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Journal of Antimicrobial Chemotherapy (2004) 54, 971–981DOI: 10.1093/jac/dkh474 Advance Access publication 16 November 2004 Guidelines for the antibiotic treatment of endocarditis in adults: report of the Working Party of the British Society for T. S. J. Elliott1, J. Foweraker2, F. K. Gould3*, J. D. Perry3 and J. A. T. Sandoe4 1Department of Microbiology, Queen Elizabeth Hospital, Birmingham; 2Department of Microbiology, Papworth Hospital, Cambridge; 3Department of Microbiology, Freeman Hospital, Newcastle-upon-Tyne; 4Department of Medical Microbiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK The BSAC Guidelines on Endocarditis were last published in 1998. The Guidelines presented herehave been updated and extended to reflect changes in both the antibiotic resistance characteristics ofcausative organisms and the availability of new antibiotics. Randomized, controlled trials suitable forthe development of evidenced-based guidelines in this area are still lacking, and therefore a consensusapproach has again been adopted. The Guidelines cover diagnosis and laboratory testing, suitableantibiotic regimens and causative organisms. Special emphasis is placed on common causes ofendocarditis, such as streptococci and staphylococci, however, other bacterial causes (such as entero-cocci, HACEK organisms, Coxiella and Bartonella) and fungi are considered. The special circum-stances of prosthetic endocarditis are discussed.
Keywords: antibiotic therapy, guidelines, endocarditis, BSAC 5.7 Prosthetic valve endocarditis (PVE)5.8 Treatment of streptococcal endocarditis for patients 3.4 Alternative antibiotics for patients with penicillin 3.5 Empirical therapy3.6 Duration of therapy In 1998, the Endocarditis Working Party of the British Society for Antimicrobial Chemotherapy published updated guidelines for the treatment of streptococcal, enterococcal and staphylococ- cal endocarditis.1 In the light of the introduction of new antibiotic agents and the emergence of increasingly antibiotic- resistant bacteria causing endocarditis the existing guidelines have been revised. They have been widened to include recom- 5.3 Nutritionally variant streptococci (NVS) mendations for the treatment of other bacterial and fungal causes 5.5 Streptococcus pyogenes (Group A streptococcus) Guidelines such as these have, in the past, received criticism 5.6 Streptococcus agalactiae (Group B streptococcus), for not being evidence based. Whereas we appreciate that the gold standard for all clinical guidelines should ideally be based *Corresponding author and Chair of the Working Party. Tel: +44-191-233-6161; Fax: +44-191-223-1224; E-mail: [email protected] JAC vol.54 no.6 q The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.
on good, prospective, randomized controlled trials, no such trials same reasons, the measurement of serum bactericidal titres is not have ever been performed to assess the benefit of antibiotic regimens in the treatment of endocarditis. Consequently we have Failure to culture a causative microorganism in IE is most not attempted to classify the evidence for our recommendations, commonly due to the administration of antimicrobials prior to which remain consensus based. An extensive review of the lit- sampling, but may also be due to IE caused by fastidious or erature—encompassing a number of different search methods slow-growing microorganisms. Possible microorganisms that and a range of criteria (e.g. endocarditis, staphylococci, etc.)— should be considered include the HACEK group, Bartonella has been carried out, and publications used to support any spp., Brucella spp., Chlamydia spp., Coxiella burnetii (Q-fever), changes we have made to the existing guidelines have been Legionella spp., mycobacteria and various fungi.3,13–15 Diagnos- cited. Publications referring to in vitro or animal models have tic methods should include serological investigations where they only been cited if appropriate clinical data are not available.
