¹School of Medicine
²Department of Dermatology, The University of Texas Medical Branch, Galveston, TX, USA

Conflict of interest disclosure: None reported.

ABSTRACT
Rituximab is an anti-CD20 monoclonal antibody with considerable potential in dermatology due to an increase in off-label indications. Chronic graft-versus-host disease and pemphigus vulgaris are two of the most promising indications for off-label use of rituximab. It is a generally safe alternative that should be considered when traditional therapy with corticosteroids or immunosuppressants has failed or caused significant intolerance. Currently, rituximab is only FDA-approved for treatment of follicular and diffuse large B-cell non-Hodgkin’s lymphoma, rheumatoid arthritis, chronic lymphocytic leukemia, granulomatosis
with polyangiitis (formerly Wegener’s granulomatosis) and microscopic polyangiitis. Herein, off-label uses of rituximab and its efficacy in the treatment of cutaneous diseases are reviewed.

Key Words:
anti-CD20 antibody, dermatology, rituximab

Introduction

Rituximab is an anti-CD20 monoclonal antibody with considerable potential in the medical field. Rituximab is currently FDA-approved for treatment of follicular and diffuse large B-cell non-Hodgkin’s lymphoma (NHL), rheumatoid arthritis (RA), chronic lymphocytic leukemia (CLL), and, most recently, granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) and microscopic polyangiitis (MPA).¹ However, off-label indications have increased in recent years due to the discovery that rituximab may be useful not only in diseases in which autoantibodies are involved, but also in diseases where B cells play a major role, such as autoimmune and many dermatologic diseases.^1-3

In order to use rituximab more frequently and appropriately, dermatologists should be aware of the characteristics of anti-CD20 antibodies and the role of B cells in multiple skin diseases. Herein, we provide physicians with an overview of trends in rituximab’s clinical outcomes so that they can evaluate current therapy and make adjustments to achieve optimal goals.⁴

Mechanism of Action

Rituximab consists of a mouse Fab region and human Fc portion. Anti-CD20 antibodies bind CD20 antigen present on normal and malignant mature B lymphocytes and eliminate these CD20+ cells via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and induction of apoptosis.¹ The targeted CD20 antigen is not found on hematopoietic stem cells or plasma cells.^2,5 Although the antibodyproducing plasma cells are not directly eliminated, memory B cells, which are the precursors of CD20-negative plasma cells, are targeted, thereby indirectly inhibiting autoantibody production for a prolonged timespan.^1,2,6 Additionally, since rituximab does not distinguish pathologic from normal B cells, B cell levels are completely depleted for several months after treatment.⁴

The therapeutic efficacy of rituximab is derived from its effect on B cells; therefore, the discovery that B cells role in autoimmune disease is more significant than previously thought has led to its increased use for off-label indications.¹ Current understanding about the actions of B cells has been expanded to include the following mechanisms:¹

1. Autoantibodies detect antigen and cause a specific disease. The autoantibody Fc region can also bind to inflammatory cells and increase local inflammation leading to increased tissue damage.¹
2. Autoantibodies form circulating immune complexes, which accumulate and cause tissue damage.¹
3. B cells can act as antigen presenting cells (APC) for T cells, leading to a proinflammatory effect due to the production of cytokines.¹ For example, atopic dermatitis (AD) involves delayed-type/cell-mediated hypersensitivity, and rituximab success is thought to be due to blockage of T cell activation.^6,7

Clinical Uses

Primary Cutaneous B-cell Lymphoma (PCBCL)

PCBCL encompasses B cell lymphomas that originate in the skin, including primary cutaneous follicle center lymphoma, primary cutaneous marginal zone lymphoma, and primary cutaneous diffuse large B-cell lymphoma (leg-type and other). It is one of the first cutaneous disorders successfully treated with rituximab. Multiple case reports have demonstrated success with systemic and intralesional rituximab.^5,6,8-11 A study by Gellrich et al. established that rituximab should be considered in patients with aggressive recurrent PCBCL, especially for the elderly and patients with multiple skin lesions.¹⁰

