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J F Hansbrough

Publications and source records attributed to J F Hansbrough.

At least 19 recordsLinked to original sources
PubMed1999

Fibroblast sheets enable epithelialization of sounds that do not support keratinocyte migration.

Keratinocyte migration over the wound bed is the single most important parameter for wound epithelialization. Therefore, improvement of the wound bed matrix holds considerable promise for the shortening of hospitalization time in patients with ulcers, burns, and chronic wounds. We investigated wound epithelialization in athymic mice in the presence or absence of a sheet of cultured human fibroblasts. The physiology of keratinocyte growth on fibroblast sheets was investigated in tissue culture using histology, immunofluorescence, and electron microscopy. Keratinocytes from human skin explants were unable to attach or migrate on full-thickness dorsal wounds of athymic mice. Placement of a fibroblast-seeded polyglactin mesh on the wounds resulted in dramatically increased keratinocyte outgrowth. Similarly, human keratinocytes showed good outgrowth on fibroblast sheets at the air/liquid interface in tissue culture. Outgrowth was correlated inversely with fibroblast viability, indicating that the observed effect was due to the complex extracellular matrix secreted by the fibroblasts and matrix-bound growth factors rather than ongoing growth factor release. Collagen IV, a promoter of keratinocyte migration, was found to be abundant in the fibroblast-derived matrix. This study demonstrates that wounds which are unable to support keratinocyte migration can undergo epithelialization if a conducive substrate, supplying appropriate extracellular matrix and/or matrix-bound growth factors, is applied.

Animals↗
PubMed1999

The effects of diaspirin cross-linked hemoglobin on hemodynamics, metabolic acidosis, and survival in burned rats.

OBJECTIVE: Diaspirin cross-linked hemoglobin (DCLHb) is a vasoactive hemoglobin-based oxygen carrier or "blood substitute" that has been shown to improve base deficit in several experimental studies of hemorrhagic shock. Our objective was to determine if the addition of DCLHb to the resuscitation regimen would improve hemodynamic parameters, metabolic acidosis, and survival in our rat burn shock model compared with currently used resuscitation therapy. METHODS: This was a randomized, controlled, experimental rat study. Male Wistar rats, weighing 200 to 250 g, were surgically prepared for an acute study. After placement of indwelling catheters, baseline hemodynamic values (mean arterial pressure, cardiac output, systemic vascular resistance, stroke volume, and base excess) were obtained. Thirty-two rats were used in the study, and they were either subjected to a 30% scald burn (experimental group) or sham burned (control group). The experimental animals were immediately intravenously resuscitated and followed for 6 hours. The resuscitation was based on the Parkland formula (4 mL/kg for each 1% of total body surface area [TBSA] burn), with 50% of the calculated fluid amount to be administered at a constant rate during the first 8 hours after burn. The animals were resuscitated for 6 hours and received between 9.00 and 11.25 mL of fluid depending on weight. The experimental animals were randomly assigned to one of three treatment groups: group I, lactated Ringer's solution; group II, lactated Ringer's solution-human serum albumin; group III, lactated Ringer's solution-DCLHb. Group I (n = 8) received 4 mL/kg lactated Ringer's solution for each 1% of TBSA burn. Group II (n = 8) received 2 mL/kg lactated Ringer's solution and 2 mL/kg human serum albumin for each 1% of TBSA burn. Group III (n = 8) received 2 mL/kg lactated Ringer's solution and 2 mL/kg DCLHb for each 1% of TBSA burn. The sham group (n = 8) was not burned and was not resuscitated. Animals that survived up to 6 six hours were killed. RESULTS: We found that mean arterial pressure, cardiac output, stroke volume, and base excess were all improved in the DCLHb-lactated Ringer's solution-treated animals compared with the other experimental treatment groups. The 6-hour mortality rates were zero of eight (lactated Ringer's solution-DCLHb group), zero of eight (sham group), three of eight (lactated Ringer's solution-human serum albumin group), and six of eight (lactated Ringer's solution only group). CONCLUSION: Early resuscitation with DCLHb is superior to non-oxygen-carrying resuscitative fluids in improving hemodynamics and survival in this model of burn shock. DCLHb might improve general tissue perfusion in the acute postburn period, and it could be useful in the early management of patients with severe burns.

