Difference between revisions of "Metronidazole"

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| IUPAC_name =  2-(2- methyl- 5-nitro- 1''H''- imidazol- 1-yl) ethanol
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| routes_of_administration = oral, [[topical]], [[suppository|rectal]], [[intravenous|IV]], [[vaginal]]
 
| routes_of_administration = oral, [[topical]], [[suppository|rectal]], [[intravenous|IV]], [[vaginal]]
 
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'''Metronidazole''' ([[International Nonproprietary Name|INN]]) ({{pronEng|mɛtrəˈnaɪdəzoʊl}}) is a [[nitroimidazole]] [[antibiotic]] medication used particularly for [[anaerobe|anaerobic]] [[bacterium|bacteria]] and [[protozoa]]. Metronidazole is an antibiotic, amebicide, and antiprotozoal.<ref>Merck Manual for Professionals http://www.merck.com/mmpe/lexicomp/metronidazole.html</ref> It is the drug of choice for first episodes of mild-to-moderate ''Clostridium difficile'' infection.<ref>The Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America, guidelines for the management of Clostridium difficile infection, Infection Control and Hospital Epidemiology. http://www.journals.uchicago.edu/toc/iche/0/0 Accessed Mar. 22, 2010 9:00am. Article will appear shortly.</ref> It is marketed by [[Pfizer]] under the trade name '''Flagyl''' in the US, by [[Sanofi-Aventis]] globally under the same tradename '''Flagyl''', and by various generic manufacturers.
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'''Metronidazole''' ([[International Nonproprietary Name|INN]]) ({{pronEng|mɛtrəˈnaɪdəzoʊl}}) is a [[nitroimidazole]] [[antibiotic]] medication used particularly for [[anaerobe|anaerobic]] [[bacterium|bacteria]] and [[protozoa]]. Metronidazole is an antibiotic, amebicide, and antiprotozoal.<ref>[http://www.merck.com/mmpe/lexicomp/metronidazole.html Merck Manual for Professionals]</ref> It is the drug of choice for first episodes of mild-to-moderate ''[[Clostridium difficile]]'' infection.<ref>The Society for Healthcare Epidemiology of America and the Infectiouslogy]. Accessed Mar. 22, 2010 9:00am.</ref> It is marketed by [[Pfizer]] under the trade name '''Flagyl''' in the US, by [[Sanofi-Aventis]] globally under the same tradename '''Flagyl''', in '''Pakistan''' it is also available with the brand name of '''Nidagyl''' manufactured and marketed by '''Star Laboratories'''. In Thailand it  is marketed as '''Mepagyl''' by Thai Nakhorn Patana.
  
 
Metronidazole is also used as a gel preparation in the treatment of the [[dermatology|dermatological]] conditions such as [[rosacea]] ('''Rozex''' and '''MetroGel''' by [[Galderma]]) and [[neoplasia|fungating]] [[tumour]]s ('''Anabact''', Cambridge Healthcare Supplies).
 
Metronidazole is also used as a gel preparation in the treatment of the [[dermatology|dermatological]] conditions such as [[rosacea]] ('''Rozex''' and '''MetroGel''' by [[Galderma]]) and [[neoplasia|fungating]] [[tumour]]s ('''Anabact''', Cambridge Healthcare Supplies).
  
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== Mechanism of Action ==
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==Mechanism of action==
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Metronidazole, taken up by diffusion, is selectively absorbed by [[anaerobic bacteria]] and sensitive [[protozoa]]. Once taken up by anaerobes, it is non-enzymatically reduced by reacting with reduced [[ferredoxin]], which is generated by pyruvate:ferredoxin oxido-reductase. This reduction causes the production of toxic products to anaerobic cells, and allows for selective accumulation in anaerobes.
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Metronidazole, taken up by diffusion, is selectively absorbed by [[anaerobic bacteria]] and sensitive [[protozoa]]. Once taken up by anaerobes, it is non-enzymatically reduced by reacting with reduced [[ferredoxin]], which is generated by pyruvate oxido-reductase. This reduction causes the production of toxic products to anaerobic cells, and allows for selective accumulation in anaerobes.
  
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The metronidazole metabolites are taken up into bacterial DNA, and form unstable molecules. This function only occurs when metronidazole is partially reduced, and because this reduction usually happens only in anaerobic cells, it has relatively little effect upon human cells or [[aerobic bacteria]].<ref>{{cite book |first1=Barry I. |last1=Eisenstein |first2=Moselio |last2=Schaechter |chapter=DNA and Chromosome Mechanics |chapterurl=http://books.google.com/books?id=1Zl70SLDU3oC&pg=PA28 |editor1-first=Moselio |editor1-last=Schaechter |editor2-first=N. Cary |editor2-last=Engleberg |editor3-first=Victor J. |editor3-last=DiRita |editor4-first=Terence |editor4-last=Dermody |title=Schaechter's mechanisms of microbial disease |publisher=Lippincott Williams & Wilkins |location=Hagerstwon, MD |year=2007 |page=28 |isbn=978-0-7817-5342-5}}</ref>
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The metronidazole metabolites are taken up into bacterial DNA, and form unstable molecules. This function only occurs when metronidazole is partially reduced, and because this reduction usually happens only in anaerobic cells, it has relatively little effect upon human cells or [[aerobic bacteria]].<ref>{{Cite book|first1=Barry I. |last1=Eisenstein |first2=Moselio |last2=Schaechter |chapter=DNA and Chromosome Mechanics |chapterurl=http://books.google.com/books?id=1Zl70SLDU3oC&pg=PA28 |editor1-first=Moselio |editor1-last=Schaechter |editor2-first=N. Cary |editor2-last=Engleberg |editor3-first=Victor J. |editor3-last=DiRita |editor4-first=Terence |editor4-last=Dermody |title=Schaechter's mechanisms of microbial disease |publisher=Lippincott Williams & Wilkins |location=Hagerstwon, MD |year=2007 |page=28 |isbn=978-0-7817-5342-5}}</ref>
  
 
==Indications==
 
==Indications==
 
Systemic metronidazole is indicated for the treatment of:
 
