Current And Emerging Modalities For MRSA

Given the increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and that improperly managed diabetic foot infections can lead to tissue loss, amputation or even death, it is crucial to have a grasp of effective treatment options. In a thorough review of the literature, these authors discuss a range of MRSA treatments, including systemic antimicrobial therapy, topical therapy and local antibiotic delivery. 

Diabetic foot infections (DFIs) are the most common reason for diabetes-related hospitalization and represent a serious complication. If clinicians do not manage diabetic foot infections appropriately, these infections can result in lower extremity amputation, especially in patients with peripheral artery disease (PAD), which frequently coexists in patients with diabetes.^1-3 Diabetic foot ulcers (DFUs) serve as a point of entry for pathogens. Roughly 60 percent of DFUs are infected on presentation.⁴

Gram-positive cocci, especially Staphylococcus aureus, and to a lesser degree Streptococcus species or coagulase-negative staphylococci, have been the main pathogens in DFIs.^2,5,6 The prevalence of Gram-negative bacteria, mostly including Pseudomonas and Enterobacteriaceae species, is lower but it increases in chronic wounds already treated with antibiotics. One must consider anaerobic infection especially in neuroischemic ulcers. The isolation of antibiotic-resistant organisms has been an increasing problem the last decades, particularly methicillin-resistant Staphylococcus aureus (MRSA) and multidrug resistant Gram-negative strains as well. Most concerning has been the development of highly resistant Pseudomonas and lately the rise of extended-spectrum b-lactamase (ESBL) and carbapenemases producing Gram-negative bacilli with MRSA being the predominant pathogen among them.^6,7

Around 33 percent of people carry Staphylococcus aureus in their noses, usually without any illness, and 2 percent of people carry MRSA.⁸ Individuals colonized with MRSA serve as a reservoir for transmission. MRSA can colonize the skin and nares of hospitalized patients, healthcare workers and healthy individuals.^9,10 MRSA has developed due to antibiotic selective pressure.^11,12 Antibiotic use, particularly cephalosporin and fluoroquinolones, strongly correlates with the risk for MRSA colonization and infection.^13,14

The mode of MRSA transmission, according to the United States Centers for Disease Control and Prevention (CDC), is through contact with an infected wound or contaminated hands, usually those of healthcare workers, via broken skin or a medical procedure.¹⁵ Healthcare-associated MRSA (HA-MRSA) strains most commonly transmit to patients via the transiently contaminated hands of healthcare workers. Hospitalized patients may also acquire HA-MRSA from contaminated environmental surfaces. Community-associated MRSA (CA-MRSA) strains most commonly transmit by direct contact with a colonized or infected individual.¹⁵ The infection is more likely to flare in people with cuts, abrasions or wounds, or in people with chronic skin conditions such as psoriasis. Researchers have cited hand hygiene as the single most effective strategy for preventing cross-contamination via healthcare workers.^16,17 However, door handles and commonly touched surfaces may be important secondary reservoirs for cross-contamination between healthcare workers and patients.

Clinicians identified the first MRSA isolates in a British study in 1960 and until 1967, MRSA caused infrequent hospital outbreaks in Western Europe and Australia.¹⁸ The first hospital outbreak of MRSA in the United States at the Boston City Hospital occurred in 1968.¹⁹ Studies from the 1990s had indicated a prevalence of MRSA around 15 percent among all isolates while reports from the 2000s indicated a growing prevalence with MRSA strains being present in 30 percent of DFIs.^20,21 Although it is certainly difficult to extrapolate the results coming from different centers and countries, most recent reports suggest that the prevalence may be coming down, probably reflecting the improvement in awareness and infection control measures.^6,22,23

The likelihood of acquiring MRSA increases with previous antibiotic treatment, a history of prior hospitalization, hemodialysis and residency in a long-term care facility. Antibiotic use positively correlates with risk for MRSA colonization and infection.¹² Multiple studies have shown that prior antibiotic exposure is linked to MRSA colonization/infection.^12,24 The risk of MRSA is positively associated with the number of antimicrobial agents that clinicians have prescribed for the individual patient. Penicillin, cephalosporins, macrolides and fluoroquinolones are included among the antibiotics researchers found to select MRSA with fluoroquinolones exhibiting the higher risk.^12,24 In patients with DFI, frequency and duration of hospitalization apart from prior antibiotic use and its duration are significant factors for infection with multidrug resistant microorganisms including MRSA.²⁵ Other factors that are reportedly associated with an increased risk of MRSA diabetic foot infections include long duration of the wound, presence of osteomyelitis and previous history of MRSA infection.^23,26

