Common Pathogens in Orthopaedic Infections

Bone, joint and implant infections are caused by a short and predictable list of organisms, and the list shifts with the setting: the native joint, the implant, the contaminated wound, the host. Gram-positive cocci account for 70-80% of cases, and the staphylococci lead that group. The rest of this page is about which organism to expect where, how to prove it, and what the answer changes.

Why the organism matters. Empiric antibiotics are chosen before any culture result, and delay in appropriate cover increases morbidity and mortality. Knowing the likely pathogen makes that choice rational: S. aureus cover is essential in most scenarios, and local MRSA prevalence decides which agent provides it. The organism also sets the shape of treatment. Staphylococci in biofilm need prolonged therapy (6-12 weeks), Gram-negatives may allow shorter courses, and polymicrobial infections need broad cover.

Where this sits. The organisms are only half the problem; the other half is biofilm, which is why implant-retention decisions and extended cultures behave the way they do. The clinical syndromes are worked up on periprosthetic joint infection and osteomyelitis, and the drugs themselves on orthopaedic antibiotic therapy and antibiotic pharmacology and resistance.

Prevalence follows context. The distribution of pathogens follows predictable patterns based on the clinical setting, and that predictability is what makes rational empiric therapy possible. An acute native joint infection is a high-virulence, rapid-onset, destructive process; a chronic prosthetic joint infection is an indolent biofilm infection that needs the implant out; a child's haematogenous infection has an age-dependent spectrum; a diabetic foot carries a mixed aerobic and anaerobic flora that needs broad cover.

Virulence factors. Bacterial virulence mechanisms explain the clinical presentation and guide treatment, and they fall into four classes. Adhesins are surface proteins that attach the organism to bone matrix, collagen and prosthetic materials; toxins destroy tissue or evade the immune response; enzymes such as coagulase, hyaluronidase and proteases open tissue for invasion; and biofilm is the polysaccharide matrix that shields the colony from antibiotics and the immune system. The specific factors of S. aureus, the template organism, are set out under that pathogen below.

Resistance. In MRSA the altered penicillin-binding protein PBP2a has low affinity for beta-lactams and renders every one of them ineffective except ceftaroline. Extended-spectrum beta-lactamases are plasmid-encoded enzymes produced by Enterobacteriaceae such as E. coli and Klebsiella; they hydrolyse penicillins, cephalosporins and aztreonam, which leaves the carbapenems.

Biofilm. Biofilm is the primary reason prosthetic joint infections are difficult to cure with antibiotics alone. It forms in stages: bacteria attach to the surface through their surface proteins; attachment becomes irreversible as extracellular matrix secretion begins; the cells organise into microcolonies, three-dimensional communities threaded by water channels that carry nutrients; and the colony matures inside a polysaccharide matrix, the polysaccharide intercellular adhesin (PIA) glycocalyx that encases the bacteria.

Why biofilm defeats treatment. The matrix is a physical barrier that antibiotics, antibodies and phagocytes cannot penetrate, and the bacteria inside it communicate by quorum sensing. Part of the population drops into a dormant, metabolically inactive state as persister cells, which are resistant to antibiotics that target dividing cells and active cell processes. The result is a 1000-fold increase in MIC and the need for implant removal for cure. Rifampicin is one of the few antibiotics that penetrates biofilm, and it is always used in combination to prevent resistance.

View larger

Small colony variants. SCVs are a slow-growing subpopulation, classically Staphylococcus aureus and also CoNS, that underlie many persistent, relapsing and apparently culture-negative orthopaedic infections. They are stable phenotypic and genetic variants with a markedly reduced metabolic rate, forming pinpoint colonies roughly one-tenth normal size that are easily overlooked or misidentified in the laboratory. They are typically auxotrophic for components of the electron-transport chain (menadione, haemin or thymidine), so they generate little ATP, divide slowly and down-regulate the toxins and enzymes that normal cells express.

Why they persist. The low metabolic state lets them survive intracellularly, within osteoblasts and other host cells, shielded from antibiotics and immune clearance. It also confers reduced susceptibility to cell-active antibiotics, especially aminoglycosides, which require an active electron-transport chain to enter the cell; slow division blunts the cell-wall-active beta-lactams and vancomycin as well. SCVs are stable variants and not the same as persister cells, which are transiently dormant normal cells; persister and biofilm biology are developed in the dedicated biofilm topic.

