›Cefepime 2 g intravenously every 8 hours
›Or piperacillin-tazobactam 4.5 g intravenously every 6 to 8 hours
›Or meropenem 1 g intravenously every 8 hours when extended-spectrum beta-lactamase organisms are likely
›Adjust every dose for renal function and watch for cefepime neurotoxicity in renal failure
›Beta-lactam allergy
›Aztreonam 2 g intravenously every 8 hours provides gram-negative cover, a monobactam with negligible cross-reactivity in severe penicillin allergy, combined with vancomycin for gram-positives
›Add ciprofloxacin 400 mg intravenously every 8 to 12 hours only if aztreonam is unavailable, recognizing its QT and tendon risks
›Arrange formal allergy assessment during admission to widen future options
›De-escalation
›Narrow to organism-directed therapy as soon as cultures and susceptibilities return
›Stop empiric gram-negative cover if cultures grow only a susceptible gram-positive organism
›Antifungal cover is not routine and is added only for documented candidal infection or strong risk factors
Organism-directed therapy
›Staphylococci
›Meticillin-susceptible Staphylococcus aureus: cefazolin 2 g intravenously every 8 hours, or nafcillin 2 g intravenously every 4 hours
›Use cefazolin 3 g intravenously every 8 hours if body weight is above 120 kg
›Add rifampin once the wound is dry and any bacteremia has cleared when the implant is retained
›Vancomycin is inferior to a beta-lactam for susceptible strains and is reserved for true allergy
›Meticillin-resistant Staphylococcus aureus: vancomycin dosed to target as above, or daptomycin 8 to 10 mg/kg intravenously every 24 hours with weekly creatine kinase
›Coagulase-negative staphylococci and Cutibacterium acnes are treated as true pathogens when criteria are met, not dismissed as contaminants
›Streptococci and enterococci
›Streptococci: penicillin G 4 million units intravenously every 4 hours, or ceftriaxone 2 g intravenously every 24 hours
›Enterococci: ampicillin 2 g intravenously every 4 hours, with vancomycin as the alternative in penicillin allergy
›Add an aminoglycoside or ceftriaxone for synergy only on infectious diseases advice
›Gram-negative bacilli
›Susceptible Enterobacterales and Pseudomonas aeruginosa: an intravenous beta-lactam guided by susceptibilities, such as cefepime 2 g intravenously every 8 hours
›A fluoroquinolone such as ciprofloxacin 750 mg orally every 12 hours has high bioavailability and biofilm activity and supports oral step-down
›Confirm two active agents for Pseudomonas in severe infection per local guidance
›Culture-negative infection
›Continue vancomycin plus a beta-lactam such as ceftriaxone 2 g intravenously every 24 hours or cefepime pending the surgical specimens
›Re-culture off antibiotics where feasible and send extended cultures and molecular testing
›Reconsider mycobacterial, fungal, and Cutibacterium causes and the possibility of a non-infectious diagnosis
Rifampin and biofilm-active adjuncts
›Role of rifampin
›Rifampin is added for staphylococcal infection when the implant is retained, because it penetrates biofilm and acts on adherent bacteria
›Dose 300 to 450 mg orally or intravenously every 12 hours, always combined with a second active antistaphylococcal agent
›Never give rifampin as monotherapy; resistance emerges within days
›Timing and prerequisites
›Start only once the surgical wound is dry and drainage has stopped and any bacteremia has cleared, typically after debridement
›Pair it with an agent of reliable oral bioavailability such as a fluoroquinolone for the oral phase
›Do not start rifampin while blood cultures remain positive
›Interactions and adverse effects
›Potent cytochrome P450 inducer: it lowers levels of warfarin, direct oral anticoagulants, many antiretrovirals, azoles, calcineurin inhibitors, oral contraceptives, and statins
›Hepatotoxicity, gastrointestinal intolerance, cytopenias, and harmless orange discoloration of secretions
›Review the full medication list with pharmacy before the first dose
Surgical management options
›Debridement, antibiotics, and implant retention
›Considered for symptom duration under about 3 to 4 weeks, a well-fixed implant, intact soft tissues, no sinus tract, and a susceptible organism
›Includes exchange of modular parts such as the polyethylene liner and thorough lavage
›Followed by pathogen-directed therapy, commonly with a biofilm-active oral phase
›Exchange arthroplasty
›Two-stage exchange with an antibiotic-loaded cement spacer is the most common approach for chronic infection in many centers
›One-stage exchange is used in selected patients with a known susceptible organism and good soft tissue and bone stock
›Antibiotic-loaded cement typically carries vancomycin with an aminoglycoside such as tobramycin, delivered locally by the surgeon
›Salvage and non-operative paths
›Resection arthroplasty, arthrodesis, or amputation for uncontrolled infection or failed exchange
›Chronic oral suppressive therapy after debridement for patients who are not surgical candidates
›Palliative approach with shared decision-making when the burden of repeated surgery is unacceptable
Analgesia, antipyretics and supportive care
›Analgesia
›Acetaminophen 1 g intravenously or orally every 6 hours, maximum 4 g in 24 hours, reduced to 3 g in 24 hours in low body weight, frailty, hepatic impairment, or high alcohol intake
›Opioids sparingly and titrated: morphine 0.05 to 0.1 mg/kg intravenously every 3 to 4 hours as needed, or oxycodone 5 mg orally every 4 to 6 hours as needed, with reduced doses and closer monitoring in older adults
›Avoid non-steroidal anti-inflammatory drugs in sepsis, acute kidney injury, and the immediate preoperative period; if used for a coexisting crystal flare in a well patient with normal renal function, ibuprofen 400 mg orally every 6 to 8 hours for the shortest course
›Antipyretics and route cautions
›Acetaminophen as above is the preferred antipyretic
