Non-spore forming anaerobes form part of the commensal flora of the GI and GU tracts, therefore infection is usually endogenous and opportunistic. We are absolutely teaming with bacteria (the number of commensal bacteria is greater than the number of cells in the body). In one gram of faeces there are upwards of 10,000,000,000 anaerobes – to put that number into perspective, ten thousand million seconds is 317 years! Anaerobic infections are polymicrobial, and will include organisms that have not yet been identified.
In the same way that obligate anaerobes don’t survive in oxygen, Metronidazole doesn’t work in the presence of oxygen, which explains it’s spectrum of activity. It is a pro-drug, and once inside the cell is reduced (gains electrons) to the active form (a free radical that destroys DNA). This doesn’t happen in the presence of oxygen because the oxygen molecule has a higher affinity for the electron than the Metronidazole – oxygen can even turn activated Metronidazole back to the pro-drug.
Bacterial resistance to Metronidazole is rare, but it does occur (there’s a couple of review articles here and here). H. Pylori resistance is common (20-45%), but the resistance we’d be more interested in from a critical care perspective is that of the Bacteroides and Clostridium species.
Bacteroides resistance was first reported in 1978 in in a patient receiving long term Metronidazole for Chron’s disease. In 1998, the UK Anaerobic Reference Unit reported the incidence of Bacteroides resistance may be as high as 7.5%, but this figure is open to some interpretation as some of the samples tested were only included because resistance was suspected. Other estimates are lower, in the region of <1%. The mechanism of resistance is explained better in the review articles than I could reproduce here.
Clostridium resistance has been found in horses, and whilst C. Diff resistant strains have been isolated in humans, they have fortunately been in the non-toxigenic forms.
There is, however a twist………It could be however that resistance is simply under-recognised…....
In many microbiology labs, the specificity of Metronidazole is used to identify the presence of obligate anaerobes. When the plated sample is incubated in an anaerobic environment, a disc of Metronidazole is added. After growth, if there is a zone of inhibition around the Metronidazole this is taken to signify the presence of obligate anaerobes (as Metronidazole can only inhibit the growth of anaerobes). Organisms that are not inhibited by the Metronidazole are assumed to be facilitative anaerobes (which have reduced susceptibility) and are not investigated further. But what if there’s a resistant obligate anaerobe?
I think it’s fair to say that Metronidazole’s niche mechanism and activity profile make it a fantastically useful drug. To lose it to resistance would be a disaster, not least because resistance to Metronidazole means resistance to all other 5-nitroimidazoles (none of which I’ve heard of – Tinidazole, Nimorazole, Dimetridazole, Ornidazole, Megazol and Azenidazole). Clearly, Metronidazole should be subject to the same stewardship as all other antimicrobials.
In the meantime, it might be interesting to ask how your lab identifies obligate anaerobes.…