Autoimmune Bullous Disorders

First-line treatment typically includes systemic corticosteroids as monotherapy or combination with alternative immunosuppressants and/or intravenous immunoglobulin (IVIG). When these therapies are ineffective or require high dosages associated with serious adverse events, rituximab may be indicated.^1,4,6,12,13

Pemphigus Vulgaris (PV), Paraneoplastic Pemphigus (PP)
and Pemphigus Foliaceus (PF)

Rituximab use for pemphigus began after it was discovered that its use in NHL led to improvement of associated PP.² Remission of PP occurs due to the effect on the underlying neoplasm.⁵ Over 450 cases have documented the benefit of rituximab in PV, even in severe disease.^2-6 A major benefit is that the clinical response is rapid, and the majority of patients demonstrate resolution of lesions. Remission ranges from a few months to 2 years. Of note, it has been suggested that response to skin lesions is more rapid than mucosal lesions, and that most patients have remained on a decreased dose of concomitant systemic therapy.⁴ Several cases of treatment-resistant PF have also responded to rituximab.^14-16

Bullous Pemphigoid (BP)

Conventional treatment is sufficient in the majority of cases; however, alternatives such as rituximab are occasionally necessary due to lack of response or side effects with standard therapy.¹ At least 16 patients with BP have been treated with rituximab, and the majority achieved clinical remission.⁴ Most cases required more than one cycle of rituximab to achieve remission.⁴ Additionally, prior to initiation of rituximab in BP patients, immune status and cardiac risk should be evaluated.^2,4 Since many patients with BP are elderly and rituximab suppresses immune function, an increased risk of infections may be observed. Three patients have died due to bacterial sepsis and cardiac complications.⁴

Mucous Membrane Pemphigoid (MMP)

Rituximab has been beneficial for patients with severe MMP unresponsive to standard therapy. Reports of 40 patients with MMP have been treated with rituximab and 60% achieved clinical remission; however, some were non-responsive, and in one patient scarring continued despite treatment.⁴ Thus, rituximab therapy likely has better results when initiated before the onset of significant scarring.

Ocular Cicatricial Pemphigoid (OCP)

OCP is a subset of MMP in which 25% of patients progress to blindness even with aggressive therapy. Conventional therapy includes systemic immunosuppressants and dapsone.⁴ A recent report compared treatment with IVIG and rituximab versus high-dose immunosuppressants in patients who were blind in one eye and experienced progression of disease in the remaining eye despite systemic immunosuppressive therapy. Patients treated with IVIG and rituximab had no further progression of disease and maintained vision; however, those treated with immunosuppressants only resulted in complete blindness. Rituximab cannot reverse blindness, but it may have the ability to preserve vision and prevent progression of disease for a sustained period of time. In these patients, remission has lasted 9 years.⁴

Epidermolysis Bullosa Acquisita (EBA)

From a literature review, at least 16 patients with EBA have responded to rituximab.^1,2,4,6,14 All cases have responded within 6 months of initiating therapy; however, many relapses occurred and required additional cycles of rituximab.⁴ Unfortunately, one death was reported due to pneumocystis pneumonia.⁴

Chronic Graft-Versus-Host-Disease (GVHD)

GVHD is one of the most promising indications for rituximab within dermatology, along with pemphigus vulgaris.^1,6,14,15 B cells have been implicated in the pathogenesis of GVHD in which antibodies against platelet-derived growth factor can trigger an inflammatory cascade in the endothelium that eventually leads to cutaneous fibrosis.^1,6 It is important to note that cutaneous and musculoskeletal manifestations improved much more than the hepatic manifestations of the disease.⁶

Autoimmune Connective Tissue Diseases

Dermatomyositis (DM)

Traditional therapy includes systemic immunosuppressives as well as photoprotection.⁶ Since B cells play a vital role in the pathogenesis of DM, rituximab is another viable treatment option.^5,6,14 Rituximab with adjuvant immunosuppressive therapy has shown clinical benefit and improvement in several cases.^1,5,6,14,15 One case report illustrates rituximab’s use in immunosuppressive-naïve DM that achieved complete resolution of muscle and skin disease, and did not require maintenance immunosuppressive therapy or additional cycles of rituximab.¹⁷

