S epidermidis

The large majority of CoNS-NVE is caused by S. epidermidis, accounting for rates of 85-91% of cases [239,242]. S. epidermidis can cause a rapidly progressive and destructive endocarditis, and observational series suggest that successful management requires a combination of surgery and antibiotics [239,241,244,245]

The susceptibility of CoNS to antimicrobial agents is extremely variable. Although community-acquired isolates are frequently susceptible to a wide variety of agents, strains isolated from hospitalized patients are typically resistant to multiple antibiotics [241,242,246]. Such multiresistance makes management of serious infections with CoNS particularly difficult.

The optimal antimicrobial management of S. epidermidis NVE is extrapolated from experience with S. aureus [12,52]. If standardized antimicrobial susceptibility testing demonstrates susceptibility to P-lactams, then these agents are the drugs of choice, as they have been associated with improved survival [175]. Of the P-lactams, penicillin is rarely an option. An earlier report had suggested that among cases of CoNS-NVE, those that were community-acquired were usually sensitive to penicillin [242]. However, determination of penicillin susceptibility among CoNS has since been refined. Resistance to penicillin among CoNS is mediated by a plasmid-borne, inducible P-lactamase [247]. This resistance phenotype is not detected by routine microdilution techniques and is best identified by pre-exposing the isolate to an appropriate inducing agent, such as oxacillin [246]. Such a technique has demonstrated that only a very low percentage of S. epidermidis appear susceptible to penicillin in vitro; of these "penicillin susceptible" isolates, a significant percentage were P-lactamase producers [247]. As such, these isolates were considered resistant. A different study had identified P-lactamase activity in 75% of S. epidermidis isolates [248]. These studies demonstrate that resistance to penicillin via an easily transferable plasmid carrying an inducible P-lactamase enzyme is highly prevalent.

More problematic, however, is the development of methicillin resistance among CoNS. Although there is geographic variation, methi-cillin-resistant S. epidermidis (MRSE) is very common, particularly among nosocomially acquired isolates, with prevalence rates as high as 60-70% [249]. Methicillin resistance is mediated by the inducible mecA gene, which encodes an altered penicillin-binding protein (PBP 2a) that has reduced affinity for P-lactams [250]. As such, it confers resistance to all penicillins, including the semi-synthetic penicillinase-resistant penicillins, as well as to cephalosporins and carbapenems [246,251].

Detection of methicillin resistance is hampered by the fact that MRSE isolates are phenotypically heteroresistant. As such, only a small fraction of organisms (~10-8-10-4 [246,252]) actually express the resistant phenotype under in vitro testing conditions. Consequently, these isolates may be missed during antimicrobial susceptibility testing. Currently, most clinical laboratories use pheno-typic methods to detect MRSE [251]. For all screening methods, oxacillin was preferred, as it was the most sensitive member of the semi-synthetic pencillinase-resistant P-lactams for the detection of resistance [251]. Currently, cefoxitin is recommended [33]. These generally produce reliable and satisfactory results. However, there is the possibility that some resistant strains may not be detected by this method, which could lead to suboptimal therapy. The most accurate method of detecting methicillin resistance is by detection of the mecA gene [253]. However, a practical clue on the antibiogram to the presence of MRSE is the presence of resistance to multiple other antibiotics, including erythromycin, clindamycin, tetra-cycline, chloramphenicol, and gentamicin [246].

S. epidermidis also may possess plasmid-mediated aminoglycoside-modifying enzymes, particularly AAC(6')/APH(2'') [251,254]. This latter enzyme has the capacity to inactivate various clinically useful aminoglycosides, including gentamicin, tobramycin, netilmicin, and amikacin. As a result, isolates possessing such enzymes may be resistant to these amino-glycosides. Concomitant methicillin and amino-glycoside resistance has been reported in approximately 50% of isolates surveyed in one study [255].

S. epidermidis may also possess the MLSb phenotype, encoded by various erm genes (predominantly ermC [251]), and conferring resistance to macrolides, lincosamides, and streptogramin B.

