We did a randomized clinical trial to compare the efficacy of cloxacillin alone with that of cloxacillin plus gentamicin as short-course therapy for right-sided S. aureus endocarditis in intravenous drug users.

Methods

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Patients

All patients who were suspected of having right-sided staphylococcal endocarditis, who were hospitalized at our institution between March 1988 and February 1993, and who admitted that they used intravenous drugs were considered for inclusion in our study. Patients who presented with tricuspid endocarditis caused by S. aureus according to the criteria shown in Table 1 were eligible. The institutional review board of our hospital approved the study, and all patients gave informed consent.

Patients were excluded if they had any of the following: allergy to study medications, infection with methicillin-resistant S. aureus, confirmed or suspected left-sided endocarditis shown by clinical examination (indicated by characteristic regurgitation murmur or systemic embolization) or echocardiography (indicated by vegetation or valvular insufficiency), vegetation on the pulmonic valves shown by echocardiography, systemic complications requiring prolonged therapy (osteomyelitis, abscesses that could not be drained surgically), or antibiotic therapy given for longer than 48 hours before hospitalization. Clinically significant hemodynamic compromise, extensive pulmonary embolism, and large tricuspid vegetations were not considered exclusion criteria.

Study Design and Treatment

Our study was an open, randomized trial. Consecutive patients were randomly assigned to receive cloxacillin, 2 g intravenously every 4 hours for 14 days, alone or combined with gentamicin, 1 mg/kg of body weight intravenously every 8 hours for the first 7 days. Randomization was done using a random-number Table i n sets of 10: In each consecutive set, 5 patients received cloxacillin alone and 5 received combination therapy. A sealed envelope labeled with the randomization number was opened at the start of treatment. The decision to start treatment was based on microbiological criteria (positive blood cultures) or clinical criteria (fever and evidence of pulmonary embolism or poor general condition attributable to the infection). Thus, some patients were randomly assigned to treatment before the results of some procedures (echocardiography and isolation of microorganism) that might have uncovered exclusion criteria were available.

Follow-up

Initial patient assessment included medical history, physical examination, chest radiography, radionuclide body scanning with technetium pyrophosphate, electrocardiography, and the following laboratory tests: complete blood count, standard blood chemistries, urinalysis, serologic testing for human immunodeficiency virus (HIV), and lymphocyte subpopulation counts (when the HIV test result was positive). Standard laboratory tests and chest radiography were done every week. Two-dimensional transthoracic echocardiography was done within 4 days of hospital admission and at the end of treatment. Blood cultures were done at the time of hospital admission, 3 days after the initiation of treatment, and 2 days after the end of treatment. Aerobic and anaerobic cultures were done by using the BACTEC NR 660 System (Becton Dickinson, Mountain View, California).

Follow-up visits were scheduled at 2 weeks and at 1, 3, and 6 months after the end of therapy. At the 2-week visit, a physical examination, standard laboratory tests, chest radiography, and two blood cultures were done. Subsequent blood cultures were done only if evidence suggested infection. Nine patients did not attend a follow-up visit; outcome information for these patients was obtained by telephone.

Evaluation Criteria

In all patients who met the exclusion criteria after random assignment, treatment was modified accordingly. In the intention-to-treat analysis, these patients were considered to have had treatment failure.

Three primary end points were considered to indicate treatment failure: 1) death during treatment, 2) continued clinical or microbiological evidence of active infection after 2 weeks of therapy, and 3) relapse of staphylococcal infection. Clinical recovery was defined as the disappearance of clinical evidence of infection and the absence of radiologic abnormalities (pleural effusion or active pulmonary abscesses) at 14 days of treatment. Bacteriologic recovery was defined as a negative blood culture obtained 48 hours after the end of treatment. Successful therapy was defined as clinical and microbiological recovery without subsequent relapse. Patients who showed signs of active infection after 14 days of treatment continued to receive cloxacillin for 2 more weeks. Relapses were treated with cloxacillin alone for 4 weeks. To differentiate between relapse and reinfection, we considered clinical criteria (resumption of drug use and duration of symptom-free interval after stopping treatment) and comparison of S. aureus isolates by phage-typing. Phage-typing was done at the National Reference Center of Microbiology, Virology and Immunology, Majadahonda, Madrid, by using the international set of phages applied sequentially at the standard test dilution and a 1:100 test dilution; typing was also done after heat treatment. Reverse phagotyping was done as described elsewhere [12].

