Pathaphysiology of septic arthritis and clinical manifestation and relate to case study

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ORIGINAL RESEARCH Clinical Medicine 2017 Vol 17, No 6: 150–8CME INFECTIOUS DISEASES Clinical Medicine 2018 Vol 18, No 2: 150–4

Authors: A academic clinical lecturer in microbiology and infectious diseases, Oxford University Hospitals NHS Foundation Trust,

Oxford, UK ; B consultant microbiology and infectious diseases,

Nuffield Orthopaedic Centre, Oxford University Hospitals NHS

Foundation Trust, Oxford, UK

Authors: Julia Colston A and Bridget Atkins B

Bone and joint infections include septic arthritis, prosthetic joint infections, osteomyelitis, spinal infections (discitis, vertebral osteomyelitis and epidural abscess) and diabetic foot osteomyelitis. All of these may present through the acute medical take. This article discusses the pathogenesis of infection and highlights the importance of taking a careful history and fully examining the patient. It also emphasises the importance of early surgical intervention in many cases. Con- sideration of alternative diagnoses, appropriate imaging and high-quality microbiological sampling is important to allow appropriate and targeted antimicrobial therapy. This article makes some suggestions as to empiric antibiotic choice; how- ever, therapy should be guided by local antimicrobial policies and infection specialists. Involvement of a multidisciplinary team is essential for optimal outcomes .

Introduction

Bone and joint infections cause serious morbidity and pose

significant management challenges. They may cause acute

sepsis with bone and joint destruction, chronic pain, discharging

wounds and permanent disability. With expanding populations

and increasing age, bone and joint infections, especially those

involving devices, will have a growing impact on healthcare

resources. For effective management, well-coordinated

multidisciplinary working is important.

General considerations

Pathogens can gain access into bone and joints through the blood

stream (haematogenous route) or via direct inoculation from a

contiguous focus of infection. Acute haematogenous infections

are most common in children and the elderly.

The presence of foreign material such as implanted devices or

dead bone significantly reduces the number of organisms required

to cause infection. 1 Foreign or non-viable material also allows normal

skin commensals, such as coagulase-negative Staphylococcus spp,

to become significant pathogens. Micro-organisms adhere to the

inert surface where they are relatively protected from the blood

supply, immune processes and antibiotics. Organisms, such as

A B

S T

R A

C T

Bone and joint infection

Key points

In suspected bone and joint infections quality microbiological

sampling is important. In those with features of sepsis or acute

skin and soft tissue infection (SSTI), blood cultures and, where

possible, aspirates should be taken immediately followed by

prompt empiric antibiotic therapy. In other cases antibiotic

therapy should wait until intraoperative samples are taken. In all

acute bone and joint infections, orthopaedic surgeons, infection

specialists and radiologists should be involved early

Acute septic arthritis should be managed with diagnostic

aspiration followed by prompt arthroscopy or arthrotomy and

washout in conjunction with antibiotics. In some cases, where

surgery may not be possible, serial closed joint aspirations might

be an alternative option

Acute haematogenous osteomyelitis needs prompt surgical

drainage if there is a purulent collection. Other cases can be

managed by antibiotics alone but with repeat imaging if there is

failure to settle

Patients with possible spinal infection need blood cultures,

prompt MRI and spinal surgery review. In stable patients not

requiring surgical intervention, a radiological biopsy should be

considered to direct antimicrobial therapy. Tuberculosis, Brucella ,

Nocardia and/or fungal cultures should be requested in patients

with appropriate risk factors

In diabetic foot infections it is important to recognise severe

limb-threatening infections that require urgent surgical

management. Signs of this are systemic sepsis, poor glycemic

control, gas in soft tissues, abscess and infection from an ulcer

tracking deeply through the foot to another site (eg plantar ulcer

to dorsum of foot)

KEYWORDS: bone and joint infection, osteomyelitis, septic

arthritis, prosthetic joint infection, biofilm, diabetic foot infection,

discitis, vertebral osteomyelitis ■

Staphylococcus spp can produce extracellular polymeric substance

(EPS). Micro-organisms embedded in EPS create a biofilm on the inert

surfaces. By communicating with each other they are able to up and

downregulate gene expression enabling regulation of growth and

adaptation to the environment. Biofilm formation is an important

mechanism for bacterial survival in chronic bone and joint infection. 2

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Chronically established bone and joint infection can be persistent,

evolve or relapse, even in the face of prolonged antimicrobial

therapy. Biofilm has important implications for diagnostics, as well as

surgical and antibiotic management.

