Gastrointestinal ADRS:

Severe Diarrhea and Colitis, Severe Hepatotoxicity and Acute
Pancreatitis

Additional digestive disorders such as: acid reflex, erosion of the
esophagus, severe bloating, loose bowels, trench mouth, yeast
infections of the throat and tongue, gallbladder attacks, hypo and
hyperglycemia, liver and kidney diseases, as well as severe nausea.

No specific structural changes of the quinolone ring have been
identified as a contributory factor in these adverse reactions. Such
adverse reactions are to be considered a class effect.

Although gastro distress (nausea and diarrhea) is supposedly the
number one adverse reaction to the fluoroquinolones we find little to
no research regarding these events. The predominant mechanisms of
action identified so far is the reduction of the "good" bacteria
found in the human gut as well as dangerous increases of the Candida
species and yeast. Additionally damage to other organs that play a
significant role in the digestive process, such as the intestinal
lining as well as the liver and pancreas, are also to be blamed in
some cases.

The human gut is the natural habitat of many bacterial species. The
normal bacterial microflora of the gut, especially the zillions of
anaerobes, prevent colonization by pathogenic bacteria. The use of
the fluoroquinolones is the main reason for the loss of the normal
flora and its replacement by potentially pathogenic microorganisms,
such as gram-negative aerobic bacilli and Candida species. Research
has shown conclusively that Levofloxacin and Moxifloxacin can
significantly increase the concentration of Candida species in the
human gut to dangerous levels. Other quinolones, such as
Ciprofloxacin, Norfloxacin, and Ofloxacin, cause smaller increases in
the human gut colonization by Candida species than we find with
Levofloxacin or Moxifloxacin, but such increases are still to be
considered statistically significant and a contributing factor in the
gastro adrs.

For example in one study Enterobacteriaceae was the predominant
aerobic flora present in every volunteer. Enterococcus sp. were found
in five of the eight subjects. After treatment with a fluoroquinolone
these species totally disappeared from the stool samples.

Streptococcus sp. were initially present in five subjects,
Staphylococcus sp. in one, Lactobacillus sp. in three, and
Corynebacterium sp. in four subjects. These bacteria responded
variably: disappearing in some cases, persisting in others, or even
arising after the use of the fluoroquinolone.

Yeasts were not originally present in any volunteer, but appeared at
levels of 1.0 × 104 and 6 × 104 cfu/g in two subjects out of eight
after fluoroquinolone therapy.

These drastic changes taking place in the human gut after
fluoroquinolone therapy may also lead to Clostridium difficile. This
is a lethal bacterium, which surfaces in people being treated with
the fluoroquinolones. Clostridium difficile is spreading in North
America due to the scripting abuse associated with the
fluoroquinolones and has grown resistant to most drugs used to treat
it. Clostridium difficile, which infects the colon and causes severe
diarrhea and colitis, (a severe inflammation of the intestine), has
been linked directly to the indiscriminate use of the
fluoroquinolones.

A Clostridium difficile infection is the principal cause of
nosocomial, fluoroquinolone-associated diarrhea and pseudomembranous
colitis. Colitis is mediated by 2 potent exotoxins produced by this
organism:

(1) toxin A, an enterotoxin that induces increased fluid secretion
and elicits an acute intestinal mucosal inflammatory response with
granulocyte infiltration, epithelial cell necrosis, ulceration, and
hemorrhagic edema and

(2) toxin B, a powerful cytotoxin. Toxin A seems to be the principal
mediator of intestinal disease.

C difficile can be fatal if left untreated. The spectrum of this
disease ranges from asymptomatic carrier state to life-threatening
pseudomembranous colitis and toxic megacolon. Pathogenesis of
pseudomembranous colitis results from the fluoroquinolones
suppression of the natural microflora of the colon, which creates an
environment favorable for C difficile proliferation.

Recently a large outbreak of Clostridium difficile-associated disease
with an unexpected proportion of deaths and colectomies at a teaching
hospital was linked to the increased fluoroquinolone useage. The
exposure to Levofloxacin was an independent risk factor for C.
difficile-associated diarrhea and appeared to contribute
substantially to this outbreak.

As stated earlier we find little to no research of value which would
explain the exact mechanisms of action, other than those outlined
above. However one cannot discount the part that damage to the
nerves that control the digestive functions would play in such gastro
issues.

