Guest guest Posted May 3, 2005 Report Share Posted May 3, 2005 I think there is some confusion about the action of Metranidazole (Flagyl) here. It's action is intracellular, and it disrupts the structure of DNA in the cell, it doesn't inhibit replication (like most abx do) so it doesn't need a gene which encodes it. It is bacteriacidal, not bacteriastatic. See reference below. My understanding is that the cystic form of Lyme's is anaerobic, hence why an agent like metranidazole is so essential during the stage of the organism which is non-replicating, similar in chlamydia pneumonia. Interesting that the reference below also describes it as " immunosuppressive and antiinflammatory actions " similar to some other abx. My experience of the " metranidazole wall " someone referred to is that it is the toxicity, not the herx, which becomes problematic. THis is the whole principle of pulsing it: giving time to recover from thee toxicity. Jim From: http://sprojects.mmi.mcgill.ca/cases/drugs/Metronidazol/CP_metronidazole_mono.ht\ m Mechanism of Action: Metronidazole is amebicidal, bactericidal, and trichomonicidal. Unionized metronidazole is readily taken up by anaerobic organisms and cells. Its selectivity for anaerobic bacteria is a result of the ability of these organisms to reduce metronidazole to its active form intracellularly. The electron transport proteins necessary for this reaction are found only in anaerobic bacteria. Reduced metronidazole then disrupts DNA's helical structure, thereby inhibiting bacterial nucleic acid synthesis. This eventually results in bacterial cell death. Metronidazole is equally effective against dividing and nondividing cells. Because of its mechanism of action, low molecular weight, and limited binding to serum proteins, metronidazole is a highly lethal antimicrobial. Resistance to metronidazole is almost nonexistent. Metronidazole's spectrum of activity includes protozoa and obligate anaerobes including: Bacteroides group (including B. fragilis), Fusobacterium, Veillonella, the Clostridium group (including C. difficile and C. perfringens), Eubacterium, Peptococcus, and Peptostreptococcus. It is effective against B. fragilis isolates that are resistant to clindamycin. It is not effective against the common aerobes but is active against the aerobe Gardnerella (Haemophilus) vaginalis. The protozoan coverage of metronidazole includes Entamoeba histolytica, Giardia lamblia, and Trichomonas vaginalis Metronidazole also has immunosuppressive and antiinflammatory actions, and it has been used in patients with rosacea. The antimicrobial actions of metronidazole alter the bacterial metabolism of bile acids in the GI tract, decreasing pruritus in patients with cholestasis secondary to primary biliary cirrhosis.[671 And another one from PubMed: Mechanism of action of metronidazole on Bacteroides fragilis. Sigeti JS, Guiney DG Jr, CE. Metronidazole (10 micrograms/ml) was rapidly bactericidal when added to log-phase cultures of Bacteroides fragilis strain 2624. DNA synthesis stopped immediately after addition of metronidazole, whereas synthesis of RNA and protein continued at linear rates for at least 60 min. Gel electrophoresis of DNA extracted from metronidazole-treated cells revealed no nicking or strand breakage in either the 2.9- or 2.0-megadalton plasmid of strain 2624. Also, no degradation of chromosomal DNA was seen. DNA polymerase activity, measured in vitro, was not diminished by prior treatment of the cells with metronidazole. Thus, the primary action of metronidazole is a rapid inhibition of DNA replication. The DNA remains structurally intact, DNA polymerase activity is not directly affected, and cells retain metabolic activity, synthesizing RNA and protein at unaltered rates. PMID: 6197496 [PubMed - indexed for MEDLINE] Quote Link to comment Share on other sites More sharing options...