›Avoid intramuscular injections into or near the affected limb and near the surgical field
›Regional nerve blocks only in coordination with anesthesia and surgery, and not when therapeutic anticoagulation or urgent surgery is planned
›Glycemic and metabolic support
›Target blood glucose 7.8 to 10 mmol/l in the acutely ill inpatient, accepting a looser target in frail older adults and in hypoglycemia unawareness, and treat a value below 3.9 mmol/l with oral or intravenous dextrose
›Correct hypovolemia and electrolyte deficits, checking potassium in mmol/l, particularly with acute kidney injury and vancomycin
›Nutrition review and correction of vitamin D and protein deficits as part of surgical optimization
›Immobilization and prophylaxis
›Splint or brace the painful joint and keep it non-weight-bearing until orthopedic review
›Update tetanus immunization when a sinus tract or open wound is present
›Pressure area care and early physiotherapy planning
VTE prophylaxis and anticoagulation management
›Balancing thrombosis and bleeding
›Arthroplasty patients are at high venous thromboembolism risk, heightened further by immobility and sepsis
›Imminent debridement and neuraxial anesthesia raise bleeding and epidural hematoma concern
›Decide prophylaxis timing jointly with the surgical team
›Regimens
›Mechanical prophylaxis with intermittent pneumatic compression from arrival
›Pharmacologic prophylaxis with enoxaparin 40 mg subcutaneously once daily, or 30 mg subcutaneously every 12 hours, reduced to 30 mg subcutaneously once daily if creatinine clearance is below 30 ml/min, held 12 hours before surgery
›Unfractionated heparin 5000 units subcutaneously every 8 to 12 hours when rapid reversibility is preferred
›Managing existing anticoagulation
›Hold direct oral anticoagulants and warfarin once operative intervention is anticipated and document the last dose
›When urgent surgery is required, reverse warfarin with four-factor prothrombin complex concentrate plus intravenous vitamin K 5 to 10 mg, and reverse a direct oral anticoagulant with its specific agent or four-factor prothrombin complex concentrate per local protocol
›Remember that rifampin started later lowers anticoagulant levels and requires dose review and closer monitoring
Monitoring and treatment failure
›Routine response monitoring
›C-reactive protein trend, expecting a fall within 3 to 5 days of effective source control and antibiotics
›Daily renal and hepatic panel, vancomycin levels at steady state and daily during acute kidney injury, and weekly creatine kinase on daptomycin
›Repeat blood cultures every 24 to 48 hours until documented clearance in Staphylococcus aureus bacteremia, then arrange echocardiography
›ECG and electrolyte surveillance
›Baseline ECG for the QT interval before starting fluoroquinolones, azole antifungals, ondansetron, or other QT-prolonging drugs, and avoid stacking them
›Repeat potassium and magnesium in mmol/l during acute kidney injury and vancomycin therapy, and check the ECG for peaked T waves or QRS widening if potassium rises
›Correct hypokalemia and hypomagnesemia to reduce arrhythmia risk with QT-prolonging agents
›Signs therapy is not working
›Persistent fever or positive cultures beyond 72 hours, a rising C-reactive protein after an initial fall, or worsening local findings
›Consider inadequate source control with an undrained collection, biofilm on retained hardware that requires exchange rather than debridement, an unrecognized or resistant organism including fungi and mycobacteria, and antibiotic underdosing
›Reconsider a non-infectious diagnosis such as adverse local tissue reaction or crystal disease
›Actions on failure
›Repeat cross-sectional imaging and re-aspiration, or return to the operating room for further debridement or implant removal
›Transesophageal echocardiography and an endovascular source search in persistent Staphylococcus aureus bacteremia
›Infectious diseases review of dosing, drug levels, and the possibility of combination or suppressive therapy
›Iatrogenic harms: review every routine intervention
›Empiric antibiotics: in the stable patient they sterilize synovial and tissue cultures and forfeit the diagnosis that drives 6 or more weeks of therapy; withhold until deep samples are taken
›Intra-articular corticosteroid: never inject a prosthetic joint; it seeds the implant and worsens infection
›Arthrocentesis or surgery through infected skin: passing instruments through cellulitis or a superficial abscess can inoculate an uninfected prosthesis
›Fluid loading: needed for sepsis but give in aliquots with reassessment and temper it in dialysis dependence, heart failure, and pulmonary hypertension to avoid pulmonary edema
›Oxygen: treat hypoxemia only, target SpO2 94 to 98 percent, or 88 to 92 percent in chronic hypercapnic lung disease, and avoid routine hyperoxia
›Vasopressors: do not use them to substitute for inadequate volume resuscitation or unaddressed source control
›Sedation and intubation: reserve for standard airway or procedural indications; frail older adults are prone to hypotension and delirium, and rifampin later induces the metabolism of many sedatives
›Analgesia: avoid non-steroidal anti-inflammatory drugs in sepsis, acute kidney injury, and before surgery, avoid intramuscular injection near the joint, and limit opioids in older adults
›Anticoagulation: balance high venous thromboembolism risk against imminent surgery and neuraxial anesthesia; hold therapeutic agents preoperatively and reverse if surgery is urgent
›Fibrinolysis and intra-aortic balloon counterpulsation: not indicated for this condition; if considered for an unrelated reason, weigh the bleeding risk against impending orthopedic surgery and the infection risk of groin access near a lower-limb prosthesis
›Nephrotoxin stacking: vancomycin plus piperacillin-tazobactam plus iodinated contrast plus non-steroidal anti-inflammatory drugs compounds acute kidney injury; space and substitute where possible