International Journal of Applied Science www.ijas.org.uk

Review Article Significance of MRSA in nosocomial Infections

Dr. Javid Ahmad Bhat*1 and Dr Rajesh Tenguria2

1Division of Microbiology, M.V.M College Bhopal, M.P. India 2Department of Microbiology, M.V.M. College Bhopal, M.P. India.

A R T I C L E I N F O A B S T R A C T

Received 25 June 2014 Received in revised form 29 June 2014 Staphylococcus aureus is one of the most virulent microbial pathogen Accepted 04 July 2014 amongst gram positive bacteria to cause nosocomial and community acquired infections. An additional concern is the emergence and Keywords: dissemination of nosocomial organisms with increased resistance to MRSA, antimicrobial agents. Such microbes include methicillin resistant VRE, Nosocomial, S.aureus (MRSA), S.epidermidis, vancomycin resistant Enterococci mecA gene, (VRE) and VISA. The development of vaccines and drugs that prevent CA-MRSA. and cure bacterial infections was one of the twentieth century’s major contributions to human longevity and quality of life. Antibacterial agents are amongst the most commonly prescribed drugs of any kind

worldwide. Used appropriately, these drugs are lifesaving however, their indiscriminate use drives up the cost of health care leading to a plethora of side effects and drug interactions and fosters the emergence of bacterial resistance rendering previously valuable drugs useless.

Corresponding author: Division of Microbiology, M.V.M College Bhopal, M.P. India © 2014 International Journal of Applied Science- All rights reserved E-mail address: [email protected]

INTRODUCTION

Staphylococcus aureus is one of the Staphylococcus aureus is universal in most common and important pathogen, distribution found in pus, boils, abscess, skin, responsible for the majority of nosocomial throat, nasophrynx, oral mucosa, soil, sewage, infections. S.aureus is an opportunistic milk and water. They are gram positive cocci bacterium, normally, part of the human micro- arranged singly ranging from 1µm in diameter; flora but, attacks immediately when the immune pairs, tetrads and short chains but appear system of the host becomes susceptible. Even predominantly in grape like clusters. The cell though S.aureus can be found in different parts wall is composed of peptidoglycan and teichoic of the body but anterior nares are the principal acid3,4. ecological sites in humans1. A study had reported nasal carriage as a major risk factor for Mechanism of antibiotic resistance S.aureus infection that differs from person to person. It had been reported that 20% of the Penicillin resistance healthy individuals carry S.aureus persistently, 60% intermittently and 20% never carry History and epidemiology S.aureus2. The mortality of patients with S. aureus bacteremia in the pre-antibiotic era exceeded Bhat______ISSN: 2394-9988