Acidosis↗
PubMed1999

Multicenter trial to evaluate the safety and potential efficacy of pooled human fibrin sealant for the treatment of burn wounds.

OBJECTIVE: The primary purpose of this multicenter study was to evaluate the safety and potential efficacy of a solvent/detergent-treated commercial fibrin sealant (human) for topical hemostasis in skin grafting. METHODS: The study involved a prospective evaluation of changes in viral titers in patients with burns less than 15% after treatment with fibrin sealant (human). Each patient served as his/her own control for an unblinded, randomized comparison of donor site hemostasis and healing. Preoperative serum was obtained to screen for viral titers. At autografting, the recipient site and one of two randomly chosen donor sites were treated with fibrin sealant (human). The use of other hemostatic agents, including epinephrine was prohibited. Each donor site was covered with gauze to collect blood for estimation of the relative amount of bleeding. The healing of the graft and donor sites was observed. Viral titers and wounds were checked monthly for 6 months, and at 9 and 12 months postoperatively. RESULTS: Viral titers for human immunodeficiency virus; hepatitis A, B, and C; Epstein-Barr virus; and cytomegalovirus were obtained before and after treatment. Of 47 patients, 34 completed the full year of observation. After treatment, there were no seroconversions to any of the aforementioned viruses. Bleeding at the recipient site appeared well controlled with fibrin sealant (human). Although investigators felt that fibrin sealant (human) improved donor site hemostasis, differences in hemoglobin measurements of blood-soaked dressings failed to reach significance. No differences were noted with regard to acceleration of donor site healing, graft take, or scar maturation at the two groups of donor sites. Anecdotally, the maturation of the recipient site appeared to be accelerated. CONCLUSION: Fibrin sealant (human) is safe for use during excision and grafting, and its topical hemostatic potential needs to be examined in patients with larger burns. Its role in scar maturation also needs to be investigated.

Adolescent↗
PubMed1999

Pediatric burns.

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Burns↗
PubMed1999

Comparison of resuscitation with diaspirin crosslinked hemoglobin (DCLHb) vs fresh blood in a rat burn shock model.

Diaspirin crosslinked hemoglobin (DCLHb; Baxter Healthcare Corp, Deerfield, IL) is hemoglobin-based oxygen carrier which, in our laboratory, improved hemodynamic parameters in a rat burn shock model. Our objective was to compare the effects on hemodynamic parameters and metabolic acidosis of resuscitation with different doses of fresh blood (FB) vs DCLHb. Male Wistar rats (200 to 250 g), surgically prepared for an acute study, were randomly assigned to one of five treatment groups. (n = 8): I. SHAM (not burned, not resuscitated), II. DCLHb 2 ml/kg/% Total Body Surface Area (TBSA) burn and 2 ml/kg/% TBSA burn of Lactated Ringers (LR), III. DCLHb 1 ml/kg/% TBSA burn and 1 ml/kg/% TBSA burn of LR IV. FB 2 ml/kg/% TBSA burn and 2 ml/kg/% TBSA burn of LR V. FB 1 ml/kg/% TBSA burn and 1 ml/kg/% TBSA burn of LR After placement of indwelling catheters, the following baseline hemodynamic values were obtained mean arterial pressure (MAP), cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR) and base excess (BE). The animals were immediately intravenously resuscitated after receiving a 30% scald burn and were followed for 6 hours. Resuscitation was based on the Parkland formula. Blood was obtained from donor male Wistar rats. The animals were euthanized at 6 hours. MAP remained within normal range in all groups. The SVR, CO, SV and BE were normalized earlier in the LR-DCLHb groups when compared to the LR-FB groups (p < 0.05). Early resuscitation with DCLHb is superior to FB in improving hemodynamics in this model. There appears to be a direct relationship between dose and effect with the use of DCLHb. DCLHb could be useful in decreasing resuscitation fluid requirements in acute burns without compromising general tissue perfusion.

