Treatment Of Soft Skin Tissue Infections Biology Essay

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Soft Skin Tissue Infection also known as SSTI is the infection of the epidermis, dermis or subcutaneous tissue . It is one of the most common types of bacterial infection occurring in human and can vary widely in severity.

SSTIs can be differentiated into two different types of cases: complicated and uncomplicated.

1.1 Uncomplicated Skin and Soft Tissue

Uncomplicated SSTIs can be treated on an outpatient basis using oral antibiotics and topical care. Examples of uncomplicated skin and soft tissue infection are:

Cellulitis: Superficial spreading skin infection. Cellulitis if progress can extend to abscess. Abscess is a collection of pus in tissue or organ and is caused by bacteria .

Impetigo: Superficial skin infection, most commonly seen in children.

1.2 Complicated Skin and Soft Tissue Infection (cSSTIs)

It involves infection in deep tissues and thus requires different treatment methods such as hospitalization, intravenous IV therapy and/or surgery. They are associated with a significant number of underlying diseases such as diabetes or human immunodeficiency viruses .

One example for cSSTIs developed in diabetic patient because of skin and soft tissue infection is Acute Dermal Gangrene Syndrome which is a deep tissue infection and dermal necrosis. It involves two conditions namely necrotizing fasciitis and progressive bacterial gangrene .

Complicated skin and skin structure infection (cSSTIs) now known as Acute bacterial skin and skin structure infections (ABSSIs) has been identified to be one of the common causes of morbidity in the community and the hospital sector and therefore commands a large part of the cost involved with health care sector

This report aims at providing a brief insight to a novel drug, Tedizolid that is under a Clinical Trial Phase III for treating Acute Bacterial Skin and Skin Structure Infections (ABSSIs). It gives a short description about the drug starting with a brief introduction following on to its structure, mode of action, its advantages, disadvantages and finally the conclusion.  Furthermore, the report also provides a recommendation on the area that needs to be further researched before the drug is rolled out into the market for the access of general public.

2. Causative Organism

Various research have shown that the majority of ABSSIs are caused by aerobic gram-positive Cocci i.e. Staphylococcus Aureus, Beta-Hemolytic Streptococci, Enterococci, and certain Coagulase-negative Staphylococci .

Methicillin-resistant S. Aureus (MRSA) is the most prominent pathogen responsible for causing ABSSIs. A recent rise in antibiotic resistance amongst the Methicillin-resistant Staphylococcus Aureus (MRSA) has complicated management of cSSTIs. The situation is further worsened by the fact that these pathogens are increasingly being found in communities whereas in the past they were confined to the hospital environment , thereby making the treatment more complicated to handle .

3. Antimicrobial Therapy

The choice of antimicrobial therapy for treating ABSSIs is utterly important because incorrect selection of antibiotics will risk patient's life, delay clinical outcome and also increase length of hospital stay [1].

Vancomycin is one of the most common treatments for infections due to methicillin-resistant Gram-positive infections. However, resistant strains of pathogens such as vancomycin-intermediate and vancomycin resistant S. Aureus strains, has affected the use of vancomycin .

Thus the increased resistance and toxicity of Vancomycin has led to the development of a new anti-MRSA agents such as Oxazolidinone (Linezolid), Beta Lactams (Ceftaroline), Glycopeptides (Televancin, Dalbavancin), Glycylcyline (Tigecycline) and Daptomycin .

Table 1 lists the antimicrobial for treatment of gram positive resistant bacterial. Each drug has its own characteristics, mechanism of action and spectrum of activity .

Antibiotic

Class

Mechanism of Action

Mode of Action

Route

In-Vitro Spectrum of Activity Against Bacteria

Vancomycin

Glycopeptide

Cell wall synthesis inhibitor

Bactericidal

IV only

MRSA

Daptomycin

Cyclic Lipopeptide

Cell membrane disruption

Bactericidal

IV only

MRSA/VRE

Linezolid

Oxazolidinone

Inhibits Protein synthesis

Bacteriostatic

Oral, IV

MRSA/VRE

Quinupristin-dalfopristin

Streptogramin

Protein synthesis inhibitor

Bactericidal

IV only

MRSA/VRE

Televancin

Lipoglycopeptide

 Inhibits cell wall synthesis and disrupts membrane integrity.

Bactericidal

IV only

MRSA/VRE

Ceftaroline

Cephalosporin

Cell wall synthesis inhibitor

Bactericidal

IV only

MRSA

Tigecycline

Glycycline

Inhibits protein synthesis

Bacteriostatic

IV only

MRSA/VRE, CRB

Out of all the options available for the treatment of infections caused by resistant gram-positive, their use is limited because of emergence of new resistant bacteria, toxicity and cost as well as the need for parenteral administration .

Linezolid, which is the first generation oxazolidinone used for treatment of infection caused by the multiresistant gram-positive bacteria offers many advantages over other antimicrobials available for treatment of cSSITs such as availability in both oral and intravenous formulations, excellent tissue penetration [3]. However, linezolid resistant strains have been identified in clinical isolates of staphylococci in which the resistance has occurred possibly due to long duration of therapy or clonal spread within the hospital setting of linezolid-resistant isolates with the cfr gene .

There is a new resistance mechanism that has been identified and is called as cfr (chloramphenicol-florfenicol) resistance mechanism. This mechanism of resistance is worrisome particularly because it is associated with transposons and plasmids, which results in high probability of spread. So a new antibiotic is urgently needed to treat infections due to these resistant bacteria .

