Staphylococcus epidermidis and other Coagulase-Negative Staphylococci

MICROBIOLOGY

Staphylococci are members of the family Micrococcaceae. They are Gram-positive, catalase-positive and occur singly and in irregular grapelike clusters, a description from which is the origin of their name. Staphylococci are broadly divided into a group that produce coagulase (S. aureus) and those that do not (96). Historically, S. aureus has been the major species producing serious human infection and a host of classic and new syndromes. The more benign coagulase-negative staphylococci have surfaced more recently as a cause of human infections (210). Host factors that predispose to coagulase-negative staphylococci infections include immunosuppression and the presence of a medical device. Under any of these circumstances there appears to be no one species that predisposes to such infections (103), however, there are some species of coagulase-negative staphylococci that have been associated with particular infections other than immunosuppression or a medical device (239). For example, S. saprophyticus accounts for up to 10% of uncomplicated urinary tract infections in young women (110,194). S. schleiferi, S. lugdunensis and S. haemolyticus are associated with native valve endocarditis (59,112,123). S. lugdunensis when isolated from an otherwise sterile bodily site is almost always a pathogen (97, 249) and its broadened importance is discussed in a separate chapter. New species like S. pettenkoferi and S. nepalensis have been described as causing human infections (184,156). Commercially available identification systems, based on the original work of Kloos and Schleifer (135), have been developed to provide an easy and rapid means of speciation (57).

When there are multiple isolates from infected sites, it is useful to determine their relatedness to aid in deciding if they are contaminants. Pulsed field gel electrophoresis (PFGE) is considered the gold standard for determining relatedness, however, because it is labor intensive, timely results are unlikely to be available to aid in the management decision process (257). Yet, PFGE can point to intra- and interhospital spread. Simplified molecular methods like rapid random amplification of polymorphic DNA (RAPD) or other approaches using a combination of antibiograms and biotyping are much less labor intensive (48,52,72,74,123,39). Khatib et al., determined the MICs of isolates to 10 antibiotics (102). They found that identical antibiograms were highly predictive of strain relatedness, whereas a 4-fold difference in a single MIC was not. Other molecular techniques such as multilocus sequence typing (MLST) using the DNA sequence of specific alleles can also detect clonal emergence in S. epidermidis species (141). Unfortunately CNS do not display by MLST as much species diversity as S. aureus but the use of an expanded array of alleles may make the technique more useful (www.mlst.org).

EPIDEMIOLOGY

Most of the coagulase-negative staphylococci associated with clinical disease are common inhabitants of the skin and mucous membranes. S. epidermidis is the most prevalent species, accounting for approximately 60-70% of all coagulase-negative Staphylococci on the skin. Coagulase-negative staphylococci are frequently associated with nosocomial infections, 41% of the time when bacteremia is present, and of these many are line infections (74). Conversely, due to their ubiquity on the skin, they are the most frequent contaminants of blood cultures often complicating the interpretation of these tests (Beekman). Nevertheless, even when a single positive blood culture along with multiple positive blood cultures were reviewed retrospectively, crude mortality was as high as 24.4% (74). Non-S. epidermidis species are also emerging as new pathogens in areas like implant infections (250) and in neonatal intensive care units (47,78). New species like S. pettenkoferi and S. nepalensis have been described as causing human infections (184, 156).

CLINICAL MANIFESTATIONS

Typically, the coagulase-negative staphylococci are considered to be less virulent than S. aureus and present as indolent rather than acute infections. Despite this, they are associated with a myriad of disease, both community and hospital acquired. The coagulase-negative staphylococci have been implicated as the causative agents in urinary tract disease, catheter related infections, shunt infections, pneumonia, endophthalmitis, (263), surgical wound infections, breast abscess (172), osteomyelitis (165), and native valve endocarditis (96). In particular, these infections are associated with medical devices; most notably prosthetic valve endocarditis and prosthetic joint infections, because of their propensity to form a protective biofilm (267). Prosthetic joint infections in particular are hard to cure and may require multiple steps in the process (166). Perhaps the same type of biofilm may be active in devitalized tissue like the diabetic foot infection which may often be associated with isolates of coagulase-negative staphylococci (48,236,234).

Of 393 bacteremias cause by Gram-positive cocci at Buffalo General Hospital in 2001, 75% were due to coagulase-negative staphylococci (113). In developing countries, the etiology of bacteremia, particularly in immunocompromised patients, continues to change (Safdar 2006). In developing countries, however, such as Nigeria, the rate of bacteremia due to coagulase-negative staphylococci is much lower, below 2% (217). Regardless of the setting the approach to single or even multiple coagulase-negative staphylococci in blood remains problematic, Even using molecular tools, it is not easy to distinguish between true pathogens and colonizers, probably because the colonizing population of coagulase-negative staphylococci, particularly in the hospital, is the very same one that gives rise to invasive strains (193).

LABORATORY DIAGNOSIS

Laboratory tests for coagulase negative staphylococci usually do not support a diagnosis of an infectious process or help resolve whether an isolate is a pathogen or contaminant A single isolate from a blood culture is usually considered of indeterminate significance or to represent contamination. Even two or three positive culture sets does not always represent true infection in the view of physicians but the clinician must exercise caution in declaring even a single blood isolate as a contaminant (74,104,195). Moreover, the initial presentation of a foreign body associated infection is so benign that the diagnosis of infection is only entertained after a positive culture of the infected material (13,62). Even the isolation of coagulase-negative staphylococci from an otherwise sterile surgical site may sometimes be erroneously regarded only as a contaminant (147).

