Can bacterial cryptic form develop resistance to Flagyl?

Submitted by arthritic on Sat, 2009-02-07 18:38

Yesterday I took my first Flagyl 250 mg, no reaction. Today took 2 x 250 mg and started to wonder, is it possible to develop resistance to Flagyl if taken in small doses? I'll be increasing the dose in future pulses if tolerated. My dr wants me to take 500 mg x 2/day for 14 days a month eventually.

Nata. CAPi since Jan'08 for arthritis, tendonitis, sinusitis, pelvic pain, fatigue and muscle pain. Hypertension, HypoT Hashi's. Lyme, Cpni, HPV & CMV (+). Rif 600 mg + Minoi 200 mg + Bactrim.

I don't know if it can but I doubt it. Flagyl actually tears apart the bacterial DNA. Someone correct me if I have this wrong. I will tell you I made a mistake in my first dose of Flagyl and took it for 7 days. Nothing much happened until the next pulse two weeks later. I took two days dose and all hell broke loose. Could not finish the pulse I was so sick. My theory is that it took that long to get the cryptic forms broken up and killed. So you could too be looking at a delayed reaction. Or maybe you will be one of those lucky few who don't get hammered. Keep your fingers crossed and expect the unexpected. Raven

Feeling 98% well-going for 100. Very low test for Cpn. CAP since 8-05 for Cpn/Mycoplasma P.,Lyme, Bartonella, Mold exposure,NAC,BHRT, MethyB12 FIR Sauna. 1-18-11 begin new treatment plan with naturopath

I'd be holding out for the 'lucky few who don't get slammed' explanation.  (I'm one of them).

As for developing resistance by starting flagyl slowly, I'm sure David Wheldon would not have developed a protocol that would damage his charming wife, or us, or make it so terribly public that he had done so.  Image removed.  He recommends a slow ramp-up.  You might want to review his pages again.

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems. Mohandas Gandhi

Although there is no lab data on this, both Dr.'s Stratton and Wheldon believe from the biology of the whole thing that this is very unlikely. Other, more complex, bacteria can develop resistance to flagyl, but Cpn is quite primitive in many ways and doesn't appear to have the adaptive mechanisms for this.


CAP for Cpn 11/04. Dx: 25+yrs CFS & FMS. Currently: 250 aithromycin mwf, doxycycline 100mg BID, restarted Tini pulses; Vit D2000 units, T4 & T3, 6mg Iodoral

Rationale for Use of Metronidazole for Chronic Chlamydial Infections 

Most bacteria possess a number of different metabolic pathways and are able to switch from one to another in response to alteration of redox potential and other changes in their environment. Chlamydiae, which have a unique and complex life-cycle (extracellular/nonreplicating, intracellular/nonreplicating and intracellular/replicating) may use different pathways at various stages of this cycle. It is known that C. trachomatis possesses genes that code for oxidative pathways; these operate during the actively replicating intracellular phase to supplement ATP taken from host mitochondria. As the organism enters the persistent or cryptic phase it evidently becomes dependent on host mitochondrial ATP, downregulating its own glycolytic and pentose phosphate pathways (discussed by Gérard et al. [1]). C. pneumoniae is known to have the ability to enter a similar persistent phase. [2]

The persistent form may be analogous to the stringent response found in many free-living bacteria. This is a survival mechanism involving a phenotypic simplification of the metabolic economy under the onset of stress conditions. Survival in this form may depend on a non-oxidative metabolic pathway. [3] The finding that Chlamydiae enter the cryptic form when starved of amino acids [4] lends support to the idea of this transformation being a stringent response. Such a transformation may occur naturally during untreated infection as interferon-gamma (IF-γ) is produced by the host in an attempt to curtail intracellular infection (reviewed by Rottenburg et al.[5]) IF-γ has been shown to induce persistence in C. pneumoniae in vitro by means of host-cell mechanisms which reduce the availability of intracellular tryptophan [6,7]. C. psittaci (but not C. pneumoniae) possesses a pathway which by-passes host-mediated tryptophan starvation. [8] A tryptophan starvation strategy on the part of the host seems to be important in the genesis of conditions, which favour chronic disease. IFN-γ acts by inducing host enzyme indoleamine 2,3-dioxygenase, which converts tryptophan to formylkynurenine [6,9] and by the induction of host tryptophanyl-tRNA synthetase, which denies the organism access to remaining tryptophan [10]. Another host strategy against intracellular infection is the depletion of iron reserves. [11]. From this it seems clear that the endurance of starvation conditions is a part of the evolutionary history of persistent infection with C. pneumoniae. Induction of hypoxia within the phagosome may be another possible non-specific component of the host-cell starvation strategy against intracellular bacterial pathogens. Schnappinger and co-workers, examining gene-expression of Mycobacterium tuberculosis in artificial media and in macrophages, found that genes expressed differentially as a consequence of intraphagosomal residence included an IFNγ and NO induced response which intensified an iron-scavenging program, induced a dormancy regulon and forced the bacterium to convert from aerobic to anaerobic respiration [12].