80%, and over 70% developed metastatic cassette chromosome mec (SCCmec), harboring infections5. The introduction of penicillin in the the mecA gene and other resistance early 1940s dramatically improved the prognosis determinants. Methicillin resistance is mediated of patients with staphylococcal infection. by production of an altered penicillin binding However, as early as 1942, penicillin-resistant protein PBP-2a encoded by the mecA staphylococci were recognized, first in hospitals gene12,14,15-17. and subsequently in the community6. By the late Methicillin, like all penicillins exerts its 1960s, more than 80% of both community and battle by jamming the proteins called penicillin hospital-acquired staphylococcal isolates were binding protein (PBPs) which are liable for the resistant to penicillin. This pattern of resistance, construction and protection of the bacterial cell first emerging in hospitals and then spreading to wall. S.aureus resistant strains acquired a new the community, is now a well-established pattern protein called PBP2a (Figure 1b) which was not that recurs with each new wave of antimicrobial barren by methicillin and could restore the other resistance7. PBPs, thus, allowing the continued existence of S.aureus in the company of methicillin. PBP2a Mechanism of resistance is encoded by the gene mecA, which is the Staphylococcal resistance to penicillin is trademark of MRSA. As different to the mediated by blaZ, the gene that encodesβ- penicillinase gene mecA, it does not live on a lactamase (Figure 1a). This predominantly plasmid but on the chromosome fixed in a large extracellular enzyme, synthesized when movable genetic element called Staphylococcal staphylococci are exposed to β-lactam chromosome cassette mec or SCCmec 18. The antibiotics, hydrolyzes the β-lactam ring, occurrence of PBP2a means MRSA is not only rendering the β-lactam inactive. The gene blaZ opposing to methicillin but, moreover to all β- is under the control of two adjacent regulatory lactam antibiotics together with synthetic genes, the anti-repressor blaR1 and the repressor penicillins, cephalosporins and carbapenems. blaI 8. Recent studies have demonstrated that the Various methicillin resistant isolates had signaling pathway responsible for β-lactamase been reported with alterations in their synthesis requires sequential cleavage of the PBPs19,20,13. These isolates had been termed regulatory proteins BlaR1 and BlaI. Following moderately resistant S.aureus (MODSA). These exposure to β-lactams, BlaR1, a transmembrane isolates are not so ubiquitous in nature with low sensor-transducer, cleaves itself9,10. A study put resistance and without any clinical significance. forward that the cleaved protein functions as a It had been reported that isolates which protease that cleaves the repressor BlaI, directly produce large amounts of penicillinase or indirectly (an additional protein, BlaR2, may (penicillinase hyper-producers) may express low be involved in this pathway) and allows blaZ to level resistance under some test conditions21,22. synthesize enzyme11. These isolates had been referred to as borderline oxacillin resistant S.aureus (BORSA). There are Methicillin resistance no reports of failure of treatment with Staphylococcus aureus is a dynamic and penicillinase resistant penicillins in infections adaptable bacterium that has an incredible talent with such isolates and animal model to attain antibiotic resistance. Methicillin experiments indicate that their clinical resistant Staphylococcus aureus (MRSA) strains significance is doubtful23. Methicillin was the had rapidly emerged during 1960 and became a first penicillinase resistant penicillin used in 60s major problem in hospitals immediately after the and was recognized at that time as the most methicillin was introduced in 1959. At that time reliable agent for routine susceptibility testing, those nosocomial MRSA strains were highly though methicillin is now a day’s not used in multidrug resistant (MDR) but, many being treatment. That’s why; resistant strains were susceptible only to glycopeptides12-14. termed methicillin resistant S.aureus (MRSA). The genome of methicillin resistant Later, oxacillin resistant S.aureus (ORSA) came staphylococci contains a 21-67kb heterologous into existence after the use of oxacillin as an mobile genetic element termed staphylococcal alternative to methicillin in susceptibility tests.