PATHOGENESIS

Patients most at risk for infection due to coagulase negative staphylococci frequently have a disruption in their host defense mechanisms due to surgery, foreign body placement, or immunosuppression. In general, colonization and adherence are thought to be a prerequisite for coagulase-negative staphylococci infection (267). Following adhesion, mediated by a complex process involving at least 8 genes, many isolates produce copious amounts of a complex extra-cellular biofilm. A major component of the accumulated biofilm is polysaccharide intercellular adhesion PIA mediated by icaADBC that promotes adherence to plastic polymers and functions as an antiphagocytic capsule Biofilm may also function as a non-specific barrier to cellular and humoral defense mechanisms and may inhibit the penetration of antibiotics (55,83). Staphylococci also form phenotypic variants that are termed small colony variants and contribute to the particularly resistant type of biofilm-associated infections (251). Small colony variants may emerge as a major form of resistance for the coagulase-negative staphylococci. Finally, S. epidermidis contribute to persistence of other pathogens like Candida albicans when present in polymicrobial infections (Vankatesh 2007).

SUSCEPTIBILITY IN VITRO AND IN VIVO

The unpredictability of antimicrobial susceptibility and the need to identify methicillin-resistance, requires that susceptibility testing be routinely performed on all clinical isolates of coagulase-negative staphylococci. The list of antimicrobials to be tested are derived from recommendations found in manuals from the Clinical and Laboratory Standards Institute (CLSI) formerly called the The National Committee for Clinical Laboratory Standards (NCCLS) (137, 138, 139, 140). Clinical laboratories may choose from among several manual or commercial instrument based susceptibility methods. These include disk diffusion, agar or broth microdilution, antibiotic gradient and manual or automated commercial methods. The CLSI Subcommittee on Antibiotic Susceptibility Testing has published documents regularly which describe methods, contain guidelines for interpreting results and outline quality control test criteria. Fortunately, when using the currently available systems, susceptibility testing of staphylococci is generally accurate, reproducible and predictive of clinical outcome, with the exception of methicillin resistance.

The detection of oxacillin (methicillin) resistance is essential in order to determine the most effective antimicrobial. In addition to special testing methodology recommended by the CLSI, there are several commercial systems now available, including non-automated, semi-automated and automated ones (83,84,105,106,142). Additionally, the problem of what is termed heteroresistance (implying reduced susceptibility to agents like vancomycin) in S. aureus, may be as significant a problem in the coagulase-negative staphylococci but laboratories are not usually staffed to examine strains for that subtle resistance mechanism (185).

In Vitro Susceptibility Testing

Single Drugs

The coagulase-negative staphylococci most frequently associated with clinical infections share similar antimicrobial susceptibility profiles with the exception of S. saprophyticus and S. haemolyticus. S. saprophyticus is typically susceptible to most antimicrobials, including the aminopenicillins. S. haemolyticus is not only often multi-drug resistant, but may also be resistant to teicoplanin and vancomycin (171,191). Recently, several new antimicrobials with good activity against coagulase-negative staphylococci have been introduced into clinical practice: linezolid, tigecycline and daptomycin.  Linezolid displays good activity against the coagulase-negative staphylococci, including glycopeptide resistant strains (4,18,40,75,150). Resistance to linezolid in coagulase-negative staphylococci has recently been described (46), in particular in a patient with acute myeloid leukemia who failed linezolid for therapy of a bacteremia due to S. epidermidis. A mutation in the V region of the 23S rRNA gene was present in multiple linezolid-resistant blood isolates (hong 2007). Very little resistance to daptomycin and tigecycline has been reported to date (142, 122) The in vitro activity of antimicrobials that have been used to treat staphylococcal infections has been recently reviewed by John and Harvin and is presented in the Table. Most of these agents have an MIC90 < 0.5 µg/ml.

Combination Drugs

Lowy et al., studied the synergistic effect of antimicrobial combinations in vitro using a time kill method (125). Gentamicin was the single most effective agent. The addition of vancomycin to gentamicin did not significantly improve the bactericidal activity. The combination of rifampin and vancomycin was as effective as gentamicin alone. Antagonism was observed with the combinations of gentamicin and cephalothin or nafcillin and cephalothin and vancomycin. A further study by Lowy et al., re-examined the combinations of rifampin with vancomycin or gentamicin (124). The combination of rifampin and gentamicin demonstrated enhanced killing in 13 of 17 strains, while the combination of rifampin and vancomycin showed enhanced killing in 13 of 25 strains. However, rifampin resistance emerged in 12 of 25 strains with the latter combination.

Clindamycin has been shown to enhance the bactericidal effect of rifampin in vitro (8). Synergy between clindamycin and rifampin was observed in 6 of 12 strains of methicillin susceptible S. epidermidis when examined using time kill methodology. Svensson et al., studied the effect of antimicrobial combinations on both growing and non-growing cells of methicillin-resistant S. epidermidis (179). They demonstrated that imipenem combined with either amikacin or vancomycin displayed synergy against actively growing cells. In non-growing cells, synergy was not observed with any combination of drugs. Now that there are new classes and agents to treat methicillin-resistant coagulase-negative staphylococci, there will certainly be new energy to develop more effective antibiotic combinations (171).

In Vivo

Single and Combination Drugs

There are very few in vivo studies evaluating the efficacy of single drug therapy for coagulase-negative staphylococci, since the majority of infections are treated with a combination of drugs. Typically antimicrobial combinations are used to provide broad-spectrum empiric coverage or because an identified pathogen is resistant to inhibition and/or killing by conventional doses of single antimicrobials. The two most frequent reasons, however, for the use of combination antimicrobial therapy for coagulase-negative staphylococci infections are 1. to improve the outcome of foreign body related infections and 2. to prevent the emergence of resistance. Improvements in cure rates and the reduction in the emergence of resistance have been found in both animal and human studies, by the addition of gentamicin, rifampin, or both to vancomycin (97,108,190,196). Although combinations of rifampin with other agents has occasionally resulted in antagonism in vitro, the clinical relevance of such findings are unknown (70,126).

Brandt et al., compared the efficacy of cefazolin and cefpirome, alone or in combination with rifampin, to vancomycin, alone or in combination with rifampin, in an experimental model of methicillin-resistant coagulase-negative staphylococcal endocarditis (25). They found that vancomycin and cefpirome had similar activities and both were more effective than cefazolin alone. Cefpirome in combination with rifampin was more effective than cefazolin in combination with rifampin. Both cephalosporin-rifampin regimens were significantly more effective than was cephalosporin or vancomycin monotherapy and were as effective as vancomycin combined with rifampin. The in vitro results were not predictive of the in vivo results. The addition of a second agent to rifampin prevented the emergence of rifampin resistance in vivo.