Rifampin, a bacterial DNA-dependent RNA-polymerase inhibitor, possesses significant anti-staphylococcal activity. Monotherapy with rifampin, however, is strongly discouraged, as it consistently selects for the development of resistant mutants. Resistance to rifampin often develops by mutations in the rpoB gene that encodes the P-subunit of DNA-dependent RNA polymerase [256]. Evidence of clinical benefit with the use of rifampin against MRSE has been predominantly in patients with prosthetic valve endocarditis who were being concomitantly treated with glycopeptides and aminoglycosides [257] and is thus indicated in these situations [12,52]. The use of rifampin (along with teicoplanin) in CoNS-NVE was associated with emergence of rifampin resistance (and teicoplanin resistance) while on therapy in 1 patient [244]. A contributing factor may have been the simultaneous use of teicoplanin, an alternate glycopeptide, which has been associated with treatment failure when used in the management of staphylococcal endocarditis [12]. Therefore, the use of rifampin for CoNS-NVE remains debatable, with the British guidelines recommending it as a second agent when vancomycin is used for MRSE [12], while the American guidelines do not refer to it as an option [52].

The glycopeptide, vancomycin, remains a cornerstone of therapy for CoNS-related infections. Teicoplanin has also been used, although as mentioned previously, it is not available for use in North America. Furthermore, teicoplanin resistance seems to be particularly common among CoNS [258-260], and has emerged while on therapy in associaton with clinical failure [244,261]. As with S. aureus, there is concern that the efficacy of vancomycin in CoNS NVE may not be as good as expected. There are two major reasons that contribute to the suboptimal efficacy of vancomycin in the treatment of CoNS NVE. Firstly, as extrapolated from the literature on S. aureus IE, the pharmacology of vancomycin may be inadequate, with poor penetration into cardiac vegetations and altered bactericidal activity due to the high bacterial inoculum inherent in such vegetations (i.e., inoculum effect) [222,262,263].

The second factor relates to the microbiology of S. epidermidis, which possesses the capacity to produce a surrounding biofilm, as well as inherent resistance mechanisms to glycopep-tides that can provide a survival advantage.

Under in vitro testing conditions (e.g., time-kill studies), both vancomycin and teicoplanin exhibit good bactericidal activity against CoNS [264]. However, such testing is done on planktonic (i.e., free floating) organisms. One of the major virulence factors of S. epidermidis is biofilm formation, whereby the bacteria adhere to various surfaces and produce glycocalyx, resulting in colonies of bacteria embedded in a biofilm. S. epidermidis bacteria existing in this state demonstrate altered metabolism, with a remarkable ability to tolerate significantly higher levels of antibiotics when compared to their planktonic form [240]. As such, the killing efficacy of achievable peak serum concentration of various antibiotics, including vancomycin, is drastically decreased [263,265]. Although biofilm formation is a well-known explanation for failure of antibiotics to cure S. epidermidis infections associated with prostheses, it likely also contributes to the unsatisfactory results seen in CoNS NVE treated with antimicrobial therapy alone, as evidenced by the high rates of cardiac surgery required [239].

The resistance of S. epidermidis to glycopep-tides, however, is not mediated solely through biofilm formation. CoNS, including S. epider-midis, inherently possess chromosomally encoded mechanisms of resistance, consisting of overproduction of an abnormally thick cell wall and increased capacity to bind and sequester glycopeptides in the cytoplasm [265,266]. Furthermore, there is altered peptidoglycan cross-linkage, which may further inhibit van-comycin binding to target sites [193,266]. This glycopeptide resistance is heterogeneously present among populations of CoNS. Complete resistance to glycopeptides at the population phenotype level can be easily selected under laboratory conditions by serial or prolonged exposure of isolates to such antibiotics [267,268]. It has been hypothesized that extensive use of vancomycin in hospitals may also lead to such selection in vivo, allowing for the emergence of CoNS with increased MICs to vancomycin, with subsequent clinical failure [265,268]. This feature is alarming, in view of the fact that decreased susceptibility to glycopeptides is correlated with resistance to other antibiotics, including P-lac-tams, leaving little room for antimicrobial therapy [193,269].

Due to the emergence of glycopeptide resistance among CoNS, novel classes of antibiotics with alternate mechanisms of action are desirable.

Of these, Q/D, LZL, daptomycin, and telavancin are potentially the most promising, based on the following preliminary data. Conclusive clinical efficacy data on these agents, however, is currently limited.

