Thrombin peptide Chrysalin stimulates healing of diabetic foot ulcers in a placebo-controlled phase I/II study.

Thrombin and thrombin peptides play a role in initiating tissue repair. The potential safety and efficacy of TP508 (Chrysalin) treatment of diabetic foot ulcers was evaluated in a 60-subject, prospective, randomized, double-blind, placebo-controlled phase I/II clinical trial. Chrysalin in saline or saline alone was applied topically, twice weekly, to diabetic ulcers with standardized care and offloading. A dose-dependent effect was seen in the per-protocol population where 1 and 10 mug Chrysalin treatment resulted in 45 and 72% more subjects with complete healing than placebo treatment. Chrysalin treatment of foot ulcers more than doubled the incidence of complete healing (p<0.05), increased mean closure rate approximately 80% (p<0.05), and decreased the median time to 100% closure by approximately 40% (p<0.05). Chrysalin treatment of heel ulcers within this population resulted in mean closure rates 165% higher than placebos (p<0.02) and complete healing in 86% (6/7) of ulcers compared with 0% (0/5) of placebo ulcers (p<0.03). Local wound reactions and adverse events (AEs) were equal between groups with no reported drug-related changes in laboratory tests or serious AEs. These results indicate the potential safety and efficacy of Chrysalin for treatment of diabetic foot ulcers.

Diagnosis and treatment of diabetic foot infections.

EXECUTIVE SUMMARY: 1. Foot infections in patients with diabetes cause substantial morbidity and frequent visits to health care professionals and may lead to amputation of a lower extremity. 2. Diabetic foot infections require attention to local (foot) and systemic (metabolic) issues and coordinated management, preferably by a multidisciplinary foot-care team (A-II). The team managing these infections should include, or have ready access to, an infectious diseases specialist or a medical microbiologist (B-II). 3. The major predisposing factor to these infections is foot ulceration, which is usually related to peripheral neuropathy. Peripheral vascular disease and various immunological disturbances play a secondary role. 4. Aerobic Gram-positive cocci (especially Staphylococcus aureus) are the predominant pathogens in diabetic foot infections. Patients who have chronic wounds or who have recently received antibiotic therapy may also be infected with Gram-negative rods, and those with foot ischemia or gangrene may have obligate anaerobic pathogens. 5. Wound infections must be diagnosed clinically on the basis of local (and occasionally systemic) signs and symptoms of inflammation. Laboratory (including microbiological) investigations are of limited use for diagnosing infection, except in cases of osteomyelitis (B-II). 6. Send appropriately obtained specimens for culture before starting empirical antibiotic therapy in all cases of infection, except perhaps those that are mild and previously untreated (B-III). Tissue specimens obtained by biopsy, ulcer curettage, or aspiration are preferable to wound swab specimens (A-I). 7. Imaging studies may help diagnose or better define deep, soft-tissue purulent collections and are usually needed to detect pathological findings in bone. Plain radiography may be adequate in many cases, but MRI (in preference to isotope scanning) is more sensitive and specific, especially for detection of soft-tissue lesions (A-I). 8. Infections should be categorized by their severity on the basis of readily assessable clinical and laboratory features (B-II). Most important among these are the specific tissues involved, the adequacy of arterial perfusion, and the presence of systemic toxicity or metabolic instability. Categorization helps determine the degree of risk to the patient and the limb and, thus, the urgency and venue of management. 9. Available evidence does not support treating clinically uninfected ulcers with antibiotic therapy (D-III). Antibiotic therapy is necessary for virtually all infected wounds, but it is often insufficient without appropriate wound care. 10. Select an empirical antibiotic regimen on the basis of the severity of the infection and the likely etiologic agent(s) (B-II). Therapy aimed solely at aerobic Gram-positive cocci may be sufficient for mild-to-moderate infections in patients who have not recently received antibiotic therapy (A-II). Broad-spectrum empirical therapy is not routinely required but is indicated for severe infections, pending culture results and antibiotic susceptibility data (B-III). Take into consideration any recent antibiotic therapy and local antibiotic susceptibility data, especially the prevalence of methicillin-resistant S. aureus (MRSA) or other resistant organisms. Definitive therapy should be based on both the culture results and susceptibility data and the clinical response to the empirical regimen (C-III). 11. There is only limited evidence with which to make informed choices among the various topical, oral, and parenteral antibiotic agents. Virtually all severe and some moderate infections require parenteral therapy, at least initially (C-III). Highly bioavailable oral antibiotics can be used in most mild and in many moderate infections, including some cases of osteomyelitis (A-II). Topical therapy may be used for some mild superficial infections (B-I). 12. Continue antibiotic therapy until there is evidence that the infection has resolved but not necessarily until a wound has healed. Suggestions for the duration of antibiotic therapy are as follows: for mild infections, 12 weeks usually suffices, but some require an additional 12 weeks; for moderate and severe infections, usually 24 weeks is sufficient, depending on the structures involved, the adequacy of debridement, the type of soft-tissue wound cover, and wound vascularity (A-II); and for osteomyelitis, generally at least 46 weeks is required, but a shorter duration is sufficient if the entire infected bone is removed, and probably a longer duration is needed if infected bone remains (B-II). 13. If an infection in a clinically stable patient fails to respond to 1 antibiotic courses, consider discontinuing all antimicrobials and, after a few days, obtaining optimal culture specimens (C-III). 14. Seek surgical consultation and, when needed, intervention for infections accompanied by a deep abscess, extensive bone or joint involvement, crepitus, substantial necrosis or gangrene, or necrotizing fasciitis (A-II). Evaluating the limb's arterial supply and revascularizing when indicated are particularly important. Surgeons with experience and interest in the field should be recruited by the foot-care team, if possible. 15. Providing optimal wound care, in addition to appropriate antibiotic treatment of the infection, is crucial for healing (A-I). This includes proper wound cleansing, debridement of any callus and necrotic tissue, and, especially, off-loading of pressure. There is insufficient evidence to recommend use of a specific wound dressing or any type of wound healing agents or products for infected foot wounds. 16. Patients with infected wounds require early and careful follow-up observation to ensure that the selected medical and surgical treatment regimens have been appropriate and effective (B-III). 17. Studies have not adequately defined the role of most adjunctive therapies for diabetic foot infections, but systematic reviews suggest that granulocyte colony-stimulating factors and systemic hyperbaric oxygen therapy may help prevent amputations (B-I). These treatments may be useful for severe infections or for those that have not adequately responded to therapy, despite correcting for all amenable local and systemic adverse factors. 18. Spread of infection to bone (osteitis or osteomyelitis) may be difficult to distinguish from noninfectious osteoarthropathy. Clinical examination and imaging tests may suffice, but bone biopsy is valuable for establishing the diagnosis of osteomyelitis, for defining the pathogenic organism(s), and for determining the antibiotic susceptibilities of such organisms (B-II). 19. Although this field has matured, further research is much needed. The committee especially recommends that adequately powered prospective studies be undertaken to elucidate and validate systems for classifying infection, diagnosing osteomyelitis, defining optimal antibiotic regimens in various situations, and clarifying the role of surgery in treating osteomyelitis (A-III).