The level of evidence about when to cover for MRSA in the empiric treatment of DFI has been weak so far. The Infectious Diseases Society of America (IDSA) published guidelines in 2012 on the treatment of DFIs and the International Working Group on the Diabetic Foot (IWGDF) also published guidelines in 2016.^2,22 These guidelines suggest that providing empiric treatment to cover MRSA while awaiting culture results should be a consideration if there is substantial risk of infection from MRSA as in the setting of a high local prevalence of MRSA or a patient with a recent admission in a healthcare institution, recent antibiotic usage, known MRSA colonization, a prior history of MRSA infection, or if the infection is clinically severe.^2,22

When it comes to retrospective analyses of data comparing outcomes between diabetic foot infections with multidrug resistant organisms with infections due to other pathogens, the data have been conflicting. One study reported an increased likelihood of the need for surgical intervention in the presence of multidrug resistant organism infection while two other studies found that infection of diabetic ulcers with multidrug resistant organisms was not associated with a longer healing time.^27-29

Studies reporting data that is more focused on MRSA diabetic foot infections have reported prolonged ulcer healing time in comparison to methicillin-susceptible Staph aureus (MSSA) infection but no increased rate of hospitalization due to MRSA infection.^20,30 In a study aiming to compare outcomes of surgical treatment of osteomyelitis between MRSA and MSSA infections, MRSA infection was associated with a higher incidence of fetid odor, swelling, cutaneous necrosis and higher body temperature and white blood cell count as well as the need for more surgical interventions and a longer healing time after surgical treatment than those with MSSA infection.³¹ However, there was no significant difference in limb salvage rates between the two groups.

Certainly, the limited amount of data does not allow the drawing of any definite conclusions about potential differences between the courses of MRSA infections versus other DFIs. Current data do not support the need for any special treatment for diabetic foot infection caused by MRSA other than proper antibiotic coverage.²¹   

What The Literature Reveals About Topical Applications

Apart from the systemic use of antibiotics, other local/topical modalities can be effective against MRSA colonization. These modalities include a variety of topical applications ranging from dressings to the secretions/excretions of larval therapy. Unfortunately, to date, there is paucity of evidence around dressing regimens with the majority of evidence being level IV (case studies).

Silver dressings. There are few clinical trials available that examine the effectiveness of silver against MRSA but data from in vitro studies provides information that is transferable to the clinical scenario. Strohal and colleagues tested the activity of nanocrystalline silver within a dressing against MRSA-inoculated agar.³² Their findings demonstrated significant anti-MRSA activity and they also showed that the dressing was impermeable to MRSA. The authors used the same dressings to treat seven patients (10 wounds), all heavily colonized with MRSA. At 72 hours, the MRSA load was either reduced to a low loading (semi-quantitative analysis) or eradicated. Furthermore, a second inoculation of the sites in previous contact with the dressings failed to show any new growth.³²

Ip and coworkers compared the activity of five silver dressings, using Aquacel non-silver dressing (ConvaTec) as a control.³³ In vitro tests were carried out with a range of bacteria including MRSA and MSSA. All of the test dressings demonstrated some level of bactericidal activity with increased activity against Gram-negative bacteria. Contreet (ionic silver within foam) (Coloplast) and Acticoat (polyethylene net with nanocrystalline) (Smith and Nephew) had the greatest activity against the full range of bacteria while Contreet demonstrated the most rapid and sustained killing of MRSA.

Other further in vitro studies of note are investigations of the activity of four silver dressings against two different and highly virulent strains of epidemic MRSA, EMRSA-15 and EMRSA-16.^34,35 The strength of the investigations lie in the fact that authors directly compare two silver-donating dressings against two silver-impregnated dressings. The silver donation came from elemental nanocrystalline silver, which delivers a solution of silver at approximately 70 to 100 ppm in a controlled and steady stream. Previous research suggested a figure of 20 ppm as a concentration for killing of MRSA and the nanocrystalline preparations far exceed that number.³⁶ Results demonstrated a significant difference in favor of the nanocrystalline with the other silver-impregnated dressings having poor activity against EMRSA, and little or no barrier effect. This is clearly in contrast to the sequestration properties demonstrated in other studies for a range of microorganisms.

In the study by Ip and coworkers, the activity of a nanocrystalline dressing was comparable with an ionic silver-based dressing against MRSA.³³ Therefore, one explanation for the vastly different findings could be a different virulence between MRSA and epidemic MRSA.

There is a clear difference between results of in vitro studies and clinical studies. A possible explanation is that the gap between the aims of laboratory studies and the aims of clinical studies is too great. Additionally, the in vitro environment is not representative of the clinical wound environment, which involves a complex interaction between tissue level oxygenation, perfusion, exudate, biofilm, individual host responses and any MRSA risk factors.