are available, and such methods are central to the identificationof Bartonella spp., Brucella spp., Chlamydia spp., C. burnetii,Legionella pneumophila and Mycoplasma pneumoniae. A sys- tematic approach to the serological diagnosis of culture-negativeIE is advised, based on the clinical history of the patient and Since 1994, the Duke criteria have formed the basis for the diag- their exposure to possible risk factors.13–16 Molecular techniques nosis of infective endocarditis (IE).2 Major diagnostic criteria for the detection of microbial nucleic acids show promise as an include positive blood cultures or positive echocardiogram. A adjunct to existing methods for the diagnosis of endocarditis range of minor criteria are included in the Duke strategy and caused by fastidious or slow-growing microorganisms.17–22 supplementary criteria have since been proposed to enhancediagnosis further.3–6 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 Gentamicin dosage regimens are based on 8 hourly adminis- antimicrobial chemotherapy is given. Three sets of blood cul- tration of 1 mg/kg body weight, intravenously (iv)/intramuscu- tures should be taken in the first 24 h from separate venepunc- larly (im). Once-daily regimens are now widely used for other tures. It is recommended that at least 30 mL of blood is cultured infections, but data regarding their efficacy in endocarditis are in total.7 The timing of the initiation of therapy after this period limited. Levels should be measured regularly to ensure pre-dose depends upon the condition of the patient. In patients who are (trough) levels remain <1 mg/L. Maintaining post-dose (peak) acutely ill, three sets of blood cultures should be taken within levels between 3 – 5 mg/L has been advocated by other auth- 2 h before starting empirical therapy.
orities, although the evidence to support this is limited. Where a Blood cultures should be incubated for a minimum of 7 days, patient has normal renal function that is stable, twice weekly which should result in a positive culture for 95% of IE cases.7 In monitoring may suffice. In patients with impaired renal function, exceptional circumstances, where blood cultures remain negative dosage should be adjusted according to measured or estimated after 7 days in the absence of prior antibiotic therapy, and IE creatinine clearance and drug monitoring results, and levels remains strongly suspected, extended incubation of cultures should be initiated that may facilitate the isolation of some fasti- Streptomycin dosage is usually 7.5 mg/kg body weight 12 dious microorganisms.3,8–10 In such cases, incubation of blood hourly and should be monitored at least twice weekly, (more cultures should be continued for at least 3 weeks, with weekly often in renal impairment—see above) by maintaining pre-dose subculture onto chocolate agar, which in turn should be incu- levels <3 mg/kg, and adjusted according to renal function as bated for 3 weeks in air plus 5% carbon dioxide.
Once the causative microorganism has been isolated, suscep- tibility testing should be performed with suitable antimicro- bials. The choice and duration of treatment depend upon thetype of microorganism and its susceptibility profile, allergy to 3.2.1 Vancomycin. For patients with normal renal function we antimicrobials and whether infection involves a native or pros- recommend 1 g iv 12 hourly. Levels should be monitored to thetic valve. A cidal antimicrobial, or combination of anti- maintain a pre-dose level between 10 – 15 mg/L, although in microbials, is required to eradicate infection. A minimum enterococcal endocarditis some authorities recommend pre-dose inhibitory concentration (MIC) of the chosen antimicrobial levels of 10 – 20 mg/L. Further monitoring and dose adjustment should be established by a standardized laboratory method to in patients with impaired renal function should be performed as ensure susceptibility.11 Etest strips may be useful for establish- ing the susceptibility of fastidious or slow-growing bacteria, 3.2.2 Teicoplanin. Teicoplanin must be administered at a high such as the HACEK group12 (Haemophilus spp., Actinobacillus dosage (10 mg/kg body weight 12 hourly then 10 mg/kg daily).
actinomycetemcomitans, Cardiobacterium hominis, Eikenella Trough levels must be measured to ensure levels of at least 20 mg/L and repeated at least weekly.
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 factorsthat result in poor intra-laboratory reproducibility and there In our recommendations for sensitive organisms, amoxicillin/ remains a lack of evidence regarding its clinical value. For the ampicillin 2 g iv 4 – 6 hourly may be used instead of benzyl Table 1. Recommendations for empirical therapy Flucloxacillin (8 – 12 g iv daily in 4 – 6 divided doses)plusgentamicin (1 mg/kg body weight iv 8 hourly, modified according to renal function) Penicillin (7.2 g iv daily in 6 divided doses) or ampicillin/amoxicillin (2 g iv 6 hourly)plusgentamicin (1 mg/kg body weight 8 hourly iv, modified according to renal function) Vancomycin (1 g 12 hourly iv, modified according to renal function) rifampicin (300 – 600 mg 12 hourly by mouth)plusgentamicin (1 mg/kg body weight 8 hourly iv, modified according to renal function) penicillin. The time-dependent killing of streptococci by penicil- lin means that the drug should be given at least six times a day Apart from the treatment of certain strains of penicillin-sensitive because of its short serum half-life. There are theoretical streptococci, we recommend a minimum of 4 weeks therapy.
