The Pre-brief
There is a common dogma taught and perpetuated amongst clinicians that bactericidal (cidal) antibiotics are preferred to bacteriostatic (static) antibiotics because they are more effective – especially in severe infections. But how much truth is there really to this statement?
First, let’s review some pertinent definitions.
The dangers of simply categorizing antibiotics as either -cidal or –static:
- The definitions for cidal versus static antibiotics are not absolute.
- Here’s a shocker. Static drugs can actually kill bacteria, they just need higher concentrations to do so.
- Similarly, cidal drugs can actually exhibit static activity at low concentrations.
- Non-microbiological factors that affect response to antibiotic treatment such as the ability of the antibiotic to penetrate the site of infection and PK/PD parameters are equally important when choosing an antibiotic regimen.
What does the literature say?
In 2018, Wald-Dickler and colleagues conducted a systematic literature review. They identified 56 randomized, controlled trials that compared the efficacy of static versus cidal antibiotics for serious, life-threatening infections.
- 49 of the 56 studies (87%) found no significant difference in efficacy between cidal and static antibiotics. This included trials evaluating life-threatening infections such as bacteremia, typhoid fever, and plague.
- 6 of the 56 studies (11%) found that the static agent was actually more effective than the cidal agent.
- 1 of the 56 studies (2%) found that the cidal agent (imipenem) was superior in efficacy to the static agent (tigecycline) for ventilator associated pneumonia. However, it was discovered that the tigecycline dose utilized in the trial was subtherapeutic. As a result, the trial was repeated using the appropriate dose of tigecycline and they concluded that both tigecycline and imipenem were similar in efficacy.
Some limitations of the trials included in this literature review include frequent exclusion of patients with more severe infections, mixed study quality (32 of the 56 studies were unblinded; however, the blinded studies came to the same conclusions as the unblinded studies), and lastly no randomized controlled trials were identified comparing static agents to cidal agents for the treatment of bacterial endocarditis or bacterial meningitis.
Based on this literature review, there is extensive evidence that static agents and cidal agents are similar in efficacy for skin and soft tissue infections (SSTIs), pneumonias, intra-abdominal infections, genital infections, and even bacteremias without associated endocarditis.
When efficacy differences were found, the static agent was usually found to be superior and more cost-effective than the cidal agent.
Lastly, when static agents were found to be inferior, the cause was likely related to inadequate dosing of the medication or inability to achieve penetration at the site of infection.
What is the evidence for severe infections?
Endocarditis
- Bacteria in cardiac vegetations reach very high concentrations leading to reduced susceptibility to cidal agents which act on the cell wall.
- Prolonged treatment with cidal, cell-wall active agents is generally required to truly sterilize the vegetation.
- There have been several cases in which static agents (clindamycin, linezolid) have successfully cured endocarditis; however, these findings were not from high-quality, reliable studies.
Meningitis
- Cidal agents have long been preferred for meningitis due to the need to eradicate the infection as quickly as possible and because of the poor immunologic competence of the CNS.
- Penetration of many antibiotics into the CNS is poor or dependent on the degree of inflammation.
- There have been several cases in which static agents (tetracycline, chloramphenicol, linezolid, TMP-SMX) have successfully treated gram-positive bacterial meningitis; however, these findings were not from high quality, reliable studies.
Osteomyelitis
- The aforementioned 2018 literature review did not extensively focus on osteomyelitis infections.
- Because of decreased vascular supply, drug penetration is difficult in osteomyelitis. However, the static agent clindamycin achieves high concentrations in bone and has been shown to be effective in gram-positive bacterial osteomyelitis as long as adequate surgical debridement is achieved and the organism is susceptible based on culture results.
The Debrief
- The definitions for cidal versus static antibiotics are not absolute. Static agents can actually kill bacteria, they just need higher concentrations to do so. Similarly, cidal agents can actually exhibit static activity at low concentrations.
- There is extensive evidence that static agents and cidal agents are similar in efficacy for skin and soft tissue infections (SSTIs), pneumonias, intra-abdominal infections, genital infections, and even bacteremias without associated endocarditis.
- Clinicians should be wary about using static agents in bacterial endocarditis and bacterial meningitis as the evidence for static agents is poor and no randomized controlled trials have been identified comparing cidal agents and static agents in these infections. The decision regarding which antimicrobial agent(s) to select in these infections should be made in conjunction with infectious disease specialists.
- Non-microbiological factors that affect response to antibiotic treatment such as the ability of the antibiotic to penetrate the site of infection and PK/PD parameters are equally important when choosing an antibiotic regimen.
References
References:
- Pankey G, Sabath L. Clinical Relevance of Bacteriostatic versus Bactericidal Mechanisms of Action in the Treatment of Gram-Positive Bacterial Infections. Clin Infect Dis. 2004; 38: 864-70.
- Calhoun C, Wermuth H, Hall G. Antibiotics. Stat Pearls. StatPearls Publishing. Updated: June 8, 2021.
- Wald-Dickler N, Holtom P, Spellberg B. Busting the Myth of Static vs Cidal: A Systemic Literature Review. Clin Infect Dis. 2018; 66(9):1470-4.
