We have assessed the effect of different regimes of antibiotic prophylaxis on the survival of total hip implants, comparing antibiotics administered both systemically and in the bone cement, systemically only, in the bone cement only and with no antibiotics given. We studied 10 905 primary cemented total hip replacements, performed for osteoarthritis of the hip and reported to the Norwegian arthroplasty register between 1987 and 1995. Cox-estimated failure-rate ratios (FRR) are presented with adjustment for gender, age, the brand of cement, the prosthesis, the type of operating theatre and the operating time. For revisions performed for infection (39 operations), the lowest rate of revision was found among patients receiving antibiotic-containing cement plus systemic antibiotics (n = 5804). The revision rate for the 4586 patients receiving systemic antibiotics only was 4.3 times greater (95% CI 1.7 to 11.0, p = 0.001); in 239 with antibiotics in the bone cement only it was 6.3 times greater (CI 1.6 to 25.0, p = 0.003); and in the 276 who did not receive antibiotics it was by 11.5 times greater (CI 2.1 to 63.0, p = 0.002). Adjustment for the total amount of systemic antibiotic administered did not change the results. We also observed an increased revision rate for aseptic loosening (109 operations) comparing the systemic-only (FRR = 1.8, CI 1.1 to 2.9, p = 0.01) and the cement-only regimes (FRR = 2.6, CI 1.2 to 5.9, p = 0.02) with the combined dosage. Our findings show that systemic antibiotics combined with antibiotic-containing bone cement led to fewer revisions than the other methods

Aims. The aim of this study was to determine if a three-month course of microorganism-directed oral antibiotics reduces the rate of failure due to further infection following two-stage revision for chronic prosthetic joint infection (PJI) of the hip and knee. Methods. A total of 185 patients undergoing a two-stage revision in seven different centres were prospectively enrolled. Of these patients, 93 were randomized to receive microorganism-directed oral antibiotics for three months following reimplantation; 88 were randomized to receive no antibiotics, and four were withdrawn before randomization. Of the 181 randomized patients, 28 were lost to follow-up, six died before two years follow-up, and five with culture negative infections were excluded. The remaining 142 patients were followed for a mean of 3.3 years (2.0 to 7.6) with failure due to a further infection as the primary endpoint. Patients who were treated with antibiotics were also assessed for their adherence to the medication regime and for side effects to antibiotics. Results. Nine of 72 patients (12.5%) who received antibiotics failed due to further infection compared with 20 of 70 patients (28.6%) who did not receive antibiotics (p = 0.012). Five patients (6.9%) in the treatment group experienced adverse effects related to the administered antibiotics severe enough to warrant discontinuation. Conclusion. This multicentre randomized controlled trial showed that a three-month course of microorganism-directed, oral antibiotics significantly reduced the rate of failure due to further infection following a two-stage revision of total hip or knee arthroplasty for chronic PJI. Cite this article: Bone Joint J 2020;102-B(6 Supple A):3–9

The release of various penicillins and other antibiotics from two brands of polymerised bone cement has been studied in vitro and in vivo in mice. Bone cement plugs containing antibiotics demonstrated antibacterial activity as a result of diffusion of antibiotic from the plugs into the surrounding medium. With all antibiotics tested, from 2-5 to 10 per cent of the antibiotic in the cement was released in vitro in active form within twenty-four hours. Most of the activity appeared within three hours of the start of the test, but in some cases low levels of activity were detected after four days. Antibiotic cement plugs implanted in mice and rats produced low concentrations of antibiotic in the blood up to two hours after implantation, but activity was seldom detected subsequently. In general, penicillins and non-penicillin antibiotics showed similar diffusion characteristics, and the pattern of release in vitro and in vivo was consistent with the leaching of antibiotic from, or near, the surface of the bone cement