Guest guest Posted May 3, 2005 Report Share Posted May 3, 2005 Jim, What a HELPFUL post! I love it when information comes me like this, as if on request. A good reminder, too, that Flagyl kills the heck out of all sorts of things. I bet you're right about toxicity vs. herx. Very glad to have you here on I & I. > I think there is some confusion about the action of > Metranidazole (Flagyl) here. It's action is > intracellular, and it disrupts the structure of DNA in > the cell, it doesn't inhibit replication (like most > abx do) so it doesn't need a gene which encodes it. It > is bacteriacidal, not bacteriastatic. See reference > below. My understanding is that the cystic form of > Lyme's is anaerobic, hence why an agent like > metranidazole is so essential during the stage of the > organism which is non-replicating, similar in > chlamydia pneumonia. > > Interesting that the reference below also describes it > as " immunosuppressive and antiinflammatory actions " > similar to some other abx. My experience of the > " metranidazole wall " someone referred to is that it is > the toxicity, not the herx, which becomes problematic. > THis is the whole principle of pulsing it: giving time > to recover from thee toxicity. > Jim > > From: > http://sprojects.mmi.mcgill.ca/cases/drugs/Metronidazol/CP_metronidaz ole_mono.htm > Mechanism of Action: Metronidazole is amebicidal, > bactericidal, and trichomonicidal. Unionized > metronidazole is readily taken up by anaerobic > organisms and cells. Its selectivity for anaerobic > bacteria is a result of the ability of these organisms > to reduce metronidazole to its active form > intracellularly. The electron transport proteins > necessary for this reaction are found only in > anaerobic bacteria. Reduced metronidazole then > disrupts DNA's helical structure, thereby inhibiting > bacterial nucleic acid synthesis. This eventually > results in bacterial cell death. Metronidazole is > equally effective against dividing and nondividing > cells. > > Because of its mechanism of action, low molecular > weight, and limited binding to serum proteins, > metronidazole is a highly lethal antimicrobial. > Resistance to metronidazole is almost nonexistent. > Metronidazole's spectrum of activity includes protozoa > and obligate anaerobes including: Bacteroides group > (including B. fragilis), Fusobacterium, Veillonella, > the Clostridium group (including C. difficile and C. > perfringens), Eubacterium, Peptococcus, and > Peptostreptococcus. It is effective against B. > fragilis isolates that are resistant to clindamycin. > It is not effective against the common aerobes but is > active against the aerobe Gardnerella (Haemophilus) > vaginalis. The protozoan coverage of metronidazole > includes Entamoeba histolytica, Giardia lamblia, and > Trichomonas vaginalis > > Metronidazole also has immunosuppressive and > antiinflammatory actions, and it has been used in > patients with rosacea. The antimicrobial actions of > metronidazole alter the bacterial metabolism of bile > acids in the GI tract, decreasing pruritus in patients > with cholestasis secondary to primary biliary > cirrhosis.[671 > > And another one from PubMed: > Mechanism of action of metronidazole on Bacteroides > fragilis. > > Sigeti JS, Guiney DG Jr, CE. > > Metronidazole (10 micrograms/ml) was rapidly > bactericidal when added to log-phase cultures of > Bacteroides fragilis strain 2624. DNA synthesis > stopped immediately after addition of metronidazole, > whereas synthesis of RNA and protein continued at > linear rates for at least 60 min. Gel electrophoresis > of DNA extracted from metronidazole-treated cells > revealed no nicking or strand breakage in either the > 2.9- or 2.0-megadalton plasmid of strain 2624. Also, > no degradation of chromosomal DNA was seen. DNA > polymerase activity, measured in vitro, was not > diminished by prior treatment of the cells with > metronidazole. Thus, the primary action of > metronidazole is a rapid inhibition of DNA > replication. The DNA remains structurally intact, DNA > polymerase activity is not directly affected, and > cells retain metabolic activity, synthesizing RNA and > protein at unaltered rates. > > PMID: 6197496 [PubMed - indexed for MEDLINE] Quote Link to comment Share on other sites More sharing options...