The clinical footprint is chronic, low-grade, relapsing osteomyelitis and PJI, frequent prior antibiotic exposure, and cultures that are negative or slow to grow; reversion to the normal phenotype on subculture can cause diagnostic confusion. Alert the laboratory and request extended incubation. SCVs are also a difficult-to-treat organism and a recognised contraindication to implant-retaining DAIR.

True pathogen or contaminant. A single positive culture of a coagulase-negative staphylococcus may be contamination or true infection, and telling them apart needs the microbiology and the clinical context together. The Musculoskeletal Infection Society (MSIS) criteria call it infection when two or more cultures grow the same organism, or when a single positive culture sits with a consistent clinical picture; the organism's virulence, the inflammatory markers and the presence of an implant all weigh in.

The Gram-positive wall. A thick peptidoglycan layer (20-80 nm) with teichoic acids embedded in it and lipoteichoic acids anchored to the single phospholipid membrane beneath. The thick peptidoglycan retains crystal violet, so these organisms stain purple, and it is the target of the beta-lactams; vancomycin binds D-Ala-D-Ala.

The Gram-negative wall. Thin peptidoglycan (2-7 nm) in a periplasmic space between an inner phospholipid membrane and an outer membrane carrying lipopolysaccharide (LPS). Thin peptidoglycan loses the crystal violet on decolourisation and takes up the safranin counterstain, so these organisms stain pink. The outer membrane limits antibiotic entry, and LPS is what causes sepsis and endotoxaemia.

Why the stain matters. The Gram stain distinguishes bacteria by cell wall thickness, and that simple test guides initial antibiotic selection.

Other structures matter for particular organisms: the capsule that defeats phagocytosis, the pili that mediate adhesion, the flagella that carry an organism through tissue, the spore that survives the environment, and the biofilm matrix already described.

By Gram stain. The stain is the first classification and the one that shapes the first prescription.

Why Gram-positives dominate. S. aureus and CoNS colonise the skin and are the source of operative contamination; they adhere to implant materials; and they form biofilm. Gram-negatives come from elsewhere, and the history says when to expect them:

• Elderly or diabetic patients
• A suspected urinary or gastrointestinal source
• Open fractures (environmental contamination)
• Hospital-acquired infection
• Immunocompromised hosts

By resistance. The second axis is the resistance phenotype (MRSA, ESBL, VRE, CRE, multidrug-resistant Pseudomonas), tabulated under Biology above; it decides whether the standard agent will work at all.

By clinical behaviour. The third axis predicts the tempo of disease and the urgency of surgery. High-virulence organisms (S. aureus including MRSA, Group A Streptococcus, Clostridium perfringens) produce rapid onset, high fever, systemic toxicity and tissue destruction, and need urgent intervention. Low-virulence organisms (coagulase-negative staphylococci, Cutibacterium acnes, some enterococci) produce slow-onset, low-grade, biofilm-associated infection over months to years, and may tolerate suppression.

What to send. Deep tissue, not swabs, which grow contaminants. For PJI diagnosis take 5-7 tissue samples from different locations (MSIS criteria), sample multiple sites in osteomyelitis, and send synovial fluid from a septic joint for cell count, culture and crystal analysis. Blood cultures accompany every acute infection, because bacteraemia is common. The operative technique of sampling is under Surgical Technique.

When to send it. Hold antibiotics before cultures if possible; a 2-4 hour delay is acceptable. If the patient is already on antibiotics and revision surgery is planned, stop them 2 weeks before the operative cultures if feasible.

The Gram stain is a rapid bedside test that takes minutes: crystal violet, then iodine, then decolouriser, then safranin. Gram-positives stain purple and Gram-negatives pink, which guides initial empiric therapy, but the sensitivity on joint fluid is 60-80%.

Culture remains the gold standard for pathogen identification, on blood agar, chocolate agar and MacConkey, growing common pathogens in 24-48 hours and providing antimicrobial susceptibility testing. Fastidious organisms need extended incubation, and anaerobes, fungi and mycobacteria need to be requested.