Vasculitis

Vasculitis is an immune complex-mediated hypersensitivity reaction; therefore, it is plausible that rituximab would be effective since it leads to decreased antibody production. Rituximab is currently approved for treatment of refractory GPA and MPA. Other potential indications include giant cell arteritis⁵, cryoglobulinemia-associated vasculitis¹, and Churgstrauss syndrome. Rituximab use in these off-label situations should be considered in cases of severe disease, ulcerative lesions, neuropathy, and nephropathy.¹

Other

Vasculitis is an immune complex-mediated hypersensitivity reaction; therefore, it is plausible that rituximab would be effective since it leads to decreased antibody production. Rituximab is currently approved for treatment of refractory GPA and MPA. Other potential indications include giant cell arteritis⁵, cryoglobulinemia-associated vasculitis¹, and Churgstrauss syndrome. Rituximab use in these off-label situations should be considered in cases of severe disease, ulcerative lesions, neuropathy, and nephropathy.¹

Dosing

Rituximab is a beneficial agent used in the treatment of autoimmune blistering and other dermatological diseases; however, many patients suffer from relapses and require additional therapy. An emerging concept is that optimal goals are not being reached because appropriate protocols specifically tailored for dermatological diseases have not been designed. Systemic corticosteroids and alternative immunosuppressants are often continued after rituximab therapy, while their dosages can be significantly reduced. Two protocols for rituximab therapy exist: lymphoma protocol (LP) and rheumatoid arthritis protocol (RAP). LP is a single cycle-infusion of 375 mg/m² weekly for 4-8 consecutive weeks.⁴ RAP consists of one cycle of two 1000 mg infusions administered on day 1 and day ^15.4,20

LP, originally developed for PCBCL, is the protocol most commonly used in autoimmune blistering disorders. Dermatomyositis, AD, and SLE have often been treated using RAP, which was initially designed for RA treatment. Dosing protocols in off-label indications have not been extensively studied, and contradictory results have been published. Some series suggest just two cycles of rituximab is sufficient, while others report ongoing maintenance therapy is required to sustain remission.¹ Future studies and randomized controlled trials with longer follow-up periods should be completed to establish definitive treatment protocols for each disease in order to shorten disease course, reduce morbidity, and allow for sustained clinical remission.

Side Effects

The side effects of rituximab therapy are generally mild and tolerable in comparison to corticosteroid/immunosuppressant therapy.¹² The most common adverse events, reported in more than half of patients, are infusion-related reactions including headache, angioedema, nausea, vomiting, fever, and chills.⁴ They usually appear in the first or second hour of infusion. Slowing the infusion rate generally resolves symptoms, and it can be gradually increased again once symptoms resolve. Anaphylactic hypersensitivity reactions may also occur during the first few minutes of infusion due to sensitivity to murine proteins.⁴ The presentation can resemble infusion-related reactions but the onset is more immediate. Premedication with methylprednisolone, acetaminophen, and diphenhydramine can prevent hypersensitivity reactions.

Other rare but serious side effects have been reported. Serious infections and septicemias have occurred when rituximab is used with adjuvant immunosuppressive therapy.^4,12 Respiratory infections, pharyngitis, and urinary tract infections are most commonly reported. Numerous reports of hepatitis B virus reactivation resulted in a black box warning; some severe cases resulted in fulminant hepatitis, hepatic failure, and death.²¹ Over 100 cases of progressive multifocal leukoencephalopathy (PML) have been associated with rituximab, prompting the inclusion of a black box warning.^21-24 PML is a rare demyelinating disease caused by reactivation of latent JC polyoma virus, which can present subacutely with cognitive impairment, motor weakness or poor coordination, speech problems, or vision changes. Recently, six cases of vulvovaginal pyoderma gangrenosum have been reported in the setting of rituximab used to treat B cell NHL.^25-27 Rituximab can reactivate severe cardiac conditions such as myocardial infarctions, congestive heart failure, pulmonary
edema, and atrial fibrillation, so it is contraindicated in patients with pre-existing cardiac conditions.¹ Other rare side effects include tumor lysis syndrome, renal failure, mucocutaneous reactions such as Stevens-Johnson Syndrome, cytopenias, bowel obstruction and perforation, and Kaposi sarcoma.²¹

The incidence of life-threatening adverse effects with rituximab is very low.⁴ Rituximab remains an option for patients refractory or intolerant to conventional therapies; however, long-term safety data is needed regarding side effects in off-label indications.

