1 Department of Microbiology, Queen Elizabeth Hospital, Birmingham; 2 Department of Microbiology, Papworth Hospital, Cambridge; 3 Department of Microbiology, Freeman Hospital, Newcastle-upon-Tyne; 4 Department of Medical Microbiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
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Abstract |
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Keywords: antibiotic therapy , guidelines , endocarditis , BSAC
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Contents |
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1. Introduction |
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Guidelines such as these have, in the past, received criticism for not being evidence based. Whereas we appreciate that the gold standard for all clinical guidelines should ideally be based on good, prospective, randomized controlled trials, no such trials have ever been performed to assess the benefit of antibiotic regimens in the treatment of endocarditis. Consequently we have not attempted to classify the evidence for our recommendations, which remain consensus based. An extensive review of the literatureencompassing a number of different search methods and a range of criteria (e.g. endocarditis, staphylococci, etc.)has been carried out, and publications used to support any changes we have made to the existing guidelines have been cited. Publications referring to in vitro or animal models have only been cited if appropriate clinical data are not available.
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2. Diagnosis and laboratory testing |
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In terms of laboratory testing, blood culture remains the cornerstone of diagnosis for the vast majority of IE cases. Patients with suspected IE, such as those with pyrexia and a heart murmur, should have blood cultures taken promptly before antimicrobial chemotherapy is given. Three sets of blood cultures should be taken in the first 24 h from separate venepunctures. It is recommended that at least 30 mL of blood is cultured in total.7 The timing of the initiation of therapy after this period depends upon the condition of the patient. In patients who are acutely ill, three sets of blood cultures should be taken within 2 h before starting empirical therapy.
Blood cultures should be incubated for a minimum of 7 days, which should result in a positive culture for 95% of IE cases.7 In exceptional circumstances, where blood cultures remain negative after 7 days in the absence of prior antibiotic therapy, and IE remains strongly suspected, extended incubation of cultures should be initiated that may facilitate the isolation of some fastidious microorganisms.3,810 In such cases, incubation of blood cultures should be continued for at least 3 weeks, with weekly subculture onto chocolate agar, which in turn should be incubated for 3 weeks in air plus 5% carbon dioxide.
Once the causative microorganism has been isolated, susceptibility testing should be performed with suitable antimicrobials. The choice and duration of treatment depend upon the type of microorganism and its susceptibility profile, allergy to antimicrobials and whether infection involves a native or prosthetic valve. A cidal antimicrobial, or combination of antimicrobials, is required to eradicate infection. A minimum inhibitory concentration (MIC) of the chosen antimicrobial should be established by a standardized laboratory method to ensure susceptibility.11 Etest strips may be useful for establishing the susceptibility of fastidious or slow-growing bacteria, such as the HACEK group12 (Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella spp., and Kingella spp.).
As in previous guidelines1 we do not recommend routine measurement of the minimum bactericidal concentration (MBC). MBC determination is affected by a range of technical factors that result in poor intra-laboratory reproducibility and there remains a lack of evidence regarding its clinical value. For the same reasons, the measurement of serum bactericidal titres is not recommended as a routine assay.
Failure to culture a causative microorganism in IE is most commonly due to the administration of antimicrobials prior to sampling, but may also be due to IE caused by fastidious or slow-growing microorganisms. Possible microorganisms that should be considered include the HACEK group, Bartonella spp., Brucella spp., Chlamydia spp., Coxiella burnetii (Q-fever), Legionella spp., mycobacteria and various fungi.3,1315 Diagnostic methods should include serological investigations where they are available, and such methods are central to the identification of Bartonella spp., Brucella spp., Chlamydia spp., C. burnetii, Legionella pneumophila and Mycoplasma pneumoniae. A systematic approach to the serological diagnosis of culture-negative IE is advised, based on the clinical history of the patient and their exposure to possible risk factors.1316 Molecular techniques for the detection of microbial nucleic acids show promise as an adjunct to existing methods for the diagnosis of endocarditis caused by fastidious or slow-growing microorganisms.1722
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3. Antibiotic regimens |
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Gentamicin dosage regimens are based on 8 hourly administration of 1 mg/kg body weight, intravenously (iv)/intramuscularly (im). Once-daily regimens are now widely used for other infections, but data regarding their efficacy in endocarditis are limited. Levels should be measured regularly to ensure pre-dose (trough) levels remain <1 mg/L. Maintaining post-dose (peak) levels between 35 mg/L has been advocated by other authorities, although the evidence to support this is limited. Where a patient has normal renal function that is stable, twice weekly monitoring may suffice. In patients with impaired renal function, dosage should be adjusted according to measured or estimated creatinine clearance and drug monitoring results, and levels monitored on a daily basis.