The culture-negative infection. Cultures are negative in 10-30% of orthopaedic infections in practice, but the reference review reports 7-12% despite optimal technique (PMID 24696437), so most of the gap is recoverable and lies in things under your control. Prior antibiotic therapy is the most common cause; the others are fastidious organisms (Kingella, Cutibacterium, fungi, mycobacteria), biofilm with its organisms in a dormant state, inadequate sampling (superficial swabs, a single sample) and technical faults (transport delay, improper media). The approach to a culture-negative PJI is the mirror image:

• Review antibiotic exposure and stop antibiotics 2 weeks before sampling if possible
• Request extended incubation (7-14 days) and anaerobic cultures specifically
• Consider PCR or molecular diagnostics (16S rRNA sequencing)
• Sonicate the explanted implant to release biofilm bacteria
• Histology showing inflammation supports infection even when culture is negative

Molecular diagnostics. PCR and next-generation sequencing can identify pathogens in culture-negative infection. PCR returns a result in hours rather than days, detects non-viable organisms, and is therefore useful after antibiotics have been given; Kingella PCR improves paediatric detection, and specific targets such as mecA and vanA can be sought. It cannot provide susceptibility testing, may detect colonisers rather than pathogens, and is expensive and not universally available. 16S rRNA sequencing amplifies a conserved bacterial gene and identifies unculturable organisms, taking 1-2 weeks; it is used in culture-negative PJI with high clinical suspicion, after prior antibiotic exposure, and when atypical or fastidious organisms are suspected. ITS sequencing does the same for fungi. None of this is routine, but it earns its cost in culture-negative PJI and when a specific pathogen (TB, Kingella) is suspected.

Sonication. The explanted prosthesis is placed in fluid and subjected to low-frequency ultrasound, which dislodges bacteria from the biofilm; the sonicate fluid is then cultured. Studies show 10-20% improved sensitivity over tissue culture alone for PJI. The protocol is under Surgical Technique.

Synovial fluid. The thresholds differ between a native joint and a prosthetic one.

Alpha-defensin is an antimicrobial peptide released by neutrophils in response to infection, with 97% sensitivity and 97% specificity for PJI. It is available as a bedside lateral flow test or a laboratory ELISA, and it is not affected by prior antibiotics, systemic inflammation or time from surgery.

Empiric therapy for native joint and fracture infection. Flucloxacillin 2 g IV 6-hourly for MSSA cover, adding a vancomycin loading dose of 25-30 mg/kg where there is MRSA risk and gentamicin 5-7 mg/kg for Gram-negative cover. The MRSA risk factors are:

• Previous MRSA colonisation or infection
• Recent hospitalisation (within 90 days)
• Nursing home residence
• Intravenous drug use
• Chronic wounds

Empiric therapy for prosthetic joint infection. Vancomycin 25-30 mg/kg loading, then 15-20 mg/kg 12-hourly, for the CoNS and MRSA that are common here, plus piperacillin-tazobactam 4.5 g IV 6-hourly for Gram-negative cover, which also covers Pseudomonas in chronic wounds; ceftriaxone or cefepime is the other Gram-negative partner used. Four to six weeks of IV therapy is typical.

Pathogen-directed therapy. Once the organism and its susceptibilities are known, narrow.

DAIR: Debridement, Antibiotics, Implant Retention

Who is a candidate. DAIR keeps the implant, and the selection criteria are strict:

• Early infection (under 30 days post-operatively) or acute haematogenous infection (under 3 weeks of symptoms)
• A stable, well-fixed implant
• A healthy soft tissue envelope
• A susceptible organism identified

Who is not. A loose implant, a sinus tract and a difficult-to-treat organism (MRSA as a relative contraindication, Enterococcus, fungi, small colony variants) are absolute contraindications. Symptoms over 3 weeks, an immunocompromised host and multiple previous surgeries are relative.

What predicts success. Symptom duration under 21 days, a CRP under 115 mg/L at presentation, and exchange of the modular components at the same operation.

Biofilm-active therapy. Rifampicin is the biofilm-active drug for staphylococcal infection with retained hardware, and it is never given alone: resistance emerges within 24-48 hours of monotherapy. Start it 2-5 days into IV therapy, which reduces the emergence of resistance, pair it with a companion drug that has good biofilm activity, watch for hepatotoxicity, and check its many drug interactions (warfarin, immunosuppressants).

