Michelle’s Osteomyelitis Story: from http://www.sharp.com/ortho/michelle-osteomyelitis-story.cfm

For most cancer patients, hearing the words “cancer free” signifies victory — the end of a long and painful battle. Unfortunately, that wasn’t the case for 62-year-old Michelle Ashwell.  In 2005, Michelle had a malignant tumor removed from her left leg, just above the knee. “I made it through the cancer, and at first, it seemed like everything was going to be OK,” she said. “However, the treatment that followed actually prevented my recovery from moving forward.”  The radiation therapy Michelle underwent after having the tumor removed set in motion a series of debilitating complications. The  radiation treatments, which were only intended for the soft tissues surrounding the tumor site, extended deeper into the bone. As a result, the tissue deep within her wound pulled away from the bone and would not heal. This complication required Michelle to undergo a second surgery, which was intended to repair and heal the wound.

Unfortunately, the second surgery did not produce the desired outcome; and on top of that, the wound became infected. Michelle had developed osteomyelitis, which is an infection of the bone or bone marrow. The infection prevented the open wound in her leg from healing and severely limited the motion in her knee.  “It was very discouraging,” said Michelle. “I went through many different kinds of surgeries and none of them helped.”

After being advised to consider amputation, and preparing herself for the possibility that this course of action was the only way to eliminate the infection, Michelle was referred to Sharp-affiliated orthopedic surgeons Drs. George Cierny and Doreen DiPasquale.

Following a preliminary consultation and exam, Dr. Cierny told Michelle he was confident that he could save her leg. “When I heard him say that, part of me was wondering if it was too good to be true.”  Subsequent surgeries performed under Dr. Cierny’s direction included placement of antibiotic-impregnated beads into the wound and stabilization of the upper leg bone via a bone-plate and screws to prevent fracture. Finally, a flap of living tissue from Michelle’s abdomen was transplanted onto the wound. Unlike previous surgeries in which a similar procedure had been performed, the new living flap was, this time, attached to blood vessels outside the area treated with radiation.  Following this multidisciplinary treatment plan and continuous physical therapy, Michelle emerged infection free in January 2008.  

She is especially grateful for the fact that she has since regained full motion in her knee.  “I love taking care of my one-year-old grandson, Brayden,” said Michelle. “He just started walking, and he’s fast!”  At the height of her medical complications, Michelle struggled to keep up with her favorite pastimes, which include gardening. Following recovery, she has been able to return to and even grow some of those activities. She recently relandscaped her entire backyard, a symbol of her personal growth and passion for life.  Today, Michelle remains cancer- and infection-free.

George Cierny, MD; REOrthopaedics in San Diego

In acute pediatric osteomyelitis  and osteomyelitis of the spine (verbetral osteomyelitis; sacroiliitis) in all ages,  surgery is not always necessary to affect cure.  In other forms of acute osteomyelitis  (infection following open fracture; surgical site infections following trauma or reconstructive surgery) and nearly all forms of the chronic disease, treatment will have to combine various aspects of surgery (with antibiotics) to result in cure .
The treatment of a refractory (chronic) osteomyelitis is governed by its pathophysiolgy —– it is a ‘biofilm disease’.    Unlike the mobile (planktonic), environmentally sensitive microbes found in an acute infection, chronic wound pathogens are sessile and resilient, transformed into colony-forming units by environmental triggers (quorum-sensing) and the successful attachment to ‘unprotected’ surfaces within the wound (inert materials; non-viable tissues or organisms, etc.).    Thereafter, individual cells become colony-forming units that mature (2-4 weeks) to secrete and maintain a mucopolysaccharide “slime” that protects them from host defenses and the penetration of most antimicrobial agents .   To cure this biofilm infection, a LIVE, CLEAN WOUND is paramount: the biofilm-colony its attachment surfaces must be completely excised.

The type of surgery will depend on the duration of the infection (acute or chronic), the contents of the wound (extent of necrosis; substrate surfaces), the anatomic site, the health and well-being (impairment) of the host, and the experience of the healthcare team.

However, surgery, as a form of treatment, is not available to everyone. Patients who are very ill may not be able to endure the extensive surgery and recovery. In these cases, doctors may use antibiotics for long periods in an attempt to suppress (rather than cure) the infection.  Then, if the infection persists and, again, threatens the patient’s well-being, lesser morbid procedures, such as amputation of all or part of an infected limb, may be necessary.  

