Emerging Options for Treatment of Invasive, Multidrug-Resistant Staphylococcus aureus Infections

Richard H. Drew, Pharm.D.

Pharmacotherapy.  2007;27(2):227-249.  ?2007 Pharmacotherapy Publications
Posted 03/19/2007

Abstract and Introduction

Abstract

Limited established treatment options exist for the treatment of serious, invasive infections caused by multidrug-resistant Staphylococcus aureus, most notably nosocomially acquired methicillin-resistant S. aureus (MRSA). Although vancomycin represents the gold standard for therapy of such invasive infections, reports of increasing in vitro resistance to vancomycin, combined with reports of clinical failures (with this and other anti-staphylococcal agents), underscore the need for alternative therapies. Older agents with favorable in vitro activity available in both oral and intravenous dose forms include trimethoprim-sulfamethoxazole and clindamycin. Limited clinical data exist to support their routine use as initial therapy in the treatment of invasive disease. However, these and other options (e.g., tetracyclines) are being reexplored in the setting of increasing concern over MRSA acquired in the community setting. Newer treatment options for MRSA include linezolid, quinupristin-dalfopristin, daptomycin, and tigecycline. With the exception of linezolid, these newer agents require intravenous administration. Combination therapy may be considered in select invasive diseases refractory to standard monotherapies. These diseases include infections such as endocarditis, meningitis, and prosthetic device infections. Additional alternatives to vancomycin are under clinical investi-gation. Those in later stages of development include oritavancin, dalbavancin, telavancin, and ceftobiprole.

Introduction

Staphylococcus aureus was first documented as a human pathogen in the 19th century. Today, it is a frequently isolated pathogen causing serious, invasive infections such as soft tissue infections, endocarditis, osteomyelitis, bacteremia, septic arthritis, and nosocomial pneumonia. Available treatment options for serious invasive disease due to S. aureus are limited because of increasing antimicrobial resistance. Of particular concern is the increasing frequency of methicillin-resistant S. aureus (MRSA), especially in the United States. Recent surveys of S. aureus isolates report MRSA rates in the United States as high as 50%.[1, 2] The rates of MRSA are higher in patients in the intensive care unit and in those with nosocomial infections (often > 60%).[2–4] In addition to the increased rates of methicillin resistance isolated from hospitalized patients, recent reports cite concern regarding the growing frequency of MRSA acquired in the community setting, known as community-onset or community-acquired MRSA (CA-MRSA).[5, 6] Clinical, microbiologic, and economic outcomes associated with invasive S. aureus infections are less than optimal[7] and generally worse for patients with infections caused by MRSA.[8–10]

Vancomycin is considered by many to be the mainstay for the treatment of invasive infections caused by multidrug-resistant S. aureus, in part because of extensive published experience in the treatment of serious, invasive infections and a favorable safety profile.[11] However, vancomycin treatment outcomes in serious infections other than skin and skin structure infections (such as nosocomial pneumonia, endocarditis, and meningitis) are less than optimal.[11, 12] For example, vancomycin cure rates were reported to be 35.5% in a subset of patients with nosocomial pneumonia due to MRSA who participated in a randomized trial.[13] More recently, patients with MRSA endocarditis or bacteremia who participated in a randomized trial and were treated with vancomycin had a clinical success rate of only 31.8%.[14] Several drug-related factors may contribute to such poor outcomes. Vancomycin's microbiologic activity may be compromised in the presence of biofilms produced by some S. aureus organisms.[15, 16] In addition, investigators evaluating S. aureus isolates from patients receiving long-term vancomycin therapy for bacteremia concluded that loss of an accessory gene-regulator function in MRSA contributed to treatment failure.[15] Bacterial eradication rates for vancomycin may also be related to a ratio of drug exposure (characterized as area under the concentration-time curve [AUC]) to minimum inhibitory concentration (MIC).[17] Therefore, vancomycin's failure to reach sufficient concentrations in selected tissues and fluids (such as lung tissue) could also contribute to poor outcomes.[18, 19]

Despite maintaining 100% susceptibility in vitro (based on published interpretive breakpoint standards) against S. aureus in numerous surveillance studies,[11, 20, 21] there is growing concern regarding escalating MICs of staphylococci to vancomycin.[12, 15, 22] Case reports have been published of infections due to S. aureus with intermediate in vitro susceptibility to vancomycin (VISA), with MICs of either 4 or 8 ?g/ml.[23–29] In addition, there are reports of S. aureus with MICs of 1–4 ?g/ml that, when subjected to stepwise passage through increasing concentrations of vancomycin, yield subpopulations with increased MICs to vancomycin (usually at least 8 ?g/ml).[30–33] Such resistance in S. aureus has been termed "heteroresistant" (h-VISA). Finally, isolated case reports in the United States of patients with infections due to vancomycin-resistant S. aureus (VRSA)[34, 35] underscore the need to identify new treatment alternatives.

Patients with multidrug-resistant S. aureus infections intolerant to or failing vancomycin therapy previously have had limited treatment options. Newer therapies (e.g., linezolid, quinupristin-dalfopristin, daptomycin, and tigecycline) are available, but they need to be compared with other agents that have favorable in vitro activity against S. aureus ( Table 1 ).

Older Antibacterials for Resistant Staphylococcus aureus Infections

Nosocomially acquired MRSA, VISA, and h-VISA often exhibit in vitro resistance to numerous antibiotics. In contrast, CA-MRSA isolates carry a type of the gene complex different from that seen in nosocomially acquired isolates. This is known as staphylococcal cassette chromosome mec [SCCmec]).[36] As a result, CA-MRSA isolates frequently exhibit in vitro susceptibility to a variety of antibiotic classes (with the notable exception of β-lactams).[5, 37–40]

Trimethoprim-Sulfamethoxazole

Staphylococcus aureus is frequently susceptible in vitro to trimethoprim-sulfamethoxazole, especially those isolates that are community acquired and/or methicillin susceptible.[2, 38, 39] For example, the in vitro susceptibility of 888 methicillin-susceptible S. aureus (MSSA) and 334 MRSA European isolates to trimethoprim-sulfamethoxazole was reported to be 98.4% and 90.4%, respectively.[41] For isolates in the United States, susceptibilities were 96.9% and 87.9%, respectively.[42] The CA-MRSA isolates from Minnesota (97%),[38] Atlanta (100%),[6] and elsewhere[43] also demonstrated high in vitro susceptibility to trimethoprim-sulfamethoxazole. For VISA isolates with reported testing results to trimethoprim-sulfamethoxazole, all but one[27] exhibited in vitro susceptibility.[25, 26, 28, 44–47] Modest susceptibility was seen to trimethoprim-sulfamethoxazole in h-VISA strains.[48]

Clinical efficacy data for the use of trimethoprim-sulfamethoxazole in patients with serious S. aureus infections are sparse. Most of these are limited to single case reports and frequently involve infections such as endocarditis, bacteremia, and bone and joint infections. Published series have reported the efficacy of trimethoprim-sulfamethoxazole in bone and joint infections.[49, 50] In the only published, randomized trial, vancomycin and trimethoprim-sulfametho-xazole 320 mg (based on the trimethoprim component) every 12 hours were compared in a variety of S. aureus infections (including endocarditis, suppurative thrombophlebitis, and skin and skin structure infections) in intravenous drug users.[51] Among 101 patients evaluated, infections were due to MRSA in 47% and 65% were bacteremic. Overall cure rates were 98% (57/58) and 86% (37/43) of vancomycin- and trimethoprim-sulfamethoxazole–treated patients, respectively (p<0.02). All patients with MRSA infections in both groups were considered cured.