Animals↗
PubMed1998

Enteral nutritional support in burn patients.

Early and continued nutritional support has been determined to be an important component of therapy for seriously burned patients. The hypermetabolic response to severe injury requires increased calorie and protein intake to blunt the catabolism and loss of lean muscle mass. Enteral feeding has been found to directly nourish the gastrointestinal tract and may help reverse the defective gut barrier which accompanies burn shock. In contrast, intravenous nutritional support appears to lack effectiveness in burn patients and may actually increase morbidity and mortality.

Body Constitution↗
PubMed1998

Skin replacements.

There is much progress to be made to optimize the development of laboratory-grown temporary and permanent skin replacements. Replacement of both epidermal and dermal layers is important for achieving optimal take of cultured grafts and for optimizing the quality of wound healing. Although the use of retained cadaver allodermis on the wound bed may improve the performance of cultured epithelium, the development of successful, complete dermal-epidermal skin replacements (composite grafts) would greatly simplify burn management. In the future, handling and stability of the cultured grafts should be improved, and clinical outcomes should be expected to be superior. Unfortunately, funding for this type of applied research has not achieved high priority from the federal government granting agencies, despite the great clinical need for improved technology. Future progress depends largely upon commercial support.

Biological Dressings↗
PubMed1997

Functions of the POU domain genes Skn-1a/i and Tst-1/Oct-6/SCIP in epidermal differentiation.

Here we report on investigation of the role of the POU domain genes Skin-1a/i (Skn-1a/i/Epoc/Oct-11) and Testes-1 (Tst-1/Oct-6/SCIP) in epidermis where proliferating basal keratinocytes withdraw from the cell cycle, migrate suprabasally, and terminally differentiate to form a multilayered, stratified epithelium. The expression of the Skn-1a/i and Tst-1 genes is linked to keratinocyte differentiation in vivo and in vitro, whereas the ubiquitous POU domain factor Oct-1 is expressed highly in both proliferating and post-mitotic keratinocytes. Analysis of Skn-1a/i gene-deleted mice reveals that the Skn-1a/i gene modulates the pattern of expression of the terminal differentiation marker loricrin and inhibits expression of genes encoding markers of the epidermal keratinocyte wounding response. Although epidermis from Tst-1 gene-deleted mice develops normally, epidermis from mice deleted for both Skn-1a/i and Tst-1 is hyperplastic and fails to suppress expression of K14 and Spr-1 in suprabasal cells when transplanted onto athymic mice. This suggests that Skn-1a/i and Tst-1 serve redundant functions in epidermis. Therefore, at least two POU domain genes, Skn-1a/i and Tst-1, serve both distinct and overlapping functions to regulate differentiation of epidermal keratinocytes during normal development and wound healing.

Animals↗
PubMed1997

Role of melanoma growth stimulatory activity (MGSA/gro) on keratinocyte function in wound healing.

Melanoma growth stimulatory activity/gro alpha (MGSA), a member of the alpha-chemokine family, is produced by a variety of dermal and epidermal cells and can act in a paracrine and autocrine fashion. However, little is known about the importance of MGSA in wound healing. In this study, we quantified the levels of MGSA protein in burn blister and donor site wound fluids. We studied the effects of MGSA on proliferation and migration of primary human keratinocytes and modulation of their integrin expression. Blister fluids contained 0.79 ng/ml (range 0.018 to 4.86 ng/ml) MGSA. Substantial increasing amounts of MGSA were found in donor site fluids from day 1 through day 5 with mean levels ranging from 1.77 to 103 ng/ml at postoperative day 5, which correlated with increasing amounts of tumor necrosis factor alpha (r = 0.86), a known stimulus for MGSA production. In vitro proliferation experiments revealed a maximum stimulation (2.6-fold) with 10 ng/ ml MGSA for 7 days over unstimulated keratinocyte controls; the ED50 was 0.2 ng/ml. DNA content analysis revealed an increase in S phase with 10 ng/ml MGSA stimulation. In cultured keratinocytes, MGSA enhanced the mean fluorescence intensity for alpha 6, while no significant change was seen for beta 1, alpha 2 and alpha 5. We also studied the effect of topically applied MGSA (50 ng/cm2) on the healing of meshed split-thickness human skin grafts on athymic mice. In these wounds, MGSA stimulated the rate of epithelialization (P < 0.05) at day 7, and an increased proportion of mitotic keratinocytes was observed. Wound contraction was significantly (P < 0.05) reduced on days 7 and 14 in the MGSA-treated group. These results suggest that MGSA participates in wound healing by stimulating keratinocyte proliferation.