Blaser et al., compared an in vitro pharmacodynamic model to an in vivo tissue cage infection model using several antimicrobial combinations (21). Both models demonstrated that rifampin combined with either vancomycin, teicoplanin, fleroxacin or ciprofloxacin were significantly more bactericidal against adherent bacteria than were netilmicin combined with vancomycin or daptomycin. A similar in vivo model was used by Widmer et al., to study both monotherapy and combination therapy in the treatment of implant associated infections (197). Rifampin monotherapy demonstrated significantly better efficacy than either ciprofloxacin or teicoplanin monotherapy or combination therapy with daptomycin and teicoplanin.

The antimicrobial regimens of amoxicillin-clavulanate, vancomycin, or teicoplanin, combined with netilmicin or amikacin were examined using an experimental subcutaneous fibrin clot model in rabbits (39). The combination of amoxicillin-clavulanate and netilmicin was highly synergistic and was more active in vivo than vancomycin alone or in combination. As mentioned, biofilms pose a special barrier for antimicrobial agents and there is renewed effort to understand the interaction of different antimicrobials with medically significant biofilm.

ANTIMICROBIAL THERAPY

There are many challenges in the management of patients who have cultures positive for coagulase-negative staphylococci. The foremost clinical challenge is to determine whether or not the isolate represents the etiologic agent of an infectious process or is a contaminant. Although coagulase-negative staphylococci consist of at least 32 species, only about 14 are associated with clinical disease (96). Even those that have been recognized as important pathogens, with the exception of S. saprophyticus, usually cause infection in the presence of a foreign body and/or the patient that is severely immunocompromised. Once having decided that an infection is likely due to coagulase-negative staphylococci, the clinician is faced with finding a suitable antimicrobial regimen. Compounding the problem is the fact that coagulase-negative staphylococci isolated from nosocomial infections are usually resistant to multiple antibiotics, therefore limiting traditional treatment options, like those with semi-synthetic penicillins. Finally, for those infections associated with a medical device, a decision must be made regarding its removal and if not, the length of treatment.

Drugs of Choice

β-Lactam Antibiotics

Coagulase-negative staphylococci may rarely be penicillin-susceptible, but the majority of strains are resistant (>80 to 90%) based on the production of an inducible, potent β-lactamase, mediated through a plasmid-located gene known as blaZ.(6,188). Staphylococcal penicillinases confer resistance to penicillins,ampicillin, amoxicillin, azlocillin, mezlocillin, carbenicillin, piperacillin, and ticarcillin. Some strains of staphylococci may only produce detectable amounts of enzyme only after exposure to an inducing agent, which may be generally a β-lactam, which are best detected in the laboratory with the chromogenic cephalosporin, acidometric, and iodometric tests (180).

If an isolate of staphylococci is found to be β-lactamase negative, then penicillin remains drug of choice. The semisynthetic antistaphylococcal penicillins, which formerly include methicillin, the isoxazolyl penicillins (oxacillin, cloxacillin, dicldo oxacillin and flucloxacillin) and nafcillin, are derivatives of penicillin that are poorly hydrolyzed by staphylococcal β-lactamase. They are bactericidal against growing cells, with MICs of < 2 mg/L for nafcillin and oxacillin, and < 8 mg/L for methicillin. There does not appear to be any significant differences in efficacy between these semisynthetic agents, and they have similar pharmacokinetic profiles (49,111). These agents are the drugs of choice for the treatment of staphylococcal infections unless the patient has a hypersensitivity to β-lactams or the infection is due to a methicillin-resistant strain (37). Their intrinsic potency is less than that of penicillin against β-lactamase-negative staphylococci. Oxacillin, cloxacillin, nafcillin and flucloxacillin can be administered intravenously 1-2 gram every 4-6 hours depending on the severity of the illness. In the presence of severe renal impairment, the dose of cloxacillin or flucloxacillin should be reduced. Oxacillin and nafcillin dosage adjustment may not be necessary (111).

Glycopeptides

The MICs of vancomycin to staphylococci are typically <4 mg/ml, however the MICs of the coagulase-negative staphylococci may be one to two-fold higher (122). Reduced susceptibility and resistance to vancomycin has been described in strains of S. haemolyticus (171,191). Resistance has not been described in other staphylococcal species, however a strain of Staphylococcus aureus with reduced susceptibility to vancomycin (MIC=8 mg/L ) has been described in Japan (78). These findings may warrant routine susceptibility testing of those strains that fail vancomycin therapy. Vancomycin is less rapidly bactericidal than nafcillin, which may explain in part why it appears to be less efficacious then the β-lactams (119,183). The dose of vancomycin in adults is 1gram q12h intravenously over 1 to 2 hours, in order to decrease infusion related events such as the "red man syndrome". Higher doses of vancomycin are currently in vogue to raise the trough levels to address strains with elevated MIC’s, however this maneuver may be associated with some increase of renal toxicity. Recently, experts have questioned the overall efficacy of vancomycin in treating staphylococcal infections not only because of its increasing MIC’s but also because of poorer tissue penetration and slower bacterical killing than was previously appreciated (Stevens 2006).

Alternative Drugs

Cephalosporins

Cephalosporins, particularly those of the first generation, are poor substrates for staphylococcal β-lactamase. However, the slow hydrolysis of cefazolin may account for failures in treatment of endocarditis and prophylaxis for cardiac surgery (101,163). Doses of cefazolin are 1 gram every 8 hours. It is cleared renally and the dose must be adjusted according to real function.

Third generation cephalosporins have been considered as second-line agents for the treatment of staphylococcal infections, despite good in vitro activity. Aldridge reviewed both in vitro and in vivo studies over the last 15 years on the activity and efficacy of cefotaxime (2). He found that cefotaxime was highly active against methicillin-sensitive strains and that therapy of staphylococcal infections was associated with clinical cures/improvement rates ranging from 78%-100%. This suggests that where there is a mixed infection, including staphylococci, that monotherapy with cefotaxime may be adequate.