Systemic metronidazole is indicated for the treatment of:
 +
 
===Bacterial===
 
===Bacterial===
 
{{Unreferenced section|date=February 2010}}
 
{{Unreferenced section|date=February 2010}}
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* [[Bacterial vaginosis]], commonly associated with overgrowth of ''[[Gardnerella]]'' species and coinfective anaerobes (Mobiluncus, Bacteroides), in symptomatic patients
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*[[Bacterial vaginosis]], commonly associated with overgrowth of ''[[Gardnerella]]'' species and coinfective anaerobes (Mobiluncus, Bacteroides), in symptomatic patients
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*[[Pelvic inflammatory disease]] in conjunction with other antibiotics such as [[ofloxacin]], [[levofloxacin]], or [[ceftriaxone]]  
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*[[Pelvic inflammatory disease]] in conjunction with other antibiotics such as [[ofloxacin]], [[levofloxacin]], or [[ceftriaxone]]
 
*Anaerobic bacterial infections such as ''[[Bacteroides|Bacteroides fragilis, spp]]'', ''[[Fusobacterium|Fusobacterium spp]]'', ''[[Clostridium|Clostridium spp]]'', ''[[peptococcus|Peptococcus spp]]'',  ''[[Peptostreptococcus|Peptostreptococcus spp]]'', ''[[Prevotella|Prevotella spp]]'', or any other anaerobes in [[intra-abdominal abscess]], [[peritonitis]], [[empyema]], [[pneumonia]], [[aspiration pneumonia]], [[lung abscess]], diabetic foot ulcer, meningitis and [[brain abscess]], bone and joint infections, septicemia, [[endometritis]], [[tubo-ovarian abscess]], or [[endocarditis]]
 
*Anaerobic bacterial infections such as ''[[Bacteroides|Bacteroides fragilis, spp]]'', ''[[Fusobacterium|Fusobacterium spp]]'', ''[[Clostridium|Clostridium spp]]'', ''[[peptococcus|Peptococcus spp]]'',  ''[[Peptostreptococcus|Peptostreptococcus spp]]'', ''[[Prevotella|Prevotella spp]]'', or any other anaerobes in [[intra-abdominal abscess]], [[peritonitis]], [[empyema]], [[pneumonia]], [[aspiration pneumonia]], [[lung abscess]], diabetic foot ulcer, meningitis and [[brain abscess]], bone and joint infections, septicemia, [[endometritis]], [[tubo-ovarian abscess]], or [[endocarditis]]
 
*[[Pseudomembranous colitis]] due to ''[[Clostridium difficile]]''
 
*[[Pseudomembranous colitis]] due to ''[[Clostridium difficile]]''
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===Protozoal===
 
===Protozoal===
 
{{Unreferenced section|date=February 2010}}
 
{{Unreferenced section|date=February 2010}}
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[[Amoebiasis]]: Infections caused by [[Entamoeba histolytica]].
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[[Amoebiasis]]: Infections caused by ''[[Entamoeba histolytica]]''.
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[[Giardiasis]]: infection of the small intestine caused by the ingestion of infective cysts of a single-celled organism called Giardia lamblia. Giardiasis occurs worldwide with a prevalence of 20–30% in developing countries. The Centers for Disease Control and Prevention reports that in the US Giardia infects over 2.5 million people annually. There are multiple modes of transmission including person-to-person, water-borne, and venereal. Person-to-person transmission accounts for a majority of Giardia infections and is usually associated with poor hygiene and sanitation. Water-borne transmission is common in United States Giardia epidemics, which are often associated with the ingestion of unfiltered water (contaminated). Venereal transmission happens through fecal-oral contamination. Additionally, diaper changing and inadequate hand washing are risk factors for transmission from infee epidemics of Giardia have developed through the contamination of food by infected food-handlers.
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[[Giardiasis]]: infection of the small intestine caused by the ingestion of infective cysts of a single-celled organism called ''[[Giardia lamblia]]''. Giardiasis occurs worldwide with a prevalence of 20–30% in developing countries. The Centers for Disease Control and Prevention reports that in the US Giardia infects over 2.5 million people annually. There are multiple modes of transmission including person-to-person, water-borne, and venereal. Person-to-person transmission accounts for a majority of Giardia infections and is usually associated with poor hygiene and sanitation. Water-borne transmission is common in United States. Giardia epidemics, which are often associated with the ingestion of unfiltered water (contaminated). Venereal transmission happens through fecal-oral contamination. Additionally, diaper changing and inadequate hand washing are risk factors for transmission from infee epidemics of Giardia have developed through the contamination of food by infected food-handlers.
  
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[[Trichomoniasis]]: infection caused by [[Trichomonas vaginalis]], which is a common cause of [[vaginitis]] and is the most frequently presenting new infection of the common sexually transmitted diseases.<ref>Associated Press, [http://www.msnbc.msn.com/id/18093769/ Abstinence students still having sex], [[MSNBC]], April 16, 2007.  Retrieved March 12, 2008.</ref>
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[[Trichomoniasis]]: infection caused by ''[[Trichomonas vaginalis]]'', which is a common cause of [[vaginitis]] and is the most frequently presenting new infection of the common sexually transmitted diseases.<ref>Associated Press, [http://www.msnbc.msn.com/id/18093769/ Abstinence students still having sex], [[MSNBC]], April 16, 2007.  Retrieved March 12, 2008.</ref>
  
 
A small number of infected individuals experience an abrupt onset of abdominal cramps, explosive, watery diarrhea, vomiting, foul flatus, and fever which may last for 3–4 days before proceeding into a more sub-acute phase. The majority of infected persons develop gradual symptoms that become recurrent or resistant.
 
A small number of infected individuals experience an abrupt onset of abdominal cramps, explosive, watery diarrhea, vomiting, foul flatus, and fever which may last for 3–4 days before proceeding into a more sub-acute phase. The majority of infected persons develop gradual symptoms that become recurrent or resistant.
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In both the acute and insidious onsets of symptoms, stools become greasy and malodorous but do not contain blood or pus because giardiasis does not involve dysenteric symptoms. Watery diarrhea may cycle with soft stools and constipation. Upper GI symptoms including nausea, early satiety, bloating, substernal burning, egg-smelling halitosis, and acid indigestion may be exacerbated by eating and are generally present in the absence of soft stools.
 
