Gram-positive organisms, particularly staphylococci and streptococci, are responsible for the majority of bone and joint infections. Treatment of these infections can be difficult, usually involving a prolonged course of antibiotics, often with surgical intervention. The selection of antibiotics depends on sensitivity profile, patient tolerance and long-term goals, e.g. cure or suppression, but there are few randomized con- trolled trials in patients comparing efficacy of different antibiotics. Different degrees of bone penetration and clinical outcome for specific antibiotics, e.g. the β-lactams, clindamycin and quinolones, have been described, although the methodology in these studies is not standardized and findings cannot always be applied directly to patients. The effect of attaining minimum serum bactericidal concentrations in patients has also been studied but this is no longer routinely recommended in clinical practice. Comparative clinical trials are few but have demonstrated efficacy of oral fluoroquinolones in combination with either rifampicin or fusidic acid for selected Gram-positive infections. In the past decade, increasingly resistant organisms, e.g. methicillin- resistant Staphylococcus aureus and vancomycin-resistant enterococci have been recognized as causes of orthopaedic infection. Individual case reports describe successful treatment using the newer antibiotics, e.g. linezolid and quinupristin/dalfopristin, but results of clinical trials are awaited.

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Antibiotic treatment of gram-positive bone and joint infections.

The use of antibiotic-loaded bone cement is an accepted treatment method for infected joint arthroplasties. It is helpful to separate the use of antibiotic-loaded bone cement as a method of prophylaxis as compared with the treatment of an established infection. A low dose of antibiotic-loaded bone c

Practical applications of antibiotic-loaded bone cement for treatment of infected joint replacements.

Staphylococcal infections are one of the main causes of complications in patients with implanted foreign prosthetic material. Implants are associated with a significant reduction of the threshold at which contaminating Gram-positive bacteria, particularly Staphylococcus epidermidis, become infectious and develop a biofilm with phenotypic resistance to almost all antibiotics. A 1000-fold increase in minimal bactericidal levels against most antibiotics except rifampin has been repeatedly observed. Since only removal of the foreign material reverses these phenomena, the clinical challenge consists in finding approaches to cure the infection without removal of the implanted device. Rifampin combinations with other antibiotics, administration of exceedingly high antibiotic concentrations in situ, and early therapy before biofilm development are efficacious. Although these strategies have dramatically improved the outcome of foreign body infections, an improved understanding of biofilm-grown S. epidermidis is necessary to develop new antibacterial agents. Here, we review the pathogenesis, prevention, and treatment of implant infections due to S. epidermidis and highlight some new compounds with already promising in vitro results.

https://www.tandfonline.com/doi/pdf/10.1080/07853890802337045

Foreign body infections due to Staphylococcus epidermidis.

The pathogenesis of implant-associated infection involves interaction between the microorganisms (biofilm formation), the implant and the host. Despite improvement of perioperative prophylaxis, orthopaedic implants still remain highly susceptible to bacterial or fungal contamination, generally resulting in persistent implant-associated infection. Therefore, perioperative and life-long prevention of infection is important. For perioperative prophylaxis, a first- or second-generation cephalosporin is recommended, which should be administered between 60 and 30 minutes before incision. The duration of prophylaxis should not exceed 1 day. In centres with a low incidence of infection, a single dose is sufficient. Treatment of infections associated with orthopaedic devices usually requires appropriate surgical intervention combined with prolonged antimicrobial therapy. The choice of the antimicrobial regimen depends on the duration and pathogenesis of infection, stability of the implant, antimicrobial susceptibility of the pathogen and condition of the surrounding soft tissue. The role of rifampicin (rifampin), which has excellent activity on adherent staphylococci, in combination with β-lactams, glycopeptides, fluoroquinolones, minocycline, cotrimoxazole or fusidic acid, in the treatment of staphylococcal infections is outlined. Increasing antimicrobial resistance requires the use of alternative agents, such as quinupristin/dalfopristin, linezolid and daptomycin, but results of clinical trials with these agents are limited. Also reviewed are potential new antimicrobial agents currently undergoing investigation, such as the novel oxazolidinone RWJ-416457, the new glycopeptide dalbavancin, the glycylcycline compound tigecycline, the new carbacephem BP-102 and novel rifamycin derivatives. Vaccination against Staphylococcus aureus with StaphVAX® induced specific antibodies potentially preventing bacteraemia; however, there are no studies on efficacy in the prophylaxis of device-associated infections with this vaccine.

Antimicrobial agents in orthopaedic surgery: Prophylaxis and treatment.