Suppressive Antibiotic Therapy

When. Lifelong suppression is considered when the infection cannot be resected, when the patient is unfit for revision surgery or declines it, and when a difficult-to-treat organism sits on a retained implant. The goals are to prevent systemic sepsis, maintain function and preserve quality of life; it controls symptoms rather than curing.

With what. The oral agents are chosen against the organism:

• Cefalexin 500 mg BD (MSSA)
• Cotrimoxazole 160/800 mg daily (MRSA)
• Doxycycline 100 mg BD (CoNS)
• Ciprofloxacin 500 mg BD (Gram-negative)

Monitoring is a clinical review every 3-6 months with CRP and ESR trends, and renal function where the agent is nephrotoxic.

Intraoperative tissue sampling. Take at least five samples for PJI diagnosis, each with a separate instrument, away from the skin edges, before any antibiotic is given, and into sterile containers rather than formalin:

• Synovium (two samples from different locations)
• Periprosthetic membrane
• Bone-implant interface tissue
• Capsule

Synovial fluid aspiration. Prepare with chlorhexidine rather than iodine when culture is the aim, use an 18G needle with a 20-50 mL syringe, obtain at least 2 mL, and inoculate directly into blood culture bottles. Allocate the fluid to an EDTA tube for cell count and differential, a plain tube for crystal analysis, a sterile container or blood culture bottle for culture, and alpha-defensin if available.

Debridement is the other half of source control, and its goal changes with the setting.

DAIR Technique

Two-Stage Exchange

First stage. Complete exposure and tissue sampling, removal of all components and cement, debridement of all infected and necrotic tissue, then an antibiotic-loaded cement spacer placed to maintain tension and closure over drains. A static spacer suits the less mobile patient; an articulating spacer preserves motion. The antibiotic load is 3-4 g vancomycin plus 3-4 g tobramycin per 40 g of cement.

Second stage. Reimplantation follows the antibiotic course and the antibiotic holiday described under Postoperative Care, once the repeat aspiration is culture-negative and the CRP and ESR have normalised. Take fresh tissue samples at reimplantation, manage bone loss with augments and cones, preserve soft tissue tension, and consider antibiotic cement for fixation.

Sonication Protocol

Local complications. Untreated infection forms an abscess in 25-30%, and chronic infection develops a sinus tract; the wound may dehisce and the skin necrose. In bone the infection progresses to osteomyelitis with sequestrum formation, pathological fracture, and joint destruction or ankylosis.

Systemic complications. Bacteraemia complicates 15-20% of deep infections and runs on into severe sepsis with organ dysfunction and septic shock, which carries a mortality of 20-40%. Metastatic infection takes the form of infective endocarditis, septic emboli, secondary osteomyelitis at distant sites and septic arthritis in other joints.

Antibiotic toxicity is the price of the long courses these infections need, and each drug has its own monitoring.

DAIR failure. The odds of failure rise with the host and with the infection:

• Rheumatoid arthritis (OR 3.1), diabetes mellitus (OR 1.8), BMI over 35 (OR 2.2), ASA grade 3 or higher (OR 2.5)
• S. aureus infection (OR 2.0), symptom duration over 3 weeks (OR 2.8), a rifampicin-resistant organism, polymicrobial infection

Resistance emergence. Subtherapeutic antibiotic levels, prolonged courses without source control, rifampicin monotherapy and persisting biofilm all select for resistance. The patterns to know are MRSA (mecA, PBP2a), fluoroquinolone resistance from DNA gyrase mutations, and vancomycin-intermediate S. aureus (VISA), which resists by thickening its cell wall.

Complications by strategy. Each treatment trades recurrence against a different set of surgical problems.

The antibiotic course runs in phases, from empiric IV cover through culture-directed narrowing to an oral tail, with the total set by the infection: 6-12 weeks for PJI and 4-6 weeks for native infection. The care is multidisciplinary, between orthopaedics, infectious diseases and allied health.

