Biodegradable implantable teicoplanin beads for the treatment of bone infections

Parenteral antibiotic therapy for acute bone infections, soft tissue infections and osteomyelitis may result in high serum concentrations, associated with nephrotoxic, ototoxic and allergic complications. After taking these above mentioned disadvantages into consideration, recent investigations have explored the use of antibiotic-loaded biodegradable implants, incorporating antibiotics for potential use in the treatment of bone infections. In this study, biodegradable implants containing teicoplanin for the prevention or the treatment of bone infections were designed by using sodium alginate as the polymer material. Therefore, teicoplanin, a glycopeptide antibiotic, active against gram-positive bacteria was incorporated in a natural polymer in order to prepare bead formulation for implantation purpose in bone for the localized treatment of osteomyelitis. In vitro characterization was realized by determining particle size, surface characteristics, loading capacity and in vitro release characteristics of the beads.     

Sodium fusidate-poly(D,L-lactide-co-glycolide) microspheres: preparation, characterisation and in vivo evaluation of their effectiveness in the treatment of chronic osteomyelitis

PURPOSE: The aim of this study was to prepare poly(D,L-lactide-co-glycolide) (PLGA) microspheres containing sodium fusidate (SF) using a double emulsion solvent evaporation method with varying polymer:drug ratios (1:1, 2.5:1, 5:1) and to evaluate its efficiency for the local treatment of chronic osteomyelitis. METHODS: The particle size and distribution, morphological characteristics, thermal behaviour, drug content, encapsulation efficiency and in vitro release assessments of the formulations had been carried out. Sterilized SF-PLGA microspheres were implanted in the proximal tibia of rats with methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. After 3 weeks of treatment, bone samples were analysed with a microbiological assay. RESULTS: PLGA microspheres between the size ranges of 2.16-4.12 microm were obtained. Production yield of all formulations was found to be higher than 79% and encapsulation efficiencies of 19.8-34.3% were obtained. DSC thermogram showed that the SF was in an amorphous state in the microspheres and the glass transition temperature (T(g)) of PLGA was not influenced by the preparation procedure. In vitro drug release studies had indicated that these microspheres had significant burst release and their drug release rates were decreased upon increasing the polymer:drug ratio (p < 0.05). Based on the in vivo data, rats implanted with SF-PLGA microspheres and empty microspheres showed 1987 +/- 1196 and 55526 +/- 49086 colony forming unit of MRSA in 1 g bone samples (CFU/g), respectively (p < 0.01). CONCLUSION: The in vitro and in vivo studies had shown that the implanted SF loaded microspheres were found to be effective for the treatment of chronic osteomyelitis in an animal experimental model. Hence, these microspheres may be potentially useful in the clinical setting.     

Preparation and characterization of ofloxacin microspheres for the eradication of bone associated bacterial biofilm

Biodegradable polymers for localized delivery of antibiotics have emerged as an important approach to treating orthopaedic infections. In chronic forms of osteomyelitis which arethought tobeassociated with bacterial biofilm, localized delivery of a suitable antibiotic is desirable. This paper describes the formulation and in vitro evaluation of biodegradable ofloxacin microspheres for the eradication of bone associated bacterial biofilm infections. Ofloxacin microspheres were formulated using poly(glycolic acid-co-dl-lactic acid) (PGLA) by the emulsion solvent evaporation technique. The effects of process parameters such as phase volume, poly(vinyl alcohol) (PVA) concentration, and viscosity grade of the polymer during preparation on encapsulation efficiency (EEF) and in vitro release profiles were investigated. An increase in the phase volume or volume fraction from 21 to 35% at a constant internal phase volume resulted in an increase in EEF from 34 to 74%. Increasing PVA concentration from 0.25 to 2.5% w/v at a constant phase volume or volume fraction did not have an effect on the EEF. Ofloxacin release from the microsopheres was biphasic with an initial burst release followed by a slow release phase. An optimum slowing down of release was observed when the phase volume was 29%. Above and below this phase volume, release of ofloxacin was higher. The higher the viscosity grade of the polymer used for the preparation of microspheres, the higher the PVA concentration needed to prepare microspheres with slower release. The study indicates that various rates of ofloxacin release is possible by varying formulation conditions. This should provide a means for formulating sustained release microspheres of antibiotics for the treatment of biofilm infections associated with the bone.     