Most of the additional published experience on the efficacy of trimethoprim-sulfamethoxazole for the treatment of staphylococcal infections is in children.[52–54] Efficacy of trimethoprim-sulfamethoxazole in patients with infections due to VISA has been difficult to determine because of previous and concomitant therapies administered to these patients.[25, 45]

Potential advantages to the use of trimethoprim-sulfamethoxazole include convenient dosing (i.e., twice/day), availability of both intravenous and oral dosage forms, and low cost. Trimethoprim-sulfamethoxazole has been advocated by expert consensus guidelines as a treatment option for skin and skin structure infections,[55, 56] particularly mild-to-moderate CA-MRSA infections, when intravenous therapy is not required.[56] Empiric use of trimethoprim-sulfamethoxazole for treatment of skin and skin structure infections that may be due to CA-MRSA infections should not be used if group A strepto-cocci are also suspected, since trimethoprim-sulfamethoxazole lacks reliable activity against group A streptococci.[56]

Fluoroquinolones

Significant differences exist in the in vitro activity of various fluoroquinolones against S. aureus. In general, MICs to newer fluoro-quinolones (e.g., moxifloxacin, gatifloxacin, and levofloxacin) are lower than those seen for older fluoroquinolones (e.g., ciprofloxacin).[57] In contrast to MSSA, however, the in vitro potency of fluoroquinolones against MRSA is significantly reduced. For example, the in vitro activity of ciprofloxacin was evaluated against 888 MSSA and 334 MRSA European isolates.[41] Only 7.2% of MRSA isolates were ciprofloxacin susceptible (vs 91.2% of MSSA isolates). Similar discrepancies have been reported in the United States.[42] All six VRSA strains tested were resistant to fluoroquinolones.[48] Fluoroquinolones have also demonstrated high resistance rates (up to 96%) in h-VISA.[48, 58]

Although CA-MRSA isolates have been shown to have more favorable in vitro susceptibilities than do nosocomially acquired isolates to fluoroquinolones, such susceptibilities vary widely geographically.[5, 39, 59, 60] Use of fluoroquinolones has also been identified as a risk factor for the isolation of MRSA,[61, 62] and efforts to reduce institutional use have been associated with a reduced rate of nosocomial MRSA infection.[63] Therefore, based on these associations and the lack of reliable activity in vitro against MRSA, fluoroquinolones are not routinely recommended in suspected or documented MRSA infections.[56, 64]

Erythromycin

In vitro erythromycin resistance rates in MRSA often exceed 70%.[65, 66] Although CA-MRSA strains are more susceptible to erythromycin than are nosocomially acquired MRSA strains,[65] their susceptibilities are also poor.[59, 67, 68] In one series involving the USA 300 clone of CA-MRSA, resistance to erythromycin was reported in 136 (87%) of 157 strains tested.[6] Therefore, similar to fluoroquinolones, erythromycin would have limited use in the treatment of multidrug-resistant S. aureus infections.

Clindamycin

Clindamycin resistance rates in vitro for worldwide isolates of S. aureus ranged from 23.4–35.5% in one report.[69] However, in vitro activity often differs significantly in isolates that are methicillin resistant.[41, 42] For example, in one report, 96.3% of 888 MSSA isolates were susceptible compared with only 39.8% of 334 MRSA isolates.[41] In vitro susceptibility rates of CA-MRSA isolates are higher than those seen in nosocomial isolates. In one report, in vitro susceptibility was reported in 81% and 19% for community and nosocomial isolates, respec-tively.[70] However, as with fluoroquinolones, wide geographic variations in CA-MRSA resistance rates have been reported. Susceptibility of CA-MRSA to clindamycin has been reported as high as 94% in south Texas,[71] 97% in Atlanta,[6] and 100% in Detroit,[72] whereas others have reported resistance rates for this pathogen exceeding 20–25%.[73, 74] Clindamycin has limited activity against h-VISA; 98% of isolates were resistant to clindamycin in one report.[48]

Caution should be used in interpreting the potential utility of clindamycin based on in vitro testing, since infections due to clindamycin-susceptible, erythromycin-resistant isolates would be inappropriately treated with clindamycin in the setting of inducible macrolide-lincosamide-streptogramin B (MLSBi) resistance reported in S. aureus. A phenotypic method for detecting such inducible resistance has been described with use of a double-disk diffusion assay.[75, 76] In one series examining 14 patients with 15 episodes of CA-MRSA, 8 (53.3%) episodes were erythromycin resistant and clindamycin susceptible; however, all of these isolates exhibited inducible resistance to clindamycin.[77] Other institutions have reported MLSBi resistance ranging from less than 10%[78] to 56%[79] of their erythromycin-resistant, clindamycin-susceptible S. aureus isolates. Clindamycin-inducible resistance can also vary over time within the same institution. For example, a Dallas pediatric hospital reported that CA-MRSA isolates susceptible to clindamycin increased from 77.9% to 88.9% in 1999 and 2002, respectively.[80]

Most published experience with the use of clindamycin is in the treatment of skin and skin structure infections.[81, 82] Case reports cite varying degrees of success for invasive S. aureus infections treated with clindamycin (including refractory cases of endocarditis). Recent reports reviewed the use of clindamycin for the treatment of invasive CA-MRSA and CA-MSSA infections in children.[71, 83] Infections in these series included bacteremia, osteomyelitis, septic arthritis, pneumonia, and lymphadenitis.

The availability of clindamycin in an oral dosage form makes it an attractive treatment option for outpatient and/or long-term treatment of select infections. Recent published guidelines identify clindamycin for the treatment of skin and skin structure infections,[55] CA-MRSA,[56] and bone and joint infections[64] caused by susceptible MRSA in which isolates with MLSBi resistance have been excluded.

