The possible development of antibiotic resistance in Chlamydia pneumoniae


This is often a cause of deep concern for those who begin combined antibiotics to eradicate a chronic infection with C. pneumoniae. There are many good reasons why the development of resistance in C. pneumoniae is likely to be a rarity provided an appropriate antichlamydial combination is used. Here is a list of such reasons:

a) The organism in chronic infections is likely to be metabolically sluggish and not actively reproductive: production of infectious EBs is rare. (This is one of the reasons why the diagnosis of chronic infections with C. pneumoniae is difficult.)

b) The organism has lost a lot of its genome vis a vis freeliving Gram negatives, and will thus find difficulty in finding the genetic capability to express resistance.

c) Corollary to the above: freeliving Gram negatives constantly have naturally occurring antibiotics in their milieu, and thus have numerous genetic arms, plasmids etc to counter these antibiotics. Intracellular organisms, such as C. pneumoniae would not encounter naturally occurring antibiotics; genes coding for active mechanisms against them would be redundant and thus lost. (An evolutionary rule, especially cogent in the prokaryotes: use it or, in time, lose it.)

d) Any resistant EBs released would be destroyed by N acetyl cysteine on leaving the cell (and resistance to NAC is likely physiologically impossible.)

e) Development of resistance to metronidazole is possible but unlikely. MTZ works by being reduced to highly active metabolites which break the DNA at the AT base pairs; such breaks are single-stranded. (If, however, you had an AT base-pair next to a TA base-pair you might expect a double-stranded break.) Now, the bacterium has a mechanism called the SOS 'last ditch' system whereby it repairs DNA breaks by pushing in any base-pair which comes to hand. Thus this system is mutagenic, and, while most mutations are neutral or deleterious, a mutation delivering resistance is possible. It is unlikely though: the SOS DNA repair system requires the production of at least 15 unique proteins. If protein-synthesis inhibiting antibiotics (doxycycline / macrolide or rifamipicin) are also taken, adequate production of these repair proteins is highly unlikely.

f) There is some evidence that the active reticular body of chlamydiae can spread directly from one host cell to to adjacent cells, possibly by exploiting lipid raft microdomains in the host cell membrane. The transmigration of C. pneumoniae from peripheral blood monocytes to endothelial cells has been described
[Rupp J, Koch M, van Zandbergen G, et al., Transmission of Chlamydia pneumoniae infection from blood monocytes to vascular cells in a novel transendothelial migration model. FEMS Microbiol Lett. 2005 Jan 15;242(2):203-8.] (This, incidentally, is the likely mechanism of the vasculitis often seen at the centre of a recent MS lesion.) Transmigration is an active process and one would not expect it to take place in the presence of protein synthesis inhibitors. The cessation of gadolinium leakage in the presence of minocycline provides evidence for this [Metz LM, Zhang Y, Yeung M, et al., Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol. 2004 May;55(5):756.] though these authors believe that minocycline works by acting as an immunomodulator.

All this is very different from the examination of MICs in actively replicating organisms in vitro, where the development of resistance is much more likely. This is particularly with rifampicin. This agent should never be given in isolation. [Kutlin A, et al., Emergence of resistance to rifampin and rifalazil in Chlamydophila pneumoniae and Chlamydia trachomatis. Antimicrob Agents Chemother. 2005 Mar;49(3):903-7.]

In conclusion, we have plenty of evidence that the development of resistance in chronic C. pneumoniae infections is likely to be remote provided complementary antibiotic combinations are taken. Metronidazole delivers the coup de grace to the organism, littering the tissues with bacterial corpses, proteins, lipopolysaccharides and nucleic acids. All this stuff is pro-inflammatory, which is why it is best to go for a slow die-off with bacterial protein-inhibitors before beginning metronidazole, and that cautiously. The danger of developing resistance to metronidazole while the organism's metabolism is suppressed by protein-synthesis inhibitors is slender, so this agent can be given in cautious intermittent pulses.

back to MS index page

This page uploaded 27th October 2007