A Guide To Current And Emerging Antibiotics For MRSA

Eliza Addis-Thomas, DPM, Jon Key, DPM, FACFAS and Peter A. Blume, DPM, FACFAS

Staphylococcus aureus is a common pathogen that can result in everything from minor skin infections to osteomyelitis, bacteremia, endocarditis and pneumonia.1 In podiatry, infections with Staphylococcus aureus, especially methicillinresistant Staphylococcus aureus (MRSA), are something physicians see on a daily basis.
In a study determining the prevalence of MRSA in infected and uninfected diabetic foot ulcers, 61 percent of infected diabetic foot ulcers were infected with MRSA.2 With the emergence of multi-drug resistant Staphylococcus aureus organisms, the need for effective antibiotics has become critical.
Staphylococcus aureus is a highly adaptable gram-positive bacterium that has garnered a lot of attention in the community and the media.There are reports that nearly 50 percent of Staphylococcus aureus isolates are methicillin-resistant.1 While the incidence of hospital-acquired MRSA (HA-MRSA) has increased, there has been a more concerning emergence of communityacquired MRSA (CA-MRSA). This was first reported in the late 1990s when four Native American children died of CA-MRSA related illnesses.
The Staphylococcus aureus involved in these infections have genes that code for Panton-Valentine leukocidin and mecA, the gene that encodes for the organism’s methicillin resistance. In the United States, the most common variant of CA-MRSA is USA300 and accounts for 60 to 75 percent of all Staphylococcus aureus isolates.3

Recognizing The Limitations Of Vancomycin
Vancomycin is generally considered the first line treatment for MRSA infections. Patients take vancomycin in doses of 1g every 12 hours intravenously.
While there is good evidence supporting the use of vancomycin in treating skin and skin structure infections, the outcomes in treating more severe infections such as pneumonia, endocarditis and meningitis are less favorable. For example, researchers found that vancomycin had a clinical success rate of 31.8 percent in a randomized trial for the treatment of MRSA endocarditis and bacteremia.1
While vancomycin has maintained near 100 percent susceptibility in vitro, there is concern regarding increasing minimum inhibitory concentrations (MICs) of Staphylococcus aureus to vancomycin.There have been reports of MRSA isolates with intermediate susceptibility and complete resistance to vancomycin, the so-called vancomycin-intermediate and vancomycin- resistant Staphylococcus aureus (VISA and VRSA).These trends stress the importance of finding new treatment options for MRSA.

Assessing The Research On Trimethoprim- Sulfamethoxazole And Clindamycin
Trimethoprim-sulfamethoxazole. There is in vitro evidence that trimethoprim- sulfamethoxazole (TMP-SMX) is a viable option for treating MRSA. For MRSA isolates in the United States, researchers have documented susceptibility to TMP-SMX at 87.9 percent.4 However, there is very little evidence of the clinical efficacy of TMP-SMX in treating serious MRSA infections. Perhaps the best data comes from a 1992 study by Markowitz, et al., comparing TMP-SMX with vancomycin in 101 Staphylococcus aureus infections in intravenous drug users.5 Fortyseven percent of infections were caused by MRSA and in 37 out 43 of these patients, TMP-SMX cured the infection. There is no published data that defines the most appropriate dosage for the treatment of MRSA infections. Typically, the dose ranges from one to two doublestrength tablets (160/800 mg) every 12 hours.6 Trimethoprim-sulfamethoxazole is indicated in mild to moderate skin and skin structure infections, especially CAMRSA infections that do not require intravenous therapy.1
Clindamycin. Pediatric patients commonly take clindamycin for the treatment of skin and soft tissue infections, including those due to CA-MRSA. There is increased in vitro susceptibility to clindamycin in CA-MRSA in comparison to nosocomial Staphylococcus aureus. One study reported susceptibility as 81 percent and 19 percent for CA-MRSA and HAMRSA respectively.7 There is wide geographic variability in the susceptibility of CA-MRSA to clindamycin.
An important caveat to consider is the potential for inducible clindamycin resistance in erythromycin-resistant and clindamycin- susceptible isolates. These isolates should undergo a double disk diffusion test to determine the presence of inducible macrolide-lincosamide-streptogramin B (MLSBi) resistance.1
Again, there are no randomized, prospective trials in regard to the use of clindamycin in treating CA-MRSA. Most evidence is anecdotal.The oral dosing most commonly recommended is 300 to 600 mg every six to eight hours and the parenteral dosing is 600 to 900 mg every 12 hours.1,6 The MRSA indications for clindamycin include skin and soft tissue and bone and joint infections, especially in CA-MRSA in which MLSBi resistance has been ruled out.

