Osteomyelitis is an infection occurring in the bone tissue, and one can use the term for both infection of the bone marrow or infection of the bone cortex. It can be caused by spread of infection from other loci due to haematogenous factors (about 20%), by surgery or trauma, or by ischaemic issues such as osteomyelitis in the feet of diabetic patients.

Osteomyelitis is a rare infection occurring in only two in every 10,000 people throughout their lifetime. However, due to the length of antibiotic treatment and potential for serious morbidity and even mortality, clinicians should be vigilant when suspected.

Acute osteomyelitis is different to chronic osteomyelitis, but there is no real time frame to differentiate between the two forms. What can be distinguishable between the two forms is the sequelae and thus consequences of the infection. In the chronic form, you will find dead bone tissue and subsequent host reparative actions. Due to the potential morbidity and mortality associated with the chronic form, early diagnosis is critical to reducing this burden.

In developed countries with first-class healthcare systems, most cases of acute osteomyelitis can be successfully treated if diagnosed early. However, chronic osteomyelitis may form if treatment-refractory infections are present. The most common cause of infection is due to injury, and the risk is unsurprisingly greater for open fractures rather than closed fractures. Infectious complications in total knee replacement (TKR) and total hip replacement (THR) occur in about 0.5% to 2% of patients. After aseptic revision of TKR and THR, this incidence increases to 5%, and for septic revision, this has been suggested to be as high as 20%.

It has been suggested 10% to 30% of cases will become chronic. A delay in treatment of just four days has the potential to cause long-term sequelae associated with chronic infection. Pre-disposing risk factors such as malnutrition, diabetes, HIV, malignant tumour, extremes of age, small vessel vasculitis, and other patient-specific factors can increase an individual’s risk to develop the more severe chronic form of infection. Children normally present with the acute form of the disease and are more likely to have a haematogenous aetiology due to increased blood flow supplying their growing bones.

Definitive diagnosis is difficult and well beyond the scope of this article. The symptoms are that of other infections plus swelling and heat around the infected bone and, in the case of vertebral involvement, severe back pain at night. A series of imaging tests will be required and a bone biopsy may be undertaken. Three culture samples are necessary during the biopsy due to the high risk of false negatives. Even when samples are negative, treatment may still commence if other tests indicate infection.

Chronic osteomyelitis is normally associated with much greater morbidity and mortality. This form is a lot harder to treat and requires the surgical removal of dead bone tissue. The bacteria form what is called a biofilm, the trademark of chronic osteomyelitis. The biofilm acts as a protective layer for the bacteria from host defences and antibiotics. Therefore, when treated with antibiotics, it must be treated more aggressively and for a longer period of time.

Chronic osteomyelitis is divided into two treatment algorithms depending on whether the goal is curative or palliative. When opting for a cure, major orthopaedic surgery is required to remove infected bone tissue. A similar approach to removing a malignancy is required, with some healthy bone and soft tissue removed to ensure eradication of infection. In severe cases, amputation may be required. Hyperbaric oxygen has also been used with some success.

Staphylococcus aureus is the most common pathogen associated with osteomyelitis, followed by Streptococcus pneumoniae and S. pyogenes. Gram-negative bacilli are also implicated in some cases. Methicillin-resistant Staphylococcus aureus (MRSA) is on the rise in osteomyelitis and some suggest even treating for this empirically while awaiting culture results after bone biopsy.

When considering the minimum inhibitory concentration (MIC) for any identified pathogen, it is essential to consider the penetration of antibiotics into bone. When analysing the available data in the literature, it is important to remember this data is collected mainly in non-human animals and is taken in uninfected bones. A good summary of bone concentrations achieved in animal studies is shown in Table 1.

Table 1. Bone penetration of antibiotics

Antibiotic Time interval since last dose (hours) Bone/Serum concentration ratio
Amoxycillin 2 0.17 – 0.31
Piperacillin 1 0.18 – 0.23
Ceftriaxone 0.2 – 8 0.07 – 0.17
Rifampicin (osteomyelitis) 3.5 – 4.5 0.57
Vancomycin (osteomyelitis) 1 – 7 0.27
Ciprofloxacin (osteomyelitis) 2 – 4.5 0.42

 

Rifampicin has shown its merits in being able to eradicate slow-growing bacteria in the protective biofilms described above. However, this should not be used alone due to the ability of resistant bacteria to form fast.

