Oral antibiotic therapy for the treatment of infective endocarditis: a systematic review

The hallmark lesion of IE is the endocardial vegetation, a meshwork of platelets, fibrin, bacteria and inflammatory cells in which bacteria proliferate, invade adjacent tissues, and disseminate as septic emboli [1, 2]. So long as bacteria are embedded in vegetations, the ability of the immune system to assist with the eradication of these organisms is greatly impaired [1, 2]. This characteristic underlies the concept, supported by experimental and clinical observations, that high serum levels of bactericidal antibiotics for prolonged periods of time are needed for curing this infection [1‐3]. Before the advent of antibiotic therapy, infective endocarditis (IE) was invariably fatal.

Antibiotics delivered intravenously achieve rapid therapeutic concentrations in blood and perfused tissues, and they are generally regarded as more potent and reliable than their oral counterparts. For these reasons, intravenous (IV) antibiotics are considered the cornerstone of IE treatment [4]. The recommended duration of IV antibiotic therapy for IE varies depending on the characteristics of the infecting organism and the affected endocardial structure but in no instance it is <2 weeks and in most cases it extends beyond 4 weeks [5]. However, there are instances in which the options of effective intravenous antibiotics are limited (patients with multiple allergies, resistant bacteria, etc.) or the maintenance of prolonged intravenous access is not desirable (i.e. active intravenous drug users) or at all feasible (i.e. patient’s inability to maintain intravascular access). In these situations, oral antibiotic therapy can be an attractive and convenient alternative. However, little is known about the value of this strategy in the setting of IE.

Using a systematic approach, this review examines the literature on the efficacy of oral antibiotic therapy in the treatment of IE.

Our review protocol conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [6].

Of a total of 709 titles retrieved by our search strategy, 25 articles were considered for review based on their title and abstract. Hereafter, 14 more articles were excluded based on exclusion criteria (Additional file 2), leaving 11 studies for the final analyses [9‐19] (Figure 1). Of these, 9 were observational [9‐17] and 2 were randomized controlled trials (RCTs) [18, 19]. Tables 1 and 2 summarize the characteristics of the selected studies.

Previous narrative reviews advocated a limited role for oral antibiotics in the treatment of IE [4]. These opinions, however, were largely based on theoretical considerations and anecdotal experience [4]. In contrast, this study is the first systematic analysis of the existing published evidence on this topic.

The success of antibiotics in controlling bacterial growth and replication is dependent on: a) The susceptibility of the pathogen to the anti-infective that is used; b) The pharmacokinetics of this drug (i.e. whether its bioavailability and distribution allow it to reach the site of infection in sufficient concentration); and, c) Appropriate duration of therapy (especially when the 2 previous criteria are not fully met). Although the first available formulations of antibiotics had unpredictable absorption when given orally, more stable and absorbable compounds soon became available [4]. Oral beta-lactams used in the studies of this review included, among others, ampicillin, amoxicillin, phenithicillin and penicillin V [11‐15]. Although the pharmacokinetic profile of oral ampicillin is known to be suboptimal [20], the studies in which this antibiotic was used reported high response rates [12‐14]. This is likely explained by the fact that the organisms causing IE in those series were mainly streptococci (which remain highly sensitive to beta-lactams to this date - penicillin MIC ≤0.12), and that large doses of oral ampicillin were used, frequently supplemented with probenecid [12, 14]. Oral amoxicillin, on the other hand, has excellent bioavailability (>90%) and low binding to serum proteins (17%), which maximizes its tissue penetration [21]. Typical doses of oral amoxicillin (1 g q8h) produce peak and 6-hour serum concentrations of 16ug/ml and 1.1 ug/ml, respectively [4, 22, 23]. Further, adding probenecid 1 g to each dose of amoxicillin increases its peak and trough serum concentrations by 30% and 4-fold, respectively [22]. In our review, we found only one observational study reporting 80% cure rate with oral amoxicillin in 15 cases of IE caused mainly by susceptible streptococci, and one poor-quality small clinical trial (n = 30) in which the use of high-dose oral amoxicillin for 2 weeks after 2 initial weeks of IV ceftriaxone resulted in the cure of all patients in the treatment arm [11, 19]. Therefore, while pharmacological considerations make oral amoxicillin a plausible alternative for the treatment of IE caused by susceptible bacteria, the clinical evidence supporting this approach is still not robust. However, because streptococci continue to be a leading cause of IE (40% - 60% of native valve endocarditis in the community setting) [1] and oral amoxicillin is inexpensive and widely available, this therapeutic approach should be further investigated in adequately designed clinical trials. Beacause oral penicillin V and phenithicillin also have favourable pharmacokinetic profiles, the same considerations apply to these drugs [24‐26].

