Community Associated Methicillin-Resistant Staphylococcus Aureus: A Review

Michael J. Rybak, PharmD; Kerry L. LaPlante, PharmD

Disclosures

Pharmacotherapy. 2005;25(1):74-85. 

In This Article

Treatment Options

Although the epidemiology of CA-MRSA has been widely explored, therapeutic management of this infection has not been well studied and is not well established. Infections caused by CA-MRSA fall into a broad spectrum, ranging from uncomplicated skin and soft tissue infections, which can be treated in outpatient settings, to severe sepsis and toxic shock syndrome, which require hospitalization and aggressive treatment. Because CA-MRSA strains tend to be susceptible to a wide variety of non-β-lactam antibiotics, it would seem that several treatment options are available ( Table 2 ). However, most potential treatments have not been tested clinically, and their efficacy is therefore unknown. Moreover, there is great uncertainty about development of resistance. Researchers have expressed renewed interest in the use of clindamycin, tetracyclines, and trimethoprim-sulfamethoxazole (TMP-SMX) in treating MRSA infections, as these drugs generally have activity against CA-MRSA ( Table 3 ).[33,40,75] For severe infections requiring hospitalization together with intravenous antibiotics, vancomycin and newer agents, such as linezolid, quinupristin-dalfopristin, and daptomycin, can be feasible options.

Clindamycin remains a viable treatment option for CA-MRSA, as it demonstrates in vitro susceptibility to most MRSA isolates. However, inducible resistance and treatment failure have been reported.[76,77] The disk diffusion (D-test) method can detect S. aureus isolates with inducible macrolide-lincosamide-streptogramin B (iMLSB) resistance.[78] However, this is a cumbersome procedure, and hospital laboratories have had difficulty applying this method to each S. aureus isolate. The D-test is conducted with erythromycin-clindamycin disk pairs placed by hand on an agar dish streaked with the isolate in question. After incubation, zone diameters are measured, and significant[]ingrowth within a zone up to the edge of the disk is considered[]constitutive (already present) resistance. In contrast, flattening or blunting of the clindamycin zone (D shape) indicates inducible resistance (Figure 2).[78]

Double disk diffusion test (D-test) demonstrating erythromycin induction of clindamycin resistance. Blunting of the clindamycin inhibition zone produces a D shape as indicated.

Inducible isolates (those with positive results on the D-test) are a source of concern because they may have a heightened rate of mutations, which would enable them to develop constitutive resistance to clindamycin during therapy. One clinical laboratory screened over 150 S. aureus isolates for iMLSB resistance in erythromycin-resistant and clindamycin-susceptible clinical S. aureus isolates and found 56% of isolates to have inducible resistance by the D-test.[76] Little information is available to characterize iMLSB resistance in CA-MRSA. However, a recent investigation examined 85 clinical MRSA isolates for iMLSB resistance.[75] Isolates were evaluated based on CDC definition and molecular typing. In SCCmec type II isolates (HA-MRSA), 50% of strains harbored iMLSB resistance, whereas only 17% of SCCmec type IV isolates (CA-MRSA) had this type of resistance pattern. The number of CA-MRSA strains worldwide harboring this inducible type of resistance is unknown. It is therefore not recommended to use clindamycin to treat MRSA infections unless the appropriate D-test for iMLSB resistance is conducted on the specified isolate according to the guidelines of the National Committee for Clinical Laboratory Standards.[79,80]

Trimethoprim-sulfamethoxazole is another antibiotic with potential for treatment of CA-MRSA. However, limited clinical studies and patient cases have found TMP-SMX to be useful in treating MRSA infections. The reported rate of TMP-SMX resistance in S. aureus is highly variable, but most CA-MRSA strains appear to be susceptible. The sulfa moiety of TMP-SMX, sulfamethoxazole, is bacteriostatic, whereas the trimethoprim component blocks dihydrofolate reductase, thus inhibiting production of metabolically active folic acid. When both agents are used together, TMP-SMX appears to produce a bactericidal effect against most isolates.