Were the cryptic form of C. pneumoniae forced, by host starvation-strategies and by anti-replicating antimicrobials, to adopt an anaerobic survival-metabolism, metronidazole, a member of the nitroimidazole class of antibiotics and a potent anti-anaerobic agent [13], would be expected to be an efficient killer. There may be parallels once more with M. tuberculosis, which, though considered an aerobe, can be induced, by the gradual depletion of oxygen from the culture-media, to enter a sluggishly metabolising but non-replicating state in which the organism is killed by metronidazole [14]. This may also happen in vivo; metronidazole has been found, under certain specific conditions, to assist resolution in chronic but not acute M. tuberculosis infection in a mouse model [15].


The bactericidal effect of nitroimidazoles such as metronidazole or nitrofurantoin involves reduction of these agents to create short-lived but highly reactive intermediates (here designated M▪), which damage the DNA of the target cell. This can take place only within a strongly reducing environment where electrons will be donated preferentially to metronidazole. The direct donors of electrons in anaerobic bacteria are a family of electron transport proteins, which include ferredoxin [16]. The iron-sulfur protein ferredoxin is an electron acceptor that participates in the redox-based metabolism in mitochondria and anaerobic bacteria. If C. pneumoniae has the ability to utilise an anaerobic pathway it should have the potential to fabricate ferredoxin or a ferredoxin-like protein, and, indeed, C. pneumoniae has recently been found to possess a gene that codes for a novel predicted ferredoxin (CT312) [17]. M▪ damages DNA by acting on the AT base-pair and causing strand-breakage (reviewed by Edwards D [18].) The death or survival of an organism in the presence of metronidazole rests on the equation of the rate of M▪ induced DNA damage versus the rate of DNA repair [19]. If the rate of M▪ induced DNA damage outstrips the ability of the cell to effect DNA repair, then the cell will die. The dynamics of metronidazole have been extensively studied in the Enterobacteriacae [19-22]. Escherichia coli is normally highly resistant to metronidazole, surviving concentrations in excess of 500 μg/mL [23]. However, metronidazole is not inert within this bacterium. E. coli mutants with a defective ability to repair damaged DNA are much more susceptible to metronidazole than strains not possessing this mutation [24,25]; this implies that metronidazole is actively reduced to M▪ in E. coli, and that highly efficient DNA repair takes place under normal circumstances. Anaerobic co-cultivation of E. coli with Bacteroides fragilis in the presence of metronidazole results in enhanced killing of the Bacteroides [20,24] indicating that E. coli growing under anaerobic conditions effectively converts metronidazole to M▪ and then passes M▪ out into the substrate with such efficiency that other, more susceptible, bacilli are more rapidly killed. Production of M▪ in E. coli is likely to be a continuous process; although metronidazole enters the cell by passive diffusion, inward flow is maintained by a concentration gradient as intracellular metronidazole is removed by irreversible reduction [25]. DNA repair mechanisms in bacteria call upon complex and ancient pathways, which operate by way of induced proteins (reviewed in detail by Kuzminov A [26].) Nitroimidazoles are known to activate the S.O.S. ‘last resort’ repair system in bacteria [27]; this system requires at least 15 enzymes. It is not surprising that repair of DNA damage is curtailed by low-nutrient conditions [28,29]. Blocking the induction of proteins involved in DNA repair mechanisms should enhance the effects of DNA damage. This has been shown to be so: preincubation of E. coli with the protein-synthesis inhibitor rifampicin interferes with the organism’s ability to repair damage to DNA caused by X radiation [30]. One might hypothesize that nutritionally-starved intracellular Gram-negatives, surrounded by a double membrane system derived from host as well as bacterium, may be unable to pass M▪ efficiently beyond the phagosome and so may accrue higher concentrations of active intermediates.

