Antibiotic Activity Enhancement

In vitro studies on Minimum Inhibitory Concentrations (MIC) and Minimum Bactericidal Concentrations (MBC) of various antibiotics and oxygen pressure have clearly demonstrated that antibiotic activity decreased in anaerobiosis. In anaerobiosis, the MIC of aminoglycosides (amikacin, gentamycin, kanamycin, tobramycin) are significantly greater for E. coli, Enterobacter, Klebsiella, Salmonella, Staphylococcus and Streptococcus sp16'11. The decrease of aminoglycosides activity in hypoxic conditions is combined with a decrease of the oxygen-dependent penetration of the antibiotic through the cytoplasmic membrane. This is why anaerobes are not susceptible to aminoglycosides since they do not have the aerobic metabolism required for oxygen transport through the cytoplasmic membrane. Some facultative anaerobes are susceptible to aminoglycosides in normal pressures of oxygen but their susceptibility decreases in hypoxia, anoxia and acidosis16,17. The enhancement of aminoglycosides activity in hyperoxia seems to depend on the type of antibiotic and the strain of bacteria. However, the decrease of aminoglycosides activity in anaerobiosis and its recovery to normal in normoxic conditions are a universal phenomenon58.

The activity of a number of other antibiotic classes decreases in anaerobiosis, although the mechanisms involved are not yet understood. The bacteriostatic activity of sulfamethoxazole and trimethoprime against E. coli, Klebsiella sp, Proteus sp and Staphylococcus sp is greatly reduced in anaerobiosis59. The MIC and MBC of vancomycin against Staphylococcus aureus is 4 times greater in anaerobiosis than in normoxia60. The bactericidal activity of fluoroquinolones such as ciprofloxacin, ofloxacin and norfloxacin against E. coli decreases in anaerobiosis. However ciprofloxacin does retain a bacteriostatic effect.

In contrast, the MIC of cefazolin, cefalotin, chloramphenicol, clindamycin, moxalactam and piperacillin for various positive and negative Gram-stain bacteria are not altered in anaerobic environments16.

Metronidazole activity is at its best in anaerobiosis and stops in aerobiosis. It is enhanced by the decrease in redox potential.

A series of studies have proven that pressures of oxygen had an influence on post-antibiotic effects. Bayer observed that for a PO2 of 80mmHg instead of 40mm Hg, amikacin had a greater bactericidal effect on Pseudonomas aeruginosa and double the post-antibiotic effect61. Park also showed how hyperoxia increased the post-antibiotic effect of tobramycin on Pseudonomas aeruginosa62. HBO increases the bacteriostatic activity of sulfisoxazole against Pseudonomas aeruginosa and increases the bacteriostatic effect of sulfisoxazole and trimethoprime on Corynebacterium diphteriae. HBO also enhances the activity of nitrofurantoin on E. coli16.

These in vitro data have been confirmed in experimental models in vivo. On a model of experimental osteomyelitis in rabbits, HBO (100 % 2 ata 2 hour sessions) was found as effective in eliminating Staphylococcus aureus as cefalotin63. Knighton came to similar conclusions : after intradermal injection of E. coli, infectious necrosis in guinea pigs decreased when oxygen concentrations rose from 12 to 45 %; they also observed that oxygen and ampicillin had a greater effect when combined than oxygen or ampicillin alone51 (Figure 1.6-3).

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amefcr Of necrotizing infect ian lesion (in mm)

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Figure 1.6-3. Effects of oxygen provided alone or combined with ampicillin on the diameter of necrotizing infection lesions after intradermal infection of Escherichia coli in guinea pigs

In another study, Mader showed that HBO (100 %, 2.5 ata, 1.6 hours, twice daily) combined with tobramycin provided a greater effect than HBO or tobramycin on their own64. The enhancement of the activity of tobramycin in HBO has been explained by the recovery of oxygen levels in the infected bone which enables both aminoglycoside activity to resume and PMN's bactericidal activity to increase. In a model of polymicrobial infection in rats, Marzella studied on the additive effects of HBO and some antibiotics58. They confirmed that in terms of reduced mortality, HBO enhanced the activity of piperacillin, clindamycin and vancomycin;, this was not the case for metronidazole. Finally, as far as improved survival time was concerned, they observed that the effects of HBO were additive when it was combined with vancomycin or clindamycin.

At least three mechanisms can account for the role HBO plays in antibiotic activity17 :

• increase of pressure of oxygen in ischemic tissues improving the activity of antibiotics such as aminoglycosides, some sulfonamides; fluoroquinolones, vancomycin and trimethoprime,

• inhibition of some of the reactions involved in bacterial biosynthesis such as the enhancement of sulfonamide activity and increased duration of the post-antibiotic effect of aminoglycosides in Pseudomonas induced infections,

• altered redox potential of the bacteria, combined with an increase in reactive intermediates such as nitrofurantoin and decreased activity of antimicrobial agents such as metronidazole, which require a low redox potential.

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