Conclusion

Rituximab has demonstrated therapeutic efficacy in a variety of autoimmune and immune-mediated cutaneous disorders in which traditional therapy has failed or caused significant intolerance. Rituximab is generally safe and tolerable with mild infusion-related and infectious complications. In the majority of patients, clinical symptoms resolve completely in a relatively
short amount of time. Another well-documented benefit of rituximab thus far is the reduced dose of corticosteroids and immunosuppressants required to maintain clinical remission; however, high rates of recurrence have also been documented. Recurrence may be due to the use of protocols designed by oncologists and rheumatologists. More directed studies are needed to develop innovative and relevant protocols specifically designed for use in dermatology. Guidelines designating appropriate and timely intervention that maximizes long-term remission while limiting recurrence will further enhance the value and use of rituximab in dermatology. Until long-term efficacy, tolerability, and dosing guidelines have been firmly established for rituximab in dermatology, care must be taken to individualize treatment regimens based on several factors, including immunologic status, disease severity, comorbidities, and response to standard therapy.

References

1. Espana A, Ornilla E, Panizo C. Rituximab in dermatology. Actas Dermosifiliogr. 2013 Jun;104(5):380-92.
2. Hertl M, Zillikens D, Borradori L, et al. Recommendations for the use of rituximab (anti-CD20 antibody) in the treatment of autoimmune bullous skin diseases. J Dtsch Dermatol Ges. 2008 May;6(5):366-73.
3. Schmidt E, Hunzelmann N, Zillikens D, et al. Rituximab in refractory autoimmune bullous diseases. Clin Exp Dermatol. 2006 Jul;31(4):503-8.
4. Ahmed AR, Shetty S. The emerging role of rituximab in autoimmune blistering diseases. Am J Clin Dermatol. 2015 Jun;16(3):167-77.
5. Scheinfeld N. A review of rituximab in cutaneous medicine. Dermatol Online J. 2006 Jan 27;12(1):3.
6. Emer JJ, Claire W. Rituximab: a review of dermatological applications. J Clin Aesthet Dermatol. 2009 May;2(5):29-37.
7. Simon D, Hosli S, Kostylina G, et al. Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol. 2008 Jan;121(1):122-8.
8. Valencak J, Weihsengruber F, Rappersberger K, et al. Rituximab monotherapy for primary cutaneous B-cell lymphoma: response and follow-up in 16 patients. Ann Oncol. 2009 Feb;20(2):326-30.
9. Kerl K, Prins C, Saurat JH, et al. Intralesional and intravenous treatment of cutaneous B-cell lymphomas with the monoclonal anti-CD20 antibody rituximab: report and follow-up of eight cases. Br J Dermatol. 2006 Dec;155(6):1197-200.
10. Gellrich S, Muche JM, Wilks A, et al. Systemic eight-cycle anti-CD20 monoclonal antibody (rituximab) therapy in primary cutaneous B-cell lymphomas–an applicational observation. Br J Dermatol. 2005 Jul;153(1):167-73.
11. Fink-Puches R, Wolf IH, Zalaudek I, et al. Treatment of primary cutaneous B-cell lymphoma with rituximab. J Am Acad Dermatol. 2005 May;52(5):847-53.
12. Nigam R, Levitt J. Where does rituximab fit in the treatment of autoimmune mucocutaneous blistering skin disease? J Drugs Dermatol. 2012 May;11(5):622-5.
13. Meurer M. Immunosuppressive therapy for autoimmune bullous diseases. Clin Dermatol. 2012 Jan-Feb;30(1):78-83.