In both the acute and insidious onsets of symptoms, stools become greasy and malodorous but do not contain blood or pus because giardiasis does not involve dysenteric symptoms. Watery diarrhea may cycle with soft stools and constipation. Upper GI symptoms including nausea, early satiety, bloating, substernal burning, egg-smelling halitosis, and acid indigestion may be exacerbated by eating and are generally present in the absence of soft stools.
  
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'''Treatment with metronidazole'''
  
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'''Treatment with Metronidazole'''
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Adult dosage: 250&nbsp;mg three times a day for 5 days, or 400&nbsp;mg 3 times a day for 7 days.
 +
Alternative: 2000&nbsp;mg one time only.
  
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Adult dosage: 250 mg three times a day for 5 days.
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Metronidazole should always be taken with a large glass of water and with or after food.
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Alternative: 2000mg one time only
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Pediatric dosage: 15 mg per kilogram of body weight per dose, 3 times per day, for 5 days
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Pediatric dosage: 15&nbsp;mg per kilogram of body weight per dose, 3 times per day, for 5 days
  
 
===Nonspecific===
 
===Nonspecific===
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*Acute [[gingivitis]] and other dental infections ([[Therapeutic Goods Administration|TGA]] approved, non-[[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA) approved)
 
*Acute [[gingivitis]] and other dental infections ([[Therapeutic Goods Administration|TGA]] approved, non-[[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA) approved)
 
*[[Crohn's disease]] with colonic or perianal involvement (non-FDA approved){{ndash}} believed to be more effective in combination with [[ciprofloxacin]]{{Citation needed|date=February 2010}}
 
*[[Crohn's disease]] with colonic or perianal involvement (non-FDA approved){{ndash}} believed to be more effective in combination with [[ciprofloxacin]]{{Citation needed|date=February 2010}}
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*Topical metronidazole is indicated for the treatment of [[rosacea]], and in the treatment of malodorous [[neoplasia|fungating]] wounds.<ref name="AMH2006">{{cite book |editor1-last=Rossi |editor1-first=Simone |title=[[Australian Medicines Handbook]] 2006 | publisher=Australian Medicines Handbook Pty Ltd |location=Adelaide |year=2006 |isbn=978-0-9757919-2-9 |oclc=224831213}}{{pn}}</ref>
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*Topical metronidazole is indicated for the treatment of [[rosacea]], and in the treatment of malodorous [[neoplasia|fungating]] wounds.<ref name="AMH2006">{{Cite book|editor1-last=Rossi |editor1-first=Simone |title=[[Australian Medicines Handbook]] 2006|publisher=Australian Medicines Handbook Pty Ltd |location=Adelaide |year=2006 |isbn=978-0-9757919-2-9 |oclc=224831213}}{{Page needed|date=September 2010}}</ref>
  
 
===Prevention of preterm births===
 
===Prevention of preterm births===
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A 2005 study found "Metronidazole therapy before 32 weeks was associated with an increased risk of preterm birth", possibly as a result of "changes in the vaginal flora… seen with vaginal clindamycin or oral metronidazole therapy."<ref name="Carey et al. 2005">{{cite journal |author=Carey JC, Klebanoff MA |title=Is a change in the vaginal flora associated with an increased risk of preterm birth? |journal=American Journal of Obstetrics and Gynecology |volume=192 |issue=4 |pages=1341–6; discussion 1346–7 |year=2005 |month=April |pmid=15846235 |doi=10.1016/j.ajog.2004.12.069}}</ref>
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A 2005 study found "Metronidazole therapy before 32 weeks was associated with an increased risk of preterm birth", possibly as a result of "changes in the vaginal flora… seen with vaginal clindamycin or oral metronidazole therapy."<ref name="Carey et al. 2005">{{Cite journal|author=Carey JC, Klebanoff MA |title=Is a change in the vaginal flora associated with an increased risk of preterm birth? |journal=American Journal of Obstetrics and Gynecology |volume=192 |issue=4 |pages=1341–6; discussion 1346–7 |year=2005 |pmid=15846235 |doi=10.1016/j.ajog.2004.12.069}}</ref>
  
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Metronidazole has also been used in women to prevent preterm birth associated with [[bacterial vaginosis]], amongst other risk factors including the presence of cervicovaginal fetal fibronectin (fFN). A [[randomised controlled trial]] demonstrated that metronidazole was ineffective in preventing preterm delivery in high-risk pregnant women and, conversely, the incidence of preterm delivery was actually higher in women treated with metronidazole.<ref name="Shennan2006">{{cite journal |author=Shennan A, Crawshaw S, Briley A, ''et al.'' |title=A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study |journal=BJOG |volume=113 |issue=1 |pages=65–74 |year=2006 |month=January |pmid=16398774 |doi=10.1111/j.1471-0528.2005.00788.x}}</ref>
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Metronidazole has also been used in women to prevent preterm birth associated with [[bacterial vaginosis]], amongst other risk factors including the presence of cervicovaginal fetal fibronectin (fFN). A [[randomised controlled trial]] demonstrated that metronidazole was ineffective in preventing preterm delivery in high-risk pregnant women and, conversely, the incidence of preterm delivery was actually higher in women treated with metronidazole.<ref name="Shennan2006">{{Cite journal|author=Shennan A, Crawshaw S, Briley A, ''et al.'' |title=A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study |journal=BJOG |volume=113 |issue=1 |pages=65–74 |year=2006 |pmid=16398774 |doi=10.1111/j.1471-0528.2005.00788.x}}</ref>
  