The duration of fever and appearance of complications during treatment were also evaluated. In patients without previous renal dysfunction, acute renal insufficiency was defined as a serum creatinine level greater than 176.8 µmol/L. In patients with previous renal dysfunction, renal insufficiency was defined as an increase in the serum creatinine level of more than 50%.

Statistical Analysis

We did two analyses. An intention-to-treat analysis was done for all randomly assigned patients, and an efficacy analysis was done after we excluded patients who were found, after treatment began, to have met an exclusion criterion.

We used the Fisher exact test to compare categorical baseline characteristics and outcomes of the two groups, and we used the Student t-test or the Mann-Whitney U test to compare continuous characteristics and outcomes. In the primary efficacy analysis, we compared the rates of successful treatment. Because we assumed that treatment would be successful in 95% of patients who received combination therapy [9], we estimated that almost 38 evaluable patients had to receive each regimen in order for us to detect a difference in efficacy of 20% or more, with a power of 80% at a one-sided level of 0.05. Because we anticipated that 10% to 15% of patients might have to be excluded after random assignment, 45 patients were assigned to each group. Two-tailed P values were used for all calculations; thus, the power of the study to find no differences in the efficacy of the two regimens was 70%.

Results

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Patients

During the 5-year study period, 45 patients were randomly assigned to each treatment group. Of these 90 patients, 6 (13%) of those assigned to receive cloxacillin alone and 8 (18%) of those assigned to receive combination therapy were later excluded for the following reasons. Three patients (1 receiving cloxacillin alone and 2 receiving combination therapy) had endocarditis caused by Streptococcus viridans; 7 patients (3 receiving cloxacillin alone and 4 receiving combination therapy) had involvement of the mitral, aortic, or pulmonic valves; 3 patients (1 receiving cloxacillin alone and 2 receiving combination therapy) were allergic to penicillin or had methicillin-resistant S. aureus infection; and 1 patient receiving cloxacillin alone had osteomyelitis. Two patients (1 in each group) refused further in-hospital treatment 5 and 8 days after enrollment, respectively. Thus, 74 patients (38 receiving cloxacillin alone and 36 receiving combination therapy) remained available for the efficacy analysis.

Clinical, radiologic, and echocardiographic findings and laboratory values were similar in the two groups. The exclusion of 16 patients from the efficacy analysis after randomization did not change these similarities (Table 2).

Efficacy of Therapy

Table 3 shows the outcome of all patients randomly assigned to treatment, as determined by the intention-to-treat analysis. A successful overall outcome was seen in 34 of the 45 patients (76% [95% CI, 61% to 87%]) assigned to receive cloxacillin only and 31 of the 45 patients (69% [CI, 53% to 82%]) assigned to receive combination therapy (P > 0.2).

Table 4 shows the outcomes for the 74 patients that were available for the efficacy analysis. Treatment was successful in 34 of the 38 patients receiving cloxacillin alone (89% [CI, 75% to 97%]) and 31 of the 36 patients receiving cloxacillin plus gentamicin (86% [CI, 71% to 95%]) (P > 0.2). The overall mortality rate was 4%: One patient in the cloxacillin group and two patients in the combination group died (rates of 2.5% and 5.5%, respectively; P > 0.2). All deaths occurred within the first 3 days of therapy.

Of the 37 patients who completed 2-week treatment with cloxacillin, 34 (92%) recovered completely. The remaining 3 (8%) continued to have evidence of active infection after 14 days of treatment, despite negative blood cultures. These patients received cloxacillin therapy for 2 more weeks, and all patients completely recovered. Of the 34 patients who completed 2-week combination treatment, 32 (94%) recovered and 2 required continued treatment for 2 more weeks. Outcomes did not statistically significantly differ between the two groups.

We evaluated all patients in both groups who completed 2 weeks of treatment for relapse during the 6-month follow-up. Only one relapse occurred, in a patient treated with cloxacillin and gentamicin. Five patients had reinfection with S. aureus between 2 and 6 months after the initial treatment (Table 5).

During the treatment of endocarditis, the interval to clinical recovery and the rate of complications did not differ significantly between groups (Table 4). No patient discontinued therapy because of nephrotoxicity.

