IF YOU HAVE DIABETES, A JOINT REPLACEMENT OR ARTHRITIS…. YOU’RE AT INCREASED  RISK FOR A BONE INFECTION?  George Cierny, MD, and Doreen DiPasquale, MD; *BottomLine Health, 2010; Vol 24(3), pp9-11

* Bottom Line/Health interviewed George Cierny, MD, and Doreen DiPasquale, MD, physician-partners at REOrthopaedics in San Diego.  Dr. Cierny is an international lecturer in orthopedic surgery who has published more than 100 scien­tific papers and/or book chapters in the field of musculoskeletal pathology and infection. Dr.Di­Pasquale, an orthopedic-trauma surgeon, is former resi­dency program director at George Washington University in Washington, DC, and National Na­val Medical Center in Bethesda, Maryland.

—————- When most people think of bone problems, broken bones and osteoporosis (re­duced bone density and strength) come to mind. But our bones also can be the site of infections that can sometimes go unrecognized for months or even years. This is especially the case if the only symptoms of bone infection (a condition known as osteo­myelitis) are ones that are commonly mis­taken for common health problems, such as ordinary back pain or fa­tigue. What you need to know…

ARE YOU AT RISK? Older adults (age 70 and older), people with diabetes or arthritis and anyone with a weakened immune sys­tem (due to chronic disease, such as cancer, for example) are among those at greatest risk for osteo­myelitis.   Anyone who has an artificial joint (such as a total hip replacement or total knee replacement) or metal implants attached to a bone also is at increased risk for osteomyelitis and should discuss the use of anti­biotics before any type of surgery, including routine dental and oral surgery. Bacteria in the mouth can enter the bloodstream and cause a bone infection.

TYPES OF BONE INFECTIONS: Before the advent of joint-­replacement surgery, most bone in­fections were caused by injuries that expose the bone to bacteria in the en­vironment (such as those caused by a car accident) or a broken bone…or an infection elsewhere in the body, such as pneumonia or a urinary tract infection, that spreads to the bone through the bloodstream. Now: About half the cases of osteo­myelitis are complications of surgery in which large metal implants are used to stabilize or replace bones and joints (such as in the hip or knee).   

Osteomyelitis is divided into three main categories, depending on the origin of the infection… Blood-born osteomyelitis occurs when bacteria that originate else­where in the body migrate to and in­fect bone. People with osteoarthritis or rheumatoid arthritis are prone to blood-borne infections in their af­fected joints due to injury to cells in the lining of the joints that normally prevent bacteria from entering the bloodstream. Contiguous-focus osteomyelitis oc­curs when organisms— usually bacte­ria, but at times fungal species —infect bone tissue. These cases usually occur in people with diabetes, who will often de­velop pressure sores on the soles of their feet or ­buttocks due to poor cir­culation and impaired immunity.   Post-traumatic osteomyelitis: Trau­ma or surgery to a bone and/or sur­rounding tissue can open the area to bacteria and other microbes. The use of prosthetic joints, surgical screws, pins or plates also makes it easier for bacteria to enter and in­fect the bone.  Important: any of the three types of bone infections described above can lead to chronic osteomyelitis, an initially low-grade infection that can persist for months or even years with few or no symptoms. Eventu­ally it gets severe enough to liter­ally destroy bone. Left untreated, the affected bone may have to be amputated.