14. Carr DR, Heffernan MP. Off-label uses of rituximab in dermatology. Dermatol Ther. 2007 Jul-Aug;20(4):277-87.
15. Fatourechi MM, el-Azhary RA, Gibson LE. Rituximab: applications in dermatology. Int J Dermatol. 2006 Oct;45(10):1143-55.
16. Goebeler M, Herzog S, Brocker EB, et al. Rapid response of treatment-resistant pemphigus foliaceus to the anti-CD20 antibody rituximab. Br J Dermatol. 2003 Oct;149(4):899-901.
17. Haroon M, Devlin J. Rituximab as a first-line agent for the treatment of dermatomyositis. Rheumatol Int. 2012 Jun;32(6):1783-4.
18. Mok CC. Current role of rituximab in systemic lupus erythematosus. Int J Rheum Dis. 2015 Feb;18(2):154-63.
19. McQueen FM, Solanki K. Rituximab in diffuse cutaneous systemic sclerosis: should we be using it today? Rheumatology (Oxford). 2015 May;54(5):757-67.
20. Buch MH, Smolen JS, Betteridge N, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2011 Jun; 70(6):909-20.
21. Rituxan® (rituximab) injection, for intravenous use [Full prescribing information]. San Francisco, CA: Genentech, Inc.; revised April 2016.
22. Paues J, Vrethem M. Fatal progressive multifocal leukoencephalopathy in a patient with non-Hodgkin lymphoma treated with rituximab. J Clin Virol. 2010 Aug;48(4):291-3.
23. Al-Tawfiq JA, Banda RW, Daabil RA, et al. Progressive multifocal leukoencephalopathy (PML) in a patient with lymphoma treated with rituximab: A case report and literature review. J Infect Public Health. 2015 Sep-Oct;8(5):493-7.
24. Sikkema T, Schuiling WJ, Hoogendoorn M. Progressive multifocal leukoencephalopathy during treatment with rituximab and CHOP chemotherapy in a patient with a diffuse large B-cell lymphoma. BMJ Case Rep. 2013 Jan 25;2013.
25. Selva-Nayagam P, Fischer G, Hamann I, et al. Rituximab causing deep ulcerative suppurative vaginitis/pyoderma gangrenosum. Curr Infect Dis Rep. 2015 May; 17(5):478.
26. Dixit S, Selva-Nayagam P, Hamann I, et al. Vulvovaginal pyoderma gangrenosum secondary to rituximab therapy. J Low Genit Tract Dis. 2015 Jan;19(1):e6-9.
27. Walsh M, Leonard N, Bell H. Superficial granulomatous pyoderma of the vulva in a patient receiving maintenance rituximab (MabThera) for lymphoma. J Low Genit Tract Dis. 2011 Apr;15(2):158-60.

¹School of Medicine, ² Department of Dermatology, The University of Texas Medical Branch, Galveston, TX, USA

ABSTRACT
Acute bacterial skin and skin-structure infections (ABSSSIs), often caused by aerobic gram-positive cocci, are most often mild-tomoderate infections that can easily be treated in an outpatient setting. With the rates of these infections substantially increasing in the past decade, owing in part to the emergence of community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), alternative options for the treatment of ABSSSIs are necessary. This editorial reviews the mechanism of action, efficacy, bacterial coverage, and potential side effect profiles for dalbavancin and oritavancin, both semisynthetic lipoglycopeptide antibiotics, and tedizolid, an oxazolidinone. Dalbavancin, oritavancin, and tedizolid have been extremely valuable additions to treatment options for ABSSSIs due to the convenient dosing regimen and the fact that there are fewer resistant organisms to these therapies at this time.