Rifampin

Although rifampin demonstrates potent in vitro activity against S. aureus[84, 85] (including CA-MRSA[6]), recent in vitro reports demonstrate limited activity of rifampin against VISA and h-VISA.[58] Because of the concern regarding rapid development of rifampin resistance by S. aureus, it should not be used as monotherapy.[56] Rather, it is used as part of combination therapy (usually with vancomycin) in selected cases of serious invasive and/or treatment-refractory infection, such as MRSA prosthetic valve endocarditis[86] and prosthetic joint infections.[87] Efficacy in these situations may be due, in part, to the favorable activity of rifampin against organisms producing biofilms.[88]

Aminoglycosides

Aminoglycosides (specifically gentamicin) demonstrate favorable activity in vitro against S. aureus (up to 92% susceptible in a recent survey).[89] In contrast, activity in vitro against h-VISA and VISA is poor.[58] Like rifampin, use as monotherapy for invasive staphylococcal infections should be avoided.[64] Therefore, aminoglycosides are generally reserved for use in combination therapy (most commonly with β-lactams) for the treatment of select invasive staphylococcal infections.[86] However, data to support such use are lacking.[90, 91] Published guidelines describe the role of gentamicin in the treatment of staphylococcal endocarditis.[86, 92] Although considered as an optional addition to a β-lactam (such as cefazolin or nafcillin) for endocarditis due to methicillin-susceptible staphylococci in the absence of prosthetic material (according to the U.S. guidelines),[86] aminoglycosides should be used as part of combination therapy for both methicillin-susceptible and methicillin-resistance staphylo-cocci in the presence of prosthetic material.[86, 92] In contrast, the United Kingdom guidelines for the treatment of MRSA infections do not support the routine use of aminoglycosides.[64]

Tetracyclines

In contrast to nosocomial isolates of MRSA, CA-MRSA isolates are frequently susceptible to tetracyclines (most notably doxycycline and minocycline).[93, 94] In a recent report, 348 isolates of MRSA demonstrated MICs for 50% and 90% of tested strains (MIC50 and MIC90) of less than 0.25 and 1 ?g/ml, respectively, to tetracycline.[95] Based on breakpoint analysis, 96.8% of these isolates were susceptible in vitro. In another recent series, 86% of the 89 MRSA isolates obtained from patients seen in a California emergency department were susceptible in vitro to tetracycline.[39] Rates of in vitro resistance to tetracycline may overestimate the frequency of resistance to both minocycline and doxycycline, since the mechanisms for tetracycline resistance may affect members of the class differently.[59]

A review of the literature examining the efficacy of doxycycline and minocycline in the treatment of tetracycline-susceptible MRSA infections was recently published.[93] Most of the infections treated in this series were complicated skin and skin structure infections, and clinical cure was achieved in 83% of 24 patients. Other case series have reported the successful treatment of CA-MRSA sinusitis with either minocycline or doxycycline.[96]

Published data are lacking to support the use of tetracyclines for invasive disease.[56] Therefore, their use is generally restricted to the treatment of adults with skin and skin structure infections.[64] Although published MRSA treatment guidelines recognize tetracyclines as a treatment option for urinary tract infections,[64] clinical data to support this are sparse. Similar to trimethoprim-sulfa-methoxazole, tetracyclines lack reliable activity against group A streptococci. Therefore, empiric use of tetracyclines for suspected CA-MRSA skin and skin structure infections should be avoided if group A streptococci are also suspected.

Newer Alternatives to Vancomycin for Serious, Invasive Staphylococcus aureus Infections

Linezolid

Linezolid is an oxazolidinone with bacteriostatic activity against S. aureus due to inhibition of protein synthesis at the 50S ribosome.[97, 98] In vitro surveys of susceptibility demonstrate consistent (i.e., 99–100%) activity against S. aureus.[2, 41, 99–103] The MIC90 in most of these published reports is 2 ?g/ml and generally does not appear to differ between S. aureus isolates susceptible to and those resistant to methicillin.[41, 100, 101] Linezolid also demonstrates similar in vitro potency against CA-MRSA.[72] The VISA isolates have remained susceptible in vitro to linezolid.[44, 58] Based on a limited number of isolates, linezolid has also demonstrated bacteriostatic activity in vitro against VRSA.[48, 104]

Linezolid resistance in S. aureus is infrequently reported,[105] even in isolates of MRSA that are multidrug resistant.[2] The first published report of treatment-emergent linezolid-resistant S. aureus was published in 2001.[106] The 85-year-old patient had end-stage renal failure requiring continuous ambulatory peritoneal dialysis. Methicillin-resistant S. aureus was initially isolated from peritoneal fluid and demonstrated an MIC to linezolid of 2 ?g/ml. The patient was treated with linezolid for 4 weeks without removal of the dialysis catheter. An MRSA isolate obtained during subsequent hospitalization for recurrent peritonitis revealed a linezolid MIC of greater than 32 ?g/ml. The mechanism of resistance was thought to be secondary to a point mutation of the 23S ribosomal RNA.[107] Although subsequent cases have been reported,[108, 109] treatment-emergent in vitro resistance in MRSA to linezolid is rarely reported.

Linezolid is approved by the U.S. Food and Drug Administration (FDA) for the treatment of invasive staphylococcal infections, including MRSA. In general, microbiologic and clinical outcomes for linezolid-treated patients are comparable to those treated with vancomycin for pneumonia,[110–112] urinary tract infections,[112] complicated skin and skin structure infections,[112, 113] surgical site infections,[114] and as empiric therapy in febrile patients with neutropenia.[115] Further analyses of many of these trials have compared the efficacy of linezolid in the subset of patients with MRSA infection. A retrospective subset analysis of patients with nosocomial pneumonia due to MRSA who participated in a phase III trial compared linezolid with vancomycin.[13] The authors concluded that linezolid was superior to vancomycin as initial empiric therapy in both clinical cure rates and survival. However, such benefit could only be demonstrated by subset analysis in 160 of the 1019 patients empirically treated under this protocol. Similar superiority of linezolid over vancomycin was observed in subset analyses of patients with surgical site infections due to MRSA[114] and complicated skin and skin structure infections,[113, 116] but not in those with bacteremia.[117]