One of the greatest shortfalls in the field of silver research is the lack of compatibility between products in terms of the concentrations required for bacterial killing/growth inhibition. Types of silver preparation differ greatly as does the carrier material and this is likely to contribute to the huge variability in the bactericidal properties of different products.³³

Could Larval Excretions And Secretions Have An Impact?

Larval excretions and secretions. The wound healing properties of larvae are complex and recent investigations have led to the identification of proteolytic-type enzymes, similar in nature to trypsin, leucine aminopeptidase (LAP), carboxypeptidase A (CPA) and carboxypeptidase B (CPB).³⁷ The highest level of proteolytic activity was extracted from first instar larvae. Researchers have employed complex molecular investigations, including electron microscopy, nucleic acid sequencing, electrophoresis and peptide sequencing, to explore the components of larvae excretions/secretions. Studies have confirmed proteolytic activity and identified a chymotrypsin-like serine protease with activity for degradation of human extracellular matrix.³⁷

Larvae possess antimicrobial properties and an interesting investigation, using green fluorescent protein-producing Escherichia coli, demonstrated a possible mechanism for this.³⁸ Researchers observed the passage of the bacteria throughout the larvae digestive tract, revealing significant fluctuations in levels of bacteria during progression through the gut. The highest concentration was in the crop and anterior midgut, which decreased as the tract continued. In the midgut and hindgut, bacteria were limited to the peritrophic (semipermeable lining of the gut) membrane and continued to decline until disappearing in the hindgut.

Antimicrobial products of low molecular weight are theoretically constitutively present in insects. This has led to the identification of peptide-like substances, such as beta alanyl-tyrosine. Researchers have investigated the activity of larval secretions and excretions against other bacteria, including MRSA. Authors have reported significant antibacterial effects against Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus thuringiensis and, when MRSA isolates were exposed to larval secretion and excretions, 86 percent growth inhibition occurred.³⁸

What You Should Know About Systemic Antimicrobial Treatment Of MRSA

Empirical treatment of DFI is guided by several factors, such as clinical severity of the infection, the likely pathogenic organisms and the local prevalence of antibiotic resistance.³⁹

The IDSA and the International Working Group on the Diabetic Foot provide recommendations and therapeutic guidelines for antibiotic selection.^2,22 Glycopeptides such as vancomycin and teicoplanin (Targocid, Sanofi) are still considered the antibiotics of choice for MRSA treatment. However, the downsides of these antibiotics are risks of nephrotoxicity, less efficacious results and a gradual increase in resistance.^40,41

These concerns led to the development of new antibiotics active against Gram-positive bacteria, including MRSA. The options for appropriate antibiotics are very wide across Europe and the choice seems to depend on local susceptibility and personal experience because there are no comparative trials to support the use of specific older agents.^42,43 Oral therapies that physicians commonly use in the treatment of MRSA infections are trimethoprim-sulfamethoxazole (TMP-SMX), tetracycline, clindamycin, rifampin (Rifadin) (only in combination therapy) and linezolid (Zyvox, Pfizer).^26,44,45 The Food and Drug Administration (FDA) has not approved TMP-SMX for MRSA treatment but many studies have shown its effectiveness against MRSA.⁴⁶ TMP-SMX is contraindicated in patients with hepatic impairment, folate deficiency, glucose-6-phosphate dehydrogenase deficiency and a history of anemia or thrombocytopenia.

Tetracyclines including tetracycline derivatives such as doxycycline and minocycline (Minocin, the Medicines Company) are well tolerated, cost effective and usually retain activity against MRSA infection.
Clindamycin can be an effective antibiotic for community-acquired MRSA skin soft tissue infection (SSTI) but inducible resistance is increasing. Therefore, one avoid using this drug in patients with erythromycin-resistant isolates despite in vitro sensitivity. Furthermore, clindamycin side effects include diarrhea and risk of Clostridium difficile infection.

Rifampicin can treat staphylococcal infections, including MRSA, but one should not use it as monotherapy due to the high risk of resistance.⁴⁷ A systematic review found that adjunctive rifampicin therapy is most promising for osteomyelitis and prosthetic device-related infections, but further clinical data are needed.⁴⁸ The additive effect of rifampicin and vancomycin combination therapy offers the advantage of rifampicin’s enhanced biofilm penetration.^47,49

Linezolid has a specific indication for diabetic foot skin soft tissue infections and is clinically efficacious against MRSA and vancomycin resistant Enterococcus (VRE). The oral bioavailability of linezolid is very good, making it equal to parenteral use.⁵⁰ Use linezolid cautiously in all patients as it may induce hematological toxicity, thrombocytopenia and anemia. Therefore, weekly monitoring of the full blood cell count is required in patients who are on therapy for more than one week.

