New developments in the treatment of infective endocarditis (infective cardiovasculitis)

International Journal of Antimicrobial Agents 13 (1999) 79 – 92 www.elsevier.com/locate/isc

Review

New developments in the treatment of infective endocarditis (infective cardiovasculitis) Erno¨ Gutschik * Department of Oral Microbiology, Faculty of Health Ser6ices, School of Dentistry, Uni6ersity of Copenhagen, Nørre Alle 20, DK-2200 Copenhagen, Denmark Received 14 April 1999; accepted 21 May 1999

Abstract The natural history of infective endocarditis has undergone remarkable changes over the past 100 years as regards both the demographic characteristics of the disease and changes in the incidence of the so-called diagnostic signs. Alongside these changes and the development of new and better diagnostic tools and criteria, we are also facing new problems with the precise definition of cardiovascular infections and calculation of the incidence of the disease. Nosocomial endocarditis presents an emerging problem of diagnosis and treatment after heart valve surgery, with pace-maker catheters, defibrillators and a very large variety of foreign materials used in connection with heart valve surgery. New technological progress including new types of prosthetic valves and use of homografts or the Ross operation will give a greater possibility of choosing the best solution in a particular case. Antimicrobial chemotherapy is mainly based on our understanding of the pathophysiology of the disease and efficacy of the antibiotics achieved in an experimental animal model of endocarditis. Important recommendations of single or combined drug therapy or the dosing regimens of antibiotics are still an expression of expert opinion not always supported by experimental or clinical proof. A typical example is the recommendation of two divided doses of gentamicin for treatment of streptococcal endocarditis. Nevertheless, it is the author’s opinion that the development of uncomplicated, easy to handle diagnostic and treatment regimens are justified in order to achieve better compliance with these recommendations. © 1999 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Infective endocarditis; Treatment; Bacterial infection; Cardiovasculitis

1. Introduction

1.1. The pre-antibiotic era

Infectious endocarditis (IE) is probably the most dramatic bacterial infection, universally fatal without treatment and still with a mortality of 15 – 40%, despite the best efforts of experienced clinicians and surgeons. IE is usually described as a microbial infection of the endothelial lining of the heart and the term IE has been generally used since 1966 [1 – 4]. The natural history of IE has undergone remarkable changes over the past century:

The natural course of the disease was described and the terminology used reflected the clinical symptoms from the initial diagnosis towards the patients death; acute, subacute and chronic endocarditis [5].

* Tel.: +45-35-313404; fax: + 45-35-3133962. E-mail address: [email protected] (E. Gutschik)

1.2. The early post-antibiotic era 1940 – 1960 The incidence, the age of the patients contracting the disease, the nature of underlying cardiac lesions, and the microorganisms involved changed considerably. Late in the period, there was a sharp decrease of peripheral diagnostic signs, like Osler nodes, petechiae, subungual haemorrhages and Janeway lesions. The epidemiology, demography and the pathophysiology of

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the disease was still exclusively described on native valves.

1.3. Late post-antibiotic era from 1960; the ad6ent of modern diagnosis and treatment The introduction of open heart surgery, first applied in an episode of fungal endocarditis in 1961 [6], lead to a considerable widening of our therapeutic modalities as well as development of echocardiography. The changing feature of the disease and the challenge to make early diagnosis for better outcome prompted the necessity for strict diagnostic criteria, first proposed by von Reyn et al. [7] and later by Durack et al. [8]. New problems of nosocomial endocarditis arose in connection with heart surgery involving pace-maker catheters, a large variety of foreign materials used as patches, sutures, plagets, different mechanical or biological heart valves, homografts, autografts or heart-transplantation. These changes have resulted in an acknowledgement that the early term of the disease and the definition is no longer valid. The focus of the infection is not exclusively on the endocardium as described earlier [5] or on the endothelium. Cryopreserved heart valve allografts and bioprosthetic valve leaflets (homografts) are not endothelialised in vivo [9,10]. The Duke criteria for endocarditis [8], now generally accepted, describe intracardiac abscess, pseudoaneurysm or new partial dehiscence of a prosthetic valve as major criteria of the disease. The name infective cardiovasculitis (ICV) is proposed, because this term is in accordance with modern concepts of the disease and better captures infection of an arteriovenous shunt, an arterioarterial shunt (e.g. patent ductus arteriosus) or coarctation of the aorta, which is per se not an endocarditis.

ation of certain therapeutic principles [12,13], but even with the development of a more rational approach using computer-controlled, simulated human serum profiles in these models [14], it is difficult to extrapolate to the clinical situation.