Outpatient parenteral antibiotic therapy. OPAT suits the medically stable patient with adequate IV access (a PICC line is preferred), who is compliant with the plan and has a safe home environment; a history of intravenous drug use is a relative exclusion. The antibiotic should ideally be once-daily (ceftriaxone, daptomycin, ertapenem), stable at room temperature, and infusable in under 2 hours. Review is weekly: clinical (wound, symptoms), bloods (FBC, renal, LFTs, CRP), vancomycin levels if applicable, and the PICC site. Recurrent fever, new pain or swelling, PICC occlusion or infection, and laboratory deterioration are the triggers for urgent review.

The interval between stages. During the spacer period the patient bears weight protectively (hip or knee), works on range of motion to prevent stiffness, and has VTE prophylaxis throughout; wounds are checked weekly, CRP and ESR trended, and the spacer imaged at 4 weeks to confirm its integrity. Antibiotics run for a minimum of 6 weeks IV or oral with CRP normalisation as the target, followed by a 2-4 week antibiotic holiday, which allows a persisting organism to regrow and declare itself. Reimplantation goes ahead when the repeat aspiration is culture-negative (ideally), the CRP and ESR are normal or near-normal, the wound has healed without drainage and the soft tissue envelope is adequate. A positive culture in the interval means a repeat spacer exchange, an alternative antibiotic regimen, and consideration of suppression.

Success by strategy. The exchange procedures are the reliable ones; DAIR is the gamble that pays when the patient is selected well and the rifampicin combination is used.

Success by organism. Streptococci do best, with cure rates over 90%, because they form less biofilm, have excellent beta-lactam susceptibility and recur less; susceptible CoNS, monomicrobial infection and early treatment also favour cure. The other side of the ledger is S. aureus (cure 60-75% with DAIR), MRSA (50-65%), Enterococcus (40-60%), polymicrobial infection and fungi (cure under 50%). The difficult-to-treat organisms require implant removal for cure and prolonged antibiotic courses, and suppression is considered. Across all strategies, patient selection is the most important determinant of outcome: early presentation (under 3 weeks of symptoms), a susceptible organism, a healthy host without diabetes, rheumatoid arthritis or immunosuppression, a good soft tissue envelope, and rifampicin-susceptible staphylococci.

Function after PJI treatment. The joint that survives infection is not the joint it would have been:

• Hip: Harris Hip Score 65-80, range of motion 10-20° less than a primary THA, a limp in 25-40%, return to function at 6-12 months
• Knee: Knee Society Score 60-75, range of motion typically 90-100° against 115° for a primary, walking aids in 20-30% long-term, worse with each repeated surgery
• Quality of life: SF-36 significantly lower than matched controls, WOMAC 30-40% worse than primary arthroplasty, depression in 25-40%, return to work in 40-60% of working-age patients

Multiple surgeries, prolonged antibiotic courses, chronic pain and social isolation during treatment are what drive the quality-of-life deficit.

Mortality. In a Medicare cohort the 5-year cumulative PJI risk was 1.09% after THA and 1.38% after TKA, but among those who developed one, 5-year survival was only 67.2% after THA and 71.7% after TKA (PMID 29914821). Set against a 5-year mortality of 9-12% after primary THA, that excess is equivalent to some malignancies, and it is the reason prevention and prompt, correct microbiological diagnosis matter more than the infection rate alone suggests. Frailty assessment is critical to treatment planning, and a goals-of-care discussion is appropriate in elderly and comorbid patients.

Recurrence. Early recurrence, within 2 years, points to inadequate debridement, retained biofilm, non-compliance with antibiotics, the wrong antibiotic, or a persistent nidus such as cement or a spacer; it calls for repeat tissue cultures, a different strategy, and mandatory infectious diseases input. Late recurrence, after 2 years, is new haematogenous seeding, reactivation of dormant organisms, or a genuinely new infection. The same organism suggests recurrence or persistence, a different organism a new infection, and genetic typing may be needed to tell them apart.

Choosing empiric therapy. The likely organism is read off the scenario. In an immunocompetent adult with a native joint infection S. aureus is most likely, so flucloxacillin or cefazolin, adding vancomycin if the MRSA risk is greater than 20%. In a prosthetic joint CoNS and S. aureus lead, so vancomycin plus Gram-negative cover (ceftriaxone or cefepime). A diabetic foot is polymicrobial and takes broad-spectrum cover (piperacillin-tazobactam or ertapenem). A child under 4 years needs Kingella and S. aureus covered, which ceftriaxone does; a patient with sickle cell disease needs Salmonella and S. aureus covered, which ciprofloxacin or ceftriaxone does. The full table, with durations, is under Pathogens by Clinical Scenario.