Can Tetracyclines Have An Impact?

Tetracyclines. Researchers have found that doxycycline and minocycline are useful in treating skin and soft tissue infections due to CA-MRSA. In a study in 2005, Ruhe, et al., found that 96 percent of patients with skin and soft tissue infections with CA-MRSA were treated successfully with tetracyclines.8 The majority of patients had abscesses that were also surgically drained.
As with clindamycin, there is wide geographic variability in the susceptibility of MRSA to the long acting tetracyclines. The accepted dose for both doxycycline and minocycline is 100 mg every 12 hours by mouth.6 The indications for the tetracyclines are limited to mild to moderate skin and skin structure infections with CA-MRSA.

A Closer Look At Linezolid
Linezolid (Zyvox, Pfizer). Linezolid is an oxazolidinone with activity against many gram-positive organisms.9 It is bacteriostatic and it selectively binds the 50S ribosome, thereby preventing formation of the initiation complex. Linezolid has 100 percent bioavailability in the oral form, making it a reasonable option for treating MRSA on an outpatient basis.
In a study comparing the treatment of complicated skin and soft tissue infections with MRSA using linezolid and vancomycin, 88.6 percent of patients treated with linezolid were cured as opposed to 66.9 percent with vancomycin.9
Be aware that researchers found thrombocytopenia in 3.5 percent of the patients treated with linezolid in this study. It is recommended that one perform close hematologic monitoring, especially when treatment lasts longer than two weeks and in patients with renal insufficiency.1,10 Another side effect that can potentially limit the drug’s use is the possibility of serotonin syndrome in patients on monoamine oxidase inhibitors.10
The dose is the same for both oral and intravenous administration: 600 mg every 12 hours.6 Linezolid is indicated in the treatment of MRSA bacteremia, complicated skin and soft tissue infections, pneumonia, and VISA and VRSA infections.1 Linezolid is FDA-approved for the treatment of diabetic foot infections.

What About The Roles Of Quinupristin-Dalfopristin And Tigecycline?

Quinupristin-dalfopristin. While quinupristin-dalfopristin has only been FDA-approved to treat methicillin-sensitive Staphylococcus aureus (MSSA) infections, there have been reports of its effectiveness in treating MRSA as well. Researchers have found that quinupristin- dalfopristin is effective in treating skin and skin structure and bone and joint infections with MRSA when other first line therapies have failed.11 Success rates were reportedly close to 70 percent.
This antibiotic is a 70:30 mixture of streptogramins groups B and A respectively.1 One can only administer quinupristin- dalfopristin intravenously through a central line and it is dosed at 7.5 mg/kg every eight to 12 hours.1
Tigecycline (Tygacil, Wyeth). Tigecycline is a bacteriostatic glycylcycline antibiotic that has been approved by the FDA for the treatment of complicated skin and soft tissue infections secondary to MRSA.10
Two phase III, double-blind studies comparing tigecycline and vancomycin with aztreonam found clinical efficacy rates to be 86.5 percent and 88.6 percent respectively.14 The most commonly reported side effects of the medication are nausea and vomiting, but a study by Breedt, et al., found that 96 percent of the nausea and vomiting was mild to moderate, and treatable with antiemetics.12 As the agent is similar to the tetracyclines, physicians should avoid it in patients with contraindications to tetracyclines. Tigecycline is only available intravenously and the accepted dosing regimen is a 100-mg loading dose and then 50 mg every 12 hours.1,10

