Bristol Centre for Antimicrobial Research and Evaluation, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK
Received 30 July 2003; returned 4 December 2003; revised 17 February 2004; accepted 18 February 2004
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Abstract |
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Keywords: staphylococci, streptococci, osteomyelitis, septic arthritis, prosthetic joint infections
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Introduction |
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Causal organisms in bone and joint infection |
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Osteomyelitis |
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Osteomyelitis in paediatric patients is usually haematogenous in origin and mainly occurs in the long bones. The vascular supply of the developing bone facilitates early spread of medullary infection to the epiphysis, which may result in septic arthritis of the proximal joint. The highly vascular nature of developing bone and very effective response to bone infection means children can often be managed with shorter courses of antibiotics with early switch to oral therapy often without need for surgical excision.20,21
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Septic arthritis |
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Prosthetic joint infection |
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Traditionally it has been understood that the effective treatment of deep-seated bone infection necessitates a prolonged course of parenteral antibiotics. Alternatives to lengthy hospitalization for parenteral antibiotic therapy have evolved, including Outpatient and Home Parenteral Antibiotic Therapy schemes,3538 but also the increasing use of oral antibiotic agents that have both acceptable bone penetration and high oral bioavailability. This review will consider antibiotics available and appropriate for therapy of Gram-positive osteomyelitis and joint infection.
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Antibiotic choices: general points |
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The initial choice of antibiotic inevitably depends on the causal pathogen and its sensitivity pattern. Antibiotics considered bactericidal against the infecting organisms are often considered necessary (the logic being similar to that of treating infective endocarditis or meningitis), although the need for this with respect to osteomyelitis has not been experimentally proven. Measurement of peak and trough serum cidal ratios to guide dosing has been advocated. In a study by Weinstein et al.,41 trough serum bactericidal titres of >1:2 and >1:4 for acute and chronic osteomyelitis, respectively, accurately predicated cure in 48 cases of osteomyelitis (average follow-up 40 months). Use of serum cidal titres to guide dosing has been reported in other studies of bone and joint infection17,19,34 but the selection of titre appears somewhat arbitrary.42 The effect on outcome of deliberately maintaining a dose despite lower titres has not been compared. With the difficulties in performing serum bactericidal tests and the generally poor reproducibility of in house results,43 serum bactericidal tests are probably not helpful in the routine management of osteomyelitis.
Ideally all dead or diseased bone should be removed surgically at the earliest opportunity and this is the gold standard of treatment; however, this is not always possible and even when early debridement is aggressive it takes 34 weeks for adult bone to revascularize. As a result areas of poor penetration and low oxygen tension may exist at the site of infection. Anaerobiasis at the site of deep infection may adversely affect the activity of antibiotics, for example gentamicin (which has good bone penetration) and vancomycin, while it does not affect activity of rifampicin and cephalosporins.44,45
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Antibiotic bone penetration and clinical studies |
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ß-Lactams and lincosamides |
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In the UK flucloxacillin is commonly used for first-line therapy of deep S. aureus infection. Bone concentrations of between 0.9 and 1.3 mg/L flucloxacillin have been achieved corresponding to bone: serum rations of 0.120.16 following a single dose of 0.51 g prior to hip replacement.57 By exceeding the MIC for sensitive S. aureus, Unsworth et al.57 concluded that 1 g flucloxacillin offered effective prophylaxis when given 2 h prior to hip excision but the spectrum of cover might now be considered rather narrow for total hip replacement. Other reports have demonstrated bone concentrations of oxacillin and methicillin, the preferred anti-staphylococcal penicillins used in other countries, to be in excess of the MIC following iv injection to subjects undergoing joint replacement. Bone:serum ratios of 0.180.22 and 0.11 for methicillin and oxacillin, respectively, were reported and are comparable to those for flucloxacillin above.23,55 Clinical success was reported in 44 patients treated with iv, followed by oral, co-amoxiclav for chronic bone infections following debridement or surgery. Serum and bone concentrations were not measured. Follow-up was limited to 12 months, at which time all had clinical cure or improvement with one relapse and one infection;58 however, follow-up of <2 years is generally considered too short to determine efficacy in chronic osteomyelitis. Furthermore, in the absence of comparative trials there appears no reason to treat S. aureus with co-amoxiclav rather than flucloxacillin unless patient tolerance is a problem, but the additional Gram-negative and anaerobic cover is useful for polymicrobial infection.
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Quinolones |
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More recently, newer quinolones have been introduced, e.g. moxifloxacin and levofloxacin, which have lower MICs than ciprofloxacin in vitro for Gram-positive organisms.72 Studies on their use in respiratory tract infection have been published particularly with respect to Streptococcus pneumoniae but data on penetration and efficacy in bone infection and use against other Gram-positive pathogens are not yet available. The safety of the newer quinolones in long-term use and the existence of any cross-resistance to older quinolones will need to be established.
Currently available quinolones therefore offer an attractive and effective alternative to standard parenteral therapy for sensitive Gram-positive infections. The possibility of acquired resistance must be considered and the use of a second agent in the treatment of S. aureus infection is advisable.
