Methicillin Resistant Staphylococcus Aureus A Global Issue Biology Essay

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The use of antibiotics to control prevalent and often fatal bacterial diseases, when accompanied with good public health practices and improvements in sanitation, housing, and nutrition; significantly contributed to the increased life expectancy in the last 30 years. The phenomenal success of these new, "wonder drugs" led to their widespread use for almost every clinical application in all disciplines of health care, regardless of the indication. In an almost ironic twist, the very success of these drugs has contributed to their loss of effectiveness. After decades of use and misuse of antibiotics, microorganisms have developed resistance to the very drugs that clinicians have depended upon to treat bacterial disease, and rendering them less and less effective. Some organisms have developed such a high degree of resistance antibiotics like methicillin resistant Staphylococcus aureus(MRSA). MRSA is a organism which has become resistant to many antibiotics. MRSA is spread through contact with infected people and contact frequently occurs in health care facilities. Control of the disease requires compliance with disinfection practices by all health care professionals and education of the public of symptoms and the likelihood of transmission. How did this happen? This Global issue of the antimicrobial resistance, emphasizing the growing threat of MRSA.

The clinical importance of methicillin-resistant Staphylococcus aureus (MRSA) is that the bacteria have resistance not only to methicillin, but also to the entire β-lactam class of antimicrobials. The β-lactams, which include penicillins, cephalosporins and carbapenems, inhibit Gram-positive bacterial cell wall synthesis and are the most commonly prescribed class of antibiotics. Since the initial reports of methicillin-resistant isolates in the UK in 1960, shortly after the introduction of the drug to market, MRSA has grown in terms of both distribution and number of epidemic strains. While Staphylococcus aureus itself can be a virulent pathogen,strains that are methicillin-resistant are not more virulent than those that are methicillin-sensitive.

Infection by MRSA is categorised as being either hospital-acquired (HA) or community-acquired (CA). CA-MRSA differs from the conventional endemic nosocomial HA-MRSA in several ways. Not only are the genotypes different from those found in hospitals, but CA-MRSA strains also have different methicillin-resistance cassettes [1] and have been found to be more virulent owing to an increased probability that they encode the Panton-Valentine leukocidin (PVL) virulence factor. [2]Documented cases of CA-MRSA being isolated in tissue infections, septic arthritis, bacteraemia, toxic shock syndrome, necrotising fasciitis and necrotising pneumonia are indicative of the bacterium's virulence and propensity to spread through communities. Not surprisingly, the admission of asymptomatic CA-MRSA carriers has led to outbreaks within hospitals. [3]There is currently much interest and concern about MRSA specifically and multidrug resistance in general; not only are treatment options limited, but there is also the risk of MRSA emerging as a threat to public health.

Genetic Determinants of Antibiotic Resistance

Methicillin resistance is conferred when mecA, carried by the mobile genetic element staphylococcal cassette chromosome mec (SCCmec), is introduced into methicillin-susceptible S. aureus (MSSA).

The alternative penicillin-binding protein PBP2A encoded by mecA has a reduced affinity for b-lactam antibiotics and can produce peptidoglycan and maintain stable bacterial cell walls, bypassing the inhibition of the native PBP2 that is otherwise blocked in the presence of b-lactam antimicrobials. Also within SCCmec are specific genes designating cassette chromosome recombinases (ccrA/ccrB, ccrC) that allow for excision, integration and mobilisation into host chromosomes. To date, six types of SCCmec (I-VI) and several variants have been described according to the mec and ccr genes present. [4] HA-MRSA strains are generally associated with SCCmec types I, II or III, whereas the majority of CA-MRSA strains carry SCCmec type IV. Various molecular typing techniques suggest that MRSA arose through separate and distinct introductions of SCCmec into MSSA lineages; [5] however, the mode of transfer of SCCmec remains unclear.[6]

Genetic Determinants of Antibiotic Resistance

(Fig-1)This schematic of clinical investigation illustrates Genetic Determinants of Antibiotic Resistance MRSA. Methicillin resistance requires the presence of the chromosomally localized mecA gene. The mec A gene is the gene responsible for methicillin resistance and is part of a mobile genetic element found in many MRSA strains called SCCmec. To date, There are at least five different SCCmec elements. These elements integrate at the same time site in the chromosome by a mechanism involving site-specific recombination and excision from the chromosome at attBscc, that is a part of an open reading frame of unknown function near the origin of replication. The genetic mechanism responsible for the transfer of these mobile elements are uncertain. However, what we do know is that mecA gene in MRSA is responsible for the synthesis of penicillin binding protein2A. The MecA gene expression alters PBP2A in S aureus resulting in a loss of target affinity. The mecA gene encodes a new b-lactam-insensitive to penicillin.

