Is a bacterium resistant to penicillin (Penicillin) also resistant to cephalosporins (Cephalosporins)?

From the Guidelines

Bacteria resistant to penicillin may still be susceptible to cephalosporins, though cross-resistance can occur depending on the specific resistance mechanism. Penicillin resistance often develops through production of beta-lactamase enzymes that break down the beta-lactam ring in penicillins. While cephalosporins also contain beta-lactam rings, many newer generations of cephalosporins (like cefepime or ceftriaxone) have been specifically designed with chemical modifications that protect them from certain beta-lactamases, as noted in a study published in the British Journal of Anaesthesia 1. Additionally, some bacteria develop resistance through altered penicillin-binding proteins (PBPs) that may have different affinities for cephalosporins versus penicillins.

This is why empiric therapy might include a cephalosporin even when penicillin resistance is suspected, and why antimicrobial susceptibility testing is important to determine the exact resistance profile of a bacterial isolate. In clinical practice, the generation of cephalosporin matters significantly - first-generation cephalosporins are more likely to show cross-resistance with penicillins than third or fourth-generation agents. According to a study published in Clinical Infectious Diseases 1, the majority of strains with reduced susceptibility to penicillin are susceptible to certain third-generation cephalosporins, such as cefotaxime or ceftriaxone.

Some key points to consider include:

• The true incidence of cross-reactivity between penicillins and cephalosporins is likely to be lower than previously thought, as noted in a study published in the British Journal of Anaesthesia 1.
• The susceptibility of S. pneumoniae to penicillin is currently defined by the National Committee for Clinical Laboratory Standards (NCCLS), and resistance to penicillin is only one small part of the picture, with cross-resistance to other antimicrobial agents, such as cephalosporins, macrolides, fluoroquinolones, carbapenems, and even vancomycin, increasing in frequency, as noted in a study published in Circulation 1.
• In patients with IE and meningitis, high doses of cefotaxime may be used, and if the isolate is resistant to cefotaxime, then the addition of vancomycin and rifampin should be considered, as noted in a study published in Circulation 1.

From the FDA Drug Label

Microbiology Mechanism of Action Ceftriaxone is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis Ceftriaxone has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria. Mechanism of Resistance Resistance to ceftriaxone is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability

Resistance to penicillin does not necessarily imply resistance to cephalosporins, as the mechanisms of resistance can be different. However, cross-resistance between penicillin and cephalosporins can occur, especially in bacteria that produce beta-lactamases that can hydrolyze both penicillins and cephalosporins.

• Key factors that influence the likelihood of cross-resistance include:
  • The specific type of beta-lactamase produced by the bacteria
  • The degree of similarity between the penicillin and cephalosporin structures
  • The presence of other resistance mechanisms, such as altered penicillin-binding proteins or decreased permeability In general, it is not possible to predict with certainty whether a bacteria that is resistant to penicillin will also be resistant to cephalosporins, and susceptibility testing should be performed to determine the effectiveness of a particular cephalosporin against a specific bacterial isolate 2.

From the Research

Bacterial Resistance to Penicillin and Cephalosporins

• Bacteria resistant to penicillin may not necessarily be resistant to cephalosporins, as these are different classes of antibiotics with distinct mechanisms of action 3.
• A study from 1994 found that certain cephalosporins, such as cefotaxime, ceftriaxone, and ceftazidime, were effective against penicillin-resistant pneumococci, with MIC90s ranging from 0.06 to 2.0 micrograms/ml 3.
• Another study from 2019 noted that cephalosporins have a low potential for cross-reactivity with penicillins, and that clinicians should consider the structural R1 side chain when prescribing alternate β-lactams in allergic individuals 4.

Mechanisms of Resistance and Cross-Reactivity

• The development of resistance to cephalosporins is a complex process, involving various mechanisms such as β-lactamase production, altered penicillin-binding proteins, and efflux pumps 5.
• Cross-reactivity between penicillins and cephalosporins is generally low, but can occur in certain individuals with specific allergies or sensitivities 4.
• A study from 2003 emphasized the importance of appropriate antibiotic use to prevent the development of bacterial resistance, including the use of targeted spectrum antibiotics and judicious dosing and duration 6.

Clinical Implications and Treatment Options

• Cephalosporins remain a viable treatment option for certain bacterial infections, including those caused by penicillin-resistant strains 3, 5.
• Clinicians should be aware of the potential for resistance and cross-reactivity when prescribing cephalosporins, and consider alternative treatment options or combination therapies as needed 4, 5.
• The development of new antibiotics and improved antibiotic stewardship practices are crucial to addressing the growing problem of bacterial resistance 7, 6.