and experimental reasons for using a continuous infusion of There is evidence from patients with enterococcal endocarditis penicillin.23 There are, however, no prospective comparisons of and some data from early studies of streptococcal endocarditis to continuous with intermittent penicillin for streptococcal endocar- suggest that patients who have had symptoms for more than 3 ditis. Dosage modifications for b-lactams may be necessary in months benefit from 6 weeks of penicillin.24–25 Often these indi- patients with impaired renal function and according to the viduals have larger vegetations and mitral valve disease (also indicators of a poorer response). These factors should be takeninto consideration when determining treatment length. Apparent 3.4 Alternative antibiotics for patients with penicillin allergy failure to respond to treatment may indicate the need for surgical It is important to establish the nature of a reported ‘allergy’ to intervention. There is no evidence to support the use of oral ‘fol- penicillin, as there is less experience with alternative antibiotics low-on’ therapy after completion of a course of treatment.
and a higher rate of side effects. For example, a history of a rashwith ampicillin or amoxicillin may not indicate true allergy.
Unless signs of immediate-type hypersensitivity (anaphylaxis, Home therapy for endocarditis has been described. Suitability angio-oedema, bronchospasm, urticaria) were reported, a trial for home therapy will depend on the patient, the availability of with penicillin may be warranted. The American Heart Associ- the infrastructure to support such therapy and the sensitivity of ation (AHA) advises ceftriaxone for the penicillin-allergic the infecting organism to antibiotics, which lend themselves to patient—but this should only be used for allergy other than immediate-type hypersensitivity because of the risk of cross- Home treatment is often considered for streptococcal endocar- ditis, 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 See Table 1 for a summary. Bacterial endocarditis (particularly teicoplanin, which can be given once daily iv or im, have been prosthetic or Staphylococcus aureus endocarditis) may progress advocated as the patient may not need a central venous catheter.
rapidly and in such cases antibiotic therapy must be commenced Neutropenia is, however, a well described side effect of ceftriax- as soon as all the appropriate specimens have been collected. If one, occurring in two of 55 patients in one study.28 Teicoplanin the diagnosis of endocarditis is in doubt, the patient is clinically also has side effects, including a high rate of drug fever (see stable and has already received antibiotics, we recommend stop- ping any antibiotics for 2 – 4 days and re-culturing.
If empirical therapy is indicated, we recommend a combi- nation of flucloxacillin (8 – 12 g daily in 4 – 6 divided doses) plusgentamicin (1 mg/kg body weight 8 hourly according to renal See Table 2 for a summary. The choice of treatment for function) if the patient is acutely unwell, or penicillin (or ampi- staphylococcal endocarditis will depend more on the antibiotic cillin/amoxicillin) plus gentamicin if the presentation is more sensitivity of the isolate than whether it is coagulase positive or indolent. If the patient has intra-cardiac prosthetic material, or negative. In the previous guidelines, therapy with benzyl penicil- MRSA is suspected, we recommend vancomycin (1 g 12 hourly lin was recommended for penicillin-sensitive strains. In practice, according to renal function) plus rifampicin (300 – 600 mg 12 hourly, orally) plus gentamicin (1 mg/kg 8 hourly iv). Therapy For methicillin-sensitive strains, we recommend flucloxacillin should be reviewed as soon as the aetiological agent is 2 g 6 hourly29,30 increasing to 2 g 4 hourly in patients weighing >85 kg. There is no evidence that the addition of gentamicin is Table 2. Summary of treatment recommendations for staphylococcal endocarditis Vancomycin (1 g iv 12 hourly), modified according to renal functionplusrifampicin (300 – 600 mg 12 hourly by mouth)*orgentamicin (1 mg/kg body weight 8 hourly, modified according to renal function)*orsodium fusidate (500 mg 8 hourly by mouth)* Flucloxacillin (2 g 4 – 6 hourly iv) or vancomycin (1 g iv 12 hourly, modified plusrifampicin (300 – 600 mg 12 hourly by mouth)*and/orgentamicin (1 mg/kg body weight 8 hourly, modified according to renal function)*and/orsodium fusidate (500 mg 8 hourly by mouth)* more likely to result in a successful outcome, but it is associated with an increased incidence of adverse effects.31,32 Therefore, we Since the publication of the last guidelines, new antibiotics such no longer recommend its routine use in the treatment of staphy- as linezolid51 and quinupristin/dalfopristin52 have become avail- lococcal endocarditis. There is no evidence that the addition able. The use of these agents in the treatment of endocarditis has of sodium fusidate offers any advantage,33 and the benefit of been described in the literature, but experience is still limited.
