Antimicrobial Prophylaxis

Because VGS are felt to be the predominant pathogens potentially to cause IE after dental/oral, respiratory, and esophageal procedures, aminopenicillins are the recommended prophylaxis. In the past, VGS were nearly uniformly susceptible to penicillin and other P-lactams, as well as to lincosamides and macrolides [102]. Therefore, the current AHA guidelines on IE prophylaxis, which were published in 1997 [39], recommend the use of amox-icillin (ampicillin if the patient is unable to tolerate oral intake). Amoxicillin was recommended over penicillin because it is better absorbed from the GI tract and because it provides higher and more sustained levels [39]. In humans, the elimination half-life of amoxicillin is 50-60 minutes [103]. Clindamycin or macro-lides are alternatives in those unable to tolerate P-lactams. A contemporary review of the antimicrobial susceptibility of VGS demonstrated that amoxicillin at a concentration of < 0.5 |g/mL inhibited 87%, 64%, and 100% of isolates in the S. sanguis, S. mitis, and S. milleri groups, respectively, as well as two of the three isolates in the S. salivarius group [104]. Hence, the use of amoxicillin as a prophylactic regimen was justified. However, several studies have since demonstrated increasing rates of VGS isolates from oropharyngeal specimens [105] and blood stream infections [102,106-109] that are not susceptible to penicillin, macrolides, or lin-cosamides. Furthermore, resistance to these antibiotics can occur with repeated prophylaxis doses for serial procedures distributed closely in time [39,41]. Therefore, continued monitoring of such resistance patterns is mandatory, and modifications of future guidelines may be necessary. Until such time, amoxicillin remains the recommended prophylaxis regimen for the above-mentioned procedures. When comparing the AHA guidelines from those of Europe (BSC, French), differences in amoxicillin dose is seen. The latter recommend a single 3-g oral dose, which produces serum levels above the MIC of most oral streptococci for a period of 6-14 hours

[110]. The AHA proposes 2-g, instead of 3-g, because the serum kinetics produced by the two different doses are very similar, although the lower dose is associated with fewer side effects

[111]. For patients with a history of penicillin allergy, clindamycin remains appropriate. Alternatives include macrolides, such as clari-thromycin or azithromycin, which have demonstrated efficacy in experimental models and have convenient dosing regimens, although they are more expensive. Cephalosporins also have demonstrated efficacy, but should not be used in patients with a history of type 1 (immedi-ate-type/anaphylaxis) hypersensitivity reaction to P-lactams. For patients unable to take medication orally, intravenous regimens are recommended, and administration of the full dose should be completed within 30 minutes of the procedure.

For procedures involving the biliary system or the gastrointestinal or genitourinary tracts, the predominant pathogen of concern is Enterococcus spp. Previous studies have reported that among cases of enterococcal IE, ~40% were associated with a recent gastrointestinal or genitourinary procedure (i.e., within 2-6 weeks) [28]. Enterococci however, are notoriously more resistant than VGS, with typically higher MICs to P-lactams [112]. Thus, after administration of amoxicillin, the corresponding serum levels fall below the MIC of enterococci sooner than for VGS, resulting in a decreased period of bacterial growth inhibition. To overcome this issue in high-risk patients, a second dose of the P-lactam is currently recommended six hours after the first dose to ensure prolongation of adequate serum levels and to enhance protective efficacy. The rationale for the combination of amoxicillin and gentamicin is based on the rat model of

Enterococcus IE, in which administration of both agents was necessary for successful prophylaxis against inocula >ID90 [32]. Alternatively, administration of a single dose of vancomycin (in conjunction with gentamicin) can be used in high-risk patients unable to tolerate P-lactams. The evidence for this recommendation derives from experimental studies in which vancomycin demonstrated prolonged serum half-life, producing serum levels greater than MIC for a longer period of time (compared to ampicillin-based regimens), which resulted in significantly greater area under the curve (AUC) and serum inhibitory activity, and more consistent protective effect [28]. Because of vancomycin's phar-macokinetics, a second dose is not considered necessary. For moderate-risk patients, the second dose of aminopenicillins is optional.

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