|Year : 2017 | Volume
| Issue : 1 | Page : 4-8
Methicillin-resistant Staphylococcus aureusmenace: A dermatologist's perspective
Manjunath Hulmani, Shruti Kakar, V Jagannath Kumar
Department of Dermatology, SS Institute of Medical Sciences, Davanagere, Karnataka, India
|Date of Web Publication||28-Dec-2016|
Department of Dermatology, SS Institute of Medical Science and Research Centre, Davanagere - 577 005, Karnataka
Source of Support: None, Conflict of Interest: None
Staphylococcus aureus is a facultative anaerobic, Gram-positive coccal bacterium. In contemporary times, one of the major concerns in all fields of medicine is the emerging resistance to S. aureus. There are two types of methicillin-resistant S. aureus (MRSA), that is, hospital acquired (HA) and community acquired (CA). HA-MRSA strains contain staphylococcal cassette chromosome mec (SCCmec) I and II, which are larger and have the capacity for multidrug resistance. High expression of Panton-Valentine leukocidin (PVL), phenol-soluble modulins (PSM), α-toxin, core genome-encoded superantigen SEIX, and teichoic acid contributes to increased virulence in CA-MRSA strains. Methicillin resistance in staphylococci is due to the acquisition of a mobile genetic element (mec) called the SCCmec. All SCCmec types include the mecA gene, which codes for the low-affinity penicillin-binding protein (PBP) 2a. Resistance is due to the fact that β-lactam antibiotics cannot inhibit PBP2a. Biofilms are surface-attached bacterial agglomerations embedded in extracellular matrix. There are various toxins such as PVL, PSMs, surface-anchored S. aureus-binding proteins, and SasX protein. It can cause folliculitis, furunculosis, abscesses, carbuncles, cellulitis, necrotizing pneumonia, urinary tract infection, osteomyelitis, septic arthritis, thrombophlebitis, endocarditis, and toxic shock syndrome. Many diagnostic modalities are available to identify MRSA. The mainstay of treatment is incision and drainage. Systemic antibiotics such as clindamycin, doxycycline, trimethoprim-sulfamethoxazole, linezolid, daptomycin, tigecycline, and tedizolid are the most commonly used antibiotics. The prevalence of CA-MRSA is on the rise, and as a dermatologist, our concern is to prevent the occurrence of recurrent furunculosis and patient dissatisfaction.
Keywords: Methicillin-resistant Staphylococcus aureus, skin and soft tissue infection, Staphylococcus aureus
|How to cite this article:|
Hulmani M, Kakar S, Kumar V J. Methicillin-resistant Staphylococcus aureusmenace: A dermatologist's perspective. Clin Dermatol Rev 2017;1:4-8
|How to cite this URL:|
Hulmani M, Kakar S, Kumar V J. Methicillin-resistant Staphylococcus aureusmenace: A dermatologist's perspective. Clin Dermatol Rev [serial online] 2017 [cited 2017 Oct 18];1:4-8. Available from: http://www.cdriadvlkn.org/text.asp?2017/1/1/4/196941
| Introduction|| |
Staphylococcus aureus is a facultative anaerobic, Gram-positive coccal bacterium. It is both catalase and nitrate positive. It was first identified in 1880 in Aberdeen, Scotland, by the surgeon Sir Alexander Ogston in pus from a surgical abscess in a knee joint.  The name staphylococcus was given by the German physician Friedrich Julius Rosenbach. It is a normal inhabitant of the reproductive tract of females and also many individuals carry the organism in their nostrils and skin. 
In contemporary times, one of the major concerns in all fields of medicine is the emerging resistance to S. aureus. The emergence of resistance dates back to 1942 when the penicillin-resistant S. aureus due to penicillinases were detected by Rammelkamp and Maxon. To overcome this problem, Beecham in 1959, introduced the semisynthetic antibiotic methicillin which was resistant to β-lactamase inactivation. However, within a year of its introduction the resistance towards methicillin was also reported. This mechanism of resistance protected the bacteria from entire class of beta-lactum antibiotics including penicillin, canbapenems and cephalosporins. 
Methicillin-resistant S. aureus (MRSA) is a strain of S. aureus responsible for difficult-to-treat infections that are resistant to a large group of antibiotics.
| Clinical Types|| |
There are two types of MRSA: Hospital acquired (HA) and community acquired (CA). HA-MRSA is an infection in a hospitalized patient that was not incubating at the time of admission. Whereas, CA-MRSA is an infection that was incubating at the time of admission and was not caused by an organism acquired during previous health care. Initially, MRSA was essentially a nosocomial disease, but in the 21 st century, it has been seen outside the hospital settings. 