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Vancomycin resistance in Staphylococcus aureus which result in trapping of more and more It had been recorded that MRSA vancomycin molecules in the peptidoglycan infections are difficult to treat as compared to layers before they could reach to the cytoplasmic MSSA infections if, they are located at membrane where the synthesis of peptidoglycan anatomical sites because, at those sites antibiotic takes place33- 35. penetration is very less24. Vancomycin was the first glycopeptide MECHANISM OF PATHOGENESIS AND antibiotic that was introduced into clinical VIRULENCE FACTORS practice in 1958 after it was isolated in the mid 1950s25. Vancomycin had been the drug of Staphylococci are opportunistic choice for treatment of staphylococcal organisms that require following steps to start an nosocomial infections especially MRSA infection in its host such as inoculation and local throughout the world for the last 20 years. colonization of tissue surfaces, invasion, evasion Vancomycin is the second most common of the host response, and metastatic spread to 36 antibiotic used in hospitals throughout the invade the host and cause infection . A breach world, about 16 tons of the vancomycin is being in cutaneous or mucosal barriers is essential for used every year. Only 8 clinical vancomycin initiation of infection. resistant S.aureus (VRSA) isolates had been S.aureus expresses many potential isolated to date, all in the USA and mostly from virulence factors: (1) Surface proteins that the state of Michigan26. However, recent reports promote colonization of host tissues (2) Invasins proved some sort of concern regarding that promote bacterial spread in tissues vancomycin27. The first clinical vancomycin (leukocidin, kinases, hyaluronidase) (3) Surface intermediate resistant S.aureus (VISA) with a factors that inhibit phagocytic engulfment minimum inhibitory concentration (MIC) of (capsule, Protein-A) (4) Biochemical properties 8mg l-1 was documented in 1996 while, as the that enhance their survival in phagocytes first hetero vancomycin intermediate resistant (carotenoids, catalase production); (5) S.aureus (hVISA) with an MIC range of <4 mg Immunological disguises (Protein A, coagulase, l-1 but, possess stable sub populations (ca. 1/106) clotting factor) and (6) Membrane-damaging that can grow in the presence of >4 mg l-1 of toxins that lyse eukaryotic cell membranes vancomycin was computed by28. (hemolysins, leukotoxin, leukocidin (7) Since then, vancomycin intermediate Exotoxins that damage host tissues or otherwise resistant S.aureus (VISA) strains had been provoke symptoms of disease (enterotoxin B, reported in many parts of the different countries TSST-1, α-toxin (8) Inherent and acquired 37 around the world where such reports were not resistance to antimicrobial agents . recorded earlier29. Although, the mechanism of Nasal Colonization vancomycin resistance is different, e.g., VRSA In human, the principal site of 38 has acquired vanA gene cluster mediated staphylococcal colonization is anterior nares . resistance in contrast glycopeptides intermediate Little is known about the biology of this S.aureus / hetero glycopeptide intermediate colonization process in S.aureus. Nasal mucin S.aureus (GISA/hGISA) have achieved mutation and keratinized epithelial cells of the anterior directed resistance30-32. Although the genetic nares are involved in the attachment of S.aureus. mechanism had not been fully understood but, Other factors like influence of other resident the thickening of the cell wall through nasal flora and their bacterial density, nasal accumulation of increased amounts of mucosal damage (e.g., that resulting from peptidogly can with reduced levels of cross inhalational drug use), the antimicrobial linking, either by increased synthesis or by properties of nasal secretions, and host genetic reduction of the turn over seems to be common factors e.g., human leukocyte antigen (HLA) 37 factor to all VISA and hVISA strains. This type, may contribute to colonization rate . causes an increase of free D-Ala-D-Ala (Figure 2) side chains to which vancomycin can bind

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Inoculation and Colonization of Tissue Surfaces polysaccharides are characterized by a zwitter Staphylococci may get introduce into ionic charge pattern (the presence of both tissue as a result of minor abrasions, negatively and positively charged molecules) administration of medication such as insulin, or that is critical to abscess formation. Protein-A an establishment of intravenous access with MSCRAMM unique to S.aureus acts as an Fc catheters. A bacterium replicates and colonizes receptor. This protein can bind the Fc portion of the host tissue surface after their introduction IgG subclasses 1, 2 and 4 preventing opsono- into a tissue site. A family of structurally related phagocytosis by polymorphonuclear leukocytes S.aureus surface proteins referred as microbial (PMNs)39. surface components recognizing adhesive matrix An additional mechanism of S.aureus molecules plays a major role as a mediator of evasion of the host response is its capacity for adherence to these sites38. intracellular survival. Both professional and Various MSCRAMMs such as nonprofessional phagocytes are capable of fibronectin binding protein, clumping factor and internalizing staphylococci. Staphylococcal collagen binding protein enable the bacteria to internalization by endothelial cells provides a colonize different tissue surfaces. They sanctuary that protects bacteria against the host’s contribute to the pathogenesis of invasive defenses. It also results in cellular changes such infections such as endocarditis and arthritis by as the expression of integrins and Fc receptors facilitating the adherence of S.aureus to surfaces and the release of cytokines. These cellular with exposed fibronectin, fibrinogen or changes may contribute to systemic collagen39. manifestations of disease including sepsis and vasculitis. Invasion After colonization, S.aureus replicates at Host Response to Staphylococcus aureus the initial site of infection produces enzymes Infection like serine, proteases, hyaluronidases, The primary host response to S.aureus thermonucleases and lipase36. These enzymes infection is the polymorpho-nuclear leukocytes. facilitate local spread across tissue surfaces and Bacterial components such as formylated bacterial survivals although, their precise role in peptides or peptidoglycan attract the PMNs to infections is still not clear. The lipases help the the site of infection36. These cells are also organism to survive in lipid rich areas such as attracted by the cytokines tumor necrosis factor the hair follicles where S.aureus infections are (TNF) and interleukins (ILs) 1 and 6, which are often initiated. The S.aureus produces a toxin released by activated macrophages and panton valentine leukocidin which is cytolytic to endothelial cells. polymorphonuclear leukocytes (PMN), macrophages and monocytes. The cell wall of Staphylococcus aureus Infections S.aureus contains alternating N-acetyl muramic S.aureus has the ability to cause a broad acid and N-acetyl glucosamine units in range of infections that had been divided in to combination with an additional cell wall three general types: (i) Superficial lesions such component lipoteichoic acid that can initiate an as wound infections (ii) Systemic and life- inflammatory response that includes the sepsis threatening infections such as endocarditis, syndrome1. osteomyelitis, pneumonia, brain abscesses, meningitis and bacteremia and (iii) Toxinoses Evasion of Host Defense Mechanisms such as food poisoning, scalded skin syndrome Evasion of host defense mechanisms is and toxic shock syndrome40. critical to invasion. Staphylococci possess an anti-phagocytic polysaccharide microcapsule. INCREASED COSTS AND MORTALITY Most human S.aureus infections are due to capsular types 5 and 8. The S.aureus capsule As per the National Nosocomial also appears to play an important role in the Infections Surveillance System (NNIS) induction of abscess formation36. The capsular estimation around 80,000 patients get an MRSA