Discussion

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We were not able to show that the addition of gentamicin improves the therapeutic effectiveness of cloxacillin in terms of mortality, clinical and microbiological recovery, or relapse rates in patients with S. aureus tricuspid endocarditis who were treated for 2 weeks. Therapy was successful in 34 of the 38 patients who received cloxacillin and in 31 of the 36 who received cloxacillin plus gentamicin. Furthermore, the addition of gentamicin provided no additional benefit for duration of symptoms, incidence of complications, or duration of bacteremia after initiation of treatment. The duration of fever was slightly shorter (3.7 days compared with 4.2 days) and the incidence of renal failure was slightly higher (14% compared with 8%) in the combination therapy group than in the cloxacillin-only group, but these differences were neither clinically nor statistically significant.

Although ß-lactam antibiotics and aminoglycosides act synergistically against S. aureus in vitro [13] and although this synergism has been shown in animal models [14, 15], clinical studies of this combination have not shown a clinically significant advantage over single-drug therapy in standard 4- to 6-week treatment [4, 16-19]. Thus, it is accepted that single-drug therapy given for 4 weeks is adequate for most cases of S. aureus endocarditis [20].

Because right-sided endocarditis is usually less aggressive than left-sided disease [6, 21-23], the idea that right-sided S. aureus endocarditis in users of parenteral drugs could be treated with shorter regimens was suggested almost 20 years ago [24]. Parker and Fossieck [25] treated 32 cases of staphylococcal endocarditis with intravenous nafcillin for a mean of 16 days, followed by 4 weeks of oral dicloxacillin or oxacillin at oral doses unlikely to reach bactericidal levels within the vegetations. However, all patients completely recovered without relapse. In another study [26], all 13 patients who had right-sided endocarditis caused by methicillin-sensitive S. aureus who stopped treatment prematurely after receiving 10 to 14 days of cloxacillin plus an aminoglycoside recovered completely without relapse in the following 3 to 18 months.

Three recent studies [9-11] have shown that combination intravenous therapy with a penicillinase-resistant penicillin and an aminoglycoside for 2 weeks is adequate to treat uncomplicated right-sided S. aureus endocarditis. In the study by Torres-Tortosa and colleagues [10], 2-week treatment with cloxacillin plus amikacin was successful in 93% of 72 cases. Severe cardiac complications were an exclusion criterion; 8 patients were also excluded because of pleural empyema. In the study by Chambers and coworkers [9], 94% of 50 patients were cured with nafcillin and tobramycin. Only 16% of the patients had tricuspid vegetations. These characteristics suggest that the patients had less severe disease at baseline and thus better prognosis than did our patients, but the study results are similar to ours.

In these previous studies [9-11], combination treatment was given for 2 weeks on the basis of the assumption that the synergism seen in vitro and in animal models could decrease the duration of bacteremia. Our rationale for using cloxacillin alone in one group was that no clinically significant benefits of combination therapy have been shown even with longer courses of treatment. In the combination therapy group, we administered gentamicin only during the first week because this period is sufficient to eliminate bacteremia. The fact that we did not use gentamicin for 2 weeks may have been irrelevant because cloxacillin alone appeared to be so effective that the therapeutic results could not have been improved with any regimen.

Our study had several potential limitations, including the somewhat limited statistical power of our study design and the possibility that in some of the cases labeled "possible endocarditis," the source of staphylococcal bacteremia may not have been endocarditis. Additional studies are needed to confirm the therapeutic equivalence of short-course therapy with penicillinase-resistant penicillin alone and combination therapy.

In summary, our data suggest that a penicillinase-resistant penicillin used as single-agent therapy for 2 weeks is effective for most patients with isolated tricuspid endocarditis caused by methicillin-susceptible S. aureus and that the addition of gentamicin does not provide any important therapeutic advantages. As already suggested [8], we emphasize that single-drug treatment should be stopped at 2 weeks only if no evidence suggests active infection or complications at that point, especially with regard to new septic pulmonary metastasis. Otherwise, therapy should last for at least 4 weeks.

Drs. del Valle and Planes: Servicio de Microbiologia y Parasitologia, Unidad A.P.M.P., Hospital Vall d'Hebron, Paseo Vall d'Hebron 119-129, 08035 Barcelona, Spain.

Dr. Gonzalez-Alujas: Servicio de Cardiologia, Hospital General Vall d'Hebron, Paseo Vall d'Hebron 119-129, 08035 Barcelona, Spain.