Infected Nonunion

Infected nonunion is a fracture that has failed to unite in the presence of bone and implant infection (chronic osteomyelitis). It follows open fractures (especially Gustilo types IIIB and IIIC), fixation of closed fractures with postoperative infection, and, rarely, haematogenous spread. It is most frequent in the tibia, femur, and humerus.

The Cierny-Mader classification stages the host and anatomy: stage 1 medullary, stage 2 superficial, stage 3 localised (stable) and stage 4 diffuse (unstable). Host class A is a normal host, B has local or systemic compromise, and C is a host in whom treatment is worse than the disease.

Organisms are Staphylococcus aureus (including meticillin resistant strains) in about 50%, coagulase negative staphylococci, Gram negative bacilli (Pseudomonas, Enterobacteriaceae), anaerobes, and polymicrobial mixtures. Biofilm formation on implants and dead bone (sequestrum) makes eradication difficult.

Complications are persistent infection, sinus formation, recurrent abscess, deformity, bone loss, implant failure, limb shortening, amputation (up to 5 to 10% in complex cases), squamous cell carcinoma in a long standing sinus (Marjolin ulcer), and amyloidosis.

Pathophysiology.

Bacteria adhere to implants and necrotic bone and form biofilm, where they resist antibiotics and host defences. Infection and devitalised bone prevent union. The key surgical principle is to remove all dead bone and infected tissue, and to supply a stable fixation, a good blood supply and soft tissue cover.

Persistent pain at the fracture site, swelling, erythema, warmth, drainage from a sinus or wound, fever (less common in chronic cases), loosening of implants, instability or movement at the nonunion, and, sometimes, only unexplained failure of union with pain. Look for diabetes, smoking, peripheral vascular disease, immunosuppression, malnutrition and intravenous drug use.

Examine the wound, scars, sinus, limb alignment, leg length, neurovascular state and range of adjacent joints.

• Blood tests: white cell count, C-reactive protein and erythrocyte sedimentation rate (often raised but may be normal), HbA1c, albumin, and 25-hydroxyvitamin D.
• Radiographs: bone lucency around implants, sequestrum, periosteal reaction, bone loss, implant loosening. CT shows sequestra and bone stock. MRI shows marrow involvement and abscess.
• Nuclear imaging (labelled white cell scan, bone scan, or positron emission tomography) when MRI is limited by implants.
• Microbiology: at least 5 deep tissue samples from the nonunion site (not swabs of sinus drainage), taken before antibiotics where possible and with separate instruments, plus histology (over 5 neutrophils in each high power field) and sonication of implants.
• Sinus tract swabs are unreliable; blood cultures if febrile.

Differential diagnosis.

• Aseptic nonunion (hypertrophic or atrophic).
• Septic arthritis and soft tissue infection.
• Chronic osteomyelitis without a fracture.
• Charcot arthropathy and tumour (pathological fracture, Marjolin ulcer).

Management combines surgery, antibiotics, and optimisation of the host.

Surgery (staged is common).

• Stage 1:
  • remove infected implants (or retain stable implants in early infection with debridement, antibiotics and implant retention)
  • radical debridement of all necrotic bone and soft tissue until bleeding bone (paprika sign) is seen
  • multiple deep cultures
  • local antibiotic carriers (vancomycin and gentamicin in cement beads, spacer or absorbable carrier)
  • temporary stabilisation by external fixation or antibiotic coated nail
• Stage 2 (at 6 weeks, after normal inflammatory markers and negative cultures):
  • bone reconstruction by the Masquelet induced membrane technique with autograft, bone transport with a ring fixator (Ilizarov), vascularised fibular graft, or shortening with lengthening
  • fix with a plate or intramedullary nail (a new implant in a clean field)
• Soft tissue cover: local or free flap, to provide vascularised cover (orthoplastic approach).
• Amputation for a nonreconstructable limb, a poor host who cannot tolerate staged reconstruction, or recurrent infection.

Antibiotics. Start only after deep samples are taken, unless the patient is septic. Choose by culture and sensitivity with infectious diseases input.