The FDA warns against the concurrent use of linezolid with serotonergic psychiatric drugs unless they are indicated for life-threatening or urgent conditions. Linezolid may increase serotonin levels in the central nervous system as a result of monoamine oxidase-A inhibition, increasing the risk of serotonin syndrome.⁵¹ In a severe, life-threatening DFI, hospital admission and parenteral antibiotics are the mainstay interventions to manage critical cases.² Good outcomes following diabetic foot infection depend on the tissue penetration of the systemic antibiotics.

What Are The Other IV Antibiotic Options?

Currently in addition to vancomycin and teicoplanin, there are other intravenous antibiotics available for use for MRSA infections.

Tigecycline (Tygacil, Pfizer) is a relatively new parenteral antibiotic that developed in response to the increasing drug resistance of Gram-positive organisms such as MRSA and VRE, Gram-negative organisms such as extended-spectrum b-lactamase (ESBL) producing Escherichia coli, Klebsiella pneumoniae, some carbapenemase-producing Enterobacteriaceae (CPE) and anaerobic organisms such Bacteroides fragilis. Although tigecycline is not approved for treatment of diabetic foot infections, physicians have used it as an “off–label” treatment.⁵²

Daptomycin (Cubicin, Merck) is a lipopeptide antibiotic with potent activity against Gram positive organisms, including MRSA and VRE, through its unique mechanism of action involving calcium-dependent binding to disrupt the bacterial cell membrane.⁵³ The FDA approved daptomycin for SSTI and its combination with b-lactam may significantly enhance both the in vitro and in vivo efficacy against MRSA treatment. This combination represents an option in preventing daptomycin-resistant selection in persistent or refractory MRSA infections.⁵⁴

Quinupristin-dalfopristin (Synercid) is a combination of two streptogramins and shows activity against Gram-positive bacteria, including MRSA. Reserve the use of this antibiotic for unresponsive infections and patients intolerant to the initial therapy.⁵⁵

How Newer Antibiotics Compare With Vancomycin

There are several new agents that are at least as effective as or non-inferior to vancomycin.  

Telavancin (Vibativ, Theravance Biopharma) is a parenteral lipoglycopeptide antibiotic with activity against most Gram positive organisms, including MRSA. The FDA approved it in 2009 for the treatment of complicated SSTI, but the antibiotic does not have specific FDA approval for DFIs.³⁹

Ceftaroline (Teflaro, Allergan) is an intravenous, novel fifth-generation cephalosporin with activity against Gram-positive organisms such as MRSA and Gram-negative bacilli, but no activity against Pseudomonas and ESBL. Researchers have found high clinical success with the use of ceftaroline for DFI, including the treatment of inpatients with obesity, comorbidities, mixed infections or infections requiring surgical intervention.⁵⁶

Dalbavancin is another parenteral lipoglycopeptide antibiotic with excellent activity against Gram-positive organisms, including MRSA. This agent is unique in having an exceptionally long half-life that allows for once weekly dosing. Patients tolerate it well and it is as effective as linezolid for treatment of complicated SSTI.⁵⁷

Tedizolid (Sivextro, Merck) has similar therapeutic activity as linezolid, requires a once daily regimen, lacks drug interactions with selective serotonin reuptake inhibitors and has less potential to cause myelosuppression and neuropathy than linezolid during prolonged treatment courses.⁵⁸

Nemonoxacin (Taigexyn, TaiGen Biotechnology), recently licensed in the Latin American market, is a new once daily dosed, oral non-fluorinated quinolone that is among the first of this antibiotic class to show activity against both MRSA and vancomycin-resistant pathogens in DFI and SSTI.⁵⁹

Teixobactin is the first novel new class of antibiotic produced by a soil microorganism that was not described before (provisionally named Eleftheria terrae). It was isolated with a new tool, the iChip, that allowed the environmental bacterium to grow and for the antibiotic it produced to be isolated and subsequently identified. Teixobactin kills a range of pathogens including MRSA without detectable resistance through inhibiting peptidoglycan biosynthesis of the organism.⁶⁰

Does Local Delivery of Antibiotics Hold Promise For Treating MRSA?

The local delivery of antibiotics represents an emerging field in the treatment of DFI.^61,62 Topical application of antibiotics has the advantage of yielding a high concentration of antibiotics targeted to the area of infection, avoiding significant absorption and toxicity. This would be especially useful in patients with a history of intolerance to specific antibiotics or frail patients with other comorbidities that limit the options of systemic antibiotic use.

