Antibiotic impregnated PMMA beads: Use and misuse (Proceedings)

In order for AI-PMMA beads to produce a positive outcome, many factors must be taken into consideration. They are not for systemic infections, antibiotic selection should be based on culture results, heat will denature some antibiotics, antibiotics will only penetrate a few mm of surrounding tissue, only antibiotics and carriers whose elution properties have been studied should be used to avoid ineffective concentrations and to minimize the risk of toxic effects to the patient, more than one antibiotic should not be mixed in the same cement, and the smallest volume of antibiotic should be used.

Because of the high recurrence rate of abscesses in rabbits, it appears that excising the abscess en bloc as one would remove a tumor is more likely to result in a cure. Reasons cited for recurrence include that the abscess wall harbors bacteria isolating them from topical treatments, the thick caseous pus does not drain adequately, and the skin wound seals before second intention healing can force out the infection. Most abscesses of the head involve bone or teeth making it difficult to remove them en bloc without rupturing them. Still, it is best to treat rabbit abscesses as tumors that are locally invasive but do not metastasize making excision with minimal margins an appropriate surgical approach. Dissect the abscess down to bone, quickly remove the abscess at the level of the bone, curette the bone and remove any teeth that are involved in the abscess, and irrigate copiously to decrease the contamination from the ruptured abscess. It may not be possible to completely excise abscesses associated with osteomyelitis or tooth abscesses; however, it is vital to remove all abnormal tissues - soft and hard. Back to the tumor analogy, at this point, treat the abscess as if you have removed gross but not microscopic disease. The next part of therapy is to treat the residual microscopic disease.

"Marsupialization" is a term used by some authors when describing their recommendation for managing residual disease in abscesses in rabbits. Utilizing this technique, the abscess is excised as described above or opened and curetted out. The skin is then sutured to the abscess wall or whatever tissue is left surrounding the excision bed circumferentially. The idea behind this technique is to delay wound healing allowing prolonged management of the open wound hoping that the infection will then be eliminated. This requires a lot of open wound management which is difficult for the rabbit and the owner. Some authors, however, claim a high success rate with this technique and it might be a method to consider if the abscess is in an anatomically difficult area where the surgeon is not comfortable trying to excise the entire capsule.

Instead of treating the wound open, an alternative is to implant antibiotic impregnated polymethylmethacrylate (AIPMMA) beads which release relatively high concentration of antibiotic locally with little systemic absorption. This allows primary closure of the site and eliminates the need for open wound care. The rabbit is still placed on systemic antibiotics for 2 weeks but long term therapy is not necessary as the beads release antibiotic for many months or even years.

The antibiotic chosen is best based on culture and sensitivity results and/or Gram's stain prior to surgery. Tyrrell showed that all bacteria isolated from rabbit jaw abscesses in their study were susceptible to clindamycin; 96% were susceptible to penicillin, ceftriaxone, and cefazolin; 86% were susceptible to azithromycin and tetracycline; only 54% were susceptible to metronidazole and ciprofloxacin (the active metabolite of enrofloxacin); and only 7% were susceptible to trimethoprim/sulfa. No aminoglycosides were tested; however, they are typically ineffective against anaerobic bacteria and Gram positive bacteria which were the main isolates from the abscesses. Based on these results clindamycin, penicillin, ceftriaxone, and cefazolin would be good antibiotic choices; however, these antibiotics have potentially fatal consequences when used parenterally in rabbits. Note that enrofloxacin and trimethoprim/sulfa would not be expected to be of much benefit.

