Newer therapies to consider for SSTI since 2014 treatment guidelines
Skin and soft-tissue infections, or SSTIs, present clinically in a multitude of ways, and the treatment strategies vary even more. SSTIs, generally, have been categorized as uncomplicated vs. complicated, ranging in severity from simple cutaneous presentation to life-threatening necrotizing infections. Uncomplicated infections are typically self-limiting or at most require incision and debridement with or without oral antibiotics. Complicated SSTIs are more severe, as they can extend into the subcutaneous tissue, fascia or muscle, and patients typically have significant systemic signs and symptoms of infection. Understanding the key difference will allow a provider to determine the appropriate treatment approach.
In 2014, the Infectious Diseases Society of America (IDSA) provided updated, comprehensive guidelines for the diagnosis and management of SSTIs. These guidelines divided SSTIs into nonpurulent vs. purulent and further delineated the disease by severity of illness. An appropriate treatment strategy and antibiotic therapy can then be selected based on this categorization. Primary treatment is targeted at the most likely causative pathogens, including Staphylococcus aureus (including MRSA) and Streptococcus spp. The gold standard of treatment includes either penicillins, cephalosporins, clindamycin, trimethoprim-sulfamethoxazole, doxycycline or linezolid. IV therapies primarily targeting MRSA recommended in the guidelines include vancomycin, Cubicin (daptomycin, Cubist Pharmaceuticals), Vibativ (telavancin, Theravance Biopharma) or Teflaro (ceftaroline, Actavis). Since the publication of the 2014 guidelines, three new antimicrobial agents have been approved for the treatment indication of acute bacterial SSTI: Dalvance (dalbavancin, Durata Therapeutics) in May 2014, Sivextro (tedizolid, Cubist Pharmaceuticals) in June 2014 and Orbactiv (oritavancin, The Medicines Company) in August 2014.
Dalbavancin and oritavancin will be covered here, given their unique properties as compared with other available products for the treatment of SSTI.
Dalbavancin is a lipoglycopeptide antibiotic similar to vancomycin. Its primary mechanism of action is inhibition of cell wall peptidoglycan cross-linking by binding to the terminal of the D-alanyl-D-alanine pentapeptide chain in nascent peptidoglycan, making it bactericidal in vitro. The spectrum of coverage includes susceptible isolates of the following gram-positive microorganisms: S. aureus (including MRSA and methicillin-susceptible S. aureus, or MSSA), Streptococcus pyogenes, S. agalactiae and S. anginosus group.
One unique feature of dalbavancin is the dosing strategy, being administered as a 1,000-mg IV dose followed by a 500-mg IV dose 1 week later. This administration is made possible given the extended half-life (t ½) of approximately 8.5 days (average, 6-10 days) and its plasma protein binding of 93%. Dalbavancin is primarily excreted by the kidneys (33% unchanged in the urine). A dose adjustment for renal impairment is required for patients with a creatinine clearance (CrCl) of less than 30 mL/min or for patients who do not have regularly scheduled hemodialysis (HD), which is defined as being dialyzed three times per week. Patient populations with scheduled dialysis compared most closely in pharmacokinetic studies with those patients with mild-to-moderate impairment, and less than 6% of the drug is eliminated after a 3-hour HD session. The dose adjustment for patients with CrCl of less than 30 mL/min or those not on scheduled dialysis is 750 mg IV for one dose followed by 375 mg IV 1 week later. Dalbavancin was evaluated in patients with mild, moderate and severe hepatic dysfunction, and area under the curve (AUC) values (0-336 hr) were compared with healthy individuals. No difference was identified in AUC (0-336 hr) for patients with mild hepatic impairment. However, those with moderate-to-severe hepatic impairment had a decrease in AUC (0-336 hr) of 28% and 31%, respectively. Dose adjustments for patients with mild hepatic impairment are not required, but extreme caution should be taken if using dalbavancin in moderate-to-severe hepatic impairment, with close monitoring of liver function tests.