Moreover, minimal systemic exposure could reduce antibiotic pressure to microbial flora in the rest of the body and thus reduce the development of antibiotic-resistant strains. Significant experience and positive results with the use of topical antibiotics have already occurred with the use of calcium sulfate dissolvable beads loaded with vancomycin and tobramycin.⁶³ Apart from vancomycin, daptomycin, an agent that can cover MRSA, has shown excellent elution results in vitro.⁶² Only sparse data exist so far regarding the treatment of DFIs. However, authors have reported good results with a combination of bone debridement or resection with the application of beads impregnated with vancomycin with or without gentamicin in the treatment of diabetic foot osteomyelitis.^64-66

Although topical antibiotic treatment seems promising, there are several questions to answer, including the selection of patients for topical antibiotic application alone or in combination with systemic antibiotic treatment and/or surgery; dose of antibiotic and the need for repetition; and effect on healing rate. Randomized controlled trials are certainly needed to define outcomes with the use of local treatment and address the issues we have mentioned above.

Another emerging option for topical treatment is pexiganan cream (Locilex, Dipexium Pharmaceuticals). Pexiganan is a synthetic analogue of the natural antimicrobial peptide magainin II. It is a broad spectrum agent that is active against most of the microorganisms isolated in DFIs, including MRSA and multidrug resistant Gram-negative strains.⁶⁷ A large randomized, controlled double-blinded trial showed equivalent results between pexiganan and oral ofloxacin in mildly infected diabetic foot ulcers in terms of clinical improvement, overall microbiological eradication and wound healing rates.⁶⁸

In Conclusion

The prompt treatment of diabetic foot infections is a vital aspect of care to prevent significant morbidity and even mortality. Some studies suggest that a DFI due to MRSA increases infection severity and worsens outcomes. Therefore, international guidelines suggest considering MRSA coverage empirically in antibiotic selection.

There is a regrettable lack of evidence to guide optimum treatment modalities for DFIs. Topical therapy of the DFU to treat the infection source seems intuitive but trial evidence does not back up promising in vitro work. We cannot currently justify applying pricier silver-containing dressings and expensive larvae from a microbiological perspective alone. Therefore, systemic antibiotics are the mainstay of treatment. For MRSA, that is mainly parenteral glycopeptides and when it comes to the oral options, linezolid has a specific indication for diabetic foot infections. Side effects, interactions and monitoring requirements means newer antibiotics like tedizolid, nemonoxacin and teixobactin are needed. Perhaps of greater interest is the use of dissolvable beads containing antibiotics, which allow high local drug delivery but lower systemic absorption and hence side effects. Recently, pexiganan cream, derived from a natural antimicrobial peptide, showed equivalence in a trial for DFI treatment in comparison to oral ofloxacin.⁶⁸

Therefore, with the current epidemic of diabetes and hence DFUs and DFIs, there is a pressing need for research to define optimum treatments whether in the form of dressings, systemic antibiotics or topical therapies with the hope that locally delivered treatments to the DFU will be sufficient for all but the more serious infections.

Dr. Markakis is a Consultant Physician (diabetologist) at Central Manchester Foundation Trust in Manchester, UK.  

Dr. Faris is a Consultant Physician (microbiologist) at Central Manchester Foundation Trust in Manchester, UK.  

Dr. Rashid is a Consultant Surgeon (vascular, endovascular surgery) at Central Manchester Foundation Trust and Honorary Senior Lecturer at the University of Manchester in Manchester, UK.   

Dr. Armstrong is the Director of the Southern Arizona Limb Salvage Alliance and a Professor of Surgery at the University of Arizona Medical Center in Tucson, Ariz.

Dr. Boulton is the President of the Worldwide Initiative for Diabetes Education. He is a Professor of Medicine at the University of Manchester and a Visiting Professor at the University of Miami. He is a Consultant Physician (diabetologist) at the Central Manchester Foundation Trust and the Past President of the European Association for the Study of Diabetes.

Dr. Bowling is a Fellow in Podiatric Medicine and Surgery (podiatric surgeon) at Central Manchester Foundation Trust and a Clinical Research Fellow at the University of Manchester in Manchester, UK.

