What is the recommended approach for antibiotic synergy testing in patients with Klebsiella infections?

Antibiotic Synergy Testing in Klebsiella Infections

Antibiotic synergy testing should be performed selectively for Klebsiella infections when drug choices are limited—specifically when patients fail monotherapy, conventional susceptibility testing shows no effective options, or treatment options are severely restricted, particularly in carbapenem-resistant Klebsiella pneumoniae (CRKP) cases. 1

When to Order Synergy Testing

Synergy testing is not routinely indicated for all Klebsiella infections but becomes critical in specific clinical scenarios 1:

• Poor response to initial monotherapy after 48-72 hours of appropriate antibiotics 1
• Carbapenem-resistant isolates where conventional susceptibility testing reveals limited or no treatment options 1
• Multidrug-resistant (MDR) Klebsiella infections in critically ill patients, particularly those with hypotension or septic shock 2, 3
• Severe infections including bloodstream infections, ventilator-associated pneumonia, or deep-seated infections where treatment failure would be catastrophic 4, 3

Preferred Testing Methods (In Order of Priority)

Since synergy testing is not routinely performed in most clinical microbiology laboratories, you must communicate directly with your laboratory to ensure appropriate methodology 1:

First Choice: Checkerboard Method

• Uses fractional inhibitory concentration (FIC) as a quantitative index to evaluate synergy level 1
• Most frequently applied standard method with highest accuracy 1
• Limitation: Complex procedure and time-consuming, which may delay results 1

Second Choice: Broth Disc Elution Method

• Demonstrates 100% sensitivity and 100% specificity when compared to modified broth microdilution 1
• Particularly valuable in resource-constrained laboratories due to lower complexity 1
• Provides rapid, reproducible results with high categorical agreement 1

Third Choice: MIC Strip Crossing or Stacking Methods

• MIC test strips (MTS) show 100% sensitivity and 100% specificity 1
• E-test strip crossing shows 95.8% sensitivity, 100% specificity 1
• E-test strip stacking shows 87.5% sensitivity, 100% specificity 1
• Avoid conventional disc stacking method: only 42.7% sensitivity despite 100% specificity 1

Alternative: Time-Kill Curve Assay

• Highly accurate but complex and time-consuming, limiting clinical application 1
• Reserved for research settings or when other methods are unavailable 1

Most Effective Antibiotic Combinations Based on Evidence

For Carbapenem-Resistant Klebsiella pneumoniae (CRKP)

Polymyxin-based combinations show the strongest evidence for synergy 1:

• Colistin + Meropenem: 12.5% mortality when used in combination versus 66.7% with colistin monotherapy 3
• Colistin + Amikacin: 70% synergism rate in biofilm-producing isolates 4
• Colistin + Tigecycline: Effective combination with enhanced bactericidal activity 1, 5

Carbapenem-based combinations despite resistance 1:

• Polymyxin + Carbapenem + Tigecycline/Fosfomycin/Amikacin shows considerable synergistic effect 1
• Combination therapy reduces 28-day mortality to 13.3% versus 57.8% with monotherapy 3

Amoxicillin/clavulanate combinations for planktonic bacteria 4:

• Amoxicillin/clavulanate + Meropenem: 60-70% synergism 4
• Amoxicillin/clavulanate + Colistin: 60-70% synergism 4
• Amoxicillin/clavulanate + Amikacin: 60-70% synergism 4

For Non-Carbapenem-Resistant Klebsiella

Beta-lactam + Aminoglycoside combinations 2:

• Indicated for severely ill patients with hypotension (24% mortality with combination vs. 50% with monotherapy) 2
• Monotherapy is sufficient for less severely ill patients (immunocompetent, urinary tract source, hemodynamically stable) 2

Critical Implementation Considerations

Laboratory Communication

• Contact your microbiology laboratory before ordering synergy testing to confirm availability and turnaround time 1
• Specify the testing method based on local laboratory capabilities 1
• Request testing against specific antibiotic combinations based on available formulary agents 1

Patient Selection Criteria

• Perform synergy testing in critically ill patients, those with CRKP bloodstream infections, or ventilator-associated pneumonia 4, 3
• Skip synergy testing in uncomplicated urinary tract infections or hemodynamically stable patients where monotherapy is appropriate 2

Therapeutic Drug Monitoring

• Perform TDM for polymyxins and aminoglycosides when using synergy-guided combination therapy 1
• Critical for narrow therapeutic index drugs to optimize efficacy and minimize nephrotoxicity 1, 6

Important Caveats and Pitfalls

In Vitro-In Vivo Discordance

• One study showed that in vitro synergism between colistin and meropenem did not translate into clinical benefit in severe CRGNB infections 1
• Synergy testing results should guide but not dictate therapy—clinical judgment remains paramount 1

Resistance Development

• Monitor for emergence of resistance during combination therapy, particularly with Acinetobacter and Klebsiella 7
• Obtain repeat cultures if clinical deterioration occurs despite synergy-guided therapy 7

Mortality Considerations

• CRKP infections carry inherently high mortality regardless of therapy 8
• Combination therapy is independently associated with survival (odds ratio 0.07, P=0.02) compared to monotherapy 3
• Newer agents like ceftazidime/avibactam show significantly lower mortality (18.3%) compared to older regimens (40.8%, P=0.005) 8

When Synergy Testing May Not Help

• Monotherapy with newer beta-lactam/beta-lactamase inhibitor combinations (ceftazidime/avibactam, meropenem/vaborbactam) may be sufficient for non-severe infections without requiring synergy testing 8
• Local epidemiology and rapid molecular testing for carbapenemase types should guide empiric therapy while awaiting synergy results 8