As discussed previously, Q/D (quinupristin/ daltopristin) is a combination of two semi-synthetic derivatives of pristinamycin. This combination antimicrobial binds to the 50S bacterial ribosome, resulting in irreversible inhibition of protein synthesis, with subsequent bactericidal effects [141]. Its spectrum of activity is limited to Gram-positive bacteria; however, it has good activity against MRSE. In one study analyzing Q/D activity against 658 isolates of CoNS, >97% of tested isolated had Q/D MICs of <4 g/L [270]. Of the 186 clinical isolates of S. epidermidis specifically, resistance rates to Q/D were <1% [270]; such rates have been confirmed in other studies [271]. As well, clindamycin susceptibility appears to be predictive of Q/D susceptibility [270], which may allow for clinical laboratories to use clindamcyin as a surrogate antibiotic for Q/D during antimicrobial susceptibility testing. Animal models of endocarditis to determine the efficacy of Q/D have focused on S. aureus (see above); based on this data, Q/D displays homogeneous distribution throughout experimental vegetations with effective sterilization [272]. There is at this time, however, a paucity of clinical data. As such, there are no formal recommendations regarding the use of Q/D for the treatment of CoNS NVE with reduced vancom-cyin susceptibility. However, Q/D therapy was effective in three critically ill (non-endocarditis) patients with MRSE infection unresponsive to vancomycin [273]. Thus, future studies are required for this promising antibiotic. The major limitations in the use of Q/D is incompatibility with several drugs, which is problematic because Q/D is given parenterally, and its numerous drug interactions [274]. Furthermore, there appears to be geographic differences in inherent Q/D resistance among CoNS. For example, 16% of such isolates were resistant in a study from Taiwan, suggesting that Q/D may not be appropriate empiric therapy in certain regions [275].

LZL (linezolid), an oxazolidinone, also possesses activity against MRSE. Among 186 clinical isolates of S. epidermidis, the MIC50 was 2.0 mg/L, the MIC90 was 4 mg/L, and there was 0% resistance to lZl [270]. As with Q/D, there is a paucity of clinical data on the use of LZL in

CoNS NVE, although one case report describes the successful treatment of S. epidermidis NVE using an oral LZL regimen. Oral management was likely effective because of the 100% bioavailability of LZL. The major adverse events associated with the use of LZL include gastrointestinal disturbances, peripheral neuropathies, and hematologic abnormalities [276]. This latter complication, consisting of anemia and/or thrombocytopenia, is particularly problematic with prolonged use (> 2 weeks) of this agent [277]. Prolonged therapy, however, is necessary in the management of endocarditis. As such, it is recommended to monitor for the development of cytopenias with periodic complete blood counts (e.g., weekly [276] ). There is some suggestion that supplementation with vitamin B6 may mitigate the cytopenias [278], although further evidence is required.

Daptomycin, a cyclic lipopeptide, also exhibits activity against MRSE. Its mechanism of action involves the calcium-dependent insertion of the compound into the bacterial cyto-plasmic membrane, with subsequent alteration of membrane integrity and transmembrane potential [279]. The data on the use of dapto-mycin for endocarditis, though, is inconclusive. In a rabbit model of endocarditis, a single dose of daptomycin at 10 mg/kg IV produced an apparently effective response, resulting in a mean bacterial burden of 1.8 ± 1.9 log10 CFU per gram of vegetation, compared to 6.9 ± 1.0 log10 CFU per gram of vegetation among rabbits receving no treatment [280]. However, in another rabbit model using high doses of dapto-mycin (20 mg/kg or 50 mg/kg) [234], the authors demonstrated a significant antibiotic gradient from the periphery to the core of the fibrin clot, with associated increased survival of staphylo-cocci in the core. For MRSE, differences between bacterial counts in the periphery and in the core of the same clots were approximately 2 to 3 log10 CFU/g. However, in an in vitro simulated endo-cardial vegetation pharmacodynamic model [232], >70% penetration was achieved by dapto-mycin, associated with large bacterial density reductions (>4 log10 CFU/g). Currently, there is no clinical experience with daptomycin in MRSE NVE. As such, more information is required before recommending the use of daptomycin the treatment of MRSE NVE.

Telavancin, a novel lipoglycopeptide, demonstrates bactericidal activity against staphylo-cocci and exhibits substantial antimicrobial activity against staphylococcal biofilms, producing a decrease in the number of bacteria eluted from in vitro biofilms [281]. Currently, there are no reports of the use of telavancin in the treatment of CoNS NVE.

Based on the most recent data from the International Collaboration of Endocarditis (ICE), CoNS NVE (85% of which were due to S. epidermidis) was frequently complicated by heart failure (49/99 patients, 49%) and intracar-diac abscess (15/99, 15%). For these reasons, patients with S. epidermidis NVE more frequently required cardiac surgery when compared to S. aureus NVE (54% vs. 35%, respectively, P < 0.001) [239]. Furthermore, the rates of mortality with CoNS NVE were similar to those of S. aureus NVE (19% vs. 25%, respectively, P =.21), dispelling the belief that CoNS NVE is a benign disease. Given the high rates of cardiac complications associated with S. epider-midis NVE, early cardiac surgery consultation is suggested.

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