Some other considerations with dalbavancin administration include infusion solution and length of infusion. Dalbavancin must be reconstituted and then diluted into 5% Dextrose Injection USP. It should not be diluted or coadministered with saline-based products, and lines should not be flushed with saline-based products prior to or after dalbavancin administrations, as this may cause precipitation. This antibiotic, similar to vancomycin, does have the risk for red-man syndrome (upper-body urticaria, pruritis and/or rash) with rapid infusion of the product. Therefore, an infusion time of 30 minutes or greater should be considered. If a patient does experience this type of reaction, the infusion can be slowed or stopped and reinitiated at a slower rate. This is not considered an allergic (immunoglobulin E-mediated) reaction.
Dalbavancin is not a substrate, inhibitor or inducer of CYP450 isoenzymes. Therefore, there are minimal reported drug-drug interactions. It also has a relatively clean adverse effect profile when evaluated in phase 2 and phase 3 clinical trials. The comparator agents were vancomycin, cefazolin, cephalexin and linezolid. The most common or significant adverse effects reported were nausea (5.5%), headache (4.7%), diarrhea (4.4%) and an increase in alanine aminotransferase (ALT) elevation greater than three times the upper limit of normal (0.8%).
Oritavancin is a semisynthetic lipoglycopeptide similar to vancomycin and dalbavancin. It acts by inhibiting the polymerization step by binding to stem peptides of peptidoglycan precursors; inhibiting crosslinking by binding to bridging segments; and disrupting bacterial membrane integrity, therefore exhibiting concentration-dependent bactericidal activity. It has shown activity in vitro and in clinical infections against the following isolates of bacteria: MSSA, MRSA, S. agalactiae, S. anginosus, S. intermedius, S. constellatus, S. dysgalactiae, S. pyogenes, Enterococcus faecalis and E. faecium (vancomycin-susceptible isolates only).
The most unique feature of oritavancin is its one-time administration. It is recommended as a single, 1,200-mg IV dose administered over 3 hours in patients aged older than 18 years. It is supplied as a package consisting of 3 mL to 50 mL glass vials of lyophilized powder equivalent to 400 mg oritavancin each, for a total of 1,200-mg dose treatment. Similarly to dalbavancin, oritavancin has an extended t ½ of approximately 10 days and is approximately 85% bound to human plasma proteins, allowing for the one-time administration. It is not metabolized and only 5% is excreted unchanged in the urine. Therefore, no renal adjustments are required for patients with mild-to-moderate renal impairment. The pharmacokinetics of oritavancin has not been evaluated in patients with severe renal impairment, and it is not removed by dialysis. Given the limited data and clinical experience in these two populations, oritavancin administration should be avoided.
Oritavancin has some significant clinical considerations compared with dalbavancin, including drug-drug and drug-lab interactions and adverse effects. Oritavancin was found to be a nonspecific, weak inhibitor of CYP2C9 and CYP2C19 and a weak inducer of CYP3A4 and CYP2D6. Caution should be used in patients who are taking narrow therapeutic window drugs (such as warfarin) that are metabolized by the CYP enzymes. Coadministration of oritavancin and warfarin may increase the risk for bleeding and should only be used in patients on warfarin if the benefits of this antibiotic outweigh the potential risk for bleeding. In addition, it has been shown to prolong the activated partial thromboplastin time (aPTT) for 48 hours and the prothrombin time and international normalized ratio for 24 hours by binding to and preventing the action of phospholipid reagents, which activate coagulation in commonly used laboratory coagulation tests. A nonphospholipid coagulation test, such as a Factor Xa (chromogenic) assay, should be used in patients requiring aPTT monitoring, or an alternative anticoagulant that does not require aPTT monitoring should be chosen. The use of IV unfractionated heparin sodium is contraindicated for 48 hours after administration of oritavancin due to this notable interaction. Like dalbavancin and vancomycin, oritavancin carries the risk for red-man syndrome with rapid infusion of the product. Therefore, an infusion time of 3 hours is recommended. It also is not compatible with saline-based products, and so coadministration with this should be avoided.