The clinical issues surrounding the use of linezolid therapy are reviewed in detail else-where.[97, 118, 119] Linezolid is administered orally or intravenously at standard dosages of 600 mg every 12 hours. Dosage adjustments are not necessary when converting from intravenous to oral administration (oral bioavailability is approximately 100%), for renal insufficiency, or for mild-to-moderate hepatic impairment. Linezolid is generally well tolerated, with few minor adverse effects (gastrointestinal intoler-ance and headache in < 5% of patients).[120–123] Dose- and duration-dependent reversible blood dyscrasias are infrequent and usually manifest as thrombocytopenia.[120–123] The occurrence of thrombocytopenia may be more frequent in patients with end-stage renal disease.[124] Complete blood counts should be monitored in patients receiving therapy for more than 2 weeks, as well as in patients with other risk factors for hematologic toxicity. Case reports of toxicities associated with linezolid have also included peripheral[125, 126] and optic neuropathy,[127, 128] as well as lactic acidosis[129] in patients receiving long courses of therapy. The potential for elevations in blood pressure exist when linezolid is used concomitantly with adrenergic agents (e.g., pseudoephedrine).[118] In addition, linezolid administered concomitantly with selective serotonin reuptake inhibitors used for depression may result in the serotonin syndrome.[130–132]

The role of linezolid in the treatment of multidrug-resistant gram-positive infections is evolving. Analyses of data from clinical trials conducted with linezolid consistently demonstrate that the potential to convert linezolid to an oral therapy would result in a pharmacoeconomic advantage over vancomycin.[116, 133, 134] Linezolid has been identified as an option to vancomycin for the treatment of nosocomial, ventilator-, and/or health care–related pneumonia due to MRSA.[64, 135] Linezolid should also be considered for infections due to VISA or VRSA. For the treatment of MRSA-related complicated skin and skin structure infections,[55] surgical site infections,[136] or bacteremia (including catheter-related infections),[137] linezolid is more frequently prescribed to patients for whom initiation or continued intravenous therapy with vancomycin is not appropriate (due to failure, intolerance, or the ability to take oral drugs). It may have a limited role in the treatment of many mild-to-moderate CA-MRSA infections because of the availability of less-expensive treatment options.[56] Although published data do exist that report the use of linezolid for the management of both endo-carditis[138, 139] and bone and joint infections,[138, 140] linezolid is not recommended as first-line therapy for the treatment of these infections until further long-term safety and efficacy data are obtained.

Quinupristin-Dalfopristin

Quinupristin-dalfopristin was introduced in the United States in 1999. This 30:70 mixture of streptogramins groups B and A, respectively, acts by producing conformational changes in the ribosome.[97] The in vitro activity against clindamycin-susceptible strains (i.e., without constitutive macrolide-lincosamide-streptogramin type B resistance) is bacteriocidal at concen-trations 10–40 times the MIC.[141] However, quinupristin-dalfopristin may demonstrate reduced activity in isolates containing consti-tutive macrolide-lincosamide-streptogramin B resistance, exhibiting static activity against isolates that are both clindamycin and erythromycin resistant.[141–143] These changes in bactericidal activity depend more on the activity of quinupristin than the erm phenotype of resistance.[143] The in vitro susceptibility of both MSSA and MRSA ranged from 96.7–99.7% in various reports.[99, 144–146] In one report, only 35 of 13,052 isolates of S. aureus in Europe were nonsusceptible.[147] Relative potencies against 888 MSSA and 334 MRSA European isolates were MIC90 of 0.25 and 0.5 ?g/ml, respectively.[41] This compares with Clinical and Laboratory Standards Institute (formerly known as the National Committee for Clinical Laboratory Standards) criteria for susceptible, intermediate, and resistant isolates as being 1 or less, 2, and 4 ?g/ml or greater, respec-tively. In vitro activity has also been demon-strated against VISA[44, 58, 148–150] and VRSA.[48, 104, 150]

Although quinupristin-dalfopristin is approved by the FDA only for MSSA infections, data regarding the use of quinupristin-dalfopristin in patients with a variety of invasive staphylococcal infections (including other staphylococcal sp and MRSA) have been published.[151] Patients failing or intolerant to first-line therapies for MRSA infections were treated with quinupristin-dalfopristin. The primary infections studied were those of bone and joint, and skin and skin structure. Success rates in the intent-to-treat population were approximately 70%. This report failed to demonstrate a correlation between macrolide-lincosamide-streptogramin B resistance and clinical failure.

Summaries of the clinical issues surrounding administration of quinupristin-dalfopristin have been published elsewhere.[97, 152] Briefly, quinupristin-dalfopristin is available only in intravenous formulation and is administered at a dosage of 7.5 mg/kg every 8 hours for the treatment of vancomycin-resistant Escherichia faecium and 7.5 mg/kg every 12 hours for complicated skin and skin structure infections. Administration should be performed with use of a central venous line in an attempt to minimize drug-related phlebitis. In addition, other signifi-cant toxicities include arthralgias, myalgias, and hyperbilirubinemia. Metabolism by the cytochrome P450 3A4 isoenzyme results in a number of potentially significant interactions with drugs that include (but are not limited to) simvastatin, diltiazem, and cyclosporine.[153]

Daptomycin

Daptomycin is a cyclic lipopeptide, approved by the FDA in September 2003, that has potent activity in vitro against a variety of gram-positive pathogens.[154] Its mechanism of activity is thought to be as a result of binding to cell membranes in a calcium-dependent manner.[155] Daptomycin disrupts bacterial cell membranes without penetrating into the cytoplasm or rupturing the cell, resulting in an efflux of potassium and inhibition of protein, DNA, and RNA synthesis, leading to cell death.[155, 156] The resultant activity against staphylococci is concen-tration dependent and rapidly bactericidal.[157–159]

Numerous in vitro studies have confirmed the activity of daptomycin against S. aureus.[41, 42, 156, 160–167] Isolates with an MIC of 1 ?g/ml or less are considered susceptible.[168] An MIC90 of 0.13 ?g/ml was reported for 50 isolates of MSSA.[160] Favorable in vitro and in vivo activity against MRSA has also been reported,[156, 160] including community-acquired strains.[72] Although no difference in in vitro potency was reported between 888 MSSA and 334 MRSA European isolates (both demonstrating an MIC90 of 0.5 ?g/ml) in one study,[41] another European survey[166] reported a 2-fold difference between the MIC90 values (0.25 and 0.5 ?g/ml, respectively). Isolates of MSSA and MRSA obtained from U.S. hospitals have demonstrated MIC90 values of 0.25 and 0.5 ?g/ml, respectively.[42, 169]

Some evidence suggests that S. aureus isolates exhibiting reduced susceptibility to vancomycin (i.e., vancomycin MICs of 4–16 ?g/ml) may also exhibit higher MICs to daptomycin (i.e., ≥ 2 ?g/ml).[170–172] In vitro activity against three strains of VISA ranged from 0.25–0.5 ?g/ml in one report.[173] Other reports have confirmed MICs of 2 ?g/ml or less for a variety of multidrug-resistant S. aureus, VISA, and h-VISA.[150, 174, 175] For 55 isolates of h-VISA, MIC50 and MIC90 values were 2 and 4 ?g/ml, respectively.[176] Daptomycin also displayed potent activity in vitro against three strains of VRSA.[150] No cross-resistance with daptomycin to other classes of antibacterials has been reported, even when isolates with a variety of resistant determinants were evaluated.[167, 177, 178] Treatment-emergent resistance in S. aureus is infrequent but has been reported.[179–182]

