ON THE USE OF ANTIBIOTICS IN CROHN’S DISEASE.
Van Kruiningen HJ, Department of Pathobiology, University of Connecticut, Storrs 06269-3089, USA. J Clin Gastroenterol, 1995 Jun, 20:4, 310-6
It is difficult to understand how a disease process characterized by
ulcerations, fissures, abscesses, fistulas, lymphangitis, and granulomas
has not attracted greater use of antibiotics, particularly as the sites
are constantly contaminated by intestinal bacteria. I have had a favorable
experience with broad-spectrum antibiotics in the treatment of a variety
of forms of ileocolitis in animals and now advocate that Crohn’s disease
be treated at length with these drugs. Microbiologic culture of serosa,
mesenteric lymph nodes, and fistulas has demonstrated that bacterial species
are present in a significant proportion of cases, and serology has shown
that patients have elevated antibody levels to many of these same microorganisms.
Now immunocytochemistry provides documentation of Escherichia coli and
streptococcal antigen within the lesions of a majority of patients. That
these bacteria may be secondary invaders should not decrease our need to
address them. Several chronic granulomatous diseases that were once
thought to be intractable now yield to long-term antibiotic treatment,
including Whipple’s disease, malakoplakia, and granulomatous colitis of
Boxer dogs. Many of the perianal lesions of Crohn’s disease respond
to short-term metronidazole, and the medium-term (3-6 months) use of broad-spectrum
antibiotics, most recently ciprofloxacin, has shown promising results.
In view of the increasing evidence of bacterial participation in this disease,
it is now important that physicians test some of our newer broad-spectrum
antibiotics, in a controlled format, and over an extended time.
COMBINATION CIPROFLOXACIN AND METRONIDAZOLE FOR ACTIVE CROHN’S DISEASE.
Greenbloom SL; Steinhart AH; Greenberg GR; Division of Gastroenterology,
Mount Sinai Hospital, Toronto, Ontario. Can J Gastroenterol, 1998 Jan,
12:1, 53-6
Recent experimental evidence underscores the contribution of intestinal
bacteria to the inflammatory process of Crohn’s disease. This open study
examined the efficacy and safety of combination ciprofloxacin and metronidazole
for patients with active Crohn’s disease of the ileum and/or colon. Seventy-two
patients with active Crohn’s disease of the ileum (n = 27), ileocolon (n
= 22) or colon (n = 23) were treated with ciprofloxacin 500 mg bid and
metronidazole 250 mg tid for a mean of 10 weeks. Clinical remission was
defined as a Harvey-Bradshaw index of three points or less; an index reduction
of at least three points indicated a clinical response. Clinical remission
was observed in 49 patients (68%), and 55 patients (76%) showed a clinical
response. A clinical response was noted in 29 of 43 patients (67%) who
were not taking concurrent prednisone treatment and in 26 of 29 patients
(90%) receiving prednisone (mean dose of 15 mg/day). A clinical response
also occurred in a greater proportion of patients with colonic disease,
with or without ileal involvement (84%), compared with patients with ileal
disease alone (64%), and in patients without resection (86%) compared with
those with previous resection (61%). Five patients discontinued antibiotics
because of adverse events. After a mean follow-up of nine months, clinical
remission was maintained in 26 patients off treatment and in 12 patients
who continued antibiotic therapy. Ciprofloxacin in combination with metronidazole
is well tolerated and appears to play a beneficial role in achieving clinical
remission for patients with active Crohn’s disease, particularly when there
is involvement of the colon.
AN ANTIBIOTIC REGIMEN FOR THE TREATMENT OF ACTIVE CROHN’S DISEASE: A
RANDOMIZED, CONTROLLED CLINICAL TRIAL OF METRONIDAZOLE PLUS CIPROFLOXACIN.
