Clinical trial NCT06266494: Prevention and Treatment of Frostbite Infection With Antimicrobial Pharmacokinetic Analysis
Official title: Prevention and Treatment of Frostbite Infection With Antimicrobial Pharmacokinetic Analysis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Frostbite
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: Congressionally Directed Medical Research Programs
First posted: 2024-02-20
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will compare the effectiveness of two different treatments for preventing infection from frostbite injuries. These two treatments are A) aloe vera and B) long-acting silver wound dressings. The investigators will also study the safety and effectiveness of Dalbavancin, an FDA approved antibiotic used for treating people who develop frostbite wound infections, as well as evaluate how frostbite damage to individuals' bodies may affect how fast their kidney clear drugs from their systems.


Eligibility criteria: Inclusion Criteria:

* All aims, aged ≥18 - \< 99 years old admitted to UCH Burn Center with frostbite injury
* Aim 1: Admitted to UCH Burn Center with acute (within 4 days of cold exposure) frostbite injury
* Aim 2: Admitted to UCH Burn center with a clinically confirmed or suspected infected frostbite wound

Exclusion Criteria:

* Pregnant patients
* Prisoners
* Anticipated death within 48 hours of admission
* Inability to obtain consent from patient, legally authorized representative, or proxy
* Aim 1:Patients admitted five days and later from frostbite injury. Patients who have a clinical infection at baseline. Any patients that have a contra-indication for the use of either aloe (allergy), or silver (allergy).
* Aim 2: Any patients that have a contraindication for use of dalbavancin, including known history of hypersensitivity to dalbavancin, vancomycin, or other glycopeptide antibiotics. Patients with infections known to be caused by vancomycin-resistant Enterococcus; or those with Stage IV or V chronic kidney disease, or with cirrhosis (Childs-Pugh C); or those with anticipated death within 48 hours of infection.
* Aim 3: Anuria due to chronic kidney disease (CKD)

Primary outcomes:
measure: The number of positive microbial wound cultures on admission
timeFrame: Admission
measure: The number of positive microbial wound cultures on hospital day 4
timeFrame: Hospital Day 4
measure: The number of positive microbial wound cultures on hospital day 8
timeFrame: Hospital Day 8
measure: The number of positive microbial wound cultures on hospital day 12
timeFrame: Hospital Day 12
measure: The number of positive microbial wound cultures on hospital day 16
timeFrame: Hospital Day 16
measure: The number of positive microbial wound cultures on hospital day 20
timeFrame: Hospital Day 20
measure: The number of positive microbial wound cultures on hospital day 24
timeFrame: Hospital Day 24
measure: The number of positive microbial wound cultures on hospital day 28
timeFrame: Hospital Day 28
measure: The number of positive microbial wound cultures on hospital day 32
timeFrame: Hospital Day 32
measure: The number of positive microbial wound cultures on hospital day 36
timeFrame: Hospital Day 36
measure: The number of positive microbial wound cultures on hospital day 40
timeFrame: Hospital Day 40
measure: The number of positive microbial wound cultures on hospital day 44
timeFrame: Hospital Day 44
measure: The number of positive microbial wound cultures on hospital day 48
timeFrame: Hospital Day 48
measure: The number of positive microbial wound cultures on hospital day 52
timeFrame: Hospital Day 52
measure: The number of positive microbial wound cultures on hospital day 56
timeFrame: Hospital Day 56
measure: The number of positive microbial wound cultures on hospital day 60
timeFrame: Hospital Day 60
measure: Number of gram positive cultures at admission