2.1. Dosing regimens of b-lactam antibiotics It is recommended that patients with IE caused by an organism susceptible to penicillin G should be treated with doses ranging from 4–6 to 20–30 million U/day in four divided doses [15]. Recent recommendations from the Working Party of the British Society for Antimicrobial Chemotherapy (BSAC) specify six divided doses by intravenous (i.v.) bolus injection [16] and the Endocarditis Working Group of the International Society for Chemotherapy (ISC) recommend i.v. administration continuously or in equally divided doses without specification of dosing interval [17]. The author’s recommendation is 8–20 million U/day split with four to six divided doses, higher doses to treat enterococci and microorganisms with decreased susceptibility to penicillin. Continuous i.v. administration should be reserved for special circumstances of ‘‘difficult to treat’’ microorganisms. Ceftriaxone has an excellent pharmacokinetic profile to treat non-enterococcal streptococcal endocarditis [18]. Equivalence to penicillin has been documented in vitro in experimental models and in clinical investigations [19]. It is generally accepted to use a single daily dose of 2 g ceftriaxone i.v. or intramuscularly (i.m.). [17,19]. It is important to notice that the 2 g dose can be administered as an intravenous infusion, while for intramuscular injection, ceftriaxone 2 g should be administered as two separate 1 g doses injected well within the body of a relatively large muscle [20].

2. Dosing schedules of antibiotics

2.2. Dosing regimens of 6ancomycin and teicoplanin

The optimal interval between doses in patients with IE is not well established. The therapeutic goal is to produce an effective level of drugs at the infected site and to maximise the duration of contact of the microorganism with the drug. There is, however, no firm data to justify the relevance of in vitro investigations, like minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), killing curves, test for synergism between drugs, and the post-antibiotic effect (PAE) to the clinical situation. In vivo models have been developed to investigate the entry of the antimicrobial agents into vegetation, and some of these models, e.g. the autoradiographic method described by Cremieux and Carbon [11], have been useful to identify the pattern of diffusion of drugs into the periphery and the core of the thrombus. The animal model of experimental endocarditis has been extremely useful in evalu-

It is generally accepted that vancomycin should be administered at 30 mg/kg/day i.v. in two divided doses, and the trough serum level should be maintained between 10 and 15 mg/l to ensure optimal efficacy [16,17]. Teicoplanin is an attractive drug for use in the treatment of IE, being easily administered once daily. However, treatment with this antibiotic has been associated with a significant number of failures, leading to early termination of a prospective trial [21]. This was attributed to inadequate dosage, and one of the explanations, investigated in a multicentre Scandinavian trial, has been that the teicoplanin steady-state concentration in serum was achieved only after 1 week compared with three doses of vancomycin [22]. In order to overcome this obstacle, it is recommended to give 10 mg/kg i.v. twice daily for nine doses, then 10 mg/kg/day i.v. or i.m. as a single dose [17] .

E. Gutschik / International Journal of Antimicrobial Agents 13 (1999) 79–92

2.3. Dosing regimens of aminoglycoside antibiotics in combination with b-lactam antibiotics, 6ancomycin or teicoplanin In 1993, Prins et al. [23] documented the superiority of once daily dosing of gentamicin compared with a divided dose regimen, and this has been confirmed by a number of publications [24]. However, infected vegetation represent a very particular microbial environment; a high density of bacteria, with reduced metabolic activity. Autoradiography studies demonstrated homogeneous distribution of aminoglycosides into the vegetation [25]. However, an investigation using an integrative computerised model in rabbits showed that supra-MBC concentrations of amikacin in the vegetations were achieved only with doses two to four times higher than those ordinarily recommended [26]. This finding supports single, daily, high-dose administration of aminoglycosides. On the other hand, an investigation in rabbits using simulated human serum profiles of amikacin once daily versus thrice daily dosing found both regimens equally effective [27]. These results, however, are only valid for single drug therapy with an aminoglycoside, uncommon for treatment of IE. Table 1 summarises the clinical and experimental evidence for single or divided daily dose administration of aminoglycosides in combination with another drug. There are two prospective, non-comparative clinical investigations [28,29] only, for once daily dosing of aminoglycosides. Comparative investigation of divided doses thrice a day versus the same total dose given once in a rabbit model of enterococcal endocarditis demonstrate the superior-

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ity of thrice daily dosing regimen [30]. No differences were found between once versus thrice daily dosing in a model of experimental Streptococcus adjacens [31] or in Streptococcus sanguis endocarditis [32]. An experimental model simulating human serum profiles of ceftriaxone plus netilmicin [33] recommend a single dose regimen of aminoglycoside, but investigated only the single dose regimen. Experimental animal models in rabbits or rats make a comparison between different dosing regimens difficult because of the very short half-life of these compounds in small animals [34,35]. The conclusion must be that we still have no clinical or experimental evidence for the recommendation single [17] dose regimens. Furthermore, recommendation for twice daily dosing of aminoglycosides is entirely speculative [16] both in streptococcal endocarditis and staphylococcal endocarditis (Table 1). The particular properties of vegetations with an absence of phagocytic cells and a high density of bacteria with reduced metabolic activity explain the absence of PAE described in vivo [36,37]. This observation supports a divided dose regimen of aminoglycosides.

