What is the recommended antibiotic regimen for multidrug-resistant Klebsiella bone infections, considering the use of ceftazidime and avibactam with aztreonam?

Treatment of Multidrug-Resistant Klebsiella Bone Infections with Ceftazidime-Avibactam and Aztreonam

Primary Recommendation

For multidrug-resistant Klebsiella bone (musculoskeletal) infections, the antibiotic regimen depends critically on the carbapenemase type: use ceftazidime-avibactam alone for KPC-producing or OXA-48-producing strains, but use ceftazidime-avibactam combined with aztreonam for metallo-β-lactamase (MBL)-producing strains. 1

Treatment Algorithm Based on Carbapenemase Type

Step 1: Identify the Carbapenemase Mechanism

• Ascertain the carbapenemase type before initiating treatment whenever possible through phenotypic testing (mCIM and eCIM) or genotypic PCR testing for MBL genes (blaNDM, blaVIM, blaIMP). 1, 2

• If rapid carbapenemase typing is unavailable and the patient is critically ill, empiric therapy decisions should be based on local epidemiology and prior patient culture history.

Step 2: Select Regimen Based on Carbapenemase Type

For KPC-Producing or OXA-48-Producing Klebsiella:

• Use ceftazidime-avibactam monotherapy at 2.5 g IV every 8 hours as a prolonged 3-hour infusion. 1

• Nearly 100% of KPC-producing and OXA-48-producing strains are susceptible to ceftazidime-avibactam. 1

• Prolonged 3-hour infusions are associated with improved 30-day survival compared to standard infusions. 1, 3

• Time-kill assays demonstrate significant bactericidal efficiency at concentrations of 2×MIC, 4×MIC, and 8×MIC against KPC-2 and OXA-232 carbapenemase-producing K. pneumoniae. 4

For MBL-Producing Klebsiella (NDM, VIM, IMP):

• Use ceftazidime-avibactam 2.5 g IV every 8 hours PLUS aztreonam 2 g IV every 6 hours (total 8 g/day), both administered simultaneously as 2-hour infusions or continuous infusions. 1, 5

• This combination demonstrates synergistic activity in 90% of MBL-producing strains. 4, 2

• The combination achieves significantly lower 30-day mortality (19.2% vs 44%, HR 0.37,95% CI 0.13-0.74) and lower clinical failure rates (HR 0.30,95% CI 0.14-0.65) compared to other antimicrobial therapies including colistin-based regimens. 1

• Administer both drugs simultaneously, NOT staggered - simultaneous administration results in superior bacterial killing and resistance suppression compared to staggered dosing. 5

• Higher aztreonam doses (8 g/day vs 6 g/day) and longer infusion durations (2 hours or continuous infusion vs 30 minutes) result in enhanced bacterial killing. 5

Duration of Therapy for Bone Infections

• For bone and musculoskeletal infections, treat for a minimum of 4-6 weeks, though specific duration data for ceftazidime-avibactam in osteomyelitis is limited. 6, 3

• Continue therapy for at least 48 hours after clinical improvement is evident. 6, 3

• Clinical improvement should be evident within 48-72 hours of initiating appropriate therapy; if not, reassess for source control issues or resistance development. 6, 3

Critical Dosing Considerations

• Adjust doses appropriately for renal function - ceftazidime-avibactam requires dose reduction in renal impairment. 7

• Standard dosing: ceftazidime-avibactam 2.5 g (ceftazidime 2 g + avibactam 0.5 g) IV every 8 hours. 6, 7

• Aztreonam dosing: 2 g IV every 6 hours for optimal MBL coverage (total 8 g/day). 6, 5

Important Clinical Caveats

Resistance Development

• Emergence of ceftazidime-avibactam resistance occurs in 3.8-10.4% of KPC-producing CRE infections, though this is not associated with monotherapy versus combination use. 1

• For MBL-producing strains, the combination with aztreonam provides resistance suppression that monotherapy does not achieve. 5

Source Control

• Adequate surgical debridement and source control are essential for bone infections - antibiotics alone are insufficient without addressing infected hardware, sequestra, or devitalized tissue. 8

• One case report demonstrated cure of recurrent KPC-producing K. pneumoniae soft tissue infection only after removal of infected external fixators combined with ceftazidime-avibactam therapy. 8

Combination Therapy Considerations

• The addition of meropenem to ceftazidime-avibactam may provide additional benefit in severe infections, as avibactam can rescue meropenem activity against KPC-producers. 8

• For MBL-producers, do NOT add polymyxin or fosfomycin routinely - the ceftazidime-avibactam plus aztreonam combination alone demonstrates superior outcomes compared to colistin-containing regimens. 1

Susceptibility Testing Pitfall

• There are currently no standardized antimicrobial susceptibility testing methods or clinical breakpoints approved for the ceftazidime-avibactam plus aztreonam combination. 1

• Testing aztreonam/avibactam by broth microdilution can serve as a reliable surrogate when considering the combination. 9

• Ceftazidime in the triple combination does not affect the in vitro activity of aztreonam/avibactam (MICs remain within one 2-fold dilution). 9

Monitoring Parameters

• Monitor for clinical improvement (resolution of fever, decreased inflammatory markers, improved pain) within 48-72 hours. 6, 3

• Obtain repeat cultures if clinical deterioration occurs to assess for resistance development. 1

• Monitor renal function closely as both agents require dose adjustment in renal impairment. 7