We would only recommend the use of such agents as salvage strains, or in patients with penicillin allergy we recommend van- therapy, in patients unable to tolerate conventional therapy, or comycin 1 g 12 hourly. Levels should be monitored and trough from whom particularly resistant stains have been recovered.
levels maintained between 10 – 15 mg/L. Owing to the reported Similarly, the use of co-trimoxazole, quinolones and clindamy- incidence of treatment failure, we do not recommend the routine cin has also been described in the literature, but we cannot advo- use of teicoplanin in the treatment of staphylococcal endo- carditis.35–37 As vancomycin is less active than flucloxacillin,38,39we recommend the addition of a second antibiotic to the treat-ment regimen. The choice of the second antibiotic will depend on the sensitivity of the infecting organism, with rifampicin40,41as the preferred choice, but may include gentamicin or sodium See Table 3 for a summary. Streptococci are common causes of native valve and late prosthetic valve endocarditis. They vary intheir susceptibility to penicillin and degree of resistance toaminoglycosides. Early clinical studies showed that short courses (10 – 14 days) with standard doses of penicillin had a high The complex nature of staphylococcal infection of prostheses relapse rate, even for streptococci that were extremely sensitive.
leads us to recommend combination therapy including rifampicin The combination of penicillin with an aminoglycoside gave bet- (if sensitive) for both methicillin-sensitive and -resistant strains ter results than penicillin alone, especially for streptococci that of staphylococci for at least the first 2 weeks of therapy. If the were relatively penicillin resistant or tolerant. A well considered isolate is resistant to rifampicin, other agents may be considered review of clinical evidence plus animal and in vitro studies led (see above). The use of three antibiotics (if the isolate is sensi- to the development of the AHA guidelines for the treatment of tive) has been advocated by some authorities.43 streptococcal endocarditis.43 We propose that they should beused, but there are areas where we would modify or expand theadvice as follows (see also Table 1).
The majority of patients will require at least 4 weeks therapy, which should be extended to at least 6 weeks in patients withintra-cardiac prostheses, and after removal of infected permanent For native valve endocarditis, there is evidence that 4 weeks of pacing. However, in patients with right-sided endocarditis (often high-dose penicillin can be used for sensitive streptococci iv drug abusers), several trials have demonstrated the efficacy of _ 0.1 mg/L), and that short-course treatment (2 weeks peni- short course iv combination therapy32,44–48 and oral therapy.49 cillin in combination with gentamicin) may be as effective. The Other studies have demonstrated that iv to oral switch therapy to short regimen should not be used if there is an intra-cardiac complete a course of antibiotics is effective,50 and may be con- abscess or infected emboli. The AHA recommends 4 weeks sidered in selected patients, for whom iv access is difficult.
penicillin plus gentamicin for the first 2 weeks for relatively Table 3. Summary of treatment options for streptococcal endocarditis Streptomycin is an alternative to gentamicin for streptomycin-sensitive, gentamicin-resistant isolates. (See sections on susceptibility testing, drug toxicity and monitoring levels.)aPenicillin and gentamicin for 2 weeks should not be used if there is an intracardiac abscess or extra-cardiac focus of infection.
bIf gentamicin or streptomycin is contraindicated (unacceptable risk of toxicity or a resistant bacterium).
cUse only for isolates that are susceptible to ceftriaxone (MIC < 0.5 mg/L).
dSix weeks treatment.