4. Overview of the Drug

For improved antibacterial potency especially against linezolid resistant strains Trius Therapeutics, Inc., San Diego, CA has developed a second-generation oxazolidinone called Tedizolid (TR-700) . Tedizolid was previously known as TR-700 and Torezolid. It has successfully completed a phase 3 trial in patients with ABSSIs. (www.triusix.com)

4.1 Chemistry

Torezolid is a methyltetrazolyl oxazolidinone and its chemical formula is 3-{3-Fluoro-4-[6-(2-Methyl-2H-Tetrazol-5-yl)-Pyridin-3-yl]-Phenyl}-5-Hydroxymethyl-Oxazolidin-2-one .

The molecular weight of TR-701 is 494.28 and of TR-700 are 370.17 respectively

Tedizolid phosphate is a prodrug, which is converted to the active Tedizolid by phosphatases after oral or intravenous (iv) administration [10].

The chemical structure of Tedizolid is shown in figure 1.

Figure 1: Chemical structure of Tedizolid (TR-701 and TR-700)

4.2 Dosage Forms

Tedizolid is available in an intravenous and oral dosage form. Three oral dosage regimens (200, 300 and 400 mg/day) was studied in the Phase II clinical trial for the treatment of cSSTIs and on the basis of the results obtained, the Phase III trial was continued with 200 mg dose. A daily dose of 200 mg was shown to be as effective as a higher dose. [9]

4.3 Mechanism of Action

Tedizolid are bacterial protein synthesis inhibitor. The ribosomes of bacteria are made up of two subunits: 30S and 50S. Tedizolid binds to the 50S ribosomal subunit and has no affinity for binding to the 30S subunit. Binding to 50S subunit causes inhibition of 70S formation, which suppresses the protein synthesis initiation. If the 70S is already formed then Tedizolid inhibits translocation of the peptide chain to P site from A site, during peptide bond formation .

Protein synthesis involves three different stages namely, initiation, elongation and termination as shown in Figure 1. The mechanism of action of oxazolidinone is different from other protein synthesis inhibitor such as chloramphenicol, which inhibits protein synthesis by inhibiting peptidyl transferase, an enzyme needed for protein elongation. Oxazolidinone interfere with the protein termination process and thus restrains the protein synthesis initiation .

Figure (2): Protein Synthesis Initiation Process

5. Pharmacokinetics

Tedizolid has an excellent oral bioavailability. In a study conducted by health volunteers, the absolute oral bioavailability was found to be 91.7% . Food does not influence the oral absorption of Tedizolid. A study was conducted with a single oral dose of 600mg TR-701. The rate of absorption (tmax and cmax) was affected after high fat meal, possibly because of delay in gastric emptying rate, yet it didn't affect the extent of absorption, which provides the evidence that Tedizolid can be taken with or without food .

The volume of distribution in plasma was 108.25l for XXXX and protein binding is 89.4%. 81.5% of Tedizolid is excreted as the sulfate analog via fecal and only a small fraction (18%) is excreted through the urine .

6. Advantages

Currently, Linezolid is the most prominent and potent drug with minimal resistance reported till date hence for this reason, the advantages of Tedizolid is primarily compared to linezolid. Basically, there are 3 distinct advantages of Tedizolid over Linezolid.

1. One of the advantages of Tedizolid is its bactericidal action, which helps in faster eradication of the pathogens as compared to Linezolid, which is bacteriostatic.

2. Tedizolid is potent with broad antibacterial coverage. It has shown to have excellent activity in vitro against the majority of Gram-positive strains, with 4 to 8 times more activity than linezolid. It has displayed a high activity particularly against methicillin susceptible and resistant staphylococci, the enterococci and all streptococci. It also exhibits high in-vitro potency against staphylococci as well as vancomycin-nonsusceptible strains, which are resistant to linezolid. It is 32 times more active against the seven cfr-positive MRSA strains tested as compared to Linezolid. As Tedizolid phosphate is more potent than Linezolid, it results in shorter course of treatment.

3. For the treatment of cSSSI, results have shown that once daily dosing of Tedizolid for 5-7 days is as effective as compared to Linezolid, which requires 10 to 14 days therapy twice a day. Shorter course of therapy of Tedizolid offers advantages over linezolid such as patient compliance, reducing risk of developing new resistant bacteria as well as improvement in safety profile due to low dose accumulation.

7. Disadvantages

Despite of several advantages over available drugs, Tedizolid have following drawbacks as well.

1. Cost: Tedizolid is a new generation drug so it would be expensive than antibiotics currently available in market to treat ABSSSIs such as vancomycin, Daptomycin and Linezolid.

2. Development to Resistance: It took over 30 years to develop new antibiotics such as Linezolid but it took only ten years for the bacteria causing ABSSSI to evolve resistance against the drug. Because both these drugs have similar mechanism of action, there is a high probability that the resistance will also develop soon enough for Tedizolid.

8. Discussion

Although, majority of the research that has been carried out till date compares the effectiveness of Tedizolid and Linezolid over one another, there is a lack of adequate research and results to compare the safety of the Tedizolid. A set of results published by a Phase II Clinical Trial for safety of Tedizolid, reports the most common treatment related adverse effects such as nausea (18.6%), secondary abscess (11.7%), headache (11.2%), and vomiting (10.1%). However, the study has been carried out on comparatively limited number of patients (n=192) which some researcher might consider, not being adequate.

Also, the data regarding the safety issues of the long-term use of Tedizolid are scarce. However, of the very few existing ones, the manufacturer of the drug Tedizolid exhibits the data for safety of 21 day multiple ascending oral doses of TR-701 in the company website, which mentions a higher incidence of mild to moderate adverse effects with multiple dose of 400 mg TR-701. Therefore, it is prudent to recommend the study of long-term safety of the drug amongst the user so as to make it more beneficial for the patient.

9. Conclusion

Like everything else, Tedizolid has its own pros and cons. However, for the various reasons mentioned earlier, it might as well, prove to be an effective yet safer medical option for treating ABSSSIs.

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