Because the fumes are annoying and potentially damaging to contact lenses and feti, many prefer to make the beads in a hood prior to surgery. The cement comes in 20 and 40 g packets (Surgical Simplex; Howmedica, Rutherford, NJ or Bone Cement; Zimmer, Patient Care Division, Charlotte, NC) which is enough to treat several rabbit abscess. The antibiotic is mixed with the copolymer powder prior to adding the liquid monomer. Once the polymerization begins, the cement hardens within 10 minutes. Refrigerating the reagents prior to use will extend this time. It can be challenging to make all the beads that quickly and the aid of some assistants is very helpful. Beads may be rolled into spheres and strung on a fine gauge wire. Unfortunately, the size of bead that can physically be made with the fingers is often too large for use in rabbit abscesses. As an alternative, the mixture is placed in a syringe (catheter tip for larger beads and regular tip for small beads) and squirted out onto a plastic or metal surface (such as a table drape intraoperative). A scalpel is then used to cut the tube of cement into small pieces. In this manner, a group of small cylinders will be created to function as beads. These beads will be too small to string on a wire. When placing the beads, count the number implanted and record it in the patient record. A bead maker is commercially available from Orthopaedic Laboratory Biomechanics in Minneapolis at 612-336-6600 or FAX 612-336-6619. Unfortunately, the beads made with this device are generally too large for use in rabbit dental abscesses.

If removal of the beads is planned, it is ideal to place the beads on an orthopedic wire or nonabsorbable suture when making them, forming a string of beads. In this manner when the beads are to be removed the surgeon need only locate one bead and the remainder can be removed by pulling the string. Unfortunately the beads are often too small to string making bead removal more challenging.

Dos and Don'ts

The rationale behind the use of AIPMMA is to provide high local concentration of antibiotic with low systemic absorption and, therefore, less toxicity. It is also useful in infections where long-term use or the systemic use of the antibiotic of choice would be contraindicated as is often the case with rabbit abscesses. And it is also useful when an expensive antibiotic is indicated as repeated administration is not required. Beads have also been used for soft tissue and orthopedic infections where the patient is intractable and repeated administration of antibiotics is not feasible.

Don't – Do Not Use To Treat Systemic Infections

The ideal antibiotic for use in AIPMMA beads is one that is bacteriocidal, broad spectrum, effective in low concentration, heat stable (up to 100o C), and has high water solubility and low tissue toxicity. Gentamicin has been studied extensively and has been shown to elute concentrations above the break point susceptibility concentration for over 80 days with levels detectable for over 5 yrs. The average serum concentration (1 g gentamicin/20 g PMMA) was only 0.5 mcg/ml and the wound fluid concentration was 80 mcg/ml. The elution properties of the injectable gentamicin are the same as the powered. The equine product (100 mg/ml) is preferred to reduce the amount of liquid required.

Don't

If the bacteria are not sensitive to the antibiotic selected, the beads will not be effective at controlling residual disease. Therefore, it is best to have culture and sensitivity testing prior to surgery so the proper antibiotic can be selected. Unfortunately, culture often yields no growth. In this situation, do a Gram's stain and identify the class of bacteria present, Gram negative vs. Gram positive, rods vs. cocci, and select antibiotics most likely to be effective against the classes of bacteria present. If no bacteria are seen, it is best to use antibiotics with broad spectra of activity. Cefazolin and amikacin have been studied and provide a broad spectrum of activity against most Gram positive (cefazolin) and Gram negative (amikacin) as well as anaerobic bacteria (cefazolin).

Any unused beads are gas sterilized and used in future patients. The shelf life for these beads is unknown but assumed to be the normal expiration date of the antibiotic. The beads can be gas sterilized which does not affect their elution or antimicrobial properties (Ramos). The package containing the beads should be labeled with the expiration date of the antibiotic as well as the sterilization date.

Don't

Do not autoclave the beads as the high heat will denature most antibiotics. Beads should be re-sterilized in gas every 3 months.

The elution of the antibiotic is bimodal with a rapid release in the first few days followed by a slow, long term release of antibiotic over weeks to months. The beads become encapsulated with fibrous tissue within a few weeks and then only tissues within about 3 mm receive the high concentration of antibiotic.

Don't

Because of this it is essential to remove the abscess as completely as possible before placing the beads. They should not be placed within the abscess capsule and expected to cure the abscess. The antibiotic will not penetrate the wall of the capsule deeply enough to control bacteria within the capsule and recurrence is likely.