The Effect of Antibiotic Treatment

The pressures of Darwinian natural selection are clear when considering antibiotic use, as this exposes bacterial populations to evolutionary stresses. If excessive or unnecessary antibiotics are prescribed, the bacteria's environmental conditions are effectively altered such that those with resistance mechanisms have a competitive advantage and will therefore proliferate rapidly, owing to the increased availability of nutrients and space.

Certain classes of antibiotics, namely cephalosporins and quinolones, have been reported to encourage nosocomial infection with MRSA in hospital settings. [7-9]In a recent meta-analysis, previous antibiotic exposure was found to equate to a 1.8-fold increase in risk of patients acquiring MRSA. The risk ratio for separate antibiotic classes varied as well: 3.0 for quinolones, 2.9 for glycopeptides, 2.2 for cephalosporins and 1.9 for other β-lactams. [10] Antibiotic therapy therefore greatly increases the chances of acquiring MRSA. Conversely, reductions in the number of MRSA infections have been reported following restrictions in patient consumption of cephalosporin and quinolones. [11,12] It is also the case that a sub-optimal therapeutic dosage or duration will only weaken rather than destroy the target, allowing stronger bacteria to survive and resume propagation.

Antibiotics are able to induce differential effects on bacterial metabolism depending on the agent and the pathogen. When grown in the presence of the β-lactam nafcillin, S. aureus can express the β-toxin at an increased lethality in rats. [13]This suggests that β-lactams may increase virulence and exacerbate symptoms of serious MRSA infections. This suggestion is confirmed by an experiment in which subinhibitory concentrations of several other β-lactams - including cephalosporins and imipenem - lead to expression of the staphylococcal β-toxin gene hla being significantly induced. [14]β-lactams are also able to induce the SOS response in S. aureus, a reaction that occurs when damage to bacterial DNA caused by hostile environmental conditions is detected, resulting in the upregulation of genes involved in DNA repair and cell survival. This ultimately leads to enhanced replication and horizontal transfer of pathogenicity islandencoded virulence factors. [15]

The Effect of Antibiotic Resistance on Treatment Options

The association between antibiotic resistance and virulence has been highly debated. MRSA is generally linked to a poorer clinical outcome, although the difficulty in managing MRSA infections may be a more important factor in higher morbidity and mortality rates than virulence. However, virulence may appear enhanced if a resistant strain is exposed to an ineffective antibiotic. This perceived increase in virulence and, by association, mortality could therefore stem from initial antibiotic exposure, rather than from an inherently stronger pathogenicity in MRSA than MSSA. [16]

Since the emergence of MRSA, glycopeptides - namely vancomycin - have typically been the drugs of choice against MRSA infection. Glycopeptides inhibit bacterial cell wall biosynthesis following intravenous administration. However, in recent years there have been several reports of clinical strains of MRSA with reduced susceptibility to vancomycin, referred to as vancomycin-intermediate S. aureus (VISA). Although currently uncommon, there is concern that MRSA strains that are heteroresistant to vancomycin (hVRSA) are becoming more prevalent, [17] and may actually be under-reported owing to difficulties in detecting these strains. [18] This problem is not limited to vancomycin: isolates resistant to the glycopeptide teicoplanin have also been found and have been proposed to be more common than VISA. [19] This broader resistance profile has been termed glycopeptide intermediate-resistant S. aureus (GISA), although VISA is a more widely recognised term.

The emergence of VISA is only one example of the increasing difficulty in prescribing treatments for MRSA infections. With growing documentation and complications about antibiotic resistance, physicians are increasingly facing limitations with regard to available treatment options. Published guidelines on controlling and preventing MRSA in healthcare facilities advise clinicians to consider antibiotic choices carefully, to avoid excessive antibiotic therapy and prophylaxis in general healthcare settings and to limit the useof glycopeptide antibiotics and broad-spectrum antibiotics such as cephalosporins and fluoroquinolones to minimise the emergence and further spread of glycopeptide resistance in MRSA. [20]

In the case of bacteraemia where the causative strain has not been identified and no antibiogram exists, the choice of antibiotic is often left up to the healthcare provider. This indicates the problems surrounding the management of MRSA. A retrospective study of 549 patients with MRSA sterile-site infections over a three-year period showed that within 48 hours of admission to a hospital, fewer than 25% of patients received the appropriate antimicrobial therapy, with this percentage increasing to ~40% after 48 hours.