References

1.     Fisher TK, Wolcott R, Wolk DM, et al. Diabetic foot infections: A need for innovative assessments. Int J Lower Extremity Wounds. 2010;9(1):31-6.
2.     Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012;54(12):e132-73.
3.     Prompers L, Schaper N, Apelqvist J, et al. Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease. The EURODIALE Study. Diabetologia. 2008;51(5):747-55.
4.     Prompers L, Huijberts M, Apelqvist J, et al. High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia. 2007;50(1):18-25.
5.     Citron DM, Goldstein EJ, Merriam CV, et al. Bacteriology of moderate-to-severe diabetic foot infections and in vitro activity of antimicrobial agents. J Clin Microbiol. 2007;45(9):2819-28.
6.     Uckay I, Gariani K, Pataky Z, Lipsky BA. Diabetic foot infections: state-of-the-art. Diabetes Obes Metabol. 2014;16(4):305-16.
7.     Boyanova L, Mitov I. Antibiotic resistance rates in causative agents of infections in diabetic patients: rising concerns. Expert Rev Anti-Infect Ther. 2013;11(4):411-20.
8.     Centers for Disease Control and Prevention. Active bacterial core surveillance report, emerging infections program network, methicillin-resistant Staphylococcus aureus 2014. Available at https://www.cdc.gov/abcs/reports-findings/survreports/mrsa14.pdf .
9.     Davis KA, Stewart JJ, Crouch HK, et al. Methicillin-resistant Staphylococcus aureus (MRSA) nares colonization at hospital admission and its effect on subsequent MRSA infection. Clin Infect Dis. 2004;39(6):776-82.
10.     Hidron AI, Kourbatova EV, Halvosa JS, et al. Risk factors for colonization with methicillin-resistant Staphylococcus aureus (MRSA) in patients admitted to an urban hospital: emergence of community-associated MRSA nasal carriage. Clin Infect Dis. 2005;41(2):159-66.
11.     Barber M. Methicillin-resistant staphylococci. J Clin Pathol. 1961;14:385-93.
12.     Horr AF. Epidemiology of staphylococcal resistance. Clin Infect Dis. 2007;45(Suppl 3):S171-6.
13.     Couderc C, Jolivet S, Thiebaut AC, et al. Fluoroquinolone use is a risk factor for methicillin-resistant Staphylococcus aureus acquisition in long-term care facilities: a nested case-case-control study. Clin Infect Dis. 2014;59(2):206-15.
14.     Enright MC, Robinson DA, Randle G, et al. The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA). Proc Natl Acad Sci USA. 2002;99(11):7687-92.
15.     Lucet JC, Paoletti X, Demontpion C, et al. Carriage of methicillin-resistant Staphylococcus aureus in home care settings: prevalence, duration, and transmission to household members. Arch Intern Med. 2009;169(15):1372-8.
16.     Boyce JM, Pittet D, Healthcare Infection Control Practices Advisory C, Force HSAIHHT. Guideline for Hand Hygiene in Health-Care Settings. Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Society for Healthcare Epidemiology of America/Association for Professionals in Infection Control/Infectious Diseases Society of America. MMWR Recomm Report. 2002;51(RR-16):1-45, quiz CE1-4.
17.     Jumaa PA. Hand hygiene: simple and complex. Int J Infect Dis. 2005;9(1):3-14.
18.     Jevons MP. “Celbenin”-resistant staphylococci. Br Med J. 1961;1(5219):124-5.
19.     The University of Chicago Medical Center MRSA History Timeline: The First Half-Century, 1959-2009. Available at https://mrsa-research-center.bsd.uchicago.edu/timeline.html . Published 2010.
20.     Dang CN, Prasad YD, Boulton AJ, Jude EB. Methicillin-resistant Staphylococcus aureus in the diabetic foot clinic: a worsening problem. Diabet Med. 2003;20(2):159-61.
21.     Zenelaj B, Bouvet C, Lipsky BA, Uckay I. Do diabetic foot infections with methicillin-resistant Staphylococcus aureus differ from those with other pathogens? Int J Low Extrem Wounds. 2014;13(4):263-72.
22.     Lipsky BA, Aragon-Sanchez J, Diggle M, et al. IWGDF guidance on the diagnosis and management of foot infections in persons with diabetes. Diabet Metab Res Rev. 2016;32(Suppl 1):45-74.
23.     Reveles KR, Duhon BM, Moore RJ, et al. Epidemiology of methicillin-resistant Staphylococcus aureus diabetic foot infections in a large academic hospital: implications for antimicrobial stewardship. PloS One. 2016;11(8):e0161658.
24.     Schneider-Lindner V, Delaney JA, Dial S, et al. Antimicrobial drugs and community-acquired methicillin-resistant Staphylococcus aureus, United Kingdom. Emerg Infect Dis. 2007;13(7):994-1000.
