Local Antibiotic Delivery Systems (2005)

The use of local antibiotic delivery systems has become an accepted treatment method that continues to evolve for a variety of reasons. There has been an explosion of new technologies that are designed to facilitate the delivery of local antibiotics in new and creative ways. The primary reason for using these local antibiotic delivery vehicles is the ability to achieve very high local concentrations of antibiotics without associated systemic toxicity. In the typical infected wound environment, which frequently has zones of avascularity, the ability to achieve high levels of antibiotics in these otherwise inaccessible areas is highly desirable.5 Additional reasons for use of these delivery vehicles include the desire to treat remaining planktonic organisms and sessile organisms in biofilms more effectively with high concentrations of antibiotics. Because bone regeneration often is required as a part of the treatment plan, a recent trend has been simultaneously to provide a framework of osteoinductive and osteoconductive materials along with antibiotic delivery.11 Despite the rapid acceptance of these antibiotic delivery vehicles, there are many unanswered questions related to their use, particularly when viewed within the environment of biofilms that were discussed in this symposium. Some of the questions discussed are outlined below. How high do we need to get the concentration of these antibiotics and what is the desirable duration of these high levels? What are the adverse clinical consequences of extremely high levels of antibiotics, particularly at the local level and specifically with regard to the process of bone regeneration? Are new and creative dosing regimens required with multiple combinations of antibiotics to address unique patterns of resistance associated with biofilms? Can the traditional methods of assessing antimicrobial susceptibility of pathogenic organisms be extrapolated to the efficacy obtained with these high concentrations of antibiotics? What types of models are required to study the efficacy of antibiotics on sessile organisms contained within biofilms? Are there nonantimicrobial options to consider that can augment the efficacy of current antimicrobials? And finally, how do clinical investigators actively use these new concepts and rapidly changing technologies when the burdens of federal regulation seem to prevent their use? High Local Antibiotic Concentrations Local antibiotic delivery vehicles are capable of achieving extremely high local tissue concentrations when compared with the antibiotic tissue levels obtained with traditional systemic antibiotic therapy. Antibiotic concentrations with local antibiotic delivery vehicles that reach levels of 3800 μg/mL21 and 4746 μg/mL24 have been reported. Although the symposia participants all agreed that the higher levels obtained with local delivery seem desirable and present the potential for improved efficacy, it was recognized that very little data are available to determine the optimal level of these antibiotics that are required for efficacy against these pathogenic organisms. The optimal antibiotic concentration likely is to be variable depending on the characteristics of the organism, the organism’s bioenvironment, and the specific antibiotic being used. One of the most obvious concerns regarding extremely high levels of local antibiotics is the potential for systemic toxicity, particularly in patients with abnormal renal function. Although there is considerable clinical experience to suggest that systemic toxicity associated with the use of high-dose antibiotic-loaded cement (ABLC) spacers is relatively rare, this remains a notable concern.32 One of the reasons for this concern is the inability to control the variables of antibiotic elution accurately in the postsurgical wound environment. The potential exists for large depots of antibiotics to be released erratically as a result of unexpected degradation patterns with newer biodegradable delivery vehicles. The concern regarding extremely high concentrations of local antibiotics particularly is valid in the face of dose-dependant, adverse consequences of bone regeneration with many currently used antibiotics.15,16,17,18,22 The need to profile the advantages of increasing higher doses of antibiotics must be balanced with the adverse effects of each specific antibiotic so that dosing regimens can be created and understood. It is also recognized that the antibiotic release characteristics of the various delivery systems need to be documented carefully so that the antibiotic concentrations that are achieved are known when these implants are used in vivo. Biofilms It is well recognized that biofilms play an important role in many chronic bacterial infections.6,13 Using tools such as the scanning electron microscope and the confocal laser scanning microscope, it is now understood that biofilms are not unstructured, homogeneous deposits of cells and accumulated slime, but complex communities of surface-associated cells enclosed in a polymer matrix containing open water channels.9 Current intervention strategies against biofilm infections are designed to prevent initial device colonization, to minimize microbial cell attachment to the device, and to penetrate or to disrupt the biofilm matrix to kill the associated cells.9 One of the most effective strategies to deal with biofilms in orthopaedic infection has been to remove the affected device or tissue that harbors the biofilm completely.13 The diagnostic and therapeutic strategies developed