Surgical treatment options  – Drain the infected area: Opening up the area around the infected bone allows the surgeon to drain any pus or fluid that has accumulated in response to the infection.  This is usually applied in the acute setting to decrease strain on host defenses and amplify the effects of antibiotics.  Remove the attached, biofilm-colony:  In a procedure called debridement, the surgeon removes the diseased bone and tissue. In some cases, foreign objects, such as surgical plates or screws, used in previous surgeries, may also be removed. Restore the bone and soft-tissue envelope: Your surgeon may fill any empty space left by the debridement procedure with a piece of bone or other tissue, such as skin or muscle, from another part of your body. Sometimes temporary fillers containing antibiotics (antibiotic depots) are placed in the space until the infection is cured and the patient is healthy enough to undergo a definitive reconstruction. Bone grafts and tissue flaps help the body recruit new blood vessels into the site and form new bone.  Protect against instability: Immediately following debridement, the surgeon may use an external fixatation device (external fixator) to hold and protect the bone from further injury.  This method limits the amount of implanted, foreign material (metal) in the still-contaminated wound by attaching thin wires or pins (that pass through the limb) to a frame positioned around the limb (outside the skin).  The fixator can be the only method used throughout treatment or, after a course of local antibiotic therapy, replaced with internal methods of fixation such as metal plates, rods or screws.

Article:

EARLIER DEBRIDEMENT AND ANTIBIOTIC ADMINISTRATION DECREASE INFECTION:   Maj. Brown KV, Walker JA, Cortz DS et al.  J. Surg. Ortho.p Advances, 2010;  Vol 19(1): 18-22.    Goals: ascertain the effects of 1) earlier debridement (debridement alone or in combination with locally delivered antibiotics) and 2) the use of local antibiotic-depots on bacterial load following contamination of open fractures.  A contaminated, critical sized, rat femur, defect model was used.  Results: early debridement and early administration of local antibiotics resulted in lower bacterial loads in bone.  There was a significant increase in the rate of infection between 2 and 6 hours and a further increase between 6 and 24 hours when treatment was limited to debridement (alone) as well as when debridement was combined with local antibiotics.  Treatment with local antibiotics resulted in a significant reduction in infection at 2 and 6 h hours compared to debridement, alone.          

Dr. Cierny’S  comments:  Surgical antibiotic prophylaxis refers to the administration of antibiotics to patients without clinical evidence of infection in the operative field.  The objectives of prophylaxis are to prevent naturally occurring organisms in one site from proliferation in a normally sterile site; to prevent organisms contaminating a normally sterile site from producing diseases; and to prevent infection by exogenous organism.  In order to achieve this goal, the surgeon must recognize the high-risk patient, operate in an effective and efficient manner, and keep abreast of local hospital flora and sensitivity patterns.  Antibiotic prophylaxis is indicated in the surgical patient when there is an unacceptable incidence of infection or when the incidence of infection is low but such an infection would be devastating or lethal.  Prophylaxis accounts for approximately 30% of the antibiotic administration on surgical services in the United States.  In most instances, these antibiotics are not justified and may lead to multiple problems, including the selection of resistant organisms.  However, when the theory and practice of surgical antibiotic prophylaxis are correctly applied, the patient benefits.

            The pathogenesis of a surgical wound infection lends itself to a rational approach to surgical antibiotic prophylaxis.  The first step is bacterial contamination of surgically manipulated tissue.  Bacterial contamination, a component of every surgical wound, arises from two sources: exogenous contamination from the operative theater; or endogenous contamination from the skin, respiratory, or urogenital tracts of the patient.  Whether or not the bacterial contamination produces infection depends on the number and the virulence of the organisms, the adequacy of the patient’s defenses, and the condition of the disrupted (injured) tissue.

The first response to surgical injury and subsequent bacterial contamination is local inflammation.  Small vessels leak plasma, and leukocytes emerge in response to local leukotactic substances, migrate into the contaminated area, and begin phagocytosis.  Inflammation continues, wound induration develops, local macrophages and vascular components proliferate, and the stage is set for wound maturation.  The early local inflammatory phase is virtually identical to what is called the “decisive period” as defined by Burke (see below).  If inflammation is not appropriate and phagocytosis is overwhelmed, the patient will develop an infection.  Necrosis, ischemia, hemorrhage, and the presence of debris and/or foreign bodies impair the local host-defense mechanisms and decrease the number of bacterial organisms required to cure infection. The overall integrity of the host is important because a compromised host is at increased risk for infection. 

