Increasing antibiotic resistance necessitates new approaches to treating and preventing methicillin-resistant S. aureus infections
Methicillin-resistant Staphylococcus aureus (MRSA) infected more than 90,000 Americans and caused nearly 19,000 deaths in 2005. To put these figures into perspective, the death toll from AIDS was 16,000 in the same year.1,2 Most MRSA-related illnesses and fatalities occur in healthcare settings, hence the name healthcare-associated MRSA (HA-MRSA). Infections typically occur in individuals who have undergone invasive medical procedures such as surgery or installation of medical devices or those who have weakened immune systems, including patients suffering from chronic medical conditions like diabetes, cancer, or immunosuppression following organ transplantation.3 However, an increasing number of serious MRSA infections now occur outside of hospitals in otherwise healthy individuals, hence the name community-associated MRSA (CA-MRSA).4-6
According to the Centers for Disease Control and Prevention (CDC), the spread of CA-MRSA is associated with close skin-to-skin contact, cuts and abrasions in the skin, the sharing of personal items such as towels, contact with contaminated objects, and lack of personal hygiene. CA-MRSA outbreaks in schools and sports have propelled MRSA into the public consciousness through alarming television and print news reports.
The phrase "methicillin resistant" refers to the inability of the antibiotic methicillin to eliminate S. aureus (staph) infections. Methicillin was introduced in 1959 to combat S. aureus strains that had become resistant to penicillin and cephalosporin antibiotics such as amoxicillin and cephalexin. Limited resistance to methicillin was noted as far back as 1961, with the first recognized MRSA outbreak occurring in a Boston hospital in 1968. Nowadays, however, methicillin resistant has become a misnomer; MRSA strains are typically multi-resistant.7
S. aureus is responsible for a wide range of infections, from minor skin and soft tissue infections-such as pimples, impetigo, boils, cellulitis, folliculitis, furuncles, carbuncles, scalded skin syndrome, and abscesses-to life-threatening diseases that include toxic shock syndrome (TSS), pneumonia, meningitis, osteomyelitis, endocarditis, and septicemia. Diagnosis is usually confirmed by culturing the bacterium from the skin, blood, or urine; therapy is guided by checking antibiotic susceptibility.
S. aureus pathogenicity is enhanced by several secreted toxins: TSST-1, a superantigen associated with toxic shock syndrome; exfoliative toxins associated with the staphylococcal scalded skin syndrome; cytolytic peptides; and membrane-acting toxins such as Panton-Valentine leukocidin (PVL), which is associated with severe necrotizing pneumonia in children.8,9 Cytolytic peptides and PVL commonly characterize strains of CA-MRSA; hence, CA-MRSA infections can occur in individuals without predisposing risk factors.
In addition to being a major pathogen and one of the four most common causes of nosocomial infections, S. aureus is a common commensal of the human skin. MRSA colonizes about 30% of humans without infecting them.10 Colonization-primarily in the nostrils and on the skin-may go on for years without causing symptoms. Colonized individuals are at significantly higher risk of developing an MRSA infection after suffering a wound as innocuous as a scratch. Perhaps more importantly, colonization serves as a reservoir for infection, transmission, and further development of resistance by S. aureus to antimicrobial agents.
RESISTANCE NOT LIMITED TO MRSA
Infectious diseases remain a leading cause of death worldwide despite available therapies. The reasons are increasing resistance of old, common pathogens-such as S. aureus-to available therapies and increasing prominence of uncommon pathogens due to the proliferation of immunocompromised patients. Another example of the first trend is Escherichia coli, an enterobacterium responsible for the majority of urinary tract infections. In this case, co-expression of extended-spectrum � -lactamases-such as CTX-M types-has, along with fluoroquinolone resistance, eroded the reliability of cephalosporins and ciprofloxacin as first-line drugs. An example of the second trend is Acinetobacter baumannii, an environmental, normally multi-resistant bacterium.
Both trends underscore the urgent need for new therapies, better utilization (improved regimens and less unnecessary use) of available antimicrobials, and more effective infection control. Addressing this subject in 2002, the World Health Organization noted that "most alarming of all are diseases where resistance is developing for virtually all currently available drugs, thus raising the spectre of a post-antibiotic era."
In the Unites States, resistant microbes cost the healthcare system dearly in terms of follow-up and supportive care.11,12 It was estimated around the turn of the millennium that managing a single case of hospital-acquired MRSA costs the U.S. healthcare system between $27,000 and $34,000 above and beyond the treatment for which the patient was originally admitted to the hospital. The economic impact of hospital-acquired resistant infections in the United States has been estimated at $17 billion.
MANAGEMENT OF MRSA INFECTIONS
There are several therapeutic options for treating MRSA infections, though they all have caveats.13 Of the older drugs, the glycopeptide antibiotic vancomycin is still being used despite decreased effectiveness against MRSA-MIC creep-and toxicity concerns, particularly nephrotoxicity.14,15 Patients undergoing vancomycin therapy must have their blood monitored for toxicity, which adds approximately $100 per day to the cost of treatment. In addition, vancomycin is not available in oral form, so outpatients must carry an infusion bag for the duration of treatment.