Dosage (NB all need to be adjusted in renal impairment): penicillin, 1.2 – 2.4 g, 4 hourly or by continuous infusion; gentamicin, 1 mg/kg (ideal body weight), 8 – 12 hourly; ampicillin or amoxicillin, 12 g,over 24 h; vancomycin, 1 g, 12 hourly; streptomycin, 7.5 mg/kg body weight, 12 hourly.
resistant strains of viridans streptococci (penicillin MIC > 0.1 – <0.5 mg/L), but there is little evidence for this. We would agree There is limited evidence on the optimum treatment of strepto- that aminoglycosides should ideally be given for the first 2 coccal PVE infections, and sensitive organisms may be difficult weeks, but where the risks of using aminoglycosides are high, 4 to treat. This is partly due to the involvement of the valve ring weeks penicillin alone at the higher dose (2.4 g 4 hourly, and myocardial abscesses. Early studies showed a high relapse adjusted for renal function) could be tried. The treatment of rate with 2 weeks penicillin plus an aminoglycoside. We more resistant viridans streptococci (penicillin MIC > agree with the recommendation of a minimum of 6 weeks of should follow the recommendations for treating enterococci.
penicillin, plus gentamicin for the first 2 weeks, for penicillin-sensitive streptococci (MIC < advises 6 weeks penicillin with 4 weeks gentamicin for more Streptococcus bovis should be treated using the same regimens penicillin-resistant strains, but there are no studies comparing 4 for the viridans-type streptococci, based on the penicillin MIC.
and 6 weeks gentamicin. In view of the difficulty in replacing a There is a strong association between endocarditis due to S. bovis prosthetic valve and the toxicity from a second course of amino- and benign and malignant tumours of the gut and liver disease.57 glycosides should initial treatment fail, it seems prudent to give It is easy in our experience to neglect investigation of the gut in 6 weeks of gentamicin (see Table 1) with penicillin for strains the understandable drive to treat the endocarditis.
with a penicillin MIC > 0.1 mg/L.
5.3 Nutritionally variant streptococci (NVS) 5.8 Treatment of streptococcal endocarditis for patientsallergic to penicillin Endocarditis with NVS is characterized by an indolent course,frequent embolization and bacteriological relapse. Many NVS Vancomycin tolerance is said to be common, but there is evi- are relatively resistant to penicillin and show tolerance. Anti- dence of synergy with aminoglycosides. The AHA advises 4 biotic susceptibility testing is difficult and may need to be weeks of vancomycin alone for moderately penicillin-resistant carried out by a specialist laboratory. Four to six weeks of peni- streptococci (MIC > 0.1 < 0.5 mg/L). There is no clinical evi- cillin plus an aminoglycoside is recommended.58 Until more evi- dence to justify the omission of an aminoglycoside and the clini- dence is available on alternatives, NVS should also be treated cian has to balance the potential risks of toxicity against concern according to the recommendations for treating enterococci. In over relapse that could lead to a longer course of a potentially view of the high relapse rate, blood should be cultured weekly toxic combination. With close monitoring of vancomycin and during treatment and after completion of therapy.
gentamicin levels, we would advise vancomycin for 4 weekswith gentamicin for the first 2 weeks, for moderately resistant streptococci. Teicoplanin is considered less nephrotoxic bysome, both alone and in combination with gentamicin. There is, Pneumococcal endocarditis is usually associated with pneumonia however, less experience with its use and in early studies many and/or meningitis.59 The high mortality (28% – 60%) seems due patients on long-term teicoplanin developed drug fever.64 A dose to the destructive nature of the disease and patient factors rather of 6 mg/kg is advised for streptococcal endocarditis. Loading than inadequate antibiotic treatment, as no bacteriological doses should be given and a trough level of 15 mg/L estab- relapses were seen in patients with sensitive pneumococci trea- lished.65 We recommend just a single measurement to establish a ted with penicillin alone. There is little experience with high- therapeutic level if the renal function is stable. Following a level penicillin-resistant pneumococci, but a similar approach to single report of S. bovis carrying the