No mercy for MRSA: treatment alternatives to vancomycin and linezolid

Medical Laboratory Observer, Jan, 2005 by Dennis L. Wegner

The prevalence of both community- and hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) has gone through the roof of our incubators. Some have speculated that the increase may be due to the inappropriate use of third-generation cephalosporins, (1) while others have suggested widespread use of quinolones is responsible. (2)

Laboratorians may not appreciate the extremely limited antibiotic options available to treat MRSA infections. Because many MRSA isolates test clindamycin-resistant, susceptibility reports using the standard Gram-positive panels list vancomycin and linezolid as the only antibiotics to which the offender is sensitive.

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Because vancomycin-resistant staphylococci are very rare, vancomycin has long been considered the gold standard for treating MRSA infections. Unfortunately, despite its in vitro activity, when vancomycin is used as single-drug therapy to treat MRSA infections, cure rates in serious infections have been very disappointing. Sakoulas (3) has reported 44% failures in treating bacteremia, and Moise and Schentag (4) have shown 40% failures in treating lower respiratory-tract infections.

In treating nonserious MRSA infections, such as wounds, skin, and urinary-tract infections (UTIs), in addition to slow cure rates and failures, vancomycin is practically and economically burdensome. Because there is no oral form, a patient for whom vancomycin is prescribed must wear an infusaport around the clock. Additionally, he must visit daily an infusion center or have home infusion service. To avoid toxicity, blood levels must be monitored. Vancomycin drug acquisition, administration, and laboratory costs are approximately $100 per day.

Most MRSA isolates test sensitive to linezolid, an oral drug that is usually well tolerated, but which carries a risk of hematological abnormalities, including myelosuppression and thrombocytopenia. Linezolid costs $120 per day (i.e., $1,200 for a 10-day course). For the many patients in our community who do not have health insurance, both vancomycin and linezolid are extremely unaffordable, making these nonviable treatment options.

The increase in childhood MRSA infections, especially ear and wound infections, was distressing to our pediatricians. When they prescribed vancomycin, they were unhappy about having to defend themselves to parents complaining about the practical problems of caring for a child who had to continuously wear an infusaport and have multiple blood draws. In response to their pleas for vancomycin and linezolid alternatives, queries to colleagues and subsequent multiple literature searches on the Internet resulted in some "hot tips."

Rifampin combination therapy to the rescue

Rifampin, which kills bacteria by inhibiting DNA-dependent RNA polymerase, was first introduced for use in the United States in 1971 and was approved for use to treat pulmonary tuberculosis and meningococcal carriage. It continues to be used today as part of long-term oral-combination therapy for mycobacterial infection. More recently, although it is ineffective single-drug therapy for treating staphylococcal infections, numerous studies have shown that when rifampin is combined with vancomycin, trimethoprim-sulfamethoxazole (trimeth/sulfa), minocycline, or ciprofloxacin, the resulting in vivo synergy markedly improves clinical outcomes.

When an isolate tests sensitive for rifampin in combination with vancomycin, trimeth/sulfa, minocycline, or ciprofloxacin, depending on the site of the infection, the appropriate combination therapy is suggested to the physician as an additional option to consider. A flowchart (Figure 1) shows which rifampin combination therapy may be appropriate. These are not given as a substitute for the report on the routine Gram-positive antibiotics specified by NCCLS (now known as the Clinical Laboratory Standards Institute) but, rather, as additional options for the clinician to consider.

Pharmacology

Because rifampin is eliminated by the liver, reduced doses may be needed if the patient has elevated liver enzymes. Rifampin is available in both oral and intravenous (IV) forms. The IV form is very irritating to veins and must be diluted in large volumes of fluid and infused over several hours. Because the IV form offers no advantages in antibiotic levels over the oral form, the IV form is usually avoided except for use in patients who are not able to tolerate oral medications.

No severe interactions with other medications are indicated; however, rifampin speeds up the metabolism of other medications eliminated by the liver, such as anticoagulants, antiseizure drugs, narcotics, and birth control pills, which might require pharmacist consultation to adjust dosages of these other medications to maintain the same effect.

Minocycline, a tetracycline with unusual clinical efficacy against S aureus, is contraindicated in pregnant and pediatric patients. It must be taken with a full glass of water, and the pills must be swallowed whole to avoid esophagitis. Additionally, to prevent it from binding with calcium, minocycline must be taken between meals. It can also be bound and inactivated by magnesium and aluminum present in some antacids.