IJAS [1][1]2014 027-036 Bhat______ISSN: 2394-9988 infection after entering in to the hospitals per  Patients with non-intact skin including year. Reports indicate that infection with MRSA wounds and ulcers. increases the cost and the risk of mortality41. The  Patients due to undergo elective high-risk higher cost of treating MRSA infections is due surgery (e.g. cardiothoracic surgery, to a variety of factors such as patients with orthopedic implant surgery). On admission MRSA infection resides for the longer periods in to ICU/high-risk areas with weekly the hospitals, preventive measures are taken to screening thereafter other patients as, isolate the patients suffering with MRSA and determined by local risk assessment keep them away from infecting other patients,  There is no indication for the routine vancomycin has become the drug of choice for screening of patients prior to discharge i.e. MRSA infections, but is more expensive than discharge screening. the drugs normally used to treat S.aureus  When screening patient’s swabs from the 42 infections . It had been determined that the anterior nares, perineum or groin, any skin death rate of patients with MRSA bacteremia is lesions (e.g. surgical site) and any medical about two times higher than the death rate due to device sites (e.g. urinary catheter, central 43 bacteremia caused by MSSA . venous catheter) should be obtained from A 1.9 fold increase in hospital charges the patient. Other samples may be taken e.g. and a 3.4 fold increase in mortality rate during throat swab if, MRSA is persistent following the 90 day post operative period had been attempts at decolonization. described when compared patients with MSSA  Periodic e.g. weekly surveillance cultures surgical site infections (SSI) with patients of should continue to be taken from patients MRSA (SSI) because, the patients with MRSA 44 remaining in high-risk areas of the hospital SSI had to stay five additional days in hospital . e.g. ICU, special baby care unit, orthopedic In a study it was expected that an amount of unit, and solid organ or bone marrow US$250,000 is required to bring an outbreak of transplant unit and especially where MRSA MRSA (in which three to five patients are is epidemic or where it has been endemic in infected) under control in the Utrecht University 45 the past. Hospital, The Netherlands . This would involve  Patients with MRSA who have had three closure of the intensive care unit (ICU) or ward, consecutive negative sets of screening postponing operating programs, surveillance samples at least 72 hours apart after cultures etc. Mortality rate and societal costs of decolonization regimens can be removed S.aureus infections can be decreased by from isolation. However, such patients reducing the incidence of methicillin resistant 46 should continue to be screened at weekly and sensitive nosocomial infections . intervals whilst in hospital.  Patients with MRSA who have wounds or SPECIFIC MEASURES TO CONTROL AND large areas of non-intact skin (e.g. decubitus PREVENT MRSA ulcers), are not likely to lose MRSA and Surveillance and screening of patients generally require isolation until the wound is According to the (SARI, 1999) effective healed. When re-admitted to hospital in the control strategies are dependent on good future these patients should be placed in surveillance data and early detection and isolation pending the results of screening following patients should be screened for samples. MRSA:  Patients known to be previously positive and Infection Control Measures in Hospitals who are being re-admitted to hospital.  Hand hygiene must be carried out before  Patients admitted from another hospital or and after each patient contact, before and health-care facility unless, that hospital or after handling or manipulation of any facility is known to be free of MRSA. invasive device, before entering and upon leaving critical care areas, isolation rooms  During an outbreak as determined by the infection control team.

