POST-ANTIBIOTIC ERA

© ERWIN PURNOMOSIDI | DREAMSTIME.COM

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.

Figure 1. Comparison of Aganocides with common bactericidal agents.

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.

Agents in clinical development include glycopeptides (dalbavancin, oritavancin, telavancin) and anti-MRSA cephalosporins (ceftobiprole).^24-28

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.

DUAL-ACTING AGENTS

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 ndakou@novabaypharma.com or (510) 899-8875.

REFERENCES

1. Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA. 2007;298(15):1763-1771.

2. Boyles S. More U.S. deaths from MRSA than AIDS. In 2005, more than 18,000 deaths attributed to MRSA, CDC Reports. WebMD Web site. October 16, 2007; Available at www.webmd.com/news/20071016/more-us-deaths-from-mrsa-than-aids. Accessed March 14, 2008.

3. Klevens RM, Edwards JR, Tenover FC, et al. Changes in the epidemiology of methicillin-resistant Staphylococcus aureus in intensive care units in US hospitals, 1992-2003. Clin Infect Dis. 2006;42(3):389-391.

4. Chambers HF. Community-associated MRSA-resistance and virulence converge. N Engl J Med. 2005;352(14):1485-1487.

5. King MD, Humphrey BJ, Wang YF, et al. Emergence of community-acquired methicillin-resistant Staphylococcus aureus USA 300 clone as the predominant cause of skin and soft-tissue infections. Ann Intern Med. 2006;144(5):309-317.

6. Maree CL, Daum RS, Boyle-Vavra S, et al. Community-associated methicillin-resistant Staphylococcus aureus isolates causing healthcare-associated infections. Emerging Infect Dis. 2007;13(2):236-242.

7. Styers D, Sheehan DJ, Hogan P, et al. Laboratory-based surveillance of current antimicrobial resistance patterns and trends among Staphylococcus aureus: 2005 status in the United States. Ann Clin Microbiol Antimicrob. 2006;5:2.

8. Tristan A, Ferry T, Durand G, et al. Virulence determinants in community and hospital methicillin-resistant Staphylococcus aureus. J Hosp Infect. 2007;65(Suppl 2):105-109.

9. Wang R, Braughton KR, Kretschmer D, et al. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nat Med. 2007;13(12):1510-1514.

10. Graham PL III, Lin SX, Larson EL. A U.S. population-based survey of Staphylococcus aureus colonization. Ann Intern Med. 2006;144(5):318-325.

11. Lodise TP, McKinnon PS. Clinical and economic impact of methicillin resistance in patients with Staphylococcus aureus bacteremia. Diagn Microbiol Infect Dis. 2005;52(2):113-122.

12. International Federation of Infection Control. The costs of hospital infection. International Federation of Infection Control Web site. Available at www.theific.org/oldsite/Manual/cost.htm. Accessed March 14, 2008.

13. Drew RH. Emerging options for treatment of invasive, multidrug-resistant Staphylococcus aureus infections. Pharmacotherapy. 2007;27(2):227-249. Review.

14. Mohr JF, Murray BE. Point: Vancomycin is not obsolete for the treatment of infection caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2007;44(12):1536-1542. Epub 2007 May 4.

15. Deresinski S. Counterpoint: Vancomycin and Staphylococcus aureus-an antibiotic enters obsolescence. Clin Infect Dis. 2007;44(12):1543-1548. Epub 2007 May 4.

16. Lewis JS II, Jorgensen JH. Inducible clindamycin resistance in Staphylococci: should clinicians and microbiologists be concerned? Clin Infect Dis. 2005;40(2):280-285. Epub 2004 Dec 21.

17. Cenizal MJ, Skiest D, Luber S, et al. Prospective randomized trial of empiric therapy with trimethoprim-sulfamethoxazole or doxycycline for outpatient skin and soft tissue infections in an area of high prevalence of methicillin-resistant Staphyloccus aureus. Antimicrob Agents Chemother. 2007;51(7):2628-2630. Epub 2007 May 14.

18. Ruhe JJ, Menon A. Tetracyclines as an oral treatment option for patients with community onset skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2007;51(9):3298-3303. Epub 2007 Jun 18.

19. Weigelt J, Itani K, Stevens D, et al. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother. 2005;49(6):2260-2266.

20. Rose WE, Rybak MJ. Tigecycline: first of a new class of antimicrobial agents. Pharmacotherapy. 2006;26(8):1099-1110. Review.

21. French GL. Bactericidal agents in the treatment of MRSA infections-the potential role of daptomycin. J Antimicrob Chemother. 2006;58(6):1107-1117. Epub 2006 Oct 13.

22. Cui L, Tominaga E, Neoh HM, et al. Correlation between reduced daptomycin susceptibility and vancomycin resistance in vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother. 2006;50(3):1079-1082.

23. Papadopoulos S, Ball AM, Liewer SE, et al. Rhabdomyolysis during therapy with daptomycin. Clin Infect Dis. 2006;42(12):e108-e110. Epub 2006 May 10.

24. Pope SD, Roecker AM. Dalbavancin: a novel lipoglycopeptide antibacterial. Pharmacotherapy. 2006;26(7):908-918. Review.

25. Mercier RC, Stumpo C, Rybak MJ. Effect of growth phase and pH on the in vitro activity of a new glycopeptide, oritavancin (LY333328), against Staphylococcus aureus and Enterococcus faecium. J Antimicrob Chemother. 2002;50(1):19-24.

26. Higgins DL, Chang R, Debabov DV, et al. Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2005;49(3):1127-1134.

27. Leuthner KD, Cheung CM, Rybak MJ. Comparative activity of the new lipoglycopeptide telavancin in the presence and absence of serum against 50 glycopeptide non-susceptible staphylococci and three vancomycin-resistant Staphylococcus aureus. J Antimicrob Chemother. 2006;58(2):338-343. Epub 2006 Jun 20.

28. Chambers HF. Evaluation of ceftobiprole in a rabbit model of aortic valve endocarditis due to methicillin-resistant and vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother. 2005;49(3):884-888.

29. Wertheim HF, Vos MC, Boelens HA, et al. Low prevalence of methicillin-resistant Staphylococcus aureus (MRSA) at hospital admission in the Netherlands: the value of search and destroy and restrictive antibiotic use. J Hosp Infect. 2004;56(4):321-325.

30. Nagl M, Hess MW, Pfaller K, et al. Bactericidal activity of micromolar Nchlorotaurine: evidence for its antimicrobial function in the human defense system. Antimicrob Agents Chemother. 2000;44(9):2507-2513.

31. Robson MC, Payne WG, Ko F, et al. The potential role of di-chlorodimethyltaurine as a wound topical antimicrobial that does not inhibit healing. Paper presented at: 20th Annual Symposium on Advanced Wound Care and the Wound Healing Society Meeting; May 1, 2007; Tampa, Fla. Abstract 79.

32. NovaBay Pharmaceuticals. Aganocide technology overview. NovaBay Pharmaceuticals Web site.