3. Combined therapy of infective endocarditis due to streptococci, enterococci and staphylococci The majority of patients with IE will be treated with combinations of drugs, although there is evidence that penicillin G [15] (or ceftriaxone) [19] and semisynthetic b-lactamase stable penicillins are safe treatments for monotherapy streptococcal and staphylococcal endo-

Table 1 Administration of aminoglycosides: clinical or experimental evidence for single dose or divided dose regimens with recommendations of dose interval Investigations

Appointed dosing regimens of aminoglycosides in streptococcal or staphylococcal endocarditis Once daily

Clinical investigations

Viridans group of streptococci treated with ceftriaxone plus netilmicin [28] Ceftriaxone plus gentamicin [29] Animal models of experimental Viridans group of streptococci endocarditis treated with ceftriaxone plus netilmicin [33] Ceftriaxone plus gentamicin and procaine penicillin plus gentamicin [32] Recommendations by Endocarditis Recommended for viridans Working Group of ISCa group of streptococci [17,29,79] Recommendations by Working Not recommended Party of BSACb [16]

a b

ISC, International Society of Chemotherapy. BSAC, British Society of Antimicrobial Chemotherapy.

Twice daily

Thrice daily

Not studied

Not studied

E. faecalis treated with penicillin plus netilmicin [30] Not studied

S. adjacens treated with penicillin plus tobramycin [31]

Not recommended

Recommended for enterococci and staphylococci?

Recommended for viridans group Recommended for staphylococci of streptococci and for enterococci

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Table 2 Principal decision-making for treatment of streptococcal, enterococcal or staphylococcal endocarditis: the author’s recommendation Viridans and other non-enterococcal strains Fully sensiti6e to penicillin; MIC50.1 mg/l First choice Penicillin G 12–20 million U/24 h i.v., divided into four to six doses for 4 weeks plus gentamicin 3 mg/kg/24 h i.v., divided into two doses for 2 weeks Second choice Two-week treatment with penicillin plus gentamicin (same dose as first choice; for conditions, see Table 3) Third choice (penicillin allergy) Ceftriaxone 2 g/24 h i.v. as single dose, for 4 weeks plus gentamicin for 2 weeks (same dose as first choice) Fourth choice: (cephalosporin allergy) Vancomycin 30 mg/kg/24 h i.v. divided into two doses for 4 weeks. There are insufficient data to recommend addition of an aminoglycoside to vancomycin Reduced susceptibility to penicillin 0.1 mg/lBMIC50.5 mg/l or prosthetic 6al6e Penicillin G for 4 weeks plus gentamicin for 2 weeks, or ceftriaxone for 4 weeks plus gentamicin for 2 weeks, or vancomycin as single drug treatment for 4 weeks Reduced susceptibility to penicillin; MIC\0.5 mg/l. Prosthetic 6al6e endocarditis with MIC\0.1 mg/l and nutritionally 6ariant 6iridans streptococci Treat these patients the same way as recommended for enterococcal endocarditis Enterococcal strains If the isolates are resistant to penicillin (MIC\8 mg/l), vancomycin or teicoplanin (MIC\4 mg/l) or highly resistant to gentamicin (MIC]500 mg/l), it is necessary to consider alternative combinations of drugs with assistance of an expert in clinical microbiology and in case of failing therapy cardiac valve replacement should be considered First choice Penicillin G 12–24 millions U/24 h divided into four to six doses plus gentamicin 3 mg/kg i.v./24 h, divided into two doses per day, for 4–6 weeks Second choice Vancomycin (dose the same as first choice) or teichoplanin 10 mg/kg i.v. q12 for nine doses and then 10 mg/kg/24 h thereafter, plus gentamicin (same dose as first choice), for 4–6 weeks Staphylococcal strains Left-sided endocarditis First choice b-Lactamase-resistant penicillin for 4–6 weeks plus gentamicin 3 mg/kg/24 h divided into two doses for 1 week. Add rifampicin 600 mg/24 h divided into two doses for 4 weeks in case of abscess/metastatic foci Second choice Vancomycin (same dose as first choice) for 4–6 weeks plus gentamicin for 1 week (same dose as first choice). Add rifampicin (same dose as first choice) for 4–6 weeks in case of abscess/metastatic foci Right-sided endocarditis First choice Two-week treatment with b-lactamase-resistant penicillin i.v. plus gentamicin (same dose as first choice); add rifampicin in case of abscess/metastatic foci) for 2 weeks Second choice Optional oral treatment with Tbl. ciprofloxacin 750 mg b.i.d. plus Tbl. Rifampicin 300 mg b.i.d. for 4 weeks Comments MRSA endocarditis should be treated with vancomycin for 4–6 weeks plus gentamicin added the first week of treatment. Alternatively, combination of vancomycin plus rifampicin should be used for 4–6 weeks The author is not convinced that teicoplanin could be used as a safe alternative for vancomycin Note, MRSA endocarditis specially on prosthetic valves is a relative indication for surgical treatment

carditis, respectively. However, these drugs and others have been combined customarily with gentamicin, rifampicin, fucidic acid, or ciprofloxacin for treatment of IE.