Key Words:
acute bacterial skin and skin-structure infections, antibiotics, glycopeptide, dalbavancin, oritavancin, tedizolid

Introduction

Acute bacterial skin and skin-structure infections (ABSSSIs), often caused by aerobic gram-positive cocci, are estimated to cause more than 15 million infections and 870,000 hospital admissions annually in the United States.1 SSSIs are most often mild-to-moderate infections that can easily be treated in an outpatient setting. Rates of these infections have substantially increased in the past decade, owing in part to the emergence of community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA).² The economic burden of SSSIs remains substantial and is driven by the high costs of hospitalization, which is often required for severe SSSIs since the agents used to treat these infections require daily intravenous (IV) administration for multiple days.³ Early clinical detection of severe or necrotizing SSSIs is difficult because the disease is often indistinguishable from its milder counterparts early in the disease course. Signs of a severe infection include pain disproportionate to the clinical findings, violaceous bullae, cutaneous hemorrhage, skin sloughing, skin anesthesia, rapid progression, and gas in the tissue.⁴ Additionally, it is recommended that patients with SSSIs accompanied by signs and symptoms of systemic toxicity, such as hypotension, fever, hypothermia, tachycardia, increased creatinine level, decreased serum bicarbonate, increased creatinine phosphokinase, marked left shift, or C-reactive protein >13 mg/L, be considered for hospitalization.⁴

Glycopeptide antibiotics, such as vancomycin, have been used in treatment of SSSIs for over half a century and are still used extensively today; however, reduced vancomycin susceptibility in CA-MRSA strains as well as difficulty in therapeutic drug monitoring compromise the clinical efficacy of vancomycin.^2,5 Second generation semisynthetic lipoglycopeptide derivatives such as dalbavancin and oritavancin, which possess a broader spectrum of activity and improved pharmacokinetic properties, will be discussed in this article. The new glycopeptide antibiotics provide efficacious alternatives for the treatment of complicated ABSSSIs.¹ A major benefit is management in an outpatient setting, which could significantly decrease or omit the costs and risks of hospitalization, as well as eliminating the need for laboratory monitoring.¹

Oxazolidinones are another important class of antibiotics used in the treatment of ABSSSIs, particularly vancomycin resistant Enterococcus(VRE) infections. Historically, linezolid has been the antibiotic of choice; however, tedizolid is a novel oxazolidinone that offers enhanced antimicrobial potency, low rates of bacterial resistance, and potential safety advantages. Additionally, the recommended dosing of once per day may be more convenient and is associated with higher compliance than twice per day dosing for linezolid.⁶

To maintain effectiveness of new antibiotics, their use should be limited to ABSSSIs where the bacteria are susceptible to the new medication and are resistant to other more cost effective options. Although tedizolid, dalbavancin, and oritavancin have been approved for SSSIs caused by MRSA, they probably should not be used as a first-line treatment when there are less expensive and more easily accessible antibiotics, such as trimethoprimsulfamethoxazole or doxycycline, that are very effective for MRSA infections.⁷

Glycopeptide Therapeutics – Dalbavancin and
Oritavancin

Dalbavancin is a long-acting IV semisynthetic lipoglycopeptide antibiotic with bactericidal activity against gram-positive cocci, including MRSA.^6-10 It is the first US FDA approved drug for adults with ABSSSIs that requires only 2 IV doses administered 1 week apart: the first dose is 1000 mg IV infused over 30 minutes, followed 1 week later by the second dose of 500 mg IV.^6-10

Dalbavancin is effective for treatment of adult patients with ABSSSI caused by susceptible isolates of gram-positive organisms. Susceptible gram-positive organisms include Staphylococcus aureus (S. aureus), including MRSA and MSSA, and Streptococcus groups (S. pyogenes, S. agalactiae, and S. anginosus).^6-11 In vitro studies suggest it may also be effective against vancomycinsusceptible Enterococcus faecium and Enterococcus faecalis (E. faecalis), as well as vancomycin-intermediate S. aureus; however, clinical importance has not been established.^6,11 The safety and efficacy in pediatric patients 18 years of age and younger has not been demonstrated.^8,11 However, vancomycin has been successfully used in treating these bacterial infections in the pediatric patient population.11 Dalbavancin is pregnancy category C meaning there has been some fetal toxicity in animals, but no adequate human studies.^6,8,11