Penicillin/β-lactamase Inhibitor combinations and Other β-lactams

Although staphylococcal β-lactamases are inhibited by the currently available β-lactamase inhibitor combinations, these agents may induce β-lactamases, as well as inhibit them (23). Currently available combinations include ampicillin/sulbactam, amoxicillin/clavulanic acid, ticarcillin/clavulanic acid, and piperacillin/tazobactam. There are no advantages with these agents over other narrower spectrum anti-staphylococcal antibiotics for the therapy of infections due only to coagulase-negative staphylococci. The carbapenems, imipenem and meropenem, may appear in vitro to have activity against methicillin-resistant coagulase-negative staphylococci, but are not effective in vivo (19,36). They display good activity against methicillin-sensitive coagulase-negative staphylococci in vitro and in animal models but provide no advantage over the antistaphylococcal penicillins (19). The monobactams (e.g., aztreonam) have no activity against staphylococci.

Glycopeptides

Teicoplanin has a similar mechanism of action and spectrum of activity as vancomycin, but its long half-life (>48 hours) allows it to be given as a once daily dose. Teicoplanin is highly protein bound (>95%) which may explain in part why it appears to be less efficacious then vancomycin. Early studies with teicoplanin showed a significant clinical failure rate which was thought to be due to the low doses (a loading dose of 400 mg followed 200 mg per day) selected for initial studies (30). However, even with doses twice those used in the original study, breakthrough bacteremia occurred (58). Of greater concern is resistance and the emergence of resistance while on therapy, in particular S. haemolyticus and S. aureus (35,93,122).

Oxazolidinones

The oxazolidinones are a new class of synthetic antimicrobials. Linezolid is the first of this class to be introduced into clinical practice (4,18,40,75). The oxazolidinones exert their antibacterial effect by binding to the 50S ribosomal subunit, inhibiting protein synthesis by interfering with the formation of the initiation complex. Linezolid is administered orally 400-600 mg q12h or 600 mg IV q12h. Clinical trials have demonstrated that linezolid is effective against a number of multi-drug resistant gram positive cocci, including vancomycin resistant pathogens. The few trials that have been done have shown linezolid to be efficacious in the treatment of infection due to coagulase negative staphylococci (4,40,150).

Macrolides, Lincosamides and Streptogramins

Macrolides, lincosamides and streptogramins are referred to as the MLS group of antimicrobials. Although they are chemically distinct they are related by their mechanism of action, which is by binding to the 50S ribosomal subunit and blocking protein synthesis. The macrolides include erythromycin, clarithromycin, and azithromycin. The lincosamides include clindamycin and the streptogramin group consists of a combination of two chemically unrelated molecules, groups A and B. Group A compounds include streptogramin A and group B compounds include streptogramin B.

In staphylococci, resistance to MLS antibiotics is acquired and is usually due to target modification, or active efflux of the antibiotic. Methylation of the ribosome, causing target modification, confers broad cross-resistance to all macrolides, lincosamides, and streptogramin B antibiotics (the MLSB phenotype) (116). Streptogramin A type antibiotics are unaffected and remain active against MLSB resistant phenotypes.

Expression of MLSB resistance may be constitutive or inducible. Clindamycin and streptogramin B are poor inducers of resistance and therefore in the laboratory they will appear susceptible. However, mutations are common and may occur while on treatment, resulting in a change from inducible to constitutive resistance. The second type of resistance, active efflux, involves erythromycin inducible cross resistance to other macrolides and streptogramin B, but not to clindamycin. This is referred to as the MS phenotype.

Macrolide antibiotics may be either bacteriostatic or bactericidal, depending on drug concentration and bacterial susceptibility (148). Clarithromycin is more active and azithromycin less active then erythromycin (1). Although erythromycin has been used extensively for the treatment of S. aureus infections, there are few clinical examples where it would be used for the treatment of infections due to coagulase-negative staphylococci. Clindamycin is bacteriostatic. Most strains of susceptible staphylococci are inhibited by concentrations of 0.1 mg/L of clindamycin. Strains that are resistant to erythromycin, but sensitive to clindamycin, should be assumed to be on the basis of an inducible methylase mechanism. In such circumstances it has been recommended not to use clindamycin (117).

Synercid is a combination (30:70 w/w) of quinupristin (streptogramin B) and dalfopristin (streptogramin A). MICs are 0.25 to 1 mg/L for both methicillin-susceptible and methicillin-resistant staphylococci. Unlike macrolides, synercid is bactericidal for staphylococci. Inducible MLSB resistance remain sensitive to quinupristin because it is not an inducer of methylase. However, if methylase is constitutively produced, quinupristin activity and its synergy with dalfopristin is lost and failure may occur (51,55). Therefore, as with clindamycin, caution should be taken when treating a patient with a coagulase-negative staphylococci infection due to a strain that is resistant to erythromycin on the basis of target modification, whether inducible or constitutive.

Trimethoprim-sulfamethoxazole

The combination of trimethoprim-sulfamethoxazole, which blocks folate synthesis, is bacteriostatic against staphylococci. Many multiresistant coagulase-negative staphylococci remain susceptible to trimethoprim-sulfamethoxazole, but susceptibility to these drugs is highly variable (185). Most of the experience in treating staphylococcal infections has been with S. aureus (7,120,128). Although it has been used successfully to treat staphylococcal endocarditis and meningitis, it has not proven to be as efficacious as vancomycin (43,182).

Fluoroquinolones

The second generation fluoroquinolones, such as norfloxacin and ciprofloxacin, had their greatest activity against gram-negative bacteria. Shortly after their introduction, fluoroquinolone resistance became frequent in methicillin-resistant S. aureus (MRSA) and coagulase-negative staphylococci (186). This has limited the usefulness of these agents for the treatment of staphylococcal infections with the exception of S. saprophyticus(140). The newer generation or respiratory fluoroquinolones, levofloxacin, moxifloxacin, and gatifloxacin have enhanced activity against gram positive organisms, however, published data suggest that their MIC’s are elevated against strains that are oxacillin resistant activity against coagulase negative staphylococci (64).