Table 2 demonstrates the treatment recommendations for acute osteomyelitis as detailed in the Therapeutic Guidelines: Antibiotic.

Table 2. Recommended treatment duration for acute osteomyelitis

Age IV Total Duration (May use oral)
Neonate 4 weeks 4 weeks (all IV)
Child 3 days Minimum 3 weeks
Adult 4 weeks Minimum 6 weeks

 

Table 3 demonstrates the recommended treatment duration for chronic osteomyelitis as detailed in the Therapeutic Guidelines: Antibiotic.

Table 3. Recommended treatment duration for chronic osteomyelitis

Age IV Total Duration (May use oral)
Child May not be necessary Minimum 6 weeks
Adult 2 weeks Many months

 

When deciding on empirical therapy, the location of the infection, as well as patient factors, should be taken into consideration. For example, the likely causative pathogen is influenced by risk factors including if the patient is an IV drug user, has a gastrointestinal infection, or has experienced major trauma.

Some authors suggest using empirical antibiotics during anaesthesia when performing the bone biopsy as this does not interfere with culture results and reduces the risk of bacteraemia occurring.

For long bone osteomyelitis, the following is a guide from the Therapeutic Guidelines: Antibiotic:

  • Flucloxacillin IV 2g four times daily (child 50mg/kg). For critically ill patients, use a 4-hourly dosing interval.
  • For patients with a sensitivity to penicillins, use cefazolin 2g IV 8-hourly (child 50mg/kg).
  • For patients with immediate hypersensitivity, use vancomycin as monotherapy. It is important to remember that higher trough levels may be required due to the bone penetration needed to provide cover. Also, it has been shown that relapse rates are higher when vancomycin is used as monotherapy and there are even reports of resistance emerging (MIC>8mcg/mL).

Vertebral osteomyelitis can often involve pathogens other than S. aureus and is treated differently in adults. In paediatrics, the pathogen is usually S. aureus. The Therapeutic Guidelines recommends the following for adults:

  • Ceftriaxone 2g IV daily plus vancomycin IV. 10-20% of S. aureus isolates in vertebral osteomyelitis are now MRSA.

Once susceptibilities are available, antibiotic therapy will be directed. The Therapeutic Guidelines state that IV therapy is given first and then usually the patient should be put onto oral therapy, provided it is appropriate, to finish the course.

Due to the long-term antibiotic courses required when treating osteomyelitis, it is important for pharmacists to be involved as part of the multi-disciplinary team to help maintain adherence and fully eradicate the infection. This involves monitoring of side-effects, therapeutic drug monitoring, monitoring the trajectory of infection, supplying outpatient parenteral antibiotic therapy (OPAT), and ensuring peripherally inserted central catheters are kept sterile for such patients.

References:

  1. Antibiotic Expert Group. Therapeutic Guidelines: Antibiotic. Version 15. Melbourne: Therapeutic Guidelines; 2017.
  2. Chiappini E, Mastrangelo G, Lazzeri S. A case of acute osteomyelitis: an update on diagnosis and treatmentJ Environ Res Public Health. 2016; 13(6): 539.
  3. Copley LA, Kinsler, Ma, Gheen T, Shar A, Sun D, Browne R. The impact of evidence based clinical practice guidelines applied by a multidisciplinary team for the care of children with osteomyelitis. J Bone Joint Surg Am. 2013; 95(8): 686-93.
  4. Fraimow HS. Systemic antimicrobial therapy in osteomyelitisSemin Plast Surg. 2009; 23(2): 90-9.
  5. Lima A, Oliveira PR, Carvalho VC, Cimerman S, Savio E. Recommendations for the treatment of osteomyelitisThe Brazilian Journal of Infectious Diseases 2014; 18(5): 526-34.
  6. Walter, G. Kemmerer, M. Kappler, C. Hoffman, R. Treatment Algorithms for Chronic Osteomyelitis. Dtsch Arztebl Int 2012; 109(14): 257-264.

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