DIFFICULT TO DIAGNOSE – When osteomyelitis first develops (acute osteomyelitis), the symptoms —such as pain, swelling and tender­ness—are usually the same as those caused by other infections. If the initial infection is subtle (low-grade) or doesn’t resolve completely with treatment, it can result in chronic osteomyelitis. In this case, you may have no symptoms or symp-toms that are not specific.  For example, some one who has had surgery might blame discomfort on delayed recovery, not realizing what they have a bone infection.  A surprising finding: When we stud­ied the histories of more than 2,000 osteomyelitis patients, we found that most of those with chronic infections had relatively little pain from the in­fection itself. About 28% of those who required surgery for infection had normal white blood cell counts—suggesting that, over time, the body adjusts to lingering infections.  If a doctor suspects that you may have osteomyelitis because of chron­ic pain…swelling…possibly fever…fatigue…or other symptoms, he/she will usually order special laboratory tests that detect the formation of an­tibodies and/or cellular signaling compounds. If the results indicate the presence of infection, he/she may then order an X-ray, a magnetic reso­nance imaging (MRI) scan or a nuclear scan(bone scan). These and other imaging tests can readily detect damaged­ bone tissue and re­veal the presence of infection.

BEST TREATMENT OPTIONS   About 60% to 70% of people with acute osteomyelitis can be cured with antibiotics (or anti­fungal agents, if a fungal infection is present) if treat­ment begins early enough to prevent the infection from becoming chronic. In these cases, patients exhibit symp­toms…test positive for infection…and readily respond to drug treatments. Most patients can be cured with a four- to six-week course of antibiotics. Fungal infections are more resistant to treatment—antifungal drugs may be needed for several months.

For chronic osteomyelitis, surgical debridement (the removal of dam­aged tissue and bone using such in­struments as a scalpel, dental burrs and/or chisels) usually is necessary. Reasons: dam­aged bone can lose its blood supply, die and remain in the body without living cells or circu­lation. Such “dead bone” is invulnerable to the effects of antibiotics and provides safe haven to organisms attached to its surface.  To address this, the surgeon, after debridement, may insert a slow-release antibiotic depot (antibiotic beads) that release antibiotic for up to a month. This approach can increase drug concentrations up to 100 times more than oral antibiotic therapy and help to eliminate the sequestered microorganisms.   Using these and other innovations, the REOrthopaedics  center in Southern California now posts an overall success rate of 95%.    Nevertheless,  up to 6% of patients who are otherwise healthy may require a second or even a third operation to completely cure the infec­tion;  and, iIn patients suffering from diabetes or oth­er disorders affecting wound healing (compromised hosts) , the percentage may be as high as 25%.    To improve your chances of a full recovery from chronic osteomyeli­tis following treatment: eat well, maintain healthy blood sugar levels, stay active after treat­ment (to promote blood circulation, prevent blood clots and help main­tain an appetite) and don’t use to­bacco products.

_{Copyright © 2009 by Boardroom Inc., 281 Tresser Blvd., Stamford, Connecticut 06901-3229.                          www.BottomLineSecrets.com}

The Orthopaedic Supervisory of Sharp Memorial Hospital in San Diego has asked the Infection Prevention and Clinical Epidemiology Department to periodically distribute individual, surgeon specific, surgical site infection (SSI) rates.  Practices proven to minimize the risk of post-operative SSI include:  1) asking patients to shower or bathe with chlorhexidine(Hibiclens) for several days pre-op; 2) the administration of prophylactic antibiotics within 1 hour of incision (2 hours for Vancomycin); 3) using electric clippers (not a razor) to remove hair at the operative site if it will interfere with wound closure; 4)to identify and treat all infections remote to the surgical site before elective operation.

Pre-operative colonization screening for Methicillin-sensitive (MSSA) and Methicillin-resistant (MRSA) Staphylococcus aureus, the application of 2% nasal Mupirocin (Bactroban) in the anterior nares twice a day for 5 days for those colonized and assuring that patients colonized with MRSA receive the appropriate preoperative prophylaxis are further strategies to reduce risk .

The attached figure compares the SSI rates of REOrthopaedics physicians to the SMH aggregate rates and rates generated by the National Healthcare Safety Network (NHSN) at the CDC in Atlanta.  As seen, Dr. Cierny and Dr. DiPasqaule have a 0.00%  post-operative SSI rate following 55 consecutive hip and knee arthroplasties performed 2006-2008. The Risk index is scored from 0-3 points (the higher the risk index, the higher the score), with one point each for: a) wound class of contaminated or dirty; b) ASA score of III, IV or V; c) duration of surgery >2 hours.  NHSN rates reflect the National Healthcare Safety Network Report: a data summary for 2006-2008 (AJIC: Nov 2008; 609-626).  SMH = Sharp Memorial Hospital; San Diego, Calfiornia.  REO = REOrthopaedics, Inc in San Diego, CA; Drs.George Cierny, MD and Doreen DiPasquale, MD.   

