What is the management guideline for a patient with periprosthetic joint infection (PJI) due to Enterobacteriaceae sensitive only to Amikacin?

Management of Periprosthetic Joint Infection with Amikacin-Only Sensitive Enterobacteriaceae

For this challenging scenario of PJI with multidrug-resistant Enterobacteriaceae sensitive only to amikacin, you must pursue surgical intervention combined with intravenous amikacin therapy, recognizing that aminoglycoside monotherapy is suboptimal and requires careful consideration of combination therapy and prolonged treatment duration.

Surgical Management Decision

The surgical approach depends critically on timing and clinical presentation 1:

Debridement and Implant Retention (DAIR) criteria 1, 2:

• Duration of symptoms <3 weeks AND
• Prosthesis age <30 days AND
• Well-fixed prosthesis on imaging AND
• Absence of sinus tract AND
• Organism susceptible to oral biofilm-active agents

If DAIR criteria are NOT met (which is likely given amikacin-only susceptibility), proceed with prosthesis removal via two-stage exchange, which is the gold standard in North America for established PJI 2, 3.

During surgery, obtain 3-6 intraoperative tissue samples for aerobic and anaerobic culture 1, 3.

Antimicrobial Therapy

Acute Treatment Phase

Intravenous amikacin dosing 4:

• Loading dose: 15 mg/kg/day divided into 2-3 equal doses (7.5 mg/kg q12h or 5 mg/kg q8h)
• Maximum daily dose: 1.5 grams/day
• Duration: 4-6 weeks following definitive surgical intervention 1

Critical monitoring requirements 4:

• Measure peak serum concentrations (30-90 minutes post-injection): keep <35 mcg/mL
• Measure trough concentrations (just before next dose): keep <10 mcg/mL
• Monitor renal function daily with serum creatinine and creatinine clearance
• Assess auditory and vestibular function during treatment
• Ensure adequate hydration to minimize renal tubular irritation

Combination Therapy Considerations

Given the limitations of aminoglycoside monotherapy for biofilm infections 5:

Consider adding a second agent if any susceptibility exists 1, 5:

• The IDSA guidelines note that addition of aminoglycoside is optional for Pseudomonas and Enterobacter species, suggesting combination therapy may be beneficial 1
• For MDR gram-negative PJI, combination therapy is preferred, particularly for DAIR procedures 5
• If the organism shows intermediate susceptibility to any β-lactam, consider high-dose extended/continuous infusion β-lactam in combination with amikacin 5

Renal Dose Adjustment

For impaired renal function 4:

• Calculate dosing interval: multiply serum creatinine (mg/dL) by 9 to get hours between doses
• Example: If creatinine = 2 mg/dL, give 7.5 mg/kg every 18 hours
• Alternatively, reduce dose proportionally: Maintenance dose = (observed CrCl/normal CrCl) × loading dose, given q12h

Duration of Therapy

Based on surgical approach 1:

• After DAIR: 4-6 weeks IV therapy 1
• After two-stage exchange: 4-6 weeks IV therapy after reimplantation 1
• Between stages of two-stage exchange: Antibiotic-free interval of 2-6 weeks is typical, though practices vary

Chronic Suppression

Following completion of IV therapy 1:

The IDSA guidelines recommend indefinite chronic oral antimicrobial suppression for Enterobacteriaceae 1:

• Preferred: Cotrimoxazole 1 double-strength tablet PO twice daily 1
• Alternative: β-lactam oral therapy based on in vitro susceptibilities 1

However, there is controversy: Chronic suppression after treatment of gram-negative bacilli was not unanimously recommended by the IDSA panel 1.

Critical Pitfalls to Avoid

Nephrotoxicity and ototoxicity 4:

• Amikacin is potentially nephrotoxic, ototoxic, and neurotoxic 4
• Avoid concurrent use of other nephrotoxic or ototoxic agents 4
• Increased nephrotoxicity occurs with concomitant cephalosporins 4
• Irreversible deafness and renal failure have been reported 4

Drug interactions 4:

• In vitro mixing of aminoglycosides with β-lactams causes significant mutual inactivation 4
• Administer by separate routes if combination therapy is used 4
• This inactivation is clinically significant in patients with severely impaired renal function 4

Inadequate surgical debridement 5:

• Aminoglycoside monotherapy has poor biofilm penetration 5
• Success depends heavily on adequate surgical source control 6, 5
• DAIR has high failure rates with MDR gram-negative organisms 5, 7

Premature discontinuation 4:

• Treatment duration of 7-10 days is typical for other infections, but PJI requires 4-6 weeks 1
• If no clinical response occurs within 3-5 days, recheck susceptibilities 4

Multidisciplinary Approach

Mandatory consultations 1, 2, 3:

• Orthopedic surgery for surgical decision-making 1, 3
• Infectious disease for antimicrobial optimization 1, 2, 3
• Consider plastic surgery if soft tissue coverage is needed 1

The ultimate surgical decision should be made by the orthopedic surgeon with appropriate infectious disease consultation 1.

Monitoring During Treatment

Clinical monitoring 4:

• Daily assessment of renal function (creatinine, BUN, urine output) 4
• Watch for signs of renal irritation (casts, white/red cells, albumin in urine) 4
• Auditory and vestibular function assessment 4
• If azotemia increases or progressive oliguria occurs, stop treatment 4

Laboratory monitoring 1:

• Serial inflammatory markers (CRP is most sensitive) 8
• Amikacin peak and trough levels 4
• Adjust dosage based on levels and renal function 4

Special Considerations for MDR Gram-Negative PJI

This represents a particularly challenging scenario 5, 7:

• MDR gram-negative PJI has worse outcomes than susceptible organisms 5
• Two-stage exchange provides higher cure rates than DAIR for MDR organisms 5, 7
• Consider outpatient parenteral antibiotic therapy (OPAT) to minimize hospitalization while ensuring adequate treatment 5
• The lack of oral biofilm-active options (fluoroquinolone resistance) makes this case especially difficult 5