The adverse effects most commonly experienced include nausea, diarrhea, and headaches, reported in 5% or less of patients.^6-8,10,11 Infrequent serious hypersensitivity reactions, including anaphylaxis, have been reported and caution should be exercised with patients who have a known allergy to other glycopeptides.^8,10 Additionally, rapid IV infusion could cause infusion-related reactions (pruritus, urticaria, and flushing).^6-8,10 Slowing or interrupting the infusion may be helpful if this occurs.⁷

Oritavancin is a long-acting IV semisynthetic lipoglycopeptide antibiotic with potent activity against gram-positive pathogens, including MRSA.³ Oritavancin is bactericidal and has an extended plasma half-life.^3,11,12 It is the first single-dose antibacterial drug approved by the US FDA for treatment of adult patients with ABSSIs.¹² The recommended single dose is 1200 mg IV infused over 3 hours.^7,11 Dose adjustment for advanced age, decreased renal function, or moderate hepatic impairment is not required.^3,7

Oritavancin is approved for use in adults with ABSSSIs caused by susceptible gram-positive microorganisms. Susceptible grampositive microorganisms include S. aureus (including MRSA and MSSA), various Streptococcus groups (S. pyogenes, S. agalactiae, S. dysgalactiae, and S. anginosus), and E. faecalis (vancomycinsusceptible isolates only).¹¹ The safety and efficacy have not been established in patients 18 years of age and younger.¹¹ Oritavancin is pregnancy category C.¹¹

The adverse effects most often reported include nausea, headache, vomiting and diarrhea, all occurring in less than 10% of patients.^3,7,11,12Osteomyelitis is a rare adverse event occurring in 0.3% of patients.^11,12 If osteomyelitis is suspected an antibacterial agent other than oritavancin should be used.^11,12 Infrequent reports of serious hypersensitivity reactions have occurred.^3,11 It is important to be aware of patients who have a history of allergies to other glycopeptides, including vancomycin.¹¹ Additionally, infusion-related reactions (pruritus, urticaria, flushing) have been experienced, as with other glycopeptides.^3,11,12 If this occurs, slowing or interrupting the infusion should be considered.¹¹

The current therapeutic options for the treatment of ABSSSIs require multidose and multiday regimens, with some patients requiring dosage adjustments for renal insufficiency or monitoring of plasma drug concentration.³ Multiday regimens may require patients to be hospitalized over their course of treatment, which increases the risk of nosocomial complications.³ Additionally, oral antibiotic regimens have an increased rate of noncompliance, which increases the potential for pathogen resistance. Oritavancin achieves a sustained clinical response with a single dose and does not require dosage adjustments for renal insufficiency. Oritavancin and dalbavancin could potentially reduce or eliminate hospital stays, improve treatment compliance, reduce utilization of health care resources, and add flexibility to the treatment of these serious infections. Despite the advantages, other more cost effective antibiotics with a history of effective use in treatment of ABSSSIs should be considered before deciding to treat with dalbavancin or oritavancin.

Oxazolidinone Therapeutic – Tedizolid Phosphate

The oxazolidinones are a synthetic class of agents now commonly relied on for the treatment of ABSSSIs, including more serious infections like MRSA and VRE.¹³ With increasing utilization of linezolid, resistant pathogens have begun to emerge.¹³ Tedizolid phosphate is a second-generation oxazolidinone antibiotic that offers enhanced antimicrobial potency and low rates of bacterial resistance.^13-15 Available in both IV and oral forms, tedizolid exhibits bacteriostatic activity by binding the 50S subunit of the bacterial ribosome, resulting in inhibition of bacterial protein synthesis.^11,13-15 The recommended dosage is 200 mg once daily for 6 days,^6,7,14,16 which may offer increased convenience and compliance when compared to twice daily linezolid.