 Dr. Cierny’s comments:  Unfortunately, this registry does not differentiate between primary vs revision arthroplasties or clean vs infected arthropasties performed at Sharp Memorial Hospital.   All of the REOrthopaedics’ cases began, initially, as peri-prosthetic total joint infections (54: 2-stage revisions vs 1: primary exchange). 

In a recent article published out of Oxford, England, researchers have found a very high incidence of early and late failures following total joint, hip arthroplasties using a metal-on-metal hip resurfacing prostheses in women under 40 years of age (Glyn-Jones S, Pandit H, Doll H, et al; The Risk Factors for Developing an Inflammatory Pseudotumor following Hip Resurfacing: a survival analysis. British Orthopaedic Association Annual Congress. September 15-18,2009, Manchester).  The study is based on information from their experience with 1,419 patients between the years of 1999 and 2008.    The overall revision rate for revision and psuedotumors was 4% at 8 years.  However, women younger than 40 years had a 25% revision rate for the condition.   

A pseudotumor is an accumulating mass of inflammatory tissue that forms in response to an irritant: “pseuo-“ because it mimics a tumor with its presence /appearance.  It is thought that a high metal ion release can originate from a metal-on-metal interface if there is excessive edge-loading ( women require smaller components and more attention to component positioning due to their increased range of motion).  The tissue reaction within the “pseudotumor” consists numerous histiocytic cells and lymphocytes accompanied by a proliferation of a variable amount of dense fibrous tissue: a chronic granulomatous inflammation.

The tissue reaction can be called a pseudotumor, AVAL (aseptic lymphocyte dominated vasculitis associated lesion) or simply “metalosis”.    When it occurs, it can cause pain, prosthetic loosening /or more severe medical reactions (hemorrhage, loss of function, peri-prosthetic fracture, etc.).   Dr. Cierny’s comment:    It takes a great deal of experience to consistently place these components at the proper angle and to know which smaller patients can successfully receive a hip resurfacing.

How does malnutrition affect outcomes of patients with musculoskeletal infection?”     Good nutrition is essential for normal wound healing and host defense against infection.  A lack of proteins, fats, vitamins and minerals creates a welcome environment for invading bacteria:  1) decreased production of new blood vessels to heal wounds, potentiate antimicrobial effectiveness and thereby prevent infection; 2) lack of proteins to seal and heal wounds, stop bleeding and kill bacteria (antibodies against bacteria and viruses);  3) impotent white blood cells (natural  killer cells ) to destroy invaders.   In our protocols and staging system, patients with obesity and/or mal-nutrition are considered B-hosts with co-morbidities affecting wound healing and treatment outcomes.

 How can I be obese and still be malnourished?  Concomitant  obesity and malnutrition can offend occur if the obesity is linked to: 1)  the consumption of empty calories in a diet of processed, fast  foods lacking minerals and containing additives to prolong shelf life; 2) bariatric patients following bariatric surgery where absorption is altered; 3) dietary deficiencies in folate, selenium, zinc and vitamins A, B-12, B-1, C, D and E.  Obesity, for these purposes, is defined as a Mean Body Index (BMI) > 40.   Our treatment center has introduced many innovations in treatment that have improved outcomes for all B-hosts.

How do you diagnose mal-nutrition?  Common measurements of nutritional status include: laboratory tests (serum albumin, transferring, pre-albumin and total lymphocyte count); body measurements such as BMI, tricps skin fold thickness (fat reserves) and a  mid-humeral circumference (protein reserves).  

