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Bactericidal vs. Bacteriostatic antibiotics

ANTIMICROBIALS, , , , , ,

Does it matter whether we use a bactericidal antibiotic or a bacteriostatic one? Surely, the bactericidal one would be more effective, right? The answer is not that simple.

Bactericidal = antibiotics that kill bacteria

Bacteriostatic = antibiotics that inhibit the growth of bacteria (i.e. prevent the bacteria from continuing to grow/proliferate) without killing bacteria in vitro OR it is able to kill the bacteria in vitro but at a slower rate than bactericidal agent does.

– there is thought out there that bacteriostatic agents require more activity from the immune system to eradicate the bacteria (this has not been studied well in literature and there is no data to support or negate this hypothesis).

Bactericidal drugs:                                          Bacteriostatic drugs:
Aminoglycosides                                                Glycylcyclines (tigecycline)
Beta-lactams                                                        Lincosamides (clindamycin)
Fluoroquinolones                                               Macrolides (azithromycin, fidaxomicin)
Glycopeptides (vancomycin)                           Oxazolidinones (linezolid, tedizolid)
Lipopeptides (daptomycin)                             Streptogramins (quinipristin/dalfopristin)
Nitroimidazoles/nitrofurans                           Sulphonamides (sulfamethoxazole)
(metronidazole/nitrofurantoin)                     Tetracyclines
Rifampin

*Keep in mind – bactericidal and bacteriostatic effects depend on several factors, including the amount of:
1) bacterial inoculum: the burden of bacteria can change the antibiotic’s properties
2) the pathogen: certain antibiotics are “cidal” to certain pathogens, while “static” to others
–examples:
a)  vancomycin is “cidal” against staph and strep, but “static” against enterococci
b) azithromycin is “cidal” against strep, but “static” against staph
c) linezolid may be “cidal” against strep, but “static” against staph/enterococci
3) medium/location of infection: certain antibiotics are more effective in certain parts of the body (IV vancomycin doesn’t penetrate GI mucosa, tigecycline doesn’t achieve high concentrations in the bloodstream, etc.)

Why could this be potentially clinically irrelevant?

A systematic review published in CID in 2017 looked at all the 59 randomized-controlled trials on clinical outcomes when using bactericidal vs. bacteriostatic agents. They found that 49 (81%) of the trials showed no differences in clinical outcomes when using “cidal” vs. “static” agents.

Similarly, studies demonstrated that using linezolid (a bacteriostatic agent) against MRSA was non-inferior to vancomycin (a bactericidal agent) against MRSA.
Because clinical outcomes depend on 3 factors:

  1. The host
  2. The pathogen
  3. The drug (with many internal factors coming into play as listed below
    -Tissue penetration
    -Pharmacokinetics
    -Drug interactions
    -Optimal dosing

TAKE-HOME POINTS:

  1. Antibiotics can be bacteriostatic for some pathogens and bactericidal for others
  2. Clinical outcomes depend on a variety of factors and the bactericidal property of an antibiotic ultimately appears to have little clinical relevance.

References:

  • Nemeth, J., Oesch, G., and Kuster, S.P. 2015. Bacteriostatic versus bactericidal antibiotics for patients with serious bacterial infections: systematic review and meta-analysis. Journal of antimicrobial chemotherapy. 70:382-395.
  • French, G.L. 2006. Bactericidal agents in the treatment of MRSA infections – the potential role of daptomycin. Journal of Antimicrobial Chemotherapy. 58 (6): 1107-1117.
  • Wald-Dicker, N, Holtom, P, and Spellberg, B. 2017. Busting the myth of “static vs. cidal”: A systemic literature review. CID
  • Panckey, G.A. and Sabath, L.D. 2004. Clinical relevance og bacteriostatic versus bactericidal mechanisms of action in the treatment of gram-positive bacterial infections. CID, 38(6): 864-870.

 

SPICE organisms

PATHOGENS, , , , ,

First topic at hand is SPICE organisms. These are the organisms that appear to be sensitive to many antibiotics, but once they are exposed to certain antibiotics (ex. 3rd generation cephalosporins), they quickly develop resistance to them.

SPICE stands for:

S: Serratia spp.

P: Providencia

I: “indole-positive” Proteus spp. (this includes: P. vulgaris) *NOT P.mirabilis

C: Citrobacter spp.

E: Enterobacter spp.

*There are other, less known bacteria included in this group (Cronobacter, Edwardsiella, Hafnia, Morganella, Aeromonas)

*[Organisms like Pseudomonas and Acinetobacter produce AmpC gene normally – which is why they have intrinsic resistance to 3rd generation cephalosporins and do not technically fall into the AmpC inducer SPICE group.]

The SPICE pathogens can be induced to produce an AmpC beta-lactamase gene that encodes an enzyme that cleaves the beta-lactam group in the antibiotic and renders it inactive.

This gene may not be detected initially (low level of expression of the gene) but may appear (induced to express higher levels of gene) after a period of exposure to beta-lactam antibiotics.

(Clinical translation: Initially they will appear susceptible to beta-lactams, but eventually will develop resistance to them)

Once beta-lactam is removed, the AmpC gene production is reduced once more and the pathogens will appear sensitive to 3rd generation cephalosporins and penicillins again. .

Resistance develops anywhere from 24h to 2-3 weeks.

Clinical relevance:

  • If the course of antibiotics is short or if the antibiotic can easily overcome the MIC concentration needed for bacterial killing, then the risk of inducing AmpC gene production is low
    • Clinical examples (~<1 week duration of antibiotics):
      • UTI
      • Pneumonia
  • Short course for intra-abdominal infectionHowever, this becomes an issue in areas where antibiotics have difficulty penetrating (because it is less likely to overcome the MIC concentration needed) or when antibiotics are needed to be given over a longer period of time.
    • Clinical examples:
      • Endocarditis
      • Bacteremia
      • Osteomyelitis
      • Septic arthritis
      • Abscesses

Antibiotics to avoid:

  • Penicillin class (including piperacillin-tazobactam)
  • Most cephalosporins (1st, 2nd, and 3rd generation)

Antibiotics to use:

  • 4th generation cephalosporins (i.e. cefepime at higher doses, q8h)
  • Carbapenems
  • Aminoglycosides
  • Fluoroquinolones

TAKE-HOME POINTS:

  1. Remember the members of the SPICE group
  2. You may be successful in treating an infection in short courses of therapy or in infections where antibiotic penetration is high. But in patients with bacteremia, bone, joint, or valve infections – strongly consider 4th generation cephalosporin or a carbapenem.

Have a question, comment, or a suggestion for a future blog post? Post your comment below!

References:

  • http://m.antimicrobialstewardship.com/clinical_summaries/index.php?page=esbl_and_spice
  • Jacoby, G.A. AmpC beta-lactamases. Clinical Microbiology Review. 2009. 22(1):161-182. doi: 10.1128/CMR.00036-08
  • Harris, P.N.A, and Ferguson, J.K. Antibiotic therapy for inducible AmpC beta-lactamase-producing Gram-negative bacilli: what are the lternatives to carbapenems, quinolones, and aminoglycosides? 2012. International Journal of Antimicrobial Agents, 40: 297-305.