• Meticillin sensitive Staphylococcus aureus: flucloxacillin 2 g intravenously every 6 hours (maximum 12 g daily; reduce at creatinine clearance under 10 mL/min; check liver function and avoid with a history of flucloxacillin cholestatic jaundice) or cefazolin 2 g intravenously every 8 hours.
• Give for 2 weeks then oral step down for a total of 6 weeks after debridement (12 weeks when implants are retained).
• Meticillin resistant organisms or severe penicillin allergy: vancomycin 25 mg/kg intravenously loading dose (maximum 2 g), then 15 to 20 mg/kg every 8 to 12 hours, adjusted to a trough level of 15 to 20 mg/L (area under the curve to minimum inhibitory concentration of 400 to 600), with creatinine monitored; avoid with a history of vancomycin reaction.
• Linezolid 600 mg orally or intravenously every 12 hours is an alternative (limit to 4 weeks; monitor full blood count weekly; avoid with serotonergic drugs).
• Gram negative infection including Pseudomonas: piperacillin-tazobactam 4.5 g intravenously every 6 hours (reduce at creatinine clearance under 40 mL/min).
• Or ciprofloxacin 750 mg orally twice daily (maximum 1.5 g daily; avoid with tendon disorders, QT prolongation, epilepsy and in older adults; separate from calcium and iron).
• Biofilm active adjunct for retained implants or Staphylococcus aureus: rifampicin 450 mg orally twice daily (300 mg twice daily if weight is under 50 kg), always with a second active antibiotic.
• Check liver function at baseline and every 2 weeks; interactions (warfarin, direct anticoagulants, hormonal contraception and antiretrovirals) need review.
• Duration: 6 weeks after clearance of infected bone (12 weeks when implants remain), then reassess with markers.

Operative antibiotic prophylaxis. Withhold until deep samples are taken. Then cefazolin 2 g intravenously (3 g when weight is 120 kg or over) within 60 minutes before incision as a single dose.

With severe penicillin allergy or meticillin resistant organisms, give vancomycin 15 mg/kg intravenously starting 90 to 120 minutes before incision as a single dose, with levels and creatinine checked in prolonged cases.

Thromboprophylaxis.

• Enoxaparin 40 mg subcutaneously once daily, started 6 to 12 hours after surgery.
• Continue for 10 to 14 days for upper limb and tibial surgery, and 28 to 35 days for femoral surgery or when mobility is reduced.
• Use 20 mg once daily at creatinine clearance under 30 mL/min; adjust by anti-Xa level in obesity and renal impairment; check the platelet count on days 5 to 14 for heparin induced thrombocytopenia.
• Use mechanical prophylaxis until then.

Analgesia.

• Paracetamol 1 g orally every 6 hours as needed for up to 5 to 7 days (maximum 4 g daily; 3 g daily when weight is under 50 kg, with chronic alcohol use or hepatic impairment).
• Oral morphine 5 to 10 mg every 4 hours as needed for severe pain for up to 3 days (start 2.5 to 5 mg with age over 75 or eGFR under 30 mL/min/1.73 m2; avoid exceeding 60 mg in 24 hours without senior review).
• Monitor sedation and respiration and prescribe a laxative.
• Avoid NSAIDs while healing is delayed.

Monitoring. C-reactive protein and erythrocyte sedimentation rate weekly during intravenous therapy, then every 2 weeks. Creatinine, drug levels and full blood count as needed for the antibiotic used. Radiographs at 6 weeks, 3 months, 6 months and 12 months. Wound and limb perfusion at each visit. Clinical review for at least 12 months after treatment to detect recurrence.

Referral and escalation. Refer every infected nonunion to a specialist bone infection or limb reconstruction centre, with orthopaedic, plastic surgery and infectious diseases input. Emergency referral for sepsis, spreading cellulitis, necrotising infection, vascular compromise or implant failure.

Special groups.

• Diabetes and peripheral vascular disease: optimise glucose and perfusion first; higher amputation risk.
• Smokers: cessation is needed before reconstruction.
• Intravenous drug users: broaden microbiology (include Gram negative and polymicrobial cover) and support addiction treatment.
• Kidney impairment: adjust vancomycin and piperacillin-tazobactam, avoid NSAIDs, and reduce morphine doses.