Bacterial infection in orthopaedic surgery can be devastating, and is associated with significant morbidity and poor functional outcomes, which may be improved if high concentrations of antibiotics can be delivered locally over a prolonged period of time. The two most widely used methods of doing this involve antibiotic-loaded polymethylmethacrylate or collagen fleece. The former is not biodegradable and is a surface upon which secondary bacterial infection may occur. Consequently, it has to be removed once treatment has finished. The latter has been used successfully as an adjunct to systemic antibiotics, but cannot effect a sustained release that would allow it to be used on its own, thereby avoiding systemic toxicity. This review explores the newer biodegradable carrier systems which are currently in the experimental phase of development and which may prove to be more effective in the treatment of osteomyelitis

Antibiotics are often administrated prophylactically in spinal procedures to reduce the risk of infection of the disc space. It is still not known which antibiotics are able to penetrate the intervertebral disc effectively. In a prospective, randomised, double-blind clinical study, we examined the penetration of the intervertebral discs of two commonly used antibiotics, cefuroxime and gentamicin. The patients, randomised into two groups, received either 1.5 g of cefuroxime or 5 mg/kg of gentamicin prophylactically two hours before their intervertebral discs were removed. A specimen of blood, from which serum antibiotic levels were determined, was obtained at the time of discectomy. Therapeutic levels of antibiotic were detectable in the intervertebral discs of the ten patients who received gentamicin. Only two of the ten patients (20%) who received cefuroxime had a quantifiable level of antibiotic in their discs although therapeutic serum levels of cefuroxime were found in all ten patients. Our results show that cefuroxime does not diffuse into human intervertebral discs as readily as gentamicin. It is possible that the charge due to ionisable groups on the antibiotics can influence the penetration of the antibiotics. We therefore recommend the use of gentamicin in a single prophylactic dose for all spinal procedures in order to reduce the risk of discitis

Objectives. Thermal stability is a key property in determining the suitability of an antibiotic agent for local application in the treatment of orthopaedic infections. Despite the fact that long-term therapy is a stated goal of novel local delivery carriers, data describing thermal stability over a long period are scarce, and studies that avoid interference from specific carrier materials are absent from the orthopaedic literature. Methods. In this study, a total of 38 frequently used antibiotic agents were maintained at 37°C in saline solution, and degradation and antibacterial activity assessed over six weeks. The impact of an initial supplementary heat exposure mimicking exothermically curing bone cement was also tested as this material is commonly used as a local delivery vehicle. Antibiotic degradation was assessed by liquid chromatography coupled to mass spectrometry, or by immunoassays, as appropriate. Antibacterial activity over time was determined by the Kirby-Bauer disk diffusion assay. Results. The heat exposure mimicking curing bone cement had minimal effect on stability for most antibiotics, except for gentamicin which experienced approximately 25% degradation as measured by immunoassay. Beta-lactam antibiotics were found to degrade quite rapidly at 37°C regardless of whether there was an initial heat exposure. Excellent long-term stability was observed for aminoglycosides, glycopeptides, tetracyclines and quinolones under both conditions. Conclusions. This study provides a valuable dataset for orthopaedic surgeons considering local application of antibiotics, and for material scientists looking to develop next-generation controlled or extended-release antibiotic carriers. Cite this article: E. Samara, T. F. Moriarty, L. A. Decosterd, R. G. Richards, E. Gautier, P. Wahl. Antibiotic stability over six weeks in aqueous solution at body temperature with and without heat treatment that mimics the curing of bone cement. Bone Joint J 2017;6:296–306. DOI: 10.1302/2046-3758.65.BJR-2017-0276.R1