Tetracyclines

Many strains of staphylococci are now resistant to tetracycline (177). Minocycline and doxycycline are highly lipophilic analogues which have greater staphylococcal activity and have been used in the treatment of S. saprophyticus urinary tact infections (113). Minocycline maintains its potency against many tetracycline-resistant staphylococci, and is used as the primary agent for the treatment of MRSA infections in some countries (115,203). Those strains resistant to tetracycline on the basis of ribosomal protection (TetM) are resistant to tetracycline and minocycline, whereas those strains resistant on the basis of active efflux (TetK) are resistant to tetracycline and susceptible to minocycline (155,172).

Aminoglycosides

The aminoglycosides are bactericidal inhibitors of protein synthesis. Aminoglycosides have been widely used to treat staphylococcal infections, often in combination with other antistaphylococcal agents. The major mechanism of aminoglycoside resistance observed in the staphylococci is drug inactivation by enzymes. Amikacin and netilmicin are the most active aminoglycosides in vitro (42,66). They are usually used in combination with another antistaphylococcal agent.

Fusidic Acid

Fusidic acid, a steroid-like antibiotic, has been in clinical use since 1962 as a topical and oral preparation, but has not been available in the United States. It is often used in combination with another anti-staphylococcal agent to reduce the occurrence of resistance (3,56,60,77,87). It has retained excellent activity againstS. aureus and coagulase-negative staphylococci, including methicillin-resistant strains, although there are exceptions (54,132,184,192). One of the characteristics of fusidic acid is that it is able to penetrate, and be effective, into collections of pus, including cerebral abscesses. It is usually administered either orally or parenterally in a dose of 0.5 gram q8h. The dosage for children is 20 mg/kg body weight daily. It is also available in a topical preparation.

Rifampin

Rifampin is the most active anti-staphylococcal antibiotic (89). It blocks protein synthesis by inhibiting DNA-dependent RNA polymerase. High-level resistance can occur frequently as the result of a single amino acid change in the β-subunit of the RNA polymerase, therefore it is always used in combination with another anti-staphylococcal antibiotic. It can be given orally or parenterally in doses of 300 to 600 mg bid.

New Antimicrobials Agents

As mentioned in the Susceptibility Section, several new classes of antistaphylococcal agent are now available including linezolid, tigecycline, and daptomycin. For infections involving oxacillin-resistant isolates or in penicillin-allergic patients, these agents may have certain advantages. Daptomycin, for example, may have the advantage of being bactericidal, for example, in patients or neonates with persistent bacteremia (132). Other new agents that are awaiting FDA approval include cephalosporins that bypass the abberant penicillin-binding protein causing oxacillin resistance (ceftaroline and ceftobiprole), lipoglycopeptides (dalbavancin, telavancin) and dihydrofolate reductase inhibitors (icalprim). Many of these agents look very promising as agents that will be useful clinically against coagulase-negative staphylococci (208,58,112,113).

Special Infections

Bacteremia

The treatment of bacteremia due to coagulase-negative staphylococci is also evolving. Since almost all nosocomial bacteremias are due to oxacillin-resistant strains, vancomycin has been the keystone of therapy. Now, however, clinicians feel more comfortable with newer, alternative agents, as we have hinted in previous sections. Very recent data suggest that for bacteremia, daptomycin may be a reasonable alternative, particularly in patients failing on previous therapy (216). In the therapy of 34 patients with coagulase-negative staphylococci bloodstream infections, 35% of which were non-catheter related, overall success was almost 90% (216).

Catheter-Related Bacteremia

Coagulase-negative staphylococci are the most frequently isolated organisms in blood cultures, accounting for greater than 40% of all nosocomial bloodstream infections. This is due primarily to the increasing use of intravascular and implanted prosthetic devices (14,38,163). Other populations at risk for coagulase-negative staphylococci bacteremia are the immunocompromised and low-birth weight, premature infants (67,149).

Management of catheter related infections has traditionally included the removal of the infected line. However, there is increasing evidence for conservative medical management when these infections are due to coagulase-negative staphylococci and especially when occurring in children (15,173,181,200). Since these infections are typically nosocomial, vancomycin is often recommend as the antimicrobial of choice until results of susceptibility testing are available. Use of more bactericidal agents like daptomycin may supplant vancomycin as a first-choice agent pending further studies (216). In some cases, however, central vein catheter-related coagulase-negative staphylococci bacteremias in febrile neutropenic bone marrow transplant patients, where vancomycin was not included in the initial empiric antimicrobial regimen, may still had a benign clinical course. These infections could be treated successfully without removing the catheter (50). Generally it is recommended that if the infection responds to therapy, treatment should be continued for 2 to 3 weeks. If the infection has not responded in 48 hours, then some experts recommend that the catheter should be removed and an abbreviated course of 5- to 14-days of antimicrobials be given (71,76,158). In patients with central lines, catheter removal is almost always required when a tunnel infection or thrombophlebitis is present, however, most exit site infections can be managed medically. Caution is the key word here, still, because some isolates of coagulase-negative staphylococci may be more invasive and, like S. aureus, produce unappreciated metastatic foci that do not manifest for weeks or months (1).

Marr et al., determined the incidence and outcome of catheter-related bacteremia in dual-lumen cuffed catheters used for vascular access in patients undergoing hemodialysis (129). They found that salvage attempts with antibiotics were less likely to succeed in those patients with gram-positive bacteremias than in patients with gram-negative bacteremia. However, they also found that antibiotic salvage attempts were sometimes successful, but more importantly they were not associated with increase risk for complications.

