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Giardia, flagyl resistance and quinacrine

Richard Speare Richard.Speare at jcu.edu.au
Fri Jun 28 03:27:48 EST 1996


> A couple of cases of giardiasis have recently given us reason to suspect 
> flagyl resistance.   Previously most suspected resistance we could 
> attribute to non-compliance or reinfection.  Our problem is that quinacrine is 
> getting harder and harder to get.   Here in Canada, Tinidazole is not an 
> option.  Any other alternatives?  Any suggestions? 

Albendazole has some efficacy against Giardia. For a good, if dated
review, see Reynoldson, J.A., Thompson, R.C.A. and Horton, R.J. 1992.
Albendazole as a future antigardial agent. Parasitology Today 8: 412-414.

A recent search of Current Contents combining Giardia and albendazole
produced the following: 

<1>
Authors
  Xiao LH.  Saeed K.  Herd RP.
Title
  EFFICACY OF ALBENDAZOLE AND FENBENDAZOLE AGAINST GIARDIA INFECTION IN
  CATTLE
Source
  Veterinary Parasitology.  61(1-2):165-170, 1996 Jan.
Abstract
  Efficacies of albendazole and fenbendazole in suppressing Giardia cyst
  output of infected calves were evaluated in two clinical trials. In the
  first trial, 18 naturally infected calves were allocated to an untreated
  control group (n = 9) and an albendazole-treated group (n = 9). Calves in
  the treated group were given 20 mg kg(-1) oral albendazole once daily for
  3 days. Compared to controls, treated calves showed 98.5%, 97.6% and 90.8%
  reductions in cysts per gram of feces (cpg) 1, 2 and 6 weeks respectively
  after the start of treatment. In a second trial, 13 infected calves were
  allocated to an untreated control group (n = 6) and a fenbendazole-treated
  group (n = 7). Calves in the treated group were given 10 mg kg(-1)
  fenbendazole orally twice daily for 3 days. Compared to the control group,
  treatments reduced cpg counts by 100%, 98.5% and 59.5% 1, 2, and 3 weeks
  respectively after the start of treatment. Both albendazole and
  fenbendazole appeared to be effective in suppressing cyst excretion by
  Giardia-infected calves. [References: 29]

<3>
Authors
  Farbey MD.  Reynoldson JA.  Thompson RCA.
Title
  IN VITRO DRUG SUSCEPTIBILITY OF 29 ISOLATES OF GIARDIA DUODENALIS FROM
  HUMANS AS ASSESSED BY AN ADHESION ASSAY
Source
  International Journal for Parasitology.  25(5):593-599, 1995 May.
Abstract
  Twelve isolates of Giardia duodenal is from Caucasian hosts in the Perth
  metropolitan area, along with 16 isolates from Aborigines in the north of
  Western Australia and the reference isolate P1C10 were examined for their
  in vitro drug sensitivity. Dose-response curves were constructed for each
  isolate for metronidazole, the most common clinically used antigiardial
  agent, as well as for the benzimidazole compound albendazole. Less than a
  9-fold variation was found in the susceptibility of the isolates to
  albendazole, while for metronidazole there was well over a 16,000-fold
  variation between the same group of isolates. In addition, it was found
  that isolates of Giardia obtained from Aboriginal hosts were significantly
  less sensitive to albendazole than those obtained from Caucasians. The
  results of this study have important implications for the continued use of
  metronidazole and the potential use of albendazole for the treatment of
  giardiasis. [References: 48]

<4>
Authors
  Andrews BJ.  Panitescu D.  Jipa GH.  Vasilebugarin AC.  Vasiliu RP. 
  Ronnevig JR.
Title
  CHEMOTHERAPY FOR GIARDIASIS - RANDOMIZED CLINICAL TRIAL OF BACITRACIN,
  BACITRACIN ZINC, AND A COMBINATION OF BACITRACIN ZINC WITH NEOMYCIN
Source
  American Journal of Tropical Medicine & Hygiene.  52(4):318-321, 1995 Apr.
Abstract
  This study describes a prospective, randomized, clinical trial in patients
  infected with the protozoa Giardia lamblia. Patients received a 10-day
  treatment with twice a day doses of either 120,000 U (USP) of bacitracin
  zinc, 120,000 U (USP) of bacitracin, 120,000 U (USP) of neomycin, or
  60,000 U (USP) of bacitracin zinc and 60,000 U (USP) of neomycin. At the
  first assessment (day 11), all 21 subjects (100%) treated with bacitracin
  zinc had ceased to show Giardia parasites in their stools compared with 19
  (95%) of 20 receiving bacitracin, 20 (90.9%) of 22 subjects receiving
  neomycin, and 17 (89.5%) of 19 subjects receiving bacitracin zinc plus
  neomycin. During the two-week follow up period, one (5.3%) of the 19
  subjects examined who received bacitracin zinc experienced a recurrence
  compared with one (6.7%) of 15 receiving bacitracin, one (5.0%) of 20
  receiving neomycin, and 0 (0%) of 14 receiving the combination treatment.
  Final cure rates of 94.7% for bacitracin zinc, 87.5% for bacitracin, 86.4%
  for neomycin, and 87.5% for bacitracin zinc plus neomycin were obtained.
  No synergistic activity was noted between bacitracin zinc and neomycin.
  Side effects were generally limited to nausea, abdominal discomfort, and
  diarrhea in a small number of patients. [References: 25]