Can I still be operated if I am malnourished?  In order to prevent post-operative wound complications (healing) and infection (SSI), surgery is often delayed until a mal-nourished patient can first be restored to good health and nutrition.  However, in the case of a serious infection or tumor, when a delay of surgery cannot be advised, alternative and sometimes more circuitous methods must be employed to reach a similar goal (TREATMENT OUTCOMES: slide #4).  

Hypersensitivity reactions: a source of failure following total hip arthroplasty: New-generation metal-on-metal bearings made from cobalt-chromium alloys for use in total hip arthroplasty are now being utilized worldwide.  There is a unique histological response in patients with these implants in which there is a prominent, perivascular and/or diffuse lymphocytic infiltration reminiscent of a delayed type hypersensitivity response (type IV). This response has been termed ALVAL (aseptic lymphocyte dominated vasculitis associated lesion) and it is reported around metal-on-metal implants from various manufacturers (total hip arthroplasties). Degradation products, either in the form of ionic or particulate debris, can complex with local proteins to alter their confirmation and elicit an allergic response.   This type of hypersensitivity is mediated by T-lymphocytes which become reactive to metal ion-modified proteins. In this paradigm, there is co-operation between innate and adaptive immunity to produce antigen-driven clonal proliferation and differentiation.   The cells and byproducts accumulate, locally, to acclude the small vessels, resulting in an early loosening of implants, the accumulation of inflammatory tissues (pseudotumors) and, if prolonged, ischemic death of bone and soft tissues.  Recently, Langton and colleagues in Stockton, England, reviewed 650 metal-on-metal arthroplasties from different manufacturers and observed a 4.4% incidence of ALVAL in one make of joint(500) and a 0% incidence in another(150).  When the lymphocytes of the patients with failure were studied in the lab, they were not hyper-reactive to metal ions, alone.  This made sense: ALVAL is mediated by a local, toxic reaction (primary and secondary). Their study also showed there are specific design, geometric, and manufacturing parameters that contribute to the failures, independent of gender, composition of the bearing couple and positioning of the components, in situ.   Hanseen et al ⁽¹⁾ has reported elevated ESR and CRP levels in a case of ALVAL failure, adding to the difficulty in the making the diagnosis of an aseptic vs septic failure.   

In the last three years, 15% of the peri-prosthetic, total hip infections ( slide #3) treated at our treatment center in San Diego were associated with hyper-sensitivity reactions following metal-on-metal bearing arthroplasties.  

Ref: 1) Mikhael MM, Hanssen AD, Sierra RJ.  Failure of Metal-on-Metal Total Hip Arthroplasty Mimicking Hip Infection.  Department of Orthopedic Surgery, Mayo Clinic College of Medicine, Rochester, MN.  The Journal of Bone and Joint Surgery (American),2009; 91:443-446.   2) Jacobs JJ, Hallab NJ. Loosening and osteolysis associated with metal-on-metal bearings: a local effect of metal hypersensitivity? J Bone Joint Surg Am. 2006;88:1171-2

( CLICK FOR SLIDE SHOW: FIVE FIGURES )

Outcomes for adult patients treated for osteomyelitis over a 20 year period (1986-2006);  methods of reconstruction used to manage 314 consecutively treated segmental osseous defects (2003-2008); results following staged treatment of 194 peri-prosthetic total joint infections; the impact of our center’s innovations on treatment outcomes for patients with wound-healing deficiencies;  long-term treatment results for 2207 patients with all types of osteomyelitis (A-hosts and B-hosts).

