Can azithromycin (Zithromax) and levofloxacin (Levaquin) be used in combination?

Combination of Azithromycin and Levofloxacin is Not Recommended

The combination of azithromycin and levofloxacin is not recommended as there is no evidence supporting clinical benefit of using these two antibiotics together, and this combination may increase the risk of adverse effects and antimicrobial resistance. 1

Rationale Against Combined Use

Lack of Clinical Benefit

• Current guidelines from medical societies do not support using these two antibiotic classes (macrolides and fluoroquinolones) together 1
• The WHO's Essential Medicines guidelines and AWARE recommendations do not endorse this combination 2
• There is no evidence that combining these two antibiotics provides additional clinical benefit over using either one alone

Potential Risks

• Increased risk of adverse effects, particularly:
  • QT interval prolongation (both medications can prolong QT) 3
  • Gastrointestinal side effects
  • Central nervous system complications 4
• Higher likelihood of developing antimicrobial resistance 1
• Unnecessary increased healthcare costs 1

Appropriate Antibiotic Combinations When Needed

When combination therapy is clinically indicated, guidelines typically recommend:

1. β-lactam plus macrolide (preferred combination for hospitalized non-ICU patients with community-acquired pneumonia) 2

   • Example: Ceftriaxone + azithromycin

2. β-lactam plus fluoroquinolone (alternative combination) 2

   • Example: Ceftriaxone + levofloxacin

Evidence from Clinical Studies

• A retrospective nationwide database analysis found no significant differences in 28-day mortality or in-hospital mortality between azithromycin plus β-lactam versus levofloxacin plus β-lactam for severe community-acquired pneumonia 5
• A prospective randomized trial comparing levofloxacin monotherapy with ceftriaxone plus azithromycin found similar efficacy in treating hospitalized patients with community-acquired pneumonia 4
• Neither study evaluated the combination of azithromycin and levofloxacin together

Special Circumstances

In specific clinical scenarios, these antibiotics are used individually or in other combinations:

• For travelers' diarrhea: Azithromycin is preferred for dysentery or febrile diarrhea 2
• For community-acquired pneumonia: Either a respiratory fluoroquinolone alone or a β-lactam plus macrolide combination is recommended 2
• For sarcoidosis: The CLEAR regimen (Concomitant Levofloxacin, Ethambutol, Azithromycin, and Rifampin) is mentioned but did not reach consensus recommendation 2
• For gonococcal infections: Ceftriaxone plus azithromycin is recommended, not levofloxacin plus azithromycin 2

Conclusion

When antibiotic therapy is indicated, clinicians should follow evidence-based guidelines that recommend either monotherapy with an appropriate agent or specific combinations that have proven clinical benefit. The combination of azithromycin and levofloxacin specifically is not supported by current evidence or guidelines and may increase risks without providing additional benefit.