Animals↗
PubMed1996

Neutrophil activation and tissue neutrophil sequestration in a rat model of thermal injury.

Neutrophil (PMN) deposition in tissues (leukosequestration) after shock may produce local tissue injury from proteases and oxygen intermediaries which are released from sequestered PMNs. We quantified leukosequestration in tissues in burned rats using two methods of analysis: 1), measurement of lung myeloperoxidase (MPO); 2), measurement of radiolabeled PMNs and erythrocytes deposited in multiple tissues. After tracheostomy and venous cannulation, rats received 17% TBSA full-thickness contact burns and were resuscitated with 20 cc intraperitoneal saline. Lung PMNs were estimated by measuring MPO in lung tissue. PMN influx into lung, liver, spleen, gut, skin, muscle, kidney, and brain was determined by removing (preburn) and differentially radiolabeling PMNs (111In) and erythrocytes (51Cr), reinfusing cells 4.5 hr postburn, and measuring tissue radioactivity 5 hr postburn. Tissue edema was measured by determining extravasation of 125I-labeled albumin in tissues. Peripheral blood PMNs were analyzed for intracellular H2O2 content utilizing a fluorescent dye which reacts with H2O2 coupled with analysis of cell fluorescence by flow cytometry. MPO was elevated in lungs 8 hr postburn (P < 0.05). PMN influx into lung tissues was confirmed by histologic examination. Radioisotope studies demonstrated significant (P < 0.05) leukosequestration into lung, gut, kidney, skin, and brain tissues at 5 hr postburn. Respiratory burst activity of peripheral blood PMNs was increased 5 hr postburn (P < 0.05). Flow cytometric analysis indicated that peripheral blood PMNs were capable of producing markedly increased H2O2 levels 5 hr postburn. Tissue edema, manifested by radiolabeled albumin influx, was not seen in any tissues. Since others have shown that sequestration of metabolically active PMNs may induce remote tissue injury, therapies which block postburn leukosequestration may be able to improve clinical outcomes by limiting remote tissue injury.

Animals↗
PubMed1996

Current concepts in the development of cultured skin replacements.

Current tissue-culture techniques permit the rapid expansion of keratinocyte populations, such that an area of cultured epithelium equivalent to that of the surface of an adult can be obtained from an initial small skin biopsy. Unfortunately, technical obstacles have delayed the widespread clinical use of multilayered sheets of epithelium. These factors include difficulties in preparing and transferring fragile cultured epithelial sheets, as well as frequent unsatisfactory "take" of cultured grafts on the wound bed. As greater understanding of the complex interactions of cells and matrix evolves, so have new techniques in the field of cultured keratinocytes for grafting. We have utilized an animal model that allows us to examine some of these new methods and the factors which influence graft take. It has become clear that adhesion properties of keratinocytes, early delivery of proliferative keratinocytes to the wound, the development of dermal replacements, and improved delivery systems for keratinocytes are important factors which must be considered for the optimal provision of skin replacements.

Animals↗
PubMed1996

Wound closure with human keratinocytes cultured on a polyurethane dressing overlaid on a cultured human dermal replacement.