BLOOD TESTS TO DIAGNOSE OSTEOMYELITIS / BONE and SOFT TISSUE  INFECTIONS - 

The Erythrocyte Sedimentation Rate (ESR):   When inflammation is present in the body, proteins are produced by the liver and the immune system under many abnormal conditions, such as an infection, an autoimmune disease, and/or cancer.  The increased presence of these proteins will cause red blood cells to stick together in solution (whole blood) and, therefore, settle out of solution more slowly than when these proteins are absent or in lower concentrations.   The Erythrocyte Sedimentation Rate (ESR) is, therefore, a non-specific test to indicate thickening of the blood due and can be used to rule in or rule out disease processes that, when present, stimulate production of these proteins (see below discussion of acute phase proteins).   Since there are many possible causes of an elevated sedimentation rate, this blood test is done with other tests to confirm a diagnosis such as a chronic osteomyelitis.  Once a sed rate (ESR) blood test is conducted, the course of a disease or the effectiveness of treatment can be monitored.

C-reactive protein (CRP): CRP is believed to play another important role in innate immunity, as an early defense system against infection.  It is a protein found in the blood, the levels of which rise in response to inflammation due to trauma, infection or serious illnesses; it is an “acute-phase protein” synthesized by the liver.  It is not related to C-peptide or protein C.   A rise in C-RP is due to a rise in the plasma concentration of IL-6(see below), which is produced predominantly by macrophages and fat cells.   CRP binds to microbes and is thought to enhance the process of phagocytosis (cellular ingestion/digestion) of bacteria by macrophages.  

When signaled, the CRP level rises above normal limits within 6 hours, and peaks at 48 hours.  Thereafter, its level is determined by the rate of production (and hence the severity of the precipitating cause).  Measuring and charting C-reactive protein values can prove useful in determining the presence of disease, disease progress and/or the effectiveness of various treatments.

Acute-phase proteins:  a class of proteins whose plasma concentrations increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response is called the acute-phase reaction (also called acute-phase response).  In response to injury, local inflammatory cells (neutrophils, granulocytes and macrophages) secrete a number of cytokines; cytokines are chemical signals between cells that have an effect on other cells, the most most notable of which are the interleukins IL-1, IL-6 and IL-8 and tumor-necrosis factor alpha (TNF- α).   

Interleukin-6 (IL-6) is both a pro-inflammatory and anti-inflammatory cytokine.  It is secreted by T-cells and macrophages to stimulate immune response to trauma, especially burns or other tissue damage leading to inflammation. IL-6 has been shown to be required for resistance against certain bacteria (i.e.; Streptococcus pneumoniae).  IL-6, one of the most important mediators of fever and of the acute phase response, can be secreted in response to specific microbial molecules referred to as pathogen associated molecular patterns (PAMPs).  These PAMPs bind to highly important group of detection molecules of the innate immune system called pattern recognition receptors (PRRs) which signal cascades giving rise to inflammatory cytokine production.

 At our Osteomyelitis Treatment Center in Sand Diego, CA we use the ESR, CRP and IL-6 blood tests in the diagnosis of bone and soft tissue infections as well as in the follow up following treatment results and peri-prosthetic total joint infections.

The Fate of the Unexpected Positive Intraoperative Cultures After Revision Total Knee Arthroplasty.  Robert L. Barrack,  Ajay Aggarwal,  R. Stephen J. Burnett,  John C. Clohisy,  Elie Ghanem,  Peter Sharkey and Javad Parvizi.  Washington University & Barnes-Jewish Hosp., St. Louis, MO;  Thomas Jefferson University & Rothman Inst,  Philadelphia, PA.  Journal of Arthroplasty, 2007; 22(6) pp94-99.