Implantation of vancomycin microspheres in blend with human/rabbit bone grafts to infected bone defects

In orthopaedic applications, allografts are used for restoration of bone defects. In order to combine the effects of bone repair and to prevent the infection, antibiotic-impregnated bone grafts are under current investigation with promising early results. In this study, to preserve the stability of antibiotics and to provide appropriate release profiles for 4-6 weeks, antibiotic-loaded microspheres were administered in combination with allografts and vancomycin was the antibiotic loaded to microspheres. Particle size, surface characteristics, loading capacity and in vitro release characteristics of the microspheres with and without allografts were determined. In vivo studies were performed on rabbits and antibiotic amount was determined by a fluorescence polarization immunoassay (FPIA) method from synovial fluid sample aspirated. According to the results, although the in vitro study demonstrated effective antibiotic release of vancomycin from antibiotic-impregnated allografts for 5 weeks, in vivo conditions led to an early instability of the antibiotic (in powder form) and contrary to the high initial loading dose an effective release could not be obtained from the allografts after the first week. Following these studies, it was determined that antibiotic release over a minimum inhibitory concentration (MIC) for 6 weeks was realized from vancomycin-loaded microspheres which were implanted in a blend with allografts in bone defects. In conclusion, preservation of the antibiotic in microspheres maintained the bioactivity and provided the controlled antibiotic release, thus implantation of microspheres in a blend with allografts seemed to be a promising carrier system for the orthopaedic applications.     

Characterization of biodegradable chitosan microspheres containing vancomycin and treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus with prepared microspheres

The biodegradable chitosan microspheres containing vancomycin hydrochloride (VANCO) were prepared by spray drying method with different polymer:drug ratios (1:1, 2:1, 3:1 and 4:1). Thermal behaviour, particle size and distribution, morphological characteristics, drug content, encapsulation efficiency, in vitro release assessments of formulations have been carried out to obtain suitable formulation which shows sustained-release effect when implanted. Sterilized VANCO loaded microspheres were implanted to proximal tibia of rats with methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. Intramuscular (IM) injection of VANCO for 21 days was applied to another group for comparison. After 3 weeks of treatment, bone samples were analysed with a microbiological assay. According to the results, encapsulation efficiency and yield of microspheres in all formulations were higher than 98% and 47%, respectively. Particle sizes of microspheres were smaller than 6 microm. All microsphere formulations have shown sustained-release effect. In vitro drug release rate decreased due to the increase in polymer:drug ratio but no significant difference was seen between these results (p>0.05). Based on our in vivo data, rats implanted VANCO-loaded chitosan microspheres and administered IM injection showed 3354+/-3366 and 52500+/-25635 colony forming unit of MRSA in 1g bone samples (CFU/g), respectively. As a result, implanted VANCO-loaded microspheres were found to be more effective than IM route for the treatment of experimental osteomyelitis.     

支架外固定抗生素骨水泥填充治疗胫骨骨折术后骨髓炎的临床疗效观察

目的:探讨支架外田定抗生索骨水泥填充治疗胫骨骨折术后骨髓炎的手术治疗方法,并对手术疗效进行随访分析.方法:自2008-08～2010-01我院采用支架外固定抗生素骨水泥填充治疗胫骨骨折术后骨髓炎23例,所有患者均取出原内固定物,重新复位,采用支架外固定,并于骨折断端或骨缺损处填充抗生素骨水泥治疗.术后随访10～20个月...     

Sodium fusidate-poly(D,L-lactide-co-glycolide) microspheres: Preparation,characterisation and in vivo evaluation of their effectiveness in the treatment of chronic osteomyelitis

Purpose: The aim of this study was to prepare poly(D,L-lactide-co-glycolide) (PLGA) microspheres containing sodium fusidate (SF) using a double emulsion solvent evaporation method with varying polymer:drug ratios (1:1, 2.5:1, 5:1) and to evaluate its efficiency for the local treatment of chronic osteomyelitis.

Methods: The particle size and distribution, morphological characteristics, thermal behaviour, drug content, encapsulation efficiency and in vitro release assessments of the formulations had been carried out. Sterilized SF-PLGA microspheres were implanted in the proximal tibia of rats with methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. After 3 weeks of treatment, bone samples were analysed with a microbiological assay.

