed to the decrease of drug levels and bactericidal activity in the second week. Furthermore, serum levels in parenteral drug abusers are lower than those in healthy controls because of the higher clearance of teicoplanin due to an increase in glomerular filtration [20]. Because of these data, in the present study, we chose a high teicoplanin dosage (12 mg/kg per day) that was maintained throughout the whole course of therapy.

The major drawback of this high teicoplanin dosage is its safety. In our series, 3 (30%) of the 10 patients who were receiving teicoplanin presented with rash, and fever also persisted significantly longer than it did among the rest of the patients. Although teicoplanin is a well-tolerated drug, the doses recommended for treatment of S. aureus endocarditis are clearly associated with higher rates of adverse effects. With regard to patients who received dosages higher than 12 mg/kg per day, Greenberg et al. [21] reported that 28% had drug-related fever and rash. Thrombocytopenia has also been reported in patients who receive high-dose teicoplanin; we were unaware of hematological toxicity in our trial. We noted a single case of nephrotoxicity that was self-limited; it appeared in a patient who received treatment with vancomycin. The incidence of renal toxicity among patients who are receiving vancomycin is estimated to be 1.5%–15% [22, 23]. Nephrotoxicity seems to be more frequently associated with vancomycin than with teicoplanin, particularly when concomitant nephrotoxic agents are used [24].

Our conclusions may be limited by the open design of the study. We tried to minimize the bias that could have resulted from this design by use of strict definitions of the outcomes. Because mortality rates are extremely low in patients with right-side endocarditis, clinical failure was defined according to objective features: persistence of fever after 7 days of therapy and/or progression of infiltrates or new pulmonary embolisms. It cannot be ruled out that persistent findings would have resolved had the patient continued to receive the same therapy. However, patients responded rapidly after they switched to therapy with cloxacillin, which argues against the efficacy of teicoplanin and vancomycin and suggests that cloxacillin is a more effective therapy.

In conclusion, in the treatment of drug addicts with right-side endocarditis due to S. aureus, short-course therapy with vancomycin or teicoplanin, even when combined with an aminoglycoside, is not a good alternative to a short course of cloxacillin. New therapeutic options should be explored for patients with this disease who cannot receive β-lactams.

• Received April 18, 2000.
• Revision received October 13, 2000.

• © 2001 by the Infectious Diseases Society of America