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absssi

(a) The most abominable medical acronym ever
(b) The most challenging tongue-twister in the Romulan language
(c) Regulatory-speak from the US FDA
(d) a 1989 American science fiction film written and directed by James Cameron and starring Ed Harris and Mary Elizabeth Mastrantonio
(e) (a) and (c)
(f) (b) and (d)

Many—but certainly not all—clinicians will recognize that the correct answer is (e), and that the FDA coined the term Acute Bacterial Skin and Skin Structure Infections (ABSSSI—some say “A-B-triple S-I,” some say “AB-SEE”, and some gluttons for punishment repeatedly utter “A-B-S-S-S-I”) to replace the terms cSSTI, or “complicated skin and soft tissue infections”, and cSSSI, or “complicated skin and skin structure infections.” I remain unsure why these descriptive terms were deemed inadequate, or how the new term came to be. A 2009 article in Emerging Infectious Diseases is entitled “Trends in US Hospital Admissions for Skin and Soft Tissue Infections” and does not mention the term.1 The first mention of it in FDA documents seems to be in 2013 in a “Guidance for Industry” document.2 (And BTW, I don’t speak Romulan, and the movie referenced in choice (d) above is The Abyss—so close, but no cigar.)

It seems that the change in nomenclature was aimed by FDA largely to standardize definitions and outcomes to be used in applications for new antibiotics pending approval in the skin/soft tissue space. It defined ABSSSI as cellulitis/erysipelas, wound infection, or major cutaneous abscess that has a minimum lesion surface area of approximately 75 cm2, measured by area of redness, edema, or induration, but did not take into account systemic signs or symptoms . The definition specifically excluded less serious skin infections, such as impetigo and minor cutaneous abscess, as well as serious and/or polymicrobial infections needing more complex treatment regimens, such as infections resulting from animal or human bites, diabetic foot infection, decubitus ulcer infection, burn wounds, and necrotizing fasciitis.2

Perhaps even more importantly, the FDA published specific guidance for drug development programs aimed at an ABSSSI indication:

  • Trials should include both genders
  • Trials should include a “mixture” of ABSSSI subtypes (cellulitis/erysipelas, wound infection, major cutaneous abscess), but abscess should be limited to 30% of a study population because surgical incision and drainage might influence treatment outcomes
  • OK to exclude neutropenic or otherwise immunocompromised patients, suspected or confirmed osteomyelitis, suspected or confirmed septic joint, and patients who have already received > 24 hours of (expected to be) effective antibiotic therapy for the current infection
  • Microbiologic specimen collection with culture and (if positive) sensitivities is required; they even included leading edge aspirate of cellulitis, which today is not considered helpful3
  • Adjunctive therapy, such as dressing changes, topical nonspecific antimicrobials (think Betadine®), debridement, hyperbaric oxygen treatments,4 or other surgical management planned at initiation of treatment, was allowable as long as specified

Perhaps more important was the standardization of efficacy outcomes for ABSSSI, given that in the past the outcomes were clinical and (despite low yield) bacteriologic proof of cure. These new outcomes were mandated to be measured early, starting at 48-72 hours:

  • Primary efficacy endpoint of lesion response at 48 to 72 hours
    • Clinical response based on the percent reduction in the lesion size at 48 to 72 hours compared to baseline, measured in patients who did not receive rescue therapy and are alive. A satisfactory clinical response was defined as a percent reduction in lesion size > 20% compared to baseline.
  • Secondary endpoint
    • Resolution of ABSSSI evaluated at 7 to 14 days after completion of therapy (end-of-treatment = “EOT” endpoint)

A number of new antibiotics have been approved under these criteria, and we’ll discuss some of them in subsequent posts. The FDA projected in 2013 that “common bacterial pathogens causing ABSSSI are Streptococcus pyogenes and Staphylococcus aureus including methicillin-resistant S. aureus” (MRSA). Since 2013, the general focus has indeed been on MRSA, which was introduced sensationally to the public as the notorious “flesh-eating bacteria.” While the incidence of MRSA varies regionally, and it was considered a rare pathogen in community-acquired infections as recently as 2000,5 it was viewed by 2015 as a predominant cause of purulent ABSSSI in the United States. We’ll discuss MRSA in a subsequent post as well.