If an appropriate antimicrobial agent is present in adequate concentrations, a wound infection in the contaminated tissue is less likely.  The antibiotics must be in the tissues during the early, “decisive period” to effectively present bacterial invasion and proliferation.  If given later, when the bacteria are well established, the antibiotics will have no prophylactic effect.  Similarly, if the compromised host can be protected with prophylactic antibiotics until the local defense mechanisms are capable of eradication local bacterial invasion, the subsequent stages of wound healing can proceed normally.

The concept of a “decisive period” was first recognized when Burke (1961) administered an anti-Staphylococcal antibiotic one to three hours after inoculation of S. aureus into the dermis of a guinea pig model …. early antibiotic administration would reduce the size of the lesion.  However, if the anti-Staphylococcal antibiotic was given three hours after dermal infection, the antibiotic was less effective in reducing the size of the lesion.  Clinical studies have subsequently demonstrated, conclusively,  that antibiotic administered one hour before the surgery significantly decreases the incidence of postoperative infection when compared to placebo.  However, if the antibiotic is begun one to four hours after the operation, there is no reduction in the postoperative infection rate.

The correlation between the frequency of infection and the density of microorganisms present in a homogenized sample taken from the wound closure site has been established. Since it is not immediately possible to determine the microbial density of every surgical wound, a system for categorizing a surgical wound based on the probability and degree of microbiologic contamination has been developed.  The accuracy with which this clinical classification predicts the incidence of wound infection for general and orthopaedic surgery is well established.

Clean surgical procedures account for 75% of all operations.  These procedures are performed under ideal and sterile operating room conditions.  The procedures are generally elective and no entry is made into the oropharyngeal cavity or the lumen of the respiratory, alimentary, or genitourinary tract.  Inflammation is not encountered and no break in surgical technique occurs.  The incidence of wound infection in clean procures is less than 5%.

Clean-contaminated surgical procedures involve entry into the oropharyngeal cavity or the lumen of the respiratory, alimentary, or genitourinary tract without significant contamination from these sites.  Clean wounds are included in this category when there is a major break in the surgical technique. Clean- contaminated surgical procures occur in approximately 15% of all surgical operations and wound infection is reported in approximately 10% of these cases.  Since the mucosa of the oropharyngeal , respiratory, alimentary and genitourinary tracts harbor diffuse and dense microbiologic flora, some contamination of the wound is e inevitable.  Antibiotic prophylaxis is indicated in these patients and should be appropriately tailored to the flora expected in the particular region of surgery.  Clean surgery on a compromised host ( ) or transoral fixation of lesions involving the first and second cervical vertebra are examples of clean-contaminated procedures.

Contaminated-dirty surgery includes surgery through traumatic wounds, operative procedures with a major break in sterile technique and operations into a site of active infection.  The infection rate is between 20% and 40% in surgery involving these patients.  Antibiotic “prophylaxis”, in these circumstances, is directed at the prevention of infection in the soft-tissue planes and wounds previously uncontaminated by bacteria.  As such, the antibiotic(s) used  may be modified by the preoperative Gram stain or culture results stemming from biopsies of exposed granulating surfaces and/or wounds, themselves.  Surgery of open fractures is an example of contaminated-dirty surgery.  The risk of subsequent infection increases with the amount of tissue devitalization, the extent of contamination and the systemic compromise of the host. 

Final comment:  There are few controlled trials to scientifically support a practice mandating emergency-debridement of all open fractures  (< 6hrs). However, it is in agreement that 1) all open fractures require immediate, systemic antibiotic coverage and 2) that additional coverage with a local antibiotic-depot (antibiotic beads ) will reduce the incidence even further when treating  severe open injuries (Seligson D, Henry SL) when used in conjunction with systemic coverage.   BEST PRACTICE:  all methods of treatment should impact outcomes within the  “decisive period”:  immediate antibiotic coverage; host resuscitation; the earliest possible debridement; avoidance of large surgical implants; adequate (and safe) methods of stabilization; soft-tissue coverage within 7 days of injury –  Primary_versus_Delayed_Soft_Tissue_Coverage_for.8 .

RECENT REVIEW: ANTIBIOTIC DEPOTS:

1) Does antibiotic elution from PMMA beads deteriorate after 1-year shelf storage?   Balsamo LH; Whiddon DR; Simpson RB; Bone and Joint/Sports Medicine Institute, Naval Medical Center Portsmouth, Portsmouth, VA.  Clin Orthop Relat Res, 2007; 462:195-9.

