Antibiotics delivered by an implantable drug pump. A new application for treating osteomyelitis.

Osteomyelitis is usually treated with wide surgical debridement and prolonged intravenous antibiotics. The advent of the implantable drug pump has led us to evaluate this therapeutic modality for the treatment of osteomyelitis. We have previously shown that amikacin retains microbiologic activity in an implantable drug pump over a six-week period when incubated at 37 degrees C. We have also demonstrated in rabbits that high local levels and low systemic levels of antibiotic can be achieved using an implantable drug pump as a delivery system and that this method can be used to sterilize infected wounds. This method was applied in the treatment of osteomyelitis in 14 patients whose duration of symptoms ranged from one month to 22 years. In 13 patients, active drainage had been present for more than six months, and all patients had undergone one or more attempts at eradication of their infection. Prior therapy included surgical debridement alone (one patient), one or more attempts at debridement and extended intravenous antibiotic therapy (13 patients), debridement and local flap procedures (four patients), and extended oral antibiotic therapy (two patients). The bones involved were the tibia (six patients), femur (four patients), and elbow, shoulder, hip, and radius (one patient each). Intra-operative cultures indicated that the infecting organism was Staphylococcus aureus alone (seven patients), S. aureus in combination with gram-negative bacteria (five patients), or gram-negative organisms alone (two patients). Debridement and pump implantation were performed in one stage. On an outpatient basis, the pumps were filled with amikacin in a concentration determined by each patient's serum level. Duration of therapy was based upon cessation of drainage and erythrocyte sedimentation rate. During therapy, serum amikacin levels ranged from less than 2.5 micrograms/ml to 8.2 micrograms/ml. The amikacin concentration in the wound drainage was always greater than the upper limits of what could be measured (greater than 55 micrograms/ml to greater than 5,000 micrograms/ml). There were no cases of ototoxicity and one case of minimal renal toxicity (posttreatment creatinine clearance of 66 ml per minute; normal equal to 70 ml per minute). Length of therapy ranged from 32 to 140 days (mean equal to 63 days). Length of hospitalization ranged from five to 52 days (mean equal to 24 days). Drainage in all patients stopped during therapy, but resumed in three patients after pump removal--in two patients, for brief periods of time, and in one patient, it continues. Twelve patients have posttreatment erythrocyte sedimentation rates less than or equal to 20 mm per hour.(ABSTRACT TRUNCATED AT 400 WORDS)

Major pelvic fractures.

Pelvic fractures associated with blunt trauma contributed significantly to morbidity and mortality in 593 patients with high-velocity deceleration injuries. Those with open, hemorrhagic pelvic fractures required massive blood volume replacement and intensive care for long periods of time and had a 60% mortality. Patients with hemorrhagic pelvic fractures also had a notable blood replacement requirement (mean, 29 units) and a 50% mortality. Patients with open pelvic fractures without significant hemorrhage had a 25% mortality and were at an increased risk of pelvic sepsis. The overall mortality associated with pelvic fractures following high-velocity deceleration accidents was 16.6%. The identifiable causes of death in patients with pelvic fractures were associated injuries, particularly closed head injury, hemorrhage from pelvic vessels, and sepsis. An improved survival rate requires better, more prompt use of available treatment, as well as development of new and better methods of caring for severely injured patients with blunt trauma.

Antibiotic stability in an implantable pump.

We measured the stability of vancomycin, amikacin, netilmicin, tobramycin, gentamicin, clindamycin, and aztreonam in an implantable drug pump. Two pumps were filled with the antibiotic being tested and were incubated at 37 degrees for 3 weeks. Samples were taken daily. At 3 weeks the pumps were disassembled and examined microscopically for signs of deterioration. If the pumps were intact, bioassays were used to quantitate the biologic activity of each daily antibiotic sample. Vancomycin degraded the pump. Amikacin, netilmicin, tobramycin, gentamicin, clindamycin, and aztreonam had no effect on the pump and maintained their biologic activity over the 3-week period.

A new surgical approach to fractures of the lateral tibial plateau.

We are reporting on a previously undescribed surgical approach and postoperative protocol for the treatment of fractures of the lateral tibial plateau in which there is a split pattern and depression of the articular surface. In this approach the anterior horn of the lateral meniscus is incised and detached so that the split fragment can be opened like a book. Detachment and incision of the anterior horn minimizes the need to free the lateral meniscus from its tibial attachment. The postoperative protocol includes continuous passive motion followed by non-weight-bearing in a toe-to-groin plaster cast for three months. Our preliminary results have been encouraging, and arthroscopic examination in the seven knees so studied indicated a healed fracture, restoration of the tibial articular surface, and a healed lateral meniscus.

Experience with a sliding screw in intertrochanteric fractures.

A retrospective study of our first year's experience with a sliding screw in intertrochanteric fractures was conducted. Forty-five patients with intertrochanteric fractures were admitted to St. Louis City Hospital in the year considered. All those who came to surgery were treated with a sliding screw. We were impressed by the ability of the sliding screw plate to adapt to the forces which, under other circumstances, cause the unstable I-T fractures to collapse or displace. The characteristics of unstable hip fractures are discussed.

Isolated avulsion of the tibial origin of the anterior tibiofibular ligament.

A case report of a patient with an isolated avulsion of the anterior tubercle of the tibia is presented. This is the origin of anterior tibiofibular ligament, and this injury is the first stage of a supination external rotation injury of the ankle. It can be easily missed and, if not treated properly, can result in an unstable ankle. The patient was not treated initially and the result was an unstable ankle.