The increasing emergence of antimicrobial-resistant organisms, especially methicillin-resistant Staphylococcus aureus (MRSA), has resulted in the increased use of rifampin combination therapy. The data supporting rifampin combination therapy in nonmycobacterial infections are limited by a lack of significantly controlled clinical studies. Therefore, its current use is based upon in vitro or in vivo data or retrospective case series, all with major limitations. A prominent observation from this review is that rifampin combination therapy appears to have improved treatment outcomes in cases in which there is a low organism burden, such as biofilm infections, but is less effective when effective surgery to obtain source control is not performed. The clinical data support rifampin combination therapy for the treatment of prosthetic joint infections due to methicillin-sensitive S. aureus (MSSA) after extensive debridement and for the treatment of prosthetic heart valve infections due to coagulase-negative staphylococci. Importantly, rifampin-vancomycin combination therapy has not shown any benefit over vancomycin monotherapy against MRSA infections either clinically or experimentally. Rifampin combination therapy with daptomycin, fusidic acid, and linezolid needs further exploration for these severe MRSA infections. Lastly, an assessment of the risk-benefits is needed before the addition of rifampin to other antimicrobials is considered to avoid drug interactions or other drug toxicities.

Rifampin Combination Therapy for Nonmycobacterial Infections

We compared the efficacies of quinupristin-dalfopristin (Q-D; 30 mg/kg of body weight every 8 h) and vancomycin (60 mg/kg twice daily), alone or in combination with rifampin (10 mg/kg twice daily), in a rabbit model of methicillin-resistant Staphylococcus aureus knee prosthesis infection. In contrast to vancomycin, Q-D significantly reduced the mean log10 CFU per gram of bone versus that for the controls. The combination of rifampin with either Q-D or vancomycin was significantly more effective than monotherapy.

Combination of Quinupristin-Dalfopristin (Synercid) and Rifampin Is Highly Synergistic in Experimental Staphylococcus aureus Joint Prosthesis Infection

Prosthesis infections are difficult to cure. Infection with methicillin-resistant staphylococci is becoming more common in patients with orthopedic implants. Using a recently developed model of methicillin-resistant Staphylococcus aureus (MRSA) infection of a knee prosthesis, we compared the efficacies of teicoplanin and vancomycin. [14C]teicoplanin diffusion in this model was also studied by autoradiography. A partial knee replacement was performed with a silicone implant fitting into the intramedullary canal of the tibia, and 10(7) CFU of MRSA was injected into the knee. Treatment with teicoplanin or vancomycin (20 or 60 mg/kg of body weight, respectively, given intramuscularly twice daily) was started 7 days after inoculation and was continued for 7 days. The teicoplanin and vancomycin MICs for MRSA were 1 microg/ml. Mean peak and trough levels in serum were 39.1 and 23.5 microg/ml, respectively, for teicoplanin and 34.4 and 18.5 microg/ml, respectively, for vancomycin. Fifteen days after the end of therapy, the animals were killed and their tibias were removed, pulverized, and quantitatively cultured. Teicoplanin and vancomycin significantly reduced (P < 0. 05) the bacterial density (2.7 +/- 1.3 and 3.3 +/- 1.6 log10 CFU/g of bone, respectively) compared to those for the controls (5.04 +/- 1.4 log10 CFU/g of bone). The bacterial covents of teicoplanin- and vancomycin-treated rabbits were comparable. The [14C]teicoplanin autoradiographic diffusion patterns in rabbits with prostheses, two of which were uninfected and two of which were infected, were studied 15 days after inoculation. Sixty minutes after the end of an infusion of 250 microCi of [14C]teicoplanin, autoradiography showed that in the infected animals, the highest levels of radioactivity were located around the prosthesis and in the periosteum, bone marrow, and trabecular bone. Radioactivity was less intense in epiphyseal disk cartilage, femoral cartilage, articular ligaments, and muscles and was weak in compact bone. A similar distribution pattern was seen in uninfected rabbits. Thus, teicoplanin may represent an effective alternative therapy for the treatment of these infections.

Efficacy of teicoplanin and autoradiographic diffusion pattern of [14C]teicoplanin in experimental Staphylococcus aureus infection of joint prostheses.

Using a rabbit model of methicillin-resistant Staphylococcus aureus knee-prosthesis infection, we studied the efficacy of teicoplanin cement alone or in combination with systemic intramuscular (i.m.) injections of teicoplanin. Seven days after infection, surgical debridement and removal of the infected prostheses were performed, and five rabbits were randomly assigned to one of five different treatment groups: untreated controls, prosthesis replacement by drug-free cement spacer, prosthesis replacement by teicoplanin-loaded cement spacer (1.2 g of teicoplanin/40 g of cement), i.m. injections of teicoplanin (20 mg/kg of body weight, twice a day for 7 days), or systemic antibiotic treatment combined with teicoplanin-loaded spacers. The most effective regimen combined systemic teicoplanin and antibiotic spacers.

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Farid Ismael

Papers

Combination of Quinupristin-Dalfopristin (Synercid) and Rifampin Is Highly Synergistic in Experimental Staphylococcus aureus Joint Prosthesis Infection

Efficacy of teicoplanin and autoradiographic diffusion pattern of [14C]teicoplanin in experimental Staphylococcus aureus infection of joint prostheses.

Teicoplanin-Containing Cement Spacers for Treatment of Experimental Staphylococcus aureus Joint Prosthesis Infection