What Bacteria Are Resistant to Cefazolin? A Comprehensive Guide

October 12, 2025 •

3 min read

As a first-generation cephalosporin, cefazolin is a widely used antibiotic for treating infections from susceptible bacteria and for surgical prophylaxis. However, its effectiveness is limited by various pathogens and evolving resistance mechanisms, making it crucial to understand exactly what bacteria are resistant to cefazolin. For instance, methicillin-resistant Staphylococcus aureus (MRSA) is uniformly resistant to this drug.

Quick Summary

A diverse range of bacteria exhibit resistance to cefazolin, from naturally resistant Gram-negative organisms like Enterobacter and Pseudomonas to acquired resistance in Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). These resistance mechanisms, including beta-lactamase production and altered cell wall targets, significantly impact clinical treatment decisions.

Key Points

MRSA Resistance: Methicillin-resistant Staphylococcus aureus (MRSA) is uniformly resistant to cefazolin due to altered penicillin-binding proteins.
Natural Gram-Negative Resistance: Many Gram-negative bacteria, including Enterobacter spp., Pseudomonas, Morganella, and Serratia, are naturally resistant to cefazolin.
Beta-Lactamase Production: Some bacteria, particularly Gram-negative ones, become resistant by producing enzymes like AmpC and ESBLs that degrade cefazolin.
Atypical Bacteria and Enterococcus: Atypical organisms (Mycoplasma, Chlamydia) and Enterococcus species are not susceptible to cefazolin.
Clinical Failures from Inoculum Effect: A high bacterial load of certain AmpC-producing bacteria can cause cefazolin treatment failure, even if standard lab tests indicate susceptibility.
Surgical Prophylaxis Concerns: In settings with high rates of resistant Gram-negative bacteria, cefazolin may not be an appropriate choice for surgical prophylaxis.
Alternative Antibiotics Required: For infections involving cefazolin-resistant pathogens, alternative antibiotics like vancomycin or later-generation cephalosporins are necessary.

Cefazolin, a first-generation cephalosporin, is a beta-lactam antibiotic effective against many Gram-positive bacteria, including methicillin-susceptible Staphylococcus aureus (MSSA) and various Streptococcus species. It also shows limited activity against some Gram-negative organisms like E. coli and Proteus mirabilis. Understanding bacteria that are resistant to cefazolin is essential due to the rise of antimicrobial resistance.

Naturally Resistant Bacteria

Certain bacteria are inherently resistant to cefazolin due to their intrinsic properties, rendering the antibiotic ineffective. Many naturally resistant Gram-negative bacilli produce chromosomal beta-lactamases like AmpC, which can degrade cefazolin.

Gram-Negative Organisms

Key Gram-negative bacteria with natural resistance include:

Enterobacter spp.: Resistant due to inducible chromosomal AmpC beta-lactamase.
Morganella morganii: Typically considered resistant.
Pseudomonas spp.: Universally resistant.
Proteus vulgaris and Providencia spp.: Most indole-positive Proteus and all Providencia are resistant.
Serratia spp.: Also typically resistant.

Atypical and Other Non-Susceptible Organisms

Other pathogens naturally resistant to cefazolin include:

Atypical Bacteria: Lack the peptidoglycan cell wall target (e.g., Mycoplasma, Chlamydia).
Anaerobic Bacteria: Cefazolin lacks sufficient activity.
Enterococcus spp.: Intrinsically resistant.

Acquired Resistance

Some bacteria can develop resistance to cefazolin through genetic changes or gene transfer.

Methicillin-Resistant Staphylococcus Aureus (MRSA)

MRSA is a significant example of acquired resistance and is uniformly resistant to cefazolin. This resistance is caused by a modified penicillin-binding protein (PBP2a), encoded by the mecA gene, which prevents cefazolin from binding effectively.

Extended-Spectrum Beta-Lactamase (ESBL) Producers

Certain Gram-negative bacteria like E. coli and Klebsiella pneumoniae can acquire genes for ESBLs, enzymes that inactivate many cephalosporins. While many strains remain susceptible, ESBL production can lead to acquired resistance, noted in studies of infections like prosthetic joint infections.

Mechanisms of Cefazolin Resistance

Several mechanisms explain bacterial resistance to cefazolin.