Most animal studies indicate that early irrigation and debridement reduce infection after an open fracture. Unfortunately, these studies often do not involve antibiotics. Clinical studies indicate that the timing of initial debridement does not affect the rate of infection but these studies are observational and fraught with confounding variables. The purpose of this study was to control these variables using an animal model incorporating systemic antibiotics and surgical treatment. We used a rat femur model with a defect which was contaminated with Staphylococcus aureus and treated with a three-day course of systemic cefazolin (5 mg/kg 12-hourly) and debridement and irrigation, both of which were initiated independently at two, six and 24 hour time points. After 14 days the bone and hardware were harvested for separate microbiological analysis. No animal that received antibiotics and surgery two hours after injury had detectable bacteria. When antibiotics were started at two hours, a delay in surgical treatment from two to six hours significantly increased the development of infection (p = 0.047). However, delaying surgery to 24 hours increase the rate of infection, but not significantly (p = 0.054). The timing of antibiotics had a more significant effect on the proportion of positive samples than earlier surgery. Delaying antibiotics to six or 24 hours had a profoundly detrimental effect on the infection rate regardless of the timing of surgery. These findings are consistent with the concept that bacteria progress from a vulnerable planktonic form to a treatment-resistant biofilm

We investigated the antibiotic concentration in fresh-frozen femoral head allografts harvested from two groups of living donors. Ten samples were collected from patients with osteoarthritis of the hip and ten from those with a fracture of the neck of the femur scheduled for primary arthroplasty. Cefazolin (1 g) was administered as a pre-operative prophylactic antibiotic. After storage at −80°C for two weeks the pattern of release of cefazolin from morsellised femoral heads was evaluated by an in vitro broth elution assay using high-performance liquid chromatography. The bioactivity of the bone was further determined with an agar disc diffusion and standardised tube dilution bioassay. The results indicated that the fresh-frozen femoral heads contained cefazolin. The morsellised bone released cefazolin for up to four days. The concentration of cefazolin was significantly higher in the heads from patients with osteoarthritis of the hip than in those with a fracture. Also, in bioassays the bone showed inhibitory effects against bacteria. We concluded that allografts of morsellised bone from the femoral head harvested from patients undergoing arthroplasty of the hip contained cefazolin, which had been administered pre-operatively and they exhibited inhibitory effects against bacteria in vitro

Iontophoresis is a novel technique which may be used to facilitate the movement of antibiotics into the substance of bone using an electrical potential applied externally. We have examined the rate of early infection in allografts following application of this technique in clinical practice. A total of 31 patients undergoing revision arthroplasty or surgery for limb salvage received 34 iontophoresed sequential allografts, of which 26 survived for a minimum of two years. The mean serum antibiotic levels after operation were low (gentamicin 0.37 mg/l (0.2 to 0.5); flucloxacillin 1 mg/l (0 to 1) and the levels in the drains were high (gentamicin 40 mg/l (2.5 to 131); flucloxacillin 17 mg/l (1 to 43). There were no early deep infections. Two late infections were presumed to be haemotogenous; 28 of the 34 allografts were retained. In 12 patients with pre-existing proven infection further infection has not occurred at a mean follow-up of 51 months (24 to 82)

All major studies have incorporated the use of prolonged courses of parenteral or oral antibiotic therapy in the management of two-stage revision of an infected total knee arthroplasty. We present a series of 59 consecutive patients, all with microbiologically-proven deep infection of a total knee arthroplasty, in whom a prolonged course of antibiotic therapy was not routinely used. The mean follow-up was 56.4 months (24 to 114). Of the 38 patients who underwent a staged exchange, infection was successfully eradicated in 34 (89%) but recurrent or persistent infection was present in four (11%). Our rate of cure for infection is similar to that reported elsewhere. We conclude that a prolonged course of antibiotic therapy seems not to alter the incidence of recurrent or persistent infection. The costs of the administration of antibiotics are high and such a regime may be unnecessary

The role of antibiotics in the treatment of disc-space infection is controversial. This study assessed the tissue penetration of flucloxacillin and cephradine into the normal intervertebral disc after intravenous administration of a bolus dose of antibiotic. Twenty-five discs were removed from 12 adolescent patients having anterior spinal surgery to correct scoliosis; antibiotic had been administered between 30 minutes and four hours before operation. Despite high blood levels, no antibiotic could be detected by bioassay or by high-pressure liquid chromatography (h.p.l.c.) in any of the specimens from the nucleus pulposus or the annulus fibrosus

Aims

Delayed postoperative inoculation of orthopaedic implants with persistent wound drainage or bacterial seeding of a haematoma can result in periprosthetic joint infection (PJI). The aim of this in vivo study was to compare the efficacy of vancomycin powder with vancomycin-eluting calcium sulphate beads in preventing PJI due to delayed inoculation.