<6>
Authors
  Katiyar SK.  Gordon VR.  Mclaughlin GL.  Edlind TD.
Title
  ANTIPROTOZOAL ACTIVITIES OF BENZIMIDAZOLES AND CORRELATIONS WITH
  BETA-TUBULIN SEQUENCE
Source
  Antimicrobial Agents & Chemotherapy.  38(9):2086-2090, 1994 Sep.
Abstract
  Benzimidazoles have been widely used since the 1960s as anthelmintic
  agents in veterinary and human medicine and as antifungal agents in
  agriculture. More recently, selected benzimidazole derivatives were shown
  to be active in vitro against two protozoan parasites, Trichomonas
  vaginalis and Giardia lamblia, and clinical studies with AIDS patients
  have suggested that microsporidia are susceptible as well. Here, eve first
  present in vitro susceptibility data for T. vaginalis and G. lamblia using
  an expanded set of benzimidazole derivatives. Both parasites were highly
  susceptible to four derivatives, including mebendazole, flubendazole, and
  fenbendazole (50% inhibitory concentrations of 0.005 to 0.16 mu g/ml).
  These derivatives also had lethal activity that was time dependent: 90% of
  T. vaginalis cells failed to recover following a 20-h exposure to
  mebendazole at 0.17 mu g/ml. G. lamblia, but not T. vaginalis, was highly
  susceptible to five additional derivatives. Next, we examined in vitro
  activity of benzimidazoles against additional protozoan parasites: little
  or no activity was observed against Entamoeba histolytica, Leishmania
  major, and Acanthamoeba polyphaga. Since the microtubule protein
  beta-tubulin has been identified as the benzimidazole target in helminths
  and fungi, potential correlations between benzimidazole activity and
  beta-tubulin sequence were examined. This analysis included partial
  sequences (residues 108 to 259) from the organisms mentioned above, as
  well as the microsporidia Encephalitozoon hellem and Encephalitozoon
  cuniculi and the sporozoan Cryptosporidium parvum. beta-tubulin residues
  Glu-198 and, in particular, Phe-200 are strong predictors of benzimidazole
  susceptibility; both are present in Encephalitozoon spp. but absent in C.
  parvum. [References: 29]

<7>
Authors
  Oxberry ME.  Thompson RCA.  Reynoldson JA.
Title
  EVALUATION OF THE EFFECTS OF ALBENDAZOLE AND METRONIDAZOLE ON THE
  ULTRASTRUCTURE OF GIARDIA DUODENALIS, TRICHOMONAS VAGINALIS AND
  SPIRONUCLEUS MURIS USING TRANSMISSION ELECTRONMICROSCOPY
Source
  International Journal for Parasitology.  24(5):695-703, 1994 Aug.
Abstract
  The three closely related parasitic protozoa, Giardia duodenalis,
  Trichomonas vaginalis and Spironucleus muris, all have very different
  sensitivities to albendazole and metronidazole. Ultrastructural studies
  reveal that the cytoskeletal elements of the ventral disk in G. duodenalis
  are affected by albendazole, whereas the other two parasites, neither of
  which possess this structure, are not affected by albendazole to the same
  extent. This suggests that albendazole may be having its primary affect on
  G. duodenalis by binding to cytoskeletal proteins and ultimately causing
  death of the parasite. Death may be occurring as the parasite loses its
  ability to adhere to the intestinal villi and obtain nutrients.
  Metronidazole showed a different pattern of activity against the three
  parasites. The evidence obtained from these ultrastructural studies
  supports the current theory that metronidazole adversely affects protozoa
  by disrupting inner cell membranes. [References: 22]

<8>
Authors
  Katelaris PH.  Naeem A.  Farthing MJG.
Title
  ACTIVITY OF METRONIDAZOLE, AZITHROMYCIN AND THREE BENZIMIDAZOLES ON
  GIARDIA LAMBLIA GROWTH AND ATTACHMENT TO A HUMAN INTESTINAL CELL LINE
Source
  Alimentary Pharmacology & Therapeutics.  8(2):187-192, 1994 Apr.
Abstract
  Background: Attachment of Giardia lamblia trophozoites to enterocytes is
  essential for colonization of the small intestine and is considered a
  prerequisite for Giardia-induced enterocyte damage. Inhibition of
  attachment may therefore have therapeutic potential.
   