Endocarditis

Although coagulase-negative staphylococci can cause host valve endocarditis, they are most often associated with prosthetic valve endocarditis (PVE) or pacemaker infections (51, 145). PVE can be characterized as "early onset" if infection develops within 60 days of surgery and "late onset" if infection develops more than 60 days after surgery (24,31,187). However, several reports have demonstrated that nosocomial PVE due to coagulase-negative staphylococci may not become evident until many months after surgery (31,187,176). Coagulase-negative staphylococci account for approximately 25 to 48% of all cases of PVE, including 30 to 67% of early onset PVE and 20 to 28% of late onset PVE. When speciated, coagulase-negative staphylococci associated with PVE are most often S. epidermidis (96,97).

Coagulase-negative staphylococci associated with early onset PVE are characteristically methicillin resistant (>80%), whereas the majority of strains associated with late PVE are susceptible (10,34,96). Treatment regimens with the greatest clinical success have included vancomycin alone or in combination with rifampin, an aminoglycoside, or both as compared to a β-lactam alone or in combination with rifampin, an aminoglycoside, or both (97). A study compared the outcomes of patients with methicillin-resistant coagulase-negative staphylococci PVE treated with 6 weeks of vancomycin and rifampin to those receiving this regimen plus gentamicin during the first two weeks (98). Outcomes of the two regimens were similar (77% versus 85% cure), however, rifampin resistant organisms emerged with the first regimen but not the three drug regimen.

Current recommendations are for treatment with vancomycin and rifampin for 6 weeks with gentamicin added for the first 2 weeks of therapy (21,22,198). For optimal therapeutic efficacy, the peak and trough levels of vancomycin should be maintained at 25 to 35 mg/L and 10 to 15 mg/L respectively (10,196). Fluoroquinolones are an acceptable substitute if the organism is resistant to all the aminoglycosides (198).

Indications for surgical intervention include increasing or refractory congestive heart failure due to prosthetic valve dysfunction, persistent fever due to the invasion of annular or myocardial tissue, valve dehiscence or paravalvular regurgitation seen on echocardiography, persistent bacteremia on appropriate antimicrobial therapy, recurrent systemic embolization, and/or relapse after appropriate therapy.

Coagulase-negative staphylococci account for only 5% of cases of native valve endocarditis, which are more frequently being associated with the hospital setting (99,167,196). For methicillin-resistant coagulase-negative staphylococci, vancomycin for 4-6 weeks is advocated (20). The routine use of rifampin is not recommended for native valve endocarditis, unless patients do not respond to conventional antimicrobial therapy (189). Methicillin-sensitive coagulase-negative staphylococci strains can be treated with a β-lactam (19,196,198). β-lactam allergic individuals may be treated with a first generation cephalosporin or vancomycin.

CNS Shunt Infections

Ventriculoperitoneal and ventriculoatrial shunt infections are the most common central nervous system infections attributable to coagulase-negative staphylococci. The majority of shunt infections (70%) usually develop within 2 months of insertion and almost 80% occur within 4 months (62,154). Infants less than 6 months of age have a significantly higher incidence of shunt infections than do infants older than 6 months (154). Approximately 60% of all shunt infections are due to coagulase-negative staphylococci (62,154).

The treatment of choice for the management of infected shunts is the prompt and early removal of the shunt (133,30). Immediate replacement should not be attempted if organisms have been demonstrated in the cerebrospinal fluid or if the patient has an infected wound near the insertion site (170).

As oxacillin-resistant coagulase-negative staphylococci are the predominate etiology of shunt infections, vancomycin is the initial empiric drug of choice. Parenteral vancomycin does not however, penetrate well into the cerebrospinal fluid. Thus treatment should consist of both intravenous vancomycin (2g / day or 40 mg/kg/day in divided doses q12h) and either intra-shunt or intraventricular vancomycin (10 mg once daily in children, 20 mg once daily in adults) (53). Vancomycin administration should be combined with oral rifampin (900-1200 mg/day or 20 mg/kg/day in divided doses q8h) (146,159). For a proven methicillin-susceptible coagulase-negative staphylococci shunt infection, IV nafcillin (9 - 12g / day or 300mg/kg/day in divided doses q4h) is recommended (64). Vancomycin is still the preferred choice for intraventricular therapy but other agents like llinezolid have been used with success (22).

Endophthalmitis

Coagulase-negative staphylococci are the most common cause of endophthalmitis (73,81,153). The source of the infection is characteristically the endogenous flora of the ocular surface that is introduced during cataract surgery, trauma or phacoemulsification of the lens. Endophthalmitis caused by coagulase-negative staphylococci is often slow to develop, painless and is usually less virulent with better outcome than infections caused by other bacteria (145). The management of postoperative endophthalmitis due to coagulase-negative staphylococci remains controversial. Treatment options include parenteral antibiotics, intravitreal antibiotics, or vitrectomy and intraocular antibiotic (24,58,143). More recently the use of steroids has been advocated either topically, subconjunctivally, or by intravitreal injection (129,175). The intraocular lens usually can be left in place (146). Since the source of the coagulase-negative staphylococci is often the patient’s periocular skin flora, strains may be methicillin-sensitive (14). The adequate length of intravitreal and/or subconjunctival antibiotics has not been determined. Systemic antibiotics are usually administered concomitantly in order to reduce the concentration gradient and increase the half-life of vitreal drugs. The intravitreal and subconjunctival dose of vancomycin are 1 mg and 25mg respectively. The intravitreal and subconjunctival dose of gentamicin are 0.1 mg and 20mg respectively. The subconjunctival route of drug administration is being used less frequently. Newer agents liketigecycline and daptomycin may have advantages for ocular penetration over traditional agents like vancomycin.

Sternotomy and Prosthetic Joint Infections

The two most common forms of osteomyelitis attributable to coagulase-negative staphylococci infection are sternal osteomyelitis, following cardiothoracic surgery, and infection of bone surrounding a prosthetic joint (44,85) Sternal osteomyelitis is due to coagulase-negative staphylococci in 30 to 45% of cases (43,130,136). Treatment of superficial and deep infections include, in addition to antibiotics, the use of diagnostic techniques to determine the location and extent of infection so that infected bone and soft tissue can be debrided. Additional measures for the management of deep infections remains controversial. Treatment options include delayed primary closure versus a muscle flap (26,82,204). The most appropriate antimicrobial, or combination of antimicrobials, and length of therapy has not been established, but usually up three weeks of intravenous therapy is recommended (162). Newer agent like linezolid hold promise for orthopedic infections (204), however, some studies using newer antimicrobials like daptomycin have questioned their efficacy for use in prosthetic joint infections (205).