-Tobramycin-impregnated antibiotic beads were manufactured using a bead mold. The antibiotic was either hand-mixed into the polymethylmethacrylate powder (1.2 g/40 g) or came premixed from the factory (1 g/40 g). Packages of beads were gas-sterilized and stored at room temperature. Beads were tested at 0, 1, 2, 3, 6, and 12 months and antibiotic levels in the eluent from each day of the month measured.  

There was no difference in the amount of antibiotic elution between beads tested immediately after manufacture and beads manufactured and stored for 6 or 12 months. Beads with hand-mixed antibiotics eluted higher levels of antibiotics than the beads prepared with factory-mixed antibiotics. We conclude antibiotic beads can be made, sterilized, and used after 1 year of storage with no deleterious effect on antibiotic elution characteristics.  DR. CIERNY’S COMMENTS:  THIS KIND OF LONGITUDINAL STUDY IS LONG OVERDUE AND WILL BRING FURTHER EFFICIENCY TO THE PROCESSING OF HAND-MADE ANTIBIOTIC BEAD PREPARATIONS AND THEIR STORAGE.  ANTIBIOTIC BEADS; TREATMENT OF OSTEOMYELTIS AND BONE INFECTIONS 

2) Comparative study of antibiotic-containing polymethylmetacrylate capsules and beads. Borzsei L; Mintal T; Horvath A; Koos Z; Kocsis B; Nyarady.  J Department of Traumatology and Hand Surgery, Faculty of Medicine, University of Pecs, Hungary. Chemotherapy 2006;52(1):1-8.    

-PMMA capsules were produced with a pressing machine designed and laid out by us. The characteristics of antibiotic penetration from this novel carrier were compared to those of standard-made, PMMA beads. METHODS: The time-dependent outflow of amikacin, clindamycin, pefloxacin, piperacillin + tazobactam, amoxicillin + clavulanic acid and cefotaxime was examined from the capsules and the beads with standard microbiological techniques using the Micrococcus luteus ATCC9341 test strain. The diameter of the inhibitory zones was measured after 24 h incubation at 37 degrees C and converted to mug/ml antibiotic concentrations. RESULTS AND CONCLUSIONS: Our results revealed that all antibiotics showed longer-lasting and higher concentration outflow from the PMMA capsules than from the beads. Therefore, these capsules can provide a more promising new opportunity for specific local antimicrobial treatment in cases of chronic suppurative bone and soft tissue injuries. In these cases the polymerization has already been completed and the heat does not influence the structure of the antibiotics; therefore, it can be inserted into the capsules in powder or solution form. [Copyright 2006 S. Karger AG, Basel.].   DR. CIERNY’S COMMENTS:   THE PROBLEM, HERE, IS THAT THIS REQUIRES A PRESSING OUTSIDE THE OPERATING ROOM, AGAIN BRINGING OUR FOCUS BACK TO THE 2008 USP CHAPTER 797 REVISION PERTAINING TO COMPOUNDING, STERILE PREPARATIONS, ETC.  IN THE PAST, SUCH PREPARATIONS HAVE NOT PASSED FDA OR HOSPITAL REGULATIONS AND ARE UNLIKELY TO DO SO IN THE NEAR FUTURE.  ANTIBIOTIC BEADS, TREATMENT OF OSTEOMYELITIS AND BONE INFECTIONS 

3) Two-stage revision hip arthroplasty for infection: comparison between the interim use of antibiotic-loaded cement beads and a spacer prosthesis.  Hsieh PH; Shih CH; Chang YH; Lee MS; Shih HN; Yang WE. Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Kweishian, Taoyuan, Taiwan. J Bone Joint Surg Am 2004 Sep;86-A(9):1989-97.