timeFrame: Admission
measure: Number of gram positive cultures on hospital day 4
timeFrame: Hospital Day 4
measure: Number of gram positive cultures on hospital day 8
timeFrame: Hospital Day 8
measure: Number of gram positive cultures on hospital day 12
timeFrame: Hospital Day 12
measure: Number of gram positive cultures on hospital day 16
timeFrame: Hospital Day 16
measure: Number of gram positive cultures on hospital day 20
timeFrame: Hospital Day 20
measure: Number of gram positive cultures on hospital day 24
timeFrame: Hospital Day 24
measure: Number of gram positive cultures on hospital day 28
timeFrame: Hospital Day 28
measure: Number of gram positive cultures on hospital day 32
timeFrame: Hospital Day 32
measure: Number of gram positive cultures on hospital day 36
timeFrame: Hospital Day 36
measure: Number of gram positive cultures on hospital day 40
timeFrame: Hospital Day 40
measure: Number of gram positive cultures on hospital day 44
timeFrame: Hospital Day 44
measure: Number of gram positive cultures on hospital day 48
timeFrame: Hospital Day 48
measure: Number of gram positive cultures on hospital day 52
timeFrame: Hospital Day 52
measure: Number of gram positive cultures on hospital day 56
timeFrame: Hospital Day 56
measure: Number of gram positive cultures on hospital day 60
timeFrame: Hospital Day 60
measure: Change in serum concentration of dalbavancin in plasma (mcg/ml) over time
timeFrame: 1, 4, 12 hours, and 1,2,3,4,6,8,10,13,16 (or date of discharge if earlier) days post dalbavancin infusion
measure: Dalbavancin concentrations in subcutaneous tissue
timeFrame: Up to 12 weeks
measure: Change in presence of Augmented Renal Clearance
timeFrame: Baseline, Up to 12 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Denver Anschutz Medical Campus
state: Colorado
Study officials:
affiliation: University of Colorado Anschtuz
name: Arek Wiktor, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mueller SW, Blass B, Molina KC, Gibson C, Krsak M, Kohler AD, Deeter L, Stalilonis J, Wiktor AJ. Augmented Renal Function in Burn Patients: Occurrence and Discordance With Commonly Used Methods to Assess Renal Function. J Burn Care Res. 2023 Nov 2;44(6):1298-1303. doi: 10.1093/jbcr/irad107.
citation: Carmichael H, Michel S, Smith TM, Duffy PS, Wiktor AJ, Lambert Wagner A. Remote Delivery of Thrombolytics Prior to Transfer to a Regional Burn Center for Tissue Salvage in Frostbite: A Single-center Experience of 199 Patients. J Burn Care Res. 2022 Jan 5;43(1):54-60. doi: 10.1093/jbcr/irab041.
citation: Torian SC, Wiktor AJ, Roper SE, Laramie KE, Miller MA, Mueller SW. Burn Injury and Augmented Renal Clearance: A Case for Optimized Piperacillin-Tazobactam Dosing. J Burn Care Res. 2023 Jan 5;44(1):203-206. doi: 10.1093/jbcr/irac138.
citation: Barletta JF, Mangram AJ, Byrne M, Sucher JF, Hollingworth AK, Ali-Osman FR, Shirah GR, Haley M, Dzandu JK. Identifying augmented renal clearance in trauma patients: Validation of the Augmented Renal Clearance in Trauma Intensive Care scoring system. J Trauma Acute Care Surg. 2017 Apr;82(4):665-671. doi: 10.1097/TA.0000000000001387.
citation: Udy AA, Jarrett P, Stuart J, Lassig-Smith M, Starr T, Dunlop R, Wallis SC, Roberts JA, Lipman J. Determining the mechanisms underlying augmented renal drug clearance in the critically ill: use of exogenous marker compounds. Crit Care. 2014 Nov 29;18(6):657. doi: 10.1186/s13054-014-0657-z.
citation: Cook AM, Hatton-Kolpek J. Augmented Renal Clearance. Pharmacotherapy. 2019 Mar;39(3):346-354. doi: 10.1002/phar.2231. Epub 2019 Mar 11.
citation: Dunne MW, Puttagunta S, Giordano P, Krievins D, Zelasky M, Baldassarre J. A Randomized Clinical Trial of Single-Dose Versus Weekly Dalbavancin for Treatment of Acute Bacterial Skin and Skin Structure Infection. Clin Infect Dis. 2016 Mar 1;62(5):545-51. doi: 10.1093/cid/civ982. Epub 2015 Nov 26.