3.1. Penicillin– gentamicin and other b-lactam–gentamicin combinations In vitro and in vivo synergism is well documented both against non-enterococcal streptococci [38] and against enterococci [15,39]. Among aminoglycoside antibiotics, gentamicin exerts the widest range of synergistic potential with penicillin, and other b-lactam antibiotics [39]. This synergistic action with rapid and increased killing made it possible to introduce the 2week treatment of penicillin- or ceftriaxone-susceptible

non-enterococcal endocarditis (Tables 2 and 3). The efficacy and safety of this treatment has been documented in clinical series [28,38,40]. Tolerance in non-enterococcal strains is a phenomenon in which the MBC of the drug exceeds its MIC by at least a factor of 10. There is no evidence that this phenomenon has any clinical relevance [15], and routine determination of MBC is not recommended [41]. The nutritionally variant viridian’s streptococci (Abiotrophia sp.). on the other hand (5–10% of viridian’s streptococci), are difficult to kill with penicillin alone [15] and prolonged therapy with penicillin–gentamicin [17] is recommended (Table 2). Enterococci are uniformly tolerant or moderately resistant to penicillin, and penicillin treatment alone will result in an unacceptable high relapse rate [42].

E. Gutschik / International Journal of Antimicrobial Agents 13 (1999) 79–92

Only 39% of patients treated with penicillin alone were cured, similar to the results by Gutschik et al. in an experimental enterococcal model of endocarditis, without an indwelling catheter, using end-point design with 4 weeks treatment and 4 – 6 weeks observation for relapse [43]. In this model, 37 and 39% of the rabbits were cured when treated with low- or high-dose penicillin alone, but all were successfully treated with combination of penicillin plus streptomycin [44] or penicillin plus gentamicin [45]. Although the bactericidal activity of ampicillin is twofold greater than penicillin against Enterococcus faecalis [46], the author prefers penicillin (Table 2) because higher serum concentrations of penicillin compensate for this difference, and because it is important to avoid an ampicillin rash during the long-term treatment. A low dose regimen of gentamicin (3 mg/kg/day) is now accepted [15,16] based on investigations by Wilson et al. [47,48]. The duration of treatment is usually at least 4 weeks [16,17], although this has been questioned recently [49]. The opinion of the author is that 4 – 6 weeks combined treatment should be used routinely (Table 2) and 6 weeks in complicated cases, patients with symptoms of longer than 3 months duration [50], and prosthetic valve endocarditis. In high-level gentamicin resistance (MIC] 500 mg/l), an investigation of the susceptibility to other aminoglycosides should be done, but the treatment in many cases will continue to be a largely empirical endeavour as described by Eliopoulos [51]. The treatment of staphylococcal endocarditis with a b-lactamase-resistant penicillin combined with gentamicin in the first week (Table 2) is based on investigations documenting faster killing of the staphyloccci in the Table 3 Conditions for the 2-week treatment regimen or for home therapy of infective endocarditis Definite diagnosis by the Duke criteria Streptococcal non-enterococcal isolate fully sensitive to penicillin, MIC50.1 mg/la Native valve infection No vegetation more than 10 mmb on echocardiography No cardiovascular risk factors such as heart failure, aortic insufficiency, conduction abnormalities or thromboembolic disease Clinical response within 7 days For home therapy, requirements for the patient’s home circumstances should be defined a

Patients who met the criteria but had a streptococcal isolate with reduced susceptibility (0.1BMIC50.5 mg/l) for penicillin G or ceftriaxone can be a candidate for home therapy. In this situation, subsequent to the 2-week penicillin plus gentamicin treatment in the hospital, an additional 2-week treatment with ceftriaxone 2 g i.v. (or i.m.) as a single daily dose can be administered as home therapy. b The risk for embolisation is greater when the vegetation increases in size during therapy and when vegetation is located on the anterior leaflet of the mitral valve.

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blood stream, reducing the time to negative blood cultures by several days, but not the mortality or need for valvular surgery [52]. It is interesting to notice that there is no experimental or clinical evidence supporting single or divided doses of gentamicin. This explains why Mortara and Bayer recommend two doses daily [53], the BSAC recommend three doses, and the ISC do not specify the dosing interval (Table 1).