Reviews have summarized the numerous animal models that have investigated the efficacy of daptomycin for a variety of infections caused by gram-positive organisms, including skin and soft tissue infections, pyelonephritis and urinary tract infections, pneumonia, endocarditis, and osteomyelitis.[183, 184] Results of two clinical trials evaluating the safety and efficacy of daptomycin in the treatment of complicated skin and skin structure infections in adult patients have been published.[185] Daptomycin 4 mg/kg intravenously every 24 hours was compared with either a semisynthetic penicillin 4–12 g/day or vancomycin 1 g every 12 hours intravenously. Infections included abscesses, surgical and traumatic wound infections, as well as infected ulcers in patients with and without diabetes mellitus. Concomitant administration of aztreonam and/or metronidazole was permitted. A total of 628 subjects (69.9%) in the modified intent-to-treat population had infections due to S. aureus (either alone or in combination with other pathogens). The clinical success rates in clinically evaluable patients were 83.4% and 84.2% in the daptomycin and comparator treatment groups, respectively. The difference was not statistically significant. Infections due to MRSA were limited to approximately 10% of the study population. Data on a subset of 103 clinically evaluable diabetic patients with cellulitis of the lower extremities (i.e., diabetic foot infections) in these trials have also been published and demonstrated similar efficacy rates to that of the comparators.[186] Limited published experience also exists for the treatment of bone and joint infections with daptomycin.[187]

In an analysis of data obtained from an international, randomized, double-blind trial comparing the efficacy of daptomycin 4 mg/kg once/day with ceftriaxone 2 g once/day for the treatment of community-acquired pneumonia, the clinical success rate in a subset of Eastern European patients receiving daptomycin (74.3%) was not noninferior to that of ceftriaxone (85.3%).[188] Subsequent studies have revealed the role of pulmonary surfactant in inhibiting the antibacterial activity of daptomycin.[189] Thus, pulmonary infections that are acquired hematogenously may be of less concern than those acquired through inhalation. However, based on these data, daptomycin is not recommended for the treatment of pneumonia.

Data regarding the use of daptomycin in the treatment of MRSA bacteremia and endocarditis have recently been presented.[14] This phase III, multicenter, randomized, open-label, noninfe-riority study compared daptomycin 6 mg/kg once/day with conventional therapy, either nafcillin or vancomycin. Gentamicin was added to daptomycin only in the setting of left-sided endocarditis and to all conventional therapies (independent of pathogen and diagnosis) for the first 4 days or until blood cultures had been negative for 48 hours. In the intent-to-treat population, endocarditis was diagnosed in 23% of patients and complicated bacteremia was diagnosed in 51%. The patients with MRSA infection constituted 37% and 38% of the daptomycin- and comparator-treated patient populations, respectively. In the sponsor's primary intent-to-treat patient population analysis, comparable success rates were reported at the test-of-cure visit (44.2% for daptomycin and 41.7% for conventional treatment). In a subset analysis of patients with MRSA infection, 44.4% of patients treated with daptomycin and 31.8% treated with the comparator were considered cured.

Previous human trials in bacteremia and endocarditis were limited by reversible skeletal muscle toxicity as manifested by elevations in serum creatine kinase level, myalgias, and muscle weakness with the divided daily dosing regimen of 2–4 mg/kg every 12 hours.[190] Recent animal[191] and clinical[192] experience has demonstrated that this effect was related to the frequency of administration (rather than total daily dose, peak serum concentration, or AUC), since signifi-cantly improved tolerability has been reported with the use of consolidated (i.e., once-daily) administration.

In a recently published clinical trial for the treatment of complicated skin and skin structure infections, no difference between daptomycin and comparator treatments was observed in creatine kinase levels before or after treatment.[185] Daptomycin was discontinued in 2 of 534 daptomycin-treated patients, with rapid resolution of the creatine kinase levels. The current recom-mendation is that patients receiving daptomycin should be monitored for muscle pain or weakness.[168] Creatine kinase levels should be monitored weekly, and daptomycin should be discontinued in patients with unexplained signs of myopathy in conjunction with elevations in creatine kinase level greater than 1000 U/L.[168]

Daptomycin is approved by the FDA for the treatment of complicated skin and skin structure infections at a dose of 4 mg/kg intravenously once/day, and for S. aureus bloodsteam infections (including patients with right-sided endocarditis) at a dose of 6 mg/kg intravenously once/day.[168] Because daptomycin does not require rapid cell division[193] and maintains its activity against S. aureus in the presence of a biofilm,[194] the potential exists for daptomycin to be useful in the management of catheter-related infections. Dosing adjustment is necessary in patients with significant renal impairment.[168, 195]

As with linezolid, the role of daptomycin for the treatment of invasive staphylococcal infec-tions continues to evolve. It should be considered an option for the treatment of infections due to VISA or VRSA. Daptomycin is generally considered in patients requiring intravenous therapy for serious, invasive infection when starting or continuing vancomycin therapy is inappropriate. Clinical uses for daptomycin include complicated skin and skin structure infections,[55] surgical site infections,[55] or bacteremia due to MRSA (including catheter-related infections).[64, 137] Although not recognized in the current published guidelines for the management of either catheter-related infec-tions[137] or endocarditis,[86] daptomycin 6 mg/kg/day should be considered a treatment option for bacteremia and right-sided endocarditis.[14]

Tigecycline

Tigecycline, a glycylcycline, is a protein inhibitor with a broad spectrum of activity.[156] Although its mechanism of action is similar to that of tetracyclines, it demonstrates increased potency against tetracycline-resistant organisms (especially those resistant due to the presence of an efflux pump).[196, 197] Both in vitro and in vivo activities have been demonstrated against MSSA, MRSA, and VISA.[156, 197–204] In a recent report, 99.2% of 819 global isolates of S. aureus were susceptible in vitro to tigecycline (using a breakpoint of < 2 ?g/ml).[205] The reported MIC50 and MIC90 to approximately 3500 isolates of S. aureus were 0.25 and 0.5 ?g/ml, respectively.[206] In this report and elsewhere,[94, 95] no difference in in vitro potency was observed among isolates based on susceptibility to methicillin. The MIC90 against 19 VISA isolates was 0.5 ?g/ml.[156] Others have reported MICs ranging from 0.12–0.5 ?g/ml against six VISA isolates and 0.12–0.5 ?g/ml against three VRSA isolates.[207]