HA-MRSA strains contain staphylococcal cassette chromosome mec (SCCmec) I and II, which are larger and have the capacity for multidrug resistance. However, CA-MRSA strains contain SCCmec IV, which is much smaller and does not confer multidrug resistance. ,
High expression of Panton-Valentine leukocidin (PVL), PSMs, α-toxin, and core genome-encoded superantigen SEIX contributes to increased virulence in CA-MRSA strains.  In the recent times, it has been observed that the genome for HA-MRSA is shifting toward CA-MRSA, thus giving serious issues for therapy in the future. 
| Pathogenesis|| |
resistance in staphylococci is due to the acquisition of a mobile genetic element called the SCCmec. SCCmec is a DNA fragment, and currently, there are around 11 types.  All SCCmec types include the mecA gene, which codes for the low-affinity penicillin-binding protein (PBP) 2a. Resistance is due to the fact that β-lactam antibiotics cannot inhibit PBP2a. SCCmec elements also include ccr genes for integration and excision from the chromosome. 
Biofilms provide significant protection from antibiotics and host defenses, in addition enables the bacteria to remain attached to biotic or abiotic surfaces. Biofilms may contribute to prolonged infection and colonization and the spread of MRSA in hospital and community settings. 
Types of isolates
There are five types of isolates which are called clonal complexes (CCs), which are also called as MRSA clones: CC5, CC8, CC22, CC35, and CC40.  The first clone harbored the SCCmec element of Type 1 and belonged to CC8. The New York/Japan clone and the "paediatric" clone, both of which belong to CC5, are the newly emerged clones. 
PVL is a member of the bi-component family of staphylococcal leukocidins associated with CA-MRSA. It can cause toxic death of neutrophils, eosinophils, and basophils.  It has been associated with specific forms of skin infections, such as furunculosis. Lung infection and osteomyelitis are also associated with PVL toxin.
PSM is another virulence factor present in S. aureus. They have cytopathic capacities. CA-MRSA has higher expression of PSM as compared to HA-MRSA.
A core genome-encoded superantigen, SElX, was recently described, which contributes to CA-MRSA necrotizing pneumonia.  Surface-anchored S. aureus-binding proteins that interact with human matrix molecules (microbial surface components recognizing adhesive matrix molecules [MSCRAMMs]) likely play a role in nasal colonization, particularly when the mucin layer is breached and matrix proteins are exposed. Clumping factor B and S. aureus surface proteins G and X (SasG and SasX) have been demonstrated to bind to nasal epithelial cells.  The recently described SasX protein is of particular interest because it has been linked to an MRSA epidemic wave.  Recently, anionic molecules called teichoic acid were identified in the cell walls of Gram-positive bacteria. They have a role in protection of bacteria from neutrophilic killing. They also have a role in biofilm formation. They also play a role in colonization of bacteria in nasal epithelium. 
| Clinical Presentation|| |
Furunculosis is the main clinical presentation of CA-MRSA infections characterized by infection of hair follicle and the subcutaneous tissue [Figure 1] and [Figure 2]. Other common presentations include superficial folliculitis, carbuncle, felon and nonbullous impetigo.  Patients can also present with cellulitis [Figure 3] and abscess [Figure 4]. 
|Figure 1: Furuncle with abscess over mandibular area (Courtesy Dr. Mohan K H)|
Click here to view
Extracutaneous MRSA infections include urinary tract infection, postcatheterization, necrotizing pneumonia, enterocolitis, mediastinitis postcardiac surgery, osteomyelitis, septic arthritis, thrombophlebitis, endocarditis, myositis, parotitis, eye infections, and toxic shock syndrome. Furthermore, together with coagulase-negative staphylococci, S. aureus is the most common cause of infections on indwelling medical devices. The mortality rate of severe, invasive MRSA infections is about 20%, and it has been estimated that MRSA infections are the leading cause of death by a single infectious agent, exceeding deaths caused by HIV/AIDS. ,
| Risk Factors|| |
Close contact within a household, living facility, or workplace has been associated with outbreaks of MRSA skin and soft tissue infections (SSTIs). The ability of S. aureus to survive on fomites creates a potential source of cross-contamination. Individuals who live in hot, humid climates are at a higher risk for developing skin lesions. Obesity, anemia, diabetes mellitus, immunotherapy, HIV infection, and end-stage renal disease are the predisposing factors.  Established skin diseases increase the susceptibility to bacterial colonization, and patients with atopic dermatitis, burn injuries, chronic wounds, or leg ulcers are more prone to developing refractory furunculosis. Inherited immune-deficiency states, in particular those with impaired neutrophil function, increase the risk of bacterial colonization. 
| Laboratory Diagnosis of Methicillin-resistant Staphylococcus aureus|| |
The treatment and prevention of MRSA infections depends on laboratory diagnosis and susceptibility testing. Several laboratory tests and methods are available for identification of S. aureus and methicillin susceptibility testing.  The detail discussion on each methods is out of scope of this review. Hence, only current recommendations for laboratory detection of MRSA are provided.
Identification of Staphylococcus aureus
coagulase test and latex agglutination tests are routinely used for identification of S. aureus and to confirm the results of other tests such as slide coagulase test and DNase tests. 
Minimum inhibitory concentration (MIC)-based tests, disc diffusion tests, latex agglutination test which detects PBP2a, quenching fluorescence methods which uses oxygen-sensitive fluorescent indicator, automated methods, and molecular methods are used for methicillin susceptibility testing. MIC-based methods include Agar (Mueller-Hinton or Columbia agar) dilution and broth microdilution, Etest method, breakpoint method, and agar screening method. Dilution methods have been used traditionally as reference methods of susceptibility testing. Now, these have been replaced by molecular methods which include detection of mecA gene using real-time or gel-based polymerase chain reaction, DNA probes, or peptide nucleic acid probes. However, disc diffusion methods are the most widely used susceptibility tests in clinical laboratories. 