Results: PLGA microspheres between the size ranges of 2.16–4.12?µm were obtained. Production yield of all formulations was found to be higher than 79% and encapsulation efficiencies of 19.8–34.3% were obtained. DSC thermogram showed that the SF was in an amorphous state in the microspheres and the glass transition temperature (T_g) of PLGA was not influenced by the preparation procedure. In vitro drug release studies had indicated that these microspheres had significant burst release and their drug release rates were decreased upon increasing the polymer:drug ratio (p?<?0.05). Based on the in vivo data, rats implanted with SF-PLGA microspheres and empty microspheres showed 1987?±?1196 and 55526?±?49086 colony forming unit of MRSA in 1?g bone samples (CFU/g), respectively (p?<?0.01).

Conclusion: The in vitro and in vivo studies had shown that the implanted SF loaded microspheres were found to be effective for the treatment of chronic osteomyelitis in an animal experimental model. Hence, these microspheres may be potentially useful in the clinical setting.     

Serum and bone concentrations of teicoplanin and vancomycin: study in an animal model

Teicoplanin and vancomycin are antibiotics widely used in the therapy of bone and joint infections. The aim of this study was to compare bone and serum concentrations of each antibiotic in guinea pigs after administration of 50 mg/kg of teicoplanin or vancomycin by the intravenous route. Serum and bone concentrations were determined immediately before and 0.5, 1, 2, 6, 12 and 24 h after drug administration by means of high performance liquid chromatography. Teicoplanin concentrations were always higher than vancomycin levels. Area under the concentration/time curve was significantly greater for teicoplanin than for vancomycin. In bone, teicoplanin concentration increased up to 6 h, while vancomycin reached its peak after 2 h. Moreover, teicoplanin showed markedly higher levels at 6, 12 and 24 h than vancomycin. In conclusion, the ability of teicoplanin to penetrate bone in greater amount than vancomycin confirms the potential use of teicoplanin in the treatment of bone infections and in the prophylaxis of orthopedic surgery.     

抗生素骨水泥治疗创伤性胫骨骨髓炎的创面愈合效果

目的探讨抗生素骨水泥治疗创伤性胫骨骨髓炎患者的临床效果。方法 96创伤性胫骨骨髓炎患者,依据患者入院单双号分为观察组和常规组,每组48例。常规组患者给予局部抗生素灌注治疗,观察组患者给予局部抗生素骨水泥治疗。比较两组患者治疗效果、并发症发生率、骨缺损长度、软组织缺损面积及手术前后疼痛评分。结果观察组患者总有效率为97.92%,常规组总有效率为85.42%;观察组患者总有效率明显高于常规组,差异有统计学意义(P<0.05)。观察组患者骨缺损长度为(1.42±0.23)cm,软组织缺损面积为(0.76±0.25)cm^2;常规组患者骨缺损长度为(1.79±0.37)cm,软组织缺损面积为(0.99±0.48)cm^2;观察组患者骨缺损长度及软组织缺损面积均优于常规组,差异有统计学意义(P<0.05)。手术前,两组患者疼痛评分比较差异无统计学意义(P>0.05);手术后,观察组患者疼痛评分(2.47±0.79)分显著低于常规组的(3.85±0.98)分,差异有统计学意义(P<0.05)。观察组患者并发症发生率6.25%低于常规组的25.00%,差异有统计学意义(P<0.05)。结论对于创伤性胫骨骨髓炎患者在临床上可以根据患者病情发展的实际情况采取抗生素骨水泥治疗,一方面能够促进患者临床治疗效果的提升,另一方面还可有效减少骨缺损的长度、面积,降低并发症发生率,有较高的使用和推广价值。     

Gatifloxacin biodegradable implant for treatment of experimental osteomyelitis: in vitro and in vivo evaluation

Osteomyelitis is an inflammatory bone disease caused by pyogenic bacteria. The advantages of localized biodegradable therapy for osteomyelitis include high local antibiotic concentration at the site of infection and obviation of the need for removal of the implant after treatment. The purpose of this study was to develop and evaluate a biodegradable implantable delivery system containing gatifloxacin (GAT) for the localized treatment of osteomyelitis, experimentally induced by methicillin resistant Staphylococcus aureus (MRSA). Implants, prepared by solvent casting technique, showed reasonable tensile strength. DSC examination indicated that GAT is present in an amorphous form in the implant. The in vitro release of GAT showed a profile characterized by an initial burst followed by a second stage of gradual delivery over 27 days. The in vivo release study revealed that GAT concentrations achieved during the first 3 weeks after implantation exceeded the MIC of GAT against MRSA by > 100,000 times. Bacterial tibial bone count performed in rabbits tibia 2 and 4 weeks after implantation of GAT implant in infected bone indicated complete eradication of infection in all treated rabbits as indicated by the significant decrease in bacterial count. The results show that the proposed implant may have a promising role in the therapeutic approach to osteomyelitis.     