Prantera C; Zannoni F; Scribano ML; Berto E; Andreoli A; Kohn A; Luzi
C; Division of Gastroenterology, Ospedale Nuovo Regina Margherita, Rome,
Italy. Am J Gastroenterol, 1996 Feb, 91:2, 328-32
OBJECTIVES: Bacteria in the gut lumen may play a role in the etiology
and/or the symptoms of Crohn’s disease (CD). Although various antibacterial
drugs have been employed in clinical practice, few controlled trials have
been conducted, and those had conflicting results. The aim of this study
was to investigate the efficacy and the safety of a combination of metronidazole
and ciprofloxacin, compared with methylprednisolone, in treating 41 consecutive
patients with active CD. METHODS: Eligible patients, 13 men and 28 women,
mean age 38 yr, were randomly allocated to receive, for 12 wk, ciprofloxacin
500 mg twice daily plus metronidazole 250 mg four times daily or methylprednisolone
0.7-l mg/kg/day, with variable tapering to 40 mg, followed by tapering
of 4 mg weekly. RESULTS: Ten of the 22 antibiotic patients (45.5%)
and 12 of the 19 steroid patients (63%) obtained clinical remission (Crohn’s
Disease Activity Index < or = 150) at the end of the 12-wk study (p
= NS). Five patients on antibiotics (22.7%) and five patients on steroids
(26.3%) were considered treatment failures because of deterioration or
persistent symptoms. Six patients receiving antibiotics (27.3%) and two
on steroids (10.6%) were withdrawn from the trial because of side effects.
One patient on antibiotics was not compliant. CONCLUSIONS: metronidazole
and ciprofloxacin could be an alternative to steroids in treating the acute
phase of CD.
ORNIDAZOLE IN THE TREATMENT OF ACTIVE CROHN’S DISEASE: SHORT-TERM RESULTS.
Triantafillidis JK; Nicolakis D; Emmanoullidis A; Antoniou A; Papatheodorou
K; Cheracakis P; Department of Gastroenterology, Saint Pantelelmon General
State Hospital, Nicea, Piraeus, Greece. Ital J Gastroenterol, 28(1):10-4
1996 Jan
The object of this work was to test the efficacy of ornidazole in patients
with active Crohn’s disease. Twenty-five patients with active Crohn’s disease
(Crohn’s disease activity index greater than 150 points) participated in
this open study. The analysis of results was based on changes in the severity
of the Crohn’s disease activity index measured at entry and at the end
of the first, second, and third and fourth week. Analysis of variance,
correlation analysis, multiple regression analyses and chi-square test
were used for statistical evaluation of results. The results showed that
the Crohn’s disease activity index fell gradually from week 0 to week 4
(p < 0.001), while the number of patients going into remission increased
gradually from week 0 to week 4 (18/25 patients, 75%). Sex, location
of disease, age at onset, first attack or recurrence and duration of disease
were not statistically related to response to treatment. Presence and severity
of abdominal pain both decreased and bowel movements were also reduced.
General well-being improved significantly, the loss of weight stopped and
an increase in body weight was noted at the end of the fourth week.
Side effects were minimal. It is concluded that ornidazole is an effective
and safe drug for the treatment of active Crohn’s disease.
METRONIDAZOLE. A THERAPEUTIC REVIEW AND UPDATE.