The ‘hot’ joint

An inflamed ‘hot’ joint has a wide differential including

inflammatory causes (septic arthritis, reactive, rheumatoid

arthritis, spondyloarthropathies, SLE, gout or pseudo-gout) and

non-inflammatory causes (degenerative joint diseases, trauma,

avascular necrosis and Charcot’s arthropathy). 3,4

Septic arthritis

is important to exclude, as delayed or inadequate treatment can

lead onto cartilage and then joint destruction.

Acute septic arthritis

Acute septic arthritis can affect any joint. It most commonly

affects the knee but may also involve wrists, ankles, hips and the

symphysis pubis. Polyarticular septic arthritis is more common

in patients with inflammatory joint disease or overwhelming

sepsis. 5 Injecting drug use is a risk factor for septic arthritis of the

sternoclavicular, sternomanubral or sacroiliac joints, often also

associated with endocarditis. 6

The presentation can be similar to other inflammatory causes, such

as crystal arthropathy, with an acutely painful, swollen, warm, red

joint and a reduced range of movement. Features suggesting septic

arthritis include fever and/or chills and absence of prior history or

risk factors for gout, but dual pathology can occur. Risk factors for

septic arthritis include extremes of age, bacteraemia, inflammatory

joint disease, diabetes, intravenous drug use, alcoholism,

immunosuppression, malignancy, recent trauma, intra-articular

injections, arthroscopy or a prosthetic joint. The clinical history should

include a sexual history (for gonococcal arthritis). A history of tick bite

in an endemic area may raise the possibility of Lyme arthritis.

Blood cultures may be positive in up to 50% of cases but are usually

negative in gonococcal septic arthritis. 7 Plain X-rays should be done

to exclude other causes of hot joint, but are usually normal in early

septic arthritis. Ultrasound is sensitive for detecting joint effusions

and synovitis. Synovial fluid should be aspirated and examined for

leucocytes, urate and pyrophosphate crystals and by Gram stain and

culture. A semiquantitative synovial leucocyte count can differentiate

inflammatory from non-inflammatory causes but cannot differentiate

infection from other inflammatory causes. 4 Gram stain has low

sensitivity (<75%) especially in gonococcal arthritis (<25%). 4 Cultures are also often negative in the latter and, if suspected, molecular

diagnostics (16S polymerase chain reaction) on synovial fluid may be

considered and a urethral swab or urine should be sent for culture /

nucleic acid amplification testing. Rectal and pharyngeal swabs may

be indicated. If Lyme arthritis is suspected diagnosis is by serology.

Diagnostic joint aspiration should be performed before antibiotics

are given, except when the patient is acutely septic and aspiration

delayed. Table 1 highlights the common bacterial causes and

example antibiotic choices. All cases of suspected acute septic

arthritis should be referred urgently to orthopaedics. Prompt

arthroscopic or open washout is generally recommended despite

the absence of good quality clinical trials. Observational studies

show that in patients where surgery may be high risk, a more

conservative approach of repeated aspirations may be effective. 8

There is no good evidence to guide duration of antibiotic therapy

for septic arthritis in adults. If synovial fluid Gram stain and cultures

Table 1. Suggested empiric antibiotics for native joint septic arthritis in adults (but consult local guidelines). Modify, with microbiological advice, when culture results are available

Suggested empiric antibiotic choice (after blood cultures and joint aspirate)

Patient group Possible organisms No known drug allergies

Penicillin allergy (non-severe eg rash)

Penicillin allergy (severe eg anaphylaxis)

No specific risk factors Staphylococcus spp, beta-

haemolytic streptococci

IV flucloxacillin IV anti-staphylococcal

cephalosporin (eg

cefuroxime)

Clindamycin

Frail, recurrent UTIs, end-

stage renal failure, recent

abdominal surgery?