vanB gene,66 a vancomycin the treatment of resistant pneumococcal meningitis is proposed, MIC should be measured for streptococci, rather than relying on 5.5 Streptococcus pyogenes (Group A streptococcus) Group A streptococci often behaves like S. aureus, causing acutedestructive endocarditis and right-sided disease in iv drug abu- Enterococci are responsible for  10% of endocarditis episodes, sers. Four weeks penicillin alone for these sensitive organisms an incidence that has remained stable since the introduction of has had a good success rate and is recommended.61 penicillin. Enterococcus faecalis accounts for the majority ofcases, but other species such as Enterococcus faecium, Entero- 5.6 Streptococcus agalactiae (Group B streptococcus), coccus durans and Enterococcus gallinarum are occasionallyimplicated. Older men (mean age, >60 years) are most com- monly affected, but younger women may also be affected in Group B streptococci can cause acute endocarditis with a high association with pregnancy. Over 40% of the patients have no mortality, often in patients with diabetes.62 Some strains are underlying heart disease. Although one study has shown worse tolerant and relatively penicillin resistant; there is very little outcomes in patients with more than 3 months of symptoms published on treatment. We therefore endorse the AHA cau- prior to presentation,67 a more recent analysis has failed to corro- tionary approach of recommending 2 weeks of aminoglycosides in addition to 4 weeks penicillin for even sensitive strains. As Treatment of native valve infection requires a minimum of information on endocarditis caused by group C and G strep- 4 weeks of iv antibiotics, whereas prosthetic valve endocarditis tococci is so limited, 4 weeks penicillin with 2 weeks gentamicin should be treated for a minimum of 6 weeks (see earlier com- ments on duration of therapy). Thereafter, the clinical response Table 4. Recommended regimens for treatment of enterococcal endocarditis caused by an ampicillin-susceptible(MIC < patient provided isolate isvancomycin susceptible (MIC < patient provided isolate isteicoplanin susceptible (MIC < aProvided isolate is high-level gentamicin-susceptible (MIC <_ 128 mg/L).
Table 5. Regimens for treatment of enterococcal endocarditis caused by high-level gentamicin-resistant (MIC > 128 mg/L)isolate patient or ampicillin-resistant(MIC > 8 mg/L) isolate patient or ampicillin-resistant(MIC > 8 mg/L) isolate aStreptomycin can be added if the isolate is not high-level resistant. If streptomycin is considered inappropriate or the isolate is streptomycinresistant, the cell-wall acting agent should be continued for a minimum of 8 weeks.
Table 6. Regimens for treatment of enterococcal endocarditis VanB phenotype (vancomycin resistant, teicoplanin susceptible) caused by an ampicillin-resistant isolate (MIC > 8 mg/L) have been treated with teicoplanin, but resistance may developduring monotherapy with this agent and treatment failures have The HACEK group of microorganisms includes Haemophilus parainfluenzae, Haemophilus influenzae, Haemophilus aphrophi-lus, Haemophilus paraphrophilus, Actinobacillus actinomycetem- If high-level gentamicin-susceptible (MIC < and Kingella spp. These fastidious extracellular Gram-negativebacteria cause an estimated 3% of all cases of IE.16,58,70–74 to therapy, inflammatory markers, repeat cultures and echocar- Previously, treatment was based on ampicillin and gentamicin.
diographic findings should guide the need for further anti- As a result of the emergence of b-lactamase-producing strains, a biotics. Recommended regimens for the more frequently b-lactamase-stable cephalosporin should be selected for empiri- encountered resistance patterns are given in Tables 4 – 6. Endo- cal treatment.12,43 Native valve IE should receive 4 weeks of carditis caused by penicillin-resistant, glycopeptide-resistant, treatment and those with prosthetic valve IE, 6 weeks.
infrequently. In the event of such a case, antimicrobial options include linezolid, or quinupristin/dalfopristin or combinations ofantibiotics according to in vitro susceptibility and new agents If amoxicillin sensitive, 2 g amoxicillin/ampicillin should be in development. Endocarditis caused by isolates displaying a administered iv 4 – 6 hourly, plus gentamicin 1 mg/kg body weight according to renal function (for the first 2 weeks only).