Based on pooled results from clinical trials, the most common adverse effects similar to dalbavancin include nausea (9.9%), headache (7.1%), vomiting (4.6%), diarrhea (3.7%) and increased alanine aminotransferase (2.8%). In addition to these adverse effects, oritavancin has been associated with abscess formation (3.8%), dizziness (2.7%), infusion-site phlebitis (2.5%) and tachycardia (2.5%). In phase 3 clinical trials — named SOLO II and SOLO I — more cases of osteomyelitis were reported in the oritavancin-treated arm compared with the vancomycin-treated arm. Therefore, close evaluation and monitoring for osteomyelitis is recommended. It is important to note that among patients taking oritavancin, five cases of osteomyelitis were reported in SOLO II and two cases in SOLO I, compared with no cases reported in the vancomycin arms, between days 1 and 9 of therapy. This led to the clinical assessment that this advanced disease state may have been present before enrollment. Regardless, oritavancin has not been sufficiently studied for the treatment of osteomyelitis.
What’s their place in therapy?
It is always difficult to determine where new medications will fit into the treatment strategy. These two agents are no different, and their unique features, while appealing, make this decision more complicated. What do I mean? First and foremost, the safety of our patients and the efficacy of the antibiotic are most important. These agents should not be considered first-line therapies over other available antibiotic agents for the treatment of SSTI. In addition, we need to consider the most cost-effective strategy for patients and our health care settings.
Both dalbavancin and oritavancin have reported relatively good safety profiles, but if a patient experienced a significant adverse effect or a life-threatening allergic reaction, with the extended t ½, extensive protein binding and limited removal from dialysis, the clinical question is: How do we manage this? I am not sure. Often with SSTI, particularly with severe or complicated infections, we are assessing for bacteremia. It is reported that less than 5% of blood cultures are positive in less severe SSTI, but upwards of 30% are positive in more severe SSTI infections. These two agents have not been studied for the treatment of bacteremia, and therefore if there is high clinical suspicion for bacteremia given the clinical presentation of your patient, these agents should not be considered as first-line therapy. As previously mentioned, osteomyelitis may also be present, and these agents have not been studied for this infection syndrome either. Lastly, as with all new agents, dalbavancin and oritavancin are expensive and cost prohibitive in many inpatient clinical settings. These products cost between $1,000 and $2,000 per vial, with an estimated treatment course cost of $3,000 to $6,000. Outpatient administration may be appealing, and reimbursement in this setting should be evaluated. In addition, avoidance of admission to the hospital for treatment may be a consideration and benefit, but close clinical follow-up after administration (looking for adverse reactions and infection resolution) are prudent. IDSA reviews the guidelines every 12 to 18 months following publication. It will be interesting to see when these guidelines are revisited and updated how dalbavancin and oritavancin will fit into the treatment strategies. It is likely by that time we will have some more clinical experience with these two agents.
Editor’s note: The September Pharmacology Consult column, titled “Cresemba: A novel, broad-spectrum triazole antifungal agent,” should have clarified that Cresemba (isavuconazonium sulfate, Astellas Pharma) should be given as a loading dose of 200 mg every 8 hours for 2 days (6 doses) followed by the routine dose of 200 mg once daily. The editors regret this error.
- Dalvance prescribing information. Durata Therapeutics. www.dalvance.com/#. Accessed September 28, 2015.
- Orbactiv package insert. The Medicines Company. http://orbactiv.com. Accessed September 12, 2015.
- Perl B, et al. Clin Infect Dis. 1999;29:1483-1488.
- Stevens DL, et al. Clin Infect Dis. 2005;doi:10.1093/cid/ciu444.
- For more information:
- Kimberly D. Boeser, PharmD, BCPS AQ-ID, is an infectious diseases clinical pharmacist and antimicrobial stewardship coordinator at the University of Minnesota Medical Center-Fairview and the University of Minnesota Masonic Children’s Hospital.
Disclosure: Boeser reports no relevant financial disclosures.