Microbiology Department, Freeman Hospital, High Heaton, Newcastle upon Tyne NE7 7DN, UK
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Abstract |
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Introduction |
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Viridans streptococci and Streptococcus bovis |
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Animal models of endocarditis demonstrated that penicillin and streptomycin in combination was more effective than penicillin alone in fully susceptible as well as penicillin-tolerant and -resistant (MIC 1.0 mg/L) strains.5,6 More rapid eradication of fully susceptible streptococci from vegetations (determined by bacterial counts and relapse after discontinuation of therapy) has been demonstrated with both streptomycin and gentamicin,7 but combination therapy is less effective against tolerant and resistant strains than fully susceptible isolates.
As these studies indicate that a shorter duration of combination therapy could be effective, clinical studies using a 2 week regimen were carried out, largely with streptomycin as at that time gentamicin was not widely used. An overall relapse rate of 2% was reported, but higher relapse rates occurred when dihydrostreptomycin was used instead of streptomycin.8 Of the 142 patients in the Mayo Clinic series, 18% were infected with penicillin-tolerant strains and 5% were infected with relatively resistant strains (MIC 0.2 1 mg/L). Only one relapse was seen and that was due to a fully susceptible (non-tolerant) strain.8 Although the 2 week regimen was successful, patients with shock' or extracardiac foci of infection were excluded and therefore conclusions about the efficacy of abbreviated therapy cannot be applied to these patient groups or to patients with prosthetic valves.
Length of hospital stay contributes significantly to the treatment costs of bacterial endocarditis, and although outpatient therapy has always been possible it is facilitated by antibiotics such as ceftriaxone that can be administered od. Furthermore, in vivo animal studies have shown that od aminoglycosides could be used with the same efficacy as multidose regimens. Penicillin and gentamicin (1 mg/kg im tds) was compared with penicillin and gentamicin (3 mg/kg im od); reductions in bacterial counts from vegetations were seen with both regimens, in infections from penicillin-susceptible, -tolerant and relatively resistant strains. However, a significant fall in efficacy was seen when the daily dose of gentamicin was reduced to 1 mg/kg/day.9
Sexton et al.10 compared ceftriaxone and iv gentamicin (3 mg/kg od) for 2 weeks with ceftriaxone monotherapy for 4 weeks. Higher rates of cardiac surgery were noted in the combination group but in both groups only one microbiological failure was recorded. Similarly, ceftriaxone and iv netilmicin (4 mg/kg od) has been used in a non-comparative study.11 However, only a small number of patients were evaluated, and exclusion of patients with prosthetic valves and intracardiac or extracardiac abscesses mean that this regimen cannot be widely applied.
Although most published clinical data are with penicillin and streptomycin, there are good laboratory and animal data to support the use of gentamicin. In viridans streptococci high-level aminoglycoside resistance is uncommon but is more frequently reported with streptomycin than gentamicin.3 Streptomycin-resistant isolates can still be killed in vitro synergically by the combination of penicillin and gentamicin; greater efficacy is seen against such strains in an animal model.1214 Conversely, gentamicin-resistant isolates do not always demonstrate high-level streptomycin resistance, and synergy may be lost at lower MIC values (64 mg/L in one study).15 Loss of synergy results in slower sterilization of vegetations and the need for more prolonged antibiotic therapy, and a 2 week regimen is unsuitable when high-level aminoglycoside resistance is found.
Dosage regimens recommended in current UK guidelines are not supported by the literature.1 The AHA guidelines suggest a post-dose level of c. 3 mg/L, and in 1986 the BSAC working party recommended concentrations of 35 mg/L 20 min after a dose. If the latter are multiplied by 0.67, a 1 h post-dose range of 24 mg/L should be the aim, not 35 mg/L at 1 h post-dose as is currently recommended.2,16 Animal data suggest using either 1 mg/kg tds or 3 mg/kg od. If a tds regimen is used a 1 h post-dose level of 3 mg/L should be aimed for, and pre-dose levels with either regimen should be <1 mg/L. Ideally, a prospective study should compare the effectiveness of these two regimens, but differences in efficacy are likely to be small, and ongoing clinical demands are likely to result in od regimens being more widely adopted.