Freeman CD; Klutman NE; Lamp KC Department of Medicine, University
of Missouri-Kansas City School of Medicine, USA. cfreeman@cctr.umkc.edu
Drugs, 1997 Nov, 54:5, 679-708
The nitroimidazole antibiotic metronidazole has a limited spectrum of
activity that encompasses various protozoans and most Gram-negative and
Gram-positive anaerobic bacteria. Metronidazole has activity against protozoans
like Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis,
for which the drug was first approved as an effective treatment. Anaerobic
bacteria which are typically sensitive are primarily Gram-negative anaerobes
belonging to the Bacteroides and Fusobacterium spp. Gram-positive anaerobes
such as peptostreptococci and Clostridia spp. are likely to test sensitive
to metronidazole, but resistant isolates are probably encountered with
greater frequency than with the Gram-negative anaerobes. Gardnerella vaginalis
is a pleomorphic Gram-variable bacterial bacillus that is also susceptible
to metronidazole. Helicobacter pylori has been strongly associated with
gastritis and duodenal ulcers. Classic regimens for eradicating this pathogen
have included metronidazole, usually with acid suppression medication plus
bismuth and amoxicillin. The activity of metronidazole against anaerobic
bowel flora has been used for prophylaxis and treatment of patients with
Crohn’s disease who might develop an infectious complication. Treatment
of Clostridium difficile-induced pseudomembraneous colitis has usually
been with oral metronidazole or vancomycin, but the lower cost and similar
efficacy of metronidazole, coupled with the increased concern about imprudent
use of vancomycin leading to increased resistance in enterococci, have
made metronidazole the preferred agent here. Metronidazole has played an
important role in anaerobic-related infections. Advantages to using metronidazole
are the%age of sensitive Gram-negative anaerobes, its availability as oral
and intravenous dosage forms, its rapid bacterial killing, its good tissue
penetration, its considerably lower chance of inducing C. difficile colitis,
and expense. Metronidazole has notable effectiveness in treating
anaerobic brain abscesses. Metronidazole is a cost-effective agent due
to its low acquisition cost, its pharmacokinetics and pharmacodynamics,
an acceptable adverse effect profile, and its undiminished antimicrobial
activity. While its role as part of a therapeutic regimen for treating
mixed aerobic/anaerobic infections has been reduced by newer, more expensive
combination therapies, these new combinations have not been shown to have
any therapeutic advantage over metronidazole. Although the use of
metronidazole on a global scale has been curtailed by newer agents for
various infections, metronidazole still has a role for these and other
therapeutic uses. Many clinicians still consider metronidazole to be the
‘gold standard’ antibiotic against which all other antibiotics with anaerobic
activity should be compared.
CONTROLLED TRIAL OF METRONIDAZOLE TREATMENT FOR PREVENTION OF CROHN’S
RECURRENCE AFTER ILEAL RESECTION [SEE COMMENTS]
Rutgeerts P; Hiele M; Geboes K; Peeters M; Penninckx F; Aerts R; Kerremans
R, Department of Medicine, University Hospital Gasthuisberg, University
of Leuven, Belgium. Gastroenterology, 1995 Jun, 108:6, 1617-21
BACKGROUND/AIMS: New lesions recur within weeks to months after ileal
resection and ileocolonic anastomosis for Crohn’s ileitis. A double-blind
controlled trial was performed using metronidazole to prevent recurrence
after ileal resection. METHODS: Sixty patients who underwent curative ileal
resection and primary anastomosis were included within 1 week after surgery.
Thirty patients received metronidazole (20 mg/kg body wt) daily for 3 months,
and 30 patients received placebo. Treatment was then discontinued. Nine
patients dropped out during treatment, 7 in the metronidazole group and
2 in the placebo arm. RESULTS: At 12 weeks, 21 of 28 patients (75%) in
the placebo group had recurrent lesions in the neoterminal ileum as compared
with 12 of 23 patients (52%) in the metronidazole group (P = 0.09). The
incidence of severe endoscopic recurrence was significantly reduced by
metronidazole (3 of 23; 13%) as compared with placebo (12 of 28; 43%; P
= 0.02). Patients in the metronidazole arm had more frequent side effects.
Metronidazole therapy statistically reduced the clinical recurrence rates
at 1 year (4% vs. 25%). Reductions at 2 years (26% vs. 43%) and 3 years
(30% vs. 50%) were not significant. CONCLUSIONS: Metronidazole therapy
for 3 months decreases the severity of early recurrence of Crohn’s disease
in the neoterminal ileum after resection and seems to delay symptomatic
recurrence.
A COMPARATIVE STUDY OF METRONIDAZOLE AND SULFASALAZINE FOR ACTIVE CROHN’S
DISEASE: THE COOPERATIVE CROHN’S DISEASE STUDY IN SWEDEN. II. RESULT.