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and areas used for cohorting of MRSA avoided if possible, as this is strongly cases. associated with the selection of  Cuts or breaks in the skin of careers should glycopeptides resistance47. be covered with impermeable dressings.  The hospital environment must be visibly Treatment Options clean, free of dust, soil-age and acceptable Daptomycin is an acidic lipopeptide to patients, visitors and staff and all hospital with a mode of action requiring calcium. surfaces should be intact and made of a Daptomycin has recently demonstrated durable, washable material. This is significantly better bactericidal activity than fundamental to the control of all healthcare vancomycin against S.aureus and enterococci associated infections including MRSA. and has activity against a small number of  Hospital management should ensure that all glycopeptide intermediate S.aureus strains and hospital staff (including supervisory staff) vancomycin resistant enterococcus. involved in cleaning processes must be Mupirocin is a bacteriostatic antibiotic trained and certified as competent in such used exclusively as a topical agent. It exerts its processes. Training should commence antimicrobial effect by specifically and within the first week of employment. irreversibly binding to bacterial isoleucyl tRNA  The Chief Executive Officer or equivalent of synthetase, thus preventing protein synthesis. It every healthcare facility must take corporate has been used widely for the clearance of nasal responsibility for ensuring cleanliness methicillin-resistant Staphylococcus aureus standards are maintained and for providing (MRSA) carriage during outbreaks and has been adequate resources for both cleaning and recommended for the decolonization of training. National recommendations on hand methicillin sensitive S.aureus (MSSA) in hygiene should be followed. healthcare personnel. Intranasal application of  All healthcare staff should comply with best mupirocin ointment is effective in reducing practice for insertion and care of invasive surgical site infections and the likelihood of medical devices such, as intravascular broncho pulmonary infection. catheters, urinary catheters etc. Additional Few other drugs including linezolid (a cleaning and disinfection measures are synthetic oxazolidinone), tigecycline (a necessary on discharge of MRSA patients derivative of minocycline) and daptomycin (a and in outbreak situations cyclic lipopeptide) appear promising in treatment. Antibiotic Stewardship Other alternatives include minocycline,  Inappropriate or excessive antibiotic therapy clindamycin, or a macrolides antibiotic and prophylaxis should be avoided in all depending on local susceptibility patterns. healthcare settings. Particular attention should be given to obtaining an accurate CONCLUSION diagnosis when considering antibiotic The increasing prevalence of MRSA therapy and ensuring that antibiotic therapy infections in the hospitals, day care centers and in if required is appropriate to the diagnosis. the community has become a worldwide incident.  Antibiotics should be given at the correct The wide spread distribution of multiple drug dosage, correct timing and for an resistant strains and antibiotic clones of the appropriate duration. Excessive duration of bacterium facilitated by inherent or acquired antibiotic therapy is particularly associated molecular element is perturbing as it complicates with selection of resistance and should be diagnosis and chemotherapy. More so, the avoided. presence of wide array of virulence and potential  The use of glycopeptides antibiotic should risk and spreading factors compounds morbidity be limited to situations where their use has and control measures. There is need for adequate been shown to be appropriate. Prolonged policy framework on infection control that will courses of glycopeptide therapy should be reflect the current realities on the epidemiologic

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Figure 1. (a) Induction of staphylococcal β-lactamase synthesis in the presence of the β- lactam antibiotic penicillin. I. The DNA-binding protein BlaI binds to the operator region, thus repressing RNA transcription from both blaZ and blaR1- blaI (b) Mechanism of S. aureus resistance to methicillin49.

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Figure 2. Mechanism of Vancomycin resistance in S.aureus 49

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