Beyond 2 weeks aminoglycosides may not be beneficial and indeed a number of patients with tolerant and relatively resistant isolates have been successfully treated with a 2 week regimen.8 The Mayo series included seven patients with relatively resistant strains: MIC of 0.2 mg/L for four, 0.5 mg/L for two and 1 mg/L for one. The UK guidelines suggest continuing gentamicin for 4 weeks if the MIC >0.1 mg/L, but the USA guidelines only recommend this when the MIC is 0.5 mg/L. They do, however, suggest that if the isolate MIC is >0.1 but <0.5 mg/L then a ß-lactam alone should be continued for a further 2 weeks. As this latter regimen offers a number of advantages in terms of reduced risk of aminoglycoside toxicity and outpatient administration of antimicrobials it should be considered and studied more widely.
In the UK guidelines one condition that needs to be present when a 2 week regimen is used is that vegetations 5 mm diameter are seen on echocardiography.1 We could find no clinical studies to support this. Animal studies indicate that delay in treatment, and therefore vegetation size, may alter outcome but efficacy varies depending on which drug is used.17 However, those patients with right-sided vegetations >1 cm require surgical intervention more frequently for persistent fever,18 and vegetations >1 cm or increasing in size during therapy carry a higher risk of embolization and are unsuitable for outpatient therapy.19
Many fewer data are available on penicillin-allergic patients for whom a glycopeptide is recommended in the UK.1 The USA guidelines also suggest ceftriaxone in this clinical situation.2 Penetration of glycopeptides into vegetations is poor and tolerance to vancomycin is common, although synergy is demonstrated with aminoglycosides.20,21 We may not, however, be able to draw direct comparisons until more animal and human data are available. Bouvet et al.22 found vancomycin to be as effective as the combination of penicillin plus an aminoglycoside in the treatment of experimental endocarditis due to nutritionally variant streptococci. It would seem prudent to use these agents with an aminoglycoside but this has to be weighed up against increased risks of toxicity23 and, in the absence of experimental data, the use of aminoglycosides with glycopeptides should be decided on an individual patient basis.
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Enterococci |
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Clinical data comparing gentamicin at 3 mg/kg/day or less or more than 3 mg/kg/day (combined with benzyl penicillin using a tds iv regimen) show similar efficacy, but nephrotoxicity was greater in the high dose group (2/10 versus 10/10, respectively). The increase in creatinine in the two patients in the low dose group occurred at 22 and 24 days, but in the high dose group it occurred after a mean of 10.4 days into the 28 day course of therapy.31 Patients given gentamicin faired worse in this study than those given streptomycin but this may have been due to the longer duration of symptoms as this, along with involvement of the aortic valve, seems to be a risk factor for relapse or death.32 Four weeks of therapy is usually adequate but, as suggested by Wilson's study, the USA guidelines advise 6 weeks if symptoms are of >3 months duration.2,3134
All enterococci display intrinsic low-level aminoglycoside resistance as a result of facultative anaerobic metabolism that limits drug uptake, but synergy is, however, maintained with cell wall agents.35 Strains of Enterococcus faecium also possess an aminoglycoside acetyltransferase [AAC(6')] that confers high-level resistance to tobramycin, netilmicin and kanamycin, and eliminates synergy of these aminoglycosides with cell wall active agents.35
Clinically significant high-level aminoglycoside resistance with loss of synergic activity with penicillin was first demonstrated with kanamycin and streptomycin.36 High-level streptomycin resistance is due either to modification of a ribosomal protein or to the presence of aminoglycoside-modifying enzymes. Although gentamicin may still be active when resistance of this type is encountered, a recent study from the Central Public Health Laboratory in England showed that 26% of referred enterococci causing endocarditis displayed high-level gentamicin and streptomycin resistance.37 Resistance to gentamicin does not preclude streptomycin susceptibility, and levels of resistance to these and other aminoglycosides for each isolate must be fully assessed.35 High-level resistance precludes use of aminoglycosides and amoxicillin monotherapy may need to be given.