for acute bacterial diseases have not yielded accurate data or favorable outcomes when applied to these biofilm diseases.6 Bacteria residing within the biofilms (sessile) are less susceptible to antimicrobial agents than free-living (planktonic) cells. It is also known that young sessile cells are not as resistant to therapy as are older sessile cells associated with chronic infection.2 Several mechanisms have been proposed to explain this phenomenon of resistance within biofilms. Sessile bacteria may survive antibiotic exposure because of delayed penetration of the antimicrobial into the biofilm, marked slowing of growth rate of organisms within biofilms, but also because of an increased frequency of resistance traits within these sessile organisms.7,8 Practical implications of the altered response of sessile organisms within biofilm is that alternative strategies must be devised for susceptibility testing of these organisms and that new antimicrobial dosing regimens may be required to treat organisms within biofilms. Some of the possibilities include using higher concentrations of antibiotic, combination antimicrobial therapy that creates synergy,25 repetitive pulsing of antibiotic delivery,6 and nonantimicrobial strategies that disrupt the biofilm or augment the response of antibiotics against organisms contained within the extracellular matrix.9 These antibiotic delivery strategies need to be developed within the context of known information because simply increasing the concentration of antibiotics may be illogical in some circumstances. For example, cell-wall active antibiotics, such as vancomycin, would not be expected to be very effective against sessile organisms within biofilm, which exhibit a reduced growth rate, and indeed it has been shown in animal models that vancomycin is relatively ineffective when used as single-agent therapy.10,29 In one of these studies, rifampin alone, among 35 antibiotics studied, penetrated the biofilm.10 Importantly, antibiotics of the cell-wall active class (including vancomycin) were synergistic with rifampin whereas some other antibiotics (including aminoglycosides) antagonized rifampin activity. One of the industrial concepts that has been effective in the treatment of organisms within biofilms is to provide intermittent pulsing of high doses of antibiotics as this facilitates attack of sessile cells that have become planktonic.6 Although this technique can be shown to be effective in controlled industrial models, the difficulties associated with using this approach in the setting of large orthopaedic wounds that are dynamic and have considerable variability make this approach relatively unrealistic at this time. The concept of providing high local loading doses of antibiotic and then providing constant sustained levels of antibiotics seems to be an achievable goal with local antibiotic delivery devices and indeed there are many developmental products that use this as a part of the device design. Antimicrobial Susceptibility Testing Traditional culture and susceptibility testing have been based on retrieval, identification, and assessment of planktonic bacteria. Finally, susceptibility patterns based on traditional culture techniques with relatively low levels of antibiotics may or may not correlate with the susceptibility of planktonic or sessile bacteria confronted with antibiotic concentrations are 10-fold or even 1000-fold higher. Based on current knowledge, this information may not be relevant to the susceptibility of any remaining sessile bacteria contained within biomaterial that is left in the wound. In an in vitro study, all Propionibacterium acnes isolates in biofilm showed considerably greater resistance to cefamandole, ciprofloxacin and vancomycin.30 All staphylococcus species biofilm isolates showed large increases in resistance to gentamicin and cefamandole with a considerable increase in resistance to vancomycin; however there was little difference observed with ciprofloxacin.30 Based on these results, it seems that the susceptibility of antibiotics against organisms growing within biofilms should be determined to ensure optimal treatment. An experimental Staphylococcus aureus rat osteomyelitis model was designed to correlate in vitro testing with in vivo findings using cefuroxime, vancomycin, and tobramycin.12 The implants were studied for presence of bacteria by adenosine triphosphate (ATP) bioluminescence after treatment and compared with an in vitro assay using three concentrations of each antibiotic (8, 100, and 500 μg/mL).12 In the in vivo model, cefuroxime reduced the number of bacteria more effectively than vancomycin (p < 0.05) whereas tobramycin had no effect. The in vitro assay directly correlated with the in vivo data as cefuroxime significantly (p < 0.05) reduced the number of viable bacteria at all concentrations, tobramycin did not affect viability, and vancomycin affected viability except at the lowest concentration studied (8 μg/mL).12 These results show the usefulness of such an osteomyelitis model to provide evidence for correlation between the in vitro and in vivo findings on the effect of antibiotics being studied. Methods of Monitoring Antibiotic Effect on Biofilms It generally was accepted by symposium participants that methods to monitor biofilm activity in real time would be helpful to assess the effect of treatment strategies on cells contained within biofilms in experimental models. There currently are many methods being investigated, which include measurements with a specialized respirometer, use of nuclear magnetic