25.     Kandemir O, Akbay E, Sahin E, et al. Risk factors for infection of the diabetic foot with multi-antibiotic resistant microorganisms. J Infect. 2007;54(5):439-45.
26.     Yates C, May K, Hale T, et al. Wound chronicity, inpatient care, and chronic kidney disease predispose to MRSA infection in diabetic foot ulcers. Diabetes Care. 2009;32(10):1907-9.
27.     Gadepalli R, Dhawan B, Sreenivas V, et al. A clinico-microbiological study of diabetic foot ulcers in an Indian tertiary care hospital. Diabetes Care. 2006;29(8):1727-32.
28.     Hartemann-Heurtier A, Robert J, Jacqueminet S, et al. Diabetic foot ulcer and multidrug-resistant organisms: risk factors and impact. Diabet Med. 2004;21(7):710-5.
29.     Richard JL, Sotto A, Jourdan N, et al. Risk factors and healing impact of multidrug-resistant bacteria in diabetic foot ulcers. Diabet Metab. 2008;34(4 Pt 1):363-9.
30.     Tentolouris N, Jude EB, Smirnof I, et al. Methicillin-resistant Staphylococcus aureus: an increasing problem in a diabetic foot clinic. Diabet Med. 1999;16(9):767-71.
31.     Aragon-Sanchez J, Lazaro-Martinez JL, Quintana-Marrero Y, et al. Are diabetic foot ulcers complicated by MRSA osteomyelitis associated with worse prognosis? Outcomes of a surgical series. Diabet Med. 2009;26(5):552-5.
32.     Strohal R, Schelling M, Takacs M, et al. Nanocrystalline silver dressings as an efficient anti-MRSA barrier: a new solution to an increasing problem. J Hosp Infect. 2005;60(3):226-30.
33.     Ip M, Lui SL, Poon VK, et al. Antimicrobial activities of silver dressings: an in vitro comparison. J Med Microbiol. 2006;55(Pt 1):59-63.
34.     Bhattacharyya M, Bradley H. Management of a difficult-to-heal chronic wound infected with methycillin-resistant Staphylococcus aureus in a patient with psoriasis following a complex knee surgery. Int J Wounds. 2006;5(2):105-8.
35.     Edwards-Jones V. Antimicrobial and barrier effects of silver against methicillin-resistant Staphylococcus aureus. J Wound Care. 2006;15(7):285-90.
36.     Wright JB, Hanson HD, Burrell RE. The comparative efficacy of two antimicrobial barrier dressings: in vitro examination of two controlled-release of silver dressings. Wounds. 1998;10(6):179-88.
37.     Thomas S, McCubbin P. Silver dressings: the debate continues. J Wound Care. 2003;12(10):420; discussion.
38.     Mumcuoglu KY, Miller J, Mumcuoglu M, et al. Destruction of bacteria in the digestive tract of the maggot of Lucilia sericata (Diptera: Calliphoridae). J Med Entomol. 2001;38(2):161-6.
39.     Kosinski MA, Lipsky BA. Current medical management of diabetic foot infections. Expert Rev Anti Infect Ther. 2010;8:1293-305.
40.     Awad SS, Elhabash SI, Lee L, et al. Increasing incidence of methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: reconsideration of empiric antimicrobial therapy. Am J Surg. 2007;194(5):606-10.
41.     Moise-Broder PA, Sakoulas G, Eliopoulos GM, et al. Accessory gene regulator group II polymorphism in methicillin-resistant Staphylococcus aureus is predictive of failure of vancomycin therapy. Clin Infect Dis. 2004;38(12):1700-5.
42.     Dryden M, Andrasevic AT, Bassetti M, et al. A European survey of antibiotic management of methicillin-resistant Staphylococcus aureus infection: current clinical opinion and practice. Clin Microbiol Infect. 2010;16(Suppl 1):3-30.
43.     Dryden MS. Complicated skin and soft tissue infection. J Antimicrob Chemother. 2010;65(Suppl 3):iii35-44.
44.     Itani KM, Dryden MS, Bhattacharyya H, et al. Efficacy and safety of linezolid versus vancomycin for the treatment of complicated skin and soft-tissue infections proven to be caused by methicillin-resistant Staphylococcus aureus. Am J Surg. 2010;199(6):804-16.
45.     Jones ME, Karlowsky JA, Draghi DC, et al. Epidemiology and antibiotic susceptibility of bacteria causing skin and soft tissue infections in the USA and Europe: a guide to appropriate antimicrobial therapy. Int J Antimicrob Agents. 2003;22(4):406-19.
46.     Gorwitz RJ, Jernigan DB, Powers JH, et al. Strategies for clinical management of MRSA in the community: summary of an experts’ meeting convened by the Centers for Disease Control and Prevention. CDC. Available at https://www.cdc.gov/mrsa/pdf/MRSA-Strategies-ExpMtgSummary-2006.pdf . Published March 2006.