 Based on this theoretical approach for the use of metronidazole to clear cryptic forms of C. pneumoniae, one of the authors (CWS) has demonstrated in cell cultures that the addition of metronidazole was able to clear these cultures that otherwise were not cleared [31]. Clearing of cryptic forms of C. pneumoniae was demonstrated in these cell cultures by the absence of chlamydial DNA by PCR testing.  References 

1. Gérard HC, Freise J, Wang Z, et al (2002) Chlamydia trachomatis genes whose products are related to energy metabolism are expressed differently in active vs persistent infection. Microbes Infect 4:13-22


2. Villareal C, Whittum-Hudson JA, Hudson AP (2002) Persistent Chlamydiae and chronic arthritis. Arthritis Res 4:5-9

3. Vannucci SA, Mitchell WM, Stratton CW, King LE Jr (2000) Pyoderma gangrenosum and Chlamydia pneumoniae infection in a diabetic man: pathogenic role or coincidence? J Am Acad Dermatol 42:295-297

 4. Coles AM, Reynolds DJ, Harper A et al. (1993) Low-nutrient induction of abnormal chlamydial development: a novel component of chlamydial pathogenesis?  FEMS Microbiol Lett 106:193-200 5. Rottenberg ME, Rothfuchs AG, Gigliotti D et al. (2000) Regulation and role of IFN-g in the innate resistance to infection with Chlamydia pneumoniae. J Immunol 164:4812-4818 

6. Byrne GI, Oeyjahhkn LK, Landry GJ (1986) Induction of tryptophan catabolism is the mechanism for gamma-interferon-mediated inhibition of intracellular Chlamydia psittaci replication in T24 cells. Infect Immun 53:347-351


7. Beatty WL, Belanger TA, Desai AA et al. (1994) Tryptophan depletion as a mechanism of gamma interferon-mediated chlamydial persistence. Infect Immun 62:3705-3711


8. Xie G, Bonner C A, Jensen RA (2002) Dynamic diversity of the tryptophan pathway in chlamydiae: reductive evolution and a novel operon for tryptophan recapture. Genome Biol 3: res0051.1-17

9. Byrne GI, Lehmann LK, Kirschbaum JG (1986) Induction of tryptophan degradation in vitro and in vivo: a gamma interferon-stimulated activity. J Interferon Res 6:389-396

10. Fleckner J, Rasmussen HH, Justesen J (2002) Human interferon γ potently induces the synthesis of a 55-kDa protein (γ2) highly homologous to rabbit peptide chain release factor and bovine tryptophanyl-tRNA synthetase. Proc Natl Acad Sci USA 88:11520-11524


11. Igietseme JU, Ananaba GA, Candal DH et al. (1998) Immune control of chlamydia growth in the human cell line RT4 involves multiple mechanisms that include nitric oxide induction, tryptophan catabolism and iron deprivation. Microbiol Immun 42:617-625


12. Schnappinger D, Ehrt S, Voskuil MI et al. (2003) Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment. J Exp Med 198:693-704


13. Samuelson J (1999) Why metronidazole is active against both bacteria and parasites. Antimicrob Agents Chemother 43:1533-1541


14. Wayne LG, Sramek HA (1994) Metronidazole is bactericidal to dormant cells of Mycobacterium tuberculosis. Antimicrob Agents Chemother 38:2054-2058


15. Brooks JV, Furney SK, Orme IM (1999) Metronidazole therapy in mice infected with tuberculosis. Antimicrob Agents Chemother 43:1285-1288


16. Edwards DI (1980) Mechanisms of selective toxicity of metronidazole and other nitroimidazole drugs. Brit J Vener Dis 56:285-290
17. Griffiths E, Ventresca MS, Gupta RS (2006) BLAST screening of chlamydial genomes to identify signature proteins that are unique for the Chlamydiales, Chlamydiaceae, Chlamydophila, and Chlamydia groups of species. BMC Genomics 7:14


18. Edwards DI (1992) Nitroimidazole drugs — action and resistance mechanisms. I: Mechanisms of action. J Antimicrob Chemother 31: 9-20.