Guest guest Posted May 3, 2005 Report Share Posted May 3, 2005 Most excellent info. I'm savin' it. Barb > I think there is some confusion about the action of > Metranidazole (Flagyl) here. It's action is > intracellular, and it disrupts the structure of DNA in > the cell, it doesn't inhibit replication (like most > abx do) so it doesn't need a gene which encodes it. It > is bacteriacidal, not bacteriastatic. See reference > below. My understanding is that the cystic form of > Lyme's is anaerobic, hence why an agent like > metranidazole is so essential during the stage of the > organism which is non-replicating, similar in > chlamydia pneumonia. > > Interesting that the reference below also describes it > as " immunosuppressive and antiinflammatory actions " > similar to some other abx. My experience of the > " metranidazole wall " someone referred to is that it is > the toxicity, not the herx, which becomes problematic. > THis is the whole principle of pulsing it: giving time > to recover from thee toxicity. > Jim > > From: > http://sprojects.mmi.mcgill.ca/cases/drugs/Metronidazol/CP_metronidazo le_mono.htm > Mechanism of Action: Metronidazole is amebicidal, > bactericidal, and trichomonicidal. Unionized > metronidazole is readily taken up by anaerobic > organisms and cells. Its selectivity for anaerobic > bacteria is a result of the ability of these organisms > to reduce metronidazole to its active form > intracellularly. The electron transport proteins > necessary for this reaction are found only in > anaerobic bacteria. Reduced metronidazole then > disrupts DNA's helical structure, thereby inhibiting > bacterial nucleic acid synthesis. This eventually > results in bacterial cell death. Metronidazole is > equally effective against dividing and nondividing > cells. > > Because of its mechanism of action, low molecular > weight, and limited binding to serum proteins, > metronidazole is a highly lethal antimicrobial. > Resistance to metronidazole is almost nonexistent. > Metronidazole's spectrum of activity includes protozoa > and obligate anaerobes including: Bacteroides group > (including B. fragilis), Fusobacterium, Veillonella, > the Clostridium group (including C. difficile and C. > perfringens), Eubacterium, Peptococcus, and > Peptostreptococcus. It is effective against B. > fragilis isolates that are resistant to clindamycin. > It is not effective against the common aerobes but is > active against the aerobe Gardnerella (Haemophilus) > vaginalis. The protozoan coverage of metronidazole > includes Entamoeba histolytica, Giardia lamblia, and > Trichomonas vaginalis > > Metronidazole also has immunosuppressive and > antiinflammatory actions, and it has been used in > patients with rosacea. The antimicrobial actions of > metronidazole alter the bacterial metabolism of bile > acids in the GI tract, decreasing pruritus in patients > with cholestasis secondary to primary biliary > cirrhosis.[671 > > And another one from PubMed: > Mechanism of action of metronidazole on Bacteroides > fragilis. > > Sigeti JS, Guiney DG Jr, CE. > > Metronidazole (10 micrograms/ml) was rapidly > bactericidal when added to log-phase cultures of > Bacteroides fragilis strain 2624. DNA synthesis > stopped immediately after addition of metronidazole, > whereas synthesis of RNA and protein continued at > linear rates for at least 60 min. Gel electrophoresis > of DNA extracted from metronidazole-treated cells > revealed no nicking or strand breakage in either the > 2.9- or 2.0-megadalton plasmid of strain 2624. Also, > no degradation of chromosomal DNA was seen. DNA > polymerase activity, measured in vitro, was not > diminished by prior treatment of the cells with > metronidazole. Thus, the primary action of > metronidazole is a rapid inhibition of DNA > replication. The DNA remains structurally intact, DNA > polymerase activity is not directly affected, and > cells retain metabolic activity, synthesizing RNA and > protein at unaltered rates. > > PMID: 6197496 [PubMed - indexed for MEDLINE] Quote Link to comment Share on other sites More sharing options...