The pharmacodynamic properties of tigecycline have also been reported.[208–210] Tigecycline is bacteriostatic against gram-positive pathogens[199] and may be more slowly bactericidal than vancomycin against MRSA.[211] For most drug-organism combinations tested, tigecycline exhibits time-dependent activity.[209] In vitro time-kill studies demonstrated less bacterial growth suppression with tigecycline than with vancomycin for all tested strains of MRSA and VISA. Activity was generally superior to gentamicin in all S. aureus strains but superior to rifampin in only rifampin-resistant isolates based on time-kill studies.[208] Although synergy studies with tigecycline and rifampin, vancomycin, or doxycycline have not yielded beneficial results (based on time-kill studies), use in combination with gentamicin resulted in enhanced activity against MRSA and VISA isolates.[208]

Numerous animal models have been reported to evaluate the efficacy of tigecycline in a variety of infections, including pneumonia, peritonitis, endocarditis, skin and skin structure, and peritonitis.[196, 212] Published experience in humans is limited to patients with complicated skin and skin structure infections and for treatment of intraabdominal infections.[213] Data from two phase III, double-blind studies in hospitalized adults with complicated skin and skin structure infections that compared tigecycline 100 mg followed by 50 mg intravenously twice/day with vancomycin plus aztreonam have been recently reported.[214] Clinical efficacy rates were 86.5% and 88.6%, respectively (p = 0.4233). In the 65 patients with MRSA at baseline (including 21 patients with CA-MRSA), microbiologic eradication was reported in 25 (78.1%) of 32 tigecycline-treated patients and 25 (75.8%) of 33 vancomycin-aztreonam–treated patients.

Tigecycline is approved for treatment of adult patients with complicated skin and skin structure infections (including those caused by MSSA and MRSA) and complicated intraabdominal infections (including MSSA) at an initial intravenous dose of 100 mg followed by 50 mg every 12 hours.[215] No dosing adjustments are necessary for patients with renal dysfunction (including those undergoing dialysis), but the maintenance dosage should be reduced to 25 mg every 12 hours in patients with severe hepatic insufficiency.[215] Because the glycylcycline class is similar to the tetracyclines, caution should be used in patients for whom tetracyclines should be avoided. The major adverse effect associated with tigecycline in these trials was gastrointestinal intolerance (including nausea, vomiting, and dyspepsia).[213, 214, 216, 217]

Combination Therapies

Various combinations of antibacterials have been examined in both in vitro and animal models of staphylococcal infection, with varying degrees of success.[98] Caution must be used in interpreting these results, since a variety of testing methods and conditions were used in these studies. In addition, the definitions of additive or synergistic activity can differ significantly among studies.

Combinations of vancomycin and gentamicin have been evaluated in several in vitro and animal models and generally demonstrated favorable activity.[218–221] Recent reports demon-strate increased rate of kill when gentamicin was added to vancomycin in CA-MRSA isolates.[221] This combination has been used clinically in the treatment of selected S. aureus infections, such as endocarditis.[91] In patients with MSSA bacteremia, although the addition of an aminoglycoside to a b-lactam antibiotic did not improve outcome, it did shorten the duration of bacteremia.[90] Currently, the combination of vancomycin with gentamicin is considered a treatment option for catheter-related infections (based on consensus treatment guidelines published in 2001.)[137] However, little additional clinical data to support the benefits of such an approach are available.[91] As previously mentioned, published data suggest nephrotoxicity secondary to vancomycin therapy is more commonly seen in patients receiving concomitant aminoglycosides.[222]

Perhaps the most common combination therapy used for invasive MRSA infections is vancomycin plus rifampin. Animal models of prosthetic device infection demonstrated benefit of combination therapy.[223, 224] Retrospective clinical data in orthopedic implant–related infections[87, 225] and refractory septicemia secondary to burns[226] also suggest a potential role of combination therapy in such infections. In one study, the mortality rate in patients with septicemia associated with S. aureus was lowest (4%) in patients treated with vancomycin plus rifampin whose isolates remained rifampin susceptible.[225] The rate increased to 38% in patients whose isolates became rifampin resistant during therapy and 78% in patients not receiving rifampin therapy.

Vancomycin in combination with rifampin is recommended for prosthetic infections due to MRSA.[64] The addition of rifampin to vancomycin or b-lactam therapy should be considered in the treatment of prosthetic valve endocarditis due to methicillin-resistant staphylococci.[86] However, only limited data exist to compare the combination therapy with vancomycin alone in such patients.[14, 227] Therefore, some guidelines suggest that such combinations be reserved for patients failing monotherapy.[64]

The role of the newer agents (linezolid and quinupristin-dalfopristin) in combination with vancomycin has been evaluated in several models. The combination of quinupristin-dalfopristin has shown increased activity over monotherapy with either agent in various models of infection (based primarily on time-kill studies).[224, 228–230] In addition, clinical reports highlighted the potential role of quinupristin-dalfopristin plus vancomycin therapy in the treatment of MRSA infections unresponsive to vancomycin therapy.[231, 232] In patients failing to clinically respond to vancomycin after 5 days, the addition of quinupristin-dalfopristin resulted in median time to bacterial eradication of 3.5 days versus 11 days with continued vancomycin alone (p<0.005).[231] In contrast, combination of an oxazolidinone (such as linezolid) plus vancomycin (although rarely antagonistic) generally lack evidence of synergy between the combination.[233]

In vitro studies demonstrate the potential role of combinations of vancomycin and β-lactam antibiotics against staphylococci with reduced susceptibility to vancomycin.[234, 235] These evaluations have included S. aureus strains with reduced susceptibility to vancomycin. Both oxacillin and nafcillin have been tested in in vitro and animal models and showed increased activity over monotherapy.[234] However, the published clinical experience with such combinations is lacking.

Combination antimicrobials excluding vancomycin have also been investigated. For example, quinupristin-dalfopristin showed promise in combination with cefepime in one in vitro model.[98] Cefepime combined with gentamicin was also shown to be a potent combination in an in vitro model (based on time-kill studies).[236] Combination therapies involving linezolid against S. aureus rarely demonstrate synergy. In contrast, daptomycin in combination with β-lactams demonstrated synergy in vitro.[237] The clinical relevance of these in vitro data, however, is unknown. In vitro[238, 239] and case reports[240] also indicate that minocycline in combination with rifampin may have activity in refractory infection.