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Lamont has argued that Metronidazole is not the right antibiotic to administer in these circumstances and was often administered too late to be of use. [[Clindamycin]] administered early in the second trimester to women who test positive for [[bacterial vaginosis]] seems to be more effective.<ref name="Lamont2005">{{cite journal |author=Lamont RF |title=Can antibiotics prevent preterm birth--the pro and con debate |journal=BJOG |volume=112 |issue=Suppl 1 |pages=67–73 |year=2005 |month=March |pmid=15715599 |doi=10.1111/j.1471-0528.2005.00589.x}}</ref>
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Lamont has argued that Metronidazole is not the right antibiotic to administer in these circumstances and was often administered too late to be of use. [[Clindamycin]] administered early in the second trimester to women who test positive for [[bacterial vaginosis]] seems to be more effective.<ref name="Lamont2005">{{Cite journal|author=Lamont RF |title=Can antibiotics prevent preterm birth--the pro and con debate |journal=BJOG |volume=112 |issue=Suppl 1 |pages=67–73 |year=2005 |pmid=15715599 |doi=10.1111/j.1471-0528.2005.00589.x}}</ref>
  
 
==Adverse effects==
 
==Adverse effects==
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Common [[adverse drug reaction]]s (≥1% of patients) associated with [[systemic]] metronidazole therapy include: [[nausea]], [[diarrhea]], and/or metallic taste in the mouth. [[Intravenous]] administration is commonly associated with [[thrombophlebitis]]. Infrequent adverse effects include: [[hypersensitivity]] reactions (rash, itch, flushing, fever), headache, dizziness, [[vomiting]], [[glossitis]], [[stomatitis]], dark urine, and/or [[paraesthesia]].<ref name="AMH2006" />
 
Common [[adverse drug reaction]]s (≥1% of patients) associated with [[systemic]] metronidazole therapy include: [[nausea]], [[diarrhea]], and/or metallic taste in the mouth. [[Intravenous]] administration is commonly associated with [[thrombophlebitis]]. Infrequent adverse effects include: [[hypersensitivity]] reactions (rash, itch, flushing, fever), headache, dizziness, [[vomiting]], [[glossitis]], [[stomatitis]], dark urine, and/or [[paraesthesia]].<ref name="AMH2006" />
  
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High doses and/or long-term systemic treatment with metronidazole is associated with the development of [[black hairy tongue]], [[leukopenia]], [[neutropenia]], increased risk of [[peripheral neuropathy]] and/or [[central nervous system|CNS]] toxicity.<ref name="AMH2006" />
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High doses and/or long-term systemic treatment with metronidazole is associated with the development of
 +
[[leukopenia]], [[neutropenia]], increased risk of [[peripheral neuropathy]] and/or [[central nervous system|CNS]] toxicity.<ref name="AMH2006" />
  
 
Metronidazole is listed by the US [[National Toxicology Program]] (NTP) as reasonably anticipated to be a human [[carcinogen]]. Although some of the testing methods have been questioned, it has been shown to cause cancer in experimental animals.<ref name=RoC /> Yet, metronidazole was shown to be safe in humans.<ref name=RoC>
 
Metronidazole is listed by the US [[National Toxicology Program]] (NTP) as reasonably anticipated to be a human [[carcinogen]]. Although some of the testing methods have been questioned, it has been shown to cause cancer in experimental animals.<ref name=RoC /> Yet, metronidazole was shown to be safe in humans.<ref name=RoC>
  
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{{cite web
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{{Cite web
 
|url=http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s112metr.pdf
 
|url=http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s112metr.pdf
 
|title=Metronidazole CAS No. 443-48-1
 
|title=Metronidazole CAS No. 443-48-1
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|accessdate=2009-12-11
 
|accessdate=2009-12-11
 
}}</ref><ref>[http://www.pfizer.com/pfizer/download/uspi_flagyl_375.pdf ''Flagyl 375 U.S. Prescribing Information''] Pfizer  (PDF)</ref> It appears to have a fairly low potential for cancer risk and under most circumstances the benefits of treatment outweigh the risk. Metronidazole is listed as a possible carcinogen according to the [[WHO]] [[International Agency for Research on Cancer]] (IARC).<ref>
 
}}</ref><ref>[http://www.pfizer.com/pfizer/download/uspi_flagyl_375.pdf ''Flagyl 375 U.S. Prescribing Information''] Pfizer  (PDF)</ref> It appears to have a fairly low potential for cancer risk and under most circumstances the benefits of treatment outweigh the risk. Metronidazole is listed as a possible carcinogen according to the [[WHO]] [[International Agency for Research on Cancer]] (IARC).<ref>
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{{cite web
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{{Cite web
 
|url=http://monographs.iarc.fr/ENG/Classification/index.php
 
|url=http://monographs.iarc.fr/ENG/Classification/index.php
 
|title= Agents Classified by the IARC Monographs, Volumes 1–100
 
|title= Agents Classified by the IARC Monographs, Volumes 1–100
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Because metronidazole is an important drug in treatment of human pathogens including C. difficile, metronidazole is banned in the [[EU]] and the [[USA]] for veterinary use in the feed of animals and is banned for use in any food animals in the [[USA]].<ref>
 
Because metronidazole is an important drug in treatment of human pathogens including C. difficile, metronidazole is banned in the [[EU]] and the [[USA]] for veterinary use in the feed of animals and is banned for use in any food animals in the [[USA]].<ref>
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{{cite web
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{{Cite web
 
|url=http://www.emea.europa.eu/pdfs/vet/mrls/017396en.pdf
 
|url=http://www.emea.europa.eu/pdfs/vet/mrls/017396en.pdf
 
|title=Metronidazole Summary Report EMEA/MRL/173/96-FINAL
 
|title=Metronidazole Summary Report EMEA/MRL/173/96-FINAL
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|accessdate=2009-12-11
 
|accessdate=2009-12-11
 
}}</ref><ref>
 
}}</ref><ref>
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{{cite web
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{{Cite web
 
|url=http://www.farad.org/eldu/prohibit.html
 
|url=http://www.farad.org/eldu/prohibit.html
 
|title= FDA's prohibited drug list
 
|title= FDA's prohibited drug list
 
|work=Food Animal Residue Avoidance and Depletion Program (FARAD)
 
|work=Food Animal Residue Avoidance and Depletion Program (FARAD)
 
|publisher = [[USA Food and Drug Administration]]
 
|publisher = [[USA Food and Drug Administration]]
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|format=html
 
 
|year=2010
 
|year=2010
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|month=unk
 
 
|accessdate=2010-06-06
 
|accessdate=2010-06-06
 
}}</ref>
 
}}</ref>
  
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Earlier studies suggested a relation between metronidazole and various birth defects. Those studies are nowadays considered flawed and more recent studies "do not support a significant increased risk for birth defects or other adverse effects on the fetus."<ref name="otis">OTIS: Metronidazole (Flagyl®) and Pregnancy. http://www.otispregnancy.org/pdf/Flagyl.pdf</ref>
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Earlier studies suggested a relation between metronidazole and various birth defects. Those studies are nowadays considered flawed and more recent studies "do not support a significant increased risk for birth defects or other adverse effects on the fetus."<ref name="otis">OTIS: [http://www.otispregnancy.org/pdf/Flagyl.pdf Metronidazole (Flagyl®) and Pregnancy]</ref>
  