What The Research Reveals About Daptomycin
Daptomycin (Cubicin, Cubist Pharmaceuticals). In 2003, the FDA approved daptomycin, a cyclic lipopeptide for the treatment of infections caused by many gram-positive pathogens, including staphylococci, enterococci and steptococci.1,13 Daptomycin has very rapid in vitro time-kill kinetics.13
Researchers have found that daptomycin has comparable efficacy to vancomycin and semi-synthetic penicillins in treating complicated skin and soft tissue infections.15 In 628 patients with Staphylococcus aureus infections including abscesses, surgical and traumatic wound infections, and infected ulcers, researchers found clinical success rates to be 83.4 percent and 84.2 percent for the daptomycin and comparator treatment groups respectively.
In another study by Lipsky and Stoutenburgh examining daptomycin in the treatment of 103 infected diabetic foot ulcers, researchers found no statistical difference in the success rates of daptomycin in comparison with other common comparator antibiotics.16 Lipsky and Stoutenburgh recommend using daptomycin in treating diabetic foot ulcers, especially those infected with resistant gram-positive organisms.
A study by Holtom, et al., found daptomycin to have highly resolved and improved short-term efficacy for the treatment of patients with foot and ankle osteomyelits.17 The authors also point out the need for prospective, randomized clinical trials to further elucidate the role of daptomycin in the treatment of osteomyelitis.
The recommended dose of daptomycin for the treatment of bacteremia and endocarditis is 6 mg/kg/day intravenously and 4 mg/kg/day intravenously for complicated skin and skin structure infections. Rhabdomyolysis is a potential side effect and one should accordingly monitor creatine kinase concentrations.
The FDA indications for daptomycin are in the treatment of complicated skin and skin structure infections and bacteremia due to MRSA, including rightsided endocarditis. Daptomycin is not indicated in Staphylococcus aureus pneumonia. The research indicates that it is best to consider daptomycin for serious, invasive infections when starting or continuing vancomycin is inappropriate.1

What Antibiotics Are In The Pipeline?