Validation and in vitro characterization of antibiotic-loaded bone cement release

Antibiotic-loaded polymeric bone cement is used in orthopedic surgery to deliver local high concentrations of antibiotics to the tissues. The precise mechanism by which antibiotic is released from the polymeric matrix is still not very well known. This research was conducted to investigate the in vitro drug release behavior of antibiotic from acrylic bone cement. A spectrophotometric method for the quantitative analysis of gentamicin sulfate using o-phtaldialdehyde as a derivatizing reagent was thoroughly validated, in order to assure a minimum quality level of the measures. The method proved to be quick, reliable, less expensive than methods such as polarization fluorescence immunoassay and others, and therefore more convenient for the routine analysis of the numerous samples generated during in vitro liberation assays. The release of gentamicin from commercial CMW1 acrylic bone cement samples was investigated following proposed in vitro release experiments.     

In vitro antibiotic release from poly(3-hydroxybutyrate-co-3-hydroxyvalerate) rods

Provision and maintenance of adequate concentrations of antibiotics at infection sites is very important in treating highly resistant infections. For diseases like implant related osteomyelitis (IRO) it is best to provide this locally via implanted drug formulations, as systemic administration of the antibiotic may not be effective due to damaged vasculature. In this study, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) rods containing 7, 14 and 22% (mol) 3-hydroxyvalerate were loaded with sulbactam:cefoperazone or gentamicin, and their antibiotic release behaviours were studied under in vitro conditions in physiological phosphate buffer at room temperature. The release patterns were representative of release from monolithic devices where a rapid early release phase is followed by a slower and prolonged release. With PHBV 22 rods, the latter phase continued for approximately 2 months. This duration is critical because a proper antibiotic therapy of IRO requires the minimal effective concentration for at least 6 weeks. After in vitro release, voids with sharp edges were detected on the rods, indicating that the drug crystals dissolved but the polymer did not undergo erosion within this test period. Changing the polymer:drug ratio from 2:1 to 20:1 substantially decreased the drug release rate. A change of polymer type, however, did not lead to any detectable changes in the release patterns. Gentamicin release also followed a similar pattern, except that the concentration of the drug in the release medium exhibited a decrease after long release periods, indicating degradation (or decomposition) of the antibiotic in the release medium.     

Microencapsulation of gentamicin in biodegradable PLA and/or PLA/PEG copolymer

Biodegradable carriers containing gentamicin for local treatment of bone infection were developed. This paper describes the preparation and in vitro evaluation of these biodegradable implants. Poly-l-lactic acid (PLA) and polyl-lactic acid/polyethylene glycol (PLA/PEG) disk implants containing gentamicin sulphate were obtained by compression of microspheres prepared by a double emulsion process. The mean particle size distribution of the microspheres, based on volume, ranged from 95-270 µm. The gentamicin sulphate loading of the microspheres, after a methylene chloride-water extraction procedure, exceeded 90% of the theoretical value. In vitro dissolution studies on the microspheres and implants with drug loadings 10-40% w/w indicated that the rate of drug release from both PLA and PLA/PEG implants increased, with an increase in drug loading. The release of gentamicin from microspheres was dependent on the properties of PLA and/or PLA/PEG. The PLA/PEG copolymer was more hydrophilic than the PLA homopolymer, and with a smaller pH change in the microenvironment with polymer being degraded. In comparison, the PLA/PEG implant released antibiotic faster and had a larger inhibitory zone based on the Bauer-Kirby experiments used to test the inhibitory activity of antimicrobial devices. Experimental results showed that the biodegradable PLA/PEG gentamicin delivery system had a potential for prophylaxis of post-operative infection.     

Microencapsulation of gentamicin in biodegradable PLA and/or PLA/PEG copolymer.