 
Common adverse drug reactions associated with topical metronidazole therapy include local redness, dryness, and/or skin irritation; and eye watering (if applied near eyes).<ref name="AMH2006" />
 
Common adverse drug reactions associated with topical metronidazole therapy include local redness, dryness, and/or skin irritation; and eye watering (if applied near eyes).<ref name="AMH2006" />
  
 
===Interaction with alcohol===
 
===Interaction with alcohol===
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Consuming [[ethanol]] (alcohol) while using metronidazole has long been thought to have a [[disulfiram]]-like reaction with effects that can include [[nausea]], [[vomiting]], [[flushing (physiology)|flushing]] of the skin, [[tachycardia]] (accelerated heart rate), and [[shortness of breath]],<ref name="cina">{{cite journal |author=Cina SJ, Russell RA, Conradi SE |title=Sudden death due to metronidazole/ethanol interaction |journal=The American Journal of Forensic Medicine and Pathology |volume=17 |issue=4 |pages=343–6 |year=1996 |month=December |pmid=8947362 |doi=10.1097/00000433-199612000-00013}}</ref> however there are studies calling that notion into question.<ref>{{cite journal |author=Gupta NK, Woodley CL, Fried R |title=Effect of metronidazole on liver alcohol dehydrogenase |journal=Biochemical Pharmacology |volume=19 |issue=10 |pages=2805–8 |year=1970 |month=October |pmid=4320226 |doi=10.1016/0006-2952(70)90108-5}}</ref> Consumption of alcohol should be avoided by patients during systemic metronidazole therapy and for at least 48 hours after completion of treatment.<ref name="AMH2006" /> However, the mechanism of this reaction in the clinical setting has recently been questioned by some authors,<ref name="Williams2000">{{cite journal |author=Williams CS, Woodcock KR |title=Do ethanol and metronidazole interact to produce a disulfiram-like reaction? |journal=The Annals of Pharmacotherapy |volume=34 |issue=2 |pages=255–7 |year=2000 |month=February |pmid=10676835 |doi=10.1345/aph.19118 |quote=the authors of all the reports presumed the metronidazole-ethanol reaction to be an established pharmacologic fact. None provided evidence that could justify their conclusions}}</ref><ref name="Visapaa2002">{{cite journal |author=Visapää JP, Tillonen JS, Kaihovaara PS, Salaspuro MP |title=Lack of disulfiram-like reaction with metronidazole and ethanol |journal=The Annals of Pharmacotherapy |volume=36 |issue=6 |pages=971–4 |year=2002 |month=June |pmid=12022894 |doi=10.1345/aph.1A066}}</ref> and a possible central toxic serotonin reaction for the alcohol intolerance suggested.<ref name="pmid17963129">{{cite journal |author=Karamanakos PN, Pappas P, Boumba VA, ''et al.'' |title=Pharmaceutical agents known to produce disulfiram-like reaction: effects on hepatic ethanol metabolism and brain monoamines |journal=International Journal of Toxicology |volume=26 |issue=5 |pages=423–32 |year=2007 |pmid=17963129 |doi=10.1080/10915810701583010}}</ref>
+
Consuming [[ethanol]] (alcohol) while using metronidazole has long been thought to have a [[disulfiram]]-like reaction with effects that can include [[nausea]], [[vomiting]], [[flushing (physiology)|flushing]] of the skin, [[tachycardia]] (accelerated heart rate), and [[shortness of breath]],<ref name="cina">{{Cite journal|author=Cina SJ, Russell RA, Conradi SE |title=Sudden death due to metronidazole/ethanol interaction |journal=The American Journal of Forensic Medicine and Pathology |volume=17 |issue=4 |pages=343–6 |year=1996 |pmid=8947362 |doi=10.1097/00000433-199612000-00013}}</ref> however there are studies calling that notion into question.<ref>{{Cite journal|author=Gupta NK, Woodley CL, Fried R |title=Effect of metronidazole on liver alcohol dehydrogenase |journal=Biochemical Pharmacology |volume=19 |issue=10 |pages=2805–8 |year=1970 |pmid=4320226 |doi=10.1016/0006-2952(70)90108-5}}</ref> Consumption of alcohol should be avoided by patients during systemic metronidazole therapy and for at least 48 hours after completion of treatment.<ref name="AMH2006" /> However, the mechanism of this reaction in the clinical setting has recently been questioned by some authors,<ref name="Williams2000">{{Cite journal|author=Williams CS, Woodcock KR |title=Do ethanol and metronidazole interact to produce a disulfiram-like reaction? |journal=The Annals of Pharmacotherapy |volume=34 |issue=2 |pages=255–7 |year=2000 |pmid=10676835 |doi=10.1345/aph.19118 |quote=the authors of all the reports presumed the metronidazole-ethanol reaction to be an established pharmacologic fact. None provided evidence that could justify their conclusions}}</ref><ref name="Visapaa2002">{{Cite journal|author=Visapää JP, Tillonen JS, Kaihovaara PS, Salaspuro MP |title=Lack of disulfiram-like reaction with metronidazole and ethanol |journal=The Annals of Pharmacotherapy |volume=36 |issue=6 |pages=971–4 |year=2002|pmid=12022894 |doi=10.1345/aph.1A066}}</ref> and a possible central toxic serotonin reaction for the alcohol intolerance suggested.<ref name="pmid17963129">{{Cite journal|author=Karamanakos PN, Pappas P, Boumba VA, ''et al.'' |title=Pharmaceutical agents known to produce disulfiram-like reaction: effects on hepatic ethanol metabolism and brain monoamines |journal=International Journal of Toxicology |volume=26 |issue=5 |pages=423–32 |year=2007 |pmid=17963129 |doi=10.1080/10915810701583010}}</ref>
  