Dalbavancin (Zeven, Vicuron/ Pfizer). Dalbavancin is a lipoglycopeptide that has increased in vitro activity for most gram-positive pathogens as well as having an extremely long halflife.18 The long half-life permits onceweekly intravenous dosing. Dalbavancin is more potent than vancomycin in treating MSSA and MRSA as well as VISA and the rare, linezolid-nonsusceptible Staphylococcus aureus.
In a randomized, double-blind study comparing dalbavancin and linezolid in the treatment of complicated skin and skin structure infections in which MRSA was a common pathogen, researchers obtained comparable clinical and microbiologic success rates.19 They found that dalbavancin’s clinical and microbiologic success rates of 88.9 percent and 89.5 percent, respectively, compare favorably to those of linezolid (91.2 percent and 87.5 percent respectively).
In a recently published phase III study comparing dalbavancin, linezolid, cefazolin and vancomycin, the authors reported that 77 percent of infections were caused by Staphylococcus aureus (with 38 percent of those being caused by MRSA).1,18 They reported clinical and microbiologic efficacies of dalbavancin as 89 to 90 percent and 88 to 93 percent, respectively, with no differences between MSSA and MRSA.
Goldstein, et al., determined that dalbavancin had a much greater in vitro activity against MSSA, MRSA and 120 anaerobe isolates from diabetic foot infections than vancomycin, linezolid, daptomycin and clindamycin.20
The safety of dalbavancin has been studied in over 1,000 patients and researchers have found that the drug is well tolerated with the adverse effects similar to the comparators.18 No evidence of renal or hepatic toxicity has been reported and researchers have found minimal impact on the normal intestinal flora.18
The once-weekly dosing is very advantageous in the outpatient setting. Dalbavancin is currently being reviewed by the FDA for a possible diabetic foot infection indication.
Telavancin (Theravance/Astellas Pharma). Telavancin is another semisynthetic lipoglycopeptide that is similar to vancomycin and has rapid bacteriocidal activity.21 It has a half-life of seven to nine hours, allowing for once-a-day dosing.10
In vitro activity levels against MRSA, VISA and VRSA have been promising. Stryjewski, et al., found that in 45 patients with MRSA, telavancin demonstrated a clinical cure rate of 96 percent in comparison to 90 percent with standard therapy of vancomycin.22 More impressive is the microbiologic cure rate of telavancin in treating MRSA: 92 percent versus 68 percent with standard treatment.
The most common adverse effects reported are nausea, vomiting and headaches.1 Researchers have also reported incidences of infusion-related reactions similar to the “red man syndrome” associated with vancomycin. Telavancin is also currently being reviewed by the FDA for a possible indication for diabetic foot infections.
Ceftobiprole (Ortho-McNeil). Ceftobiprole is an intravenous cephalosporin that is bacteriocidal against MRSA, penicillin-resistant Streptococcus pneumoniae and Pseudomonas aeruginosa. It also has demonstrated activity against VISA and VRSA.23 Ceftobiprole is often considered a fifthgeneration cephalosporin that is broad spectrum in action.
Two studies by Noel, et al., in 2008 found that ceftobiprole is non-inferior to comparators in the treatment of complicated skin and soft tissue infections.24,25 One study compared ceftobiprole to vancomycin in the treatment of gram-positive infections while a second study compared ceftobiprole to vancomycin with ceftazidime regardless of bacterial pathogen. The clinical cure rates in the first trial were 93.5 percent and 93.3 percent for ceftobiprole and vancomycin, respectively, and 90.5 percent and 90.2 percent in the second study for ceftobiprole and vancomycin/ ceftazidime respectively.25
The second trial by Noel, et al., specifically evaluated diabetic foot infections. Patients with severe diabetic foot infections seemed to respond better to ceftobiprole than vancomycin/ceftazidime with a cure rate of 70.6 percent versus 53.8 percent respectively, although the authors noted these findings were not statistically significant.24 In findings that were statistically significant, Noel, et al., noted the mean duration of treatment of the diabetic foot infection was shorter with ceftobiprole than vancomycin/ceftazidime.
Adverse effects are similar to comparators and most commonly include nausea and taste disturbances.24,25 The advantage of this antibiotic is its broad spectrum of activity against both gram-positive and gram-negative organisms, as well as resistant pathogens. Ceftobiprole may be an effective empiric monotherapy agent in the treatment of complicated skin and skin structure infections.

In Conclusion
Methicillin-resistant Staphylococcus aureus is a highly adaptable, very widespread human pathogen that has become a major problem in modern medicine.While there are antibiotics on the market today that treat MRSA, we are seeing more and more resistance.
Vancomycin, the workhorse of MRSA treatment today, is proving less effective than originally thought with new isolates showing partial or total resistance to the drug. Newer antibiotics such as linezolid, daptomycin and tigecycline have come on the market attempting to address this pressing issue. There are more anti- MRSA antibiotics in various stages of possible approval by the FDA.
There remains a need for more clinical studies to evaluate the efficacy of FDA-approved anti-MRSA antibiotics as well as the investigational antibiotics for the treatment of diabetic foot infections.

Dr. Addis-Thomas is a first-year resident at Yale-New Haven Hospital/ DVA CT Healthcare Podiatric Surgical Residency Program. Dr. Key is an Assistant Clinical Professor of Orthopedics and Rehabilitation at the Yale School of Medicine in New Haven, Ct. Dr. Blume is an Assistant Clinical Professor of Surgery, Anesthesia and Orthopedics and Rehabilitation at the Yale School of Medicine in New Haven, Ct.








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**i**Editor’s note: For a related article, see “Understanding The Impact Of MRSA On Limb Preservation” in the July 2007 issue of Podiatry Today.


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