Enterococci may be resistant to amoxicillin, and penicillin allergy may also necessitate the use of a glycopeptide. Tolerance to these agents is common and this, along with their reduced penetration into vegetations, indicates that combination with an aminoglycoside should be used.19 Both streptomycin and gentamicin have been shown to exert a synergic effect in strains not showing high-level resistance. Gentamicin may be efficacious in od dose but few clinical data are available.30,38 Venditti et al.39 treated six patients with teicoplanin and od aminoglycoside, three receiving gentamicin 5 mg/kg/day. Duration of combination therapy was at least 28 days and all patients were cured, as was one patient treated with teicoplanin alone. Combining aminoglycosides with vancomycin increases the risk of nephrotoxicity by 13.3% compared with therapy with vancomycin alone.23
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Staphylococcus aureus |
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In both retrospective and prospective studies, the addition of an aminoglycoside has not been shown to improve overall clinical outcome, although in one study it did reduce embolic complications and may be associated with increased renal toxicity.40,4649 As mentioned above, patients with endocarditis due to a tolerant strain fare less well than those infected with a fully susceptible strain and this seems to occur despite the addition of an aminoglycoside.46 The clinical evidence to indicate that aminoglycosides are beneficial in the treatment of endocarditis is predominantly anecdotal and may be based on the more rapid clearance of bacteraemia when these agents are used with ß-lactams.47 It is also worth noting that combination therapy produces a more rapid clinical response (defervescence of pyrexia and normalization of white cell count) amongst intravenous drug users.47 It is difficult to recommend the routine use of aminoglycosides although some will advocate them in complex cases, such as those with persistent bacteraemia or metastatic sequelae.
Aminoglycosides may be of benefit when short-course treatment is used, for example in combination with cloxacillin for right-sided endocarditis in intravenous drug abusers. In this situation aminoglycosides are given for 2 weeks; however, monotherapy with ß-lactams may be equally effective.4951 Short-course therapy is less successful with glycopeptides, even in combination with an aminoglycoside.52
If aminoglycosides are to be used in non-drug users, the shorter duration and lower dose recommended by the AHA would seem appropriate. No studies comparing different dosing regimens of aminoglycosides have been published and we could find no data to support the higher doses and levels recommended by BSAC.1 However, in experimental endocarditis, rats given cloxacillin and only 2.5 mg/kg of gentamicin (1 h post-dose levels of 2.9 ± 0.6 mg/L) have significantly more sterile blood cultures than those given cloxacillin alone.44 Furthermore, no consistent data are available on single daily dose administration in this clinical situation.53
Vancomycin is recommended for the treatment of methicillin-resistant S. aureus and for patients allergic to ß-lactams. Killing with this agent is slower and treatment failures of up to 30% with monotherapy have been reported, falling to 15% when combined with gentamicin or rifampicin.5355 In vitro addition of aminoglycosides has been shown to be beneficial in pharmacodynamic and rabbit models.56,57 The optimal management of such patients is difficult and ideally a study comparing vancomycin with rifampicin or vancomycin with gentamicin should be carried out. Studies looking at treatment of experimental endocarditis due to Staphylococcus epidermidis in the rabbit model indicate that a combination of all three agents is the most effective and may help prevent the emergence of rifampicin-resistant clones.58 The evidence to support prolonged gentamicin administration is not well documented or established.53
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Prosthetic valve endocarditis |
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For PVE due to S. aureus, valve replacement surgery during medical therapy, even in the absence of cardiac complications, improves outcome.59 Duration of therapy will depend on surgical findings and peri-operative culture results, essentially 6 weeks of therapy is given following valve replacement if cultures are positive or there is surgical evidence of infection.53 Coagulase-negative staphylococci are a common cause of endocarditis in this group. Early clinical studies, although small, indicate that monotherapy with a ß-lactam may be adequate for susceptible isolates but current recommendations suggest that, as with vancomycin, combination therapy with an aminoglycoside (for the first 2 weeks of therapy) and with rifampicin for the full 6 week course should be used.2,60 This regimen may prevent the emergence of rifampicin-resistant clones.58 However, all treatment must be individually tailored on the basis of susceptibility testing.
Gram-negative organisms such as coliforms and Pseudomonas aeruginosa may cause endocarditis. Although third-generation cephalosporins and an aminoglycoside are frequently administered, treatment must always be tailored to the individual isolate. When used, aminoglycosides are usually given for the full 6 weeks of therapy and may need to be given in high dose such as tobramycin 8 mg/kg/day in three divided doses. It should be recognized that resistance may emerge on therapy and that prompt surgical intervention is often necessary in such patients.61
Aminoglycosides are also used (usually in combination with a ß-lactam) for endocarditis due to a number of organisms less frequently encountered. These include Abiotrophia spp., Listeria monocytogenes, ß-haemolytic streptococci and the HACEK group of organisms.2,62
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Conclusions |
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Notes |
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References |
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3
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