We examined the usefulness of neutrophil CD64 expression in detecting local musculoskeletal infection and the impact of antibiotics on its expression. Of 141 patients suspected of musculoskeletal infection, 46 were confirmed by microbiological culture to be infected and 95 had infection excluded. The median CD64 count of patients with localised infection was 2230 molecules per cell (interquartile range (IQR) 918 to 4592) and that of the patients without infection was 937 molecules per cell (IQR 648 to 1309) (p < 0.001). The level of CD64 correlated with the CRP level in patients with infection, but not in those without infection (r = 0.59, p < 0.01). Receiver operator characteristic curve analysis revealed that CD64 was a good predictor of local infection. When the patients were subdivided into two groups based on the administration of antibiotics at the time of CD64 sampling, the sensitivity for detecting infection was better in those who had not received antibiotics. These results suggest that measurement of CD64 expression is a useful marker for local musculoskeletal infection

Intramedullary infection in long bones represents a complex clinical challenge, with an increasing incidence due to the increasing use of intramedullary fixation. We report a prospective case series using an intramedullary reaming device, the Reamer–Irrigator–Aspirator (RIA) system, in association with antibiotic cement rods for the treatment of lower limb long bone infections. A total of 24 such patients, 16 men and eight women, with a mean age of 44.5 years (17 to 75), 14 with femoral and 10 with tibial infection, were treated in a staged manner over a period of 2.5 years in a single referral centre. Of these, 21 patients had had previous surgery, usually for fixation of a fracture (seven had sustained an open fracture originally and one had undergone fasciotomies). According to the Cierny–Mader classification system, 18 patients were classified as type 1A, four as 3A (discharging sinus tract), one as type 4A and one as type 1B. Staphylococcus species were isolated in 20 patients (83.3%). Local antibiotic delivery was used in the form of impregnated cement rods in 23 patients. These were removed at a mean of 2.6 months (1 to 5). Pathogen-specific antibiotics were administered systemically for a mean of six weeks (3 to 18). At a mean follow-up of 21 months (8 to 36), 23 patients (96%) had no evidence of recurrent infection. One underwent a planned trans-tibial amputation two weeks post-operatively due to peripheral vascular disease and chronic recalcitrant osteomyelitis of the tibia and foot. The combination of RIA reaming, the administration of systemic pathogen-specific antibiotics and local delivery using impregnated cement rods proved to be a safe and efficient form of treatment in these patients. Cite this article: Bone Joint J 2014; 96-B:783–8

We have studied the ability of a range of antibiotics to penetrate intervertebral disc tissue in vitro, using a mouse disc model. Equilibrium concentrations of antibiotics incorporated into the entire disc were determined by bioassay using a microbial growth-inhibition method. Uptake was significantly higher with positively-charged aminoglycosides compared with negatively-charged penicillins and cephalosporins. Uncharged ciprofloxacin showed an intermediate degree of uptake. Our results support the hypothesis that electrostatic interaction between charged antibiotics and negatively-charged glycosaminoglycans in the disc is an important factor in antibiotic penetration, and may explain their differential uptake

