Key messages

• The presentation of endocarditis varies widely and fever in the presence of a cardiac lesion may be the only initial signs.

• Serum concentrations of b-lactams and glycopeptides should be kept well above the minimum inhibitory concentration, but high peaks are more important for aminoglycosides and quinolones.

• Serum assays of aminoglycosides must be performed every 1 to 2 days.

• Penicillin G (benzylpenicillin) is used to treat infections due to a-hemolytic streptococci but gentamicin is added if not fully susceptible.

• Both flucloxacillin and nafcillin with gentamicin are effective against Staphylococcus aureus, but the aminoglycoside is probably only needed for the first 5 days for native valves.

• Glycopeptides are reserved for methicillin-resistant staphylococci and some enterococci. Introduction

Bacteria are present in large numbers in vegetations (109 organisms/g); they divide slowly and are protected from host defenses. Antibiotics, particularly the glycopeptides, may not penetrate well into the substance of a vegetation. Medical treatment of prosthetic valve endocarditis without replacement of the valve will often fail, even if the organism is apparently susceptible in vitro. A persistent fever without obvious cause, blood cultures positive for a typical organism, echocardiographic evidence of vegetations, abscess, or paraprosthetic leak, and a documented new regurgitant murmur are the common indications for treatment. Vascular and immunological signs (e.g. arterial emboli, microscopic hematuria, or subungual hemorrhages in a non-manual worker) can be helpful. However, patients rarely present in the same way, and in some cases fever in the presence of a cardiac lesion or prosthetic valve may be the only initial grounds for suspicion.

Treatment of infective endocarditis must be tailored to the species and antibiotic susceptibility of the pathogen, and the presentation of the disease and its complications. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration can be used to guide choice of antibiotic. A bactericidal regimen is required, usually in the form of a synergistic combination of antibiotics which protect each other from the emergence of resistance. However, patients with large vegetations, intracardiac abscess, continued fever, emboli, or congestive cardiac failure require early surgery.

Penicillins and glycopeptides (vancomycin and teicoplanin) have a relatively slow bactericidal activity ( Besnier and 1995). The extent of bacterial killing depends on the time during which serum concentrations exceed the MIC. Aminoglycosides and quinolones have a faster bactericidal effect which depends on concentration (e.g. high peaks). If the concentration falls below the MIC, regrowth of the organism does not occur until after a delay; this is known as the postantibiotic effect. Gram-positive bacteria may not grow for 2 to 3 h after removal of b-lactams or vancomycin. The slow rate of division of bacteria in vegetations reduces the bactericidal effect that b-lactams can exert, resulting in relapse if the treatment time is too short. Autoradiographic methods in animal models show that some antibiotics (e.g. teicoplanin) do not diffuse into a vegetation but are limited to the periphery. Others (e.g. penicillin) form a gradient to the center of the vegetation, and still others (aminoglycosides and quinolones) diffuse throughout the vegetation.

When using b-lactams or glycopeptides, the dose should be sufficient to maintain concentrations in the vegetation above the MIC. High serum concentrations may be necessary, particularly in the case of teicoplanin in staphylococcal endocarditis. High peaks are necessary for aminoglycosides and quinolones. The postantibiotic effect will maintain suppression of Gram-negative bacteria, but not enterococci, between doses. Parenteral therapy is normally necessary, although ciprofloxacin and rifampin (rifampicin) can be given by mouth. To maintain high trough concentrations, penicillins should be given every 4 h (i.e. three to four half-lives) or as a continuous infusion. Ceftriaxone and teicoplanin can be given once daily because of their long half-lives, but teicoplanin requires three loading doses of 6 mg/kg at 12-h intervals to achieve therapeutic concentrations.

Serum monitoring of aminoglycosides at intervals of 1 to 2 days is essential to avoid potentially toxic concentrations, particularly in the critically ill (trough, below 2 mg/l; peak, 5-10 mg/l), although low levels may be acceptable when used against susceptible streptococci (trough, below 1 mg/l; peak, 4 mg/l). Nephrotoxicity may be reduced by administration of gentamicin once daily (7 mg/kg/day), but experience in endocarditis is limited. Vancomycin concentrations should be 10 to 15 mg/l at trough to ensure efficacy without nephrotoxicity, and trough concentrations of teicoplanin in excess of 20 mg/l are associated with improved outcome in staphylococcal endocarditis if it is used alone.

Recurrence of fever can be due to uncontrolled infection, but it is sometimes a reaction to the treatment itself or is due to thrombophlebitis. Further blood cultures should be taken during treatment to ensure bacterial eradication. The serum bactericidal titer is sometimes determined; it is defined as the greatest dilution of serum, taken at trough and peak of antibiotic administration, which still inhibits the infecting pathogen in vitro. It is limited in its clinical use and a low titer does not necessarily predict failure of treatment. Persistent bacteremia and fever suggest a cardiac abscess or metastatic abscesses, and surgery should be considered.

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