Other, older drugs that are often used systemically are clindamycin, doxycycline, and trimethoprim-sulfamethoxazole.16-18 Non-life-threatening, skin infections are often treated with topical antibacterial ointments containing mupirocin or fusidic acid. Newer systemic agents include the oral oxazolidinone linezolid, the anthracycline tigecycline, and the cyclic lipopeptide daptomycin.19-22 These agents have serious toxicity issues such as myelosuppression (linezolid) and rhabdomyolysis (daptomycin).23 They are also quite expensive. For example, linezolid therapy costs $120 per day and requires monitoring for rare but serious hematologic toxicity.
AN OUNCE OF PREVENTION?
Surveillance, hygiene, and the will to prevent transmission are the keys to controlling MRSA. We know this because MRSA is much less common in countries where-unlike those in the United States-health systems emphasize good hygiene. Serious MRSA outbreaks are rare, for example, in Australia, the Netherlands, and Scandinavia, where outbreaks are rapidly identified and contained. More than half of S. aureus infections in the Unites States are methicillin resistant; in the Netherlands, the figure is less than 1%.29 The prevalence of methicillin-resistant S. aureus strains in Parisian hospitals was greater than 50% fifteen years ago; by 2002, it had fallen to 25%.
A 2006 study on emergency room admissions at Washington University Hospital in St. Louis showed that one-third of patients harbored S. aureus. About half of those were methicillin resistant. Interestingly, 6.7% of patients who were MRSA-positive had contracted MRSA infection during their hospital stay, while only 1.2% of MRSA-negative patients developed an infection.
Treating those who harbor MRSA-in a process known as decolonization-has become an accepted strategy for preventing MRSA infections in patients and family members. Decolonization involves the topical application of an antibacterial agent such as mupirocin, chlorhexi-dine, bleach, over-the-counter topical disinfectants, or combinations of these agents. Household cleaning products have begun touting their ability to kill MRSA on kitchen and bathroom surfaces, but their effectiveness is questionable.
Agents suitable both for MRSA decolonization and for treatment of MRSA infections are rare. Chemicals that kill bacteria on contact are usually pharmacologically unacceptable due to poor pharmacokinetics/dynamics or high toxicity. For example, household bleach kills almost any pathogen but is highly poisonous when ingested.
The chlorinating agent N,N-dichlorotaurine (NCT) has provided some interesting results in pilot studies for treating MRSA-related keratoconjunctivitis, outer ear infections, leg ulcers, and urinary tract infections.30 Unfortunately, NCT is chemically unstable at room temperature.
NovaBay Pharmaceuticals (Emeryville, Calif.) is developing a second generation analog of NCT, the compound NVC-422, which solves NCT's stability problems and circumvents the poor pharmacodynamics of chemical bactericidal agents. We have dubbed NVC-422 and similar compounds we are working on Aganocides.
In vitro, NVC-422 at low micromolar concentrations eliminates the pathogens S. aureus, E. coli, Staphylococcus epidermidis, Proteus mirabilis, and Pseudomonas aeruginosa with kill times measured in minutes. Most importantly for drug development, NVC-422 is the only bactericidal compound we know of with a drug-like therapeutic index. Figure 1 (see p. 24) compares the therapeutic index of NVC-422 with those of common bactericidal agents.
Preclinical studies of NVC-422 in animal models of dermatologic MRSA infections have been extremely encouraging. In a recently completed Phase I human trial, NVC-422 was safe and well tolerated when applied topically to the nostrils. We are currently awaiting results from a second study at a higher dose. We are also planning a Phase IIa study for this year that we hope will demonstrate the ability of NVC-422 to eradicate nasal colonization by S. aureus, a known starting point for infections. We believe that NVC-422 has the potential to prevent MRSA infections by eliminating colonization in the most common reservoirs for this pathogen, the nose and skin.31,32
NovaBay's licensee, Alcon Research Laboratories, is exploring the potential for NVC-422 to treat bacterial infections of the eye, ear, and sinuses. Topical agents (Aganocide compounds) are also in development for use in nasal decolonization, sterilization of surgical wounds, and irrigation of the urinary catheters often responsible for bladder and kidney infections.
Each twist and turn in the fight against emerging and resistant microbial infections brings new knowledge and renewed hope that one day medical science will conquer these terrible diseases. Success will depend on rigorous surveillance, hygiene-based prevention, and the discovery of new anti-infective treatments. Among the strategies used to prevent and treat MRSA infections will be agents, like NVC-422, that achieve both patient decolonization and therapy for less serious MRSA infections. �
Dr. Georgopapadakou is vice president of research at NovaBay Pharmaceuticals in Emeryville, Calif. Reach her at firstname.lastname@example.org or (510) 899-8875.
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