Guest guest Posted May 3, 2005 Report Share Posted May 3, 2005 Metronidazole in itself is inactive... it becomes active when reduced by certain enzymes, as Jims ref says. This is almost certainly what is meant by the statement that a bacterium needs to express certain gene(s) - genes encoding such enzyme(s) - in order to be sensitive to metronidazole. I wouldnt know whether any bacterium can be unequivocally stated to lack any genes suitable for reducing metronidazole at an appreciable rate. I was under the very vague impression that all bacterial taxa had many genes whose products and functions are yet unknown, but that could be totally wrong - and perhaps there is a way to prove, without knowing its function positiviely, that a certain gene does not code a reducing enzyme. I wouldnt know. This paper, posted by Matt when he discussed metro, suggests that under some circumstances multiple classes of enzymes may be able to contribute to reduction of metro, at least in a some amount (Discussion, paragraph 2). One would have to do some quantitative reckoning to decide whether these phenomena might be theraputically relevant. http://jb.asm.org/cgi/content/full/182/18/50 Finally, I think to decide whether Bb can be sensitive to metro one really needs to examine the Brorsons empirical work on the subject, and herxoid experiences described by patients. SOmething also of interest in this question would be Wheldons assertion (I think) that doxy and azithromycin cause Cpn to become metro-sensitive or more metro-sensitive. Also, another factor re metro in general is that the presence of much oxygen may reconvert the reduced, active metro back into inactive from, spontaneously, without enzymatic action - I cant remember where I read that, or if I totally made it up - anyway heres the other paper Matt posted, which addresses some of this chemistry: http://www.ub.rug.nl/eldoc/dis/medicine/e.j.van.der.wouden/c8.pdf > I think there is some confusion about the action of > Metranidazole (Flagyl) here. It's action is > intracellular, and it disrupts the structure of DNA in > the cell, it doesn't inhibit replication (like most > abx do) so it doesn't need a gene which encodes it. It > is bacteriacidal, not bacteriastatic. See reference > below. My understanding is that the cystic form of > Lyme's is anaerobic, hence why an agent like > metranidazole is so essential during the stage of the > organism which is non-replicating, similar in > chlamydia pneumonia. > > Interesting that the reference below also describes it > as " immunosuppressive and antiinflammatory actions " > similar to some other abx. My experience of the > " metranidazole wall " someone referred to is that it is > the toxicity, not the herx, which becomes problematic. > THis is the whole principle of pulsing it: giving time > to recover from thee toxicity. > Jim > > From: > http://sprojects.mmi.mcgill.ca/cases/drugs/Metronidazol/CP_metronidazole_mono.ht\ m > Mechanism of Action: Metronidazole is amebicidal, > bactericidal, and trichomonicidal. Unionized > metronidazole is readily taken up by anaerobic > organisms and cells. Its selectivity for anaerobic > bacteria is a result of the ability of these organisms > to reduce metronidazole to its active form > intracellularly. The electron transport proteins > necessary for this reaction are found only in > anaerobic bacteria. Reduced metronidazole then > disrupts DNA's helical structure, thereby inhibiting > bacterial nucleic acid synthesis. This eventually > results in bacterial cell death. Metronidazole is > equally effective against dividing and nondividing > cells. > > Because of its mechanism of action, low molecular > weight, and limited binding to serum proteins, > metronidazole is a highly lethal antimicrobial. > Resistance to metronidazole is almost nonexistent. > Metronidazole's spectrum of activity includes protozoa > and obligate anaerobes including: Bacteroides group > (including B. fragilis), Fusobacterium, Veillonella, > the Clostridium group (including C. difficile and C. > perfringens), Eubacterium, Peptococcus, and > Peptostreptococcus. It is effective against B. > fragilis isolates that are resistant to clindamycin. > It is not effective against the common aerobes but is > active against the aerobe Gardnerella (Haemophilus) > vaginalis. The protozoan coverage of metronidazole > includes Entamoeba histolytica, Giardia lamblia, and > Trichomonas vaginalis > > Metronidazole also has immunosuppressive and > antiinflammatory actions, and it has been used in > patients with rosacea. The antimicrobial actions of > metronidazole alter the bacterial metabolism of bile > acids in the GI tract, decreasing pruritus in patients > with cholestasis secondary to primary biliary > cirrhosis.