One study investigated the use of TMP-SMX in MRSA bacteremia in intravenous drug users.[81] The investigators reported that TMP-SMX may be considered as an alternative to vancomycin in selected cases of MRSA infection; however, treatment failures were reported. More recent studies report allergic reactions to sulfonamide antibiotics in approximately 10% of patients; therefore, caution is warranted in this patient population.[82] The development of resistance and the therapeutic use of TMP-SMX in MRSA have not been fully established. However, a small retrospective study suggested that prompt incision and drainage, followed by a 2-3-week course of TMP-SMX in combination with rifampin was an effective treatment option for cutaneous infections caused by CA-MRSA.[70] Although in vitro testing revealed susceptibility to TMP-SMX and rifampin, infection recurred in a patient treated with TMP-SMX alone compared with the combination of TMP-SMX and rifampin. Resistance to rifampin develops rapidly when it is given as monotherapy. Therefore, rifampin should be considered only when given in combination.

Minocycline is a tetracycline antibiotic that has been used in the past for the treatment of MRSA.[83] Doxycycline, another tetracycline compound, has a similar susceptibility profile. Although these agents have been used clinically, limited published data are available on the use of tetracyclines in the treatment of MRSA; therefore, the efficacy of doxycycline and minocycline in the treatment of MRSA have not been established.

Caution is warranted in using fluoroquinolones to treat MRSA infections. Historically, overuse of fluoroquinolones has been associated with MRSA selection.[84,85] Moreover, use of fluoroquinolones for treating MRSA infections is correlated with rapid acquisition of fluoroquinolone-resistant MRSA. The newer fluoroquinolones may have a role in the treatment of complicated skin and soft tissue infections, especially in patients who are allergic to penicillin. More clinical studies are needed before a formal recommendation can be made.

Until the arrival of newer agents, most clinicians would agree that vancomycin, a glycopeptide antibiotic, is the drug of choice for treating serious MRSA infections. However, recent reports have described glycopeptide- intermediately susceptible S. aureus (GISA) and heteroresistant GISA. Vancomycin-resistant S. aureus (VRSA) has been identified in Michigan, Pennsylvania, and New York.[86,87] These organisms are often not responsive to vancomycin.[79,80]

Although vancomycin has been proved as a safe and effective treatment option for MRSA, increasing reports document glycopeptide resistance. These reports have heightened awareness of the need for newer and more effective agents. The relationship between CA-MRSA and heteroresistant GISA has not yet been described.

Linezolid, which in 2000 became the first oxazolidinone to be approved by the Food and Drug Administration (FDA), has good penetration into skin and soft tissue infections and is available in an oral formulation. Although it is considered a bacteriostatic agent, linezolid has demonstrated effectiveness in skin and soft tissue infections, bacteremia, and pneumonia caused by gram-positive bacteria. Linezolid shows activity against MRSA, although S. aureus resistance has been reported. Researchers have expressed concern that linezolid is being overused.[88]

Quinupristin-dalfopristin is a streptogramin combination product with a gram-positive spectrum of activity that includes MRSA. Although the FDA has not approved quinupristin-dalfopristin for use in MRSA infections, the product is approved for use in complicated skin and soft tissue infections. The poor tolerability profile of quinupristin-dalfopristin limits its use.[89] Moreover, S. aureus may demonstrate inducible or constitutive MLSB. Cross-resistance to macrolides, lincosamides, and streptogramin B-type antibiotics by methylation of the ribosomal target is the most common mechanism of S. aureus resistance to streptogramin combination products. If inducible resistance is present, quinupristin remains active because it is not an inducer of the methylase. However, if constitutive, quinupristin is inactive, and quinupristin-dalfopristin becomes bacteriostatic rather than bactericidal. Thus, loss of activity may occur. This process has been demonstrated both in vitro and in vivo.[90,91]

Daptomycin is a novel lipopeptide antibiotic approved by the FDA in 2003 for treatment of complicated skin and soft tissue infections, including those caused by MRSA. This drug has received much interest because of its activity against multidrug-resistant gram-positive bacteria, especially MRSA.[92] Daptomycin has demonstrated rapid bactericidal (99.9% kill) activity in several in vitro and animal pharmacodynamic studies.[71,93] Although considered a viable treatment option, its role in the treatment of CA-MRSA has not yet been fully established.

Overall, there appear to be several antimicrobial therapeutic options for treating CA-MRSA infections. However, as stated above, no definitive studies have tested these options clinically. Since a number of toxins are associated with CA-MRSA, research is needed to address the appropriate selection of antimicrobial agents with regard to the threat posed by toxin release.

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