Staphylococci are the most frequently isolated pathogens from prosthetic joint infections, with coagulase-negative staphylococci implicated in 20 to 50% of these infections (85). Conventional treatment includes long-term intravenous antibiotic therapy with a one- or two-stage replacement of the infected implant (199). The use of antimicrobial impregnated cement has been shown to be effective at reducing reinfection (65,100). In an open-label study, Drancourt et al., treated susceptible Staphylococcal-infected orthopedic implants orally with rifampin, 900 mg/day, plus ofloxacin, 600 mg/day (46). Patients with hip prosthesis infection were treated for 6 months, with removal of only unstable prosthesis after 5 months of treatment; and patients with knee prosthesis infection were treated for 9 months, with removal of all the prosthesis after 6 months. The overall cure rate was 74%. In a subsequent non-blinded randomized study by Drancourt et al., using identical treatment schedules, the previous regimen of rifampin plus ofloxacin was compared to rifampin 900 mg/day and fusidic acid, 1.5 g/day for the first 5 days followed by 1 g/day thereafter (45). The cure rates were similar in both groups, 50% and 55% respectively.

Urinary Tract Infections

S. saprophyticus is associated with approximately 10 to 30% of all urinary tract infections in women aged 16 to 30 years of age (169,194). The organism has been associated with recent menses and sexual intercourse (164). A seasonal variation in colonization has also been observed with rates higher during the summer and fall months (164,194). In contrast to women, S. saprophyticus urinary tract infections in men is associated with indwelling urinary catheters or obstruction (80).

S. saprophyticus is generally susceptible to most antibiotics, including penicillins (12,80). Although there has been a report of β-lactamase production in S. saprophyticus, the MIC of those strains are easily clinically attainable (114). Only rarely has resistance to methicillin been reported (57). Treatment with trimethoprim-sulfamethoxazole, ampicillin, and nitrofurantoin are effective (178). Several studies have demonstrated that failure rates for single-dose therapy are significantly higher than 3 or 7 day regimens (11,80,167).

Continuous Ambulatory Peritoneal Dialysis Peritonitis

Infection remains the major complication of continuous ambulatory peritoneal dialysis. The majority of infections are due to coagulase-negative staphylococci, accounting for approximately 40-50% of all infections (28,69,151). In view of the high incidence due to methicillin-resistant coagulase-negative staphylococci, vancomycin should be included in empiric treatment of staphylococcal peritonitis. Therapy can be administered intraperitoneally at 20 mg/L. For methicillin-sensitive coagulase-negative staphylococci, cephalexin can be used orally with a one gram loading dose and a maintenance of 500 mg q6h (46). The combination of vancomycin and gentamicin intraperitoneally has been shown to be effective and significantly more efficacious when compared to oral fluoroquinolone monotherapy for the treatment of coagulase-negative staphylococci peritonitis (17,183). Intraperitoneal ciprofloxacin (20 mg/L) was as effective as intraperitoneal vancomycin plus gentamicin (63). Oral therapy with rifampin (600 mg/day) in conjunction with vancomycin, may be of value for refractory or recurrent peritonitis due to staphylococci (29). Both systemic and intraperitoneal routes of antimicrobial administration will achieve sufficient drug levels required to treat the infection, however the intraperitoneal route is preferred (17,150). In the absence of a tunnel infection or intraperitoneal abscess, antimicrobial treatment is usually successful without catheter removal.

Vascular Graft Infections

The incidence of vascular graft infections is about 1.5%, with coagulase-negative staphylococci accounting now for 15%-40% of cases overall. The approach to surgical therapy of vascular graft infections has been complete excision of the graft and revascularization through a clean tissue bed with an extra-anatomic bypass. For infected aortic grafts one approach is extra-anatomic bypass performed prior to graft excision, with graft resection and oversewing of the aorta performed several days later. Appropriate antibiotics are given for 6-8 weeks. Others have promoted a more conservative approach. Gordon et al., used parenteral and oral antibiotics with minimal surgery, only when needed, and were able to preserve the aortic graft in 9 of 11 patients (68).

For extracavitary grafts Calligaro et al., attempted either subtotal graft excisions, for those infected thrombosed grafts, or complete graft preservation, for those infected non-disrupted grafts in non-septic patients (32). They carried out early aggressive wound debridement with excision of all surrounding infected tissue, wound healing by secondary intention and appropriate antibiotics for 6 weeks parenterally. This resulted in partial or complete graft preservation in 85% and 71% of patients respectively.

ADJUNCTIVE THERAPY

There have been several novel approaches to prevent and treat catheter related infections. Spafford et al., were able to prevent central venous catheter-related coagulase-negative staphylococci sepsis in neonates by adding 25 mg/L of vancomycin to the total parenteral nutrition solution (176). However catheter colonization, although reduced, was not eliminated. Kacica et al., using low-dose vancomycin prophylaxis in low-birth-weight infants, eliminated gram-positive bacteremia (94). Despite the apparent short-term benefit, one must weigh the risk of the possible emergence of vancomycin-resistant strains, especially with coagulase-negative staphylococci (171,191).

The antibiotic lock technique has been used in an attempt to sterilize in vivo a catheter that has become infected. It consists of filling and closing the catheter lumen with an antibiotic solution that acts locally, in hope of sterilizing the device (33). Although randomized controlled trials have not been carried out, anecdotal reports and open-non-comparative studies have found this to be a promising means by which to preserve catheters and to treat catheter-related sepsis, especially those due to coagulase-negative staphylococci (88,110 Fernandez-Hidalgo 2006)). For coagulase-negative staphylococci infections, vancomycin 1 mg/ml dissolved in isotonic solution is instilled for 12 hours daily for 5 days (33). Modifications of this technique have included the addition of heparin, to prevent thrombosis, and the use of fibrinolytic agents, to lyse blood clots that could be the focus of infection (10,27,86).

