If a culture grows two different organisms, should I prescribe two separate antibiotics or can a single antibiotic regimen cover both?

Management of Polymicrobial Cultures: Single vs. Multiple Antibiotic Approach

When a culture grows two organisms, you should first attempt to identify a single broad-spectrum antibiotic that covers both pathogens based on susceptibility data, rather than reflexively prescribing two separate antibiotics. 1

Initial Empiric Approach

For empiric therapy before culture results:

• Use multidrug therapy (multiple antibiotics) to broaden coverage when treating life-threatening infections or septic shock, as inadequate initial coverage significantly increases mortality. 2, 3
• The Surviving Sepsis Campaign recommends empiric combination therapy for septic shock to ensure at least one effective agent covers the causative pathogen(s). 2
• Each hour of delay in appropriate antimicrobial therapy decreases survival by 7.6%. 3

Definitive Therapy After Culture Results

Once susceptibility data are available, the strategy changes fundamentally:

Single-Agent Coverage When Possible

• Prioritize monotherapy with a single broad-spectrum agent if it covers both organisms based on susceptibility testing. 2, 1
• Piperacillin-tazobactam is frequently effective as monotherapy for polymicrobial infections involving gram-positive, gram-negative, and anaerobic organisms. 1
• The European Respiratory Society recommends de-escalation to single-agent therapy within 3-5 days when clinically appropriate and susceptibilities allow. 2, 1

When Two Antibiotics Are Necessary

You need two separate antibiotics only in these specific situations:

• When no single agent covers both organisms based on susceptibility testing. 4
• For infections with Pseudomonas aeruginosa in septic shock, where combination therapy (typically a beta-lactam plus aminoglycoside or fluoroquinolone) is recommended even after identification. 2, 1
• For extensively drug-resistant (XDR) or pan-drug-resistant (PDR) gram-negative bacteria where combination therapy should be maintained. 2
• When treating polymicrobial infections involving organisms with different resistance patterns that cannot be covered by a single agent. 4

Clinical Decision Algorithm

Step 1: Assess infection severity

• Septic shock or severe sepsis → Start empiric combination therapy immediately 2, 3
• Stable patient → Consider empiric monotherapy if local resistance patterns allow 2

Step 2: Review culture and susceptibility results (Day 3)

• Identify if a single broad-spectrum agent covers both organisms 2, 1
• Check institutional antibiogram for local resistance patterns 3

Step 3: De-escalate when appropriate

• If single agent covers both organisms → Switch to monotherapy 2, 1
• If organisms require different drug classes → Continue two antibiotics 4
• Discontinue combination therapy within first few days if clinical improvement occurs and susceptibilities allow 2

Common Pitfalls to Avoid

• Continuing combination therapy unnecessarily after susceptibilities show single-agent coverage is adequate, which increases toxicity risk and cost without benefit. 2
• Assuming combination therapy is always superior when in vitro synergy does not consistently translate to improved clinical outcomes. 5
• Using two antibiotics from the same class, which provides no additional benefit and increases resistance pressure. 4
• Failing to obtain cultures before starting antibiotics, which limits ability to de-escalate appropriately. 3

Special Considerations

For specific pathogen combinations:

• Bacteroides fragilis + Enterobacter cloacae + Proteus vulgaris: Piperacillin-tazobactam monotherapy provides comprehensive coverage for all three organisms. 1
• Pseudomonas aeruginosa (one of two organisms): Maintain combination therapy if patient has septic shock or healthcare-associated infection, even after identification. 2, 1
• MRSA + gram-negative organism: Requires two agents (anti-MRSA agent plus gram-negative coverage) as no single agent adequately covers both. 1

Duration considerations:

• The European Respiratory Society recommends 7-8 days of therapy for most hospital-acquired and ventilator-associated pneumonia with good clinical response, regardless of whether one or two organisms are present. 2
• Longer courses may be needed if initial empiric therapy was inappropriate or clinical response is suboptimal. 2