Clinical studies have proven tedizolid phosphate to be effective against susceptible isolates of gram-positive organisms including S. aureus (including MRSA and MSSA), various Streptococcus groups (S. pyogenes, S. agalactiae, and S. anginosus), and E. faecalis (including VRE).^6,7,11,13-16 In vitro studies have suggested it may also exhibit activity against some strains of Staphylococci and Enterococci that are not susceptible to vancomycin or linezolid; however, the clinical importance of this data has not been established.^{6,11,13,14,16} The safety and effectiveness in pediatric patients 18 years of age or younger has not been demonstrated; whereas, linezolid is indicated for use in pediatric patients.^11,16 Tedizolid phosphate is pregnancy category C.^6,11,16

Structural differences between tedizolid and linezolid are thought to contribute to tedizolid’s decreased rates of resistance and enhanced potency.^13,14 Bacteria confer resistance to linezolid by acquiring the chloramphenicol-florfenicol resistance gene, which can be horizontally transferred.^13,15 However, because of structural distinctions, tedizolid has decreased vulnerability to this resistance mechanism.^13,15 Interactions with the ribosomal subunit are thought to contribute to the increased potency of tedizolid.^13,15

Another potential advantage of tedizolid compared to linezolid is an improved safety profile.^14,15 The most common adverse effects are similar to those seen with linezolid and include nausea, headache, diarrhea, vomiting, and dizziness, each occurring in less than 8% of patients.^6,7,14-16 Toxicity linked to duration of treatment with linezolid includes peripheral and optic neuropathy as well as hematologic toxicity and thrombocytopenia.^13,16 Tedizolid has not had reports of peripheral and optic neuropathy.^13,16 Although tedizolid exposure has been limited to 21 days or less in patients, a rat study using tedizolid doses up to 10-fold greater than human doses did not induce a neuropathy.¹³ This data indicates a possible safety advantage of tedizolid. Additionally, at recommended doses, tedizolid has not been associated with hematologic toxicity or thrombocytopenia¹³; however, higher doses or longer treatment durations might increase the risk. Linezolid has been associated with the occurrence of myelosuppression, especially in patients who have underlying hematologic abnormalities or renal insufficiency, which requires complete blood counts to be monitored weekly.¹³ An additional concern exists for the oxazolidinone class, which has been shown to act as weak, reversible monoamine oxidase (MAO) inhibitors in some in vitro studies.^6,13 However, based on two randomized, double-blind, placebo-controlled crossover studies, as well as another study including both humans and animals, tedizolid failed to interact with serotonergic drugs, adrenergic agents, or result in MAO inhibitor activity.^6,13,16 Data from post marketing experience will be beneficial to confirm the encouraging results that are currently available.

Conclusion

Dalbavancin, oritavancin, and tedizolid have been extremely valuable additions to treatment options for ABSSSIs due to the convenient dosing regimen and the fact that there are fewer resistant organisms to therapy at this time. In practice, other antibiotics with a history of effective use for ABSSSIs, which also cost less, should be considered first in order to prevent bacterial resistance.

References

1. Chambers HF. Pharmacology and the treatment of complicated skin and skin-structure infections. N Engl J Med. 2014 Jun 5;370(23):2238-9.
2. Holmes NE, Howden BP. What’s new in the treatment of serious MRSA infection? Curr Opin Infect Dis. 2014 Dec;27(6):471-8.
3. Corey GR, Kabler H, Mehra P, et al. Single-dose oritavancin in the treatment of acute bacterial skin infections. N Engl J Med. 2014 Jun 5;370(23):2180-90.
4. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005 Nov 15;41(10):1373-406.
5. Tacconelli E, Kern WV. New antibiotics for skin and skin-structure infections. Lancet Infect Dis. 2014 Aug;14(8):659-61.
6. Two new drugs for skin and skin structure infections. Med Lett Drugs Ther. 2014 Aug 18;56(1449):73-5.
7. New MRSA drugs: tedizolid, dalbavancin, and oritavancin. Duke Antimicrobial Stewardship Outreach Network (DASON): Infection Prevention News. 2014 Aug; 2(8).
8. Dalvanceô (dalbavancin) for injection, for intravenous use [Prescribing information]. Chicago, IL: Durata Therapeutics U.S. Limited; revised May 2014.
9. Dalvanceô for acute bacterial skin and skin structure infections (ABSSSI). J Drugs Dermatol. 2014 Jun;13(6):772.
10. Boucher HW, Wilcox M, Talbot GH, et al. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med. 2014 Jun 5; 370(23):2169-79.
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