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Antibiotics for Orthopedic Infections

Introduction:

Gram-positive organisms are responsible for the majority of bone and joint infections. Bone infection, at sites of relatively poor vascularity, can be difficult to treat, often requiring prolonged courses of antimicrobial therapy in association with surgical drainage or debridement.

 

Causal organisms in bone and joint infection

Staphylococcus aureus is the single most common organism causing osteomyelitis(1,2) and septic arthritis.(3,4) Coagulase-negative staphylococci (CoNS) are more prevalent in prosthetic joint infection (PJI) followed by S. aureus.(5) β-Haemolytic streptococci are also responsible for bone infection, e.g. Lancefield group B osteomyelitis in neonates and group A septic arthritis in other age groups.

In contrast, Streptococcus pneumoniae is a relatively rare cause of septic arthritis and raises the question of underlying Immunosuppression(6).  Anaerobes may contribute to polymicrobial osteomyelitis in vasculopathic infection (7) such as diabetic foot infection and in septic arthritis following animal bites.(8)

Haemophilus influenzae was a major cause of septic arthritic joint in children of pre-school age but this is now a much rarer cause while Neisseria gonorrhoea may be responsible for septic arthritis in young adults.

 

Osteomyelitis:

More simply, osteomyelitis can be described as ‘acute or chronic’ and ‘haematogenous or contiguous’, according to the duration and source of infection, respectively.

Some studies on the use of oral Beta-lactams in adults have been published, (9,10) but the majority report success in paediatric osteomyelitis, (11-15) which heals much more rapidly than in adults. Osteomyelitis in paediatric patients is usually haematogenous in origin and mainly occurs in the long bones.

 

Septic arthritis

Septic arthritis of a native joint is most commonly caused by S. aureus followed by Lancefield group A β-haemolytic streptococci as a consequence of direct trauma or haematogenous spread. Polymicrobial infection is not usual but may be anticipated following penetrating injuries including animal bites. Aminoglycosides are less active in synovial fluid (and in bone).(17) Penetration of flucloxacillin and cefradine, used frequently to treat septic arthritis, was disappointing in one study,(18). Direct intra-articular instillation of antibiotics is not necessary and not recommended.(16,19) The duration of treatment is not clearly evidence based but typically 2–3 weeks for uncomplicated infection is appropriate,(20) though this need not be parenteral throughout.(17).

 

Prosthetic joint infection

PJI is fortunately a relatively uncommon complication following hip and knee joint replacement (incidence approximately <1% and 0.5%, respectively 21). The most common pathogens implicated are CoNS followed by S. aureus,(3) but almost any organism may be implicated including enterococci, streptococci, corynebacteria, Enterobacteriaceae and anaerobes.(5) PJI requires antibiotic treatment for ≥6 weeks to several months in addition to surgery.(24) Chronic suppression with long-term antibiotics has been used as a ‘last resort’ when further surgery has not been possible. (23)

 

β-Lactams and lincosamides

Against S. aureus osteomyelitis, lincomycin was more effective in sterilizing bone at 14 days but after 28 days there was no difference between the two. Smilack et al. (26) found no detectable cefalothin (and  no penicillin) in hip bone at 0.5 and 2 h after a single injection in patients with uninfected hips, but found significant uptake of methicillin, clindamycin and carbenicillin. In contrast, in a similar study Fitzgerald et al. (18) compared bone penetration of cefalothin, methicillin and oxacillin measured in excised hip 1 h after injection and found no significant difference between bone concentrations. He commented that more patients given cefalothin attained bone concentrations of >1 µg/g than those given oxacillin or methicillin, and concluded that cefalothin was superior for bone prophylaxis.

 

Cefuroxime and cefamandole are often used as prophylaxis for orthopaedic procedures.

 

In contrast to cephalosporins, clindamycin exhibits consistently high penetration in bone (27,28-30) and in synovial fluid (31)54 in the presence of relatively low serum concentrations.

 

Clindamycin, with both good bioavailability and high bone:serum ratios is an ideal choice for switch therapy in patients who no longer require hospital admission. In the UK, flucloxacillin is commonly used for first-line therapy of deep S. aureus infection.

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.

 

Quinolones

Quinolones have an effect on adherent bacteria, penetrate macrophages and polymorphs, (32) exhibit high bone:serum concentrations after oral administration (33) and have a low side-effect profile.

 

The efficacy of these quinolones against Gram positive osteomyelitis is impressive and compares well with standard therapy. There are several excellent reviews of trials of quinolone in bone and joint infections, which summarize encouraging results in studies including Gram-positive, Gram-negative and polymicrobial infections.(34-36)

 

Increasing resistance amongst S. aureus has been observed since the introduction of quinolones,(37) and has resulted in the addition of rifampicin to attempt to prevent this occurring during treatment.

 

Rifampicin and fusidic acid

It is particularly useful in eradicating bacteria adherent to prosthetic material in joint infection or chronic osteomyelitis.

Rifampicin has excellent anti-staphylococcal activity and bioavailability, can penetrate white blood cells to kill phagocytosed bacteria and can eradicate adherent organisms in the stationary phase making it the (almost) ideal antibiotic for bone infection.

 

Fusidic acid, like rifampicin, reaches high intracellular concentrations and has good activity against S. aureus.

 

Antibiotics used to treat MRSA bone infection

The glycopeptides, vancomycin and teicoplanin have become the mainstay of treatment in the UK for MRSA infection. Individual preferences for one or the other vary although it is considered by some that vancomycin offers superior treatment for staphylococci with more rapid killing due to lower protein binding than teicoplanin. (38) High-dose and prolonged therapy with teicoplanin has been associated with thrombocytopenia and neutropenia, particularly when pre-dose concentrations exceed 60 mg/L. (39)

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. (25,40,41)

While streptococcal infections are particularly amenable to treatment with teicoplanin, (42) higher doses to give high trough serum concentrations appear necessary to treat deep-seated staphylococcal bone infection. (25,41,43-45)

 

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. (46) 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. (47) It has activity against Enterococcus faecium, including vancomycin-resistant strains and S. aureus (including MRSA).

 

Finally, the most recent addition to the armamentarium licensed in the UK is linezolid, an oxazolidinone. 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.

 

Conclusions

In conclusion, Gram-positive infection accounts for the majority of bone and joint infections. Antibiotics penetrate well into the synovial fluid of infected joints and following drainage, treatment of septic arthritis can be achieved with 2–3 weeks iv and oral therapy. High bone penetration of some antibiotics, notably the fluoroquinolones and clindamycin, enable early oral switch therapy for some patients.

 

References

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