-Of a consecutive series of 692 revision total knees at 3 centers, intra-operative cultures were unexpectedly found to be positive in 41cases (5.9%). Of the 41, 29 (71%) cases had a single positive intra-operative culture and were determined to be a probable false positive based on absence of any other evidence of infection, of which 5 were treated with extended course of intravenous antibiotics after hospital discharge and the remaining 24 received no further treatment. None of these 24 patients manifested any sign of infection at follow-up, averaging 46 months (range, 24-74 months): Staph. epi (46%); enterococcus (11%); Staph. aureus (14%); Strep (9%); Corynebact. (7%); Diptheroids(7%); Prop. Acne(4%). Twelve patients were determined to have probable type 1 peri-prosthetic infection, 11 of which were treated with a course of antibiotics: Staph. epi.(50%); Enterococcus 29%; Staph. aureus 7%; MRSE (7%); Strep(7%).   Two (18%) of these patients became re-infected within one year.  CONCLUSION: A single positive intra-operative culture after revision total knee arthroplasty does not mandate further treatment in the absence of any other signs of infection.  DR. CIERNY’S COMMENTS: THIS ARTICLE EMPHASIZES TWO VERY IMPORTANT POINTS WHEN SENDING WOUND  CULTURES: 1) ALWAYS SEND MORE THAN ONE SPECIMEN WHEN CULTURING A WOUND. —–  FALSE POSITIVE CULTURES DO OCCUR;  2) BIOPSY WHAT YOU CULTURE AND CULTURE WHAT YOU BIOPSY.  A  POSITIVE CULTURE +  TISSUE WITH NO EVIDENCE OF ACUTE INFLAMMATION = A FALSE POSITIVE CULTURE.  IF, HOWEVER, THERE IS A POSITIVE CULTURE WITH POSITIVE HISTOLOGY IN AN UNEXPECTED SCENARIO FOLLOWING IMPLANTATION OF HARDWARE (SEE PROTOCOL),  AT THE VERY LEAST WE WOULD RECOMMEND OPEN IRRIGATION/DEBRIDEMENT OFTHE WOUND, SYSTEMIC ANTIBIOTICS AND ANTIBIOTIC-DEPOT FILLING OF THE ADJACENT DEAD SPACE. 

Time-related Concordance Between Swab and Biopsy Samples in the Microbiological Assessment of Burn Wounds  Ebrahim Salehifar, PharmD; Ghasemali Khorasani, MD; Shahram Ala, PharmD.  Mazandaran University of Medical Sciences; Emam Square, Valliasr Blvard; Sari, Mazandaran.   Wounds, VOLUME: 21Mar 01 2009.

-The aim of this study was to investigate the concordance between swab and tissue biopsy samples in terms of microbiological isolates and their time-related changes. A total of 156 samples (78 swab and 78 biopsy) were collected from 39 cases of partial- or full-thickness burns and compared at days 7 and 14 after admission regarding the type of microorganisms and their time-related changes. Pseudomonas aeruginosa and Citrobacter freundii were the two most common microorganisms found by both sampling methods. While the majority of swab and biopsy samples were concordant in day 7, the rate of concordance in day 14 was less than day 7—87.1% versus 66.6%, respectively. After comparing the ratio of P aeruginosa and C freundii in positive swab and biopsy cultures on days 7 and 14, unlike the swab samples, the biopsy samples yielded similar results both times (75% P aeruginosa and 25% C freundii, respectively).      DR. CIERNY’S COMMENTS:  THE RESULTS OF THIS STUDY SUGGEST THAT TISSUE SWABS ARE SUFFICIENT FOR WOUND MONITORING ONLY DURING THE ACUTE-PHASE OF AN  INFECTION.  BY THE SECOND WEEK, THE MAJORITY OF THE PATHOGENS ARE SESSILE (WITHIN THE BIOFILM COLONY) AND NO LONGER FREE-SWIMMING (PLANKTONIC) OR AMENABLE TO GROWTH IN STANDARD CULTURE MEDIA.   IN THIS STUDY, AS IN OTHERS DEALING WITH BIOFILM INFECTIONS, DEEP TISSUE SPECIMENS WERE REQUIRED TO HARVEST ENOUGH PLANKTONIC (CULTURABLE) ORGANISMS TO YIELD POSITIVE RESULTS.  HOWEVER,  EVEN THEN, 20-40% OF OUR CULTURES WILL  STILL COME UP  “NO GROWTH”  UNTIL WE DEVELOP METHODS TO FREEING OR INTICE SESSILE ORGANISMS BACK TO  PLANKTONIC PHENOTYPES.

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