3.2. Should we prefer rifampicin or fusidic acid in combination therapy? Fusidic acid was developed by Leo Laboratories in Copenhagen, Denmark [54] in 1962, but even though it has been used for more than 35 years for treatment of staphylococcal infections, there is no proof for the efficacy of this drug in treatment of endocarditis or staphylococcal septicaemia. Fusidic acid and rifampicin are recommended to be used always in combination with another potent antistapylococcal drug. Unfortunately, there are no clinical trials to show an advantage for b-lactam plus fusidic acid combinations. We need a prospective, clinical investigation comparing the efficacy of a standard antistaphylococcal agent, alone and in combination with the fusidic acid. There are only a few experimental investigations, all with negative results: no effect in the experimental endocarditis model [55], no effect in a model of intramuscular staphylococcal infection in mice [56], no effect on the killing of intracellular staphylococci alone and in different combinations of drugs [57], and no enhancement of dicloxacillin in intracellular killing of staphylococci [58]. The lack of well-controlled clinical and experimental investigations is partly explained by the missing marketing authorisation of this drug in the US. Rifampicin, on the other hand, has recently been a target of tremendous interest for its potential role in implant-related staphylococcal infections with salvage of stable prosthetic devices [59,60] and is also described as the most active antistaphylococcal agent in vitro, and in intracellular staphylococcal infections [61,62]. It is also effective in the experimental model of endocarditis [63]. The risk is the potential for staphylococci to become resistant for rifampicin. Increasing resistance to rifampicin has been described [64], and this could give concern using this drug for the empirical initial treatment of endocarditis or as prophylactic agent. However, as shown by Scheel et al. from Hong Kong [65], the vast majority of methicillin-resistant Staphylococcus aureus (MRSA) strains are still extremely susceptible for rifampicin (MIC90 5 0.06 mg/l), although significant geographic differences are described [64]. In contrast, the prevalence of multiple antibiotic resistant coagulase-negative staphylococci (CoNS) is high and evenly distributed world-wide, even in Scandinavia [66]. A nation-wide study in Denmark showed that 30% of

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multiply resistant Streptococcus epidermidis strains were resistant to fusidic acid, while rifampicin resistance were rare (0–9%) among clinical isolates of CoNS [66]. Thus, the author’s choice is rifampicin (Table 2).

3.3. The role of quinolones (ciprofloxacin) in combination therapy The newer quinolone antibiotics have been promising candidates for treatment of IE for several reasons; they show only a slight inoculum effect, remaining bactericidal at high inoculum, and also against stationary-phase bacteria in vitro and at acidic pH. Finally, they exhibit concentration-dependent killing kinetic in vivo [67]. The emergence of resistance to ciprofloxacin during single drug therapy of human as well as experimental S. aureus infections is, however, of concern [68,69]. Furthermore, early killing curve investigations showed that rifampicin and fusidic acid uniformly antagonised the bactericidal effect of ciprofloxacin [70] including S. aureus phagocytosed by PMN [57], but each antimicrobial prevented the emergence of subpopulations that were resistant to the other [71]. The relevance of in vitro antagonism to efficacy in vivo is not clear. The effect is variable in animal models [72], but clinical data indicate that ciprofloxacin and rifampicin are not antagonistic in vivo to any significant degree [72]. Oral treatment of right-sided endocarditis with rifampicin plus ciprofloxacin for 4 weeks is a safe treatment demonstrated in clinical series [72], and is equally effective but with less toxicity in comparison with parenteral therapy [73]. Recently, several new quinolones with markedly improved activity against gram-positive pathogens have been licensed. Trovafloxacin was found to be more effective than vancomycin against methicillin-resistant S. aureus in the rabbit endocarditis model [74]. Additional studies of newer oral quinolones and other oral antibiotics are needed, as well as new therapeutic modalities using oral regimens, as follow-up to parenteral therapy.

4. Home and outpatient treatment Outpatient in Europe refers to a healthcare setting in which the patients attends a hospital clinic, receives an injection (outpatient treatment) and then returns home. Home treatment refers to the situation where patients receive their injections at home, either from a visiting nurse, at the general practitioner’s surgery or by selfadministration [75]. Finally, a combination of these two terms is proposed by a working party in the UK as a consensus statement: outpatient and home parenteral antibiotic therapy (OHPAT) [76]. The use of parenteral antibiotic outside the hospital has been established in the US for more than 20 years, but is a relatively recent

practice in Europe [77]. There is no prospective study of IE, comparing inpatient treatment with partial or total OHPAT, but several studies have shown that selected patients can safely receive home treatment [77]. Some of the conditions for OHPAT are defined in Table 3. It is the author’s opinion that all patients with IE should be admitted to hospital for evaluation by an multidisciplinary expert team, and the patient should be treated for at least 2 weeks in the hospital and observed for cardiac complications (Table 3) and for emboli. The incidence of embolic events will fall rapidly during the first week of antimicrobial treatment and will be an unusual event after 2 weeks optimal treatment [78]. A significant proportion of patients with IE could be candidates for OHPAT, but this approach needs to be carefully assessed by good clinical studies. Simultaneously, the conditions for OHPAT should be assessed by different countries, taking into account the diversity of healthcare infrastructure, the same way as the working party recommend in the UK [76].