bacterial endocarditis, antifungal regimens that are fungicidal Monitoring should be regular. If amoxicillin resistant: ceftriax- may be preferable, although considerable work in terms of vali- one 2 g should be administered (to a maximum of 4 g) iv (once dation remains. Specific regimens must be given for a minimum of 6 weeks, but usually for much longer and in some circum-stances (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, how- C. burnetii is an obligate intracellular pathogen. Endocarditis is ever, toxic, particularly if given for prolonged periods, and there the prime manifestation of chronic Q-fever16,75,76 and C. burnetii are few data concerning the efficacy of lipid-associated formu- causes up to 3% of all cases of IE in England and Wales.77 The estimated incidence of IE in those who contract Q-fever ranges fungistatic and is only active against some Candida spp., from 7%78 to 67%.79 Patients likely to develop Q-fever IE are Trichosporon spp. and some other yeasts. Flucytosine is also those with predisposing valvular damage or prosthetic heart fungistatic, although the combination of amphotericin plus flu- valves.80 Antibody titres should be determined every 6 months cytosine is more likely to be fungicidal. Flucytosine, however, is while on treatment and then every 3 months once treatment has associated with bone marrow toxicity and trough levels should been discontinued, for a minimum of 2 years. Long-term treat- not exceed 50 mg/L. Caspofungin is usually fungicidal for Can- ment (3 years) with tetracycline and a quinolone has been rec- dida spp. (although some isolates of Candida parapsilosis and Candida guilliermondii are less susceptible). However, there isas yet no experience of the use of caspofungin in endocarditis, and the penetration of caspofungin and other echinocandins intovegetations is unknown.
Doxycycline 100 mg should be administered once daily orally, Susceptibility testing must be undertaken for any fungus caus- plus ciprofloxacin 500 mg 8 hourly orally for at least 3 years.
ing endocarditis, including the determination of minimal fungici-dal concentrations. For drugs with variable bioavailability, therapeutic drug monitoring is important.
Bartonella spp. are facultative intracellular Gram-negativeaerobic bacteria that cause up to 3% of all cases of IE.14,16,83–89 100 mg/kg should be administered in four divided doses, Amoxicillin/ampicillin 2 g iv should be administered 4 – 6 according to renal function (first choice).
hourly, plus gentamicin 1 mg/kg 8 hourly. If penicillin allergic, use a tetracycline or a macrolide. Treatment should be continued Fluconazole 400 mg 12 hourly orally (second choice) 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 intoler- ance or resistance precludes other options).
A wide range of other Gram-negative species with different sus- Voriconazole 6 mg/kg 12 hourly for two doses ceptibility patterns has been described and it is therefore difficult (loading) should be administered, then 4 mg/kg 12 hourly to recommend general treatment guidelines.3,16,58,90–108 Clinical intravenously or 400 mg 12 hourly for 24 h, followed by 200 mg experience has been well reviewed,16,91 and the contribution of animal studies to combination therapy has been described.96 The general themes are that a combination of antibiotics may offer Amphotericin B 1 mg/kg daily according to renal function.
synergy and prevent the emergence of resistance in long-termtreatment. The prognosis is generally poor, but best outcomesresult from using high-dose antibiotics (chosen after careful sen- sitivity testing) and early surgery.
The Working Party would like to thank Dr David Denningfor his input on the section relating to fungal endocarditis.
We would also like to thank Dr Ruth Rae and Dr Richard Fungal endocarditis is an unusual form of endocarditis compris- ing 2% – 4% of all cases. It is most common in iv drug abuseand prosthetic valve endocarditis, but has also been described in patients with neutropenia or haematological malignancy, follow- 1. Working Party of the British Society for Antimicrobial Chemo- ing cardiac surgery, solid organ transplantation and chronic gran- therapy (1998). Antibiotic treatment of streptococcal, enterococcal and ulomatous disease. The most common fungi causing endocarditis staphylococcal endocarditis. Heart 79, 207 – 10.
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MRCP Part 2 A Revision for the New Format of the Written Section FARHAD U HUWEZ - Basildon General Hospital, UK UDAYARAJ UMASANKAR - Lewisham General Hospital, UK CHRISTOPHER AH WAH CHAN - Colchester General Hospital, UK KEY SELLING POINTS BOOK INFORMATION Includes both interesting “rarities” and This revision guide has been written to assist candidates s


CURRICULUM VITAE Sriram Dasu Associate Professor Data Sciences and Operations Marshall School of Business University of Southern California Los Angeles CA 90089 I. EDUCATION 1980 B.Tech (Mechanical Engineering) Indian Institute of Technology, Bombay. 1982 MBA (Operations Management) Indian Institute of Management, Calcutta II. RESEARCH PUBLICATIONS 1. S. Dasu, R. Ahmadi, and S.M.

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