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Sepsis Treatment Options Are Often Lacking

Kunj Gohil PharmD, RPh

Sepsis, sometimes called blood poisoning, is defined as 1) the presence of pathogenic organisms or their toxins in the blood and tissues, or 2) the poisoned condition resulting from the presence of pathogens or their toxins, as in septicemia.1 This life-threatening condition presents with varying symptoms due to the range of pathogens—including bacteria, viruses, fungi, or parasites originating in any tissue or organ in the body. This rapidly progressing systemic reaction may lead to shock or death.2 The 2016 incidence in the U.S. and the European Union is estimated to be 845,000 and is expected to grow to 875,000 by 2021.3

Sepsis involves numerous complexities, such as the wide array of pathogens, multiple infection sites, patient-specific pre-existing conditions, and sepsis-induced conditions. As sepsis begins to affect various organs and disrupt homeostasis within the body, a multi-modal approach is used to manage the disease.3,4

Unfortunately, sepsis-specific treatment options are lacking. Patients are managed through monitoring, pathogen-targeting therapies, supportive care, and symptomatic treatment. A timely diagnosis is crucial, since early administration of pathogen-specific therapies may help eradicate the disease; these therapies typically consist of antibiotics meant to combat specific bacteria.5 Because of the limitations of some antimicrobials, combination therapies may be needed to adequately manage an infection. Subsequent supportive care and symptomatic management may include hydration, vasopressors, mechanical ventilation, and hemodialysis.3,4

Various organizations are addressing the substantial unmet needs that exist for sepsis-specific therapies. A plethora of agents are under development with different therapeutic targets. Entrance of these agents onto the market will drive growth from $20.3 million in 2016 to $277.7 million in 2021.3

Future Therapies

Drug
Manufacturer
Status Regimen Information Therapeutic Class Expected Approval Anticipated Peak Year Sales/Pricing
Thrombomodulin alfa (ART-123)
Asahi Kasei Pharma America
Phase 3 0.06 mg/kg/day up to a maximum of 6 mg/day for six days via IV injection Anticoagulant Late 2016 Premium pricing is expected for thrombomodulin alfa.
Toraymyxin
Spectral Diagnostics
Phase 3 Two PMX-20R cartridges administered 24 hours apart. Each treatment targets two hours at a flow rate of 100 mL/minute. Hemofiltration device Late 2016 Premium pricing is expected for toraymyxin.
Selepressin
Ferring Pharmaceuticals
Phase 2 IV injection Vasopressor 2019 Pricing is expected to be similar to Vasostrict (Par Pharmaceutical).
Recombinant chimeric antitissue factor monoclonal antibody (ALT-836)
Altor BioScience
Phase 2 One to four doses at 0.06 mg/kg via IV injection Anticoagulant 2020 Pricing is expected to be similar to ART-123.
Tranexamic acid (LB-1148)
Leading BioSciences
Phase 2 7.5 g daily via enteral route Autodigestion inhibitor 2021 Pricing is expected to be similar to Lysteda (Ferring Pharmaceuticals).
Recombinant human alkaline phosphatase (recAP)
AM-Pharma
Phase 2 0.4, 0.8, or 1.6 mg/kg once daily for three days via IV injection Anti-inflammatory 2021 Pricing is expected to be similar to ART-123.
Levosimendan
Tenax Therapeutics
Phase 2 One-time 0.05–0.2 mcg/kg/min for 24 hours via IV injection Cardiac stimulant After 2022 Not available
Allogeneic expanded adipose- derived stem cells (Cx-611)
TiGenix
Phase 1 IV injection Stem cell therapy After 2022 Not available

