Keflex (Cephalexin) Coverage of Gram-Negative Rods
Keflex has limited and unreliable activity against gram-negative rods and should not be relied upon as primary therapy when gram-negative coverage is needed. 1
Spectrum Against Gram-Negative Organisms
Organisms with Documented Activity
According to the FDA label, cephalexin demonstrates activity against only a narrow subset of gram-negative bacteria: 1
- Escherichia coli - susceptible strains
- Klebsiella pneumoniae - susceptible strains
- Proteus mirabilis - susceptible strains
- Haemophilus influenzae - susceptible strains
- Moraxella catarrhalis - susceptible strains
Critical Gaps in Coverage
Cephalexin has NO activity against: 1
- Most strains of Enterobacter species
- Morganella morganii
- Proteus vulgaris
- Pseudomonas species (completely inactive)
- Acinetobacter calcoaceticus
Clinical Guideline Recommendations
When Cephalexin Is Appropriate
IDSA guidelines list cephalexin only for mild diabetic foot infections where the expected pathogens are primarily gram-positive (Staphylococcus aureus and Streptococcus species), with the caveat that it requires QID dosing and is inexpensive. 2
When Cephalexin Is Inadequate
For infections requiring reliable gram-negative coverage, IDSA guidelines explicitly recommend alternative agents: 2
- Moderate-to-severe infections with Enterobacteriaceae: Use levofloxacin, ceftriaxone, ertapenem, or ampicillin-sulbactam 2
- Animal bite wounds: First-generation cephalosporins (including cephalexin) "miss P. multocida and anaerobes" - amoxicillin-clavulanate is preferred 2
- Human bite wounds: Cephalexin "misses E. corrodens and gram-negative anaerobes" 2
Comparative Potency Data
Historical research demonstrates cephalexin is the weakest among first-generation cephalosporins against gram-negative rods: 3
- Against E. coli, the relative potency in decreasing order is: cefazolin > cephaloridine > cephalexin > cephalothin 3
- Only 49.1% of Staphylococcus aureus strains were suppressed by cephalexin at ≤3.13 mcg/mL, compared to >90% for other first-generation agents 3
Clinical Pitfalls to Avoid
Never use cephalexin when: 4, 5
- Gram-negative rods are the suspected or confirmed pathogen requiring definitive therapy
- Polymicrobial infections involving gram-negative organisms are present
- Pseudomonas or other non-fermenting gram-negative rods are possible
- Hospital-acquired infections are suspected (high risk of resistant gram-negatives) 5
If gram-negative coverage is uncertain but needed, choose agents with broader and more reliable activity: 2
- Oral options: Levofloxacin, amoxicillin-clavulanate, or moxifloxacin
- Parenteral options: Ceftriaxone, ertapenem, or piperacillin-tazobactam
Bottom Line for Clinical Practice
While the FDA label lists some gram-negative organisms in cephalexin's spectrum, this does not translate to reliable clinical coverage. 1 The drug is positioned by major guidelines exclusively for gram-positive infections or very mild community-acquired infections where gram-positive organisms predominate. 2 When gram-negative rods are documented or suspected, select an agent with proven broader gram-negative activity rather than risking treatment failure with cephalexin.