-The results associated with the interim use of antibiotic-loaded cement beads were compared with those associated with the interim use of an antibiotic-loaded cement prosthesis in an outcomes study of two-stage revisions following a peri-prosthetic total hip infection.  METHODS: 128 consecutive PPI-THA patients were followed clinically and radiographically for an average of 4.9 years. Cement beads were implanted following resection arthroplasty in the first 70 hips, and a custom cement prosthesis was implanted in the subsequent 58. RESULTS: There was no evidence of recurrent infection in 122 patients (95.3%); the infection-free rates in both groups were similar. The use of a spacer prosthesis was associated with a higher hip score, a shorter hospital stay, and better walking capacity in the interim period; a decreased operative time, less blood loss, and a lower transfusion requirement at the time of reimplantation; and fewer postoperative dislocations. CONCLUSIONS: The present study supports the safety and efficacy of the routine use of an antibiotic-loaded cement prosthesis in the interim between the stages of a two-stage revision procedure for the treatment of an infection at the site of a hip arthroplasty.   DR. CIERNY’S COMMENTS:  IT IS IMPORTANT TO NOTE HERE THAT THESE AUTHORS USED ONLY HIGH-DOSE ANTIBIOTIC COCKTAILS IN BOTH GROUPS AND THAT THE PROSTALAC IMPLANT WAS A CEMENT-ON-CEMENT ARTICULATION, CAPABLE OF ELUTING ADEQUATE LEVELS INTO THE JOINT, ITSELF.    ALTHOUGH THE CONCENTRATIONS OF ANTIBIOTICS IN THE JOINT AND DRAIN FLUIDS WERE NOT DOCUMENTED IN THIS STUDY, THESE SAME AUTHORS HAVE  SUBSEQUENTLY PUBLISHED THIS DATA ELSEWHERE (J Arthroplasty, 2009; 24(1):125-30) AND BELOW IN PAPER #4 OF THIS REVIEW.    THIS IS ONE OF THE FIRST STUDIES TO  CONFIRM EQUANIMITY OF THE TWO METHODS.    PERI-PROSTHETIC TOTAL JOINT INFECTIONS; INFECTED TOTAL HIP ARTHROPLASTY.

4) Liquid Gentamicin in bone cement spacers: in vivo antibiotic release and systemic safety in two-stage revision of infected hip arthroplasty. Hsieh PH; Huang KC; Tai CL.  Department of Orthopedics, Chang Gung Memorial Hospital, Taoyuan, Taiwan. J Trauma, 2009; 66(3):804-8.    

-This study investigated the application of liquid gentamicin in bone cement  to treat musculoskeletal infections. METHODS: Forty-two patients undergoing two-stage revision hip arthroplasty for periprosthetic infection were managed with an interim cement spacer loaded with liquid gentamicin (480 mg per 20 mL pack of cement monomer) with or without vancomycin (3.0 g per 40 g pack cement polymer). Serum and aliquots of drainage collected after the first-stage surgery; joint fluid obtained at the time of the second-stage surgery were analyzed for antibiotic concentrations and bioactivity. RESULTS: Antibiotic levels in joint fluid peaked on the first day after implantation of the spacer and then gradually declined during the first week, with levels of gentamicin and vancomycin reached 43.6 mg/L +/- 12.3 mg/L and 485.5 mg/L +/- 103.5 mg/L, respectively. Bioassay confirmed the antimicrobial activity of the released antibiotics.  At a mean 87 days after implantation, antibiotic concentrations in joint fluid remained clinically effective (gentamicin, 5.1 mg/L +/- 2.2 mg/L and vancomycin, 21.6 mg/L +/- 8.5 mg/L). CONCLUSIONS: Incorporation of liquid gentamicin in bone cement spacers led to effective drug delivery with systemic safety. Substantial health care dollars could be saved by the use of liquid gentamicin in bone cement to treat musculoskeletal infections.   DR. CIERNY’S COMMENTS:  I HAVE CONTACTED THE AUTHORS TO ASK HOW THEY WERE ABLE TO INCORPORATE SO MUCH LIQUID INTO THEIR CEMENT CONSTRUCTS.  DR. HSIEH REPLIED THAT THEY FIRST MIX THE 12CC OF GENTAMICIN (480MG) WITH THE LIQUID MONOMER.  AFTER THE POWDERS ARE MIXED (VANCOMYCIN +  POLYMER),  THE WET AND DRY BATCHES ARE MIXED, TOGETHER.   SIMPLEX HAS PROVEN SUPERIOR TO PALECOS CEMENT IN THIS CAPACITY.  TREATMENT OF OSTEOMYELITIS AND BONE INFECTIONS; PERI-PROSTHETIC TOTAL JOINT INFECTIONS

5) Persistence of bacterial growth on antibiotic-loaded beads: is it actually a problem? Anagnostakos K; Hitzler P; Pape D; Kohn D; Kelm J.  Klinik fur Orthopadie und Orthopadische Chirurgie, Universitatsklinikum des Saarlandes, Homburg/Saar, Germany. Acta Orthop, 2008; 79(2):302-7