IV = intravenous

Sources: FDA; GlobalData; manufacturer websites; ClinicalTrials.gov

Current Antibacterial Therapies*

Class Common Examples Class Mechanism of Action Pharmacokinetic Characteristics Gaps in Coverage
Carbapenems Imipenem, meropenem, doripenem, ertapenem Inhibits bacterial cell-wall synthesis through binding to various penicillin-binding proteins. Time-dependent killing Carbapenemase-producing organisms
Beta-lactams Piperacillin/tazobactam, cephalosporins Inhibits bacterial cell-wall synthesis through binding to various penicillin-binding proteins. Time-dependent killing Carbapenemase- and ESBL-producing organisms
Quinolones Moxifloxacin, ciprofloxacin, levofloxacin Interferes with bacterial cell division by inhibiting DNA gyrase and topoisomerase IV. Concentration-dependent killing Quinolone-resistant organisms (including many carbapenemase- and ESBL-producing organisms)
Aminoglycosides Gentamicin, tobramycin, amikacin Interferes with bacterial protein synthesis, leading to formation of nonfunctional or toxic proteins. Irreversibly binds to specific 30S ribosomal subunit proteins and 16S rRNA, which disrupts RNA-dependent protein synthesis. Concentration-dependent killing Most gram-positive organisms, aminoglycoside-resistant organisms, and most carbapenemase- and ESBL-producing organisms
Macrolides Azithromycin, clarithromycin, erythromycin Interferes with bacterial protein synthesis, leading to formation of nonfunctional or toxic proteins. Irreversibly binds to 50S ribosomal subunit, which disrupts RNA-dependent protein synthesis. Time-dependent killing Macrolide-resistant organisms, including many gram-positive organisms and most carbapenemase- and ESBL-producing organisms
Glycopeptides (anti-gram-positive) Vancomycin, oritavancin, televancin Inhibits incorporation of key peptides (NAM and NAG) into the bacterial cell wall and thus alters bacterial cell membrane permeability and RNA synthesis. Time-dependent killing Gram-negative organisms. Typically used in combination with another class of antimicrobial agents.
Oxazolidinone (anti-gram-positive) Linezolid Interferes with bacterial protein synthesis, leading to formation of nonfunctional or toxic proteins. Irreversibly binds to 50S ribosomal subunit, which disrupts RNA-dependent protein synthesis. Time-dependent killing Gram-negative organisms. Typically used in combination with another class of antimicrobial agents.
Cyclic lipopeptides (anti-gram-positive) Daptomycin Binds to bacterial cell membranes and leads to rapid depolarization of membrane potential, which causes inhibition of DNA, RNA, and protein synthesis. Concentration-dependent killing Gram-negative organisms. Typically used in combination with another class of antimicrobial agents.

Sources: GlobalData; Lyle et al.;6 RxKinetics7

ESBL = extended spectrum beta-lactamase

*This list is not all-inclusive; additional therapies are available for this disease state.

Author bio: 
Dr. Gohil is Central Services Manager with Medical Services at MediMedia Managed Markets in Yardley, Pennsylvania.

References

  1. Sepsis Alliance. Definition of sepsis. Available at: http://www.sepsis.org/sepsis/definition/. Accessed June 4, 2015
  2. Centers for Disease Control and Prevention. Sepsis questions and answers. May 2014;Available at: https://www.cdc.gov/sepsis/basic/qa.html. Accessed June 3, 2015.
  3. GlobalData. Sepsis—Opportunity Analysis and Forecasts to 2021 March 2015;
  4. Kleinpell RM. Working out the complexities of severe sepsis [Review]. Nurse Pract 2005;30;(4):43–44.46–48.
  5. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41;(2):580–637.
  6. Lyle NH, Pena OM, Boyd JH, Hancock RE. Barriers to the effective treatment of sepsis: antimicrobial agents, sepsis definitions, and host-directed therapies [Review]. Ann N Y Acad Sci 2014;1323:101–114.
  7. RxKinetics. A PK/PD approach to antibiotic therapy. October 2012;Available at: http://www.rxkinetics.com/antibiotic_pk_pd.html. Accessed June 3, 2015.