Severe constipation rather than diarrhea may result if the nerves
controlling the colon are impaired. This would result in a "lazy
colon" in which fecal matter remains stagnant rather than moving
along the colon to be expelled. Often times these adrs are
misdiagnosis as irritable bowel syndrome as the patient may alternate
between severe constipation as a result of impaired nerve signals to
the colon and the severe diarrhea resulting from the change in the
natural flora of the gut. Painful gas attacks are also quite common
as a result of decreases in the rate of ethanol elimination due to
the fluoroquinolones.

Additionally other gastro issues including acid reflex, (the stomach
contents are normally acidic and are generally kept in the stomach by
a valve at the lower end of the esophagus. Reflux is the term used
when stomach acids come back up into the esophagus or throat), the
resultant erosion of the esophagus (from the acid reflux), severe
bloating, loose bowels, trench mouth, yeast infections of the throat
and tongue, gallbladder attacks, pancreatitis, hypo and
hyperglycemia, food sensitivities,(due to the inability to properly
digest), as well as liver and kidney diseases, have all been
associated with the use of the fluoroquinolones. Yet we once again
find scant research as to the exact mechanisms of such injuries and
disease states.

The fluoroquinolones may also induce transient abnormalities in serum
aminotransferase levels. Severe hepatotoxicity and acute pancreatitis
are both associated with the use of the fluoroquinolones as noted
above. Such injury to the pancreas and liver are to be considered a
contributory factor in some the gastrointestinal adverse reactions.

All of the gastro issues discussed above are to be considered a class
effect independent of any structural modifications of the quinolone
ring, with some fluoroquinolones having a more pronounced effect as
compared to others in this class. With the main mechanisms being the
reduction of the "good" bacteria found in the human gut as well as
the risk of developing Clostridium difficile together with dangerous
increases of the Candida species and yeast. The decreases in the rate
of ethanol elimination plays a major role in the painful gas attacks.

Do fluoroquinolones predispose patients to Clostridium difficile associated disease? A review of the evidence.

Evaluation of Clostridium difficile-associated diarrhea with a drug formulary change in preferred fluoroquinolones.

Levofloxacin and Moxifloxacin Increase Human Gut Colonization by Candida Species

Gatifloxacin-induced hepatotoxicity and acute pancreatitis.
Cheung O, Chopra K, Yu T, Nalesnik MA, Amin S, Shakil AO.
Publication Types: Case Reports Letter
PMID: 14706991 [PubMed - indexed for MEDLINE]

Deadly bacteria spreading through US hospitals

Switching Fluoroquinolones in Patients with Neutropenia May Increase Infection Risks

Fluoroquinolone use and Clostridium difficile-associated diarrhea - Dispatches
Emerging Infectious Diseases, June, 2003 by Margaret E. McCusker, Anthony D. Harris, Eli Perencevich, Mary-Claire Roghmann

Severe ciprofloxacin-associated pseudomembranous colitis in an eight-year-old child

03/15/2004 - RESEARCH: C. difficile infection in long-term care facility appears to be linked with Tequin use, new case-control study finds

Tenn Med. 2002 Mar;95(3):113-5.
Clostridium difficile infection associated with levofloxacin treatment.
Ozawa TT, Valadez T.

Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis
Tina Papastavros, Lisa R. Dolovich, Anne Holbrook, Lori Whitehead, and Mark Loeb

From PubMed/Medline

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6    Yip C, Loeb M, Salama S, Moss L, Olde J.Quinolone use as a risk factor for nosocomial Clostridium difficile-associated diarrhea.
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21    Gatifloxacin-induced hepatotoxicity and acute pancreatitis.
Cheung O, Chopra K, Yu T, Nalesnik MA, Amin S, Shakil AO.
Publication Types: Case Reports Letter
PMID: 14706991 [PubMed - indexed for MEDLINE]

22.    Ann Fr Anesth Reanim. 2002 Jan;21(1):68-9. 
[Acute pancreatitis secondary to administration or norfloxacin]
[Article in French]
Drabo YJ, Niakara A, Ouedraogo H.
Publication Types: Case Reports Letter
PMID: 11878127 [PubMed - indexed for MEDLINE]

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Publication Types: Case Reports Letter
PMID: 11852403 [PubMed - indexed for MEDLINE]

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Letters to the Editor
Journal of Clinical Gastroenterology. 31(4):336, December 2000.
Mann, Steven M.R.C.P.; Thillainayagam, Andrew M.D., M.R.C.P.
Publication Types: Case Reports Letter
PMID: 11129278 [PubMed - indexed for MEDLINE]