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Rifampicin and fusidic acid |
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Fusidic acid, like rifampicin, reaches high intracellular concentrations and has good activity against S. aureus. Bactericidal concentrations have been attained in infected bone and penetration of sclerotic bone and sequestra has been demonstrated in the presence of high serum concentrations.82,83 As with rifampicin, resistance to fusidic acid (which may be reversible) develops rapidly if it is not used in combination with a second agent.83
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Antibiotics used to treat MRSA bone infection |
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Teicoplanin has been particularly useful, enabling patients to be discharged from hospital while continuing with parenteral therapy as it can be given by bolus injection once daily or less frequently.36,91,92 Bone concentrations of a mean of 65% serum concentrations have been measured 3 h post injection during cardiac surgery.93 A summary of non-comparative studies (n = 23) has demonstrated between 50% and 100% efficacy for bone infections (median success rate 83%),94 although this would incorporate the initial studies using lower doses with decreased efficacy. While streptococcal infections are particularly amenable to treatment with teicoplanin,95 higher doses to give high trough serum concentrations appear necessary to treat deep-seated staphylococcal bone infection.36, 92,9698 Le Frock et al.99 used doses of 612 mg/kg to treat bone and joint infection in 90 evaluable patients. After an average of 6 weeks therapy for osteomyelitis and 3 weeks for septic arthritis, cure rates were 90%, 88% and 100% for acute and chronic osteomyelitis and septic arthritis, respectively. The reasons for selection of higher doses for some osteomyelitis patients in this study were not clear; 12 mg/kg is recommended for septic arthritis.
Oral minocycline (with and without rifampicin) has been shown to be useful in the treatment of MRSA infection, including osteomyelitis.74,80,100,101 Despite combination with a second agent, rifampicin resistance has emerged with the combination and whether the combination is actually superior to minocycline alone has been questioned.74 High-dose oral co-trimoxazole has also been used to treat MRSA implant infection as an alternative to glycopeptides. After prolonged high-dose therapy the overall cure rate at 6 years was 66.7% but side effects were a cause for cessation in eight patients.102 (The use of quinupristin/dalfopristin and linezolid for MRSA infection is discussed below.)
New antibiotics
The appearance of vancomycin-resistant enterococci (VRE) and glycopeptide-intermediate S. aureus (GISA) as causal pathogens in orthopaedic infection has challenged clinicians and microbiologists to find new antibiotics or combinations effective in deep infection but also tolerable over prolonged courses.103 Synercid is the proprietary name of a streptogramin consisting of quinupristin and dalfopristin, and is a bactericidal antibiotic that inhibits protein synthesis by binding to the 50S ribosome subunit.104 It has activity against Enterococcus faecium, including vancomycin-resistant strains and S. aureus (including MRSA). It is not active against E. faecalis.104 Quinupristin/dalfopristin must be administered via central line in dextrose infusion three times daily; the most troublesome side effect is myalgia, which may necessitate cessation. In a study of 40 patients treated for MRSA bone and joint infections (mean duration 42 days), clinical and bacteriological success was observed in 77.5% and in 69% of those evaluable.105 There is also reported success in the treatment of single cases of VRE osteomyelitis of the vertebra106 and the foot,107 although in the latter case outcome was not reported beyond a few weeks post-cessation of antibiotics. Using a rabbit model of PJI with MRSA, improved outcome and more rapid killing was demonstrated with the combination of quinupristin/dalfopristin and rifampicin compared with vancomycin and rifampicin.108 Caution must be used if a Staphylococcus sp. is resistant to erythromycin as, due to cross-resistance of the MLSB type, this antibiotic may be only inhibitory, but not cidal. Organisms with an MIC of 2 mg/L are considered susceptible.109 Finally, the most recent addition to the armamentarium licensed in the UK is linezolid, an oxazolidinone. Bacterial protein synthesis is inhibited by binding of a specific site on the 50S ribosomal subunit. Linezolid represents a new class of antibiotic with no cross-resistance to other antibiotics. It is licensed in the UK for the treatment of soft tissue infection and pneumonia and is active against Gram-positive organisms including VRE (E. faecium and E. faecalis) and MRSA. Organisms with an MIC of
4 mg/L are considered susceptible.109 In contrast to quinupristin/dalfopristin, linezolid can be given by peripheral infusion and orally has 100% bioavailability.110 While it appears promising in other fields there are few published data on the treatment of bone infection although linezolid concentrations measured in bone samples from 10 individual patients ranged from 3.3 to 17.4 mg/kg, mean 8.5 mg/kg.111 It has potential to interact with other drugs, e.g. monoamine oxidase inhibitors and may cause reversible anaemia or thrombocytopenia with continued use. At present it is not recommended for more than 28 days; however, there are anecdotal reports of longer use, under careful observation, without adverse effect. Successful treatment for MRSA has been reported in two cases of osteomyelitis,109 one of vertebral osteomyelitis113 and in a case of VRE PJI.114 In contrast, results were poor in an animal study comparing 25 mg/kg twice daily linezolid given intraperitoneally twice daily or thrice daily with cefazolin 50 mg/kg given intramuscularly thrice daily for S. aureus osteomyelitis, with no difference in outcome between linezolid and the control group.115 As linezolid offers one of the only options for oral treatment of some of the most resistant Gram-positive organisms, results of further studies are keenly awaited.
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Conclusions |
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Footnotes |
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References |
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