Streptomycin dosage is usually 7.5 mg/kg body weight 12 hourly and should be monitored at least twice weekly, (more often in renal impairmentsee above) by maintaining pre-dose levels <3 mg/kg, and adjusted according to renal function as with gentamicin.
3.2. Glycopeptides
3.2.1. Vancomycin
For patients with normal renal function we recommend 1 g iv 12 hourly. Levels should be monitored to maintain a pre-dose level between 1015 mg/L, although in enterococcal endocarditis some authorities recommend pre-dose levels of 1020 mg/L. Further monitoring and dose adjustment in patients with impaired renal function should be performed as for aminoglycosides.
3.2.2. Teicoplanin
Teicoplanin must be administered at a high dosage (10 mg/kg body weight 12 hourly then 10 mg/kg daily). Trough levels must be measured to ensure levels of at least 20 mg/L and repeated at least weekly.
3.3. ß-Lactams
In our recommendations for sensitive organisms, amoxicillin/ampicillin 2 g iv 46 hourly may be used instead of benzyl penicillin. The time-dependent killing of streptococci by penicillin means that the drug should be given at least six times a day because of its short serum half-life. There are theoretical and experimental reasons for using a continuous infusion of penicillin.23 There are, however, no prospective comparisons of continuous with intermittent penicillin for streptococcal endocarditis. Dosage modifications for ß-lactams may be necessary in patients with impaired renal function and according to the patient's body weight.
3.4. Alternative antibiotics for patients with penicillin allergy
It is important to establish the nature of a reported allergy to penicillin, as there is less experience with alternative antibiotics and a higher rate of side effects. For example, a history of a rash with ampicillin or amoxicillin may not indicate true allergy. Unless signs of immediate-type hypersensitivity (anaphylaxis, angio-oedema, bronchospasm, urticaria) were reported, a trial with penicillin may be warranted. The American Heart Association (AHA) advises ceftriaxone for the penicillin-allergic patientbut this should only be used for allergy other than immediate-type hypersensitivity because of the risk of cross-sensitivity with penicillin.
3.5. Empirical therapy
See Table 1 for a summary. Bacterial endocarditis (particularly prosthetic or Staphylococcus aureus endocarditis) may progress rapidly and in such cases antibiotic therapy must be commenced as soon as all the appropriate specimens have been collected. If the diagnosis of endocarditis is in doubt, the patient is clinically stable and has already received antibiotics, we recommend stopping any antibiotics for 24 days and re-culturing.
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3.6. Duration of therapy
Apart from the treatment of certain strains of penicillin-sensitive streptococci, we recommend a minimum of 4 weeks therapy. There is evidence from patients with enterococcal endocarditis and some data from early studies of streptococcal endocarditis to suggest that patients who have had symptoms for more than 3 months benefit from 6 weeks of penicillin.2425 Often these individuals have larger vegetations and mitral valve disease (also indicators of a poorer response). These factors should be taken into consideration when determining treatment length. Apparent failure to respond to treatment may indicate the need for surgical intervention. There is no evidence to support the use of oral follow-on therapy after completion of a course of treatment.
3.7. Home therapy
Home therapy for endocarditis has been described. Suitability for home therapy will depend on the patient, the availability of the infrastructure to support such therapy and the sensitivity of the infecting organism to antibiotics, which lend themselves to home therapy.
Home treatment is often considered for streptococcal endocarditis, as it can be less destructive, with fewer complications, than infection caused by other organisms. Trials of home therapy have been reviewed.26,27 Antibiotics such as ceftriaxone or teicoplanin, which can be given once daily iv or im, have been advocated as the patient may not need a central venous catheter. Neutropenia is, however, a well described side effect of ceftriaxone, occurring in two of 55 patients in one study.28 Teicoplanin also has side effects, including a high rate of drug fever (see section 5.8).
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4. Staphylococcal endocarditis |
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4.1. Prosthetic endocarditis
The complex nature of staphylococcal infection of prostheses leads us to recommend combination therapy including rifampicin (if sensitive) for both methicillin-sensitive and -resistant strains of staphylococci for at least the first 2 weeks of therapy. If the isolate is resistant to rifampicin, other agents may be considered (see above). The use of three antibiotics (if the isolate is sensitive) has been advocated by some authorities.43
4.2. Duration of therapy
The majority of patients will require at least 4 weeks therapy, which should be extended to at least 6 weeks in patients with intra-cardiac prostheses, and after removal of infected permanent pacing. However, in patients with right-sided endocarditis (often iv drug abusers), several trials have demonstrated the efficacy of short course iv combination therapy32,4448 and oral therapy.49 Other studies have demonstrated that iv to oral switch therapy to complete a course of antibiotics is effective,50 and may be considered in selected patients, for whom iv access is difficult.
