Uncomplicated Skin And Soft Tissue Biology Essay


Skin and soft 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)

CSSTI involves infection in deep tissues and requires different treatment methods such as hospitalization, intravenous (IV) therapy and/or surgery . They are associated with underlying diseases such as diabetes or human immunodeficiency viruses.

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An example of 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 .

Complicated skin and skin structure infection (CSSTIs), now known as Acute bacterial skin and skin structure infections (ABSSSIs) 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 Phase III Clinical Trial for treating Acute Bacterial Skin and skin structure Infections (ABSSSIs). 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 discussion and conclusion.

2. Causative Organism

ABSSIs are caused by aerobic gram-positive Cocci i.e. Staphylococcus Aureus, Beta-Haemolytic Streptococci, Enterococci, and certain Coagulase-negative Staphylococci .

Methicillin-resistant Staphylococcus aureus (MRSA) is the most prominent pathogen responsible for causing ABSSSIs. Due to the emergence of Methicillin-resistant Staphylococcus aureus, treatment of ABSSSIs has become very difficult. 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 ABSSSIs is utterly important because incorrect selection of antibiotics will risk patient’s life, delay clinical outcome and also increase length of hospital stay.

Vancomycin is one of the most common treatments for infections due to methicillin-resistant Gram-positive bacteria. However, resistant strains of pathogens such as vancomycinâ€"intermediate and vancomycin resistant S. Aureus strains, has affected the use of vancomycin So, new anti-MRSA agents have been developed for the treatment of infection caused by resistant gram positive bacteria. These agents are listed in Table 1.

Table 1: Antimicrobials for the treatment of gram positive resistant bacterial infection with its own characteristics, mechanism of action and spectrum of activity .



Mechanism of Action

Mode of Action





Cell wall synthesis inhibitor


IV only

Gram positive infections caused by MRSA


Cyclic Lipopeptide

Cell membrane disruption


IV only

Infections caused by MRSA when other agents are unsuitable.



Inhibits bacterial Protein synthesis


Oral, IV

For the treatment of serious gram-positive infections when other agents are unsuitable.

Alternative to vancomycin for MRSA



Protein synthesis inhibitor


IV only

For severe MRSA or vancomycin resistant enterococcus faecium infections when other antibacterial are inappropriate



Inhibits cell wall synthesis and disrupts membrane integrity.


IV only




Cell wall synthesis inhibitor


IV only




Inhibits protein synthesis


IV only

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For the treatment of infections due to susceptible organisms where other treatment is unsuitable

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, first generation oxazolidinone used for the treatment of infection caused by the multiresistant gram-positive bacteria offers advantages over other antimicrobials available for treatment of CSSITs such as availability in both oral and parenteral (IV) 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 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 .

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 parenteral (IV) 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. 200 mg of daily dose showed similar effectiveness as compared to higher doses. [8]

4.3 Mechanism of Action

The mechanism of action of oxazolidinone is different from other protein synthesis inhibitor. Chloramphenicol inhibits protein synthesis by inhibiting peptidyl transferase, an enzyme needed for protein elongation. However, oxazolidinone interfere with the protein termination process and thus restrains the protein synthesis initiation

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 .

Figure (2): Protein synthesis involves three different stages namely, initiation, elongation and termination

5. Pharmacokinetics

Tedizolid has an excellent oral bioavailability. The pharmacokinetic parameter was studied in healthy volunteers. The absolute oral bioavailability was found to be 91.7% and mean half-life was 9.23 hours. Because of its long half-life it can be given as once daily dosing. The primary route of elimination is faeces. 81.5% of Tedizolid is excreted as the sulphate analog via faecal and only a small fraction (18%) is excreted through the urine .

Food does not influence the oral absorption of Tedizolid. 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 .

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 .

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2. Tedizolid is potent and 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 a 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 CSSTIs, 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.

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.

Antibacterial coverage: It has narrow spectrum of activity with focussed treatment of infections caused mainly by gram-positive bacteria.

It took over 30 years to develop new antibiotics such as Linezolid but it took only ten years for the bacteria causing ABSSSIs to evolve resistance against the drug. Because both of these drugs have similar mechanism of action, there is a high probability that the resistance might also develop sooner or later for Tedizolid.

8. Discussion and Conclusion:

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).

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. (http://www.triusrx.com/pdfs/TR701-101-ECCMID-MAD-Poster-1089.pdf)

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.