  Methods: Enterocyte-like differentiated Caco-2 cells were used as a
  biologically appropriate attachment surface to determine the effect of
  three benzimidazole compounds (albendazole, mebendazole and
  thiabendazole), azithromycin and metronidazole on Giardia attachment. The
  results were compared with the ability for each drug to inhibit Giardia
  growth, measured using [H-3]-thymidine uptake.
   
  Results: The benzimidazoles inhibited Giardia attachment at much lower
  concentrations than did metronidazole. However, metronidazole was a much
  more potent inhibitor of growth than any of the benzimidazoles.
  Azithromycin did not significantly impair Giardia attachment or growth.
  The benzimidazoles decrease attachment but are less giardiacidal than
  metronidazole.
   
  Conclusion: This model appears useful for testing potential antigiardial
  compounds and investigating mechanisms of drug action. [References: 24]

<9>
Authors
  Kollaritsch H.  Jeschko E.  Wiedermann G.
Title
  ALBENDAZOLE IS HIGHLY EFFECTIVE AGAINST CUTANEOUS LARVA MIGRANS BUT NOT
  AGAINST GIARDIA INFECTION - RESULTS OF AN OPEN PILOT TRIAL IN TRAVELLERS
  RETURNING FROM THE TROPICS
Source
  Transactions of the Royal Society of Tropical Medicine & Hygiene. 
  87(6):689, 1993 Nov-Dec.
Institution
  Reprint available from:
  Kollaritsch H
  UNIV VIENNA
  INST SPECIF PROPHYLAXIS & TROP MED
  KINDERSPITALGASSE 15
  A-1095 VIENNA
  AUSTRIA

<10>
Authors
  Bell CA.  Dykstra CC.  Naiman NA.  Cory M.  Fairley TA.  Tidwell RR.
Title
  STRUCTURE-ACTIVITY STUDIES OF DICATIONICALLY SUBSTITUTED
  BIS-BENZIMIDAZOLES AGAINST GIARDIA LAMBLIA - CORRELATION OF ANTIGIARDIAL
  ACTIVITY WITH DNA BINDING AFFINITY AND GIARDIAL TOPOISOMERASE II
  INHIBITION
Source
  Antimicrobial Agents & Chemotherapy.  37(12):2668-2673, 1993 Dec.
Abstract
  Nine dicationically substituted bis-benzimidazoles were examined for their
  in vitro activities against Giardia lamblia WB (ATCC 30957). The potential
  mechanisms of action of these compounds were evaluated by investigating
  the relationship among in vitro antigiardial activity and the affinity of
  the molecules for DNA and their ability to inhibit the activity of
  giardial topoisomerase II. Each compound demonstrated antigiardial
  activity, as measured by assessing the incorporation of
  [methyl-H-3]thymidine by giardial trophozoites exposed to the test agents.
  Three compounds exhibited excellent in vitro antigiardial activities, with
  50% inhibitory concentrations which compared very favorably with those of
  two currently used drugs, quinacrine HCl and metronidazole. Putative
  mechanisms of action for these compounds were suggested by the strong
  correlation observed among in vitro antigiardial activity and the affinity
  of the molecules for natural and synthetic DNA and their ability to
  inhibit the relaxation activity of giardial topoisomerase II. A strong
  correlation between the DNA binding affinity of these compounds and their
  inhibition of giardial topoisomerase II activity was also observed.
  [References: 20]

<11>
Authors
  Barr SC.  Bowman DD.  Heller RL.  Erb HN.
Title
  EFFICACY OF ALBENDAZOLE AGAINST GIARDIASIS IN DOGS
Source
  American Journal of Veterinary Research.  54(6):926-928, 1993 Jun.
Abstract
  Efficacy of albendazole for treating giardiasis in dogs was assessed in 3
  experiments. In experiment 1, Giardia cysts were cleared from feces of 5
  of 7 dogs (as determined by the zinc-sulfate concentration technique)
  after the dogs received a single dose of albendazole (25 mg/kg of body
  weight, PO), whereas feces of 3 of 7 dogs became clear of cysts without
  treatment. In experiment 2, feces of 5 of 5 dogs became clear of cysts
  after albendazole treatment (25 mg/kg, PO, q 12 h for 4 doses); feces of 1
  of 5 untreated control dogs became clear. In experiment 3, feces of 18 of
  20 dogs became clear of cysts after albendazole (25 mg/kg, PO, q 12 h for
  4 doses) was given; none of the 20 control dogs had feces clear of cysts.
  Signs of toxicosis were not observed in any dog. These results indicate
  that a single dose of albendazole (25 mg/kg, PO) is not effective for
  treating giardiasis in dogs. However, 4 doses of albendazole (25 mg/kg,
  PO, q 12 h) are highly effective and nontoxic for treatment of giardiasis
  in dogs. [References: 18]



Rick Speare

Department of Public Health and Tropical Medicine
James Cook University
Townsville
AUSTRALIA

Phone:	-61-(0)77-225700
Fax:	-61-(0)77-715032
email:	Richard.Speare at jcu.edu.au





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