When using a staged approach to eradicate chronic infection after total hip replacement, systemic delivery of antibiotics after the first stage is often employed for an extended period of typically six weeks together with the use of an in situ antibiotic-eluting polymethylmethacrylate interval spacer. We report our multi-surgeon experience of 43 consecutive patients (44 hips) who received systemic vancomycin for two weeks in combination with a vancomycin- and gentamicin-eluting spacer system in the course of a two-stage revision procedure for deep infection with a median follow-up of 49 months (25 to 83). The antibiotic-eluting articulating spacers fractured in six hips (13.9%) and dislocated in five patients (11.6%). Successful elimination of the infecting organisms occurred in 38 (92.7%) of 41 hips with three patients developing superinfection with a new organism. We conclude that prolonged systemic antibiotic therapy may not be essential in the two-stage treatment of a total hip replacement for Gram-positive infection, provided that a high concentration of antibiotics is delivered locally using an antibiotic-eluting system

Porous blocks of calcium hydroxyapatite ceramic were evaluated as delivery systems for the sustained release of antibiotics. We tested gentamicin sulphate, cefoperazone sodium, and flomoxef sodium in powder form placed in a cylindrical cavity in calcium hydroxyapatite blocks, using in vitro studies of elution and in vivo studies in rats. Gentamicin sulphate gave a maximum concentration within the first week, which gradually decreased but was still effective at 12 weeks, when 70% of the antibiotic had been released. Even at this stage the antibiotic concentration from a 75 mg dose was five times the minimum inhibitory concentration for staphylococci. In the in vivo studies the release of gentamicin sulphate into the normal bone of rats was at similar rates and levels. The bacteriocidal activity of the drugs was not affected by packing into calcium hydroxyapatite ceramic and the blocks were completely biocompatible on histology. This new system overcomes the disadvantages of other drug delivery systems, avoiding thermal damage to the antibiotics and a second operation for the removal of the carrier. Some mechanical strength is provided by the ceramic and healing may be accelerated by bone ingrowth into its micropores

A randomised prospective trial was undertaken of antibiotic prophylaxis given at various intervals before inflation of the tourniquet for arthroplasty of the knee. Cefuroxime assays of bone and subcutaneous fat from samples collected throughout the operation demonstrated that an interval of 10 minutes was necessary to obtain adequate prophylaxis. Improvement in the timing of antibiotic prophylaxis may result in a reduction in the incidence of infection

Infection of orthopaedic implants is a significant problem, with increased antibiotic resistance of adherent ‘biofilm’ bacteria causing difficulties in treatment. We have investigated the in vitro effect of a pulsed electromagnetic field (PEMF) on the efficacy of antibiotics in the treatment of infection of implants. Five-day biofilms of Staphylococcus epidermidis were grown on the tips of stainless-steel pegs. They were exposed for 12 hours to varying concentrations of gentamicin or vancomycin in microtitre trays at 37°C and 5% CO. 2. The test group were exposed to a PEMF. The control tray was not exposed to a PEMF. After exposure to antibiotic the pegs were incubated overnight, before standard plating onto blood agar for colony counting. Exposure to a PEMF increased the effectiveness of gentamicin against the five-day biofilms of Staphylococcus epidermidis. In three of five experiments there was reduction of at least 50% in the minimum biofilm inhibitory concentration. In a fourth experiment there was a two-log difference in colony count at 160 mg/l of gentamicin. Analysis of variance (ANOVA) confirmed an effect by a PEMF on the efficacy of gentamicin which was significant at p < 0.05. There was no significant effect with vancomycin

We report two cases of epicondylitis of the elbow occurring after treatment with fluoroquinolone antibiotics. Both patients had intense pain which appeared very shortly after the first dose of the drug and was not relieved by conservative treatment. Ultrasonography revealed extensive inflammatory lesions with pseudonecrotic areas. MRI confirmed the lesions and also showed a subclinical abnormality of the adjoining tendons. The persistent nature of the pain was the indication for surgical release of the extensor mechanism. After operation pain disappeared completely and the patients were able to return to their normal activities. Lesions of the tendo Achillis are a well-known side-effect of treatment with fluoroquinolone. Our two cases show that such lesions may occur elsewhere. They also indicate the need for caution when prescribing these antibiotics to patients at risk of tendon lesions, such as top-level sportsmen or patients on dialysis or steroid treatment