[671 > > And another one from PubMed: > Mechanism of action of metronidazole on Bacteroides > fragilis. > > Sigeti JS, Guiney DG Jr, CE. > > Metronidazole (10 micrograms/ml) was rapidly > bactericidal when added to log-phase cultures of > Bacteroides fragilis strain 2624. DNA synthesis > stopped immediately after addition of metronidazole, > whereas synthesis of RNA and protein continued at > linear rates for at least 60 min. Gel electrophoresis > of DNA extracted from metronidazole-treated cells > revealed no nicking or strand breakage in either the > 2.9- or 2.0-megadalton plasmid of strain 2624. Also, > no degradation of chromosomal DNA was seen. DNA > polymerase activity, measured in vitro, was not > diminished by prior treatment of the cells with > metronidazole. Thus, the primary action of > metronidazole is a rapid inhibition of DNA > replication. The DNA remains structurally intact, DNA > polymerase activity is not directly affected, and > cells retain metabolic activity, synthesizing RNA and > protein at unaltered rates. > > PMID: 6197496 [PubMed - indexed for MEDLINE] Quote Link to comment Share on other sites More sharing options...
Guest guest Posted May 3, 2005 Report Share Posted May 3, 2005 Jim Thanks for referring us to Stratton's patent a while back. I read it this weekend and it was very informative. Am I reading it wrong, or have they solved the problem posed by these papers?: http://tinyurl.com/cbc76 PMID: 12760877 http://tinyurl.com/dhj2t PMID: 11157684 These two papers have been in my " PubMed's Top 10 Most Upsetting Citations " list. It seems that Dr. Stratton has been developing assays and collecting data that can not be found on PubMed. Is that right? Your first reference states: " Resistance to metronidazole is almost nonexistent. " My read on metronidazole is quite different. This statement not only seems to be wrong, it implies that one can take small doses of nitroimidazoles without concern for the development of resistance. Here are some citations suggesting that resistance is something we need to take seriously: http://tinyurl.com/dc9lp PMID: 12951241 http://tinyurl.com/7gwj6 PMID: 12160635 http://tinyurl.com/8d6sp PMID: 11814762 This book chapter: http://www.ub.rug.nl/eldoc/dis/medicine/e.j.van.der.wouden/c8.pd f or try this link, if the one above is not clickable: http://tinyurl.com/b26zb says, " As metabolites of nitroimidazoles are mutagenic the use of a nitroimidazole results in an increased mutation frequency in all genes, including the rdxA gene. This causes a rapid induction of nitroimidazole resistant mutants. Moreover, in the presence of a nitroimidazole the resistant mutants have a survival advantage over the susceptible strains. A nitroimidazole, therefore, both induces the mutation leading to nitroimidazole resistance and selects these mutants. It is, therefore, not unexpected that nitroimidazole resistance in H. pylori is so rapidly observed after the use of a nitroimidazole containing treatment. " This next paper not only discusses the tendency for sublethal doses to cause mutations in the bacteria, but also shows that this can " stimulate forward mutations to rifampin resistance " : http://tinyurl.com/86r7w PMID: 10960092 So not only can bacteria become resistant to nitroimidazoles, the use of sublethal doses of nitroimidazoles can lead to resistance against unrelated antibiotics. This is stated in Pfizer's product insert: http://www.pfizer.com/download/uspi_flagyl_375.pdf " Skipping doses or not completing the full course of therapy may decrease the effectiveness of the immediate treatment and increase the likelihood that bacteria will develop resistance and will not be treatable by Flagyl OR OTHER ANTIBACTERIAL DRUGS in the future. " (See page 5; I've capitalized the most relevant words). Notice also that the second-to-last