BACKGROUND: Burn excision followed by immediate wound coverage has become the clinical standard for managing extensive burn injuries in much of the world. When sufficient autograft skin to achieve permanent wound closure is unavailable, cell culture technology has made the use of cultured human keratinocyte (HK) sheets clinically feasible. Whereas previous techniques have focused on development of multilayered, differentiated HK sheets, our attention has been drawn to using HK in a highly proliferative, less differentiated state. Time requirements for preparation of multistratified cultured HK are high, and preparatory steps may destroy important integrin adhesion molecules. METHODS: We describe the use of HK cultured to single layer confluence on a polyurethane membrane(HD), with serum-free medium. HK-HD grafts were transplanted to full-thickness wounds on athymic mice (n = 31). A second group of mice (DG-HK-HD), n = 28) received a living human dermal replacement containing cultured fibroblasts before placement of HK-HD. Control mice received HD alone (n = 4). Basement membrane proteins on healed wounds and surface integrins on cultured HK were identified by means of immunostaining and direct microscopic visualization. RESULTS: HK cultured just to the confluent state on polyurethane membrane were positive for integrins alpha(5) and alpha(6), major integrins on proliferating HK. Histologic analysis showed epithelialized wounds in all groups after 21 days. Using an anti-human involucrin antibody we demonstrated the presence of HK in 64.5% of the HK-HD group, 61% of the DG-HK-HD group, and 0% in the HD group. Mice that received the living human dermal replacement containing cultured fibroblasts in combination with HK-HD grafts developed a thick, well-vascularized neodermis. Strong laminin and collagen IV staining was observed in wound areas covered with HK. CONCLUSIONS: These data show that full-thickness wounds can be closed by application of a single layer of proliferating HK cultured on a biocompatible polyurethane membrane. This technique is an alternative to the use of multilayered, differentiated HK sheets. Preparation times for HK-HD grafts should be significantly shorter than required for multilayered HK sheets, technical efforts should be less, and more extensive wound areas could be covered.

Animals↗
PubMed1996

Effects of E-selectin and P-selectin blockade on neutrophil sequestration in tissues and neutrophil oxidative burst in burned rats.

OBJECTIVE: Neutrophil deposition in tissues (leukosequestration) after shock may produce local tissue injury from proteases and high-energy oxygen species released from sequestered neutrophils. The initial step in the binding of neutrophils to capillary endothelium is the interaction of adhesion molecule (selectin) receptors between neutrophils and endothelial cells. We quantified leukosequestration in the tissues of burned rats using two methods of analysis: a) measurement of lung myeloperoxidase; and b) measurement of radiolabeled neutrophils and erythrocytes deposited in multiple tissues. We then determined the ability of a selectin receptor blocking agent to affect neutrophil deposition in tissues after burn injury. DESIGN: Prospective, controlled, laboratory study. SETTING: University research laboratory. SUBJECTS: Male Wistar rats (200 to 300 g). INTERVENTIONS: After tracheostomy and venous cannulation, rats received 17% total body surface area full-thickness contact burns and were resuscitated with saline (20 mL i.p.). Experimental animals received 2 mg/kg body weight i.v. administration of a P- and E-selectin blocking monoclonal antibody, CY-1747, immediately after burn. Lung tissue neutrophils were estimated by measuring myeloperoxidase in lung tissue. Neutrophil retention in lung, liver, spleen, gut, skin, muscle, kidney, and brain tissues was determined by removing (preburn) and differentially radiolabeling neutrophils (111In) and erythrocytes (51Cr), reinfusing cells 4.5 hrs after burn, and measuring tissue radioactivity 30 mins later. Edema was estimated by measuring extravasated 125 I-labeled albumin in the various tissues. Peripheral blood neutrophils were analyzed for intracellular hydrogen peroxide content, utilizing a fluorescent dye that reacts with hydrogen peroxide, coupled with analysis of cell fluorescence by flow cytometry. MEASUREMENTS AND MAIN RESULTS: Myeloperoxidase concentration was increased in lungs 5 hrs after burn (p < .05), indicating neutrophil deposition. Radioisotope studies demonstrated significant (p < .05) leukosequestration into the lung, gut, kidney, skin, and brain tissues at 5 hrs after burn. Flow cytometry showed increased intracellular hydrogen peroxide content in peripheral blood neutrophils 5 hrs after burn. Tissue edema, manifested by radiolabeled albumin retention, was not seen in any tissues. Postburn neutrophil deposition in lungs and liver was blocked (p < .05) by administration of CY-1747 after burn, but maximal neutrophil hydrogen peroxide content was unaffected. CONCLUSION: Burn injury in rats results in accumulation of neutrophils in multiple tissues. Neutrophil deposition in the lungs and liver is blocked by administration of the E/P-selectin blocking antibody, CY-1747. Since sequestration of metabolically active neutrophils may induce tissue injury, therapies that block postburn leukosequestration may improve clinical outcomes by limiting remote tissue injury.