Recent drug development, again under these rules, has interestingly yielded both parenteral and oral antimicrobials that have predictably solid activity against MRSA—the pathogen we want to treat empirically in ABSSSI—and against Streptococcus pneumoniae or pneumococcus—the pathogen we want to be sure we cover empirically when treating community-acquired bacterial pneumonia. Such drugs have proved useful in the emergency department, where we don’t have any microbiologic guidance available to us. Drugs included in this group are ceftaroline (Teflaro®), omadacycline (Nuzyra®), and linezolid (Zyvox®).

Recently, antibiotic development has slowed dramatically, as reported even to the lay public.6 Despite ongoing development of resistance even among common pathogens, and the report from the Centers for Disease Control that drug-resistant infections now cause 35,000 deaths and nearly 3 million significant illnesses,7 financial pressure is driving pharma out of the new antimicrobial business. The economics are daunting: antibiotics are prescribed only episodically for relative brief intervals, and the high cost of development—translated into high cost—has lessened hospitals’ enthusiasm to admit them to formulary. In addition, antimicrobial stewardship programs often strictly limit prescriber access to newer drugs, in the hope that their “differential” activity can be preserved. On the other hand, the Times reports that bringing a new antibiotic to market can cost $2.6 billion. The response among pharma: reduce R&D on antibiotics. This is another issue for another post.

Re what we used to call “SSTI,” just keep in mind:

  • ABSSSI is a specifically defined term and drugs with “ABSSSI” in their labeled indications have been approved through the consistent pathway described above.
  • ABSSSI is a high-volume condition in both out- and in-patient settings, and by most measures, the prevalence of ABSSSI is increasing in both8
  • Empiric antimicrobial coverage for ABSSSI must be an agent known to treat MRSA.9

REFERENCES

  1. Edelsberg J, Taneja C, Zervos M, et al. Trends in US Hospital Admissions for Skin and Soft Tissue Infections. Emerg Infect Dis. 2009;15(9):1516-1518. doi:10.3201/eid1509.081228
  2. US Department of Health and Human Services. Guidance for Industry Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment.; 2013:4. https://www.fda.gov/downloads/Drugs/Guidances/ucm071185.pdf. Accessed April 9, 2019.
  3. Piso RJ, Pop R, Wieland M, et al. Low sensitivity of needle aspiration cultures in patients with cellulitis/erysipelas. SpringerPlus. 2016;5(1):1578. doi:10.1186/s40064-016-3293-z
  4. Eskes A, Vermeulen H, Lucas C, Ubbink DT. Hyperbaric oxygen therapy for treating acute surgical and traumatic wounds. Cochrane Database Syst Rev. 2013;(12):CD008059. doi:10.1002/14651858.CD008059.pub3
  5. Moran GJ, Abrahamian FM, LoVecchio F, Talan DA. Acute Bacterial Skin Infections: Developments Since the 2005 Infectious Diseases Society of America (IDSA) Guidelines. J Emerg Med. 2013;44(6):e397-e412. doi:10.1016/j.jemermed.2012.11.050
  6. Jacobs A. Crisis Looms in Antibiotics as Drug Makers Go Bankrupt. The New York Times. https://www.nytimes.com/2019/12/25/health/antibiotics-new-resistance.html. Published December 25, 2019. Accessed February 8, 2020.
  7. More People in the United States Dying from Antibiotic-Resistant Infections than Previously Estimated | CDC Online Newsroom | CDC. https://www.cdc.gov/media/releases/2019/p1113-antibiotic-resistant.html. Published December 4, 2019. Accessed February 8, 2020.
  8. Kaye KS, Petty LA, Shorr AF, Zilberberg MD. Current Epidemiology, Etiology, and Burden of Acute Skin Infections in the United States. Clin Infect Dis Off Publ Infect Dis Soc Am. 2019;68(Suppl 3):S193-S199. doi:10.1093/cid/ciz002
  9. Golan Y. Current Treatment Options for Acute Skin and Skin-structure Infections. Clin Infect Dis Off Publ Infect Dis Soc Am. 2019;68(Suppl 3):S206-S212. doi:10.1093/cid/ciz004

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