Beta-Lactamase Production

Bacteria produce beta-lactamase enzymes that break down cefazolin. This includes chromosomal AmpC, inducible in many naturally resistant Gram-negative bacteria, and acquired plasmid-mediated ESBLs, often seen in E. coli and Klebsiella.

Target Site Modification

Bacteria like MRSA modify their penicillin-binding proteins (PBPs), the target of cefazolin, preventing the antibiotic from inhibiting cell wall synthesis.

The Cefazolin Inoculum Effect

High bacterial density can lead to functional resistance in some bacteria that appear susceptible in standard tests, particularly AmpC-producing Enterobacteriaceae. This inoculum effect can result in poor clinical outcomes with cefazolin treatment.

Comparison of Cefazolin Susceptibility


Bacterial Category	Examples of Susceptible Strains	Examples of Resistant Strains	Primary Resistance Mechanism
Gram-Positive	MSSA, Streptococcus pyogenes	MRSA, Enterococcus spp.	Altered PBP (MRSA), intrinsic resistance (Enterococcus)
Gram-Negative	E. coli, Proteus mirabilis (non-ESBL)	Enterobacter spp., Pseudomonas spp., ESBL-producing E. coli, Morganella morganii	Chromosomal AmpC, ESBLs, reduced penetration
Atypical	N/A	Mycoplasma, Chlamydia	Lack of cell wall target
Anaerobic	N/A	Many species	Intrinsic resistance

Clinical Implications of Resistance

Cefazolin resistance has significant clinical consequences.

Surgical Prophylaxis: Resistance in Gram-negative bacteria can make cefazolin unsuitable for prophylaxis.
Treatment Failure: Using cefazolin against resistant organisms like MRSA or those exhibiting the inoculum effect can lead to treatment failure.
Need for Alternative Antibiotics: Resistant infections require alternative antibiotics, such as vancomycin for MRSA or later-generation cephalosporins for some Gram-negative bacteria.
Antimicrobial Stewardship: Rising resistance underscores the need for careful antibiotic use, relying on susceptibility testing and local antibiograms to inform prescribing.

Conclusion

Cefazolin is a valuable antibiotic for susceptible Gram-positive bacteria, but its use is limited by resistance in various pathogens. Naturally resistant bacteria include Gram-negative organisms like Enterobacter and Pseudomonas, while acquired resistance is seen in MRSA and some Gram-negative species. Mechanisms like beta-lactamase production and altered PBPs necessitate careful diagnosis and the use of alternative treatments for resistant infections. Understanding bacterial resistance is vital for effective patient care.

For more detailed information on antimicrobial resistance mechanisms, consult authoritative sources like the National Center for Biotechnology Information (NCBI) and the Clinical & Laboratory Standards Institute (CLSI).

Frequently Asked Questions

Yes, methicillin-resistant Staphylococcus aureus (MRSA) is uniformly resistant to cefazolin. This is because MRSA has an altered penicillin-binding protein (PBP2a) that prevents cefazolin from binding effectively.

Several Gram-negative bacteria are naturally resistant to cefazolin, including Enterobacter spp., Morganella morganii, Pseudomonas spp., Proteus vulgaris, and Serratia spp.

No, cefazolin is not effective against Enterococcus species. Enterococcus is intrinsically resistant to this first-generation cephalosporin.

The inoculum effect is a phenomenon where some bacteria, particularly AmpC-producing Enterobacteriaceae, can become resistant to cefazolin when present at a high bacterial density. This can lead to treatment failure even if standard laboratory tests (using a lower inoculum) suggest susceptibility.

Mycoplasma and Chlamydia are naturally resistant to cefazolin because they lack a rigid cell wall, which is the specific target of beta-lactam antibiotics like cefazolin. Cefazolin works by inhibiting the cell wall synthesis of susceptible bacteria.

Yes, bacteria can acquire resistance to cefazolin through genetic mutations or the transfer of resistance genes. Examples include the development of MRSA and the acquisition of ESBL genes by some Gram-negative bacteria like E. coli.

For MRSA infections, alternatives to cefazolin often include vancomycin or linezolid. For resistant Gram-negative bacteria, clinicians might switch to a third-generation cephalosporin or other broad-spectrum antibiotics, guided by susceptibility testing.