Animals↗
PubMed1995

Effects of small-volume bolus treatment with intravenous normal saline and 7.5 per cent saline in combination with 6 per cent dextran-40 on metabolic acidosis and survival in burned mice.

Standard murine burn models include the administration of intraperitoneal (i.p.) saline solutions which are intended to resuscitate the animals during subsequent burn shock. Prehospital administration of small volumes of concentrated salt solutions has been recommended for the early treatment of haemorrhagic shock, and have also been utilized for burn shock. We studied the effects of bolus intravenous (i.v.) hypertonic saline (HS) or hypertonic saline/dextran-40 (HS + DEX) on animal survival and acid-base balance following 25 per cent total body surface area, full-thickness burn injury in mice. I.v. injections were administered via a tail vein immediately prior to burn injury. Some mice received 1 ml i.p. normal saline (NS) immediately after burn injury. Acid-base balance of vena caval blood was measured during the period of maximal metabolic acidosis following burn injury (12 h postburn). Preburn i.v. administration of 5 ml/kg of HS or HS+DEX, followed by 1 ml i.p. NS, only slightly decreased the degree of metabolic acidosis compared to animals receiving i.p. fluid alone, the standard resuscitation regimen for burned mice. Preburn i.v. administration of 0.2 ml volumes of HS or HS + DEX, without i.p. fluid administration, resulted in extremely high mortality. Immediate preburn i.v. administration of HS or HS + DEX did not eliminate metabolic acidosis in this murine burn model, and markedly increased the mortality when subsequent i.p. fluids were not administered. The degree of metabolic acidosis in the murine experimental burn model has not previously been clearly described. Furthermore, adequate fluid resuscitation of these animals may be difficult to achieve without indwelling vascular catheters which could deliver continuous i.v. fluids following burn injury.

Acid-Base Equilibrium↗
PubMed1995

Effects of early and delayed wound excision on pulmonary leukosequestration and neutrophil respiratory burst activity in burned mice.

BACKGROUND: Tissue myeloperoxidase (MPO) is a marker of neutrophil (PMN) accumulation in tissues (leukosequestration). We measured MPO in the livers, guts, and lungs of mice after burn injury and studied the additive effect of burn excision on lung MPO. Lung histologic characteristics were also examined. PMN respiratory activity was assessed by measuring intracellular H2O2 content. METHODS: Mice received 32% total body surface area (TBSA) burns; some underwent burn excision followed by wound closure with allograft skin, either immediately or 48 hours after burn. Tissue MPO was measured by a colormetric assay, and intracellular H2O2 was quantified by flow cytometry. RESULTS: MPO was elevated in lungs 8 to 24 hours after burn (p < 0.05) but not in the liver or ileum. Other burned mice received either immediate or 48-hour-delayed wound excision and allografting. In controls a similar-size area was excised and grafted with normal or burned skin. Burned animals had increased lung MPO compared with nonburned animals (p < 0.05). Highest lung MPO levels were seen after burn/immediate excision (p < 0.001). Lung MPO levels were not different comparing unburned mice undergoing skin excision and grafting with either nonburned or burned skin. When burn excision was delayed 48 hours, lung MPO was increased moderately (p < 0.05) but remained far below levels in mice that were excised immediately after burn. PMN influx into lung tissues was confirmed by histologic examination. PMN H2O2 production was increased in burned mice and was additionally increased after immediate wound excision. CONCLUSIONS: Although burn injury produces pulmonary leukosequestration, the phenomenon is unrelated to local effects of burned skin. In this experimental model immediate postburn wound excision increased pulmonary leukosequestration to higher levels than after burn injury alone, and intracellular H2O2 content also increased. Pulmonary leukosequestration may predispose to lung injury, possibly limiting the benefits of wound excision performed extremely early postburn.