citation: Carrothers TJ, Chittenden JT, Critchley I. Dalbavancin Population Pharmacokinetic Modeling and Target Attainment Analysis. Clin Pharmacol Drug Dev. 2020 Jan;9(1):21-31. doi: 10.1002/cpdd.695. Epub 2019 May 14.
citation: Mangum LC, Garcia GR, Akers KS, Wenke JC. Duration of extremity tourniquet application profoundly impacts soft-tissue antibiotic exposure in a rat model of ischemia-reperfusion injury. Injury. 2019 Dec;50(12):2203-2214. doi: 10.1016/j.injury.2019.09.025. Epub 2019 Sep 20.
citation: Kam PC, Kavanagh R, Yoong FF. The arterial tourniquet: pathophysiological consequences and anaesthetic implications. Anaesthesia. 2001 Jun;56(6):534-45. doi: 10.1046/j.1365-2044.2001.01982.x.
citation: Dunne MW, Puttagunta S, Sprenger CR, Rubino C, Van Wart S, Baldassarre J. Extended-duration dosing and distribution of dalbavancin into bone and articular tissue. Antimicrob Agents Chemother. 2015 Apr;59(4):1849-55. doi: 10.1128/AAC.04550-14. Epub 2015 Jan 5.
citation: Nicolau DP, Sun HK, Seltzer E, Buckwalter M, Dowell JA. Pharmacokinetics of dalbavancin in plasma and skin blister fluid. J Antimicrob Chemother. 2007 Sep;60(3):681-4. doi: 10.1093/jac/dkm263. Epub 2007 Jul 12.
citation: Morrisette T, Miller MA, Montague BT, Barber GR, McQueen RB, Krsak M. On- and off-label utilization of dalbavancin and oritavancin for Gram-positive infections. J Antimicrob Chemother. 2019 Aug 1;74(8):2405-2416. doi: 10.1093/jac/dkz162.
citation: Molina KC, Lunowa C, Lebin M, Segerstrom Nunez A, Azimi SF, Krsak M, Mueller SW, Miller MA. Comparison of Sequential Dalbavancin With Standard-of-Care Treatment for Staphylococcus aureus Bloodstream Infections. Open Forum Infect Dis. 2022 Jul 14;9(7):ofac335. doi: 10.1093/ofid/ofac335. eCollection 2022 Jul.
citation: Cain AR, Bremmer DN, Carr DR, Buchanan C, Jacobs M, Walsh TL, Moffa MA, Shively NR, Trienski TL. Effectiveness of Dalbavancin Compared With Standard of Care for the Treatment of Osteomyelitis: A Real-world Analysis. Open Forum Infect Dis. 2021 Dec 18;9(2):ofab589. doi: 10.1093/ofid/ofab589. eCollection 2022 Feb.
citation: Rappo U, Puttagunta S, Shevchenko V, Shevchenko A, Jandourek A, Gonzalez PL, Suen A, Mas Casullo V, Melnick D, Miceli R, Kovacevic M, De Bock G, Dunne MW. Dalbavancin for the Treatment of Osteomyelitis in Adult Patients: A Randomized Clinical Trial of Efficacy and Safety. Open Forum Infect Dis. 2018 Dec 10;6(1):ofy331. doi: 10.1093/ofid/ofy331. eCollection 2019 Jan.
citation: Boucher HW, Wilcox M, Talbot GH, Puttagunta S, Das AF, Dunne MW. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med. 2014 Jun 5;370(23):2169-79. doi: 10.1056/NEJMoa1310480.
citation: Jones RN, Fritsche TR, Sader HS, Goldstein BP. Antimicrobial spectrum and potency of dalbavancin tested against clinical isolates from Europe and North America (2003): initial results from an international surveillance protocol. J Chemother. 2005 Dec;17(6):593-600. doi: 10.1179/joc.2005.17.6.593.