Investigational Antibacterials

Oritavancin

Oritavancin is a semisynthetic glycopeptide derivative demonstrating potent concentration-dependent bactericidal activity in vitro against S. aureus.[195, 241–244] In one study, the MIC90 against MSSA was 1.0 ?g/ml (range 0.13–1.0 ?g/ml).[242] Most recently, in vitro activity against more than 1400 isolates of S. aureus from the United States and Europe was reported, with MIC90 of 2 ?g/ml for both MRSA and MSSA.[245] In vitro activity was also demonstrated against MRSA and multidrug-resistant S. aureus.[246] Despite a mechanism of action similar to that of vancomycin, it exhibits activity against vancomycin-resistant pathogens. Oritavancin in vitro activity has been described against three strains of VISA, where MICs ranged from 1–2 ?g/ml[173] and 2–4 ?g/ml.[245] In vitro activity has also been reported against 13 h-VISA strains, with MIC90 values ranging from 2–4 ?g/ml.[245] Finally, a report of the in vitro activity of oritavancin against one isolate of VRSA suggests favorable activity.[104]

Oritavancin has demonstrated efficacy in a variety of animal models of gram-positive infections, including catheter-associated infection, endocarditis, meningitis, and skin and soft tissue infection.[244] In a double-blind, randomized clinical trial in adult patients with complicated skin and skin structure infections, oritavancin 1.5 or 3.0 mg/kg/day for 3–7 days was compared with vancomycin (all followed by oral cephalexin) and demonstrated comparable efficacy.[247] More recently, results from a phase III, double-blind, randomized trial of oritavancin 200 mg/day intravenously for 3–7 days compared with vancomycin-cephalexin for a total of 10–14 days for complicated skin and skin structure infections reported clinical cure rates of 79% and 76%, respectively, and bacteriologic cure rates of 75% and 73%, respectively.[248] In this trial, fewer oritavancin-treated patients reported adverse events (47% vs 58%, p<0.001) and fewer required discontinuation of intravenous therapy due to an adverse event (1.8% vs 4.8%, p = 0.003).

Oritavancin is administered by intravenous infusion. Because of an extended half-life and its pharmacodynamic profile, the drug will likely be dosed on either a daily or alternate-day schedule.[219]

Dalbavancin

Like oritavancin, dalbavancin is a semisynthetic glycopeptide derivative with a similar mechanism of activity to that of vancomycin.[249, 250] It demonstrates potent activity in vitro against both MSSA and MRSA, with MIC90 values for both organisms generally 0.06–0.25 ?g/ml.[242, 251–256] Two isolates of VISA were reported to have MICs and minimum bactericidal concentrations to dalbavancin of 4 ?g/ml.[257] One isolate of VRSA also was reported to be susceptible to dalbavancin in vitro.[104]

In an open-label, phase II trial, patients were randomly assigned to receive either dalbavancin 1100 mg intravenously as a single dose, dalbavancin 1000 mg intravenously followed by 500 mg 1 week later, or a prospectively defined standard-of-care therapy for the treatment of skin and skin structure infections.[258] Clinical success rates at the test-of-cure visit were 61.5%, 94.1%, and 76.2%, respectively. Microbiologic success rates were 58%, 92%, and 71%, respectively. Dalbavancin, administered as 1000 mg intravenously on day 1 followed by 500 mg intravenously on day 8, was also compared with linezolid in a randomized, double-blind trial for the treatment of complicated skin and skin structure infections.[259] The most common pathogen was S. aureus, and many (51%) were MRSA. Dalbavancin's clinical and microbiologic success rates (88.9% and 89.5%, respectively) were comparable to those observed for linezolid (91.2% and 87.5%, respectively). More recently, data from three phase III studies comparing dalbavancin once/week with the comparators linezolid, cefazolin, and vancomycin were summarized.[260] In this report, 77% of infections were caused by S. aureus, 38% of which were MRSA. The clinical efficacy of dalbavancin ranged from 89–90%, with microbiologic cure in 88–93%. No differences were observed in outcomes based on methicillin susceptibility.

Based on in vitro models of catheter infections, dalbavancin has a potential role for catheter-related infections.[261] Dalbavancin has been compared with vancomycin for the treatment of catheter-related bloodstream infections. In a phase II, open-label, randomized trial, 75 adults with catheter-related bacteremia received either dalbavancin 1000 mg on day 1 followed by 500 mg 1 week later or vancomycin twice/day for 14 days.[262] The overall success rate in the 33 patients receiving dalbavancin (87.0%, 95% confidence interval [CI] 73.2–100.0%) was significantly higher than that in patients who received vancomycin (50.0%, 95% CI 31.5–68.5%).

Dalbavancin appears to be well tolerated. Safety data obtained from 1126 patients partici-pating in phase II and III trials were recently summarized.[263] Adverse events and event rates were generally similar to those of comparators.

Telavancin

Telavancin is a semisynthetic glycopeptide with a chemical structure similar to that of vancomycin. It is thought to work by inhibiting late-stage peptidoglycan biosynthesis (similar to vancomycin), as well as by interfering with bacterial cell membrane potential and permeability.[264]

In vitro activity of telavancin against S. aureus is thought to be concentration dependent and rapidly bactericidal.[265] The MIC90 for both MRSA and MSSA was reported to be 1 ?g/ml for both strains.[266, 267] In other reports, the MIC90 for telavancin against S. aureus was 0.25 ?g/ml, which was similar among methicillin-susceptible and -resistant isolates.[268] Telavancin has demonstrated favorable in vitro activity against both VISA and VRSA.[150, 268, 269] Its in vitro activity against VISA ranged from 0.25–1 ?g/ml in one report of six isolates[268] to 4 ?g/ml in another isolate.[269] The VRSA strains exhibited MICs to telavancin of 1, 4, and 4 ?g/ml.[268]

Telavancin appears to be generally well tolerated. Gastrointestinal disturbances (nausea, abdominal pain, vomiting) and headache appear to be dose related. Infusion-related reactions similar to the red man syndrome (pruritis, maculopapular rash) reported with vancomycin were also reported with telavancin and appear to be dose related.[270]

Results of a randomized, double-blind, phase II trial comparing the efficacy of telavancin 10 mg/kg intravenously every 24 hours with standard therapy of an antistaphylococcal penicillin 2 g every 6 hours or vancomycin 1 g every 12 hours in the treatment of adults with complicated skin and skin structure infections due to gram-positive pathogens were recently reported.[271] In a subset of 91 microbiologically evaluable patients with S. aureus at baseline, cure rates were 96% and 90% for the telavancin and standard-therapy groups, respectively. Of the 45 patients with MRSA, clinical cure rates were 96% and 90%, respectively. telavancin was superior to standard therapy for microbiologic eradication in patients with S. aureus infection (92% vs 78%, p=0.07) and in patients with MRSA (92% vs 68%, p=0.04).