Biodegradable carriers containing gentamicin for local treatment of bone infection were developed. This paper describes the preparation and in vitro evaluation of these biodegradable implants. Poly-L-lactic acid (PLA) and poly-L-lactic acid:polyethylene glycol (PLA/PEG) disk implants containing gentamicin sulphate were obtained by compression of microspheres prepared by a double emulsion process. The mean particle size distribution of the microspheres, based on volume, ranged from 95-270 microm. The gentamicin sulphate loading of the microspheres, after a methylene chloride-water extraction procedure, exceeded 90% of the theoretical value. In vitro dissolution studies on the microspheres and implants with drug loadings 10-40% w/w indicated that the rate of drug release from both PLA and PLA/PEG implants increased, with an increase in drug loading. The release of gentamicin from microspheres was dependent on the properties of PLA and/or PLA/PEG. The PLA/PEG copolymer was more hydrophilic than the PLA homopolymer, and with a smaller pH change in the microenvironment with polymer being degraded. In comparison, the PLA/PEG implant released antibiotic faster and had a larger inhibitory zone based on the Bauer-Kirby experiments used to test the inhibitory activity of antimicrobial devices. Experimental results showed that the biodegradable PLA/PEG gentamicin delivery system had a potential for prophylaxis of post-operative infection.     

In vitro antibiotic release from poly(3-hydroxybutyrate-co-3-hydroxyvalerate) rods

Provision and maintenance of adequate concentrations of antibiotics at infection sites is very important in treating highly resistant infections. For diseases like implant related osteomyelitis (IRO) it is best to provide this locally via implanted drug formulations, as systemic administration of the antibiotic may not be effective due to damaged vasculature. In this study, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) rods containing 7, 14 and 22% (mol) 3-hydroxyvalerate were loaded with sulbactam:cefoperazone or gentamicin #174;, and their antibiotic release behaviours were studied under in vitro conditions in physiological phosphate buffer at room temperature. The release patterns were representative of release from monolithic devices where a rapid early release phase is followed by a slower and prolonged release. With PHBV 22 rods, the latter phase continued for #168 2 months. This duration is critical because a proper antibiotic therapy of IRO requires the minimal effective concentration for at least 6 weeks. After in vitro release, voids with sharp edges were detected on the rods, indicating that the drug crystals dissolved but the polymer did not undergo erosion within this test period. Changing the polymer:drug ratio from 2:1 to 20:1 substantially decreased the drug release rate. A change of polymer type, however, did not lead to any detectable changes in the release patterns. Gentamicin #174; release also followed a similar pattern, except that the concentration of the drug in the release medium exhibited a decrease after long release periods, indicating degradation (or decomposition) of the antibiotic in the release medium.     

Current concepts in the management of infections in bones and joints

Significant changes have taken place in the epidemiology, microbiology and antibiotic therapy of bone and joint infections. Gram-negative bacilli have become an increasingly common cause, particularly in immunocompromised patients; anaerobes have been implicated in osteomyelitis associated with metallic foreign bodies; and there is increasing use of oral antibiotic regimens following an initial period of parenteral treatment. Gram-negative bacilli and anaerobes are found in polymicrobial non-haematogenous osteomyelitis (e.g. post-traumatic, post-surgical), but Staphylococcus aureus remains the most common cause of acute haematogenous osteomyelitis, with streptococci and Haemophilus influenzae responsible for most of the remainder. A precise microbiological diagnosis is essential. Diagnosis is based on Gram stain and culture of bone biopsies or aspirated pus, or on blood cultures. Specimens should be obtained before starting therapy. Any suspected primary foci of infection should be cultured. Parenteral antibiotics are given as soon as specimens are obtained, and continued for at least 3 weeks. The common causative organisms in septic arthritis are the same as in osteomyelitis, with the addition of Neisseria gonorrhoeae in young, sexually active adults. As in osteomyelitis, a precise microbiological diagnosis is of paramount importance, ideally by joint aspiration for cell count, Gram stain, biochemical analysis and culture, or by blood cultures. Optimum therapy is with antibiotics, repeated therapeutic aspirations, and resting the joint. Parenteral antibiotics should be started as soon as specimens are obtained and continued for 4 to 6 weeks. Gonococcal arthritis, however, can be treated successfully with 1 week of antibiotics. When treatment of either osteomyelitis or septic arthritis is continued with oral antibiotics, serum antibiotic concentrations or serum bactericidal levels are mandatory to ensure adequate absorption.     