citation: Molina KC, Miller MA, Mueller SW, Van Matre ET, Krsak M, Kiser TH. Clinical Pharmacokinetics and Pharmacodynamics of Dalbavancin. Clin Pharmacokinet. 2022 Mar;61(3):363-374. doi: 10.1007/s40262-021-01088-w. Epub 2021 Dec 21.
citation: Sader HS, Castanheira M, Huband MD, Shortridge D, Carvalhaes CG, Mendes RM. Antimicrobial activity of dalbavancin against Gram-positive bacteria isolated from patients hospitalized with bloodstream infection in United States and European medical centers (2018-2020). Eur J Clin Microbiol Infect Dis. 2022 May;41(5):867-873. doi: 10.1007/s10096-022-04437-0. Epub 2022 Mar 30.
citation: Goldstein EJ, Citron DM, Warren YA, Tyrrell KL, Merriam CV, Fernandez HT. In vitro activities of dalbavancin and 12 other agents against 329 aerobic and anaerobic gram-positive isolates recovered from diabetic foot infections. Antimicrob Agents Chemother. 2006 Aug;50(8):2875-9. doi: 10.1128/AAC.00286-06.
citation: Madry R, Struzyna J, Stachura-Kulach A, Drozdz L, Bugaj M. Effectiveness of Suprathel(R) application in partial thickness burns, frostbites and Lyell syndrome treatment. Pol Przegl Chir. 2011 Oct;83(10):541-8. doi: 10.2478/v10035-011-0086-5.
citation: Heil K, Thomas R, Robertson G, Porter A, Milner R, Wood A. Freezing and non-freezing cold weather injuries: a systematic review. Br Med Bull. 2016 Mar;117(1):79-93. doi: 10.1093/bmb/ldw001. Epub 2016 Feb 12.
citation: Gonzaga T, Jenabzadeh K, Anderson CP, Mohr WJ, Endorf FW, Ahrenholz DH. Use of Intra-arterial Thrombolytic Therapy for Acute Treatment of Frostbite in 62 Patients with Review of Thrombolytic Therapy in Frostbite. J Burn Care Res. 2016 Jul-Aug;37(4):e323-34. doi: 10.1097/BCR.0000000000000245.
citation: Goertz O, Hirsch T, Buschhaus B, Daigeler A, Vogelpohl J, Langer S, Steinau HU, Ring A. Intravital pathophysiologic comparison of frostbite and burn injury in a murine model. J Surg Res. 2011 May 15;167(2):e395-401. doi: 10.1016/j.jss.2011.01.034. Epub 2011 Feb 18.
citation: Cauchy E, Cheguillaume B, Chetaille E. A controlled trial of a prostacyclin and rt-PA in the treatment of severe frostbite. N Engl J Med. 2011 Jan 13;364(2):189-90. doi: 10.1056/NEJMc1000538. No abstract available.
citation: Imray C, Grieve A, Dhillon S; Caudwell Xtreme Everest Research Group. Cold damage to the extremities: frostbite and non-freezing cold injuries. Postgrad Med J. 2009 Sep;85(1007):481-8. doi: 10.1136/pgmj.2008.068635.
citation: Woodmansey EJ, Roberts CD. Appropriate use of dressings containing nanocrystalline silver to support antimicrobial stewardship in wounds. Int Wound J. 2018 Dec;15(6):1025-1032. doi: 10.1111/iwj.12969. Epub 2018 Aug 17.
citation: Silverstein P, Heimbach D, Meites H, Latenser B, Mozingo D, Mullins F, Garner W, Turkowski J, Shupp J, Glat P, Purdue G. An open, parallel, randomized, comparative, multicenter study to evaluate the cost-effectiveness, performance, tolerance, and safety of a silver-containing soft silicone foam dressing (intervention) vs silver sulfadiazine cream. J Burn Care Res. 2011 Nov-Dec;32(6):617-26. doi: 10.1097/BCR.0b013e318236fe31.