5. Comments on the recent ISC and BSAC recommendations for treatment of IE The ISC recommendations [17,41,77,79] and updated BSAC recommendations [16,80] have recently been published. Four weeks penicillin plus gentamicin treatment is recommended by the BSAC for relatively penicillin-resistant streptococcal endocarditis, defined by an MIC\0.1 mg/l. It is important to recognise that a recent multicentre study from the US [81] found 56.3% of these streptococcal isolates relatively penicillin resistant, with MIC values \ 0.12 mg/l, and even in Denmark, a ‘‘low-resistance’’ area in Europe, 44.4% of S. mitis strains were relatively penicillin resistant [82]. The majority of these strains, however, will have a MIC between 0.1 and 0.5 mg/l [17]. These strains are not as resistant as enterococci, and treatment with penicillin for 4 weeks combined with only 2 weeks gentamicin is a safe treatment [83], as recommended by the ISC [17]. Moellering et al. [84] found that data available suggest that these organisms can be treated successfully with the same regimens used to treat infections due to more penicillin-susceptible organisms, and 4 weeks combined penicillin-aminoglycoside treatment should be reserved for endocarditis due to strains with MIC] 1.0 mg/l. The author supports the BSAC recommendation [16] of two divided daily doses of aminoglycosides until carefully assessed clinical studies are available (Table 2). Treatment of enteroccal endocarditis with glycopeptide antibiotics when the isolate is not fully susceptible to vancomycin is not considered in these recommendations. Enterococci fully susceptible to vancomycin have MIC5 4 mg/l as defined by NCCLS [85]. The ‘‘grey area’’ of low resistance to vancomycin MIC (4–16

E. Gutschik / International Journal of Antimicrobial Agents 13 (1999) 79–92

mg/l) represents a new therapeutic problem and will be seen with increasing frequency [86,87]. Teicoplanin treatment combined with gentamicin should be considered in this situation [88].

6. New drugs, new treatment modalities The rate of emergence of resistant and multiresistant bacteria has increased during the past two decades, especially among gram-positive microorganisms, and evaluation of new treatment regimens is needed [89]. Table 4 presents some details in new classes of drugs that are, or soon will be, available. Some of the new quinolone antibiotics with significantly improved activity against MRSA are already in clinical use [90]. They have been tested in an experimental model of endocarditis and have a low propensity for selection of resistance in vivo [91]. The new macrolide/ketolide antibiotics exert excellent activity against multiresistant gram-positive strains, including erythromycin-resistant pneumococci, staphylococci, and Haemophilus spp. [89,92,93]. However, pharmacodynamic aspects of endocarditis treatment such as bactericidal effect remain to be elucidated. The new glycopeptide antibiotic LY333328 has an impressive in vitro activity against vancomycin-resistant enterococci (VRE) and MRSA [90], and is also effective in an experimental model of endocarditis [94,95]. The protein binding of this drug is, however, extremely high: \ 99% in rabbits [94], \ 80% in rats [96]. Protein binding is not reported in man, but decreased activity in human serum, with decreased killing of S. aureus over time, is of concern [96]. This pharmacokinetic feature could give rise to problems in achieving early steady-state concentrations in the blood, analogous to the situation with teicoplanin [22]. Streptogramins are a very large group of cyclic peptides produced by a Streptomyces species. Each member of the class is a combination of at least two structurally unrelated molecules (group A and group B) [97]. An example of this group is a synergistic combination of streptogramin A (dalfopristin) and streptogramin B (quinupristin). Excellent activity in vitro [98] and in different animal models of infection demonstrate potential as an alternative to vancomycin in treatment of MRSA or VRE [99]. However, studies in the animal model of endocarditis indicate decreased activity of this streptogramin against macrolide – lincosamin –streptogramin B-resistant strains of S. aureus [100,101], and a combination of several resistance mechanisms have been reported to lead to high-level resistance to the drug [102]. Nevertheless, successful use of this drug in treatment of infectious endocarditis is described [103] and, confident of the clinical significance of this class of drugs, Leclercq and Courvalin [102] designated them as

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‘‘an answer to antibiotic resistance in Gram-positive bacteria’’ (Table 4). The oxazolidinones, an investigational class of antibiotics [90], have attracted significant attention because they represent a synthetic class of drugs structurally unrelated to any agent presently marketed. They are bacteriostatic in action, so the possibilities for their use in endocarditis are called in question [104,105]. The everninomycins are oligosaccharide antibiotics [90] produced from Micromonospora species [106]. Safety, tolerance and pharmacokinetics have been investigated in healthy volunteers [90]. Unfortunately, another oligosaccharide, avilamycin, which is structurally very similar, has been used as a growth promoter in animals for several years and created a reservoir of E. faecalis, and Enterococcus faecium with decreased susceptibility to everninomycin, even before this antibiotic has been finally developed for human use [107]. Thrombin-induced platelet microbial protein (tPMP) [108,109], b-sheet antibiotic peptides [110], and microbially produced peptides [111] are all in a very early stage of development. The clinical significance could be an influence on the initial stage of adhesion, multiplication, and dissemination of microorganisms intravascularly (tPMP) or in the oral cavity, gaining a role in prevention of endocarditis.

