Eagle effect

The Eagle effect, Eagle phenomenon, or paradoxical zone phenomenon, named after Harry Eagle who first described it, originally referred to the paradoxically reduced antibacterial effect of penicillin at high doses,[1][2] though recent usage generally refers to the relative lack of efficacy of beta lactam antibacterial drugs on infections having large numbers of bacteria.[3] The former effect is paradoxical because the effectiveness of an antibiotic generally rises with increasing drug concentration.

Mechanism

Proposed mechanisms:

  • Reduced expression of penicillin binding proteins during stationary growth phase[4]
  • Induction of microbial resistance mechanisms (such as beta lactamases with short half-lives) by high drug concentrations[5]
  • Precipitation of antimicrobial drug in vitro,[1] possibly also leading to the crystallized drug being mis-detected as colonies of the microbe.
  • Self-antagonising the receptor with which it binds (penicillin binding proteins, for example, in the case of a penicillin).[6]

Penicillin is a bactericidal antibiotic that works by inhibiting cell wall synthesis but this synthesis only occurs when bacteria are actively replicating (or in the log phase of growth). In cases of extremely high bacterial burden (such as with Group A Strep), bacteria may be in the stationary phase of growth. In this instance since no bacteria are actively replicating (presumably due to nutrient restriction) penicillin has no activity. This is why adding an antibiotic like clindamycin, which acts ribosomally, kills some of the bacteria and returns them to the log phase of growth. [7]

References
  1. Eagle, Harry; Musselman, A. D. (July 1948). "The rate of bactericidal action of penicillin in vitro as a function of its concentration, and its paradoxically reduced activity at high concentrations against certain organisms". The Journal of Experimental Medicine. 88 (1): 99–131. doi:10.1084/jem.88.1.99. PMC 2135799. PMID 18871882.
  2. Yourassowsky, E; Vander Linden, MP; Lismont, MJ; Schoutens, E (1978). "Qualitative study of paradoxical zone phenomenon of penicillins against 17 bacterial species of clinical importance". Chemotherapy. 24 (2): 92–6. doi:10.1159/000237766. PMID 340171.
  3. Stevens, DL; Gibbons, AE; Bergstrom, R; Winn, V (July 1988). "The Eagle effect revisited: efficacy of clindamycin, erythromycin, and penicillin in the treatment of streptococcal myositis". The Journal of Infectious Diseases. 158 (1): 23–8. doi:10.1093/infdis/158.1.23. PMID 3292661.
  4. Pollard, Andrew J.; McCracken, George H.; Finn, Adam (2004). Hot Topics in Infection and Immunity in Children. Springer. p. 187. ISBN 9780306483448.
  5. Ikeda, Y; Fukuoka, Y; Motomura, K; Yasuda, T; Nishino, T (January 1990). "Paradoxical activity of beta-lactam antibiotics against Proteus vulgaris in experimental infection in mice". Antimicrobial Agents and Chemotherapy. 34 (1): 94–7. doi:10.1128/AAC.34.1.94. PMC 171526. PMID 2183712.
  6. Pharmaceutical Microbiology, pg188, 7th Edition, Denyer, Hodges, Gorman
  7. Hasan, Nurhasni; Cao, Jiafu; Lee, Juho; Hlaing, Shwe Phyu; Oshi, Murtada A.; Naeem, Muhammad; Ki, Min-Hyo; Lee, Bok Luel; Jung, Yunjin; Yoo, Jin-Wook (2021-06-02). "Bacteria-Targeted Clindamycin Loaded Polymeric Nanoparticles: Effect of Surface Charge on Nanoparticle Adhesion to MRSA, Antibacterial Activity, and Wound Healing". Pharmaceutics. 11 (5): 236. doi:10.3390/pharmaceutics11050236. PMC 6571677. PMID 31096709.
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