Other antibiotics commonly used where elution information is available include the following: tobramycin (1g/20g PMMA), cephalothin (2g/20g PMMA), cefazolin (2g/20g PMMA), amikacin (1.25g/20g PMMA) (the liquid form eluted slower than the powder), and ceftiofur (2g/20g PMMA). In an in vitro study with ceftiofur, antimicrobial concentrations were only maintained for 7 days. Clindamycin has been studied at doses of 1.5-3.0 g/20 g PMMA and shows good elution properties when compared with other antibiotics (Adams, Khaliq) but no studies have been conducted with clindamycin in rabbits in which systemic administration is potentially toxic.

Don't

It is best to avoid using drugs for which there are no studies evaluating elution and absorption if the drug is known to be toxic to rabbits. While there are studies evaluating the elution of clindamycin from PMMA beads, clindamycin can cause a fatal enterotoxemia in rabbits and there are no studies to define if there is enough systemic absorption to result in fatal diarrhea. This would be especially a problem soon after implantation when elution from the beads is highest. However, Tyrrell's article reports one author (Jenkins) observed "clindamycin and/or ceftiofur beads resulted in no recurrence in 97 of 104 (93%) rabbits within 90 days of implantation." Unfortunately, no concentrations were published and the report did not indicate if both antibiotics were put into the same beads or individually in beads.

In order to increase the spectrum, clinicians may combine two antimicrobials into the PMMA beads. This is strongly discouraged based on a few elution studies.

Don't

Do not use more than one antibiotic in the same cement mix unless there is research to support the elution is appropriate. In a recent study (Ramos) the in vitro elution properties of gentamicin and metronidazole were studied individually and combined in the same beads. Metronidazole doses of 0.5, 0.75 and 1.0g/20g PMMA were evaluated, gentamicin at 1 g/20g PMMA, and the combination contained 1 g each in 20g PMMA. When combined in the same beads, elution of both was more rapid than when they were alone. In a study in my lab at the University of Pennsylvania (Phillips, et al), we showed that the same happens when cefazolin and amikacin are combined in the same mixture (publication in progress).

A systemic antibiotic is used in addition to the beads for 10-14 days postoperatively if feasible. It is expected that bacteremia will result from the dissection and manipulation of the abscess. Because systemic absorption of the antibiotic from the beads may not be in concentrations high enough to control infection in remote locations, it is recommended to also use a systemic antibiotic. However, I generally choose a different antibiotic from what is in the beads as the addition of whatever might be absorbed from the beads to a therapeutic dose may be too much. Some antibiotics have a wide margin of safety and this is not a significant risk.

Don't

Be careful not to overdose the patient by giving the same antibiotic systemically and locally in the beads. Depending on the antibiotic (its safety and therapeutic range) this may or may not be a concern.

The rate of elution is affected by various factors. The amount of fluid flowing past the beads influences the rate such that highly vascular areas elute the antibiotic more rapidly with more systemic absorption and more rapid depletion of the antibiotic within the beads. The diffusion properties of the antibiotic and its heat stability also affect elution rates. The exothermic polymerization reaction can denature antibiotics such as penicillins making them less effective. The previously mentioned antibiotics are heat stable.

Don't

It is best to use antibiotics for which elution studies have been conducted. These studies will help define the amount needed. For example, penicillin is heat labile. It has been studied and can be used in PMMA beads but it is partially inactivated during the exothermic polymerization reaction. Enrofloxacin does not mix into PMMA bone cement at all. The liquid injectable enrofloxacin will stay separate from the polymer leaving the clinician with a lump of cement and a pool of enrofloxacin. Ciprofloxacin is available as a sterile powder which is meant to be reconstituted prior to injection. The powder can be mixed into PMMA and there are studies evaluating its elution properties. Basically, until elution studies have been conducted it is not recommended that new antibiotics be used clinically.

Many antibiotics have been studied for use in PMMA beads in a sterile powdered form. When used to secure joint implants (such as THR) the strength of the cement is of concern. Too much antibiotic will weaken the biomechanical properties of the cement resulting in premature loosening of cemented implants. This is NOT a concern in antibiotic PMMA beads as they are not under biomechanical stress. Still it easier to make the beads if a powder is used. The powder should be mixed well with the cement powder to distribute it as evenly as possible throughout the beads prior to adding the liquid monomer. I have done a study with gentamicin and amikacin showing there is no difference in elution when liquid or powder is used and that liquid amikacin elutes slightly more slowing than powdered amikacin. These antibiotics are not readily available in a sterile powdered form. Gentamicin is available at a concentration of 100 mg/ml and amikacin at 250 mg/ml, both being used primarily in equine medicine. Using these products will decrease the amount of liquid used and make it easier to make the beads.