Antibiotic treatment of osteomyelitis: what have we learned from 30 years of clinical trials?

OBJECTIVES AND DESIGN: To determine the most appropriate approach to antibiotic therapy for osteomyelitis, the medical literature for articles published from 1968 to 2000 was reviewed. RESULTS: Ninety-three clinical trials in children and adults were identified using almost every antibiotic class. Most studies were non-comparative and the comparative trials involved relatively few patients. Publications generally did not provide clinically important information regarding infection staging or classification, surgical treatment provided, or the presence of orthopedic hardware. The median duration of follow-up after treatment was only 12 months. The clinical outcome was better for acute than chronic osteomyelitis in eight of the 12 studies allowing comparison. In the comparative trials, few statistically significant differences were observed between the tested treatments. In one small trial, the combination of nafcillin plus rifampin was more effective than nafcillin alone. In pediatric osteomyelitis, oral therapy with cloxacillin was more effective than tetracycline in one study, and oral clindamycin was as effective as parenteral anti-staphylococcal penicillins in another. In several investigations oral fluoroquinolones were as effective as standard parenteral treatments. CONCLUSIONS: Although the optimal duration of antibiotic therapy remains undefined, most investigators treated patients for about six weeks. Despite three decades of research, the available literature on the treatment of osteomyelitis is inadequate to determine the best agent(s), route, or duration of antibiotic therapy.

An articulated antibiotic spacer used for infected total knee arthroplasty: a comparative in vitro elution study of Simplex and Palacos bone cements.