Ceftobiprole

Changes in binding affinity to penicillin binding protein 2a is a major determinant of the resistance in staphylococci to most b-lactams, including methicillin. Ceftobiprole is an intravenously administered cephalosporin demonstrating high affinity in vitro to penicillin binding protein 2a and has demonstrated potent activity in vitro against MRSA,[272] VISA,[273] VRSA,[104] and in an endocarditis model against MRSA.[273] Published peer-reviewed data regarding the efficacy of ceftobiprole in humans are lacking. It is undergoing phase III trials in the United States for the treatment of complicated skin and skin structure infections as well as community-acquired pneumonia.

Iclaprim

Iclaprim is a selective dihydrofolate inhibitor demonstrating in vitro activity against S. aureus, including MRSA.[274, 275] Iclaprim was also active against one strain of VRSA.[104] Data from a randomized comparative study with vancomycin that examined two intravenous doses of 0.8 and 1.6 mg/kg twice/day are available in abstract form.[276] Overall efficacy rates (92.9% and 90.3% for the two doses, respectively) were comparable to those observed with vancomycin. At the test-of-cure visit, MRSA was eradicated in all four patients in this study who received iclaprim. This agent is currently undergoing phase III trials for the treatment of skin and skin structure infections.[277] An oral preparation is in early stages of development.

Faropenem

Faropenem is an orally available carbapenem with in vitro activity against S. aureus.[278, 279] The MIC90 against 217 isolates of MSSA in Europe was reported to be 0.12 ?g/ml in one study.[278] However, MIC90 values for 146 isolates of MRSA from the same study were substantially higher (i.e., > 32 ?g/ml). Such differences between MSSA and MRSA were also noted in other studies.[279] Faropenem 300 mg orally twice/day has been evaluated in the treatment of uncompli-cated skin and skin structure infections.[280, 281] The prevalence and response of MRSA to faropenem could not be elicited from the reports (available as abstracts only). However, based on the drug's dosage form (oral only) and the reduced activity (relative to MSSA) against MRSA, faropenem is not likely to be used as primary therapy for invasive, multidrug-resistant S. aureus infections.

Adjunctive Therapies

A new approach to the treatment of S. aureus infections is the use of immunotherapeutics as adjuncts to antibacterials. Altastaph is a prepa-ration of antibodies to capsular S. aureus types 5 and 8 that is in phase I–II trials.[282] Recent data have documented its pharmacokinetic profile and safety in very low-birthweight infants.[283] In addition, a monoclonal antilipoteichoic antibody is undergoing phase I–II trials.

Tefibazumab is humanized monoclonal antibodies to the MSCRAMM protein found on S. aureus. Results of pharmacokinetic and safety studies in human volunteers demonstrate that this agent exhibits linear pharmacokinetics and is generally well tolerated.[284] This agent is undergoing phase I–II trials. Results of a phase II, double-blind, randomized (1:1), placebo-controlled trial evaluating tefibazumab in patients with S. aureus bacteremia were recently reported.[285] Patients received a single intravenous dose of either tefibazumab 20 mg/kg or placebo within 72 hours of positive blood culture for S. aureus. A composite clinical end point (new-onset S. aureus bacteremia, infection-related complication or relapse, or all-cause mortality) was used. Of the 60 patients enrolled, four patients in the placebo group and two in the tefibazumab group reached the end point. The low event rate limited the ability to conduct meaningful comparisons between the interventions. One patient receiving tefibazumab experienced a hypersensitivity reaction that resolved after the infusion was discontinued.

A S. aureus conjugate vaccine containing types 5 and 8 capsular polysaccharide was investigated in a randomized, double-blind, placebo-controlled trial conducted in 1804 patients undergoing hemodialysis.[286] With the end point of bacteremia, the vaccine's efficacy at week 54 was 26%, not statistically significantly different from placebo. However, the week 40 results (57%) did reach statistical significance (p = 0.02). The authors concluded that partial, transient immunity was conferred by the vaccine.

Unresolved Issues

Despite an apparently large body of evidence, many issues regarding the treatment of invasive multidrug-resistant S. aureus infections remain unanswered. For example, the role of newer agents (such as quinupristin-dalfopristin, linezolid, daptomycin, and tigecycline) as initial empiric therapy for suspected MRSA infections in hospitalized patients remains unclear. Large-scale, prospective, randomized, controlled trials in patients with MRSA are needed to adequately compare these treatment options. The optimal duration of treatment for most invasive infections also remains undefined. The role of combination therapy continues to be debated. Optimal methods to prevent infection and minimize the impact of infection with resistant isolates continues to be investigated. In particular, the need to eradicate S. aureus carriage needs to be better defined.

Conclusion

A growing number of treatment guidelines for infections due to MRSA identify vancomycin therapy as the standard-of-care for many serious, invasive infections. Perhaps the most expansive list of alternative treatment options to vancomycin for MRSA infections exist for the treatment of skin and skin structure infections. In particular, skin and skin structure infections due to CA-MRSA in patients with mild-to-moderate disease without evidence of systemic infection or bacteremia may often be treated with oral agents, including trimethoprim-sulfamethoxazole, clindamycin, and tetracyclines (most notably doxycycline or minocycline). Linezolid use is generally reserved in such settings, due primarily to its expense. These oral agents are also often considered for patients initially treated with parenteral therapy for skin and skin structure infections or uncomplicated bacteremia due to susceptible isolates. In addition, oral clindamycin has been recommended as an option for long-term therapy of bone and joint infections after initial treatment with parenteral agents.

Alternatives to vancomycin for severe infections include clindamycin, daptomycin, linezolid, quinupristin-dalfopristin, tigecycline, and trimethoprim-sulfamethoxazole. Although trimethoprim-sulfamethoxazole and clindamycin may be used for infections due to CA-MRSA, most treatment guidelines continue to identify vancomycin as the initial treatment of choice for such infections. Linezolid and daptomycin may be considered as treatment options to vancomycin for complicated skin and skin structure infections due to MRSA, as well as for the treatment of bac-teremia. Published experience with MRSA infec-tions treated with tigecycline is limited primarily to patients with skin and skin structure infections. Linezolid is a treatment option for nosocomial pneumonia due to MRSA, whereas daptomycin should be avoided for the treatment of respiratory tract infections. New information suggests that daptomycin may have a role in the management of right-sided endocarditis. In the setting of vancomycin resistance, quinupristin-dalfopristin, linezolid, and daptomycin should be considered.

Table 1. Current Alternatives to Vancomycin for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults


Table 1: Current Alternatives to Vancomycin for the Treatment of Methicillin-Resistant <i>Staphylococcus aureus</i> Infections in Adults

 



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