19. Chrystal EJ, Koch RL, McLafferty MA, Goldman P (1980) Relationship between metronidazole metabolism and bactericidal activity. Antimicrob Agents Chemother 18:566-573


20. McLafferty MA, Koch R L, Goldman P (1982) Interaction of metronidazole with resistant and susceptible Bacteroides fragilis. Antimicrob Agents Chemother 21:131-134


21. Yeung TC, Beaulieu BB Jr, McLafferty MA, Goldman P (1984) Interaction of metronidazole with DNA repair mutants of Escherichia coli. Antimicrob Agents Chemother 25:65-70


22. Jackson D, Salem A, Coombs GH (1984) The in-vitro activity of metronidazole against strains of Escherichia coli with impaired DNA repair systems. J Antimicrob Chemother 13:227-236


23. Tally FP, Goldin BR, Sullivan N, Johnston J, Gorbach SL (1978) Antimicrobial activity of metronidazole in anaerobic bacteria. Antimicrob Agents Chemother 13:460-465


24. Soriano F, Ponte MC, Gaspar MC (1982) Reciprocal antimicrobial synergism between Escherichia coli and Bacteroides fragilis in the presence of metronidazole. J Clin Pathol 35:1150-1152


25. Ings RMJ, McFadzean JA, Ormerod WE (1974) The mode of action of metronidazole in Trichomonas vaginalis and other microorganisms. Biochem Pharmacol 23:1421-1429


26. Kuzminov A (1999) Recombinational repair of DNA damage in Escherichia coli and bacteriophage lambda. Microbiol Mol Biol Rev 63:751-813


27. Widdick DA, Edwards DI (1991) A comparison of the relative activities of 8 radiosensitizers in the SOS chromotest. Mutat Res 259:89-93


28. Sargentini NJ, Diver WP, Smith KC (1983) The effect of growth conditions on inducible recA-dependent resistance to X rays in Escherichia coli. Radiat Res 93:364-380


29. Dzidic S, Salaj-Smic E, Trgovcevic Z (1986) The relationship between survival and mutagenesis in Escherichia coli after fractionated ultraviolet irradiation. Mutat Res 173:89-91


30. Sargentini NJ, Smith KC (1985) Growth-medium dependent repair of DNA single-strand and double-strand breaks in X-irradiated Escherichia coli. Radiat Res 104:109-115


31. Stratton CW, Mitchell WM. Methods for in vitro susceptibility testing of Chlamydia. Patent Number: US 6,258,532 B1. Issued July 10, 2001

Male 38 years (Germany),CFIDS, IBS, Enterovirus, Cpn and Bartonella, Dientamoeba fragilis positive. Started Cap on 02/19/08, Currently taking Bactrim, Flagyl, soon adding Malarone and Clindamycin for suspected protozooa. 

Thank you all for sharing your experiences and posting comments and info. The way I understood, if tolerated better to take a full dose and the reason for Flagyl pulsing is also mainly tolerance of the drug.

This is what's happening now. I took first day 250 mg, then 500 mg, 3rd day 750 mg, and last 2 days 500 mg x 2 /day. I haven't had any significant reactions except I was a bit more tired by eve, especially on the days I excercise, mildly unpleasant taste in the mouth one of the days and mild episode of tachycardia last night and difficulty to fall. I've been very watchfull of how I feel and planning to stop the pulse on a first warning. Otherwise I'll go for a full 14 days. Also, my appt with my dr will be happening during this pulse, on Mon. and see what he says.

I was VERY nervous prior to starting Flagyl and it's not that bad so far, knock-knock on wood. Jim tossed a theory recently in one post that perhaps Rifampicin inhibited conversion to cryptic form, hope he is right. 


CAP Jan'08 to Dec'09 for arthritis. Doxy, Rif, Azith, Bactrim, Mino, Clarith, Flagyl, Amoxicillin. Re-started Dec.'10 for residual joint pain and painful heartbeat.Now: Mino 200 mg/day, Clarith  1000 mg/day, Flagyl 1000 mg/

Cesare- Could you post a link to this article rather than the whole article please? I don't want us to run into copyright problems as we don't have permission from the publisher. Excerpts are fine as they fall under "fair use."


CAP for Cpn 11/04. Dx: 25+yrs CFS & FMS. Currently: 250 aithromycin mwf, doxycycline 100mg BID, restarted Tini pulses; Vit D2000 units, T4 & T3, 6mg Iodoral

Speedbird, Spam post now deleted. Again. Twice in one day. Annoying.

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems. Mohandas Gandhi