−
===Stevens-Johnson Syndrome with Mebendazole===
+
===Stevens-Johnson syndrome with mebendazole===
−
Metronidazole alone rarely causes [[Stevens-Johnson syndrome]] but is reported to occur at high rates when combined with [[mebendazole]].<ref name=Chen>{{cite journal |author=Chen KT, Twu SJ, Chang HJ, Lin RS |title=Outbreak of Stevens-Johnson syndrome/toxic epidermal necrolysis associated with mebendazole and metronidazole use among Filipino laborers in Taiwan |journal=American Journal of Public Health |volume=93 |issue=3 |pages=489–92 |year=2003 |month=March |pmid=12604501 |pmc=1447769 |doi=10.2105/AJPH.93.3.489}}</ref>
+
Metronidazole alone rarely causes [[Stevens-Johnson syndrome]] but is reported to occur at high rates when combined with [[mebendazole]].<ref name=Chen>{{Cite journal|author=Chen KT, Twu SJ, Chang HJ, Lin RS |title=Outbreak of Stevens-Johnson syndrome/toxic epidermal necrolysis associated with mebendazole and metronidazole use among Filipino laborers in Taiwan |journal=American Journal of Public Health |volume=93 |issue=3 |pages=489–92 |year=2003 |pmid=12604501 |pmc=1447769 |doi=10.2105/AJPH.93.3.489}}</ref>
  
 
===Potentially fatal serotonin syndrome===
 
===Potentially fatal serotonin syndrome===
−
It is important to know Serotonin Syndrome is not fully understood. The complex drug interaction can happen after a couple days or take up to months. The exact mechanism is not known, a theory of serotonin dysfunction helps explain how the syndrome presents and how it is to be treated. Signs and symptoms are muscle rigidity, headache, elevated blood pressure, and changes in blood chemistry. The only direct treatment is to discontinue the offending drugs. Recently, there have been reported cases of [[SSRI]]/[[SNRI]] antidepressant drugs and metronidazole induced [[serotonin syndrome]],<ref>{{cite journal |author=Karamanakos PN |title=The possibility of serotonin syndrome brought about by the use of metronidazole |journal=Minerva Anestesiologica |volume=74 |issue=11 |pages=679 |year=2008 |month=November |pmid=18971895 |url=http://www.minervamedica.it/index2.t?show=R02Y2008N11A0679}}</ref><ref>{{cite journal |author=Karamanakos PN, Pappas P, Boumba VA, ''et al.'' |title=Pharmaceutical agents known to produce disulfiram-like reaction: effects on hepatic ethanol metabolism and brain monoamines |journal=International Journal of Toxicology |volume=26 |issue=5 |pages=423–32 |year=2007 |pmid=17963129 |doi=10.1080/10915810701583010}}</ref> this information is not included on the metronidazole patient information leaflet. SSRI and SNRI antidepressants include Prozac, Lexapro, Celexa, Zoloft, Effexor, Cymbalta, etc.
+
It is important to note that Serotonin Syndrome is not fully understood. The complex drug interaction can happen after a couple days or take up to months. The exact mechanism is not known, a theory of serotonin dysfunction helps explain how the syndrome presents and how it is to be treated. Signs and symptoms are muscle rigidity, headache, elevated blood pressure, and changes in blood chemistry. The only direct treatment is to discontinue the offending drugs. Recently, there have been reported cases of [[SSRI]]/[[SNRI]] antidepressant drugs and metronidazole induced [[serotonin syndrome]],<ref name="pmid17963129"/><ref>{{Cite journal|author=Karamanakos PN |title=The possibility of serotonin syndrome brought about by the use of metronidazole |journal=Minerva Anestesiologica |volume=74 |issue=11 |pages=679 |year=2008 |pmid=18971895 |url=http://www.minervamedica.it/index2.t?show=R02Y2008N11A0679}}</ref> this information is not included on the metronidazole patient information leaflet. SSRI and SNRI antidepressants include Prozac, Lexapro, Celexa, Zoloft, Effexor, Cymbalta, etc.
  
 
==References==
 
==References==
−
{{Cleanup-link rot|date=February 2010}}
 
 
{{Reflist|2}}
 
{{Reflist|2}}
  
 
==External links==
 
==External links==
−
* [http://www.wedgewoodpharmacy.com/monographs/metronidazole.asp Metronidazole monograph]
+
*[http://www.wedgewoodpharmacy.com/monographs/metronidazole.asp Metronidazole monograph]
−
* [http://www.merck.com/mmpe/lexicomp/metronidazole.html Merck manuals]
+
*[http://www.merck.com/mmpe/lexicomp/metronidazole.html Merck manuals]
−
* [http://www.patient.co.uk/showdoc/30003224/]
+
*[http://www.patient.co.uk/showdoc/30003224/]
−
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Metronidazole U.S. National Library of Medicine: Drug Information Portal - Metronidazole]
+
*[http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Metronidazole U.S. National Library of Medicine: Drug Information Portal - Metronidazole]
  
 
{{Stomatological preparations}}
 
{{Stomatological preparations}}

Latest revision as of 16:43, 27 September 2010

Metronidazole
200px
200px
Systematic (IUPAC) name
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol
Clinical data
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration		 oral, topical, rectal, IV, vaginal
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability 100% (oral)
59–94% (rectal)
Metabolism Hepatic
Biological half-life 6–7 hours
Excretion Renal (60-80%), biliary (6–15%)
Identifiers
CAS Number 443-48-1
ATC code A01AB17 (WHO) , D06BX01, G01AF01, J01XD01, P01AB01, QP51AA01
PubChem CID 4173
DrugBank APRD00631
ChemSpider 4029
Chemical data
Formula C6H9N3O3
Molar mass 171.15 g/mol[[Script error: No such module "String".]]
Physical data
Melting point 159 to 163 °C (318 to 325 °F)
  (verify)
Script error: No such module "TemplatePar".Expression error: Unexpected < operator.