4.3. New antibiotics
Since the publication of the last guidelines, new antibiotics such as linezolid51 and quinupristin/dalfopristin52 have become available. The use of these agents in the treatment of endocarditis has been described in the literature, but experience is still limited. We would only recommend the use of such agents as salvage therapy, in patients unable to tolerate conventional therapy, or from whom particularly resistant stains have been recovered. Similarly, the use of co-trimoxazole, quinolones and clindamycin has also been described in the literature, but we cannot advocate their routine use.5356
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5. Streptococcal endocarditis |
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For native valve endocarditis, there is evidence that 4 weeks of high-dose penicillin can be used for sensitive streptococci (MIC 0.1 mg/L), and that short-course treatment (2 weeks penicillin in combination with gentamicin) may be as effective. The short regimen should not be used if there is an intra-cardiac abscess or infected emboli. The AHA recommends 4 weeks penicillin plus gentamicin for the first 2 weeks for relatively resistant strains of viridans streptococci (penicillin MIC > 0.1<0.5 mg/L), but there is little evidence for this. We would agree that aminoglycosides should ideally be given for the first 2 weeks, but where the risks of using aminoglycosides are high, 4 weeks penicillin alone at the higher dose (2.4 g 4 hourly, adjusted for renal function) could be tried. The treatment of more resistant viridans streptococci (penicillin MIC
0.5 mg/L) should follow the recommendations for treating enterococci.
5.2. Streptococcus bovis
Streptococcus bovis should be treated using the same regimens for the viridans-type streptococci, based on the penicillin MIC. There is a strong association between endocarditis due to S. bovis and benign and malignant tumours of the gut and liver disease.57 It is easy in our experience to neglect investigation of the gut in the understandable drive to treat the endocarditis.
5.3. Nutritionally variant streptococci (NVS)
Endocarditis with NVS is characterized by an indolent course, frequent embolization and bacteriological relapse. Many NVS are relatively resistant to penicillin and show tolerance. Antibiotic susceptibility testing is difficult and may need to be carried out by a specialist laboratory. Four to six weeks of penicillin plus an aminoglycoside is recommended.58 Until more evidence is available on alternatives, NVS should also be treated according to the recommendations for treating enterococci. In view of the high relapse rate, blood should be cultured weekly during treatment and after completion of therapy.
5.4. Streptococcus pneumoniae
Pneumococcal endocarditis is usually associated with pneumonia and/or meningitis.59 The high mortality (28%60%) seems due to the destructive nature of the disease and patient factors rather than inadequate antibiotic treatment, as no bacteriological relapses were seen in patients with sensitive pneumococci treated with penicillin alone. There is little experience with high-level penicillin-resistant pneumococci, but a similar approach to the treatment of resistant pneumococcal meningitis is proposed, using ceftriaxone or vancomycin.60
5.5. Streptococcus pyogenes (Group A streptococcus)
Group A streptococci often behaves like S. aureus, causing acute destructive endocarditis and right-sided disease in iv drug abusers. Four weeks penicillin alone for these sensitive organisms has had a good success rate and is recommended.61
5.6. Streptococcus agalactiae (Group B streptococcus), Group C and G streptococci
Group B streptococci can cause acute endocarditis with a high mortality, often in patients with diabetes.62 Some strains are tolerant and relatively penicillin resistant; there is very little published on treatment. We therefore endorse the AHA cautionary approach of recommending 2 weeks of aminoglycosides in addition to 4 weeks penicillin for even sensitive strains. As information on endocarditis caused by group C and G streptococci is so limited, 4 weeks penicillin with 2 weeks gentamicin is also recommended.
5.7. Prosthetic valve endocarditis (PVE)
There is limited evidence on the optimum treatment of streptococcal PVE infections, and sensitive organisms may be difficult to treat. This is partly due to the involvement of the valve ring and myocardial abscesses. Early studies showed a high relapse rate with 2 weeks penicillin plus an aminoglycoside. We agree with the recommendation of a minimum of 6 weeks of penicillin, plus gentamicin for the first 2 weeks, for penicillin-sensitive streptococci (MIC 0.1 mg/L).63 The same author advises 6 weeks penicillin with 4 weeks gentamicin for more penicillin-resistant strains, but there are no studies comparing 4 and 6 weeks gentamicin. In view of the difficulty in replacing a prosthetic valve and the toxicity from a second course of aminoglycosides should initial treatment fail, it seems prudent to give 6 weeks of gentamicin (see Table 1) with penicillin for strains with a penicillin MIC > 0.1 mg/L.