去甲万古霉素链珠个体化治疗耐甲氧西林葡萄球菌感染的慢性骨髓炎的研究

目的:探索治疗耐甲氧西林葡萄球菌(MRS)感染的慢性骨髓炎的新途径。方法:选择确诊为MRS感染的慢性骨髓炎患者27例,将其随机分为2组,术前均静脉滴注去甲万古霉素防止感染,试验组(15例)以去甲万古霉素链珠(去甲万古霉素与骨水泥混合物)填充缺损处;对照组(12例)仅以骨水泥填充缺损处。比较2组感染治愈率、治愈感染所需抗生素治疗成本、不良反应发生率、治愈所需时间。结果:2组治疗MRS感染的慢性骨髓炎皆有效,但试验组不良反应发生率和抗生素治疗成本较低,同时控制感染也较快。结论:采用去甲万古霉素链珠个体化治疗MRS感染的慢性骨髓炎优于仅静脉给予去甲万古霉素的治疗方法。     

Management of osteomyelitis

Early diagnosis and aggressive treatment, which includes thorough debridement and culture-directed antibiotic therapy, are essential for effective management of patients with osteomyelitis. Definitive diagnosis of osteomyelitis usually requires microbial culture of bone specimens obtained either by surgery or by percutaneous needle biopsy. The most common pathogen involved in osteomyelitis is Staphylococcus aureus; however, other organisms, including gram-negative pathogens and coagulase-negative staphylococci, may be found. Often, bone infections may be polymicrobial. Antimicrobial therapy, ideally initiated after complete surgical debridement and microbial confirmation of the diagnosis, is usually maintained for at least 6 weeks. Although therapy has traditionally been administered parenterally during an extended hospital stay, oral antibiotic therapy (often following initial parenteral therapy) and parenteral therapy on an outpatient basis are gaining acceptance for use in patients with osteomyelitis.     

In vitro controlled release of bupivacaine from albumin microspheres and a co-matrix formed by microspheres in a poly(lactide-co-glycolide) film

Albumin microspheres cross-linked with glutaraldehyde and loaded with bupivacaine, a local anaesthetic, were synthesized (138 +/- 59 microm diameter). A matrix formed by bupivacaine-loaded microspheres in a poly(lactide-co-glycolide) film was prepared in order to improve the controlled release of the drug. In vitro release of the drug was determined in phosphate buffer at 37 degrees C in the absence and in the presence of protease type VIII to mimic a biological system. The effect of temperature and protease on bupivacaine as a function of time was examined; both of them cause a degradative effect on the drug. A rapid release (60 +/- 8% of the drug) takes place at 1 h, and maximum release is found at 50 +/- 6 h from microspheres with swelling. In the presence of protease, maximum release of bupivacaine from microspheres is found at 28 +/- 2 h; the microspheres disappear at 8 days. Inclusion of bupivacaine-loaded microspheres in a poly(lactide-co-glycolide) film causes a slower release of the drug, up to 18 days, with swelling. In the presence of protease, the polymer protects bupivacaine-loaded microspheres from degradation, which takes place at 20 days.     

Controversies in antimicrobial therapy: innovative methods of administration

The clinical use of novel means of antibiotic administration--continuous infusion, endotracheal instillation and aerosol delivery, peritoneal dialysate, and antibiotic-impregnated catheters, bone cement, and beads--is discussed. Antibiotic infusions have traditionally been administered intermittently, but recent data support the use of continuous infusions in treating gram-negative bacillus bacteremias in neutropenic patients. Local instillation of antibiotics--endotracheally or by aerosols--may be indicated in patients with pulmonary infections and damaged pulmonary-defense systems; in other patients, normal host defenses make local therapy unnecessary. Patients undergoing chronic ambulatory peritoneal dialysis often develop intraperitoneal staphylococcal and streptococcal infections, and these are best treated with antibiotics added directly to the dialysate. Other recent studies support the use of antimicrobial agents in medical devices. Antibiotic-impregnated catheters are being tested as means of preventing difficult-to-treat catheter-related infections. Bone cement containing aminoglycosides has proven useful in preventing deep-bone infections in patients undergoing total-hip arthroplasty, and antibiotic-impregnated beads are useful, along with debridement, in patients with osteomyelitis. Innovative and unique methods of antibiotic administration are useful in overcoming problems of drug toxicity and failure of agents to reach sites of infection.