[21] For patients with inappropriate initial treatment, morbidity was significantly greater than for those receiving the correct treatment (26.1 versus 16.6%; p=0.015).

Diagnostic Testing

A large part of the success in treating MRSA lies in the efficiency and reliability of diagnostic tests. Obtaining a specimen and confirming a diagnosis of MRSA can typically take anywhere from 24 to 48 hours. During this time vancomycin is often the prescription of choice, meaning that the drug tends to be unnecessarily overly prescribed. Improved identification of MRSA variants and the presence of resistance can therefore enhance treatment strategies. Polymerase chain reaction (PCR) tests are able to identify MRSA rapidly within four hours, but are expensive and not yet determined to be cost-effective. Microbiological cultures have good reliability, but face time limitations, as they can take up to five days to generate a result. Although there are many commercially available tests that can detect MRSA, the problem is not so much the actual detection, but the more lengthy process required to test for antibiotic susceptibility. There are similar difficulties in detecting VISA and hVRSA strains by disc diffusion and the standard minimum inhibitory concentration (MIC) methods. What is needed is a reliable, sensitive and simple method of testing that can determine responsiveness to antibiotics. Although the population analysis profile area under the curve (PAP-AUC) is currently the most reliable method to definitively identify glycopeptide-resistant strains, the technique is too slow and labour-intensive. [22]

Diagnostic Testing

(Fig-2)Photograph: A zone of Inhibition is evident around the oxacillin disk for S. aureus, left, but not for MRSA right.

Expansion of Treatment Options

Many new agents have recently been introduced to the armamentarium against Gram-positive bacteria, some of which hold great promise in their activity against MRSA strains unresponsive to treatment with glycopeptides. These include linezolid, daptomycin and tigecycline, the latter two of which must be administered intravenously. Studies have shown that these agents are at least as efficacious as vancomycin, if not more so. Patients with MRSA complicated skin and skin structure infections (cSSSIs) demonstrated superior outcomes with linezolid than with vancomycin (88.6 versus 66.9%),[23] with better clinical cure (62.2versus 21.2%) and survival rates (84.1 versus 61.7%; p≤0.02) [24] and a shorter median length of stay by three days (p=0.003). [25]

Daptomycin has shown rapid concentration-dependent bactericidal activity, with demonstrated non-inferiority to other standard therapies such as nafcillin, oxacillin, flucloxacillin and vancomycin in treating bacteraemia and infective endocarditis caused by S. aureus. [26]Patients with MRSA cSSSIs treated with daptomycin also had an increased clinical success rate compared with those on semi-synthetic penicillins or vancomycin (75 versus 69%), with significantly shorter length of intravenous therapy. [27]

Tigecycline is an anti-MRSA glycylcycline with anti-MRSA activity that also has broad-spectrum activity, and has also shown non-inferiority to a vancomycin/aztreonam combination in treating MRSA cSSSIs, with similar cure rates and microbiologic eradication rates. [28]However, these drugs are associated with side effects: myelosuppression, [29] lactic acidosis, [30] peripheral and toxic optic neuropathy[31] with linezolid; gastrointestinal side effects with tigecycline; [32] and additional reversible myopathy with daptomycin. [33] Oritavancin and telavancin are new lipoglycopeptides in late stages of development with potentially much more rapid bactericidal activity than the classic glycopeptides, although there are concerns that there will still be a risk of crossresistance. Ceftobiprol is reported to have anti-MRSA activity, despite the fact that it is clearly a cephalosporin. This agent is currently under clinical investigation.

Future Directions

Given the effect of antibiotics, the unintended detrimental effects to the patient and environment and the ultimate development of resistance and resulting complications in treatment options, the importance of treating MRSA infections with the right drug at the right dosage and for the right duration must continue to be stressed. In order to achieve appropriate treatment, however, proper diagnostic testing must first be carried out to ascertain that the infection in question is indeed treatable with a specific drug, and not resistant. With physicians endeavouring to improve antibiotic usage and control infection, it is hoped that the accumulation of further drug resistance in MRSA can be slowed. New treatments have been introduced in response to resistance, but what will it mean for community and healthcare facilities alike if drug resistance continues to progress?