Treatment options exist for CA-MRSA infection

November 2005

To coincide with the special section on antibiotic resistance, this month’s Pharmacology Consult will review the treatment of an increasingly common bacterial infection resulting from a unique strain of Staphylococcus aureus, community-associated methicillin-resistant S. aureus (CA-MRSA).

S. aureus isolates displaying resistance to ß-lactam antibiotics have been identified for more than 30 years and are referred to as methicillin-resistant S. aureus (MRSA). Methicillin, an antibiotic no longer available, is in the same class of antibiotics as nafcillin and cloxacillin. MRSA infection typically has occurred in patients with recent exposure to health care facilities or other risk factors, including past antibiotic use, indwelling catheter use or a recent medical procedure.

Infection with MRSA in a patient with these risk factors is described as health care–associated MRSA (HA-MRSA). These pathogens are usually resistant to not only ß-lactam antibiotics but other classes of antibiotics as well, and thus they can be difficult to treat. Infection with CA-MRSA can be made when MRSA is isolated in the outpatient setting, or if MRSA is isolated within 48 hours of hospital admission; no history of MRSA infection or colonization; no history within the past year of hospitalization, nursing home, skilled nursing facility, or hospice admission, dialysis, surgery, or permanent indwelling catheter. Another important characteristic differentiating HA-MRSA and CA-MRSA relates to antibiotic resistance patterns, as CA-MRSA usually does not display resistance to antibiotic classes other than ß-lactam antibiotics.

Outbreaks of CA-MRSA have been documented for more than 20 years, and reports of infection from CA-MRSA are increasing. Clinicians may suspect CA-MRSA when treatment of a skin or soft tissue infection with a ß-lactam antibiotic in a patient without the risk factors discussed above is not effective. While infection with CA-MRSA most likely results in skin or soft tissue disease (eg, boil, abscess, “spider bites”), more severe clinical manifestations may occur. Invasive disease from CA-MRSA, including sepsis and pneumonia, has been documented in children. The CDC reported on the deaths of four children from invasive disease by CA-MRSA in 1999. The potential for severe disease by CA-MRSA may be due in part to a unique virulence factor, Panton-Valentine leucocidin (PVL). PVL, a cytotoxin not typically found in HA-MRSA, may cause significant tissue destruction and illness.

In addition to the differences described above, another important difference between HA-MRSA and CA-MRSA relates to mechanisms of resistance that antibiotics displayed toward these pathogens. The methicillin resistance cassette gene found in CA-MRSA differs from that found in most HA-MRSA isolates. ß-lactam resistance is conferred in CA-MRSA by the mecA gene. This gene encodes for a penicillin-binding protein that has reduced affinity for ß-lactam antibiotics. As a result, ß-lactam antibiotics cannot interfere with bacterial cell wall synthesis.

This mecA gene is part of the staphylococcal cassette chromosome (SCC) mec. Five types of SCCmec have been identified: types II and III result in resistance to multiple antibiotic classes other than ß-lactam antibiotics, and are frequently found in HA-MRSA. SCCmec type IV, found in CA-MRSA, results in resistance to ß-lactam antibiotics, and does not include genes encoding for multi-drug resistance. Other genes responsible for resistance, erm or msrA, may also be present in CA-MRSA. These genes encode for resistance to erythromycin and potentially clindamycin. Mechanisms of resistance include altered ribosomal binding or antibiotic efflux (ie, antibiotic pumped to outside of the bacterium).

These resistant genes may result in constitutive or inducible resistance to clindamycin. Constitutive clindamycin resistance refers to resistance (already present) as demonstrated in the microbiology laboratory, and as listed in susceptibility reports as “resistant.” Inducible clindamycin resistance refers to resistance that is induced by exposure to erythromycin or another macrolide antibiotic. CA-MRSA with inducible resistance may initially be reported as “sensitive” to clindamycin. However, resistance to clindamycin may develop quickly after treatment. The D-test can be used by microbiology laboratories to detect CA-MRSA with inducible resistance. After placement of erythromycin-clindamycin disc pairs on an agar dish with the staphylococcal isolate, bacterial growth is measured. A flattening of the growth zone of inhibition (“D” shaped) near the clindamycin disc indicates inducible resistance. Some microbiology laboratories routinely perform the D-test on staphylococcal isolates. A “positive” D-test implies therapy with clindamycin should not be used, although the isolate may be initially reported as “susceptible” to clindamycin.