Don't

It is best to use the smallest amount of antibiotic liquid (especially) or powder to make the beads. The equine injectable gentamicin (100 mg/ml) and amikacin (250 mg/ml) are useful. Amikacin separates from the PMMA early during the polymerization process. Don't freak out, keep stirring and it will eventually go back into the mixture.

There are many studies in the human literature and several in the veterinary literature evaluating beads and elution. Sterilized Plaster-of-Paris (POP), hydroxyapatite, and Matrix III have all been studied and are bioabsorbable. Plaster-of-Paris is inexpensive and there are various studies looking at the elution properties of various antibiotics from POP beads as well. A new bone cement has recently become available. Biofusion (formerly Kryptonite) manufactured by Doctor's Research Group in Gainesville, Fl and marketed through Biomedtrix, has not yet been investigated scientifically to see if antibiotics elute from this cement.

Don't

As the popularity of local antibiotic delivery systems has grown, practitioners are attempting to implant various antibiotic impregnated substances into rabbits. I have heard anecdotal reports of using antibiotic-soaked Gelfoam, antibiotic-soaked Consil, and antibiotic soaked gauze with single and multiple antibiotic agents and concentrations. I caution practitioners regarding this activity without more scientific knowledge about elution and systemic absorption of the drugs. Gelfoam, Consil, and gauze would all be expected to release antibiotic much faster than PMMA would. This could result in excessive systemic absorption of potentially dangerous antibiotics. Additionally, if the antibiotic elutes too rapidly, there will be no long term elution which may decrease the efficacy.

If the beads are not removed, they do not cause clinical problems as they are biologically inert. Indications for removal are the presence of a fistulous tract, recurrence of the abscess, poor cosmetic results, and interference with normal function. Removal is indicated if they are in a mucosal lined structure such as the nasal cavity as they may cause a chronic discharge. If they are placed within a joint they may interfere with function and contribute to arthritis. And if they are placed in a pressure location, such as the bottom of the foot for pododermatitis, they may cause pressure sores. I have used beads in this application and not seen pressure sores develop. If a new abscess forms around the beads, it is an indication that the antibiotic is not effective and the bead can serve as a nidus for infection. The abscess should be treated again and all beads in the vicinity removed.

Don't

In humans, studies have shown a better long term prognosis if the beads are not removed, presumably because they continue to elute antibiotic and control infection.

Additional Reading

Ethell MT, Bennett RA, Brown MP, et. al. In vitro elution of gentamicin, amikacin, and ceftiofur from polymethylmethacrylate and hydroxyapatite cement. Vet Surg 29:375-382, 2000.

Tyrrell KL, Citron DM, Jenkins JR, Goldstein EJC. Periodontal bacteria in rabbit mandibular and maxillary abscesses. J Clin Micro 40(3): 1044-1047, 2002.

Ramos JR, Howard RD, Pleasant RS, et. al. Elution of metronidazole and gentamicin from polymethylmethacrylate beads. Vet Surg 32:251-261, 2003.

Adams K, Couch L, Cierny G, et. al. In vitro and in vivo evaluation of antibiotic diffusion from antibiotic-impregnated polymethylmethacrylate beads. Clin Orthop Rel Res 278:244-252, 1992.

Khaliq Y, Rouse M, Piper KE, et. al. Amikacin or clindamycin release kinetics from polymethylmethacrylate or Matrix III beads in a continuous flow chamber. Abstract of the Interscience Conference on Antimicrobial Agents & Chemotherapeutics 41:37, 2001.

Phillips H, Boothe DM, Davidson JS, Bennett RA: In vitro elution of amikacin, cefazolin, and a combination of amikacin and cefazolin from polymethylmethacrylate beads. Proceedings of the Veterinary Orthopedic Society, 2005.