-This Paper assessed whether bacterial adherence and growth could be determined on gentamicin- and gentamicin-vancomycin-loaded beads that had been removed after eradication of infection. MATERIAL AND METHODS: They bacteriologically examined 18 chains of antibiotic-loaded beads (11 gentamicin-loaded, 7 gentamicin-vancomycin-loaded) that had been previously implanted for infection.  Staphylococcus epidermidis, Staph-ylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) were the most frequent organisms identified. RESULTS: In 4 cases (3 with S. epidermidis and one with MRSA), there was persistence of bacterial growth on the beads. S. epidermidis strains persisted only on gentamicin-loaded beads, while MRSA could grow on gentamicin-vancomycin-impregnated cement. In one case, the emergence of a gentamicin-resistant S. epidermidis strain was observed despite the fact that preoperative samples of S. epidermidis from this patient had been susceptible to the antibiotic.   DR. CIERNY’S COMMENTS:  PERSISTENCE OF BACTERIAL GROWTH ON BONE CEMENT REMAINS A CONCERN.   IN OUR PAPER ON PERI-PROSTHETIC TOTAL JOINT INFECTIONS, THE INCIDENCE OF POSITIVE, SONICATED CULTURES OF THE RETIRED IMPLANTS AT THE TIME OF REIMPLANTATION WAS 23% (pp.25).     THIS, AGAIN, DRIVES HOME THE MESSAGE THAT PROSTALAC COMPONENTS (ARTICULATED SPACERS) ARE MEANT FOR TEMPORARY, NOT PERMANENT IMPLANTATION.   IT IS UNCLEAR WHEN ADHERENT, INACTIVE BACTERIA  WILL RE-EMERGE AS WOUND PATHOGENS.  IN OUR PRESENT PROTOCOLS, EVERY EFFORT IS MADE TO REIMPLANT WITHIN 3 – 6MOS OF DEBRIDEMENT.   PERI-PROSTHETIC TOTAL JOINT INFECTIONS; TREATMENT OF OSTEOMYELITIS AND BONE INFECTIONS; ANTIBIOTIC BEADS

6) Vancomycin covalently bonded to titanium beads kills Staphylococcus aureus. Jose B; Antoci V; Zeiger AR; Wickstrom E; Hickok NJ. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.  Chem Biol, 2005; 12(9):1041-8.

-The authors designed a covalent modification to titanium implant surfaces to render them bactericidal.  Specifically, they aminopropylated titanium and extended a tether by solid phase coupling of ethylene glycol linkers, followed by solid phase coupling of vancomycin.   Vancomycin covalently attached to titanium still bound soluble bacterial peptidoglycan, reduced Staphylococcus aureus colony-forming units by 88% +/- 16% over 2 hr, and retained antibacterial activity upon a repeated challenge.   DR. CIERNY’S COMMENTS: THERE HAVE BEEN SEVERAL ARTICLES PUBLISHED ON TETHERING ANTIBIOTICS TO IMPLANT  SURFACES, SUGGESTING THE POSSIBILITY OF AN EVERLASTING PROTECTION AGAINST BIOFILM FORMATION.   ON THE OTHER HAND, THESE ANTIBIOTIC TETHERS DO LITTLE, IF ANYTHING, TO PREVENT INFECTION IN SURROUNDING SOFT TISSUES OR DEAD SPACE SINCE THERE IS NO RELEASE OF ANTIBIOTIC INTO SOLUTION.  PERI-PROSTHETIC TOTAL JOINT INFECTIONS; TREATMENT OF OSTEOMYELITIS AND BONE INFECTIONS.

7) Cierny-Mader Type III chronic osteomyelitis: the results of patients treated with debridement, irrigation, vancomycin beads and systemic antibiotics. Kinik H; Karaduman M.  Department of Orthopaedics and Traumatology, Ankara University School of Medicine, Ankara, Turkey. Int Orthop, 2008; 32(4):551-8.    