Aerobic Gram-negative rods IV co-amoxiclav IV 3rd generation

cephalosporin (eg

ceftriaxone)

Clindamycin plus ciprofloxacin

MRSA risk Meticillin-resistant S aureus Add IV

glycopeptide a

Add IV glycopeptide a Add IV glycopeptide

Suspected gonococcal

septic arthritis 18

, b

Neisseria gonorrhoeae IV 3rd generation

cephalosporin (eg

ceftriaxone)

IV 3rd generation

cephalosporin (eg

ceftriaxone)

Clindamycin plus ciprofloxacin

(stop clindamycin if proven

Neisseria infection)

Intravenous drug usage S aureus . Less likely

Pseudomonas aeruginosa ,

Fungal

IV flucloxacillin IV anti-staphylococcal

cephalosporin (eg

cefuroxime)

Clindamycin

Known colonised with multidrug resistant organism

MRSA, ESBL, CPE etc Discuss with microbiology

Table adapted from 3,4

a Glycopeptides include vancomycin and teicoplanin. These should be used at high doses in bone and joint infection ie vancomycin at 10–12 mg/kg and teicoplanin at

10 mg/kg. Modifications to dosing will need to be made in the setting of low body weight and/or impaired renal function.

b Consult local infectious diseases / micro or genitourinary medicine physicians

ESBL = extended-spectrum beta-lactamases; CPE = carbapenemase-producing enterobacteriaceae; IV = intravenous; MRSA = Meticillin-resistant Staphylococcus aureus

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(taken before antibiotics) are negative, gonococcal arthritis is not

suspected and surgical findings are inconclusive then antibiotics

should be reviewed, and stopped if there is a likely alternative

diagnosis (eg crystal arthropathy). In proven septic arthritis, antibiotics

are typically given for 2–4 weeks. The longer (4-week) course may be

indicated with difficult organisms, such as Staphylococcus aureus or

Pseudomonas aeruginosa infections. Failure to settle or relapse may

mean a repeat washout is required; however, inflammatory changes

often persist for several weeks after presentation. There is no evidence

as to when antibiotics can be changed to the oral route. This would

depend on clinical progress, extent of infection, bioavailability of oral

agents and likely patient compliance. In likely gonococcal arthritis,

the patient should also be referred to a genitourinary clinic for a full

sexually transmitted infection screen.

Infections involving prosthetic joints (PJI) should always be

referred back to orthopaedics, who should also involve infection

specialists. Acute PJI occurs either postoperatively (up to 3 months

after the initial arthroplasty) or through haematogenous spread

after a period in which the prosthesis has been sound. For acute PJIs,

blood cultures, plain X-ray, ultrasound and aspiration of the joint

are the initial diagnostic modalities. 9 The prosthesis at this stage is

usually sound (not loose) and the most appropriate management

is a DAIR procedure (a radical open Debridement with exchange

of modular components but Retention of the Implant followed by

Antibiotics). 10

This needs to be done by an orthopaedic surgeon

experienced in managing PJIs. Joint aspiration / arthroscopic

washout may be required as an interim measure to drain pus if

the relevant expertise is not immediately available. More chronic

infections (usually presenting as increasing pain, loose prosthesis or

a discharging sinus) may be managed by revision of the prosthesis

in one or two stages or excision arthroplasty. When the prosthesis is

sound, a DAIR may be considered. Expert management of the soft

tissues and dead space is important and may require plastic surgery

input eg a muscle flap. When surgery is performed for chronically

infected prosthetic joints, this should be done off antibiotics and

multiple samples taken using separate instruments for separate

sites, for microbiology and histology. Postoperative antibiotics need

to be managed by infection specialists and may be prolonged. 11

Osteomyelitis

In children the most common site for acute haematogenous

osteomyelitis is the growing end of long bones. In adults, it is the spine.

The most common organism is S aureus but other pathogens such as

beta-haemolytic Streptococcus spp, Haemophilus influenzae , Kingella

kingae or Mycobacterium tuberculosis are possible. In patients with

sickle cell disease, osteomyelitis is commonly due to Salmonella spp.