For the staged management of infected total knee arthroplasty (TKA), antibiotic laden polymethylmethacrylate (PMMA) spacers have been recommended. Antibiotic-impregnated PMMA spacers target drug delivery, achieving high local levels while limiting the potential for host toxicity associated with parenteral antimicrobial therapy. This study examined the elution characteristics of an articulating PMMA TKA spacer that has been useful clinically. Tobramycin and vancomycin are both active against many organisms leading to joint infections. We used various combined antibiotic concentrations (maintaining a relative ratio of 55% tobramycin to 45% vancomycin w/w), and then assayed the elution profile of the TKA spacer in vitro. Additionally, the elution qualities of two brands of bone cement, Simplex and Palacos, were compared. Briefly, three groups of PMMA spacers, impregnated with different antibiotic loads, were fashioned from a mold replicating a femoral TKA component. The entire spacer surface area was immersed in sterile phosphate buffered saline (PBS) in a 1:6 ratio of grams of cement to milliliters of PBS and incubated at 37 degrees C for 24 h. After 24 h, aliquot eluates were taken, the PBS discarded, and replaced with fresh, sterile PBS. PBS was changed daily and an aliquot was taken at least weekly for nine weeks. Eluate samples were stored at -70 degrees C until assayed. Each spacer eluate sample's antibiotic concentration was determined by disc diffusion bioassay against Bacillus subtilis. Mean zone inhibition diameters were extrapolated from the standard curve to yield micrograms per milliliter of antibiotic in PBS. In all groups the Palacos spacers demonstrated higher elution levels, above the MIC for the organism used, for a longer period of time than those made with Simplex. Based on the observed elution profiles, antibiotic-impregnated Palacos bone cement may offer a more effective vehicle for local drug delivery during staged treatment of infected TKA.

Osteomyelitis in long bones.

Osteomyelitis in long bones remains challenging and expensive to treat, despite advances in antibiotics and new operative techniques. Plain radiographs still provide the best screening for acute and chronic osteomyelitis. Other imaging techniques may be used to determine diagnosis and aid in treatment decisions. The decision to use oral or parenteral antibiotics should be based on results regarding microorganism sensitivity, patient compliance, infectious disease consultation, and the surgeon's experience. A suppressive antibiotic regimen should be directed by the results of cultures. Standard operative treatment is not feasible for all patients because of the functional impairment caused by the disease, the reconstructive operations, and the metabolic consequences of an aggressive therapy regimen. Operative treatment includes debridement, obliteration of dead space, restoration of blood supply, adequate soft-tissue coverage, stabilization, and reconstruction.

The application of bioimplants in the management of chronic osteomyelitis.

The management of musculoskeletal infections is an increasing challenge to clinicians. Bioimplants provide a unique system for skeletal specific drug delivery. Antibiotic-impregnated beads and spacers can be used to treat chronic osteomyelitis and deep soft-tissue infections locally with higher antibiotic concentrations, while avoiding potential systemic side effects.

Acute septic arthritis.

Acute septic arthritis may develop as a result of hematogenous seeding, direct introduction, or extension from a contiguous focus of infection. The pathogenesis of acute septic arthritis is multifactorial and depends on the interaction of the host immune response and the adherence factors, toxins, and immunoavoidance strategies of the invading pathogen. Neisseria gonorrhoeae and Staphylococcus aureus are used in discussing the host-pathogen interaction in the pathogenesis of acute septic arthritis. While diagnosis rests on isolation of the bacterial species from synovial fluid samples, patient history, clinical presentation, laboratory findings, and imaging studies are also important. Acute nongonococcal septic arthritis is a medical emergency that can lead to significant morbidity and mortality. Therefore, prompt recognition, rapid and aggressive antimicrobial therapy, and surgical treatment are critical to ensuring a good prognosis. Even with prompt diagnosis and treatment, high mortality and morbidity rates still occur. In contrast, gonococcal arthritis is often successfully treated with antimicrobial therapy alone and demonstrates a very low rate of complications and an excellent prognosis for full return of normal joint function. In the case of prosthetic joint infections, the hardware must be eventually removed by a two-stage revision in order to cure the infection.

Treatment of experimental osteomyelitis with a fibrin sealant antibiotic implant.