of my citations refers to the ability of nitroimidazoles to induce DNA strand breakage. This contradicts the findings of your second citation. So I think the behavior of nitroimidazoles is still being worked out, and may be species-dependent. Matt > I think there is some confusion about the action of > Metranidazole (Flagyl) here. It's action is > intracellular, and it disrupts the structure of DNA in > the cell, it doesn't inhibit replication (like most > abx do) so it doesn't need a gene which encodes it. It > is bacteriacidal, not bacteriastatic. See reference > below. My understanding is that the cystic form of > Lyme's is anaerobic, hence why an agent like > metranidazole is so essential during the stage of the > organism which is non-replicating, similar in > chlamydia pneumonia. > > Interesting that the reference below also describes it > as " immunosuppressive and antiinflammatory actions " > similar to some other abx. My experience of the > " metranidazole wall " someone referred to is that it is > the toxicity, not the herx, which becomes problematic. > THis is the whole principle of pulsing it: giving time > to recover from thee toxicity. > Jim > > From: > http://sprojects.mmi.mcgill.ca/cases/drugs/Metronidazol/CP_met ronidazole_mono.htm > Mechanism of Action: Metronidazole is amebicidal, > bactericidal, and trichomonicidal. Unionized > metronidazole is readily taken up by anaerobic > organisms and cells. Its selectivity for anaerobic > bacteria is a result of the ability of these organisms > to reduce metronidazole to its active form > intracellularly. The electron transport proteins > necessary for this reaction are found only in > anaerobic bacteria. Reduced metronidazole then > disrupts DNA's helical structure, thereby inhibiting > bacterial nucleic acid synthesis. This eventually > results in bacterial cell death. Metronidazole is > equally effective against dividing and nondividing > cells. > > Because of its mechanism of action, low molecular > weight, and limited binding to serum proteins, > metronidazole is a highly lethal antimicrobial. > Resistance to metronidazole is almost nonexistent. > Metronidazole's spectrum of activity includes protozoa > and obligate anaerobes including: Bacteroides group > (including B. fragilis), Fusobacterium, Veillonella, > the Clostridium group (including C. difficile and C. > perfringens), Eubacterium, Peptococcus, and > Peptostreptococcus. It is effective against B. > fragilis isolates that are resistant to clindamycin. > It is not effective against the common aerobes but is > active against the aerobe Gardnerella (Haemophilus) > vaginalis. The protozoan coverage of metronidazole > includes Entamoeba histolytica, Giardia lamblia, and > Trichomonas vaginalis > > Metronidazole also has immunosuppressive and > antiinflammatory actions, and it has been used in > patients with rosacea. The antimicrobial actions of > metronidazole alter the bacterial metabolism of bile > acids in the GI tract, decreasing pruritus in patients > with cholestasis secondary to primary biliary > cirrhosis.[671 > > And another one from PubMed: > Mechanism of action of metronidazole on Bacteroides > fragilis. > > Sigeti JS, Guiney DG Jr, CE. > > Metronidazole (10 micrograms/ml) was rapidly > bactericidal when added to log-phase cultures of > Bacteroides fragilis strain 2624. DNA synthesis > stopped immediately after addition of metronidazole, > whereas synthesis of RNA and protein continued at > linear rates for at least 60 min. Gel electrophoresis > of DNA extracted from metronidazole-treated cells > revealed no nicking or strand breakage in either the > 2.9- or 2.0-megadalton plasmid of strain 2624. Also, > no degradation of chromosomal DNA was seen. DNA > polymerase activity, measured in vitro, was not > diminished by prior treatment of the cells with > metronidazole. Thus, the primary action of > metronidazole is a rapid inhibition of DNA > replication. The DNA remains structurally intact, DNA > polymerase activity is not directly affected, and > cells retain metabolic activity, synthesizing RNA and > protein at unaltered rates. > > PMID: 6197496 [PubMed - indexed for MEDLINE] Quote Link to comment Share on other sites More sharing options...
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