Ursing B; Alm T; Bárány F; Bergelin I; Ganrot-Norlin
K; Hoevels J; Huitfeldt B; Järnerot G; Krause U; Krook A; Lindström;
B; Nordle O; Rosén A; Gastroenterology, 1982 Sep, 83:3, 550-62
Seventy-eight patients with active Crohn’s disease participated in a
randomized, double-blind,
cross-over trial. The study comprised two 4-mo period. The purpose
was to test the efficacy of
metronidazole in comparison with that of sulfasalazine. As the main
evaluation criteria the Crohn’s
Disease Activity Index and plasma levels of orosomucoid were chosen.
In the first period no
difference in efficacy as measured by Crohn’s Disease Activity Index
was found between the
treatment groups. The reduction of the plasma orosomucoid level was
significantly more pronounced in the metronidazole group. The hemoglobin
concentration increased more in this group than in the
sulfasalazine group, possibly due to a toxic effect of sulfasalazine.
The erythrocyte sedimentation rate decreased similarly with both drugs.
In 15 patients who had active disease throughout the first
period, Crohn’s Disease Activity Index decreased significantly in the
second period for those who
switched to metronidazole, but not for those who switched to sulfasalazine.
After crossover, no
apparent further change in Crohn’s Disease Activity Index occurred
in either of the treatment groups
among patients who had responded favorably in the first period. The
plasma concentration of
orosomucoid increased significantly among the patients in the sulfasalazine
group but not in the
metronidazole group. It is therefore concluded that metronidazole is
slightly more effective than
sulfasalazine in the treatment of crohn’s disease. It is worthwhile
switching the drug regimen from
sulfasalazine, when it fails, to metronidazole, but not from metronidazole
to sulfasalazine.
THE COURSE OF CROHN DISEASE AND SIDE EFFECT PROFILE WITH LONG-TERM TREATMENT
USING METRONIDAZOLE
Gugler R; Jensen JC; Schulte H; Vogel R, Medizinische Universitätsklinik,
Bonn. Z Gastroenterol, 1989 Nov, 27:11, 676-82
In a prospective study 21 patients with Crohn’s disease not responding
to standard treatment (salazosulfapyridine and/or corticosteroids) received
metronidazole in a dose of 12 to 20 mg per kg body weight over 6 and 12
months respectively. The objectives were documentation of side effects
and pharmacokinetic behaviour of metronidazole in relation to the course
of the disease. In 3 months intervals and 3 months after the end of treatment
activity indices were determined, the side effects of metronidazole were
recorded and the drug plasma concentration was measured. Compliance of
drug intake was excellent (94%). Best-Index decreased to a minimum after
6 months, orosomucoid after 3 months. Side effects from metronidazole (black
tongue, dark urine, paraesthesia, metallic taste, epigastric pain, skin
reactions, nausea) were reported by over 80% of the patients at any time
of the study. Nearly 50% of patients developed paraesthesia, which was
still present 3 months after the end of treatment. A mean dose of 15.4
mg per kg corresponded to a mean plasma concentration of 10.9 micrograms/ml
of metronidazole. Plasma concentrations were not related to treatment success
nor to the incidence of side effects. Treatment of Crohn’s disease with
metronidazole for longer than 3 months is not recommended both because
of lack of additional therapeutic gain and because of the increasing risk
of side effects.
In animal experiments investigating induction of chronic intestinal
disease by inoculating them with isolates from Crohn's patients, "the addition
of an antibiotic (ampicillin) prevented the appearance of these Crohn’s-like
changes in 12 out of 12 rabbits" (Donnelly BJ, Delaney PV, Healy TM. Gut
1977 May;18(5):360-3), pointing to an infectious agent rather than a toxic
chemical content in the isolate from Crohn's patient's intestines.
Use of antibiotics against H. hepaticus in mice IBD
EVALUATION OF ANTIBIOTIC THERAPIES FOR ERADICATION OF H. HEPATICUS.
Foltz CJ; Fox JG; Yan L; Shames B Division of Comparative Medicine,
Massachusetts Institute of
Technology, Cambridge 02139, USA. Antimicrob Agents Chemother, 1995
Jun, 39:6, 1292-4
The newly recognized murine pathogen Helicobacter hepaticus is known
to colonize the ceca and
colons of several strains of mice from a variety of commercial suppliers.