5.8. Treatment of streptococcal endocarditis for patients allergic to penicillin
Vancomycin tolerance is said to be common, but there is evidence of synergy with aminoglycosides. The AHA advises 4 weeks of vancomycin alone for moderately penicillin-resistant streptococci (MIC > 0.1 < 0.5 mg/L). There is no clinical evidence to justify the omission of an aminoglycoside and the clinician has to balance the potential risks of toxicity against concern over relapse that could lead to a longer course of a potentially toxic combination. With close monitoring of vancomycin and gentamicin levels, we would advise vancomycin for 4 weeks with gentamicin for the first 2 weeks, for moderately resistant streptococci. Teicoplanin is considered less nephrotoxic by some, both alone and in combination with gentamicin. There is, however, less experience with its use and in early studies many patients on long-term teicoplanin developed drug fever.64 A dose of 6 mg/kg is advised for streptococcal endocarditis. Loading doses should be given and a trough level of 15 mg/L established.65 We recommend just a single measurement to establish a therapeutic level if the renal function is stable. Following a single report of S. bovis carrying the vanB gene,66 a vancomycin MIC should be measured for streptococci, rather than relying on disc-diffusion testing.
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6. Enterococcal endocarditis |
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Treatment of native valve infection requires a minimum of 4 weeks of iv antibiotics, whereas prosthetic valve endocarditis should be treated for a minimum of 6 weeks (see earlier comments on duration of therapy). Thereafter, the clinical response to therapy, inflammatory markers, repeat cultures and echocardiographic findings should guide the need for further antibiotics. Recommended regimens for the more frequently encountered resistance patterns are given in Tables 46. Endocarditis caused by penicillin-resistant, glycopeptide-resistant, high-level aminoglycoside-resistant enterococci is reported infrequently. In the event of such a case, antimicrobial options include linezolid, or quinupristin/dalfopristin or combinations of antibiotics according to in vitro susceptibility and new agents in development. Endocarditis caused by isolates displaying a VanB phenotype (vancomycin resistant, teicoplanin susceptible) have been treated with teicoplanin, but resistance may develop during monotherapy with this agent and treatment failures have occurred.69
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7. HACEK endocarditis |
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Treatment
If amoxicillin sensitive, 2 g amoxicillin/ampicillin should be administered iv 46 hourly, plus gentamicin 1 mg/kg body weight according to renal function (for the first 2 weeks only). Monitoring should be regular. If amoxicillin resistant: ceftriaxone 2 g should be administered (to a maximum of 4 g) iv (once daily) plus gentamicin as above.
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8. Q fever |
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Treatment
Doxycycline 100 mg should be administered once daily orally, plus ciprofloxacin 500 mg 8 hourly orally for at least 3 years.
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9. Bartonella endocarditis |
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Treatment
Amoxicillin/ampicillin 2 g iv should be administered 46 hourly, plus gentamicin 1 mg/kg 8 hourly. If penicillin allergic, use a tetracycline or a macrolide. Treatment should be continued for a minimum of 4 weeks.
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10. Other Gram-negative bacteria |
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11. Fungal endocarditis |
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The treatment of fungal endocarditis is currently unsatisfactory and usually requires surgical intervention. Analogous to bacterial endocarditis, antifungal regimens that are fungicidal may be preferable, although considerable work in terms of validation remains. Specific regimens must be given for a minimum of 6 weeks, but usually for much longer and in some circumstances (e.g. prosthetic valves) therapy may be life long.
Amphotericin B does not penetrate well into vegetations, but has been used successfully in Candida endocarditis. It is, however, toxic, particularly if given for prolonged periods, and there are few data concerning the efficacy of lipid-associated formulations in the treatment of endocarditis. Fluconazole is fungistatic and is only active against some Candida spp., Trichosporon spp. and some other yeasts. Flucytosine is also fungistatic, although the combination of amphotericin plus flucytosine is more likely to be fungicidal. Flucytosine, however, is associated with bone marrow toxicity and trough levels should not exceed 50 mg/L. Caspofungin is usually fungicidal for Candida spp. (although some isolates of Candida parapsilosis and Candida guilliermondii are less susceptible). However, there is as yet no experience of the use of caspofungin in endocarditis, and the penetration of caspofungin and other echinocandins into vegetations is unknown.
Susceptibility testing must be undertaken for any fungus causing endocarditis, including the determination of minimal fungicidal concentrations. For drugs with variable bioavailability, therapeutic drug monitoring is important.
Candida
Amphotericin B 1 mg/kg/day and flucytosine 100 mg/kg should be administered in four divided doses, according to renal function (first choice).
Or
Fluconazole 400 mg 12 hourly orally (second choice)
Or
Caspofungin 70 mg as a loading dose followed by 50 mg once daily, or 70 mg per day if weight >80 kg (first choice if intolerance or resistance precludes other options).
Aspergillus
Voriconazole 6 mg/kg 12 hourly for two doses (loading) should be administered, then 4 mg/kg 12 hourly intravenously or 400 mg 12 hourly for 24 h, followed by 200 mg 12 hourly orally
Or
Amphotericin B 1 mg/kg daily according to renal function.
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Acknowledgements |
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Footnotes |
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References |
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