- 26 patients (19 men and 7 women; average age: 34.7 years) with Cierny-Mader(C-M) Type III osteomylelitis were treated with radical debridement, irrigation, vancomycin-impregnated custom-made beads and culture-specific systemic antibiotics.  Type III osteomyelitis is defined as a localised lesion with both medullary and cortical involvement that is stable mechanically after debridement.Those patients with metaphyseal involvement were treated with deroofing of the cortex and debridement by means of a “trough” (16 patients); those with diaphyseal involvement were treated with both intramedullary reaming and debridement from a trough (ten patients). Antibiotic cement rods were used as an additional therapy in five patients with diaphyseal involvement. Recurrence developed in three patients and was attributed to inadequate debridement; all three patients were treated again in the same manner with success. The mean follow-up is currently 3.6 years (range: 2-6 years). All of the patients have normal clinical, radiographic and laboratory parameters, and all are ambulatory and have returned to their pretreatment level of activity or better.    DR. CIERNY’S COMMENTS:   WELL DONE, INDEED!   THE CLINCIAL STAGING SYSTEM ARTICULATES THE NATURAL HISTORY OF THE DISEASE WITH TREATMENT OPTIONS AND ALLOWS COMPARISON OF TREATMENT PROTOCOLS FOR ALL TYPES OF OSTEOMYELITIS  AND  PATIENT COHORTS. TREATMENT OSTEOMYELITIS AND BONE INFECT ION; CLINICAL STAGING OF OSTEOMYELITIS

ANTIBIOTIC BEADS: USP 797 Compliance and
Pharmaceutical Compounding Regulations

What is USP Chapter 797 ?    The United States Pharmacopeia (USP) is an official public standards–setting authority for all prescription and over–the–counter medicines and other health care products manufactured or sold in the United States.  USP is a non-governmental, not-for-profit public health organization whose independent, volunteer experts work under strict conflict–of–interest rules to set its scientific standards.  USP’s standards are JCAHO-mandated and recognized and used in more than 130 countries around the globe to ensure public health.  

In 2004, Pharmaceutical Compounding: Sterile Preparations, was the first set of enforceable sterile compounding standards issued by the United States Pharmacopeia. The chapter describes the procedures and requirements for compounding sterile preparations and sets the standards that apply to all settings in which sterile preparations are compounded.  (see ASHP Discussion Guide on USP Chapter 797 [PDF] ).   The purpose of USP 797 is to protect the health of patients by reducing the potential for microbial contamination caused by an unclean environment, excessive bacterial endotoxins, large errors in the strength of ingredients and the use of incorrect ingredients. The chapter was developed for use in healthcare institutions, pharmacies, and physician practice facilities. It also applies to other facilities in which compounded sterile preparations (CSPs) are prepared, stored and dispensed, such as pharmacy intravenous rooms, chemotherapy clinics, hospital nursing stations and in operating rooms by anesthesiologists.

What is a “compounded sterile preparation” according to USP Chapter 797?

A “compounded sterile preparation” (CSP) is defined in USP Chapter 797 as a dosage unit that (1) is prepared according to manufacturer’s labeled instructions; (2) contain nonsterile ingredients or employ nonsterile components and devices that must be sterilized before administration; or (3) is biologic, diagnostic, drug, nutrient, or pharmaceutical that possesses either of the two previous characteristics and which include, but are not limited to, baths and soaks for live organs and tissues, implants, inhalations, injections, powder for injection, irrigations, metered sprays, and ophthalmic and otic preparations.   HIGH RISK compounding will include any compound prepared from bulk, non-sterile components or final containers that are non-sterile and must be terminally sterilized.   

On June 1, 2008, a revision to USP Chapter 797 was issued and became the new official standard, published in the Second Supplement to USP 31-NF 26 and in the Pharmacists’ Pharmacopeia.   The new emphasis is on (1) the actual person who is compounding the product: pharmacists, physicians, assistants and technicians; (2)  to mandating training, competency, and documentation of the training to thereby hold these people accountable. Antibiotic beads , pre- made in a pharmacy prior to sterilization and subsequent patient-implantation, are the end result of  HIGH RISK compounding.   It is unlikely the 2008 revisions will apply to PMMA and/or CASO₄ beads made under sterile conditions in the operating room; drug dosages and patient tolerance are well within the realm of standard physician training/education.

Case presentation for Dr. Cierny:   52 yo diabetic woman with recent history of pancreatitis and MRSA sepsis (3 months prior to her presentation) presented to ER in early July with several week history of progressive knee pain, left worse than right (ESR in the 70s, WBC 15).  ED staff aspirated the left knee sent fluid for cell count(65,000 WBCs) started antibiotics and we took her to OR for arthroscopic lavage, both knees (right knee with similar effusion).  Pt placed on Vancomycin, was up walking POD 3 and went home on Vanco post op day4. . Intra op cultures all negative.