Osteomyelitis in children may relapse decades later in adulthood.

Osteomyelitis may also occur in relation to infected fracture fixation

devices. Infection may then contribute to delayed or non-union of the

fracture. Figure 1 demonstrates the pathogenesis of osteomyelitis.

Acute osteomyelitis usually presents with fever and pain at the site

of infection. Other skeletal sites should be examined as multifocal

osteomyelitis can occur. Blood cultures and plain films should be

performed. The purpose of plain films is to look for other causes of

pain (eg fracture) and evidence of periosteal reaction or lucency. The

imaging modality of choice for osteomyelitis, however, is MRI, which

may show bone oedema, abscess formation, and periosteal reaction.

If infection is chronic there may also be evidence of a sinus, cloacae,

periostitis, sequestrum and/or involucrum (Fig 2 ). Occasionally,

Subperiosteal abscess

Periosteum

(a) (b)

Seeding of infec�on

Metaphyseal vessels

Sequestrum

Sinus

Involucrum Cloacae: discharging pus and bone

Fig 1. The pathogenesis of osteomyelitis. (a) Haematogenous bone infection results in medullary pus formation, acute infl ammation, systemic

illness and often, secondary bacteraemia. Pus may then track into joints or

through the cortex. (b) In cases that progress to chronicity, a subperiosteal abscess may form leading to periosteal stripping and devitalisation of bone.

Viable bone is resorbed leading to lucency. (c) Bacteria on the surface of dead bone persist leading to chronic suppuration, tissue destruction, sinus formation

and often further bone death. Dead bone form sequestra. Involucrum is new

bone formation outside existing bone as a result of periosteal stripping and

then new bone growth from the periosteum. (d) This may be breached by cloacae, through which pus and fragments of dead bone escape.

(a) (b)

Fig 2. X-ray (a) and MRI (b) of the left femur, showing an area of osteomyelitis, with a central sequestrum (dead bone) and involucrum (new bone formation) around this – marked with white arrows. Chronic disease is noted through the shaft of the femur, as well as visible overlying

soft tissue deformity.

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pathological fractures occur. If there are soft tissue collections, prompt

aspiration for microbiology is appropriate. In acute osteomyelitis,

many patients will respond to antibiotic treatment but those with

evidence of pus on imaging require urgent surgical drainage /

decompression. When osteomyelitis is chronic and/or related to a

fracture fixation device it needs management by a multidisciplinary

team experienced in the management of bone infections. Ideal

management is with a combination of surgical resection with

meticulous intraoperative sampling with/without stabilisation, with/

without reconstruction, soft tissue management by plastic surgeons

and appropriately managed postoperative antibiotics.

Spinal infections (vertebral osteomyelitis, discitis, epidural abscess)

Spinal infections are most commonly either haematogenous or

postsurgical. Haematogenous infections are most commonly due

to S aureus . Streptococcus spp, aerobic Gram-negative bacilli and

M tuberculosis should also be considered as should Brucella spp

in endemic areas and fungi in immunocompromised patients. 12

All patients with known fever and weight loss and/or bacteraemia

and/or endocarditis should have prompt spinal imaging if they

have new or worsening back pain. Imaging, usually by MRI (or

computed tomography if MRI is contraindicated), should look

for evidence of epidural abscess, discitis, vertebral osteomyelitis

and, critically, for evidence of cord / cauda equina compression

or vertebral instability requiring urgent surgical intervention. 13

Epidural collections usually require surgical drainage. 14

Unless

blood cultures have already revealed a causative organism, deep

microbiological samples should be obtained. This can be with

intraoperative samples if surgery is indicated, or by radiological

biopsy in other cases. This should be done urgently and, where

possible, antibiotics withheld until after the biopsy has been

taken (antibiotic therapy should not be delayed however in septic/

unstable patients). Cases should be discussed with microbiology to

ensure the relevant tests are done in the laboratory.

Native vertebral osteomyelitis should be managed with 6 weeks

of appropriately targeted therapy (possibly longer in complicated

cases or where organisms such as Brucella spp are identified). 15

Duration of therapy for epidural abscesses depends upon whether

it was surgical drained and clinical/radiological response.