Additionally, the organism
persistently infects mice, causes a chronic hepatitis, and is linked
to hepatic tumors in the A/JCr
inbred mouse strain. For this reason, eradication of the organism from
infected mouse colonies is
desirable. Treatment modalities for eradication of H. hepaticus from
the gastrointestinal system
consisted of oral administration of various antibiotic combinations
previously evaluated for
eradication of experimental H. felis gastric infection in mice. A/JCr
mice (8 to 10 weeks old)
naturally infected with H. hepaticus were divided into six treatment
groups of 10 animals each.
Animals received monotherapy of amoxicillin, metronidazole, or tetracycline
or triple therapy of amoxicillin-metronidazole-bismuth (AMB) or tetracycline-metronidazole-bismuth
(TMB). All medications were administered by oral gavage three times daily
for 2 weeks. One month after the final treatment, mice were euthanatized
and livers, ceca, and colons were cultured for H. hepaticus. All untreated
control animals had H. hepaticus isolated from the cecum and/or colon.
H. hepaticus was not recovered from the livers, ceca, or colons of the
AMB or TMB treatment groups. All animals receiving the various antibiotic
monotherapies had H. hepaticus isolated from the cecum and colon. We
conclude that at the doses and the route evaluated, AMB and TMB triple
therapies are effective for eradication of H. hepaticus in 8- to 10-week
old A/JCr mice.
THE GOOD NEWS IS THAT ONCE DIAGNOSED, H. HEPATICUS APPEARS TO BE
TREATABLE WITH THE SIMILAR 2 WEEK TREATMENT (in mice) APPROVED BY FDA
FOR H. PYLORI (or may be 3 months in chronic IBD):
From the Journal of American Medical Association( AMA ), June 18, 1997:
The FDA has also approved 3 combination regimens for treatment of H pylori infection: omeprazole plus clarithromycin(cure rate about 70%), ranitidine bismuth citrate plus clarithromycin (cure rate about 80%), and bismuth subsalicylate plus metronidazole plus tetracycline combined with an antisecretory drug (cure rate about 80%), each given for 2 weeks. However, most experts believe the best therapy may be a combination of ranitidine bismuth citrate or a proton pump inhibitor plus clarithromycin plus either amoxicillin or metronidazole given for 7 to 10 days (cure rate about 90%).
NOTE: Metronidazole is not the only antibiotic used successfully
in both H pylori and Crohn's. According to Prof. Hermon-Taylor, St. George's
Hospital Medical School, London, about 80% of more than 100 Crohn's patients
he treated with a combination of rifabutin and clarithromycin had
"a profound and lasting remission" of their illness. David Graham, MD,
VA Medical Center and Baylor College of Medicine in Houston, and colleagues
conducted a placebo-controlled trial looking at the efficacy of clarithromycin
as a treatment for Crohn's disease. They randomly assigned 17 people with
severe Crohn's disease to receive either conventional therapy plus a placebo
or conventional therapy plus clarithromycin. They did not determine whether
the patients harbored M. paratuberculosis. Forty percent of the patients
in the antibiotic arm became well and stayed well for up to three years,
said Graham, who is chief of gastroenterology at the Veterans Administration
Medical Center in Houston. In contrast, one person in the placebo arm became
well but did not remain well. (Graham, D.Y., M.T. Al-Assi, and M. Robinson.
Prolonged remission in Crohn's disease following therapy for Mycobacterium
paratuberculosis infection. 1995. Gastroenterology, vol. 108, no. 4, A826
AGA Abstracts). To confirm their findings, Graham and colleagues are conducting
a larger placebo-controlled study looking at the efficacy of clarithromycin
plus ethambutol.
In conclusion, regardless if the presumed infective agent in Crohn's
disease is Mycobacterium paratuberculosis or Helicobacter species, clinical
studies have shown the following similarities with H pylori (and H hepaticus):