citation: Norman G, Christie J, Liu Z, Westby MJ, Jefferies JM, Hudson T, Edwards J, Mohapatra DP, Hassan IA, Dumville JC. Antiseptics for burns. Cochrane Database Syst Rev. 2017 Jul 12;7(7):CD011821. doi: 10.1002/14651858.CD011821.pub2.
citation: Dat AD, Poon F, Pham KB, Doust J. Aloe vera for treating acute and chronic wounds. Cochrane Database Syst Rev. 2012 Feb 15;2012(2):CD008762. doi: 10.1002/14651858.CD008762.pub2.
citation: Miller MB, Koltai PJ. Treatment of experimental frostbite with pentoxifylline and aloe vera cream. Arch Otolaryngol Head Neck Surg. 1995 Jun;121(6):678-80. doi: 10.1001/archotol.1995.01890060076015.
citation: Klein AD, Penneys NS. Aloe vera. J Am Acad Dermatol. 1988 Apr;18(4 Pt 1):714-20. doi: 10.1016/s0190-9622(88)70095-x.
citation: Heggers JP, Robson MC, Manavalen K, Weingarten MD, Carethers JM, Boertman JA, Smith DJ Jr, Sachs RJ. Experimental and clinical observations on frostbite. Ann Emerg Med. 1987 Sep;16(9):1056-62. doi: 10.1016/s0196-0644(87)80758-8.
citation: Khaira HS, Coddington T, Drew A, Roberts PN, Imray CH. Patellar tendon bearing orthosis--application as adjunctive treatment in healing of lower-limb tissue loss. Eur J Vasc Endovasc Surg. 1998 Dec;16(6):485-8. doi: 10.1016/s1078-5884(98)80238-4.
citation: Imray CH, Oakley EH. Cold still kills: cold-related illnesses in military practice freezing and non-freezing cold injury. J R Army Med Corps. 2005 Dec;151(4):218-22. doi: 10.1136/jramc-151-04-02. No abstract available.
citation: Cauchy E, Chetaille E, Marchand V, Marsigny B. Retrospective study of 70 cases of severe frostbite lesions: a proposed new classification scheme. Wilderness Environ Med. 2001 Winter;12(4):248-55. doi: 10.1580/1080-6032(2001)012[0248:rsocos]2.0.co;2.
citation: Cauchy E, Marsigny B, Allamel G, Verhellen R, Chetaille E. The value of technetium 99 scintigraphy in the prognosis of amputation in severe frostbite injuries of the extremities: A retrospective study of 92 severe frostbite injuries. J Hand Surg Am. 2000 Sep;25(5):969-78. doi: 10.1053/jhsu.2000.16357.
citation: Handford C, Thomas O, Imray CHE. Frostbite. Emerg Med Clin North Am. 2017 May;35(2):281-299. doi: 10.1016/j.emc.2016.12.006.
citation: Zaramo TZ, Green JK, Janis JE. Practical Review of the Current Management of Frostbite Injuries. Plast Reconstr Surg Glob Open. 2022 Oct 24;10(10):e4618. doi: 10.1097/GOX.0000000000004618. eCollection 2022 Oct.
citation: Bruen KJ, Ballard JR, Morris SE, Cochran A, Edelman LS, Saffle JR. Reduction of the incidence of amputation in frostbite injury with thrombolytic therapy. Arch Surg. 2007 Jun;142(6):546-51; discussion 551-3. doi: 10.1001/archsurg.142.6.546.
citation: Bennett BL, Holcomb JB. Battlefield Trauma-Induced Hypothermia: Transitioning the Preferred Method of Casualty Rewarming. Wilderness Environ Med. 2017 Jun;28(2S):S82-S89. doi: 10.1016/j.wem.2017.03.010. Epub 2017 May 5.
citation: DeGroot DW, Rappole CA, McHenry P, Englert RM. Seasonal Trends for Environmental Illness Incidence in the U.S. Army. Mil Med. 2022 May 3;187(5-6):e672-e677. doi: 10.1093/milmed/usab072.