Diabetic foot osteomyelitis

Diabetic foot infections usually occur following skin ulceration

in patients with neuropathy and/or vascular insufficiency. 16

Infections can go on to cause adjacent osteomyelitis. In severe

infections this can rapidly become limb and life threatening. It is

essential for all patients, especially diabetics, presenting though

acute medical services to have a full foot examination including

Table 2. Diabetic foot infections: pathogens and suggested empiric antimicrobial therapy (but consult local guidelines)

Severity a Usual pathogens Treatment

No known drug allergy Penicillin allergy (non- severe eg rash)

Penicillin allergy (severe eg anaphylaxis)

Uninfected

Mild (usually treated

with oral agents)

Meticillin-sensitive

Staphylococcus aureus

(MSSA); Streptococcus spp

Flucloxacillin or

co-amoxiclav

Doxycycline, clindamycin or trimethoprim/

sulfamethoxazole

Meticillin-resistant S

aureus (MRSA)

A glycopeptide A glycopeptide

Moderate (may be

treated with oral or

initial parenteral agents)

MSSA; Streptococcus

spp; Enterobacteriaceae;

anaerobes

Co-amoxiclav 3rd generation cephalosporin

eg ceftriaxone plus

metronidazole

Clindamycin and

ciprofloxacin

Risk of Pseudomonas

aeruginosa

Anti-pseudomonal beta-

lactam eg piperacillin-

tazobactam or ceftazidime

plus metronidazole

Anti-pseudomonal beta-

lactam eg ceftazidime plus

metronidazole

MRSA If high risk of MRSA, add a

glycopeptide

Severe (usually treated

with parenteral

agents)

MRSA; Enterobacteriacae;

Pseudomonas ; anaerobes

Antipseudomonal beta-lactam eg ceftazidime and

metronidazole

If high risk of MRSA, add a glycopeptide

Clindamycin and

ciprofloxacin

a Severity based on the Infectious Diseases Society of America severity score

16 as follows:

Uninfected : No symptoms or signs of infection present (symptoms/signs defined as at least two of local swelling or induration, erythema, local tenderness or pain, local warmth, purulent discharge)

Mild : Local infection involving only the skin and subcutaneous tissue. If erythema, must be >0.5–≤2 cm around the ulcer. Exclude other causes of inflammatory response of the skin

Moderate : Local infection (as above) with erythema >2 cm, or involving structures deeper than skin and subcutaneous tissue, and no systemic inflammatory response signs

Severe : Local infection with signs of systemic inflammatory response with two or more of temperature >38°C or <36°C, heart rate >90 beats/min, respiratory rate >20 breaths/min or PaCO2 <32 mmHg, white blood cell count >12,000 or <4000 cells/μL or ≥10% immature (band) forms

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the removal of dressings. An audit (England and Wales) in 2015

showed that two-thirds of diabetic inpatients did not have a

specific diabetic foot risk examination while an inpatient. 17

Urgent surgical intervention may be required in those

patients with abscesses, necrotising soft tissue infections and/

or uncontrolled sepsis. Clinical evidence of pus tracking from

one area (eg ulcer) to another may be indicative of deep

spreading infection. Less urgent surgery may be required for

those with substantial non-viable tissue or extensive bone or joint

involvement. An early vascular assessment and involvement of

a vascular surgeon to consider revascularisation in appropriate

cases, especially those with critical ischaemia, is essential.

Table 2 gives a guide to empiric antibiotic management based

upon the severity of disease. Tissue sampling can be helpful for

antimicrobial management. Superficial swabs often represent

colonisation only, whereas deep tissue curettings / bone sampling

can allow for appropriately targeted treatment.

Conclusions

Bone and joint infections can present through the acute medical

take. It is important to take a careful history and remove any

dressings during initial assessment and to recognise when

urgent surgical intervention is required. Microbiological sampling

should be done in all cases, to allow for targeted antimicrobial

management. Comorbidities must be adequately managed.

Involvement of the multidisciplinary team is essential. ■

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Address for correspondence: Dr Bridget Atkins, Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Windmill Road, Headington, Oxford OX3 7LD, UK. Email: [email protected]

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