In an attempt to reduce sternal wound infections, Vander et al., carried out a non-blinded randomized study to determine the efficacy of the topical application of vancomycin to the cut edges of the sternum (189). Sternal infection occurred in one of 223 patients that received the vancomycin and seven of 193 controls (p=0.02). Possibly an agent could be evaluated that is not used systemically, such as bacitracin or ramoplanin.

Evidence is accumulating for the use of catheters impregnated with antiseptics or antimicrobials to reduce catheter-related infections (127,157). Maki et al., found that chlorhexidine-silver sulfadiazine catheters were well tolerated and reduced the incidence of catheter-related infections (127). Although there were only two infections in the antiseptic catheter group, both were due to coagulase-negative staphylococci. Raad et al., studied the value of central venous catheters coated with minocycline and rifampin in preventing catheter-related colonization and bloodstream infections (157). Colonization with coagulase-negative staphylococci was significantly reduced. There were no bloodstream infections per 1000 catheter-days with the antibiotic coated catheters as compared with 7.34 bloodstream infections per 1000 catheter days in the control group. Although authors of both studies argued that the development of resistance to these regimens was unlikely, it is too early to make such predictions. If resistance was to develop in the gram-positives, then coagulase-negative staphylococci would be the most likely candidates (5).

ENDPOINTS FOR MONITORING THERAPY

There are several reasons why defining endpoints for therapy of coagulase-negative staphylococci infections is difficult. The isolation of coagulase-negative staphylococci from a clinical specimen, including a sterile site, does not necessarily imply infection. Patients often present with minimal non-specific signs and symptoms. Having once made the diagnosis of infection, knowing if the agent, dose, and duration for therapy is appropriate is plagued by the same problems. In addition, even what regimen had been assumed to be effective therapy may eventually result in relapse months later, especially if the the implicated medical device has not been removed (155,202). We await better serologic, as is being studied in S. aureus infections (38) and imaging markers to determine the activity of infections due to coagulase-negative staphylococci.

VACCINES

There are no vaccines for coagulase-negative staphylococci.

PREVENTION AND INFECTION CONTROL

The single most important factor that can reduce the incidence of infections due to coagulase-negative staphylococci is strict adherence to hand washing, both prior to and after examining patients. Meticulous surgical technique is paramount to limit intra-operative bacterial contamination, particularly in procedures where foreign bodies such as prosthetic valves and joints are being introduced. Strict attention to technique when inserting lines and catheters may also contribute to an overall reduction in infection rates.

Catheters, intravascular devices, and surgical cements impregnated with antibacterial compounds or antibiotics have been developed, although their ability to prevent infection is still unclear. Current strategies surrounding appropriate antimicrobial prophylaxis during cardiac, neurosurgical, and orthopedic surgeries remain an important first line defense in minimizing infection in surgical patients.

Coagulase-negative staphylococci are part of the normal nasal and cutaneous flora so they will never be, nor should they be fully eradicated. There may be healthcare-related clones, much like some clones of S. aureus, that are move virulent and eradication of such clones may be desirable when there are proven methods for effective decolonization.

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Tables

Table 1.     In-Vitro Susceptibilities of the Coagulase-Negative Staphylococci

Antimicrobial		No. of Isolates	Susceptibility (mg / ml)
Class	Drug		MIC50	MIC90	Range
Fluoroquinolones
	Ciprofloxacin	163	0.25	0.5	0.06 - 32
	Norfloxacin	145	0.25	2	0.12 - 64
	Ofloxacin	139	0.25	1	0.12 - 64
	Sparfloxacin	69	0.12	0.25	0.12 - 8
	Levofloxacin	58	2	4	0.25 - 32
	Moxifloxacin	58	0.5	1	<0.06 - 4
	Gatifloxacin	41	1	2	0.06 - 8
Aminoglycosides
	Gentamicin	18	0.03	16	0.015 - 32
	Tobramycin	158	<0.25	>16	<0.25 - > 16
	Netilmicin	58	0.03	0.125	0.03 - 4
MLS antibiotics
	Erythromycin	150	0.25	≥64	0.125 - ≥64
	Clindamycin	14	0.06	0.12	<0.06 - ≥64
	Quinupristin / dalfopristin	202	0.25	0.5	0.25 - 1
β-lactams
	Penicillin	126	0.25	64	<0.06 - 64
	Amoxicillin /clavulanate	102	0.12	0.5	≤ 0.015 - 2
	Cephalexin	60	1	4	0.12 - 8
	Cefuroxime	95	0.5	2	0.25 - 128
	Ceftriaxone	160	4	16	0.06 - 32
	Cefixime	81	16	> 64	0.06 - > 64
	Imipenem	277	0.03	0.25	0.016 - 2
	Meropenem	319	0.25	8	0.0075 - 8
Others
	Linezolid	789	1	2	0.25 - 4
	Doxycycline	58	0.5	2	0.06 - 16
	Vancomycin	325	1	2	0.25 - 4
	Teicoplanin	231	1	4	0.25 - 32
	Trimethoprim	20	0.25	4	0.12 - 4
	*TMP / SMX	117	0.125	0.5	0.03 - 4
	Rifampin	45	0.008	0.016	< 0.002 - 0.03
	Fusidic acid	NS**	0.125	0.125	0.064 - 32

*Trimethoprim-sulfamethoxazole

**Not stated 

Collated from the following references: (9,11,18,39,40,75,77,78,79,88,89,90,91,109,121,130,135,141,160,161,165, 193, 201).

Bard JD, et al.  Rationale for Eliminating Staphylococcus Breakpoints for β-lactam Agents Other Than Penicillin, Oxacillin or Cefoxitin, and Ceftaroline.  Clin Infect Dis 2014;58:1287-1296.

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