7. New techniques and new possibilities for successful endocarditis surgery In cases of ‘‘advanced endocarditis’’ [112], the infection extends beyond the valve cusps and colour Doppler flow imaging is necessary to increase sensitivity for the detection of channels, fistulas, abscesses or pseudoaneurysms [113]. Modern echocardiography, especially the Multiplan transoesophageal echocardiography (TEE) (Table 5), provide the surgeon with precise description of pathology before and during surgery [112]. The ideal prosthetic heart valve should be nonthrombogenic and durable. However, the variety of available choices attests to the inability of any single one to fulfil this requirement [114]. New materials like pure pyrolytic carbon [115] and new designs like a new tri-leaflet polyurethan valve [116] have been developed, with new techniques and devices to test prosthetic heart valves in the laboratory [117,118]. This new technological progress improves the chances of further improvements, although most of the available prosthetic heart valves functioning remarkably well [113,114]. The Ross operation was described in 1967, but only in recent years has it been used for endocarditis surgery [119]. Important advantages are freedom from the need for anticoagulation, low risk of thromboembolic com-

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Table 4 New possibilities of endocarditis treatment by new class of drugs Microbial activity

Comments

New quinolones: trovafloxacin, moxifloxacin, gatifloxacin, grepafloxacin and CFC-222

Extended spectrum against Gram-positive microorganisms, good oral bioavailablity

New possibilities for ‘‘difficult-to-treat’’ enterococcal and staphylococcal endocarditis and for home treatment

Macrolides/Ketolides: HMR 3647-HMR 3004

Excellent spectrum against Gram-positive and –negative cocci, Legionella, and Mycoplasma spp. Effective against methicillin-resistant staphylococci and vancomycin-resistant enterococci Rapid bactericidal action against a wide range of aerobic and anaerobic Gram-positive organisms

The potential clinical efficacy in endocarditis treatment deserves further exploration Currently undergoing clinical investigation. Problems with dose escalation? Described as ‘‘an answer to antibiotic resistance in gram-positive bacteria’’. Successful in animal models of endocarditis and in clinical use Bacteriostatic in action, currently in preclinical investigations In preclinical stage

Glycopeptides: LY 333328 Streptogramins: Quinapristin/Dalfopristin

Oxazolidinones

Synthetic compounds directed against gram-positive cocci

Everninomicin

Oligosacharide antibiotic with good activity against gram-positive bacteria This small cationic peptide secreted by rabbit platelets following thrombin stimulation kills common endovascular pathogens in vitro Small cystein-rich peptide antibiotics are found throughout the Animalia Bacteriocins (mutacins) exert a biological function related to the mutual competition between microorganisms. Some peptides exert antibiotic effects over a broad spectrum, others are more selective

Thrombin-induced platelet microbial protein

b-Sheet antibiotic peptides, and microbially-produced peptides: a- and b-defensins, insect defensins, protegrins, bactenecin dodecapeptides, and bacteriocins, a large class of heterogeneous bacterial antagonists produced by microorgnisms

Significance for the bacterial adhesion and development of endocardial infection, investigated in the experimental model of endocarditis Antibiotic peptides provide attractive templates for ‘‘designer’’antibiotics The clinical importance and their potential role in treatment and prevention of endocarditis is promising, but not explored

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Antimicrobial compounds

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Table 5 New possibilities for successful endocarditis surgery by new techniques New techniques

Clinical relevance

Comments

Better diagnosis by TEE before surgery and intraoperatively

Color Doppler TEE* is conditional for a well-conceived strategy before and during surgery

This technique is now an essential component of the state-of-the-art management Large comparative studies on valve performance reveals that the overall results with tissue and mechanical valves are about equal Difficult operations technique, but with important advantages. No data on long-term function Concerns about infectivity (virus). Not licensed in several countries. An automated preparation of autologous fibrin sealant has been developed There is experimental and clinical evidence that fibrin sealant–antibiotic compound results in significant protection from infection The clinical efficacy is doubtful; local, chemical tissue damage is a potential risk for certain antibiotics There is experimental evidence that Silzone® inhibits the initial attachment and colonisation of microorganisms onto the cuff fabric. Awaiting the results of experimental and clinical investigations VEGF has been shown to promote re-endothelialisation in arteries damaged by balloon denudation