Treatment

While several antibiotics may be used to treat CA-MRSA infection, evidence from controlled clinical trials documenting their comparative efficacy is lacking.

Current recommendations for treatment strategies are largely based upon in vitro data and anecdotal and case reports, mostly from the adult published literature. Mild skin or soft tissue infection without systemic illness may be successfully treated with warm soaks and drainage alone.

Treatment choices for initial mild-moderate infection include clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX) or doxycycline. Susceptibility testing should be performed on all isolates; however, in vitro susceptibility testing may not always correlate with in vivo efficacy. Clindamycin should not be used if D-testing is positive. TMP-SMX may also provide effective therapy, based upon much anecdotal reporting. Some have advocated using large TMP-SMX doses (15 to 20 mg/kg/day of trimethoprim component) for increased efficacy. Some evidence indicates that a combination of rifampin and TMP-SMX may provide increased efficacy. Rifampin should not be used as monotherapy, as resistance to this antibiotic develops rapidly. As rifampin is a potent hepatic drug metabolizing enzyme inducer, increased TMP-SMX clearance and decreased clinical efficacy may occur with this antibiotic combination, and thus increased TMP-SMX dosing may be helpful. Rifampin may cause staining of body fluids, including urine, tears and perspiration. Staining of optical contact lenses may occur. Doxycycline and minocycline are additional antibiotics that may provide effective therapy. As doxycycline and minocycline are members of the tetracycline class of antibiotics, they should be avoided in children 8 or younger.

Should treatment failure occur with the antibiotics discussed above, additional treatment choices include linezolid (Zyvox, Pfizer), daptomycin (Cubicin, Cubist), quinupristin-dalfopristin (Synercid, Monarch Pharmaceuticals) or vancomycin. Linezolid is active against MRSA, although resistant isolates have been reported. Linezolid is available as an oral dosage form (tablet and suspension) but it is relatively costly. Its use may also result in significant drug-drug interactions, including selective serotonin reuptake inhibitors. Daptomycin is active against MRSA. Daptomycin is costly and is available only as a parenteral dosage form. Quinupristin-dalfopristin is also active against MRSA, although inducible resistance may occur. This antibiotic is also costly and is available only as a parenteral dosage form; it is often not well tolerated (pain upon injection, thrombophlebitis, myalgia). Many experts continue to consider vancomycin the drug of choice for severe MRSA infection.

For more information:

• Marcinak JF, Frank AL. Treatment of community-acquired methicillin-resistant Staphylococcus aureus in children. Cur Opin in Infect Dis. 2003;16:265-269.
• Rybak MJ. Community-associated methicillin-resistant Staphylococcus aureus: a review. Pharmacotherapy. 2005;25:74-85.
• Andrews TM. Current concepts in antibiotic resistance. Curr Opin Otolaryngol Head Neck Surg. 2003;11:409-415.
• Grim SA, Rapp RP, Martin CA, et al. Trimethoprim-sulfamethoxazole as a viable treatment option for infections caused by methicillin-resistant Staphylococcus aureus. Pharmacotherapy. 2005;25:253-264.
• Federal Bureau of Prisons. Clinical practice guidelines for the management of methicillin-resistant Staphylococcus aureus. August 2005. www.bop.gov/news/PDFs/mrsa.pdf.
• Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus – Minnesota and North Dakota, 1997-1999. MMWR. 1999;48:707-710.
• Rybak MJ. Community-associated methicillin-resistant Staphylococcus aureus: a review. Pharmacotherapy. 2005;25:74-85.

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy and a clinical specialist at Blank Children’s Hospital, Des Moines, Iowa.