Stress fracture of the radius following a fracture of the ulna diaphysis.

A 70-year-old woman incurred a stress fracture of the radius following a fracture of the ulna. The patient had osteomalacia secondary to a Billroth II procedure. The primary reasons for the development of osteomalacia following a Billroth II procedure are: decreased transit time through the gut, which causes less Vitamin D and calcium absorption, and bypassing of the duodenum, where calcium absorption is highest. After treatment of the osteomalacia with calcium and Vitamin D, the fracture healed uneventfully. The present case report emphasizes the need to identify and treat diseases associated with fractures. Patients with severe osteomalacia and ulnar shaft fractures should have the forearm immobilized because motion at the fracture site may lead to a stress fracture of the radius.

Neurological complications resulting from supracondylar fractures of the humerus in children.

One hundred thirty-eight children with supracondylar fractures of the humerus were reviewed. Seventeen (12%) exhibited neurological deficits. Nine median, four ulnar, and four radial neuropathies were encountered. The neurological deficit was treated expectantly. The osseous injury was treated by a variety of methods. All patients except two recovered spontaneously in an average of 9 weeks. One patient was still improving at 9 months' follow-up. Another patient with radial neuropathy underwent exploration 6 months after injury and was found to have a transected radial nerve. This study demonstrates that neurological deficits from supracondylar humeral fractures remain common, involve all three major nerves of forearm, and, with rare exception, recover with conservative therapy.

Local administration of antibiotics with an implantable osmotic pump.

A totally implantable drug pump was evaluated as a delivery system in the treatment of osteomyelitis. Gentamicin levels in rabbit serum and bone obtained by systemic administration are compared with levels in rabbit serum and bone obtained by local administration via an implantable drug pump. Systemic administration gave mean gentamicin bone levels ranging from less than 1 microgram/gm to 3.6 micrograms/gm, while drug pump administration gave bone levels ranging from 10.8 micrograms/gm to 64.0 micrograms/gm (micrograms = microgram, or 10(-6) gram). To evaluate the drug pump as a mode of therapy, acute staphylococcal osteomyelitis was induced in ten rabbits. Drug pumps filled with amikacin were inserted in five of the infected animals. Three of these were culture-negative at one week. One had a scant growth of Staphylococcus from the pump, and one had scant growth from the pump and the wound. Clinically, none of these five rabbits appeared infected at seven days. The remaining five rabbits were all culture-positive, with heavy growths of staphylococci from their wounds, and clinically, all appeared grossly infected at seven days. These data demonstrate that high local and low systemic levels of antibiotics can be achieved with an implantable drug pump and that this method can sterilize an infected musculoskeletal wound. Therefore, antibiotic administration via an implantable drug pump is an important potential mode of therapy in the treatment of osteomyelitis.

Cefamandole levels in serum and necrotic bone.

Seven patients with chronic osteomyelitis were treated by surgical debridement. Cefamandole was administered intravenously before surgery. During the debridement, cefamandole concentrations were measured in serum and necrotic bone. Although adequate levels of antibiotic were achieved in the serum, minimal or no concentration of antibiotic was found in the necrotic bone. There was only minimal penetration of cefamandole into necrotic bone.

An inexpensive alternative approach to bone compression analyses.

A new method for testing the compression strength of vertebrae was developed and implemented using minimal resources and time expenditure. The device digitally measured and analyzed the torque and force necessary to load rat lumbar and thoracic vertebrae to failure. The system was calibrated using a series of known lead masses. Similar to other standardized force/compression and torque devices, this method has been shown to provide reliable and reproducible results. Furthermore, although vertebrae were the only specimens used to collect data in these initial studies, this measurement system could be altered quite easily to allow for a variety of test materials.

Impairment of the collagenase-3 endocytotic receptor system in cells from patients with osteoarthritis.

OBJECTIVE: Collagenase-3, a matrix metalloproteinase (MMP-13) that can degrade collagen II and aggrecan, is produced by osteoarthritic (OA) chondrocytes and may contribute to matrix destruction in this disease. Our laboratory has previously identified a specific endocytotic receptor for collagenase-3 on osteoblastic and fibroblastic cells, which couples with the low-density lipoprotein receptor-related protein (LRP1) to mediate the internalization and degradation of this enzyme. We hypothesized that the activity of this receptor system is reduced in OA chondrocytes which may lead to increased local extracellular levels of collagenase-3 and increased destruction of the cartilage matrix at pericellular sites. METHODS: Human chondrocytes and synoviocytes were obtained from OA knees at the time of joint replacement surgery and from non-arthritic control specimens following autopsy or surgery. Enzyme-linked immunosorbant assay (ELISA) was used to measure collagenase-3 secreted from primary cultures. Iodinated collagenase-3 was used to analyze the cell-surface binding, internalization and intracellular degradation of collagenase-3. Reverse-transcriptase polymerase chain reaction was used to confirm chondrocyte phenotype and the expression of collagenase-3 and LRP1 mRNAs. RESULTS: OA chondrocytes and synoviocytes demonstrated significantly reduced (75-77%) binding of recombinant 125I collagenase-3. Internalization and degradation of the ligand was also significantly reduced (64-72%) in OA cells. Collagenase-3 removal was inhibited by the LRP1 receptor-associated protein (RAP). CONCLUSION: These results suggest a mechanism whereby impaired receptor-mediated removal of collagenase-3 in OA chondrocytes may lead to enhanced local degradation of the cartilage matrix. This work also implicates an LRP family member in endocytotic receptor-mediated collagenase-3 processing and suggests a novel therapeutic target for OA.