Metronidazole (INN) (pronounced /mɛtrəˈnaɪdəzoʊl/) is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal.[1] It is the drug of choice for first episodes of mild-to-moderate Clostridium difficile infection.[2] It is marketed by Pfizer under the trade name Flagyl in the US, by Sanofi-Aventis globally under the same tradename Flagyl, in Pakistan it is also available with the brand name of Nidagyl manufactured and marketed by Star Laboratories. In Thailand it is marketed as Mepagyl by Thai Nakhorn Patana.

Metronidazole is also used as a gel preparation in the treatment of the dermatological conditions such as rosacea (Rozex and MetroGel by Galderma) and fungating tumours (Anabact, Cambridge Healthcare Supplies).

Mechanism of action

Metronidazole, taken up by diffusion, is selectively absorbed by anaerobic bacteria and sensitive protozoa. Once taken up by anaerobes, it is non-enzymatically reduced by reacting with reduced ferredoxin, which is generated by pyruvate oxido-reductase. This reduction causes the production of toxic products to anaerobic cells, and allows for selective accumulation in anaerobes.

The metronidazole metabolites are taken up into bacterial DNA, and form unstable molecules. This function only occurs when metronidazole is partially reduced, and because this reduction usually happens only in anaerobic cells, it has relatively little effect upon human cells or aerobic bacteria.[3]

Indications

Systemic metronidazole is indicated for the treatment of:

Bacterial

Protozoal

Amoebiasis: Infections caused by Entamoeba histolytica.

Giardiasis: infection of the small intestine caused by the ingestion of infective cysts of a single-celled organism called Giardia lamblia. Giardiasis occurs worldwide with a prevalence of 20–30% in developing countries. The Centers for Disease Control and Prevention reports that in the US Giardia infects over 2.5 million people annually. There are multiple modes of transmission including person-to-person, water-borne, and venereal. Person-to-person transmission accounts for a majority of Giardia infections and is usually associated with poor hygiene and sanitation. Water-borne transmission is common in United States. Giardia epidemics, which are often associated with the ingestion of unfiltered water (contaminated). Venereal transmission happens through fecal-oral contamination. Additionally, diaper changing and inadequate hand washing are risk factors for transmission from infee epidemics of Giardia have developed through the contamination of food by infected food-handlers.

Trichomoniasis: infection caused by Trichomonas vaginalis, which is a common cause of vaginitis and is the most frequently presenting new infection of the common sexually transmitted diseases.[4]

A small number of infected individuals experience an abrupt onset of abdominal cramps, explosive, watery diarrhea, vomiting, foul flatus, and fever which may last for 3–4 days before proceeding into a more sub-acute phase. The majority of infected persons develop gradual symptoms that become recurrent or resistant.

In both the acute and insidious onsets of symptoms, stools become greasy and malodorous but do not contain blood or pus because giardiasis does not involve dysenteric symptoms. Watery diarrhea may cycle with soft stools and constipation. Upper GI symptoms including nausea, early satiety, bloating, substernal burning, egg-smelling halitosis, and acid indigestion may be exacerbated by eating and are generally present in the absence of soft stools.

Treatment with metronidazole

Adult dosage: 250 mg three times a day for 5 days, or 400 mg 3 times a day for 7 days. Alternative: 2000 mg one time only.

Metronidazole should always be taken with a large glass of water and with or after food.

Pediatric dosage: 15 mg per kilogram of body weight per dose, 3 times per day, for 5 days

Nonspecific

Prevention of preterm births

A 2005 study found "Metronidazole therapy before 32 weeks was associated with an increased risk of preterm birth", possibly as a result of "changes in the vaginal flora… seen with vaginal clindamycin or oral metronidazole therapy."[6]

Metronidazole has also been used in women to prevent preterm birth associated with bacterial vaginosis, amongst other risk factors including the presence of cervicovaginal fetal fibronectin (fFN). A randomised controlled trial demonstrated that metronidazole was ineffective in preventing preterm delivery in high-risk pregnant women and, conversely, the incidence of preterm delivery was actually higher in women treated with metronidazole.[7]

Lamont has argued that Metronidazole is not the right antibiotic to administer in these circumstances and was often administered too late to be of use. Clindamycin administered early in the second trimester to women who test positive for bacterial vaginosis seems to be more effective.[8]

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with systemic metronidazole therapy include: nausea, diarrhea, and/or metallic taste in the mouth. Intravenous administration is commonly associated with thrombophlebitis. Infrequent adverse effects include: hypersensitivity reactions (rash, itch, flushing, fever), headache, dizziness, vomiting, glossitis, stomatitis, dark urine, and/or paraesthesia.[5]

High doses and/or long-term systemic treatment with metronidazole is associated with the development of leukopenia, neutropenia, increased risk of peripheral neuropathy and/or CNS toxicity.[5]

Metronidazole is listed by the US National Toxicology Program (NTP) as reasonably anticipated to be a human carcinogen. Although some of the testing methods have been questioned, it has been shown to cause cancer in experimental animals.[9] Yet, metronidazole was shown to be safe in humans.[9][10] It appears to have a fairly low potential for cancer risk and under most circumstances the benefits of treatment outweigh the risk. Metronidazole is listed as a possible carcinogen according to the WHO International Agency for Research on Cancer (IARC).[11]

Because metronidazole is an important drug in treatment of human pathogens including C. difficile, metronidazole is banned in the EU and the USA for veterinary use in the feed of animals and is banned for use in any food animals in the USA.[12][13]

Earlier studies suggested a relation between metronidazole and various birth defects. Those studies are nowadays considered flawed and more recent studies "do not support a significant increased risk for birth defects or other adverse effects on the fetus."[14]

Common adverse drug reactions associated with topical metronidazole therapy include local redness, dryness, and/or skin irritation; and eye watering (if applied near eyes).[5]