Animals↗
PubMed1995

Soft tissue infection prophylaxis with gentamicin encapsulated in multivesicular liposomes: results from a prospective, randomized trial.

OBJECTIVES: Systemically administered antibiotic agents are not evenly distributed in the body, which frequently results in subtherapeutic regional drug concentrations, particularly in areas of poor vascularization, including wound sites. We have developed a lipid-based drug delivery system to provide prolonged levels of gentamicin in local tissues after local administration. Multivesicular liposomes are microspheres composed of lipid bilayer membranes surrounding multiple aqueous compartments that can contain drug. The preparation may be effective for the prevention and treatment of a variety of infections, including infections associated with indwelling vascular catheters. DESIGN: Prospective, randomized trial. SETTING: Animal laboratory. SUBJECTS: Mice, 6 to 12 wks of age, weighing 20 to 30 g. INTERVENTIONS: We administered 0.5 mg of gentamicin encapsulated in multivesicular liposomes to dorsal subcutaneous tissue in mice. Animals were inoculated with 10(5) to 10(7) colony-forming units (cfu) of Staphylococcus aureus 2, 4, 6, and 8 days later. The cfu/g of tissue values were determined 2 days after inoculation. MEASUREMENTS AND MAIN RESULTS: With a 10(7) cfu challenge, animals that received 2- and 4-day pretreatment with multivesicular liposome/gentamicin had a 4 log10 reduction in cfu/g of tissue compared with controls. When 10(5) cfu of Staphylococcus aureus were inoculated after 2- and 4-day pretreatment with multivesicular liposome/gentamicin, a 6 log10 reduction in bacteria colony-forming units was observed. CONCLUSION: Local injection of multivesicular liposome/gentamicin provides sustained drug concentrations in regional tissues that protect against a massive bacterial challenge for at least four subsequent days.

Animals↗
PubMed1995

Lipid-based slow-release formulation of amikacin sulfate reduces foreign body-associated infections in mice.

Treatment and prophylaxis of uncomplicated infections with standard systemic antibiotics are usually successful. However, standard systemic antibiotic therapy alone is frequently unsatisfactory in certain circumstances, such as the presence of a foreign body (FB), necrotic tissue, overwhelming bacterial inoculum, or poor vascular supply to the involved tissues. We have developed a lipid-based sustained release formulation of amikacin sulfate (DepoFoam encapsulated amikacin sulfate [DEAS]) as a biodegradable, locally injectable antibiotic for such circumstances. The encapsulated drug is released over 7 to 10 days. We tested the efficacy of this formulation in an FB infection model in which Teflon tubes (length, 1 cm; outside diameter, 1.6 mm) were implanted into the subcutaneous tissue in mice and the local site was inoculated with 0.87 x 10(7) CFU of Staphylococcus aureus 3 days later. Inoculation was followed by either no treatment or a local injection of DEAS, free amikacin sulfate, non-drug-containing DepoFoam, or systemic free amikacin sulfate. All drug applications contained 1 mg of amikacin. One group was implanted with the FB and left unchallenged with bacteria and untreated as a sterile control group. All animals were sacrificed 10 days following FB implantation. FBs were retrieved from tissues by an aseptic technique and incubated in liquid culture media for 7 days. Local wound tissue was excised and processed to determine the number of CFU per gram of tissue. Treatment with local or systemic free amikacin had no effect on the number of infected FBs or on the log CFU in wound tissue compared with the untreated or non-drug-containing DepoFoam group. Compared with local free amikacin therapy, the number of infected FBs was reduced from 86 to 25% (P=0.02) following treatment with DEAS, and log CFU per gram of tissue was significantly decreased from 4.8 +/- 0.9 to 1.3 +/- 0.6 (P<0.0005). DEAS may have clinical utility as locally injected antibiotic in certain infections.

Amikacin↗