S. aureus is the second most prominent cause of community acquired IE and the leading cause among those who acquired the infection in healthcare settings and among IVDUs [2]. Ciprofloxacin has bactericidal activity against S. aureus and a favourable pharmacokinetic profile when given orally (70% bioavailability and serum protein binding rate of 30%), but the emergence of resistance during treatment of S. aureus experimental disease is well described [27, 28]. Similarly, rifampin is bactericidal against S.aureus, has almost complete oral bioavailability, and shows little binding to serum proteins; however, it also has a low threshold for the development of spontaneous resistance during therapy [29]. Although combining both agents has unpredictable effects in their anti-bacterial activity in vitro (i.e. synergistic versus antagonistic), it consistently reduces the development of resistance to either drug [30, 31]. We identified one prospective observational study [10] and one randomized clinical trial [18] in which the combination of oral ciprofloxacin and rifampin proved not only effective against uncomplicated S. aureus right-sided IE in IVDUs but, in the latter case, it was better tolerated than conventional IV therapy. However, the methodological limitations of these studies (Tables 3 and 4) warrant confirmatory investigations before this approach could be widely adopted. In the meantime, this antibiotic combination regimen should only be used in selected cases for which currently favored IV regimens (including beta-lactams or glycopeptides) are not suitable. Notably, development of resistance to the combination of ciprofloxacin and rifampin has been reported in at least one human case of IE [32]. Newer fluoroquinolones such as levofloxacin and moxifloxacin also have favourable pharmacologic profile when given orally and are bactericidal against S. aureus, and in contrast to ciprofloxacin, the development of in-vivo resistance appears rare [27, 33, 34]. Both levofloxacin and moxifloxacin have also proved effective in animal models of infective endocarditis [35, 36] and in anecdotal human cases [37, 38]. Therefore, it would also be reasonable to consider the oral formulations of these drugs in future studies for the treatment of this infection. We found that clinical experience with the use of oral anti-staphylococcal penicillins such as cloxacillin and flucloxacillin (used in one report of our review) [13] for the treatment of S. aureus IE is very limited and therefore, this approach should only be considered in controlled research settings.

Other oral antibiotics used in the reports identified by our review include linezolid, aureomycin, sulphonamide, and erythromycin [9, 10, 13, 17]. Oral linezolid has excellent pharmacologic profile (bioavailability >99% and serum protein binding rate 30%) and there is a growing body of evidence of its efficacy in serious infections caused by Gram-positive cocci [39]. The promising results with the use of oral linezolid for the treatment IE reported by Colli et al [9] warrant further confirmation in clinical trials. Aureomycin (chlortetracyclin) is an old tetracycline derivative with almost complete GI absorption that is no longer available for clinical use [40]. Aureomycin was only 36% effective in a small series of 11 patients with IE mainly due to E. faecalis and strepcocci [16]. However, newer tetracyclines such as minocycline and doxycycline (which also have excellent bioavailability and are active against gram positive organisms) have more recently been proposed as potential oral alternatives for treatment of IE caused by common bacteria [4]. Doxycycline has long been used for treatment of Q fever IE [41, 42] but its unpredictable efficacy against S.aureus would limit its use in other IE settings. Minocycline, on the other hand, has consistent and reliable activity against gram-positive organisms, including S. aureus, and has been effective in animal models of IE caused by this bacterium [43, 44]. Anecdotal reports of clinical success with the use oral minocyline in the treatment S. aureus IE in humans further support its consideration in future investigations [45, 46]. The report by Schein et al [17] describing single sulfa therapy (i.e. sulphonamide) for IE has only historical relevance, as this therapy is no longer available for oral use. Trimethroprim – sulfamethoxazole, however, a more contemporary sulfa-containing drug with excellent oral bioavailability has been shown to be inferior to vancomycin in treating uncomplicated right-side S. aureus IE in IVDU when given intravenously [47]. Finally, experience with the use of oral macrolides such as erythromycin in the treatment of severe infections is very limited and the growing rates of resistance to macrolides among streptococci and staphylococci are a further concern [48‐50].

Our review has limitations. It is possible that we missed evidence beyond the boundaries of our search strategies. As mentioned above, a majority of the studies included in our analyses had poor methodological quality. The significant heterogeneity in their study populations and designs prevented us from calculating any meaningful pooled estimates. Comprehensive analyses of drug safety, side effects, and comparative costs were largely lacking. We cannot rule out potential publication bias against studies that found poor effectiveness of oral antibiotic therapy in IE. Finally, since we limited our review to studies in which no parenteral antibiotic was used beyond the two weeks of treatment, the value of oral regimens as step-down therapy for IE beyond this time interval might have not been fully captured.

In conclusion, oral antibiotics with favourable pharmacokinetic profiles appear effective in treating selected cases of IE caused by susceptible organisms. Because of its favourable pharmacokinetic profile, high-dose oral amoxicillin for the treatment of IE caused by susceptible streptococci is particularly appealing but studies of better quality are needed before further recommendations can be made about this approach in clinical settings. The same considerations apply to the use of oral linezolid in cases of S. aureus IE. Oral combination therapy with ciprofloxacin and rifampin appears to be an acceptable alternative for the treatment of uncomplicated right-side endocarditis caused by susceptible strains of S. aureus in IVDUs but until adequate clinical trials are available, this approach should be reserved for special situations in which conventional IV antibiotic therapy is not possible or it is undesirable. Ongoing and future investigations should help to better define the role of oral antibiotics in the treatment of IE [51].