New mechanical valves and bioprosthetic valves The thrombogenicity of mechanical valves, and the limited durability of bioprosthetic valves is a persistent challenge Ross operation

Human fibrin sealants

Pulmonary autograft used for the treatment of advanced aortic valve endocarditis as total root replacement Used as haemostatic and adhesive agents based on human fibrinogen prepared from pooled plasma donation and thrombin

Fibrin glue with antibiotic mixtures

Fibrin glue alone may serve as a culture medium for infection, when blood mingles with it. Prevention with antibiotics needed

Pretreatment of prosthetic valve sewing-ring with antibiotics

A method of passively soaking all heart valves in a variety of solutions containing antibiotics before valve implantation Oxidised silver from the Silzone® coating slowly and continuously leaches from the Silzone cuff. These small molecules can also traverse trough the pores within biofilms

Silver-based coating of cardiac biomaterials

Vascular endothelial growth factor (VEGF)

Promotion of fast endothelilisation of sutures, pledgets and the sewing cuffs may increase the resistance against infection and decrease thrombogenicity

* TEE, transoesophageal echocardiography.

plications, normal haemodynamics, low risk of endocarditis and potential for growth [119]. Conventional fibrin sealants are concentrated preparations of human fibrinogen, co-administered with human or bovine thrombin for clot formation [120]. Problems of infection led to development of an autologous fibrin sealant with a preparation process of 30 min, using the patient’s blood, immediately before surgery with no exogenous thrombin added [120]. Fibrin sealant has been especially useful in heparinised patients because it does not require an intact haemostatic system to be effective [121]. Most vascular prosthetic graft infections are caused by contamination at the time of implantation, despite pre-operative antibiotic prophylaxis, and it appears that incorporation of antibiotics in fibrin glue will prevent post-operative residual endocarditis [122,123] due to sufficient local antibiotic levels being maintained for 1 week. Impregnation of the sewing ring with antibiotics [124,125] before valve implantation by passive soaking

of the heart valves in different antibiotic solution is difficult to standardise, and the effect is doubtful. The Silzone® technique developed by St. Jude Medical for a silver-coated polyethylene terephthalate fabric demonstrated broad antimicrobial effectiveness in vitro and in an animal model [126], with controlled tissue ingrowth and relative lack of toxicity [127]. There is no doubt that silver ions are active against a broad spectrum of bacteria [128]; however, the efficacy of silvercoated medical devices is not yet well established in clinical use [128]. Furthermore, the nidus of infection is not only the sewing cuffs, but also the sutures [129] and the pledget. Intact endothelium does not attract adhesion of bacteria [130]. Thus, there has been considerable interest in seeding endothelial cells on graft material for use in vascular surgery [131]. The use of vascular endothelial growth factor (VEGF) in conjunction with cardiac prosthetic grafts and valves would be a logical development (Table 5). VEGF-treated porcine aortic valve leaflets have been colonised with endothelial cells after

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5 days of culture in a preliminary in vitro investigation [131,132]. This experiment represents the first step toward designing a tissue-engineered valve.

8. Summary The natural history of infective endocarditis has undergone remarkable changes over the past 100 years as regards both the demographic characteristics of the disease and changes in the incidence of the so-called diagnostic signs. Alongside these changes and the development of new and better diagnostic tools and criteria, we are also facing new problems with the precise definition of cardiovascular infections and calculation of the incidence of the disease. Nosocomial endocarditis presents an emerging problem of diagnosis and treatment after heart valve surgery, with pace-maker catheters, defibrillators and a very large variety of foreign materials used in connection with heart valve surgery. New technological progress including new types of prosthetic valves and use of homografts or the Ross operation will give a greater possibility of choosing the best solution in a particular case. Antimicrobial chemotherapy is mainly based on our understanding of the pathophysiology of the disease and efficacy of the antibiotics achieved in an experimental animal model of endocarditis. Important recommendations of single or combined drug therapy or the dosing regimens of antibiotics are still an expression of expert opinion not always supported by experimental or clinical proof. A typical example is the recommendation of two divided doses of gentamicin for treatment of streptococcal endocarditis. Nevertheless, it is the author’s opinion that the development of uncomplicated, easy to handle diagnostic and treatment regimens are justified in order to achieve better compliance with these recommendations.

9. Conclusion The duration of antimicrobial treatment should be revised. The dogmatic 4 – 6 weeks intravenous treatment regimens we have used since 1950 – 1960 is no longer valid in all cases. Two-week treatment regimens of penicillin-sensitive streptococcal endocarditis are recommended, and oral treatment of right-sided staphylococcal endocarditis seems to be safe. This is conditional on close teamwork between the microbiologist, cardiologist, and the cardiac surgeon, and referral of advanced cases of endocarditis to larger centres with special interest in the treatment of these patients.

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