Two methods currently are available for the delivery of antibiotics: intravenous injection with a long-term indwelling catheter and local implant of antibiotic-containing polymethylmethacrylate beads. Both of these methods have significant disadvantages. A fibrin sealant implant, impregnated with tobramycin, was evaluated in a rabbit model of osteomyelitis to determine whether it has the potential of supplying a basis for bone reconstruction and providing an improved treatment method for the delivery of antibiotics to orthopaedic infections. Localized tibial osteomyelitis, with methicillin-sensitive Staphylococcus aureus, was developed surgically in female New Zealand White rabbits. After 2 weeks, rabbits with evidence of osteomyelitis were treated with debridement alone, debridement plus systemic tobramycin, debridement plus fibrin sealant, debridement plus fibrin sealant loaded with tobramycin, polymethylmethacrylate beads loaded with tobramycin, or not treated at all (control). After 4 weeks of therapy, the rabbits were sacrificed and the involved bones were cultured for concentrations of methicillin-sensitive Staphylococcus aureus per gram of bone and marrow. Preliminary data (N = 14) indicate fibrin sealant plus tobramycin may be as effective as polymethylmethacrylate beads plus tobramycin against methicillin-sensitive Staphylococcus aureus osteomyelitis in a rabbit model.

Long Bone Osteomyelitis.

Osteomyelitis is a complex disease that is often associated with high morbidity and considerable health care costs. Bacteremia, contiguous focuses of infection, penetrating trauma, or surgery are the major predisposing factors for this infection. Bone necrosis and bone destruction occur early in the course of osteomyelitis, leading to a chronic process and eliminating the host's ability to eradicate the pathogens. The presence of poorly vascularized tissues, the adherence to bone structures and implants, and a slow bacterial replication rate are recognized as important factors for the persistence of the infection. Treatment of osteomyelitis is particularly challenging and involves adequate antimicrobial therapy and surgical debridement of all necrotic bone and soft tissues. Antibiotic treatment is usually started on an empiric basis and then modified according to the results of cultures and sensitivity tests. Surgical treatment consists of debridement, obliteration of dead space, adequate soft tissue coverage, restoration of blood supply, and stabilization.

Molecular interactions in biofilms.

A biofilm may be defined as a microbially derived, sessile community characterized by cells that attach to an interface, embed in a matrix of exopolysaccharide, and demonstrate an altered phenotype. This review covers the current understanding of the nature of biofilms and the impact that molecular interactions may have on biofilm development and phenotype using the motile gram-negative rod Pseudomonas aeruginosa and the nonmotile gram-positive cocci Staphylococcus aureus as examples.

Experimental osteomyelitis treatment with antibiotic-impregnated hydroxyapatite.

A calcium hydroxyapatite antibiotic implant was evaluated to determine its efficacy as an antibiotic delivery system in a localized osteomyelitis rabbit model. Localized rabbit tibial osteomyelitis was developed with an intramedullary injection of methicillin resistant Staphylococcus aureus. Infected rabbits were randomized and divided into eight groups depending on treatment with or without debridement, systemic antibiotics, antibiotic-impregnated polymethylmethacrylate beads, or calcium hydroxyapatite implants with and without antibiotic impregnation. All treatments began 2 weeks after infection. After 4 weeks of therapy, the involved bones were cultured for concentrations of Staphylococcus aureus per gram of bone. Rabbits (n = 11) that had calcium hydroxyapatite (impregnated with vancomycin) implanted into the dead space after the debridement surgery had an 81.8% infection clearance after treatment. Rabbits (n = 10) that had polymethylmethacrylate beads (impregnated with vancomycin) implanted into the dead space after debridement surgery had a 70% clearance rate. All other treatment modalities resulted in less than 50% clearance rates. Calcium hydroxyapatite may be an effective alternative to polymethylmethacrylate for providing local antibiotic therapy in cases of methicillin resistant Staphylococcus aureus osteomyelitis.

Gatifloxacin efficacy in treatment of experimental methicillin-sensitive Staphylococcus aureus-induced osteomyelitis in rabbits.

The effectiveness of oral gatifloxacin was compared to that of standard parenteral antibiotic therapy (nafcillin) for the treatment of experimental methicillin-sensitive Staphylococcus aureus-induced osteomyelitis in a rabbit model. Gatifloxacin was as effective as nafcillin in clearing the infection. Therefore, oral gatifloxacin treatment of osteomyelitis may be an effective alternative to intravenous nafcillin treatment.

Systemic Apophysomyces elegans after trauma: case report and literature review.

We present a case of systemic fungal infection caused by Apophysomyces elegans in a 50-year-old patient who developed a progressive skin lesion after a motor vehicle crash. Histopathological and mycological examination of the surgical sample showed non-septated hyphae characteristic of mucoraceous fungi. Despite extensive surgical debridement, and parenteral administration of amphotericin B, the patient died of multi-organ failure. Autopsy findings suggested systemic involvement. The fungi recovered from culture had non-apophyseal and globose sporangi, and branched sporaniophores and was identified as Apophysomyces elegans.