47.     Forrest GN, Tamura K. Rifampin combination therapy for nonmycobacterial infections. Clin Microbiol Rev. 2010;23(1):14-34.
48.     Perlroth J, Kuo M, Tan J, et al. Adjunctive use of rifampin for the treatment of Staphylococcus aureus infections: a systematic review of the literature. Arch Intern Med. 2008;168(8):805-19.
49.     Raad I, Hanna H, Jiang Y, et al. Comparative activities of daptomycin, linezolid, and tigecycline against catheter-related methicillin-resistant Staphylococcus bacteremic isolates embedded in biofilm. Antimicrob Agents Chemother. 2007;51(5):1656-60.
50.     Sharpe JN, Shively EH, Polk HC, Jr. Clinical and economic outcomes of oral linezolid versus intravenous vancomycin in the treatment of MRSA-complicated, lower-extremity skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus. Am J Surg. 2005;189(4):425-8.
51.     Huang V, Gortney JS. Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists. Pharmacotherapy. 2006;26(12):1784-93.
52.     Martin A MG, Fisher M. Tigecycline. Practical Diabetes. 2014;31(1):84-5.
53.     Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant Gram-positive pathogens. Clin Infect Dis. 2004;38(7):994-1000.
54.     Mehta S, Singh C, Plata KB, et al. Beta-lactams increase the antibacterial activity of daptomycin against clinical methicillin-resistant Staphylococcus aureus strains and prevent selection of daptomycin-resistant derivatives. Antimicrob Agents Chemother. 2012;56(12):6192-200.
55.     Drew RH, Perfect JR, Srinath L, et al. Treatment of methicillin-resistant Staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy. For the Synercid Emergency-Use Study Group. J Antimicrob Chemother. 2000;46(5):775-84.
56.     Lipsky BA, Cannon CM, Ramani A, et al. Ceftaroline fosamil for treatment of diabetic foot infections: the CAPTURE study experience. Diabetes Metab Res Rev. 2015;31(4):395-401.
57.     Leuthner KD, Buechler KA, Kogan D, et al. Clinical efficacy of dalbavancin for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Thera Clin Risk Manage. 2016;12:931-40.
58.     Burdette SD, Trotman R. Tedizolid: the first once-daily oxazolidinone class antibiotic. Clin Infect Dis. 2015;61(8):1315-21.
59.     Poole RM. Nemonoxacin: first global approval. Drugs. 2014;74(12):1445-53.
60.     Piddock LJ. Teixobactin, the first of a new class of antibiotics discovered by iChip technology? J Antimicrob Chemother. 2015;70(10):2679-80.
61.     Lipsky BA, Hoey C. Topical antimicrobial therapy for treating chronic wounds. Clin Infect Dis. 2009;49(10):1541-9.
62.     Panagopoulos P, Drosos G, Maltezos E, Papanas N. Local antibiotic delivery systems in diabetic foot osteomyelitis: time for one step beyond? Int J Low Extrem Wounds. 2015;14(1):87-91.
63.     McPherson EJ DM, Sherif MS. Dissolvable antibiotic beads in treatment of periprosthetic joint infection and revision arthroplasty. The use of synthetic pure calcium sulfate (Stimulan) impregnated with vancomycin & tobramycin. Joint Implant Surgery & Research Foundation. Available at https://www.biocomposites.com/media/1402/dissolvable_antibiotic_beads_in_treatment_of_periprosthetic_joint-infection_and_revision_arthroplasty.pdf .
64.     Jogia RM, Modha DE, Nisal K, et al. Use of highly purified synthetic calcium sulfate impregnated with antibiotics for the management of diabetic foot ulcers complicated by osteomyelitis. Diabetes Care. 2015;38(5):e79-80.
65.     Karr JC. Management in the wound-care center outpatient setting of a diabetic patient with forefoot osteomyelitis using Cerament Bone Void Filler impregnated with vancomycin: off-label use. J Am Podiatr Med Assoc. 2011;101(3):259-64.
66.     Morley R, Lopez F, Webb F. Calcium sulphate as a drug delivery system in a deep diabetic foot infection. Foot. 2016;27:36-40.
67.     Flamm RK, Rhomberg PR, Simpson KM, et al. In vitro spectrum of pexiganan activity when tested against pathogens from diabetic foot infections and with selected resistance mechanisms. Antimicrob Agents Chemother. 2015;59(3):1751-4.
68.     Lipsky BA, Holroyd KJ, Zasloff M. Topical versus systemic antimicrobial therapy for treating mildly infected diabetic foot ulcers: a randomized, controlled, double-blinded, multicenter trial of pexiganan cream. Clin Infect Dis. 2008;47(12):1537-45.