resonance imaging, and bioluminescence imaging.6 Some bacteria produce or can be made to produce bioluminescent signals allowing real-time assessment of the physiologic state of the biofilms.19 This method measures the metabolic activity of viable cells nondestructively, which is appealing for drug-efficacy studies of chronic biofilm infections. In an S. aureus isolate made bioluminescent by inserting a modified lux operon into the bacterial chromosome model, treatment with rifampin, tobramycin, and ciprofloxacin was assessed.20 A rapid dose-dependent decline in metabolic activity in rifampin-treated groups was observed and the disappearance of light emission correlated with colony counts. Because the metabolic activities of viable cells and a post antibiotic effect could be detected directly, this methodology is appealing for investigating the effects of antibiotics on biofilms. Adjunctive Biofilm Therapies The application of low-frequency ultrasound to enhance vancomycin activity against coagulase negative staphylococcal (CNS) and Escherichia coli biofilm has been shown to be effective because pulsed ultrasound significantly reduced bacterial viability below that of nontreated biofilms.4,31 Although the CNS biofilms responded favorably to various combinations of ultrasound and vancomycin, longer treatment times were required for CNS than those observed for E. coli biofilms.4 The possible mechanisms of this phenomenon were explored with the enhanced action of gentamicin against Pseudomonas aeruginosa biofilms.28 The dependence on peak power density suggests that acoustic pressure plays a notable role. There is also a strong frequency component that causes the killing effect to decrease as frequency increases. It is possible that stable cavitation and the accompanying microstreaming contribute to the bioacoustic effect.28 Others have investigated the in vitro effects of pulsed electromagnetic fields (PEMF) on the efficacy of antibiotics in CNS biofilms.26 Exposure to a PEMF increased the effectiveness of gentamicin against 5-day CNS biofilms with a reduction of at least 50% in the minimum biofilm inhibitory concentration (p < 0.05). There was no significant effect with vancomycin. In one arm of the experiment, there was a two-log difference in colony count at 160 mg/L of gentamicin indicating that synergy was more pronounced at higher levels of gentamicin. Other study results indicate that application of static magnetic fields may also enhance the activity of gentamicin against biofilm-forming P. aeruginosa.3 The effect seems to be limited to magnetic fields between 5 and 20 G and the effect was independent of substrate surface. One of the intriguing aspects of these observations regarding use of these adjunctive methods to augment the efficacy of certain antibiotics is that these methods could be used to augment the process of bone restoration simultaneously. Although still controversial, it increasingly is accepted that signals from electromagnetic fields (EMF) and ultrasound (US) have a clinically significant effect on bone repair, and both methods are now a common part of the orthopaedist’s armamentarium.1,27 It has been shown that both have common waveform characteristics at the treatment site and therefore can deliver similar doses of electrical stimulation to the bone.24 Further investigations into this area-to unify the effects of EMF and US on antibiotics and bone healing-seem warranted because it may be possible to modulate the bone reparative process by several different mechanisms during the treatment of musculoskeletal infection. The most obvious would be caused by the direct effects of EMF and US on bone healing and also an indirect effect might be realized by limiting the dosage of locally delivered antibiotics because of increased efficacy with EMF or US, reducing the dose related adverse effects of antibiotics on osteoblasts. Regulatory Issues One of the sources of great frustration for clinicians engaged in the treatment of musculoskeletal infection has been the inevitable delays that have occurred with FDA approval for local antibiotic delivery vehicles.23 Only recently, after decades of use as a clinician-directed application, is there now approval of commercial ABLC.23 Unfortunately, these approvals are for low-dose aminoglycoside ABLC, which is suitable for prophylaxis; current treatment strategies for established infection require higher doses and multiple choices of antibiotics.14 As such, physicians who choose to treat established musculoskeletal infection with high-dose ABLC must continue to do so as a clinician-directed application. The emergence of composite local antibiotic delivery vehicles, which have the potential to deliver different types of antibiotics, provide creative methods of antibiotic dosing, and also provide materials that contribute to osteogenesis will need to be used as clinician-directed application for the foreseeable future. Hopefully with careful development of these composite biomaterials combined with efficacy and safety data will enable FDA approval for wider use in the treatment of musculoskeletal infections. There is still much to do regarding the investigation and development of treatment tools for treatment of musculoskeletal infection. However, the potential opportunities appear optimistic particularly if biofilm researchers, infectious disease specialists, microbiologists, and orthopaedic surgeons continue to interact and to communicate openly so that some of their seemingly disparate activities ultimately can be combined in a synergistic manner.