What is the role of antibiotic synergy testing in treating Klebsiella infections, particularly those caused by carbapenem-resistant strains?

Antibiotic Synergy Testing in Klebsiella Infections

Antibiotic synergy testing should be performed for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections when drug choices are limited, such as when conventional susceptibility testing shows no effective options, when patients fail to respond to monotherapy after 48-72 hours, or when only toxic agents like colistin remain available. 1, 2

When to Order Synergy Testing

Order synergy testing in these specific clinical scenarios:

• Limited treatment options: When conventional susceptibility testing indicates resistance to all first-line agents or only polymyxins remain susceptible 1
• Clinical failure: Poor response to appropriate monotherapy after 48-72 hours of treatment 2
• Critically ill patients: Severe sepsis or septic shock with multidrug-resistant Klebsiella where optimizing therapy is crucial for survival 2
• Polymyxin-resistant isolates: When even colistin or polymyxin B show elevated MICs (≥4 μg/ml), leaving virtually no therapeutic options 3

The rationale is straightforward: while novel agents like ceftazidime/avibactam and meropenem/vaborbactam are first-line for KPC-producing Klebsiella 1, many institutions lack access to these agents, and resistance can emerge during therapy 4. In these situations, synergy testing becomes essential for identifying effective combination regimens.

Preferred Testing Methods

The checkerboard microdilution method is the gold standard for synergy testing, providing quantitative fractional inhibitory concentration (FIC) indices to evaluate synergy levels. 1, 2

Alternative methods in order of preference:

• Broth disc elution method: Demonstrates 100% sensitivity and 100% specificity compared to modified broth microdilution, making it ideal for resource-constrained laboratories 1
• MIC strip crossing or stacking methods: Show 100% sensitivity and specificity when using MIC test strips, superior to E-test methods 1
• Time-kill assays: Useful for confirming synergy results, particularly for bactericidal activity assessment 5, 6

Critical implementation step: Contact your microbiology laboratory before ordering to confirm availability, turnaround time (typically 48-72 hours), and specify the preferred testing method based on local capabilities 1, 2. Most laboratories do not perform synergy testing routinely, so advance communication is essential.

Most Effective Antibiotic Combinations

For KPC-producing CRKP, the most effective combinations based on synergy testing are:

First-Tier Combinations (Highest Synergy Rates):

• Imipenem + tigecycline: Shows synergy in 88% of CRKP isolates, with bactericidal activity at 24 hours 5
• Meropenem + colistin: Demonstrates synergy in 78% of isolates, though clinical benefit may not always match in vitro results 5
• Double-carbapenem regimen (ertapenem + high-dose meropenem): Shows synergy in 78.6% of isolates by checkerboard method and 100% bactericidal activity at 24 hours, with 80% clinical/microbiological response 6

Second-Tier Combinations:

• Polymyxin B + rifampin: Produces at least 4-fold decrease in polymyxin B MIC at physiologically achievable concentrations, even against polymyxin-resistant strains 3
• Polymyxin B + doxycycline: Similar synergistic effect as rifampin combination 3
• Polymyxin B + tigecycline: Shows 100% synergistic/cumulative effects in some studies 7
• Ceftazidime/avibactam + tigecycline: Demonstrates 87.5% synergistic effects 7

Three-Drug Combinations (For Salvage Therapy):

• Imipenem + tigecycline + fosfomycin: Best clinical efficacy in retrospective analysis 7
• Imipenem + tigecycline + polymyxin: Shows 75% synergistic effects 7

Critical Caveats and Pitfalls

Major limitation: In vitro synergism does not always translate to clinical benefit. One study showed that colistin-meropenem synergy in vitro failed to improve outcomes in severe carbapenem-resistant Gram-negative infections, highlighting the importance of clinical judgment over laboratory results alone 1, 2

Avoid these common mistakes:

• Do not delay appropriate therapy waiting for synergy results: If novel agents (ceftazidime/avibactam, meropenem/vaborbactam) are available and the isolate is KPC-producing, start these immediately rather than waiting for synergy testing 1
• Do not use levofloxacin + polymyxin B: This combination shows no synergy against CRKP 5
• Monitor for nephrotoxicity: Polymyxin and aminoglycoside combinations require therapeutic drug monitoring to optimize efficacy while minimizing kidney injury 2, 4
• Watch for resistance emergence: Particularly with ceftazidime/avibactam (resistance rates 0-12.8%) and during combination therapy 4, 2

Practical Algorithm for Implementation

Step 1: Identify carbapenem resistance mechanism through rapid molecular testing (KPC, MBL, OXA-48) 1

Step 2: If KPC-producing and novel agents available → Use ceftazidime/avibactam or meropenem/vaborbactam as monotherapy (STRONG recommendation) 1

Step 3: If novel agents unavailable OR patient failing monotherapy after 48-72 hours OR polymyxin-resistant → Order synergy testing 1, 2

Step 4: While awaiting synergy results (48-72 hours), initiate empiric combination based on local susceptibility patterns:

• If polymyxin-susceptible: Meropenem + colistin or imipenem + tigecycline 5
• If polymyxin-resistant: Consider double-carbapenem regimen (ertapenem + meropenem) 6

Step 5: Adjust therapy based on synergy results and clinical response, with therapeutic drug monitoring for nephrotoxic agents 2, 4