Methicillin-resistant Staphylococcus aureus screening
It is done to identify the potential MRSA colonization in an individual. The screening tests are designed to detect only the MRSA strains and no other pathogens. The test medium generally contains an indicator to identify S. aureus, an inhibitor to select only S. aureus and methicillin, oxacillin, or cefoxitin to detect MRSA. Baird Parker agar with ciprofloxacin is used for detecting ciprofloxacin resistance MRSA strains. Mannitol salt agar or oxacillin resistance screening agar can be used for ciprofloxacin-susceptible MRSA strains. Enrichment of screening swab in a broth before plating in screening agar medium improves the sensitivity. Molecular methods (see above) can be used for rapid screening of samples for MRSA. 
| Treatment|| |
The mainstay of therapy for acute furunculosis is simple incision and drainage. Drainage alone without use of adjunctive antibiotic is usually sufficient to treat a single abscess smaller than 5 cm.  Systemic antibiotics should be reserved for abscesses larger than 5 cm or if cellulitis or fever is present. Clindamycin, doxycycline, and trimethoprim-sulfamethoxazole (TMP-SMX) are the most commonly used antibiotics for outpatient treatment of MRSA-related SSTI.  TMP-SMX is an effective and inexpensive drug for MRSA furunculosis. The long-acting tetracyclines, specifically minocycline (50-200 mg/day bd or qid) and doxycycline, are good drugs for MRSA furunculosis.  Fusidic acid is a bacteriostatic agent, effective against Gram-positive organisms, including methicillin-susceptible S. aureus and MRSA. 
For patients who require hospitalization, a variety of parenteral agents are available (e.g. vancomycin, linezolid, daptomycin, quinupristin-dalfopristin, and tigecycline). Vancomycin is the gold standard of therapy for serious MRSA infections. 
Linezolid, an oxazolidinone, is a new antibiotic available intravenously and orally. It is the only oral antibiotic with proved efficacy against MRSA in controlled clinical trials.  Linezolid exhibits bacteriostatic activity against MRSA via binding to the 50S ribosomal subunit and preventing toxin formation. It also has excellent activity against Group A streptococci. 
Daptomycin is a bactericidal, cyclic lipoprotein that causes depolarization of bacterial cell membranes. Its clinical efficacy is comparable to vancomycin, and 97% of S. aureus strains are susceptible to daptomycin, including some vancomycin-resistant S. aureus (VRSA) strains. Daptomycin is the drug of choice for patients with severe MRSA infections or bacteremia who are intolerant of vancomycin or for patients with VRSA infections, which are sensitive to daptomycin. 
The streptogramin combination of quinupristin-dalfopristin has synergistic antibacterial activity in vitro against a wide array of Gram-positive organisms.  Tigecycline is bacteriostatic against MRSA with documented in vitro activity against VRSA and vancomycin-insensitive S. aureus. 
Newer MRSA agents include the semisynthetic lipoglycopeptides, dalbavancin, telavancin, and oritavancin, all of which are bactericidal and inhibit cell wall synthesis. Dalbavancin has a long half-life, which allows a simple dosing schedule (100 mg on day 1 and 500 mg on day 8 of treatment). 
Ceftobiprole and ceftaroline are novel cephalosporins that target aberrant bacterial penicillin-binding proteins involved with MRSA furunculosis. 
Recently, tedizolid, an oxazolidinone antibiotic, was approved by the Food and Drug Administration as once daily regimen for treatment of MRSA infections. It is better tolerated than linezolid in terms of nausea, GI side effects, and platelet dysfunction. 
| Recent Developments|| |
Vaccines to prevent emergence of MRSA strains have been under trials. S. aureus polysaccharide 5 and 8 vaccine conjugated with nontoxic recombinant Pseudomonas aeruginosa has demonstrated partial immunity against S. aureus bacteremia for 40 weeks after which the effect wanes out.  V710 vaccine against IsdB surface protein was found to be ineffective. Thus, it was concluded that vaccines targeting multiple virulence mechanisms is likely to protect against S. aureus.  The SA4Ag vaccine, the MSCRAMM ClfA; the manganese transporter component, MntC (aka rP305A or SA0688); and capsular polysaccharides Type 5 and 8 have been under development. It is anticipated that this strategy should work out against S. aureus. 
| Conclusion|| |
Novel MRSA clones keep occurring in hospitals and more recently in the community, often causing sustained epidemics. It is therefore a daunting task to delineate factors that define virulence of the entire range of infectious due to MRSA strains and thus to generate drugs with as broad and as long-lasting anti-staphylococcal potential as possible. The prevalence of CA-MRSA is on the rise, and as a dermatologist, our concern is to prevent the occurrence of recurrent infections leading to patient dissatisfaction. We need to stop the aberrant use of antibiotics. This way we can always be a step ahead in the fight against MRSA.
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Conflicts of interest
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