What the organism predicts. Pathogen identity predicts treatment success and the need for surgery. S. aureus PJI fails DAIR (debridement, antibiotics, implant retention) in 30-40% and often needs two-stage exchange. CoNS PJI succeeds with DAIR in 50-60% if caught early (under 3 weeks), and chronic CoNS infection requires removal. Pseudomonas is difficult to eradicate, recurs often and usually needs prolonged combination therapy. Fungi almost always require implant removal and 6-12 months of therapy, and still recur in 20-40%.

Special populations. The immunosuppressed host has an expanded spectrum, opportunistic organisms (atypical mycobacteria, fungi) and more Gram-negatives, and needs broader empiric cover and longer treatment. The diabetic patient has polymicrobial infection in 50-75% of diabetic foot infections, anaerobes in deep infection and often Pseudomonas in chronic wounds. The intravenous drug user carries MRSA rates of 60-70%, Pseudomonas in 15-20%, fungal infection (Candida) and infection at unusual sites (sternoclavicular, sacroiliac, cervical spine); empiric therapy is vancomycin plus an antipseudomonal agent.

Surgical decision-making. The organism shapes the operation as well as the prescription. Biofilm-forming organisms (S. aureus, CoNS) allow DAIR in early infection (under 3 weeks) and demand removal when chronic. Low-virulence organisms such as CoNS may tolerate chronic antibiotic suppression if surgery is contraindicated, whereas high-virulence organisms (S. aureus, Streptococcus) make aggressive surgical debridement essential. Fungi almost always require implant removal for cure, and in polymicrobial infection source control by debridement is as important as the antibiotics.

The local antibiogram. Every institution has its own resistance patterns, and they must guide empiric therapy. Know your hospital's MRSA prevalence (10-60% between regions), its ESBL rate in Enterobacteriaceae, which sets empiric Gram-negative cover, and its VRE prevalence, which sets empiric enterococcal cover. Where MRSA is prevalent, moderate to severe infection gets vancomycin or linezolid cover. Adjust the empiric regimen to local data, then narrow on the cultures.

Infection or mimic. Before committing to a pathogen, exclude the conditions that mimic bone and joint infection. The 2018 scored definition helps separate true PJI from aseptic processes (Parvizi 2018, PMID 29551303).

Empiric therapy must cover the most likely pathogens while the cultures are pending. For most acute orthopaedic infections that means S. aureus, with Gram-negative cover added for the elderly, the diabetic, the immunosuppressed and the urinary or gastrointestinal source. Obtain cultures before starting antibiotics whenever possible; a delay of 2-4 hours for sampling is acceptable.

Fracture-Related Infection: The Consensus Definition

The definition. Just as periprosthetic joint infection has the 2018 ICM/MSIS scored definition, fracture-related infection (FRI), infection associated with a fractured bone with or without internal fixation, has its own AO Foundation / EBJIS consensus definition, which sorts the diagnostic features into two tiers.

• Confirmatory criteria (any one establishes FRI):
  • A fistula, sinus or wound breakdown communicating with the bone or implant
  • Purulent drainage from the wound, or pus at surgery
  • Phenotypically indistinguishable pathogens isolated from two or more separate deep tissue or implant specimens
  • Microorganisms confirmed on histopathology of deep tissue (specific staining)
• Suggestive criteria (prompt further investigation; do not alone confirm):
  • Clinical signs: new redness, warmth, swelling, persistent or increasing pain, fever
  • Radiographic or nuclear signs: peri-implant osteolysis, sequestrum, non-union, periosteal reaction
  • Raised inflammatory markers (CRP, ESR, white cell count), which are non-specific
  • A single positive deep culture, or persistent, increasing or new wound drainage

Management mirrors PJI. Obtain multiple deep tissue cultures, never superficial swabs, withhold antibiotics before sampling when safe, and combine source control (debridement, dead-space and soft-tissue management, and a decision on implant retention versus removal or revision) with pathogen-directed, biofilm-active therapy. Implant retention is reasonable in early, stable FRI with a healing fracture, whereas an infected non-union or a loose implant generally requires removal or revision.