Interaction with alcohol

Consuming ethanol (alcohol) while using metronidazole has long been thought to have a disulfiram-like reaction with effects that can include nausea, vomiting, flushing of the skin, tachycardia (accelerated heart rate), and shortness of breath,[15] however there are studies calling that notion into question.[16] Consumption of alcohol should be avoided by patients during systemic metronidazole therapy and for at least 48 hours after completion of treatment.[5] However, the mechanism of this reaction in the clinical setting has recently been questioned by some authors,[17][18] and a possible central toxic serotonin reaction for the alcohol intolerance suggested.[19]

Stevens-Johnson syndrome with mebendazole

Metronidazole alone rarely causes Stevens-Johnson syndrome but is reported to occur at high rates when combined with mebendazole.[20]

Potentially fatal serotonin syndrome

It is important to note that Serotonin Syndrome is not fully understood. The complex drug interaction can happen after a couple days or take up to months. The exact mechanism is not known, a theory of serotonin dysfunction helps explain how the syndrome presents and how it is to be treated. Signs and symptoms are muscle rigidity, headache, elevated blood pressure, and changes in blood chemistry. The only direct treatment is to discontinue the offending drugs. Recently, there have been reported cases of SSRI/SNRI antidepressant drugs and metronidazole induced serotonin syndrome,[19][21] this information is not included on the metronidazole patient information leaflet. SSRI and SNRI antidepressants include Prozac, Lexapro, Celexa, Zoloft, Effexor, Cymbalta, etc.

References

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Use <references />, or <references group="..." />

External links

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da:Metronidazol de:Metronidazol es:Metronidazol fa:مترونیدازول fr:Métronidazole it:Metronidazolo hu:Metronidazol nl:Metronidazol ja:メトロニダゾール pl:Metronidazol pt:Metronidazol ro:Metronidazol ru:Метронидазол sl:Metronidazol fi:Metronidatsoli ta:மெட்ராநைடஸால்

uk:Метронідазол
  1. ↑ Merck Manual for Professionals
  2. ↑ The Society for Healthcare Epidemiology of America and the Infectiouslogy]. Accessed Mar. 22, 2010 9:00am.
  3. ↑ Eisenstein, Barry I.; Schaechter, Moselio (2007). "DNA and Chromosome Mechanics". In Schaechter, Moselio; Engleberg, N. Cary; DiRita, Victor J.; Dermody, Terence. Schaechter's mechanisms of microbial disease. Hagerstwon, MD: Lippincott Williams & Wilkins. p. 28. ISBN 978-0-7817-5342-5. 
  4. ↑ Associated Press, Abstinence students still having sex, MSNBC, April 16, 2007. Retrieved March 12, 2008.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Rossi, Simone, ed. (2006). Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook Pty Ltd. ISBN 978-0-9757919-2-9. OCLC 224831213. [page needed]
  6. ↑ Carey JC, Klebanoff MA (2005). "Is a change in the vaginal flora associated with an increased risk of preterm birth?". American Journal of Obstetrics and Gynecology. 192 (4): 1341–6; discussion 1346–7. doi:10.1016/j.ajog.2004.12.069. PMID 15846235. 
  7. ↑ Shennan A, Crawshaw S, Briley A; et al. (2006). "A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study". BJOG. 113 (1): 65–74. doi:10.1111/j.1471-0528.2005.00788.x. PMID 16398774. 
  8. ↑ Lamont RF (2005). "Can antibiotics prevent preterm birth--the pro and con debate". BJOG. 112 (Suppl 1): 67–73. doi:10.1111/j.1471-0528.2005.00589.x. PMID 15715599. 
  9. ↑ 9.0 9.1 "Metronidazole CAS No. 443-48-1" (PDF). Report on Carcinogens, Eleventh Edition. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Retrieved 2009-12-11. 
  10. ↑ Flagyl 375 U.S. Prescribing Information Pfizer (PDF)
  11. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  12. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  13. ↑ "FDA's prohibited drug list". Food Animal Residue Avoidance and Depletion Program (FARAD). USA Food and Drug Administration. 2010. Retrieved 2010-06-06. 
  14. ↑ OTIS: Metronidazole (Flagyl®) and Pregnancy
  15. ↑ Cina SJ, Russell RA, Conradi SE (1996). "Sudden death due to metronidazole/ethanol interaction". The American Journal of Forensic Medicine and Pathology. 17 (4): 343–6. doi:10.1097/00000433-199612000-00013. PMID 8947362. 
  16. ↑ Gupta NK, Woodley CL, Fried R (1970). "Effect of metronidazole on liver alcohol dehydrogenase". Biochemical Pharmacology. 19 (10): 2805–8. doi:10.1016/0006-2952(70)90108-5. PMID 4320226. 
  17. ↑ Williams CS, Woodcock KR (2000). "Do ethanol and metronidazole interact to produce a disulfiram-like reaction?". The Annals of Pharmacotherapy. 34 (2): 255–7. doi:10.1345/aph.19118. PMID 10676835. the authors of all the reports presumed the metronidazole-ethanol reaction to be an established pharmacologic fact. None provided evidence that could justify their conclusions 
  18. ↑ Visapää JP, Tillonen JS, Kaihovaara PS, Salaspuro MP (2002). "Lack of disulfiram-like reaction with metronidazole and ethanol". The Annals of Pharmacotherapy. 36 (6): 971–4. doi:10.1345/aph.1A066. PMID 12022894. 
  19. ↑ 19.0 19.1 Karamanakos PN, Pappas P, Boumba VA; et al. (2007). "Pharmaceutical agents known to produce disulfiram-like reaction: effects on hepatic ethanol metabolism and brain monoamines". International Journal of Toxicology. 26 (5): 423–32. doi:10.1080/10915810701583010. PMID 17963129. 
  20. ↑ Chen KT, Twu SJ, Chang HJ, Lin RS (2003). "Outbreak of Stevens-Johnson syndrome/toxic epidermal necrolysis associated with mebendazole and metronidazole use among Filipino laborers in Taiwan". American Journal of Public Health. 93 (3): 489–92. doi:10.2105/AJPH.93.3.489. PMC 1447769 Freely accessible. PMID 12604501. 
  21. ↑ Karamanakos PN (2008). "The possibility of serotonin syndrome brought about by the use of metronidazole". Minerva Anestesiologica. 74 (11): 679. PMID 18971895. 
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