She came back 3 weeks later with large effusions and pain.  Taken back to OR for open I and D, synovectomies. Started on clinda and high-dose vanco but failed to clear the synovial aspirate. Repeat I and D done several days later. Again, all cultures negative (including AFB, fungus).  Tigecycline added by ID.  Again, no improvement and at the next wash out, pus was noted coming from the femur, suggesting a juxta-articular osteomyeltis.  Cortical window made to debride a bone infection: the medullary canal was irrigated; antibiotic cement beads were placed to treat the dead space.  Repeat I & D done in 4 days and the beads were exchanged.

She came back in less than one week with purulant fluid draining from both knees and drain sites.  Xrays were consistent with osteomyelitis of the distal femurs with periosteal elevation/bone formation.  The patient was taken back to the OR and the femurs reamed abnd lavaged; antibiotic rods were positioned.  Antibiotics were then changed to Daptomycin, Ciprofloxacin and Flagyl.  All cultures remained negative.   

Rheumatology recommended trial of steroids on the chance this is a “post infectious inflammatory arthropathy.”  She was started on Prednisone 60mg, quickly improved but the left knee continued to drain.  She was taken back for another I and D.  The knee appeared less inflamed and the femoral canals appeared clean.  She is now home on antibiotics and steroids. Could this not be infection?   Thanks!

Answer:   I have never been confronted by such a scenario but do have rules of thumb for a clinical course that defies reason: 1) Define the status of the host.  In this case: normoglycemia? mal-nutrition? impaired cellular immuno-competence? Remote site infection? ; and 2)  Establish the anatomic extent of disease: MRI, bone scans, whole-body PET/CT scan.   Your rheumatology colleagues were savvy in recommending systemic steroids.  It is interesting tonote that Pyoderma gangrenosum and acne (PAPA) syndrome is an autosomal dominant auto-inflammatory disease associated with multiple, sterile, ‘purulent’ joint effusions.  I refer you to the following readings:    Anakinra for flares of pyogenic arthritis in PAPA syndrome – http://rheumatology.oxfordjournals.org/cgi/content/full/44/3/406-a ; MRI Findings of Septic Arthritis and Associated Osteomyelitis in Adults – http://www.ajronline.org/cgi/reprint/182/1/119.pdf ; Hematogenous Septic Ankle Arthritis – http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2384014 .

Regarding a refractory, joint sepsis (pyoarthrosis) – no problem in leaving a joint open to drainage.  Indeed, this was our routine when treating high volumes of Gonorrheal arthritis back in the 70’s … In the knee, a through-and-through  penrose drain was often looped across the joint line (medial to lateral) and tied anteriorly (as an earring loops the earlobe) .   GCIII

USING CLINDAMYCIN IN BONE CEMENT:

This question came up in a discussion regarding the treatment of osteomyelitis (bone infections) and/or treatment of peri-prosthetic total joint infections caused by anaerobic bacteria.  The experience using Clindamycin (Cleocin) to impregnate bone cements has been limited due to its liquid (non-miscible) form and the availability of more user-friendly agents to treat anerobes.  You can, however, whip liquids (and therefore drugs) into a freshly mixed batch of polymethyl-methacrylate (PMMA) and capture enough agents to effectively work in prophylaxis but (probably) not in treatment for active infection. References include: JBJS,2005; 87A: 268-272;  J Arthroplasty Vol.24 (1); 125-130.
My preference:  Powdered Claforan (Cephotaxime): covers Bacteroides species (including Bacteroides fragilis), Clostridium species, and anaerobic cocci (including Peptostreptococcus species and Peptococcus species) and Fusobacterium species (including F. nucleatum).  If you are dealing with a Penicillin allergy you may be limited to this drug.  But, if not, these derivatives can be used: Oxacillian, Zosyn, Primaxim (Imipenem and Cilastatin) and other  -penems in powder form.

Methods:  The amount you mix, per pack of cement will, of course, vary according to use of the depot and the pathogens treated ( ie; 3gr Vanc + 3.375gr Zosyn ).   Here are the rules: 1) first mix dry ingrediants and then add the monomer;  2) Active bone infections:  25-30cc of finely-sifted, antibiotic powder /pk /PMMA;  it is always better to make 0.8cm antibiotic-beads than to use large blocks of antibiotic-cement due to their superior surface area /elution kinetics. 3) Prophylaxis:  I usually mix around 12-15cc antibiotic /pk /PMMA (variable/depending).